SUMMARY OF THE INVESTIGATION AND CONCLUSIONS REACHED
EUGENE L. OPIE, M.D.
There is no reason for believing that the influenza which prevailed in
this country differed in any essential feature from that of previous
epidemics and particularly of the pandemic of 1889–90. Our studies have
shown that an organism with the morphologic and cultural characters of
B. influenzæ of Pfeiffer has been constantly found in association with
the disease, and so frequently demonstrated in association with its
pulmonary complications that there is little doubt of its constant
presence. The bronchial and pulmonary complications of influenza present
characters which, while varied, are not usually observed in the absence
of epidemic influenza, and in this pandemic agree with those of the
former pandemic so far as it is possible to determine from the
descriptions available.
Especially noteworthy is the severity of the changes within the
bronchial passages. Clinical studies have shown that purulent bronchitis
has occurred in 36 per cent of instances of influenza. The sputum with
this condition has contained B. influenzæ in all instances, but although
there were no signs of pneumonia it has been constantly associated with
other microorganisms, namely, pneumococci (in 11 of 13 instances), S.
hemolyticus, S. viridans, M. catarrhalis, etc.
Identification of the bacteria which have been present in the bronchi of
those dead with pneumonia following influenza have determined what
microorganisms have penetrated into the lower respiratory passages. B.
influenzæ has been found so frequently (80 per cent) that there is good
reason to believe that it has been constantly present and has not been
isolated in every instance because it has been overgrown by other
microorganisms on the plates or after long continued illness has
disappeared from the bronchi. Mixed infections of B. influenzæ and other
microorganisms are constantly found in the inflamed bronchi;
combinations of B. influenzæ and pneumococci, B. influenzæ and hemolytic
streptococci or these combinations with staphylococci or the four
organisms together are common. Other microorganisms such as B. coli, S.
viridans, M. catarrhalis and diphtheroid bacilli are not infrequently
associated with those which have been mentioned.
Purulent bronchitis has been found in 137 of 241 autopsies; its
bacteriology differs in no respect from that which has just been
described and indeed no line can be drawn between this condition and the
bronchitis invariably present with the pneumonias of influenza. Other
evidence of profound injury to the bronchi is the frequent occurrence of
hemorrhage in a zone ensheathing the smaller bronchi, and the common
occurrence of bronchiectasis when the fatal disease has lasted more than
two or three weeks.
Microscopic study demonstrates that the changes in the bronchial walls
are such as destroy the defences against invasion by microorganisms. The
bronchial epithelium undergoes destruction which is not infrequently
limited to the superficial ciliated cells, but often complete loss of
epithelium occurs. The mucous glands of the larger bronchi exhibit a
special susceptibility to injury, and in the early stages of the lesion
profound degenerative changes are found in the secreting cells, whereas
at a later stage chronic inflammatory changes are almost invariably
present.
Pneumonia following influenza is in most instances bronchopneumonia, but
typical lobar pneumonia has been found in autopsies representing 40.7
per cent of pneumonias of influenza. Lobar pneumonia is frequently
accompanied by purulent bronchitis, and in a considerable number of
autopsies (34 of 98 with lobar pneumonia) lobar and bronchopneumonia
have occurred in the same individual.
Statistics based upon the clinical diagnosis of lobar and
bronchopneumonia following influenza are so inaccurate that they have
little if any value. Notwithstanding careful study of the symptomatology
of the disease, lobar and bronchopneumonia following influenza are not
accurately distinguishable by the means usually employed, and an
erroneous diagnosis has been recorded on the patient’s history in 36.6
per cent of 227 fatal cases with autopsy. A diagnosis of suppurative
pneumonia is rarely if ever made. The difficulties of diagnosis are in
part explained by the frequent association of lobar pneumonia with
purulent bronchitis, with bronchopneumonia or with both, and by the
occurrence of bronchopneumonia with confluent lobular consolidation
involving a large part of a lobe or whole lobes.
There are many defects in the present knowledge of the symptomatology of
the pneumonias under consideration. The symptoms of suppurative
pneumonia are not clearly defined. Many of these deficiencies might be
supplied by further application of the time-honored method of comparing
the clinical course of the disease with the changes found at autopsies,
supplemented by bacteriologic studies made during life and confirmed
after death.
With peribronchial pneumonia bronchi of medium size, on the cut surface
of the lung, are surrounded by sharply defined zones of pneumonic
consolidation perhaps 0.5 cm. in radius, and this lesion furnishes
conclusive proof that the inflammatory process can extend directly
through the bronchial wall reaching all alveoli within a limited
distance for these alveoli bear no relation to the distribution of the
terminal bronchi of the affected bronchus. This peribronchial pneumonia
is usually characterized by fibrinous exudate, and pneumococcus has been
found either in the blood of the heart or in the lung in all of 6
instances in which peribronchial consolidation has been recognized at
autopsy; in half of these autopsies Pneumococcus Type II has been
isolated and this relationship is especially noteworthy because Type II
has been uncommonly associated with the pneumonias of influenza.
=Lobar Pneumonia.=—The distribution of lobar pneumonia has repeatedly
furnished evidence that the process spreads like the peribronchial
lesion directly through the tissue of the lung and is not necessarily
disseminated by way of the bronchial tree. Pneumococci doubtless enter
the lung by way of the bronchi; the occurrence of lobar pneumonia in
frequent association with influenza which exhibits a peculiar capacity
to destroy the defences of the lower respiratory passages is in harmony
with this view. The presence of pneumococci in the blood furnishes no
evidence that infection is hematogenous, for bacterial infections,
particularly at their onset, are frequently accompanied by bacteriemia.
The wave-like spread of lobar pneumonia may be indicated by a narrow
zone of red hepatization separating a large patch of firm, gray
consolidation from engorged but air containing lung tissue. A
semicircular patch of consolidation not infrequently extends from the
left lower lobe into the upper lobe at the site where the interlobular
cleft is absent. This patch may be firm and gray in continuity with
similar consolidation in the lower lobe but surrounded over its convex
surface by a zone of red hepatization.
There is no reason to doubt that the lobar pneumonia which we have found
with influenza has been constantly caused by pneumococci. We have
encountered no instance of lobar pneumonia caused by the capsulated
bacillus of Friedländer. The incidence of different types of pneumococci
in the lung with lobar pneumonia has been as follows: Type IV, 32.4 per
cent; Type II, atypical, 26.5 per cent; Type III, 17.6 per cent; Type
II, 5.9 per cent; Type I, 2.9 per cent; no pneumococci found 14.7 per
cent. It is noteworthy that this distribution of types is in sharp
contrast with the lobar pneumonia of civil life with which Types I and
II constitute the cause of two-thirds of all instances, and is in
agreement with the etiology of the pneumonias found in an army camp
(Funston) in the absence of influenza in epidemic proportion.
=Bronchopneumonia.=—Bronchopneumonia is associated with intense
bronchitis penetrating to the finest bronchioles and is characterized by
consolidation distributed in such definite relation to the bronchial
tree that dissemination of the inflammatory irritant by way of the
bronchi is evident. Consolidation occurs (_a_) in foci affecting alveoli
in immediate proximity to the respiratory bronchioles and in consequence
clustered about the terminal bronchi, the intervening alveolar tissue
containing air; (_b_) in foci of the same character surrounded by
intraalveolar hemorrhage which occupies all alveolar tissue between
adjacent foci; (_c_) throughout whole lobules or groups of lobules,
intervening lobules being unaffected; (_d_) surrounding bronchi of
medium size like a sheath.
The lobar pneumonia of influenza is characterized by frequent
association with purulent bronchitis and bronchopneumonia. The
bronchopneumonia of influenza exhibits characters which serve to
distinguish it from other forms of bronchopneumonia; (_a_) The
associated lesions of the bronchi are unusually severe; purulent exudate
accumulates within the lumen and the lining membrane is destroyed. (_b_)
Pneumonia is frequently hemorrhagic with accumulation of blood within
the alveoli and within and surrounding the bronchi. (_c_) There is
unusual susceptibility of the injured bronchi and of the pulmonary
tissue to secondary invasion by streptococci and staphylococci with
consequent necrosis and suppuration. (_d_) Bronchiectasis frequently
accompanies bronchitis. (_e_) Bronchopneumonia frequently fails to
resolve and the lesion assumes the character of a chronic pneumonia.
With bronchopneumonia pneumococci are found with B. influenzæ in the
bronchi and lungs in nearly half and in the blood in approximately
one-third of instances of the disease, but hemolytic streptococci,
staphylococci, S. viridans, B. coli, M. catarrhalis and other
microorganisms are very frequently found in various combinations: they
undoubtedly have a part in the production of the lesion. Mixed infection
of the lung and even of the blood with pneumococci and hemolytic
streptococci is often found, and study of the sputum during life has
repeatedly shown that pneumococci alone are present shortly after the
onset of the disease, whereas hemolytic streptococci appear later or are
first discovered at autopsy. In such instances pneumococci have not
infrequently disappeared from the lung and at autopsy hemolytic
streptococci alone are demonstrable.
The part which B. influenzæ has in the production of bronchopneumonia is
of great interest. This microorganism is demonstrable by cultures in at
least three-fourths of all instances of bronchopneumonia but is obtained
from the inflamed lung tissue in less than half. In no instance of
pneumonia have we found B. influenzæ unassociated with other
microorganisms, whereas repeatedly pneumococci have been the only
microorganism demonstrable in the lung and very frequently the only
organism present in the blood. In view of the difficulty of
demonstrating the microorganism in plates overgrown by other bacteria,
it is probable that its incidence in the bronchi is much higher, if it
is not constantly present, whereas its isolation from the lung is in
part referable to its presence in the small bronchi where it can be
readily demonstrated by cultures or by microscopic preparations. We have
been almost uniformly unsuccessful in demonstrating the microorganism in
the alveoli of the lung. Goodpasture and Burnett,[106] who have devised
a special method for the demonstration of B. influenzæ in tissues, have
found few of these microorganisms in the alveoli of the lungs.
Pneumonia characterized by the occurrence of small (peribronchiolar)
spots of leucocytic pneumonia upon an almost homogeneous background of
intraalveolar hemorrhage, was regarded by Pfeiffer as the characteristic
lesion produced by his microorganism. B. influenzæ in our autopsies has
borne the same relation to this lesion which it has exhibited to other
forms of bronchopneumonia; pneumococci have been present with
approximately the same frequency and hemolytic streptococci have often
been found.
=Streptococcus Pneumonia.=—The occurrence of streptococcus pneumonia
with suppuration occurring in the trail of influenza was frequently
observed during the pandemic of 1889–90. It is now well recognized that
the streptococcus concerned is one capable of causing hemolysis.
