Carriers of Hemolytic Streptococci

During the winter of 1917–18, with the establishment of the army camps, it very soon became evident that in many of the serious and fatal complications of measles and other respiratory diseases, hemolytic streptococci were playing a very important rôle. The epidemic prevalence of hemolytic streptococci among hospital cases, and later among men on duty in the camps, was established by bacteriologic studies. Prior to this time in civil life, hemolytic streptococci under epidemic conditions had been studied in milk-borne epidemics of septic sore throat, such as are reported from Chicago in 1911–13[[92]]; from Boston in 1911[[93]]; and from Baltimore in 1911–12[[94]]. Contact air-borne infection has not been emphasized in considering the dissemination of hemolytic streptococci. Smillie[[95]] reports a few cases of hemolytic streptococcus throat infections which he attributes to contact infection. Conditions within the army camps were such as to suggest the dissemination of hemolytic streptococci by contact air-borne infection. Some knowledge of the percentage of individuals showing positive throat cultures became desirable at the very beginning of studies of contact dissemination of hemolytic streptococci.

Smillie found that only one of 100 normal throats harbored the Beta hemolytic streptococci of Smith and Brown. Levy and Alexander[[96]] report the presence of hemolytic streptococci in 83.2 per cent of healthy men at Camp Taylor, and hemolytic organisms (not definitely identified as streptococci) in 14.8 per cent of recruits arriving at Camp Taylor. Irons and Marine[[97]] found hemolytic streptococci among 70 per cent of healthy men at Camp Custer.

Among measles patients on admission to the hospital at Fort Sam Houston, Cole and MacCallum[[98]] report 11.4 per cent and Cummings, Spruit and Lynch,[[99]] 35 per cent of throat cultures positive for hemolytic streptococci. At Camp Taylor, Levy and Alexander report 77.1 per cent positive among 388 cases of measles on admission to the hospital.

The spread of hemolytic streptococci in measles wards was shown by Cole and MacCallum when on admission 11.4 per cent of cases had positive throat cultures, 38.6 per cent after from three to five days, and 56.8 per cent after from eight to sixteen days in the ward. In our study of hemolytic streptococci with measles at Camp Funston, 2.6 per cent of the cases had positive throat cultures on admission, 12.8 per cent after three to ten days, and 24.1 per cent after eight to twenty-three days in the hospital. In a similar study at Camp Pike we found 1.7 per cent positive on admission; 10.9 per cent after one week; 22.8 per cent after two weeks; 26.2 per cent after three weeks; and, 33.1 per cent after four weeks in the hospital.

Hemolytic Streptococci in the Throats of Normal Men.—The percentage of normal individuals harboring hemolytic streptococci in their throats was investigated in three distinct classes of men, classified according to the degree of exposure to contact infection.

The first group includes men largely from country districts, cultured within an hour after being assembled by their local draft board. The laboratory car “Lister” was sent to Hot Springs, Ark. to meet the November draft of men to be sent to Camp Pike. These men were returned to their homes when the armistice was signed, so that there was no opportunity to study them after they had lived under camp conditions.

The second group includes men on duty in Camps Funston and Pike. These men, while largely from country districts, had been living crowded together in the camp for a period varying from a few weeks to several months.

The third group includes normal men resident in the base hospitals at Ft. Riley and Camp Pike. This group includes at Camp Pike the medical personnel of the measles and measles pneumonia wards and represents individuals most exposed to contact infection with hemolytic streptococci. On the other hand, the group includes doctors, nurses and seasoned medical detachment men who are perhaps less susceptible to respiratory infections than are raw recruits.

The results of studies of these groups are presented in Tables LXVI and LXVII.

Table LXVI
Hemolytic Streptococci in Throats of Normal Men Not Resident in the Base Hospital
PLACE OF STUDY
DATE		NO. OF CASESNO. POSITIVE FOR HEM. STREP.PER CENT POSITIVE FOR HEM. STREP.REMARKS
Camp Funston, Kan.,
Aug., 1918.		2746021.9Men on duty in camp including 201 white and 73 colored; in great part newly drafted men
Camp Pike, Ark.,
Nov. 5 to Dec. 10, 1918		337257.4Largely white men on duty in camp
Hot Springs, Ark.,
Nov. 12, 1918		[[100]]6400.0Men from country districts, assembled by the local draft board
Table LXVII
Hemolytic Streptococci in Throats of Normal Men Resident in the Base Hospital
PLACE OF STUDY
DATE		NO. OF CASESNO. POSITIVE FOR HEM. STREP.PER CENT POSITIVE FOR HEM. STREP.REMARKS
Ft. Riley, Kan.,
Aug., 1918		24729.214 convalescent patients in a surgical ward; 10 laboratory workers
Camp Pike, Ark.,
Sept. 10 to Nov. 30, 1918.		15322[[101]]7.5Personnel of measles wards

The group of men studied at Hot Springs represents individuals among whom there was little chance for contact dissemination of hemolytic streptococci. It is a control series of men from outlying districts examined before their throat bacteriology has been complicated by the interchange of mouth organisms which occurs when a group of men are crowded into close quarters. The entire absence of hemolytic streptococci by the throat culture method is noteworthy. By multiplying the chances of identifying hemolytic streptococci by making parallel cultures from the saliva, and from the peritoneal exudates of mice inoculated with saliva, hemolytic streptococci were found, in small numbers, in 3 instances. The findings in this group were only three throats lightly infected with hemolytic streptococci. They are in direct contrast with the findings among individuals living in camps under crowded conditions and are in accord with the findings among recruits arriving in camp as recorded by Levy and Alexander.

In the second group, men living for a time in camp, the findings at Camp Funston and at Camp Pike show rather striking differences. The lower percentage incidence at Camp Pike is the more remarkable since the studies were made soon after the influenza epidemic had swept the camp and made necessary the hospitalization of about 20 to 25 per cent of the camp population.

In the third group, namely, individuals resident in the hospital, percentage rates at Camp Funston are slightly higher than for men resident in camp. This difference disappears for the entire group at Camp Pike if we consider a single throat culture, as we must for the sake of comparison. The majority of these individuals at Camp Pike served in measles wards from which patients carrying hemolytic streptococci were removed at weekly intervals. Seven and one-half per cent of the ward personnel were positives when first cultured. An additional 7.5 per cent acquired the streptococcus while under observation.

Duration of the “Carrier” State.—Unfortunately there are very few observations with regard to the duration of the “carrier” state which can be determined only by repeated cultures at short intervals. We have made no observations of the duration of the “carrier” state in healthy men. Two hundred and forty-two individuals carrying hemolytic streptococci were identified in the ward treatment of measles. All except 37 of these cases were “noncarriers” when first observed. The remaining 205 include 166 contact “carriers” and 39 patients with acute symptoms of infection by hemolytic streptococci.

The complete record of throat cultures on these cases is presented in Table LXVIII.

Group I includes 37 cases positive for hemolytic streptococci on admission.

(a) Twenty-two of these remained positive throughout the period of observation. Four patients became negative after one or two weeks and later showed positive findings, leaving the hospital as positives. These are classified as “irregular.” The results of culture were as follows: Cultured once only, 7; positive after one week, 7; positive after two weeks, 6; positive after three weeks, 2; irregular, 4.

