Chapter XIX: 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.

INDEX

A

Abscess of lung, bacteriology of, 203
empyema with, 233
healing of, 208
measles with, 347
parotitis with, 356
pathogenesis of, 205, 375
scarlet fever with, 357
staphylococcus causing, 199, 225, 366, 377
S. hemolyticus causing, 199, 365

Autopsies, table of, 118, 120, 335

Autopsy protocols, No. 280, 226;
No. 286, 226;
No. 312, 254;
No. 322, 228;
No. 330, 214;
No. 333, 229;
No. 370, 229;
No. 376, 206;
No. 379, 215;
No. 380, 204;
No. 387, 206;
No. 397, 223;
No. 406, 204;
No. 416, 204;
No. 420, 279;
No. 425, 229;
No. 428, 280;
No. 433, 280;
No. 445, 257;
No. 465, 238;
No. 467, 208;
No. 473, 236;
No. 474, 221;
No. 487, 273;
No. 499, 224;
No. 504, 238

B

Bacillus influenzæ, 369
bronchi and, 178, 215, 346
bronchitis and, 153, 371
experimental inoculation with, 389
history of, 25
influenza and, 30, 42, 43, 46, 49, 76, 370
isolation of, 30, 32, 38, 44
measles with, 26, 40, 43, 295, 351
meningitis and, 26
normal men carrying, 34, 42, 45, 369
pathogenicity of, 26, 48, 370, 387, 396
pneumococcus pneumonia with, 62, 178
pneumonia with, 72, 75, 76, 173, 364, 371

Bronchi, inflammation of mucous glands of, 146

Bronchiectasis, 239, 269, 355, 367
abscess with, 254
bacteriology of, 244
bronchitis with, 245
measles with, 336
pathogenesis of, 245, 259

Bronchiolitis, organizing, 264

Bronchitis, 40, 142, 195, 359
bacteriology of, 56, 150, 164, 359, 371
bronchiectasis with, 245
chronic, 262
clinical course of, 58
measles with, 336
organizing, 264
purulent, 47, 56, 60, 63, 74, 143, 149, 153, 360

Bronchopneumonia, 60, 63, 66, 162, 360, 363
bacteriology of, 68, 163, 171, 176, 181, 184, 189, 194, 197, 345, 364
fibrin with, 182
lobar pneumonia with, 155, 157
measles with, 340
secondary infection by S. hemolyticus with, 172, 177, 181, 374

C

Carriers of B. Influenzæ, 46, 101, 369
of S. hemolyticus, 99, 285, 287, 298, 303, 309, 310, 315, 319, 321,
332, 379

Cartilage, atrophy with bronchiectasis of, 254

Contact infection in influenza, prevention of, 98
in measles, 289
in pneumonia, prevention of, 98

Cubicles to prevent contact infection, 98, 290

Cyanosis, 144

E

Empyema, 64, 67, 224, 226, 233, 304, 366
abscess of lung and, 233
encapsulated, 235
interstitial suppurative pneumonia with, 216, 234
measles with, 349
pneumococcus, 236, 350
streptococcus, 233, 350

Endophlebitis, 219

H

Hemorrhagic and edematous consolidation with bronchopneumonia, 188
peribronchiolar consolidation with bronchopneumonia, 163, 173, 272,
340

Hepatization with bronchopneumonia, 179, 181
with lobar pneumonia, 160

I

Influenza, B. influenzæ with, 30, 73
bronchitis with, 55, 56
clinical course of, 28, 53, 73, 80
coryza with, 54
cyanosis with, 54
epidemic in fall of 1918, 52, 108, 359
epidemic in spring of 1918, 47
fever with, 53
gastrointestinal symptoms with, 55
laryngitis with, 54
lobar pneumonia and, 161
measles and, 292, 319, 331, 351, 357, 380
pandemic of 1889–90, 109, 115
pandemic of 1918–19, 27, 359
pharyngitis with, 54
pneumococcus with, 33
pneumonia with, 55, 59, 74, 81, 139
pulmonary lesions of, 137
pulse with, 54
secondary infection with, 28, 45, 57, 95
sputum with, 55
S. hemolyticus with, 103

