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Title: Studies on Epidemic Influenza
       Comprising Clinical and Laboratory Investigations

Author: University of Pittsburgh School of Medicine

Release Date: December 1, 2019 [EBook #60822]

Language: English

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PUBLICATIONS FROM THE UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE


[Illustration]




                    _Studies on Epidemic Influenza_
                               COMPRISING
                 CLINICAL AND LABORATORY INVESTIGATIONS


                                   BY

                         MEMBERS OF THE FACULTY
                                 OF THE
                           SCHOOL OF MEDICINE

                        UNIVERSITY OF PITTSBURGH

                                  1919




                           TABLE OF CONTENTS


                                                                    Page

 History and Epidemiology of Epidemic Influenza                     9–33

          James I. Johnston, M.D., F.A.C.P.,
            Assistant Professor of Medicine.

 A Clinical Description of Influenza as It Appeared in the
   Epidemic of 1918–19                                             35–63

          J. A. Lichty, Ph.M., M.D.,
            Associate Professor of Medicine.

 The Urine and Blood in Epidemic Influenza                         65–79

          P. I. Zeedick, M.D.,
            Demonstrator in Medicine.

 The Treatment of Influenza                                        81–95

          W. W. G. Maclachlan, M.D., C.M.,
            Assistant Professor of Medicine.

 The Prevention of Epidemic Influenza with Special Reference to
   Vaccine Prophylaxis                                            97–153

          S. R. Haythorn, M.D.,
            Director of the Singer Memorial Research
            Laboratories.

 Physiological and Physiological Chemical Observations in
   Epidemic Influenza                                            155–160

          C. C. Guthrie, Ph.D., M.D.,
            Professor of Physiology.

 The Bacteriology of Epidemic Influenza with a Discussion of B.
   Influenzæ as the Cause of This and Other Infective Processes  161–205

          W. L. Holman, B.A., M.D.,
            Professor of Bacteriology.

 The Pathology of Epidemic Influenza                             207–293

          Oskar Klotz, M.D., C.M.,
            Professor of Pathology.




                                PREFACE


This report is based upon a series of investigations carried on during
the epidemic of influenza at Pittsburgh. This epidemic reached
Pittsburgh about the last week of September, 1918, rapidly spreading
through the community during the first days of October. Pittsburgh had
been warned of its coming through the experience of Boston, where the
epidemic made its appearance during the late days of August. To a
certain extent the warning from the East permitted the making of
preparations to control its ravages. But even with the attempt for the
protection of public health the epidemic advanced with all its
virulence, rapidly picking out the susceptible individuals and leading
to a high death rate.

At the time of the coming of the epidemic there were stationed at
Pittsburgh two military camps, comprising about 7,000 men. It was with
the presence of the disease among these men that our investigations were
chiefly concerned. The men at their respective camps (on the campus of
the University of Pittsburgh and at the Carnegie School of Technology)
were housed in barracks which had been erected only a short time
previously. These barracks contained large dormitories, in which the
individuals freely mingled with each other. In them there was no
opportunity of complete isolation, and by this means of housing good
opportunity was available for the propagation of any communicable
infectious disease. The ordinary sanitary arrangements for these groups
were well provided. The first cases of recognized influenza made their
appearance on October 2. On this day two men were found with the disease
and were isolated. On the following day there were four, and on the
third day eight. It was soon recognized that the increasing number of
the infected cases was growing so rapidly that definite arrangements for
their segregation and care had to be undertaken. This was provided for
on October 4, when the Elizabeth Steel Magee Hospital was in part taken
over by the military authorities and wards were rapidly adapted for the
coming epidemic. For the foresight in making the adequate arrangements
for its control and management we shall always remain indebted to Major
E. W. Day. His indefatigable work in the early days of the epidemic will
always be remembered, and the fact that the epidemic was kept within
reasonable bounds of control was the result of his stringent quarantine
regulations along with the organization of his medical forces. Working
under his direction, Capt. H. H. Hendershott undertook the management of
the hospital and rendered most efficient service. The capacity of the
hospital was soon overburdened, so that from a normal 150–bed
institution it was on the sixth day of its conversion into an emergency
hospital carrying more than 300 cases of influenza. This hospital in
itself was unable to accommodate all of the cases falling ill, and
provision for these had to be made in some of the municipal
institutions. On October 5, 1918, the Medical School of the University
of Pittsburgh undertook to provide the laboratory facilities for the
emergency Military Hospital. It was at first intended to equip only
those laboratory departments which were deemed essential for the
clinical care of the patients in the wards. Inasmuch, however, as the
epidemic of influenza was spreading with alarming rapidity throughout
the city, it was deemed advisable to close the Medical School and to
place at the disposal of the Military Hospital all the laboratory
facilities which could in any way be of use in the care and study of the
influenza patients. This permitted the establishment of departments in
pathology, bacteriology, physiology, physiological-chemistry and
clinical microscopy. The following workers partook in the investigations
which were here carried out: Dr. Oskar Klotz, director of laboratories;
physiology, Dr. C. C. Guthrie (chief), Dr. A. Rhode, Dr. M. Menten, Mrs.
C. C. Macklin, Miss S. Waddell and Miss M. Lee; bacteriology, Dr. W. L.
Holman (chief), Miss A. Thorton, Miss C. Prudent and Miss R. Jackson;
pathology, Dr. Oskar Klotz (chief), Mr. A. D. Frost, Mr. J. L. Scott and
Miss A. Totten; clinical microscopy, Miss R. Thompson, Mr. M. Marshall
and Mr. H. Mock; records, Miss H. Turpin. Intensive work was undertaken
by each over a period of about five weeks, when the epidemic was again
on the road to disappearance and few new cases were being admitted.
These laboratories discontinued their work at the Military Hospital on
November 9.

The clinical observations which are contained in this report were made
at the Mercy Hospital. This institution set aside upward of 100 beds for
the care of the overflow which could not be accommodated at the Military
Hospital. It is unfortunate that the clinical observations and the
laboratory findings contained in this report were not made upon the same
cases. With the number of cases suddenly thrust upon the medical staff
of the army, it was not possible for them to devote detailed attention
to clinical investigation. Furthermore, during the progress of the
epidemic these medical officers were transferred to new posts, so that
it was impossible to obtain a summary of the clinical findings at the
Military Hospital by any of the officers who had but recently been
detailed to the work. We were fortunate, however, that the clinical
investigations were carried out on a similar group of cases to those
studied by the laboratory, and it might be said that their clinical
findings on the patients housed at the Mercy Hospital are parallel with
those observed in other institutions. Necessarily the researches carried
out during such an epidemic were intensive, and all the workers in the
various branches feel that if they had to live through another such
plague they would be much better prepared to approach their problem.
During the heat of such investigations valuable time is often lost in
perfecting methods of technique, and one sorrowfully finds oneself
without available material when the technical work has been accomplished
but the epidemic has passed by. In the studies in bacteriology we were
fortunate in having some of the technical difficulties for the isolation
of the B. influenzæ previously solved. It may be that this in part
explains the broad success which Dr. Holman has had in isolating the B.
influenzæ from so many cases. In other fields the road was less broken,
and it was not until late in the course of the epidemic that results
were obtained in the investigation which seemed to point to valuable
leads.

Dr. S. R. Haythorn, director of the Singer Memorial Laboratory, early in
the epidemic became interested in the protection of individuals against
the infection. In certain quarters much was claimed for the immunity
which could be conferred by vaccination, either by the inoculation of
pure B. influenzæ vaccines or by mixed vaccines. Hoping for some results
by the use of such vaccines, Dr. Haythorn undertook the preparation of
these materials. The value of this procedure could only be estimated
after the lapse of some time and at a period when the epidemic was again
waning.

The clinical work at Mercy Hospital was carried on under the direction
of Dr. J. A. Lichty, and assisted by Dr. W. W. G. Maclachlan, Dr. P. I.
Zeedick, Dr. F. Klein and Dr. W. J. Fetter. By the close co-operation of
the members of this group it was possible to put the clinical findings
of one or other member to severe test, so that the recorded observations
and deductions are of the greater value and less flavored by the
personal element. This is of the more value, since, with the great
amount of work which had to be done at the time of the height of the
epidemic, it was often not possible for the same individual to bestow
the amount of time upon each and all cases as he desired.

We are much indebted to Dr. Ogden M. Edwards, dean of the School of
Medicine, for making available the facilities for carrying out the work,
and for encouraging the publication of the reports.

                                                            OSKAR KLOTZ.

 _Pittsburgh_, June, 1919.




                 HISTORY AND EPIDEMIOLOGY OF INFLUENZA

                      By JAMES I. JOHNSTON, M. D.


The history of epidemic influenza extends back with definite
authenticity to the Middle Ages, with a fair amount of assurance to the
beginning of the Christian Era and with presumptive reliability even
before that period. Beyond this statement, nothing definite can be said
until the first epidemic reported by Short and found in the English
Annals in the year 1510. This, the first reliable record, presented some
features not unlike those occurring in the present epidemic. Two or
three striking things stand out in this record—namely, the presence of
nose bleed, pneumonia and the very great danger to gravid women. Here,
for the first time, the meteorological conditions were elaborately
studied and persistently dwelt upon. One other impressive thing, also
reported by Short, was that in 1580 the disease showed a tendency to
return after a period of quiescence. Attention is called to this because
the epidemic, while it was exceedingly prevalent in the months of August
and September, became pandemic in October and November. Another feature
was that during the years intervening between 1580 and 1658 sporadic
cases of this disease were frequently reported. During the latter year
another epidemic appeared in the month of April. In 1657 and 1658 at
London the summer was very warm, the winter came on early, there was
much snow and the spring was very moist.

The prevailing opinion at this time, and the first stated by Willis, was
that the widespread disease was due to the weather influences on the
circulation, poisoning the blood of the patients, and “not blasts of
malignant air.” The disease prevailed in the large cities, recurring
again in the autumn in an extensive form through the villages and
country. Sydenham, in his communication on the epidemic in 1675, wrote
emphatically on the influence of the infection on pregnant women, and
here used the term “tussis epidemicus” as a name for the disease. The
summer of 1675 was wet with an inconstant autumn. La Grippe prevailed in
France and Germany, according to Atmuller. In England in 1676, the
autumn was pleasant, but suddenly became cold and moist. La Grippe then
started in Germany during September after a summer and a beginning
autumn which was very rainy. Molyneux in his description of the epidemic
of 1693 in Dublin called attention to a feature, very striking to the
recent pandemic, that the aged to a great extent escaped the infection.
This would seem a somewhat unique feature until that epidemic is
compared with the present one. In 1729 Morgagni and others stated that
over all Europe the winter of 1728 was very rigorous, the spring was
cold and the summer and autumn very variable, while January and February
of that year were very moist. Huxham in his record of 1729, the fifth
extensive one on record in the English Annals, which extended into 1733,
stated from his study at Plymouth that the epidemic was exceedingly mild
in the year 1733, and, with the exception of infants and consumptive old
people, the mortality was very low. Like many of his predecessors, he
emphasized greatly the conditions of the weather at the time and
presented an elaborate study of it. The epidemic of 1732 was one of the
longest and most persistent, extending up to 1737. All authors do not
hesitate to attribute as a cause the very frequent variations of
temperature which characterized this period. Of this epidemic Arbuthnot
also emphasized the importance of the air, assigning the prevalence and
widespread features of the disease to the thick and frequent fogs. From
November, 1732, until March, 1733, this disease spread from Germany to
Italy and thence to England. He called attention to a very striking
feature—namely, that people in prisons and in hospitals escaped the
disease. This, as we know, where such institutions are placed under
preventive quarantine, is not such a unique feature during this present
scourge. He, more than former writers, devoted pages to the elaborate
and accurate description of instruments for meteorological observation
and their findings, which meteorological records were published in
detail, covering the whole period of a year—June, 1732, to June,
1733—with almost daily regularity. Huxham in 1737 in his record first
used the term “epidemic catarrhal fever”—a name often used subsequently
to describe this disease. Here attention was first called to the
prostration which characterized the convalescents, and his belief that
consumption frequently followed the disease. The next epidemic, which
occurred in 1742 and 1743, was also reported by Huxham, who stated that
the weather was very rigorous. This disease, according to his
description, extended over all Europe, and the term “influenza” seems to
have been first used by him during this time. The cases were mild in
England, but more severe in Southern Europe. Whytt in his record of the
epidemic of 1758 was the first who did not consider that the air
condition or the seasons had the significance attributed to them by
former writers, since the weather conditions during the prevalence of
the disease were generally mild and dry. In Edinburgh at this time not
even one out of seven escaped. Nevertheless, he did not hesitate to
express his opinion that the disease did not spread by contagion from
one person to another. One other observation of his is worthy of note,
which is: that frequent relapses occurred when patients were re-exposed
too soon after the first infection and such relapses were much more
severe than the original disease.

The epidemic of 1762 called forth the opinion of Baker, emphasizing an
opinion already expressed by Whytt, that the origin of epidemic disease
is not due to changeable winds nor to their nature or character as
recorded by the barometer. This epidemic also prevailed over all Europe
and appears to have begun following sharp alterations of cold and
moisture. In 1766 in Spain, France and other parts of Europe the
epidemic appears to have begun after a warm summer, followed by an
autumn moist and cold. In 1767 Heberden placed on record his
observations during this period, but nothing new was reported. In 1775
the disease began in Germany in the summer after a dry and warm spring
and spread over all Europe. During the prevalence of the disease in 1775
a questionnaire was sent to the leading English physicians, and letters
from Fothergill, Sir John Pringle, Heberden, Reynolds and others seemed
to express a consensus of opinion that weather conditions had nothing to
do with the prevalence or spread of the disease, and that the cause and
reason for its spread were unknown. Following sharp alterations in
temperature in 1780, the disease appeared in France and then throughout
the world. The epidemic of 1782 began in Russia, starting January 2 at
St. Petersburg. The thermometer underwent a variation of 40 degrees and
the same day 4,000 were afflicted with La Grippe. It reached Koenigsburg
in March, Copenhagen in April, London in May, France in June and July,
Italy in July and August, Spain and Portugal in August and September,
and then reached America. Edward Gray, writing of the epidemic of 1782
for the first time, expressed emphatically his opinion on the
contagiousness of the disease and stated what we now know—that close
contact is necessary. To him also is attributed the opinion first
mentioned by him, that there is a possibility of carriers in this
disease. During this time Dr. Hamilton, in a published letter, protested
against venesection in influenza, a practice long prevalent, and Hogarth
called attention to the fact that the disease began in cities and
villages first and that it was brought to these places by visitors from
without.

The first American writer on this subject was Noah Webster in 1647 and
1655. Following him was Warren, writing of the epidemic of 1789 and
1790, just 100 years before the last and greatest epidemic which
preceded the present one. Rush and Drake also reported this epidemic.
During that epidemic which prevailed in America from September to
December, 1789, and appeared again in the spring of 1790, President
Washington suffered a very severe attack. The year before, in 1788, when
the epidemic prevailed abroad, the summer temperature in Paris was very
variable, variations of 8, 10 and 12 degrees occurring on various days.
La Grippe predominated all the time. The same variations were true in
Vienna. At the end of the year 1799 the epidemic struck Russia,
following very cloudy, misty weather, was prevalent in Lithuania in
January of the year 1800 and in Poland during February.

The next great epidemic occurred in 1802 and 1803, was very general,
beginning in France and coinciding with a cold and moist autumn
following a very dry summer. It was of six months’ duration in England.
Many schools, jails, asylums and workhouses, although located in the
area swept by this plague, at first escaped. As mentioned before, this
striking feature has not been so unique in subsequent epidemics. One
feature noticed here and commented upon freely was that elsewhere
throughout the country there seemed to arise endemic foci. During this
time there was also the prevailing belief that the disease was followed
by phthisis. One other observation made here, which was accurate,
lasting and is accepted today, was that no family was affected _en
masse_, but always one individual case occurred first, to be followed by
general infection of the others. At this time early bleeding was still
adhered to. The French spoke of seven varieties of the disease, but one
can only see in the classification emphasis laid on certain individual
symptoms in this disease of complex symptomatology. During this epidemic
pneumonia is said to have been very infrequent. The disease was
particularly fatal to pregnant women, and the patients suffering from
pulmonary tuberculosis were hurried off by the influenza.

Burns, writing of the epidemic of 1831, mentioned that in 1810 the
disease was very widespread in China and Manila, and also emphasized the
fact mentioned in many works that certain epidemics prevailed among
animals at the same time, stating that in 1831 these diseases were of
choleric nature. This epidemic began in 1830 in the East, reached Paris
in the summer of 1831, reappeared in Europe in 1833, following the same
route that cholera had taken in 1832. In the epidemic of 1833, Hingeston
also laid great stress on the fact that horses were often affected.
These features, as mentioned by Burns and Hingeston, are frequently
quoted by authors, and such observations seem to have been widely
accepted.

One of the greatest epidemics of influenza began in 1836 and extended
until 1837, and was called at this time epidemic catarrh. It began in
England in January, spread to France, and during all the time that it
was in Paris there were continual penetrating rains with cold and
humidity. At Montpelier on February 20, 1837, the thermometer passed
from 12 to 15 degrees above to 2 and 3 degrees below zero, and it was
then that La Grippe appeared suddenly. In reply to the circular letter
sent out by the Council of the Provincial Medical Association of
England, comprising 18 questions, the following opinions prevailed. The
disease was greatest from September to February; the great prevalence of
the epidemic in all parts of the kingdom was recognized—attacks were
irrespective of age, sex or temperament; it was milder in children, and
the aged suffered most from it. Further, the disease was extensive in
all neighborhoods; the mortality was 1 in 50, old age predisposed to
fatal termination, and the duration of the disease occupied two periods,
one terminating in 4 or 5 days and one in 5 to 14 days. Also relapses
were frequent; those exposed to employment in the open air were not more
liable to the disease than others; there was no proof of the disease
being communicated from one person to another, and influenza aggravated
an existent pneumonia or pulmonary phthisis. And finally previous
attacks of influenza offered no protection; the symptoms were uniform;
the most common of unusual symptoms were those of meningitis,
inflammation of the lungs and syncope, and aside from ordinary care and
treatment, general venesection was not endorsed. Evidence of fine
weather and good telluric conditions were at this time also appended.
The same symptoms and complications, particularly those of the lungs,
occurred irrespective of seasons, civilization or place. It was believed
and stated that the plague described in Homer was probably influenza.
For the first time there is noticed here a point well worth
consideration—the association of other epidemics with influenza, either
anticipating, following or superseding. That some such association may
follow the present pandemic is not to be entirely ignored. For example,
cholera is already reported as prevailing abroad, following an earlier
influenza outbreak. During the period, as if anticipating bacteriology,
one writer explained the epidemic in an article called “The Dust of
Regular Winds,” and Groves (1850) wrote on “Epidemics Examined, or
Living Germs as a Source of Disease.”

In 1846 and 1847 a slight epidemic occurred in London, Paris, Nancy and
Geneva. In France during the last week of 1857, and extending into
January and February, 1858, there was a mild epidemic. During this
period there alternated frequent frosts with soft weather, misty and
humid. Among the numerous small epidemics between 1837 and 1889, one
occurred on the continent of Europe in 1860, but little of value or
interest was noted. In Paris in March, after great and sharp variations
in temperature, a series of epidemics extended from 1870 to 1875. These
were unimportant. Atmospheric modifications occupied first rank in the
minds of some as a cause for the outbreaks. Rapid changes from hot to
cold or from cold to hot were given weight. Other undetermined
modifications of conditions were probably important.

In a recent article published by Loy McAfee (J. A. M. A., 1917, 72, 445)
he discussed the confusion which existed between the diagnosis of
cerebro-spinal meningitis and epidemic influenza in 1863. These were
believed the same by some—that is, the same disease of varying degree.
There was a great diversity of opinion among clinicians at this time,
and the American Medical Association appointed a committee to make an
investigation. McAfee quotes from the Medical and Surgical History of
the War of the Rebellion that in 1861 and 1862 an epidemic existed among
the troops called epidemic catarrh, which was afterward changed to read
acute bronchitis. In September, 1861, there existed an epidemic of
influenza in one of the regiments which lasted more than two weeks, and
in another camp there was a similar epidemic at the same time. It is
stated that there were in all 168,715 cases among the white troops, with
a mortality of 650, and 22,648 among the negro troops, with a mortality
of 255, making about 4 per thousand, and over 11 per thousand,
respectively.

The next great epidemic, and the last until the present, occurred in the
years 1889 and 1892, and was pandemic in its nature. The death rate
during this time was lower in the cities than in the country. This was
probably due to the fact that the greatest mortality was among children
and old people, and as old people were generally left in the country,
this explains the observation. The highest number of deaths was among
males, believed to be due to the exposure and fatigue of work. Forty per
cent. of the world’s population was said to have been attacked during
this period. The yearly or seasonal repetition, as shown in this
pandemic, had occurred in other epidemics. In the great pandemic of 1889
and 1890, five decades after the last important epidemic, it was stated
that the medical profession found itself confronted by a new disease of
which it had knowledge through medical history, so also in our time few
physicians recognized at first the reappearance of influenza. This 1889
epidemic is extensively reported in the literature, and has been
elaborately worked out by many observers. One important feature has been
emphasized by Leichtenstern, which, although recognized by the
profession after the last epidemic had been fully reported and recorded,
is not appreciated by the profession during the present epidemic—namely,
that while shortly after the last epidemic there were smaller
relightings of the infection throughout various parts of the country,
those diseases which we erroneously call grippe or influenza, occurring
commonly in the spring and fall, are in no way connected with the
disease with which we are dealing, and which occurs at rather long
intervals. Any speculation in regard to these periods, which history has
shown to be fairly wide apart, has very little basis. This pandemic,
like many of former days, is believed to have originated in Asia, and
from there to have spread over Europe and hence over the world. The
disease spread rapidly over countries, affected probably about 40 per
cent. of the world’s population, disappeared rapidly after several
weeks, was thought to have had nothing to do with weather conditions,
had a great morbidity but small mortality, and affected all ages and
occupations. There is no doubt, as stated by some, that the development
of traffic and travel was a large factor in the rapid and extensive
spread of influenza during this pandemic. The course which the disease
followed, springing from its supposed beginning in Asia, has been fully
and amply described by writers after that period, but the great rapidity
of its dissemination over all countries is the most remarkable feature
in the epidemiology of any disease. This, during 1889, made many
prominent physicians disregard the opinion that influenza spread by
contagion and accept again the opinion expressed by observers of
epidemics in former ages, that miasma as a pathogenic agent was
responsible for its distribution; but anyone who reads closely the
history of this epidemic, and in the light of modern medical science,
must feel that the rapidity of distribution was nowhere greater than the
most speedy means of transportation. This very necessary close
connection was demonstrated also in regard to the mode of spread of the
disease; the large cities and the commercial centers were affected
earlier, smaller and country districts followed later, railroad towns
were more frequently attacked than isolated villages, and even from
jails, prisons and workhouses, where quarantine was immediately
attempted, as well as from remote villages where the disease had been
brought, there could be traced a zone of infection spreading into the
country. One interesting point was raised at this time—namely, that in
some places it seemed to spread by leaps and bounds, and at other places
radiating as stated above.

The old controversy of whether influenza is distributed in a radiating
manner or in so-called leaps and bounds is believed to be settled by
consensus of opinion that it occurs in both ways. An opinion expressed
by the study at this time as to whether influenza spreads more rapidly
than any other infectious disease is found in the statement that the
contagion is markedly virulent, the micro-organisms are easily conveyed
from their original seat in the mucous membrane by coughing, sneezing
and expectoration, the great number of persons who, though slightly
affected, carried on their ordinary way of life without hindrance, the
probable longevity of the organisms in convalescents, the brief period
of incubation of two or three days, the susceptibility of all people of
every age and vocation, and the possibility of carrying the contagion by
merchandise and even through short distances in the air, are all
suggestive reasons for this. No one at present accepts the so-called
miasmatic nature of the contagion. Proofs are ample to show that one
case must be present in a locality or even family, although it may be
frequently overlooked, from which the epidemic spreads. During this
period of 1889 and 1890 the duration of the actual epidemic period in
different localities in Europe was from four to six weeks. This was
subsequently shown to be consistent with the recorded reports from the
various cities in the United States. Following this pandemic in the
first part of the year in 1891 there were numerous epidemic outbreaks in
various parts of America, including New Orleans, Chicago, Boston, and
simultaneously in England. Strange to say, at this time neither Germany
nor France had such epidemics, although both were exposed by travelers,
particularly from England and America. The question was raised at that
time whether the Germans, French or other continental nations were more
immune than Americans and English. In the fall of 1891 and the entire
winter of 1892 the disease was extensively prevalent both in Europe and
Northern America. In these later epidemics there was no definite
direction of spread. They probably would come more clearly under the
so-called radiation from numerous rural districts. In almost every case
at the point of its origin in these countries the epidemic developed and
spread slowly, lasting months and with very varying morbidity and
mortality. They had none of the explosive characteristics of the
pandemic. The general diminished morbidity of the later epidemic, the
diminished geographic distribution of the disease and the scarcely
recognizable character of its contagion, its slow development and
extension over several months, the continuous diminution in frequency
and in intensity since its onset in 1889, have been explained by
presumptive successive lessening of susceptibility of the population,
possibly due to acquired immunization. Observers at that time, as well
as ourselves, could question this last statement.

There was observed one noteworthy thing about seasons. While the great
pandemic of 1889 and 1890 had no definite connection with seasons, the
epidemic types which followed in 1891 and 1892 seemed to show a lighting
up in either spring or fall, remaining dormant in the summer months. It
has also been shown by the history of former epidemics that almost all
the pandemics started from Russia in the fall, winter and spring months.
Such was the case in 10 of the great pandemics of 1729 to 1889. This, no
doubt, was the reason so many of the former historical writers were
impressed by seasons and meteorological conditions. The statement made
by observers during the epidemic that influenza presented two phases,
one pandemic and the other endemic, and that each follows different
epidemiological rules, seems possible. The question raised during the
last epidemic of the spread of the disease in families, the disease
occurring at high altitudes and even at sea, we know does not interfere
with the recognition of its spread by direct contagion. Definite
examples of families or villages being infected by a returned member of
such family or citizen from abroad are reported frequently, and even the
appearance of the disease in isolated places has often been traced and
verified from a definite source, to say nothing of the question of
carriers and those supposed to be suffering from other diseases.

Striking examples are shown also in this epidemic that many
institutions, frequently those isolated from the world, were markedly
exempt until, through servants or outside visitors, the disease gained
access to them. This gave a most favorable field for the study of
invasion, spread and decline of the disease. Observations made at this
time in regard to hospitals seemed to suggest that certain institutions
were more or less exempt, although not closed institutions, while others
suffered from the first. These two types of hospital invasion are hard
to reconcile.

Great stress was laid in this epidemic upon the very great morbidity and
the low mortality. Simple, uncomplicated influenza at this time was
looked upon as a disease that was rarely dangerous to life. Studies have
shown that after this period there seemed to have been lessened
morbidity. As previously stated, nearly all the numerous pandemics at
various times have had their origin in Russia and arose in the late
autumn or winter months. This pandemic of 1889 and the succeeding severe
epidemics in Europe and North America in the years of 1891 and 1892
occurred almost exclusively in the cold weather, the summer remaining
free. It is generally believed now, and was at the end of that pandemic,
that atmospheric or telluric conditions had nothing to do with the
spread. The origin of epidemics following the pandemics seemed to be
influenced in their recurrence by the season of the year. It was
conceded by observers in that pandemic also that contagion might be
carried by merchandise and even flies and healthy individuals.


                    _1918 Epidemic in Large Cities_

In the city of Boston during the week ending August 28, at the Naval
Station at the Commonwealth Pier, 50 cases of influenza occurred and
within the next two weeks more than 2,000 were reported in the naval
forces of the First Naval District. Of these 5 per cent. developed
broncho-pneumonia with a mortality of more than 60 per cent. From here
it probably spread to Camp Devens and thence ran rapidly over the
country. There can hardly be a question that it spread along the lines
of traffic. Up to November 9 there were reported 3,339 cases among the
civilian population of Boston. There were 3,430 deaths from influenza,
the presumption being that these were due to bronchial pneumonia,
although not reported as such. The deaths from all forms of pneumonia
were reported as 942, making in all 4,372 deaths from September 7 to
November 9. This discrepancy—that is more deaths than reported cases of
influenza—is due to the fact that influenza was not made a reportable
disease until the date of October 4, fully a month from the time the
epidemic appeared. The weather conditions were generally fair and no
noted abnormality is recorded as compared with other years. The
statement of the Health Department of this city was that, after a
practical disappearance of influenza in October, there was a slight
recurrence in November and a more pronounced recurrence about the first
of December, since which time the cases have slowly but steadily
decreased, until at present—December 21—the fatalities attributable to
influenza are about 20 daily.

In the city of New York the epidemic first appeared September 18. Up to
and including December 27 there were reported to the Department of
Health 136,061 cases of influenza and 21,388 cases of pneumonia. The
number of deaths since September 18 was 11,725 attributed to influenza
in the death certificates filed in the Health Department and 11,601
attributed to pneumonia. The epidemic reached its peak during the week
of October 19, slowly subsided and was practically at an end on November
9. While the epidemic is reported as ending on this date, the mortality
rate from influenza and pneumonia is still very much above normal. No
particular features concerning the meteorological conditions were noted,
except that in this city the weather was clear and delightful during the
months of September and October when the epidemic was rampant.

In the city of Philadelphia on July 22 the Health Department issued its
first health bulletin on so-called Spanish influenza, announcing the
possible spread of this disease into the United States. On September 18
a warning was issued against an epidemic, the department starting a
public campaign against coughing, sneezing and spitting. On September 21
the Bureau of Health made influenza a reportable disease. At this time
the authorities stated an epidemic of influenza was recognized as
existing among the civil population of similar type to that found in the
naval stations and cantonments; that a large percentage of cases was
accompanied by pneumonia; that patients should be isolated and
attendants wear masks; that isolation be practiced for a period of ten
days after recovery to prevent carriers; that patients be guarded
against relapse and that the public be cautioned against large
assemblages and crowded places, as well as to avoid coughing, sneezing
and spitting. On October 3 the churches, saloons and theatres were
closed, funerals were made private and food handlers were required to
protect their wares. The number of cases reported from September 23 to
November 8 was 48,131, but the Bureau states, from a rough estimate, the
number of cases was probably 150,000. The total number of deaths
reported was 7,915 from influenza and 4,772 from pneumonia in all its
forms, the presumption being that the deaths during this period were due
to influenzal pneumonia. The weather condition during this time is
recorded as mild and fair.

The influenza cases began to be reported in Cleveland on October 5, and
up to December 20, 22,703 cases had been recorded. Certificates
recording deaths due to influenza alone numbered 2,497, while pneumonia
amounted to 833. The epidemic was at its height in the latter half of
October and the weather was spoken of as pleasant fall weather. During
the week of October 26 the epidemic reached its greatest height, abated
in the week ending November 23, increased later, but showed a drop for
the week ending December 21.

The epidemic first reached Chicago on September 21, and from that date
on it rapidly increased throughout the city for a period of 26 days
until October 17, when it reached its maximum both in the number of
deaths from influenza and from pneumonia. On that day the total number
of deaths from influenza and from pneumonia reported was 2,395. From
September 21 until November 16 there were reported 37,921 cases of
influenza and 13,109 cases of pneumonia. On September 8 at the Great
Lakes Naval Training Station, which is 32 miles north of the city, an
extensive outbreak of influenza occurred. This was 13 days before the
outbreak in the city of Chicago itself. Camp Grant, located at Rockford,
92 miles northwest of the city, suffered an outbreak on September 21. A
suggestion of the likelihood that influenza was prevalent in this
country in a mild and unrecognized form in the spring of this year is
shown by the fact that numerous local outbreaks of acute respiratory
diseases were brought to the attention of the Health Department of
Chicago. These occurred especially in large office buildings and in
industrial departments. The total number of deaths from influenza and
pneumonia during 14 weeks was 51,915. This would indicate that a very
great number of cases were not reported to the Bureau of Health until
they died or else there must have been a large number of deaths due to
lobar pneumonia. One naturally obtains from these figures the impression
that the disease was not recognized for a long time, that the pneumonia
must have been called lobar pneumonia, and that the actual figures
gathered by this city, as well as others, must have been greatly
confused at the onset of the epidemic. It is not unlikely that records
from many of the army cantonments and naval stations may be considered
from the same viewpoint. Weather conditions were considered normal at
the height of the epidemic, the weather being dry. There has been a
flare-up of influenza recently, but not in sufficient numbers to justify
calling it epidemic.

In the city of Louisville, Ky., the epidemic started September 26, and
the total number of cases up to December 21 is reported as being 9,445.
Out of this number 772 deaths occurred from pneumonia. No distinction is
made here between broncho-pneumonia and lobar pneumonia, but the
presumption from the records of other cities at this time is that these
were cases of broncho-pneumonia following influenza. The weather was
described as being delightful fall weather. The statement is made by the
authorities that while the epidemic is still prevalent, it is confined
largely to children and is rapidly abating.

The first case in the city of St. Louis was reported about October 7,
and up to December 23 there had been 31,531 cases reported to the Bureau
of Health. They recorded 1,920 deaths with influenza given as a
contributing cause. Preceding the time when the epidemic was at its
height the weather was fair and warm, and the statement is made that,
“without going into the matter exactly, we have been of the opinion that
damp, rainy weather has been a help in controlling the disease.” The
opinion was expressed by the Commissioner of Health that the disease had
now abated.

No information could be obtained as to when the epidemic first reached
the city of New Orleans, but during the months of October and November
43,954 cases of influenza were recorded. Of this number 2,188 died from
a combination of influenza and pneumonia. They stated in their health
report that during the period from January 1 to December 31 there were
239 deaths attributable to broncho-pneumonia. The weather was mild and
on December 24 the epidemic was stated to have abated.

The city of Minneapolis recorded its first case on October 7, but the
authorities expressed their belief that a few cases had appeared before
that date. Up to December 21, 15,000 cases had been reported to the
Bureau of Health and of these there had been 735 deaths from
broncho-pneumonia. They had in their city a late, rainy fall and up to
that period they had had no cold weather.

The record obtained from the city of San Francisco stated that the
epidemic first appeared September 23 and that it was very widespread in
that city early in October. There were two invasions and 53,260 cases
reported. At the height of the epidemic more than 2,000 cases were
reported in one week; 188 deaths occurred from influenzal pneumonia. The
following week, after the institution of mask wearing, in which between
80 and 90 per cent. of the population concurred, it was stated that the
number of cases decreased to about 200. It was stated that the weather
was generally very fair during the epidemic.

From the city of Portland, Oregon, the following information was
obtained: The epidemic first appeared October 11, with a second one
toward the end of the year. There were 8,079 cases reported, with 658
deaths from influenza and 250 from pneumonia. Weather conditions were
stated to be varied, but the health officer believed that during the
worst wave the weather was clear and dry, with easterly wind. He
believed that a decrease in influenza was noticed immediately after a
Chinook wind and warm rain. Similar observations were made by Coutant in
Manila.

A weather comparison of 12 large cities, well distributed over the
United States, studied during this pandemic of influenza and checked
with normal weather during that of many years, shows: Boston, fair with
no abnormality; New York, clear and delightful, no abnormality;
Philadelphia, mild and fair; Pittsburgh, mild and cloudy; Cleveland,
pleasant fall weather; Chicago, normal and dry; Louisville, delightful
fall weather; St. Louis, fair and warm-damp, rainy weather later seemed
to control the epidemic; New Orleans, mild; Minneapolis, a rainy fall
and no cold weather, which is unusual there; San Francisco, generally
fair, and Portland, Oregon, clear and dry.


              _The Epidemic in Universities and Colleges_

At Bryn Mawr College, in Pennsylvania, an institution devoted to the
higher education of women, located within 10 miles of the city of
Philadelphia, the epidemic occurred at the beginning of the college
year—October 1. This college at the time had an enrollment of 465
students. There were 85 cases of influenza, with an additional 25 who
suffered from influenza in their homes. There were no deaths from
pneumonia. The weather conditions were clear and warm, and since
November 29 there have been no new cases occurring in the college and
only three or four of the students have been ill at their homes since
that time.

[Illustration:

  DATES OF THE APPEARANCE OF INFLUENZA ENDEMIC IN VARIOUS CITIES OF THE
    UNITED STATES
  1918.
]

The enrollment at Smith College, Northampton, Mass., was 2,103, and the
first case of influenza appeared with the arrival of the students on
September 18 and reached its height on September 30. All group
gatherings indoors were stopped from October 3 to October 18, and the
epidemic was over by October 20. A recurrence began November 15 and
continued until December 17. There were 182 cases in the first epidemic
and 100 cases in the second. There were only two deaths from influenza
pneumonia. During the rise of the epidemic the weather was rainy,
followed by good, clear weather. The change in weather conditions seemed
to make no difference. The second epidemic was still prevalent when the
students left for their holidays.

In Wellesley College, where there were enrolled 1,593 students, the
epidemic first appeared on September 18. Up to the middle of December
they had had 280 cases. During six weeks of the epidemic 265 cases were
reported and only one death occurred from broncho-pneumonia. For the
most part, bright and sunny days were present, with only a few cloudy
and rainy days. This college has not been without cases since September,
but the epidemic lasted only about six weeks.

In a communication from Columbia University it is stated that the
epidemic appeared during the week beginning September 22. No records
were available for the student body at the time of inquiry, but in the
Student Army Training Corps of 2,200 men between 8 and 9 per cent. had
the disease during the period from October 1 to December 14. In this
army group during this period two deaths from influenza and pneumonia
occurred. The weather conditions in the city during this time were
considered normal for fall weather—that is, mostly clear, with high
winds. The opinion expressed was that the epidemic was still prevalent
and increasing, and that a return wave seemed to be more virulent and
affected the children of the city more than had the first one in the
early fall.

There were enrolled at Harvard on October 1, 3,193 students. The first
case of influenza occurred on September 20. There were 227 cases of
influenza reported; of these there were 46 cases of broncho-pneumonia,
with five deaths. There were two waves to the epidemic; the first wave
height was in October and the second the last of November. The weather
conditions were not severe nor particularly unfavorable at either time.
The epidemic abated at the university largely because of the
demobilization of the Student Army Training Corps. At that time it was
still prevalent in Cambridge and Greater Boston.

At Yale University the disease first appeared in the New Haven Hospital
on September 21. There were registered in all departments of the
university 2,265 students. Up to the date of December 24, 1,013 cases
have been treated. The number of deaths from broncho-pneumonia has been
249. At the height of the epidemic, which occurred in the third week of
October, typical fall weather prevailed. An unusually clear, dry October
with very little rain, much sunshine and rather low humidity was the
weather report.

During the period of the epidemic at Princeton that university had 1,050
students, and the first cases appeared shortly after the opening of the
college term on September 24. As a precautionary measure, every case,
when even only suspicious, was sent to the infirmary. In all, there were
about 70 cases in the university and about 45 cases from the United
States School of Military Aeronautics. Only one member in the latter
school died of pneumonia. There were no deaths among the students at the
university. In this part of the country the weather was most delightful
all autumn, being warm and dry, very little rain having occurred since
the end of July. At the date of the inquiry the epidemic had
disappeared—that is, about December 21—there being only two very mild
cases under suspicion. In the town of Princeton, outside of the
university, the conditions were much more serious than in the university
itself. Influenza appeared in the homes of many of the poor people of
the immigrant class, so that it was not uncommon for four or five
members of one family to be infected at once. In one family of seven,
five serious cases of pneumonia developed. An emergency hospital was
opened by the authorities and 40 cases of pneumonia were treated. Of
these approximately one-half died. At the time this report was furnished
the epidemic seemed to have disappeared.

The number of students enrolled at the University of Virginia was 957.
The first cases occurred as early as September 24. There were 290 of
these in number, and three died of broncho-pneumonia. The epidemic was
reported as having abated on December 15, but a few cases appeared after
that date.


                     _1918 Epidemic at Pittsburgh_

At the Army General Hospital No. 24, located at Hoboken, a few miles
outside of the city of Pittsburgh, on September 28 two soldiers were
taken ill and, with the disease unrecognized, they were removed to the
cantonment hospital at Point Breeze, within the city proper. The men
were found a few days later to be suffering from influenza, and from
this presumable source an epidemic spread rapidly among the troops and
student soldiers located here.

From September 28 until November 20, 1,392 cases of influenza occurred
among the enlisted men. How the infection reached the first two cases at
Hoboken is not known. The command here consisted of the Student Army
Training Corps of the University of Pittsburgh, and Carnegie Institute
of Technology, Motor Mechanics of the University of Pittsburgh and the
Ordnance and Quartermasters’ Department on detached service. The
strength of this command was approximately 7,000. The first case
appeared on September 30 and the diagnosis was made on the following
day. Beginning October 13, all soldiers of this group were inoculated
with two 1 cc. doses of vaccine, obtained from the New York State Board
of Health. At the height of the epidemic there were about 840 soldier
patients in the several hospitals of the city at one time. Cubicles were
used in the hospitals, and in the barracks a floor space of 50 square
feet was allowed to each man. The men slept alternately head to foot,
with paper screens intervening, which were changed daily. In company
formation they were instructed to gargle their throats and clean their
teeth morning and night under the supervision of their officers. Strict
military quarantine was maintained throughout the entire camp, no
congregating was allowed, classes were suspended and only open-air
drills were permitted. For the entire command there were 220 cases of
pneumonia, with 99 deaths, an average mortality of 44 per cent. The
dishes were boiled in the hospitals, and sanitary dishwashers were used
in all mess halls. The kitchen help and personnel were inoculated with
influenza vaccine, with apparently good results. The Magee Hospital,
with 375 beds, was under strict military control. When this was full,
all others were treated in the civilian hospitals.

In the city of Pittsburgh the disease was not made reportable until
October 5. However, one case was reported on October 1, and it was known
that there were a few isolated cases in Pittsburgh previous to that
date. During the months of October, November and up to December 21 there
were 23,268 cases of influenza reported, and the deaths were 1,374 from
lobar pneumonia and 678 from broncho-pneumonia. We cannot but feel that
most of the deaths reported during the period of the epidemic as lobar
pneumonia were broncho-pneumonia associated with influenza. It was well
known among civilians that true lobar pneumonia was exceedingly rare and
has remained so up to the present time. This is especially noticeable,
as this is the time of the year when lobar pneumonia is usually
widespread in Western Pennsylvania. This district was particularly
favored with a mild fall and winter. On October 1 the first case was
reported, on October 15 the epidemic reached its peak—on that day 957
persons being reported ill with the disease. From October 16 until
October 28 it maintained an average of 600 cases daily; from October 29
until October 31 there was a sharp decline from 600 cases daily down to
200 cases daily. From November 1 until December 21 the decline has been
uniform, and on this latter date 58 cases of influenza and 7 of
pneumonia were reported. The height of the epidemic was reached between
October 15 and October 29. During the period of the epidemic in
Pittsburgh, from October 1 until December 15, 62 days were recorded as
cloudy, or partially cloudy, and only 14 days as clear, although the
cloudy days seemed distributed and not in decided groups. The mean
temperature for October was 58 degrees, with normal 54.9; for November,
44 degrees, normal 42.9; for December, 41 degrees, normal 34.7. The
precipitation in October was 3.08, as against a normal of 2.36; in
November, 1.79, with normal 2.55; and in December, 3.50, normal 2.73.
From a study of these weather reports we see that the epidemic occurred
during a period of abnormally warm, cloudy and slightly more moist
autumnal season than usual, but these variations were relatively slight
and far from decided. The confusion of diagnosis between lobar pneumonia
and broncho-pneumonia, associated with or following influenza, occurred
in the Pittsburgh health reports as well as in other cities. The
presumption that almost all, if not all, of the cases reported as
pneumonia of different types were really cases of influenzal pneumonia,
seems justified.


 _Epidemic Incidents in Institutions and Towns of Western Pennsylvania_

During the time the epidemic was at its height in Pittsburgh the Western
Pennsylvania Institution for the Blind was in session. This school is
located in the heart of the educational center and was surrounded by the
barracks of the Student Army Training Corps of the University of
Pittsburgh and the Carnegie Institute of Technology. When the influenza
was recognized as epidemic in this neighborhood, the attending physician
at this institution advised a quarantine against the public. The
children were refused visitors in the buildings, and the usual week-end
trips home were forbidden. This school was continuously in session from
September 24 until November 30. During this time there was not a single
case of influenza in the school and the children were free from any
infectious disease. On December 1 the pupils returned to school after
the Thanksgiving holiday, and one week later, on December 8, the first
case of influenza appeared. In a period of five days following 15 cases
developed. It was considered wise to close the school, and all well
children were sent to their homes. The institution was kept closed until
January 1, since which time no cases have developed. Very few of these
children had influenza at home, and only one death occurred.

A reliable report, subsequently confirmed by the health officer, stated
that in Masontown, Pa., the start and course of the epidemic were very
striking. A dance was held in the town and the musicians were brought
from nearby cities. One of the musicians employed was not very well upon
his arrival, and became so ill that after the dance he was put to bed in
the hotel. He was found to be suffering from influenza when examined the
following day, and from him as the primary case the town was swept by
the epidemic.

In Mercer, Pa., the physician to the Board of Health reported that
during September they had a general epidemic of coryza and sneezing,
with slight fever, which lasted for three or four days. This was looked
upon by the people as hay fever. In the midst of this, or about
September 16, a man, 74 years of age, who had been away from home,
developed true influenza, followed by pneumonia, from which he recovered
about October 10. Another man, employed in Greenville, a nearby town,
where influenza was already prevalent, returned to his family here
suffering from the disease. The whole family and all who were exposed to
this family were infected. From this family as a focus the disease
spread rapidly in every direction. There were about 350 cases in the
town of 2,000 inhabitants, and there were 9 deaths. Sporadic cases have
occurred since, ranging in number from one to a dozen at a time. These
numbers do not include scores of cases called colds by the people, but
it seems that all these cases had an influenza element.

In the town of New Castle it was not possible to trace the onset of the
influenza epidemic to a definite case. As the health officer stated,
several cases were reported at once.

The first case of influenza in Indiana, Pa., of which there was any
definite knowledge occurred on September 15. A clothing merchant who had
just arrived from New York, where he had been buying stock for his
store, was the first case identified. The next case occurred several
weeks later, the disease being contracted at the mining town of Coal
Run, in Indiana County.

A man resident in Sharpsburg who had suffered from influenza visited
friends in Fraser Township, Allegheny County, to convalesce. Previous to
his coming that section had been free from the disease. He was still
coughing at the time, and, moreover, he is said to have been a great
talker and visited largely among the neighbors of his host. Threshings
in that part of the township were going on and these he also attended.
The date of his coming was October 13. By October 15 his hostess was
taken ill. By October 16 some of the threshers were affected, and by
October 17 enough were sick to break up the work of threshing.
Eventually all the men engaged became ill, and 11 families were infected
from this source.


                               _Summary_

Reviewing the history of former epidemics and pandemics, I have gained
the impression, as have many others, that we are not dealing with any
new disease. Further, our knowledge of this pandemic with its high
incidence of broncho-pneumonia shows that it is in no way markedly
different from that of former manifestations of influenza. One is
impressed by the fact that in different outbreaks of this disease of
complex symptomatology certain symptoms or complications have been
prominent, overshadowing others, and making such complications the
striking feature at the time. The failure to recognize that these
varying features are merely different manifestations of one disease has
resulted in much confusion. The observation made in the last
epidemic—and one which can be endorsed during the present plague—is that
influenza has been and is the most widespread, rapid and extensive of
all diseases. One thing also that attracts attention at the present time
is the long period existing between the several pandemics. Whether, as
one observer during the present pandemic has stated, it requires a long
period for the infection to become active and easily carried, or whether
any possible reason can be suggested for these phenomena, admits of no
satisfactory explanation. The outstanding feature during this epidemic
is the complication of broncho-pneumonia, and yet, from very early
times, this complication has been repeatedly spoken of as a striking
characteristic. Reviewing the health reports from the large cities of
deaths from pneumonia, the presumptive opinion seems justified that
almost all, if not all, pneumonias reported as associated with influenza
were of the broncho-pneumonia type. The infrequent presence, indeed the
rare finding, of lobar pneumonia during this period in Pittsburgh seems
to verify the aforesaid opinion. The great frequency and the high
mortality of broncho-pneumonia were particularly noted during the
present epidemic. During the present epidemic the great mortality among
pregnant women was another striking feature, and yet this is by no means
new, having been recorded by some of the earliest writers. Such also may
be said of the recurrence of the disease in the same patient. One
important observation brought out in the study of the pandemic of 1889
to 1892 was that the ordinary infections occurring in the spring and
fall known as grippe or La Grippe are in no way connected with the
pandemics which have occurred. There seems to be a consensus of opinions
among the records of the more recent epidemics, as well as during the
present pandemic, that weather conditions in no way influence the spread
of the disease. Furthermore, a study of weather conditions throughout
the United States, and particularly those of our own city, seem to bear
out the truth of this observation. While clinicians during other
epidemics expressed their belief in the incident of a primary case
producing infection, it has only been during the present one that such
an opinion has not been assailed. The large number of military training
camps and cantonments have undoubtedly offered splendid opportunity for
the spread of influenza. The futility of attempting to control it even
under normal conditions is still questionable. Consistent with former
reported invasions of the disease, the present epidemic lasted a
definite period. This period was about six weeks in most of our large
cities, colleges and institutions, extending approximately from October
1 to November 15.

It is imperative to note the accurate clinical observations recorded
from the numerous epidemics of the past by men with far less data to go
upon than is available at the present day. The high morbidity among the
personnel of many of our hospitals and institutions where the infection
occurred and the relatively low mortality deserve attention. This may be
partly explained by the methods of treatment of those infected, but not
entirely. The great likelihood of carriers of influenza, who either are
not ill or who are suffering from very mild infection, is an observation
also noted by former writers which cannot be ignored. The value of the
masks has not been established, although they have been extensively used
in many parts of the country. Frequent throat lavage was generally
accepted as a rational preventive measure. Relightings of the disease
have been noted in most of our cities after the subsidence of the
epidemic. Vaccination against influenza is fully discussed in Dr.
Haythorn’s paper in this series.

The presence of influenza in San Quentin prison, California, in April,
1918 (Public Health Reports, May 9, 1919); an epidemic of respiratory
disease in Chicago in the spring of 1918; the report of Soper of
influenza in our army camps in March and April, 1918; the occurrence of
influenza in Porto Rico in June; influenza on a United States Army
transport from San Francisco, as reported by Coutant, seem to point to
the possibility that influenza had a footing in America long before the
disease became pandemic. The view held by some that the beginning of
influenza was in America, subsequently being transferred to Europe and
then reimported here, is worthy of consideration. Coutant believed the
disease originated in Manila, others that it traveled from “a permanent
endemic focus in Turkestan,” and there are many other theories which
attempt to discover the original source of the disease. The question is
today an unsettled one. The pandemic of influenza in its severest form
swept so suddenly over the world that before the profession realized it
or had become stabilized it had changed its character and the great
plague was gone. The consequence has been that we have really learned
little that is new and have done scarcely more than establish on a firm
basis many of the opinions formed after the great outbreak of some 30
years ago. Because transportation is today more rapid than it was at
that time, so the spread of the disease has been correspondingly swift.
Our modern life, the congregating crowds in theatres, moving-picture
houses and in lecture halls, as well as of the men in our training
camps, the development of street cars and the more frequent traveling by
train—these and many more changes in our mode of living have served to
aggravate the conditions favoring the widespread distribution of the
infecting agent. A higher proportion of the population was, therefore,
attacked than in any previous pandemic, and the period during which the
disease was widely prevalent has for the same reason been relatively
much shorter.

The characters differed somewhat in different regions, but the evidence
shows clearly that we are not dealing with any new disease. It will be
years before we are able to fully analyze the data that have been
collected from such wide sources and by so large a body of trained men,
so that important epidemiological facts may still be forthcoming from
the material already at hand. We are too close to the events to get the
most helpful perspective, and the object of this report has been to add,
in however small a degree, to the general knowledge of this great
pandemic as it has appeared to us in Pittsburgh and its surroundings.




 A CLINICAL DESCRIPTION OF INFLUENZA AS IT APPEARED IN THE EPIDEMIC OF
                               1918–1919

                         By J. A. LICHTY, M. D.


The epidemics of influenza which have been recorded from time to time
during the past few centuries have always contributed an interesting
chapter to the history of medicine. The protean character of the disease
with its many complications is always an excuse for another attempt at
the description of the clinical manifestations of a recent epidemic.
This is not, however, the only incentive at the present time for
describing the clinical aspect of the disease as it appeared in the
epidemic through which we have just passed. The study of the disease
from other aspects, such as the pathological, the bacteriological and
the physiological, by well-organized groups of workers has made it
necessary to co-ordinate, if possible, the clinical findings in every
detail with these apparently basic principles. It would be interesting
to review here the peculiarly fortunate circumstances which have led to
the investigations. On account of the great war many temporary
laboratory organizations which otherwise would not have existed were in
operation, and these organizations, moreover, were keen to undertake any
laboratory problem which might arise. The present epidemic presented the
opportunity, and that the work was taken up with great enthusiasm is
evidenced by the reports coming from the various army hospitals, base
hospitals and civilian hospitals throughout the world. The permanent
laboratories connected with medical schools and with institutions for
medical research took up the problems with equal endeavor. This brief
reference is made only to call attention to the fact that from such
organizations a great mass of information has come which must be
critically reviewed and coordinated before it can add to the permanent
fund of our knowledge of the disease under consideration.

The material upon which the following clinical observations have been
made is peculiarly adapted to review because it consists of two distinct
groups of patients which were admitted to the Mercy Hospital. One group
of 153 men was composed of soldiers between the ages of 18 and 23, which
had been recently inducted into the Student Army Training Corps, and
were living in barracks in the immediate vicinity of the hospital.
Another group consisted of civilians (394), ranging from youth to old
age, which came from various parts of the city and surrounding towns and
country. The first group came to the hospital early, or as soon as the
disease was recognized; the second group came usually after several days
of illness had elapsed, or when a complication had already arisen. Many
of this group had been ambulatory cases for the first part of the
disease. The entire number of patients admitted to the Mercy Hospital
from the first admission, September 21 to December 1, the end of the
quarantine, was 547. After December 1 very few simple influenza cases
were admitted. These 547 cases form the basis of the observations which
will be referred to in this paper.

From the last great epidemic or pandemic of influenza, that of 1889 and
1890, have come clinical descriptions which should be reviewed before
speaking of the clinical manifestations which have characterized the
present epidemic as shown in the two groups studied.

One of the best descriptions of that epidemic was given by Dr. O.
Leichtenstern in Nothnagel’s Encyclopedia of Practical Medicine. This
contribution, among many others, describing the epidemic of 1889 and
1890 is one of the first to refer to the Pfeiffer bacillus as being
etiologically associated with the disease. It differs, therefore,
greatly from descriptions of previous epidemics. Leichtenstern says:
“The typical influenza consists of a sudden pyrexia of from one to
several days duration, commencing with a rigor, and accompanied by
severe headache, generally frontal, with the pains in the back and
limbs, by prostration quite out of proportion to other symptoms and
marked loss of appetite.” He continues by saying that to these
characteristic symptoms may be added the catarrhal phenomena arising
from the affection of the respiratory tract, particularly the upper
(coryza) and “occasionally” the lower, the trachea and bronchi. This
description is so in accord with the symptoms of uncomplicated influenza
as found in the present epidemic that very little need be added. Any
difference which may occur in the description of the disease is likely
to be accounted for by the peculiarity of onset, whether in the upper or
lower respiratory tract, and by the different ways of interpreting
complications which may have arisen. It is evident from this description
that the upper respiratory tract was affected more generally than the
lower in the epidemic of 1889 and 1890. In the present epidemic it can
safely be said that the reverse was the usual state of affairs. It was a
rather unusual occurrence when the affection was limited only to the
nose, pharynx, larynx, trachea and larger bronchi. A very large number,
no doubt, had a peculiar œdema, a so-called “wet lung,” which we shall
discuss later; others went on to a capillary bronchitis or a
bronchiolitis, and a large number had broncho-pneumonia. This sequence
we shall attempt to show in the statistics at hand. In some cases the
lesion in the lower respiratory tract seemed to be primary, there having
been no initial coryza. At least none was observed and no history was
obtained.


                 _Prodromal Stage and Communicability_

The length of the prodromal stage—the stage from the time of contact to
the earliest onset of symptoms—has always led to interesting
observations and discussion. In this epidemic we have rather definite
information bearing upon this subject.

A young married farmer living in a rural community where no influenza
had occurred up to the time of the present experience went to a city
about 40 miles distant. On the train he sat in the same seat with a man
who was apparently ill, and who was sneezing and coughing. He was in the
city only a few hours, and was not in any place of congregation except
the railway train. Forty-eight hours after his return to his home he
noticed the first symptoms and began a mild course of influenza. About
50 hours later his wife was taken with the same symptoms, and in two
days more their only child was afflicted. Other members of the household
were also afflicted, and one of them died of pneumonia.

It might be interesting to quote a similar observation made by Macdonald
and Lyth, of York, England, published in a recent issue of the British
Medical Journal (November 2, 1918, p. 488), which corroborates this
experience. They say: “We traveled from London together on Thursday,
October 3, by train, leaving King’s Cross at 5.30 P. M., arriving in
York at 9.30, and as we were leaving the carriage a young flying
officer, who had come the whole way with us and was coughing and
sneezing at intervals, informed us that he was ill and had had influenza
for several days. On Saturday, October 5, we both became ill and had
developed typical attacks of influenza. With both of us the illness
developed suddenly with laryngitis; in both the first signs were a
severe attack of coughing; and in both the time was noted fairly
accurately as being between 2 and 2.30 P. M. One case was quite mild,
the temperature never over 101. The other was more severe; the
temperature arose to 104½ and the catarrh extended to the bronchi. His
wife and two children also developed influenza, and in their case the
symptoms showed suddenly, about 2 P. M., on Monday, October 7. Now we
are convinced that we became infected from our traveling companion
during the train journey—more likely toward the end of the journey; and
if we take the time of infection as 9.30, this fixes the incubation
period for both of us at a minimum of 41 hours, with a maximum margin of
error of 4 hours. The three cases developing in the family of one of us
point to a similar incubation period, as their illness started almost
exactly 48 hours after his, and as it is likely that the infection would
not take place until a few hours after the first symptom, the incubation
period in these three cases must have been nearly the same as our own
two.

“It can be readily understood that we were in no position to conduct
extensive bacteriological examinations, but a culture taken from the
posterior nares of one of us on October 10 with a guarded swab showed
colonies of Pfeiffer’s bacillus and of micrococcus catarrhalis.”

This observation is so convincing, I have quoted it at length and in
full.

The communicability of influenza has been observed by all, and the ease
with which it passes from one individual to another noted. One
observation made by us was of considerable interest. In a house where a
patient lay sick with a severe attack of influenza for nearly three
weeks several members of the household passed the door of the sick room
a number of times daily, and yet they did not contract the disease. This
is in marked contrast with the immediate contact between the two
physicians and the young flying officer, who sat in the same railway
carriage compartment for four hours. The same observation was made in
the hospital among nurses in direct contact with patients. A large
number of these contracted the disease, while those not immediately
associated with influenza patients almost invariably escaped. This
speaks strongly against the idea that the epidemic was a so-called
“plague,” or that it passed without intermediate means through the air
and pervaded all places.

From information thus far at hand it seems, therefore, that the
prodromal stage, or stage of incubation, is one which covers about 48
hours, and that it is usually without symptoms unless it be a peculiar
prostration which had been described by some patients. It would also
appear from the experiences just narrated that it was necessary to be in
rather close contact with a patient, so that there could be an exchange
of respired air before infection could take place.


                       _Duration of the Disease_

In all descriptions of the disease the duration is spoken of as “several
days, more or less,” “a three-day fever,” or “a seven-day fever.”
Because of the careful supervision under which the soldiers were kept
while in the barracks an excellent opportunity was afforded to note the
duration of uncomplicated cases. The shortest time observed was 1 day,
and the longest 10 days. The average duration of temperature among 87
soldiers without inflammation of the lungs or other certain
complications was 6⅓ days. Among the civilians the shortest time of
pyrexia was a few hours only, while the longest in 73 male patients was
14 days, and in 84 female patients was 16 days. The average length of
pyrexia in the males was 4⅝ days, and in the females was 5¼ days.

While the very definite clinical description of the former epidemics of
a so-called uncomplicated influenza seems to have served satisfactorily
to the present time, the laboratory studies and the possibly more
thorough clinical observations which have been carried out recently in
this epidemic make it necessary to present anew the whole disease
picture of influenza, with the hope of suggesting a classification more
in accord with our present knowledge of the disease.


                   _Forms and Varieties of Influenza_

A few words as to “forms” or varieties of influenza might be helpful
before suggesting a classification of symptoms. In former epidemics of
influenza considerable importance was attached to the early
manifestations or first symptoms as characterizing the “form” of
influenza which was in evidence in the individual patient. These were
reported as a “respiratory form,” a “nervous form,” a “gastro-intestinal
form,” and other forms—circulatory, renal, psychic, etc. In the epidemic
of 1889 and 1890 particularly these types were noted, and they have been
described in the subsequent small epidemics, practically characterizing
them as being of one or the other, and frequently as being without any
respiratory symptoms. In the study of our group of cases in the present
epidemic every effort was made to recognize the non-respiratory cases,
but we were unable to find a single case which did not have definite
respiratory symptoms, either early or late, in addition to any other
symptoms present. Only occasionally were nausea, vomiting and diarrhea
or tachycardia, or certain neuroses or psychoses, the leading symptoms.
The respiratory symptoms in some cases seemed to be at the onset
primarily of the lower respiratory system—that is, without the
preliminary coryza. These usually ran a rapidly fatal course,
characterized by marked cyanosis and confusingly irregular chest signs.
We would say, therefore, in so far as our experience goes in this
epidemic, we are not justified in speaking of any particular forms
except the respiratory form, and whenever pronounced manifestations
occurred justifying a characterization of any other form they could more
easily be interpreted as a complication, or the manifestation of a
coincident disease, or of a severe toxæmia.

The classification of the symptoms, therefore, takes into consideration
largely those symptoms arising from the respiratory system. We are of
the impression that the pathology demonstrated by Dr. Klotz and
described by others justifies the following classification. Clinically
we would recognize two distinct groups of epidemic cases.

The first includes those _without lung involvement_ having symptoms
arising from the upper respiratory tract, including the trachea and the
larger bronchi. These were practically without any chest signs except
for the rather indefinite signs of an acute bronchitis, and the only
symptoms referable to the respiratory tract were a coryza, soreness of
the throat, hoarseness and a cough of varying degree and character. If
to these symptoms are added those of Leichtenstern just mentioned, one
will have a good description of a so-called simple, uncomplicated
influenza.

The second includes those _with lung involvement_ and associated with
physical chest signs, in some indefinite and confusing, while in others
definitely conforming with the existing pathology. These symptoms and
chest signs were those associated at one time with what appeared to be
an acute œdema of the lungs. At another time the physical signs were
those of a bronchiolitis (capillary bronchitis), or most frequently of a
broncho-pneumonia, of an isolated type or of a massive type. Finally
there were some forms of lobar pneumonia which at times we were unable
to differentiate from a true lobar (croupous) pneumococcic pneumonia.


                  _Influenza Without Lung Involvement_

Of the group without lung involvement nothing further would seem
necessary to be said in addition to what one finds in standard
text-books describing the disease picture of former epidemics. The
incidence of influenza of this type among our group was as follows: Of
153 soldiers 93, or about 60 per cent., had a so-called simple,
uncomplicated influenza, and of the 394 civilians 185, or about 52 per
cent., had no lung involvement. There are a few points in which the
symptoms of the present epidemic seem to be so peculiar that they merit
special consideration.


                           _The Temperature_

This can be described as showing a sudden rise to 102–104, at which
point it is maintained for a few days, and subsides by lysis in a few
days more. A typical chart is as follows:

[Illustration:

  CHART I
]

Or the temperature might fall one or two degrees for a day or so after
the first rise, and then go up again for one or two more days, and
subside by lysis as is shown in Chart II.

[Illustration:

  CHART II
]

This would occur without our being able to find any lung lesion unless
we accept the acute œdema or wet lung as a complication, and this we
were rarely able to recognize by any definite physical signs in the
chest. Cyanosis frequently accompanied this second rise of temperature,
and was later interpreted as being associated with the so-called wet
lung. When the temperature remained up longer than five days it could
safely be concluded that lung involvement must be present.


                      _The Pulse and Respirations_

The pulse was invariably slow, or rather out of proportion to the
temperature. Even when the patient seemed very ill the pulse remained
from 84 to 96, and of surprisingly good quality. This was noted also
when some of the more severe pulmonary involvements or some
complications arose. The pulse frequently did not become rapid until
shortly before death. The respirations in an uncomplicated case also
remained about normal. The rate was not accelerated until lung
complications arose, and then a gradually increasing rate was often the
first herald of oncoming danger and a sign of grave prognostic import.
The relation of the pulse phenomena toward the end of a fatal case was
most remarkable. The respiratory rate was accelerated, as has been noted
above, but the pulse rate frequently remained unchanged, being
characteristically slow. In a patient seen in consultation with Dr.
Lester H. Botkin, of Duquesne, Pa., death took place while we were in
the sick room. It was a case of apparently uncomplicated influenza of
seven days’ duration. The respirations were rapid and the pulse was only
96. In the last five minutes of life the heart beats as observed with
the stethoscope never varied, until they suddenly ceased; during the
same time the respiratory efforts were only three agonal ones, the last
being a minute or so before the last heart beat. There were no physical
signs of consolidation at any time recognized in this case, but we feel
that the lung, had we seen it at autopsy, would in all likelihood have
shown the peculiar hemorrhagic and œdematous character so often observed
in the fatal cases.

There were, of course, marked exceptions to the description of slow
pulse and later rapid respirations observed. In some the pulse rate and
respirations increased, together with or without definite signs of a
grave complication.


                               _Cyanosis_

This was recognized early in the epidemic. It was sometimes preceded by
a peculiar flushing of the face, such as accompanies belladonna
poisoning. It might be noticed in the very first days of the attack. The
cyanosis was looked upon as being a very early symptom of lung
involvement. With our later knowledge from autopsies, and especially as
shown by Dr. Klotz, we feel it was surely an accompaniment of, or may
even have preceded, the changes in the lung which have been designated
as œdematous, “wet” or cyanotic. At the earliest appearance of the
cyanosis we were frequently unable to find any change in the physical
signs of the chest. Of course, the indefinite signs of an acute
bronchitis were present, and in some cases an additional “impaired
resonance” was noted over one or both lower lobes, but when this was
definitely present other more definite signs soon followed, and our case
was shifted suddenly from Group I, i. e., without apparent lung
involvement, to Group II, i. e., with definite lung involvement. This
cyanosis was noticed first in the face, and frequently was marked on the
dorsal surface of the hands. It was not unlike the cyanosis which may
sometimes be seen when large doses of certain coal tar derivatives are
taken. In fact, the question arose whether in the epidemic of 1889 and
1890, when the coal tar derivatives were prescribed with such freedom
and with accompanying cyanosis and apparently such deleterious effects,
the cyanosis may not after all have been due more largely to the
infection than to the medication. After that epidemic it was said:
“Influenza has slain its thousands, but the coal tar products have slain
their tens of thousands.” There was no gross hæmaturia or hæmoglobinuria
present in these cases, although a few red blood cells were seen
microscopically. There was, however, epistaxis, sometimes early in the
disease or later associated with the cyanosis. In a few cases there was
hæmoptysis, which we regard as always arising in cases where the wet or
hemorrhagic lung was present. Cyanosis in disease of the lungs, and
especially in the terminal stage of lobar pneumonia, is a familiar and
common occurrence, but the cyanosis observed in this epidemic seemed
quite different from the ordinary. The points of difference were these:
(a) it came early in the disease; (b) it seemed to be more generally
present when very little lung involvement could be demonstrated
physically, and was just as likely to disappear when more definite chest
signs were demonstrable; (c) it was not associated with embarrassment of
respiration; (d) it had no relation with a demonstrable circulatory
disturbance. The pulse did not become rapid; the quality of the pulse
did not change; _the right heart was not dilated_, as is so frequently
the case in the terminal stage of a lobar pneumonia when cyanosis
appears; (e) and finally there was no associated œdema of the lungs, or
at least that œdema of the lungs which occurs in the later stage of
lobar pneumonia, when the pulse becomes rapid, when there is rapid and
labored respiration, when the right heart dilates, when there is cold
perspiration, and when the signs of impending death are plainly evident.
The cyanosis of influenzal pneumonia seemed to be due to an entirely
different cause or combination of conditions from those present in lobar
or pneumococcic pneumonia. The cyanosis of influenzal pneumonia was,
therefore, most confusing, and became all the more so when it was
recognized that it did not yield to the respiratory and circulatory
stimulants usually employed when cyanosis is present. The inhalation of
oxygen was resorted to rather routinely early in the epidemic. It seemed
to temporarily influence the cyanosis, but the results were not
permanent, and the outcome of the cases did not seem to be different
from those in which oxygen inhalations were not used.

The blood pressure in those cases in which cyanosis was observed was
invariably low. This seemed to be due to the infection, for in several
private patients not belonging to this group of patients with previously
known high blood pressures the blood pressure was observed as much lower
throughout the course of the infection.


                              _Leucopenia_

The peculiar behavior of the white blood corpuscles will be discussed
more fully in another paper of this series. Our remarks will deal more
particularly with the clinical observations and interpretations. The
leucocytes fell below the normal from the very onset of the disease;
they varied very little regardless of great changes in temperature; they
did not always increase, or if they did increase at all it was
comparatively little, even in an extensive invasion of the lungs or in
severe complications. Concerning the leucopenia we have no explanation
to suggest, save that it is a clinical characteristic of the disease.
Our first thought was that the infection came on so suddenly and
profoundly there was no time for a leucocyte reaction. But when we
recall other diseases associated with a leucopenia, notably typhoid
fever, which does not come on with such suddenness, our explanation for
the leucopenia of influenza does not seem to hold. The leucopenia must
be simply a peculiar toxic blood reaction characteristic of the Pfeiffer
bacillus invasion. Such an explanation has long been accepted in the
Eberth bacillus infection.