Table LXVIII
Results of Throat Cultures in 242 Hospital Patients Identified as “Carriers” of Hemolytic Streptococci; Cultures Taken at Weekly Intervals
GROUP1st Culture2nd Culture3rd Culture4th Culture5th Culture6th Culture7th Culture8th Culture9th Culture10th Culture11th Culture12th CultureNo. of Contact “Carriers.”No. with Acute Hem. Strep. Complications
I37Cases
+ 7
++ 7
+++ 6
++++ 2
+− 8
+−− 1
+−−−− 1
++− 1
+−+ 2
+−−−−+++ 1
++−−+++ 1
II67Cases
−+ 263
−++ 125
−+++ 22
−+− 91
−+−− 01
−++− 21
−++++−−+− 1
−+−+ 2
III74Cases
−−+ 385
−−++ 53
−−+++ 41
−−++++ 02
−−+−−− 01
−−+− 4
−−++−−−− 1
−−++− 02
−−++−−− 1
−−++++− 01
−−+−+ 1
−−+−++ 2
−−+−+++ 1
−−+−−++ 1
−−+++−−+ 1
IV34Cases
−−−+ 124
−−−++ 5
−−−+++ 4
−−−+− 31
−−−+−− 1
−−−++− 1
−−−+++− 1
−−−+−−++ 1
−−−++−−−−− 01
V16Cases
−−−−+ 11
−−−−++ 11
−−−−+− 31
−−−−+−− − 02
−−−−+−−−−− 1
−−−−++− 1
−−−−+−+ 2
−−−−++− + 1
−−−−++−−−+ 1
VI7Cases
−−−−−+ 1
−−−−−++ 2
−−−−−+− 3
−−−−−+−− 1
VII4Cases
−−−−−−+ 2
−−−−−−++ 1
−−−−−−+−−−−−1
VIII3Cases
−−−−−−−+ 2
−−−−−−−+++ 1

(b) Eleven of the patients entering as positives became negative, 10 after one week and 1 after two weeks.

This group of cases furnishes no data concerning the duration of the “carrier” state, since all cases were positive when first observed. In 30 per cent of instances, hemolytic streptococci disappeared within the first two weeks of observation.

Groups II to VIII include 205 patients who became positive at some time during their stay in the hospital. The arrangement in groups depends upon the length of time the patients remained in the hospital before acquiring S. hemolyticus. Ninety-five of these patients had no further cultures after the initial positive culture. Fourteen appear as “irregular,” as defined above. These two classes of cases are omitted in the following summary of these groups. The initial positive culture is arbitrarily considered the day of infection and subsequent cultures mark off weekly intervals.

(a) Thirty-nine patients had acute infections due to hemolytic streptococci. Thirteen of these patients passed from observation after their initial positive culture. The cases with repeated cultures after initial positive may be summarized as in Table LXIX.

Table LXIX
NO. PATIENTS CULTUREDNO. BECOMING NEGATIVEPER CENT BECOMING NEGATIVE
Recultured after one week26726.9
Recultured after two weeks14857.1
Recultured after three weeks7457.1
Recultured after four weeks22100.0

The records within this small group of cases indicate that hemolytic streptococci tend to disappear with the passing of the acute infection.

(b) One hundred and sixty-six contact “carriers” are included in Groups II to VIII. Eighty-two of these passed from observation after their initial positive culture and 14 appear as “irregular.” The cases with repeated throat cultures after the initial positive are summarized in Table LXX.

Table LXX
NO. PATIENTS CULTUREDNO. BECOMING NEGATIVEPER CENT BECOMING NEGATIVE
Recultured after one week702637.1
Recultured after two weeks22940.9
Recultured after three weeks55100.0
Recultured after four weeks44100.0

These records indicate that contact carriers in great part harbor hemolytic streptococci during short intervals. A longer period of observation after the disappearance of hemolytic streptococci would have been desirable in many instances. Some patients were followed with consistently negative cultures during three, four and five weeks after hemolytic streptococci had disappeared.

It is difficult to explain those instances in which negative cultures are interposed between positives. Where one negative interrupts positive cultures, it is possible that the throat culture failed to demonstrate hemolytic streptococci which were present. Such cases in this series fall within the limits of the percentage error of throat culture identification. Where two or three, or even four negative cultures intervene, reinfection is not impossible.

Relation of S. Hemolyticus “Carriers” to the Complications of Acute Respiratory Diseases.—In the present study of measles it has been shown that pneumonia following measles has been no more common in “carriers” than in “noncarriers.” Nevertheless, pneumonia occurring in badly infected wards has been modified by streptococcus complications.

More cases of otitis media have appeared in “carriers” than in “noncarriers.” The possibility that mild otitis media, which would ordinarily pass unnoticed, might become evident as the result of streptococcus invasion must be considered. Levy and Alexander have made an important contribution to our knowledge of the rôle of hemolytic streptococci in measles. They find that “carriers” of hemolytic streptococci among measles patients are especially predisposed to complications following measles.

Their cases were drawn from a camp population highly saturated with S. hemolyticus “carriers.” In the organization from which 89 per cent of their patients with measles came, there were 83 per cent hemolyticus “carriers” among men on duty. Among patients with measles, throat cultures were positive for hemolytic streptococci on admission in 77 per cent. It is evident that all patients with measles have been exposed to hemolytic streptococci during the first day or two after admission. Failure to carry streptococcus would appear to be dependent upon ability to resist it rather than upon lack of opportunity for acquiring it. Of 388 cases observed by Levy and Alexander only 79 were “noncarriers” of hemolytic streptococci on admission, and of these, 27 became positive while under observation; only 52 remain as “noncarriers” of hemolytic streptococci. This small group must be regarded as a highly selected one, composed of individuals more than ordinarily resistant to hemolytic streptococci and perhaps to all complications of measles. The chances are that these 52 cases placed under any circumstances might very well have been among the large number of measles cases in which no complications develop.

Furthermore, it is not unlikely that any complication of measles may be modified by a streptococcus secondarily when about 85 per cent of the cases show S. hemolyticus in the throat. The complications in the cases of Alexander and Levy appear to have been caused in large part by streptococcus, but a complete bacteriologic study of them is not recorded. Complications among streptococcus “carriers” are not identical with complications due to the streptococcus, and it is desirable to know what percentage of complications actually due to hemolytic streptococci occurred among the 85 per cent of patients with measles who carried hemolytic streptococci.

Summary.—No hemolytic streptococcus complications occurred in 112 cases of measles observed at Ft. Riley, among which streptococcus “carriers” rose from 2.6 per cent on admission to 24.1 per cent before discharge from the hospital. The percentage of “carriers” of hemolytic streptococci among normal men in the camp supplying these cases was about 25.5 per cent.

The influenza epidemic and a small epidemic of measles occurred in part simultaneously at Camp Pike during September and October, 1918. The complications following measles at Camp Pike were to a considerable extent dependent upon the combined effects of influenza and measles.

Thirty-five per cent of the measles patients showed throat cultures positive for B. influenzæ on admission to the hospital. On repeated cultures, this rose to 84 per cent before discharge.

Ward separation of cases of measles carrying hemolytic streptococci in their throats and cases not carrying these organisms were practiced in handling this epidemic. Of 867 cases of measles treated in this manner, 37 were positive for hemolytic streptococci on admission, and 205 developed positive throat cultures for these organisms during their period of observation in the hospital.