Interstitial bronchopneumonia, 261, 278, 348
suppurative pneumonia, 199, 209, 366, 376
bacteriology of, 214
chronic inflammation with, 221
empyema with, 216, 234
healing of, 222, 224
measles with, 348
pericarditis with, 237

L

Lobar pneumonia, 60, 63, 154, 360, 362
bacteriology of, 64, 156, 164, 339, 362
bronchopneumonia with, 155, 157
experimental production in monkeys of, 394, 397
influenza and, 161
measles with, 337
purulent bronchitis with, 60, 63, 66
secondary infection by hemolytic streptococci with, 64, 159, 340, 374
spread in lung of, 339, 354
typhoid fever with, 353

Lobular consolidation, confluent, 188, 341
with bronchopneumonia, 163, 178, 272, 341

Lymphatics, suppurative inflammation of, 217, 218, 376
thrombosis of, 217, 218

Lymphangitis, experimental production with S. hemolyticus of, 392

M

Masks to prevent contact infection, 98, 290

Mastoiditis, 303, 312, 332

Measles, 119, 288
B. influenzæ with, 26, 40, 43, 295
bronchiectasis with, 336
bronchitis with, 336
bronchopneumonia with, 340
complications of, 303, 378
empyema with, 349
influenza and, 292, 319, 331, 351, 357, 380
interstitial suppurative pneumonia with, 348
lobar pneumonia with, 337
pneumococcus pneumonia with, 312
pneumonia and, 292, 303, 312, 332, 334, 378
secondary infection with, 282
S. hemolyticus with, 285, 287, 297, 319, 330, 331, 353, 378
suppurative pneumonia with, 345, 347
unresolved bronchopneumonia with, 342

Methods, 29, 51, 283, 291

Mortality of pneumococcus pneumonia, 140
of pneumonia following influenza, 139
of streptococcus pneumonia, 140

Mumps, 119, 355

N

Necrosis with bronchopneumonia caused by S. hemolyticus, 186, 375
with lobar pneumonia caused by S. hemolyticus, 160, 374
with S. hemolyticus, 199, 200

O

Oedema, interstitial, 209

Organization of pneumonic exudate, 197

Otitis media, 289, 303, 312, 317, 329, 332

P

Peribronchiolar consolidation with bronchopneumonia, 163, 166, 267, 340

Pericarditis, 64, 237

Peribronchial consolidation with bronchopneumonia, 163, 192, 361
hemorrhage, 189

Peritonitis, 238

Phagocytosis of red blood corpuscles, 272

Pneumococcus, 372
bronchitis and, 153
bronchopneumonia with, 165, 184, 373
empyema, 236
experimental lobar pneumonia with, 393
influenza with, 33
lobar pneumonia with, 158, 372
pneumonia, 60, 75, 104
clinical course of, 62
measles and, 312, 332
mortality of, 140
secondary pneumococcus infection with, 61
secondary streptococcus infection with, 62
transmission of, 91, 383
secondary infection in pneumonia with, 91

Pneumonia, B. influenzæ causing, 72, 76, 371
bacteriology of influenza and, 60, 74, 107
bacteriology of measles and, 351
chronic fibroid, 273
clinical course of influenza with, 62
diagnosis of, 136, 334, 361
dissecans, 209
immunity following, 373
influenza with, 59, 76, 81, 109, 360
measles and, 119, 292, 303, 312, 332, 334, 378
mumps and, 119
pneumococcus, see Pneumococcus pneumonia
prevention of, 98, 319, 383
scarlet fever and, 119
secondary infection with, 83, 106
spread through lungs of, 194, 373
staphylococcus, see Staphylococcus pneumonia
streptococcus, see Streptococcus pneumonia
S. hemolyticus in throat with, 310, 329, 379

Pseudoinfluenza bacilli, 26

S

Scarlet fever, 119, 356

Squamous transformation of bronchial epithelium, 149, 251, 275, 336

Staphylococcus, 153, 377
pneumonia, 112, 225, 354, 366
pneumonia, pathogenesis of, 230

