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.

FIG. XI. AUTOPSY NO. 140. ILLUSTRATES A LATE CHANGE IN THE BRONCHIOLE; THE EXUDATE IS BEING ORGANIZED AND THE EPITHELIAL LINING IS PROLIFERATING AND HAS INVADED THE SURROUNDING LUNG TISSUE. COMPARE FIGURESXLVIIIANDXLIX.

FIG. XII. AUTOPSY NO. 209. A SMALL BRONCHIECTATIC CAVITY FILLED WITH PUS. THE GROSS APPEARANCE IS ILLUSTRATED IN FIGUREL.

FIG. XIII. AUTOPSY NO. 96. RIGHT LUNG. A WATER COLOR DRAWING OF A GROSS LUNG IN THE ACUTE STAGE. NOTE THE SIZE OF THE LUNG, THE HEMORRHAGES ON THE PLEURAL SURFACE, AND THE BLUE AREAS OF CONSOLIDATION.

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.

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).

FIG. XIV. AUTOPSY NO. 96. LEFT LUNG. NOTE ITS SIZE AND THE PATCHY CONSOLIDATION.

FIG. XV. AUTOPSY NO. 149. ILLUSTRATES ONE OF THE MOST STRIKING EARLY PULMONARY LESIONS; THE DILATATION OF THE TERMINAL BRONCHIOLES AND THE HYALINIZATION OF THEIR EPITHELIUM. COMPARE FIGUREXVI.

FIG. XVII. AUTOPSY NO. 133. HYALINE THROMBI AND NECROSIS OF THE ALVEOLAR WALL. COMPARE FIGURESV,XV,XVIII,XIX,XXXIANDXXXII.

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).

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, mottledwith 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).

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.

As might be expected from the gross appearance, the alveoli vary in size. At times slightly collapsed and at other times overdistended, their lumina are still the seat of the inflammatory exudate, although the mechanical change may allow of some variation in the appearance of their walls. As a rule, however, the alveolar wall is prominent and owes its conspicuousness to the tortuous, engorged vessels within. These vessels contain red blood cells almost exclusively, and on account of the partial, occasionally complete, loss of the lining epithelium, the alveolar wall appears as a huge, dilated arteriole (101) separating the lakes of coagulated material in the spaces (Fig.XXIII). There are areas, as indicated above, where the alveolar content may be more definitely arranged in the form of beaded or homogeneous strands of different caliber; the smallest resemble delicate threads. They tend to converge toward the alveolar wall like wheat in a sheaf, and often pass through this wall by way of the so-called pores of Cohn; as soon as the body of the neighboring alveolus is reached, they again present a fan-like expansion into innumerable, fine strands (Fig.XXII). Where the exudate is more fibrinous, the alveolar wall is less likely to be distended, its vessels are not so prominent, and their content of red blood cells is definitely decreased. Still this is not the most extreme type of alveolar exudate met with at this stage. Perhaps, the most striking, although not the most frequent, exudate has a superficial resemblance to a huge, red blood clot, and it may be difficult to make out the alveolar walls separating the masses of well preserved red blood cells that fill the alveolar spaces. These areas are indistinguishable from infarcts and may be associated with thrombotic arteritis in near-by pulmonary vessels (47) (Figs.XXIVandXXV). Among the red blood cells an occasional strand of fibrin, a desquamated alveolar epithelial cell, and rarely a polymorphonuclear leucocyte may be encountered. The alveolar wall itself varies in the definition of its outline. When its vessels are greatly distended, when its alveolar epithelium is gone, and when its content consists largely of red blood cells, it is difficult to distinguish from the exudate which it encloses. However, when it is more compressed or when its epithelial lining cells are still more or less intact, it may be seen as a blue-staining strand under the low power of the microscope, for the well preserved nuclei lend it prominence.

FIG. XVI. AUTOPSY NO. 112. BACTERIA DEVELOP IN THE HYALINE NECROTIC EPITHELIUM OF THE TERMINAL BRONCHIOLES. HERE THEY FORM CIRCUMSCRIBED MASSES THAT SIMULATE NUCLEI. COMPARE FIGURESV,VIII,XV, ANDXVII.HELIOTYPE CO. BOSTON

FIG. XVIII. AUTOPSY NO. 155. ILLUSTRATES A MILD FORM OF PULMONARY INTERSTITIAL EMPHYSEMA.

FIG. XXII. AUTOPSY NO. 175. AN ALMOST PURE FIBRINOUS EXUDATE. THE ALVEOLAR WALLS ARE SLIGHTLY HYALINIZED AND THEIR EPITHELIUM IS ALMOST ENTIRELY LACKING.