At Camp Pike, the percentage incidence of S. hemolyticus “carriers,” on admission to the measles wards, was 4.2 per cent. In cases recultured after one week, it was 10.9 per cent; after two weeks 22.8 per cent; after three weeks 26.2 per cent; and after four weeks 33.1 per cent. The weekly development of “carriers” in the “clean” treatment wards was during the first week 9.1 per cent; during the second week 17.4 per cent; during the third week 17.4 per cent; and during the fourth week 17.4 per cent.

The principal complications of these 867 cases of measles at Camp Pike were: pneumonia, 56 cases; otitis media, 48 cases, with subsequent mastoiditis in 23 cases, 2 of which had extensions to the meninges and brain. The greater part of the pneumonia occurred early in the period of observation, while most of the otitis media occurred later. Incidence of hemolytic streptococci was low during the pneumonia period and high during the prevalence of otitis media.

Hemolytic streptococci complicated 9 of these pneumonias; caused a large percentage of otitis (bacteriology incomplete), and 21 of the 23 cases of mastoiditis.

The bacteriology of 35 of the 56 pneumonias showed: Pneumococcus Type II atypical, in 36 per cent, Type IV in 22.9 per cent, Type I in 2.8 per cent and Type III in 2.8 per cent; hemolytic streptococci in 22.4 per cent; and B. influenzæ in 88.6 per cent.

The culturing of wards as units revealed widespread contact dissemination of hemolytic streptococci, at times 25 to 50 per cent of the patients in a ward becoming “carriers” within the period of a week. Streptococcus pneumonias, otitis media and its complications were furnished in large part by wards in which active dissemination occurred.

Streptococcus complications did not occur among 37 patients who were “carriers” of hemolytic streptococci when admitted to the hospital.

The epidemic dissemination of hemolytic streptococci occurs in measles wards, and is a serious danger. Many, patients whose throats become infected, develop no symptoms. In some instances streptococcus invades, and renders much more serious lesions caused by other microorganisms.

Methods to prevent transfer of infection within the ward and separation of “carriers” from “noncarriers” in different wards are efficient in keeping epidemic dissemination of hemolytic streptococci under control. Frequent throat cultures and prompt report of the results of cultures are essential.

The dissemination of B. influenzæ in patients with measles was not controlled by segregation of “carriers” and “noncarriers” of this organism as identified by throat cultures in separate wards.

CHAPTER VI
THE PATHOLOGY AND BACTERIOLOGY OF PNEUMONIA FOLLOWING MEASLES

Eugene L. Opie, M.D.; Francis G. Blake, M.D.; James C. Small, M.D.; and Thomas M. Rivers, M.D.

Among 18 autopsies upon men who have died with pneumonia following measles there are pulmonary lesions representing almost every type of pneumonia which has been found in association with influenza. In most instances pneumonia made its appearance during the second week of measles and death occurred during the third week. Of 16 instances in which the record is definite, pneumonia had its onset during the first week of measles in 4 instances, during the second week in 11 instances, and in one instance (Autopsy 390) perhaps not referable to measles in the fifth week. The duration of pneumonia varied from three to thirty-two days; in 10 instances it did not exceed one week, in 5 instances it was between one and two weeks and in one instance, thirty-two days. When the duration of pneumonia exceeded ten days some evidence of chronic pulmonary disease was found at autopsy.

The same lack of correspondence between clinical diagnosis and pulmonary lesions noted with influenza was found following measles. In accordance with the prevailing opinion concerning the character of pneumonia following measles, the diagnosis of bronchopneumonia was made in 13 instances and in all of these cases bronchopneumonia was found at autopsy. The diagnosis of lobar pneumonia was made 5 times and was correct only once. Nevertheless, lobar pneumonia was present 4 times, but was recognized only once (Autopsy 486.) Failure to recognize lobar pneumonia, was doubtless due in part at least to its association with purulent bronchitis and peribronchiolar pneumonia (Table LXXI).

Table LXXI
NO. OF AUTOPSYRACELENGTH OF MILITARY SERVICEDURATION OF ILLNESSDURATION OF PNEUMONIACLINICAL DIAGNOSISPURULENT BRONCHITISLOBAR PNEUMONIAPERIBRONCHIOLAR CONSOLIDATIONHEMORRHAGIC PERIBRONCHIOLAR CONSOL.LOBULAR CONSOLIDATIONPERIBRONCHIAL CONSOLIDATIONABSCESSINTERSTITIAL SUPPURATIVE PNEUMONIAMULTIPLE ABSCESSES IN CLUSTERSEMPYEMABRONCHIECTASISUNRESOLVED BRONCHOPNEUMONIAORGANIZING BRONCHITISBACTERIA IN SPUTUMBACTERIA IN BRONCHUSBACTERIA IN LUNGBACTERIA IN BLOOD OF HEART
390W1m.356L M + No S. Hem. Pneum. II a
438W2m.2212?BP + + + E + B. inf.S. hem., B. inf.Pneum. II, S. vir.,0
B. inf., S. hem.
439W10d.1411?BP M++ + +No S. hem.B. coliPneum. IIa, S. aur.0
441W1m.1611BP +++M + B. inf., S. aur.B. inf., S. aur.0
442W1m.172+LP M + N+ E No S. hem.B. inf., S. hem. S. hem.
443W21d.2314BP + M ++ No S. hem.B. inf., B. coli.B. coli.0
444W1m.93BP M++ B. inf.Pneum. IIa, B. inf.Pneum. IIa, B.inf.Pneum. II a.
450W29d.195B +M B.inf., No. S. hem.B. inf., Staph.B. inf.Pneum. IV.
453W36d.136BP + +M + Pneum. I, B. Inf.Pneum. I.Pneum. I.
481W54d.4+3?BP + + ++ No S. hem.B. inf., Pneum. IIa, S.hem.B. inf.0
484W42d.207BP + +M ++ Pneum. IV, B. inf.B. inf., Diploids 0
486C6d.178LP+ No S. hem.B. inf., Pneum. IIa, S. hem., Staph.B. inf.0
491W2m.195B + + E S. hem.B. inf., B. coli.S. hem., B. coli.S. hem.
492W49d.20?11?LP M++M+ E++ S. hem., B. inf. S.hem., Pneum. IV, B. coli., B. inf.S. hem.
496W1m.4332LP + + +++B. inf., no S. hem.B. inf.00
505C4m.166BP+ No S. hem.Pneum. II a., S. hem.Pneum. II a.Pneum. II a.
507C5m.143B N+ E S. hem.S. hem., B. inf., S. aur.S. hem., S. aur.S. hem.
508C2m.165B +M M S. hem.Pneum. IIa, B. inf., S. hem.Pneum. II a.Pneum. II a.

Changes in Bronchi.—The changes in the bronchi do not differ in character from those associated with pneumonia following influenza. Purulent bronchitis recognized at autopsy by the presence of mucopurulent material in the small bronchi was found in a much larger proportion of instances in this group of autopsies occurring in 13 of 18 instances (72.2 per cent), whereas it was present in only 55.6 per cent of autopsies on individuals with pneumonia following influenza. There was peribronchial hemorrhage recognizable on gross examination in 3 autopsies and microscopically in 3 additional instances.