Streptococcus empyema, 233
hemolyticus, 374
bronchitis with, 153
dissemination in wards of, 315
experimental production of acute
lymphangitis with, 392
identification of, 283
influenza with, 103
lobar pneumonia with, 64, 159
measles with, 285, 287, 297, 330, 331, 345, 353, 378
normal men with, 285, 322
secondary infection in pneumonia with, 84, 106, 178, 204, 374
nonhemolytic, 376
peritonitis, 238
pneumonia, 60, 70, 75, 115, 307, 365
bacteriology of, 71
clinical features of, 71
measles with, 303, 305, 307, 318
mortality of, 140
transmission of, 84, 381
viridans, 377

Suppurative pneumonia, 199, 347
with measles, 345, 347

T

Thrombosis of capillaries with bronchopneumonia, 184

Typhoid fever, lobar pneumonia with, 353
staphylococcus pneumonia with, 354

U

Unresolved bronchopneumonia, 261, 266, 342, 368
bacteriology of, 276
interstitial suppurative pneumonia with, 278

-----

Footnote 1:

Report of the Surgeon General, U. S. Army to the Secretary of War,
1918, p. 44.

Footnote 2:

Stillman, F. G.: A Study of Atypical Type II Pneumococci, Jour. Exper.
Med., 1919, xxix, 251.

Footnote 3:

Opie, E. L., Freeman, A. W., Blake, F. G., Small, J. C., Rivers, T.
M.: Pneumonia at Camp Funston, Jour. Am. Med. Assn., 1919, lxxii, 108.

Footnote 4:

Vaughan, V. C., and Palmer, G. T.: Communicable Diseases in the
National Guard and National Army of the United States, Jour. Lab. and
Clin. Med., 1918, iii, 635.

Footnote 5:

Miller, J. L., and Lusk, F. B.: Jour. Am. Med. Assn., 1918, lxxi, 702.

Footnote 6:

Report of the Surgeon General to the Secretary of War, 1919, i, 637.

Footnote 7:

MacNeal, W. J.: The Influenza Epidemic of 1918 in the American
Expeditionary Forces in France and England, Arch. Int. Med., 1919,
xxiii, 657.

Footnote 8:

Pfeiffer: Ztschr. f. Hyg., 1893, xiii, 357.

Footnote 9:

Wollstein: Jour. Exper. Med., 1916, viii, 681.

Footnote 10:

Kretz: Wien. klin. Wchnschr., 1897, x, 877.

Footnote 11:

Süsswein: Wien. klin. Wchnschr., 1901, xiv, 1149.

Footnote 12:

Liebscher: Prag. med. Wchnschr., 1903, xxviii, 85.

Footnote 13:

Jehle: Ztschr. f. Heilk., 1901, xx, n. s. 2, Int. Med.

Footnote 14:

Davis: Jour. Infect. Dis., 1906, iii, 1.

Footnote 15:

Lord: Boston Med. Sur. Jour., 1905, clii, 537, 574.

Footnote 16:

Boggs: Am. Jour. Med. Sc., 1905, cxxx, 902.

Footnote 17:

Wollstein: Am. Jour. Dis. Child., 1911, i, 42.

Footnote 18:

Rosenthal: Comp. rend. Soc. Biol., 1903, lv, 1500.

Footnote 19:

Wollstein: Jour. Exper. Med., 1915, xxii, 445.

Footnote 20:

Med. Sup. October 1, 1918 also Jour. Am. Med. Assn., 1918, lxxi, 1573.

Footnote 21:

Opie, Freeman, Blake, Small, and Rivers: Jour. Am. Med. Assn., 1919,
lxxii, 108.

Footnote 22:

Vaughn and Palmer: Jour. Lab. and Clin. Med., 1918, iii, 635.

Footnote 23:

Soper: Jour. Am. Med. Assn., 1918, lxxi, 1899.

Footnote 24:

Cole and MacCallum: Jour. Am. Med. Assn., 1918, lxx, 1146.

