The Project Gutenberg EBook of The pathology of influenza, by M. C. Winternitz and Isabel M. Wason and Frank P. McNamara This eBook is for the use of anyone anywhere in the United States and most other parts of the world at no cost and with almost no restrictions whatsoever. You may copy it, give it away or re-use it under the terms of the Project Gutenberg License included with this eBook or online at www.gutenberg.org. If you are not located in the United States, you'll have to check the laws of the country where you are located before using this ebook. Title: The pathology of influenza Author: M. C. Winternitz Isabel M. Wason Frank P. McNamara Release Date: February 24, 2019 [EBook #58960] Language: English Character set encoding: UTF-8 *** START OF THIS PROJECT GUTENBERG EBOOK THE PATHOLOGY OF INFLUENZA *** Produced by Richard Tonsing and the Online Distributed Proofreading Team at http://www.pgdp.net (This file was produced from images generously made available by The Internet Archive) PUBLISHED ON THE FOUNDATION ESTABLISHED IN MEMORY OF ANTHONY N. BRADY FIG. I. AUTOPSY NO. 99. ACUTE HEMORRHAGIC AND ULCERATIVE LARYNGOTRACHEITIS. THE PATHOLOGY OF INFLUENZA BY M. C. WINTERNITZ, ISABEL M. WASON AND FRANK P. MCNAMARA FROM THE BRADY LABORATORY OF PATHOLOGY AND BACTERIOLOGY, YALE UNIVERSITY SCHOOL OF MEDICINE AND THE NEW HAVEN HOSPITAL NEW HAVEN YALE UNIVERSITY PRESS LONDON · HUMPHREY MILFORD · OXFORD UNIVERSITY PRESS MDCCCCXX COPYRIGHT, 1920, BY YALE UNIVERSITY PRESS The present volume is the fourth work published by the Yale University Press on the Anthony N. Brady Memorial Foundation, which was established June 15, 1914, by members of the family of the late Anthony N. Brady to enable the University to declare operative the agreement for an alliance between the New Haven Hospital and the Yale School of Medicine. In addition to the pledge of endowment for this purpose, the donors erected for the University on the grounds of the Hospital a clinical and pathological laboratory, and have since, through additional gifts to supplement the income of the Memorial Foundation, made possible the publication of this and other works by members of the faculty of the School of Medicine at Yale. Our grateful acknowledgment is due the Staff of the New Haven Hospital, especially the members of the Department of Medicine, for their hearty co-operation and for the use of the clinical notes. We also wish to thank the members of the Medical Corps of the United States Army who were stationed at the Yale Army Laboratory School while the work was in progress and who aided in many ways:—Colonel Charles F. Craig, Captain R. A. Lambert, Lieutenants C. A. McKinlay, Frederick Parker, Jr., Ellis Kellert, Henry R. Muller, and J. H. Globus. TABLE OF CONTENTS Page Introduction 9 I. The Pathology of the Respiratory Tract in Influenza 13 (A) Lesions of the Trachea and Bronchi 13 (a) Gross Picture 13 (b) Histological Picture 14 (c) Summary 16 (B) Lesions of the Lung 16 (1) Acute Diffuse Fulminating Type 18 (a) Gross Picture 18 (b) Summary 19 (c) Histological Picture 20 (d) Summary 22 (2) Localization and Necrotization of the Pneumonic Process 22 (a) Gross Picture 22 (b) Histological Picture 24 (c) Summary 26 (3) Organization of the Bronchiolar and Pneumonic Processes 26 (a) Illustrative Protocols 27 (b) Summary 30 II. Influence of the Respiratory Complications of Influenza upon Tuberculosis of the Lung 32 (a) Illustrative Protocols 32 (b) Summary 33 III. Extrarespiratory Lesions in Influenza 34 (A) Lesions of the Hematopoietic System 34 (a) Lymphadenoid Tissue 34 (b) Spleen 35 (c) Bone Marrow 35 (B) Lesions of the Blood Vessels and Elsewhere in the Body 36 (a) Vascular System 36 (b) Skeletal System 36 (c) Parenchymatous Organs 36 (d) Alimentary Canal 37 (e) Urinary Bladder 37 (C) Miscellaneous Lesions 38 (a) Parenchymatous Organs 38 (b) Jaundice 39 (c) Central Nervous System 39 7 (d) The Pregnant Uterus 39 (e) Summary 39 IV. A