Part 2

There is considerable evidence to support the view that the disease spreads from bronchus to bronchus, and in keeping with this view, various stages in the inflammatory processes are more readily determined in these smaller structures than in the trachea. Furthermore, it must be emphasized that even the mildest and the most extreme of these stages are not infrequently encountered in the same lung. The earliest lesion is manifested by an increased homogeneity of the protoplasm of the epithelial lining of the bronchus. The cell protoplasm loses its normal granulation and the nucleus, somewhat darker than usual, becomes conspicuous on a red base (Fig. V). In the lumen of such a tube a serous exudate, perhaps mixed with mucus, is encountered, and there is some spreading apart of the surrounding muscular tissue with engorgement of the vessels. This picture merges gradually into one where the epithelium appears as a homogeneous, red-staining ribbon, devoid of nuclei, often exfoliated, in part at least, from the underlying submucosa (92). The change is traceable through the larger bronchi, even to the ducti alveolares, and not infrequently, bacteria, either as a diffuse, minute dotting or in the form of circumscribed, colony-like formations, are spread through the red, ribbon-like strand (Fig. XVI). With the exfoliation of the epithelial lining, the submucous vessels become more and more conspicuous and may bulge into the lumen of the tube (Fig. VI). That they actually weep into the lumen is proved by the presence of red blood cells in the exudate, now rich in mucus, broken-down nuclei, and desquamated cells. The necrotizing process may not extend deeper than the epithelial lining as is the status described above (140, 162), but it also frequently involves the underlying submucous and muscular layers, so that these lose their identity and stand out as homogeneous masses, in which fragmented nuclei and bacterial accumulations are prominent. Such deeper necrotizing areas may be focal (Fig. VII), or may involve the entire circumference of the tube (Fig. VIII). Occasionally, the epithelium, now dead and staining homogeneously, is lifted from the underlying submucosa in the form of a blister (66), and has very much the same appearance as the well known, early reaction which follows the application of croton oil to the rabbit’s ear. Where this occurs, the submucosa is less involved, as though the necrotizing agent had not penetrated to the same depth and the serous reaction beneath were actually a beneficent exudate. These blisters are in contrast with the deeper areas where the fibrinous mass, mixed with the dead tissue, forms an intensely staining ring or band, which extends through the bronchiolar wall even to the surrounding alveoli.

In the early stage of this process one of the most outstanding features is the absence of polynuclear leucocytes in the reactionary process, but gradually as the dead tissue sloughs away, these cells wander into the exudate and form a purulent ring, more intense in the lumen, but extending for a variable distance through the still viable wall of the structure (47) (Fig. IX). Later mononuclear cells accumulate in this wall and occur either as a diffuse mottling or as circumscribed foci in the muscle and submucous layer of the bronchiole, just as they do in the trachea. Occasionally, a striking change is found in a small bronchiole within a portion of the lung which is otherwise uninvolved by an inflammatory process. Perhaps the alveoli were the seat of a change which has subsided, but, whatever the history, the purulent mass in the bronchiole and involving its wall, stands out effectively (Fig. X).

Sooner or later, with the subsidence of the irritating agent, repair begins in the bronchus or bronchiole. If its walls have been destroyed and the lesion has extended into the surrounding alveoli to form an abscess of greater or lesser extent, or if the necrotizing process has been superficial and confined to the epithelium in large part, the reparative process is very much the same. Mitotic figures in the fibroblasts and in the endothelial cells of the capillaries abound in the young granulations (Fig. XI). However, the granulation tissue does not have an unrestricted path of growth, for if a remnant of epithelium remains, this is stimulated to grow probably in this disease as in no other. Mitotic figures are common and the young epithelial cells stretch across the denuded submucosa or granulation (Fig. XLVIII) and extend downward into the surrounding alveoli, not only as strands, but also as solid nests of cells (47) (Fig. XLIX). The bronchioles, therefore, show changes dependent upon the extent of the damage suffered by their walls. The vast majority, in all probability, will be restored; but if the wall has actually been necrotized, the bronchioles may be converted into small, saccular, bronchiectatic cavities (48, 110, 162) (Figs. XII and L), or obliterating bronchiolitis may result from the organization of the exudate within their lumina (82) (Fig. XI). The importance of the epithelial proliferation cannot be ignored; in many cases, it invades the surrounding lung tissue and a typical, histological picture results—an infiltrating, malignant, epithelial neoplasm (Figs. XLVIII and XLIX).