Bronchiectasis was present in a considerable proportion of these autopsies, dilatation of bronchi being noted in 7, but it was usually moderately advanced and at times limited to the bases of the lungs. The short duration of respiratory disease perhaps explains the infrequency of advanced bronchiectasis. The incidence of the lesion is greater with measles (43.7 per cent) than with influenza (22.4 per cent).

Microscopic changes in the bronchi do not differ from those found after influenza. Evidence of acute inflammation, often hemorrhagic in character, is found within the lumen of the bronchus and in the tissues immediately in contact with the lumen. Not infrequently the epithelium is lost; there is superficial necrosis and deposition of fibrin upon the surface and within the tissue. In the deeper tissues of the bronchial wall there is infiltration with lymphoid and plasma cells, which in the larger bronchi is particularly advanced about the mucous glands of which the acini exhibit degenerative changes. With the onset of chronic changes new formation of fibrous tissue occurs in the wall of the bronchus and in the contiguous interalveolar walls. The lining epithelium often loses its columnar cells and assumes a squamous type.

Changes in the bronchi with bronchiectasis have been similar to those following influenza. Weakening of the wall permitting dilatation is brought about by necrosis extending outward from the lumen a varying distance into the bronchial wall and permitting the formation tears which diminish resistance to intrabronchial pressure.

Lobar Pneumonia.—Lobar pneumonia following measles occurred in 4 instances. Onset in these cases was on approximately the 9th, 10th, 11th, or 14th day of measles; the onset of bronchopneumonia bore a similar time relation to the onset of measles, the average interval being nine days. Hepatization with lobar pneumonia was in 1 instance red, in 3 instances gray, and in all save 1 instance the consolidation was firm and coarsely granular on section. In the exceptional instance the greater part of the right upper lobe was laxly consolidated and rather finely granular but the microscopic appearance was in all instances that of lobar pneumonia. Lobar pneumonia in 2 of these cases was associated with purulent bronchitis present in parts of the lung that had not undergone consolidation, whereas in the other 2 instances there were acute bronchitis and peribronchiolar pneumonia recognized by microscopic examination.

In one instance hepatization of the lung presented some noteworthy features.

Autopsy 450.—G. D., white, aged twenty-one, a farmer, resident of Arkansas, had been in military service twenty-nine days. Onset of illness began on October 2, nineteen days before death, and on admission on the same day the diagnosis of measles was made. Signs of pneumonia, regarded as bronchopneumonia, were recognized five days before death. Three days later there was otitis media and paracentesis was performed. On October 3 and 10 neither S. hemolyticus nor B. influenzæ was found in the sputum; on October 17 and 20 S. hemolyticus was not found but B. influenzæ was present.

Anatomic Diagnosis.—Acute lobar pneumonia with gray and red hepatization in right upper and lower lobes; edema and peribronchial hemorrhage in left lung.

Fig. 29.—Lobar pneumonia following measles, showing extension of gray hepatization from lower to upper lobe through a defect in the septum separating the two lobes. Autopsy 450.

The entire lower lobe of the right lung (Fig. 29) with the exception of a narrow air-containing zone in contact with basal surface is firmly consolidated. The greater part of the consolidated tissue is yellowish gray, firm and coarsely granular. The uppermost part of the consolidated tissue is softer than elsewhere as if it has undergone autolysis. The lowermost part of the consolidated tissue in a zone from 2.5 to 3.5 cm. in breadth is firmly consolidated but deep red. The bronchi contain stiff plugs of fibrin. In the upper lobe continuous with the consolidated part of the lower is a semicircular patch of yellowish gray consolidation. It overlies the line of the interlobular cleft at the site of a break in its continuity. Consolidation appears to have spread from the lower lobe into the upper at the site where the alveolar tissue of the two lobes is continuous but is absent from that part of the upper lobe separated from the lower by the interlobular cleft. This semicircular patch of yellowish gray consolidation is separated from air containing tissue of the upper lobe by a zone of red hepatization about 1 cm. in thickness.

Bacteriologic examination showed the presence of Pneumococcus IV in the blood of the heart; B. influenzæ alone was obtained from the right lower lobe and B. influenzæ and staphylococcus from the left main bronchus.

The distribution of lobar pneumonia in the foregoing autopsy indicates that it has spread like a wave from the upper part of the lower lobe (Fig. 32) penetrating into the upper where the alveolar tissue of the two lobes is in contact; gray hepatization is everywhere separated from air containing tissue by an advancing zone of red hepatization.

It may be assumed that lobar pneumonia was caused by Pneumococcus II atypical in 3 instances although it was recovered from the lungs only twice, for in the third instance (Autopsy 486) it was found in the bronchus and in the inflamed pleural cavity; pneumococci were doubtless previously present in the lung, but had disappeared at least from that part from which the culture was made. Pneumococcus IV was evidently the cause of pneumonia in 1 instance (Autopsy 450), for it was found in the blood of the heart although it was absent in the culture from the lung.

Little significance can be attributed to the observation that B. influenzæ was present in pure culture in the lungs from Autopsies 450 and 486, for the presence of Pneumococci IV in the blood of the heart in Autopsy 450 and of Pneumococcus II atypical in the pleura in Autopsy 486 furnishes evidence in view of the occurrence of lobar pneumonia that pneumococci had disappeared from the lungs. B. influenzæ was found both in the lungs and bronchus or in the bronchus alone in 3 of these 4 cases.

The relation of hemolytic streptococci to the lesion is of interest. In 3 of 4 instances of lobar pneumonia this microorganism had entered the bronchi but was not found in the lungs or in the heart’s blood; and gross and histologic examination showed none of the lesions which are usually caused by it. In 1 instance (Autopsy 508) hemolytic streptococci, absent from the throat when the patient was admitted to the hospital with measles sixteen days before death, appeared in a culture made five days later and was subsequently found three times; it had penetrated into the bronchus but failed to reach the lung. Observations made upon lobar pneumonia following influenza have shown the relative insusceptibility of lobar pneumonia with gray hepatization to secondary infection with hemolytic streptococci (p. [160]). Autopsy 508 demonstrates that occurrence of hemolytic streptococci in the sputum of a patient with pneumonia does not furnish conclusive proof of the existence of streptococcus pneumonia.

Bronchopneumonia.—Bronchopneumonia has been found in every instance of pneumonia following measles save 3, namely in Autopsy 486, Autopsy 505 with lobar pneumonia and Autopsy 507 with interstitial suppurative pneumonia. It is not improbable that further histologic study might have demonstrated small patches of peribronchiolar pneumonia, for purulent bronchitis was present in the two autopsies with lobar pneumonia. This small group of cases has reproduced all of the important features of bronchopneumonia following influenza. Hemorrhagic peribronchiolar consolidation characterized by the presence of small gray spots clustered about terminal bronchi upon a homogeneously red background has been found in 5 of 18 instances of pneumonia with measles. Pfeiffer regarded this lesion as characteristic of the pneumonia of influenza. Peribronchiolar patches of consolidation with no surrounding hemorrhage were found in 14 instances, being recognized first by microscopic examination in half of this number. Lobular consolidation occurred in 11 autopsies and peribronchial fibrinous pneumonia was present in a third of the autopsies on patients with pneumonia of measles.