Suppurative pneumonia referable to hemolytic streptococci is of two
types which are readily separable by their anatomic characters: (_a_)
One or several abscesses are situated below the pleura and accompanied
by empyema. Their relation to severe lesions of the bronchi is not
infrequently demonstrable, for a destructive lesion of the bronchial
wall has penetrated into the surrounding alveolar tissue so that
necrosis of tissue and subsequent abscess formation occur in continuity
with the bronchial lumen. The localization of the abscess below the
pleura is referable to the greater severity of the lesions of the small
bronchi which are most numerous at the periphery, to the greater
severity of these bronchial lesions at the bases of the lung, and to the
relation of lymphatics within the interior of the lung to those of the
pleura. It is not improbable that stasis of lymph caused by thrombosis
of the lymphatics has a part in the production of abscess. Preceding or
accompanying abscess formation, the lung tissue undergoes consolidation
and in a wide area about the abscess has a homogeneous gray cloudy
appearance occasionally mottled by opaque patches of necrosis. (_b_)
Interstitial suppurative pneumonia is a lesion not infrequently found in
association with influenza (21 times among 241 autopsies) and rarely, if
ever, seen in its absence. There are few references to this lesion in
the pathologic literature of the English language and those of German
origin in great part refer to the period of the pandemic of 1889–90. The
lesion is essentially suppurative lymphangitis, and both thrombosis and
suppuration of the lymphatics are widespread throughout the affected
lung. In proximity to the inflamed lymphatics and the surrounding
interstitial septa, lung tissue throughout parts of the lobes or even
throughout a whole (lower) lobe has undergone consolidation and has the
gray, cloudy appearance of streptococcus pneumonia.
=Staphylococcus Pneumonia.=—Abscesses produced by staphylococci differ
in anatomic characters and sequelæ from those caused by hemolytic
streptococci. Small abscesses occur in one or several localized
clusters; these abscesses are grouped about a bronchus and have their
origin in its terminal branches. This relation may be readily
demonstrated in microscopic sections. The lesion tends to remain
localized and pneumonic consolidation is limited to the immediate
neighborhood of the group of abscesses. There is no lymphangitis and the
lesion is not accompanied by empyema.
=Empyema.=—Empyema is almost invariably associated with suppurative
pneumonia caused by hemolytic streptococci. Among our autopsies purulent
fluid has been found in the pleural cavity 55 times; it occurred 15
times among 178 instances of lobar or bronchopneumonia and 50 times
among 60 instances of suppurative pneumonia referable to S. hemolyticus.
In our experience hemolytic streptococci and pneumococci are the only
microorganisms which exhibit a noteworthy capacity to penetrate from the
lung to the pleural cavity. We have not found nonhemolytic streptococci
(_e. g._, S. viridans) in association with empyema.
Staphylococcus has failed to invade the pleural cavity even when a
pulmonary abscess has been present below the pleura, and in the only
instances in which staphylococci have been isolated from the pleural
cavity thoracotomy had been performed for empyema caused by hemolytic
streptococci (2 instances) or an abscess communicating with both
bronchus and pleura. B. influenzæ has been found in the pleural cavity
with empyema only once and in this instance cannot be regarded as the
cause of the lesion, for it has accompanied hemolytic streptococci.
=Bronchiectasis.=—Bronchiectasis has been frequently found as a sequela
of the severe bronchitis of influenza and there has been abundant
opportunity to study the lesion in process of development. These
observations have furnished a satisfactory explanation of its etiology
and pathogenesis. Infection of the bronchi by B. influenzæ, accompanied
by a variety of other microorganisms, notably hemolytic streptococci and
staphylococci, has caused profound changes in the bronchial wall
beginning with destruction of the epithelial surface, and followed by
necrosis penetrating partially or completely through the wall and
occasionally extending into the surrounding alveolar tissue. The
difference between the atmospheric pressure within the bronchi and the
lower inspiratory pressure within the surrounding alveoli, accentuated
by forced inspiration at intervals and by occlusion of the bronchioles
with mucopurulent exudate, ruptures the necrotic tissue and produces
longitudinal fissures which are recognizable both macroscopically and
microscopically. In consequence of the separation of the edges of these
fissures by intrabronchial pressure the circumference is increased.
These rents in the wall are limited and partially healed by fibrinous
pneumonia about them, by new formation of fibrous tissue from the
bronchial wall, and adjacent interalveolar septa, by organization of
fibrin within adjacent alveoli and finally by growth of epithelium over
the denuded surfaces.
Bronchitis caused by B. influenzæ and pyogenic micrococci with necrosis
of the bronchi wall is the essential factor in the production of
bronchiectasis, but advanced bronchiectasis is found only in those
individuals who have survived the onset of illness during several weeks,
for dilatation under the influence of positive intrabronchial and
negative extra-bronchial pressure occurs slowly.
=Unresolved Bronchopneumonia.=—Unresolved lobar pneumonia has not been
recognized among instances of pneumonia following influenza, but
unresolved bronchopneumonia is of frequent occurrence and has well
definable gross and microscopic characters. There are purulent
bronchitis, bronchiectasis and distention of the lung tissue, so that it
fails to collapse; particularly characteristic are the indurated foci of
peribronchiolar pneumonia, which being firm and sharply defined, have
the appearance of miliary tubercles. When the process is sufficiently
long continued there are recognizable patches of fibroid pneumonia.
Microscopic examination shows that the lesion is characterized by
organization of fibrinous exudate not only within the alveoli but within
bronchioles as well, and by thickening of the alveolar walls, thickening
of fibrous tissue about the bronchi and blood vessels, and thickening of
interstitial septa. These changes may occur as peribronchiolar patches
of consolidation, producing tubercle-like nodules, or may involve areas
of hemorrhagic peribronchiolar or of lobular consolidation, or may be
limited to the immediate neighborhood of bronchi (peribronchial).
No peculiarity of the bacterial flora of the bronchi or of the lung
offers a satisfactory explanation of the failure of pneumonic exudate to
resolve. Mixed infections have been common and S. hemolyticus,
staphylococci, pneumococci, S. viridans, B. coli, etc., have been found
in association with B. influenzæ but the incidence of these
microorganisms has not been greater than with bronchitis. The lesion has
occurred in association with B. influenzæ and pneumococci unassociated
with other microorganisms. It seems probable that the severity of injury
to the bronchial and alveolar walls accompanied by recurring bacterial
invasion or by continued infection with B. influenzæ and one or several
cocci, is the factor concerned in the inhibition of resolution and the
production of chronic pneumonia. If the disease does not result in early
death, chronic pneumonia has an opportunity to manifest itself.
In this investigation of the bacteriology and pathology of influenza and
its complications, certain microorganisms have been found so frequently
that it is desirable to discuss the pathogenicity of each and to define
the character of the lesions which it causes.
=Bacillus Influenzæ.=—The microorganism has been constantly found in
association with influenza when cultures and animal inoculations have
been made from various parts of the respiratory tract within from one to
five days after the onset of the disease at a time when there have been
acute symptoms of the disease.
It is often identified with difficulty in the presence of other
microorganisms and may be overlooked when a single culture is made.
Repeated cultures from the throat alone made from the fourth to the
eighth day after admission to the hospital, at a time when temperature
had fallen to normal, have demonstrated the presence of B. influenzæ in
30.5 per cent, whereas the incidence of the microorganism in similar
cultures on admission had been 63.4 per cent. The incidence of B.
influenzæ in the present epidemic of influenza is not less than that
found by Pfeiffer in the epidemic which he studied in 1892.
Nevertheless we have found that B. influenzæ is frequently an inhabitant
of the mouth and throat of normal individuals. By inoculation of mice
with the saliva or sputum of 76 patients with influenza, the
microorganism has been found in 80.3 per cent; by inoculation of mice
with the saliva of 185 normal men at army cantonments, it was found in
41.6 per cent; by inoculation of mice with saliva from 50 recruits
immediately after they were assembled from isolated farming communities
where only a few cases of influenza had occurred, it was found in 22 per
cent. Figures for the same groups examined by a single throat culture
were as follows: 65.7 per cent, 25.9 per cent and 0 per cent.
Experiments which we have performed on monkeys show that inoculation of
the nasopharynx with B. influenzæ obtained from patients with influenza
is followed by ill-defined symptoms associated with the presence of B.
influenzæ within the throat. After from two to eleven days the symptoms
and the microorganism disappear. Injection of B. influenzæ into the
trachea causes bronchitis and the microorganism may be recovered from
the inflamed bronchi two or three days after inoculation.
The constant association of B. influenzæ with influenza suggests that it
is the cause of the disease. Its widespread occurrence in the throats of
normal individuals does not contradict this view, since pneumococci long
indistinguishable from those which usually cause lobar pneumonia are
commonly found in the throats of healthy men. It is possible that B.
influenzæ is a secondary invader, entering the respiratory tract when
susceptibility is increased by an unknown virus causing influenza; but
there is no convincing evidence in favor of this view. It is desirable
to determine if microorganisms having the characters of B. influenzæ
found with influenza differ in type from those found in the throats of
healthy men and if the invasion of the respiratory tract by B. influenzæ
is followed by the appearance of immunity reactions in the serum of the
patient. Experiments on monkeys demonstrate the pathogenicity of the
microorganism.
The relation of B. influenzæ to the bronchitis of influenza indicates
that it has a part in the production of the pulmonary sequelæ of
influenza. The microorganism has been found by a single culture from the
bronchial passages in 80 per cent of instances of bronchitis with fatal
pneumonia following influenza and is probably constantly present,
usually in immense number, in the bronchial mucus. It is obtained from
the pneumonic lung in only about 40 per cent of instances, and
microscopic examination of prepared tissue shows that a bacillus with
the morphology of B. influenzæ is often demonstrable in the bronchial
passages but seldom in the alveoli of the lung. The microorganism is
well adapted to multiply under conditions present in the bronchi but
doubtless readily disappears from the alveoli which are the site of an
inflammatory reaction. The microorganism has an important part in the
production of the associated mucopurulent and hemorrhagic inflammation
of the bronchi, but it is rarely if ever found in pure culture, being
associated with a considerable variety of pyogenic cocci and
occasionally bacilli. Infection of the bronchi with B. influenzæ in
immense numbers offers an explanation of the severity of the
inflammatory process within the bronchi, and of the subsequent
dilatation and other chronic changes which occur in them. The presence
of the microorganism and the accompanying injury to the ciliated
epithelium and mucous glands are important factors in lowering the
resistance of the bronchial passages to secondary bacterial infection.
We have obtained no evidence that B. influenzæ alone is capable of
causing pneumonia. Its occurrence in less than half of all pneumonic
lungs is explainable, in part at least, by its presence in the terminal
bronchi which are cut across whenever the lung is punctured for culture.
B. influenzæ alone has been found only once among 153 pneumonic lungs
from which cultures were made, and in this instance (Autopsy 487) S.
hemolyticus present in the blood of the heart, pleural cavity and
bronchus doubtless had a part in the production of the associated
pneumonia. Pfeiffer maintained that the lesion we have designated
hemorrhagic peribronchiolar consolidation was characteristic of
infection with his microorganisms. With this lesion B. influenzæ has
been found in the lungs in slightly more than half of our autopsies but
never alone, pneumococci being found in a third, hemolytic streptococci
in more than a half and staphylococci in a fourth of the lungs examined.
