Part 7

The similarity between the acute lesions of influenzal pneumonia and those following the inhalation of poisonous gases led to the prediction, in the early studies, that if the process were not terminated by death, the bronchiolar and alveolar changes would not result in a restoration of the tissue to normal, but in an organization which would in its turn bring about mechanical changes in the pulmonary tissue. This prediction has been fulfilled; obliterating bronchiolitis (Figs. XI and XLVIII), bronchiectasis (Figs. L and XII), and organizing pneumonia (47, 92, 156, 162) (Figs. XXXIX, XL, XLI, XLIV, XLV) have been encountered despite the fact that the time interval for fatalities from extraneous or subsidiary causes has been short.

Resolution of the exudate in pneumonia, with the restoration of the tissue to normal, is a result at such variance with the usual fate of an inflammatory exudate, that it has attracted a great deal of attention. Perhaps the most striking results of the study of this subject have been published recently by Kline (69). Arguing from previous experiments (70) in which it was demonstrated that the circulation of the pneumonic lung is impaired, and that for this reason sufficient serum cannot reach the exudate to inhibit the proteolytic action of leucocytic ferments, Kline introduced normal serum into the consolidated lung by the tracheal route, and showed conclusively that this resulted in an organization of the alveolar exudate. This, of course, might explain resolution, but it is difficult to see without further study how serum can reach the exudate to inhibit autolysis, and in this way stimulate organization, in one case of pneumonia and not in another.

Comparison with certain processes in other portions of the body suggest the nature of this stimulus to organization in pneumonia. For example, it is well known that epithelial necrosis of the liver that results from chloroform is followed by a restitution of the organ to normal. On the other hand, if the liver necrosis is produced by a chemical agent plus a bacterial one, the destructive lesion not only involves the liver cell, but extends to the framework of the organ and terminates in a cirrhosis. Unquestionably, the difference between the reaction after the chemical alone and that after chemical plus bacterial injury is a more extensive destruction in the latter case resulting in a stimulation of all the elements of the organ, including liver cell, connective tissue, and blood vessel. The connective tissue and vascular elements have a greater capacity to regenerate than has the liver cell; consequently, granulations form which impede the less active reparative process of the hepatic cell. If this comparison be applied to the pulmonary changes in influenza and after the inhalation of poisonous gases, it will be seen that in both processes the initial damage is extensive, as has been indicated in the discussion of necrotization. Where the lesion is superficial, tracheal, bronchial, and alveolar epithelia rapidly regenerate and restore the injured surface. Where, however, the lesions are more extensive, alveolar and bronchiolar exudates are transformed into granulation tissue, even though the epithelium may manifest unusual activity in its attempt to repair a denuded area.

VI. INFECTION AS A POSSIBLE ETIOLOGICAL FACTOR FOR MALIGNANT NEW GROWTHS

It is rare to see such activity on the part of the epithelium as that frequently encountered in influenza. The alveoli may be lined by newly formed cubical cells (Figs. IV, XI, XLVII), and mitotic figures in the injured bronchiolar lining occur in abundance. This might lead to the supposition that, if the epithelium were restricted in its path of development, it would pile up to form a typical nest, just as the epithelium at the edge of a healing chronic ulcer of the skin may pile up and extend fairly deep into the tissue. In a number of cases, epithelial proliferation has been so extensive that it could not be differentiated histologically from an invasive, malignant neoplasm (47) (Figs. XLVIII and XLIX). There is no reason to believe that malignancy might not result from the continuous stimulation of the epithelium to proliferate, in the chronic inflammatory process of the lung in influenza, just as chronic infection in the lung of a mouse results in a much higher percentage of spontaneous neoplasms of the respiratory tract in this species (132) than in those animals where chronic pulmonary inflammatory processes are uncommon. It will be interesting, indeed, to see whether, as a late manifestation, there is an increase in the number of now relatively rare epithelial new growths in the respiratory tract of man.

VII. THE BACTERIOLOGY OF INFLUENZAL PNEUMONIA

A. ORGANISMS ASSOCIATED WITH INFLUENZAL PNEUMONIA

Certain conclusions may be drawn from the literature on the bacteriology of the respiratory lesions associated with influenza. All reports show that a few organisms have been found more or less constantly in influenza and influenzal pneumonia: the pneumococcus group, the streptococci (hemolytic, non-hemolytic, pandemicus, etc.) and the Pfeiffer bacillus. They may occur alone, together, or with less frequently found organisms. Among the latter, the staphylococcus, the Micrococcus catarrhalis, Bacillus pneumoniæ (Friedlander), diphtheroids, and undetermined organisms, all have been reported (2, 48, 62, 67, 68, 92).