Comparison between the Respiratory Lesions of Influenza and those Initiated by the Inhalation of Poisonous Gases with Special Reference to:— 40 (A) The Inflammatory Response versus the Systemic Capacity to Compensate 40 (B) The Primary Injury 41 (C) The Tendency to Organization of Bronchiolar and Alveolar Exudates with Bronchiolitis and Bronchiolectasis as Sequelæ 42 (D) The Importance of the Trachea and its Ramifications as a Protective Mechanism against Infection of the Pulmonary Parenchyma 42 V. Peculiarities of the Histology of Influenzal Pneumonia 44 (A) The Extent of the Initial Pulmonary Lesion 44 (B) The Hemorrhagic Exudate—The Relation of Red to Grey Hepatization 44 (C) The Aplastic Exudate 45 (D) The Hyaline Necrosis of the Pulmonary Tissue 46 (E) The Organization Process 46 VI. Infection as a Possible Etiological Factor for Malignant New Growths 48 VII. The Bacteriology of Influenzal Pneumonia 49 (A) Organisms Associated with Influenzal Pneumonia 49 (B) The Relation of the Type of Organism to Pleural Involvement 50 (C) The Relation of Different Organisms to the Type of Pneumonia 50 (D) Summary and Discussion 54 VIII. Conclusions 55 IX. Bibliography 56 X. Illustrations 63 FIG. II. AUTOPSY NO. 98. DRAWING OF A SECTION THROUGH A TRACHEA SHOWING NECROTIZING HEMORRHAGIC INFLAMMATORY PROCESS OF THE MUCOSA. 8 INTRODUCTION The epidemic of influenza, prevalent in Europe during the Great War, was watched with interest everywhere, not only because of its military importance, but also because of the danger of its spreading to other continents. The prediction that this would occur, made months before its realization, was verified on an even larger scale than had been anticipated, for in the autumn of 1918, this acute respiratory infection passed over the United States like a huge wave, taking a tremendous toll in human lives; later smaller waves followed leaving in their wake corresponding degrees of devastation. The first cases of the disease appeared on the New England coast, and New Haven was among the cities to be early invaded, though here the epidemic was somewhat less severe than in other cities along the Atlantic Seaboard. Forewarned and alert to the danger, medical men spared no effort in studying the disease; as a result, no malady, perhaps, has ever been investigated so intensively and from so many different points of attack in an equal length of time. Proof of this appears in the abundant literature issuing from every quarter. Among the various contributions to this subject, many include the anatomical changes associated with the disease. In general, however, these are brief; and although they serve their special purpose well, they have not been elaborated sufficiently to close the chapter. During a period of about three months beginning with September 18, 1918, while the epidemic raged and waned in New Haven, there were approximately eleven hundred cases of the disease admitted to the New Haven Hospital. As is so often true, only the more critically ill sought hospital care, and few, if any, patients affected by other respiratory infections are included in these statistics. The mortality here, as elsewhere, was very high; of two hundred eighty (280) cases that ended fatally, eighty-two (82) were investigated at the post-mortem table. An attempt was made to make the studies very complete, and this was favored since the headquarters of the Yale Army Laboratory School, under the command of Colonel Charles F. Craig, were located at the Brady Laboratory where a large number of men were being instructed in Pathology and Bacteriology. It was also fortunate that competent illustrators were available who made a splendid series of water-colors and drawings of the characteristic lesions, both gross and microscopic. The number of autopsied cases at the New Haven Hospital was augmented by a series of acute fatalities from the same disease at the United States General Hospital No. 16, at Allingtown, West Haven, where the anatomical studies were carried on by the same group of men. The latter autopsies offered nothing new, but served to corroborate the conclusions reached at the New Haven Hospital. The majority of the fatalities occurred in the acute stage of the disease, the anatomical aspects of which have been elaborated more or less completely.