                               _Asthenia_

A condition which was frequently noted by the patient was an
indescribable weakness and prostration which appeared early, sometimes
before any other symptoms were noted or before any elevation of
temperature. The young soldier was in apparent perfect condition when he
arose in the early morning. During the “setting up” exercises he did not
feel so fit, and a few hours later appeared extremely weak. When his
condition was called to the attention of the medical officers he was
found to have a slight elevation of temperature and was sent to his bed.

In former epidemics, as also in this one, marked prostration was
recognized as coming at the height of the disease and remaining
persistently during convalescence. But it does not seem to be recorded
as among the first symptoms.


                   _Influenza with Lung Involvement_

Of the group with lung involvement much may be written from a clinical
standpoint, and much confusion may be brought about. Especially is this
so if one has no definite idea of the pathology present, or if one
enters into a discussion of the character of the infection—a point upon
which there is as yet no unanimity of opinion. From the many reports
which have been put forth from the base hospitals of the various
cantonments, and also from the reports coming from civilian practice, it
is evident that scarcely any two groups of laboratory men or any two
individuals of those separate groups have the same idea as to the
bacteriology and the pathology peculiar to this epidemic.

As long as there is this confusion and element of doubt in the minds of
those to whom we are accustomed to look, the clinician must necessarily
speak with considerable hesitancy, especially when he attempts to
interpret the physical signs observed. In our own group the observations
of Klotz, Guthrie, Holman and others have given us an interpretation of
our clinical findings which, at present at least, is more or less
satisfactory. We shall definitely keep in mind their observations and
conclusions as we go on with the description of the physical signs of
the chest in cases having lung involvement.

In the description of this group it will readily be seen that the lower
respiratory tract stood the brunt of the infection. Of the 153 soldiers
under our care, 60, or about 40 per cent., were recognized as having
pneumonia. Of these, 34 had undoubted demonstrable signs, while 26 were
questionable, and yet from the temperature and other symptoms we
concluded there was a pneumonia. Of the 394 civilians, 189, or about 50
per cent., had pneumonia. Of this group there were again some 28 or 30
in which the diagnosis was doubtful, according to the ordinary way of
making a diagnosis, but we felt sure from the temperature course that
more than a simple influenza was present. In the description of the
physical findings of the chest in these influenzas with lung involvement
it will be readily seen why the diagnosis must sometimes be in doubt.

Before referring to the physical signs it might be well to describe the
condition and general appearance of the patient when the lungs became
involved. The patient who had been progressing with an apparently simple
influenza, with no chest signs except those of bronchitis or tracheitis,
occasionally slightly cyanotic, became more cyanotic, the elevation of
temperature continued longer than three to seven days, or if it came to
the normal began to rise again, his respirations gradually increased and
the pain in the chest became well localized. One could safely assume
that the patient had developed a lesion in the chest. This could not
always be localized during the first few hours or on the first day. The
evidence of increased bronchial disturbance was frequently recognized,
and later impairment of resonance and diminished breath sounds
associated with “a few crackles” were noted. This, so far as we can
tell, may have been the only evidence of the stage of œdema or “wet
lung.” After this, as the disease advanced, definitely increased vocal
fremitus and rather definite tubular breathing with greater impairment
of resonance were noticed. These signs were usually observed first at
the apex of the left lower lobe, and from here they extended forward
along the inter-lobar sulcus, or downward along the spinal column. If
the lesion was noticed first on the left side, in a day or two it was
found more or less definitely in the right lower lobe also. It seemed to
occur more frequently first in the body of the right lobe, instead of in
the apex of the lobe as on the left side. In both lobes it might spread
to contiguous areas and form a massive consolidation, or it might be
found in small separate areas, some of which would clear up in a day,
while others would persist.

The expectoration was frothy, containing either blood or masses of
yellowish, greenish purulent material floating in a watery sanguiolent
or clear fluid, or enmeshed in frothy mucus. The amount of expectoration
in some cases was enormous, but as a rule it was scanty. It was thick
and ropy at times and distinctly annoying to the patient.

At this stage the physical signs were very much in accord with those of
broncho-pneumonia. In a few hours sometimes, or in a day, the small
areas of consolidation became confluent and massive consolidation was
formed. It appeared as though the whole lobe would in time become solid,
as in a true lobar pneumonia. Or the original areas may apparently have
cleared and other areas involved, became the centers of massive
consolidations. In many cases both lower lobes were thus similarly
affected, and one had the physical signs of a double lobar pneumonia.
However, nearly always a small angle of the lobe remained clear, thus
differing from the entire lobe involvement characteristic of a true
croupous pneumonia. Other signs, such as the absence of vesicular
breathing and presence of the crepitant râle, moist râles of all sizes
to very coarse râles, could be noted. As in certain stages of a complete
consolidation, the lung might be dry; no râles present, but definite
tubular breathing present. This in a day or two, or after a longer time,
might give the signs of resolution. The stage of resolution, however,
was almost invariably prolonged, sometimes extending over weeks. With
these variable lung signs were often mingled the signs of a fibrinous or
serofibrinous pleurisy, which occasionally but remarkably infrequently
went on to effusion or empyæma.

[Illustration]

[Illustration]

[Illustration]

As stated above, the demonstrable pathology was in the lower lobe, and
more frequently in the left than in the right, only occasionally in the
middle lobe, and never, we might say, in the upper lobes. The very
earliest definite signs were found at the apex of the left lower lobe.

This observation seems to be entirely contradictory to that of the
pathologist, who found in 65 per cent. of all cases coming to autopsy a
lesion in all the lobes of the lungs (Klotz). The only explanation we
can give which seems at all satisfactory to us is that the pathology in
the upper and middle lobes must not have been sufficient, or must have
been of such a nature that it did not yield the physical signs, i. e.,
definite impaired percussion resonance, increased vocal fremitus and
tubular breathing, with varying shades of moist râles—signs upon which
we insisted before we were willing to state definitely that there is a
demonstrable pneumonia present.

In this description it has been attempted to follow the order of
invasion in a lung which seemed to go through the entire course of the
disease. There were, necessarily, all degrees of the process, some cases
showing few signs and yet being remarkably ill, and others all of the
signs with very little other evidence of serious illness.

We were continually impressed with the notion that the pathology in the
lung, at least the pathology demonstrable physically, did not tell the
whole story of the case, and that the outcome depended as much or
possibly more upon a general infection or toxæmia of which the
recognized condition in the respiratory system was only a small part. We
were particularly impressed with this in the success or failure
following the application of any therapeutic measures. It was quite a
common remark, therefore, in the wards of the hospital among those
associated in the work that “the patient died too quickly to permit of
the succession of the various stages of pneumonia”; or, in the autopsy
room, that if the patient had lived long enough he would have had
demonstrable, well-recognized pathology of the lung, instead of the
cyanotic, wet, spongy lung which was found.

The temperature course in the pulmonary cases was characterized by its
irregularities, and by its being entirely out of harmony with the extent
and severity of the lung invasion in so far as it could be interpreted
by the physical signs. The temperature as described in a simple
influenza might not come to the normal in the time of three to seven
days, and might even go higher, with no demonstrable chest signs, but
with every other evidence of lung involvement. Later the temperature
might come down by lysis, which was the usual way, and the chest signs
gradually or suddenly become evident. The temperature might remain
normal throughout the rest of the course, and a lobe or even both lower
lobes of the lungs be as solid as in a true lobar pneumonia.
Occasionally the temperature fell by crisis, but there was no associated
change in the physical signs of the chest. In short, the temperature
seemed to run a course entirely independent of the physical signs in the
chest. In two remarkable cases seen in consultation on two consecutive
days the physicians in charge declared that no signs of consolidation
could be found, though all other evidences of pneumonia were present. In
the 12 hours which had elapsed from the time the last examination was
made the temperature fell by crisis. At the consultation, to the
surprise of the family physicians, we found both lower lobes
consolidated, it having occurred apparently with the crisis. Both
patients were healthy-looking, robust, young men, and both recovered
with delayed resolution. In the convalescence of such cases, if the
patient got up too soon or if any other indiscretion took place, a
relighting of the lung occurred. From the above description it can be
readily seen that a diagnosis of the conditions in the chest in
influenzal pneumonia was frequently impossible, because one had to
abandon all his previous ideas of pneumonia, in so far as onset, crisis,
blood picture, sputum, temperature, respiratory and circulatory
phenomena, physical signs and prognosis were concerned.

Assistance from the laboratory was meager, especially in the early days
of the epidemic. This was due largely to the inability to get laboratory
workers in sufficient numbers to follow the work through, but more
largely to the fact that we were unable to interpret the unusual
laboratory results which were available. When we were once fully aware
of the difficulties in diagnosis which confronted us, we utilized every
practical means at our disposal. Among these was an examination of the
chest with the X-ray. On account of lack of facilities and of help, it
was impossible to make routine X-ray examinations of the chest in all
cases. Besides, it was difficult to interpret the X-ray findings, on
account of the unusual character of the lesions. Also, many of the
patients were so desperately ill one hesitated to disturb them. We hear
that other clinics had similar experiences, and that very little
substantial help came from the X-ray, except in cases with
complications. Several attempts were made to determine the kind of
shadow, if any, the “cyanotic, œdematous, wet” lung would make, but no
satisfactory observations have been forthcoming. From our own
observations and from the discussions of other observers, it would seem
to us that the stereoscopic examination of these chests is the only
possible way of getting satisfactory plate readings in these cases where
the pathology seems so lawless in its extent and peculiar in its
distribution. This method of examination, however, demands facilities
convenient at the bedside and perfect co-operation of the
patient—difficult conditions to meet under the circumstances. In the
acute cases, when the desire to make a diagnosis not only of the
presence but of the extent of the disease was keen, X-ray examination
was largely impractical. In cases of delayed resolution, or in cases
with complications with prolonged convalescence, X-ray examinations were
extremely helpful.


                  _Diagnosis of Influenzal Pneumonia_

In the consideration of any disease the well-trodden path of a
painstaking history, a thorough physical examination, and reliable
laboratory investigation, together with an intelligent interpretation,
will usually lead to a definite diagnosis. In certain diseases, as is
well known, the stress must be placed about equally on all of these
factors, while in others one or other factor predominates. In influenzal
pneumonia, until more is known of the etiology (bacteriology) and of the
pathological changes and of the physiological disturbances, the
controlling factor in the diagnosis (we feel embarrassed to admit) must
be the history. This is true not only of the diagnosis of influenza with
or without pulmonary involvement, but is also true of the diagnosis of
the various complications, and will be found to be particularly true in
the recognition of the bizarre sequelæ, which no doubt in the succeeding
months or years will be attributed to or will follow in the train of
influenza.

With the knowledge that there is a prevailing epidemic of influenza and
that the manifestations are largely in the respiratory tract, any
pulmonary disturbance will necessarily make one suspicious of the
presence or the oncoming of an influenzal pneumonia in the patient under
consideration. The history of the onset, as of simple influenza, is the
greatest factor. This with a continued temperature, cough, cyanosis,
slow pulse, continued asthenia, or even an unusual leucopenia, may have
a greater weight in determining the diagnosis of lung involvement than
will the apparently definite or, as it may happen, the confusing chest
signs. To differentiate from ordinary bronchitis, broncho-pneumonia and
catarrhal pneumonia, one need only refer additionally to the severity
and persistency of the disease when it is of the influenzal type, as
compared with the mildness of the ordinary type. To differentiate it
from croupous pneumonia, one need only compare the confusing symptom
picture of the influenzal pneumonia with the definite, clear picture of
ordinary pneumonia; or the confusing kaleidoscopic chest signs of the
one with the definite, clear-cut signs of the other. The laboratory thus
far has been the smallest factor in making the diagnosis, in that sputum
examinations, blood examinations, blood cultures and urine examinations
are mostly negative in their results, or at least the findings are not
specific. We do not, however, mean to indicate that these tests are not
of the greatest value. The leucopenia is the one outstanding feature
which seems to have separated this infection from other acute lung
infections, excepting miliary tuberculosis. The differentiation of
influenzal pneumonia from an acute tuberculous process in the lung may
be difficult, especially if there is no reliable history available.
However, the fact that pulmonary tuberculosis usually begins at the
apices of the lungs and influenzal pneumonia at the bases or at the
apices of the lower lobes is quite helpful. Of course, the examination
of the sputum for tubercle bacilli will be a deciding factor.

The differentiation between influenzal pneumonia and diseases of the
pleura is one which practically rarely needs to be made, for there seem
to be very few cases of influenzal infection of the lungs in which the
pleura is not also involved to a greater or lesser extent.


                            _Complications_

In considering the complications of influenza one again comes up
squarely against the question: What is influenza and what is the
specific micro-organism responsible for it? If the Pfeiffer bacillus is
the specific cause, what pathology can be attributed to it? It has been
an almost universal observation that the lesions in the lungs and pleura
which characterized the group of cases with lung involvement rarely
yielded a pure culture of the Pfeiffer bacillus, and that secondly in a
large percentage of cases the Pfeiffer bacillus apparently was absent,
and that other micro-organisms, such as the pneumococcus, streptococcus,
micro-organisms commonly found in the pneumonic processes, were present
and predominated. The question arises, therefore, may not all the
influenzas with lung involvement be _complications_ of influenza? It is
our feeling that Pfeiffer bacillus is present throughout the respiratory
tract in all cases, and while it may of itself produce a lesion like a
broncho-pneumonia or a lobar pneumonia, it chiefly prepares the soil for
other germs which may happen to be present, and which are more commonly
found in the pneumonias. We, therefore, look upon the lesion commonly
found in the lung as being a part of rather than a complication of
influenza, and look upon lesions elsewhere, due to the influenzal or
other micro-organisms, as a definite complication.

There is no doubt that the most frequent complication of influenza,
especially in the present epidemic, is in connection with the pleural
membranes. When one recalls that pneumonia rarely occurs without there
being also a pleuritis, and also when one recognizes that in an
influenzal infection of the lungs the specific micro-organism, together
with any other micro-organism which may happen to be present, seems to
run riot, apparently abandoning its usual mode of invasion, it can be
readily understood why this complication is so frequent and so varied.
The pleurisy was usually of the fibrinous type, and rarely was
accompanied with demonstrable fluid. Of the 153 soldiers in only 3 was
fluid detected in the chest, and of the 394 civilians only 10 showed
fluid. In many more cases fluid was suspected, but X-ray examinations
and free needling of the chest showed that we had misinterpreted the
physical signs.

After our experience in the epidemic of pneumonia in the spring of 1918,
when the disease was also so prevalent in the cantonments, we of course
expected to see many cases of empyæma and lung abscess in the present
epidemic. In this we were agreeably disappointed. Only one case of
empyæma and only one case with abscess of the lung were found up to the
time of collecting our data and the compiling of our statistics. Both of
these were among the civilians. From our experience since the compiling
of our statistics, we are inclined to believe that this low incidence of
empyæma may not altogether represent the real state of affairs, as we
have since received in the hospital several cases of empyæma, as well as
of abscess of the lung, which seemed to have followed an influenzal
infection which had occurred three or four months previously. One of
these cases was a particularly remarkable one, in that the patient had
already been admitted to the hospital twice since his initial attack of
influenza in October for suspected pleurisy with effusion. We were
unable to find any fluid with the needle, though we felt certain of
having demonstrated it a number of times physically and with the X-ray.
About eight weeks after the second admission, however, pus was found
after several needlings in the left chest, axillary space, apparently
along the inter-lobar sulcus. This case was a good example of many we
have seen in which a pneumonia, or possibly, as we see it now, a
pleurisy, or even a localized empyæma, seemed to confine itself about
the sulcus or fissure between the upper and lower lobes of the lung.
Frequently the process began posteriorly, apparently at the apex of the
lower lobe, and traveled forward and downward across the axillary space
until it appeared in the anterior part of the chest. In most cases we
interpreted our signs as those of a consolidated lung, and scarcely knew
whether the consolidation was in the upper part of the lower lobe or in
the lower part of the upper, or in both. In some cases we suspected a
localized empyæma or an abscess in the sulcus, but in none did we find
pus after exploring with the needle until this recent case occurred. The
passage of the needle in this case, which was done several times before
pus was found, always gave the impression that it was going through
dense fibrous tissue for some distance before the abscess was finally
found. From this experience, and from the extensive and irregular
invasion of the pleura which we have seen demonstrated at autopsies,
there can be no doubt that the clinical history of the complications of
influenza in this epidemic is not a closed chapter.

In six patients there was a purulent inflammation of the pharynx, larynx
and trachea. It was extensive and produced profound general symptoms,
dyspnœa and profuse purulent expectoration. The lungs were clear, but
the patient seemed for a time in danger of death. The condition was
considered a grave complication. There was only one case of acute
sinusitis, one case of antrum disease, and only four cases of middle ear
infection were recognized. This is in marked contrast to other epidemics
which have occurred to our knowledge in the past fifteen years or more,
and which have been spoken of as influenza or “grippe.” Disease of the
tonsils, middle ear disease, mastoid disease and sinus disease occurred
with great frequency in those sporadic epidemics. This again seems to
show that the deep respiratory tract was more generally and more
severely affected in this epidemic than the upper respiratory tract.

With the exception of the pleura, the serous membranes were remarkably
free from infection. Only one case of acute endocarditis, three cases of
meningitis (all pneumococcic), none of pericarditis, peritonitis or
arthritis were recognized among the 547 cases of influenza.

The kidneys did not seem to be involved in the infection. Albumen was
present in the urine, as might be expected in febrile conditions, but no
evidence of acute clinical nephritis, such as suppression of urine,
general œdema or uræmia, was recognized. The condition of the urine in
this epidemic will be described more in detail in another paper of this
series.

A peculiar pathological process in the muscles was brought to our
attention by Dr. Klotz, who demonstrated a myositis or hyaline
degeneration of the lower end of the recti abdominalis. This lesion is
carefully described in the pathological section. After our attention had
been called to this lesion we recognized several cases clinically having
the same condition. One was in the right sterno-cleido-mastoid muscle
and another was in the left ilio-psoas muscle. This last patient while
he was convalescing developed a severe pain in the left hip, extending
upward into the lumbar region and downward into the thigh. His decubitus
was like that of one suffering with psoas abscess. Every test available
was made to confirm this diagnosis, but all the findings were negative.
The patient rested in the hospital, in bed, for some time, gradually
improved, and eventually made a complete recovery.

In several cases we also detected an osteitis, especially of the bodies
of the vertebræ. One was of the cervical vertebræ and the other of the
dorsal. The first died after intense suffering. An autopsy was not
obtained. The other had a plaster cast applied as in Pott’s disease, and
improved sufficiently to leave the hospital in comfort. One hesitates
under the circumstances to attribute these bone lesions definitely to
the same infecting micro-organism which was responsible for the epidemic
of influenza, as it might easily have happened that a coincident
quiescent tuberculous lesion was present and relighted during the
epidemic. However, in one case from the service of Dr. J. O. Wallace the
possibility of the bone lesions being due to the Pfeiffer bacillus was
demonstrated. This was a child of 16 months with an epiphysitis of the
upper end of the tibia. The inflamed area was incised and pus was found.
A smear at the time showed the B. influenzæ, which was grown in pure
culture.

A most interesting complication noted in a few of our cases was a
transient glycosuria. The first case brought to our attention was a
middle-aged female, who complained of failure of vision. Upon making an
ophthalmoscopic examination a papillitis of a mild type was noticed.
This led to a careful study of the urine, and sugar was found in a small
amount for a short period of three days, although the glycosuria readily
disappeared by cutting down the carbohydrate intake, the vision came
back to normal more slowly. In fact, it was almost one month before the
symptoms and signs of the retinal change had entirely disappeared. It is
interesting in this connection to recall similar cases referred to in
Allbutt’s System of Medicine, vol. vi, on influenza, following the
epidemic of 1890 in England. Other transient glycosurias showed no
visual changes. We do not consider these to be true cases of diabetes
mellitus. In all a transient hyperglycæmia was also noted.


                              _Pregnancy_

A condition which can scarcely be considered as a complication of
influenza, but which, however, was a large factor in increasing the
mortality among women, was pregnancy. Among the cases included in this
study were five pregnant women, who came to the hospital and were
referred to the medical service. As soon as a complication relative to
the existing pregnancy arose they were referred to the Obstetrical
Department. On account of the great amount of work in caring for the
influenzal patients, and on account of the scarcity of physicians and
nurses, we were unable to follow these cases closely enough to give any
such definite data as we wish. Three miscarried or went into premature
labor. Happily only one of them died. The two which did not miscarry
recovered and left the hospital well.

We very soon recognized in consultation with the obstetricians that the
pregnant woman was in a really dangerous condition if she contracted
influenza. She was likely to have a termination of her pregnancy in the
height of the infection, no matter how recent or how remote pregnancy
had taken place. If pregnancy did not terminate, the chances of recovery
were less than those of the non-pregnant woman; if it did terminate, the
chances for recovery were still less. To the pregnant woman with
pneumonia very little hope of recovery could be offered. I am indebted
to Dr. Paul Titus, of the Obstetrical Department of the School of
Medicine, University of Pittsburgh, for a report which includes the
cases seen by himself and his assistant, Dr. J. M. Jamison, during this
epidemic. Dr. Titus was kind enough to include in his report certain
conclusions which merit consideration. The report is as follows: “A
series of 50 cases, at all stages of gestation. Interruption of
pregnancy occurred in 21, or 42 per cent., of the cases; 29, or 58 per
cent., in which pregnancy was uninterrupted. Mortality of pregnant women
developing epidemic influenza is higher than that of ordinary
individuals, even though their pregnancy is undisturbed, since 14 of the
29 in whom pregnancy was not interrupted died, an incidence of 48–2/10
per cent. If a pregnant woman miscarries or falls into labor, the
mortality increases to 80–9/10 per cent. (17 of the 21 in whom pregnancy
was interrupted died). The period of gestation has less influence on the
outcome than the interruption itself. Of 10 at term, 3 lived and 7 died
after delivery.

“Two main features of this condition as a complication of pregnancy are:
First, pregnant women developing epidemic influenza are liable to an
interruption of their pregnancy (42 per cent. aborted, miscarried or
fell into labor); second, the prognosis, which is already grave on
account of the existence of pregnancy, becomes more grave if
interruption of pregnancy occurs.

“The cause of the frequency of interruption of pregnancy is probably a
combination of factors: (1) The theory of Brown-Sequard that a lowering
of the carbon-dioxid content of the blood causes strong uterine
contractions sufficient to induce labor. (2) The toxæmia causes the
death of the fœtus, particularly if not mature, when it acts as a
foreign body and is extruded (10 premature fœtuses were born dead, while
1 was born alive, although 9 out of 10 at full term were born alive and
survived).

“The cause of the frequency of death following interruption of pregnancy
is also due in all probability to a combination of factors: (1) Shock
incident to labor. (2) Increase from muscular labor of carbon-dioxid in
blood already overloaded by the deficiency of the diseased respiratory
organs. (3) Sudden lowering of intra-abdominal pressure by the delivery.
(4) Lowering of blood pressure by the hemorrhage of the delivery. (5)
Strain of labor on an already impaired myocardium.”

If one had been told a year ago that an epidemic could occur which would
result in the death of 60 per cent. of all pregnant women affected, it
would have been thought too unlikely to warrant any consideration.
Though the effect upon pregnancy of the acute infectious diseases forms
an important chapter in the pathology of pregnancy, it seems that the
profession, and in this the obstetrician is no exception, has never
realized how pernicious and tragic the results of an influenzal epidemic
can be in a community. From the experience in previous epidemics we
cannot but feel that the infection in the present epidemic was unusually
fatal. Whitridge Williams (“Text-book of Obstetrics”) speaks of the
interruption of pregnancy as having occurred in 6 out of 7 cases with
one observer, and in 16 out of 21 in another, while a third has found it
only twice in 41 cases. However, none of these writers speaks of having
had a death.


                               _Sequelæ_

In referring to some of the associated conditions of influenza one
scarcely knows whether to consider them as complications or sequelæ. The
pathological process certainly had its origin from the influenzal
attack, but at times apparently assumed an inactive stage. The patient
is usually free from any specific influenzal symptoms, but retains for a
long time other symptoms referable to various organs, or he may have
been normal for a shorter or a longer period and then suddenly develop
symptoms apparently independent of the previous infection. It may be
well to consider all such conditions which followed the febrile attack,
whether immediately or more remotely, as sequelæ, and I shall therefore
speak of them as such.

The first and probably the most interesting and confusing are the
conditions found in the lungs following influenza. A chronic bronchitis,
an old bronchiectasis, or a previous tuberculous lesion in whatsoever
stage, may present acute symptoms and signs which are difficult to
interpret. The question always arises in the individual case—is this a
process due to the recent influenzal attack, or was it there before the
attack? Is it of streptococcic, pneumococcic, or tuberculous origin? The
history of previous diseases of the lungs may help to arrive at a
diagnosis. The history of the severity of the influenzal attack is of
very little help, because the apparently mildest attack may be followed
by the most profound changes in the lungs, and the gravest attack with a
history of definite lung infection may leave the lungs without a trace
of the previous pathology. The physical examination is helpful, of
course, in determining whether the lesion is at the apices or at the
bases, and from this a reasonably safe inference may be drawn as to
whether it is from a previous tuberculous lesion or a recent influenzal
infection. The Roentgenologist depends almost entirely upon this
localization. If the linear striæ are only at the apex, it is probably
tuberculous; but if they are only at the base, or also at the base, it
is likely to be an influenzal lung. In fact, the Roentgenologist with
his present information is ready to admit that it is most difficult to
speak definitely of the lungs in these cases. The possibility of
confusing the post-influenzal lung with a tuberculous lesion is not
peculiar to this epidemic. After the epidemic of 1889 and 1890 the same
condition was observed by clinicians. Dr. Roland G. Curtin, of
Philadelphia, in 1892 and 1893 conducted a series of clinics at the
Philadelphia Hospital, in which he spoke of the “non-bacillary form of
phthisis,” and showed case after case which he said might be diagnosed
as pulmonary tuberculosis, but because of the recent epidemic and the
absence of the tubercle bacillus he diagnosed them as post-influenzal
lung.

In the present stage of our knowledge, many of these post-influenzal
lungs will not be diagnosed properly until sufficient time is given for
either the lung to clear up or the tubercle bacillus to appear in the
sputum. We would emphasize the importance at the present time of finding
the tubercle bacillus in all suspicious lung lesions before giving a
positive opinion as to the tuberculous nature, even though the physical
signs are very definite.

Another group of sequelæ is that due to thyroid disturbance, or
disturbance of the endocrin system in general. Since the epidemic a
number of patients have been seen who noticed an enlargement of a
previously normal thyroid gland or greater enlargement of a previously
hypertrophied gland. In the same way the symptoms of hyperthyroidism
appeared, new in some or a recrudescence in others.

In some of these there was a disturbance of carbohydrate metabolism, as
shown by an occasional glycosuria and an increase in the blood sugar, or
by a possible disturbance of the suprarenals, as brought out by the
administration of adrenalin hypodermatically (Goetsch test). In the
application of this test in post-influenzal patients it appeared that
the whole endocrin system was in a state of imbalance.

It appears to us not at all improbable that the so-called psychoneuroses
of which fatigue, nervousness, irritability and tachycardia play such an
important part might also be explained in the same way. These constitute
a group of sequelæ which were frequently recognized after previous
epidemics, and which are again coming to the foreground.

We are of the opinion, on account of the apparent absence of any
specific pathology of the gastro-intestinal tract and its appendages
during the attack of influenza, that the sequelæ referred to the
digestive system are largely due to exacerbations of previous
physiological disturbances or pathological processes. The patient with a
previous peptic ulcer has a recurrence of his ulcer. The patient with an
infection of the biliary tract has an acute exacerbation, or may have an
attack of biliary colic. In fact, there seem to have been many more
cases of this kind since the epidemic than before, and most of the
patients date the time of the onset from a period soon after recovering
from influenza.

Very few, if any, patients in our experience have exhibited sequelæ due
to disease of the cardio-vascular or genito-urinary systems. It may be
that these will appear later when the more remote effects of an acute
infection are recorded.

A very commonplace sequel, but of more or less interest, is the tendency
to furunculosis. Our attention was particularly called to the associated
hyperglycæmia. The blood sugar readings varied from 0.2 to 0.41. There
was no glycosuria, acetone or diacetic acid. We have no explanation to
offer for this, although one might dilate readily on many attractive
theories. The hyperglycæmia, one may add, was readily reduced by a
lowered carbohydrate intake, which also had a curative action on the
furunculosis.

Finally we would mention the peculiar epidemic which has been observed
apparently over the world, encephalitis lethargica. We do not for a
moment put ourselves on record as regarding this disease as a
post-influenzal affair, but no one will deny that it has a peculiar time
relation to the epidemic; and further, that its distribution is
apparently identical. Its bacteriology seems to be unknown. Its local
pathology in the mid-brain is not peculiar or at variance with
encephalitis produced by known organisms. We have seen five cases; three
of whom had had undoubted influenza, while the other two were entirely
free from even the slightest suggestion of any type of illness previous
to the attack. All of these cases recovered. It has been stated that
following the 1890 epidemic a clinical condition was observed in Europe
which bears a close resemblance to what has been termed at the present
time encephalitis lethargica.


                 _Prognosis and Mortality of Influenza_

In giving a prognosis of influenza one has to take into consideration
the peculiar manifestations of the disease, especially the possible and
sudden changes which are liable to take place in the lungs. The points
which lead one to feel that the outlook is grave occur in about the
following order, which is also about the order of the severity of the
symptoms. First, _cyanosis_. This usually appeared quite early and was
considered a forerunner of definite lung infection. It may have been a
symptom only of the “wet lung,” to which reference has been made, but it
was usually followed with definitely recognized pathology in the chest,
and it immediately made the outlook unfavorable. Second, _continuation
of elevated temperature_. If the temperature fell to normal in three or
four days, the outlook was, of course, good; but if it went up again, or
if the temperature did not fall in that time, the chances were that
there was a lung involvement, even though the chest signs were negative
or only those of an acute bronchitis. Strange to say, however, when
definite chest signs were once recognized, the height of the temperature
or the continuation of fever was not so important a prognostic factor.
Third, _increase in pulse rate_. The pulse, as was noted before, was
unusually slow, even though the patient seemed desperately ill; when,
however, it began to increase in rate the condition was usually very
grave. Fourth, _the extent of lung involvement_. This was of very little
prognostic value. Both lower lobes might be solid, and yet if there was
no cyanosis and the pulse and respirations were satisfactory, the
outlook was rather good. On the other hand, there might be the slightest
involvement of the lung, and if the pulse were rapid and cyanosis
present the outlook was grave. Fifth, _depression and stupor_, or loss
of so-called “morale.” If the patient remained clear in his mind, bright
and hopeful, no difference how extensive the involvement or how grave
the symptoms, the prospect of recovery was better. This is, of course,
not peculiar to influenza, but it seemed particularly striking during
the epidemic. Sixth, _a gradually rising rate in respiration_, which
often was not more than two per minute per day, if progressive, even in
the absence of other untoward signs, conveyed a serious prognosis.

Our mortality among the civilians in comparison with the soldiers was
exceedingly high. The first cases seen by us were among the soldier
patients sent to the hospital. These were as fine a lot of healthy young
men as one can well imagine. They came to the hospital comparatively
early in the infection. After the first week it appeared as though our
experience would be entirely different from those in other localities,
for we had very few deaths. In another week our mortality began to rise,
but never as high as among the civilians, as will be seen by the
following figures.

Of the 153 soldiers 87 were without lung involvement, and of these none
died; 66 had lung involvement, and of these 16 died. Mortality among the
153 was 10 per cent. Of the 394 civilians 157 were without lung
involvement, and of these 1 died; 237 had lung involvement, or some
other complication, and of these 93 died. Mortality among the 394 was
23.6 per cent.

It will be seen that the mortality in the civilians was more than twice
as high as in the soldiers. It has already been mentioned that the
soldiers were ordered to the hospital promptly. The civilian patients,
on the other hand, were later in coming to the hospital, some of them
appearing when they had already developed serious complications. Another
factor in determining the mortality were the ages of the patients. The
soldiers ranged from 18 to 34 years, with an average of 20 years. The
civilians ranged from 6 months to 73 years, with an average of 30 years.
Generally speaking, the greater the age the higher was the mortality.

A third factor which should be considered in determining the actual
mortality is the result of later complications and sequelæ. The figures
as given are those of 547 patients, 110 of whom had died in the Mercy
Hospital and 437 of whom had been discharged therefrom between September
22 and November 30, 1918, the length of the quarantine. Those who were
discharged had been up and about for a week or 10 days before leaving
the hospital. From our experience with post-influenzal patients admitted
to the Mercy Hospital since November 30, we are of the opinion that some
of the patients discharged before November 30 as recovered may have
later developed sequelæ which might have proved fatal. No follow-up
system has been pursued as yet which enables us to speak definitely and
statistically of the present condition of those discharged.

This compilation does not readily lend itself to drawing any more
specific conclusions, but we cannot desist from expressing our opinion
that in the clinical study of this recent epidemic we find very little
that may not have been observed by clinicians in previous epidemics.




               THE URINE AND BLOOD IN EPIDEMIC INFLUENZA

                       By PETER I. ZEEDICK, M. D.


Epidemic influenza, unlike other acute infectious processes as
diphtheria and scarlet fever, seemingly attacks the kidney in a rather
mild manner. This statement refers only to the uncomplicated cases, as
other bacterial or toxic agents do play a part in the nephritides
occurring so often with the pneumonias or other complications
following influenza. It is, however, true that in many simple epidemic
cases there is evidence of a transient mild nephritis, or possibly,
more correctly stated, a nephrosis. Some writers observed albuminuria
in 80 per cent. of the cases, while the incidence in other reports
varies from 4 to 66 per cent. It is not always stated with reference
to these figures that the patients clinically were free from the
common complication—pneumonia. The findings of various observers
differ greatly, but they all agree that acute nephritis as a serious
sequel is somewhat rare.

In the literature of the past epidemics general acknowledgment has been
accorded to the presence of albumin in the urine during the acute stage
of the disease. Many times this has received no further notice or
comment than “febrile albuminuria.” The association of occasional
hyaline and granular casts has also been mentioned. One is impressed
with the fact that the older observers laid but little emphasis on the
urinary findings. It also seems to be true that nephritis as a clinical
entity is not prone to follow the epidemics. In general, our conclusions
from the last epidemic are about the same.

The data for this paper was obtained from examination of 994 specimens
of urine from 750 patients; of this number 517 specimens were examined
at the Magee Hospital, where members of the S. A. T. C., all young men,
were treated, and 447 specimens from the Mercy Hospital, where, in
addition to the S. A. T. C., we had men, women and children. On account
of the large amount of material and work on hand, as a rule only one
specimen of urine was examined from each patient, but where
complications were suspected repeated daily examinations were made. We
have grouped our results in tables, so that the various points may be
more readily followed.

Table I shows the urinary findings of uncomplicated influenza cases
admitted to the wards of the Mercy Hospital. None of these cases
developed pneumonia and, after running the usual course, recovered. We
would call attention to the fact that 25 per cent. showed albuminuria.
The amount of albumin was never excessive, and very often was little
more than a faint trace. On the other hand, we have had a few patients
where a previous kidney lesion was known to be present, and naturally in
these cases a heavy cloud of albumin was met with. The albuminuria was
almost always a transient affair, lasting only during the acute part of
the illness, and would rightly come under the class of febrile
albuminuria. We regard it as being more the evidence of nephrosis than a
nephritis. As a rule, the time for the appearance of albumin was after
the fever had been present for at least two or three days. One rarely
met with it in the short attacks of influenza where the temperature came
to normal in less than 72 hours. A certain time factor appeared to be
necessary in order for the nephrosis to develop. Another point of
interest is the presence of red and white blood cells seen relatively
frequently during the early days of the illness. One wonders if this
finding is analogous to the bleeding from the nose and lung so often met
with at the onset of the disease. The red blood cells were seen
microscopically, and only very rarely did we encounter a smoky urine.


                                 TABLE I

 URINE ANALYSIS IN CASES OF UNCOMPLICATED INFLUENZA AT THE MERCY HOSPITAL

 ───────┬─────────┬───────────────────────────────┬──────┬──────┬──────
 Day of │Total No.│                               │      │      │
 Disease│   of    │       SPECIFIC GRAVITY        │ Alb. │R.B.C.│Casts
        │Specimens│                               │      │      │
 ───────┼─────────┼───────┬───────┬───────┬───────┼──────┼──────┼──────
        │         │1001–10│1011–20│1021–30│1031–40│      │      │
 ───────┼─────────┼───────┼───────┼───────┼───────┼──────┼──────┼──────
       2│      118│      8│     31│     61│     18│    29│    17│     8
       3│       97│      8│     15│     62│     12│    23│    10│    11
       4│       51│      9│     22│     17│      3│    11│     7│
       5│       24│      4│      2│     14│      4│     5│     3│     4
       6│       11│       │       │      8│      3│     4│      │
       7│       25│       │     10│     14│      1│     8│      │
       8│       12│       │      2│      8│      2│     6│      │     3
       9│        4│       │      2│      1│      1│     2│      │
      18│        2│       │      1│      1│       │      │      │
 ───────┼─────────┼───────┼───────┼───────┼───────┼──────┼──────┼──────
 Totals │      344│     29│     95│    186│     44│    88│    37│    26
 ───────┴─────────┴───────┴───────┴───────┴───────┴──────┴──────┴──────


                                 TABLE II

 URINE ANALYSIS IN CASES OF UNCOMPLICATED INFLUENZA AT THE MAGEE HOSPITAL

 ───────┬─────────┬───────────────────────────────┬──────┬──────┬──────
 Day of │Total No.│                               │      │      │
 Disease│   of    │       SPECIFIC GRAVITY        │ Alb. │R.B.C.│Casts
        │Specimens│                               │      │      │
 ───────┼─────────┼───────┬───────┬───────┬───────┼──────┼──────┼──────
        │         │1001–10│1011–20│1021–30│1031–40│      │      │
 ───────┼─────────┼───────┼───────┼───────┼───────┼──────┼──────┼──────
       1│      101│      6│     22│     49│     24│     5│      │     3
       2│      127│      1│     17│     75│     34│    13│      │     3
       3│       82│      3│     13│     55│     11│    13│     1│     4
       4│       36│      1│     14│     18│      3│     4│      │     2
       5│       40│      2│      9│     24│      5│     6│     1│     2
       6│       23│      1│      5│     15│      2│     7│     1│     3
       7│        5│       │      1│      4│       │     3│      │     2
       8│        5│      1│       │      4│       │      │      │
       9│        2│      1│       │      1│       │      │      │
      10│       10│      1│      3│      5│      1│     2│      │     1
      11│        3│       │       │      3│       │     2│      │     1
      12│        3│       │      1│      2│       │     2│     1│
      13│        1│       │      1│      3│       │      │      │
      14│        1│       │       │      1│       │      │      │
      15│        5│       │      1│      4│       │      │      │
 ───────┼─────────┼───────┼───────┼───────┼───────┼──────┼──────┼──────
 Totals │      447│     17│     87│    263│     80│    57│     4│    21
 ───────┴─────────┴───────┴───────┴───────┴───────┴──────┴──────┴──────

The results shown in Table II illustrate the urinary findings at the
Magee Hospital, and, as in the previous table, include cases of
influenza which did not develop pneumonia. The specimens examined were
obtained from young, healthy men, between the ages of 20 and 32, and
showed albumin in 13 per cent. of the cases. This age factor probably
accounts for the lower incidence of albuminuria for this group.


                                TABLE III

 URINE ANALYSIS IN CASES OF PNEUMONIA (INFLUENZAL) AT THE MERCY HOSPITAL

 ───────┬─────────┬───────────────────────────────┬──────┬──────┬──────
 Day of │Total No.│                               │      │      │
 Disease│   of    │       SPECIFIC GRAVITY        │ Alb. │R.B.C.│Casts
        │Specimens│                               │      │      │
 ───────┼─────────┼───────┬───────┬───────┬───────┼──────┼──────┼──────
        │         │1001–10│1011–20│1021–30│1031–40│      │      │
 ───────┼─────────┼───────┼───────┼───────┼───────┼──────┼──────┼──────
       1│       47│      4│     14│     25│      2│    36│     7│     6
       2│       22│      1│      8│      9│      4│    19│     1│     4
       3│        9│      2│      3│      3│      1│     7│     1│
       4│        6│      1│      3│      2│       │     4│     1│
       5│        6│      1│       │      5│       │     5│      │     1
       6│       16│      2│      7│      7│       │    13│     2│     7
       7│        9│       │      5│      3│      1│     8│      │
       8│        3│       │      1│      2│       │     3│      │
       9│        3│       │      2│       │       │     2│      │
      10│        1│       │       │       │       │     1│      │
      11│         │       │       │       │       │      │      │
      12│        3│       │      2│      1│       │     2│      │
      13│        4│       │      1│      3│       │     3│      │     1
      14│        2│       │       │      2│       │     2│      │
      15│         │       │       │       │       │      │      │
      16│         │       │       │       │       │      │      │
      17│         │       │       │       │       │      │      │
      18│        1│       │       │      1│       │     1│      │
      19│         │       │       │       │       │      │      │
      20│        1│       │      1│       │       │      │      │
 ───────┼─────────┼───────┼───────┼───────┼───────┼──────┼──────┼──────
 Totals │      133│     11│     47│     63│      8│   106│    13│    19
 ───────┴─────────┴───────┴───────┴───────┴───────┴──────┴──────┴──────

Table III includes the urinary findings of patients diagnosed as
influenzal pneumonia. In this table the term “Day of Disease” indicates
the day on which the physical signs of pneumonia could be demonstrated,
and not the day on which the patient was taken ill with influenza. The
incidence of albuminuria—79 per cent.—is very high, while the presence
of casts and red blood cells is low. These results are really what one
would expect. As we have noticed in the late stages of uncomplicated
influenza a greater tendency for urinary changes to become apparent, one
would, therefore, most likely find considerable urinary disturbance in
the pneumonia immediately following the epidemic disease. Pneumococcic
pneumonia is prone to be accompanied by an albuminuria. So when we have
both influenzal and pneumococcic etiological factors involved, it is but
natural to have most of the patients showing signs of kidney
disturbance. The amount of albumin present, although generally greater
than in uncomplicated influenza, was not excessive. At times there was
little more than a trace. We noted the relative scarcity of casts—a
condition which differs greatly from our past experience in the ordinary
lobar pneumococcic pneumonia. On the transient nature of this kidney
involvement we have considerable positive evidence, but there is no
question that the time required for the urine to return to normal is
longer after pneumonia than uncomplicated influenza. We have observed
but one or two cases which afterward returned to us presenting clinical
signs of acute nephritis. In fact, in going over our hospital records of
the winter and spring we noted that an unusually small number of acute
nephritics have been admitted. This would seem to be evidence that, as
has been noted in the past, the kidney is not a vulnerable organ in this
epidemic disease.


                                 TABLE IV

 URINE ANALYSIS IN CASES OF PNEUMONIA (INFLUENZAL) AT THE MAGEE HOSPITAL

 ───────┬─────────┬───────────────────────────────┬──────┬──────┬──────
 Day of │Total No.│                               │      │      │
 Disease│   of    │       SPECIFIC GRAVITY        │ Alb. │R.B.C.│Casts
        │Specimens│                               │      │      │
 ───────┼─────────┼───────┬───────┬───────┬───────┼──────┼──────┼──────
        │         │1001–10│1011–20│1021–30│1031–40│      │      │
 ───────┼─────────┼───────┼───────┼───────┼───────┼──────┼──────┼──────
       1│        3│       │       │      2│      1│     1│      │     1
       2│       12│       │      1│     10│      1│     8│      │     6
       3│        4│       │       │      4│       │     1│     1│     1
       4│        9│      1│      2│      4│      2│     6│      │     6
       5│        8│       │      4│      4│       │     6│      │     5
       6│        8│       │      5│      3│       │     7│     2│     6
       7│        4│       │      2│      2│       │     3│      │     2
       8│       10│       │      2│      8│       │     5│     2│     5
       9│        4│       │      2│      2│       │     4│     3│     4
      10│        6│       │      1│      5│       │     6│     3│     5
      11│        1│       │      1│       │       │     1│      │     1
      12│        1│       │      1│       │       │     1│      │
      13│         │       │       │       │       │      │      │
      14│         │       │       │       │       │      │      │
      15│        2│       │      2│       │       │     1│      │     1
 ───────┼─────────┼───────┼───────┼───────┼───────┼──────┼──────┼──────
 Totals │       70│      1│     20│     45│      4│    49│    11│    40
 ───────┴─────────┴───────┴───────┴───────┴───────┴──────┴──────┴──────

Table IV includes specimens obtained at the Magee Hospital from patients
diagnosed as pneumonia. The results among these young students were very
similar to those of the previous chart, where all ages were included.
However, casts and red blood cells were more regularly noted.

From the four tables, we are able to note one or two common facts. In
acute uncomplicated influenza albuminuria occurred 57 times in 447
specimens, or 13 per cent., at the Magee Hospital. Here we dealt
entirely with the young adult. At the Mercy Hospital 88 positive results
of albumin in 344 specimens, or 26 per cent., from patients of all types
were recorded. The common total would be 781 specimens examined, and
141, or 17 per cent., showing albumin.

With the advent of pneumonia the incidence of albuminuria was increased.
At the Magee Hospital it was seen 49 times in 70 examinations, or 70 per
cent.; while at the Mercy Hospital 106 positive results were found in
133 specimens examined, a percentage of 79. The combined figures,
therefore, would show 155 out of 203, or 76 per cent.

The incidence of albuminuria for the epidemic in all its phases would
be, from our figures, 400 in 994 specimens, or 40 per cent.

Red blood cells were present in 5 per cent. of the influenza cases, and
in 11 per cent. of the pneumonias. This was always a microscopic
observation, save in the case of a slightly smoky urine. Even
microscopically the red cells were not numerous. We noted them at times
quite early in the disease in some of the severe cases which presented
epistaxis and hematemesis. Possibly one might consider the early
presence of red blood cells in the urine as a condition analogous to
those just mentioned, although we never saw anything suggesting free
hemorrhage from the kidney. It is probably better to regard the red
cells as a manifestation of an acute nephrosis of toxic origin.

Casts were found in 35 per cent. of the cases showing albuminuria. We
are inclined to feel that this observation is somewhat low, but at the
same time we have noted that in uncomplicated influenza one frequently
sees albumin without casts. We were also impressed with the fact that
casts were not as prominent a feature in the influenzal pneumonias as
they are in frank lobar pneumonia of essentially pneumococcic origin.

During the course of routine examinations several transient glycosurias
were seen. Their transient character was the outstanding feature. The
quantity of sugar was very moderate—our figures were never above 1 per
cent.—and the daily amount of urine was always within normal limits.
Acetone and diacetic acid were absent. A few observations on the blood
sugar showed a rise (.2 to .25), which readily came to normal with
treatment. Clinically these cases were not classed as diabetes mellitus,
but rather as a nervous complication of influenza, involving in some way
the carbohydrate metabolism, probably through the central nervous
system. One case of special interest, which is mentioned elsewhere, was
the association of glycosuria with almost total blindness from a very
intense optic œdema. Sugar (1 per cent.) was present on the day of
admission, while only a trace was noted on the two following days, and
from then on the urine was free from sugar. How many days the sugar had
been present before admission to the hospital we cannot say, but we
could trace the failure of vision back to almost the day of its onset,
which was three weeks previous to our first examination. The eye
symptoms were the only complaints. The patient had had a moderately
sharp attack of influenza a little over two weeks before the first sign
of failure of vision had appeared. We may add that the vision returned
slowly to normal several weeks after admission. The urine and blood
sugar were normal, on a general diet, over a period of one month while
in the hospital. Unfortunately, we have had no further record of this
patient regarding the urine, but her vision still remains normal. Cases
of this type were observed in England after the 1890 epidemic, and are
referred to in Allbutt’s “System of Medicine,” vol. i, on influenza. Our
other glycosuria cases did not present changes in the fundus of the eye.
The glycosuria and glycæmia were transient, and we feel that they do not
represent diabetes mellitus. Most of the patients of this class had long
since recovered from an attack of influenza, and came to the hospital
usually for treatment of various nervous conditions, which at times
simulated neuritis, or otherwise one saw manifestations of general
nervousness, not unlike hyperthyroidism. In all probability, we were
dealing with a hyperglycæmia associated with a hyperactive thyroid
gland. So, after all, the glycosuria, even though rare, is not
bewildering. Symptoms and signs of toxic goitre in direct relation to
the epidemic we claim to have seen, and one is justified, temporarily at
least, in having the thyroid gland father our transient glycosuria.

In relation to the positive sugar findings, we have had numerous
negative examples of almost equal interest. Furunculosis is a very
common sequel of the epidemic. It is well known that in furunculosis
there is a hyperglycæmia, but no glycosuria and no acetone or diacetic
acid in the urine. All our blood sugar readings were above the normal,
and at times unusually high. They varied from .2 to .41. This last
unusually high amount was in a young physician with recurrent
furunculosis following influenza. There was no glycosuria at any time.
Elimination of carbohydrates not only brought the blood sugar to normal
limits in the course of a week, but also assisted in the cure of the
furunculosis, but in a longer time. In all of this group we saw no
incidence of polyuria or glycosuria.


                              _Hematology_

There is very little evidence, as shown in the literature, that special
study on the blood during past influenzal epidemics has been made. A few
references to alterations in the count of cells have been reported for
the last epidemic (1890), but they are, as a rule, very brief
statements. Cabot notes a normal leucocyte count in two-thirds of the
cases, and a moderate increase in the rest. Several observers call
attention to the leucopenia during the height of the disease, with a
subsequent rise after the temperature has fallen to normal. According to
Rieder and Herman (American Journal of Medical Science, 1893, cv. 696),
the leucocytes were not increased in simple influenza, and only very
slightly in the pneumonia following this disease. Herman also noticed a
decline in the leucocytes in pneumonia as a fatal ending ensued. This
finding was one of the few recorded for the 1890 epidemic. Emerson
(Emerson Clinic Diagnosis, 1911, 558) found in influenza almost one-half
of the cases showing more than 10,000 leucocytes, some even reaching
25,000. He further notes that early in the disease the count may be low,
3,000 to 5,000, but it usually rose sharply, to fall again when the
temperature comes to normal. He lays stress on obtaining a leucocyte
curve for each case in order to get a true picture of what changes
occur. The past epidemic has brought out many observations on this
subject. They vary somewhat, as is to be expected, but a common factor
seems to be more or less basic—namely, a leucopenia or a normal count is
the most significant single blood picture we have of uncomplicated
influenza. Further, a leucocytosis is fairly generally, and we believe
correctly, interpreted as evidence of a secondary bacterial invasion in
this particular epidemic, and usually of the respiratory system. The
leucopenia is as much a part of the clinical picture of influenza as it
is of typhoid fever. Leucocytosis always means secondary invasion by
other organisms.

During the recent epidemic the clinical laboratory department of the
School of Medicine, University of Pittsburgh, has made 747 blood counts
on influenza cases. In most of the cases blood counts were made as a
routine, while repeated counts were done only on selected patients.

The following table indicates the leucocyte count for our series,
comprising the epidemic in all of its phases. There are a few general
points which appear striking that we may refer to at this time, and
leave until later the discussion of the minor details. One-third of the
counts, including, as they do, many cases of pneumonia, showed a
leucopenia, while 70 per cent. of the total number fell under 10,000.
This last group contains more pneumonias and other complications than
simple influenza. But 5 per cent. of the cases counted showed more than
20,000. All of these undoubtedly had pneumonia or some other
complication. Comparing this finding with our experience in the past
before the epidemic with the pneumococcic lobar pneumonia, one sees at
once that, as far as this type of clinical observation is concerned, the
two pneumonias are totally different. The writer remembers but one case
of lobar pneumonia which showed a persistent white count falling below
10,000. Certainly in this community lobar pneumonia and low leucocyte
counts were unusual combinations until the present epidemic. Further,
the evident depression of leucocytosis even where there was an actual
increase is indicated by 95 per cent. of our counts being below 20,000.
This leads us to state that the pneumococcus, although present in
practically all of our pneumonias, produced in only a small percentage
of the bloods we examined its characteristic increase. The toxic factor
of this influenzal epidemic certainly causes a marked change in the
white cells of the blood.


                                TABLE V

                MERCY HOSPITAL               │     MAGEE HOSPITAL
 ───────────┬──────┬──────┬──────┬─────┬─────┼──────┬─────┬─────┬─────
            │      │      │      │     │     │Influ.│     │     │
  Leucocyte │      │Influ.│Influ.│     │     │Influ.│     │     │
   Count.   │Influ.│ Pn.  │Compl.│Total│  %  │ Pn.  │  %  │Total│  %
            │      │      │      │     │     │Influ.│     │     │
            │      │      │      │     │     │Compl.│     │     │
 ───────────┼──────┼──────┼──────┼─────┼─────┼──────┼─────┼─────┼─────
     2000 or│      │     2│      │    2│   38│     1│   28│    3│   32
        less│      │      │      │     │     │      │     │     │
   2000–3000│     3│     3│     1│    7│     │    13│     │   20│
   3000–4000│     7│    12│     4│   23│     │    34│     │   57│
   4000–5000│    14│    13│     9│   36│     │    41│     │   77│
   5000–6000│    17│    16│     6│   39│     │    42│     │   81│
            │      │      │      │     │     │      │     │     │
   6000–7000│    15│    13│     6│   34│   40│    59│   37│   93│   38
   7000–8000│     7│     8│     5│   20│     │    36│     │   56│
   8000–9000│     8│    14│     8│   30│     │    37│     │   67│
  9000–10000│    15│     9│     8│   32│     │    39│     │   71│
            │      │      │      │     │     │      │     │     │
 10000–12000│     4│    12│     9│   25│   20│    44│   27│   69│   25
 12000–14000│     1│     1│     8│   10│     │    28│     │   38│
 14000–16000│     5│     3│     2│   10│     │    22│     │   33│
 16000–18000│     3│     2│     2│    7│     │    16│     │   23│
 18000–20000│     2│     2│     2│    6│     │    15│     │   21│
            │      │      │      │     │     │      │     │     │
 20000–22000│      │     1│     1│    2│    2│     4│    5│    6│    3
 22000–24000│      │      │     1│    1│     │     8│     │    9│
 24000–26000│      │      │     1│    1│     │     4│     │    5│
 26000–28000│      │      │      │     │     │     2│     │    2│
 28000–30000│      │      │     1│    1│     │     3│     │    4│
            │      │      │      │     │     │      │     │     │
 30000–32000│      │      │      │     │     │     3│    3│    3│    2
 32000–34000│      │      │      │     │     │     3│     │    3│
 34000–36000│      │      │      │     │     │     3│     │    3│
 36000–38000│      │      │      │     │     │      │     │     │
 38000–40000│      │      │      │     │     │     1│     │    1│
 40000–42000│      │      │      │     │     │     2│     │    2│
            │      │      │      │  ———│     │   ———│     │  ———│
            │      │      │      │  287│     │   460│     │  747│
 ───────────┴──────┴──────┴──────┴─────┴─────┴──────┴─────┴─────┴─────

The blood picture in uncomplicated influenza is a normal one for the red
cells and the hæmoglobin, but the white cells are characteristically
altered. We have made many observations on the red blood cells, and from
all aspects the picture appears to be normal. Similarly, there is
nothing significant about the hæmoglobin estimations. Where we have
slight alteration in the red count and in the hæmoglobin it is probably
safer not to attribute the change to the epidemic. We have no records
showing a secondary anæmia due to the initial epistaxis.

A leucopenia or a normal count is what one should see in most of the
uncomplicated influenzal cases. We are almost ready to say that any
estimation above normal limits means secondary bacterial invasion. The
count may remain low throughout the illness, rising to the normal
rapidly as the temperature falls. We do not regard a leucocytosis at the
end of an epidemic case as part of the blood picture. Our experience is
that with convalescence the normal count returns and remains within
normal bounds. Very often hidden sinus infection is responsible for some
of the post-influenzal leucocytoses. The leucopenia may vary from a
slightly subnormal count to a point well below 2,000. Most of the simple
epidemic cases showed some degree of leucopenia. As far as we have been
able to estimate, we are led to believe that one should not lay any
special stress on the grade of leucopenia as being of prognostic
significance in uncomplicated influenza. Many of the mildest clinical
types showed very low counts, and _vice versa_. There is, however, a
prognostic relation to be noted with reference to a falling white count
in the pneumonia, but this we shall mention again later. The onset of
the leucopenia corresponds to the onset of the disease. It was present
with the earliest cases we examined, and remained fairly stationary,
although we have records of its fluctuating slightly one way or the
other. But one must remember in this regard the personal error in blood
counting, and also particularly the error of the apparatus. For careful
work only those counting chambers and pipettes should be used that have
a Bureau of Standards certificate. The duration of the leucopenia was
fairly close to the duration of the disease.

How many cases of influenza of several days’ illness having about 12,000
leucocytes, a few sticky râles in the chest, but no signs of definite
consolidation, have been observed by the clinicians? These cases recover
without further change, and the diagnosis is handed in as influenza
without a complication being mentioned. In collecting the blood reports
from this group the 12,000 cells accordingly must be considered as
having occurred in a simple influenza. We hold that this is not a case
of uncomplicated epidemic disease. There is undoubted evidence, as is
acknowledged by the clinician, of a bronchiolitis; and how many lungs
showing a bronchiolitis at autopsy fail to have a broncho-pneumonia?
True it may not be demonstrable by our physical examination. This is
often the origin of many high counts in what apparently is considered
uncomplicated influenza.

The blood picture of the pneumonia following the epidemic was more or
less constant, although at the same time the features of the count may
be quite different. One could roughly divide the results into three
groups: (1) leucocytosis, (2) leucopenia, (3) intermediate or normal.
Some pneumonias could be followed during their course through all of
these classes. Before discussing the white count we can briefly dismiss
the other phases of the blood examination by stating that the red blood
cells and hæmoglobin presented nothing by the usual examinations which
was of special significance, or in any way characteristic.

As an example of the group showing a leucocytosis let us follow a
patient through an acute influenzal attack, followed by a pneumonia with
a subsequent recovery. An initial leucopenia, gradually or suddenly
changing into a very moderate leucocytosis (10,000–15,000), was noted at
the onset of the pneumonia. During the course of the complication the
number of cells in the majority of cases increased, but rarely advanced
beyond 20,000. With lysis or crisis the count dropped toward normal, and
by the time the lung signs had disappeared the white cells were at the
usual number, or very slightly increased. The point which seemed to us
to be of importance was that, even although we had a leucocytosis, it
was nothing like the count that one would expect for a lobar pneumonia.
Of course, there were a few high counts, but looking at the group as a
whole they were relatively low. There are a number of variations to this
form of blood picture which we might briefly consider. We have observed
secondary rises in the leucocyte count concurrent with a new lung
involvement. This type was the one so prone to develop into a condition
of non-resolution, fibrosis and ultimate death, with a continuous
moderately high leucocytosis to the end. Another variation which we
learned to fear was the fall of leucocytes to normal or subnormal after
a primary rise, when the clinical course of the case in no way indicated
a crisis or lysis pending. Seemingly, the longer the primary
leucocytosis had been present the more serious was the subsequent
leucopenia. We regard this form of secondary leucopenia, if one may use
such a term, as a prognostic sign of some value. As in lobar pneumonia,
a high leucocyte count has been, as a rule, a favorable feature.

The second group, or those showing a leucopenia throughout their course,
was by no means an unusual thing. This is a cardinal point—in fact, one
of the most striking clinical features of the epidemic. The leucopenia
here does not have the prognostic value that it seems to have in the
group just referred to previously. We have observed cases go through a
pneumonia with 4,000–5,000 white cells in a relatively easy manner.
When, however, the leucocytes fall to 3,000 or under, one may be
reasonably sure that the outcome is doubtful, even with the general
condition of the patient at the time favorable. In the pneumonias of
this group which died the leucocytes have always fallen to about 2,000
cells. We have a number of observations taken from one-half to four
hours before death showing counts in the immediate neighborhood of
2,000, but never below this number. Where recovery has taken place the
cells go forward to the normal, more or less keeping pace with the
general clinical picture.

Of group three there is not much to say, except that on one hand it
tends toward a leucocytosis, and on the other to a leucopenia. This
group comprises a considerable number of the pneumonias. We are not in a
position to say anything regarding the relative mortality of this group.
The development of a leucopenia from these cases after a period of some
stability in the leucocytic curve is of bad prognostic import. Not
infrequently we have noticed rather wild abrupt rises to 20,000 in the
leucocytes toward the late half of the disease. This curve was nearly
always sustained until the end, which, as a rule, was recovery.

We do not need to consider at any length the effect on the leucocyte
count of complications not of lung origin. Acute sinuses in head, otitis
media and meningitis always produced a variable moderate leucocytosis.
The change was not so marked in meningitis, as our cases were all
preceded by a pneumonia which had independently invoked a slight
leucocytic response. As a complication of the pneumonia we have noted an
abrupt rise following an acute pleuritis with effusion, and similarly
after the onset of an empyema. These complications seemed to be able to
induce a leucocytosis with more certainty and ease than the more serious
pneumonic condition. Possibly, as they occurred toward the end of the
infection, the toxic factor of the epidemic influenza was more or less
spent, and the secondary invader had a freer hand to act in its normal
way.

Differential counts were made in 194 cases, including influenza,
influenzal pneumonia and influenzal complications. We have taken the
average percentage of each type of cell for the groups, which are purely
numerical divisions based on the leucocytic count. No differentiation is
made for the various clinical divisions of the epidemic in the following
table:

                        LEUCOCYTES 2,000–8,000.
                                P.  E. L.M. S.M. Trans.
                Total counts 86 66% 1%  13%  17%     3%

                       LEUCOCYTES 8,000–10,000.
                                P.  E. L.M. S.M. Trans.
                Total counts 33 69% 1%  11%  16%     3%

                       LEUCOCYTES 10,000–20,000.
                                P.  E. L.M. S.M. Trans.
                Total counts 45 76% 2%  10%  19%     3%

                       LEUCOCYTES 20,000–30,000.
                                P.  E. L.M. S.M. Trans.
                Total counts 17 79% 2%   8%   7%     4%

                       LEUCOCYTES 30,000–40,000.
                                P.  E. L.M. S.M. Trans.
                Total counts 13 85% 1%   5%   6%     3%

The differential count in general indicates an increase in the
polymorphonuclear leucocytes as the total leucocytic number increases.
This is really what one would expect. There also seems to be an increase
of the large mononuclear cells, with a slight diminution in the small
mononuclear elements, particularly in the count below 10,000. Abnormal
cells were encountered very seldom. One can hardly say that the epidemic
has a characteristic differential blood picture, except, perhaps, that
an increase of the large mononuclears is present in the low counts.
This, however, may hold true for any leucopenia.


                             _Conclusions_

1. Epidemic influenza is often accompanied by a transient slight
albuminuria with a few red blood cells and casts. Acute nephritis as a
clinical entity does not appear to be other than a rare sequel.

2. Epidemic influenza tends to produce a leucopenia.

3. A leucocytosis in influenza, as a rule, indicates a secondary
infection.

4. The pneumonia following influenza shows, as a rule, but a very
moderate leucocytosis, while, on the other hand, the presence of a
leucopenia is by no means infrequent.

We are greatly indebted to Miss R. Thompson, Messrs. Mock, Frost,
Marshall and Scott for their assistance in this work at the Magee
Hospital.




                       THE TREATMENT OF INFLUENZA

                     By W. W. G. MACLACHLAN, M. D.


One may frankly say there is no specific treatment for influenza.
Possibly we are in error in introducing the discussion, particularly on
treatment with such a definite and unsatisfactory conclusion. The same
statement has been made after all the previous pandemics, and one
wonders whether a like remark is going to apply to the next similar
scourge. The past two or three months should bring to the medical
profession a certain humility which should stimulate a keener sense of
research, especially as we now have at our disposal highly organized
laboratories where unsolved problems can be viewed from almost any
angle. Yet we are really, save here and there, putting our forces
together in the study of the disease. It is obvious that a fleeting
epidemic makes a most difficult subject for study, especially during a
time when there is a paucity of physicians. May we not hope, however,
that some researches on the disease may be forthcoming, so that we may
safely feel that at least preventive or protective measures will be
possible?

There is no one who is able to say that this or that drug has not been
thoroughly tried. The alkalies, salicylates, antipyretics, quinine and
the sedatives have all been freely used in the last as well as the
present epidemic. Each group of drugs has its following, although it
appears to be a general rule in this epidemic to use the antipyretics
(coal tar products) as little as possible. From the distant past we have
numerous records of treatment. Willis (1658) emphasized the value of
sweating and the use of diaphoretics, but at the same time he states
that in mild cases the cure is left to nature; Sydenham (1675) claimed
considerable value in fresh air. He also paid more attention to
restricting the diet, and was not favorable to the use of anodynes. One
certainly obtains the impression from the records of past epidemics that
many of the general principles in treatment were similar to what are now
in vogue. Medicinal remedies, of course, varied greatly, but to
enumerate them would be merely giving a résumé of the progress of
therapeutics. Sufficient is it to say that influenza has certainly,
since the earliest days, given therapeutists an ample opportunity to
test their wares.

The outstanding respiratory complication, pneumonia, has added a very
undesirable phase to the disease. In fact, the greater part of the
mortality was due to this serious sequela. Some interesting points have
been brought out in serum and blood therapy for this type of pneumonia.
The use of whole blood or serum from convalescent patients in cases of
pneumonia opens up a new and not unlikely fruitful means of treatment.
The method of treatment possibly may be applicable as an emergency
measure in other diseases, as has been shown in the case of scarlet
fever and poliomyelitis. We also have the anti-pneumococcic sera
available for therapeutic use. The drugs and the general treatment of
the pneumonia are virtually the same for the last two epidemics.

The protean manifestations of the 1890 epidemic, with its unusual
nervous sequelæ, have not been seen to any extent, as far as we yet
know. In fact, the present epidemic appears to be relatively free from
complications other than those occurring in the lung during the acute
course of the disease. Hence, in all likelihood, there will be less of
the nervous after effects to be treated. It is, however, too early to
hope that the nervous system is going to escape.

In another part of this volume the vaccine therapy is discussed in
detail, so that we shall not repeat what has been brought out in that
article. We would, however, emphasize the value of honest and accurate
clinical reports of the use of vaccines, in order to establish their
present status in epidemic influenza. Overestimation and commercialism
are very likely to ruin a method of treatment, even when it may be of
value in a certain phase of the disease. If we do not carefully weigh
the pros and cons of the vaccine treatment in this epidemic from a
purely scientific and coldly neutral attitude, we are simply doing the
public and ourselves an injustice.

The treatment of influenza as the disease presented itself to us in this
community will be considered under three divisions—acute influenza,
pneumonia, and other complications.


                           _Acute Influenza_

There is one important thing to be done in the treatment of influenza,
whether the infection be mild or severe. Have the patient go to bed as
soon as possible. In most of the acute attacks the individual went to
bed of his own accord; but there were, unfortunately, too many instances
where the patient refused to surrender, trying, as we say, to fight the
attack. Some appeared to be able to accomplish this feat. But how many
of our cases of fatal pneumonia can be clearly linked up with this group
of the mild or subacute preliminary course? No matter how light the
attack may appear to be, the patient should be told of the necessity of
remaining in bed until the pulse, respiration and temperature have
returned to the normal and remained normal for at least five days. At
the onset a hot bath, with care to avoid chilling, followed by a drink
of hot lemonade and a Dover’s powder, gave considerable relief to the
patient.

The value of good nursing cannot be overestimated. The nurse must see
that the patient is always well covered and kept warm, not even
permitting him to rise in bed to reach for a drink; also the regulation
of the temperature of the room should be carefully watched. The main
point is to have plenty of fresh air. We have noticed that the patient
appeared more comfortable if the air was slightly warmed. Water should
be given at regular intervals. Under no consideration should an acute
influenza case be allowed to get up to go to the toilet.

At the onset, and while the febrile attack is still present, there is
little desire for food—but one does not need to worry about the question
of nourishment in such an acute illness. Milk, cream, cocoa, gruels and
fruit juices may be given at first, and as the fever subsides the diet
increased. We have found that the appetite returned to normal very
readily. In view of the urinary findings indicating a slight transient
nephritis, meat broths are to be avoided until the convalescent stage is
reached. We have been very guarded in recommending cold sponging in
acute influenza. As a rule, it was not necessary. The icebag to the head
is often of great value in the intense headache, which is so frequent.
It is our opinion that in the treatment of uncomplicated influenza what
has just been mentioned constitutes the important part. Most physicians
would agree with this. However, when we advance to drug therapy, we come
into the personal realm of likes and dislikes of drugs and methods of
usage.

We do not intend in any way to give our views in a dogmatic manner, nor
to touch upon all of the remedies that have been advanced. At the onset
of the disease a moderate calomel purge, followed by a saline, was given
in all cases. We were practically free from the so-called intestinal
type of influenza which was seen in some other communities, consequently
we did not hesitate to use calomel. Castor oil or magnesium sulphate was
given afterward, as was found necessary. Abdominal distention was rarely
seen, and when it occurred a plain soapsuds enema with turpentine was
administered.