Another feature has been the variation of the predominating organism, or organisms, in different localities, and in the same locality at different times. For example, Wolbach (162) at Camp Devens, Massachusetts, demonstrated the Pfeiffer bacillus at autopsy in twenty-three out of twenty-eight cases. In fourteen, it was in pure culture. Keegan (67) at Chelsea, Massachusetts, also found it in eighty-two per cent of the lungs at necropsy, in thirty-one per cent of which it was in pure culture. MacCallum (92), working at Camp Lee, Virginia, found the pneumococcus, Type IV, the predominating organism and rarely the Pfeiffer bacillus. “At the Johns Hopkins Hospital similar methods revealed no influenza bacilli whatever.” At Camp Dix, New Jersey, however, MacCallum found the Pfeiffer bacillus in every case. At Camp Grant, Illinois, Hirsch and McKinney (60) state that the epidemic was due to a virulent strain of pneumococcus and that the Pfeiffer bacillus played no rôle. At the Puget Sound Navy Yard, Ely and co-workers (37) did not find the Pfeiffer bacillus; they attributed the epidemic to the hemolytic streptococcus. Goodpasture (48), working at the same hospital as Keegan, reports that the bacteria found in December, 1918, and January, 1919, were different from those found in the early months of the epidemic, inasmuch as in the latter group the hemolytic streptococcus was found in one hundred per cent of the cases and the Pfeiffer bacillus in twelve per cent. The foreign literature shows similar variations in the bacteriology.

The organisms associated with influenzal pneumonia are the so-called “mouth organisms.” They are not only found in the mouths and upper air passages of the influenza patients, but also in those of normal individuals. This points to the fact that the bacteria of the mouth have gained access to the lung, probably already injured by a primary agent, in sufficient numbers to bring about a serious inflammatory process. In this connection it is of interest to note the relatively high frequency of the mouth organisms, pneumococcus, Types III and IV, in influenzal pneumonia as compared to the less frequent mouth inhabitants, Types I and II, which are responsible for two-thirds of the cases of true lobar pneumonia (5, 45, 92, 121).

Only the eighty-two cases at the New Haven Hospital are included in the following report. Routine post-mortem cultures were taken from blood, lung, serous fluid wherever present, and exudates from the trachea and bronchi in the later cases. Blood and serous fluids were cultured into neutral infusion broth and plated on blood agar after twelve to thirty-six hours’ incubation. Lung and bronchial cultures were streaked on blood agar plates and for the last third of the series on Avery’s oleate media. Cultures were examined on each successive day and were discarded only after one week. Undoubtedly, we have failed to find B. influenzæ in many of the earlier cases because of lack of familiarity with the organism, of variations in its morphology (33), and of unsuitable culture media. The organisms tabulated below include only those determined by cultural methods; those found by direct smears or in histopathological preparations are not considered. (See Table No. I.)

B. THE RELATION OF THE TYPE OF ORGANISM TO PLEURAL INVOLVEMENT

The hemolytic streptococcus has been found frequently in association with purulent pleural effusions in influenza, Thomas (146), Stone and Swift (138), Ely et al (37); and Goodpasture (48) has suggested an etiologic relationship between the type of effusion and the infecting organism in influenza, as has been brought forward for the similar post-measles empyema in the army camps. At the New Haven Hospital the Streptococcus hemolyticus was found frequently in non-fatal empyema. However, at post-mortem examination the frequency of this organism in pleural effusions of various types was no greater than that of several other organisms, but it occurred in the only two cases of frank empyema of this series. (See Table No. II.)