B. influenzæ has relatively little capacity to penetrate from the
bronchi into the lung tissue and rarely penetrates into the pleural
cavity (once with Pneumococcus III, once with S. hemolyticus and once in
pure culture), and only once has it been found in the blood of the
heart, in this instance in company with S. hemolyticus. Capacity of the
microorganism to penetrate from the bronchi into other tissues, both in
man and as our experiments have shown in the monkey, is increased by
association with pyogenic cocci.
=Pneumococcus.=—Lobar pneumonia following influenza, like lobar
pneumonia in civil life unassociated with influenza, has been caused by
pneumococci, but there is the notable difference that the pneumococci
usually found are those types which are commonly present in the mouths
of healthy men, namely, Types IV, III and atypical II and not the
so-called fixed types, namely, Types I and II, which represent the usual
cause of lobar pneumonia unassociated with influenza. It appears that
influenza increases susceptibility to lobar pneumonia, so that it is
frequently caused by microorganisms which under other conditions are
less capable of producing this lesion. The association of the
pneumococci usually found in the mouth with the lobar pneumonia of
influenza does not exclude the possibility that pneumococci transmitted
from one individual to another, when newly recruited troops are brought
together, have an important part in the production of pneumonia.
Bronchopneumonia is frequently caused by pneumococci and the types which
are recovered from the lung and blood do not differ from those found
with lobar pneumonia, those usually present in the mouth being
predominant, but the incidence of pneumococci with bronchopneumonia has
been much less than with lobar pneumonia. Both lobar and
bronchopneumonia caused by pneumococci have undergone secondary
infection with hemolytic streptococci in a large proportion of instances
and both pneumococci and streptococci are often recovered at autopsy.
Nevertheless, the bacterial flora of the bronchi and lungs is much more
varied with broncho than with lobar pneumonia, and it is evident that
microorganisms other than pneumococci are capable of causing
bronchopneumonia.
In instances of bronchopneumonia associated with pneumococci, fibrin has
been abundant in the alveolar exudate.
The pneumococcus exhibits a notable tendency to produce an inflammatory
process which extends through the bronchial walls and from one alveolus
through the alveolar walls to those adjacent, for in 6 instances in
which the bronchi were surrounded by pneumonic consolidation
recognizable at autopsy, pneumococci were uniformly the causative agent,
Pneumococcus Type II, otherwise rarely found, being present in half of
these cases.
Pneumonia caused by one type of pneumococcus does not necessarily confer
immunity from other types of pneumococci, and with somewhat limited
opportunity we have observed a number of instances in which, following
recovery from pneumonia caused by one type of pneumococcus, a second
attack of pneumonia, usually fatal, has been associated with pneumococci
of a different type. This recurring pneumonia in a considerable
proportion of the relatively small number of instances observed has been
produced by Pneumococcus Type II which otherwise has been seldom found
among the cases which we have studied. The virulence of this
microorganism doubtless explains its ability to cause recurrent
pneumonia.
=Streptococcus Hemolyticus.=—Secondary infection with S. hemolyticus is
a common event during the course of lobar pneumonia following influenza.
It is noteworthy that this streptococcus infection of the lung has
almost invariably occurred in the stage of red hepatization, whereas
with gray hepatization, when the alveoli are filled with polynuclear
leucocytes, S. hemolyticus rarely invades the lung. It is possible that
infection with S. hemolyticus tends to prolong the stage of red
hepatization.
The most significant change produced in the pneumonic lung by
streptococci is necrosis. When after death with lobar pneumonia
hemolytic streptococci, usually associated with pneumococci, are found
both in the lungs and blood of the heart, the lung contains patches of
necrosis recognized microscopically, in which the alveolar walls and
exuded cells have uniformly lost their nuclei. Microscopic examination
demonstrates the presence of chains of streptococci in immense number in
these necrotic foci; elsewhere chains of streptococci occur but are much
less abundant. In some instances streptococci exhibit a tendency to
enter lymphatics and to cause acute lymphangitis with lymphatic
thrombosis and edema of the adjacent interstitial tissue.
Hemolytic streptococci have been more frequently found in association
with broncho- than with lobar pneumonia. In 24.5 per cent of instances
of lobar pneumonia, doubtless in all instances caused by pneumococci,
hemolytic streptococci have invaded the lungs and in 12.6 per cent of
instances have found their way into the blood. With bronchopneumonia
hemolytic streptococci have been obtained from the lungs in 29.8 per
cent of instances and from the blood of the heart in 34.3 per cent.
With lobar pneumonia there is little doubt that pneumococcus has been
the primary cause of pneumonia, but with bronchopneumonia pneumococci
have been less frequently found. It is difficult to determine how often
hemolytic streptococci have invaded a bronchopneumonic lesion, caused by
pneumococci because pneumococci tend to disappear. In numerous instances
in which the sputum had been studied during life, it was evident that
pneumonia was primarily referable to pneumococci, and hemolytic
streptococci made their appearance in the sputum late in the disease or
were first recognized at autopsy.
When hemolytic streptococci occur in association with bronchopneumonia,
foci of pulmonary necrosis similar to those found under the same
conditions with lobar pneumonia have been repeatedly found by
microscopic examination. In the patches of necrosis, cocci in chains are
much more abundant than in the tissue elsewhere.
In some instances of pneumonia, caused by hemolytic streptococci, opaque
gray or yellowish gray patches of necrosis occur upon a background of
flaccid homogeneous consolidation which has a peculiar cloudy, gray
color. This mottled consolidation may implicate an entire lower lobe and
has the characteristic features neither of lobar nor of
bronchopneumonia. More frequently the lesion is less widespread and
necrosis occurs in one or several spots which undergo softening so that
finally a small abscess cavity may be formed; it is surrounded by
pneumonic consolidation which is soft and has the cloudy appearance
described above. These pulmonary abscesses are almost invariably
situated below the pleural surface; the adjacent pleural cavity is
infected by streptococci and there is purulent inflammation of the
pleura.
Streptococcus infection, which has been described, doubtless has its
origin in the bronchi, for in favorable sections it is not infrequently
possible to demonstrate that necrosis extends through the bronchial
walls into the surrounding alveolar tissue and is followed by
suppuration with abscess formation. Localization of abscesses below the
pleura is in part at least referable to transmission of streptococci by
way of the lymphatics.
Streptococci in the lung, as in other tissues, often invade lymphatics
and produce an acute inflammatory reaction within and about these
vessels. The peculiar lesion which may be designated suppurative
interstitial pneumonia is a suppurative lymphangitis associated with
inflammation and edema of the interstitial tissue. Lymphatics invaded by
streptococci are the site of acute lymphangitis; occlusion by fibrinous
thrombi occurs and finally the immensely distended lymphatics, filled
with purulent fluid, take a characteristic nodular or beaded form and
pus flows from them when they are cut. Streptococci are present in vast
numbers. Suppurative inflammation may extend to the surrounding
interstitial tissue which is distended by inflammatory edema. This
interstitial suppurative pneumonia extends up to the pleural surface and
empyema is almost invariably associated with it. The lesion is seldom
seen in the absence of influenza.
One of the most significant characters of S. hemolyticus is its ability
not only to enter the bronchi and penetrate into the tissue of the lung,
but to find its way into more distant structures, namely, the pleural
cavity, pericardial sac and peritoneal cavity and to penetrate into the
blood. Among 121 examinations, hemolytic streptococci were found in the
bronchi in 47.9 per cent; among 153 examinations of the lung it was
present in approximately the same proportion, namely, 50.3 per cent;
among 218 examinations of the blood it was found in 39 per cent. In 4 of
5 fatal pneumonias in which the organism has penetrated into the bronchi
it has ultimately found its way into the blood.
=Nonhemolytic Streptococci.=—In contrast with S. hemolyticus
nonhemolytic types have rarely been encountered in association with the
pneumonias of influenza. S. viridans has been found only 5 times among
153 autopsies in which cultures have been made from the lung and has
been invariably associated with other microorganisms. In no instances
have nonhemolytic streptococci been found with empyema. In one autopsy
with lobular bronchopneumonia S. viridans has been isolated from the
blood of the heart and in this instance it has been found in the
bronchus and lung as well. This type of streptococcus is evidently
little adapted to invade the bronchi and produce lesions of the lung and
adjacent tissues.
=Staphylococci.=—Staphylococci have been very frequently isolated from
the bronchi in association with the pneumonias of influenza, being found
in approximately half of our autopsies. Their isolation in cultures from
the lung in a fourth of the autopsies examined is in part perhaps
referable to their presence in the small bronchi cut across when the
lung is punctured for cultures. S. aureus shows little ability to invade
the pleura, being found in association with empyema only 3 times; in
these autopsies there has been opportunity for entrance from the
exterior through thoracotomy wounds in 2 instances and from a bronchus
in free communication with an abscess which had ruptured into the
pleural cavity in 1 instance.
Abscesses of the lung caused by staphylococci have been found in a small
number of autopsies and have exhibited characters which differ from
those ordinarily seen in association with S. hemolyticus. Small, sharply
defined abscesses are grouped about terminal bronchi, so that they occur
in one or several isolated clusters. Microscopic examination
demonstrates that these abscesses have arisen by destruction of the
bronchial walls and extension of suppuration into the surrounding
alveolar tissue; clumps of staphylococci are found in sections through
the abscess, and cultures made from the pus within the abscess cavity
demonstrate the presence of S. aureus or albus, but the microorganism
may be missed if the culture is made from the adjacent lung tissue. It
is noteworthy that there is little tendency for the staphylococcus to
infect the pleura for even though these clusters of abscesses have been
situated just below the pleura, there has been no associated empyema.
Staphylococci have scant tendency to enter the blood and have been
obtained from the blood of the heart only once, in this instance with
hemolytic streptococci.
=Pneumonia of Measles.=—Pneumonia following measles has been responsible
for a considerable part of the deaths occurring in the United States
Army during the period of the war. The importance of measles as a factor
in the production of pneumonia is illustrated by the history of
pneumonia at Camp Funston from the establishment of the camp in
September, 1917, until September, 1918. Pneumonia following measles
occurred throughout the year; but in association with the high incidence
of measles during the second half of November and the first half of
December, 1917, there was an outbreak of related pneumonia characterized
by frequent empyema and a mortality of 45.3 per cent.
During the period of our investigation at Camp Funston there were 112
cases of measles, but no pneumonia occurred among them. At Camp Pike,
during the period of observation, there was an outbreak of measles
almost coincident with the epidemic of influenza, and among 867 cases
pneumonia occurred in 56, otitis media in 48, and mastoiditis in 23.
Pneumonia following measles was almost coincident with that of
influenza, and it is not improbable that the epidemic of influenza had
an important part in the production of pneumonia in individuals
suffering with measles.
In 9 of 56 instances of pneumonia following measles at Camp Pike, S.
hemolyticus had invaded the lung and caused pneumonia; among 48
instances of otitis media following measles a very large proportion were
caused by hemolytic streptococci, and 21 of 23 instances of mastoiditis
were caused by the same microorganism. No complication caused by S.
hemolyticus occurred among 37 patients who carried this microorganism
when admitted to the hospital.