Bronchial, peribronchial and intraalveolar hemorrhage is much more commonly associated with the pneumonias of influenza than with the more familiar types of acute bronchopneumonia. Exuded blood may undergo absorption; and with bronchopneumonia which, persisting unresolved, has assumed the characters of a chronic lesion, it is common to find mononuclear cells often in great abundance filled with brown pigment derived from the hemoglobin of red blood corpuscles.

Autopsy 439 is an example of acute hemorrhagic bronchopneumonia; there are red lobular and confluent lobular patches of consolidation which upon the pleural surface have a blue or purplish color. In the dependent part of the left lung occupying a large part of the lower lobe there is lax, red consolidation marked by gray or yellowish gray spots of peribronchiolar pneumonia and in this lobe bronchi are encircled by zones of hemorrhage. Pneumococcus II atypical was obtained from the lung. In Autopsy 444 the lesion has the same hemorrhagic character although lobular patches are in a stage of grayish red hepatization. Pneumococcus II atypical has been found in the heart’s blood, and with B. influenzæ in lungs and bronchus. Autopsy 441 is an example of the occurrence of conspicuous nodules of peribronchiolar consolidation in some parts of the lungs with the same lesion in other parts on a background of hemorrhage. B. influenzæ and S. aureus have been found in both lungs and bronchi.

Steinhaus[[102]] states that the pneumonia of measles is never lobular inflammation but occurs in small patches several of which may be found in a single lobule.

Chronic fibroid pneumonia following measles characterized by cellular infiltration and proliferation of the interstitial tissue of the lung has been described by Bartels,[[103]] Steinhaus,[[104]] Hart,[[105]] MacCallum[[104]] and others.

Fig. 30.—Unresolved bronchopneumonia with measles showing new formation of fibrous tissue about a bronchus and in immediately adjacent alveolar walls; partially obliterated alveoli occur in the peribronchial fibrous tissue. Autopsy 481.

Fig. 31.—Unresolved bronchopneumonia with measles showing a nodule of chronic fibrous pneumonia surrounding a respiratory bronchiole. Autopsy 481.

The incidence of unresolved bronchopneumonia among instances of bronchopneumonia following measles is higher than that among bronchopneumonias following influenza. There have been 6 instances of chronic or unresolved bronchopneumonia among 18 pneumonias following measles, namely 33.3 per cent. The incidence of unresolved bronchopneumonia among 241 autopsies on pneumonia following influenza has been 21, namely 8.7 per cent. The essential features of this chronic lesion have been as follows: (a) chronic peribronchiolar pneumonia indicated by the presence of firm nodules of peribronchiolar consolidation which have considerable resemblance to miliary tubercles. Induration of the nodule occurs because the walls of alveoli surrounding and adjacent to a respiratory bronchiole (Fig. 31) become thickened and infiltrated with cells and there is organization of exudate within the alveoli. New formation of fibrous tissue (Fig. 32) occurs where the acute inflammatory reaction of peribronchiolar consolidation is most advanced (p. [169] and compare with Figs. 3 and 4), namely, about the respiratory bronchiole, alveolar duct and the proximal parts of the infundibula, disappearing as the distal half of the infundibulum is approached. Distention of the alveoli explaining the distention of the lung and its failure to collapse on section is a noteworthy feature of the lesion. (b) Chronic peribronchial inflammation (Fig. 30) with new formation of fibrous tissue about the smaller and medium-sized bronchi extending into immediately adjacent alveolar walls and often associated with organization of peribronchial fibrinous pneumonia. (c) Chronic lobular inflammation with changes similar to those just cited, distributed throughout entire lobules. (d) Moderate thickening of interlobular septa. Bronchiectasis may be associated with the chronic lesion (Autopsies 443, 481, 484, 492 and 496) but with one exception (Autopsy 443) has been only moderately advanced. Suppurative pneumonia with abscess formation has occurred twice (Autopsies 438 and 492).

Fig. 32.—Unresolved bronchopneumonia with measles showing chronic pneumonia about a respiratory bronchiole and alveolar duct; alveoli about the proximal parts of three distended infundibula are filled with polynuclear leucocytes, whereas inflammatory changes disappear as the distal parts of the infundibula are approached. Autopsy 481.

With acute bronchopneumonia following measles the average duration of pneumonia, determined by the date upon which physical signs of pneumonia were first recognized and in consequence subject to some error, was seven days; in instances of chronic bronchopneumonia the average duration of pneumonia has been fifteen days.

The bacteriology of acute bronchopneumonia following measles is shown in Table LXXII.

Table LXXII
WITH NO SUPPURATIONSPUTUM IN LIFEBACTERIA IN BLOOD OF HEARTBACTERIA IN LUNGSBACTERIA IN BRONCHI
Autopsy 390 Pneum. II atyp.
439 0Pneum. II atyp. S. aur.B. coli
441 0B. inf., S. aur.B. inf., S. aur.
444B. inf.Pneum. II atyp.Pneum. II atyp. B. inf.Pneum. II atyp. B. inf.
453 Pneum. IPneum. IPneum. I, B. inf.
With suppuration:
442S. hem.S. hem. B. inf., S. hem.
491S. hem.S. hem.S. hem., B. coliB. inf., B. coli
507S. hem.S. hem.S. hem., S. aur.S. hem., B. inf., S. aur.

It is noteworthy that pneumococci have been recovered from the heart’s blood or lung in all but 1 (Autopsy 441) of 5 instances of acute bronchopneumonia with no suppuration and is doubtless the cause of this pneumonia. Pneumococcus II atypical has been found in 3 of 4 instances of lobar pneumonia following measles and is present in 3 of these 5 instances of bronchopneumonia.

Where suppuration has been found, hemolytic streptococci have been present in the sputum, in the heart’s blood and either in the lungs (Autopsy 491) or in the bronchi (Autopsy 442) or in both (Autopsy 507). In these instances pneumococci have not been found, though in view of the readiness with which pneumococci disappear from the lungs it is possible that they have been the primary cause of bronchopneumonia.

The bacteriology of 6 instances of unresolved bronchopneumonia following measles is given in Table LXXIII.

Table LXXIII
WITH NO SUPPURATIONSPUTUM IN LIFEBACTERIA IN BLOOD OF HEARTBACTERIA IN LUNGSBACTERIA IN BRONCHUS
Autopsy 443 0B. coliB. inf., B.coli
481 0B. inf.B. inf., Pneum. II, atyp., S. hem.
484Pneum. IV., B. inf.00B. inf., diphtheroids
496Pneum. IV., B. inf.00B. inf.
With Suppuration:
Autopsy 438B. inf.0Pneum. II atyp., S. vir. B. inf. S. hem.S. hem., B. inf.
492St. hem., B. inf.S. hem.S. hem., Pneum. IV, B. coli, B. inf.

Whereas with acute bronchopneumonia death has been accompanied and perhaps caused by bacterial invasion of the blood by pneumococci or streptococci in 5 of 7 instances, with unresolved or chronic bronchopneumonia, bacteriemia has been present only once, namely, in Autopsy 492 in which with suppurative pneumonia hemolytic streptococci have entered the blood. It is probable that pneumococci have likewise had an important part in the causation in these instances of bronchopneumonia which have run a chronic course but in all save 2 cases (Autopsies 438 and 492) have disappeared from the lungs. Pneumococcus II atypical has been found twice.