Quinine sulphate (gr. iii-v, three times a day) combined with
phenyl-salicylate (gr. v) was a routine measure. We often noticed
deafness after a very few doses of quinine. It was then discontinued.
Acetyl-salicylic acid (gr. v, three to six times a day) seemed to have a
palliative effect on the severe headaches, although during the height of
the disease the general muscular aching did not appear to be relieved by
its use. It was not used routinely. These drugs possibly made the
patients more comfortable, but we were very skeptical as to their
influence on the general infection. The raising of the leucocyte count
by quinine in influenza appears very unlikely. The use of alkaline salts
has been a general procedure, particularly as we are now on the alkaline
wave of therapeutics. Sodium bicarbonate was added to the drinking water
of all patients (two drams to the quart). We gave this salt for its
diuretic effect. In a few cases more active diuresis by the alkalines
was readily and easily produced by the use of “imperial drink” three or
four times a day. We felt that good kidney elimination was of
considerable importance.

The use of tartrates and citrates, as in “imperial drink” in a condition
where we know some kidney impairment is present, is possibly flying in
the face of danger—especially in view of the fact that these salts are
so available in the production of experimental nephritis. But we have
only to see their application in the human in mercury bichloride
poisoning, where an intense nephrosis usually develops, to fully realize
that these salts may be given without danger to the kidney. We do not
suggest that the kidney lesions of influenza and mercury bichloride
poisoning are the same. We are merely bringing out this point of analogy
in support of their use in certain desirable cases.

The respiratory symptoms gave us more concern than any other phase of
the uncomplicated case. The irritating, distressing, non-productive
cough suggested both a sedative and expectorant. Ammonium chloride (gr.
iii-v, t. i. d.) was the usual expectorant. It seemed to increase in
value with the more chronic type of case. It is our impression with
those acute hacking coughs that the sedatives produced more gratifying
results. Elixir terpin hydrate with heroin, codeine and occasionally
morphine were preferred. When good results were noted sedatives were
given liberally. Steam inhalations combined with tr. benzoin co.,
followed by spraying the throat with medicated liquid petroleum, gave
some relief. The tendency to œdema, however, as we saw it in the cases
complicated by pneumonia made us hesitate to use inhalations. Possibly
the fear was groundless. Morphine (grs. ⅙) was given for sleeplessness,
and it was repeated if necessary.

Cardiac stimulants were rarely needed. The tincture of digitalis was the
choice, but in the uncomplicated cases was very seldom used.

At the beginning of the epidemic we prescribed whisky in almost every
case. Our idea was that it would have a sedative action. At the present
time we are very doubtful of its value. Toward the end of the epidemic
we used it very moderately. The results obtained possibly depended for
the most part upon the type of patient. Some of the soldiers asked to
have it discontinued, not from any moral point of view, while others
wished more frequent doses. The elderly patients seemed to appreciate
this remedial agent to a fuller extent.


                              _Pneumonia_

The pneumonia following the original infection was, from the standpoint
of physical diagnosis, often difficult of diagnosis in its early stages.
The infection commencing as an influenza would at times pass
imperceptibly into pneumonia, and obviously the points brought out in
the previous paragraphs on treatment were applied until the diagnosis of
pneumonia had been established. Some new factors were peculiar to the
pneumonia and demanded further changes in the handling of the cases.

We would again emphasize the value of careful nursing to conserve the
patients’ strength. They should be kept warm, well covered, with plenty
of fresh air. Water should be given regularly and abundantly. The diet
should be light, one depending a good deal upon the severity of the
case. We believe it is safer to limit the diet to fluids while the
infection is still pronounced, but as soon as the crisis has passed one
may increase the diet freely and fairly rapidly.

Regular elimination from the bowel should be helped by the use of castor
oil every other day, the dosage made to comply with the patient. We
noticed much less abdominal distention in this form of pneumonia than
one is accustomed to see in the ordinary lobar pneumonia. If distention
were present, plain soap enemas with turpentine gave very satisfactory
results. Turpentine stupes also are of considerable value. Rest at night
is needed. When a hypnotic was necessary we gave morphine (gr. ⅙), and
repeated if the desired results were not obtained.

The day is coming when we are going to isolate our pneumonia cases. This
was almost an impossibility during the stress of the past epidemic, but
we know that temporary and fairly satisfactory methods can be applied.
Many hospitals provided for a type of isolation. In a pneumonia ward
sheets stretched between the beds keep the fine spray which a heavy
cough always produces from spreading over the next two or three beds.
This method is simple and can be easily carried out. We feel almost
certain of having seen convalescent influenza cases develop pneumonia
from the adjacent pneumonia patients. As much as is physically possible,
the uncomplicated influenza and the pneumonia cases should be separated.
Further, it is to be kept in mind that reinfection by another group of
pneumococcus is quite possible, even in a ward containing only pneumonia
patients.

We did not observe any special effect of quinine, salol, salicylates
after the pneumonia had developed and, therefore, these drugs were
discontinued. Digitalis in the form of the tincture was at first made a
routine measure, but toward the middle of the epidemic we stopped this
routine usage and gave it only as it appeared to be indicated. Our
impression was that the heart was not involved as it is in ordinary
pneumonia. A slow, full pulse, as was so often the rule, did not seem to
require digitalis. For more rapid action of the drug one of the
hypodermic digitalis preparations or strophanthin was given.

Caffein sodium benzoate or salicylate seemed to be of considerable value
given hypodermically every two or three hours, the last dose at 4 P. M.
Its action as a respiratory stimulant and also as a diuretic was what we
desired to obtain. The drug was used fairly early in the pneumonia, and
although it was never prescribed routinely we gave it frequently.

Atropine was indicated whenever signs of œdema were evident. Its action
was not always successful, but in certain severe cases we believe that
large repeated doses of atropine saved a few lives. One-fiftieth (1/50
gr.) grain hypodermically, repeated every hour for several doses, was
usually well borne. We noticed twice in each of two cases after using
small doses (1/100 every four hours) a peculiar rapid cyanosis not
associated with dyspnœa develop. This reaction remained, however, for
only a short time, about 15 to 20 minutes, but it was rather alarming
while it lasted.

The drug therapy is not very satisfactory in lobar pneumonia, and it is
less so in the form of pneumonia which follows influenza. There is
practically nothing essentially new in the drug and general treatment of
this serious complication over what was shown in 1890, or even in the
earlier epidemics, save that our nursing and hygienic measures are
undoubtedly better.

The addition of an immune serum (anti-pneumococcus serum No. 1) to the
treatment of pneumonia is a milestone in the history of the handling of
this disease, but we must keep in mind that the pneumonia of the past
epidemic was not the usual pneumococcic lobar pneumonia. That the
pneumococcus was present in a great many cases is shown in another
article of this series, but we also know that the B. influenzæ was
present in many, and that it played an active part in the disease is
evidenced by the constant low blood count or actual leucopenia. A
leucopenia in true lobar pneumonia is most unusual in the United States.
The rarity of Type I pneumococcus was noteworthy. We were practically
unable to get any anti-pneumococcic serum which was known to be of value
at the time of the epidemic, so naturally could not apply this method of
treatment as was desired. About half a dozen 50 cc. bottles were in
possession of the army medical officers here, but they unfortunately
could get no further supply after this was used. We would have liked
very much to have combined the anti-pneumococcic serum in Type I cases
with the citrated convalescent blood, as was used by us during the
epidemic. The anti-pneumococcic chicken serum of Kyes should also be
considered. This serum has had but a very localized trial, but from
competent observers who have given it to a considerable extent in some
of the army camps we are led to believe that it has a very definite
value. Major Lawrence Litchfield informed the writer that he had
observed excellent results with Kyes chicken serum during the past
epidemic in the treatment of pneumonia. This serum was not available for
our use. It is to be hoped that further experience with Kyes serum will
be favorable, because from the practical standpoint in the treatment of
pneumonia it has many commendable features. Again, we desire to point
out that the use of anti-pneumococcus sera in influenzal pneumonia may
not be a fair test of their true value.

Very early in the epidemic we realized that the pneumonia was of unusual
severity and most difficult to treat satisfactorily. We were at once
impressed by our helplessness, particularly in those patients showing
cyanosis. Nothing we did seemed to vary the course of the pneumonia
after this sign was evident.

Our work in the epidemic began about October 10 on receiving a large
batch of soldiers, about 100, from the Student Army Training Corps of
the University of Pittsburgh. At the end of the first week several
points were impressed on our mind. Firstly, in the severe cases of
pneumonia; and in the early part of the epidemic most of the pneumonia
was severe, the mortality was excessive, much higher than we have been
accustomed to experience in Pittsburgh, where, as a rule, our hospital
ward pneumonia is a very severe infection. Secondly, the wide variation
in the severity of the epidemic as presented in the student soldiers
coming from identical surroundings and conditions, the mildness on the
one hand and the malignant character of the influenza on the other, was
a very striking feature. This led to our adopting a form of treatment
which was quite successful.

We worked purely on the hypothesis that those individuals recovering
from a mild or moderate influenza infection developed a higher grade of
immunity than those in whom the disease was more severe or fatal, and
this immunity could be transferred to another. This, of course, was
merely inference. If the mild cases did present a higher immunity, one
would naturally think that immune bodies would be present in the blood,
and that in transfusion from cases which had recovered one might have a
measure of therapeutic value for this epidemic. Recently Spooner, Scott
and Heath and others have demonstrated specific agglutins in the serum
of patients convalescing from the epidemic. On October 17 we gave whole
citrated blood from a convalescent case of uncomplicated influenza to an
influenzal pneumonia patient. The result in this case was strikingly
good, and for the following five or six weeks this method was frequently
used. We decided to give the whole blood instead of the serum, as we
were able to treat the cases more readily and rapidly in this way. Our
method of transfusion was, fortunately, very simple.

We had treated but a few cases when the report of McGuire and Redden
appeared. These observers working in the Naval Hospital at Chelsea,
Mass., presented very excellent results in the use of immune serum from
convalescent influenza cases in the treatment of pneumonia. They
reported 30 recoveries out of 37 cases, with 1 death, and 6 cases still
under treatment at the time of their report. This form of treatment
began at Chelsea on September 28, 1919. In Texas, on October 15, Brown
and Sweet gave two cases of influenzal pneumonia citrated blood from
convalescent influenza patients. Their two cases recovered. Our
published results, although not showing such excellent figures as from
the Chelsea observers, agree very well with their work.

Since that time a number of confirmatory reports have been brought
forward. Ross and Hund have shown that this method has been of value in
their hands, and recently a further statement from McGuire and Redden
tends to confirm their first views as to the value of immune serum from
convalescent patients. Their last report giving a mortality of 6 in 151
cases of pneumonia cannot be other than positive proof of the value of
this method of treatment.

As the technical side of the work has been given in several articles, we
hardly think it necessary to again review it in detail. A few phases
should, however, be recalled. It would seem that either serum or the
whole citrated blood may be used. Solis-Cohen and his group of workers
believe that whole blood has stronger bactericidal properties than
defibrinated blood or the plasma. But yet one cannot complain, even on a
theoretical basis, against the results obtained with serum by McGuire
and Redden. The use of whole blood increases the detail of the
procedure, in that the agglutination reactions must be estimated.
Unfavorable results in this regard also naturally cut down the supply of
available donors. In a military hospital a dearth of donors does not
arise, but in civilian practice the problem is very different. In our
work we never gave more than 100 cc. of whole blood; usually the amount
varied between 50 cc. and 75 cc. On account of the small amount we felt
that isoagglutination would not be a serious factor, and in more than
200 injections we failed to see any evidence of ill results from this
source. Giving up to 500 cc., as was done by Ross and Hund, is probably
a different affair, and accurate agglutination tests are essential. We
feel that if the case is treated sufficiently early in the disease as
much good can be shown to occur after 50 cc. as after 100 cc. of blood.
We do believe, however, that the pooling of sera, where one is able to
carry out this method, as it means a liberal supply of donors, is really
the method of choice. Syphilis must be ruled out, both clinically and
serologically.

As we emphasized previously, the problem presented in the army hospital
and in civilian practice is a little different. We have had some
experience with both sides. Fortunately, the greater part of our work
was with the Student Army Training Corps, where army conditions were
more or less carried out. There was never any difficulty in getting
donors. In fact, the idea of giving blood appealed to these young
fellows. In civilian life it is, in our experience, a more difficult
problem. The usual personnel of the public ward has always its fair
percentage of positive Wassermann reactors, and the type of individual
is quite different from the young soldier. For a relative or friend we
could easily get a donor, but this group would cover only a small
percentage of the cases one wished to treat. The technique of giving
blood can be reduced to a very simple procedure, and by no means should
be regarded as a difficult surgical undertaking. Combining the receiving
apparatus of Ross and Hund (J. A. M. A., 72, 1919, p. 642) with the
syringe method for giving the blood which we suggested in our previous
article makes an ideal arrangement.

The results depend upon the time of treatment. The earlier the pneumonia
is recognized the better are the chances of recovery. It is our belief
that the majority of influenza cases which kept a fairly high
temperature for more than four days had a lung lesion, even if we could
not make out definite consolidation. As the convalescent influenza serum
may have value only for the influenza infection, it would, therefore,
appear but logical that a late pneumonia which almost always has other
organisms present would not react as favorably. We have seen very few of
the deeply cyanotic type recover even with serum. The essential rule is
to treat them before this stage develops.

We have observed little or no change in the leucocyte count, even after
successful treatment, and taking our group as a whole we are rather
surprised at this result. Other observers have noticed a marked increase
in the leucocytes as the case reacted favorably to the injections. We
agree with McGuire and Redden that the patients with counts below
10,000, as a rule, show the best results. This possibly indicates that
the influenza infection is predominating, and that the usual secondary
invaders (pneumococcus and streptococcus) are at this time playing but a
little part. Hence the value of early treatment is apparent.

From the published results of different workers and our own experience,
we feel that influenza immune serum or whole citrated blood given early
in the pneumonia is of undoubted value—in fact, almost specific. If the
epidemic reappears next year, unless some other better method is
forthcoming, we would advise its more general use, and would suggest the
collection of pooled serum as early as possible in the epidemic.

At the end of this article there is appended a series of our ward record
charts of patients who developed pneumonia following the influenza.
These charts are shown to indicate the results of giving immune
convalescent citrated blood in pneumonia. The ones presented are from
some of the group which recovered. We have, of course, the charts from
the fatal cases, but as they do not bring out any special point, save
that there was little or no change after treatment, we are omitting
them. It is not our idea, however, to give the impression that we have
had nothing but success with this method of treatment. It might be well
to emphasize some of the salient points which are brought out.

(1) The regularity of the drop in temperature after the injection is
almost generally demonstrated.

(2) The occasional chill following the injection seemed to have no
untoward results.

(3) The leucocytes show, as a rule, little or no variation after
transfusion. Our work agrees with McGuire and Redden’s statement that
the cases with a leucocyte count under 10,000 give the best results with
immune serum.

(4) The time of injection in many of the cases was by no means ideal, in
that the disease was advanced; and again in many the injection should
have been repeated sooner. This, however, is no fault of ours.

(5) One injection of 50 cc. of citrated blood from a good donor, if
given early enough, may be all that is necessary. Several charts bear
out this statement.

(6) The day of disease is dated from the onset of the influenza. The
demonstrable signs of pneumonia correspond roughly to the initial rise
in temperature following the influenza. The day of disease of the
pneumonia is not indicated on the chart, as this information we have
obtained from the daily notes.


                            _Complications_

The epidemic was well spent before we observed many complications, save
those referable to the lung. Later various forms of sequelæ have been
appearing. One must guard, however, against the danger of attributing
all of our ills to the past epidemic. We are not going to give in detail
the treatment of these various conditions, nor even mention all of the
many complications. The main points, however, we desire to emphasize.

We have previously considered pneumonia, which is the principal
complication with simple influenza, and the two are closely allied. As
an end result of the pneumonia, non-resolution and fibrosis of the lung
are of first importance. We cannot say very much on the treatment of
this condition. The duration varied from a few to several weeks, and
recovery was infrequent. Our treatment aimed at supplying as much
nourishment as was possible to give, with, in addition, good nursing.
The treatment otherwise was purely of a general hygienic type. Tepid
sponging appeared to give considerable relief from the profuse sweating
these patients so often had. Drugs were of value only for some local
effect. We wonder if carefully handled vaccine therapy at the onset of
such a complication might not prove of some value. The autogenous would
be the one of choice.

Empyema was not found to be as prevalent as one would imagine. With so
much non-resolution of lung following the pneumonia we were surprised to
see so little empyema. All delayed resolutions we explored with the
needle, so we feel that the condition, if present, would have been
recognized. The treatment of empyema need not be given any special
emphasis. It is, as of old, a surgical affair. One or two new points in
the technique have been brought out in the way of drainage, but possibly
they have not been sufficiently tried to lay any stress upon them at
present. Dakin’s solution in certain chronic cases appeared of value.
Our empyema cases did well.

Pleurisy with effusion was observed a number of times, although it has
been our experience to find a very few large effusions. Pleural puncture
often gave negative results, even when the signs did appear to indicate
the condition. We aspirated the fluid when present. The end results were
always good. In only one case did we have to repeat the aspiration for
reaccumulation of fluid.

Chronic bronchitis, accompanied at times with considerable dyspnœa, has
been seen on several occasions. There is very likely associated with
this condition some fibrosis of lung, and probably some organization of
small bronchioles themselves. Expectoration has been variable, profuse
or scanty, mucoid or purulent. We consider rest in bed, with as full a
diet as possible to build up the general condition of the patient, the
best form of treatment. These cases had little or no temperature, and
consequently at first absolute rest was not considered necessary, but we
now regard it as the essential part of the treatment. Atropine and
heroin are of value at certain times. We confess to have seen very
little benefit from the expectorants. We are rather surprised that this
sequela is not of more frequent occurrence.

Phlebitis, in our series usually of the formal vein, occurred about as
often as it does in typhoid fever. The end result, however, is much
better than in typhoid. We have seen only one case where “the milk leg”
has resulted. Rest and elevation of the limb were all that we required.
In the acute stage, if pain was present, a light, carefully applied
icebag was added. It is important to rest the limb for at least two or
three weeks, and to caution the patient against remaining on the feet
too long for some weeks after recovery.

We saw a great deal of acute sinus infection, often occurring even while
the attack of influenza was present, but, as a rule, this complication
followed the attack. At times several weeks intervened. The ethmoidal
sinuses are most susceptible, but a considerable number of acute frontal
sinus infections were noted, the latter often immediately following or
occurring during the acute period of the influenza attack. The majority
of these infections appeared transient, and disappeared with a little
local treatment. In fact, in frontal sinusitis cold applications seemed
to be all that was necessary. With some of the more chronic infections
nose and throat surgery has been followed by relief of symptoms. Acute
suppurative otitis media, considering the number of influenza patients,
was not common. Ear drum puncture was done if necessary. We saw one case
of acute mastoiditis develop. The mastoid process was opened and
drained.

Acute suppurative meningitis, following or associated with pneumonia,
appeared on three occasions. The pneumococcus was cultured from the
spinal fluid in all cases. Anti-pneumococcus sera intraspinally (Type I
or the Kyes serum) should be given. The Type I serum is of value in a
similar group infection. We have had no experience with this method, but
some recoveries from pneumococcus meningitis have been reported after
the early use of serum given into the spinal canal.

Following the 1890 epidemic cases complaining of blindness or partial
loss of vision, with optic œdema or neuritis and a glycosuria, were
occasionally observed. We have seen one of this type, and several
transient glycosurias without eye signs or symptoms. The glycosuria may
be of nervous origin. Our method of treatment was one of elimination and
rest. The gastro-intestinal tract was emptied with calomel, and
afterward a morning saline was given for a few days. Hot packs were
administered, one a day for about two weeks. The patient was instructed
to drink as much water as possible, and we eliminated sugar, bread and
the 20 per cent. vegetables from the diet. The glycosuria lasted for
three days, while the vision, although beginning to improve at once
after treatment, took five weeks to return to normal. The patient was
kept in bed for three weeks. How long the glycosuria had been present
before admission to the hospital we do not know. The transient
glycosuria group without the eye manifestations required very little
treatment. They also showed a transient hyperglycemia. A carbohydrate
free diet very rapidly cleared up these cases. After a time we decided
to watch the course of this group on a non-restricted diet, even with
sugar, and we found that they all returned to normal (blood and urine),
in a few days clearly indicating their transient nature. We do not
regard this process as a diabetes mellitus. We do not give the hot
packs, although free elimination by bowel was attained in all. These
cases were recognized only through routine urine examination.

Furunculosis with a high blood sugar, in one case 0.41, without
glycosuria was a very interesting complication. We saw a great deal of
furunculosis, always with the increased blood sugar from 0.2 to 0.3, but
never with glycosuria. Reducing the carbohydrates, or even a fast day
with good intestinal elimination, had excellent results.

Neuritis and general debility have often been associated with nasal or
tonsilar infection, which when surgically corrected led to the
disappearance of symptoms and improvement of health.

Finally, we wish to refer to an isolated case of acute osteomyelitis
which was incised, and from the purulent fluid present in the bone B.
influenzæ was grown in pure culture. This is a very unusual
complication, and is of particular interest on account of the positive
bacteriological finding. The patient made an uneventful recovery.

 McGuire and Redden      Jour. A. M. A., 1918; lxxi, p. 1311.
 McGuire and Redden      Jour. A. M. A., 1919; lxxii, p. 709.
 Brown and Sweet         Jour. A. M. A., 1918; lxxi, p. 1565.
 Ross and Hund           Jour. A. M. A., 1919; lxxii, p. 640.
 Spooner, Scott and      Jour. A. M. A., 1919; lxxii, p. 155.
   Heath
 Maclachlan and Fetter   Jour. A. M. A., 1918; lxxi, p. 2053.
 Heist and Cohen         Jour. Immunol., 1918; iii, p. 261.
 Kyes                    Jour. Med. Res., 1918; xxxviii, p. 495.

[Illustration]




 THE PREVENTION OF EPIDEMIC INFLUENZA WITH SPECIAL REFERENCE TO VACCINE
                              PROPHYLAXIS

                      By SAMUEL R. HAYTHORN, M. D.


                              INTRODUCTION

In developing practical measures for the prevention or control of
influenza epidemics, preventive medicine faces one of the most difficult
problems of modern times. By means of quarantine, protective vaccination
and instructions in personal hygiene many of the diseases which formerly
ravaged the world have been brought under control. At first glance it
would seem to be a simple matter to apply the principles which we have
found successful against these diseases to influenza and let it go at
that, but in the recent epidemic many of the formerly successful
measures were tried and found to be either inefficient, inapplicable, or
at least of doubtful value.

During the pandemic there was little time to think collectedly, and no
time to analyze procedures, and even now it is far from easy to
determine what things were done wisely and what things were of no
practical value. There exists the greatest difference of opinion as to
what measures should again be used when the need arises, and what ones
should be discarded. For instance, there are confirmed exponents of
prophylactic vaccines, and equally able men who are convinced of their
uselessness; enthusiastic advocates of the face mask, and almost as many
objectors; those who would close schools, churches, theatres, etc., and
those who claim that such measures serve only to prolong the epidemic.
One naval officer is said to have stated that he had accumulated figures
either to prove or to disprove the usefulness of any preventive measure
yet recommended. There is, in short, a chaos of opinions with followers
who vary from the one extreme of believing there is “virtue in all
things” to those of the other extreme who state that every susceptible
person develops the disease in the degree of his susceptibility,
regardless of any and all preventive measures used. While there remain
so many points on which definite, concrete knowledge is lacking, and so
much controversy over the relative value of various measures, this paper
can do little more than state the facts and discuss their bearing on
prevention as impartially as possible.

Great progress has been made in controlling contagious diseases in
recent years—a fact which can be easily verified by anyone who will
compare the sick reports of the Great World War with those of any war
previous to the beginning of the present century. The diseases which
have been most easily controlled have been those against which
prophylactic vaccines or prophylactic sera have been developed.
Smallpox, dysentery and typhoid fever have lent themselves readily to
control by protective vaccination, while reliable temporary immunity can
be afforded by the administration of sera for protection against
diphtheria and tetanus. These are by no means all, but are probably the
most striking illustrations; and with such examples before us, the
greatest hope for the prevention of influenza apparently lies in the
development of a prophylactic vaccine against it.


            _History of Prophylactic Vaccination in General_

The name vaccine came from “vacca,” or cow, and was originally applied
by Jenner (1796) to the virus taken from cowpox pustules for
prophylactic inoculation against smallpox. It has come to be loosely
applied to all forms of preventive inoculations except sera. We have,
therefore, a variety of vaccines which differ in their nature and method
of preparation. Some are produced by growing the virus in insusceptible
animals, some are composed of attenuated viruses, and most common of all
are the bacterial vaccines, sometimes called “bacterins,” which are
prepared from killed cultures of bacteria. Sera are used in prophylaxis,
as well as treatment, and are made by bleeding and separating off the
serum from animals which have been immunized against the cause of the
disease in question. Sera and vaccines are wholly different products,
and the distinction should be made in discussing them, although there is
a common tendency, particularly among lay writers, to use the words
interchangeably. Smallpox is the classical example of a disease which
can be completely controlled by universal vaccination. The parasite
causing smallpox has never been certainly demonstrated, but over a
century ago Jenner showed that cowpox, a localized, non-fatal disease,
protected against smallpox. Modern methods have proven that a cow
inoculated with smallpox virus develops cowpox, and that thereafter the
virus loses its power to produce smallpox when it is returned to man.
Instead, it causes a local pustule, and confers immunity to smallpox
over a considerable length of time. Rabies is another example in which
the exact cause of the disease is still in doubt, and in which a
protective vaccine has proven of great value. Rabies vaccine was
developed by Pasteur, and is prepared by drying the spinal cords of
rabbits that have been killed by a highly virulent rabies virus.
Typhoid, dysentery, pneumonia and several other diseases of known
etiology have been more or less controlled by the use of vaccines made
from their respective bacterial causes. These vaccines are of the
“killed bacteria” type of vaccines, and credit for their application to
human disease belongs to Sir Almroth Wright (1896). The preparation of
bacterial vaccines is very simple. Bacteria which are known to cause a
certain disease are isolated in pure culture, grown on artificial media,
killed either by chemicals or heat, standardized either by counting, or
drying and weighing, and suspended in salt solution for subcutaneous
injection. Salt suspension vaccines are usually given in three or four
increasing doses, about one week apart. Le Moignic and Pinoy (58) first
elaborated a lipovaccine for triple typhoid vaccination, which was used
extensively in France during the war. Whitmore, Fennel and Peterson have
recently also advised the drying of killed bacteria and the suspension
of them in oil. This method makes it possible to give a single massive
dose of bacteria which is sufficiently large to completely immunize the
individual against the disease, and which prolongs the immunizing period
by allowing slow absorption over a period of several weeks. These
vaccines are called lipovaccines, have been adopted in the United States
Army as the standard typhoid vaccine, and promise in time to supersede
the salt suspensions entirely from a commercial standpoint. Many other
modifications in the preparation of bacterial vaccines have been
advised, notably the class known as sensitized vaccines. These are
prepared by incubating bacterial vaccines for a time with the serum
taken from animals already immunized against them. The serum apparently
absorbs many of the toxic substances, and permits the injection of more
efficient doses. Besredka advised the use of living cultures which had
been incubated with immune sera, on the basis that vaccines so prepared
were very active and non-toxic. The sensitizing treatment, however, does
not stop the growing powers of the bacteria, and vaccines of the
Besredka type are generally considered dangerous and so are little used.
Sensitized killed bacterial vaccines, on the other hand, are quite
popular.

When a sufficiently large dose of vaccine is given to an individual
there is usually a transient rise in temperature for from 12 to 48
hours; the local focus of injection becomes sore and inflamed, and a
white count often shows an actual increase in the number of
polymorphonuclear leucocytes in the general circulation. A series of
doses are usually given. If after a few days blood is withdrawn from the
patient and immuniological tests made, it will generally be found that
the patient’s leucocytes take up bacteria, and particularly the type of
bacteria of which the vaccine was composed, more readily and in greater
numbers than the leucocytes of the ordinary individual. Wright and
Douglas (52) and Neufeld and Rimpau (53) have shown that this effect of
increased phagocytosis is brought about by the vaccine through the
production of substances which act specifically on the bacteria and
render them more susceptible to inclusion within the white cells. These
substances belong to the group of antibodies, and are known as
“opsonins” or “bacteriotropins,” and are specific for any given
bacteria. Moreover, the serum of the patient will, as a rule, be found
to have developed the faculty of agglutinating and bacteriolysing
suspensions of the specific organism injected and of fixing complement
in the presence of an antigen prepared from that organism. In animal
work it has been possible to go still farther, for it can be shown that
the resistance of the animal can be raised until it is no longer
possible to kill it with the same dose which is found to be fatal for
the unimmunized animals. Not only has animal work made it possible to
determine the protective powers of vaccines, but it has also served to
show the specific nature of the protective power and the relative extent
to which “group” or “crossed” protection can be conferred by vaccinating
with closely allied organisms—as, for instance, paratyphoid bacilli in
typhoid fever. The non-toxic nature of vaccines is also determined by
animal experiment before such preparations are injected into humans.

The most successful prophylactic bacterial vaccine which has been
developed so far is that for typhoid fever. A comparison of the
occurrence of typhoid fever in the United States Army before and since
the use of anti-typhoid vaccine is all that need be cited to convince
one of its value. At the time of the Spanish War there was no
vaccination against typhoid fever, and there were 20,738 cases, with
1,580 deaths, among 107,973 men who remained in the camps in the United
States during the war (54).

During the summer of 1911, the maneuver division of the United States
Army, having 12,801 men, all of whom had been vaccinated against typhoid
fever, were stationed at San Antonio, Texas. Two cases of typhoid fever
developed among them, and neither case died. Among the civilian
population of the city, living under usual conditions during the same
time, there were 49 cases of typhoid fever, with 19 deaths. Since 1912,
typhoid vaccination has been compulsory in the United States Army, and
the largest epidemic of typhoid fever which I have found reported so far
during the late war was that at Camp Greene (55), Charlotte, N. C.,
where 18 cases developed. Only 12 of these men had received the complete
series of immunizing doses. For a complete discussion of the value of
typhoid vaccine the interested reader is referred to Gay’s Monograph
(56) on typhoid fever.


              _Prophylactic Vaccination Against Influenza_

The hope of finding an early solution to the vaccine problem in
influenza appeared to be in the development of a prophylactic “bacterial
vaccine” similar to that which proved so efficient for typhoid. In his
discussion of the vaccine problem in pneumonia, Fennel pointed out that,
theoretically, any disease of microbic origin in which spontaneous
recovery is at all possible should yield to specific prophylactic
measures. The difficulty, however, of preparing a bacterial vaccine for
influenza comparable to that for typhoid fever is that the unquestioned
cause of influenza has yet to be determined. The probable cause of
influenza is the Pfeiffer bacillus, but its relationship has not been
proven beyond question. On the other hand, the innocence has likewise
not been proven, as Dr. Holman in his article of this series has ably
shown. It is not my intention to go deeply into the question of
etiology, but simply to bring out a few points which _a priori_ seemed
to indicate that the reasonable solution of vaccine prophylaxis was in
the preparation of a pure Pfeiffer bacillus suspension.

The experiments in man lead to very surprising results. Rosenau, Keegan,
Goldberger and Lake, at Gallops Island, Boston, Mass., (1) inoculated
volunteers with pure culture of B. Pfeiffer, with secretions of the
upper air passages and with blood from typical cases of influenza.
Sixteen men, of whom 13 were supposedly non-immune, had Pfeiffer bacilli
installed into their nasal passages, and none of them developed the
disease. Secretions filtered and unfiltered also gave negative results.
Contact with well-developed early cases also failed. McCoy and Richey
(1a) conducted similar experiments in San Francisco, with negative
results. The men of the latter group had been vaccinated with a mixed
streptococcic vaccine, which may have played some part. Had the
experiments with the Pfeiffer bacillus been negative and the other
experiments positive, they would have shown that the bacillus of
Pfeiffer was not the cause of influenza; but since all attempts were
negative, it merely brought out the fact that there had been a change,
due probably to some immune factor, which seemed to have acted alike on
the Pfeiffer bacillus and all other types of virus present, and to have
made them all innocuous. These experiments still leave the cause of
influenza in question.

Those who are opposed to the Pfeiffer bacillus being the cause of
influenza in its epidemic form base their position on the points that
the common finding of the bacillus might be accounted for on the grounds
of its being a secondary rather than a primary invader; that while it is
not so common at ordinary times, it does occur with other organisms in
whooping cough and sometimes in chronic diseases of the air passages,
and that the rules of Koch have not been complied with in that the
organism has not been found in every case of the disease; that where it
has been grown in pure culture and inoculated into man and animals, it
has either produced no disease, or the lesions which followed have not
been typical of epidemic influenza. On the side of those who believe
that the Pfeiffer bacillus is the chief cause, or, at any rate, that it
is partly responsible for epidemic influenza, are the facts of its
fairly constant presence in the purulent bronchial secretion of patients
suffering from epidemic influenza; its relatively uncommon occurrence at
other times; its known pathogenicity in occasional cases of meningitis,
and in the inflammation of the bony sinuses of the head and face; the
relative immunity of nearly all common laboratory animals and the fact
that the attempts to transfer epidemic influenza from man to man failed
not only when Pfeiffer bacilli were used, but also when direct contact
and direct coughing by the patient into the face of the volunteer were
tried. The argument that many cantonment laboratories failed to find the
organisms loses weight when we find that the percentage of positives
increased where the material examined was removed directly from the
lungs at autopsy, where special cultural methods were in use and where
the laboratory personnel was large enough to devote a sufficient amount
of time to each individual culture. All of these points indicate that
the organism was overlooked in a great many instances. In our laboratory
we found the examination of sputa very unsatisfactory because of the
great amount of contamination, and because the bacillus seemed to lose
its ability to grow after a relatively short time in the sputum in
vitro. Moreover, I am convinced that the bacillus changes its morphology
to such an extent under varying conditions as to make it impossible of
identification when present among other organisms in sputum smears. The
failure of animal inoculations is also not conclusive evidence against
the Pfeiffer organism, because guinea pigs, rats and mice have a natural
immunity for them. Rabbits are only slightly susceptible, and then only
to intravenous injections. The mixture of the Pfeiffer bacillus with any
one of several other pathogenic organisms will increase the
pathogenicity of both. Monkeys inoculated intracranially develop a
typical Pfeiffer bacillus meningitis.

Whatever the ultimate outcome of the investigations as to the parasitic
cause of epidemic influenza, the Pfeiffer bacillus was the generally
accepted cause at the beginning of the 1918 epidemic, though it was at
once realized that most of the deaths were due to complicating
pneumonias and to secondary infections with other organisms. Under the
circumstances, one of two courses was open: (a) the acceptance of the
Pfeiffer bacillus as the presumptive cause of influenza and the
preparation of a specific prophylactic vaccine against infections with
that organism; or (b) the use of a mixed bacterial vaccine containing
the common and most deadly secondary infecting organisms, designed to
increase the patient’s general resistance by decreasing his
susceptibility to the allied, collateral and secondary infecting agents.
Attempts were made along both lines, with more or less unsatisfactory
results.


 _The Attempt to Develop a Specific Prophylactic Vaccine by the Use of
                         Pure Pfeiffer Strains_

By a specific prophylactic vaccine for any given disease, we mean a
material which when inoculated into an individual will actively protect
that individual against the given disease. In infectious diseases, the
immunizing material is usually of microparasitic origin (in contrast to
desensitizing substances used in pollen diseases and those due to
unusual sensitiveness to foreign proteins), and is specific only for the
disease caused by the microparasite from which the material was
prepared. With the knowledge in hand during the epidemic, the logical
plan seemed to be to prepare a pure Pfeiffer bacillus vaccine, the
object of which was to eliminate primary infection with that organism
and thus prevent the secondary invaders from obtaining a fertile soil.

While specific Pfeiffer bacillus vaccines had been tried in treatment,
the field was a comparatively new one so far as prevention was
concerned. Many of the biological products companies had so-called
influenza vaccines on the market for treatment purposes, and many of
these contained Pfeiffer bacilli. A few preparations of pure strains of
the bacilli were also available, but I was unable to find any records of
their use for prophylaxis. Lacy (2) reported two cases of sinusitis
treated with autogenous vaccines made from pure Pfeiffer strains—one
patient improved rapidly and the other showed no change. Investigation
of several of the other references on influenza vaccines showed that
mixed vaccines had been used in each instance. The work of Flexner and
Wolstein (3, 4 and 5) indicated that active immunizing substances could
be prepared from the Pfeiffer bacillus, although they worked with serum
instead of vaccines. They prepared an anti-influenza-meningitis serum by
immunizing goats and horses. These sera cured monkeys of experimentally
produced influenzal meningitis. The sera showed agglutinins and
bacteriotropins for Pfeiffer bacilli, as well as positive fixation tests
in dilutions of 1 in 100, but they contained no lysins. The serum was
offered for intradural use in treating influenzal meningitis, but was
found to have no value when used in human cases.

The first references which we have found on the use of pure Pfeiffer
bacillus vaccines for the prevention of epidemic influenza were those of
Leary (6), (7), and of Rosenau (8). Shortly after the appearance of the
first influenza cases in Boston, Leary used a vaccine prepared from
several strains of Pfeiffer bacilli both for the treatment of influenza
and for its prevention. The vaccine for the latter purpose was given to
medical students and nurses, and the first results were apparently very
encouraging. Continued use has not been convincing. Barnes (9) reported
an attempt to protect the employees and patients of an institution near
Woonsocket. On October 9 a case of influenza developed in the female
ward, and was followed five days later by another. On October 22 the
disease appeared in the male ward, and the same day 172 employees and
patients were given their first inoculation with Leary’s vaccine. Doses
of 400, 800 and 1,200 million bacilli were given at 24–hour intervals.
All persons who had developed influenza before the three doses had been
completed were excluded from the computation of the disease incidence,
which was found to be 20 per cent. both among vaccinated and
unvaccinated individuals. The mortality rate was 16 per cent. for the 25
cases among the vaccinated, and 15.8 per cent. among 57 unvaccinated
patients. The result failed to show any protective qualities for the
vaccine.

The best controlled vaccine experiment in which Leary’s vaccine was used
was that reported by Hinton and Kane (10), and was carried out at the
Monson State Hospital for epileptics. The hospital had a population of
979 inmates, ranging from 4 years of age to senility; of these 461 were
vaccinated and 518 were not. Vaccination was begun on October 6, and
three doses of 400, 800 and 1,200 million were given at 24–hour
intervals. The first case of influenza developed a few hours after
vaccination was completed, but there were no more cases before October
12, when five cases developed. The table shows the result of the work,
and that the vaccine failed to protect.

               Population.   No. of      % of      No. of      % of
                             Cases.     Cases.    Deaths.    Deaths.
  Vaccinated           461        163      35.4%         28      17.1%
  Unvaccinated         518        178      32.4%         24      13.4%

Attempts to protect by the use of Leary’s influenza vaccine were made in
11 other Massachusetts institutions, but the results cannot be used to
compare the incidence and mortality rates between the vaccinated and
unvaccinated, because the epidemic was either on the wane, or at least
well advanced when the vaccinations were begun. The reports are of great
interest in showing the large number of vaccinations which failed to
protect.

In the Taunton State Hospital about 800 were vaccinated, and among them
there were 81 cases of influenza and 17 deaths from pneumonia, even
though the epidemic was on the wane when vaccinations were begun.

In the Gardner State Colony 834 were vaccinated after the peak of the
epidemic had passed. This number included all but 15 of the inmates who
had not contracted influenza up to that time. Out of this group, 62
vaccinated individuals developed the disease.

At the Massachusetts School for Feeble-Minded 457 inmates were selected
for vaccination and controls. Of the 234 vaccinated, 56 developed
influenza. Of the 223 unvaccinated, 185 developed influenza, with 16
pneumonias and 12 deaths. The vaccinated group, however, were a more
vigorous group of individuals to begin with, and represented a higher
mental grade than the unvaccinated group, so that the evidence was
considered of questionable value.

At the Wrentham State School the influenza epidemic was well under way
before vaccinations were begun, and hence the susceptible individuals
were in a large part either affected or infected with the disease. Of
1,198 unvaccinated persons, 758 developed influenza, giving a morbidity
rate of 63 per cent. Of 128 vaccinated, 13 developed influenza and 1
died. Physicians in this institution believe that the vaccinated were
not as ill as the unvaccinated patients.

In the Medfield State Hospital, having a total population of 1,940,421
cases of influenza, with 63 deaths, had occurred before vaccinations
were begun. Of the remaining unattacked inmates 902 were vaccinated.
After the completion of vaccination one new case appeared among the
unvaccinated, and there were none among the vaccinated.

At the North Hampton State Hospital there were 9 cases of influenza, 4
of whom died, among 444 unvaccinated individuals, and 9 cases, with 1
death, among 563 vaccinated patients.

Among 506 patients vaccinated at the Westborough State Hospital there
developed 15 cases of influenza, 2 of which terminated fatally. Of the
415 unvaccinated controls, 25 developed influenza and there were no
deaths. At the time vaccinations were completed only 13 had developed
influenza.

In the Worcester State Hospital vaccination was carried out after the
epidemic had entirely subsided.

At the Bridgewater State Hospital no vaccines were used, but the
morbidity rate was 29.9 per cent., as contrasted with 32.9 per cent.
among the unvaccinated at Monson.

At the Danvers State Hospital the population of 853 adults was divided
into three sections. One section was vaccinated with the Leary vaccine,
one section with an unheated influenza vaccine prepared by Dr. Rosenau
at the Chelsea Naval Hospital, and one section held as controls. The
epidemic had, however, reached its height before vaccination was begun,
and no information as to the relative value of the vaccines could be
determined.

In Hinton’s (11) report the analysis covered the studies on about 6,000
vaccinated individuals, which represented slightly less than half of the
population of 12 Massachusetts State institutions. Hinton’s conclusions
were as follows: “The heated suspension of influenza bacilli used as a
prophylactic vaccine did not prevent influenza, lessen its severity nor
its complications, and, as far as could be ascertained, resulted in no
harm.”

About the same time that Leary was working on his vaccine, Rosenau
prepared an unheated suspension of Pfeiffer bacilli, isolated from cases
of influenza of the existing epidemic, which he used at the Chelsea
Naval Hospital and in an experiment at the Pelham Bay Naval Training
Station. The writer is indebted to Surgeon-General of the Navy W. C.
Braisted for the data from which this report was compiled—the report of
the Sanitary Officer of the station not having been completed at the
time the information was furnished. The vaccine experiment was made in
the isolation regiment, which had remained practically free of
influenza. Inoculations were begun on September 30, when 638 men were
given the first dose of vaccine, 833 men being held as controls. On
October 4 the second dose was given to 589 men, and vaccination was
completed on October 8, when 565 men were inoculated. This group
comprised the total number who received three inoculations. On October
14 practically all of these men were transferred, so that it was very
difficult to get a complete record. Those cases which developed
influenza prior to October 10 have been omitted by the writer, both from
the control and vaccinated groups, because it is unfair to consider the
incidence of influenza among controls which developed prior to the time
the inoculations were completed in the vaccinated group. Between October
10 and October 24 there were 27 cases of influenza which developed among
the vaccinated, and 30 among the controls, giving a morbidity rate of
3.6 per cent. among the 833 controls, as compared to 4.7 per cent. among
the 565 vaccinated men. Emphasis is laid on the fact that these
morbidity rates were calculated for both groups on the number of cases
that appeared after vaccination had been completed. The result failed to
show protective qualities in the vaccine.

Influenza vaccines for prophylaxis were also prepared in great
quantities by the New York City Board of Health, and were made under the
direction of W. H. Parke. No reports on the value of their vaccines have
as yet appeared, and the writer has been unsuccessful in obtaining any
data on the matter. The Parke vaccine was made in the following way: A
large number of strains of Pfeiffer bacilli were isolated from cases of
influenza during the epidemic. These were grown on a veal infusion agar
containing 1 per cent. peptone, 0.5 per cent. of sodium chloride, 5 per
cent. chemically pure glycerin, and the reaction of which was made
neutral to phenolthalein in the cold. The agar was melted, and from 3
per cent. to 5 per cent. of citrated horse blood was added to it at a
temperature above 95° C. The media was then slanted and cooled in 6 × 1
inch test tubes. Most of the vaccines contained about 17 different
strains of Pfeiffer bacilli. The strains were inoculated separately on a
series of slants, and at the end of 24 hours the cultures were washed
off with sterile water and the washings from each series were placed in
a separate bottle. Smears were then made to determine whether or not
gram positive organisms were present, and as soon as each bottle was
found to be free from contamination the contents were pipetted off into
a 1,000 c.c. flask, and the dilution with sterile salt solution
containing 0.25 per cent. phenol made. All of the strains were mixed
together in the large flask. A sample was then removed for
standardization by Wright’s method, and the flask was submerged for one
hour in water at 53° C. Transplants for sterility were made and watched
for 48 hours. The vaccine was then diluted so that each cubic centimeter
contained 1,000,000,000 Pfeiffer bacilli. Prophylactic vaccination was
carried out by giving ½ c.c., 1 c.c. and 1½ c.c. doses at seven-day
intervals.


                           _Author’s Vaccine_

At the request of the Department of Public Health of the city of
Pittsburgh, the writer undertook to prepare Parke’s vaccine in large
quantities. The vaccine was to be prepared under the direction of a
committee consisting of Drs. Oskar Klotz, W. L. Holman, E. W. Willetts,
George L. Hoffman and the writer, and the vaccine was to be turned over
to the City Health authorities for distribution in the community. The
work was carried out at the Singer Memorial Laboratory, and was begun
the same day that the committee was appointed. Thirteen strains of
Pfeiffer bacilli were used. Holman contributed six strains, isolated at
autopsies done by Klotz at the Magee Hospital. Other fresh cultures were
furnished by Willetts; Wiese, of the City Laboratory, and by the Singer
Laboratory. The media used was that recommended by the New York Board of
Health, save that sheep’s blood was used instead of horse blood because
of convenience. The same technique was employed, with the exception that
a modification of the Hopkins method of standardization was used instead
of the Wright method. This was done because Pfeiffer bacilli are
extremely small, tend to form unbreakable clumps and tangles, and so
increase the difficulties of making satisfactory counts, either by means
of the Wright method or with the Helber-Glynn counting chamber, that the
methods are independable. Opalescent standards permit of such enormous
variations that it was decided to use the Hopkins method, or a slight
modification which we found so satisfactory that we will give our method
here in detail.


                      _Method of Standardization_

When the sample was removed for standardization it contained not only a
thick suspension of Pfeiffer bacilli, but also bits of agar and
blood-stained debris. It was necessary to rid the suspension of the
gross contamination, and this was done at first by filtering it through
sterile glass wool filters, and later by centrifuging it at slow speed
for about 10 minutes. The suspension then contained little but the
Pfeiffer bacilli, and was placed in the Hopkins tube and centrifuged for
½ hour on the sixth contact of the rheostat. This gave the per cent. of
Pfeiffer bacilli in the suspension, and the necessary dilutions to make
1,000,000,000 per cubic centimeter were readily determined. The Hopkins
tube consists of a centrifuge tube, with a capillary tube sealed on at
the smaller end. The centrifuge tube is graduated in 10 c.c., 5 c.c. and
1 c.c. amounts, and the capillary portion is graduated in 0.01, 0.02,
0.03, 0.04 and 0.05 c.c. amounts. To standardize the vaccine, 10 c.c. of
the sample was centrifuged in the tube and the amount of sediment read
on the capillary scale. If the amount of bacilli fell between the
graduations, an additional amount of sample was added, so that the
sediment reached one of the graduated lines, the exact amount of sample
added being noted. The percentage of the suspension could thus be
determined by dividing the number of c.c. of sample used into the amount
of the sediment obtained, and the number of bacteria calculated
according to Hopkins table. The table available to us did not list the
Pfeiffer bacillus, but according to it a 1 per cent. suspension of
staphylococcus contains 10 billion organisms to the cubic centimeter,
and we estimated that Pfeiffer bacilli were about half the size of
staphylococci. This assumption was borne out by a number of Wright’s
method counts on standardized suspension of bacilli. We, therefore,
calculated that a 1 per cent. suspension of Pfeiffer bacilli should
contain about 20 million organisms. Then, if 10 c.c. contain 0.02 c.c.
of bacterial sediment, the per cent. was calculated by taking 0.02/10 =
0.2 per cent., the strength of the suspension. If 1 per cent. contains
20 billion, then 0.2 per cent. contains 4 billion per c.c. In order to
get a 100 million per c.c. suspension, it would be necessary to dilute
the original suspension 40 times.

Every method of standardization is more or less inaccurate, but the
above described method gave a fairly uniform product. Drying and
weighing is claimed by many to be more accurate, but even with this
procedure a fair amount of non-bacterial sediment is present in the
material to be weighed.

After the vaccine was completed, cultures were made from the final
dilutions and were watched for 48 hours. Mice and guinea pigs were
injected with the first samples to make certain that the material was
non-toxic. Two laboratory employees also volunteered and received full
doses before the first batch of vaccine was released. The first five
litres were turned over to the Red Cross on October 31, one week from
the day the work was begun. In three more days the laboratory reached a
capacity of 10 litres a day, and on the fifth day the order was received
to discontinue preparation of the vaccine.

Relatively little of our vaccine was given out, and in the rush it was
not possible to determine which physicians had been given our vaccine
and which had received commercial mixed products, so there is no data on
its protective powers.

As soon as we found that there was no call for prophylactic vaccines, we
planned some animal experiments; but inasmuch as we were unable to get
our cultures of Pfeiffer bacilli virulent enough to kill mice or guinea
pigs, the minimum lethal dose could not be determined, and without it it
was impossible to determine the protective value of the vaccine. Mr.
Purwin, in our laboratory, injected a 25–gram mouse intravenously with 2
c.c. of a milk thick suspension of Pfeiffer bacilli without killing the
animal. He was successful in getting a small needle into the tail vein
and in slowly injecting the whole amount. The mouse was sick for about
36 hours, but entirely recovered. Guinea pigs were insusceptible to very
large doses. Had we succeeded by means of a vaccine in completely
immunizing a man against Pfeiffer bacilli, we still would have been
uncertain that he was immune to influenza in its “epidemic” form.

The absence of virulence in our laboratory strains may not mean that the
cultures were non-virulent when first isolated, but it suggests the
uselessness of attempting to make active vaccines from strains kept on
artificial media for months or years, such as those commonly offered for
sale by commercial houses.

The loss of virulence in strains that have been isolated for some time
is interesting in the light of Parker’s (12) work upon toxine production
by Pfeiffer bacilli. She found that toxic filtrates appeared in infusion
broth cultures in from 6 to 8 hours, and that 2 c.c. of a 20–hour
filtrate would kill a medium-sized rabbit in from 1 to 3 hours. It was
also found that the poison deteriorated so rapidly that, in order to
determine its toxicity, the tests had to be made on the same day that
the filtrate was obtained. Parker succeeded in making an anti-serum
against the poison, which appeared to be antitoxic for it both in vitro
and in vivo. This work is interesting, and may be a step toward the
development of a practical prophylactic serum.


                              _Conclusion_

From the above data, it is apparent that there is very little to
indicate that an immunity to epidemic influenza is conferred by the use
of a prophylactic vaccine composed of inert Pfeiffer bacilli alone. If a
desirable vaccine is to be obtained through the use of these organisms,
there must be radical changes in the mode of preparation of the vaccine
or in the size of the doses given.


 _The Attempt to Protect Against Epidemic Influenza by the Use of Mixed
                               Vaccines_

For some years commercial houses have been carrying mixed vaccines for
the treatment of colds, which they called influenza vaccines. These
preparations were made up usually of six or more different varieties of
bacteria, and all of them were of similar composition. There was more or
less variation in the doses, both as far as the total number of bacteria
and the relative number of the different types were concerned. A typical
example of a so-called “mixed influenza vaccine” may be given about as
follows:

          B. Influenza (Pfeiffer)  25 to  400 million per c.c.
          M. Catarrhalis           25 to  400 million per c.c.
          B. Friedlander           25 to  400 million per c.c.
          Pneumococci              25 to  400 million per c.c.
          Streptococci             25 to  400 million per c.c.
          Staph. Albus-Aureus      50 to  800 million per c.c.
                                  ———    ————
                  Totals          175 to 2800 million per c.c.

These vaccines were recommended in the various catalogues for use either
alone or together with other vaccines in the prophylaxis and treatment
of common colds, and in acute and chronic diseases of the respiratory
tract. As a matter of fact, they had been used very little in
prophylaxis, and had failed to show very much value in treatment. In
discussing these vaccines from the standpoint of treatment, R. M. Pearce
(13) had the following to say: “A mixed vaccine for common ‘colds’
containing several organisms (staphylococcus, streptococcus,
pneumococcus, micrococcus catarrhalis group, bacillus of Friedlander
group, diphtheroid group, bacillus influenza) is one of the most recent
bacterial ‘shotgun’ mixtures, which takes the chance of one lucky
bull’s-eye in seven shots.” “No one can claim a scientific or even a
common-sense basis for the treatment of a cold by such a mixture.”
Catarrhal mixed vaccines of a similar kind were refused acceptance by
the committee on “New and Non-efficial Remedies” of the American Medical
Association, in June, 1918 (14), on the grounds that insufficient
evidence of their therapeutic value had been furnished by their
manufacturers.

While the above illustrates the status of “mixed vaccine” for
therapeutic purposes, it is a well-recognized fact that it is possible
to produce an immunity for most of the bacteria composing such vaccines,
if killed cultures of the various strains are injected in sufficiently
large doses. Again referring to Pearce’s article, we find the statement:
“Prophylactic vaccination rests on a sound, scientific basis of
experimental studies and clinical observation.”

The attempt to protect against epidemic influenza by the use of mixed
vaccines was based largely on the following points. The medical
profession was confronted by a rapidly approaching deadly epidemic,
against which ordinary measures of control had failed. The epidemic was
supposed to be due to a primary infection with Pfeiffer’s bacillus, but
all of the fatal cases were found to have profound secondary or
symbiotic infections, with one or more of the strains contained in the
“mixed vaccines.” It was known that mixed bacterial proteins, even
though they were not actually specific, possessed certain qualities of
producing reactions unfavorable to infections in general, which were
characterized by a temporary rise in temperature, by an increase in the
number of leucocytes, and by a more or less demonstrable amount of
active immunity against each one of the contained bacterial toxins. The
artificial production of a leucocytosis was especially desirable,
because a characteristic of epidemic influenza was the failure of
leucocytosis on the part of the infected individual. In other words,
mixed vaccines were used because they were the only available substances
which offered the hope of creating a reaction against the secondary
invaders which were so commonly the cause of death in influenza.

Since Pittsburgh’s experience with prophylactic vaccination had chiefly
to do with the use of commercially prepared mixed vaccines, a brief
history of the local experience with them may be of interest.

About the time that the first cases of influenza were being reported
from the Pittsburgh district, articles on preventive vaccines as used in
Boston and at some of the camps began to appear in the daily papers,
shortly after which came the announcement that the Carnegie Steel
Company was offering free vaccination to their employees and to the
families of their employees. Dr. W. O. Sherman, chief surgeon for the
company, advocated the use of the vaccine because he hoped to increase
the immunity to secondary infection and to produce an active
leucocytosis in the vaccinated individuals, and at the same time to
allay panic among the employees at a time when an interruption of
manufacturing and mining pursuits might be disastrous to the entire
country; and he did it with the assurance that if the vaccine did no
good, it would at least do no harm. He took steps to arrange for the
collection of data by which he hoped to determine whether or not the
vaccine as used by their company did any good. His report has not yet
appeared. Other large corporations at once instituted prophylactic
vaccinations with commercial “mixed vaccines.”

In contrast to the altogether laudable efforts of these companies to
protect their employees, a complete history of the vaccine episode in
this community necessitates the recounting of a very different phase in
the matter. When it became known that corporations were vaccinating
their employees, people in general naturally began to investigate.
Physicians’ offices were besieged by persons who either demanded
vaccination at once or wanted to know whether or not there was “anything
in it.” Conscientious physicians in their turn called up the offices of
the medical societies, the various laboratories, and telegraphed
everywhere trying to get some definite data before recommending the
vaccine to their patients. It was impossible to answer the question
definitely, because it was a new procedure and purely in the
experimental stage. On the whole, the medical profession handled the
situation in a competent and dignified manner, for the great majority
gave vaccines only after a full explanation to the effect that its value
was in doubt, or else refused to give it altogether. There were some,
however, who were not conscientious, and the unscrupulous practitioner
seldom had a better chance to impose upon the public. The demand for
vaccine soon exceeded the supply, and it is claimed that there were
doctors who gave any type of vaccine they could obtain without regard to
its bacterial make-up or intended purpose. Anti-diphtheritic serum was
given in many instances, and it is said that even normal salt was used.
Statements to the effect that exorbitant sums were being charged and
that guarantees of prevention were being made resulted in the Red Cross
Society undertaking the distribution of the vaccine. To protect itself,
the Medical Society issued the following notice in the weekly bulletin
for October 26, 1918:

  The Society wishes it understood that at present there is no vaccine,
  serum or inoculation which will secure anyone against influenza. It is
  desirable that everyone should avoid hysteria and consider only the
  reports which are officially given out by the Health Department, since
  of late various methods of prophylaxis and treatment have found their
  way into the daily newspapers, and these may prove harmful rather than
  do good.

Almost simultaneously the daily papers published the report of
Surgeon-General Blue, of the United States Bureau of Public Health,
which expressed practically the same opinion. It was not the intention
of either of these articles to criticise the practice of vaccination,
but merely to warn the public against profiteering and fraudulent
guarantees. They had the unexpected effect, however, of causing people
to completely lose faith in prophylactic vaccines, and in many instances
to become actually antagonistic to them. It was during this period that
the preparation of vaccines from pure influenza strains was undertaken,
under supervision of the County Society and for distribution through the
Department of Public Health. Two days after the first supply of this
vaccine was ready the Red Cross authorities telephoned that there was no
further call for vaccine. The man in charge of the distribution stated
concretely that “the bottom had dropped out of the vaccine business.” A
few days later the Department of Health issued an order to stop the
preparation of the vaccine.

Many pharmacies, having small supplies of vaccines, realized the great
call for it and the difficulty of obtaining a new supply, and were also
guilty of commercialism. Certain of the large biological product
companies were no exception. One house issued a hand-bill, printed in
red on a yellow background, which stated: “Epidemic influenza is due to
the influenza bacillus. The present epidemic of influenza has a tendency
to develop pneumonia. The use of our influenza bacillus vaccine No. ——
will abort the influenza and avoid pneumonia and other sequelæ. When
pneumonia has developed, it can be reduced to less than one-third the
mortality and duration usual with other methods of treatment,” etc.
Practically all of the above statements are still unproven, and probably
will never be shown to be true. Such a bulletin undoubtedly lays this
firm of vaccine manufacturers open to prosecution under the law
protecting against false and fraudulent advertising. Several fairly
well-authenticated incidents occurred in which the representatives of
vaccine houses offered factory managers and others share and share alike
in the profits, if the brand of vaccine made by them was used. It is on
such happenings as the above that the writer advocates legal measures,
allowing Boards of Health to control the advertising of remedies and
distribution of biological products during epidemics.

How much Pittsburgh will learn from the experience with vaccines will
depend on the numerous analyses of data which were acquired during the
epidemic.


           _Data on the Prophylactic Value of Mixed Vaccines_

Proof of the prophylactic value of mixed vaccines for epidemic influenza
depends entirely upon the results of its practical application to human
subjects in times when the disease is prevalent. Animal determinations
are out of the question, because it has not been possible to produce the
epidemic form of influenza experimentally. If all people were equally
susceptible and were equally exposed, it would be a simple matter to
compare the number of vaccinated persons who developed the disease with
the number of unvaccinated persons who contracted it; but since many
thousands were vaccinated and some of them contracted the disease in
spite of it, and a greater number of persons who were not vaccinated
entirely escaped, the analysis is extremely difficult.

The time element is a big factor. In instances where vaccination was
completed in a community before the epidemic appeared there, the figures
are worth more than those in which vaccination was undertaken after the
epidemic had become established. This is true, because the most
susceptible persons in a community developed the disease as soon as they
were exposed, the less susceptible ones were not attacked until later,
and the insusceptible ones escaped altogether. Whenever vaccination is
begun during an epidemic, the persons vaccinated for prophylactic
purposes are necessarily chosen from those who have not yet developed an
attack. The later in the epidemic that vaccination is begun, the greater
will be the number of persons selected for vaccination from among those
more or less naturally immune. Then, if the total number of cases among
the vaccinated is compared with the total number of cases among the
unvaccinated, the apparent value of the vaccine is increased; but the
estimation is not a fair one, because the vaccinated group is
unavoidably selected from among relatively immune persons, while the
controls include all of the very susceptible people who were suffering
from the disease at the time vaccination was begun. Where vaccination is
begun after the epidemic is advanced, the only figures worth while are
those obtained by a day-by-day or a week-by-week comparison between the
number of cases developing among controls and the number of cases
appearing among those vaccinated, and by beginning that comparison at a
time subsequent to the day on which the prophylactic inoculations were
completed.

Aside from the interpretation of the results there is possibly a more
serious reason for objecting to the beginning of vaccination during an
epidemic. This lies in the danger of producing a temporary negative
phase in the patient, which makes him somewhat more susceptible to
natural infection for a few hours immediately following each
administration.

McCoy (15) outlined the requirements necessary for an ideal vaccine
experiment as follows: 1. The community should be as large as possible,
and should number at least 10,000 persons. 2. The conditions under which
they live should be as nearly equal as possible. 3. The turnover, or
rather the change in population, should be as small as possible. 4. The
social service should be efficient and reliable, so that it can be
definitely ascertained when anyone becomes sick and what the disease is
from which he is suffering. 5. Fifty per cent. should be vaccinated
before the epidemic arrives, and the other 50 per cent. should be held
as controls.

No examples were found which came up to the above requirements, but
there were some instances in which vaccination was completed before the
epidemic appeared, and some in which we were able to get a week-by-week
comparison between vaccinated and unvaccinated groups. Most of the data
which has been reported shows that vaccination was begun about the last
of the second or the first of the third week of the epidemic, and in
some instances not until after the peak was passed. Add to this the fact
that the vaccine was given in from three to four doses, at from three to
seven day intervals—a course which required in the neighborhood of two
weeks for completion—and it is obvious that the full protective powers
of the vaccine were not acquired by the individual until the worst of
the epidemic was over and the number of cases were rapidly subsiding.

In order to get the best understanding from these experiments, the data
will be presented in three series: I. Those instances in which
vaccination was completed before the epidemic appeared. II. Those
instances in which it is possible to compare the relative occurrence of
influenza in both the vaccinated and unvaccinated groups after
vaccination was completed. III. Those instances in which vaccination was
begun after the epidemic appeared and in which comparisons of total
figures only are available.


_Series I. Those Instances in Which Vaccination Was Completed Before the
                           Epidemic Appeared_

1. The only instance in the Pittsburgh community in which vaccination
was completed before the epidemic appeared is that reported from the
Dixmont Hospital, Dixmont, Pa., and furnished me through the courtesy of
Dr. Hutchinson (16). The institution had a population of about 1,000
patients and 300 employees. Prophylactic vaccination was begun on
October 20, and was completed about November 6. Each c.c. of the vaccine
used contained 200,000,000 each of B. Pfeiffer, Micrococcus Catarrhalis,
B. Friedlander, Pneumococci, Streptococci and Staphylococci, both Aureus
and Albus. Four doses were given of 4 minims, 8 minims, 12 minims and 16
minims, respectively. Inoculations were carried out at four-day
intervals. Owing to the isolation of the institution from the general
community, the first case did not appear until two weeks later—namely,
on November 20. The results are shown by the table.

               Population.   No. of      % of      No. of      % of
                             Cases.     Cases.    Deaths.    Deaths.
  Vaccinated           600         44       7.3%          0         0%
  Unvaccinated         700         69       9.8%          9       1.2%

None of the vaccinated patients developed pneumonia, though there were
15 cases among the unvaccinated.

This experiment shows a slight percentage in favor of vaccination, and
indicates that there was some decrease in the severity of the secondary
infections.

2. The experiment reported by McCoy, Murray and Teeter (17) showed quite
opposite results from the above, and was an excellent example of a small
though completely controlled test. In an asylum for the insane in San
Francisco all of the patients under 41 years of age were divided into
two groups—one group was kept as controls and the other was given a
vaccine furnished by F. O. Tonney, of the Chicago Health Department. The
vaccine contained 500,000,000 each of B. Influenza, Pneumococcus I, II
and III, 1,500,000,000 Pneumococcus IV, 1,000,000,000 Streptococcus
Hæmolyticus and 500,000,000 Staphylococci. Doses of 0.5 c.c., 1 c.c. and
1½ c.c., which were given at 48–hour intervals. Inoculation was
completed on November 15, and the first case of influenza appeared on
November 26. The table shows the result.

                                Vaccinated. Not Vaccinated.
             Persons in group           390             390
             Cases of influenza         119             103
             Cases of pneumonia          23              17
             Number of deaths            10               7

3. The report of Minaker and Irvine (18) included several groups of men,
the first two of which apparently belonged in our first series. They
used a vaccine, each c.c. of which contained 5,000,000,000 B. Pfeiffer,
3,000,000,000 each of Pneumococcus I and II, 1,000,000,000 Pneumococcus
III, 100,000,000 Streptococcus Hæmolyticus. In all, they vaccinated
11,179 persons.

(a) Their first group numbered 4,950 persons in quarantine at the Naval
Training Station. The quarantine was maintained for 24 days, and no
influenza appeared during that time. Three thousand five hundred and
fourteen of them were released at a time when there were still 200 to
300 cases of influenza being reported daily in San Francisco. Out of the
3,514 men, 15 had influenza, and there were no deaths.

(b) At the Mare Island Navy Yards 1,950 marines were released
immediately after completion of the inoculation. They were turned into
Valejo and San Francisco, where influenza was at its height. Only 35
cases, with 1 death, occurred, and these developed shortly after the men
were released in San Francisco. This group was controlled with an
unvaccinated group of 8,232 persons who remained at Mare Island, and
1,296 cases of influenza, with 65 deaths, occurred among the controls.

(c) At San Pedro 3,100 were vaccinated, and of these 53 had influenza,
and there were no deaths. The occurrence among these was compared with
the prevalence of the disease in Los Angeles, but this part of the
report leaves much to be desired in the way of the relative dates, etc.

(d) The fourth group, consisting of 1,080 civilians, developed 14 cases,
with no deaths. However, vaccination of this group was not completed
until 21 days after the pandemic had appeared in the community.
Minaker’s and Irvine’s analyses show a favorable percentage for
vaccination in the first two groups, but their groups three and four
were not sufficiently well controlled to be of much help.

4. In a report which appeared during October, 1918, Eyer and Lowe (29)
published the results of prophylactic inoculation of 1,000 New Zealand
troops with a mixed catarrhal vaccine. They controlled their experiments
with 19,000 New Zealand troops who were not inoculated. A comparison of
the incidence of acute respiratory disease and influenza during the
primary wave of the epidemic as it appeared during June and July, gave
two cases among the vaccinated troops and an average of 43.2 cases per
thousand among the controls.

Later they reported (58) the results of much larger experiments as
carried out at 17 different camps and hospitals. The vaccine which they
used was a typical “mixed” vaccine, save that the authors emphasized the
advantage of using strains not more than three generations removed from
the body. At some of the camps their reports were unfavorable, but upon
the whole their results, as summarized below, were most encouraging. In
most instances inoculations were completed just prior to the arrival of
the autumn epidemic.

Out of a total average strength of 21,759, approximately 16,104 men
received full prophylactic vaccination, and approximately 5,700 were
uninoculated, or had received only 1 dose; 3,366 cases of influenza
developed—15 per cent.; 1.3 per cent. occurred among the vaccinated,
while 4.1 per cent. developed in the uninoculated; 8 per cent. of the
severe cases among the protected died, as compared to 23 per cent. among
the uninoculated. The death rate for all infected cases was 0.26 per
cent. among the inoculated and 2.2 per cent. among the uninoculated.

NOTANDA.—All of the above reports, comprising the “Series I”
experiments, indicate that mixed vaccines reduced the number of severe
illnesses and lowered the death rate to some extent.


   _Series II. Those Instances in Which It Is Possible to Compare the
  Relative Occurrence in Both Vaccinated and Unvaccinated Groups After
                       Vaccination Was Completed_

1. The report on prophylactic vaccination at the Hospital for the Insane
at Retreat, Pa., was very kindly furnished by Dr. Charles B. Maberry
(20). When the epidemic approached, the institution was placed in
quarantine and remained free from influenza until October 28, when two
cases appeared in nurses who had broken quarantine. Influenza spread in
the male ward, but the female wards were kept free during the whole of
the epidemic. There were 370 male patients, but 60 were in the infirmary
and were not included in the calculation. Out of 310 patients, 210
received vaccines. Ordinary commercial mixed vaccine was used, and
vaccination was begun two days after influenza appeared. During the
first week there were 40 cases of influenza, 6 of which occurred among
those who had received a single dose of the vaccine. After the first
week there were 38 cases of influenza, with 10 pneumonias and 5 deaths,
among the unvaccinated, giving a morbidity rate of 38 per cent. and a
mortality rate of 5 per cent. In the vaccinated group there were no
cases after vaccination was completed. Maberry states further that in
ward III the only cases which appeared subsequent to vaccination were in
six patients who refused preventive inoculations. This appears to be the
most favorable of any of the reports.