A special study has been made to determine if those patients with
measles who carry S. hemolyticus in their throats are especially
susceptible to complications during the course of measles. The low
incidence of streptococcus “carriers” among those admitted to the
hospitals with measles was noteworthy both at Camp Funston (2.67 per
cent) and at Camp Pike (4.2 per cent). Indeed, it was found at both
places that the incidence of hemolytic streptococci in the throats of
normal men in the camp was higher (Camp Funston 21.9 per cent; Camp Pike
7.4 per cent) than that in the throats of those admitted with measles.
While in the hospital there was a gradual increase of the incidence of
S. hemolyticus, so that in three weeks it had risen to 19 per cent at
Camp Funston and to 26.2 per cent at Camp Pike. It seems not improbable
that hemolytic streptococci disappear from the throat in the early
stages of measles, so that they are not demonstrable by cultural
methods. During the course of the disease in the hospital ward the
number of those with S. hemolyticus has increased in some wards with
great rapidity, infection being apparently transmitted from one
individual to those adjacent. At Camp Funston the incidence of S.
hemolyticus in the throats of those convalescent with measles was almost
identical with that among normal men in organizations from which the
patients had come, but at Camp Funston the percentage of hemolytic
“carriers” among convalescents was much higher than that obtained among
normal men in the camp.
The demonstration of S. hemolyticus in the throat of a patient suffering
with pneumonia is not conclusive proof that the lungs have been invaded
by this microorganism. Pneumonia in individuals carrying S. hemolyticus
in the throat may pursue a favorable course and exhibit no evidence that
the microorganism has found its way into the lung. In some instances
hemolytic streptococci have been found in the bronchi at autopsy yet
none have entered the lung or blood and the lung exhibits none of the
lesions which are referable to hemolytic streptococci. Nevertheless, the
occurrence of S. hemolyticus in cultures from the throat of a patient
with pneumonia suggests the probability that he is suffering with
streptococcus pneumonia.
Pneumonia following measles studied in 18 autopsies upon patients who
died during or shortly after the epidemic of influenza, exhibited all
the characters exhibited by the pneumonias of influenza. In 4 instances
there was typical lobar pneumonia; bronchopneumonia was found in all but
3 instances, being associated with lobar pneumonia twice. All the
noteworthy features of the bronchopneumonia of influenza have been
reproduced among these instances of pneumonia with measles; there is
severe injury to the bronchi, and purulent bronchitis has been present
in 13 instances; pneumonia has frequently had a hemorrhagic character,
hemorrhagic peribronchiolar pneumonia occurring in 5 instances;
secondary infection of the pneumonic lungs with hemolytic streptococci
has been common; bronchiectasis has been associated with bronchitis (in
8 instances) when purulent bronchitis has persisted several weeks; and
unresolved bronchopneumonia has been more frequent (6 instances or
one-third of the autopsies) than with influenza.
The bacteriology of pneumonia following measles has been the same as
that of influenzal pneumonia. B. influenzæ is found with few exceptions
in the bronchi and much less frequently in the pneumonic lungs.
Pneumococci have been obtained from the blood or lungs in 5 of 13
instances of lobar or bronchopneumonia unaccompanied by suppuration;
when suppuration has been absent no hemolytic streptococci have been
found. Pneumococci concerned in the production of pneumonia of measles,
as with influenzal pneumonia, have been types usually found in the
mouth; Pneumococcus II atypical has been found 6 times, Type IV once,
Type I once.
Hemolytic streptococci have invaded the pneumonic lung in 5 instances.
They have produced subpleural abscesses accompanied by empyema in 2
instances. Interstitial suppurative pneumonia, a lesion repeatedly found
in consequence of secondary infection with S. hemolyticus following
influenza and rarely found in this country, at least in the absence of
an epidemic of influenza, has occurred 3 times among 18 instances of
pneumonia following measles.
The foregoing observations show that the pneumonia following measles,
which has occurred almost coincidentally with pneumonia accompanying
epidemic influenza has reproduced the lesions found with influenzal
pneumonia. They indicate that influenza attacking patients with measles
has had a part in the production of this pneumonia.
=The Transmission of Streptococcus Pneumonia.=—The importance of
streptococcus as a cause of pneumonia following influenza was recognized
during the pandemic of 1889–90. Patients suffering with pneumonia
following influenza or measles are susceptible to infection by S.
hemolyticus and this streptococcus pneumonia may be transmitted from one
patient to another throughout a ward in which patients with pneumonia
are assembled. There is no evidence that primary pneumonia caused by S.
hemolyticus has prevailed as an epidemic in the army or elsewhere in the
absence of preceding infection with influenza or measles.
Our autopsies demonstrate that at least half of all deaths which have
occurred at Camp Pike have been caused by hemolytic streptococci which
have invaded the lung and entered the blood. It is significant that this
mortality had its origin in the first half of the epidemic of influenza
at a time when the military and medical organization of the camp was
confronted with an unforeseen emergency which overwhelmed all agencies
for the care of disease. Curves prepared by referring cases of pneumonia
in which autopsy demonstrated the nature of the fatal infection back to
the date of the onset of influenza, demonstrate that fatal streptococcus
pneumonia was frequently acquired during the early period of the
epidemic, the maximum number of cases occurring September 23 and 24 and
became gradually less common as a sequela of the influenza which began
at a later period. Fatal pneumococcus pneumonia had its origin with
increasing frequency at a later period, the maximum incidence following
influenza which had its onset September 29 and 30. Overcrowding of
influenza patients in infirmaries, ambulances and hospital had an
important part in the dissemination of streptococcus pneumonia among
influenza patients whose disease might otherwise have pursued a benign
course.
The most important factor in the high incidence of streptococcus
pneumonia has been the spread of the disease in the hospital wards. On
September 24 the base hospital contained 2,789 patients, although it had
been planned to care for only 2,009. With the progress of the epidemic
the number of admissions increased very rapidly, so that on September 30
the hospital contained 3,587 patients and on October 5, 4,233. After
September 24 the milder cases of influenza were treated in barracks. The
pressing need of diminishing the overcrowding of the hospital was fully
recognized and adjacent barracks were transformed into hospital wards;
between October 3 and 6, 1,362 patients were transferred from the
hospital to these quarters.
In the main hospital, during the period of overcrowding 20 wards for
patients with pneumonia were added to the two which already existed.
These hastily organized and overcrowded wards have been attacked by
outbreaks of streptococcus pneumonia, which during certain periods have
been fatal to more than two-thirds of those who have been admitted with
pneumonia, whereas in the two long established wards for pneumonia
isolated cases of streptococcus infection, which have appeared, have
failed to spread to other patients and pneumococcus pneumonia with few
exceptions has been found in those who have died. In one newly
established ward 67.5 per cent of those admitted within a period of
three days have died, and in all of the 23 autopsies which have been
performed, streptococcus pneumonia has been found. In another ward 50
per cent of all who have been admitted during a period of one week have
died, and among the autopsies performed on these individuals
pneumococcus pneumonia has been found in 6 and streptococcus pneumonia
in 14. The sputum of 9 patients in this ward has been examined on
admission, and pneumococci, but no streptococci, have been found. All
these patients have died, and infection with S. hemolyticus has been
found at autopsy in 7.
=Transmission of Pneumococcus Pneumonia.=—Our study of secondary ward
infection has not only shown that patients with pneumococcus pneumonia
following influenza are susceptible to infection by S. hemolyticus, but
that patients suffering with pneumonia caused by one type of
pneumococcus may be infected with another type during the course of the
disease or after convalescence has begun, the second infection being
acquired from patients in adjacent beds. Pneumonia caused by Type IV has
ended in crisis and has been followed by a period of normal temperature;
recurrent pneumonia has been fatal and Pneumococcus Type II has been
found in the organs at autopsy. Pneumonia caused by Type I has been
followed by recurrent pneumonia caused by Pneumococcus II atypical
acquired from a patient in the next bed. These secondary pneumococcus
infections acquired within the hospital are apparently not uncommon.
=Prevention of the Transmission of Pneumonia.=—The essential factor in
the management of influenza and pneumonia is such isolation of each
patient that microorganisms cannot be transmitted from one to another or
from attendants or others to patients. This condition may be fulfilled
by the separation of patients in rooms or isolated compartments
especially constructed for the treatment of pneumonia and by the
employment of all possible means to prevent the transmission of
infection from one patient to another by physicians, nurses and
orderlies. It is desirable to examine attendants to determine if they
carry hemolytic streptococci in their mouths and to exclude those who
are found to be “carriers.”
Influenza is a self-limited disease which, in the absence of
complications implicating the lower respiratory tract, is of relatively
mild character. When death occurs as the result of influenza it is with
very rare, if any, exceptions referable to pneumonia; we have invariably
found pneumonia in those who have died in consequence of influenza. The
individual attacked by influenza may carry within his upper respiratory
passages pneumococci or hemolytic streptococci capable of invading the
bronchi and causing pneumonia, but in most instances the microorganism
which produces serious pulmonary complications is derived from others
with whom the influenza patient has come into contact. The greatest
source of danger to one with influenza is contact with patients who have
acquired pneumonia, and this danger is immensely increased when
infection with S. hemolyticus makes its appearance among pneumonic
patients. Hospital epidemics of streptococcus pneumonia will be
prevented when the disease is dreaded as much as puerperal fever or the
hospital gangrene of former years, and widespread knowledge of the
suppurative pneumonias of influenza will bring a clear recognition of
the fatal character of streptococcus infection in patients suffering
with pneumococcus pneumonia.
Overcrowding of barracks has been an important factor in the propagation
of acute respiratory disease and in the transformation of otherwise
trivial influenza into fatal pneumonia. Crowded troop trains have
doubtless had a part in disseminating infection among newly assembled
recruits. Should these dangers be recognized they may be avoided by
appropriate measures which will promote rather than retard those
military aims which must be placed foremost in time of war. It may be
possible by adequate expenditure to avoid the death of thousands of
recruits within one month of their entrance into military service.
A second factor in the increase of death rate from pneumonia is the
overcrowding and confusion of hospital facilities in the presence of an
epidemic disease. When troops are maintained in camps precautions should
be taken to provide effective safeguards against the overcrowding of the
base hospital.
Isolation of each patient with pneumonia is the most effective way of
protecting him from infection and of preventing him from becoming a
possible source of danger to others. The effectiveness of this isolation
will depend upon the separation of patients by some means more effective
than the cubicles composed of sheets heretofore employed, upon an
aseptic technic sufficiently rigid to prevent the transfer of pyogenic
infection to pneumonia patients, and upon the exclusion from the ward of
those who harbor S. hemolyticus.
Even should each patient be completely isolated from his neighbors, no
effort should be neglected to determine, as far as possible, the nature
of the infection with which he suffers. In the presence of an
overwhelming epidemic such as that which attacked our army camps, the
bacteriologic work which is required may be far beyond the facilities
which are available and in many instances it may be wholly impossible.