_Summary._

The lesions of the trachea and of the larger bronchi, even though they persist in their acute form for a period of weeks, are superficial and do not lead to extensive or deep scarring. In contrast to the larger respiratory passages, that portion of the bronchial tree which is not supported by cartilaginous rings becomes more and more intensely involved, not only on its surface, but in its deeper structures, and the changes in the bronchioles and the neighboring air sacs are among the more characteristic anatomical manifestations in this disease. Therefore, while it will be unnecessary to refer again to the larger air passages, further consideration of the smaller ones, which are constantly associated with the lesions of the pulmonary parenchyma, will be included in the subsequent discussion of the pulmonic involvement.

B. LESIONS OF THE LUNG

In the prosecution of the scientific study of any disease, the great temptation is to differentiate its various manifestations with the intention of elaborating a classification. While there may be more or less distinct types of pulmonary involvement in influenza, so many intermediary forms appear in an extensive series of cases, that any classification must necessarily be arbitrary. Here, such an attempt at classification is beset with unusual difficulty, because, in the vast majority of cases which come to anatomical observation, the disease is fulminating. The lesions are more uniform in character than in an experimental study where the material is arranged so as to include intermediary and chronic stages, which in man are only encountered when accident causes death. These gaps in the study cannot be supplemented with experimental observations, because attempts to reproduce this disease have failed, even in human subjects. From the literature it appears also that variations in the extent, and perhaps in the maturation, of the anatomical involvement may be represented in different proportions for different localities (1, 2, 17, 55, 92, 162). Therefore, no sharp differentiation may be drawn between the more or less definite stages which are seen at the post-mortem table; still, for convenience of description, certain of the lesions which occur more frequently and are more widely differentiated may be considered separately.

The disease, as has been indicated, may be confined to the bronchial tree. In these circumstances, it is almost necessary to suppose that the larger bronchi alone are involved. When the delicate bronchioles are affected, there is always a more or less extensive involvement of the pulmonary parenchyma (124), for the bronchioles have a more direct communication with the alveoli, and their walls present a less formidable barrier to the extension of the inflammation to the surrounding air sacs.

Clinically, there is reason to believe that the disease may begin with a period of general malaise, during which the respiratory symptoms may be more or less severe. In the fulminating cases, the malaise may be associated from the beginning, not only with a tracheobronchitis, but also with pulmonary involvement. In less severe types the malaise may be accompanied only by tracheobronchitis, and may present no symptoms referable to the pulmonary parenchyma; there may follow or not, a definite period of clinical improvement, after which pneumonic involvement becomes evident. However, even where a fulminating type of the disease is not associated with clinical evidence of pulmonary involvement, the post-mortem examination may show extensive change in the lung parenchyma (110).

Whether this grouping of the disease is correct or is based upon a fallacious deduction from more or less satisfactory clinical histories, is open to question; and a decision may be reached from comparison of the opinions based upon carefully observed cases treated in different institutions. From the report of the epidemic at the Johns Hopkins Hospital (Bloomfield and Harrop (14)), where two hundred sixty-eight cases were studied in which the complication of pneumonia was uncommon as compared with cases in other hospitals—the New Haven Hospital, for instance—and where the percentage of the deaths was low, the conclusion was reached that the disease is primarily a general one and that the pulmonary involvement is secondary, just as in an exanthem, like measles. By way of comparison, at the New Haven Hospital, where more than eleven hundred patients with influenza were observed, the type of disease described by Bloomfield and Harrop was relatively rare. Of course, there were cases of that type where general malaise, with or without respiratory symptoms, was followed by a period—usually of from two to three days—of definite improvement in the symptoms; and later extensive and serious pulmonary complications ensued. However, in another group, largely composed of individuals who entered the hospital seriously ill, the histories indicate an acute onset resembling that of lobar pneumonia and with early manifestations of pulmonary involvement (2, 17, 52, 145). This discrepancy, probably, may be explained in part by variations in the sensitivity to minor indisposition on the part of the different individuals.