[1] Other cases survived for a longer period and in these, anatomical changes existed, which, as will appear later, were prognosticated from the acute lesions. Moreover, these findings suggested that certain progressive anatomical changes occur even when the disease runs a much less severe clinical course; for example, in cases where respiratory symptoms persist for a long period before they are brought to a fatal conclusion. History, too, suggests such a chain of events; namely, in the record of the delayed crop of respiratory disorders that followed the harvest of the epidemic of ’90. Previous studies of experimental pneumonia in normal and aplastic animals by one of the authors (160) give a background for the interpretation of the histology of some phases of this disease, but more important are the studies of the respiratory inflammatory processes initiated by the inhalation of toxic gases. This subject, introduced into human Pathology with the use of poisonous gases in modern warfare, necessitated elaborate investigations which have just been concluded (159). The pathology produced by the inhalation of these poisonous vapors is analogous to that found in influenzal pneumonia. This is said with a full comprehension of the criticism that may follow such a statement, and with the knowledge that a similar analogy has been drawn between influenzal and plague pneumonia (Symmers, 141). It is, however, a criticism that is welcomed and which will be met in the body of the paper. For the reasons just cited, it has seemed desirable to contribute to the Pathology of various phases of influenzal pneumonia and to attempt to correlate this with other types of acute respiratory inflammation, in the hope that the prognostications which suggest themselves may be of aid in the prophylaxis and possibly in the treatment of the more insidious and progressive pulmonary changes that may follow this disease. A large part of the text is devoted to a description of the gross and more minute pathology of the respiratory tract associated with influenza and its complications, both in the acute and in the subacute or chronic stages. Incidental lesions of less importance in other portions of the body that have occurred in these cases are presented briefly, and emphasis is placed upon a number of special subjects. The order of discussion will be as follows:— I. The Pathology of the Respiratory Tract in Influenza. (A) Lesions of the Trachea and Bronchi. (B) Lesions of the Lung. (1) Acute Diffuse Fulminating Type. (2) Localization and Necrotization of the Pneumonic Process. (3) Organization of the Bronchiolar and Pneumonic Processes. 9 10 II. Influence of the Respiratory Complications of Influenza upon Tuberculosis of the Lung. III. Extrarespiratory Lesions in Influenza. (A) Lesions of the Hematopoietic System. (B) Lesions of the Vascular System, Parenchymatous Organs, Alimentary Tract, and in the Walls of Other Hollow Viscera. (C) Miscellaneous Lesions. IV. Comparison between the Respiratory Lesions of Influenza and those Initiated by the Inhalation of Poisonous Gases with Special Reference to:— (A) The Inflammatory Response versus the Systemic Capacity to Compensate. (B) The Primary Injury. (C) The Tendency to Organization of Bronchiolar and Alveolar Exudates with Bronchiolitis and Bronchiolectasis as Sequelæ. (D) The Importance of the Trachea and its Ramifications as a Protective Mechanism against Infection of the Pulmonary Parenchyma. V. Peculiarities of the Histology of Influenzal Pneumonia. (A) The Extent of the Initial Pulmonary Lesion. (B) The Hemorrhagic Exudate—The Relation