Footnote 25:

Hammond, Rolland, and Shore: Lancet, London, 1917, ii, 41.

Footnote 26:

Abrahams, Hallows, Eyre, and French: Lancet, London, 1917, ii, 377.

Footnote 27:

Public Health Reports, U.S.P.H. Service, 1919, xxxiv, 33.

Footnote 28:

Blake: Jour. Exper. Med., 1917, xxvi, 67.

Footnote 29:

Avery: Jour. Am. Med. Assn., 1918, lxx, 17.

Footnote 30:

Dunn: Jour. Am. Med. Assn., 1918, lxxi, 2128.

Footnote 31:

Fantus: Jour. Am. Med. Assn., 1918, lxxi, 1736.

Footnote 32:

Keegan: Jour. Am. Med. Assn., 1918, lxxi, 1051.

Footnote 33:

Christian: Jour. Am. Med. Assn., 1918, lxxi, 1565.

Footnote 34:

Blanton and Irons: Jour. Am. Med. Assn., 1918, lxxi. 1988.

Footnote 35:

Hall, Stone and Simpson: Jour. Am. Med. Assn., 1918, lxxi, 1986.

Footnote 36:

Synnott and Clark: Jour. Am. Med. Assn., 1918, lxxi, 1816.

Footnote 37:

Friedlander, McCord, Sladen and Wheeler: Jour. Am. Med. Assn., 1918,
lxxi, 1652.

Footnote 38:

Brem, Bolling and Casper: Jour. Am. Med. Assn., 1918, lxxi, 2138.

Footnote 39:

Ely, Lloyd, Hitchcock, and Nickson: Jour. Am. Med. Assn., 1919, lxxii,
24.

Footnote 40:

Camp Lewis Pneumonia Unit: Jour. Am. Med. Assn., 1919, lxxii, 268.

Footnote 41:

Jour. Am. Med. Assn., 1918, lxxi, 2068.

Footnote 42:

Wolbach: Bull. Johns Hopkins Hosp., 1919, xxx, 104.

Footnote 43:

Spooner, Scott and Heath: Jour. Am. Med. Assn., 1919, lxxii, 155.

Footnote 44:

Kinsella: Jour. Am. Med. Assn., 1919, lxxii, 717.

Footnote 45:

MacCallum: Jour. Am. Med. Assn., 1919, lxxii, 720.

Footnote 46:

Pritchett and Stillman: Jour. Exper. Med., 1919, xxix, 259.

Footnote 47:

Hirsch and McKinney: Jour. Am. Med. Assn., 1918, lxxi, 1735.

Footnote 48:

Parker: Jour. Am. Med. Assn., 1919, lxxii, 476.

Footnote 49:

Opie, Freeman, Blake, Small and Rivers: Jour. Am. Med. Assn., 1919,
lxxii, 556.

Footnote 50:

See discussion on pages 115 to 118.

Footnote 51:

Isolated by blood culture on Sept. 23. Patient recovered.

Footnote 52:

Stillman: Jour. Exper. Med., 1916, xxiv, 651.

Footnote 53:

Stillman: Jour. Exper. Med., 1919, xxix, 251.

Footnote 54:

Haller and Colwell: Jour. Am. Med. Assn., 1918, lxxi, 1213.

Footnote 55:

Doust and Lyon: Jour. Am. Med. Assn., 1918, lxxi, 1216.

Footnote 56:

Held in receiving ward 40 hours because of admission of case of
meningococcus meningitis to ward by mistake.

Footnote 57:

Finkler, D.: Infectionen der Lunge durch Streptococcen und Influenza
Bacillen, Bonn, 1895.

Footnote 58:

Ribbert: Anatomische und bacteriologische Beobachtungen über
Influenza, Deutsch. med. Wehnschr., 1890, xvi, 61, 301.

Footnote 59:

Pfeiffer: Die Aetiologie der Influenza, Ztschr. f. Hyg. 1893, xiii,
357.

Footnote 60:

Leichtenstern, O.: Influenza, Nothnagel’s Specielle Pathologie und
Therapie, Wien, 1896, vol. ii, pt. 2.