The preceding review should aid in the correlation of the clinical types of the disease with the respiratory lesions. All pulmonary lesions, from the least to the most localized, may be explained either by a subsidence of a less acute initial and diffuse involvement of the parenchyma, or by a less rapid and progressive spread of the necrotizing and inflammatory process from the upper respiratory tract through the bronchioles to the alveoli. This conception does not take into account the significance of the period of malaise, interpreted by the clinician as the period of invasion, but attempts to correlate the respiratory symptoms with the pulmonary lesions and their etiology.

Our own experience, like that of other observers (26, 104, 162), is that all fatal cases of this disease show pulmonary involvement in the form of pneumonia. The lesion varies greatly in intensity and in the amount of pulmonary tissue affected. In the descriptions which follow, the more diffuse and intense processes will be discussed first, and later those in which the inflammation localized and terminated in pseudolobar, lobar, lobular, or peribronchial pneumonia.

(1) ACUTE DIFFUSE FULMINATING TYPE OF PNEUMONIA

The majority of influenzal deaths have been examples of this acute type. Out of ninety-five cases, the total number studied, forty-four belong to this group in which the average duration of illness was nine days. They form the basis of the description which follows.

_Gross Picture._

A striking feature of the external examination of the body is the intense rigor which involves all the muscles and is broken only with difficulty (78). This is associated with a rapid settling of the unclotted blood in the dependent parts which gives them an intense blue or bluish-purple color. The erythema of the skin which has been described clinically is not recognizable at the post-mortem table. There is, however, cyanosis of the face which reaches an intensity explained by the fact that this disease so often affects healthy, well nourished, muscular individuals. In a few instances the cyanosis is more extensive and gives a plum color to the entire body. All the mucous membranes share in the intense congestion and discoloration of the face. Slight jaundice is common, but marked variations in intensity occur. The external nares and the lips are almost invariably covered with blood-stained crusts. Even in the decubitus position, a thin, sanguinous fluid tends to escape in large quantities from the nose and mouth. The large veins of the neck are usually prominent, and the chest voluminous.

Distinct splanchnic engorgement is evident as soon as the peritoneal cavity is opened. The liver extends below the costal margin and is dark in color, but otherwise the abdominal cavity presents nothing characteristic of the disease. The diaphragm does not extend as high as usual, and the pleural cavity almost invariably contains an excess of fluid. Usually the quantity is small, but, on the other hand, it may be considerable, and in twenty-one of the forty-four cases the fluid exceeded one hundred cubic centimeters. The turgidity of the mediastinal tissues varies somewhat in degree (27). Generally the pericardial sac is smooth and glistening on both visceral and parietal surfaces; the pericardial fluid is not materially changed. Frequently (seventy per cent) there is dilatation of the right side of the heart (138, 141, 157), but aside from an occasional small endocardial or subepicardial hemorrhage (90, 108, 156), there are no lesions of consequence in the heart attributable to this disease[5] (162).

The lungs are extremely voluminous (12, 17) due in part to an accumulation of liquid within them. This finds its way into the trachea and completely fills the latter structure with blood-stained, syrupy fluid, with purulent material, or with a mixture of these (2, 90, 107, 157, 162). At first the pleural surface is smooth and often quite even, but on closer inspection, a minute granulation is suggested. In many cases even close examination does not allow the conclusion that an exudation of anything but serum has occurred through this membrane, except in localized foci. These foci more frequently involve the interlobar pleura and that of the lower lobes (112, 143). The volume of the lungs, often great enough to obliterate the pericardial area, is one of the two most characteristic features of the external examination. The other feature is their color. Small, bright red hemorrhages may occur anywhere. The larger patches are the most striking. Violet, purple, or dark brown areas, irregular in shape and distribution, are more frequently found on that portion of the pleura over the lower two-thirds of the lung. Between the deeply colored zones, there are pale pink areas which involve the lowermost edge to the least degree, the anterior margin somewhat more, and the apex of the lung most of all. The darker portions just referred to may project above the surface and may be circumscribed, resembling huge, fresh hemorrhagic infarcts (41, 108). The alveolar walls are not seen through the pleural surfaces in these darker zones. The pale pink areas, usually at the level of the more intensely colored zones, may be elevated and the dilated air sacs are distinctly made out through the pleura (Fig. XIII). At the hilum, the lymph glands are large and soft. When cut, fluid escapes and is often blood-stained. The cross section may present a distinct, diffuse, hemorrhagic appearance (162). At the hilus, too, the lymphatics, distended here and there over the surface of the pleura, are most affected. The congested bronchial mucous membrane and the exudate in these structures has been described.