Nevertheless effective control of streptococcus pneumonia will depend
upon its recognition as soon as it appears, and bacteriologic
examination of the sputum offers the readiest means for its
identification. The routine performance of autopsies will furnish an
index of the success of the measures in force, and the discovery of
suppurative pneumonia will suggest the presence of imminent danger.
However perfect the organization of pneumonia wards and however accurate
the aseptic technic in force, it is desirable to separate as far as
possible those infected with streptococcus from those who are free from
this infection, so that the accuracy of the technic in force may not be
put to too severe a test. When streptococcus pneumonia has appeared in a
ward it should be closed to further admissions.
Those who are concerned in the planning and construction of military and
other similar hospitals might well give special attention to the
possibility of epidemics such as those which we have experienced, and
special provision might be made to avoid overcrowding in the presence of
a demand far in excess of the routine need for hospital facilities. In
the construction of these hospitals appropriate provision should be made
for the care of patients with pneumonia. Medical officers should receive
detailed instruction in the organization and conduct of wards designed
for the treatment of pneumonia.
APPENDIX
EXPERIMENTAL INOCULATION OF MONKEYS WITH BACILLUS INFLUENZÆ AND
MICROORGANISMS ISOLATED FROM THE PNEUMONIAS OF INFLUENZA
EUGENE L. OPIE, M.D.; ALLEN W. FREEMAN, M.D.; FRANCIS G. BLAKE, M.D.;
JAMES C. SMALL, M.D.; AND THOMAS M. RIVERS, M.D.
Experiments were undertaken at Camp Pike in December, 1918, to determine
whether bacteria freshly isolated from patients suffering with influenza
and pneumonia during the outbreak of influenza and its associated
pneumonias were capable of producing similar diseases when introduced
into the respiratory passages of monkeys. The number of animals
available for the study was limited. The attempt was made (_a_) to
determine if B. influenzæ produces in monkeys a disease comparable to
influenza of human beings, and (_b_) to determine so far as possible,
with the limited opportunity, the character of the lesions produced by
combinations of pneumococcus or S. hemolyticus with B. influenzæ and to
compare these lesions with lesions produced by pneumococcus or by
hemolytic streptococcus alone.
Pfeiffer[107] found monkeys alone susceptible to invasion by B.
influenzæ and obtained no evidence of multiplication of the
microorganism within the body of any other animal. A suspension
containing mucus from the sputum of a patient with influenza was
injected into a monkey. There was elevation of temperature and the
animal died after seven days. Lobular patches of atelectasis occurred
along the sharp edges of the lungs and the adjacent bronchial branches
contained mucus. Cultures on agar from the bronchi remained sterile.
Microscopic examination showed the presence of bacilli resembling B.
influenzæ. Death was caused, the author states, by an abscess at the
site of inoculation and not by the process in the lungs. Three monkeys
received each 0.5 c.c. of bouillon containing a blood agar culture
injected into the lung through the chest wall. There was elevation of
temperature lasting from three to five days with return to normal every
morning. There was cough but little evidence of illness. B. influenzæ
was introduced by a platinum loop into the nose of a monkey. Febrile
reaction is recorded lasting four or five days. Pfeiffer found that
guinea pigs and mice were resistant to the microorganism. Large doses
injected intravenously caused in rabbits intoxication with dyspnea and
evidence of profound muscular weakness.
Kamen[108] used a culture of B. influenzæ which was nonpathogenic for
mice, but when it was inoculated into the peritoneal cavity with
streptococcus both influenza bacilli and streptococci appeared in the
blood. Jacobson[109] found that B. influenzæ appeared in the blood and
viscera of mice killed by intraperitoneal inoculation of B. influenzæ
mixed with cultures of streptococcus either living or killed by heat. B.
influenzæ which had successively passed through mice, simultaneously
inoculated with killed streptococci, acquired such virulence that it was
capable of producing septicemia when inoculated alone.
Richie[110] introduced by lumbar puncture a suspension of two blood agar
cultures of B. influenzæ obtained from the meninges of a patient with
influenzal meningitis into the subdural space of a rhesus monkey. Death
occurred in eighteen hours and there was beginning meningitis. B.
influenzæ was present in the exudate in abundance.
In two species of monkeys Wollstein[111] produced fatal meningitis by
injecting suspensions of B. influenzæ into the subdural space by lumbar
puncture.
During the course of our investigation of pneumonia and influenza,
sputum of approximately 400 normal individuals or patients with
influenza was injected into the peritoneal cavity of mice. B. influenzæ
was found in approximately 150 instances. In only 4 instances was B.
influenzæ found in pure culture in the blood; in all other mice in which
B. influenzæ appeared in the blood it accompanied pneumococcus or S.
hemolyticus.
Before experiments were performed cultures were made from the throats of
all monkeys in order to exclude the presence of B. influenzæ. Blood agar
plates inoculated with a swab applied to the nasopharynx failed to show
in any instance B. influenzæ, pneumococci, or hemolytic streptococci.
Streptococci causing green discoloration of blood agar were usually
found.
=Inoculation of the Nose and Pharynx with B. Influenzæ.=—B. influenzæ
was introduced into the nose and pharynx of two healthy monkeys. An
actively growing culture of the microorganism made on alkaline blood
agar and sixteen hours old was used. The culture was the first
subculture from a growth obtained from the nose and throat of a patient
with influenza. A cotton swab moistened with broth was applied to the
surface of the culture. It was introduced into the nostrils and smeared
over the pharynx of the animals. A swab moistened with sterile broth was
applied to the nose and pharynx of a third monkey as a control; cultures
from this animal kept in a cage removed from those inoculated failed to
show B. influenzæ.
EXPERIMENT 1
November 21, 1918.—Small female monkey; throat culture: negative.
November 23.—10:20 A.M.—White blood corpuscles, 16,700; polynuclear
leucocytes, 68 per cent; small lymphocytes, 17.5 per cent; large
lymphocytes, 8 per cent; large mononuclears, 1 per cent;
eosinophiles, 2.5 per cent; basinophiles, 0.5 per cent. 10:30
A.M.—Mucous membranes of nose and throat were inoculated with B.
influenzæ as described above. November 25.—The animal appears sick
and is huddled in back of its cage; the nose is running. White blood
corpuscles, 13,500; polynuclear leucocytes, 44 per cent; small
lymphocytes, 30 per cent; large lymphocytes, 22 per cent; large
mononuclears, 3 per cent; eosinophiles, 1 per cent. 3:40 P.M.—Free
epistaxis occurred after culturing of nose; the swab was discolored
with old brownish blood indicating previous epistaxis. Nose culture:
B. influenzæ present in abundance; Gram-positive cocci present.
Throat culture: negative for B. influenzæ. November 28.—Monkey is
more active and appears to be fairly well. Nose and throat cultures:
negative for B. influenzæ. December 4.—Monkey is apparently well.
EXPERIMENT 2
November 21, 1918.—Small male monkey. Throat culture: negative.
November 23.—10:10 A.M.—White blood corpuscles, 10,900; polynuclear
leucocytes, 52 per cent; small lymphocytes, 18 per cent; large
lymphocytes, 25 per cent; large mononuclears, 3 per cent;
eosinophiles, 2 per cent. 10:15 A.M.—Mucous membranes of nose and
throat were inoculated by means of moist swab with 4 strains of B.
influenzæ recently isolated from acute cases of influenza. November
24.—Monkey is quiet and takes no interest in surroundings. November
25.—Animal appears sick and remains huddled at back of its cage.
Nose culture: B. influenzæ present. Throat culture: B. influenzæ
present. Swab applied to nose is stained brown with old blood
indicating previous epistaxis. November 26.—Animal is still sick;
nose is running. White blood corpuscles, 14,400; polynuclear
leucocytes, 61 per cent; small lymphocytes, 23 per cent; large
lymphocytes, 15 per cent; large mononuclears, 1 per cent. November
27.—White blood corpuscles, 11,300. November 28.—Nose culture:
negative for B. influenzæ. Throat culture: B. influenzæ present.
November 29.—Animal is active, but still appears sick. White blood
corpuscles, 19,300. December 4.—Monkey appears well. Throat culture:
B. influenzæ present.
These animals were sick two and six days following inoculation. There
was discharge from the nose. In both instances there was epistaxis. The
temperature of the animals was subject to such wide variation in
relation to external temperature that it could not be used as an index
of the progress of the disease. There was no leucocytosis, but in one
animal there was some increase in the numbers of leucocytes during
recovery. In one animal B. influenzæ present in the nose after two days
was absent after four days. In the other animal the organism was
repeatedly found in the nose and throat and was still present in the
throat eleven days after inoculation. The two animals suffered with a
self-limited disease resembling many cases of influenza.
=Introduction of Bacillus Influenzæ into the Trachea.=—In the attempt to
reproduce the bronchitis which occurs in a considerable proportion of
all cases of influenza and is almost invariably associated with B.
influenzæ, this organism was introduced into the trachea of monkeys. In
Experiment 3 a suspension containing young cultures of freshly isolated
B. influenzæ was introduced into the trachea by a silver catheter passed
through the glottis and larynx into the trachea.
Young cultures of B. influenzæ, subcultured only once after isolation
from early cases of influenza, were used. The microorganism was
recovered in abundance by throat swab two days later and again from the
bronchus at autopsy three days after inoculation. Tuberculosis of
mesenteric lymph nodes, of intestine and of liver and several small
tuberculous nodules in the lung were found at autopsy. A secondary
invasion of the lung by staphylococci had occurred. There was bronchitis
with an inflammatory infiltration of the subepithelial tissue of the
bronchi by lymphoid and plasma cells. Bronchopneumonia was present, and
the bronchi and many of the alveoli contained blood. These changes do
not differ essentially from the changes found in many instances of
pneumonia following influenza.
In three instances cultures of B. influenzæ were injected into the
trachea by means of a hypodermic syringe.
In one of these experiments (Experiment 4) intratracheal injection of 2
c.c. salt solution suspension of B. influenzæ (isolated at autopsy from
bronchus of the monkey used in Experiment 3), representing growth on 1½
blood agar plates, was made with a needle inserted into trachea just
above the suprasternal notch. On the following day a throat culture
contained B. influenzæ in abundance. Three days after inoculation the
monkey appeared to be very sick and there was profuse nasal discharge.
The animal coughed and sibilant râles were heard over the chest. There
was no leucocytosis. A throat culture contained B. influenzæ. Four days
after inoculation the monkey was still sick and weak, but appeared much
improved and was killed. The trachea and large bronchi contained thick
viscid mucus. In the middle lobe of the right lung was a patch of
grayish red, airless tissue, firmer than the lung substance elsewhere.
Cultures from the trachea, bronchus and lung contained a variety of
microorganisms, but B. influenzæ was not recovered.
In two additional experiments (Experiments 6 and 7) cultures of B.
influenzæ forty-eight hours old were injected into the trachea of
monkeys. The microorganism was recovered in cultures made from the
pharynx two days later. These animals were only slightly sick.