of Red to Grey Hepatization. (C) The Aplastic Exudate. (D) The Hyaline Necrosis of the Pulmonary Tissue. (E) The Organization Process. VI. Infection as a Possible Etiological Factor for Malignant New Growths. VII. The Bacteriology of Influenzal Pneumonia. (A) Organisms Associated with Influenzal Pneumonia. (B) The Relation of the Type of Organism to Pleural Involvement. (C) The Relation of Different Organisms to the Type of Pneumonia. (D) Summary and Discussion. VIII. Conclusions. IX. Bibliography. X. Illustrations. FIG. III. AUTOPSY NO. 90. DRAWING FROM A LESION OF THE TRACHEA (SOMEWHAT OLDER THAN THAT ILLUSTRATED IN FIGURE II). THE MUCOSA IS ENTIRELY LACKING. CONGESTION AND EDEMA ARE THE STRIKING FEATURES IN THE SUBMUCOSA. THE NECROTIZING PROCESS HAS EXTENDED INTO THE MUCUS GLANDS. THIS IS SHOWN IN THE LOWER PICTURE. FIG. IV. AUTOPSY NO. 205. CONGESTION AND EDEMA OF THE SUBMUCOSA AND REGENERATION OF THE TRACHEAL EPITHELIUM. FIG. VII. AUTOPSY NO. 94. A NECROTIZING PROCESS LIKE THAT OF THE TRACHEA ILLUSTRATED IN FIGURE II. HERE IT IS SHOWN TO INVOLVE THE WALL OF THE BRONCHIOLE. FIG. V. AUTOPSY NO. 95. AN EARLY LESION OF THE BRONCHIOLE CHARACTERIZED BY HYALINIZATION OF THE EPITHELIUM AND SEROUS EXUDATE IN THE LUMEN. FIG. VI. AUTOPSY NO. 103. ILLUSTRATES ANOTHER EARLY BRONCHIOLAR LESION. THE EPITHELIUM IS LACKING, THE CONGESTED VESSELS OF THE SUBMUCOSA PROTRUDE INTO THE LUMEN WHICH CONTAINS DESQUAMATED EPITHELIUM, MUCUS, AND RED BLOOD CELLS. PATHOLOGY OF INFLUENZA THE PATHOLOGY OF THE RESPIRATORY TRACT IN INFLUENZA If the atrium of an infection and its specific etiological agent are undetermined, the narrator of the pathology of a specific disease is confronted immediately with serious obstacles in the elaboration of a complete picture. Some writers assume that the respiratory tract is the portal of entry in influenza (162), though the specific agent is still unknown.[2] Whatever the agent, unquestionably it attacks the respiratory tract at a very early stage in the disease and produces a lesion which becomes responsible for the most serious aspect of influenza, whether this phase be primary or only a complication. Among the lesions which will be considered, therefore, those of the respiratory tract chiefly will be emphasized. They include the changes in the large air passages, as well as the pulmonary, alveolar, and interstitial involvement. Unquestionably, a very close association exists between the lesions of the larger air passages and those of the alveoli, but probably it is equally true that the former may occur alone; in many instances also they are the forerunners of the latter lesions. Consequently, it seems logical to begin with an exposition of the lesions in the trachea and its ramifications, including the bronchioles. 13 A. LESIONS OF THE TRACHEA AND BRONCHI Gross Picture. Early in the disease the congestion and the hemorrhages that have been described in the mucous membrane of the nasopharynx (14 and 94) are also conspicuous features in the lining of the trachea and bronchi (Fig. I). This membrane is swollen, turgid, red, and covered by a copious, mucous exudate which may be clear, but much more frequently is blood-stained or opaque and yellowish in color. The blood, variable in amount, may be fresh and red; and after the mucous exudate on the surface is removed, more intense red foci stand out on the congested base (47, 90, 157). Frequently, as the bronchi are approached, the red color of the mucosa becomes more intense and may have a garnet tinge. Membranes such as are encountered in the more usual necrotizing inflammatory processes, like diphtheria, have not occurred in the trachea and larger bronchi in this series (108, 128, 157).