B. influenzæ has been found in association with acute bronchopneumonia in the lungs in 1 of 6 examinations and in the bronchi in 5 of 6 examinations. These figures indicate that it is present in small numbers if at all in the consolidated lung tissue but is relatively abundant in the bronchi. With chronic bronchopneumonia B. influenzæ has been found in every instance, in half of the examinations of lungs and in all of the examinations of bronchi. In 1 instance (Autopsy 481) B. influenzæ has been found in pure culture in the lung; Pneumococcus II atypical has been found in the bronchus and has perhaps disappeared from the pneumonic lung, since this microorganism is often destroyed in the late stages of pneumonia so that its demonstration at autopsy is no longer possible. In 1 instance B. influenzæ found in the bronchus has been the only microorganism isolated at autopsy, although the sputum during life contained B. influenzæ and Pneumococcus IV.

Suppurative Pneumonia.—Suppurative pneumonia with formation of abscesses has occurred in 2 autopsies with pneumonia following measles (Autopsies 438 and 492), both instances of chronic bronchopneumonia. In Autopsy 438 the lower and posterior part of the left lower lobe has been consolidated and has had on section a cloudy, grayish red color; within this area of consolidation and immediately below the pleural surface there have been opaque, yellow spots where the tissue has been softer than elsewhere. Microscopic examination shows that the tissue has here undergone widespread necrosis so that all nuclear stain has disappeared; at the edges of the necrotic tissue polynuclear leucocytes are often present in large numbers, but necrosis is much more conspicuous than suppuration. In the necrotic tissue and at its edges streptococci are present in vast numbers. Hemolytic streptococci have been grown both from the lung and from the bronchus, but these have not been the only microorganisms present, for Pneumococcus II atypical and S. viridans have been obtained from the lungs and B. influenzæ from lungs and bronchus.

In Autopsy 492 with chronic bronchopneumonia the posterior half of the right lower lobe is laxly consolidated, deep red in color and with the cloudy appearance often associated with streptococcus pneumonia; upon this background are peribronchiolar spots of yellow color, in places well seen below the pleura; in the corresponding part of the left lower lobe similar nodules have been converted into small abscesses by central suppuration. There is empyema on the right side, fibrinopurulent pericarditis, and purulent peritonitis. Hemolytic streptococci had been found in the sputum three times, the first examination being thirteen days before death. This microorganism is found in pure culture in the blood of the heart and with Pneumococci IV, B. coli and B. influenzæ in the lung. Hemolytic streptococci were found in the right pleural exudate and peritoneum.

The pneumonias following measles give opportunity to consider the relationship of suppurative interstitial pneumonia to unresolved or chronic bronchopneumonia, which is characterized by infiltration and proliferation of the fibrous tissue of the lungs. A number of those who have studied the pneumonia of measles have recognized that this chronic interstitial lesion is a common sequela of measles. MacCallum has designated the lesion “interstitial bronchopneumonia,” and has included under this name its acute stage in which the interstitial character of the lesion is not more evident than with other forms of acute bronchopneumonia. He has regarded S. hemolyticus as the cause of “interstitial bronchopneumonia” following measles. A review of the autopsies which he has described shows that he has included under the same designation typical instances of interstitial suppurative pneumonia associated with suppurative lymphangitis. Instances of unresolved, chronic or “interstitial” bronchopneumonia and of interstitial suppurative pneumonia which we have observed after measles, demonstrate that the two lesions are distinguishable both by their anatomic characters and by their etiology.

Three instances of suppurative interstitial pneumonia occurred among the pneumonias following measles (Autopsies 442, 491 and 507). The lesion is characterized by suppuration of the interlobular septa and particularly noteworthy is the occurrence of suppurative lymphangitis, lymphatics being immensely dilated and distended with purulent fluid so that their irregularly dilated, beaded appearance is recognizable upon the section of the lung. In the group of pneumonias following measles this lesion has not been associated with unresolved or chronic bronchopneumonia; no nodular tubercle-like foci of bronchopneumonia have been found at autopsy, and there has been no thickening of the interstitial tissue. The lesion has accompanied confluent lobular pneumonia in 2 instances (Autopsies 442 and 491). In the third instance (Autopsy 507) there was in the neighborhood of the suppurative lesions diffuse consolidation which had the cloudy, gray red color of streptococcus pneumonia, but this consolidation was not lobular in distribution.

The etiology of interstitial suppurative pneumonia established by study of instances following influenza is confirmed by Table LXXII (p. [345]) showing the bacteriology of instances of acute bronchopneumonia following measles. Pneumococci are almost invariably found in uncomplicated instances of bronchopneumonia and hemolytic streptococci have been absent, whereas in 3 instances of suppurative interstitial pneumonia hemolytic streptococci have been found in the sputum during life, in pure culture in the blood of the heart and in the lungs and bronchus (missed in the bronchus in one instance, Autopsy 507). In the 3 instances of the disease B. influenzæ has been found in the bronchi.

Table LXXIII shows that suppuration has accompanied unresolved bronchopneumonia (“interstitial bronchopneumonia”) in 2 instances (Autopsies 438 and 492), but in these instances the interlobular tissue of the lung has not been the site of suppuration and there has been no suppurative lymphangitis. Localized abscesses have been formed; hemolytic streptococci, as with abscesses following influenza, have been found.

Empyema has occurred only 5 times in association with pneumonia following measles and in these 5 instances has been associated with suppurative pneumonia caused by hemolytic streptococci. In Autopsy 492 there was fibrinopurulent pleurisy on both sides. Aspiration had been performed 3 times and at autopsy the right pleural cavity contained 150 c.c. of purulent fluid. In small pockets, corresponding to shallow oval depressions upon the anterior surface of the lung, fluid was walled off from the general cavity. The pericardial cavity contained 25 c.c. of turbid yellow fluid containing yellow flakes of fibrin and the peritoneal cavity contained thick purulent fluid. Hemolytic streptococci present in the heart’s blood and lung were recovered from the right pleural cavity and from the peritoneum. Among 3 instances of empyema accompanying interstitial suppurative pneumonia, in 1 (Autopsy 491) there were walled off pockets of fluid similar to those just described. Aspiration of the right pleural cavity had been performed 3 times; at autopsy 100 c.c. of fibrinopurulent fluid was found on the right side and 450 c.c. on the left. There was general purulent peritonitis and the peritoneal cavity contained 350 c.c. of thick yellow pus. Hemolytic streptococci were obtained from the heart’s blood, right lung, right pleural cavity and peritoneum.

Among 4 instances of lobar pneumonia following measles there was serofibrinous pleurisy 3 times; in 1 instance there is no record of pleural change. In 1 instance of lobar pneumonia (Autopsy 505) the right pleural cavity contained 800 c.c. of serofibrinous exudate and the pericardial cavity contained 510 c.c. of opaque, yellow seropurulent fluid; Pneumococcus II atypical in pure culture was obtained from the blood, lung and pleural and pericardial exudates. Among 9 instances of bronchopneumonia following measles there was fibrinous pleurisy 3 times, serofibrinous 3 times, and no recorded lesion of the pleura 3 times. Empyema, like suppurative pneumonia following measles, is in most instances, but not constantly, caused by invasion of hemolytic streptococci.