=Introduction of B. Influenzæ and S. Hemolyticus into the Trachea.=—In
view of the frequent association of B. influenzæ and S. hemolyticus in
the sputum of patients with streptococcus pneumonia following influenza
and in the bronchi and lungs of those who have died with this disease,
the two microorganisms were injected simultaneously into the trachea of
monkeys.
B. influenzæ and S. hemolyticus in Experiment 7 produced bronchitis and
bronchopneumonia. There was acute inflammation of the interstitial
tissue of the lung, and acute lymphangitis with numerous polynuclear
leucocytes within the lumen of the lymphatics was present. B. influenzæ
and S. hemolyticus were present in the trachea at autopsy four days
after inoculation. It is probable that part of the injected culture
entered the tissue outside the trachea, for an abscess was formed in
this situation. It is noteworthy that acute pericarditis occurred and
both S. hemolyticus and B. influenzæ were found in the pericardial
exudate. B. influenzæ not infrequently exhibits this tendency to
penetrate in association with other bacteria localities which it does
not invade independently.
In a second experiment (Experiment 8) in which B. influenzæ and S.
hemolyticus were injected into the trachea, both microorganisms were
recovered from the throat on the day following inoculation; on the fifth
day S. hemolyticus alone was recovered and on the sixth day a throat
culture was negative both for S. hemolyticus and B. influenzæ.
=Introduction of B. influenzæ and of Pneumococcus or of Pneumococcus
Alone into the Trachea.=—In two experiments B. influenzæ and
Pneumococcus Type III were simultaneously injected into the trachea.
In Experiment 9 a large male monkey was used and intratracheal injection
made with syringe and needle of 5 c.c. salt solution suspension of
Pneumococcus Type III and B. influenzæ (growth on 5 blood agar plates of
mixed cultures of Pneumococcus III and B. influenzæ). On the following
day the animal was very sick, lying on the floor of its cage, and was
dead two days after inoculation.
The dosage of bacteria in this experiment was large. The lesions in
gross appearance and microscopically resembled those seen in many
instances of pneumonia following influenza. In the trachea there was
loss of ciliated epithelium, congestion of the subepithelial tissue,
hemorrhage and infiltration with plasma cells. The lungs were
consolidated and red and there were hemorrhage and edema. B. influenzæ,
as in human cases, was abundant in the bronchi, less abundant in the
consolidated lung, being present though scant in the left lung, and
absent in cultures from the right. B. influenzæ as in Experiment 8 with
streptococcus had entered the left pericardial cavity in company in this
experiment with Pneumococcus III.
In Experiment 10 a very large monkey received by intratracheal
injection, made with syringe and needle, 5 c.c. salt solution suspension
of Pneumococcus III and 3 strains of B. influenzæ, (2 recently isolated
from cases of influenza and 1 from autopsy in a case of postinfluenzal
pneumonia). The animal died twenty-four hours later.
This simultaneous introduction of B. influenzæ and Pneumococcus III in
large quantity has produced rapidly fatal pneumonia with lobar
distribution. Hepatization was homogeneous and red, and outside the
consolidated parts of the lung there was hemorrhage and edema. The
lesion resembled that found when death has occurred within a few days
after the onset of pneumonia following influenza, but had no distinctive
characters establishing its relation to pneumonia following influenzæ.
In Experiment 11 Pneumococcus III alone in small amount was introduced
into the trachea of a small monkey. The animal was very sick, but its
condition improved and recovery seemed probable. The animal was killed
seven days after inoculation, and typical lobar pneumonia with gray
hepatization was found at autopsy.
EXPERIMENT 11
November 20, 1918.—Small monkey; throat culture: negative for B.
influenzæ, pneumococcus and S. hemolyticus. November 28 and December
6.—Nose and throat cultures again negative for B. influenzæ.
December 9—4:30 P.M.—Intratracheal injection with syringe and needle
of 0.33 c.c. of an eighteen hour broth culture of Pneumococcus Type
III. December 10.—The animal is sick, huddled up in his cage with
head down; there is rapid respiration with expiratory grunt and the
mucous membranes are moderately cyanotic. There is frequent cough.
Throat culture: Pneumococcus III present in abundance. December
15.—The animal appears to be better. Respirations are still rapid
but less labored. December 16.—The animal is improving but very weak
and emaciated.
=Autopsy.=—The pleural cavities contain no fluid. On the right side
are several strands of fibrin. The right lower lobe with the
exception of a small patch at the summit and the lower part of the
middle lobe are voluminous, have a dull gray surface covered by a
scant layer of fibrin and are firmly consolidated. On section the
consolidated tissue has a gray color and is conspicuously granular,
the granulation resembling, on a slightly smaller scale, that seen
in human lobar pneumonia. The bronchi contain a small amount of
viscid fluid.
=Bacteriology.=—Direct smears from the trachea and the lower lobe of
the left lung contain Gram-positive diplococci. Cultures from the
trachea and from the blood of the heart contain Pneumococcus III.
Cultures from the left lower lobe, from the liver and from the
spleen remain sterile.
=Microscopical Examination.=—There is abundant infiltration of the
subepithelial tissue of the trachea with plasma cells. Superficial
ciliated epithelium is in places lost. At one point is a small focus
of hemorrhage. Alveoli in the consolidated part of the lungs contain
polynuclear leucocytes and fibrin and exhibit the appearance seen in
lobar pneumonia in man.
[Illustration:
Fig. 33.—Experimental lobar pneumonia in the stage of gray
hepatization produced by injection of Pneumococcus III into the
trachea of a monkey (Experiment 11). The alveoli are uniformly
filled with plugs of fibrinous exudate.
]
In Experiment 12 B. influenzæ was injected into the trachea and two days
later identified in a culture made from the pharynx; four days after
inoculation Pneumococcus IV was injected into the trachea. The animal
was killed seven days after the first inoculation, and three days after
inoculation with pneumococcus. The lower half of the upper lobe of the
right lung and the greater part of the lower and middle lobes were
consolidated. The pleural surface of the consolidated areas was dull red
and covered by a small amount of fibrin. The lower lobe, with the
exception of a small part at the summit, was very firmly consolidated,
on section pinkish gray in the anterior part and deep red in a small
zone at the posterior border. The cut section was conspicuously
granular. The trachea and bronchi contained mucus. Cultures from the
trachea, the right lung and the right pleural cavity contained
Pneumococcus IV in pure culture. Alveoli in the consolidated part of the
lung were filled with polynuclear leucocytes and fibrin.
Lobar pneumonia has been produced by the introduction of Pneumococcus IV
into the trachea. It is doubtful if preceding inoculation of B.
influenzæ has influenced the course of the disease.
The foregoing experiments have shown that B. influenzæ introduced into
the nasopharynx or into the trachea of monkeys is capable of causing
lesions of the mucosa of these structures; the microorganism persists
within the nasopharynx or trachea and is recoverable during a variable
period of from two to eleven days after inoculation. Spontaneous
infection of monkeys with B. influenzæ has not been observed. The
animals infected with the microorganism are ill during several days, but
the experimental disease like most instances of human influenza is self
limited. Following inoculation of the nose and throat of monkeys with B.
influenzæ there is discharge from the nose, tendency to epistaxis and
absence of leucocytosis.
Bronchitis was produced by the introduction of B. influenzæ into the
trachea of monkeys, and the microorganism was recovered from the
nasopharynx two and three days following inoculation. There was no
leucocytosis. In two experiments death occurred following inoculation,
and in both instances it was found that the animal suffered with
tuberculosis which had produced only trivial lesions of the lungs. In
both animals staphylococci were obtained from the internal organs. There
was bronchitis with changes in the bronchi which, although not
characteristic, resembled those found in association with B. influenzæ
in man. It is noteworthy that B. influenzæ is usually found mixed with
other bacteria in the bronchi of those who have died with bronchitis and
pneumonia following influenza. In the experimental animals there was in
places superficial loss of ciliated epithelium, exudation of polynuclear
leucocytes, infiltration of the subepithelial tissue with plasma cells
and hemorrhage into this tissue.
In one instance simultaneous injection of B. influenzæ and S.
hemolyticus, freshly obtained from autopsy upon a man dying with
pneumonia following influenza, caused bronchitis and bronchopneumonia;
there were acute lymphangitis and infiltration of the interstitial
tissue of the lung with polynuclear leucocytes such as occurs in human
cases, but the lesion had not proceeded to suppuration.
In man B. influenzæ is usually found in greatest abundance upon the
mucosa of the respiratory passages, less frequently it invades the
alveoli of the lungs and is almost invariably found in association with
other microorganisms. In company with other microorganisms B. influenzæ
penetrates into tissues outside the lungs. In Experiment 7 it has
entered the pericardium, with streptococcus, and in Experiment 9 with
pneumococcus. When B. influenzæ and streptococcus are injected into the
peritoneal cavity of a mouse both organisms appear in the blood, whereas
in the absence of streptococcus, B. influenzæ seldom leaves the
peritoneal cavity.
Typical lobar pneumonia has been produced for the first time in monkeys
by injecting pneumococci (in quantity as small as 0.33 c.c. of
suspension) into the trachea. With the animals available it has not been
possible to adjust the dosage of the two microorganisms so that the
influence of one upon the other might be determined. Pneumococcus III,
in small quantity, introduced into the trachea has produced typical
acute lobar pneumonia in the stage of gray hepatization. A similar
lesion has been produced with Pneumococcus IV obtained from the lung of
a man dead with pneumonia.