There are, of course, variations in the extent of the serum, the fibrin, and the hemorrhage in the exudate of the alveoli, and while these different types may occur as pure forms, often they are associated. In still other areas and varying in prominence, one finds as characteristic an exudate, not only of serum, strands of fibrin, and red blood cells, but also a diffuse dotting of the exudate with bacteria, singly, in pairs, clumps, and chains (92, 164) (Fig.XXI). This type of reaction is uncommon in pulmonary disease. It resembles more closely a streptococcus cellulitis such as is encountered frequently in the subcutaneous tissues, for example, a woody phlegmon, or a sero-hemorrhagic exudate like the avirile response to a rapidly fatal hemolytic streptococcus serositis. A similar reaction has been reproduced experimentally in animals which have been rendered aplastic with benzol previous to pulmonary insufflation, and it is conceivable that the lack of polymorphonuclear response in the inflammatory exudate may be associated with some such general destruction or temporary suspension of leucocytic formation (160).

A more striking picture, however, even than this aplastic alveolar exudate appears in the terminal bronchioles. In many instances, these are conspicuous on account of their size, for they are dilated to form prominent, often irregular, sacs (Fig.XV). The distention of these terminal bronchioles may be so great that the surrounding alveoli are compressed. What makes them even more conspicuous is their lining, once epithelium, but now a swollen, thick, homogeneously staining material, with complete loss of architecture; the material forms (with hematoxylin and eosin) a red band limiting the lung tissue and sharply demarcating it from the exudate within the bronchioles (48, 92). However, this ribbon of red, often thickened by fibrin deposition, is not always pure, for bacteria thrive in the dead tissue. They occur singly, paired, in chains, and also as circumscribed, dense masses which in size and position, simulate nuclei (162) (Fig.XVI). This same hyalinization of the epithelium, it will be recalled, occurs in the larger bronchi (Fig.V), and there, too, bacteria frequently develop in the dead tissue (Fig.VIII). In the smallest bronchiolar ramifications, acute epithelial necrosis is not infrequently encountered, even when the surrounding lung tissue is relatively normal (Fig.XVI). That the process does not stop with the epithelium, but, as in the larger bronchi, may extend through the entire structure of the bronchioles, is manifest. Even the alveolar walls may be involved and frequently homogeneous pink or red bands, now the phantom of the former viable lung tissue, mark the presence of the old wall of the alveolus (Fig.XVII). Occasionally, some architecture remains in this pink ribbon and then the involvement seems to be primarily in the vessels of the wall. Not all the vessels are involved, and next to a hyaline thrombus in one, there may be fresh blood, usually red blood, in its neighbor. The alveolar epithelium is usually denuded and thus accentuates the intensity of the change.

The acute death which involves the tracheal, bronchial, and bronchiolar epithelium and which may extend beyond the epithelium into the walls of these structures and kill en masse the walls of the alveoli, is a lesion which does not occur in other types of acute pulmonary infection. However, in influenza, as after exposure to pulmonary irritating gases, it is the lesion of characterization (158,159). The effects of this change, of course, where it involvesthe alveolar wall, will vary with the extent of the process; but given an absolutely necrotic wall, as yet unstrengthened by inflammatory reaction, an expected result would be its rupture with respiratory movement. The point of rupture is important, but where so many alveoli are involved, disturbance of continuity will occur, occasionally in such position that the result will be the escape of air into the interstitial tissues.[7]There is ample evidence that this happens. Indeed, among the clinical manifestations of the disease, interstitial emphysema of the lung spreading through the fascial planes to the subcutaneous tissues of neck and thorax is well known; the phenomenon is more frequent and extensive in influenza than in any other disease (8, 17, 52, 143).

Interstitial emphysema is very striking at the post-mortem table. The escaped air appears as beads along the interlobular septa, but on account of their size they are always most conspicuous between the lobes and along the vessels toward the hilum (162) (Fig.XVIII). Histologically, a small bubble of escaped air confined to the interlobular septum compresses the surrounding tissue with almost complete atelectasis of many neighboring alveoli (Fig.XIX).

The diffuse involvement of all the lung tissue, chiefly with a serous exudate in the subpleural, interstitial, perivascular, and peribronchial tissues, as well as in the alveoli, is associated with other elements which occur in aplastic reactions; red blood cells, fibrin, and bacteria. Added to the aplastic exudate is an acute necrosis of bronchial and alveolar epithelium involving at times the walls of these structures; consequently, the histology of this disease is almost as specific as that of any biological reaction.

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