The foregoing study has shown that pneumonia which has followed measles has reproduced all of the lesions usually found after influenza. There is no pulmonary lesion peculiar to measles. Lobar pneumonia follows the disease in some instances, but bronchopneumonia with purulent bronchitis is more common. The same tendency to hemorrhagic inflammation found with the pneumonia of influenza is seen after measles. Unresolved pneumonia with chronic inflammatory changes in the interstitial tissue of the lung has all of the characters of the similar lesion following influenza but has been found in a larger proportion of the pneumonias of measles.

B. influenzæ has been found in the bronchi in 14 of 16 examinations, namely in 87.5 per cent of fatal instances of pneumonia. In 1 instance in which B. influenzæ has not been found at autopsy, it has been isolated from the sputum during life. It is not improbable that B. influenzæ has been constantly present in the inflamed bronchi both after influenza and measles. It is noteworthy that the outbreak of pneumonia following measles has been in part coincident with, in part slightly subsequent to, an epidemic of influenza which has exposed every individual in the camp to infection with this disease.

B. influenzæ has been found in the lung with the pneumonia of measles in 7 of 17 examinations, namely, in 41.2 per cent of instances. The microorganism with measles, as with influenza, is found in the inflamed lung only half as frequently as in the bronchi. It appears to be peculiarly adapted for multiplication within the bronchial tubes, and its isolation from the inflamed lung in less than half of the cases of pneumonia is perhaps referable to its presence in the small bronchi and bronchioles. The presence of B. influenzæ in the lungs in pure culture in 3 instances at first sight suggests that the microorganism produces pneumonia, but a more intimate survey of these cases gives little support to this view. In Autopsy 450 B. influenzæ has been found in pure culture in the lung, but Pneumococcus IV has been isolated from the blood of the heart and has been with little doubt the cause of typical lobar pneumonia present in this instance. In Autopsy 486 the condition is almost identical, for in the presence of lobar pneumonia B. influenzæ has been found in the lung in pure culture, but Pneumococcus II atypical has been isolated from the pleural cavity and from the bronchus; in both autopsies the pneumococci which have caused lobar pneumonia have disappeared from that part of the consolidated lung from which a culture has been made; and here doubtless its invasion has been effectively resisted although it is still present in other organs. In Autopsy 481 in which B. influenzæ has been isolated from the lung in pure culture, the part of pneumococci in the production of the fatal disease is less evident; in this instance, Pneumococcus II atypical, S. hemolyticus and B. influenzæ have been isolated from the bronchus.

The presence of microorganisms which have a well-established etiologic relation to pneumonia explains the occurrence of pneumonia and makes unnecessary the assumption that B. influenzæ, which is present in the lungs in less than half of the instances examined, is essential to the production of the pneumonic consolidation. In view of the well-recognized etiology of lobar pneumonia we may conclude that this lesion is referable to the pneumococci (Pneumococcus II atypical in 3 instances and Pneumococcus IV in 1 instance) isolated from the autopsies in which this lesion occurred. Pneumococcus (Pneumococcus II atypical in 3 instances and Pneumococcus I in 1 instance) has been isolated from the lungs or heart’s blood in 4 of 5 instances of acute bronchopneumonia unaccompanied by suppuration. With unresolved bronchopneumonia with no suppuration, pneumococci have been in no instance found in the lungs or blood though their presence in the washed sputum during life or in the bronchus at autopsy suggests the possibility that they may have disappeared from the lungs.

In all instances in which suppuration has occurred hemolytic streptococci have been found in the lungs or blood, or in both. The occurrence of pneumococci in the lungs in 2 of 5 instances of suppurative pneumonia indicates that infection with S. hemolyticus is in some instances at least superimposed upon acute bronchopneumonia caused by pneumococci. Bronchopneumonia in 3 instances has the character of that caused by pneumococci. It is probable that the sequence of infection frequently observed after influenza, namely, bronchial infection by B. influenzæ, followed by pneumonia caused by pneumococci, followed in turn by infection by hemolytic streptococci with necrosis or suppuration, is not uncommon after measles.

Pneumonia Associated with Acute Infectious Diseases Other than Influenza and Measles.—A small group of autopsies have been excluded from the list of those which accompanied the epidemic of influenza, because pneumonia has been associated with an acute infectious disease to which it is perhaps secondary. These few instances of pneumonia, like those following measles reproduce characters of the pneumonia following influenza and may be in part referable to influenza which has attacked an individual suffering with typhoid fever, mumps or scarlet fever.

In 2 instances pneumonia followed typhoid fever and appeared on September 23 and 26 shortly after the epidemic of influenza had become evident. In the following autopsy there was acute lobar pneumonia which appeared ten days after onset of typhoid fever.

Autopsy 245.—O. H., white, aged twenty-one, a farmer, resident of Oklahoma, had been in military service twenty-one days. Onset of illness was on September 13 with chill, headache, cough and nausea. The patient was admitted two days later with the diagnosis of acute bronchitis. On September 20 the abdomen was tense, the spleen was enlarged and rose spots were present. Signs of lobar pneumonia were found September 23. Death occurred September 25, twelve days after onset of typhoid fever and two days after recognition of pneumonia.

Anatomic Diagnosis.—Typhoid fever with necrotic ulcers in lower ileum and in colon; hyperplasia of ileocecal lymphatic nodes; acute splenic tumor; parenchymatous degeneration of liver and kidneys; acute lobar pneumonia with gray hepatization in left lower lobe and red hepatization and edema in left upper lobe and in right lung; serofibrinous pleurisy on left side.

The left pleural cavity contains 75 c.c. of yellowish gray turbid fluid. Over the left lower lobe there is a layer of fibrin. The upper half of the lobe is firmly consolidated, pinkish gray and coarsely granular; the bronchi contain plugs of fibrin. The lower and posterior part of the lower lobe is consolidated deep red and edematous. The left upper lobe is edematous and a layer in the lowermost part in contact with the lower lobe is deep red and consolidated. The left lung weighs 1,490 grms. The lower half of the right upper lobe and the posterior border of the lower is consolidated deep red and edematous; the lung weighs 970 grms.

Bacteriologic examination shows that the blood of the heart contains Pneumococcus II atypical.

The foregoing autopsy is of interest because typical lobar pneumonia appears to have spread from the left lower lobe, where consolidation is firm and gray, to the adjacent part of the upper lobe where consolidation is red and edematous.

The second instance of pneumonia following typhoid fever is an instance of suppurative pneumonia caused by S. aureus.

Autopsy 329.—J. B., white, aged twenty-two, laborer, resident of Oklahoma, had been in military service two days before onset of symptoms of typhoid fever. He was admitted to the hospital on August 27 and B. typhosus was found in cultures from the blood on September 2 and 3. Acute bronchitis appeared on September 26 when the epidemic of influenza had almost reached its height. A diagnosis of bronchopneumonia was made on the day preceding death, which occurred forty-one days after onset of typhoid fever and eleven days after onset of bronchitis.

Anatomic Diagnosis.—Typhoid ulcers of ileum; acute splenic tumor; acute bronchopneumonia with red hemorrhagic peribronchiolar and lobular consolidation in right lung; multiple abscesses forming a circumscribed group in left upper lobe; purulent bronchitis.