2. Nurses on duty in hospitals everywhere suffered greatly from
influenza, and those of Pittsburgh were no exception. Some of the
hospitals vaccinated the nurses during the epidemic and some did not,
and it was hoped that by getting a week-by-week comparison of the number
of cases among vaccinated and non-vaccinated nurses some reliable data
would be obtained. A circular letter sent to all of the hospitals in the
community contained a blank asking for the number of nurses, date of
appearance of the epidemic, use of vaccine, dates of inoculations, and
for a week-by-week occurrence of influenza in each group. Only 7
hospitals complied with the request, and of them only 5 sent complete
data. Complete reports were received from the Allegheny General,
Columbia, Presbyterian, South Side and St. Francis Hospitals. Of a total
of 336 nurses in these 5 institutions, 38 developed influenza in the
first week, 48 in the second, 39 in the third, 43 in the fourth, and 45
subsequent to the fourth week, making a total of 213—a morbidity of 63
per cent. The Mercy and St. Margaret’s Hospitals reported the total
number of nurses and the occurrence of influenza among them, and adding
in their reports there were 521 nurses on duty in 7 hospitals, with 257
cases of influenza, giving a morbidity rate of 50 per cent.; 28 cases of
pneumonia and 11 deaths, giving a 2 per cent. mortality rate. The total
figures from hospitals where vaccines were used are against vaccination,
due partly to the fact that vaccination was started late. In these
hospitals the morbidity was 66 per cent. and the death rate 3 per cent.
In the hospitals where vaccines were not used the morbidity rate was 20
per cent. and the death rate 1.2 per cent. No dependable data was
obtained, but the report from the South Side Hospital was interesting.
Of 60 nurses on duty, 36 had influenza and 2 died. Of this number 19
were stricken the first week. Three days after the first cases were
admitted to the hospital vaccination was begun, and was given to most of
the nurses still on duty. Of those taking vaccines 20 developed
influenza and 1 died during the period of immunization, but after the
inoculations were completed there were no more cases in either group.

During the epidemic it was said that benefit was derived from the use of
vaccines on nurses at the West Penn Hospital, but the writer was unable
to obtain a report from this institution. The collected data on nurses
was useless, though it is interesting, in that it shows the possibility
of making figures prove almost anything you want them to prove.


 _Series III. Those Instances in Which Vaccination Was Begun After the
 Epidemic Appeared, and in Which Comparisons of Total Figures Only Are
                               Available_

Undoubtedly the largest attempt at prophylaxis against epidemic
influenza through the use of “mixed vaccines” was that made under the
direction of Dr. W. O. Sherman for the Carnegie Steel and H. C. Frick
Coke Companies. The results which Dr. Sherman hoped to attain when he
planned using the vaccine and collecting the data have already been
given. Commercial mixed vaccines similar to those described under the
“Series I” experiment were used, and four doses, three days apart, were
given. Inoculations were begun on October 20, 1918, and were completed
during the first week of November. Vaccine was administered to the
employees and their families without charge. Later cards were given to
all employees, and they were made to fill them out and return them. On
the cards were blanks calling for the name, age, sex, color, number of
inoculations, whether or not the employee himself or any member of his
family had had influenza, and how many days the sick individuals had
been in bed. Each mill and mine was then supplied with a set of blank
forms providing for a complete statistical record of the number of
inoculations and the total incidence of influenza, pneumonia and death.
From the reports of the respective mills and mines the total figures
given in the charts were compiled.

Difficulties were encountered in every part of the work. The vaccine
demand was so great that the products of three different firms were
used. So many doctors were in service that most of the vaccine had to be
given by carefully coached nurses. The bulletins of the United States
Bureau of Public Health and of the Allegheny County Medical Society,
with their warnings about influenza vaccines being only in the
experimental stage, appeared just at the time the work was begun and
caused a great many to refuse to complete vaccination after one or two
doses had been given. So few medical men were left that it was
impossible to have them see all cases and so determine the nature of
many of the illnesses which were occurring. It was assumed, therefore,
that any employee who had fever and was sick for a period of three days
had influenza, and that any who were confined to bed for seven days or
more had pneumonia. The figures of the central offices were made up from
the reports of 14 steel mills, 1 cement factory, 4 warehouses and 57
mining districts. The accuracy of data depended on the careful work of a
great many local statistical workers, which made individual variations
hard to control. The greatest difficulty of all, however, lay in finding
a common basis for comparisons of the incidence of influenza, pneumonia
and death in the vaccinated and non-vaccinated groups, since the data on
the former group included the occurrence only after the peak of the
epidemic had been passed, and that of the latter group included the
occurrence for the entire epidemic.

The total figures are given in the three charts.


                                CHART I.

                         CARNEGIE STEEL COMPANY.

  All Works Except Homestead, City Mills, Columbus, Lucy and Isabella.

          STATISTICAL REPORT ON INOCULATION AGAINST INFLUENZA.

 1. Number of employees who had influenza              5,728         18%

 2. Number of employees who did not have influenza    24,956
                                                      ——————
     Total number of employees                        30,684

 3. Total number of persons
   inoculated                      One inoculation     2,983
                                   Two inoculations    3,675
                                   Three inoculations  4,626
                                   Four inoculations  10,053
                                                      ——————
                                         Total        21,337

 4. Cases influenza developed
   after                           No inoculations     2,133         23%
                                   One inoculation       745         25%
                                   Two inoculations      776         21%
                                   Three inoculations    794         17%
                                   Four inoculations   1,280         12%
                                                      ——————
                                         Total         5,728

 5. Cases influenza pneumonia
   developed after                 No inoculations       804         37%
                                   One inoculation       356         48%
                                   Two inoculations      403         52%
                                   Three inoculations    321         40%
                                   Four inoculations     459         36%
                                                      ——————
                                         Total         2,343

 6. Deaths from influenza and “flu
   Pneumonia” after                No inoculations       104        4.7%
                                   One inoculation        32        4.3%
                                   Two inoculations       33        4.2%
                                   Three inoculations     21        2.6%
                                   Four inoculations      33        2.5%
                                                      ——————
                                         Total           223        3.9%


                                CHART II.

                        H. C. FRICK COKE COMPANY.

          STATISTICAL REPORT ON INOCULATION AGAINST INFLUENZA.

 1. Number of employees who had influenza              5,248       31.4%

 2. Number of employees who did not have influenza    11,464
                                                      ——————
     Total number of employees                        16,712

 3. Total number of persons
   inoculated                      No inoculations     3,122
                                   One inoculation     2,483
                                   Two inoculations    2,548
                                   Three inoculations  3,550
                                   Four inoculations   5,009
                                                      ——————
                                         Total        13,590

 4. Cases influenza developed                                      47.9%
   after                           No inoculations     1,495       of (3
                                   One inoculation       634       25.5%
                                   Two inoculations      770       30.2%
                                   Three inoculations  1,078       30.4%
                                   Four inoculations   1,271       25.0%
                                                      ——————
                                         Total         5,248

 5. Cases influenza pneumonia                                       6.3%
   developed after                 No inoculations        94       of (4
                                   One inoculation        33        5.2%
                                   Two inoculations       42        5.4%
                                   Three inoculations     69        6.4%
                                   Four inoculations      85        6.7%
                                                      ——————
                                                                    6.1%
                                         Total           323 of (4 total

 6. Deaths from influenza and “flu                                  2.0%
                                   No inoculations        30       of (4
                                   One inoculation        13        2.0%
                                   Two inoculations       21        2.9%
                                   Three inoculations     16        1.5%
                                   Four inoculations      37        2.9%
                                                      ——————
                                                                    2.2%
                                         Total           117       of (4


                               CHART III.

                     BESSEMER & LAKE ERIE RAILROAD.

          STATISTICAL REPORT ON INOCULATION AGAINST INFLUENZA.

 1. Number of employees who had influenza              1,275         24%

 2. Number of employees who did not have influenza     3,986
                                                      ——————
     Total number of employees                         5,261

 3. Total number of persons
   inoculated                      No inoculations     3,091
                                   One inoculation       232
                                   Two inoculations      249
                                   Three inoculations    479
                                   Four inoculations   1,210
                                                      ——————
                                         Total         2,170

 4. Cases influenza developed
   after                           No inoculations       705         55%
                                   One inoculation       111         48%
                                   Two inoculations       91         36%
                                   Three inoculations    129         27%
                                   Four inoculations     239         19%
                                                      ——————
                                         Total         1,275

 5. Cases influenza pneumonia                                        40%
   developed after                 No inoculations       283       of (4
                                   One inoculation        75         67%
                                   Two inoculations       59         64%
                                   Three inoculations     51         42%
                                   Four inoculations      69         28%
                                                      ——————
                                         Total           537

 6. Deaths from influenza and “flu                                  5.6%
   Pneumonia” after                No inoculations        40       of (4
                                   One inoculation         5        4.5%
                                   Two inoculations        0
                                   Three inoculations      0
                                   Four inoculations       3        4.3%
                                                      ——————
                                         Total            48

Charts I and III show a decrease in the incidence of influenza in direct
proportion to the number of inoculations given. This finding would have
been very important had vaccination been completed before the epidemic
appeared. There is, however, no convincing evidence in either of these
charts that the vaccine cut down the relative number of pneumonias, or
decreased the death rate to any appreciable extent. Chart I also shows
the interesting fact that influenza occurred slightly more often among
those who had one inoculation than among those who were not vaccinated
at all.

Chart II would indicate that influenza occurred much less frequently in
the vaccinated than in the control group, but a closer analysis brings
out the contradictory finding that influenza occurred at the same rate
in the group of 634 persons who had only 1 dose that it did in the group
of 1,271 who completed the course.

The reports from the separate communities were so conflicting that to
attempt to analyze them leads only to confusion.

No reports of harmful effects from the use of the vaccine were received,
and several physicians who attended sick employees say that, even though
the figures do not show it, they feel certain that the vaccinated
persons in general were not as sick as those who were not vaccinated.

On account of the conditions under which the vaccinations were done and
the reports compiled, Dr. Sherman has not felt justified in making a
report, fearing that erroneous conclusions might be drawn from the data.
We are greatly indebted to him for the use of his reports, without which
our account of the influenza epidemic in Pittsburgh would have been very
incomplete.

2. Another large steel corporation who used vaccine but asked that their
names be withheld furnished the following report. During the epidemic
the company offered free vaccination to its 27,000 employees and their
families. Commercial mixed vaccines were used, three injections given,
and vaccination begun on October 19, which was about the time of the
peak of the epidemic in Pittsburgh. The results include a record of all
employees who lost over six days between October 1 and November 30.

  ───────────────────────────────┬────────────┬───────────┬───────────
             EMPLOYEES           │ MORBIDITY  │ PNEUMONIA │ MORTALITY
  ───────────────────────────────┼──────┬─────┼─────┬─────┼─────┬─────
                                 │ No.  │  %  │ No. │  %  │ No. │  %
  ───────────────────────────────┼──────┼─────┼─────┼─────┼─────┼─────
  Received only one dose    3,895│   511│13.13│   31│  0.8│   28│ 0.72
  Received only two doses   3,329│   414│12.44│   40│  1.2│   19│ 0.57
  Received all three doses  9,897│   468│ 4.75│   46│ 0.46│   32│ 0.32
  ───────────────────────────────┼──────┼─────┼─────┼─────┼─────┼─────
  Total of above           17,119│  1393│ 8.14│  117│ 0.68│   79│ 0.46
  Received no doses        10,036│  1522│15.17│  154│ 1.53│  106│ 1.06
  ───────────────────────────────┼──────┼─────┼─────┼─────┼─────┼─────
  Total for both groups    27,155│  2915│11.66│  271│ 1.10│  185│ 0.76
  ───────────────────────────────┴──────┴─────┴─────┴─────┴─────┴─────

Before satisfactory conclusions can be drawn from these figures it is
necessary to know how many of the 10,036 persons became sick before
vaccination, and whether or not the rate of decrease in this group was
not similar to that shown by the number of patients who developed
influenza during the intervals between their doses of vaccine. The
relatively high percentage of cases following the first and second doses
are capable of explanation on one, or perhaps on all, of the three
following grounds: (a) the general subsidence of the epidemic, which
showed a rapid decrease by the time the third dose was given; (b) the
increased protection afforded by the three doses of vaccine, and (c) the
broken resistance of the patient following sudden sensitization by the
vaccine.

3. Rosenow (21) prepared a mixed vaccine by growing the various bacteria
in glucose broth, for from 18 hours to 36 hours, centrifuging and
suspending the sediment in salt solution and making up the vaccine on a
percentage basis.


                           FORMULA OF VACCINE

 Pneumococci, Types I (10 per cent.), II (14 per cent.) and
   III (6 per cent.)                                        30 per cent.
 Pneumococci Group IV and the allied
   green-producingdiplostreptococci described               30 per cent.
 Hemolytic Streptococci                                     20 per cent.
 Staphylococcus Aureus                                      10 per cent.
 Influenza bacillus                                         10 per cent.

Most of the vaccine was distributed within a radius of 200 miles of
Rochester, Minn., but samples were furnished to physicians all over the
country, who agreed to return statistics on its use. No evidence was
found that this vaccine caused a temporary break in the resistance of
the user. Out of a total of 20,972 persons vaccinated, 14.6 cases of
influenza, 1.8 cases of pneumonia, with 1.8 mortality, occurred per
thousand in the six weeks following vaccination. As controls, he took
“such persons in institutions, colleges, factories and communities where
vaccine was used, and included only those reports which contained
accurate data as to the incidence and mortality among them.” Among
61,753 such controls he found 229 cases of influenza, 15.7 cases of
pneumonia and 3.4 deaths per thousand. He concluded from his results
that “it appears possible to afford a definite degree of immunity by
prophylactic inoculations to persons against the more serious
respiratory infections during the present epidemic.” It is quite
difficult to agree with Rosenow in his interpretation of the figures as
presented by him, inasmuch as he made no allowance for the stage of the
epidemic at which vaccination was carried out, either among the
vaccinated or the non-vaccinated. Such a comparison would be well nigh
impossible where the vaccine was sent in varying quantities to such a
large number of places.

4. League Island Report (22). Vaccines were used as a preventive in 50
persons, most of whom were hospital apprentices and in the wards 12 to
15 hours a day. Other precautions were used, such as masks, but not a
single case developed in the group. The vaccine was used as a curative
agent in 50 uncomplicated cases; none of the patients injected early
developed pneumonia.

5. Puget Sound Navy Yards Report (23). The vaccine used at this station
was made from hæmolytic streptococci, no other organisms being used;
4,212 men were vaccinated, and not one died from influenza. Among 111
Philippinos isolated and vaccinated there occurred only 2 cases. Among
361 marines vaccinated early there occurred 2 cases. Among 62 marines at
the ammunition depot who were vaccinated early there occurred 3 cases,
only 1 of which occurred after completion of vaccination. Among 662
bluejackets at Seattle Training Camp only 10 men developed the disease.
Among 83 at the aviation corps there were 32 cases—31 of them developed
the disease within a few hours after the first injection. There were no
deaths in any of the above groups. The period of observation was closed
on October 21, and so few cases of influenza appeared subsequent to that
date that it seemed that the epidemic was practically over at the time
the data was obtained.

6. Kitano (24) used a vaccine for prophylaxis containing 0.2 m.g. of
Pfeiffer bacilli per c.c. on 10,300 persons with encouraging results. He
used vaccine for treatment on 87 patients, without any deaths. In the
same group were 270 cases treated in the usual way, with 23 per cent.
mortality. The vaccine lessened the severity, shortened the period of
illness, and lowered the mortality.

7. Wynn (25) used mixed vaccines in the treatment of influenza, and
believed they aborted the disease if given early.

8. Norman White (26) states that vaccination in India would be
impractical, because the disease is so brief and severe that it would be
over before innumerable doctors could complete inoculations.

9. Whitingham and Sims (27) reported the use of a mixed vaccine in an
institution where 156 were inoculated and 149 were not. The case
incidence was 5 per cent. among the vaccinated and 12 per cent. among
the controls. No statement of the stage of the epidemic at which
vaccination was done is mentioned in the report.

10. Cadham (28) reported on inoculations in a military hospital and in
the civilian population near Winnipeg. Of 282 vaccinated soldiers
admitted to the hospital, 17 had pneumonia and 5 died. Of 238 not
vaccinated, 41 had pneumonia and 17 died. Among 24,184 civilians given
two doses, 9.7 per cent. had influenza and 0.5 per cent. had pneumonia
and 0.09 per cent. died. Among 85,941 controls, 24.8 per cent. had
influenza, 2.2 per cent. pneumonia and 0.66 per cent. died. Cadham
states that most of the inoculations were made early in the epidemic,
but no accurate statistics were kept on the point.

11. A conference was held at the British War Office on October 14, 1918
(30), to discuss prophylactic vaccination and vaccines for treatment of
influenza. Elaborate plans regarding dosage and gathering of statistics
were made.

NOTANDA.—For reasons already given, the reports in Series III fail to
give very reliable data on which to base a knowledge of the value of
preventive vaccination against epidemic influenza.


_The Attempt to Prevent Pneumonia as a Complication of Influenza Through
                        the Use of Lipovaccine_

Whitmore, Fennel and Peterson (31) developed a method of preparing an
oily suspension of killed bacteria which they called “lipovaccine.” The
method was used at first in making typhoid and dysentery vaccines. The
advantages of lipovaccines (32) over salt suspensions are: the
prevention of autolysis of the bacteria, thus increasing the length of
time during which the vaccine remains active; the slow absorption of the
dose, allowing the patient to continue to absorb immunity-producing
substances over a period of days or weeks; the administration of a
single massive dose, which does away with the three doses necessary when
salt suspensions are used; and perhaps, also, the direct reduction in
the toxicity of the dose by the lipoid material.

Based upon the classification of pneumococci by Dochez and Gillespie
(33) in this country, and by Lister (34), (35), (36) in South Africa,
and upon the latter’s successful use of anti-pneumonia vaccine on the
Rand, an anti-pneumonia lipovaccine was prepared at the Army Medical
School which contained approximately 10,000,000,000 each of types I, II
and III pneumococci. The vaccine was made by growing the pneumococci in
dextrose broth, centrifuging them out of the broth with a sharpless milk
centrifuge, drying the sediment at 55° C., weighing it out so that each
cubic centimeter of the finished vaccine contains 0.83 m.g. of each
type, and making a suspension of them in olive oil. More recently
cotton-seed oil has been used.

The result of the use of a salt suspension pneumococcus vaccine at Camp
Upton was published by Cecil and Austin (37). A study of the
agglutination and protective power of the serum of 42 persons vaccinated
against pneumococcus types I, II and III demonstrated that a definite
immune response could be secured to types I and II but not to type III.
Twelve thousand five hundred and nineteen men were vaccinated at the
camp, and most of the men received three or four inoculations at
intervals of from five to seven days. The men were under observation for
ten weeks, and during that time no cases of pneumonia of the three fixed
types occurred among those who had received two or more injections. In a
control of approximately 20,000 men there were 26 cases of pneumonia of
types I, II and III. The incidence of pneumococcus type IV pneumonia was
less among the vaccinated than among the unvaccinated groups. There
were, however, 17 cases of pneumonia among the vaccinated men, compared
to 173 cases of pneumonia among the controls. The annual pneumonia death
rate for vaccinated groups in the army was 0.83 per one thousand, and
for unvaccinated groups was 12.8.

Fennell reported the use of pneumo-lipovaccine in Washington during the
influenza epidemic, but the number of cases cited by him were too small
to permit of definite conclusions. His results appeared favorable.

Cecil and Vaughan (37a) reported on the results of vaccination with
pneumo-lipovaccine at Camp Wheeler; 13,460 men, comprising 80 per cent.
of the camp, were inoculated. Most of these men were under observation
for 2 or 3 months after vaccination, and there occurred among them 32
cases of pneumococcus types I, II and III pneumonia. In one-fifth of the
camp which was not vaccinated there occurred 43 cases of pneumonia. They
observed that influenza caused a marked reduction in the resistance to
pneumonia among vaccinated as well as non-vaccinated men. Of 155 cases
of pneumonia of all types, which developed one week or more after
vaccination, 133 were secondary to influenza. The death rate among
vaccinated men one week or more after vaccination was 12.2 per cent.,
whereas the death rate for 327 cases of all types of pneumonia which
occurred among unvaccinated groups was 22.3 per cent. The death rate for
primary pneumonia among vaccinated groups was 11.9 per cent., and among
unvaccinated 31.8 per cent. It was found that protective bodies do not
begin to appear in the serum after lipovaccines are given until the
eighth day after the injection. Twenty-four cases of pneumonia occurred
in the first week after vaccination. In their conclusions Cecil and
Vaughan state that there was no evidence whatever that pneumococcus
vaccine predisposed the individual, even temporarily, toward either
pneumococcus or streptococcus pneumonia. Most of the reactions after
vaccination were mild, but one disagreeable feature was that in a
certain percentage there persisted a small fluctuating mass at the site
of the injection. Lacy saw a number of these cysts aspirated, and the
contents were found to be a sterile, oily fluid, with many leucocytes
present. In one instance the primary reaction disappeared within a few
days after vaccination, but recurred after four months and persisted for
several weeks.

NOTANDA.—The army lipovaccine apparently offers a certain definite
amount of protection against pneumonia, which was the most dangerous
complication of influenza. The protective substances do not appear in
the serum until eight days have elapsed after the vaccination, and while
no definite evidence has appeared to show that there is a temporary
increase in susceptibility immediately after vaccination, the best
results would undoubtedly be obtained where the dose is given something
more than eight days before the appearance of the epidemic. The
indications are that the vaccine will not protect against influenza, but
that the complication of pneumonia is less likely to occur in the
vaccinated than in the unvaccinated individual.


                               _Summary_

Records of attempts to confer immunity to influenza by the use of
vaccines have been separated into related groups and studied. Those
where pure Pfeiffer strains were used have been considered in one group.
Those where mixed vaccines were used have been analyzed in three
sub-groups or series, depending on the relation between the times of
vaccination and of the advent of the epidemic, upon whether or not a
week-by-week comparison of the occurrence of influenza among vaccinated
and unvaccinated groups was made, and upon whether or not statistics for
total comparison alone were available. The third group included the
reports of the use of army pneumo-lipovaccines for the prevention of the
secondary pneumonia complications of influenza.


                             _Conclusions_

From our statistics we conclude that:

1. There is as yet no evidence that vaccines composed purely of strains
of Pfeiffer bacilli will confer immunity to epidemic influenza.

2. The only data which can be used as a basis for estimating the value
of mixed vaccines as a preventive for epidemic influenza must be
obtained from experiments in which vaccination was either completed
before the epidemic appeared, or in which week-by-week comparisons
between the number of cases occurring in the vaccinated and unvaccinated
groups can be made.

3. Data obtained from experiments conducted under the above
qualifications is inconclusive, but presents little evidence of the
value of mixed vaccines in protecting against influenza. There is,
however, an indication that mixed vaccines used prior to the arrival of
the epidemic will lessen the number and the severity of secondary
pneumonias, and will probably lower the death rate to a small degree.

4. The army pneumo-lipovaccine apparently offers some protection against
primary infections with types I, II and III pneumococci, and a somewhat
lesser amount of protection against secondary pneumococcic infections
with these strains following influenza.

5. While it is impossible to say that the large number of influenza
cases developing almost immediately after vaccination would not have
occurred anyway, it is at least suggestive that a temporary break occurs
in the resistance after the inoculation, and that unusual care should be
taken by persons who have been recently vaccinated, particularly when
they are in the midst of an epidemic disease.


                 PART II. GENERAL PROPHYLACTIC MEASURES

One of the most remarkable things about the 1918 pandemic was the great
rapidity with which it spread to all parts of the world. From the report
of the first cases which landed in Boston until the epidemic arrived in
San Francisco the time consumed was less than two months, and the peaks
of the two epidemics were just about one month apart. Apparently no part
of the world escaped. Asia, Europe, Africa, North and South America, and
some of the remote islands of the Pacific, all reported large epidemics,
with high mortality and great suffering. The deplorable failure of
precautionary measures in controlling the spread, or at least in
limiting the disease, may be offset in a measure by the unusual
conditions under which almost everybody had been living. Vast numbers
from all over the world were gathered together because of the war.
Thousands of men were housed together in army camps or in training
cantonments. Other thousands were doing relief work or engaged in the
manufacture of munitions. Most of those at home were doing double duty,
and were on a severe nervous strain. Everyone everywhere was working to
the limit and was consequently fatigued. The necessities of war had cut
down the amounts of food generally, and sugar and fat rations
particularly. Traffic, both between nations and at home, had never been
so great nor accommodations so insufficient. So that it is likely that
all of these and many more changes in the daily routine of individuals
led to a condition of lowered resistance, and at the same time increased
their chances of exposure. One point, at least, stands out prominently,
and that is that “influenza as it occurred clinically during the first
great wave was different from those cases which appeared later.” This
was seen in the acuteness of the onset, in the severity of symptoms, and
in the high mortality rate. Therefore, any measure which afforded
protection, if only for the time being, is worthy of retrial.

In view of the fact that recurrences have followed closely in the wake
of all former influenza epidemics, and with the hope of stimulating
concerted investigation of preventive measures, the American Public
Health Association (57), at its meeting in Chicago in December, 1918,
appointed a committee to outline “a provisional working formula, based
on the facts and opinions brought out at the meeting.” A summary of the
opinions as taken from the report of the committee is given here. They
reported that the disease was probably due to some micro-organism or
virus as not yet identified; that while it was known as “influenza,” it
was not known to be identical with the disease generally known under
that name; that there was no known laboratory method of differentiating
it from ordinary colds, bronchitis, etc.; that there was no known
laboratory method of determining when a patient ceased to be infective;
and that the deaths from influenza were due to secondary pneumonia
resulting from an invasion by one or more forms of streptococci, or by
one or more forms of pneumococci, or by the so-called influenza bacillus
or bacillus of Pfeiffer. Because of the clear and concise manner in
which this report brings out the opinions held, at the time, by a
majority of the medical profession a portion of the report is given here
_verbatim_.

“Evidence seems conclusive that the infective micro-organisms or virus
of influenza is given off from the noses and mouths of infected persons.
It seems equally conclusive that it is taken in through the mouth or
nose of the person who contracts the disease, and in no other way except
as a bare possibility through the eyes by way of the conjunctivæ or tear
ducts.

“If it be admitted that influenza is spread solely through discharges
from the nose and throats of infected persons, finding their way into
the noses and throats of other persons susceptible to the disease, then,
no matter what the causative organism or virus may ultimately be
determined to be, preventive action logically follows the principles
named below, and, therefore, it is not necessary to wait for the
discovery of the specific micro-organism or virus before taking such
action.

“1. Break the channels of communication by which the infective agent
passes from one person to another.

“2. Render persons exposed to infection immune, or at least more
resistant, by the use of vaccines.

“3. Increase the natural resistance of persons exposed to the disease by
augmented healthfulness.”

The ways and means of carrying out these principles are many and varied,
and it is merely the intention of this paper to put together a sort of
digest of some of the more important arguments for and against some of
the seemingly more important measures proposed.


     _Methods Proposed for Breaking the Channels of Communication_

(a) Rigid quarantine for all persons suffering from the disease and all
contacts. During the epidemic quarantine was advocated by many people.
It was pointed out that the disease spread most rapidly in camps, in
ships, and in quarters generally where large numbers of persons were
closely associated; that it was quite as contagious and more rapidly
fatal than most diseases which are regularly quarantined; that while it
was admitted that there is no laboratory method to make certain the
diagnosis, and no method of telling how long convalescents are capable
of transmitting the disease, as there is, for instance, in diphtheria,
still there is no question of the value of the arbitrary quarantine used
in measles, scarlet fever and smallpox, all of which are diseases in
which the parasitic causes are not known. Further, the opinion was
expressed that complete isolation and quarantine would not only protect
the community from influenza, but that it would also in a measure
protect the patient from contact with numerous outside strains of
pneumococci and streptococci, and so lessen secondary infection and
reduce the general mortality.

There are many reasons why quarantine is not applicable in epidemic
influenza. Most important of all is probably the inability to make
certain the diagnosis, especially during the early stages in light
cases. This would work detrimentally in several ways. Really ill
patients would delay calling a physician until late, for fear of
unnecessary quarantine. Many needless and unjust quarantines would
result when the diagnosis was uncertain and the physician anxious to
carry out quarantine measures efficiently. Many patients would have
contacts running about and infecting their neighborhoods while a delayed
diagnosis was being made. Influenza was so contagious during the
epidemic that it would have necessitated general quarantine not only of
all infected persons but also of all contacts to have obtained any
favorable results, and since nearly everyone was either a patient or a
contact, all lines of business would literally have been paralyzed by
the procedure. If it is true that the infected person is most dangerous
to others before he has developed symptoms himself, he is a carrier
impossible of detection and control. Points in favor of the hypothesis
that infected persons spread the disease before they develop symptoms
are found in the following facts. As the disease passed from community
to community officials became alert for the appearance of the first
case. In army barracks and in large institutions it was often possible
to determine the first case at its development. The case was, in many
instances, removed at once and isolated, but I have seen no instance in
which such a measure was successful in curbing the disease. As
subsequent cases appeared they were likewise immediately removed, but
the cases continued to spread just the same. Bloomfield (38) cited the
incident of a student who spent a few hours visiting his sister in a
part of the country where there had been no influenza. He appeared well
at the time, but six hours after his return to school he developed
influenza. Two days after the contact the sister came down with the
disease. On the other hand, he told of a student who did not contract
the disease, though he slept for two nights in the same bed with his
roommate, who had returned to school with a well-developed case of
influenza. The unsuccessful attempts to transmit influenza in the
experiments of Rosenau (37), McCoy (37a) and others already cited would
indicate that the cases from whom the material was taken were no longer
infectious, although some of them had been showing symptoms for only
about 12 hours. Bloomfield observed that the general use of face masks
in the wards did not alter the course of the epidemic, and stated that
if face masks are protective, infection from early unisolated cases must
be assumed.

Provided influenza is generally transmitted during the period of
incubation, a theory which seems consistent with the facts, rigid
quarantine for epidemic influenza is impracticable and probably useless.


           _Partial Isolation by Means of the Cubicle System_

The so-called cubicle system consists in the dividing of rooms, or more
particularly of wards, into small compartments by means of suspending
sheets from wires so that each bed is separated from its neighbor. Capps
(39) reported favorably on the method as used at Camp Grant, where
sheets or halves of tents were suspended from wires or from the mosquito
netting frames which were a part of the standard beds. Doctors, nurses
and attendants were forced to wear masks in the wards, and patients were
not allowed out of the cubicles without them. In discussing this paper
Thayer emphasized the value of screening, masking and the wearing of
gowns, and also recommended thorough washing of the hands between the
examination of each two patients; and Emerson called attention to the
fact that the first demonstration of the cubicle system as an adequate
means of preventing acute respiratory diseases was made at the Pasteur
Institute of Paris, where it had been in operation for 10 years. The
latter stated that the system had been used in various hospitals in
America and was essential for the care of diphtheria, measles and
scarlet fever. He further indicated that if the technique of personal
cleanliness of nurses, doctors and attendants could be perfected, it was
probable that the height of the cubicle partition could be reduced to
that of a “red string.” The method certainly seems worthy of
consideration and trial, particularly in large general hospitals and
public institutions.


                       _The Use of the Face Mask_

The question of the value of wearing a gauze mask over the mouth and
nostrils during an influenza epidemic is still an open one. Masks,
however, have been found useful in protecting against some other
diseases of respiratory origin. In December, 1917, Weaver (40) reported
favorably on the use of gauze masks in the Durand Hospital of Infectious
Diseases. The masks were used by nurses in attendance upon patients with
contagious diseases, and also by patients who were convalescing from
diphtheria, meningitis or pneumonia and who were in the same wards with
those having other respiratory diseases. In a later article Weaver (41)
stated that by the use of masks they had been able to reduce the
percentage of diphtheria carriers among their nurses in the diphtheria
wards to 5.2 per cent., as compared to the average of 23.25 per cent.
during the 20 months immediately preceding their adoption of their use.
He recommended the general use of masks for physicians when in contact
with all types of respiratory diseases. In March, 1918, Capps (39a)
reported encouraging results in the control of infections through the
masking of all patients at Camp Grant. During the epidemic the wearing
of masks became quite general, and was very popular in many sections.

Several sets of laboratory experiments have been carried out recently to
determine whether the masks are of practical value or not. The
experiments have generally consisted in spraying cultures of living
bacteria over sterile bacterial plates which were protected by one or
more layers of gauze. A number of variations were made in the manner in
which this was done: (a) the distance between the nozzle of the spray
and the mask was varied, and the distance between the plate and the mask
kept constant; (b) the distance between the plate and the mask varied,
and the distance between the nozzle and the mask kept constant; (c) the
use of masks both over the nozzle of the spray and over the plate being
kept constant, and the distance between the two masks varied. In a
somewhat different set of experiments the mask was placed over the mouth
of a person, who was told to talk or cough over an agar plate, and the
bacterial plate being held at various measured distances from the face.
By counting the number of colonies which developed upon the plates it
was possible to get fairly reliable data as to the efficiency with which
the bacteria were intercepted by the gauze. Weaver (42) found that if
enough gauze was used, it would filter out all of the bacteria passing
from the spray in the direction of the plate. The efficiency of the mask
being in direct proportion to the fineness of the mesh and the number of
layers employed. Doust and Lyon (43) made a series of experiments to
determine the distance through which droplets are carried when expelled
under different circumstances. They found that in ordinary speech
infected material is projected for about four feet, and that during
coughing the material is carried about ten feet. They demonstrated that
masks of medium meshed gauze, two to ten layers thick, worn by the
person coughing did not prevent the passage of infectious material into
the air, but that a three-layer buttercloth mask was much more
efficient. Haller and Colwell (44) used three distinct sets of
experiments—one with the mask over the mouth of the patient, one with
the mask over the plate, and the third with masks over both—and
concluded that a five-layer mask made up of 24 × 20 mesh protected the
plate in the second series of experiments. They suggested marking one
side of the mask, so that it would always be worn with the same side
out. Leete (45), in England, by a similar series of experiments
concluded that a dry mask of six to eight layers of butter muslin worn
by a contact would protect him against droplet-carried infections.
Dannenberg (46) suggested making the gauze mask over a copper screen
wire frame to give it shape and keep it away from the mouth, thus
keeping it relatively dry. All observers agree that masks while dry are
more efficient than they are after they have become moist.

The efficiency of the mask has also been widely discussed from the
clinical standpoint. Mink (47) in discussing their use at the Great
Lakes Training Station said that he had no objection to the mask as it
is “intended to be worn,” but that as it “was worn” by the medical corps
men at the station 8 per cent. of those who used the mask developed
influenza, as compared to 7.75 per cent. of those who did not; 30 per
cent. of the dental officers at the station developed the disease in
spite of the fact that they were all accustomed to wear masks during
their work. In discussing the mask Vaughan (48) said: “With reference to
the mask, I am strongly of the opinion that we have overestimated its
value. * * * When I went to Camp Devens they were not using the mask. I
called the doctors together and told them its use was not compulsory,
but I said: ‘Every doctor who took care of cases of pneumonic plague and
did not wear a mask died from it, and every man who cared for pneumonic
plague cases and didn’t wear a mask did contract it.’” They were then
allowed to choose for themselves. It has been pointed out that the
epidemic dropped off at once in San Francisco with the universal
compulsory use of the mask on the street, but it is also said that the
epidemic in Los Angeles, which ran a course parallel to that in San
Francisco and in which masks were only indiscriminately used, began to
drop off simultaneously. While it is difficult to get at the facts, it
seems that, provided epidemic influenza is carried through the air or by
means of droplets, the universal use of masks should decrease the number
of exposures. The claim has been made that masks merely tend to prolong
the epidemic, and that susceptible persons develop the disease after the
epidemic proper has passed. If the mask will protect the susceptible
individual until the virulence of the disease has decreased, it will
better that individual’s chances for recovery, and so is worth the
trouble.


                        _General Closing Orders_

In most large cities orders were issued closing churches and theatres
and prohibiting public gatherings of all kinds. In New York these places
of public gathering were not closed, and it has been pointed out, as an
argument against closing orders in the future, that the death rate there
was less than in Boston, Philadelphia, Pittsburgh, etc. Copeland (49),
of the New York Board of Health, stated that the unventilated picture
shows were closed, but that the theatres were used as places of public
instruction. New York’s relatively low death rate was difficult of
explanation, but it is very certain that it had nothing to do with the
fact that closing orders were not in vogue. If it were possible to
obtain the figures, it would be interesting, indeed, to compare the
death rate from influenza among New York’s theatre-attending public
during the epidemic with the death rate of the community in general.

Generally speaking, any unnecessary public gatherings are inadvisable
during any epidemic. While our exact knowledge of the mode of
transmission of influenza is incomplete, it is unquestionably a contact
disease. People who have been exposed and who have not yet contracted
the disease are known to have transmitted it to a third person. A
certain number of people from infected homes will attend public
gatherings as long as they are able, for it is impossible to get
together any large group of persons all of whom are going to play fair.
It is true that these meeting places may be used in a measure to allay
panic and to instruct the public in health measures, but there are many
efficient and far less dangerous methods of accomplishing the same
results. Vaughan in discussing assemblies in large halls mentioned that
in a hall at Camp Forest, which held 9,000 people, the individuals had a
space of about 16 inches laterally between their noses. He pointed out
that if many of them were talking, coughing or sneezing, the air
contamination would soon become so great that it could make little
difference whether there was a roof over the building or not. He
emphasized the fact that it is just as possible to crowd men in the open
as it is indoors. Ventilation is undoubtedly an important factor, but it
cannot correct overcrowding. As far as the educational value of the
public gatherings was concerned, it may be observed that regular
attendants of theatres and moving-picture houses during the year of 1918
had become quite accustomed to appeals regarding all sorts of public
movements from speakers who appeared between the acts, or pictures, but
that the closing of these places threw a wholesome scare into them which
made them pay far closer attention to prophylactic measures than almost
anything that could have happened. “Object-lessons are always superior
to didactic teaching.” In Chicago a new argument for the closing of
theatres was advanced. It was said that with no place to go many people
retired earlier and obtained more than their accustomed amount of rest.
It was believed that this aided in increasing their natural resistance.
The argument that the closing of these places served only to delay the
epidemic is an argument in favor of the measure, because the virulence
of the disease decreased rapidly as the epidemic progressed.


                        _The Closing of Schools_

Boards of Health generally were opposed to the closing of the public
schools. This position gave rise to innumerable clashes with anxious
parents. The health authorities took the position that children were
relatively insusceptible to influenza; that while they were quiet in a
well-ventilated schoolroom they were little exposed; that those who
coughed or sneezed could be examined at once, and that daily school
inspection would lead to early discoveries of all cases, so that doctors
and nurses could take immediate steps to treat the patients and to
protect the families from which they came. Copeland advocated the
continuance of the schools in New York, and based his position on the
fact that out of 1,000,000 children in New York City 700,000 came from
tenement homes. He believed these children were far better off in
school, where they received daily medical attention, than upon the
streets or in unhygienic homes.

In Pittsburgh the school children were quizzed as to the number of sick
at home, and this gave valuable information on the stage of the
epidemic. They were sent home with printed warnings against sneezing,
coughing and spitting, and were thus used as a means of instructing
their parents. The Pittsburgh schools were kept open until the sickness
of a number of teachers and the withdrawal of many scholars made it
advisable to close.

Three very potent arguments have been brought forward in favor of
closing the schools: (1) As long as the schools are open children from
infected homes are forced into contact with children from uninfected
homes, and we are at present unaware of the extent to which the disease
may be carried by a third person. (2) Children in as yet uninfected
homes which are comfortable and hygienic are far better off than they
are in school, and can hardly be considered in the same class with
children from unclean tenements. (3) If the period of greatest contagion
is before symptoms develop, inspection, while valuable for the
institution of treatment, cannot hope to aid in curbing the epidemic. It
is evident that different measures must be employed in applying closing
orders to crowded cities, moderately large towns and rural districts.
The difficulty lies in determining the best means for serving each
community.


                  _The Closing of Public Dance Halls_

Public dances should undoubtedly be prohibited during epidemics. They
not only present all the bad features of other public gatherings, but
during the dancing people are brought in very close contact and often
breathe directly into each other’s faces. In addition, air currents are
stirred up and a certain amount of dust is raised. During the exercise
the dancers breathe more rapidly and deeply, thus inhaling unusually
large amounts of dust, droplets and contaminated air. Another feature is
found in the “resistance-breaking” element of alternate overheating and
rapid cooling of the body.


           _Regulation of Public Eating and Drinking Places_

Public eating places are a necessity and cannot be closed. People should
be cautioned against using them as places of amusement and of
congregation during epidemics. Boards of Health should feel it just as
much their duty to see to the sterilization of dishes and eating
utensils as they do to the enforcing of any other public health
functions, and they should also insist on the daily inspection of the
employees of such establishments. The beer saloon question may be passed
over for the present, but the soda-water fountain as conducted during
the 1918 epidemic was undoubtedly a great menace. Ice cream, syrupy
mixtures, etc., of various kinds are readily contaminated by pathogenic
organisms which may serve as secondary infectors, if in no other
capacity. The syrups, moreover, adhere to the spoons and glasses, which
are rarely thoroughly washed and are practically never sterilized
between customers. The use of paper dishes and glasses is probably a
step in the right direction, but the spoons should be thoroughly washed
and sterilized. The fact that soda-water employees are not always
selected for high-grade intelligence, and are generally left largely to
their own hygienic procedures, makes the chances of transferring
infections at these places enormous. If soda fountains are allowed to
continue business at all during the epidemics, it should be only under
the very strictest supervision by Boards of Health. The scalding of all
utensils should be enforced by law.

People generally should be cautioned to use exceptional cleanliness in
the preparation of all foods in the home. In discussing the recent
epidemic Lynch and Cummings (50) stated that “the mess-kit wash water
proved the major route of transmission from sick to well in the army.”
Vaughan said: “I am pretty certain, not convinced, that hand-to-mouth
infection is of more importance than droplet infection.”


                        _Regulation of Traffic_

Business must be conducted in epidemic as well as in normal time, and
employees must go to and from their places of occupation. In cities
where the distance from the residence to the business districts is
great, street cars and other public conveyances must be used. Their use
undoubtedly increases the number of contacts and leads to a wider
distribution of the disease, but, like eating in public restaurants, it
is a chance which many have to take. Few places offer better
opportunities for exposure than street cars—where people of all grades
of intelligence, representing all states of health and degrees of
cleanliness and uncleanliness, are crowded closely together, breathe
into each other’s faces, and handle the same straps and supports.

In Pittsburgh the cars have a seating capacity for from 30 to 50
persons, but during the morning and evening hours they are crowded to
capacity, and are commonly seen to carry more than 100 passengers at a
time. Here, too, the unkempt, indifferent foreign element is
conspicuous, and these people are known to disregard all hygienic
teachings. A few days after the appearance of the epidemic the street
cars were placarded with warnings against coughing, spitting and
sneezing. The cards instructed people who became ill to go home, to go
to bed and to remain there until they were well. Later a second order
appeared which gave notice that all windows in street cars were to be
kept raised six inches and that no heat was to be allowed in the car.
The order was intended to improve ventilation, and, for a wonder, it was
enforced. During the first few days the weather was fine, warm and
clear, and the draught caused by the open windows brought no discomfort;
but later the weather became cold and several days of drizzling rain set
in. The cars with open windows became very uncomfortable, but the
streetcar employees insisted upon obeying the order to the letter. No
judgment was exercised by them, and the windows were kept open night and
day, cold or warm, crowded or empty, in fair and rainy weather alike,
and no heat was allowed to be turned on. Many people preferred standing
to exposing their backs and necks to the cold draughts, and it is more
than likely that such use of open windows did far more harm than good.
As above quoted, Vaughan pointed out that crowding is just as dangerous
out of doors as indoors, and it is certain that crowding in cold,
draughty cars is dangerous, both from the close contact and because of
the added danger of lowering bodily resistance.

In an attempt to decrease the crowding on public conveyances the
so-called “stagger-hour” system was adopted in New York. Under this
arrangement manufacturers and business houses changed their working
hours in such a way that the morning and evening travel was spread out
and the average number of people carried per hour was proportionately
decreased.

Looking backward over the methods used to decrease the spread through
the use of public conveyances, it seems that the following procedures
have the best claims for retrial: (1) Placarding the cars. This appeared
to reduce the amount of coughing and sneezing, even in face of the fact
that the cars were unusually draughty and chilly. (2) The adoption of
the “stagger-hour” system where the practice is feasible. (3) The
instruction of the people to use the street cars as little as possible.


               _Enforcement of Anti-Spitting Ordinances_

All street cars and trains carry anti-spitting notices either to the
effect that spitting will be prohibited on penalty and fine and
imprisonment, or giving stated amounts of the fine. Yet spitting is
constantly indulged in in these places and one rarely sees or hears of
the enforcement of the law. If the ordinance was worth making a law, it
is certainly worth enforcing, and yet there is probably no law so
flagrantly broken. Ordinary police officers pay no attention to the
enforcement of the spitting ordinance and have been known to refuse to
even reprimand spitters. The incident of a sanitary officer wearing a
uniform and a cap, indicating to the public his official position, who
was seen sitting in the smoking car in a local suburban train and
spitting profusely on the floor has been recounted on very reliable
authority. Another incident is known in which a street car conductor was
asked by one passenger to stop another who was expectorating abundant
mucoid sputum upon the floor. The conductor replied that he had orders
not to notice such things. It is no wonder that people are indifferent
to such impotent measures. Whether it is possible to convey epidemic
influenza or not by means of sputum, it is certain that tuberculosis is
spread in this way, and that influenza predisposes to tuberculosis and
causes old healed tuberculous foci to become active. People should be
made to understand that they may have tuberculosis without knowing it
themselves, and that by spitting it may be transmitted to other persons.
Spitting by persons aware that they have tuberculosis is criminal
negligence and such persons should undoubtedly be prosecuted. If a
person knows that he has tuberculosis and deliberately spreads about the
infection so that other persons contract the disease and die from it, he
is directly responsible for the deaths. It would be hard to imagine
trying to control manslaughter committed in any other way by merely
putting up signs in conspicuous places forbidding the act. The average
boy acquires the spitting habit between the ages of 8 and 12 years, and
in many instances carries it to the grave. The one possible way of
stopping spitting seems to lie in teaching the dangers of it to
children, beginning in the kindergarten and emphasizing it throughout
the child’s education. It is possible that in this way spitting may
become obsolete in two or more generations.


       _Increasing Natural Resistance by Augmented Healthfulness_

If there is any way of increasing the natural resistance against
epidemic influenza, it is a most desirable goal toward which to work,
but it must first be determined along what lines the effort is to be
directed. It was not the aged, the unconditioned nor the physically
unfit who suffered most from influenza, but was rather the best trained,
most healthful and most robust young persons we had. Those in the army
had been selected because of their physical fitness and they had further
received excellent physical training in the various camps and
cantonments. It would not be possible to bring any large percentage of
the general public up to such a stage of “augmented healthfulness” as
healthfulness is generally understood. It has been said that men in the
military camps were more commonly infected because they were more
active, went about more and were, therefore, more frequently exposed. In
one particular this statement is true, for men marching rapidly and
exercising violently breathe more deeply and at a faster rate than they
do under ordinary conditions, so that they naturally draw greater
quantities of air into their lungs. It was an obvious fact that those
persons given to sedentary lives were less often affected than the
active and vigorous. Practically speaking, it would seem that during
influenza epidemics people should be instructed to take more than the
usual amount of sleep and rest, to indulge only in mild exercises, to
eat good, wholesome food, to wear warm clothing, to seek mental and
physical relaxation at home, and, above all, to avoid crowds and public
gatherings.

In some instances the constant use of oils in the nose and throat was
advised, the theory being that the oil served the double purpose of
preserving the healthy condition of the mucous membranes by lessening
crusting, crevicing and drying, and of mechanically protecting from
infection by the presence of the layer of oil. Many of the different
liquid paraffins, both medicated and in the natural state, were used. It
is probably advisable to apply such oils either with a swab or from a
medicine dropper, rather than to attempt to spray them, since in the
latter method there is some danger of blowing infectious material down
into the trachea and larynx.

It is hardly necessary to point out the importance of augmented
cleanliness of the mouth, teeth and throat by means of mild antiseptic
washes and tooth-cleansing materials during an epidemic.


                            GENERAL MEASURES


                     _Public Health Administration_

Unless one had had a wide experience in the administrative side of
public health matters, it would be useless for him to try to discuss the
details of handling any sort of an epidemic, and even then local
conditions vary so much in different cities and States that each
administrator’s experience must differ greatly. The difficulty with
reports of epidemics by public health officials is usually found in the
fact that the reports are impersonal compilations and convey no idea to
the reader, or rather to the student (for no mere reader is attracted to
them), of what situations were faced, of what difficulties were in the
way, of how the conditions were met, or what the administrator after due
reflection would advise doing next time under similar circumstances. In
the face of inexperience the writer ventures the following suggestions
for improvement, though no originality is claimed for the ideas.

The administrative powers should be centralized in one individual, or in
an executive officer acting for a competent board of advisers, who
should be endowed with the powers to carry out the measures which seem
best suited to meet the situation at hand, and who should be beyond the
pale of political interference and in position to prevent political
fiascos, built more or less directly on health regulations.

The United States Public Health Service should work toward standardizing
health laws and penalties for all States.

Thorough enforcement of ordinances requiring the reporting of all cases
and all deaths as now demanded by public health rulings should be
insisted upon. These reports are so important to a knowledge of the
progress of the epidemic that the section on preventive medicine of the
American Medical Association (51) has just advised the consideration of
eliminating from membership in the Association any physician who
willfully fails or refuses to comply with the regulations requiring the
reporting of communicable diseases. Additional information can be
obtained by daily canvasses of the schools, when open, of the large
industries, and of the daily admissions to hospitals. Data on the daily
facilities for the handling of additional cases in hospitals should be
on file in the office of the administrator of health.

Printed instructions giving in detail the proper procedures for
isolation of the patient and the protection of the family should be
supplied to physicians for distribution at the first visit to suspected
cases.


                            _Desirable Laws_

Some specific laws governing the following points would be of great
advantage during the progress of an epidemic: (a) A law providing for
the commandeering by boards of health of vaccines, sera or other
substances for which a sudden unusual demand may occur, and for the
distribution of such substances by the authorities to the public at the
prices ordinarily asked. (b) A law permitting the exclusion from the
daily papers by boards of health of advertisements containing obviously
false and fraudulent statements relative to the epidemic. (c) A law
permitting the health authorities to go into public eating places and
demand proper sterilization of dishes and eating utensils with the
alternative of closing the establishment. (d) A set of laws making the
penalties sufficient to prevent violations of the regulations.


                       _Education of the Public_

From the beginning to the end of an epidemic the health authorities,
aided by the medical profession, should take the public wholly into
their confidence. At the first news of the approach of the disease a
general bulletin should be issued giving all of the main facts that are
available. This was done in a way by the American Public Health Service,
but the bulletin reached only a small fraction of the people, and
although parts of it appeared later in the daily papers, it was pretty
generally missed. The papers should be used freely and the space paid
for when necessary, so that the news of the epidemic is featured
emphatically. The establishment of a question and answer department or a
bureau of information would take care of a great deal in the way of
denying misinformation. The public should be encouraged to report
helpful facts of all kinds, but with the understanding that no rumors
would be published without investigation and confirmation. In this way
it would be possible to prevent articles advising harmful and useless
remedies from reaching the press, and aid in suppressing some of the
“Sure Cures,” so many of which appeared to abuse the confidence of the
unwary during the 1918 epidemic. Several such cures have been most
interestingly discussed in a recent bulletin of the United States Public
Health Service. The bulletin divides the “Sure Cures” into three
different classes, as follows: “First comes the individual who has a
specific remedy, the formula of which he will sell for a price * * *;
next comes the person with a pseudo-scientific treatment, e. g.,
isotonic sea water, ‘orzono therapy,’ ‘harmonic vibrations.’ * * * Still
another type, who gives freely of his advice that humanity may be spared
from pestilence.” Among the latter are found advice for placing sulphur
in the shoes, wearing of amulets, inhaling of alcohol, chloroform, etc.,
as well as numerous religious and mental science treatments, etc. A
frank statement of facts and a discussion of the ridiculous side of many
of these claims would undoubtedly benefit the entire public. The
placarding of the cars and the warnings posted in conspicuous places no
doubt helped greatly, and this method undoubtedly should be continued.
As long as theatres are allowed to remain open, speakers may be used to
advantage to emphasize important points. The County Medical Societies
should be asked to appoint committees for supplying information or for
seeing that the information given to the public is authoritative. In
large cities committees may be organized among hospital superintendents,
so that the heartiest co-operation between health authorities and
hospitals will be available. The ever-ready aid of the Red Cross and of
every other auxiliary body should be employed to the fullest extent to
allay apprehension and relieve suffering.


                               _Summary_

The exact knowledge of the mode of transmission of epidemic influenza is
still wanting, but it is known to be spread by contact. Attention should
be directed toward every practical means of decreasing the number and
intimacy of contacts. Publicity campaigns and other educational measures
should be pushed strongly. Health Departments should adopt a policy of
preparedness during inter-epidemic times, should make every effort to
centralize and standardize their work, and should take steps to obtain
sufficient legal backing, so that upon the appearance of the epidemic
they can take the lead, speak with authority and enforce their
ordinances and measures. The physician’s duty is to inform himself on
the value of the various measures, and if he is at odds with the public
health methods, he should settle them between epidemics, so that when he
is called upon to carry out public health orders he can do it to the
letter and without criticism. Laymen should learn that quiet living
without violent exercise, the keeping of good hours, the avoidance of
public gatherings and of unnecessary exposure is the best policy to
pursue during influenza epidemics. They should strictly obey the orders
of those who have specialized in the control of epidemics, and all
business men must stand ready to help in every possible way and to make
their business interests subservient to the public good.


                              BIBLIOGRAPHY

   1. Rosenau, Keegan,       Public Health Report, 1919; xxxiv, No. 2,
        Goldberger and Lake    p. 33.
  1a. McCoy and Richey       Public Health Report, 1919; xxxiv, No. 2,
                               p. 34.
   2. Lacy                   Jour. Lab. and Clin. Med., 1918; iv, p. 55.
   3. Wollstein              Jour. Exper. Med., 1911; xiv, p. 73.
   4. Flexner                Jour. Amer. Med. Assoc., 1913; lxi, p.
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   5. Park and Williams      Bacteriology, 1914 Edition; p. 437.
   6. Leary                  Jour. Amer. Med. Assoc., 1918; lxxi, p.
                               2098.
   7. Leary                  Amer. Jour. Public Health, 1918; viii, p.
                               755.
   8. Rosenau                Preliminary report furnished through
                               Surgeon-General of the Navy W. C.
                               Braisted.
   9. Barnes                 Jour. Amer. Med. Assoc., 1918; lxxi, p.
                               1849.
  10. Hinton and Kane        The Commonwealth Mass. State Dept. Health,
                               1918; vi, Nos. 1 and 2, p. 28.
  11. Hinton and Kane        Hinton’s Report.
  12. Parker                 Jour. Amer. Med. Assoc., 1919; lxxii, p.
                               476.
  13. Pearce                 Jour. Amer. Med. Assoc., 1913; lxi, p.
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  14. Committee on New and
        Non-Official         Jour. Amer. Med. Assoc., 1918; lxx, p.
        Remedies               1967.
  15. McCoy                  Personal Communication.
  16. Hutchinson             Dixmont Hospital Report.
  17. McCoy, Murray and      Jour. Amer. Med. Assoc., 1918; lxxi, p.
        Teeter                 1997.
  18. Minaker and Irvine     Jour. Amer. Med. Assoc., 1919; lxxii, p.
                               847.
  19. Sherman                Report.
  20. Maberry                Report from Hospital for Insane, Retreat,
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  23. Ely, Lloyd, Hitchcock
        and Nickson          Jour. Amer. Med. Assoc., 1919; lxxii, p. 24
  24. Kitano                 Jour. Amer. Med. Assoc., 1919; lxxii, p.
                               1575.
  25. Wynn                   Pract. London, 1919; cii, p. 77.
  26. Norman White           Lancet., 1919; i, p. 707.
  27. Whitingham and Sims    Lancet., 1918; ii, p. 865.
  28. Cadham                 Lancet., 1919; ii, p. 885.
  29. Eyre and Lowe          Lancet., 1918; ii, p. 485.
  30. Conference British War
        Office
  31. Whitmore, Fennel and   Jour. Amer. Med. Assoc., 1918; lxx, p. 427;
        Peterson               also p. 902.
  32. Fennel                 Jour. Amer. Med. Assoc., 1918; lxxi, p.
                               2115.
  33. Dochez and Gillespie   Jour. Amer. Med. Assoc., 1913; lxi, p. 727.
  34. Lister                 Publications of the South African Institute
                               for Medical Research, No. 2, 1913.
  35. Lister                 Publications of the South African Institute
                               for Medical Research, No. 8, 1916.
  36. Lister                 Publications of the South African Institute
                               for Medical Research, No. 10, 1917.
  37. Cecil and Austin       Jour. Exper. Med., 1918; xxviii, p. 19.
 37a. Cecil and Vaughan      Jour. Exper. Med., 1919; xxix, p. 457.
  38. Bloomfield             Johns Hopkins Bull., 1919; xxx, p. 1.
  39. Capps                  War Med., Vol. ii, p. 371.
 39a. Capps                  Jour. Amer. Med. Assoc., 1918; lxx, p. 910.
  40. Weaver                 Jour. Amer. Med. Assoc., 1918; lxx, p. 76.
  41. Weaver                 Jour. Amer. Med. Assoc., 1918; lxxi, p.
                               1405.
  42. Weaver                 Jour. Infect. Dis., 1919; xxiv, p. 218.
  43. Doust and Lyon         Jour. Amer. Med. Assoc., 1918; lxxi, p.
                               1216.
  44. Haller and Colwell     Jour. Amer. Med. Assoc., 1918; lxxi, p.
                               1213.
  45. Leete                  Lancet., 1919; i, p. 392.
  46. Dannenberg             Jour. Amer. Med. Assoc., 1918; lxx, p. 99.
  47. Mink                   Jour. Amer. Med. Assoc. 1918; lxxi, p.
                               2175.
  48. Vaughan                Jour. Amer. Med. Assoc., 1918; lxxi, p.
                               2100.
  49. Copeland               Jour. Amer. Med. Assoc., 1918; lxxi, p.
                               2173.
  50. Lynch and Cummings     Jour. Amer. Med. Assoc., 1918; lxxi, p.
                               2174.
  51. Amer. Med. Association Public Health Report, 1919; xxxiv, p. 1413.
  52. Le Moignie and Pinoy   Compt. rendu. Soc. Biol., 1916; lxxix, pp.
                               201 and 352.
 52a. Wright and Douglas     Proc. Royal Soc. Med., 1904; lxxiii, p.
                               128, and lxxiv, p. 147.
  53. Neufeld and Rimpau     Zeitschr. f. Hyg., 1905; li, p. 283.
  54. Rosenau                Prevent. Med. and Hyg., 1918.
  55. Brown, Palfrey and     Jour. Amer. Med. Assoc., 1919; lxxii, p.
        Hart                   463.
  56. Gay                    Typhoid fever. (Published by Macmillan Co.,
                               1918.)
  57. Eyre and Low           Lancet. I, April 5, 1919; p. 557.




   PHYSIOLOGICAL AND PHYSIOLOGICAL CHEMICAL OBSERVATIONS IN EPIDEMIC
                               INFLUENZA

                    By C. C. GUTHRIE, PH. D., M. D.


The material consisted of cases in the acute stage of epidemic influenza
with and without clinical pulmonary involvement (alveolar); of
convalescents, and of normal individuals without influenzal history.

It was hoped that it would be possible to follow selected cases over
considerable time periods, observation to compromise coordinated
clinical as well as laboratory data, but the exigencies of the situation
rendered this impossible. Unfortunately, this limits the value of the
studies. But since similar observations were made on cases ranging from
normal to the gravest severity—in fact, preceding death but a few hours
in some instances—and from the nature of the findings, certain
conclusions are clearly warranted.

It is regrettable that the data on certain points is not more extensive,
and particularly that other methods of observation were not employed. As
an example of the latter, measurements and analyses of expired air may
be given, as this was planned from the beginning and unsuccessful
efforts made to provide the required apparatus. In view, however, of the
circumstances of the investigation, it is felt that the studies made
are, on the whole, reasonably comprehensive and complete. And it is only
fair here to acknowledge that this was rendered possible by the cordial
and practical support of the Medical School, the military authorities,
the director of the laboratories, clinical colleagues, particularly Dr.
W. W. G. Maclachlan, and last, but not of less importance, of the
members of the department who made the studies.

In presenting the results, it is deemed most expedient and practical to
omit extensive tabulations and to summarize the data under each subject.

From the report it will be obvious that certain studies were in
preliminary stages at the termination of the investigation. This was due
in certain instances to the lateness of their undertaking, or time
consumed in providing essential equipment and methods; or to
disappearance of suitable cases due to waning of the epidemic.


                                RESULTS


                             _Circulation_

For the most part, cases showing marked clinical symptoms were studied.
The pulse in severe cases frequently was weak and rapid but regular. In
some cases it was less rapid than the clinical state would seem to
indicate.

_Arterial Blood Pressure_ was low; systolic pressure in severe cases
ranging downward from 95, and diastolic down to 40 or under. In patients
in early stages of convalescence the pressure showed a marked advance
toward normal levels. Arterial blood pressure seemed a reliable general
index of the condition of the patient.

_Venous Blood Pressure._—The observations included patients who a few
hours later expired. The Von Recklinghausen method was used. No marked
abnormality was observed, so other methods of observation were deemed
superfluous.


                             _Respiration_

In severe cases, frequently it was rapid and of shallow character; but,
like the pulse, often it was less rapid than the clinical state would
seem to indicate.

_Cyanosis_ of dark hue and marked degree was prevalent in the earlier
severe cases, and in some cases appeared entirely out of proportion to
the state of circulation and respiration and to the post-mortem findings
as reported by Dr. Klotz.


                                _Blood_

Hemorrhage being not uncommon, the blood was tested for coagulability,
but in this respect no marked departure from the normal range was noted.

_Coagulation._—Coagulation time was observed by stirring blood in a test
tube with a wire and noting the time of the appearance of fibrin and by
means of a Biffi-Brooks coagulimeter. The extreme ranges observed were
from 2½ to 5½ minutes. The average by defibrination was 3 minutes and 36
seconds, and by the Biffi-Brooks method 4 minutes and 38 seconds.

_Red Corpuscles._—Osmotic resistance. A number of bloods were examined
by observing their resistance to osmotic laking by exposure to a series
of hypotonic sodium chloride solutions. Though some differences were
observed, from the evidence obtained, it is not permissible to conclude
that such variations were constant or of a significant magnitude.

_Color_ on exposure to air. It was early observed that venous blood from
cyanotic patients was very slow to take on arterial hue on exposure to
air.

_Plasma Bicarbonate._—The plasma bicarbonate was determined in seven
cases by Miss Waddell by the method of Van Slyke and Cullen. In all
except one of these the results were within the normal range as given by
Van Slyke. Three were in the lower normal range, being 54.1, 55.1 and
60.5 respectively, expressed in terms of cubic centimeters of CO_{2}
reduced to 0°, 760 mm. Hg. pressure, bound as bicarbonate by 100 c.cm.
of plasma. Three were in the median range, being 64, 65.5 and 71 c.cm.
In one case the bicarbonate CO_{2} was reduced to 46.6 c.cm.

There seemed to be no constant relation between the apparent severity of
the clinical condition of the patient and the bicarbonate reading. In
the one case in which this was found to be reduced below Van Slyke’s
lower normal limit the blood was taken only a few hours before death.

_Hemoglobin Per Cent._—As determined by the Sahli hemoglobinometer (by
Miss Lee) and as estimated by the total oxygen capacity (Van Slyke
method) (by Dr. Rohde and Mrs. Macklin), the hemoglobin content ranged
within normal levels.

_Relative Volume of Corpuscles._—A limited number of hematokrit tests on
severe cases gave results in normal levels.

_Spectroscopic Studies._—Sera obtained from 20 post-mortem bloods were
examined spectroscopically. In eight an absorption band in the red was
observed. In some instances such a band was observed in blood obtained
shortly after death and before coagulation had occurred, while other
similar bloods, as well as bloods obtained at longer intervals after
death, exhibited no such band. A similar band was observed in one case
from blood obtained from a patient about 12 hours before death from
pneumonia following influenza. Medication was not a causative factor. To
ammonium sulphide the band in the red reacted as methemoglobin and the
position (as estimated by Dr. Menten) corresponded with methemoglobin.
Oxyhemoglobin bands in such bloods occupied normal positions as
determined by Dr. Menten. On diluting such bloods with water no
abnormality in character or position bands was observed, save in one
instance (No. 778 below). This does not, however, disprove the
possibility of such abnormality in the hemoglobin within the cells, for
moderate dilution only of serum rendered the band in the red invisible,
presumably by dilution.

  Detailed examination of the absorption bands was made with a direct
  reading wave-length Hilger Spectroscope (which was calibrated by
  line spectra derived from salts added to an alcohol flame) by Dr.
  Menten. This spectroscope had an accuracy of about two Angstroms. In
  all, seven post-mortem bloods were examined, viz. autopsy numbers
  756, 761, 763, 773, 778, 784, and 787. In five of these, sufficient
  serum was obtained to make readings. All gave the two characteristic
  oxyhemoglobin bands in the blue-green with centers of the bands at λ
  758μμ λ and 542μμ. The second oxyhemoglobin band varied slightly in
  width in the different samples. In addition to the two oxyhemoglobin
  bands in each of four of the above sera, viz: Nos. 756, 763, 767 and
  787, an absorption band in the red was found with the center of the
  band as follows: Number 756 at λ 627μμ, number 761 at λ 634μμ,
  number 763 at λ 625μμ, and number 787 at λ 634μμ. These bands varied
  considerably in intensity and could only be identified when the two
  oxyhemoglobin bands were merged and appeared as one broad band. As
  controls for the position of the oxyhemoglobin bands two normal
  bands were examined, which showed two bands with centers also at λ
  758μμ and λ 543μμ. For comparison of the methemoglobin bands of the
  above post-mortem bloods, a sample of this hemoglobin compound was
  made by adding potassium ferricyanide to normal blood until the
  solution became brownish in color. The center of this methemoglobin
  band was found at λ 634μμ. In blood from autopsies number 773 and
  number 778 sufficient serum could not be obtained to make a reading.
  To each of these bloods distilled water was added. The laked blood
  of 778 gave a methemoglobin band with the center at λ 632μμ on
  examination 24 hours after autopsy. Similar treatment of corpuscles
  five days subsequently gave no indication of the presence of any
  methemoglobin spectroscopically.

  From the serum and from the laked corpuscles of number 784 no trace
  of methemoglobin was found when the blood was examined a few hours
  after removal at autopsy.

_Oxygen Capacity._—The total oxygen capacity was determined by the Van
Slyke method (by Dr. Rohde and Mrs. Macklin). At this stage the more
pronounced type of influenza had subsided, but in early convalescence
the capacity was within normal ranges.

Other studies using different technique gave concordant results, but
there were indications that oxygen was more slowly absorbed than
normally.

_Oxygen Content of Venous Blood_ measured by the Van Slyke method (by
Dr. Rohde and Mrs. Macklin) on the same bloods examined for total oxygen
capacity seemed to indicate a mild deficiency as compared to normal
bloods.

_Gases, Kinds, Quantity and Rate Yielded to Vacuum._—In general it may
be said that quantitative differences observed are not considered
fundamental, but that the studies indicate abnormal slowness in oxygen
absorption.

_Gases, Quantity and Rate of Absorption on Exposure to Air After
Extraction by Pump._—The results emphasize slowness of oxygen absorption
as compared to normal blood.

  The material to be examined was exhausted for three minutes in the
  receiver of the Van Slyke apparatus. One c.cm. was then transferred,
  with as little exposure to air as possible, to a small empty bottle,
  which was then closed and placed in communication with a calibrated,
  horizontal tube, containing a segment of alcohol, which served the
  dual purpose of a seal and an air volume change indicator. (See Fig.
  1.) The apparatus was made in duplicate and mounted on a common
  base, so that simultaneous readings on different samples could be
  made. After establishing the zero position of the alcohol segment,
  the base on which the bottles were mounted was vigorously shaken in
  a uniform manner. Ten seconds after the period of shaking, the
  volume readings were taken. Successive periods of shaking and
  reading were conducted at 30-second intervals, until the test was
  completed. Actual volume changes were then calculated, tabulated and
  plotted.

  The greater confidence is placed on the results obtained by
  observing the color of the blood, as described below; but since then
  the method has been checked up and the results indicate that the
  findings were of sufficient accuracy to warrant their inclusion in
  this report.[1]

Footnote 1:

  Studies along this line are being made with improved apparatus, the
  results of which, together with the description of the apparatus, will
  be published elsewhere. (See Am. Gr. Physiol., 1920, li, 195.)

[Illustration: FIG. 1.]

_Effect of Addition of Serum on Behavior on Exposure to Air._—The
persistence of venous hue of blood exposed to air was noted above. It
was observed that the addition of serum from the same blood
conspicuously shortened the time required for such blood to acquire an
arterial hue. The addition of normal serum was more effective in this
respect than pathological serum. Measurements of the rate of absorption
of such blood after the addition of serum indicated acceleration of
oxygen absorption. From this it would seem that the oxygen transmitting
capacity of the serum was diminished.

_Effect of Addition of Dry Sodium Bicarbonate on Behavior on Exposure to
Air._—The addition of a small quantity of dry sodium bicarbonate to a
blood refractory to arterialization on exposure to air enormously
accelerated the process, as judged by the color. To what extent the
change in color may have been due to causes other than oxygen absorption
was not determined.


                               _Comment_

The most significant positive findings were evidence of deficiency of
serum oxygen transmitting capacity or rate, and the detection in serum
of an absorption band in the red corresponding to methemoglobin. The
presence of the abnormal substance giving rise to the absorption band is
considered of special interest as indicating abnormal chemical
conditions in the blood, rather than material change in hemoglobin
oxygen capacity.




THE BACTERIOLOGY OF EPIDEMIC INFLUENZA WITH A DISCUSSION OF B. INFLUENZÆ
           AS THE CAUSE OF THIS AND OTHER INFECTIVE PROCESSES

                     By W. L. HOLMAN, B. A., M. D.