C. THE RELATION OF DIFFERENT ORGANISMS TO THE TYPE OF PNEUMONIA

Various observers have emphasized the types of organism associated with different gross and microscopic manifestations of influenzal pneumonia. Pfeiffer described the peribronchial type with purulent bronchitis, from which the influenza bacillus was isolated, and the same association has been noted by MacCallum (92), Wolbach (162), Wegelin (156), Dietrich (34), and others. Opie et al (110), however, in a series from which B. influenzæ was isolated in over eighty-five per cent of the necropsies rarely found this picture. Wolbach states that the gross anatomical picture in influenzal pneumonia is similar to that following measles, from which a hemolytic streptococcus has been isolated in a high percentage of cases. MacCallum (93) classified this type as interstitial pneumonia. It is interesting to note that interstitial pneumonia has been rare in many localities where the hemolytic streptococcus has been prevalent during the past year. Stone and Swift (138) state that “despite the prevalence of the streptococcus at necropsy, only eight instances of so-called interstitial pneumonia were found in a series of fifty-five cases,” and Goodpasture (48) failed to find a single example in a series of sixteen cases. The pneumococci Types I and II, frequently encountered in the usual forms of lobar pneumonia, have been found exceptionally in this epidemic. Type II, however, has been reported (67, 107) present in about the same proportion as in true lobar pneumonia (5). Chickering and Park (25) described a series of cases of pneumonia due to the staphylococcus characterized by multiple miliary abscesses. Necrotization and abscess formation, however, have been striking features of the pathology of this epidemic, even when the staphylococcus has not been demonstrable. Recently Wadsworth (154) demonstrated experimentally that organization in pneumonia does not result from the pneumococcus or the staphylococcus alone, but only follows when both organisms are associated. On the contrary, Blanton and Irons (12) found that “there was no difference to be made out in the nature of the process caused by the streptococcus, pneumococcus, or influenza bacillus.”

TABLE I. _Post Mortem Bacteriology._ ════════════════════════════════╤════════════════════════════════ │ │ Acute Fulminating │ (34 cases) ────────────────────────────────┼──────────────────────────────── │ Trachea │ Pleural and Total │Blood Lung fluid Bronchi Cases ────────────────────────────────┼──────────────────────────────── Strep. hemolyticus │ 8 12 7 2 12 Strep. non-hemolyticus │ 7 7 Strep. “viridans” │ 0 Strep. mucosus capsulatus │ 0 Pneumococcus Type II │ 3 4 3 1 4 Pneumococcus Type III │ 4 4 3 4 Pneumococcus Type IV │ 4 6 2 3 6 Pneumococcus (Type undetermined)│ 2 3 3 B. influenzæ │ 1 4 2 5 Staphylococci │ 3 2 2 4 B. mucosus capsulatus │ 1 1 1 M. catarrhalis │ 2 1 2 Diphtheroids │ 1 1 Enterococcus │ 1 1 ════════════════════════════════╧════════════════════════════════

════════════════════════════════╤════════════════════════════════ │ │ Necrotizing │ (36 cases) ────────────────────────────────┼──────────────────────────────── │ Trachea │ Pleural and Total │Blood Lung fluid Bronchi Cases ────────────────────────────────┼──────────────────────────────── Strep. hemolyticus │ 8 9 3 1 9 Strep. non-hemolyticus │ 2 5 1 5 5 Strep. “viridans” │ 2 1 2 2 Strep. mucosus capsulatus │ 0 Pneumococcus Type II │ 3 4 1 2 4 Pneumococcus Type III │ 2 1 2 Pneumococcus Type IV │ 6 11 2 5 11 Pneumococcus (Type undetermined)│ 3 2 5 5 B. influenzæ │ 1 12 0 4 12 Staphylococci │ 1 9 3 4 9 B. mucosus capsulatus │ 2 1 1 2 M. catarrhalis │ 2 2 2 Diphtheroids │ 0 Enterococcus │ 0 ════════════════════════════════╧════════════════════════════════

════════════════════════════════╤════════════════════════════════ │ │ Organizing │ (12 cases) ────────────────────────────────┼──────────────────────────────── │ Trachea │ Pleural and Total │Blood Lung fluid Bronchi Cases ────────────────────────────────┼──────────────────────────────── Strep. hemolyticus │ 7 8 5 3 8 Strep. non-hemolyticus │ 0 Strep. “viridans” │ 0 Strep. mucosus capsulatus │ 1 1 1 1 Pneumococcus Type II │ 1 3 1 3 Pneumococcus Type III │ 1 1 1 Pneumococcus Type IV │ 1 1 1 Pneumococcus (Type undetermined)│ 0 B. influenzæ │ 1 1 2 Staphylococci │ 6 2 6 B. mucosus capsulatus │ 0 M. catarrhalis │ 0 Diphtheroids │ 1 1 1 Enterococcus │ 0 ════════════════════════════════╧════════════════════════════════