The pleural cavities contain no excess of fluid. The lungs are voluminous and there is interstitial emphysema. Below the pleura are bluish red spots of lobular consolidation; in the right upper lobe is a large patch of red consolidation marked by yellowish gray spots in clusters. In the external and upper part of the left upper lobe is a patch of gray consolidation within which, beneath the pleura, there are small abscesses grouped to form a cluster 1.5 cm, across.

Bacteriologic examination demonstrates no microorganisms in the blood of the heart; of two cultures from the left lung one contains S. aureus in pure culture, the other S. aureus and a few colonies of Pneumococcus IV. Cultures from the left main bronchus and from the mucopurulent exudate in a small bronchus both contain B. influenzæ, S. aureus and Pneumococcus IV.

In the foregoing case bronchitis has appeared thirty days after onset of typhoid fever on September 26, immediately preceding the height of the epidemic of influenza. In association with hemorrhagic bronchopneumonia there is suppurative pneumonia with small abscesses forming a circumscribed group below the pleura; there is no empyema. The lesion has the characters of the staphylococcus abscesses following influenza, and S. aureus is found in association with the lesion; B. influenzæ is identified in two cultures from the bronchi.

In 2 instances pneumonia was associated with parotitis which was diagnosed mumps.

Autopsy 403.—C. T., colored, aged twenty-five, a laborer, resident of Arkansas, had been in military service one month. Illness began September 27 with swelling of face behind jaw and difficult mastication; the patient was admitted to the hospital on the same day with the diagnosis of mumps. Pneumonic consolidation was recognized on October 8. Death occurred October 13, sixteen days after onset of illness and six days after recognition of pneumonia.

Anatomic Diagnosis.—Acute lobar pneumonia with red and beginning gray hepatization of lower and parts of upper and middle right lobes; acute bronchopneumonia with lobular consolidation in left lung; purulent bronchitis; bronchiectasis in left lung.

The lower lobe of the right lung with the exception of the anterior and basal edge is firmly consolidated; the posterior part of the middle lobe and a small corner at the posterior and lower part of the upper lobe is similarly consolidated. The consolidated tissue is gray and coarsely granular on section. The remainder of the lung is dry and voluminous, and the bronchi contain purulent fluid. The left lung contains red and gray patches of consolidation, from 0.2 to 3 cm. across. Bronchi contain purulent fluid and in the lowermost parts of both upper and lower lobes are moderately dilated.

Bacteriologic examination shows that the blood of the heart contains Pneumococcus III.

It is noteworthy that there was in this case, as in many instances of influenza, both lobar and bronchopneumonia. Purulent bronchitis was present and there was bronchiectasis throughout one lung.

In the following case the diagnosis of mumps may be questioned since the lesion of the parotid has characters of terminal suppurative parotitis.

Autopsy 417.—H.W.D., white, aged twenty-four, a farmer, resident of Oklahoma, had been in military service one month. He said that he had had pneumonia four times. He was admitted to the hospital delirious and the diagnosis of lobar pneumonia was made. Parotitis regarded as mumps appeared five days before death and suppuration occurred on the right side of the face. Death of the patient occurred thirteen days after admission to the hospital.

Anatomic Diagnosis.—Acute bronchopneumonia with lobular consolidation in both lungs; suppurative pneumonia with necrosis and beginning abscess formation in left lung; purulent pleurisy in left side; purulent bronchitis; bronchiectasis; acute parotitis.

The left pleural cavity contains 100 c.c. of purulent fluid of creamy consistence. The left lung is voluminous and bound to the chest wall in places. There are numerous patches of lobular consolidation. At the apex of the lung there is a large area of consolidation, 7 cm. across, where the tissue is cloudy gray and soft in consistence. In the upper lobe is a well-defined patch of grayish yellow color, 6 by 2 cm., with opaque yellow edges; purulent fluid escapes from the cut surface. Bronchi throughout the lung are widely dilated and contain purulent fluid. The right lung is voluminous and contains lobular patches of consolidation; bronchi of this lung are widely dilated.

Bacteriologic examination shows the presence of hemolytic streptococci in the blood of the heart; hemolytic streptococci and B. influenzæ in the lung, and hemolytic streptococci, B. influenzæ and S. aureus in a main bronchus.

In association with bronchopneumonia there have been necrosis and beginning abscess formation with empyema, the suppurative lesions being caused by hemolytic streptococci which had finally entered the blood stream. There was purulent bronchitis, and the lungs had the voluminous character often associated with this lesion; there was beginning bronchiectasis. B. influenzæ was obtained both from the lung and from the bronchus.

In 2 instances (Autopsies 323 and 335) the diagnosis of scarlet fever was made in patients suffering with pneumonia following influenza. These lesions have been included in the list of influenzal pneumonias. In the following instance the patient was admitted with scarlet fever, later developed acute follicular tonsillitis, and finally suppurative pneumonia caused by hemolytic streptococcus.

Autopsy 311.—E. J., white, aged twenty-two, a tinsmith and automobile repairer, resident of Arkansas, had been in military service three months. Onset of illness was on September 18 with headache and sore throat. The patient was admitted September 24 with the diagnosis of scarlet fever; two days later there was acute follicular tonsillitis. Pneumonic consolidation on the right side was recognized October 2, three days before death.

Anatomic Diagnosis.—Acute suppurative pneumonia with three small abscesses below pleura of right lower lobe; acute fibrinopurulent pleurisy on both sides; serous pericarditis.

The right pleural cavity contains 1500 c.c. of turbid, dirty yellow fluid containing masses of fibrin; the left cavity has 500 c.c. of similar contents. The pericardium contains 30 c.c. of turbid fluid containing a small quantity of fibrin; there are ecchymoses below the epicardium. The right lung is collapsed and in the lower lobe contains three small subpleural abscesses, the largest of which is 1.5 cm. across.

Bacteriologic examination shows the presence of hemolytic streptococci in pure culture in the blood of the heart and in the right lung. From the right main bronchus are obtained hemolytic streptococci, B. influenzæ, Pneumococcus IV and a few staphylococci.

In this instance there has been infection with streptococcus which is a common sequela of scarlet fever. In the absence of evidence of bronchopneumonia there has been abscess formation below the pleura with empyema and pericarditis. B. influenzæ has been found in the bronchus.

The pneumonias found in association with measles reproduce the characters of the pneumonias described in association with influenza. Particularly noteworthy is the occurrence of lobar pneumonia, hemorrhagic peribronchiolar pneumonia, interstitial suppurative pneumonia, severe bronchitis with bronchiectasis and unresolved bronchopneumonia. In the presence of an epidemic of influenza attacking more than one fourth of the population of a camp, those suffering with diseases, such as measles, typhoid fever, mumps, etc., are unlikely to escape entirely, and it is probable that the tendency to the occurrence of pneumonia present in association with these diseases will be increased. The close resemblance between the pneumonias which we have found with the diseases mentioned, on the one hand, and the pneumonias of influenza on the other, both being characterized by the occurrence of hemorrhagic, suppurative and chronic pulmonary lesions, indicates that influenza has had a part in the production of the pneumonia found with measles and some other infectious diseases during the progress of the epidemic of influenza.

CHAPTER VII
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.

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.