                             _Introduction_

In a study of the bacteriology of a respiratory disease such as
influenza, the technical difficulties encountered are very great and
must be overcome before we can draw useful conclusions from the results
obtained or attempt to determine the etiological factors. The important
methods of attacking such a problem include: (1) the study of stained
smears and cultures from the various available materials, along with the
demonstration of the bacteria in the lesions found in the disease by a
study of sections; (2) tests with the various materials to determine the
presence of the causative agent, which includes experiments on man and
animals and is more inclusive than the mere study of the bacteria
isolated; (3) immunological studies of man suffering from the disease,
or of man and animals treated with the materials from the disease; (4)
pathological, clinical and epidemiological studies linked with the
above.

Many of the difficulties and sources of error in these methods are
manifest to all, but certain points may be indicated as more important
in the phases of the work on which I am to report.


                   _General Methods of Investigation_

Stained smears from the material available. The choice of the material
is of first importance. Sputum to be of any real value must be obtained
from the deeper portions of the respiratory tract, should be as free as
possible from the secretions of the buccal cavity, and should be washed
in saline before it is used. These are considered among the first
requirements in the study of lung infections by the pneumococci and are
equally important in influenza. Swabs from the nasopharynx should be
obtained with the same precautions as are demanded in meningococcal
work. The other available material—such as blood, lung puncture fluid,
pleural fluid and spinal fluid—must be collected with the greatest care.

The staining methods should, naturally, include those which will bring
out the various types of bacteria, and must include the Gram method,
using dilute alcoholic fuchsin (1-20) as the counterstain. The varying
morphology of the B. influenzæ and its frequent minute size make it
difficult to detect. It is not the only Gram negative small bacillus
seen in smears from the throat, but when it occurs in the typical
schools, or where there are numerous bacilli to be seen, its
characteristics are quite definite. I have recently isolated an anærobic
Gram negative bacillus from a series of swabs from the buccal cavity
which suggests in many ways the morphology of the B. influenzæ, which
will indicate one of the many difficulties to be met with in the study
of stained smears. They are, nevertheless, of great use as a control on
cultures, and most helpful in the study of the material from sources
other than the respiratory tract.

Cultures of the bacteria from the various materials. Here we have the
greatest difficulty of all. The medium chosen determines the bacteria
which will appear to predominate, and there is no single medium that
will answer all purposes. Streptococci will appear to be in excess when
serum broth is used, as I have previously shown; pneumococci with
Avery’s pneumococcus medium; and staphylococci, the Gram negative cocci,
and the diphtheria group with Loeffler’s serum. Ordinary blood agar is
perhaps the best general medium for direct and secondary plating. There
have been many special media devised for growing the B. influenzæ, but
the one I have used most and found particularly helpful is heated blood
agar made after the general method of Voges.

The extremely tiny colony of B. influenzæ on ordinary blood agar makes
it particularly difficult to detect, and one is apt to get the wrong
impression of its numbers from the macroscopic appearance of the plate.
In attempts at isolation there must be a liberal use of media in picking
colonies, as many suspicious ones will turn out to be immature growths
of B. xerosis, M. pharyngis (or M. catarrhalis), streptococci, or more
rarely pneumococci and other organisms. Replating from such picks is
frequently necessary, and further plates, from the original culture on
heated blood agar, must often be made before the B. influenzæ can be
isolated. The care required in all stages of the isolation of this
organism, the unstinted use of media for plating and for picks, the
number of stained smears to be studied, and the further transfers
necessary to verify results, all these limit the amount of material
which can be studied with any degree of accuracy. If further the
streptococci, the pneumococci, the Gram negative cocci, the capsulated
Gram negative bacilli and many others are to receive any attention, it
can readily be appreciated that a few cases carefully studied are of far
more value than a large number hurriedly examined in an uncertain
routine.

The pathological study of the same cases on which I have done the
bacteriology will be found in Dr. Klotz’s paper in these communications,
and I will merely refer to some of the bacterial findings in the
sections of the lungs and bronchi. The more inclusive methods which have
been used in attempts to determine the etiological factor in influenza
we have been unable to attempt, but I will refer later in this paper to
the findings of the investigations of others. Immunological studies have
been limited to a few investigations on the presence of agglutinins,
complement binding substance, skin reactions and the amount of
complement present in the sera of certain patients. The epidemiological
and clinical studies are reported by Drs. Johnston and Lichty in this
series of reports.


                           _Material Studied_

The material used in the study I am reporting included swabs from the
large bronchi and fluid from the lungs and pleural cavities of 32
autopsies, as well as blood cultures from 22 patients and swabs from the
nasopharynx of 31 individuals. Fifteen sera were tested for fixation of
complement with an antigen made from several strains of B. influenzæ.
Fourteen other sera were tested for agglutinins. Complement content was
determined in the sera of 25 patients. Skin tests after the Von Pirquet
method were done on 14 convalescents, and carefully stained
nasopharyngeal smears without cultures were studied from 48 patients.

The chief attention was given to the study of the autopsy material and
we concentrated on the isolation of B. influenzæ. At the same time we
did not neglect the other bacteria making up the flora of the bronchi,
lungs and pleural cavity in these cases. The various types were isolated
and most of them fully identified.


                              _Technique_

Direct smears were made on sterile slides of all material studied and
stained by Gram’s method. The counterstain was always alcoholic fuchsin
diluted 1-20 in distilled water. Direct cultures were made on a human
blood agar plate containing 5 per cent. blood, which was further smeared
just before use with defibrinated blood. This latter procedure was later
discarded, as it did not appear to assist to any marked extent the
growth of B. influenzæ. Blood broth containing a few drops of
defibrinated blood and blood agar slants smeared with blood were also
used. Heated blood agar (2-3 c.cm. of defibrinated human blood added to
100 c.cm. of ordinary agar at a temperature of from 90 to 100° C., or as
the agar comes from the sterilizer) was used in the last nine cases to
replace the blood agar slant in the direct cultures and as the medium of
choice for transfers of the B. influenzæ.

I prefer the ordinary blood agar plate to the heated blood plate because
the former gives readings which are very helpful in distinguishing
colonies of various types. B. influenzæ appears as clear, tiny,
pinpoint, inert colonies. B. xerosis or the pseudodiphtheria group gives
more opaque but often rather similar colonies. Gram negative cocci as M.
pharyngis siccus have dry, raised, soon becoming wrinkled, inert
colonies, varying greatly in size; M. catarrhalis, more moist, inert
colonies. The cocci of the streptococcus viridans group appear as very
small colonies with greening, or are not infrequently inert, while thin,
flattened colonies with central thickening may sometimes be noted. Those
of the streptococcus hemolyticus group occur as small, frequently
nipple-like colonies with clear, wide zones of hemolysis; pneumococci as
moderately small, moist, dewdrop-like colonies with center collapsing
early and with greening; streptococcus or pneumococcus mucosus as
larger, watery, sticky colonies with greening and frequently an early
clearing near the colonies.


                                TABLE I.

       BACTERIOLOGY OF THIRTY-TWO AUTOPSIES FROM INFLUENZA CASES.

 ───────┬─────┬───────────┬─────┬──────────────────┬─────────────────────
 AUTOPSY│DATE.│  DAY OF   │HOURS│      DIRECT      │    B. INFLUENZÆ
 NUMBER.│     │ DISEASE.  │P.M. │   SMEAR—GRAM’S   │
        │     │           │     │     METHOD.      │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┬─────┬───────
        │     │           │     │                  │BRONCH.│LUNG.│PLEURAL
        │     │           │     │                  │       │     │FLUID.
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     741│ 1918│          3│   16│G +staph. Few     │   0   │  +  │   0
        │ Oct.│           │     │  pneumo-like. Few│       │     │
        │    9│           │     │  chains of elong.│       │     │
        │     │           │     │  cocci.          │       │     │
        │     │           │     │                  │       │     │
        │     │           │     │                  │       │     │
        │     │           │     │                  │       │     │
        │     │           │     │                  │       │     │
        │     │           │     │                  │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     743│   11│          5│    8│Br. G—bac. from   │   +   │  0  │   –
        │     │           │     │  coccoid to short│       │     │
        │     │           │     │  threads. Mostly │       │     │
        │     │           │     │  scattered. Some │       │     │
        │     │           │     │  phagocyted.     │       │     │
        │     │           │     │  Fewer G +cooci  │       │     │
        │     │           │     │  in short chains.│       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     744│   11│          7│   11│Br. G—bac.        │   +   │  –  │   0
        │     │           │     │  moderately stout│       │     │
        │     │           │     │  about in small  │       │     │
        │     │           │     │  groups and      │       │     │
        │     │           │     │  scattered.      │       │     │
        │     │           │     │  G+diploc        │       │     │
        │     │           │     │  (pneumo) also G—│       │     │
        │     │           │     │  threads. Phago. │       │     │
        │     │           │     │  of both in a few│       │     │
        │     │           │     │  cells.          │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     745│   12│         10│    6│Br. G +—large     │   +   │  0  │  ––
        │     │           │     │  bac., strept.   │       │     │
        │     │           │     │  short, G—B, few,│       │     │
        │     │           │     │  very short, no  │       │     │
        │     │           │     │  threads.        │       │     │
        │     │           │     │                  │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     746│   12│          5│    ½│Br. G—B very      │   +   │  –  │   0
        │     │           │     │  short, no       │       │     │
        │     │           │     │  threads.        │       │     │
        │     │           │     │  Irregularly     │       │     │
        │     │           │     │  scattered. More │       │     │
        │     │           │     │  seen in left    │       │     │
        │     │           │     │  bronchus. A few │       │     │
        │     │           │     │  cells           │       │     │
        │     │           │     │  phagocyted.     │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     747│   13│          6│    3│Br. G+diploc,     │   +   │  –  │   –
        │     │           │     │  fairly numerous.│       │     │
        │     │           │     │  G—B tiny, as    │       │     │
        │     │           │     │  diplos and in   │       │     │
        │     │           │     │  long threads    │       │     │
        │     │           │     │  scattered or in │       │     │
        │     │           │     │  small groups.   │       │     │
        │     │           │     │  Pleural fluid   │       │     │
        │     │           │     │  and lung no     │       │     │
        │     │           │     │  bacteria seen.  │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     748│   13│          4│    4│Br. nothing like  │   –   │  +  │   0
        │     │           │     │  B. I. seen. G+  │       │     │
        │     │           │     │  small elong.    │       │     │
        │     │           │     │  diplo. Numerous │       │     │
        │     │           │     │  G + diploc. in  │       │     │
        │     │           │     │  lung.           │       │     │
        │     │           │     │  Comparatively   │       │     │
        │     │           │     │  few Q-B, very   │       │     │
        │     │           │     │  short.          │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     749│   14│          4│   15│Br. G+large pneumo│   –   │  –  │   0
        │     │           │     │  like, many      │       │     │
        │     │           │     │  G+large bacilli,│       │     │
        │     │           │     │  single and in   │       │     │
        │     │           │     │  pairs. Few G—B  │       │     │
        │     │           │     │  very tiny and   │       │     │
        │     │           │     │  widely          │       │     │
        │     │           │     │  scattered; lung,│       │     │
        │     │           │     │  heavy mixture as│       │     │
        │     │           │     │  in bronchi.     │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     750│   14│          9│    6│Br. G+B large like│   –   │  –  │   0
        │     │           │     │  B. welchii,     │       │     │
        │     │           │     │  G—rather stout  │       │     │
        │     │           │     │  coccoid forms,  │       │     │
        │     │           │     │  G+C in pairs and│       │     │
        │     │           │     │  short chains.   │       │     │
        │     │           │     │  Tiny G—coccoid  │       │     │
        │     │           │     │  forms like B. I.│       │     │
        │     │           │     │  Lung G+         │       │     │
        │     │           │     │  pneumo-like and │       │     │
        │     │           │     │  caps, chains; no│       │     │
        │     │           │     │  B. I.           │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     751│   14│          7│    6│Br. G +cocci large│   –   │  –  │   +
        │     │           │     │  elong.? caps,   │       │     │
        │     │           │     │  also G +C in    │       │     │
        │     │           │     │  flat pairs.     │       │     │
        │     │           │     │  G—coccoid forms.│       │     │
        │     │           │     │  Lung, numerous  │       │     │
        │     │           │     │  bacteria.       │       │     │
        │     │           │     │  G+strept. with  │       │     │
        │     │           │     │  flattened cocci.│       │     │
        │     │           │     │  Some G-short    │       │     │
        │     │           │     │  forms?          │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     752│   15│         13│   15│Br. G+pneumo-like.│   –   │  +  │   0
        │     │           │     │  G+B smaller than│       │     │
        │     │           │     │  B. welchii,     │       │     │
        │     │           │     │  occasionally    │       │     │
        │     │           │     │  tiny G          │       │     │
        │     │           │     │  -diplobacillus. │       │     │
        │     │           │     │  Lung, G+chains  │       │     │
        │     │           │     │  of cocci Gram   │       │     │
        │     │           │     │  weak. Few G—tiny│       │     │
        │     │           │     │  bacilli         │       │     │
        │     │           │     │  scattered or in │       │     │
        │     │           │     │  groups.         │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     756│   16│          8│   18│Br. numerous G+B. │   –   │  0  │   –
        │     │           │     │  B welchii like. │       │     │
        │     │           │     │  G—B large and   │       │     │
        │     │           │     │  few tiny.       │       │     │
        │     │           │     │  G+round diploc. │       │     │
        │     │           │     │  Pl. fluid almost│       │     │
        │     │           │     │  pure            │       │     │
        │     │           │     │  pneumo-like, few│       │     │
        │     │           │     │  G-forms probably│       │     │
        │     │           │     │  the same.       │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     757│   16│          6│   14│Br. G—B tiny, to  │   +   │  +  │   0
        │     │           │     │  medium. G—like  │       │     │
        │     │           │     │  M. catarrhalis. │       │     │
        │     │           │     │  G+cocci, pairs  │       │     │
        │     │           │     │  and chains. Few │       │     │
        │     │           │     │  B. W. like.     │       │     │
        │     │           │     │  Lung, many G—B  │       │     │
        │     │           │     │  like B. I. Some │       │     │
        │     │           │     │  cells filled,   │       │     │
        │     │           │     │  also G—cocci. M.│       │     │
        │     │           │     │  catarrhalis like│       │     │
        │     │           │     │  and rare B.     │       │     │
        │     │           │     │  welchii like.   │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     758│   16│         14│   16│Br. pneumo-like in│   +   │  ?  │   0
        │     │           │     │  excess. G—B from│       │     │
        │     │           │     │  tiny to forms   │       │     │
        │     │           │     │  stouter than B. │       │     │
        │     │           │     │  I. Few strept.  │       │     │
        │     │           │     │  rare M.         │       │     │
        │     │           │     │  catarrhalis.    │       │     │
        │     │           │     │  Lung,           │       │     │
        │     │           │     │  pneumo-like.    │       │     │
        │     │           │     │  Phago.          │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     761│   17│          7│   19│Br. pneumo-like.  │   +   │  –  │   0
        │     │           │     │  B. I. like      │       │     │
        │     │           │     │  common, M.      │       │     │
        │     │           │     │  catarrhalis     │       │     │
        │     │           │     │  like. Both B.I. │       │     │
        │     │           │     │  and M.          │       │     │
        │     │           │     │  catarrhalis     │       │     │
        │     │           │     │  phagocyted. B.I.│       │     │
        │     │           │     │  single or in    │       │     │
        │     │           │     │  threads. Some   │       │     │
        │     │           │     │  typical groups. │       │     │
        │     │           │     │  Lung, pneumo,   │       │     │
        │     │           │     │  caps, rare, M.  │       │     │
        │     │           │     │  catarrhalis     │       │     │
        │     │           │     │  like.           │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     762│   17│         10│   12│Br. numerous B.l. │   +   │  +  │   +
        │     │           │     │  like typical,   │       │     │
        │     │           │     │  also many       │       │     │
        │     │           │     │  pneumo. and M.  │       │     │
        │     │           │     │  catarrh. Lung   │       │     │
        │     │           │     │  same. M.        │       │     │
        │     │           │     │  catarrh.        │       │     │
        │     │           │     │  phagocyted. B.I.│       │     │
        │     │           │     │  smear, many     │       │     │
        │     │           │     │  phagocyted, many│       │     │
        │     │           │     │  pneumo.         │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     763│   17│         11│   13│Lung, pneumo-like,│   0   │  –  │   –
        │     │           │     │  slight          │       │     │
        │     │           │     │  phagocytosis.   │       │     │
        │     │           │     │  Pl. fl., pneumo │       │     │
        │     │           │     │  and few strept.,│       │     │
        │     │           │     │  slight          │       │     │
        │     │           │     │  phagocytosis.   │       │     │
        │     │           │     │                  │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     764│   17│          9│    6│Br. B.I. smear.   │   +   │  0  │   0
        │     │           │     │  Cells crowded.  │       │     │
        │     │           │     │  Pneumo-like     │       │     │
        │     │           │     │  fewer,          │       │     │
        │     │           │     │  occasional      │       │     │
        │     │           │     │  G—stouter       │       │     │
        │     │           │     │  thread.         │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     765│   17│          9│   16│Br. pneumo. B.I.  │   +   │  +  │   0
        │     │           │     │  few scattered.  │       │     │
        │     │           │     │  G+flattened     │       │     │
        │     │           │     │  diploc. Phago.  │       │     │
        │     │           │     │  of B.I. and     │       │     │
        │     │           │     │  pneumo. Lung,   │       │     │
        │     │           │     │  pneumo-like,    │       │     │
        │     │           │     │  rare strept.    │       │     │
        │     │           │     │  very            │       │     │
        │     │           │     │  questionable G—B│       │     │
        │     │           │     │  free and in     │       │     │
        │     │           │     │  cells.          │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     767│   18│         10│   14│Br. rather round  │   –   │  –  │   0
        │     │           │     │  pneumo-like with│       │     │
        │     │           │     │  caps. B.I. few. │       │     │
        │     │           │     │  Scattered, also │       │     │
        │     │           │     │  in cells. Lung, │       │     │
        │     │           │     │  few bacteria.   │       │     │
        │     │           │     │  G+strep. often  │       │     │
        │     │           │     │  phagocyted.     │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     770│   19│         11│    9│Br. crowded with  │   +   │  +  │   –
        │     │           │     │  B.I. like. Few  │       │     │
        │     │           │     │  G+cocci and     │       │     │
        │     │           │     │  fewer M.        │       │     │
        │     │           │     │  catarrh. like.  │       │     │
        │     │           │     │  Pl. fluid       │       │     │
        │     │           │     │  G+flattened     │       │     │
        │     │           │     │  pairs, pus      │       │     │
        │     │           │     │  cells,          │       │     │
        │     │           │     │  phagocyted.     │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     773│   21│         20│    3│Br. few bacteria  │   –   │  –  │   –
        │     │Recurrence.│     │  G+and           │       │     │
        │     │           │     │  G—pneumo-like.  │       │     │
        │     │           │     │  Rare G+—thread. │       │     │
        │     │           │     │  Lung, pneumo and│       │     │
        │     │           │     │  rare strept. Pl.│       │     │
        │     │           │     │  fluid,          │       │     │
        │     │           │     │  pneumo-oat      │       │     │
        │     │           │     │  shapes, etc.    │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     778│   24│         23│   17│Br. B.I. smear.   │   +   │  +  │   –
        │     │           │     │  Fewer large     │       │     │
        │     │           │     │  pneumo. Lung, G │       │     │
        │     │           │     │  + small diploc. │       │     │
        │     │           │     │  Few B.I. like.  │       │     │
        │     │           │     │  Pl. fluid, few  │       │     │
        │     │           │     │  cells, no       │       │     │
        │     │           │     │  bacteria.       │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     781│   26│          5│    4│Br. crowded with  │   –   │  +  │   –
        │     │           │     │  staph. like.    │       │     │
        │     │           │     │  Fewer G—B,      │       │     │
        │     │           │     │  larger than     │       │     │
        │     │           │     │  B.I., few M.    │       │     │
        │     │           │     │  catarrhalis     │       │     │
        │     │           │     │  like. Lung G+   │       │     │
        │     │           │     │  small staph.    │       │     │
        │     │           │     │  like, caps,     │       │     │
        │     │           │     │  cocci in pairs  │       │     │
        │     │           │     │  and chains. Few │       │     │
        │     │           │     │  tiny G—B. Pl.   │       │     │
        │     │           │     │  fluid           │       │     │
        │     │           │     │  pneumo-like and │       │     │
        │     │           │     │  elong. cocci in │       │     │
        │     │           │     │  chains          │       │     │
        │     │           │     │  capsulated.     │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     782│   26│          8│    3│Br. numerous B.I. │   +   │  –  │   0
        │     │           │     │  like scattered, │       │     │
        │     │           │     │  some phagocyted.│       │     │
        │     │           │     │  Fewer G+ flat   │       │     │
        │     │           │     │  pairs with      │       │     │
        │     │           │     │  capsule.        │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     783│   26│          8│    1│Br. G+small caps, │   +   │  –  │   0
        │     │           │     │  pneumo-like.    │       │     │
        │     │           │     │  Lung poor smear,│       │     │
        │     │           │     │  occasional      │       │     │
        │     │           │     │  pneumo-like.    │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     784│   28│          8│    6│Br. capsulated    │   +   │  +  │   0
        │     │           │     │  pneumo-like, few│       │     │
        │     │           │     │  strep. Lung,    │       │     │
        │     │           │     │  chiefly         │       │     │
        │     │           │     │  pneumo-like. few│       │     │
        │     │           │     │  G—B like B.I.,  │       │     │
        │     │           │     │  also            │       │     │
        │     │           │     │  G—pneumo-like.  │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     786│   29│          4│    2│Br. G+cocci in    │   +   │  –  │   0
        │     │           │     │  round pairs and │       │     │
        │     │           │     │  rather flat     │       │     │
        │     │           │     │  chains,         │       │     │
        │     │           │     │  suggested caps. │       │     │
        │     │           │     │  Tiny G—B very   │       │     │
        │     │           │     │  rare. Lung      │       │     │
        │     │           │     │  streptococci    │       │     │
        │     │           │     │  flattened, often│       │     │
        │     │           │     │  phagocyted.     │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     787│   29│          8│    2│Br. numerous      │   +   │  +  │   0
        │     │           │     │  pneumo-like,    │       │     │
        │     │           │     │  bacillary forms.│       │     │
        │     │           │     │  A rare          │       │     │
        │     │           │     │  suspicious B.I. │       │     │
        │     │           │     │  like, some of   │       │     │
        │     │           │     │  these in cells. │       │     │
        │     │           │     │  Lung, caps,     │       │     │
        │     │           │     │  elongated       │       │     │
        │     │           │     │  diplos, and     │       │     │
        │     │           │     │  chains of elong.│       │     │
        │     │           │     │  cocci.          │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     791│ Nov.│          6│    6│Br. few bacteria. │   +   │  +  │   –
        │    1│           │     │  G+pneumo-like   │       │     │
        │     │           │     │  round, G—B and  │       │     │
        │     │           │     │  threads, size   │       │     │
        │     │           │     │  varies, like    │       │     │
        │     │           │     │  B.I. Lung, G +  │       │     │
        │     │           │     │  caps, pneumo.   │       │     │
        │     │           │     │  G+Large B. few  │       │     │
        │     │           │     │  suspicious      │       │     │
        │     │           │     │  G—coccoid forms.│       │     │
        │     │           │     │  Pl. fl. caps,   │       │     │
        │     │           │     │  pneumo and caps,│       │     │
        │     │           │     │  elong. chains.  │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     792│    2│          6│    3│Br. caps,         │   +   │  +  │   –
        │     │           │     │  pneumo-like bac.│       │     │
        │     │           │     │  forms and       │       │     │
        │     │           │     │  chains. G-caps, │       │     │
        │     │           │     │  pneumo-like. Few│       │     │
        │     │           │     │  G—B.            │       │     │
        │     │           │     │  questionable.   │       │     │
        │     │           │     │  Lung. caps,     │       │     │
        │     │           │     │  pairs and chains│       │     │
        │     │           │     │  of elong. cocci,│       │     │
        │     │           │     │  in cells. Pl.   │       │     │
        │     │           │     │  fluid, numerous │       │     │
        │     │           │     │  caps, chains of │       │     │
        │     │           │     │  diploc.         │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
     793│    4│         10│  3/2│Br. M. catarrh.   │   –   │  –  │   –
        │     │           │     │  and G+cocci, few│       │     │
        │     │           │     │  bacteria, few   │       │     │
        │     │           │     │  G—B. Ear,       │       │     │
        │     │           │     │  G+cocci.        │       │     │
        │     │           │     │                  │       │     │
 ───────┼─────┼───────────┼─────┼──────────────────┼───────┼─────┼───────
        │     │           │     │      Total       │  20   │ 13  │   2
        │     │           │     │B. influenzæ      │  66½  │ 46  │  14
        │     │           │     │  found—Percentage│       │     │
        │     │           │     │                  │  ———  │ ——— │  ———
        │     │           │     │Total percentage  │       │ 78  │%
        │     │           │     │  for B. influenzæ│       │     │
 ───────┴─────┴───────────┴─────┴──────────────────┴───────┴─────┴───────

 ───────┬───────────┬─────────┬─────────┬─────────┬────────────────
 AUTOPSY│PNEUMCOCCI.│ STREPT. │HEMOLYTIC│ S.P.A.  │  OTHER COCCI.
 NUMBER.│           │MOCOCCI. │ STREPT. │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     741│           │         │         │+        │G+ diploc.
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     743│           │Pleural  │         │         │Br. G + diploc.
        │           │fluid and│         │         │not like pneumo.
        │           │seen as  │         │         │
        │           │diplos in│         │         │
        │           │direct   │         │         │
        │           │smear.   │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     744│Lung +     │         │         │         │M. tetrag. in
        │           │         │         │         │Br. M. pharyng.
        │           │         │         │         │in Br.
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     745│           │         │Pleural  │Pl.      │
        │           │         │fluid,   │fluid,   │
        │           │         │also seen│also seen│
        │           │         │in smear.│in       │
        │           │         │         │smears.  │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     746│           │         │         │         │Strept. viridans
        │           │         │         │         │from bronchus.
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     747│           │         │         │Bronchus │Strept. viridans
        │           │         │         │and      │from bronchi and
        │           │         │         │pleural  │lung.
        │           │         │         │fluid.   │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     748│Lung+, not │         │         │         │Strept. viridans
        │isolated   │         │         │         │from bronchus.
        │from       │         │         │         │
        │bronchus.  │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     749│Bronchus   │         │         │Bronchus │
        │Lung?      │         │         │and lung.│
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     750│Bronchus?  │         │         │         │
        │Lung?      │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     751│           │Pleura.  │         │         │M. tetragenous
        │           │Lung.    │         │         │from bronchus.
        │           │Bronchus.│         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     752│Bronchus   │         │         │         │Strep. viridans
        │and lung.  │         │         │         │from bronchus
        │           │         │         │         │and lungs.
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     756│           │         │         │Pleural  │Strep. viridans
        │           │         │         │fluid.   │from bronchus.
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     757│Bronchus   │         │         │Bronchus │M. tetragenous?
        │and lung.  │         │         │and lung.│from lung.
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     758│Bronchus   │         │         │         │M.
        │and lung.  │         │         │         │catarrhalia-like
        │           │         │         │         │from lung.
        │           │         │         │         │Strep. viridans
        │           │         │         │         │from lung and
        │           │         │         │         │bronchus.
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     761│Bronchus   │         │         │Bronchus │
        │and lung.  │         │         │and lung.│
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     762│Pleural    │         │         │         │M. catarrh. like
        │fluid and  │         │         │         │from lung and
        │bronchus.  │         │         │         │bronchus.
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     763│Pleural    │         │         │         │
        │fluid.     │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     764│Bronchus.  │         │         │         │Staph, albus
        │           │         │         │         │from bronchus.
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     765│           │         │Lung.    │         │M. catarrh. from
        │           │         │         │         │bronchus and
        │           │         │         │         │lung.
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     767│Bronchus.  │Lung.    │         │Bronchus.│
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     770│Bronchus.  │         │         │Bronchus,│
        │           │         │         │lung,    │
        │           │         │         │pleural  │
        │           │         │         │fluid.   │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     773│           │         │         │Bronchus.│Strept. viridans
        │           │         │         │         │bronchus.
        │           │         │         │         │Sarcina albus
        │           │         │         │         │lung.
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     778│Bronchus   │         │         │Lung.    │
        │and lung.  │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     781│           │Lung and │         │Bronchus │Staph. albus and
        │           │pleural  │         │and lung │sarcina from
        │           │fluid.   │         │abscess. │pleural fluid.
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     782│           │Bronchus │         │         │
        │           │and lung.│         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     783│Lung.      │         │         │Bronchus.│M. catarrh. like
        │           │         │         │         │bronchus.
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     784│Bronchus   │Bronchus │         │         │M. catarrh. like
        │and lung.  │and lung?│         │         │bronchus.
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     786│Bronchus.  │         │Bronchus │         │Staph, albus
        │           │         │and lung.│         │from bronchus.
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     787│           │         │         │Bronchus │
        │           │         │         │and lung.│
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     791│Bronchus   │         │         │Bronchus │
        │and pleural│         │         │and lung.│
        │cavity.    │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     792│Bronchus,  │         │         │         │Staph. albus,
        │lung and   │         │         │         │lung, strept.
        │pleural    │         │         │         │viridans lung,
        │fluid.     │         │         │         │M. catarrh. like
        │           │         │         │         │lung and
        │           │         │         │         │bronchi.
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
     793│?Throat.   │         │Bronchus,│Throat,  │Strept. viridans
        │           │         │lung, arm│ear and  │from throat.
        │           │         │vein,    │bronchus.│
        │           │         │spleen   │         │
        │           │         │ear.     │         │
        │           │         │         │         │
 ───────┼───────────┼─────────┼─────────┼─────────┼────────────────
        │20         │6        │4        │16       │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
        │           │         │         │         │
 ───────┴───────────┴─────────┴─────────┴─────────┴────────────────

 ───────┬───────────────┬────────────┬──────────────
 AUTOPSY│  OTHER G—B.   │   OTHER    │    NOTES.
 NUMBER.│               │ BACTERIA.  │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     741│               │            │Nine plates
        │               │            │used to
        │               │            │isolate B.I.
        │               │            │Sp.a. overgrew
        │               │            │all cultures.
        │               │            │B.I. seen in
        │               │            │blood smear
        │               │            │agar in 24
        │               │            │hours.
 ───────┼───────────────┼────────────┼──────────────
     743│Br. lux. white │            │Pericard,
        │almost coccoid.│            │fluid and
        │               │            │liver juice,
        │               │            │no growth.
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     744│               │            │Pneumococcus
        │               │            │from lung. No
        │               │            │attempt after
        │               │            │first plate to
        │               │            │isolate B.I.
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     745│               │            │Swab from
        │               │            │ruptured
        │               │            │rectus.
        │               │            │Sterile. No
        │               │            │material from
        │               │            │lung.
 ───────┼───────────────┼────────────┼──────────────
     746│B. coli from   │B. xerosis  │The overgrowth
        │bronchi and    │from        │of B. coli in
        │lung.          │bronchus.   │lung material
        │               │            │prevented
        │               │            │further
        │               │            │attempts to
        │               │            │isolate B.I.
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     747│               │B. subtilis │Five picks
        │               │group from  │from blood
        │               │pleural     │agar plate
        │               │fluid.      │failed to
        │               │            │recover B.I.
        │               │            │from lung.
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     748│               │            │B.I. not seen
        │               │            │nor isolated
        │               │            │from the
        │               │            │bronchi.
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     749│B. coli from   │            │The overgrowth
        │bronchus and   │            │of B. coli
        │lung.          │            │prevented any
        │               │            │further
        │               │            │attempts to
        │               │            │isolate B.I.
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     750│B. coli from   │            │B. coli again
        │bronchi and    │            │present as in
        │lungs.         │            │No. 749.
        │               │            │Direct smear
        │               │            │suggests heavy
        │               │            │contamination.
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     751│               │Spore-bearer│
        │               │with tiny   │
        │               │cols, pleur.│
        │               │B. xerosis  │
        │               │from bron.  │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     752│               │            │B.I. like seen
        │               │            │in original
        │               │            │culture on
        │               │            │blood agar but
        │               │            │not isolated
        │               │            │from bronchus.
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     756│B. coli from   │B. xerosis  │Compare No.
        │bronchus and   │from        │749 and 750.
        │pleural fluid. │bronchus.   │Fluid from
        │               │            │lung not
        │               │            │obtained for
        │               │            │culture.
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     757│               │B. xerosis  │This case 14
        │               │from        │hours P. M.
        │               │bronchus.   │gave B.I. from
        │               │            │all the
        │               │            │material.
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     758│B. coli from   │            │The B. coli
        │bronchus.      │            │did not
        │               │            │prevent the
        │               │            │isolation of
        │               │            │B.I. like seen
        │               │            │in original
        │               │            │blood agar
        │               │            │cultures of
        │               │            │lung.
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     761│B. coli from   │            │Even after 19
        │bronchus.      │            │hours P. M.
        │               │            │the B.I. was
        │               │            │isolated.
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     762│               │B. xerosis  │
        │               │from lung.  │
        │               │B. subtilis │
        │               │from        │
        │               │bronchus.   │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     763│               │            │No growth from
        │               │            │lung on plate.
        │               │            │B.I. like seen
        │               │            │in original
        │               │            │culture from
        │               │            │pleural fluid.
        │               │            │No material
        │               │            │from bronchus.
 ───────┼───────────────┼────────────┼──────────────
     764│               │            │Material only
        │               │            │from bronchi.
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     765│B. coli from   │            │
        │bronchus and   │            │
        │lung.          │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     767│               │            │Blood culture
        │               │            │15/10 gave
        │               │            │pure growth of
        │               │            │pneumo.
        │               │            │mucosus.
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     770│               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     773│               │B. xerosis  │No growth from
        │               │from        │lung except
        │               │bronchus. G │sarcina. Only
        │               │+ B lux.    │2 colonies
        │               │white       │from pleural
        │               │pleura.     │fluid on blood
        │               │fluid.      │agar plates.
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     778│Non-motile,    │            │Ten plates and
        │non-fermenting,│            │30 picks were
        │lux, white from│            │done for the
        │bron.          │            │isolation of
        │               │            │B.I.
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     781│               │            │B.I. like seen
        │               │            │from 24 hour
        │               │            │Ht. blood agar
        │               │            │from bronchi
        │               │            │and lung but
        │               │            │only isolated
        │               │            │from lung on
        │               │            │replating. Bl.
        │               │            │culture 25/10
        │               │            │sterile.
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     782│               │            │No B.I. like
        │               │            │on 24-hour Ht.
        │               │            │blood agar
        │               │            │from lung.
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     783│               │            │No B.I. like
        │               │            │on 24-hour Ht.
        │               │            │blood agar
        │               │            │from lung.
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     784│               │            │Numerous B.I.
        │               │            │like on
        │               │            │24-hour Ht.
        │               │            │blood agar of
        │               │            │bronchi and
        │               │            │fewer from
        │               │            │lung. Isolated
        │               │            │by replating.
 ───────┼───────────────┼────────────┼──────────────
     786│               │            │Pleural fluid
        │               │            │not collected
        │               │            │sterilly,
        │               │            │Haemol.
        │               │            │strept.
        │               │            │isolated.
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     787│B.M.C. from    │            │All the
        │bronchi.       │            │bacteria
        │               │            │isolated were
        │               │            │seen in
        │               │            │24-hour Ht.
        │               │            │blood agar
        │               │            │cultures from
        │               │            │bronchi and
        │               │            │lung.
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     791│               │            │Replated from
        │               │            │Ht. blood agar
        │               │            │to isolate
        │               │            │B.I. from
        │               │            │lung.
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     792│               │            │B.I. like seen
        │               │            │on 24-hour Ht.
        │               │            │blood agar
        │               │            │from bronchi
        │               │            │and lung but
        │               │            │not pleural
        │               │            │fluid.
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┼───────────────┼────────────┼──────────────
     793│B. coli from   │            │B.I. like
        │throat.        │            │never seen
        │               │            │except from
        │               │            │throat which
        │               │            │may have been
        │               │            │B. coli.
 ───────┼───────────────┼────────────┼──────────────
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
        │               │            │
 ───────┴───────────────┴────────────┴──────────────

 EXPLANATORY NOTE.

            B.I.—B. influenzæ.

            S.P.A.—Staphylococcus pyogenes aureus.

            M. pharyog—Micrococcus pharyngis siccus.

            Br.—Bronchus.

            Phago.—phagocytosis.

            Ht.-Heated blood agar.

            B. W.—B. welchii.

Staphylococci develop opaque, paint-like colonies of varying size, with
or without hemolysis, and so do other less frequently found bacteria
give more or less distinctive colonies. The heated blood agar does not
show these differences.

The colonies most liable to be confused with those of B. influenzæ are,
therefore, those of B. xerosis, immature colonies of the Gram negative
cocci and certain colonies of the streptococcus viridans group.
Transfers should always be made to heated blood agar of all colonies
suggestive of B. influenzæ, or when the growth of the B. influenzæ has
only occurred in the more crowded portions of the plate, and it is
difficult to pick pure cultures, attempted pickings should be made to
this medium for further platings. It is frequently necessary to make
further blood agar plates from the original blood agar, blood broth or
heated blood agar cultures after longer incubation periods, depending on
the findings in smears from these media. The heated blood agar is the
best of these to encourage the growth of B. influenzæ. It must, however,
be used at once, or within a very few days of its preparation, and
cannot be kept on hand as a stock medium. I have not found it as useful
for plating because of the difficulty of differentiating colonies. The
phenomenon of the star-like and more luxuriant growth of the colonies of
B. influenzæ about colonies of other bacteria has often been noted, and
will be referred to in a later portion of this report. Here it may be
said that this is at times a marked feature of certain mixtures and must
be recognized in studying the plates. The finding of B. influenzæ in
picks from apparently isolated colonies of other forms is not uncommon,
and is the same type of difficulty which I have discussed in papers on
streptococci. It is important to recall, in connection with cultures
taken from the lungs at autopsy, the experimental work of Norris and
Pappenheimer, who showed that B. prodigiosus put in the mouth
immediately after death could be recovered from the lungs in over 50 per
cent. of the cases studied.


                        _Results of the Author_

In Table I are shown my results from the 32 cases which came to autopsy.
The B. influenzæ was isolated from one or more sources in 25, making a
total of 78 per cent. Most of the negative cases probably also had this
organism, but I did not grow it from the material which I used for
culturing. The work of others would indicate that it may have been
present in other regions, such as the sinuses of the head or other
portions of the lung and respiratory tract. The positive results show B.
influenzæ present in 20 out of 30 cases from the bronchi; in 13 of 28
from the lungs; in 2 of 14 from the pleural cavity; in 9 of 26 from both
bronchi and lung where both were cultured; in 8 of 26 from the bronchi
with the lung negative; in 3 of 26 from the lung with the bronchi
negative; once of 10 from the pleural cavity with both the bronchi and
the lung negative, and once from all three sources.

The negative results occurred in seven cases. In three of these (749,
750, 756) B. coli overgrew the cultures from the bronchus, in two also
from the lung, and in one, without lung culture, from bronchus and
pleural cavity. The mere presence of B. coli, however, did not preclude
the isolation of B. influenzæ, as is seen in cases 746, 758, 761 and
765. The finding of B. coli would suggest a post-mortem invasion. The
hours after death before the autopsy was done were in these seven cases,
½, 15, 6, 18, 16, 19, 16, respectively. That delay in performing the
autopsy, as emphasized by Spooner, Scott and Heath, adds to the
difficulty is self-evident, but successful isolations of B. influenzæ
have been obtained after even longer periods than in the negative cases
(761). In the fourth negative case (763) the bronchus was not cultured.
A pneumococcus was grown from the pleural cavity and no growth was
obtained from the lung. In the original culture from the pleural cavity
influenza-like forms were seen but could not be isolated. In the fifth
case (767) a blood culture three days before death gave a growth of
pneumococcus mucosus which was also grown from the lung at autopsy.
Direct smear from the bronchus showed very few influenza-like forms. Our
sixth negative finding was in a case of 20 days’ illness, the patient
having had a recurrence (773). Staphylococcus pyogenes aureus,
streptococcus viridans and B. xerosis were grown from the bronchus. Only
a sarcina form grew from the lung, and a further probable air
contamination occurred on the media from the cultures of the pleural
cavity. The B. xerosis colonies were confusing, picked as possible B.
influenzæ, and, before this was discovered, the overgrowth prevented
further attempts to isolate the influenza bacilli. The last unsuccessful
case was one with a general infection of a hemolytic streptococcus from
an acute otitis media. The streptococcus was isolated from the bronchus,
lung, spleen, arm vein and the middle ear at autopsy.

It will be seen that in these seven negative cases technical
difficulties prevented the isolation of the B. influenzæ, even if it had
been present. I would not, therefore, conclude that the organisms were
necessarily absent, but rather that we have failed either to secure
material from the focus of infection or on account of the other reasons
mentioned.

It is very evident that a variety of secondary organisms very frequently
overgrow the field and become numerically predominant. In our first case
staphylococcus pyogenes aureus overgrew all the other organisms present
in cultures from the lung material. B. influenzæ was, however, seen in
the original 24-hour blood agar culture. It required 9 blood agar plates
before the organism could be isolated. In another case 10 plates were
used for the isolation.

The findings of the bacteria in the lung sections are particularly
interesting and instructive. The entire series of cases have not been
completely studied, so I am unable to tabulate the findings. In cases
761 and 762 sections of the lung showed influenza-like bacilli to be
almost pure in the earlier stages of the process, while in areas with
purulent foci pneumococcus-like and other Gram positive cocci were also
numerous. In some cases B. influenzæ-like organisms were to be seen in
overwhelming numbers. In others they were scarce, while in some nothing
resembling B. influenzæ could be found in the sections. Positive
cultures were often independent of whether the influenza-like forms were
to be seen in smears or sections or not, although they were found in the
great majority of the cases. The findings in the direct smears and the
bacteriological results make useful material for comparison.

Swabs from the nasopharynx were cultured from 31 individuals; nearly all
of these were cases suspected of diphtheria or as carrying the
diphtheria bacillus, and no particular effort was made to isolate the B.
influenzæ. They were seen in the mixed culture occasionally. In the last
eight cases the heated blood agar, ordinary blood agar and Loeffler’s
serum were seeded from the throat swabs. B. influenzæ practically
overgrew all the other bacteria from seven of these cases on the heated
blood agar medium and was isolated without difficulty; all eight showed
M. catarrhalis. The two other media gave little or no evidence of the
presence of B. influenzæ. As I have said above, our attention was
concentrated on the autopsy material. These cultures from the throat
were simply made to demonstrate the usefulness of the heated blood agar.


                                TABLE II

            BACTERIA SEEN IN DIRECT SMEARS FROM NASOPHARYNX

 ════════════╤═════════╤═══════════════╤══════════════════╤═════════════════
   Type of   │Number of│      B.       │                  │       M.
   Disease.  │Patients.│Influenzæ-Like.│Pneumococcus-Like.│Catarrhalis-Like.
 ────────────┼─────────┼───────────────┼──────────────────┼─────────────────
 Early       │       24│             14│                17│                6
 Serious     │       13│             13│                13│                9
 Convalescent│       11│              8│                11│                6
 ────────────┼─────────┼───────────────┼──────────────────┼─────────────────
    Total    │       48│             35│                41│               21
 Percentage  │         │               │                  │
   of        │         │               │                  │
   positives │         │             73│                86│               43
 ────────────┴─────────┴───────────────┴──────────────────┴─────────────────


               _Direct Smears from Nasopharyngeal Swabs_

It is recognized by most of the modern investigators that little
reliance can be put on the finding of B. influenzæ-like bacilli in
direct smears. The organism is markedly pleomorphic, occurring as
extremely small coccoid forms up to threads of various lengths.
Notwithstanding these morphological variations the organisms are usually
seen as tiny bacilli, and these are considered as the typical form. We
carried out a series of microscopical examinations of carefully made
smears from the throats of patients with influenza. Particular attention
was given to the occurrence of organisms resembling in morphology and
staining B. influenzæ, pneumococci and M. catarrhalis. We have divided
the cases roughly into three types—early, serious, and convalescent.
Table II shows our results. The term B. influenzæ-like was used for the
typical morphological picture so often described. Dr. Frost and Mr.
Scott carried out this portion of our work and their results are
interesting.

Blood cultures were done on 22 cases. Pneumococcus mucosus was grown
from one patient who three days later came to autopsy (Case 767). In
another case pneumococcus-like organisms were seen in smears from the
dextrose broth flask after 24 hours’ incubation. These, for some unknown
reason, did not grow on blood agar plates. After 48 hours smears made on
blood agar from the original flask gave a growth of B. influenzæ and a
M. catarrhalis-like organism. I consider this result a very
unsatisfactory one, being quite unable to explain the failure to grow
the pneumococci-like forms on transfer. Possibly the acidity developed
might account for it.


                               TABLE III

    AGGLUTINATION TESTS WITH SERA OF CONVALESCENT INFLUENZA PATIENTS

    ═══════════════════════════╤═══════════╤═══════════╤═══════════
         DILUTION OF SERUM     │     +     │    +–     │     –
    ───────────────┬───────────┼───────────┼───────────┼───────────
    Convalescents  │1-1        │          3│          0│          2
                   │1-10       │          5│          2│          7
                   │1-40       │          2│          3│          9
                   │1-80       │          0│          1│         13
                   │1-160      │          0│          0│         14
    ───────────────┼───────────┼───────────┼───────────┼───────────
    Normal Controls│1-10       │          1│          2│          0
                   │1-40       │          0│          1│          2
    ───────────────┴───────────┴───────────┴───────────┴───────────

  The complete agglutination as would be indicated by +++ or ++ was
  not seen.

Agglutination tests were carried out with the sera of 14 convalescents
and 3 normal individuals. A polyvalent emulsion of strains of the
influenza bacillus isolated from our cases was used. The results are
shown in Table III. Tubes were incubated at 37.5° C. The results did not
indicate anything in the nature of a specific reaction. Dr. Frost
carried out this work during the height of the epidemic, but we were
unable to continue it further. A short review of the work of others will
be found near the end of this paper. Miss Thompson and Mr. Mock studied
complement fixation, using the sera of 15 convalescents against an
antigen of B. influenzæ. Their results were negative. The antigen
appeared to be slightly more anti-complementary than were emulsions of
staphylococcus or B. coli. Huntoon also noted this anti-complementary
character of emulsions of B. influenzæ.

Attempts were made to estimate the amount of complement present in the
fresh blood serum of influenza patients. The technique was to use a 1-4
dilution of the patient’s serum, adding measured amounts of this to a 1
per cent. blood emulsion, with 1 unit of amboceptor and determine the
smallest amount necessary to bring about complete hemolysis. This test
was carried out on eight patients ill for only a few days. The average
amount of the dilute serum was 0.181 c.cm. Fifteen patients,
convalescent after a moderate illness, gave an average of 0.276 c.cm.
Two patients seriously ill with temperatures of 104.3° F. and 105° F.
required 0.4 c.cm. to bring about complete hemolysis. We would not like
to draw any very definite conclusions where we are dealing with such
small fractional differences. This lessening of complement has been
noted in other infectious diseases and may be important in the questions
of immunity in influenza. Dr. Frost carried out a number of cutaneous
tests after the method of Von Pirquet, using a polyvalent, weakly
alkaline emulsion of influenza bacilli in 25 per cent. glycerin. Eleven
convalescents were tested and none of them showed any local or general
reaction. The suggestion that these results may indicate an increase in
resistance is discussed in another place. A number of strains of
pneumococci which we had isolated from our autopsy cases were
differentiated by the agglutination method. Type I was found 3 times;
type II, 10 times; type IV, 9 times. Four showed agglutination with both
type I and type II sera. Type IV pneumococcus was isolated in one case
from the right and left bronchus as well as the lung. In another case
the same type pneumococcus was recovered from the lung and pleural
fluid. These results are similar to those found by numerous workers.


                       _The Hemophilic Bacteria_

The discovery by Pfeiffer of the hemophilic character of the bacillus
found by him in cases of influenza opened up a new group of
micro-organisms known as the hemophilic bacteria. Davis (1915) has laid
particular stress on the group character of these bacilli, and the more
they are studied the more clear does it become that there are several
distinct members. The B. influenzæ is by far the most important as well
as the most frequently found of the group and is considered as the type
organism.

All these bacteria require for their growth the presence of some form of
hemoglobin. The actual amount necessary may be very small, and Davis
suggested that it may have a catalytic action. A great deal of work has
been done in attempts to discover just what portions of the hemoglobin
are necessary to bring about this phenomenon. In our discussion on media
for the influenza bacillus we will briefly describe some of the various
hemoglobin preparations that have been used successfully. It must at
this point be emphasized that blood is very useful in many media to
stimulate the growth of a great variety of bacteria, and the transfers
made from such luxuriantly growing cultures may grow very poorly or not
at all on ordinary media, and this might easily lead to erroneous
conclusions on the hemophilic character of the organisms studied. There
are certain bacteria which grow so much better on media containing blood
that such media are sometimes necessary for their isolation, although
after a few transfers they will grow on ordinary media. This is true for
bacillus pertussis, and throughout the literature a good deal of
confusion has arisen in not recognizing this temporary hemophilic
character of certain bacteria. The true hemophilic bacteria do not grow
except in the presence of hemoglobin in some form or other. The problem
becomes almost academic when we consider the small amounts of hemoglobin
that are necessary. Davis has shown that a dilution of 1 in 180,000 is
sufficient, and in the interesting discussion between Cantani and Ghon
and Preyss it was demonstrated that hematin or other hemoglobin product
was necessary in the agar before B. influenzæ would grow in the presence
of other bacteria, and that this hematin could be derived from the blood
in the meat which was used in making the basic infusion.

_Symbiosis._—The fact that other bacteria can bring to growth the
influenza bacillus on media otherwise unsuited to its needs brings up
the interesting problem of symbiosis, which is one of the most important
characters of the influenza bacillus. Not only do other bacteria make
possible the growth of B. influenzæ on media on which the influenza
bacillus will not grow, but they stimulate a better growth on blood agar
and other more or less favorable media. Grassberger first noted this
stimulating character of other bacteria and described and illustrated
the very large colonies of B. influenzæ which develop in the
neighborhood of colonies of staphylococcus and other bacteria.
Staphylococci killed by heat were found to have a similar effect.
Meunier nicely described this phenomenon by using the term satellites
for the circles of B. influenzæ colonies which develop about the
colonies of other bacteria. A great number of workers have since noted
this characteristic relationship between B. influenzæ and other
bacteria, and occasionally have laid stress on its importance in the
problems of the infections by the influenza bacillus. Allen particularly
emphasized the probable importance of this in discussing the problem of
carriers of B. influenzæ as sources of danger. There seems no doubt that
this symbiotic relationship depends on so altering the hemoglobin
products as to render them more readily available for the influenza
bacillus. This is indicated by the fact that on various media containing
hemoglobin, altered so that it encourages the growth of B. influenzæ, no
such symbiotic stimulation can be demonstrated. This phenomenon is quite
peculiar to this bacillus, distinguishes it from most of the other
members of the group, and should be always determined before an organism
is classed as B. influenzæ.

_Other Hemophilic Bacteria._—The question of a pseudo-influenza bacillus
was first raised by Pfeiffer and has been studied by many workers after
him. Grassberger, who carefully investigated this problem, worked more
particularly with two strains showing the extreme of variation between
the small characteristic morphology of the B. influenzæ and the thread
forms supposed to be characteristic of the so-called pseudo-influenza
bacillus. The great majority of workers have agreed with him in
concluding that this morphological variation is not sufficient nor
constant enough to justify separating two such groups. Nevertheless many
reports indicate peculiar tendencies of certain strains toward thread
formation. There seems to be suggestive evidence that the organism
described by Cohen in 1909 under the name B. meningitidis
cerebrospinales septicemicus is different from true B. influenzæ.
Although the cultural characters were apparently identical, this
organism was definitely pathogenic for guinea pigs and rabbits. The
involvement of joints in the cases reported by Longo and others would
suggest a greater pathogenic power for these strains. Prasek and Zatelli
reported a similar bacillus from meningitis, and Davis found that his
meningitis strains were more pathogenic for rabbits than were others.
Wollstein has studied this question very carefully and found a marked
difference between the strains from the meninges and those from the
respiratory tract in their pathogenicity for rabbits. The strains with a
tendency to thread formation were usually also those grown from the
meninges, but she concluded from the results of serological tests that
all strains of B. influenzæ are of one race, irrespective of their
origin or virulence. The question is still an open one, as Batten and
others described strains from the meninges which are non-pathogenic, and
Ritchie found his strains from meningitis pathogenic for guinea pigs but
not for rabbits. The irregularity and wide divergence in the results of
blood cultures may have a definite relationship to these differences in
the pathogenicity of strains.

Other hemophilic bacteria include the bacillus described by Friedberger
under the name of B. hemoglobinophilus canis. This organism is to be
found in the preputial secretion of dogs. It does not show the
phenomenon of symbiosis, and I have found that it grows rather more
freely and is more resistant to drying than is the influenza bacillus.
Krage has confirmed Friedberger’s findings growing this bacillus from 60
per cent. of his dogs, and believed it a pyogenic organism just as B.
influenzæ may be.

The hemophilic and hemolytic organisms described by Davis, which he
isolated from pathological urine, were non-symbiotic and non-pathogenic.
Koch has described a similar organism from puerperal infection. Whether
the hemophilic organism described by Thalhimer from the uterus in a case
of puerperal infection, those found by Cohen in urethral discharge in
one case and the pelvic exudate of another, and the findings of Kretz in
pyelitis, Wright in pyelonephrosis and Klieneberger in cystitis cases,
possibly refer to this same bacillus is, of course, uncertain. Pritchett
and Stillman found a somewhat similar bacillus, which they called
Bacillus X, from the mouths of 24 persons. It was hemophilic and
hemolytic, stouter than B. influenzæ and showed long tangled threads in
blood broth. It was non-pathogenic and is probably the same as Davis’
organism.

Davis described another hemophilic bacillus from a patient with purulent
foci which was non-hemolytic and non-symbiotic. It was grown from an
abscess of the shoulder joint, the blood and the bronchial secretion of
an infant. Cyanosis was a marked feature of this case. Paranhos
described a hemophilic bacillus from meningitis, which, however, was
Gram positive, and Moon reported an anærobic hemophilic bacillus from an
infection of the ethmoid sinus. The work of Jordan would suggest that
there may be two groups of B. influenzæ based on the indol production.

_Morphology._—The morphology of B. influenzæ has received more than
usual attention. In what we consider its characteristic form, it is an
extremely small bacillus, usually single but sometimes in pairs, and not
infrequently exhibiting polar staining. In direct smears, where there
are many bacteria present, they are frequently arranged in the schools
so frequently described. The development of thread forms is today
considered quite characteristic for B. influenzæ. The organisms vary
from moderately long bacillary forms to very long twisted or curled
threads suggesting leptothrix. In such cultures chains of tiny bacilli
are also quite often noted. At the other extreme we have exceedingly
tiny coccoid forms, resembling in size the B. bronchisepticus, which, as
Ferry has shown, are small enough to pass through many grades of
filters.

It is the thread forms, as discussed above, that have received most
attention in relation to the so-called pseudo-influenza bacillus. The
observations of Wollstein, Lacy and many others showed these forms to be
common in meningeal infections and that, as a rule, they are more
pathogenic for animals than other strains. Another interesting and
important observation is that emphasized by Dick and Murray of the
possible confusion of these forms with Gram negative leptothrix. That
this confusion is liable to occur is illustrated by reports such as
Macdonald finding leptothrix in a meningeal infection, now looked upon
as an example of influenzal meningitis, and the probable B. influenzæ
reported by Dick, and, as quoted by Dick and Murray, the finding of a
Gram negative leptothrix as the cause of broncho-pneumonia by Kato. The
2 per cent. leptothrix reported by Nuzum and his co-workers from the
recent epidemic may be still another example. Equally important is the
recognition of the great frequency of this thread development in the
majority of B. influenzæ cultures on ordinary blood agar media, or even
in the water of condensation of fresh blood agar tubes. The delayed
growth of this bacillus on ordinary blood agar would lead to its being
frequently overlooked unless smears are made, and the irregular thread
forms are recognized as being the B. influenzæ. This development of
thread forms was particularly noted in my work before pickings were made
to the Voges heated blood agar, but because I had been forewarned by
discussing these morphological variations with Lacy, I was able to
recognize them as forms of B. influenzæ. Most of my early isolations
showed these predominating, and they were also noticed in cultures sent
from the Public Health Laboratory at Washington. These cultures on
further transfer, however, showed in 24 hours the typical small form on
ordinary blood agar as well as on the Voges medium. On the latter the
development of thread forms was greatly delayed and frequently did not
appear at all, although after long periods other abnormal, swollen and
irregular shapes sometimes developed.


                   _Media in Growth of B. Influenzæ_

The discovery of the hemophilic character of B. influenzæ has been
confirmed by a long list of investigators. The agar smeared with pigeon
blood as used by Pfeiffer has not, however, been found fully
satisfactory and many modifications have been made. The fact that
hemoglobin in some form is necessary for the growth of these bacteria
has led to a great deal of study in attempts to discover the chemical
part, or parts, essential for this purpose. Hemoglobin in very small
amount, as shown by Davis and others, is sufficient to make media
suitable for growing B. influenzæ. This fact has led to much confusion,
owing to the difficulty of eliminating all possible sources from which
some form of hemoglobin might enter the media. Kitasato used a glycerin
agar and succeeded in growing the influenza bacillus for 10 transfers.
Pielicke, however, did not consider that Kitasato was actually dealing
with the influenza bacillus, but that he as well as Babes, Bruschettini
and Markel had most probably streptococci in their cultures. Besson held
the same view of Kitasato’s organism. It would further appear from the
illustrations of Klein that he also grew streptococci and not the B.
influenzæ. The first culture of the influenza bacillus was probably
obtained by Bujiwid in February, 1890. He grew on agar smeared with the
spleen pulp of an influenzal patient a tiny bacillus which he was unable
to grow on blood free medium, but he did not appreciate its importance
until Pfeiffer’s article appeared. Teissier in his book on “L’ Influenza
en Russie” mentioned this culture.

The hemophilic character of these bacteria indicates that they are
rather strict parasites, and despite the researches of Nastjukoff with
various egg media, and Cantani with a number of supposedly
non-hemoglobin additions to the agar, as well as the studies on
symbiosis, with other bacteria, by Cantani, Neisser, Luerssen and many
others, it still remains true that some form of hemoglobin is necessary
for their growth. Fresh blood either incorporated in the medium or
smeared on the surface is not the best medium for these bacteria.
Altered hemoglobin is much more favorable, and a variety of methods have
been devised to bring about those alterations which stimulate the growth
of B. influenzæ. One of the earliest, as well as one of the very best,
of these is the method of Voges, who added blood to melted agar at a
temperature of about 100° C. I have found this medium exceptionally
suited to growing B. influenzæ, and I consider it excellent for the
primary culture from the original material, for pickings from plates and
to obtain a heavy growth of B. influenzæ for any purpose. The medium was
used by Delius and Kolle (1897), Grassberger (1898), who spoke very
highly of it, and Paltauf (1899), who said that the use of this medium
made the demonstration of B. influenzæ possible when only a very few
were present. A great many other workers have used it with success, and
during the recent epidemic it has gradually found its place. Levinthal’s
medium (1918) is practically the same, although he boiled and filtered
the agar after the addition of the blood. The growth of B. influenzæ on
the Voges agar can properly be described as luxuriant, and to anyone
only accustomed to the use of ordinary blood agar it is an agreeable
surprise to see this supposedly delicate bacillus growing so remarkably
well.

Various other methods have been used to bring about this beneficial
change in hemoglobin. Gioelli (1896) used a medium made up of 1.1 per
cent. hemoglobin and 21.5 per cent. malt extract. This is reddish brown
in color, becomes clear when neutralized with potassium hydrate and
remains so on heating. This added to agar is reported as very favorable
in growing this bacillus. Ghon and Preyss described a medium made up of
meat, peptone, salt and agar prepared in the ordinary way, but not
filtered for at least a week, and then only roughly. This medium is
favorable for symbiotic growths. He further used beef blood heated in a
soda solution and blood heated in water as hemoglobin preparations to be
added to agar. Thalhimer found an amorphous hemoglobin medium to be more
favorable than when a purer hemoglobin was used. W. F. Robertson found a
hemoglobin agar, prepared by allowing sheep’s blood to clot, decanting
off most of the serum, freezing and then thawing what remains and adding
1 c.c. of this to an agar tube at about 60° C., to be very favorable for
the growth of B. influenzæ. Cantani used a blood treated with pepsin and
hydrochloric acid, digested some days in the incubator, filtered and
made weakly alkaline. This mixture was heated for a few minutes,
refiltered and added to the medium. He speaks of it as extraordinarily
good for B. influenzæ. Blood treated with trypsin has been used by
Matthews, Averill, Young and Griffiths, Harris, A. Fleming and others.
Fleming further found that this alteration in hemoglobin can be brought
about in a number of other ways. Blood boiled in agar (suggesting the
Voges agar) and the tubes slanted while hot, blood boiled in water, the
clotted blood precipitated and the clear fluid added to agar, or more
rapidly by adding equal quantities of sulphuric acid to the blood and a
similar amount of potassium hydrate he obtained altered blood suitable
for media. He reported that by any of these methods he could obtain a
medium very stimulating to the growth of B. influenzæ. By the addition
of brilliant green (1 in 500,000) he inhibited the growth of
staphylococcus, streptococcus and pneumococcus. For storing cultures of
B. influenzæ Fleming found a minced meat medium with the addition of
blood to be the best. I have found this medium without the blood to be
an excellent one for keeping a great variety of cultures. Bernstein and
Loewe have reported the use of gentian violet (1 in 5,000) for the same
purpose as the brilliant green used by Fleming. Avery’s oleate blood
agar medium he reported to be largely selective. It checked the growth
of pneumococci and streptococci, but gave luxuriant growths of B.
influenzæ. Pritchett and Stillman have used it with excellent results
recovering B. influenzæ from a very high percentage of the cases
studied.

The use of symbiotic bacteria has been extensively studied in
investigations of the biology of B. influenzæ, and it has been shown, as
noted elsewhere, that such accessory bacteria will bring to growth B.
influenzæ on media otherwise quite unsuited to its needs. It has been
further found that on various preparations of hematin agar, on which B.
influenzæ refused to grow, such media could be rendered favorable for
their growth by the addition of living or freshly killed cultures of
staphylococcus and many other bacteria. And although the method is well
known, it has not been extensively used for the purposes of isolation.
Many of the workers, however, have pointed out the importance of looking
for growth of the influenza bacillus in the neighborhood of the more
easily grown bacteria which almost always develop in cultures from the
respiratory tract. Grassberger has particularly studied this problem and
has made practical application of the method. Accidental contamination
of plates with air bacteria have made possible, in some instances, the
isolation of B. influenzæ—as, for example, in the finding of Heyrovsky
from a case of empyema of the gall bladder—while other workers have
pointed out the difficulty of demonstrating growth where B. influenzæ is
pure in the material cultured, and the comparative ease and relative
luxuriance of growth where other bacteria are present. To just what this
stimulating effect is due has been much discussed, and it is generally
agreed that the hemoglobin is markedly changed and rendered more
available by the action of these germs. It is to be noted that on a
medium containing blood altered by heating or by the various methods as
described by Fleming the foreign bacteria no longer show any symbiotic
action on B. influenzæ. Grassberger considered the effect of the
bacteria on the blood to be the same as that of heating. Allen laid
particular stress on this symbiotic character. He used a staphylococcus,
either living or killed, in making his cultures and noted the difficulty
of growing B. influenzæ from material in which it occurred pure. W. F.
Robertson made use of these facts of symbiosis for both isolation and
stimulation of growth. He employed alternate drills of M. catarrhalis or
pneumococcus with the B. influenzæ, and Brown and Orcutt used strains of
hemolytic streptococci for the same purpose. The latter authors
considered that the beneficial effect of the streptococci was merely due
to the setting free of the hemoglobin. The fact that similar results are
to be obtained by the use of non-hemolytic bacteria as well as forms
giving green color changes to the blood makes this explanation
untenable. In my own studies I have confirmed the results of several
previous workers. I have found that B. influenzæ is stimulated in its
growth by the presence near it of colonies of staphylococcus pyogenes
aureus and albus, pneumococci, streptococcus viridans and hemolyticus
and other bacteria. The largest colonies of the bacillus I have obtained
were those growing near the periphery of a colony of an air nocardia. I
have also noted that emulsions of a staphylococcus killed by boiling for
five minutes, when added to ordinary blood agar, had a marked
stimulating effect, although no evidence of hemolysis was present. This
effect was practically absent if the emulsion was boiled for 15 minutes,
or after being killed was left at room temperature for several days.
There was no evidence of these stimulating effects by any of these
methods when heated blood agar was used, the colonies on this medium
growing equally large by themselves. Comparative studies of the effect
of different bacteria can be simply carried out as follows: Smear evenly
the surface of an ordinary blood agar plate with an emulsion of B.
influenzæ. Seed this plate at various points with minimal amounts of the
various bacteria. After various periods of incubation the size of the B.
influenzæ colonies about the other bacterial growths can be estimated,
and impression preparations on cover glasses will give very interesting
pictures.

The growth of B. influenzæ in primary cultures from sputa and similar
sources is to be explained by the probable presence of traces of blood
or altered hemoglobin as well as the symbiotic relationship with other
bacteria. Fichtner used fresh heated sputum (60 to 65° C.) in place of
blood, and Richter a medium made with sterilized pus. Parker, in her
study of a filterable poison produced by the B. influenzæ, found veal
infusion broth with 10 per cent. defibrinated blood heated to 75° C.
until the blood coagulated and settled on standing to be the best for
the purpose. Jordan in his study of indol production by these bacteria
used a meat infusion broth with 5 per cent. sheep’s blood added at 90°
C. or over and filtered through cotton or paper. Wittingham and Sims
noted that in using blood from influenza cases the bacteria frequently
did not grow, more especially B. influenzæ; and Rivers found human blood
poorer than cat or rabbit blood for growing this organism, as did
Minaker and Irvine. It would seem clear from this review of some of the
suggestive work on the methods of growing B. influenzæ that little
attention should be given to the results of many workers, where ordinary
media were used, particularly when the difficulties of isolation were
not appreciated.


                _B. Influenzæ as a Pathogenic Bacterium_

If B. influenzæ is the causative agent in clinical influenza, there is
certainly ample evidence that it is pathogenic to man. The symptoms of
toxemia, which are so manifest in the pandemic disease as well as in the
sporadic cases, would indicate that the etiological agent is markedly
toxicogenic. Animal experiments by Pfeiffer, and a long list of
investigators following him, would seem to show that the majority of
cultures of B. influenzæ do not have any power of establishing
themselves in the animal tissue. Killed cultures showed equally as high
toxic effects as the living, and so it was generally concluded that many
of the general effects in influenzal infections were of a toxic nature.

There are many exceptions to the above-mentioned failures to produce
infections in animals. Cantani obtained very constant positive results
by subdural injections. He first clearly showed that killed cultures
were markedly toxic and that virulence could be raised very definitely
by animal passage. By injecting brain emulsion with a culture he
obtained a subcutaneous abscess in a rabbit which after eight days still
contained the living organism. Nastjukoff found that animals with a
lowered resistance, or definitely ill from, for example, an artificial
tuberculosis, became infected while others did not. Jacobson showed that
B. influenzæ injected with streptococci caused a definite mixed
infection, and that after six passages the influenza bacillus alone
could produce a fatal infection. Saathoff (1907) confirmed Jacobson’s
findings and found pneumococci equally effective. Davis (1915) also
confirmed the principle established by Jacobson of the symbiotic
relation of other bacteria to infection with B. influenzæ. He used a
culture of a non-virulent staphylococcus pyogenes aureus, and was able
to produce death invariably in guinea pigs after intraperitoneal
injection. From the heart’s blood, as a rule, only the hemophilic
bacillus was recovered. He also found animal passage increased the
virulence, and further that M. catarrhalis and an avirulent
streptococcus had the same effect as the staphylococcus. Slatineanu
(1901) found that he could infect animals with B. influenzæ if the
cultures were injected along with weak solutions of lactic acid, and
that after animal passage by this method the bacillus became more
virulent and would eventually kill by itself. It must not be forgotten
in this connection that strains of B. influenzæ from meningitis cases
are frequently definitely pathogenic for animals. The importance of
considering these various factors in a discussion of infection by this
organism is, of course, very evident. Ecker found his strains pathogenic
for mice after subcutaneous injection, and the bacilli were readily
obtained from the heart’s blood. Spooner and his co-workers from their
results of more than a hundred intraperitoneal injections concluded that
the organism is not pathogenic for mice.

In all animal experiments it is of the greatest importance that the
bacteria be known which may interfere in the experiments through
spontaneous infection (often liable to be induced by the injection) from
the animal’s own flora, as well as the greater susceptibility of
previously diseased animals (Nastjukoff). It would appear from the
results of Bruschettini and Cornil and Chantemesse in the early days of
the influenza bacillus, and those of Lamb and Brannin in their recent
study, that these authors did not seriously consider the spontaneous
infection of guinea pigs and rabbits with B. bronchisepticus or the
bacillus of rabbit septicæmia, both morphologically, very similar to B.
influenzæ. Rosenow in his experiments with streptococci from cases of
influenza has also apparently failed to realize the importance of the
lung lesions produced by the B. bronchisepticus in guinea pigs as
reported by Theobald Smith, myself and many others.

