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PUBLISHED ON THE FOUNDATION ESTABLISHED IN MEMORY OF ANTHONY N. BRADY

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

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

(a) Parenchymatous Organs 38 (b) Jaundice 39 (c) Central Nervous System 39 (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

(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

(D) Summary and Discussion 54

VIII. Conclusions 55

IX. Bibliography 56

X. Illustrations 63

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.

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.

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.

(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.

(D) Summary and Discussion.

VIII. Conclusions.

IX. Bibliography.

X. Illustrations.

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.

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]