[3] The exudate peels off readily, and as indicated above, leaves a velvety red surface, dotted here and there with darker or more intensely red foci. Small ulcerations of the mucosa occur, but are inconspicuous (82, 156). As the finer ramifications of the bronchi are approached, the accumulation of the exudate in their lumina becomes more and more marked, and on cross section of the lung, they often stand out conspicuously on account of their increased size and projecting, seromucous, blood-stained content (101, 149, 162). It is remarkable how long this picture in the trachea and bronchi may persist without showing any marked variation. It is encountered, not only in the most acute and fulminating types of the disease (that have been examined), but a similar picture may be present in cases which end fatally only after a period of weeks of severe illness. In the latter cases, however, the exudate, particularly in the bronchioles, assumes a more purulent character and after this accumulation is wiped away from the surface of the tube, the intensity of the dark red color of its lining membrane presents an even more striking contrast on account of the opaque, yellowish-green exudate in the lumen. At this stage, too, the bronchioles are more distended with pus, which oozes from each one when the lung is sectioned (1, 108, 110). In the cases still more chronic, the terminal bronchioles may be sharply outlined with a thick grey wall which surrounds the dilated opening from which the accumulated yellowish exudate oozes as soon as the pressure is relieved (Figs. XXXIX and XL). Histological Picture. The changes are less marked, perhaps, in the trachea than in its finer ramifications. The mucosa is constantly more or less destroyed and large areas, usually focal, are entirely devoid of their epithelial covering. This is replaced by a sparse exudate, composed largely of red blood cells, mucus, a small amount of fibrin, and nuclear fragments (Fig. II). It may dip into the submucosa for a short distance, but usually these indentures are associated with the ducts of the mucous glands into which the inflammatory reaction extends. A more striking feature than the exudate, however, is the edema and the congestion of the submucosa. The loose areolar tissue of the submucosa is spread widely apart, and throughout it distended blood vessels are very conspicuous. Occasionally such a vessel is broken and actual hemorrhage appears in the submucosa. Occasionally, too, the inflammation extends down the duct to the mucous gland itself, and here, also, aplastic inflammatory reaction is evident, inasmuch as the acini now stain intensely red with the cells undifferentiated from each other and specked here and there by broken remains of the dead nuclei (Fig. III). After the disease has continued for a short period, even at the end of five or six days, some regeneration of the epithelial lining may be seen (3) (Fig. IV). But despite this, the acute picture persists, and there goes on, side by side, an attempted repair characterized by epithelial regeneration and the same evidence of acute change. Since the lesion is essentially a superficial one, scars or contractures of any extent are not encountered in the trachea, even in examples of the disease that have ended fatally only after many weeks.[4] FIG. VIII. AUTOPSY NO. 97. ALTHOUGH THE EPITHELIUM IS STILL VISIBLE AS A HYALINE BAND LIFTED FROM THE UNDERLYING MUCOSA, BOTH MUCOSA AND SUBMUCOSA ARE INVOLVED IN A NECROTIZING PROCESS. BACTERIA ARE ABUNDANT IN THE DEAD TISSUE. FIG. IX. AUTOPSY NO. 105. THE NECROTIC EPITHELIUM IS INVADED BY POLYMORPHONUCLEAR LEUCOCYTES AND THESE, AS WELL AS ROUND CELLS, CAUSE A THICKENING OF THE BRONCHIOLAR WALL. 14 FIG. X. AUTOPSY NO. 106. THE SMALL BRONCHIOLE IS FILLED WITH PUS CELLS, WHICH, IN SOME PLACES, EXTEND THROUGH ITS WALL. 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. 15 16 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 FIGURES XLVIII AND XLIX. FIG. XII. AUTOPSY NO. 209. A SMALL BRONCHIECTATIC CAVITY FILLED WITH PUS. THE GROSS APPEARANCE IS ILLUSTRATED IN FIGURE L. 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 17 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. 18