Parker has found a filterable poison from the influenza bacillus which
developed rapidly (6 to 8 hours) in a special heated blood broth medium,
deteriorated rapidly even in the cold, and killed rabbits in quantities
of 2 c.c. in from 1 to 3 hours. Rabbits could further be immunized
against this poison, and their sera protected other rabbits against
fatal doses. This is the first time that a true powerful toxine has been
obtained. Couret and Herbert obtained toxine from B. influenzæ in
Avery’s oleate broth. Huntoon and Ross also clearly demonstrated toxine
production by this organism so that it would appear, with this
confirmation, that the B. influenzæ can be definitely classed among the
toxine producers. Toxemia being the most striking clinical
characteristic of influenza, we have in these findings very strong
evidence of the etiological importance of this hemophilic bacillus to
the disease. A very interesting observation was made by Latapie that the
serum of a goat immunized against influenza bacillus is toxic if it is
used shortly after the injection of the microbes, but that this toxicity
is absent three weeks after the last injection. It would appear to me
that the evidence of a filterable virus from the secretions of the
respiratory tract does not eliminate the very probable toxine from such
materials. The production of toxine by this organism probably depends,
as is the case with very many of our toxine formers, on the most
favorable combinations of conditions. That it is not readily formed in
artificial cultures, or that it is very unstable if formed, is evidenced
by the frequent failures of a great many workers. It has been suggested
that different symbiotic conditions in the respiratory tract determine
the amount of toxine produced. Huntoon found a high toxine production in
mixed cultures with streptococci. This, however, does not appear to be
necessary, as there is ample evidence of severe toxemia from pure
infections with B. influenzæ in various parts, such as the accessory
sinuses of the head, the meninges, the lungs and other parts of the
respiratory tract.

It is not fundamentally necessary that a toxine producing organism be
present in overwhelming numbers before it can be accepted as the cause
of the toxemia. Nor, on the other hand, must we have toxemia every time
the organism is found. The prevalent idea among bacteriologists would
appear to be the reverse of what I have just stated. It would, indeed,
be extremely difficult to make bacteriological diagnoses of a great many
of our diseases, where the etiological factor is well established, if
these conditions were required. We do not do so, for example, in
diphtheria, examinations of stools for typhoid, nor in infections with
the tetanus bacillus. We recognize carrier cases of meningococcus, B.
typhosus, hemolytic streptococci and many others, without detracting
seriously from their importance in definite types of infection. Formerly
the specificity of the different bacteria for definite disease processes
was very rigid, but today we interpret more broadly the finding of
gonococcus in endocarditis, the meningococcus in bacteremia, B. typhosus
in osteomyelitis, streptococci and pneumococci in all manner of
infections and many other bacteriological results. True it is that the
various bacteria show predilections for attacking certain tissues, but
the varying susceptibilities bring about the greatest variations in the
manifestations of these infections.

The B. influenzæ is not confined to the causation of severe pandemic or
epidemic influenza, but includes in its field purulent bronchitis,
meningitis, sinusitis, conjunctivitis and many other pathological
processes. It further should be recognized as a relatively frequent
cause of complications in measles and other diseases.


                 _Infections of the Respiratory Tract_

The disease influenza is primarily an infection of the respiratory
tract. It varies from one of the most acute and fatal diseases we know
of through all grades of severity—from chronic infections lasting over
years to the familiar three or five day fever. This graduation is to be
found more or less marked in all our bacterial infections, but would
seem to be not generally recognized or appreciated as occurring in
infections with the influenza bacillus. That Pfeiffer was dealing with
one phase of the disease when the influenza bacillus was discovered does
not invalidate the results of numerous workers which have been added
since then.

Probably the greatest confusion in attempts to get a clear picture of
this protean disease has been and is a non-recognition of influenza as a
frequent complication of other diseases, such as measles (Jochmann,
Susswein, Tedesko and very many others). The second cause for this
confusion has been the misinterpretation of the facts demonstrating the
rather frequent occurrence of carriers. During an epidemic the vast
majority of patients show the disease as an upper respiratory infection
of varying degrees of intensity, but which usually subsides after
periods of from three to five days of fever. Along with this we have
other graded manifestations of further involvement of the tract with
laryngitis, bronchitis, bronchiolitis and all degrees of
broncho-pneumonia. To prevent the severe lung involvement prompt
treatment must be carried out, under which rest in bed is by long odds
the most important. This will be discussed in another paper of this
series, and was particularly well demonstrated in the results at the
Naval Hospital as verbally reported to me by D. G. Richey. The
interesting point is that the infection can be controlled, but this does
not indicate the etiological factor as different from that acting in the
more severe cases.

The epidemiological evidence would seem to show very clearly that the
incubation period is approximately two days, and that a period of six
weeks is the usual limit for the severe wave of the epidemic in
different localities. In my opinion, during this period every exposed
individual in a community has received the influenza bacillus in the
respiratory tract, and that all the susceptible individuals are attacked
and show more or less evidence of the infection. As a consequence of
this general distribution we have great numbers of individuals carrying
the organism, and the aftermath is to be noted in other and later
manifestations of the same infection.

Sporadic cases of influenza appear during inter-epidemic periods and
more or less healthy carriers are frequent. Scheller’s study in
Königsberg showed, if we can rely on his figures, that the carriers were
very numerous during an epidemic year (winter 1906-1907), being 24 to 33
per cent.; that as the epidemic became less widespread (winter
1907-1908) it fell to 10 to 13 per cent.; as it was disappearing (summer
1908) he found only 1.5 to 3.3 per cent.; while when the epidemic was
completely over (winter 1908-1909) there were no carriers of B.
influenzæ found. These results are taken from studies of sputa and
throat smears of 138, 218, 155 and 185 cases, respectively, for the
periods mentioned. The monumental work of Tedesko, who reported the
results of 1,479 cultures, covering 11 years (1896-1906), would indicate
that B. influenzæ is continually present in the population. However, in
carefully analyzing his results, it is very clear that in the great
majority of his cases it was of definite etiological significance.
Lobular pneumonia, acute, purulent and chronic bronchitis, and most
frequently clinical influenza, are the prominent diagnoses in all his
tables. He was able to grow B. influenzæ repeatedly from individual
patients for many months.

Lord in similar studies (1902, 1905, 1908) brought out somewhat similar
facts. He laid particular stress on the cases of chronic bronchitis with
numerous B. influenzæ in the sputum and a probable confusion of these
with pulmonary tuberculosis. He was able to follow a number of his
patients for several years. B. influenzæ was grown in culture from the
sputum of one of these in 1902; in November, 1903; in February, 1904,
and in February, 1905. In other cases the organism was shown to be
present by culture practically continuously for months and even years.
Lord, with Scott and Nye, in a recently published article (1919)
reviewed his former results and showed a relatively high incidence of B.
influenzæ in the respiratory tract of apparently healthy people. Davis
studied 534 cases, further indicating the prevalence of this organism in
the community.

The B. influenzæ has been recovered from the respiratory tract during
the clinically pure influenza, from the sputum and lung in influenzal
pneumonia, and from the purulent sputum in all grades of bronchitis.
These should all be looked upon as true infections by the influenza
bacillus, the varying manifestations merely differing with the
resistance of the individual. In the epidemic in the fall of 1918
pneumonia was the outstanding feature. Preceding this in the English
publications we have reports of outbreaks of purulent bronchitis.
Macdonald and his co-workers, finding the B. influenzæ frequently
present, considered the condition as one indication of a virulent
infection by this organism. Hammond, Rolland and Shore reported similar
cases, and Abrahams and his co-workers looked upon the cases of purulent
bronchitis as occupying a position, without any definite line of
demarcation, between those with definite broncho-pneumonia on the one
side and those with simple bronchial catarrh on the other. H. E.
Robertson emphasized the serious nature of influenzal purulent
bronchitis and the almost epidemic character and rather high mortality
of the outbreak in the winter and spring of 1917-1918. There were also
numerous mild outbreaks of influenza before the overwhelming culmination
of the last three months of 1918, as reported by Orticoni and many
others and noted by Johnston in this series of papers. Greenwood in an
epidemiological study emphasized the point, previously made evident by
Parsons for the pandemic of 1889-1892, that the mass attack is preceded
by numbers of individual cases. In this country it was noted during the
winter of 1917-1918 and the following spring that the B. influenzæ was
rather frequently found in the respiratory infection in our army camps
(Soper, Cole and MacCallum and others).

It is well recognized that when the actual epidemic struck there were
comparatively few bacteriologists familiar with the B. influenzæ. The
real difficulties of isolation, the more favorable media, the facts of
symbiosis, the importance of carriers, the varying manifestations of the
infection and many of the other vitally important points, although more
or less fully reported in the literature, were nevertheless practically
unknown. It was my own experience, and that of many others. This must be
seriously considered in analyzing many of the reports on bacteriological
findings throughout the period of the severe wave and even after.


             _Results of Others During the Recent Pandemic_

It will be impossible to review the numerous reports on the recent
epidemic that have appeared. Many of these can be discounted, as far as
the finding of B. influenzæ is concerned, for the reasons mentioned
above. The often quoted report of Little, Garofalo and Williams, who did
not even use a hemoglobin medium, will serve as an example. Little
attention should be given to others where the large numbers of cases
precluded the requisite time and media necessary for such a difficult
problem. Friedlander and his co-workers in their report from Camp
Sherman made no mention of the number of sputa, throat swabs or
autopsies which they examined bacteriologically. The incidence of
influenza showed a total of 10,979 cases, 2,001 of pulmonary œdema or
pneumonia and 842 deaths. They recorded one culture from the sputum with
pneumococcus predominating which gave two colonies of B. influenzæ, and
this bacillus was grown from the lung exudate at one autopsy. Their
conclusions that “B. influenzæ (Pfeiffer) has not been demonstrated as
the causative organism” is certainly true from their results, but that
“the frequency of its detection has not exceeded the frequency of its
existence under normal conditions” can hardly be considered as
established, if we accept the many results mentioned above as indicating
its presence during inter-epidemic times, unless they mean by normal
conditions practically complete freedom from this organism.

The prevalence of B. influenzæ in various sections of this country may
be indicated by the following reports chosen from many available ones.
Keegan, from the First Naval District Hospital, found B. influenzæ 19
times from 23 in cultures grown from the lungs. In 6 cases these
cultures were pure. Medalia reported from Camp McArthur the following.
Out of 2,279 sputa of influenza suspects, 76.8 per cent. showed “B.
influenzæ” in smears, and 445 sputa from cases of broncho-pneumonia
showed it in 54 per cent. It was found in culture in only 10.6 per cent.
of these last cases. He considered sputum smears of practical diagnostic
help. He further grew B. influenzæ twice from the blood during life,
once with a pneumococcus and once alone. Necropsy cultures gave B.
influenzæ in 2 of 3 cultures from the brain, 19 of 34 from the heart, 19
of 36 from the spleen, 54 of 65 from both lungs, 50 of 62 from the right
pleura and 47 of 62 from the left pleura. The percentage of positive
results ranged from 53 in the spleen to 83 in the lungs. Nuzum and his
associates only found B. influenzæ in 4 of 100 cases from the bronchial
secretions, but it is interesting to note that he grew it in practically
pure culture from both lungs of one case at autopsy. Synnott and Clark
in Camp Dix found streptococci and pneumococci predominating, and,
although making no particular effort to study the B. influenzæ or
determine its frequency, they found it in the majority of cases when it
was looked for. Blanton and Irons reported as follows from Camp Custer.
From cultures of the nose and throat of 357 examined before the epidemic
struck, B. influenzæ was found in 5.1 per cent.; in 366 throat cultures
of influenza cases without physical signs of pneumonia the same organism
was grown in 44, or 8 per cent.; sputa typed for pneumococci 740 times
from influenza cases with pneumonia gave isolations of B. influenzæ 38
times, or 5 per cent.—8 times alone, but here it should be remarked that
these latter isolations were only attempted after the organism was
suspected from the morphological picture of the smears; from 280
autopsies B. influenzæ was recovered 8 times from the lung and 3 times
from the heart’s blood. This report covered the period from the outbreak
of the epidemic, October 5 (or as given by Soper, September 30) to
October 22, at the outside a period of 22 days. During this time 366
throat cultures, 510 blood cultures, 740 sputa typed for pneumococci,
280 autopsies with cultures from both lung and heart’s blood, made a
total of primary cultures of well over 2,000. The technical difficulties
would make it almost impossible to handle such a mass of material and
get reliable results for the incidence of B. influenzæ.

Brem, Bolling and Casper in Camp Fremont found B. influenzæ in 259 from
537 selected cases in swabs from the nasopharynx. It was also noted in a
fair number of other examinations. Opie and his co-workers found B.
influenzæ to be very frequent at Camp Pike. Spooner, Scott and Heath
isolated B. influenzæ at Camp Devens from the sputa of 104 cases, from
nasopharyngeal swabs in 11 out of 18 attempts and from the pleural fluid
8 times out of 45, twice pure. From 37 autopsies they found B. influenzæ
in 23 and in pure culture in at least 1 lobe of the lung in 16. From 82
blood cultures at autopsy B. influenzæ was recovered twice. Nichols and
Stimmel studied lung punctures during life and grew the B. influenzæ
from 7 out of 10 attempts, 5 times in pure culture. Stone and Swift at
Fort Riley found B. influenzæ in 18.7 per cent. of 928 sputa and in 5.2
per cent. of 77 sputa from fatal cases. He recovered it from autopsy
material; 21 times from 51 lungs, once alone; twice from 26 pleural
fluids; twice from 30 heart bloods; 19 times from the sinuses of 40, and
9 times from the ear and mastoid of 17 cases.

Lamb and Brannin at Camp Cody examined 80 typical cases early in the
epidemic. They found B. influenzæ predominated in 46 per cent. being
present with pneumococci on 41 per cent. of the plates. They also grew
the influenza bacillus from a fair number of other cases.

Wollstein and Goldbloom in the Babies Hospital of the City of New York
found the B. influenzæ in 13 of 17 sputa during life and in both lungs
of all 18 autopsies as well as in the heart’s blood of one. Kotz found
it in half of his 30 cases. Pritchett and Stillman grew the influenza
bacillus from 41 of 49 cases of influenza, from 40 of 43 cases of
influenza with broncho-pneumonia, from all of six other
broncho-pneumonia cases and from 11 of 20 cases of lobar pneumonia,
making a total of 98 positive findings from 118 or 82 per cent. They
further found 25 positives from 54 convalescent and 74 from 177 normal
sputa. Wolbach found this organism in pure culture in one or more lobes
of the lungs of 9 from 23 cultured cases. It was demonstrated in 23 of
28 either by culture or in section.

Similar results are to be found in reports from Great Britain. Martin
noted a great increase in the numbers present as the sputum became more
purulent. Hicks and Gray found B. influenzæ by culture in 75 per cent.
of their cases. They were seen in direct smears in only 70 per cent.
Gotch and Wittingham considered M. catarrhalis to be the etiological
factor as it was found in all of their 50 cases. B. influenzæ was grown
in 8 per cent., although B. influenzæ-like bacilli, were seen in 62 per
cent. of their smears. Averill, Young and Griffiths studied the sputum
from 41 cases and found B. influenzæ in 32. It is interesting that
Macdonald and Lyth determined the incubation period to be 41 hours as a
minimum in their own experience and that from the posterior nares of one
of them B. influenzæ was obtained.

Schofield and Cynn found the B. influenzæ in Korea. Kraus in Brazil
found it in the sputum in 62 per cent. of his cases of influenza. It was
also found in the organs of 27 who had died, being in pure culture in
five. It has further been found in France, Italy and practically all
parts of the world where investigations have been made. The German
literature is at present only available in the report of the British
Medical Research Committee which is written in a more or less popular
manner with a rather strong tendency against the importance of B.
influenzæ. Dietrich, Simmonds, Bergmann and others, however, found B.
influenzæ rather frequently. Such quotations as “Uhlenhuth, a diehard of
bacteriologic orthodoxy, has clearly shown signs of uneasiness” and “one
empyema and one throat swab yielded the looked for growth” will indicate
why this review is of little use. It is certainly necessary to “look
for” the B. influenzæ to get results of any worth.

Secondary, ancillary or symbiotic bacteria are of cardinal importance in
these infections. It has been considered by some writers as
characteristic for the influenza bacillus to be followed so frequently
with such a variety of secondary invaders. Sahli looked upon the complex
of B. influenzæ, pneumococcus and streptococcus as the true etiological
cause of influenza. Abrahams and his associates discussed the symbiotic
effect of the B. influenzæ in raising the virulence of pneumococci
previously present in the patient and many other investigators lay
stress on these symbiotic relationships.

Pneumococci appear to be the commonest of these secondary
micro-organisms judging from the various published reports, but the fact
must not be overlooked that, particularly in America, the typing of
pneumococci has drawn a disproportionate attention to this group.
Hemolytic streptococci have received much attention (Ely and his
co-workers and several others). M. catarrhalis (Gotch and Wittingham and
several of the British writers), members of the B. mucosus capsulatus
group (Nichols and Stimmel, Rucker and Wenner), staphylococcus aureus
(Patrick), various ill-defined streptococci (Rosenow and several British
writers), capsulated cocci apparently different from pneumococci, B.
pestislike forms and many others have been given more or less attention,
often as clearly recognized secondary infections, but not infrequently
as of primary significance.

B. influenzæ, however, is the organism most regularly found in this
pandemic where carefully looked for, and the evidence of its lowering
the general resistance to bacterial invasion is very strong. The
experiments of Ghedini and Fedeli showing the effect of the toxine on
muscular tone and those of Ghedini and Breccia who found a similar
effect on blood vessels are worthy of note.

The fact that the flora differs so widely in various regions is what one
might expect and many investigators have emphasized the significance of
this. Bacteria in the mouth and throat are readily transmitted from
individual to individual and under the conditions in the training camps
and our modern life, the development of local flora is not surprising.
That it is of very great importance is recognized by all and it is often
a determining factor in the severity of the infection. Nevertheless,
influenza in this pandemic has been almost equally severe whatever the
secondary organism may have been.

I have discussed in another place the suggestion of the stimulating
effect of various bacteria on the growth and toxine production of B.
influenzæ. Huntoon showed the effect of hemolytic streptococci in
cultures to be helpful in toxine production. An important point,
however, is that no one bacterium has been shown to be exclusive in thus
affecting the growth on media of the influenza bacillus, and in the
animal experiments in raising the invasive and pathogenic power of this
organism the same appears to be true. The infection in influenza, in the
vast majority of cases, rapidly becomes a mixed one. The secondary
organisms at times completely dominating the field, at least as far as
numbers go, most frequently invade the blood stream and it would appear
often play the important role in many of the secondary conditions.


                          _Chronic Infections_

B. influenzæ is a frequent finding in the sputum of patients with
chronic bronchitis, pulmonary tuberculosis and other chronic conditions
in the respiratory tract. Boggs recovered this bacillus from two cases
of bronchiectasis, Richards and Gurd had a similar case and Tedesko
reported several. The literature is filled with references to the
finding of B. influenzæ in cases of chronic bronchitis. Those reported
by Lord, Madison and Tedesko quoted above will serve as examples. The
frequent positive cultures in cases of pulmonary tuberculosis so often
referred to in reviews of the literature and the significance of these
findings, as pointed out by Scheller, are important as bearing on the
much debated subject of the effect of influenza on this disease. These
types of chronic infection by the influenza bacillus should be more
generally recognized as they undoubtedly will become more numerous
following this last epidemic if we can judge from the experience of the
past.


                       _Infections of the Pleura_

The recovery of B. influenzæ from the pleural cavity is not uncommon as
is shown in the above review. The findings of MacCallum, Cole and others
during the spring of 1918 are particularly interesting. Beall in 1906
reported a case of empyema with large quantities of green pus in which
B. influenzæ was found in pure culture.


                         _Sinuses of the Head_

Infection of the accessory sinuses of the head has long been recognized
as occurring in influenza. Frankel found B. influenzæ in 4 from 40
infected antra. Lindenthal, who was particularly interested in the
question of sporadic influenza, found the bacillus in one or more of the
head sinuses in six of eight carefully studied cases. He considered that
the B. influenzæ remained in these areas during inter-epidemic times and
from hence caused the sporadic outbreaks of influenza. Howard and
Ingersoll reviewed the literature up to 1898 and grew B. influenzæ from
one of three acute antral diseases. They did not find it, however, in 12
chronic cases. Clemens believed the influenza bacillus to be present in
the sinuses rather frequently in cases where it was overgrown or
difficult to culture from the lower respiratory secretions. Moszkowski
grew it in one case from the pus of the antrum. Tedesko recorded several
positive results and many others are reported in the literature.

The two cases reported by Lacy (1918), the findings during the present
epidemic by Stone and Swift of B. influenzæ in 13 of 28 sphenoidal and 6
of 12 ethmoidal sinuses cultured at necropsy, those by Spooner, Scott
and Heath, of B. influenzæ in four frontal sinuses and in eight
sphenoidal, and the recovery by Wolbach of B. influenzæ in cultures from
the sinuses in certain cases where the lung cultures were negative,
emphasize the importance and frequency of the infection by this organism
in these cavities. Keegan, who laid particular stress on lung punctures
and autopsy examinations, pointed out that in throat cultures the
probability that the influenza focus is often not in the pharynx but in
some recess of the nasal cavity.

H. E. Robertson in the spring of 1918 reported the infection of the
sinuses in seven cases of tracheo-bronchitis with patches of
broncho-pneumonia and the growth of B. influenzæ from sphenoid, ethmoid
or frontal sinuses of all these cases. He also found this organism in
the sphenoid of six cases dying with various diseases as well as in two
accident cases with death under 24 hours. The importance of these
results was laid stress on by the author, not only on account of the
probable toxic absorption and the general menace of spread, but, more
particularly, because such individuals, acting as carriers, could
furnish foci for the spread of epidemics.


                             _Eye and Ear_

Infections of the eye by the influenza bacillus are quite common. This
subject is fully discussed by Axenfeld (text-book, “The Bacteriology of
the Eye”). Giani and Picchi found it in the eye in 66 per cent. of
influenza cases, in 90 per cent. of epidemic conjunctivitis, and in the
normal eye of 5.8 per cent. Wynekoop, in 1903, reported having found
this organism in cases of conjunctivitis in 1899. Guiral, in the recent
epidemic, found influenza bacillus constantly present in the secretions
in cases of what seemed to be Week’s conjunctivitis. Ulceration of the
cornea was rather common. One such case is mentioned in which there was
no pain in the eyes, but general symptoms of influenza. The middle ear
is also sometimes infected. Between the report of Kossel in 1893 and
that of Stone and Swift in 1918, who found the middle ear and mastoid to
contain B. influenzæ in 8 of 17 cases, there have been many references
in the literature to this complication by the influenza bacillus. The
evidence indicates, however, that in the middle ear, as in the pleural
cavity, the secondary bacteria are far more often the important ones.


                               _Meninges_

Influenzal meningitis seems to stand by itself as a manifestation of the
pathogenic effects of B. influenzæ. The literature is too voluminous to
review in this place, but the evidence would seem to point to a more
invasive and pathogenic type of this organism, if not to a separate
member of the group.


                     _Invasion of the Blood Stream_

The evidence in clinical influenza would suggest at times a bacteremia
in addition to the severe toxemia, which is such a constant feature of
the disease. Simultaneously with the discovery of B. influenzæ, Canon
reported finding bacilli of similar morphology in blood smears, but was
unable to grow them, and it would appear at least doubtful that he was
dealing with the influenza bacillus. Meunier is probably the first who
grew this organism from the blood. He recovered it from 8 blood cultures
out of 10 in cases of broncho-pneumonia following measles, and in one
other case of broncho-pneumonia. A very full discussion of this question
is to be found in Canon’s book on “The Bacteriology of the Blood in
Infectious Diseases.” Of particular interest are the results of Ghedini,
who made a careful study of 28 influenza patients. B. influenzæ was
grown from the blood in 18 of these at the height of the fever, while in
the 10 negative cases the disease was milder or the blood was taken only
after the temperature had fallen. The amount of blood used was 20-30
c.c., and it was cultured in lecithin broth. In practically all of his
cases several cultures were taken, and in a number of the positive cases
negative results were obtained both before and after the acme of the
fever. He also grew the bacillus from 8 of 14 spleen punctures of these
patients. Madison (1910) reported the recovery of this bacillus from the
blood of a patient with a primary broncho-pneumonia who recovered. This
author also used about 30 c.c. of blood. Thursfield, in 1910, also
reported two cases of B. influenzæ bacteremia in which the organisms
were recovered at the height of the temperature. One had influenza, the
other phlebitis, and both recovered. Tedesko and several others have
found it in the heart’s blood in many cases, more especially in
broncho-pneumonia after measles.

During the present epidemic the positive cultures of this bacillus from
the blood have been rather infrequent. J. S. Fleming had 2; 2 are quoted
in the report of the Influenza Committee of the Advisory Board to the D.
G. M. S. (Peters and Cookson); Medalia had 2 during life and 19 of 34 at
autopsy; Orticoni, Barbie and Leclerc in 5 of 10 blood cultures in one
series, and 7 of 19 in another; Stone and Swift 2 at autopsy; McKeekin,
in Australia, influenza-like bacilli in 4; Blanton and Irons three times
in the heart’s blood, one of these pure; Spooner, Scott and Heath twice
in the heart’s blood at autopsy, and Wollstein and Goldbloom from the
heart’s blood in one child. In the majority of these findings the
bacillus was not found in pure culture. Abrahams and his associates
found the B. influenzæ along with a pneumococcus and M. catarrhalis from
the heart’s blood in one case. In our positive blood culture there was
evidence of the same mixture being present.

Before drawing sweeping conclusions against the invasion of the blood by
B. influenzæ it must be remembered that the quantity of blood used has
been generally only about 10 c.c., and often much less, the difficulty
of observing growth if the culture is pure has been largely overlooked,
the use of more favorable media than blood agar and the possible
inhibitory action of influenzal blood, as suggested by Wittingham and
Sims, Rivers and others, has not been considered, and further that
sufficient care has not been exercised to obtain blood at the most
favorable period in the disease. It may be recalled that the problem is
quite similar to that of demonstrating the organisms in the blood in
patients with streptococcus viridans bacteremia.

All the available evidence, however, points to the invasion of the blood
in influenzal infections as being a very fleeting one. Unless this is
true, it would be surprising in the many hundreds of blood cultures
which have been taken in the concentrated study of patients during the
recent pandemic, if more successful cultures had not been obtained.
General infections with localization of B. influenzæ in different parts
of the body are here of interest—such as that reported by Slawyk and
others. Whether the strains causing meningitis, and which apparently
more frequently invade the blood, are really different members of the
hemophilic group or only forms with a higher invasive power is still, I
believe, an open question.


                             _Endocarditis_

In endocarditis the B. influenzæ is probably, after streptococci, the
organism most frequently isolated from the blood. Rosenthal from heart’s
blood at autopsy, Schlangenhaufer, Jehle two cases, Horder (1907) six
cases, and who believed he was the first to isolate B. influenzæ from
the blood, Tedesko in a number at autopsy, Spat, F. J. Smith, Saathoff,
Libman four cases, Sacquepee, McPhedran, Mann, Rainaford and Warren
three cultures from two patients, and a number of others all bear
witness to its frequency.

Other organs of the body are sometimes found to contain B. influenzæ.
Adrian, Schultes, Basile and Tedesko have all recovered this organism
from the diseased appendix. Several years ago a bacillus, considered, to
be B. influenzæ, was grown from the pus of an appendix abscess in our
laboratories. Wright found it in pyelonephrosis. Klieneberger found
influenza-like bacilli in cases of cystitis. Menko reported the bacillus
from orchitis, and Cohn found numerous influenza-like bacilli in the
discharge from urethritis. Meunier found it in pure culture in a case of
osteoperiostitis. Huyghe, Besancon and Griffon recovered it from
infected joints, as did Pacchioni in a general infection. Weil found it
in the pus about the hip joint one month after an attack of influenza.
This short review serves to illustrate that the influenza bacillus,
although generally limited to infections in the respiratory tract, is,
nevertheless, capable of infecting other parts.


                        _Immunity—Phagocytosis_

Phagocytosis of the B. influenzæ has been very frequently noted in the
study of sputum smears. It has been observed, moreover, that this
phenomenon occurs most frequently when the patient is on the road to
recovery (Pfeiffer, Martin, and others), and it may indicate an
important reaction on the part of the body to this organism. Tunnicliff
in a recent report, however, did not find the opsonic index to be raised
above the normal in her patients, and Tunnicliff and Davis had
difficulty with a spontaneous phagocytosis of this bacillus. This
difficulty was to a large extent absent in her later study.


                            _Agglutination_

Agglutination tests have been used by many investigators in attempts to
determine a specific reaction in the sera of persons suffering from
influenza. Such reactions develop, as we know, against secondary
infecting bacteria, so that unqualified conclusions cannot be drawn that
agglutinins in the sera of patients against B. influenzæ indicate the
etiological importance of this organism. Vagedes using a dilution of
1-50 found 8 positives among 27 patients tested. Lord found the test
most inconstant. Ghedini obtained useful results by using serum in
dilutions 1-20 to 1-30, and had 17 positives from 28 influenza cases. He
found agglutinins present three to four days after the height of the
infection, and noted that the sera became practically normal after three
to four weeks. Fichtner, although he obtained agglutination with sera of
influenza patients in high dilutions (1-100 and 1-750), found his
controls were often agglutinated, and consequently drew no conclusions.
Wollstein (1906) did a series of agglutination tests, using various
strains of B. influenzæ. The sera of patients she found very
unsatisfactory, but by immunizing rabbits with this organism she
obtained sera with titres up to 1 in 400. She could find no differences
among the various strains studied. Somewhat similar results were
obtained by her in 1915 working with strains from the meninges and the
respiratory tract. Odaira carried out a rather extensive series of
tests, using immunized rabbit sera and a special method of making his
bacterial emulsions. He was able to distinguish B. influenzæ from both
B. pertussis and the so-called Cohen’s bacillus of meningitis.
Friedberger’s dog bacillus, however, could not be differentiated from B.
influenzæ by this means. A. Fleming during the recent epidemic had good
results with the sera of 21 patients. He incubated at 50° C. for two
hours. He also used sera of immunized rabbits and got marked
agglutination against the homologous strain, but varying results with
other strains. He noted some strains agglutinated readily, while others
did not. Eyre and Lowe noted an increase in agglutinins in the sera of
people vaccinated against the influenza bacillus. Couret and Herbert
could distinguish two types and a possible third among their strains.
Park and his co-workers found numerous types by means of agglutination.
Absorption of agglutinins was found helpful by these last two workers.
There are so many factors capable of altering the sensitiveness of
bacteria to agglutination, as in the well-known experiments of Neufeld,
that we must recognize that much work is still to be done before we can
properly interpret the results of these agglutination tests.


                        _Binding of Complement_

Complement fixation tests were carried out by Odaira but his results
were much less satisfactory than those he obtained by means of
agglutination. Rapaport made an extensive study of this test, using the
sera of patients in various stages of convalescence. Three hundred and
fifteen convalescents showed 54.5 per cent. positive while 300 controls
only gave 9.5 per cent. positive results. Most of the positive cases
were in patients three to five days after their illness, but the
reaction was found in convalescents after from 1 to 45 days. Sera from
acutely ill patients at times showed negative or slightly positive
reactions but these same sera after keeping for some days and retesting
often gave strongly positive results. This would appear to be a
promising field for investigation.


                             _Anaphylaxis_

Hypersensitiveness was noted by W. F. Robertson in chronic infections
with B. influenzæ. Wollacott in a letter to the British Medical Journal
suggested that the severity of the recent outbreak of influenza may
possibly be due to the development of a state of anaphylaxis. There
would seem to be at least some evidence in favor of such a view in the
fact that the severe outbreak was preceded by epidemics of a milder form
of influenza and that the influenza bacillus was probably widely spread
during this time. Greenwood, as quoted above, noted that primary cases
always precede the mass attack. Of course, the term anaphylaxis has been
used to explain almost everything. Nevertheless, the theory is
interesting. The skin tests which we did for hypersensitiveness were, as
I have noted above, negative but there is a possibility that the failure
of the reaction may indicate a higher resistance or even an antitoxin,
now that the bacillus can be classed as a toxicogenic one.
Anti-influenza sera have been produced by a few investigators (Latapie,
Wollstein) but have not found any practical application during this
pandemic. Vaccination is discussed elsewhere in these studies.


                       _Experiments on the Human_

There has never been in the history of medicine so many experiments on
human beings as have been carried out in the attempts to discover the
etiological factor in the recent pandemic of influenza. Davis has called
attention to a successful human inoculation with pure cultures of B.
influenzæ which he performed in 1906. During the present investigation
at least 200 men have volunteered as experimental subjects, and the
results of many different methods of attempting to transmit the disease,
have been disappointing and inconclusive. I will not attempt to review
the reports at present available, as a great deal of the work done has
not yet appeared in print. The important point is that the results do
not affect the various views held as to the causative agent in pandemic
influenza nor the massive evidence for transmission of the disease under
natural epidemic conditions.

It is my opinion, as expressed above, that practically all of the
population are rapidly infected during such a pandemic as we have had.
The resistant have escaped, and it would appear to be very difficult to
break down this resistance. The human experiment carried out by
Pettenkofer on himself and his assistant with vibrion choleræ is an
example, but we have numerous others demonstrating the same kind of
phenomena in most of our diseases of established bacterial origin. In
diphtheria we have an explanation in the varying antitoxic content of
the sera, but we really know very little of what are the actual factors
in preventing or determining infection among exposed individuals in the
natural history of most diseases. The reports of Leonard Hill and Gregor
are well worth reading in this connection, as well as the editorial in
the same number of the British Medical Journal. We are not in a position
to be very dogmatic on the causes of epidemics. The mere presence of the
bacteria or any other living virus is not in itself sufficient to
explain the phenomenon, and one of the chief objects of this paper is to
indicate from the collected facts, that in the words of Flexner, “the
case against the influenza bacillus is not proved.”


                             _Conclusions_

1. B. influenzæ is one of a group of hemophilic bacteria and there are
probably strains of this organism which may be differentiated which will
lead to further subdivisions of the group.

2. B. influenzæ as we understand it today, is distinguished by its
morphological and staining characters; its requiring hemoglobin in some
form for its development; its showing symbiotic reactions with other
bacteria which stimulate its growth; the production of a toxine and its
usual low pathogenicity for animals.

3. The media found most favorable for its growth are those containing
blood with the hemoglobin content altered in certain ways, (1) by
heating, (2) the addition of various chemicals, (3) by the action of
other bacteria or their products. The heated blood agar I have found to
be a most efficient and readily prepared medium.

4. Since B. influenzæ is so difficult to isolate, it is necessary to be
very cautious in interpreting results unless the greatest effort has
been made to demonstrate the presence of this organism.

5. B. influenzæ should be considered, from the evidence at hand, as the
bacterial causative agent in epidemic influenza, and it should be
recognized that secondary infections following the primary attack by
this organism are both frequent and important. This view I believe the
logical one, unless much more convincing evidence than we have today may
demonstrate another more probable living virus as the cause.

6. B. influenzæ is a frequent etiological factor in purulent and chronic
bronchitis, broncho-pneumonia and other acute and chronic respiratory
infections, in meningitis, endocarditis, sinusitis, conjunctivitis and
other conditions, as well as in complications of many other diseases.

7. There are many carriers of the bacillus among our population, both in
apparently normal individuals and in those suffering from chronic
infections of bronchi, sinuses or other parts.

8. The problem of what constitutes resistance or susceptibility to this
infection are as far from solution as they are in most other respiratory
diseases, and the attempts to explain the reasons for epidemics have
been as futile as they are for meningitis and many other respiratory
epidemics.

9. It would not appear that the immunological reaction against this
infection has been discovered, but the possibility of its being of an
antitoxic nature opens an interesting field for investigation.


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 Wittingham and Sims     Lancet., 1918; ii, p. 865.
 Wolbach                 Bull. Johns Hopkins Hosp., 1919; xxx, p. 104.
 Wollstein               Jour. Exper. Med., 1906; viii, p. 681.
 Wollstein               Jour. Exper. Med., 1911; xiv, p. 73.
 Wollstein               Jour. Exper. Med., 1915; xxii, p. 445.
 Wollstein and Goldbloom Amer. Jour. Dis. Child., 1919; xvii, p. 165.
 Woollacott              British Med. Jour., 1918; ii, p. 530.
 Wright, J. H.           Boston Med. Surg. Jour., 1905; clii, p. 496.
 Wynekoop                Jour. A. M. A., 1903; xl, p. 574.




                  THE PATHOLOGY OF EPIDEMIC INFLUENZA

                      By OSKAR KLOTZ, M. D., C. M.


The discussion to be entered into in this report will be limited to an
experience dealing with epidemic influenza as it was met with in the
emergency Military Hospital in Pittsburgh. We shall largely confine our
attention to the observations which came directly under our supervision,
and in as much as this investigation was continued during the epidemic
as it swept over this district, the intensive study was limited to a
time period of about five weeks. During this period much material was
collected, which since then, has taken us a considerable time to
analyze. We have thought it more valuable to restrict our discussion to
this material in that it illustrates the pathological lesions as they
occurred during the acute stage of the disease. We have not entered upon
a discussion of the sequelæ or the chronic lesions which are not
uncommonly found following in the wake of an acute epidemic nor do we
deal with the lesions arising in cases of sporadic influenza, such as
are always with us. As is so well illustrated in the literature, there
is probably no disease which has so many late complications and sequelæ
as influenza. The investigations upon the protean lesions have been
fully reported in numerous papers during the intervals between
epidemics. A comprehensive bibliography upon influenza will be found at
the end of the extensive report by Leichtenstern (1905). There is very
much less accurate information available upon the actual lesions present
during the acute disease when present in epidemic or pandemic form, than
upon the many clinical complications in various systems and organs. In
fact, our knowledge of the pathology of influenza lies more largely in
the field of associated lesions such as the late events in the bronchi,
the sinuses of the head, abscesses, meningitis and other conditions,
rather to be viewed as complications than as portions of the disease.
There are relatively few thorough pathological analyses of the influenza
lesions as they are found in the acute epidemic disease.

A fair literature has already appeared upon epidemic influenza from the
many countries and regions over which the present pandemic (1918) has
swept. These reports by various authors are offered from different
viewpoints, some investigators being impressed with certain features
which they bring into marked prominence in their reports. It thus
happens that up to the present there is a decided lack of uniformity in
the opinions expressed upon different phases of the subject. The nature
of the pathology of the past epidemic has given rise to many expressions
of opinion as well as dogmatic statements, which are found to differ
from those of others. It seems to us that this apparent confusion arises
partly through the somewhat different characteristics of the disease as
it has made its appearance in different centers. We hear it repeatedly
stated that the types found in different military camps and urban
communities were quite unlike those of other regions. It is evident that
such differences in the clinical course actually did exist and that the
epidemic though having a common foundation upon which the disease
process was built differed in what might be looked upon as symbiotic
complications during the early and acute stages. Differences in the
nature of the findings in various communities also probably lay in the
fact that the bacterial flora associated with the causative agent of
influenza was quite different in different regions. We mention this here
so that a full appreciation will be obtained for the differences in the
pathological characters of the disease as they are found in one region
or another. We appreciate, of course, that if the concomitant bacterial
flora associated with the underlying cause of influenza, differs in
different regions, so, too, will the bodily reactions differ within
certain degrees. We are becoming more familiar with different types of
bacteria, and the resulting inflammatory reaction which is often unique
or at least particular, and that not uncommonly the nature of the
inflammatory process suggests the type of bacterium involved. This
argument, of course, must not be driven too far, for we well know that
the same micro-organisms under different conditions can cause types of
inflammatory reactions wholly divergent.

In as much as our observations are confined to a particular group of
cases and the study of these was undertaken during the five weeks of the
acute epidemic, these results are not to be compared with the collected
statistics on influenza as they shall be made over a period beginning
with the onset of the epidemic and ending with the last vestiges
remaining after months or it may be years of time. Our observations are
to be considered only in the light of the events taking place during the
height of an epidemic wave. In as much as influenza presents itself
during an epidemic in different forms, we shall again mainly limit the
report upon our investigations of those cases having respiratory
lesions. Our acute observations were made upon the tissues of those who
had died of this disease. It is impossible, or nearly so, to fully study
the tissues of those with lesser lesions and who recover. Hence, if we
divide the influenza cases into those (1) without pulmonary lesions and
(2) those with pulmonary lesions, we must state that all of our cases
coming to autopsy fall in the second group. It is true that one of these
having pulmonary lesions was not brought to his fatal termination by
them but by a septicæmia arising in the middle ear. He had distinct
lesions in his lungs. In other words, our autopsy material represents
epidemic influenza in which the lung was definitely involved in an
inflammatory state. In all but one of these the pulmonary lesion was the
cause of death.

No doubt, if opportunity had presented itself to follow a large epidemic
through months of its progress, during which late complications in
various portions of the body would make their appearance, our analysis
would give a different picture and the pulmonary factor for the fatal
termination would not be in such prominence.

Of the first group, those cases of epidemic influenza not showing
pulmonary lesions, we will have very little to say, in as much as the
pathological investigations of them is impossible, or nearly so, during
the height of the disease.

Such cases apparently do not die at this period. I am willing to admit
that individuals without pulmonary involvement may succumb, but I
question whether their death has been due to the result of the
influenzal lesions, be it in nose, pharynx, larynx or trachea, or be it
in the intestine, but rather that the fatal termination occurred later
in the course of this complex disease, when distant vital organs became
involved or incapacitated in a toxemia or secondary bacterial invasion.
We must clearly distinguish these cases from the clear-cut ones of
epidemic influenza, looking upon the new circumstances as complications
aside from the original disease. Such, for example, is the case we have
mentioned where a fatal streptococcus bacteriæmia followed in the wake
of an otitis media. In our experience we have not had a fatal case of
the acute epidemic disease in which the lung was not involved.

In types of epidemic disease such as we have just had, where the
epidemic wave has passed over in a period of four or five weeks, there
is always much to be regretted which has been left undone. We tried as
far as possible to gain all the information available at the time of
collecting our materials and of laying aside such of the work which
could be accomplished at a subsequent date. The materials were collected
from divergent sources in the cadaver, and the more perishable
substances were analyzed immediately. During the period of the epidemic
32 autopsies were performed and as much use as possible was made of each
for a thorough comprehension of the lesions.


                              _Materials_

During the period of our work 639 patients were admitted to the hospital
suffering from clinical influenza. The cases varied in type from the
very mild to the extremely ill. The majority of the cases were of the
type of “three-day fever.” Clinically 81 cases developed pneumonia, and
of these, 35 died. It would, of course, be impossible to say how many
other individuals had a pulmonary involvement which could not be
recognized clinically. In fact, some of the cases which did come to
autopsy were only recognized as having a pulmonary involvement when the
lungs were examined outside of the body. The physicians freely admitted
that the physical signs were quite unusual and unlike those of the
ordinary forms of pneumonia. In fact, except for the fact that we were
living in the midst of an epidemic of respiratory infections, there was
nothing to make the clinician suspect that many of these cases had a
pulmonary involvement. Obviously, when the recognized signs of different
types of pneumonia made their appearance, the clinician did not fail to
make proper interpretation of the lung involvement. This, as we shall
discuss later, is an event superadded to a lung condition which
pathologically must be recognized as pneumonia (inflammation) and which
differs so decidedly from what we know of as croupous or lobar
pneumonia, as well as ordinary broncho-pneumonia that it would be
incorrect to include them under this heading, although the distribution
of the lesion may have lobar, bronchial or lobular characters.


                                TABLE I

  ════════════════════════════════════════════════════════════════════
       DATE 1918        PATIENTS    PATIENTS    CASES IN     DEATHS
                        ADMITTED   DISCHARGED   HOSPITAL
  ────────────────────────────────────────────────────────────────────
  October            5          65           0          65           0
     〃               6          23           0          88           0
     〃               7          61           0         149           0
     〃               8          77           0         225           1
     〃               9          42           1         266           0
     〃              10          35           1         300           0
     〃              11           9           0         307           2
     〃              12           2          16         290           3
     〃              13          10           0         298           2
     〃              14           1          18         278           3
     〃              15           4          13         266           3
     〃              16           9          23         248           4
     〃              17          10          19         235           4
     〃              18          16          34         217           0
     〃              19          38          29         225           1
     〃              20          27           0         252           0
     〃              21          37          43         245           1
     〃              22          33           7         270           0
     〃              23          14          20         263           2
     〃              24          20          17         266           0
     〃              25          27          21         272           0
     〃              26          10          29         250           0
     〃              27          18           3         265           1
     〃              28          10          31         243           3
     〃              29           6          16         231           0
     〃              30          11          27         215           1
     〃              31           2          15         202           2
  November           1           2          18         185           0
     〃               2           4          18         170           1
     〃               3           5           1         174           0
     〃               4           2          19         156           1
     〃               5           5           0         161           0
     〃               6           4          16         149           0
                               ———                                  ——
           Admissions.         639                                  35
  ────────────────────────────────────────────────────────────────────

The individuals admitted to this hospital were obtained from the two
military camps at the University of Pittsburgh and the Carnegie School
of Technology. All of them were enrolled in the army service and ranged
from the ages of 18 to 30. They were vigorous individuals, who had
passed their physical examinations for the army. The epidemic made its
appearance in these camps on October 2, rapidly ascending from a report
of two ill on October 2, four on October 3, eight on October 4, to 65 on
October 5. On October 11 there were 307 cases in the hospital.

Of these cases 35 died, the day of death being indicated in the
following table.


                                TABLE II

 ═══════════════════════════════════════════════╤═══════════════════════
     DAY OF DISEASE ON WHICH DEATH OCCURRED     │    NUMBER OF CASES
 ───────────────────────────────────────────────┼───────────────────────
 Third                                          │           1
 Fourth                                         │           3
 Fifth                                          │           4
 Sixth                                          │           4
 Seventh                                        │           4
 Eighth                                         │           5
 Ninth                                          │           3
 Tenth                                          │           4
 Eleventh                                       │           3
 Thirteenth                                     │           1
 Fourteenth                                     │           1
 Twentieth                                      │           1
 Twenty-third                                   │           1
 ───────────────────────────────────────────────┴───────────────────────

The time as indicated in the above table has no relation to the length
of time that the patients were ill of pneumonia, but refer to the period
of illness from the beginning of the influenza. The duration of the
pneumonia is indicated in another table.

Of the 35 fatal cases 32 came to autopsy. Facilities were available to
do the work very satisfactorily, in that the hospital was well provided
with a modern post-mortem room and its accessories. The notes on the
autopsies were taken immediately and fully, and the materials for
subsequent study were collected in different types of preserving fluid.
Portions of tissue were collected from all of the organs for
microscopical study, while fluids from the chest, lungs, bronchi and
heart were obtained for bacteriological investigations and for some
chemical analyses.

Added to the above material we also had the opportunity of reviewing and
studying the lesions of 18 autopsies performed by Dr. J. W. McMeans.
These cases were very similar to our own series, in that they were cases
of epidemic influenza amongst soldiers who were being cared for at the
St. Francis Hospital. The disease processes were quite alike in the two
series, and the analyses made by Dr. McMeans are comparable in our own
and serve as a means of checking our results obtained in another
institution. The similarity of the lesions in the lungs and other organs
serve to indicate that what is reported in this paper is an index of the
nature of the lesions of epidemic influenza as it occurred in the
Pittsburgh district. In a few instances the autopsies performed by Dr.
McMeans revealed more advanced pulmonary lesions with abscess and
gangrene than were noted in the cases autopsied at the Military
Hospital. The process, however, in the two series of autopsies was
identical.


                      _General External Features_

There were no external characteristics of the bodies which were
autopsied by us which were constant. Some features were more commonly
present than others. Of these the cyanosis of the face, head, neck and
shoulders, and in a few instances of the upper extremities, attracted
our attention more than any other. This cyanosis was present in over
one-half of the number of cases, and it was confined almost always to
the upper part of the body. The face, ears and neck were always more
affected than other parts. This cyanosis bore no relation to the length
of time after death when the body was viewed, as we found that when it
was present during life it maintained its prominent appearance for a
long time after death.

The cyanosis differed from the bright hue or flush as it is at times
observed in ordinary pneumonia, the color in these instances being of a
dark purple, or better a purplish blue. The lips and ears showed the
most intense color. The cyanosis was not associated with any evidence of
œdema. The capillaries of the tissues were filled with blood which was
of a very dark character. Cyanosis could also be seen in the finger tips
about the nails. This was more marked in the upper extremities than in
the lower. The skin of the body rarely showed any cyanosis, these
tissues being quite pale, or at times showing a slightly yellowish
tinge. In one instance the cyanosis of the head and neck was accompanied
by a slight purplish rash upon the upper portion of the chest. This rash
was of a petechial kind, there being slight hemorrhage into the tissues.
The lesion, however, was not of the blotchy purpuric type which has been
observed by others during this and past epidemics (Cole). This single
case is the only one where we had evidence of superficial hemorrhages
into the skin.


                               TABLE III

      │CYANOSIS│                                               │   NO
      │        │                                               │CYANOSIS
 ═════╪════════╪═══════════════════════════════════════════════╪════════
   NO.│DEGREE  │DISTRIBUTION                                   │
 ─────┼────────┼───────────────────────────────────────────────┼────────
   741│+       │Chest and upper extremities                    │     747
   743│+ +     │Face, neck and ears                            │     748
   744│+ + +   │Head and neck (upper portion of chest and      │
      │        │  thighs mottled and purple)                   │     749
   745│+ +     │Head and neck and upper extremities            │     751
   746│+ +     │Ears, neck and shoulders                       │     752
   750│+ +     │Face, ears and neck                            │     764
   756│+ +     │Neck, jaw, shoulders and upper extremities     │     765
   757│+       │Face, neck, shoulders, arms and chest          │     778
   758│+ + +   │Face, ears, neck and upper chest               │     782
   761│+       │Face, ears, neck and upper chest               │     784
   762│+       │Ears, neck and chest                           │     786
   763│+       │Head and neck                                  │     793
   767│+       │Face, ears and neck                            │
   773│+ +     │Neck, ears and cheeks, extending moderately to │
      │        │  upper chest. Hemorrhage into conjunctiva     │
   781│+ +     │Eyes, lips, ears and neck                      │
   783│+ +     │Face, lips, neck and fingers                   │
   787│+ + +   │Ears, neck and shoulders                       │
   791│+ +     │Ears, neck and upper chest                     │
   792│+ +     │Ears and back of neck                          │
 ─────┼────────┼───────────────────────────────────────────────┼────────
    19│        │+   Blotchy or slight                          │
      │        │  6                                            │   12 or
    or│        │++  Moderate                                   │
      │        │  10                                           │   38.6%
 61.4%│        │+++ Well marked                                │
      │        │  3                                            │
 ─────┼────────┼───────────────────────────────────────────────┼────────
   770│        │Fine petechial rash over upper chest.          │
 ─────┴────────┴───────────────────────────────────────────────┴────────

Occasionally we met with small hemorrhages lying in the upper layers of
the subcutaneous tissue. These lesions were small and could not be seen
from the external surface. Nevertheless, some of them seemed to have
occurred in direct contact with the deep cutis and surrounded portions
of the deep skin appendages. From an examination of our cases there was
no reason at the time of autopsy to lay any particular stress upon the
occurrence of these hemorrhages. Subsequently, it has come to mind, and
since learning of the unusual frequency of boils and deep pustules
making their appearance as post-influenzal sequelæ, that these minute
lesions may have a bearing upon the localization of infection in the
skin tissues. We must appreciate, of course, that other factors of a
constitutional nature probably render the individual more susceptible to
the invasion of the staphylococcus, and that such factors are
all-important in allowing this organism to gain a foothold. Whether the
decreased sugar-tolerance with hyperglycemia, which has been observed in
the late stages of influenza, bears a relation to the increased
susceptibility, as appears to be the case in diabetes mellitus, is an
interesting point for further investigation. Other constitutional states
are also undoubtedly involved in the increased susceptibility to the
infection which the patient suffers. Elsewhere (Dr. Holman) it is shown
that the natural complement content is considerably depressed during the
height of the influenza. With such factors present and with the
available infecting micro-organisms, it is possible that the minute deep
skin hemorrhages bear a relation to the immediate localization of the
infection.

In two instances slight hemorrhages were observed into the conjunctival
tissues. In each case they were unilateral and occupied the tissues
contiguous to the inner canthus. In one case there was well-marked
icterus with yellow coloration of the scleræ and skin. In this case the
icterus was associated with degenerative changes in the liver, there
being no recognizable obstruction to the bile passages. The icterus had
come on quite acutely and without any special clinical manifestations.
In the epidemic of 1890 jaundice was present in a considerable number of
cases (Medical Record, 1890, xxxvii, 473). Cole made similar
observations in the epidemic of influenza amongst the Canadian soldiers.
Œdema of the skin was not met with in any of our cases. This point is
worthy of comment, inasmuch as some authors have been impressed with the
serious damage taking place in the kidney and the resulting incapacity
of these organs. Although, as we shall point out later, the kidney
tissues in these cases showed a decided toxic degeneration, there was no
evidence that a glomerular damage of serious degree ever occurred. The
urinary excretion, as is pointed out in a report by Dr. Zeedick, varies
considerably with the intensity of the disease. It is unusual to find
derangement of kidney function to a degree to reflect seriously upon the
general bodily state. At least this has been our experience in the
present epidemic. Even where subsequently we were able to demonstrate a
considerable tubular degeneration in the cortex of the kidney the change
in the kidney function was not of sufficient magnitude to lead to a
water-retention to be recognized in an anasarca. I wish to distinguish
clearly at this point the difference in finding an œdema in certain
involved tissue structures in various parts of the body and arising
through an inflammatory reaction due to the presence of peculiar focal
irritation, as compared with the accumulation of fluid in many and
irregular situations as it occurs through retention and faulty excretion
by the kidneys. Various organs as we have found—as, for instance, the
lung, heart and liver—showed a condition of œdema which was not to be
reconciled with an inadequate circulation because of a cardiac or renal
incompetency. These œdemas, which we will discuss later, are local and
are the result of damaging influences inducted in and upon the tissues
where they are found.


                                _Muscle_

In all of our cases we have been struck with the excellent physique of
the individuals succumbing to this epidemic. All were youths in the best
of health, of good muscular build and strong bony frame-work.
Post-mortem rigidity set in fairly rapidly after death. Where this
rigidity had “set” for six or more hours it required much force to
change the position of the muscles. The voluntary muscles of the thorax
and abdomen were always carefully observed, and in a number of instances
the muscles of the thigh were also examined. It was not possible
routinely to dissect the muscles of the extremities, so that we are
unable to give an accurate account of the occurrence of degenerations in
these structures. We have, however, observed the reactions taking place
in the pectorals, psoas and muscles of the abdominal parietes. Changes
were observed with greatest frequency in the recti of the abdomen.
Degeneration occurred in these muscles in 14 instances, while the same
tissues suffered rupture, in part or completely with hemorrhage, in six
instances. It was not uncommon to find marked degeneration in the lower
segment of the rectus muscle on one side, while degeneration and
hemorrhage had occurred in its fellow on the opposite side. In four
cases rupture of the entire belly of the muscle had taken place, so that
a considerable space had occurred between the broken ends and a large
clot of blood filled the intervening space. This degeneration, which was
seen only in the voluntary muscles, was quite interesting and in its
milder degrees was rather difficult to detect. All gradations of loss of
muscle color were seen. In some instances the muscle simply seemed to
have lost its meaty lustre, while again in the more severe instances the
muscle color had changed from the bright red to an insipid yellow or
clay color. The most marked degeneration occurred in the midportions,
while the ends of the muscle masses at the points of attachment were
less involved. Complete rupture of the rectus always occurred in the
lowermost segment, a short distance above the insertion into the pubic
bone. At times the distribution of the degeneration within the muscle
was quite patchy, and irregular islands of yellow about 2 cm. in
diameter were splashed through the muscle masses, which in themselves
were paler than normal. Where the muscle degeneration was advanced the
tissue was soft and at times even buttery. It resembled the character of
the degeneration observed in typhoid fever, although I have no
recollection amongst many enteric cases of having seen the degeneration
of the muscle occur so acutely. Recklinghausen claimed that these
hemorrhages were most unusual in influenza. This is contrary to our
findings.

Degenerations of a similar kind as those of the abdominal recti were
found in both pectorals. In the chest region, however, the degeneration
was less frequent and less severe. We observed it only twice, and in
neither instance had the degeneration led to a rupture and hemorrhage of
the muscle bundles. Kuskow observed a single case of degeneration and
hemorrhage of the pectoral muscles. In the psoas muscle we observed
degeneration on two occasions, in one of which the lesion was associated
with a partial separation of the muscle fibers and hemorrhages into its
substance. In one case clinically, but not coming to autopsy, a lesion,
which from its character we presume to have been a degeneration,
occurred in the sterno-mastoid, being accompanied by hemorrhage and the
development of a firm clot the size of a hazel nut. In the subsequent
history of this case the lesion passed through an aseptic process of
organization with contracture so that the patient has recently been
developing a “wryneck.” Kohts in 1890 reported the finding of muscle
degeneration and abscesses in the arm. The condition arose as a late
complication of influenza.

From our experience at the autopsy table in observing the relative
frequency with which muscle degeneration occurs in the severe cases of
epidemic influenza, we feel convinced that numerous cases which recover
pass undiagnosed of this condition. Furthermore we have evidence, as
illustrated in a case observed by Dr. McMeans, wherein a lesion which
occurred in the gluteal muscles was followed by a localizing infection
at this site that these muscle degenerations and hemorrhages may have
serious consequences. There are a number of instances in which
post-influenzal complications of the nature of deep-seated abscesses of
the extremities, thorax, and abdomen may have their explanation for the
localization in a primary muscle damage accompanied by hemorrhage and
followed by an infection of variable type. Cole also comments upon the
development of abscess in the deep muscles where degeneration had taken
place. In illustrating some of our findings to Dr. J. Anderson he
immediately recognized such a condition in the pectoral muscles of a
patient in which he was unable to arrive at a conclusion of the
pathological events which had taken place. It is one of the noteworthy
features in this disease that the voluntary muscles of certain regions
are apt to suffer severe damage, while the heart and the various
unstriped muscular tissues are little if at all affected by a similar
process. It would be interesting to know whether the lack of response
and the delayed functional recovery on the part of the muscles of the
extremities in so many patients who have suffered influenza is the
result of the damaging influence of a peculiar intoxication present in
this disease. One of the features in influenza is the prostration of the
patient, and with it there is definite muscular weakness. We have been
prone to lay the responsibility of this state entirely at the door of
the nervous tissues. Here, however, we are able to offer evidence that
quite aside from the lesions arising in the nervous tissue, there is
definite muscle damage which, as we shall again discuss when describing
the microscopic features, incapacitates even to the point of complete
destruction the muscle elements in various fields of the body. Before,
however, being able to state that the muscular weakness of the
extremities is the result of such damage by toxins it is necessary to
obtain more definite information regarding the frequency with which
these degenerations occur in the limbs. In our own material we are
unable to discuss the matter with adequate figures. We are, however,
impressed with the changes observed in the muscles which were available
to us. Naturally, too, a certain number of muscle degenerations have
escaped our detection because of our unfamiliarity with the mildest
grades. In fact, we have already discovered in our microscopic studies
that certain cases, which in the macroscopic had escaped us, showed
well-marked lesions under the microscope.


                                TABLE IV

                          MUSCLE DEGENERATION

             ABDOMINAL RECTI            │   PECTORAL    │     PSOAS
 ═══════════════╤═══════════════════════╪═══════════════╪═══════════════
      TOXIC     │HEMORRHAGE INTO RECTUS │     TOXIC     │     TOXIC
  DEGENERATION  │                       │ DEGENERATION  │ DEGENERATION
 ───────────────┼───────────────────────┼───────────────┼───────────────
 745 on 10th day│745 both on 10th day   │756 on  8th day│756 on 8th day
 749 on  4th    │752 both on 13th       │770 on 11th    │792 on 6th
 752 on 13th    │756 both on  8th       │               │
 756 on  8th    │764 both on  9th       │               │
 757 on  6th    │765 both on  9th       │               │
 762 on 10th    │778 both on 23d        │               │
 763 on 11th    │—————————————————      │               │
 764 on  9th    │      RUPTURE OF       │               │
 765 on  9th    │        RECTUS         │               │
 767 on 10th    │                       │               │
 770 on 11th    │745 right on 10th day  │               │
 778 on 23d     │756 both  on  8th day  │               │
 783 on  8th    │778 right on 23d  day  │               │
 791 on  6th    │                       │               │
 ───────────────┴───────────────────────┴───────────────┴───────────────

We have convinced ourselves that the marked hemorrhage taking place in
the muscle tissue follows upon a primary degeneration of this tissue and
its spontaneous rupture. The amount of hemorrhage is in proportion to
the degeneration and fracture of the muscle elements. The hemorrhage
does not precede the muscular change, nor does it have any antecedent
relation to the actual tearing of the muscle fibers.

A much better appreciation of the muscle degeneration was obtained in
the _microscopic_ studies of these tissues. The various gradations of
tissue change could be followed, which was not possible in the naked-eye
examinations. Some points respecting this degeneration were quite
noteworthy. Firstly, the process of degeneration in its early stages and
advancing through the acute destructive periods was not accompanied by
any inflammatory reaction. Evidence of inflammatory exudate was obtained
only when the degeneration had proceeded to a degree permitting of
rupture with hemorrhage, or in the late stages when the areas of marked
muscle dissolution were undergoing repair. We have no evidence to
indicate that bacteria were present during the beginning of the
degenerative process. Bacteria could not be demonstrated in section. The
appearance of the tissue suggested a purely toxic process which was
selective in its action, picking out voluntary striped muscle tissue and
attacking certain muscle groups in preference to others. It was also
interesting to observe in the early stages of the degeneration that
individual fibers lying amidst healthy and unchanged muscle elements
would show degeneration in many of its stages. This appearance was often
unique, particularly when in the early stages of the process the
involved fiber would still retain its normal position and shape though
markedly altered in its staining and chemical qualities.

The degeneration as observed in these cases showed many of the
characters like that of waxy degeneration seen in typhoid fever. Similar
appearances to these have also been described in connection with the
toxic degenerations which occur in the vicinity of infections by the gas
bacillus. In fact, all the stages observed in the one can be seen in the
other. They differ, however, only in the degree to which final
destruction takes place and in the speed with which the degeneration is
accomplished. The character of the degeneration is well studied in
sections stained with hematoxylin and eosin, eosin-methylene blue, and
best of all in the phosphotungstic acid hematoxylin. By the latter
method one is able to follow clearly the grade of degeneration as it
effects the muscle striations. On the other hand, the peculiar waxy
appearance of the early degenerating fibers is best seen in sections
stained with eosin or fuchsin, where the striated muscle fibers are
found to be changed to a more intensely staining red body of homogeneous
character and devoid of all evidence of their original internal
architecture. These bland waxy fibers were often of the size and shape
like the normal. On the other hand, the fibers are also not uncommonly
swollen, stretching the sarcolemma to almost the bursting point.
Following this primary bland degeneration the fiber takes on irregular
shapes, becoming constricted and collapsed at irregular intervals, so
that islands of the waxy contents lie within the sarcolemma, being
separated from each other by constricted areas in which the original
myoplasm has undergone decomposition and sometimes complete absorption.
This irregular destruction of the muscle contents often has a granular
stage in which the original muscle substance has become disintegrated.
The sarcolemma follows the condition within it, stretching when the
fiber is swollen and shrinking, or even becoming collapsed when the
inner substance is becoming liquified and absorbed. The sarcolemma does
not suffer the degenerative changes of the inner fiber, nor can one
observe nuclear changes in this sheath which are significant.

When first studying this process of degeneration it appeared to us that
the earliest change was a loss of the transverse striations and the
subsequent disappearance of the longitudinal fibrillæ. We have
subsequently found that this is incorrect and that the changes observed
in the markings of the fibers were not constant. At times the muscle
substance would progress through stages of degeneration up to the point
of disintegration and dissolution while the transverse striæ were still
discernible in the altered fiber. The one constant change that we have
observed in the degenerating fibers was the early loss of staining
qualities as obtained by the phosphotungstic acid hematoxylin. In such
preparations the earliest effect of the intoxication upon the muscle
fiber was a change in reaction to this stain. Sometimes within a given
fiber small irregular and poorly staining blotches could be observed,
while the remaining portion of the fiber was normal in its appearance.
Later these poorly staining areas became larger, occupying the entire
width of the fiber and being distributed at irregular intervals in its
length. Finally the characteristic staining quality was entirely lost,
although in the poorly colored cell transverse striations were still
discernible and a true waxy stage had not yet taken place.

At times the waxy degeneration advanced into the stage of disintegration
by an irregular destruction within the fiber. When this occurred the
fragments of waxy substance took on curious coiled and grotesque shapes,
while a granular destruction was taking place in their periphery.
Neither inflammation, œdema nor a vascular reaction could be determined
in these tissues of mild or severe change. The reaction as is indicated
in the table occurred quite acutely and was not accompanied by fatty
products commonly seen in the slower forms of degeneration.

Gradually the debris of the degenerated fibers is absorbed and the
sarcolemma shrinks and collapses upon itself. During this stage a
reaction occurs in the sarcolemma with nuclear proliferation. At times
the last vestiges of the muscle fiber are seen to be surrounded by a
crown of nuclei and cells reminding one of the appearance of the
degenerating nerve cells in the Gasserian ganglion in hydrophobia. The
involved area becomes active in appearance, showing proliferation of
fibroblasts and the appearance of occasional lymphocytes and plasma
cells. Scar tissue continues to develop in proportion to the amount of
damage done. In areas where hemorrhage had taken place the amount of
scar tissue is exaggerated, owing to a process of organization which is
taking place quite apart from the muscle degeneration. Thus not a few
scars scattered through the voluntary striped muscles are the final
outcome of this toxic degeneration occurring in epidemic influenza. Some
of these lesions may account for the indefinite pains and symptoms of
which the patient complains for so many months after his acute illness.
I refer particularly to lesions occurring in the psoas and muscles of
the back as possible explanations for the partial invaliding of some
individuals.

In a certain number of cases of acute influenza the patients complain of
severe abdominal pain, in the absence of any localizing symptoms or
evidence of intestinal derangement. Such was the case with a number of
the above cases coming to autopsy, and the sole evidence we could offer
was muscle degeneration with or without massive hemorrhage. The
abdominal pains complained of were more of the nature of dull aches with
occasional exacerbations and shooting or lancinating “stitches.” Rarely
was the patient able to define the position of the pain, not being able
to state whether it was within the abdomen or in the parietes. Most
frequently they claimed it was internal. We have on no occasion
demonstrated an intra-abdominal lesion which could account for such
pains. None of our cases was of the type of “intestinal influenza.” We
are, therefore, led to the conclusion that the muscle degenerations of
the various degrees, from the slight with few muscle elements involved
to the severe with rupture and hemorrhage, account for a proportion of
the clinical symptoms of (muscle) pains and aches as well as weakness.
We cannot claim that coughing was a necessary factor in inducing rupture
of the abdominal recti. In some of the cases with rupture severe
coughing had not been observed during the illness.


                       _Upper Respiratory Tract_

The pathological changes found in the nose, pharynx and larynx were of
relatively slight importance and most variable in their severity and
incidence. The majority of individuals had few clinical manifestations
of disease in these parts. Some, however, complained of dryness of the
pharynx with slight feeling of fullness. An examination of these parts
revealed some congestion, varying from a red injected mucosa to a bluish
cyanosis. In the nose the reaction was rarely as acute as is seen in
infectious coryza, but even where relatively little change was to be
seen in the tissues hemorrhage from the erectile tissue was not uncommon
during the acute stages. No particular lesion was to be found associated
with nose bleed. There was an unusual absence of excessive secretion
from nose and pharynx in the majority of cases. One was also struck with
the infrequency with which the larynx was involved. A certain number of
individuals complained of hoarseness, and in them injection of the vocal
cords with some swelling was found. In many others, however, even where
an intense infectious process was present in the lower respiratory tract
the larynx was almost without change. It was from the level below the
larynx that the acute reaction in the respiratory system was found.

In all of our cases the trachea showed definite inflammatory reaction.
Of the 32 cases there were 26 having an acute tracheitis, 5 with an
acute mucopurulent inflammation and 1 with a reaction in the subacute
stage. In the majority of the cases with acute tracheitis there was a
thin layer of exudate lying upon the mucosal surface. At times the
trachea was filled with a frothy serous fluid, the greater part of which
had its origin in the lung. Nevertheless, as we shall point out later,
we did obtain microscopical evidence indicating that during the early
acute stage of the tracheitis a considerable serous exudate escapes from
its mucosa. This serous inflammatory reaction is an important one for
all of the mucosal structures upon which the virus of influenza obtains
a footing. This we have found true for the trachea, bronchi and alveoli
of the lungs. In some cases the exudate was grey and lay in close
contact with the injected tissues. At first sight this grey exudate
suggested necrosis, but it was readily wiped from the underlying
structure. Some leucocytes and cell debris with many bacteria made up
the content of this grey exudate.

The macroscopic appearance of the trachea was that of an intensely
injected structure which had largely lost its normal lustre. The naked
eye could distinguish that anatomical change had occurred in the surface
tissue of the trachea and that there was unusual evidence of intensely
injected vessels lying in the submucosa. In only one instance was there
an appearance of a true necrotic membrane lying upon the surface of this
intensely inflamed layer. This apparent membrane was found to consist of
a wide patch of desquamated epithelial cells which was lying as a
delicate necrotic plate upon the surface. This thin layer was devoid of
a meshwork of fibrin threads as usually accompanies a true false
membrane of other sources.

The early intense inflammatory reaction of the surface membrane of the
trachea was characteristic, and in our experience was never exceeded in
intensity by other infections. A desquamation of the lining membrane was
also a common finding. Naturally this intense reaction so commonly found
in the trachea extended without interruption into the main bronchi and
their divisions. The finding of this continuous surface inflammation is
good evidence of the mode of spread of the infectious process along
these membranes, beginning in the upper portions and by direct
continuity involving more and more of the respiratory tubes toward the
lung.