Footnote 61:

Krannhals: Quoted by Leichtenstern.

Footnote 62:

Cruickshank: Brit. Med. Jour., 1895, i, 360.

Footnote 63:

Birch-Hirschfeld: Schmidt’s Jahrbücher, 1890, ccxxvi, 110.

Footnote 64:

Kuskow, N.: Zur pathologischen Anatomie der Grippe, Virchow’s Archiv.,
1895, cxxxix, 406.

Footnote 65:

Keegan, J. J.: The Prevailing Epidemic of Influenza, Jour. Am. Med.
Assn., 1918, lxxi, 1051.

Footnote 66:

Symmers, D.: Pathologic Similarity between Pneumonia of Bubonic Plague
and of Pandemic Influenza, Jour. Am. Med. Assn., 1918, lxxi, 1482.

Footnote 67:

Opie, E. L., Freeman, A. W., Blake, F. G., Small, J. C., Rivers, T.
M.: Pneumonia Following Influenza, Jour. Am. Med. Assn., 1919, lxxii,
556.

Footnote 68:

LeCount, E. R.: The Pathological Anatomy of Influenzal
Bronchopneumonia, Jour. Am. Med. Assn., 1919, lxxii, 650.

Footnote 69:

MacCallum, W. G.: Pathology of the Pneumonia Following Influenza,
Jour. Am. Med. Assn., 1919, lxxii, 720.

Footnote 70:

Lyon, M. W.: Gross Pathology of Epidemic Influenza at Walter Reed
Hospital, Jour. Am. Med. Assn., 1919, lxxii, 924.

Footnote 71:

Goodpasture, E. W. and Burnett, F. L.: The Pathology of Pneumonia
Accompanying Influenza, U. S. Naval Medical Bull., 1919, xiii, No. 2.

Footnote 72:

Wolbach: Comments on the Pathology and Bacteriology of Fatal Influenza
Cases as Observed at Camp Devens, Mass., Bull. Johns Hopkins Hosp.
1919, xxx, 104.

Footnote 73:

Cummings, J. G., Spruit, C. B., and Lynch, C.: The Pneumonias:
Streptococcus and Pneumococcus Groups, Jour. Am. Med. Assn., 1918,
lxx, 1066.

Footnote 74:

Cole, R. and MacCallum, W. G.: Pneumonia at a Base Hospital, Jour. Am.
Med. Assn., 1918, lxx, 1146.

Footnote 75:

Miller, J. L., and Lusk, F. B.: Epidemic of Streptococcus Pneumonia
and Empyema at Camp Dodge, Iowa, Jour. Am. Med. Assn., 1918, lxxi,
702.

Footnote 76:

MacCallum, W. G.: Pathology of the Epidemic of Streptococcus
Bronchopneumonia in the Army Camps, Jour. Am. Med. Assn., 1919, lxxii,
720.

Footnote 77:

Stone, W. J., Phillips, B. G., and Bliss, W. P.: A Clinical Study of
Pneumonia Based on 871 Cases, Arch. Int. Med., 1918, xxii, 409.

Footnote 78:

Opie, E. L., Freeman, A. W., Blake, F. G., Small, J. C., and Rivers,
T. M.: Pneumonia at Camp Funston, Jour. Am. Med. Assn., 1919, lxxii,
108.

Footnote 79:

Jour. Am. Med. Assn., 1919, lxxii, 556.

Footnote 80:

Miller, W. S.: Am. Rev. Tuberc., 1919, iii, 65.

Footnote 81:

Wadsworth, A. B.: A Study of Organizating Pneumonia. Jour. Med.
Research, 1918, xxxix, 147.

Footnote 82:

Kaufmann: Spezielle Pathologische Anatomie. 1909, ed. 5, p. 260.

Footnote 83:

Beitzke: Respirations Organe. Aschoff’s Path. Anat., 1913 ed. 3, Vol.
II, p. 308.

Footnote 84:

Chickering, H. T. and Park, J. H.: Staphylococcus Aureus Pneumonia,
Jour. Am. Med. Assn. 1919, lxxii, 617.