INDEX
A
Abscess of lung, bacteriology of, 203
empyema with, 233
healing of, 208
measles with, 347
parotitis with, 356
pathogenesis of, 205, 375
scarlet fever with, 357
staphylococcus causing, 199, 225, 366, 377
S. hemolyticus causing, 199, 365
Autopsies, table of, 118, 120, 335
Autopsy protocols, No. 280, 226;
No. 286, 226;
No. 312, 254;
No. 322, 228;
No. 330, 214;
No. 333, 229;
No. 370, 229;
No. 376, 206;
No. 379, 215;
No. 380, 204;
No. 387, 206;
No. 397, 223;
No. 406, 204;
No. 416, 204;
No. 420, 279;
No. 425, 229;
No. 428, 280;
No. 433, 280;
No. 445, 257;
No. 465, 238;
No. 467, 208;
No. 473, 236;
No. 474, 221;
No. 487, 273;
No. 499, 224;
No. 504, 238
B
Bacillus influenzæ, 369
bronchi and, 178, 215, 346
bronchitis and, 153, 371
experimental inoculation with, 389
history of, 25
influenza and, 30, 42, 43, 46, 49, 76, 370
isolation of, 30, 32, 38, 44
measles with, 26, 40, 43, 295, 351
meningitis and, 26
normal men carrying, 34, 42, 45, 369
pathogenicity of, 26, 48, 370, 387, 396
pneumococcus pneumonia with, 62, 178
pneumonia with, 72, 75, 76, 173, 364, 371
Bronchi, inflammation of mucous glands of, 146
Bronchiectasis, 239, 269, 355, 367
abscess with, 254
bacteriology of, 244
bronchitis with, 245
measles with, 336
pathogenesis of, 245, 259
Bronchiolitis, organizing, 264
Bronchitis, 40, 142, 195, 359
bacteriology of, 56, 150, 164, 359, 371
bronchiectasis with, 245
chronic, 262
clinical course of, 58
measles with, 336
organizing, 264
purulent, 47, 56, 60, 63, 74, 143, 149, 153, 360
Bronchopneumonia, 60, 63, 66, 162, 360, 363
bacteriology of, 68, 163, 171, 176, 181, 184, 189, 194, 197, 345, 364
fibrin with, 182
lobar pneumonia with, 155, 157
measles with, 340
secondary infection by S. hemolyticus with, 172, 177, 181, 374
C
Carriers of B. Influenzæ, 46, 101, 369
of S. hemolyticus, 99, 285, 287, 298, 303, 309, 310, 315, 319, 321,
332, 379
Cartilage, atrophy with bronchiectasis of, 254
Contact infection in influenza, prevention of, 98
in measles, 289
in pneumonia, prevention of, 98
Cubicles to prevent contact infection, 98, 290
Cyanosis, 144
E
Empyema, 64, 67, 224, 226, 233, 304, 366
abscess of lung and, 233
encapsulated, 235
interstitial suppurative pneumonia with, 216, 234
measles with, 349
pneumococcus, 236, 350
streptococcus, 233, 350
Endophlebitis, 219
H
Hemorrhagic and edematous consolidation with bronchopneumonia, 188
peribronchiolar consolidation with bronchopneumonia, 163, 173, 272,
340
Hepatization with bronchopneumonia, 179, 181
with lobar pneumonia, 160
I
Influenza, B. influenzæ with, 30, 73
bronchitis with, 55, 56
clinical course of, 28, 53, 73, 80
coryza with, 54
cyanosis with, 54
epidemic in fall of 1918, 52, 108, 359
epidemic in spring of 1918, 47
fever with, 53
gastrointestinal symptoms with, 55
laryngitis with, 54
lobar pneumonia and, 161
measles and, 292, 319, 331, 351, 357, 380
pandemic of 1889–90, 109, 115
pandemic of 1918–19, 27, 359
pharyngitis with, 54
pneumococcus with, 33
pneumonia with, 55, 59, 74, 81, 139
pulmonary lesions of, 137
pulse with, 54
secondary infection with, 28, 45, 57, 95
sputum with, 55
S. hemolyticus with, 103
Interstitial bronchopneumonia, 261, 278, 348
suppurative pneumonia, 199, 209, 366, 376
bacteriology of, 214
chronic inflammation with, 221
empyema with, 216, 234
healing of, 222, 224
measles with, 348
pericarditis with, 237
L
Lobar pneumonia, 60, 63, 154, 360, 362
bacteriology of, 64, 156, 164, 339, 362
bronchopneumonia with, 155, 157
experimental production in monkeys of, 394, 397
influenza and, 161
measles with, 337
purulent bronchitis with, 60, 63, 66
secondary infection by hemolytic streptococci with, 64, 159, 340, 374
spread in lung of, 339, 354
typhoid fever with, 353
Lobular consolidation, confluent, 188, 341
with bronchopneumonia, 163, 178, 272, 341
Lymphatics, suppurative inflammation of, 217, 218, 376
thrombosis of, 217, 218
Lymphangitis, experimental production with S. hemolyticus of, 392
M
Masks to prevent contact infection, 98, 290
Mastoiditis, 303, 312, 332
Measles, 119, 288
B. influenzæ with, 26, 40, 43, 295
bronchiectasis with, 336
bronchitis with, 336
bronchopneumonia with, 340
complications of, 303, 378
empyema with, 349
influenza and, 292, 319, 331, 351, 357, 380
interstitial suppurative pneumonia with, 348
lobar pneumonia with, 337
pneumococcus pneumonia with, 312
pneumonia and, 292, 303, 312, 332, 334, 378
secondary infection with, 282
S. hemolyticus with, 285, 287, 297, 319, 330, 331, 353, 378
suppurative pneumonia with, 345, 347
unresolved bronchopneumonia with, 342
Methods, 29, 51, 283, 291
Mortality of pneumococcus pneumonia, 140
of pneumonia following influenza, 139
of streptococcus pneumonia, 140
Mumps, 119, 355
N
Necrosis with bronchopneumonia caused by S. hemolyticus, 186, 375
with lobar pneumonia caused by S. hemolyticus, 160, 374
with S. hemolyticus, 199, 200
O
Oedema, interstitial, 209
Organization of pneumonic exudate, 197
Otitis media, 289, 303, 312, 317, 329, 332
P
Peribronchiolar consolidation with bronchopneumonia, 163, 166, 267, 340
Pericarditis, 64, 237
Peribronchial consolidation with bronchopneumonia, 163, 192, 361
hemorrhage, 189
Peritonitis, 238
Phagocytosis of red blood corpuscles, 272
Pneumococcus, 372
bronchitis and, 153
bronchopneumonia with, 165, 184, 373
empyema, 236
experimental lobar pneumonia with, 393
influenza with, 33
lobar pneumonia with, 158, 372
pneumonia, 60, 75, 104
clinical course of, 62
measles and, 312, 332
mortality of, 140
secondary pneumococcus infection with, 61
secondary streptococcus infection with, 62
transmission of, 91, 383
secondary infection in pneumonia with, 91
Pneumonia, B. influenzæ causing, 72, 76, 371
bacteriology of influenza and, 60, 74, 107
bacteriology of measles and, 351
chronic fibroid, 273
clinical course of influenza with, 62
diagnosis of, 136, 334, 361
dissecans, 209
immunity following, 373
influenza with, 59, 76, 81, 109, 360
measles and, 119, 292, 303, 312, 332, 334, 378
mumps and, 119
pneumococcus, see Pneumococcus pneumonia
prevention of, 98, 319, 383
scarlet fever and, 119
secondary infection with, 83, 106
spread through lungs of, 194, 373
staphylococcus, see Staphylococcus pneumonia
streptococcus, see Streptococcus pneumonia
S. hemolyticus in throat with, 310, 329, 379
Pseudoinfluenza bacilli, 26
S
Scarlet fever, 119, 356
Squamous transformation of bronchial epithelium, 149, 251, 275, 336
Staphylococcus, 153, 377
pneumonia, 112, 225, 354, 366
pneumonia, pathogenesis of, 230
Streptococcus empyema, 233
hemolyticus, 374
bronchitis with, 153
dissemination in wards of, 315
experimental production of acute
lymphangitis with, 392
identification of, 283
influenza with, 103
lobar pneumonia with, 64, 159
measles with, 285, 287, 297, 330, 331, 345, 353, 378
normal men with, 285, 322
secondary infection in pneumonia with, 84, 106, 178, 204, 374
nonhemolytic, 376
peritonitis, 238
pneumonia, 60, 70, 75, 115, 307, 365
bacteriology of, 71
clinical features of, 71
measles with, 303, 305, 307, 318
mortality of, 140
transmission of, 84, 381
viridans, 377
Suppurative pneumonia, 199, 347
with measles, 345, 347
T
Thrombosis of capillaries with bronchopneumonia, 184
Typhoid fever, lobar pneumonia with, 353
staphylococcus pneumonia with, 354
U
Unresolved bronchopneumonia, 261, 266, 342, 368
bacteriology of, 276
interstitial suppurative pneumonia with, 278
-----
Footnote 1:
Report of the Surgeon General, U. S. Army to the Secretary of War,
1918, p. 44.
Footnote 2:
Stillman, F. G.: A Study of Atypical Type II Pneumococci, Jour. Exper.
Med., 1919, xxix, 251.
Footnote 3:
Opie, E. L., Freeman, A. W., Blake, F. G., Small, J. C., Rivers, T.
M.: Pneumonia at Camp Funston, Jour. Am. Med. Assn., 1919, lxxii, 108.
Footnote 4:
Vaughan, V. C., and Palmer, G. T.: Communicable Diseases in the
National Guard and National Army of the United States, Jour. Lab. and
Clin. Med., 1918, iii, 635.
Footnote 5:
Miller, J. L., and Lusk, F. B.: Jour. Am. Med. Assn., 1918, lxxi, 702.
Footnote 6:
Report of the Surgeon General to the Secretary of War, 1919, i, 637.
Footnote 7:
MacNeal, W. J.: The Influenza Epidemic of 1918 in the American
Expeditionary Forces in France and England, Arch. Int. Med., 1919,
xxiii, 657.
Footnote 8:
Pfeiffer: Ztschr. f. Hyg., 1893, xiii, 357.
Footnote 9:
Wollstein: Jour. Exper. Med., 1916, viii, 681.
Footnote 10:
Kretz: Wien. klin. Wchnschr., 1897, x, 877.
Footnote 11:
Süsswein: Wien. klin. Wchnschr., 1901, xiv, 1149.
Footnote 12:
Liebscher: Prag. med. Wchnschr., 1903, xxviii, 85.
Footnote 13:
Jehle: Ztschr. f. Heilk., 1901, xx, n. s. 2, Int. Med.
Footnote 14:
Davis: Jour. Infect. Dis., 1906, iii, 1.
Footnote 15:
Lord: Boston Med. Sur. Jour., 1905, clii, 537, 574.
Footnote 16:
Boggs: Am. Jour. Med. Sc., 1905, cxxx, 902.
Footnote 17:
Wollstein: Am. Jour. Dis. Child., 1911, i, 42.
Footnote 18:
Rosenthal: Comp. rend. Soc. Biol., 1903, lv, 1500.
Footnote 19:
Wollstein: Jour. Exper. Med., 1915, xxii, 445.
Footnote 20:
Med. Sup. October 1, 1918 also Jour. Am. Med. Assn., 1918, lxxi, 1573.
Footnote 21:
Opie, Freeman, Blake, Small, and Rivers: Jour. Am. Med. Assn., 1919,
lxxii, 108.
Footnote 22:
Vaughn and Palmer: Jour. Lab. and Clin. Med., 1918, iii, 635.
Footnote 23:
Soper: Jour. Am. Med. Assn., 1918, lxxi, 1899.
Footnote 24:
Cole and MacCallum: Jour. Am. Med. Assn., 1918, lxx, 1146.
Footnote 25:
Hammond, Rolland, and Shore: Lancet, London, 1917, ii, 41.
Footnote 26:
Abrahams, Hallows, Eyre, and French: Lancet, London, 1917, ii, 377.
Footnote 27:
Public Health Reports, U.S.P.H. Service, 1919, xxxiv, 33.
Footnote 28:
Blake: Jour. Exper. Med., 1917, xxvi, 67.
Footnote 29:
Avery: Jour. Am. Med. Assn., 1918, lxx, 17.
Footnote 30:
Dunn: Jour. Am. Med. Assn., 1918, lxxi, 2128.
Footnote 31:
Fantus: Jour. Am. Med. Assn., 1918, lxxi, 1736.
Footnote 32:
Keegan: Jour. Am. Med. Assn., 1918, lxxi, 1051.
Footnote 33:
Christian: Jour. Am. Med. Assn., 1918, lxxi, 1565.