The varying grades in the intensity of the inflammatory reaction upon
the inner surface of the trachea was well illustrated in the microscopic
sections. Even with the different degrees of the reaction there was a
fairly constant character to the inflammation. In this way the response
was found to differ from that commonly observed in ordinary infections
of the respiratory tract. The first striking feature is the marked
response of the vascular channels, both blood and lymphatic. The vessels
lying in the submucosa were found intensely engorged so that their walls
were stretched to the point of bursting. In fact, not a few vessels were
seen whose walls, probably under the stress of intoxication and
dilatation, had given way leading to a flooding of the neighboring
tissue with their contents. Where such vessels lay close underneath the
surface the hemorrhage escaped into the lumen of the trachea.
Accompanying this early vascular response there was found a marked
serous exudate leading to a stretching of the submucosal tissues by
distention of the interstitial spaces. This reaction resembled an acute
inflammatory œdema and occupied the area between the mucosa and the
inner border of the cartilage rings. Beyond this region no response was
found. Thus in the earliest stages, and where the mucosa was still
intact, the main reaction was of the nature of an intense serous
inflammation with congestion of the blood vessels and frequent
interstitial hemorrhages.

Shortly following the development of the serous exudate in the
submucosal tissues, the epithelial lining is found to suffer from the
reaction. The serous exudate does not remain confined to the
interstitial tissues, but is poured out through the mucosa into the
trachea. It would appear that the amount of this clear exudate may
become greater than can be dealt with by the mucosa, with the result
that an accumulation of this serous fluid takes place between this
epithelial layer and its basement membrane. We have repeatedly seen
considerable stretches of the mucosa lifted from the basement membrane
and shed in large plaques into the lumen. These mucosal cells at the
time of their desquamation retain fairly well their morphological
characters, and do not show evidence of necrosis prior to their removal.
Disintegration of these cells naturally occurs while lying in the
secretion of the trachea, and a variable cellular mass in stages of
disintegration may often be found both in smears and sections. When the
epithelial cells are lifted in wide plates, a type of bleb develops
which is easily broken and then disintegrates.

The desquamation of the lining membrane is a fairly constant occurrence
in the cases coming to autopsy. In the majority of those which we have
examined the greater portion of the trachea was completely denuded, save
for small islands lying in the recesses near the mouths of the mucous
ducts. In one case this lesion was accompanied by a process of
ulceration, due in all probability to the invasion by other
micro-organisms. The denuded tracheal surface usually shows a further
inflammatory reaction in which a cellular exudate then makes its
appearance. This reaction is mainly one in which lymphocytes and plasma
cells infiltrate the spaces previously occupied by the serous fluid. The
reaction is limited to the submucosa and does not extend into the
tissues beyond the cartilages. We have found only occasional
polymorphonuclear leucocytes lying close below the surface. During this
period, however, varying grades of degeneration may occupy the upper
layers. The basement membrane particularly seems to suffer by losing its
characteristic outline and staining qualities. This membrane becomes
swollen, softened and indefinite. At times a homogeneous precipitate
occurs along its free surface giving rise to an appearance resembling a
false membrane. This deposit is, however, distinctively different from
the diphtheritic membrane of other infections. It is interesting,
however, that where such deposits and degeneration occur in the basement
membrane more or less degeneration and necrosis also occur in the
connective tissues immediately neighboring to it. These tissues show a
peculiar granular destruction and alter their staining qualities.
Moreover, and what is more important, under these conditions the dilated
blood vessels are found to suffer from the injuries taking place in
their neighborhood. We have repeatedly found partially or completely
thrombosed capillaries, arterioles and venules in these surface layers.
These thromboses took place while the vessel was in its distended state
and thus produced a mold of the dilated vessel. This observation is of
importance in indicating the severity of the effect of the virus and
toxin upon the tissues of the trachea, and it is also of importance to
appreciate that this damaging influence is very different from that
which we encounter in pneumococcus infections, and we shall point out in
our discussion on lung a reaction very similar to that which takes place
very superficially in the trachea may also occur in the alveolar walls
of the lung.

Having referred to the intensity of the responses of the blood vascular
system, we must also indicate the part played by the lymphatics.
Simultaneously with the reactions taking place about the blood vessels
of the trachea we observed similar responses in the lymphatic channels.
At first these dilated structures contained only fluid. Later the
migration of the lymphocytes took place along these routes, and rarely
micro-organisms could be demonstrated either free or within an
occasional leucocyte. The sharp response of the lymphatics during the
serous inflammation is noteworthy, inasmuch as we have found that the
lymph glands lying about the respiratory tubes and lungs were early in
their response to the irritating virus.

Bacteria were demonstrated in the secretions lying upon the surface of
the trachea. In those specimens in which the mucous membrane was still
intact we attempted to demonstrate the clustering of the micro-organisms
about the ciliated cells as was described by Mallory in whooping cough.
Although the organisms, and particularly small Gram negative bacilli,
could be demonstrated lying about these cells no characteristic
arrangement was found. Furthermore where the mucosa was still attached
to its basement membrane we were never able to demonstrate organisms
below the surface of the epithelial layer. In several cases where the
mucosa was lifted in bleb-like structures a number of organisms were
detected below the epithelial layer and in contact with the basement
membrane of the submucosa. We have rarely demonstrated bacteria in the
interstitial spaces of the submucosa, even where large numbers of
organisms were lying upon the inner denuded surface.

The distinction which was made by the gross examination of the trachea
between the acute tracheitis with serous exudate, subacute tracheitis
and mucopurulent tracheitis was not so readily distinguished in the
microscopic sections. In the gross the character of the exudate lying
upon the surface was the main guide suggesting the nature and intensity
of the inflammatory reaction. In the microscopic sections this exudate
was largely wanting, or was not sufficiently characteristic to confirm
the gross findings. On the other hand, differences in the nature of the
injury were to be found mainly in the reaction of the submucosa. As we
have indicated above, the early inflammatory reaction of the trachea is
mainly evident in an intense congestion accompanied by an inflammatory
œdema of the submucosal tissues, hemorrhage sometimes accompanying this
response. In the later stages of the reaction a cellular deposit takes
the place of the inflammatory œdema and usually consists of lymphocytes
and plasma cells. It is only in those cases where the intensity of the
irritant continues to act over a longer period of time that a
superficial necrosis with leucocytic infiltration makes its appearance.
The epithelial layer of the trachea is desquamated early in the acute
reaction, and hence a denudation of the surface is to be found in all
stages of the acute lesion. The mucous glands have not been found to
show any particular involvement in the inflammatory process, and in the
majority of instances they were found to have escaped entirely the
damaging effect of the virus. Their response in an over-secretion of
mucus may be the outcome of a stimulation by toxins or soluble
irritants; but on the other hand, may also probably be a reflex response
to the injury of the mucosal surface, which being bared of its covering
is highly sensitive. The increased discharge of mucus from the deep
glands may well be a protective response to such injury.


                               _Bronchi_

The lesions in the bronchi were in every way comparable to those in the
trachea. The main bronchial tubes differ in no material way from the
structure of the trachea, and the extension of the inflammatory process
from above downwards leads to a reaction in their walls similar to what
has been above described. As we follow the subdivisions of the bronchi
we gradually lose some of the characteristics contained in the larger
tubes. The mucous glands gradually become fewer and eventually
disappear. The cartilage rings become smaller and no longer completely
encircle the bronchus, and with the further diminution in the size of
these structures disappear entirely. A relatively greater amount of
muscle tissues takes the place of the cartilage rings. This change in
the anatomy of these structures has a certain influence in modifying the
character and distribution of the inflammation.


                                TABLE V

                       BRONCHITIS AND TRACHEITIS

                 ═════════════════════════════════════
                 Acute bronchitis and tracheitis    26
                 Subacute bronchitis and tracheitis  1
                 Acute mucopurulent tracheitis       5
                 Acute purulent bronchitis           2
                 Acute mucopurulent bronchitis       7
                 Ulcers of trachea                   1
                 Acute bronchiectasis                1
                 ─────────────────────────────────────

Thus whereas we have indicated that the inflammation of the trachea and
of the large bronchi is of a peculiar kind and remains confined to the
tissue lying inwardly from the cartilage rings, we found that where
these structures give place to a loose muscle tissue with a more
extensive lymphatic drainage the zone of inflammation is not so limited,
but proceeds outwardly into the neighboring tissues. We often use the
terms bronchus and bronchioles very freely without clearly
distinguishing any real difference. In a study of the inflammatory
reactions of the respiratory tubes in epidemic influenza (as well as in
other infections) it is best to accept the anatomical definition that
the bronchioles not only represent the minute tubules passing to the
alveoli, but also those small air passages which devoid of cartilage,
mucous glands and heavy connective tissue stroma are in close relation
to the parenchymatous tissues of the lung. These soft muscular tubes
possess blood and lymphatic vessels which freely communicate with the
blood vessels of the lung alveoli. It is in association with these
distant tubes that concomitant inflammatory reactions are found in the
alveoli and in the bronchial tubes.

Desquamation of the epithelial lining is to be found in every size of
bronchial tube where the infection has caused an acute inflammatory
reaction. Throughout the pulmonary tissues where the lung is found in
some stage of influenzal pneumonia the bronchial tubes, both large and
small, are either entirely denuded of the mucosa or show only remnants
attached to irregular areas. In the smaller passages dense clusters of
desquamated cells are sometimes found within the lumen and indicate the
accumulation of a desquamated epithelium obtained from portions of the
tubular system in deeper portions of the lung. In the early stages, this
desquamation is accompanied by a serous exudate and a certain amount of
hemorrhage. Later we find masses of leucocytes which fill up the tube,
and though appearing to arise from these structures have in fact largely
come from the lung alveoli. Like the larger bronchial tubes the distant
ramifications show relatively little cellular reaction in their walls in
the early period. It is only when the neighboring lung tissues are
extensively implicated in a purulent inflammation that we find a similar
exudate occupying the tissues of the bronchioles. Polymorphonuclear
leucocytes are equally distributed through the region of the basement
membrane, submucosa, muscular coat and outer connective tissue layer.
Some grades of degeneration may occupy the inner surface wherein the
basement membrane first shows a homogeneous swelling and later a
granular degeneration. In a few instances where the small bronchioles
have communicated with regions with abscess formation an ulcerating
surface occupied the inner boundary.

The evidence in the smaller bronchial tubes, both those with cartilage
and those without, that an inflammatory reaction of some degree may
occupy the muscular coat is of importance. We have found reactions of
inflammation in the muscular coat varying from a mild œdema and cellular
exudate to an intense polymorphonuclear leucocyte involvement. In the
latter the muscle fibers showed evidence of degenerative change and
suggested an acute weakening of this layer. We lay particular importance
upon this finding as indicating a causative factor in the development of
acute bronchiectasis as was met with in one of our cases. In this
particular instance the bronchi passing to the lower lobes of each lung
were unusually dilated and could be followed, in the gross, to their
distant extremities. The dilatation was more or less uniform and no
large pouches or cavities had developed. A mucopurulent exudate was
found occupying these dilated tubes. Others have likewise observed the
development of acute bronchiectasis under these conditions. Goodpasture
and Burnett found that as early as the second to the fourth day one of
the striking appearances was the gaping dilated condition of the
infundibula, and the tendency to dilatation of the air passages was
manifested in a bronchiectasis in 4 out of 30 cases. Boggs as well as
Lord have reported upon chronic bronchiectasis associated with the B.
influenzæ and there appeared to be evidence that a certain percentage of
cases recovering from influenza permanently develop irregular
dilatations of the bronchial tubes.

The recognition of inflamed bronchi or bronchioles was never difficult.
In the gross the presence of the abnormal exudate and the intense
injection of the mucosal surfaces always attracted attention to the
inflammatory state. Furthermore where the mucosa had been desquamated
the surface of these tubes was found to be quite granular if closely
observed. With moderate magnification by means of a hand lens the
granular appearance was shown to be due to the engorged vessels. Much
easier, of course, was the recognition of the inflammatory reaction by
the microscope. The importance, however, of the bronchitis and
bronchiolitis lay in the amount of involvement which had occurred in the
neighboring tissues. As we, however, indicated elsewhere, we do not
doubt that many of the cases of three-day fever have a state of
tracheitis and bronchitis equal to that which we have observed in many
of our cases. Whether the inflammatory reaction progressed beyond the
firmer bronchial tubes to the softer and more vascular structures would
be difficult to say where our evidence rests upon the clinical findings
alone. It is, however, probable that a certain number of the severe and
sharp attacks of influenza not only cause a tracheitis and bronchitis of
the larger tubes, but also extend more deeply into the smaller
ramifications tending to simulate the reactions which we have above
described. When we ask ourselves, however, how distantly must the
infection invade the smaller bronchial tubes before involving the
parenchymatous tissues of the lung we are at a loss to enunciate a
general rule. It is more than probable that there are modifying
influences which determine whether the bronchitis with a certain amount
of its bronchiolitis will progress to a true pneumonia or will remain
localized to these tubular systems. I can well appreciate that in the
event that a bronchitis has an inflammatory reaction accompanied by much
serous exudate there is great danger of flooding the neighboring alveoli
with this inflammatory fluid and of carrying the large numbers of the
micro-organisms within the tubes to the air sacs of the lung. Under
these conditions the virus has an unusual ability to develop the disease
from one localized in the air passages to that of a true pneumonia. It
is probable that the peculiar early acute reaction which is present in
the air passages in epidemic influenza is responsible for the extensive
involvement of the lung in the severe and dangerous form of
inflammation.


                               TABLE VI.

                 EXTENT AND DISTRIBUTION OF PNEUMONIA.

 ═══════╤════╤════════════════════════════╤════════════╤══════════════════════
 AUTOPSY│AGE.│        RIGHT LUNG.         │  TYPE OF   │      LEFT LUNG.
 NUMBER.│    │                            │  LESION.   │
 ───────┼────┼──────┬─────────────────────┼────────────┼────────┬─────────────
        │    │WEIGHT│INVOLVEMENT OF LOBES.│            │ WEIGHT │ INVOLVEMENT
        │    │  OF  │                     │            │OF LUNG.│  OF LOBES.
        │    │LUNG. │                     │            │        │
 ───────┼────┼──────┼──────┬───────┬──────┼────────────┼────────┼──────┬──────
        │    │      │UPPER.│MIDDLE.│LOWER.│            │        │UPPER.│LOWER.
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     741│  18│720 G.│  +   │   +   │  ++  │Lobar S. &  │  850 G.│  +   │  ++
        │    │      │      │       │      │  H.        │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     743│  20│825 G.│  +   │   +   │  +   │Lobular S. &│ 1375 G.│ +++  │ +++
        │    │      │      │       │      │  H.        │        │      │
        │    │      │      │       │      │            │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     744│  30│900 G.│  +   │   –   │  ++  │Lobar and   │  900 G.│  ++  │  ++
        │    │      │      │       │      │  Lobular S.│        │      │
        │    │      │      │       │      │  & H.      │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     745│  18│575 G.│  +   │   –   │  ++  │Lobular S. &│  480 G.│  –   │  ++
        │    │      │      │       │      │  H.        │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     746│  21│900 G.│  +   │  ++   │ +++  │Lobar S. &  │  650 G.│  +   │ +++
        │    │      │      │       │      │  H.        │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     747│  27│  1510│ +++  │  ++   │ +++  │Lobar S. &  │ 1000 G.│ +++  │ +++
        │    │    G.│      │       │      │  H.        │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     748│  22│900 G.│  +   │   +   │ +++  │Lobar and   │ 1250 G.│  +   │ +++
        │    │      │      │       │      │  Lobular S.│        │      │
        │    │      │      │       │      │  & H.      │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     749│  23│  1480│  ++  │  ++   │ +++  │Lobar S. &  │ 1250 G.│  ++  │ +++
        │    │    G.│      │       │      │  H. Slight │        │      │
        │    │      │      │       │      │  Purulent. │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     750│  24│  1200│ +++  │   +   │ +++  │Lobar and   │  825 G.│  +   │ +++
        │    │    G.│      │       │      │  Lobular.  │        │      │
        │    │      │      │       │      │  Early     │        │      │
        │    │      │      │       │      │  Purulent. │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     751│  22│  1250│  –   │   –   │ +++  │Lobar       │  610 G.│  ±   │  ±
        │    │    G.│      │       │      │  Purulent. │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     752│  27│  1125│ +++  │   +   │ +++  │Lobar S. &  │  775 G.│  ±   │ +++
        │    │    G.│      │       │      │  H.        │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     756│  22│  1000│  ++  │  ++   │  ++  │Lobar S. &  │  820 G.│ +++  │  ++
        │    │    G.│      │       │      │  H. Slight │        │      │
        │    │      │      │       │      │  Purulent. │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     757│  21│815 G.│  ++  │   –   │  ++  │Lobular S. &│ 1075 G.│ +++  │ +++
        │    │      │      │       │      │  H.        │        │      │
        │    │      │      │       │      │            │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     758│  22│  1150│ +++  │   +   │  +   │Lobar       │ 1400 G.│ +++  │ +++
        │    │    G.│      │       │      │  Purulent  │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     761│  21│  1250│ +++  │  ++   │ +++  │Lobar S. &  │  550 G.│  +   │  +
        │    │    G.│      │       │      │  H. and    │        │      │
        │    │      │      │       │      │  Lobular   │        │      │
        │    │      │      │       │      │  Purulent. │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     762│  21│680 G.│  +   │   +   │  +   │Lobular S. &│  750 G.│  +   │ +++
        │    │      │      │       │      │  H.        │        │      │
        │    │      │      │       │      │            │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     763│  22│920 G.│  +   │   –   │  +   │B. P. and   │  540 G.│  –   │  +
        │    │      │      │       │      │  Lobar S. &│        │      │
        │    │      │      │       │      │  H.        │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     764│  23│725 G.│  –   │   +   │  +   │Lobular S. &│  550 G.│  +   │  +
        │    │      │      │       │      │  H.        │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     765│  25│  1100│  ++  │   –   │  ++  │Lobar S. &  │ 1400 G.│  –   │ +++
        │    │    G.│      │       │      │  H.        │        │      │
        │    │      │      │       │      │            │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     767│  25│  1075│  +   │  +++  │ +++  │Lobar and   │  850 G.│  –   │  ++
        │    │    G.│      │       │      │  Lobular S.│        │      │
        │    │      │      │       │      │  & H. and  │        │      │
        │    │      │      │       │      │  Lobular   │        │      │
        │    │      │      │       │      │  Purulent. │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     770│  21│900 G.│  ++  │  ++   │  ++  │Lobar S. &  │  750 G.│  ++  │  ++
        │    │      │      │       │      │  H. and    │        │      │
        │    │      │      │       │      │  Lobular   │        │      │
        │    │      │      │       │      │  Purulent. │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     773│  22│  2050│ +++  │  ++   │ +++  │Lobar S. &  │  780 G.│  –   │ +++
        │    │    G.│      │       │      │  H. and    │        │      │
        │    │      │      │       │      │  Purulent. │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     778│  22│  1100│  ++  │   +   │  ++  │Interstitial│  975 G.│  ++  │  ++
        │    │    G.│      │       │      │  Pneumonia.│        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     781│  21│  1000│ +++  │  ++   │ +++  │Lobar S. &  │  540 G.│  +   │ +++
        │    │    G.│      │       │      │  H.        │        │      │
        │    │      │      │       │      │            │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     782│  18│650 G.│  +   │   –   │  ++  │Lobular S. &│  875 G.│  ++  │ +++
        │    │      │      │       │      │  H. Slight │        │      │
        │    │      │      │       │      │  Purulent. │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     783│  21│  1250│ +++  │  +++  │ +++  │Lobar S. &  │  580 G.│  +   │  ++
        │    │    G.│      │       │      │  H.        │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     784│  21│  1590│ +++  │  +++  │ +++  │Lobar       │ 1400 G.│ +++  │ +++
        │    │    G.│      │       │      │  Purulent. │        │      │
        │    │      │      │       │      │            │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     786│  20│  1100│  ++  │  +++  │ +++  │Lobar S. &  │  700 G.│  –   │  ++
        │    │    G.│      │       │      │  H. Slight │        │      │
        │    │      │      │       │      │  Lobular   │        │      │
        │    │      │      │       │      │  Purulent. │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     787│  21│750 G.│  ++  │   –   │  ++  │Lobular S. &│ 1125 G.│ +++  │ +++
        │    │      │      │       │      │  H.        │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     791│  21│775 G.│  +   │  ++   │  ++  │Lobular S. &│ 1050 G.│  ++  │ +++
        │    │      │      │       │      │  H. and    │        │      │
        │    │      │      │       │      │  Purulent. │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     792│  21│  1050│  +   │   +   │ +++  │Lobar and   │  950 G.│  +   │  ++
        │    │    G.│      │       │      │  Lobular S.│        │      │
        │    │      │      │       │      │  & H.      │        │      │
 ───────┼────┼──────┼──────┼───────┼──────┼────────────┼────────┼──────┼──────
     793│  18│500 G.│  –   │   –   │  +   │Slight      │  435 G.│  -   │  +
        │    │      │      │       │      │  Lobular S.│        │      │
        │    │      │      │       │      │  & H.      │        │      │
 ───────┴────┴──────┴──────┴───────┴──────┴────────────┴────────┴──────┴──────

 ═══════╤════════════╤════════════╤════════════╤══════════
 AUTOPSY│  TYPE OF   │  PLEURA.   │ ABSCESS OF │  DAY OF
 NUMBER.│  LESION.   │            │   LUNG.    │ DISEASE.
 ───────┼────────────┼──────┬─────┼────────────┼──────────
        │            │      │     │            │
        │            │      │     │            │
        │            │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
        │            │RIGHT.│LEFT.│            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     741│Lobar S. &  │S.F.  │S.F. │            │   3d.
        │  H.        │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     743│Lobar S. &  │F.    │S.F. │            │   5th
        │  H. Early  │      │     │            │
        │  P.        │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     744│Lobar S. &  │S.F.  │S.F. │            │   7th
        │  H.        │      │     │            │
        │            │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     745│B.P. with   │S.F.  │–    │     +      │   10th
        │  Necrosis. │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     746│Lobar S. &  │–     │–    │            │   5th
        │  H.        │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     747│Lobar S. &  │S.F.  │–    │            │   6th
        │  H.        │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     748│Lobar S. &  │–     │–    │            │   4th
        │  H. and    │      │     │            │
        │  B.P.      │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     749│Lobar S. &  │F.    │–    │            │   4th
        │  H. Slight │      │     │            │
        │  P.        │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     750│Lobar and   │F.    │F.   │            │   9th
        │  Lobular.  │      │     │            │
        │  Early P.  │      │     │            │
        │            │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     751│B.P. slight.│S.F.  │–    │            │   7th
        │            │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     752│B.P. and    │F.    │S.F. │            │   13th
        │  Lobar P.  │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     756│Lobar and   │F.    │S.F. │            │   8th
        │  Lobular S.│      │     │            │
        │  & H.      │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     757│Lobar S. &  │F.    │F.   │            │   6th
        │  H. and    │      │     │            │
        │  Purulent. │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     758│Lobar       │F.    │F.   │            │   14th
        │  Purulent. │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     761│Lobular S. &│–     │–    │            │   7th
        │  H.        │      │     │            │
        │            │      │     │            │
        │            │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     762│Lobar S. &  │S.F.  │S.F. │            │   10th
        │  H. and    │      │     │            │
        │  Lobular P.│      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     763│B.P.        │F.P.  │–    │            │   11th
        │            │      │     │            │
        │            │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     764│B.P.        │–     │–    │            │   9th
        │            │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     765│Lobar S. &  │–     │–    │            │   9th
        │  H. and    │      │     │            │
        │  Early P.  │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     767│Lobar S. &  │–     │F.   │            │   10th
        │  H. Lobular│      │     │            │
        │  P.        │      │     │            │
        │            │      │     │            │
        │            │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     770│Lobar S. &  │S.F.  │F.   │     +      │   11th
        │  H. Lobular│      │     │            │
        │  P.        │      │     │            │
        │            │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     773│Lobar S. &  │F.    │F.   │            │   20th
        │  H. Lobular│      │     │            │recurrence
        │  P.        │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     778│Interstitial│S.F.  │S.F. │            │   23d
        │  Pneumonia.│      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     781│Lobar S. &  │S.F.  │S.F. │     +      │   5th
        │  H.        │      │     │            │
        │  Purulent. │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     782│Lobar S. &  │F.    │F.   │            │   8th
        │  H. and    │      │     │            │
        │  Early P.  │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     783│Lobar S. &  │S.F.  │S.F. │            │   8th
        │  H.        │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     784│Lobar S. &  │S.F.  │S.F. │            │   8th
        │  H. and    │      │     │            │
        │  Purulent. │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     786│Lobar S. &  │S.F.  │–    │            │   4th
        │  H. and    │      │     │            │
        │  Early P.  │      │     │            │
        │            │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     787│Lobar S. &  │S.F.  │S.F. │            │   8th
        │  H.        │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     791│Lobar S. &  │F.    │S.F. │            │   6th
        │  H. and    │      │     │            │
        │  Slight P. │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     792│Lobar and   │S.F.  │S.F. │            │   6th
        │  Lobular S.│      │     │            │
        │  & H.      │      │     │            │
 ───────┼────────────┼──────┼─────┼────────────┼──────────
     793│Slight      │–     │F.   │   Strep.   │   10th
        │  Lobular   │      │     │Bacteriemia.│
        │  Purulent. │      │     │            │
 ───────┴────────────┴──────┴─────┴────────────┴──────────

  S—Serous. H—Hemorrhagic. P—Purulent. B.P.—Broncho-pneumonia.
  S.F.—Serofibrinous. F.—Fibrinous. F.P.—Fibrinopurulent.

It was very evident that the smaller bronchi and bronchioles were much
more readily involved in a severe inflammatory reaction than the larger
tubes. A purulent inflammation was not uncommonly found in the
bronchioles of the lung when a pneumonic state with leucocytic
infiltration was present. Even where such purulent infiltration of the
walls of the bronchioles was readily demonstrable the trachea and main
bronchi were devoid of this intense reaction. These purulent
inflammations were not uniformly distributed in the bronchioles of the
lung, but only occurred in those regions where the parenchymatous
tissues were in themselves involved in a purulent reaction. It was
difficult to find the evidence whether the purulent bronchitis preceded
or followed the presence of a purulent pneumonia. The intimacy of the
lung tissues with those of the small bronchioles makes it impossible for
one or other of these structures to escape when one of them is
implicated in a purulent reaction. It is equally important to appreciate
that to a considerable extent the lung tissue surrounding the small
bronchioles becomes involved by a direct radial extension through the
walls of the thin respiratory tubes. Such extension laterally is
assisted by the free lymphatic communication lying about the bronchioles
and stretching into the lung parenchyma. Purulent processes of the small
air tubes always showed a similar reaction in the interstitial tissues
of the neighboring air sacs.

Our material did not permit of following the bronchial reactions to
their conclusion. In some instances we have found that where abscesses
developed within the lung the contiguous bronchi and bronchioles either
became eroded or suffered intense suppurative inflammatory lesions on
their inner surface. The manner in which repair of the more common
inflammatory processes of the bronchi is accomplished could not be
demonstrated in the cases dying during the acute stage. In one case an
organizing bronchitis was associated with an organizing lobular
pneumonia. In this instance the connective tissues were proliferating
freely from the inner wall of the bronchi, there being no evidence of a
basement membrane at the point where the connective tissue was growing.
The development of the connective tissue appeared to be spontaneous and
was not taking place within an unresolved fibrinous exudate. In as much
as the fibrosing process was largely scattered through all of the lobes,
the numerical involvement of the respiratory tubes was quite great. In
this instance the amount of obstruction which was imposed upon the
respiratory tissues by the fibrosing pneumonia and bronchitis was
sufficient to cause considerable distress and dyspnœa during the last
few days of the patient’s life. The amount of dyspnœa was out of
proportion to the clinical manifestations of pulmonary involvement, and
from a clinical point of view it was difficult to arrive at a conclusion
of the nature of the lung lesion.

Undoubtedly during the subsidence of the inflammatory process within the
bronchi the gradual restitution of the tissues with little or no
fibrosis is accompanied by a reproduction of the lining membrane arising
from the epithelial remnants in the small mucous crypts. In a few cases
lately coming to autopsy where the patients had suffered an influenza
five or six weeks previously, the mucosa of the trachea and bronchi had
assumed its normal appearance and was fully clothed by a normal
epithelial covering.


                           _Lung—Early Stage_

We have just discussed the importance of the inflammation of the trachea
and bronchi in the cases of influenza. It is our belief that every case
of influenza has some tracheitis, and a great many have both tracheitis
and bronchitis. This is true in the absence of localizing signs and
symptoms, as was evident even in these cases in which the simple
influenza passed into its more severe type with its pulmonary lesions.
In many of these instances clinical evidences of an inflammatory
reaction in the respiratory tubes were wanting, while the reactions
observed at autopsy were often astounding.

Just as we feel that simple influenza and inflammation of the
respiratory tubes go hand in hand, or better that these respiratory
localizations are the all-important ones in every case of simple
influenza, so, too, we are of the belief that the pulmonary lesions bear
the same relation to all cases of severe and fatal epidemic influenza.
We hold that no case comes to his death through acute epidemic influenza
without having a lesion in the lung. The pulmonary condition, therefore,
is of first importance and its analysis is imperative for a proper
understanding of this disease. There has been divided opinion as to the
part played by the pulmonary lesion in epidemic influenza, some holding
that it is to be looked upon as a part of the disease and others that it
must be viewed as a complicating lesion. Complications of various kinds
are very common, and there are a number of conditions arising in the
lung (abscess, gangrene, necrosis) which must be viewed as
complications. There is, however, a type of pneumonia, and here I use
the term in its broad sense, which is not in truth a complication but
merely a wider extent of involvement of the respiratory tract by the
same virus which is always present to cause lesions in the respiratory
tubes. The reaction within the lungs is distinctive and differs from the
pneumonias which are met with under other conditions and with various
bacterial agencies. Nor are our findings in this matter unique for this
epidemic. They have been described and discussed in the past. True it is
that, like in the epidemic which has just passed us, the incidence of
clinical and pathological pneumonia varied quite widely in different
communities, so, too, the reports of past epidemics do not give a
uniform description of a pulmonary lesion. Where, however, the analysis
has been made during the four weeks’ period of the acute epidemic and
where the descriptions have been recorded by painstaking observers, the
similarity with our present findings is very striking. I would refer in
particular to one report made in 1893 in Petrograd by Kuskow. His report
deals with 40 carefully studied cases in which records both macroscopic
and microscopic were accurately made.

One of the great difficulties in placing an accurate interpretation upon
the pulmonary findings lies in the fact that true pneumonia as seen in
epidemic influenza in man has not been reproduced in animals.
Furthermore, as the majority of the fatal human cases of epidemic
influenza with their associated pneumonias present a mixed infection of
the lung tissues, it is difficult, if not impossible, to indicate the
lesions which have resulted through the activity of one of these as
against those induced by the other bacteria present. In our own
carefully studied cases wherein bacteriological cultures were taken from
every lung there was not a single instance in which the influenza
bacillus was present in pure culture. This is more fully commented upon
in the studies by Dr. Holman, but the point we wish to make here is the
difficulty in arriving at a conclusion in our material as to the actual
effects induced by any one type of organism. As it is fully discussed by
Dr. Holman we are convinced of the importance of the influenza bacillus
in this epidemic. We also appreciate that pneumonia lesions in animals
have been induced by a variety of materials gained from influenza
patients, but yet in view of the abnormal manner of producing such
lesions these are hardly comparable to those in man. We may well expect
severe œdema, inflammation and hemorrhage, if in guinea pigs, rabbits
and monkeys we introduce by intra-tracheal insufflation large quantities
of fluid suspensions of bacteria. And thus we find positive results
obtained by the use of a filtrable virus, streptococci, influenza
bacilli and other organisms. The lung is a sensitive tissue which quite
readily responds to a variety of irritants. In many respects some of
these lesions simulate those in influenza, but still we are far from the
conclusion that the disease, influenza, with all its manifestations has
been actually reproduced.

The pathology of the pulmonary lesions in acute epidemic influenza is so
distinctive that except for the late purulent stage which may resemble
types of reinfected and unresolved pneumonia the condition cannot be
confused with the stages of frank lobar pneumonia. We appreciate that
this is a very positive statement, and that opposition will be taken by
those who resting their opinion upon individual factors may claim that a
clear distinction from other forms of pneumonia is not available. We,
however, base our opinion not upon a single feature, but upon the
combined pathological complex observed in many individual cases. These
features are mainly those seen in the type of the lesion, the character
of the distribution, extent of involvement and the multiple stages so
commonly present at one time in different portions of the lung. The type
lesion that has become so well known in pneumococcus lobar pneumonia has
its distinctive stages which for teaching purposes are divided into the
stage of (1) congestion, (2) red hepatization, (3) gray hepatization and
(4) resolution. In dealing with lobar pneumonia from the standpoint of
illustrating these stages the majority of teachers annually confess
their inability to present for the student’s study the stage of
congestion. The student is impressed that the congestive stage of lobar
pneumonia is very transient and rapidly passes into the stage of red
hepatization. Patients do not die with pneumococcus pneumonia in the
stage of congestion. And this is also largely true of the stage of red
hepatization, which is but rarely seen at the autopsy table. This
community (Pittsburgh) gives its large quota to the mortality statistics
of pneumococcus pneumonia, but it is most unusual to meet with a
specimen of red hepatization except for the borders of the advancing
gray area. And, furthermore, red hepatization even when found in the
unusual cases shows remarkably little of this character when seen under
the microscope. True it is that a certain number of red blood cells will
be found in the alveoli and a certain degree of congestion will occupy
the alveolar walls, but its extent is far less than what we may have
hoped to demonstrate to others. So that broadly speaking the intensely
congested lung with or without red hepatization is unusual in our frank
lobar pneumonia. This was quite the reverse in our cases of acute
epidemic influenza-pneumonia. Furthermore lobar pneumonia in the great
majority of instances illustrates a distribution distinctive for the
name. Massive lobar, or pneumococcus pneumonia is found to occupy one or
more lobes or parts of lobes. The involved lobe is fairly uniform in the
stage of the inflammatory process. If it is in the early gray stage,
this will be seen with equal intensity in the different areas of the
lobe. Patches of pneumonia in different stages within the same lobe are
not to be found, while this finding is not uncommon in the pneumonias of
acute epidemic influenza. And lastly, the frequency with which an
inflammatory œdema occupied the lungs in the cases of influenza was in
quite striking contrast with the dry fibrinous lesion of common
pneumonia. This wet state of the lung was but a stage in the
inflammatory process varying in its extent in the different periods, but
nevertheless inducing a character in the early pulmonary lesions which
was quite foreign to our usual finding. This wet state also assisted in
modifying the subsequent picture so that when the lung assumed its gray
appearance it was rather of a slimy character than of the firm dry
nature. In this late gray stage the slimy lung somewhat resembled the
appearance of unresolved pneumonia where this condition had been brought
about by a new infection upon the original cause of the pneumonia.

It is incorrect in influenza pneumonia to speak of the lesions as lobar
pneumonia or broncho-pneumonia if by these terms we have in mind the
pathological characters observed in the pneumococcic pneumonia with its
lobar or bronchial distribution. Influenza-pneumonia appeared with both
lobar and lobular characteristics. Nearly every case had both types of
lesions present, but the nature of the inflammatory process is so
decidedly different from that of the ordinary endemic pneumonia that a
confusion in the interpretation is likely to arise and in fact has
already raised a considerable polemic. Influenza-pneumonia is commonly
lobar, lobular or bronchial in distribution. It is, however, not of the
characters that are associated with the lesions designated under these
terms. When, therefore, we here use the word “lobar” we mean lobar _in
distribution_ but not lobar in type. As will be seen from our table, it
was usual to have multiple lobes involved. But the lesions, not only in
the different lobes varied in their character and distribution, but even
within the same lobe a variety of types was present.


                               TABLE VII

 ═══════════════════════════════════════════════╤═══════════════════════
    Day of Pneumonia on Which Death Occurred    │     No. of Cases
 ───────────────────────────────────────────────┼───────────────────────
 Second                                         │                      2
 Third                                          │                      4
 Fourth                                         │                      7
 Fifth                                          │                      6
 Sixth                                          │                      7
 Seventh                                        │                      3
 Eighth                                         │                      1
 Tenth                                          │                      1
 Twentieth                                      │                      1
 ───────────────────────────────────────────────┴───────────────────────

To a certain degree we were able to analyze the types of the lesions as
they occurred in the different stages and progress of the pulmonary
inflammation. Briefly, these were as follows: the earliest stage of
congestion following rapidly upon the infection from the bronchi was
followed by (1) inflammatory œdema, (2) hemorrhage, (3) cellular exudate
(a. mononuclear cells, b. leucocytes, c. interstitial infiltration) and
(4) resolution or organization, abscess, infarct and gangrene. The
majority of our cases died during the stages of congestion, hemorrhage
or early purulent infiltration. In the early stages the amount of fibrin
was small or entirely absent, later, with the appearance of leucocytes,
some fibrin was present.

For the estimation of the time elapsing between the onset of the
pneumonia and death we are dependent upon the clinician. This is often
quite difficult to do, in as much as with a primary respiratory disease,
such as epidemic influenza represents, it is very difficult to determine
the time when there is a transition from the inflammatory process of the
upper respiratory tubes to that of the pulmonary tissue. In many of the
cases where from the onset there was intense prostration and every
evidence of marked intoxication the clinical manifestations of localized
processes taking place in the respiratory system were very much in the
background and often of insidious progress. In four of our cases it
appeared as if the pulmonary manifestations had made their appearance
with the first sudden and severe onset of the influenza. On the other
hand, also, the clinical signs and symptoms of lung involvement were
different from those of frank lobar pneumonia. We would, from our
experience at the autopsy table, say that where in the cases of epidemic
pneumonia there are present the signs of pulmonary consolidation like
those of true lobar pneumonia, that there has been an antecedent period
of a pulmonary lesion which passed unrecognized by the clinician. To
more clearly state the case, whereas in lobar pneumonia the stage of
congestion preceding the stage of red hepatization gives rise to no
signs whereby the clinician can indicate the time of its onset or
determine the time when it has passed into the succeeding stage, and
moreover, the stage of congestion is of short duration to be measured in
a period of a few hours, this stage in epidemic influenza though equally
indefinite in its clinical manifestations is much prolonged, lasting not
only a period of hours but even a period of several days. It is this
pulmonary state which is difficult or even impossible to recognize in
the living. All gradations of it occur and the clinician can only
broadly suggest from all the evidence at hand, the period when
inflammation with definite exudate began in the lung. In as much as the
total length of illness of a number of cases was only three, four and
five days, whereas there was nothing at the onset to suggest pulmonary
involvement, we can estimate approximately, at least, the duration of
the lung condition. This makes it possible to give a relative estimate
of the character of the lesions present at different periods of time.
The outstanding finding, as we will discuss again, was that a distinct
and peculiar pulmonary reaction was primarily imposed upon the lung,
which made its appearance at periods different from those of frank lobar
pneumonia.

We were repeatedly surprised at finding death to have occurred during
the stage of acute congestion with some hemorrhage and inflammatory
œdema of lung and in the absence of any sign of grey hepatization or
purulent infiltration. In many of these cases the involved areas of lung
though heavy and œdematous, were still partly air-containing and the
amount of lung involvement was insufficient, on the basis of mechanical
interference, in accounting for the severity of the clinical symptoms
and the fatal outcome. This must have impressed everyone dealing with
the autopsies during the acute epidemic. It immediately suggests that in
some cases at least the pulmonary lesion, in as far as incapacitating
the external respiratory system, was not the sole or even the important
cause of death, but that a condition of intoxication, borne out by the
evidence of damage in muscles, blood and kidney is a large factor of
danger in this disease.

We shall briefly describe the important pulmonary findings as we have
met with them in the successive stages of influenza-pneumonia. This, we
hope, will make clear the interpretation of the pathology of the lung
lesion of the epidemic as it came under our observation.

The earliest pulmonary lesion which we encountered was one of
congestion, inflammatory œdema and hemorrhage. These three conditions
were usually present at the same time and were found in the height of
intensity in all of the cases dying within the first four days of
illness. During this early period these manifestations of inflammation
were not accompanied by definite red or grey hepatization as might
ordinarily be expected. The lesions varied greatly in their intensity,
the œdema always being very prominent, while the hemorrhage varied from
a diffuse infiltration of the involved lobe or added to this, was
localized in massive collections four or five cm. in diameter and
commonly occupying the central portions of the lobes. We have seen
several hemorrhages lying in close proximity to each other with their
borders coalescing and leading to a larger central involvement. In the
regions where the hemorrhage and inflammatory œdema were diffuse, air
was still present within the lung tissue, sometimes to an extent
permitting the lung tissue to float on water but more often in quantity
sufficient only to suspend the tissue at various depths. On pressure the
fine air bubbles were recognized amidst the blood-stained fluid. Acute
compensatory emphysema often occupied the anterior borders of the lobes
or formed interstitial blebs beneath the pleura. The quantity of fluid,
inflammatory œdema and hemorrhage, contained within these bulky lobes
was often very surprising. A lobe when compressed would leak fluid with
the ease that it could be obtained from a sponge. Out of the lower lobe
on one occasion we pressed 700 c.c. of limpid blood-stained exudate. The
acute emphysema which may make its appearance suddenly, is


                               TABLE VIII

        DISTRIBUTION OF PNEUMONIC LESIONS AND GRADES OF SEVERITY

                 ═════════════════════════════════════
                 DEGREE OF INVOLVEMENT +  ++ +++ Total
                 Left upper lobe       10  6   7    23
                 Left lower lobe        4 10  17    31
                 Right upper lobe      12  8   9    29
                 Right middle lobe     10  9   4    23
                 Right lower lobe       5  9  18     3
                 ─────────────────────────────────────

                     All lobes were simultaneously
                  involved in some grade of pneumonia
                       in 18 cases—56 per cent.

at times quite remarkable. It may appear very early in disease. We have
not met with a single case where the emphysema of the lung led to a
rupture of the air sacs and an interstitial infiltration of air through
lung, mediastinum, neck and subcutaneous tissues. Some very remarkable
cases are reported by different authors where this emphysema was of
astounding grade leading to a crepitating infiltration throughout the
mediastinum, neck and the subcutaneous tissues over the thorax and
abdomen as low as the pubis. The milder grade of emphysema consisted
mainly of an abnormal expansion of the air sacs which were not
infiltrated by exudate and which probably had some effect in preventing
the diffusion of the inflammatory fluid from entering certain regions.
These emphysematous areas could be readily recognized by the naked eye
along the anterior borders of the lung as well as between the involved
pneumonic patches within the lung.

These lungs, involved in this early serous and hemorrhagic exudate
varied considerably in their appearance according to the regional and
quantitative involvement. As is seen from Table viii, the lower lobes
were more commonly occupied by massive exudate than the upper, and the
involvement of multiple lobes was the usual. Still more remarkable is
the fact that all lobes were simultaneously involved in some grade of
reaction (pneumonia) in 56 per cent. of cases. In complicated
influenza-pneumonia Goodpasture and Burnett found the inflammatory
reaction in both lungs and involving to a greater or less degree the
lobes on each side. Most commonly this involvement consisted of a lobar
distribution in one or two lobes with a lobular or patchy disposition of
exudate in one or more of the remaining lobes. Where the distribution
was lobar the involved lobe was distended to its fullest and the pleura
tightly stretched over the lung tissue which, heavy with fluid, was not
solid but flabby. The lung could be moulded under the finger and could
be compressed into various shapes. At first sight this flabby, heavy
lung tissue suggested the appearance of the waterlogged lung which one
encounters in renal disease or failing circulation. A closer analysis,
and particularly when the lung was sliced, showed an entirely different
character.

Where the inflammatory œdema was accompanied by much focal hemorrhage
the distribution was nodular and suggested the appearance of the
hemorrhagic lung of plague pneumonia. It was this appearance which led
to the suggestion that the pandemic was not one of influenza but
possibly of an infection related to the eastern plague. The nodular
masses of hemorrhage at times occupied areas varying from the size of a
walnut to that of a golf ball and were localized amidst a relatively
mildly involved lung tissue making a sharp contrast between the involved
and relatively normal tissue. With the removal of the lung from the body
and the partial collapse of the aerated tissues these nodules became
still more prominent. The greater the amount of hemorrhage within these
areas the more solid became the occupied tissue. Such sporadic
distribution of hemorrhagic lesions occurred in the two most intense and
rapidly fatal cases. Both of these individuals died within 48 hours of
the time of onset of the lung conditions. In these two cases we do not
believe that the pulmonary lesions had been prolonged over a time even
as long as 36 hours but with the difficulty of estimating the onset of
the lung involvement we are giving a liberal estimate of this time.

Besides meeting with the stages of congestion, œdema and hemorrhage
during the earliest days of the pulmonary lesions we have found that
they are to be encountered virtually through all the stages of the fatal
cases either as remnants of the original reactions which had not been
entirely obliterated by the succeeding purulent process or as was so
commonly found, new reactions occurred in other regions of the lung so
that, in the same individual, inflammatory reactions of different stages
of development could be defined. I do not recollect a single autopsy of
a case dying during the acute period which did not show evidence of some
areas in the stages of this early acute reaction. Naturally where
resolution is well advanced within the lung all trace of inflammatory
exudate of various kinds is removed and where such individuals with
their resolved pneumonia are brought to death through succeeding
complications the above finding will not be borne out. We limit,
however, our statement to the findings in the acute deaths.

We have previously intimated that the œdema present in the early stages
of the reaction is to be looked upon as an inflammatory œdema or better
as a true serous exudate, and must not be confused with the transudation
of fluids in non-inflammatory conditions. We have on several occasions
collected the fluid expressed from the soggy lungs and have made some
determinations of their chemical qualities. The difficulty immediately
arises in separating the materials arising from cellular degeneration
from the natural constituents of the serous exudate. We were unable to
obtain specimens in which laked blood was not present, so that even
though the cellular constituents and fibrin were removed, decomposition
products could not be separated. The analyses, however, gave a
differentiation from the transudate seen in renal and cardiac
conditions.

During the period of the accumulation of this inflammatory fluid the
clinician could often recognize a profuse watery exudate within the lung
or even observed an abundant serous discharge arising in bronchi and
trachea. At times the quantity of expectoration was great. Frothy serous
fluid accumulated in the air passages and would periodically be
expectorated. At other times the hemorrhage was of quite serious extent
and the patient would suddenly bring up several mouthfuls or more of
bright blood. This pulmonary hemorrhage was without manifestations
different from the acute illness with cyanosis of other individuals. The
two most acute cases, which we have referred to above, were of this
kind, both of them having marked hæmoptysis with the loss of upwards of
a pint of blood at a time.

The early pulmonary lesion which we have described, we have called acute
serous pneumonia and acute hemorrhagic pneumonia (or we might speak of
it as an acute sero-hemorrhagic pneumonia) and is one which is
distinctive for epidemic influenza. The cut surface of a lobe involved
in this reaction is wet, glassy, meaty and oozes much blood-stained
fluid. It contains no visible fibrin and presents no characters of a
“cellular consolidation.” As a serous inflammation of the lung it is
unique. The further remarkable character to the pulmonary lesion is that
in advancing through the other stages, it never passes through a stage
of “red hepatization.” Here again we have a distinctive difference from
the pneumococcus-pneumonia. From what we have previously said about the
nature of this early acute inflammation of the lung in this disease it
is apparent that red hepatization has no place in its process. The stage
of red hepatization is attained only when the inflammatory reaction is
accompanied by certain constituents in the exudate, which upon
coagulation (separation out of the fibrin) renders the lobe dry and
solid, while there is a sufficient abundance of red blood cells and
congestion to maintain a dark red color. The hepatized lung on section
is dry, more or less granular, containing fibrin, red cells and
leucocytes within the alveoli. Extensive œdema is unusual except in the
cases of hypostatic pneumonia, which in well marked cases bears some
resemblance to the gross appearance of the early influenza pneumonia. We
have not encountered a single case of the red meaty lung of influenza
which showed evidence of true red hepatization in the gross.

The _microscopical_ examination of the lung tissue confirmed the
observations which were made in the gross. In the early stages of
congestion the reaction was much more extensive than what could be
spoken of as a broncho-pneumonia. The capillary dilatation in the
alveolar walls occupied diffuse areas varying from multiple lobules and
areas several cm. in size to the common diffuse congestion of an entire
lobe. Capillaries were distended to their full capacity and often this
engorgement was associated with the leakage of blood or a serous fluid.
Not uncommonly a clear serous fluid was exuded into the interstitial
tissues of the alveolar wall and collected within the air sacs. The high
albuminous content of this fluid was seen in the homogeneous coagulation
which occurred when the tissues were placed in fixatives. The
microscopical sections of such parts demonstrated the coagulum occupying
the alveoli as a clear homogeneous substance containing relatively few
cells and looking not unlike the colloid deposit of the thyroid. The
alveolar walls, themselves, were infiltrated with fluid so that the
distended tissues and vessels made these structures thick and bulky. In
our own observations we were impressed by the differences of the early
inflammatory reaction from those ordinarily seen in pneumonia. Amongst
these differences was the quantity of fluid extruded into the lung with
a relative absence of fibrin. In some instances fibrin was completely
wanting, although small quantities could be demonstrated in isolated
areas. This observation upon the quantity of fibrin can be made only
during the early stage of the disease in as much as after secondary
infection of various kinds has become implanted the presence of fibrin
has become a variable quantity often exceeding that seen in the early
stages. This is one of the points upon which the older authors have laid
stress in differentiating influenza pneumonia from others. In this we
fully concur. Whether this lack of fibrin in the inflammatory exudate is
a characteristic to be associated with the infection by the B. influenzæ
alone is hard to say, but in as much as it was such a prominent finding
we are led to lay some stress upon it. It is, of course, to be realized,
as with all other micro-organisms that under certain conditions fibrin
will form an important part of the exudate even when the B. influenzæ is
present. This is true in the inflammatory reactions of the meninges
present in infections due to this bacillus. Under the conditions of
epidemic influenza where the lung lesion is the prominent and unique
reaction this micro-organism fails by itself to bring out this quality
in the exudate.

Not uncommonly this stage of inflammatory œdema was accompanied by
various grades of hemorrhage, varying from the presence of small
aggregations of red cells to a complete flooding of the lung tissue
making it look not unlike a red infarct of lung, save that the alveolar
walls still showed an active circulation and living cells. It was
remarkable that even though there was such an intense reaction taking
place in the lung tissue there was little or no evidence of a cellular
exudate during this stage of the process. Where much blood was extruded
into the alveoli occasional fibrin threads were found in the coagulum.
In these early cases the bronchicles and small bronchi were found to
contain an exudate similar to that in the alveoli. Not uncommonly the
vessels from which the red blood was escaping, could be demonstrated in
sections. The appearance of the vascular wall suggested that a definite
opening had occurred in the side of the capillary from which the blood
escaped. We were not able to demonstrate a fatty or other type of
degeneration in the cells of the capillary walls. It is probable that
the process of injury was much too acute to permit of the demonstration
of the products of degeneration within the surviving cells.

The hemorrhagic lesions which had existed for a longer period of time
gradually showed a varying infiltration by wandering cells. The earliest
cells not belonging to those of the hemorrhage or œdema appearing within
the alveoli were mononuclear elements partly arising from the alveolar
walls and partly coming from the circulation. Numerous mononuclear cells
of epithelial type desquamating from the inner surface of the alveoli
accumulated in the œdematous fluid and the hemorrhage within a short
time after their occurrence. These cells either appeared in clusters or
as single elements. Accompanying this were also large mononuclear cells
loaded with different quantities of pigment which had apparently escaped
from the lymphatic channels within the alveolar walls. These latter
cells belong to the wandering endothelial type which are active in
phagocytosis for foreign material and which assist so largely in
inducing the deposit of carbon in the lungs and lymph glands. A third
mononuclear cell appearing early in the reaction was the lymphocyte. The
numbers and extent of distribution of this cell were not constant. We
have seen it in some of the reactions where very few leucocytes were to
be seen, and where it constituted the main infiltrating cell of the
alveolar wall or the air sacs. We have previously mentioned its presence
in the inflammatory reactions of the bronchi. Here we find it in the
early response within the lung tissue and appearing amidst a reaction
which is intensely acute. It is not long after the finding of these
various cell elements that the polymorphonuclear leucocyte wanders in
large droves to numerically overshadow the mononuclear cells.
Nevertheless, the three types above mentioned can be recognized in the
exudate through the succeeding stages of reactions in the lung. The
large macrophage shows its phagocytic properties in taking up numerous
red blood cells, lymphocytes and occasional leucocytes.

It is not difficult to demonstrate that the inflammatory reaction within
the bronchi and bronchioles precedes the responses within the alveoli.
Quite often one may find an acute bronchiolitis with desquamation of the
lining epithelium and the early serous exudate lying amidst the lung
parenchyma unaffected by any irritant and reaction. There is every
evidence that the bacteria reach the lung tissue by extending along the
walls of the respiratory tubes and eventually reaching the air sacs
either in the distant extremities of the bronchioles or when they have
arrived at the thin-walled structures extend through them into the
neighboring air sacs.

It is during this early period that we are able to observe the
characteristics of the initial inflammatory exudate as we have described
it above. The serous exudate and the infiltration by mononuclear cells
appear early while the absence of fibrin also attracts attention. In
place of fibrin there appeared in a certain number of cases a peculiar
material of a hyaline nature which becomes plastered against the borders
of the air sacs forming a fairly thick laminated structure and within
which thread-formation is not to be seen. Occasionally a few cells lie
within this hyaline substance. Some have referred to this as a type of
fibrin. We have found, however, that it does not give the staining
reactions for fibrin and does not appear to be of the same composition.
These masses are tightly welded to the alveolar walls and the borders
are often indistinguishable. In part this material appeared to be made
up of necrotic cells of the septum which previously had suffered œdema
and circulatory interference. We have found in a number of cases hyaline
thromboses of the fine capillaries with more or less necrosis of the
alveolar septum. At times the septum was entirely destroyed so that a
thick hyaline mass alone separated neighboring air sacs. This hyaline
necrosis resembles in part the superficial necrosis which was observed
along the borders of the denuded bronchi. There is, however, more than
necrosis of cells constituting this deposit for the bulk of material
eventually deposited is much greater than could arise from tissue cells
alone. These hyaline masses have never been found to lie upon the
alveolar wall with an intact lining, but it is always accompanied by a
loss of the lining cells and more or less destruction of the wall
itself. As to the nature of the hyaline deposit which is laid down in
lamellae we do not know. Fibrin threads occasionally appear to arise
from these hyaline deposits and extend amidst the exudate in the air
sac. One cannot assume, however, that the fibrin and the hyaline
material have any relation to each other as their chemical
characteristics (and mode of deposition) appear to be quite different.
It has been suggested by some that this hyaline material represents an
imperfectly formed fibrin which has formed a jelly-like clot, not having
the property of developing the usual threads.

It is of importance to appreciate that the deposition of these hyaline
structures indicates a severe injury of the alveolar walls not commonly
observed in ordinary pneumonias.

In different areas of the same lung these constituents of the early
exudate may be observed in all proportions of admixture. Each one of the
elements of the exudate may largely overshadow the others and
prominently modify the appearance of the lesions. Broadly speaking,
however, the inflammatory œdema and hemorrhage occupying the greatest
part of the exudate in the lungs and the absence of marked leucocytic
response as well as the absence of the characteristic fibrinous meshwork
in the alveoli give to the early influenza-pneumonia a character
different from those which we ordinarily see.

It is during this early phase of the reaction that the influenza bacilli
can be shown within the lung structures. The distribution of bacteria is
not uniform. Clusters of these minute bacilli are found in the alveoli
at irregular intervals, many of the air sacs containing much exudate
being quite free from organisms. When present the bacteria appeared in
tightly aggregated schools lying free amongst cells of the exudate, but
also certain numbers being incorporated within the large mononuclear
cells. In some regions organisms of the type of the influenza bacilli
were alone seen, while elsewhere again, and particularly where the
exudate was assuming purulent characters other bacteria of the nature of
streptococci, staphylococci and micrococcus catarrhalis, were also
found.


                         _Lung—Secondary Stage_

Following upon the primary reaction in the lung as above described, a
secondary reaction makes its appearance at variable periods. This
reaction is one in which the inflammatory exudate resembles more closely
but is not identical with the responses which are observed in ordinary
lobar, lobular and pneumococcus-pneumonia. Whereas in the earlier
period, the reaction is largely one of a serous and hemorrhagic exudate
accompanied by peculiar hyaline deposits along the inner borders of the
alveoli, later there is seen a change in the quality of the exudate with
the accumulation of more cellular elements and some fibrin. The naked
eye appearance of the involved tissue changes considerably. The lung
tissue loses in weight but becomes more solid. The lung contains less
fluid and the cut surfaces are drier and the color of the reaction
changes from the dark congested appearance to one showing all varieties
of red and gray. This change from the flabby and soggy pneumonia to the
more definite type of consolidation occurs in the regions which have
been previously involved and is not to be found in the lung areas which
have escaped the early reaction. The gray consolidation appears to be
either a stage of the influenza-pneumonia or is a new reaction
superadded to those pulmonary lesions induced by the primary infection.

It is sometimes difficult to recognize the beginning of this pneumonic
stage inasmuch as the gray color does not make its appearance even with
the presence of fairly large quantities of cellular exudate. The amount
of hemorrhage that originally lay in the affected areas for a long time
overshadows the presence of the color of the cellular exudate. This is
also true of the characters that may be impressed by the presence of
fibrin. Small quantities of fibrin scattered through the congested and
œdematous lung are not readily recognized and the beginning of this
secondary reaction is also easily overlooked if one relies upon evidence
of consolidation. More or less solid exudate may occupy a flabby lung
without permitting one to appreciate its presence in the gross specimen.
When, however, the deposit is of sufficient quantity to change the color
of the involved lobe and to alter its consistency, one has little
difficulty in recognizing the changes now taking place. The earliest
development of this change in the inflammatory reaction was on the
fourth day. In the majority of instances the gray color and the
consolidation made its appearance about the sixth day. We have, however,
on several occasions observed hemorrhagic lesions as late as the seventh
and eighth day, at which time it was impossible to recognize a gray hue
to the exudate or the character of granular consolidation to the
involved lung.

The reaction naturally suggests the stage of gray hepatization as we so
well appreciate it in ordinary pneumococcus-pneumonia and from the
standpoint of its color and the greater solidification of the lung
tissue we might speak of it as such. Here, however, it must be clearly
distinguished from the gray hepatization of ordinary pneumonia. This
secondary lesion of influenza-pneumonia has but little in common other
than its color and the development of a consolidation with true lobar
pneumonia. It is never as clear cut as we see it in the latter and the
degree of the “gray hepatization” is not uniformly distributed through
the involved lobe. One portion of the lobe will show a diffuse gray hue
while in other parts more decided lobular or patchy areas are picked out
in the advanced reaction. There is not the uniformity of lobar
involvement nor is the distribution as regular as one obtains it in
broncho-pneumonia. Furthermore, the character of the consolidation
differs very decidedly in showing such a variety of hues in reds and
grays and the cut surface is not the picture of the dry granular
consolidation of our endemic disease. The gray areas are in all states
of wetness and ooze a slimy fluid on the cut surface. In the later
stages this exudate is most profuse resembling a sticky pus. In its
appearance we were reminded of the character seen in unresolved
pneumonia as well as in the pneumonias produced by the pneumococcus
mucosus, and the B. mucosus capsulatus. We would, therefore, avoid the
use of the term gray hepatization and in place of it, as the evidence
with the microscope confirms, use the term _purulent pneumonia_.

There are three other characters which differentiate this gray stage
from those of ordinary pneumonias—(1) the irregular distribution, (2)
the friability of the involved tissue and (3) the interstitial reaction.
We have never observed such an irregularity in the distribution of a
gray stage of pneumonia as we have seen it develop in acute
influenza-pneumonia. All types of involvement of the lobes are found in
different cases and even sometimes in the same case. The least frequent
type has been the broncho-pneumonia in its true form. Broncho-pneumonia
as we see it in children and the cases following measles is usually
fairly uniformly seeded through several lobes and the size of the
individual patches is about that of a split pea. The small bronchus can
be recognized about the center of the involvement. In those instances
one has studded through the lung tissue numerous small swollen areas
which are granular, dry and gray. Differing from this the patchy
distribution of the gray stage of influenza-pneumonia had no regularity
either in the size of the areas nor the distribution. A lobe may show
one or more patches. The patches may be distributed toward one portion
of the lobe more than another. Furthermore the areas do not always
encircle the small bronchi but involve the terminal portion so that an
entire lobule is more commonly affected. The lobular type rather than
the peribronchial type is most commonly seen and it is often remarkable
how sharply the gray lobule is demarcated from the surrounding congested
lung tissue. On several occasions we observed a single lobule in the
gray stage while the remaining portion of the lobe was in the serous and
hemorrhagic condition. However, multiple lobules are commonly seen
closely associated in the advancing inflammatory process. Such lobules
show peculiar geographical patches or leaflet-like configuration.
Varying with the number of lobules involved the extent of the gray
change in the lobes assumed more or less a lobar distribution. There was
no uniform position to this pneumonic state sometimes appearing in the
peripheral tissues of the lung, at other times lying centrally with less
involved or less advanced inflammatory reactions surrounding it.
Nevertheless, the gray stage made its appearance more rapidly in the
lower lobe than the upper and it was not uncommon to find this condition
appearing quite early in the upper posterior portion of the lower lobes.
This latter position is the one which is recognized during life by the
clinician as one of the earliest localizations of the demonstrable
pneumonia. It is reported by many that the first physical signs of
consolidation are to be obtained close to the lower angles of the
scapulae.

There is no doubt that the character of the pneumonic process in the
epidemic influenza was not the same in all localities. There have been
not a few who have reported a large proportion of their pulmonary
lesions as a definite broncho-pneumonia with an interstitial purulent
involvement. The prominent reaction was a small circumscribed yellow
focus about the bronchioles from which a bead of pus could be expressed.
These pea-sized foci were scattered through several or all lobes. It is
this type of reaction which appears to develop by a direct extension
through the bronchial walls and to remain quite localized in the alveoli
about these tubes. This reaction seems to be purulent from its very
beginning and does not pass through the stages as we have described them
above. There is more or less fibrin present in the exudate, but usually
not in the quantity observed in lobar pneumonia. These lesions closely
resemble those observed in the post-measles pneumonia, and it is claimed
are the result of the same agent; the hemolytic streptococcus. In only
one case did we observe a lesion of this kind. The small areas of
broncho-pneumonia were confined to the left lower lobe and in the lower
portion of the upper lobe. Each area was about the size of a split pea,
was quite yellow and in fairly sharp contrast to the background of an
acute sero-hemorrhagic pneumonia. The subsequent history of these
interstitial purulent broncho-pneumonias is like that in measles, where
the tendency toward an organizing pneumonia has been shown. The
importance of the hemolytic streptococcus in inducing purulent
interstitial lesions of the lung (and also of other organs) cannot be
over-impressed. It is not so much the type of the reaction during its
acute stage which attracts our attention, but the manner of the healing
process. It is more than probable that the organizing pneumonias of
influenza, not only of this distinct bronchial type, but also the
lobular, confluent and lobar variety have had an associated
streptococcus infection. The more intimate discussion of this type of
pneumonia has been given by MacCallum.

Our autopsy experience has led us to believe that the definite clinical
signs of pneumonia are associated with the development of this gray
consolidation of the lung. The lung tissue develops characters which
permit the physical signs to be recognized. The tissue is more solid and
more readily transmits the bronchial sounds. This is not true of the
earlier stages where the inflammatory process is contained within a lung
tissue which still is partially crepitant and when the so-called
consolidation is due to an inflammatory œdema and not to the more solid
fibrinous and cellular exudate. With the protean distribution of the
gray lesion one does not wonder at the clinical difficulties in mapping
out or even finding the consolidated tissues.

As soon as the lobes show this gray character and with the progressive
development of an acute interstitial purulent pneumonia, the lung tissue
becomes friable. All gradations of flabbiness may still be obtained and
in the early stages while the cellular exudate is accumulating to change
the color of the lung, little variation from the tough character of the
pulmonary tissues can be recognized. When, however, a true gray
character is assumed by a portion of the lobe, the tissue becomes so
soft that it is handled with difficulty without rupture. The thumb can
be pressed into the gray mass and pus will well up around the invading
phalanx. The consistency in the late stages reminds one of the pulpy
tissues in acute splenitis. In cutting such lobes it is almost
impossible to obtain slices of the tissues, their own weight often
breaking such a segment. When allowed to rest on the table for a few
moments, the cut surface becomes coated with a dirty yellow slime
representing pus and products of disintegration arising from the lung.
The stroma and alveolar tissues are themselves involved in the
inflammatory process and many of them have suffered complete or partial
destruction so that they offer but little resistance to pressure and
serve as a poor supporting stroma to the pulmonary tissues. The reaction
which has taken place within the lung producing both the gray color and
the destruction of the tissues is, indeed, an active suppurative one.
One would not be surprised to obtain not only a purulent lesion wherein
the cellular exudate occupies the air sacs and their walls but also a
further stage leading to a destruction of the tissues to the extent that
abscess cavities are produced. These we have met with in several
instances, some of them being small while others were several
centimeters in diameter. An abscess of larger extent and having a
destructive process which involved the surrounding tissues so that one
would speak of it as a process of gangrene, was observed by Dr. McMeans
in one of his cases. A lobar distribution of the purulent lesion takes
place where multiple involved lobules have fused in their periphery or
where a suppurative flooding of the tissues in this violent late
reaction has taken place.

The question at once comes to mind whether this gray stage is but the
late event of what we have previously spoken of as influenza-pneumonia
or whether this condition is superadded to what may begin as an
influenza-pneumonia but end in a pulmonary inflammation with a mixed
infection. Dr. Holman was not able to demonstrate a sufficient
difference in the bacteriology of the lobes in the gray stages from
those in the early acute stage to be able to say that the flora changes
at a certain time during the progress of the disease in the individuals.
It is possible, and there is some evidence in support of this, that the
earlier stages of the pneumonic process represent the reaction to the
influenza bacillus and that during this period the response is fairly
uniform and similar owing to the fact that this infection has but a
short incubation period and a high pathogenicity. In such an event the
particular micro-organism may bring about a peculiar response of its own
before the other organisms with which it is associated have the
opportunity of producing damage. Subsequently, however, these secondary
organisms impose their peculiar reactions upon an altered lung, thus
inducing an inflammatory lesion which differs from the preceding
reaction and also differs from the reaction usually induced by those
organisms upon relatively healthy tissues. It is difficult to account
for the very irregular distribution of the gray lesions by an
explanation concerning the influenza bacillus alone, or by the
characters peculiar to the secondary infection. There is an entire want
of character to these gray lesions which makes them differ from other
types of pneumonia known to us.

It is well to lay particular stress upon this peculiarity in the
distribution and extent of the lesions within the lobes; and it is also
important to appreciate the difference in the appearance of these gray
areas from those of true lobar or broncho-pneumonia.

Finally there is another point in which this stage of the pneumonic
process differs from that of pneumococcus lobar pneumonia. In frank
lobar pneumonia the reactions taking place in the involved portion of
the lung are fairly uniform in all its parts. The stage of red
hepatization occupies about that amount of lung which subsequently shows
itself in the state of gray hepatization. In other words, all of those
areas which appear gray are preceded by this peculiar red consolidation,
and all of the area occupied by the red hepatization will pass through
the phases of gray hepatization before entering upon the final stage of
resolution.

In influenza-pneumonia, on the other hand, the events taking place in a
given lobe are not uniform and various stages and grades of the
inflammatory reaction may be recognized at the same time, some appearing
red, some congested, some flooded with blood in hemorrhage and others
showing the purulent infiltration by the appearance of gray patches upon
the background of red. Not only do the various reactions within the same
lobe fail to show similar grades of intensity and similar stages or time
of involvement, but we find that all of the red and hemorrhagic areas
are not destined to pass through the gray stages. At times it is true an
entire lung will enter into the purulent phase and if this becomes
extreme abscess and gangrene are almost certain to develop. But often
the purulent infiltration occupies only a few or scattered lobules and
resolution may take place in a lung where the greater part of the lobes
is occupied by the inflammatory œdema and hemorrhage and has never
become truly consolidated by cellular and fibrinous exudate. This
feature that the involved lung tissues need not pass through the
sequence of events which is usually observed in frank lobar pneumonia is
so distinctive that it differentiates the character of the inflammatory
reaction very clearly. It may be that this is an indication of the
unequal distribution of the micro-organism and that the first infection
presumably by the _bacillus influenzæ_ has been much more diffuse and of
wider extent than the secondary invading bacteria which being
distributed through the bronchial tree are more or less localized to
those lobules most severely involved. It is impossible to claim for
influenza-pneumonia as clear and sharp-cut stages as we obtain them in
the pneumococcus lobar pneumonia.

During the period of the intense purulent reaction in certain portions
of the lung, the intrinsic structures within the area also partake in
the damage and response. The suppurative infiltration not only occupies
the alveolar walls but also extends through the tissues of the
bronchioles, the arteries and the veins. The polymorphonuclear
leucocytes seem to migrate into all of the parenchyma indicating some
damage by bacterial invasion. On more than one occasion have we observed
partial or incomplete thrombosis of arterioles and capillaries whose
walls showed an acute suppurative reaction. Some of these thromboses are
of importance, being associated with the interference with a blood
supply not compensated by adequate anastomosis. Necrosis and small areas
of gangrene and abscess are to be found in the region of the circulatory
disturbances. It is also during this period of the disease when the
bronchi and their ramifications contain pus or muco-pus, that the
exudate from the alveoli readily finds its way into the air passages and
becoming mixed with the mucus from these tracts forms a tenacious
discharge.