Footnote 85:

Stone, W. J., Phillips, B. G., and Bliss. W. P.: A Clinical Study of
Pneumonia Based on 871 Cases. Arch. Int. Med., 1918, xxii, 409.

Footnote 86:

Loc. cit., p. 110.

Footnote 87:

Lord, F. T.: Infections of the Respiratory Tract with Influenza
Bacilli, Boston Med. and Surg. Jour., 1905, clii, 537, 574.

Footnote 88:

Boggs, T. R.: Influenza Bacillus in Bronchiectasis, Am. Jour. Med.
Sc., 1905, cxxx, 902.

Footnote 89:

Thornton and Pratt: Bull. Johns Hopkins Hosp., 1908, xix, 230.

Footnote 90:

Two cases positive for hemolytic streptococci on this examination were
negative on next examination.

Footnote 91:

S. hemolyticus infection implanted upon a pneumococcus pneumonia.
Place in Table indicates onset of pneumonia and not appearance of
streptococcus complication.

Footnote 92:

Capps, J. A., and Davis, D. J.: Arch. Int. Med., 1914, xiv, 650;
Illinois Med. Jour., November, 1912.

Footnote 93:

Windsor, C. E. A.: Jour. Infect. Dis., 1912, x. 73.

Footnote 94:

Hamburger, L. P.: Jour. Am. Med. Assn., April 13, 1912, lviii, 1109.

Footnote 95:

Smillie, W. S.: Jour. Infect. Dis., 1917, xx, 45.

Footnote 96:

Levy and Alexander: Jour. Am. Med. Assn., 1918, lxx, 1827.

Footnote 97:

Irons and Marine: Jour. Am. Med. Assn., 1918, lxx, 687.

Footnote 98:

Cole and MacCallum: Jour. Am. Med. Assn., 1918, lxx, 1146.

Footnote 99:

Cummings, Spruit and Lynch: Jour. Am. Med. Assn., 1918, lxx, 1066.

Footnote 100:

Sputum or saliva cultures on 50 of these men yielded 1 positive for S.
hemolyticus. Sputum or saliva injected intraperitoneally into white
mice and cultures made from the peritoneal exudate of such mice,
yielded 2 additional positives in the same group of 50 men. These 3
positive cases showed very few colonies of hemolytic streptococci.

Footnote 101:

Per cent positive, on one culture only. Repeated throat cultures,
average two per person as follows:

Cultured No. Cases Positives Once 153 11 Twice 90 7 3 times 39 3
4 times 15 1

Footnote 102:

Steinhaus: Ziegler’s Beitr. 1901, xxix, 524.

Footnote 103:

Bartels: Virchows Arch. f. path. Anat.; xxi.

Footnote 104:

Loc. cit., p. 116.

Footnote 105:

Hart: Deutsch. Arch. f. Klin. Med., 1904, lxxix, 108.

Footnote 106:

Goodpasture, E. W., and Burnett, F. L.: The Pathology of Pneumonia
Accompanying Influenza, U. S. Nav. Med. Bull., 1919, xiii, No. 2, P.
21.

Footnote 107:

Pfeiffer: Ztschr. f. Hyg., 1893, xiii, 357.

Footnote 108:

Kamen, L.: Centralbl. f. Bakteriol., 1901, xxix, Erste Abt. 339.

Footnote 109:

Jacobson, G.: Arch. de méd. expér. et d’anat. path., 1901, xiii, 425.

Footnote 110:

Richie, J.: Journal Path. and Bacteriol., 1910, xiv, 615.

Footnote 111:

Wollstein, M.: Am. Jour. Dis. Child., 1911, i. 42.

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TRANSCRIBER’S NOTES

1. Silently corrected typographical errors and variations in spelling. 2. Archaic, non-standard, and uncertain spellings retained as printed. 3. Footnotes have been re-indexed using numbers and collected together at the end of the last chapter. 4. Enclosed italics font in _underscores_. 5. Enclosed bold font in =equals=.