Footnote 34:
Blanton and Irons: Jour. Am. Med. Assn., 1918, lxxi. 1988.
Footnote 35:
Hall, Stone and Simpson: Jour. Am. Med. Assn., 1918, lxxi, 1986.
Footnote 36:
Synnott and Clark: Jour. Am. Med. Assn., 1918, lxxi, 1816.
Footnote 37:
Friedlander, McCord, Sladen and Wheeler: Jour. Am. Med. Assn., 1918,
lxxi, 1652.
Footnote 38:
Brem, Bolling and Casper: Jour. Am. Med. Assn., 1918, lxxi, 2138.
Footnote 39:
Ely, Lloyd, Hitchcock, and Nickson: Jour. Am. Med. Assn., 1919, lxxii,
24.
Footnote 40:
Camp Lewis Pneumonia Unit: Jour. Am. Med. Assn., 1919, lxxii, 268.
Footnote 41:
Jour. Am. Med. Assn., 1918, lxxi, 2068.
Footnote 42:
Wolbach: Bull. Johns Hopkins Hosp., 1919, xxx, 104.
Footnote 43:
Spooner, Scott and Heath: Jour. Am. Med. Assn., 1919, lxxii, 155.
Footnote 44:
Kinsella: Jour. Am. Med. Assn., 1919, lxxii, 717.
Footnote 45:
MacCallum: Jour. Am. Med. Assn., 1919, lxxii, 720.
Footnote 46:
Pritchett and Stillman: Jour. Exper. Med., 1919, xxix, 259.
Footnote 47:
Hirsch and McKinney: Jour. Am. Med. Assn., 1918, lxxi, 1735.
Footnote 48:
Parker: Jour. Am. Med. Assn., 1919, lxxii, 476.
Footnote 49:
Opie, Freeman, Blake, Small and Rivers: Jour. Am. Med. Assn., 1919,
lxxii, 556.
Footnote 50:
See discussion on pages 115 to 118.
Footnote 51:
Isolated by blood culture on Sept. 23. Patient recovered.
Footnote 52:
Stillman: Jour. Exper. Med., 1916, xxiv, 651.
Footnote 53:
Stillman: Jour. Exper. Med., 1919, xxix, 251.
Footnote 54:
Haller and Colwell: Jour. Am. Med. Assn., 1918, lxxi, 1213.
Footnote 55:
Doust and Lyon: Jour. Am. Med. Assn., 1918, lxxi, 1216.
Footnote 56:
Held in receiving ward 40 hours because of admission of case of
meningococcus meningitis to ward by mistake.
Footnote 57:
Finkler, D.: Infectionen der Lunge durch Streptococcen und Influenza
Bacillen, Bonn, 1895.
Footnote 58:
Ribbert: Anatomische und bacteriologische Beobachtungen über
Influenza, Deutsch. med. Wehnschr., 1890, xvi, 61, 301.
Footnote 59:
Pfeiffer: Die Aetiologie der Influenza, Ztschr. f. Hyg. 1893, xiii,
357.
Footnote 60:
Leichtenstern, O.: Influenza, Nothnagel’s Specielle Pathologie und
Therapie, Wien, 1896, vol. ii, pt. 2.
Footnote 61:
Krannhals: Quoted by Leichtenstern.
Footnote 62:
Cruickshank: Brit. Med. Jour., 1895, i, 360.
Footnote 63:
Birch-Hirschfeld: Schmidt’s Jahrbücher, 1890, ccxxvi, 110.
Footnote 64:
Kuskow, N.: Zur pathologischen Anatomie der Grippe, Virchow’s Archiv.,
1895, cxxxix, 406.
Footnote 65:
Keegan, J. J.: The Prevailing Epidemic of Influenza, Jour. Am. Med.
Assn., 1918, lxxi, 1051.
Footnote 66:
Symmers, D.: Pathologic Similarity between Pneumonia of Bubonic Plague
and of Pandemic Influenza, Jour. Am. Med. Assn., 1918, lxxi, 1482.
Footnote 67:
Opie, E. L., Freeman, A. W., Blake, F. G., Small, J. C., Rivers, T.
M.: Pneumonia Following Influenza, Jour. Am. Med. Assn., 1919, lxxii,
556.
Footnote 68:
LeCount, E. R.: The Pathological Anatomy of Influenzal
Bronchopneumonia, Jour. Am. Med. Assn., 1919, lxxii, 650.
Footnote 69:
MacCallum, W. G.: Pathology of the Pneumonia Following Influenza,
Jour. Am. Med. Assn., 1919, lxxii, 720.
Footnote 70:
Lyon, M. W.: Gross Pathology of Epidemic Influenza at Walter Reed
Hospital, Jour. Am. Med. Assn., 1919, lxxii, 924.
Footnote 71:
Goodpasture, E. W. and Burnett, F. L.: The Pathology of Pneumonia
Accompanying Influenza, U. S. Naval Medical Bull., 1919, xiii, No. 2.
Footnote 72:
Wolbach: Comments on the Pathology and Bacteriology of Fatal Influenza
Cases as Observed at Camp Devens, Mass., Bull. Johns Hopkins Hosp.
1919, xxx, 104.
Footnote 73:
Cummings, J. G., Spruit, C. B., and Lynch, C.: The Pneumonias:
Streptococcus and Pneumococcus Groups, Jour. Am. Med. Assn., 1918,
lxx, 1066.
Footnote 74:
Cole, R. and MacCallum, W. G.: Pneumonia at a Base Hospital, Jour. Am.
Med. Assn., 1918, lxx, 1146.
Footnote 75:
Miller, J. L., and Lusk, F. B.: Epidemic of Streptococcus Pneumonia
and Empyema at Camp Dodge, Iowa, Jour. Am. Med. Assn., 1918, lxxi,
702.
Footnote 76:
MacCallum, W. G.: Pathology of the Epidemic of Streptococcus
Bronchopneumonia in the Army Camps, Jour. Am. Med. Assn., 1919, lxxii,
720.
Footnote 77:
Stone, W. J., Phillips, B. G., and Bliss, W. P.: A Clinical Study of
Pneumonia Based on 871 Cases, Arch. Int. Med., 1918, xxii, 409.
Footnote 78:
Opie, E. L., Freeman, A. W., Blake, F. G., Small, J. C., and Rivers,
T. M.: Pneumonia at Camp Funston, Jour. Am. Med. Assn., 1919, lxxii,
108.
Footnote 79:
Jour. Am. Med. Assn., 1919, lxxii, 556.
Footnote 80:
Miller, W. S.: Am. Rev. Tuberc., 1919, iii, 65.
Footnote 81:
Wadsworth, A. B.: A Study of Organizating Pneumonia. Jour. Med.
Research, 1918, xxxix, 147.
Footnote 82:
Kaufmann: Spezielle Pathologische Anatomie. 1909, ed. 5, p. 260.
Footnote 83:
Beitzke: Respirations Organe. Aschoff’s Path. Anat., 1913 ed. 3, Vol.
II, p. 308.
Footnote 84:
Chickering, H. T. and Park, J. H.: Staphylococcus Aureus Pneumonia,
Jour. Am. Med. Assn. 1919, lxxii, 617.
Footnote 85:
Stone, W. J., Phillips, B. G., and Bliss. W. P.: A Clinical Study of
Pneumonia Based on 871 Cases. Arch. Int. Med., 1918, xxii, 409.
Footnote 86:
Loc. cit., p. 110.
Footnote 87:
Lord, F. T.: Infections of the Respiratory Tract with Influenza
Bacilli, Boston Med. and Surg. Jour., 1905, clii, 537, 574.
Footnote 88:
Boggs, T. R.: Influenza Bacillus in Bronchiectasis, Am. Jour. Med.
Sc., 1905, cxxx, 902.
Footnote 89:
Thornton and Pratt: Bull. Johns Hopkins Hosp., 1908, xix, 230.
Footnote 90:
Two cases positive for hemolytic streptococci on this examination were
negative on next examination.
Footnote 91:
S. hemolyticus infection implanted upon a pneumococcus pneumonia.
Place in Table indicates onset of pneumonia and not appearance of
streptococcus complication.
Footnote 92:
Capps, J. A., and Davis, D. J.: Arch. Int. Med., 1914, xiv, 650;
Illinois Med. Jour., November, 1912.
Footnote 93:
Windsor, C. E. A.: Jour. Infect. Dis., 1912, x. 73.
Footnote 94:
Hamburger, L. P.: Jour. Am. Med. Assn., April 13, 1912, lviii, 1109.
Footnote 95:
Smillie, W. S.: Jour. Infect. Dis., 1917, xx, 45.
Footnote 96:
Levy and Alexander: Jour. Am. Med. Assn., 1918, lxx, 1827.
Footnote 97:
Irons and Marine: Jour. Am. Med. Assn., 1918, lxx, 687.
Footnote 98:
Cole and MacCallum: Jour. Am. Med. Assn., 1918, lxx, 1146.
Footnote 99:
Cummings, Spruit and Lynch: Jour. Am. Med. Assn., 1918, lxx, 1066.
Footnote 100:
Sputum or saliva cultures on 50 of these men yielded 1 positive for S.
hemolyticus. Sputum or saliva injected intraperitoneally into white
mice and cultures made from the peritoneal exudate of such mice,
yielded 2 additional positives in the same group of 50 men. These 3
positive cases showed very few colonies of hemolytic streptococci.
Footnote 101:
Per cent positive, on one culture only. Repeated throat cultures,
average two per person as follows:
Cultured No. Cases Positives Once 153 11 Twice 90 7 3 times 39 3
4 times 15 1
Footnote 102:
Steinhaus: Ziegler’s Beitr. 1901, xxix, 524.
Footnote 103:
Bartels: Virchows Arch. f. path. Anat.; xxi.
Footnote 104:
Loc. cit., p. 116.
Footnote 105:
Hart: Deutsch. Arch. f. Klin. Med., 1904, lxxix, 108.
Footnote 106:
Goodpasture, E. W., and Burnett, F. L.: The Pathology of Pneumonia
Accompanying Influenza, U. S. Nav. Med. Bull., 1919, xiii, No. 2, P.
21.
Footnote 107:
Pfeiffer: Ztschr. f. Hyg., 1893, xiii, 357.
Footnote 108:
Kamen, L.: Centralbl. f. Bakteriol., 1901, xxix, Erste Abt. 339.
Footnote 109:
Jacobson, G.: Arch. de méd. expér. et d’anat. path., 1901, xiii, 425.
Footnote 110:
Richie, J.: Journal Path. and Bacteriol., 1910, xiv, 615.
Footnote 111:
Wollstein, M.: Am. Jour. Dis. Child., 1911, i. 42.
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TRANSCRIBER’S NOTES
1. Silently corrected typographical errors and variations in spelling.
2. Archaic, non-standard, and uncertain spellings retained as printed.
3. Footnotes have been re-indexed using numbers and collected together
at the end of the last chapter.
4. Enclosed italics font in _underscores_.
5. Enclosed bold font in =equals=.