The presence of large amounts of exudate within the bronchi brought
these structures into unusual prominence. This was particularly true in
the purulent stage of the reaction when beads of sticky pus would well
up from the cut bronchioles. We were tempted on a number of occasions to
speak of this in terms of bronchiectasis but with the intense
inflammatory reaction occupying the bronchial wall and modifying its
contour on this account we avoided this diagnosis. In one instance,
however, the lesion was unmistakable. This was a case of purulent
pneumonia (764) dying on the ninth day of the disease. The distribution
of his pulmonary lesions was distinctly lobular, apparently following
the course of the bronchial distribution. The bronchi were followed
longitudinally and irregular pouchings of the lumen were very apparent.
The bronchi had suffered marked inflammatory reaction which had also
infiltrated the muscular tissues of the tubes. Goodpasture and Burnett
report finding two cases of acute bronchiectasis associated with abscess
and ulceration of the bronchi. In our case the bronchiectasis was found
bilateral but was more marked in the lower lobes than the upper.

The lymphatic channels within the lung tissue are found active in
establishing an internal drainage to the neighboring thoracic glands.
The lymph vessels were often found filled with leucocytes and variable
amounts of serum. During this late stage only a few of the endothelial
leucocytes were observed wandering to or from the lung with a load of
pigment or cell debris. These wandering endothelial cells, however,
appeared to become loosened from their normal situations and in the
vicinity of lymphatic nodes or communicating channels where these cells
are prone to localize with their carbon pigment, again assumed their
spherical form and took on migratory properties entering into the nearby
tissues and scattering themselves in the looser structures. It is an
interesting point to note that these pigment carrying cells, ordinarily
assuming a latent existence when their cytoplasm has been crowded with
foreign particles will assume all the activities of migrating cells when
the œdema of the tissues alters the physical properties not conducive to
a stationary existence. These cells will then be found to enter the lung
alveoli, often appearing as cells which have only recently picked up
their carbon load. When, however, the conditions of the experiment, that
is, the production of an inflammatory œdema in the lung, are produced in
the tissues of an individual with much anthracosis, he will, during the
period of his pneumonia and for some time during convalescence, bring up
a greater number of these cells in his sputum than are ever obtained
during the times when the lung is not involved. We are convinced that
inflammatory conditions of the lung tend to reduce the total number of
latent pigment bearing cells present in the involved tissues, and in
this way somewhat reduce the grade of anthracosis.

A considerable discussion has arisen concerning the proper nomenclature
for the pneumonia or pneumonias found in epidemic influenza. From some
quarters have come the reports of a true lobar pneumonia, from others a
lobular or broncho-pneumonia and others again claim that the reaction is
an interstitial pneumonia of varying distribution. It appeared to us
that the gross distribution of the lesions is not alone the criterion
for a proper appreciation of the inflammatory states which may arise
within the lung. I believe it has been amply demonstrated that the
pneumonic reactions appearing in different regions of the United States
as well as in different countries are not of a constant kind when viewed
alone in the light of the gross picture nor are they constant from the
standpoint of their bacteriology. We are of the opinion that the earlier
phases of the pulmonary reaction are fairly constant in different places
and that this constancy is dependent upon the common virus which
initiates the respiratory lesion and which then permits a variety of
micro-organisms invading as secondary agents. The secondary agents vary
with the community and depending upon their nature the character of the
reaction differs from that in other places. It has been well
demonstrated that in some regions the hemolytic streptococcus is the
important organism following the primary injury by the initial virus. In
other places the pneumococcus or the staphylococcus or the M.
catarrhalis is found to be of primary importance. Up to the present it
has not been shown that the influenza bacillus is not the important
organism causing the initial reaction and being responsible for the
opportunity of secondary invaders leading to such diverse reactions in
the lung. In our series we have met with lobar, lobular, interstitial
and broncho-pneumonic types. We have not observed a case of the miliary
bronchial reaction as described and illustrated by Goodpasture and
Burnett and fully investigated by MacCallum. Moreover we have not met
with the type of purulent bronchitis as a characteristic lesion
preceding pulmonary involvement. The occurrence of pus within the
bronchi occurred not early in the pulmonary lesion but later after the
bronchi and bronchioles had passed through their stages of acute, serous
and hemorrhagic pneumonia and were entering upon their secondary stage
with pus production. The pulmonary lesion had long preceded the
appearance of pus in the bronchi. We do not hold, however, that such
relations between the pulmonary lesion and the purulent bronchitis do
not exist for there is evidence that in particular regions this sequence
of events was closely observed.

We cannot, however, correlate our findings with the classification of
pneumonias as given by MacCallum. His claim for specific types of
pneumonia as a sequel to influenza is based upon his statement that “no
satisfactory evidence has been brought forward to show that the epidemic
influenza is a bacterial infection. It is evidently a general or
systematic infection not especially affecting the respiratory tract and
analogous in many respects, as Bloomfield has pointed out, to the acute
exanthematic diseases.” Thus we are confronted by two schools concerning
the nature of influenza. The one claiming that epidemic influenza is
essentially a disease of the respiratory system and the other completely
denying this.

I am unable to understand the claims which are put forward to
substantiate the second view.

The classification of the pneumonias as suggested by MacCallum would be
valuable if it could be applied in a practical manner. We find, however,
that his description for the pneumococcus-pneumonia hardly coincides
with common observations on endemic pneumonia and if the description is
to apply only to the pneumonias associated with influenza wherein
pneumococcus alone is isolated we find that our own observations do not
coincide with this. The picture offered by MacCallum under this heading
was reproduced when the bacteriological findings illustrated the
presence of organisms other than the pneumococcus or combinations of
these. The most characteristic of his description is the one for the
streptococcus-pneumonia which when present alone gives quite a unique
picture. The picture, however, is to a certain degree modified by the
reactions which precede the streptococcus in the lung. Furthermore to
offer as a characteristic picture for the influenza infection of the
bronchi the presence of a thick yellow pus is hardly complete inasmuch
as this exudate appeared only as a stage in the inflammatory process.
The intense serous and hemorrhagic response observed early in this type
of infection is more unique than the presence of pus which appears
somewhat later and which may occur with infections other than the B.
influenzæ. It has long been the hope in pathology to be able to
establish by the character of the tissue reaction, the nature of the
infecting agent. Up to the present this has been possible only with a
very few types of bacteria.


                       _Lung—Stage of Resolution_

The removal of the infection and the inflammatory exudate from the lung
tissue is accomplished slowly. Clinically the pulmonary process clears
up by lysis, and it is quite unusual to have a crisis with the rapid
disappearance of the serious manifestations. It is difficult to obtain a
clear conception of what takes place in any individual case recovering
from an influenza-pneumonia, but if we have an understanding of what may
occur in the inflamed lung tissue in any one of the stages or varieties
of kind, we may visualize the changing character of the lung condition
tending toward the final restoration.

We have previously pointed out that the early stage of
influenza-pneumonia is one of congestion, œdema, hemorrhage and more or
less leucocytic infiltration, and that this reaction differs materially
from that observed in pneumococcus lobar pneumonia. There being no stage
of true red hepatization, it has also become apparent that this peculiar
primary reaction need not pass into the stage of gray consolidation.
Scattered areas in the lung pass from the condition of acute serous and
hemorrhagic pneumonia to a type of purulent pneumonia while much of the
remaining tissue continues in the state as seen in the early reaction. A
certain amount of cellular exudate makes its appearance but not
sufficient to lead to a true consolidation. This variety of reaction is
present from the fifth day of the pneumonia onwards and may continue
with all of its varieties through until the tenth or twelfth day or even
longer when recovery from the infection is beginning. Thus the stage of
resolution makes its appearance before the inflammatory reaction in the
involved lobes has assumed a common character and where we are able to
recognize different grades of severity and different stages of
inflammation within the same lobe. Resolution taking place in such a
lobe has responses occurring in the different parts determined by the
nature of the antecedent reaction. We have found that those portions
which have not advanced beyond the stage of œdema and hemorrhage may
clear up with the disappearance of this early exudate and its infection.
In a neighboring portion the purulent inflammation passes through phases
differing somewhat from the preceding but also tending toward the
restoration of the parenchyma and the disappearance of the inflammation.
It would be incorrect to consider the resolution of the early type of
inflammatory reaction as an abortive process inasmuch as it is not yet
clear whether this serous and hemorrhagic process is not the
characteristic inflammation of a peculiar micro-organism or organisms
and that when acting alone these bacteria do not in themselves stimulate
a further inflammatory response. Hence if it is true that there is a
peculiar inflammatory reaction of a non-suppurative and non-fibrinous
kind the manner of resolution will differ somewhat from that where these
other constituents of the exudate are present. It becomes clear,
therefore, that in influenza-pneumonia all of the lung involved in the
early peculiar inflammatory reaction need not pass through those stages
and reactions as we recognize them in pneumococcus lobar pneumonia.

The resolution taking place in the areas of serous and hemorrhagic
pneumonia is accomplished largely by a reabsorption of the fluid,
autolytic disintegration of the red blood cells and a certain amount of
phagocytosis of red blood cells and their debris. This resolution is
quite rapidly accomplished, and the clearing up of such an area may take
place in a remarkably short period of time. The leucocytes and
endothelial cells which are present with every such reaction become
active in phagocytosis of bacteria, and we have repeatedly observed them
crowded with small Gram negative bacilli, whose morphology is similar to
that of the B. influenzæ. These areas contain but few bacteria of other
kinds. The exudate in the alveolar walls is also simple in character and
is readily removed. Slight suffusion of blood, serous fluid, and
migrating cells may occupy portions of the alveolar walls during the
acute reaction, but these, too, are easily removed and the tissue
rapidly resumes its normal character. The vascular and lymphatic
congestion again disappear and the tissues which once were soggy return
to a normal state without leaving behind evidence of the pulmonary
incapacity. The lining epithelium of trachea, bronchi and alveoli is
restored by proliferation from the neighboring less injured parts.

If this early stage in influenza-pneumonia is to be compared with the
early reactions of endemic pneumonia, it is interesting to note with
what ease the resolution may be accomplished in the former, whereas in
the latter a further sequence of stages must apparently be passed
through before the lung is cleared of its inflammatory products. As we
have intimated before, the early exudate in these two types of pneumonia
differs very essentially, the one being accompanied by much fibrin and
leucocytes which are present only in small quantities in the pulmonary
lesion of influenza.

Resolution of the other portions of the involved lobes in influenza is
not so easily accomplished. Where a progressive lesion with its
development of pus occupying both the air sacs and the tissue of the
lung, the outcome of attempts at repair are uncertain. Complete
resolution with complete disappearance of the purulent exudate may take
place as we see it in many other regions occupied by a similar reaction;
and where the purulent response is not accompanied by material damage to
the tissue the restoration of the lung is so complete that upon its
recovery no evidence is left behind of the former injury, but in as much
as the presence of a purulent reaction in the lung is often of more
severe grade than this, a certain amount of tissue destruction having
been accomplished, the repair does not completely restore the tissue to
its former normal state. The purulent lesion, however, is not uncommonly
accompanied by minute capillary thromboses, tissue derangement, organic
destruction, with even tissue alteration amounting to abscess or
gangrene, and it is too much to hope that the lung may be completely
restored. Minute abscesses varying from microscopic size to large
cavities, several centimeters in diameter, were not unusual in the
tissues severely involved in the purulent reaction. Thus in these areas,
resolution can be accomplished only by a process of slow organization of
the damaged parts with the final production of fibrosis. These fibroses
are of variable extent depending upon the initial damage. We have been
very much struck with the speed with which this process of organization
may take place and the extent of the lung tissue which may become
involved in this late lesion. In one of our cases we have evidence of
marked fibrosis present on the twenty-third day of his illness. Patches
of organization varying from one to four centimeters in diameter
occupied the different lobes of the lung. The new fibrous tissue was
well developed and the purulent reaction had largely disappeared. The
fibrosis obliterated the normal architecture of alveoli and bronchioles,
leaving only irregular islands of epithelium which assumed grotesque
glandular shapes and looked not unlike a new growth. One of the
interesting features of these late fibroses which come to occupy various
extents of the lung and bronchial tissues is that the individual after
recovering from his acute influenzal lesions again passes, in about his
third week, into a stage of dyspnœa with manifestations out of
proportion to the physical signs or constitutional derangements which
can be determined. The dyspnœa is often the outstanding sign and the
patient may die in a state of asphyxia.

We have observed evidence of organization in its earlier reactions
taking place in the patches of gray consolidation. This organization of
the lung tissue takes place as an interstitial fibrosis and as an
alveolar organization. Masses of granulation tissue grow out into and
come to occupy the lumen of the air sacs, while in other instances the
new growth of tissue takes place mainly in the alveolar walls converting
them from thin partitions to thickened and tough structures. In the
cases in which a purulent pneumonia was present for some time, and where
some of these tended towards repair, this type of restoration with the
new development of connective tissue was found. The amount of fibrosis
varied very much, and in many instances there was no evidence that
obstruction to the bronchioles occurred to a material degree. Hence,
although we believe that more or less organization occurs in all of
those cases which have passed through a purulent pneumonia, and that a
permanent mark is left upon the lung tissue, it is not probable that the
amount of involvement and final damage by fibrosis is sufficient to
seriously influence the pulmonary respiration. There is, however, a
certain percentage of cases in which this organization and fibrosis does
involve sufficient of the lung parenchyma and bronchioles to interfere
with the pulmonary ventilation.

Where the purulent pneumonia has markedly involved the parenchyma, and
particularly where vascular channels both large and small have suffered,
some of them by thrombosis, others by a sclerotic thickening, the
circulatory disturbance may be sufficiently interfered with to infarct
the area. The infarction usually occupies the purulent area itself, and
with the complete occlusion of the circulation the resulting necrosis
gives rise to an appearance different from that usually seen in
pulmonary infarcts. The area may lie in the peripheral portion of the
lobe or may occupy deeper parts. The infarct is of a cream-white color,
quite homogeneous, and resembles the appearance of a local area of
caseous pneumonia. This appearance is brought about through the local
purulent consolidation undergoing necrosis. Some of these areas rapidly
develop a cavity through liquefaction of the exudate.

The localization of the inflammatory products not only upon the surface
of the air sacs but also in the stroma of the alveoli; the interlobular
trabeculæ, and about the vascular channels indicates the intense effect
of the virus of this disease. The exudate is largely an indication of
the point of action of the irritant upon the tissues, and in influenza
with its variety of bacteria in the lung this is not limited to the
surface membrane of the air sacs. During this second stage of the
reaction the purulent exudate was found occupying all structures of the
involved area. Damage upon the component tissues was to be seen in the
endothelium of the capillaries, the muscle tissue of the bronchioles and
arterioles, the connective tissues and the epithelium. It was seldom
that bacteria were demonstrated in the interstitial parts, and it would
appear that the damage was the result of their toxins.

Hence, broadly speaking, the end result of the pneumonic process in
influenza is far more complex and indefinite than that in lobar
pneumonia. Resolution may take place early with the clearing up of the
first products of the exudate; or it may be delayed in association with
the secondary purulent process which not uncommonly occupies multiple
lobes. Where the resolution begins in purulent regions the final outcome
is most variable, depending upon the amount of damage which has been
imposed upon the lung tissue during the suppurative inflammation, ending
either in complete restoration or slight fibrosis of the lung, or
passing on to focal scarring of various degrees, sufficient to alter the
pulmonary capacity. In other instances the resolution is delayed by the
development of abscess, infarct and gangrene. Here the final outcome is
determined by the amount of tissue involved in the destructive process,
and the persistency with which the infecting micro-organisms attack the
local tissues and the constitutional resistance of the individual. Those
individuals in whom resolution begins before there is much purulent
pneumonia stand the best chance of having the lung return to its normal
characteristics.


                                _Pleura_

Inflammation of the pleura was a complication which varied in its extent
and appearance. It appeared to us that a definite interval lapsed
between the development of the lesions in the lung and the appearance of
an inflammatory reaction upon the pleural surfaces. Although we have
recorded evidence of a pleural reaction in 27 cases, this does not
indicate that we have met with that number of pleurisies of clinical
severity. In this group we include all gradations of pleural reaction
from the merest evidence of irritation and slight dulling of the surface
to the cases in which definite and marked inflammatory exudate
accumulated within the cavity. In many cases we observed a slight
increase in the amount of the fluid present in one or other pleural
cavity, while there was little or no macroscopic evidence of a cellular
or fibrinous exudate. An examination of the fluid showed the presence of
lymphocytes and endothelial cells in small numbers, and sections of the
pleural surface at points where a slight dulling of the serous membrane
was seen at autopsy showed the presence of a very thin layer of a
hyaline fibrin. By taking these reactions as indicative of pleurisy we
have recorded 6 cases of acute fibrinous pleurisy, 20 of acute
serofibrinous pleurisy, and 1 of acute fibrino-purulent pleurisy.

An increase in the quantity of fluid in the pleural sacs was the most
common indication of pleural irritation. The quantity varied from 50 to
500 c.c. of a clear or slightly turbid fluid. Not uncommonly this fluid
was blood stained and evidence of superficial extravasation of blood
could be recognized directly beneath the pleural membrane. These serous
reactions accompanied the early acute stage, while hemorrhage was the
accompaniment of the early period of the influenzal pneumonia when
similar hemorrhages were found in the lung substance. The pleural
reactions were almost entirely confined to the visceral pleura, and only
in the very severe responses did we obtain a marked inflammatory
reaction with hemorrhage upon the chest wall. Goodpasture and Burnett
state that “there is commonly a moderate serous effusion in one or both
pleural cavities amounting to 50 or 250 cubic centimeters. The fluid is
clear and has the color of blood-stained serum. The pleural surfaces are
smooth, shiny and wet, though occasionally a thin, granular fibrinous
exudate may be seen by reflected light over limited areas. Often
numerous small, red, discrete, or confluent pleural hemorrhages are
present over consolidated portions, especially posteriorly on the
surface of the lower lobes.” Where organisms other than the influenza
bacillus had invaded the pleural sac and had been present for a
sufficient time to obtain a reaction, the serous type of exudate
observed in the early lesions changed to the turbid type of fluid
accompanied by more or less fibrin deposit. There was one case where the
intense reaction with fibrin and leucocytes gave rise to a new character
to the pleural exudate, a fibrino-purulent pleurisy or empyema.

As we have subsequently learned the pleurisies developing late in the
course of the influenza and those which persist after the pulmonary
inflammation has passed are prone to be of a purulent kind. There have
been a fair number of cases of empyema brought to our attention by the
surgical department in the bacteriological laboratory of the hospital,
subsequent to the wave of epidemic influenza. If one were to base his
finding alone upon observations obtained in the operating room, he would
be impressed by the fact that the pleurisy accompanying the epidemic of
influenza is of a purulent type. On the other hand, if one were alone to
consider the findings at the autopsy table during the five weeks of the
epidemic, one would be of the opinion that the pleurisy is of very minor
consequence and of a serous type. It is this changing picture which is
particularly to be kept in mind. And our experience indicates that
during the height of the influenzal lesions of the lung when the
pulmonary lesions develop so rapidly that we obtain a pleural reaction
closely resembling the inflammatory conditions in the lung and also
containing bacteria not unlike the pulmonary flora. Dr. Holman has
obtained the influenza bacillus and other varieties from the pleura
during these early periods of the pulmonary inflammation. It is more
than probable that just as in the infection of the lung tissue where
there is a change in the type of the bacteria present, so, too, the
flora of the pleura alters in the succeeding stages of the pulmonary
reaction. In the late event of empyema we have not observed the
influenza bacillus. The majority of the empyemas possess hemolytic
streptococci and occasionally pneumococci.


                                _Heart_

During the acute epidemic and while the disease was at its height it was
remarkable how few cases showed involvement of the heart. It was the
common observation that even during intense illness the heart action
remained fairly stable and did not indicate an effect by intoxication as
might be expected from the severity of the illness. In as much as the
majority of deaths occurred within relatively few days of the onset of
the severe infection, the type of lesion that would be looked for in the
heart would be either bacterial inflammatory products within the
pericardium, myocardium or endocardium or toxic lesions of musculature
alone.

In our series we have encountered no cases of pericarditis. This lesion
in the experience of others has also been unusual, and it would appear
that bacterial invasion of this sac is accomplished mainly in the
presence of secondary infections localizing in the neighboring pleura.
It was not uncommon to find a slight increase in the serous fluid in the
sac, but this on no occasion amounted to a hydropericardium. The fluid
was always clear and with no evidence of fibrin or cellular exudate.
Petechial hemorrhages scattered over the epicardium were noted in seven
cases. In the majority of instances these minute hemorrhages were
scattered in small numbers over the ventricular walls. In one instance
these petechial hemorrhages were also present through the myocardium,
suggesting the influence of an intoxication not upon the tissues of the
heart as much as upon the finer structures of the vascular channels.
This is furthermore borne out in the presence of petechial hemorrhages
confined not to one organ, but to various tissues and structures in the
body.

More or less cloudy swelling or granular degeneration of the muscle
elements of the heart was not uncommon. It was sufficiently pronounced
in 12 cases to be readily detected by the naked eye. A lesser amount was
also observed in other cases on microscopical examination. In only one
instances was the myocardial degeneration of such extent to lead to a
definite and recognizable weakening of the musculature. In this instance
the autopsy showed a flabby myocardium which was relatively soft and
easily broken and in which all the chambers of the heart were decidedly
dilated. This was the only case in which we were convinced of a
sufficient influence of the toxic effects upon the musculature to permit
a stretching of the walls, with failure of function.

In a number of other instances, however, in which there was more or less
granular degeneration and cloudy swelling we found that the right
ventricle ceased in diastole without, however, the capacity of the
chamber being enlarged. We would make this differentiation in speaking
of dilatation of the heart. We have met with 11 cases in which the right
heart died in diastole, but in which there was no evidence that the
right ventricle had been unduly expanded. In four cases there was
evidence of an old compensatory hypertrophy of the left ventricle in
which the cavity of this chamber was also slightly larger than normal.
The lesions in these four cases, however, bore no direct relation to the
results from the influenza infection. The appearance of the musculature
with moderate grade of cloudy swelling suggested some œdema of the
tissues. In the myocardium, œdema is difficult to recognize, and we
would not place great stress upon its presence in mild degree.

The microscopic examination of the myocardium showing cloudy swelling
gave the usual picture as is seen with a variety of infections. The
muscle fibers showed a fine granular deposit in their cytoplasm and the
staining quality of the tissue was somewhat altered. The transverse
striæ were less distinct than normal, while not uncommonly the
longitudinal fibrils became more evident. Fatty degeneration was not
encountered.

In the single case showing a definite and acute dilatation of the
ventricles the cause of the myocardial lesion could not be placed at the
door of the influenzal infection. This was the case suffering from a
secondary streptococcal bacteriæmia arising in the middle ear. It is
more than probable that the streptococcus was the immediate cause of the
acute muscle change and weakening. In a number of cases we have studied
the tissues of the bundle of His, but we were unable to note any
definite change.

It is interesting that the intoxication associated with acute influenza
is selective in localizing in certain muscle tissues. We have previously
indicated the intensity of muscle degenerations occurring in the
abdominal recti. Even in these cases where these striped voluntary
muscles were markedly affected the myocardium showed nothing more than a
mild or moderate grade of cloudy swelling. We can only account for this
in a difference in the constitution of these muscular structures, some
being of such composition permitting of the localizing and damage by the
unknown intoxicant. It does not appear that the reason for localization
in certain tissues is in any way related to the character of the blood
supply, nor is it related to the activity of the part.

In three cases we have found an inflammatory lesion of the endocardial
tissues. In all of them this consisted of a slight acute verrucose
mitral endocarditis. The lesions were very small, consisting only of a
fine granular deposit looking like grains of sand localized along the
border of the mitral leaflets. In no instance was the leaflet injured or
incapacitated. Unfortunately the lesion not being suspected was
encountered after the heart had been removed and opened and when it was
too late to make bacteriological analyses. This point is greatly to be
regretted, in as much as it is of great importance to know whether some
distant lesions are induced through the influenza bacillus or its
symbiotic flora.

The majority of authors report but little upon the heart lesions in
influenza. Many deny that a heart involvement is to be found, a few
report an occasional endocarditis. Wallis and Kuskow found more or less
myocardial change similar to what is usually described as cloudy
swelling. This reaction they point out differs in no way from the
degenerations arising from other types of intoxications. Keegan in a
series of about 23 autopsies found only a single case with acute
dilatation.

Abrahams, Hallows and French had an opportunity of observing over 400
autopsies upon the influenza patients, and they comment upon the
infrequency of cardiac dilatation. A slight dilatation of the right
ventricle was seen in a few cases, and in no instance did they find
pericarditis or endocarditis. They comment upon the heart condition as
follows: “The most remarkable feature about the heart is the general
absence of dilatation. In quite a large proportion of cases there has
been no trace of dilatation; in a fair number of others there has been
some dilatation of the right side, but this has seldom been extreme,
perhaps enough to cause the apex of the heart to be formed about equally
by right and left ventricles. Most often the heart has appeared of
normal dimensions and the apex has been formed entirely by the left
ventricle. This absence of dilatation accounts for the clinical absence
of orthopnœa.” In direct contradiction to the above findings, the
Advisory Board to the D. G. M. S., France, report the findings in 30
autopsies of clinical influenza. Twenty-nine of these 30 cases showed
dilatation of the heart, chiefly of the right side, but very commonly of
the left side as well. Twenty-one showed myocarditis and two
endocarditis. In this report it is stated that these patients showed
evidence of obsolete tuberculosis. It is possible that the condition of
the patients and the presence of an unusual complicating infection led
to the high incidence of cardiac involvement. The figures in this last
series are much too high when compared with the frequency of heart
involvement as found by the majority of other investigators.

A number of heart lesions not resulting from influenza were observed.
For none of them was there an antecedent history, but in some cases the
condition may have had an influence in causing accessory cardiac
embarrassment. One case had a chronic interstitial myocarditis of the
rheumatic type, three had mild grades of chronic sclerotic mitral
endocarditis, one a bicuspid pulmonary valve and three showed old
pericardial adhesions, one of them having a complete obliteration of the
sac. The foramen ovale was patent in six of the hearts.


                               _Arteries_

The arteries in these young adults were remarkably healthy, and in none
of them did we observe the characters of arteriosclerosis or leutic
lesions. On the other hand, evidence of superficial fatty streaks lying
in the intima of the aorta and some of its large branches were not
uncommon and are believed to have had a relation to the acute infection
of which they died. In only four cases in the series of 32 autopsies was
evidence of these fatty streaks wanting. In about one-half of the
remaining number these fatty streaks were only slight or moderate in
extent, while in the rest of them these lesions were particularly
prominent and striking. They formed linear markings on the posterior
wall of the aorta, aggregating with particular prominence about the
intercostal arteries. The anterior wall was quite free from them. The
greater extent of these lesions lay in the descending thoracic and was
less marked in the arch and the abdominal aorta. At times these fatty
streaks were found to extend into the large vessels of the neck and into
the intercostal arteries, and they were also found in the coronaries of
the heart. It was uncommon to observe their presence in the arteries of
the abdominal viscera.

This type of lesion has been discussed from the standpoint of its
etiology and its possible bearing upon true arteriosclerosis. Some
believe that the frequency of its finding in autopsy material suggests
the non-importance of its presence. This we can hardly agree with. It is
true that the presence of these lesions does not materially incapacitate
the aorta in acting as the main channel for the distribution of blood.
The lesions are quite superficial in the intima and cause but little
elevation on the surface. The amount of roughening which the intima
presents to the blood is not great. Nevertheless, the presence of these
fatty streaks is an index of the disturbed metabolism of the cholesterin
products of the body. Under certain conditions they make their
appearance when there is a true hypercholesterinemia such as is readily
produced in the animal experiments by feeding cholesterin. Under these
circumstances the various tissues of the body, including the adrenal,
the corpus luteum, the spleen, liver and arteries, all participate in
localizing cholesterin in the form of cholesterin-ester in peculiar
cells which have been termed cholesterin-ester phagocytes. It has been
shown that cholesterin metabolism is quite readily altered in the human
and that the blood content will vary from the normal. In chronic kidney
disease, pregnancy, diabetes, chronic heart disease and arteriosclerosis
the blood cholesterin rises, while in many of the acute infectious
diseases the cholesterin in the blood is materially diminished. It is
particularly in these latter cases where fatty streaks of the intima are
prone to occur. Hence in human pathology we more often meet with the
development of fatty streaks of the intima associated with a
hypocholesterinemia than with a hypercholesterinemia.

The fatty streaks of the intima of the aorta to which we are referring
are lesions quite aside from true endarteritis as well as atheroma. In
naked eye appearance the lesion is of a fatty nature and suggests
atheroma, but it differs from this well-known lesion in the fact that
the fatty materials, cholesterin-esters, are contained within cells
which are of uniform type and have no reaction in their immediate
vicinity. True atheroma may occur in definite levels of the intima, most
commonly in the deepest portion, and is characterized by the fact that
we are dealing with a variety of fatty materials, neutral fat, fatty
acids, soap, cholesterin-ester and free cholesterin which lie between
the tissue cells forming a detritus following a process of true
degeneration. It is possible that some of the superficial fatty streaks
do give rise to a small atheromatous area by death of the cells which
primarily contain the fatty substances. Most commonly, however, the
fatty streaks do not progress directly to atheroma but may entirely
disappear, as we have seen it occur in our experimental animals. At
other times these fatty streaks are followed by a slight thickening of
the surface of the intima so that the resemblance to early endarteritis
is obtained. We do not believe that these fatty streaks in themselves
lead to the chronic nodular thickening of the aorta, but that other
factors giving rise to a low grade inflammatory reaction must be
present.

There appears to be a relation between the development of these fatty
streaks and the altered cholesterin metabolism, brought about by
pathological change in the blood, adrenal cortex and it may be in the
liver. It is under these conditions where these tissues are altered
particularly by bacterial toxins in a process of marked cloudy swelling
that these intimal fatty streaks arise. Analyses in other diseases have
shown that such organic changes lead to a diminution in the cholesterin
content of the blood, while at the same time there is neither an
increased intake nor an excessive output. It would appear that certain
types of tissues and cells are stimulated into activity to become depots
for the cholesterin which is not being properly handled by the adrenal
and other organs. These cells in the intima which become active in
taking up cholesterin-esters are types of endothelial cells whose origin
is not entirely clear. In these lesions it is observed that the most
superficial cells of the intima do not show an overloading with the
fatty compound, but that the cells active in absorption lie at a level
slightly beneath the endothelial lining and form colonies as if arising
through active division of cells which are present in these parts.
Active migration on the part of these cells is not to be observed. They
do not appear to wander far from the location where they are found
during the acute process. The plaque may enlarge by proliferation and
thus enlarge the extent of the involved area. We have failed to find,
however, that these cells migrate into the lowermost portion of the
intima or into the media. The possibility that these cells do arise from
the endothelium lining the blood vessels has, up to the present, not
been excluded. If such is the case, the cells appear to adopt a function
which is not commonly observed in normal arteries nor present in the
endothelial cells lying immediately above the fatty plaque.

We have searched various arterial systems in the cases of acute epidemic
influenza for inflammatory lesions lying in the adventitia and media.
These, up to the present, we have not discovered. Some years ago a
number of French authors reported the development of acute
non-suppurative influenza lesions in the outer coats of arteries which
at times had aneurysm as the outcome. These cases, however, occurred
during non-epidemic periods, when the type of influenza of which the
patient suffered was quite different from that seen in pandemics. As far
as we know none of the reported cases of arteritis and aneurysm
occurring under these conditions has shown the presence of the influenza
bacilli in the arterial lesion. It is possible that sporadic influenza
has complicating secondary infections which are of importance in
localizing in the arterial wall.

Occasional reports have been made upon the occurrence of thrombosis
immediately following an attack of influenza. These thromboses have
occurred in diverse regions, the brachial, femoral, the mesenteric, and
other arteries. It is possible that the development of the deep
hemorrhagic lesions of muscles in the extremities are associated with
thrombosis. It is impossible, however, to demonstrate within such blood
masses the presence of thrombosed vessels which had preceded the
hemorrhagic state. It was, however, possible to demonstrate capillary
thromboses through the lung and in the submucosa of bronchi and trachea.
In these instances the damage to the vascular walls was brought about by
the action of the infection immediately surrounding them, and was not
associated with a process beginning within the lumen of the channel. The
type of thrombosis within the lung to which we have referred in a
previous discussion is interesting in that it does not show the usual
type of fibrin clotting, but in place of fibrin threads a gummy
homogeneous material is deposited upon the vessel walls within which the
red blood cells soon undergo dissolution. It would appear that these
thromboses within the lung are dependent upon a toxic action on the
vessel wall and its plasma content.

Thromboses within venous channels are met with more often than in
arteries. The veins of the lower extremities are most frequently
affected, and yet amidst the many cases of influenza it is an unusual
occurrence. The various thromboses of larger vessels usually occur as
post-influenzal complications rather than as accompaniments of the acute
disease. It is possible that factors other than those present during the
acute stage play an important part, and that the virus of influenza is
not directly the cause of the thrombosis.


                  _Lymphatics of Lung and Mediastinum_

One of the prominent reactions which was almost constantly present as
the inflammatory reaction involving the lymphatic system of the chest.
The lymph glands within the chest responded to a marked degree in
hyperplasia and commonly showed enlargement quite out of proportion to
what is usually observed in lobar pneumonia. These reactions were in
direct relation to the inflammatory processes of the lung and appeared
to be involved in proportion to the inflammation occupying the tissues
drained by them. Elsewhere in the body the lymph glands responded but
slightly, and often no change was observed in the lymphatics of the
abdomen, axilla and lower extremities. The systemic intoxication thus
had no effect upon distant lymph glands, and even the presence of
micro-organisms in the circulation did not appear to cause responses in
these tissues other than in the neighborhood of the chest. Within the
chest the lymphatic system became involved through the presence of the
various bacteria migrating along the lymphatic channels as well as
through its activity in removing products of inflammation.

The response of the thoracic lymphatics, including those within the lung
and mediastinum, is observed in all stages of pneumonia. But in epidemic
influenza the reaction was much more prompt, appearing in the early
stages and rapidly developing tissue changes along the channels and in
the lymph nodes. The lymph channels during the period of the early
serous pneumonia became dilated and filled with fluid with relatively
few cells. The stroma immediately surrounding became œdematous, so that
in the gross specimen the connective tissue between the lobules of lung
were sometimes easily seen as gray strands. At this time this tissue was
not increased in quantity and did not project above the level of the cut
lung. The fibrous tissue remained soft and pliable, but formed quite
wide strands. When the pulmonary reaction became hemorrhagic, red blood
cells, leucocytes and large mononuclears were found mixed with the fluid
in the lymphatics. We had no way of determining the direction of the
lymph flow from the pulmonary tissues, but it was assumed that as there
was no excessive loss of serous fluid from the lung and the lymphatics
beneath pleura into the chest cavities that the fluid was draining
through the channels lying about the bronchi and vessels. The further
evidence of the direction of flow was seen in the rapid and comparable
responses which occurred in the lymph glands along these routes. The
glands about the bronchi and at the hilus became enlarged, red and
succulent. The glands were often two and one-half centimeters in
diameter. Their capsule was thin and stretched and the gland was quite
soft. Many of them when cut open were almost diffluent.

This acute lymph hyperplasia occurred in 30 of our cases. It is
impossible to indicate any particular type of infection as being
responsible for these lymphatic lesions. The nature of the bacteria
present in these 30 cases differed quite considerably: 25 showed
influenza bacilli, 15 pneumococci, 18 streptococci, 8 M. catarrhalis and
17 staphylococci. In as much as the pulmonary reaction was fairly
constant in certain characteristics in all of our cases, and as we
believe that the influenza bacilli were the very important factor in
these reactions, it would appear that the lymphatic responses are only a
part of the general inflammation of the respiratory organs. Comparison
can also be made of the character of the lymphatic changes with that
occurring within the pulmonary tissues. The lymphatics were filled with
fluid which dilated all the available sinuses; the lymph nodes were
œdematous and within them the reaction often had numerous small
hemorrhages.

The lesion within the lymph nodes following the early serous
inflammation was of a non-suppurative kind. The lymph follicles lost
their outline, and the lymphocytes were diffused through the stroma so
that no recognition of the germinal centers could be found. The dilated
sinuses within the lymph nodes were filled with large mononuclear cells,
of the type of endothelial cells, along with some lymphocytes and
leucocytes. Subsequently the leucocytes increased very materially so
that the lymphatic fluid became purulent. Smears obtained from larger
lymphatics showed leucocytes and varieties of bacteria. This was
particularly true in those cases where the pulmonary lesion had itself
become purulent either localized in a patchy pneumonia or with lobar
involvement. Under these circumstances focal areas of purulent
infiltration were found within the tissues of the gland occupying the
regions of the former follicles and leading to necrosis or abscess.
Where such purulent reaction and abscess formation were found within the
lymph nodes there was remarkably little reaction in the tissues of the
immediate vicinity. No attempt at the development of a pyogenic membrane
or granulation tissue was observed, though this probably does take place
in the cases recovering.

In only one instance did we observe the development of the peculiar
fibrosis along the lymphatic channels where the freshly cut section of
lung reveals prominent and raised demarcation between the lobules. This
response has been described by MacCallum as unique for the streptococcus
inflammation of the lung. The character of the exudate within the
lymphatics with many mononuclear cells and blood is not to be considered
singular for the influenza pneumonia. It has been found that in ordinary
lobar pneumonia, as well as in the pneumonia following measles, the
early pulmonary reaction is accompanied by the dilatation of the
lymphatic channels along the bronchi, containing serous fluid,
mononuclear cells, blood and leucocytes, while occasionally thrombosis
entangling bacteria is also encountered. It would seem, however, that
the lymphatics in epidemic influenza can more readily recover their
normal character when a streptococcus infection is wanting.

In the late purulent lesions of the lung we have encountered dilated
lymphatic channels whose yellow contents could be recognized by the
naked eye. At times this could be followed for short distances along the
bronchi as narrow yellow cords, or when cut transversely appeared as
small dots close to the bronchi or vessels. On pressure small droplets
of pus may be evacuated, or again where fibrin has led to a coagulation
of the exudate a yellow plug can be withdrawn from the channel. These
small plugs resembled the thick exudate seen within the bronchi and
often were misleading when first viewed. The distribution of the
purulent lymphatic masses was most irregular occupying only local or
patchy fields in the lung, particularly associated with the purulent
confluent pneumonia. In one instance such a lymphatic appeared to be
associated with the development of a small abscess lying close to the
bronchus.

Too much stress cannot be placed upon the importance of the lymphatics
in all forms of pneumonia. They play an important role in the drainage
of the lung during inflammation. In the normal lung we hardly appreciate
the lymphatic distribution except in our observations upon anthracosis.
But even under these conditions when much carbon is deposited in
conjunction with the lymphatic system we do not gain a true appreciation
of the activity of the lymph channels and nodes during an acute process.
Bacteria may be demonstrated in acute infections of the lung within the
fluid and cells of the lymph channels. Less easily may we demonstrate
bacteria in the lymph nodes under similar conditions, although when
abscess has occurred their presence is readily recognized. The transport
of bacteria is accomplished not only by a passive migration of
micro-organisms in the fluid as it drains from the lung, but organisms
are also found within the leucocytes as they travel with the current.
Only occasionally have we demonstrated bacteria within the wandering
large mononuclear cells, although we have observed them in a few
instances within the cells lining the sinuses of the nodes.

Whether the inflammation of the pleura is directly related to the
involvement of the pleural lymphatics we have not been able to
determine. In our series of cases pleurisy has not been a prominent
feature of the disease, and in many instances the grade of involvement
was so slight that it was not easily recognized by the naked eye and
showed only a slight reaction microscopically. That the presence of
bacteria within the intricate plexus of lymphatics beneath the pleura
may be responsible for the development of an inflammation of this
membrane may well be the case, and in this way simulate the mode of
transmission of the infection as seen in lobar pneumococcus pneumonia
and in the streptococcus type of infection.


                          _Abdominal Viscera_

The lesions occurring in the abdominal viscera were of less importance
than those within the thorax. In none of the cases of the epidemic was
the intestinal type of the disease, described in previous years,
encountered. The changes found in the various viscera were concomitant
with evidences of intoxication as observed clinically or at autopsy in
other regions of the body. We found no evidence that the bacteria of the
disease localized in the tissues of the abdominal viscera, and we were
led to believe that the alterations in morphology and function were the
result of diffusible toxins. The action of these toxins was either upon
the parenchymatous cells of the organs, as in the liver and kidney,
resulting in granular degeneration, or upon the capillaries with the
development of petechial or diffuse hemorrhage as was encountered in the
stomach, intestines and bladder. The absence of definite localized
inflammatory processes in these distant tissues, including the abdominal
lymphatics, speaks against the probability of a bacteriæmia playing an
important role in the disease. That transient bacteriæmias by the
influenza bacillus do occur has been repeatedly demonstrated, and that
the organisms associated with this bacillus may also enter the blood
stream has likewise been found. But these states are accessory to the
disease, and must be viewed as complications rather than the rule. Hence
the occasional observations by some, of bacterial inflammatory reactions
in liver and kidney must not be considered a part of epidemic influenza,
for in many cases it is wanting. The majority of lesions of the
abdominal viscera probably arise through the action of the unknown toxin
in the blood.

In the _stomach_ and _intestines_ the lesions were of two kinds, (1)
hemorrhage and (2) erosions. Petechial hemorrhages were present in the
stomach 15 times, in the intestines 4 times. These small dots of blood
extravasation, lying in the mucosa and submucosa, differ in no way from
those observed in other acute infections and intoxications, save that
the tendency for the leakage of blood into the lumen of the viscera was
more pronounced. Often we could observe the presence of free and more or
less altered blood in the stomach and intestines, and in 12 cases the
amount was considerable, sufficient to be spoken of as melena. It is
probable that the oozing of blood takes place not only from the areas
visible to the eye as petechial hemorrhages, but also from the more
normal-looking mucosa of stomach and bowel. The tendency to hemorrhage
was not necessarily accompanied by visible alterations in the epithelial
layer of the mucosa, though at times erosions were found. When
hemorrhage could be observed, the extravasation of blood occupied the
superficial layers of stroma, causing a separation of the tissues
beneath the epithelial layer. At times the submucosa was also
infiltrated, and in one instance the musculature. The lesions were
isolated and sporadic, but always about small capillary loops. It
appeared to us that the damage was primarily upon the vascular tissues
and particularly upon the endothelial walls of the fine channels.
Inflammation was not present, and the hemorrhage was more or less
passive—that is, a slow oozing rather than acute hemorrhage by rhexis.

The second type of lesion of the gastro-intestinal canal was erosion.
This was of the nature of a defect in the mucosa, usually multiple,
small and well circumscribed. The tissue loss was superficial. In their
appearance these lesions were similar to those encountered in these
parts in other infections, and also as described by McMeans in
experimental infections of animals. The erosions appear to arise in a
process of bland necrosis, limited in the periphery by healthy tissue
and not tending to enlarge. It is probable that these erosions are
associated in their development with the petechial hemorrhages, being a
sequel to the vascular disturbance of the mucosa and subsequent
digestion of the injured tissue. Multiple lesions of the stomach were
found 10 times and twice in the intestine. The largest was 1.25 cm. in
diameter. They are more common on the posterior than anterior wall, and
usually toward the lesser curvature. It is probable that these defects
are limited in their progress and heal readily.

The changes occurring in the _liver_ were not of striking account.
Cloudy swelling was observed 13 times, usually of moderate grade. The
usual appearances with enlargement of the organ, bulging of the
parenchyma on section and a dull gray cut surface were all that could be
found. The one case with icterus was the only one in which the natural
discharge of bile from the liver was interfered with through the
swelling. Even in this case the obstruction to the outflow of bile in
the small channels was not demonstrable in the microscopic sections, nor
was there evidence of unusual bile staining of the liver-points
suggesting the possible origin of the icterus in an unusual hemolysis.
On no occasion did we meet with recent inflammatory reactions in the
gall bladder or bile ducts, and we have no evidence that the organisms
of the infection are discharged from the body by these routes. The
cloudy swelling of the liver was accompanied by slight œdema of these
tissues in seven cases; and in six instances focal necroses were
observed. These focal necroses were similar in appearance to those seen
in typhoid fever, but were much less frequent in the tissue. Only
careful search revealed isolated pinhead gray dots with depressed
centers. They were most commonly in the mid-zone of the lobule, and in
the early stage were without inflammatory reaction. Subsequently,
leucocytes infiltrated the area, but not in an amount to form pus.
Bacteria were never demonstrated in the areas of focal necrosis. Four
cases showed old adhesions about the gall bladder and in one a gall
stone was present.

Lesions of the _pancreas_ were not encountered. In a few cases the lymph
glands about the head of the pancreas were slightly enlarged.

The _spleen_ showed relatively little reaction and in only two cases was
it enlarged. Fourteen times a diagnosis of acute splenitis was made on
examination of the gross specimen. This diagnosis rested upon the
finding of a swollen spleen with tense capsule and with a dark bulging
pulp. The Malpighian bodies were usually in part or completely
obliterated, though in a few instances these grayish nodules seemed even
larger than normal. These spleens contained an excess of blood within
the pulp. In one case several isolated areas appeared hemorrhagic as if
a local rupture of the tissues had occurred. The microscopic examination
of these specimens showed mainly a marked congestion of the sinusoids, a
diminution in the size of the lymphoid corpuscles and some increase in
the number of leucocytes within the blood spaces and reticulum. Only
occasionally did we observe a proliferative reaction of the large
mononuclear cells lying in the reticulum. This proliferation was not
sufficiently marked nor uniformly present to be considered as
characteristic. We did not find abnormal deposition of blood pigment
indicating an unusual destruction of red blood cells within the spleen.
It is interesting to note that 5 of the 32 cases showed obsolete miliary
tubercles in the spleen.

Our analysis of the changes occurring in the _kidney_ bore out the
clinical findings observed in the wards. Like in so many acute
infectious diseases urinary changes were commonly present. These are in
part dependent upon systemic changes in the metabolism of tissues and
not entirely the result of renal lesions. In acute epidemic influenza
there was no common characteristic in the urinary output. The amount
excreted in 24 hours was usually diminished to a small extent, the color
was darker, the specific gravity slightly increased, as well as the
total solids. There was no marked change in the total quantity of output
of any one of the constituents as far as they were analyzed by us.
Albumin was present in the urine in variable amounts and in the more
severe cases casts were also present. There was only one case in which
the quantitative output was much diminished and where some fear was
entertained of development of acute uremic manifestations. This
individual, however, died before these made their appearance and before
there was any evidence that the retention of waste products was causing
definite clinical symptoms.

In 30 cases coming to autopsy more or less cloudy swelling was to be
observed in the kidney. This reaction varied from a very mild swelling
and granular degeneration of the tubules of the cortex to a decided
parenchymatous degeneration with loss of nuclear structure and erosion
of some of the cells lining the tubules. The convoluted tubules were
always most markedly involved. Occasionally this tubular degeneration
was accompanied by a desquamation of the lining cells of the glomerular
capsules. We were, however, unable to recognize an acute inflammatory
reaction in the interstitial tissue or in the glomeruli in any of the
cases, except the one which had developed a streptococcus bacteriæmia as
a sequel to an otitis media. The kidney lesion reminded one very much of
the toxic lesion which is observed in the kidney in typhoid fever.
Differing, however, from the latter there was a variable congestion of
the fine vessels associated with the cyanosis which was present in a
certain percentage of these cases. At times the kidneys were quite wet
with blood from the venous engorgement.

The lesions in the kidney were of a toxic type and did not resemble
reactions following the presence of the bacteria in the stroma of the
organ. In the majority of instances in other diseases where bacteria
themselves locate in tissues we are able to recognize focal lesions of
acute necrosis or inflammation. In epidemic influenza where a variety of
micro-organisms within the lung are able to reach distant structures in
a bacteriæmia, we would, because of their type, expect to find
inflammatory reactions of a definite kind. The absence of such reactions
is very suggestive that the bacteria do not commonly localize in the
kidney, but that their toxins alone affect it during its elimination. We
have also entirely missed the finding of any vascular lesions in the
renal system. Neither degeneration nor inflammatory reactions of any of
the coats of the blood vessels could be distinguished.

The partial incapacity on the part of the kidneys must, therefore, be
viewed as a complication resulting from the effect of a diffusible toxin
reaching them by the blood stream. The damage performed in this manner
may be quite extensive upon the secreting tissues of the tubules leading
to an increased or decreased output of the urinary constituents. Because
of the nature of the lesion, it is probable that the kidney damage
incurred during the acute epidemic influenza is only temporary and not
permanent. Tubular degeneration is readily repaired, and in the absence
of an inflammatory reaction in the interstitial tissue or the glomeruli
avoids the development of a permanent mark or derangement in the system.
This is as we find it in typhoid fever.

In two cases we observed very interesting lesions in the _bladder_.
These two individuals during life had been excreting markedly
blood-stained urine for some days preceding death. In the one case the
hemorrhage was so marked that on standing, about one-tenth of the urine
was composed of sedimented red blood cells. It was assumed that the
hemorrhage was of kidney origin until the autopsy revealed a simple
cloudy swelling of the kidney associated with a hemorrhagic state of the
submucosa of the bladder. In both cases the posterior wall of the
bladder was heavily infiltrated with blood so that the mucosa was raised
from the surface and the prominent folds showed a superficial erosion
with small points of greenish necrosis. This bladder hemorrhage was
concomitant with hemorrhagic foci elsewhere in the body, pericardium,
pleura, stomach and intestine. Alone in the bladder however, the
hemorrhage formed a distinct mass and allowed a considerable escape from
the lesions on the surface. These areas of hemorrhage were not infected
and showed no local inflammatory reaction. They also appeared to be
toxic in origin and resembled the hemorrhages occurring in the muscles
of the abdomen.

Changes in the _adrenal_ gland were noted in 14 instances. In all of
these there was the picture of what is commonly known as cloudy swelling
of the cortex and, in addition to this, in three cases small petechial
hemorrhages were observed. The so-called cloudy swelling of the adrenal
consists largely in a loss of the bright golden appearance of the
cortical tissues accompanied by soft œdematous swelling. The tissues
change color to a brown or clay color, and it is not uncommon to observe
that the inner zone of pigmentation is more diffuse. There is no sharp
demarcation between the layers of the cortex. With this alteration in
the outer structure of the adrenal, the medulla not uncommonly appears
smaller. This change is more apparent than real, and we have not been
able to observe any definite lesion in the nervous portion. At times we
believed that the inner tissue appeared more cellular, but it was not
possible to determine any specific alteration in the cells.

The changes in the adrenal cortex are comparable to those observed in
typhoid fever. The analyses of these tissues showed that the cells were
almost devoid of cholesterin bodies and few doubly refractile globules
could be demonstrated. This change in the adrenal is by no means
specific for any acute disease, it being found in many of the severe
infections. We regret that systematic analysis of the blood serum in
these cases was not made to determine the cholesterin content. If the
comparison bears out with typhoid fever, we would expect to find that
the quantitative cholesterin of the blood is diminished. Some importance
attaches itself to the study of the cholesterin metabolism, particularly
in regard to the development of the peculiar fatty streaks which develop
in the aorta and other arteries during these acute infections. It has
been claimed that in the human these streaks bear an analogy to those
produced in the experimental animals and that the arterial lesions are
associated with an altered activity on the part of the adrenal cortex in
handling the cholesterin compounds. In influenza there is evidence that
the adrenal does not function in a normal fashion and that the storage
of cholesterin-esters does not take place. From this, however, we cannot
conclude that the blood content is increased, and, in fact, it is more
than probable in comparing the other reactions of the disease that it
follows the changes as seen in typhoid fever where the blood content of
cholesterin is lowered. In this way comparison with the experimentally
produced arterial lesions in animals is not clear, in as much as in the
experimental work a true hypercholesterinemia was induced. Nevertheless
it is possible that with the abnormal function on the part of the
adrenal the cholesterin materials are made more available for absorption
by other tissues and that a true hypercholesterinemia is not necessarily
a constant factor, even with the abnormal accumulation of these
substances in the intima. It may well be that the normal activity of the
adrenal is related to the presence of toxins in the circulation and an
attempt by mobilizing cholesterin to diminish the activity of these
harmful substances.


     OBSERVATIONS UPON THE PATHOLOGY OF EIGHTEEN CASES OF INFLUENZA

                            By J. W. MCMEANS

The recent epidemic of influenza has afforded a series of interesting
autopsies in view of the very extensive and peculiar involvement that
occurred in the lungs of the cases examined. Ordinary lobar pneumonia,
as we know it, was not observed, although it must be said that the lungs
many times exhibited a consolidation of a lobar distribution. The usual
dry granular lung of the more common pneumonia was absent, and in its
stead a most unusual series of pictures was observed in the several
cases. A common feature of all cases was the œdema of the lung tissue,
which in the majority of instances contained such an amount of fluid
that it ran freely from the cut surface in almost unlimited quantity.
This fluid varied in its color and consistence depending upon the age of
the process. In the very early cases the lungs were boggy, very
congested, and a thin serosanguinous fluid poured forth from the cut
surface. It actually appeared as though the fluid within the tissue was
under considerable pressure. At times blotchy deep red hemorrhages
occurred in the lung substance, and hemorrhages of a bright red color
were not infrequent in the pleura. That the circulation of the lungs was
much embarrassed was often prettily demonstrated by the dilatation of
the fine capillaries and lymphatics beneath the pleura. These small
vessels stood out prominently as a meshwork more or less outlining the
areas supplied by them. Not only was the peculiar consolidation in lobar
arrangement, but also in many cases was there evidence of a lobular
distribution. Even in some cases where the entire lobe was consolidated
the cut surface presented a peculiar lobulation with patches of lung
tissue projecting above the general surface. The wet trabeculated
structure of the lung in this stage did not give the impression of true
red hepatization, but rather a structure resembling spleen and at times
a meaty, compact, glassy picture not unlike thyroid.

As the process advanced the appearance of the lung changed from deep red
to yellowish red and finally to a quite yellowish gray color, still
retaining, however, the very moist characters. The fluid found in the
lung changed its consistency from the thin red type to a sticky, glairy
variety which could be pulled out in long strings. It was noted that the
change in the character of the fluid was accompanied by similar changes
in the lung structure, advancing in two cases to abscess formation of a
grape-bunch type. Here there was a rather extensive necrosis and
cavitation of lung substance in communication with the bronchioles.
However, there was also marked softening and necrosis of lung in a
number of cases where abscesses did not develop, but the lesion was so
advanced that the lung substance was almost diffluent. An accompaniment
of these advanced cases were irregular yellow islands which appeared
beneath the pleura. At times they reached the size of a circle 2 cm. in
diameter and were slightly raised above the surrounding pleural surface.
When these were opened they were found to be areas of softened lung
substance. This reaction was so extensive in some lungs that it
resembled to a degree the appearance of a caseous pneumonia. However,
the former process appeared to be brought about by the interference with
the lymphatic drainage, as it was not uncommon to see engorged yellow
channels beneath the pleura as well as enlarged lymph nodes at some
distance from the hilus. Another feature of the advanced cases were the
plugs of ropy yellow material which were contained within the
bronchioles, while in the early cases the bronchi and bronchioles showed
intense congestion of the mucosa with blood-stained fluid in their
lumina.

Of the more unusual reactions observed in the lungs an infarct was found
occupying a considerable part of the lower left lobe in one case. There
was a marked softening of the lung tissue with reddish, mucky-looking
lung substance arranged about small irregular cavities. This reaction
extended into the lung for a distance of 4.5 cm. Bordering close on
these softened areas there was a dry mottled yellowish gray and deep red
lung tissue. Surrounding this area again were noted a number of small
blood vessels in which there were found yellowish granular plugs. One
plug in a vessel was found at a distance of 3 cm. from the base of the
lobe, and another was found at a distance of 8 cm. from the apex of the
lobe. On further examination it was observed that the base of this
softened area was situated on the pleural surface and that the apex was
directed inward about a distance of 6 cm. from the pleura. Bathing the
cut surface there was a glairy and very sticky material of a reddish
yellow color. Near the apex of this softened area in the lung there was
found a vessel about the size of a goose-quill in which there was a
grayish yellow granular plug. This plug was adherent to the vessel.
Within the small bronchioles there were plugs of a soft yellowish brown
material. The striking feature in addition to the softening of the lung
in a number of places was the glairy material of a sticky nature which
bathed the cut surface. A white infarct was present in the spleen. The
lung described above as well as another showed gangrenous change. In the
second of these two abscesses had formed, and there was a communication
between the lung and pleural cavity in which there was a large amount of
sanguino-purulent fluid and a pyopneumothorax.

In a description of these reactions it must be added that the early and
late changes were not always observed independently, but in most cases
occurred together, giving the lung a peculiar mottled red and yellow
glassy appearance. More frequently the congested œdematous reaction was
observed singly, while the purulent alteration usually was in
combination with the former type. The acute serous pneumonia was noted
13 times, 6 times in combination with the purulent reaction and 7 times
alone, while the acute purulent pneumonia was found in 9 cases, 3 times
alone and 6 times with an acute serous process. In all but 3 of 18 cases
there was evidence of a bronchial distribution. Two of these three cases
showed a massive œdematous lung with in one case an extensive
hemorrhage, while the third presented an advanced purulent reaction with
marked necrosis and softening. An acute bronchitis which varied in
character from a hemorrhagic to a purulent one was present in all the
cases. The reaction observed within the bronchi in the individual cases
corresponded closely to the picture found in the lungs.

In all cases except one there was an exudate in one or both pleural
cavities. A serofibrinous pleurisy was noted in 11 cases with, in 2 of
this number, a fibrino-purulent reaction present in the opposite pleural
cavity, while fibrino-purulent pleurisy occurred alone in 6. In 6 cases
pleurisy occurred on one side only with the incidence equally divided in
each cavity. Both pleurae were involved in 9 cases. Seventeen of the 18
cases showed both lungs involved. One case was an individual who had had
clinical influenza and during convalescence developed gangrenous colitis
and acute ascending myelitis which terminated fatally. B. influenzæ was
isolated from the bronchioles in the lung of this individual.

The reaction of the body generally was evidenced by a widespread
distribution of petechial hemorrhages over serosal and mucosal surfaces.
However, certain other important lesions were noted such as one acute
vegetative mitral endocarditis, two acute serofibrinous pericarditis,
three cases in which focal necroses were prominent in the liver and two
examples of infarct of spleen. Further, there were four cases of slight
dilatation of the right heart. The liver was usually swollen and
œdematous and the spleen presented evidence of an acute reaction,
softening and reddening of its pulp with at times slight enlargement.

As evidence of the virulent character of the infection from which these
patients suffered, there was not only present in the lung a peculiar
hemorrhage and purulent process, but also a more or less widespread
distribution of hemorrhages in other parts of the body. The
gastro-intestinal tract was most affected with the stomach showing
petechial hemorrhages in 17 of 18 cases and the small intestine in 15 of
the same number. In the gastric mucosa of three cases there were
definite erosions, while in two instances the duodenum presented an
intense œdematous and hemorrhagic appearance of its mucosa. Further
hemorrhages were observed on one occasion each in the mesentery and in
the mesenteric and retroperitoneal lymph nodes. In the latter the
mesenteric glands were so distended with hemorrhages that a soft pulp
spurted out when the glands were sectioned. Next in order of frequency,
hemorrhages were noted 9 times in the pleura, 8 in the pelvis of the
kidney, 6 in heart muscle and 3 each in pericardium and bladder. In one
case of widespread distribution of petechial hemorrhages there was a
massive loose hemorrhage into the lower recti abdominis. Further another
case showed a large amount of a blood-stained fluid in the peritoneal
cavity.


                               _Summary_

In the analysis of the cases of acute epidemic influenza two important
features of the disease present themselves, (1) a marked systemic
intoxication with localized manifestations in certain organs, and (2)
inflammatory lesions of the respiratory tract. These manifestations
present themselves both to the clinician and to the pathologist, and to
each they have demonstrated their importance in the disease. The
pathologist not in touch with the clinical manifestations of the toxæmia
has more closely linked the occurrence of these two factors with the
actual findings in the cadaver. But there are those who look upon these
factors as separate and distinct, viewing the toxæmia as an individual
process and as illustrating the uninvolved influenza, while the
inflammatory reaction of the respiratory tract is taken to be a
complication arising through the activity of secondary invading
organisms. This is the view held by MacCallum, who compares influenza
with the acute exanthemata wherein the respiratory lesions are but
secondary to the production of a lowered resistance and an invasion by a
variety of bacteria. Such confusion presupposes an undetermined virus
for influenza. In confirmation to such views we have the reports upon a
filterable virus. Up to the present, however, the latter has been on
insecure grounds.

It would appear to us that, as has been discussed by Dr. Holman, the
case against the B. influenzæ not being the important causative agent
has not been proved. The demonstration by others of a potent toxin from
the B. influenzæ cannot be overlooked, and although the actual disease
has not been reproduced in animals, there is evidence that this toxin
will induce acute degenerations in various tissues. Furthermore, the in
vitro symbiotic relation demonstrated for the B. influenzæ with other
organisms, as the pneumococcus, streptococcus, staphylococcus pyogenes
aureus and M. catarrhalis, gives ample support to the claim for a
similar symbiosis in the human tissues. The evidence for the important
primary relation of the B. influenzæ to epidemic influenza is such that
we cannot disregard it—at least, not before we can produce some definite
positive evidence that another demonstrable virus precedes it and
produces those constitutional effects which initiate the remaining
sequelæ.

We must agree with Christian in the statement that all cases dying
during the acute stage of epidemic influenza have inflammatory lesions
in the respiratory tract and largely in the lung (pneumonia). It is
difficult to conceive of a disease comparable to the acute exanthemata,
which beginning as a separate and distinct process ends fatally within
48 hours with a pneumonia which is claimed to be secondary.

Epidemic influenza is an acute infectious process of the respiratory
tract, usually localizing in the upper respiratory system, but often and
in a fairly constant percentage of cases extending into the lower
portion of the same system and causing a type of broncho-pneumonia.
Accompanying the initial invasion there is a marked systemic
intoxication with lesions of degeneration arising in a variety of
tissues. These lesions of degeneration are to be seen both locally in
the respiratory system as well as in distant parts, as in the muscles,
kidney and liver. The primary damage arising in the respiratory organs,
and which we believe to be the result of infection by the B. influenzæ,
facilitates attacks by such other bacteria as are available and
pathogenic to man. The secondary invaders are not constant in type, but
we find variations according to the localities where the epidemic takes
place. Just as there is a difference in the bacterial flora which
constitutes the secondary invasion, so, too, there is a variation in the
picture of the inflammatory process which appears in the lungs. The
occurrence of the miliary streptococcal broncho-pneumonia has been met
with in certain localities much more frequently than in others; lobular
and confluent pneumonia has been the prevailing type in certain regions,
while a lobar purulent pneumonia with abscess and gangrene was most
frequent with others. There does not appear to be an individual and
constant character in the mode of distribution of the pneumonia in the
lungs. That the pneumonias were not the usual type otherwise seen, is
fairly agreed upon by all. The most astonishing feature presenting
itself to us was the frequency of death occurring in the early stages of
the inflammatory process and before the gray stage had definitely
developed. The gray stage of influenza pneumonia is a purulent pneumonia
which often also constitutes an acute interstitial pneumonia.

The extensive hemorrhage and inflammatory œdema of the lung are striking
during the early stages of the lung involvement. The mononuclear
infiltration which appears early and remains for a variable time, until
the purulent process is well under way, is also unique. The hyaline
deposit in the lung alveoli; the capillary thrombosis and necrosis of
the alveolar walls and bronchi are important; while the tendency to
abscess, infarct, gangrene and incomplete resolution with fibrosis
differentiates this type of pneumonia from the common lobar variety.

As an organic evidence of the acute intoxication, none stands out more
prominently than the degeneration of the voluntary muscles. These
resemble the waxy degeneration of other bacterial intoxications, and
particularly that of typhoid fever. The finding of these acute
degenerations does not assist us in arriving at a conclusion as to the
nature of the poisonous body, whether a true exotoxin. The presence,
however, of such widespread degenerative lesions in cases showing no
naked eye change suggests, at least, that the peculiar muscle weakness
associated with pain has its origin in this definite process and not in
primary nerve lesions.

Very interesting it is that the different muscular structures are not
equally affected by the intoxication. This is particularly noteworthy in
the heart and intestine. In neither of these structures have we met with
lesions comparable to those in the voluntary muscles. Wherein this
immunity resides we cannot state. In our own series, as well as in the
majority of others, there was an unusual absence of evidence of
myocardial weakness. In most of those dying during the acute illness,
the heart muscle was found firm and the cavities not dilated. This
finding was in striking contrast to that found in acute lobar pneumonia
where dilatation of the right ventricle and auricle, along with muscle
degeneration, is almost the rule. In but one case of the present series
did we find myocardial degeneration leading to dilatation of the
cavities and causing death. And in this particular case the intoxication
was due to a streptococcus septicæmia arising as a late sequel from the
middle ear. The heart in influenza withstands remarkably well the
effects of an intoxication from the disease and carries the extra load
imposed upon it by the involved lung with little evidence of fatigue.

It is also worthy of attention to note that the kidney suffers so little
in this severe disease. Bacterial localization with inflammatory
concomitants does not occur, and there is no lasting damage upon its
structure. As in so many conditions of bacterial poisoning, tubular
degeneration, varying from a cloudy swelling to a more acute damage, is
to be found in a percentage of cases, but complete restoration is
rapidly obtained in convalescence. It is unusual to find such severe
renal damage to incapacitate function to a degree to endanger life.

Finally we can add our evidence, gained from a study of the pathology of
epidemic influenza, that the primary disease induced by the invasion of
the B. influenzæ opens the way for secondary infections of a variety of
kinds, whose subsequent effect may be more serious than initial lesions.
The many late complications which arise in this manner we have not
investigated.


                              BIBLIOGRAPHY

 Abrahams, Hallows and
   French                Lancet., 1919; i, p. 1.
 Advisory Board to the
   D. G. M. S            Brit. Med. Jour., 1918; ii, p. 505.
 Blanton and Irons       Jour. A. M. A., 1918; lxxi, p. 1988.
 Boggs                   Johns Hop. Bull., 1905; xvi, p. 288.
 Brooks and Cecil        Brit. Med. Jour., 1918; ii, p. 496.
 Chickering and Park     Jour. A. M. A., 1919; lxxii, p. 617.
 Christian               Jour. A. M. A., 1918; lxxi, p. 1565.
 Cole                    Brit. Med. Jour., 1918; ii, p. 566.
 Cole                    Canadian Med. Assoc. Jour., 1919; ix, p. 41.
 Dever, Boles and Case   Jour. A. M. A., 1919; lxxii, p. 265.
 Fildes, Baker and
   Thompson              Lancet., 1918; ii, p. 697.
 Fletcher                Lancet., 1919; i, p. 104.
 Friedlander, McCord,
   Sladen and Wheeler    Jour. A. M. A., 1918; lxxi, p. 1652.
 Goodpasture and Burnett U. S. Naval Med. Bull., 1919; xiii, No. 1.
 Hall, Stone and Simpson Jour. A. M. A., 1918; lxxi, p. 1986.
 Hunt                    Lancet., 1918; ii, p. 419.
 Keegan                  Jour. A. M. A., 1918; lxxi, p. 1051.
 Kuskow                  Virchows Archiv., 1895; cxxxix, p. 406.
 Le Count                Jour. A. M. A., 1919; lxxii, p. 650.
 Lord                    Boston Med. and Surg. Jour., 1905; cl, p. 537.
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 MacCallum               Jour. A. M. A., 1919; lxxii, p. 720.
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 McMeans                 Archives of Int. Med., 1917; xix, p. 709.
 Nuzum, Pilot, Stangl
   and Bonar             Jour. A. M. A., 1918; lxxi, p. 1562.
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 Wittingham and Sims     Lancet., 1918; ii, p. 865.




                         EXPLANATION OF PLATES


 Fig. i.    Cyanosis of head and neck.

 Fig. ii.   Acute tracheitis with desquamation of epithelium and
              superficial necrosis.

 Fig. iii.  Acute serous and hemorrhagic pneumonia.

 Fig. iv.   Acute serous pneumonia with massive hemorrhage.

 Fig. v.    Acute hemorrhagic and purulent lobular pneumonia. The
              purulent process is seen to be advancing from the focal
              type to the more diffuse lobar by fusion of the
              neighboring lobules.

 Fig. vi.   Acute purulent pneumonia.

 Fig. vii.  Lobular fibrosing pneumonia. In this specimen the patches of
              new scar tissue formed irregular islands. The final stage
              of contraction of the scar had not taken place.

 Fig. viii. Acute serous pneumonia with some infiltration by mononuclear
              cells.

 Fig. ix.   Acute hemorrhagic pneumonia.

 Fig. x.    Hyaline deposits upon alveolar walls. In some areas the wall
              itself has suffered necrosis.

 Fig. xi.   Acute purulent pneumonia. In other areas of the same lung
              the interstitial infiltration by leucocytes was more
              intense.

 Fig. xii.  Acute lymph adenitis, showing the unusual numbers of
              endothelial cells while leucocytes are relatively
              infrequent.

 Fig. xiii. Rupture of abdominal rectus muscle with hemorrhage. The
              degeneration antecedent to the rupture is shown in the
              belly of the muscle.

[Illustration: Fig. i]

[Illustration: Fig. ii]

[Illustration: Fig. iii]

[Illustration: Fig. iv]

[Illustration: Fig. v]

[Illustration: Fig. vi]

[Illustration: Fig. vii]

[Illustration: Fig. viii]

[Illustration: Fig. ix]

[Illustration: Fig. x]

[Illustration: Fig. xi]

[Illustration: Fig. xii]

[Illustration: Fig. xiii]

------------------------------------------------------------------------




                          TRANSCRIBER’S NOTES


 1. Silently corrected typographical errors and variations in spelling.
 2. Anachronistic, non-standard, and uncertain spellings retained as
      printed.
 3. Footnotes have been re-indexed using numbers.
 4. Enclosed italics font in _underscores_.





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