════════════════════════════════╤═══════════ │ Total All │ Types │ (82) ────────────────────────────────┼─────┬───── │ │ │ │ Per │Total│cent. ────────────────────────────────┼─────┼───── Strep. hemolyticus │ 29│ 35.4 Strep. non-hemolyticus │ 12│ 14.6 Strep. “viridans” │ 2│ 2.4 Strep. mucosus capsulatus │ 1│ 1.2 Pneumococcus Type II │ 11│ 13.4 Pneumococcus Type III │ 7│ 8.6 Pneumococcus Type IV │ 18│ 22. Pneumococcus (Type undetermined)│ 8│ 9.7 B. influenzæ │ 19│ 23. Staphylococci │ 19│ 23. B. mucosus capsulatus │ 3│ 3.7 M. catarrhalis │ 4│ 4.9 Diphtheroids │ 2│ 2.4 Enterococcus │ 1│ 1.2 ════════════════════════════════╧═════╧═════ TABLE II. _Bacteriology of Pleural Exudates._ ════════════════════════════╤══════════════════════════════════════════ │ Acute Fulminating (34) ────────────────────────────┼────────────────────────────────────────── │ │ │ │ Sero- │ Sero- fibrino- │Fibrinous fibrinous purulent Empyema Total ────────────────────────────┼────────────────────────────────────────── Strep. hemolyticus │ 1 5 2 8 Strep. non-hemolyticus │ 1 2 3 Strep. “viridans” │ 0 Strep. mucosus capsulatus │ 0 Pneumococcus Type II. │ 2 1 1 4 Pneumococcus Type III. │ 2 1 3 Pneumococcus Type IV. │ 1 2 2 5 Pneumococcus (Type │ undetermined) │ 0 B. influenzæ │ 1 1 2 4 Staphylococci │ 3 3 B. mucosus capsulatus │ 1 1 Number of cases of pleurisy │ 3 12 6 21 Percent of cases showing │ excess of Pleural fluid. │ 53% ════════════════════════════╧══════════════════════════════════════════

════════════════════════════╤══════════════════════════════════════════ │ Necrotizing (36) ────────────────────────────┼────────────────────────────────────────── │ │ │ │ Sero- │ Sero- fibrino- │Fibrinous fibrinous purulent Empyema Total ────────────────────────────┼────────────────────────────────────────── Strep. hemolyticus │ 3 2 1 6 Strep. non-hemolyticus │ 1 2 1 4 Strep. “viridans” │ 1 1 2 Strep. mucosus capsulatus │ 0 Pneumococcus Type II. │ 2 1 1 4 Pneumococcus Type III. │ 2 2 Pneumococcus Type IV. │ 5 4 2 11 Pneumococcus (Type │ undetermined) │ 1 1 2 4 B. influenzæ │ 5 4 2 11 Staphylococci │ 3 3 3 9 B. mucosus capsulatus │ 1 1 Number of cases of pleurisy │ 13 7 10 30 Percent of cases showing │ excess of Pleural fluid. │ 47% ════════════════════════════╧══════════════════════════════════════════

════════════════════════════╤══════════════════════════════════════════ │ Organizing (12) ────────────────────────────┼────────────────────────────────────────── │ │ │ │ Sero- │ Sero- fibrino- │Fibrinous fibrinous purulent Empyema Total ────────────────────────────┼────────────────────────────────────────── Strep. hemolyticus │ 1 1 3 2 7 Strep. non-hemolyticus │ 0 Strep. “viridans” │ 0 Strep. mucosus capsulatus │ 1 1 Pneumococcus Type II. │ 1 1 2 Pneumococcus Type III. │ 0 Pneumococcus Type IV. │ 1 1 2 Pneumococcus (Type │ undetermined) │ 0 B. influenzæ │ 1 1 2 Staphylococci │ 1 1 1 1 4 B. mucosus capsulatus │ 0 Number of cases of pleurisy │ 1 1 5 2 9 Percent of cases showing │ excess of Pleural fluid. │ 67% ════════════════════════════╧══════════════════════════════════════════