After removal, the lung retains its shape, but is more flaccid than the consolidated lung of lobar pneumonia. It cuts with very little resistance and immediately a large amount of a syrupy, pink fluid escapes and obscures the entire area. With the fluid scraped away, the variations in the consistency of the lung become visible. The pale areas around the borders and chiefly at the apex in which the air sacs are discernible with the naked eye, sink slightly below the remainder of the surface, and the pleural edge inverts. The individual lobules of the lung in these areas are more conspicuous than normal, because the interstitial tissue bearing the lymphatics and vessels, as well as that around the bronchi and larger blood vessels, does not lose its edematous appearance as quickly as the alveoli (40, 92, 110, 164), and, consequently, these grey lines and points stand up somewhat more prominently.[6] In contrast with the paler areas which are prone to slight collapse, the remainder of the cross section retains its more smooth and even surface. The alveolar walls are not distinctly made out, but the terminal bronchioles often make themselves evident by the nature of the material which is within and by their distinct dilatation (1, 67, 110, 149, 162). The more firm areas stand out, too, on account of their difference in color. The scheme is not unlike that seen on the pleural surface, and while dark, almost black, infarct-like areas occur on the cut surface, the solid areas are more likely to be translucent, dull, light red, brown or even grey. They have a surface similar to a very fresh, tuberculous, gelatinous pneumonia, but the color differs from the cloudy grey of the latter on account of the admixture of blood in the exudate and the great congestion of the vessels (Fig. XIV).

_Summary._

The well developed post-mortem muscular rigidity, the lividity of the dependent parts, of the face with its mucous membranes, and often of the trunk, the jaundice variable in extent, the crusts of blood on the nares and mouth, and the splanchnic dilatation are features which prepare for the gross picture presented by the thoracic organs. The increased moisture within the pleural cavities associated with the even, translucent pleural surface, whose dilated lymphatics become more and more prominent towards the hilum, the large succulent lymph glands, and the exudate in the bronchial tree, are all striking, but more characteristic of the gross picture, is the great increase in volume of the lung itself, mottled with brilliant colors. The lung, too, is very wet and on section, after the syrupy, blood-stained fluid escapes from the less definitely consolidated zones, the latter appear, not as the usual granular, firm areas of hepatization, but have more the consistency of a gel, and also its translucence. Characteristic of this disease as these changes may be, the specificity of the fundamental lesion in the respiratory tract, becomes more emphatic after study of its histology (92, 162).

_Histological Picture._

No matter what the portion of the lung from which the sections are derived, the fundamental changes found are the same. The subpleural sheets are spread wide apart, now by empty spaces, now by coagulated fluid. The process extends from the surface through the interlobular septa (Fig. XX), and is accentuated where the connective tissue is more prominent around vessels and bronchi. The nature of the infiltrate in the subpleural and interstitial tissues becomes more evident in the alveoli, which likewise are filled. The material varies somewhat in appearance, probably dependent upon its proteid content. Not infrequently the alveoli contain a homogeneous, pink-staining mass, which resembles the colloid of the thyroid gland. Again, it may be simply a coarse granular precipitate (Fig. XXIII), and in still other instances, small sticks and strands form the bulk of the alveolar content (47, 92, 140, 156). This subpleural, interstitial, perivascular, peribronchial, and alveolar edema, which is a term applicable to this collection of fluid, is very prominent, and although its intensity varies in different portions of the lung; and although it may be replaced in some areas by other types of exudate, unquestionably, this is the dominating expression of the inflammatory process in the early stage of the disease.