The Pathology of Influenza, by M. C. Winternitz, Isabel M. Wason and Frank P. Mcnamara

III. EXTRARESPIRATORY LESIONS IN INFLUENZA — A. LESIONS OF THE HEMATOPOIETIC SYSTEM — Lymphadenoid Tissues. — Spleen. — Bone Marrow. — B. LESIONS OF THE BLOOD VESSELS AND ELSEWHERE IN THE BODY — C. MISCELLANEOUS LESIONS — Summary.

In all the fatal cases of influenza which came to autopsy, and this has been the experience of others, the respiratory lesions, as indicated above, occupy the foreground. Indeed, compared with other types of respiratory disease, the lung involvement is so great that expression of the disease need not be sought elsewhere to explain the cause of death. However, there are general systemic changes which, even though quantitatively inconstant, are sufficiently common and widespread to support the view that the disease is a systemic one. The lesions of the hematopoietic organs and those of the vascular system are the most important and will now be taken up.

There is ample evidence that both the lymphadenoid and myeloid tissues of the body are affected. The lymph glands at the hilum of the lung naturally are involved with the extensive pulmonary changes. Also, a similar change may be found in distant nodes, perhaps associated with drainage from focal lesions or perhaps brought about by general intoxication.

The myeloid involvement is unassociated with focal lesions and finds its early expression in the equation of the white blood cells of the peripheral blood. The two groups of changes, those involving the lymphadenoid and those of the myeloid structures, should be discussed separately.

By far the most extensive lesions are encountered in the lymph glands of the lung and its hilum, and from here the mediastinal and deep nodes along the trachea are affected to a greater or lesser extent. The glands are very large and succulent (2, 157, 162, etc.). Very frequently, indeed, they are hemorrhagic on cross section (34, 108) (Fig. XXXVII), and there exudes a sanguinous fluid, usually thin and syrupy in character. The cut surface projects slightly, and the edge of the gland everts. The architecture is often obscured by hemorrhage—a diffuse red color—but very frequently near the periphery, translucent or more opaque, yellowish points are visible. Rarely, larger, opaque, yellow foci are found in the gland; these may be softened and purulent in exceptional cases (2, 47, 157).

Microscopically, the picture presented by the gland is that of a non-suppurative lymphadenitis. The peripheral sinuses are markedly distended and the channels through the gland share in the change (66). The sinuses contain serum, red blood cells, and mononuclear cells for the most part, but occasionally polymorphonuclear leucocytes are also encountered. More rarely still, a megalokaryocyte finds its way into the sinus. The most characteristic feature is the presence of phagocytosed cells,—a picture comparable with that found in the typhoid lymph node. The nuclei of the phagocytic cells are vesicular and usually stand out sharply in contrast with the pyknotic nuclei of the included cells. There is conclusive evidence that the phagocytes arise from the lining cells of the channel wall, as in typhoid fever, for these cells are frequently in process of division (Fig. LIV). The blood vessels of the lymph gland, greatly congested, contain almost exclusively red blood cells. As a rule, the lymph follicles and the lymph cords take little part in the process. If there is any change in these structures, it is a rarefication. Occasionally, hemorrhage is encountered in a follicle or even in a cord, and this hemorrhage may involve not only the cells of the cord, but its supporting reticular structure, and may form the nucleus of a subsequent necrotizing or suppurative focus.

FIG. XXXI. AUTOPSY NO. 100. ACUTE FULMINATING BRONCHIOLITIS AND BRONCHOPNEUMONIA. NOTE THE NECROTIC ALVEOLAR WALLS AND THE MASSES OF BACTERIA IN THE EXUDATE. COMPARE FIGURES VIII, XVII, AND XXXII.

35The picture that has been detailed is subject to modification in those cases particularly where a leucocytic reaction is associated. Then, there may be more polymorphonuclear leucocytes in the sinuses, and necrotizing foci may be converted into miliary abscesses.

The change in the bronchial lymph glands cannot be considered other than an expression of an aplastic, inflammatory reaction. It finds an analogue especially in diseases like typhoid fever. The most constant picture includes an edematous, hemorrhagic reaction in which there is phagocytosis of sieved-out cells by the scavengers generated within the gland. Where necrosis or suppuration occurs, and this is rare, it may be considered as a complication.

Elsewhere in the body, the lymph glands rarely show the same degree of change as those of the thorax. The same general picture, however, is present to a greater or lesser extent, except that extensive necrosis and suppuration have not been encountered.

The lymphadenoid tissues of the alimentary canal share in the process only to a minor extent. In a number of cases, there is no question that the Peyer’s patches and solitary follicles are hyperplastic. Grossly, they stand out prominently, and are pale pinkish-grey in color. Histologically, there is hyperplasia, chiefly apparent from the large germinal centers in the follicles, and a slight distention of the lymph channels. This picture, so commonly found in every type of general infection, is in no way characteristic of influenza.

The spleen is the seat of the usual manifestations in generalized acute infections. In no case is the organ markedly involved, although considerable increases in its size may occur (2, 108, 141, 157, 162). It is not feasible to introduce a detailed discussion of this mild grade of splenic tumor, for there are natural variations in the size of the spleen and frequently it is modified in this respect by subsidiary conditions. In every instance the capsule of the spleen is smooth and there is no acute or chronic perisplenitis attributable to influenza. The capsule usually retracts slightly and the splenic pulp, in slight excess, is much more frequently red or garnet than grey in color. Occasionally, the splenic tumor is grey as in pneumonia. The more minute changes in the organ consist of congestion of the sinuses, increase of the mononuclear cells of the pulp, and prominence of the germinal centers of the Malpighian corpuscles (140). Hemorrhages, found occasionally (47), are more frequent in the pulp, but also occur in the corpuscles.

One of the clinical features of influenza is a leukopenia, which persists often in the face of acute pyogenic pulmonary infection (12, 138, 143, etc.). In this series of ninety-five cases, the vast majority had this type of blood picture, but occasionally a leucocytosis (14) was demonstrable even during the early part of the disease and in those cases which terminated 36fatally within a period that may be called acute. In almost all instances where fatal termination was delayed, the leucocyte count ultimately was elevated either with remission or to a constant high level. The blood studies have not been sufficiently complete to allow further discussion, though there is reason to believe that these might have yielded interesting results. The blood changes in this series are similar to those presented in the reports of the epidemic from other sources.

In the majority of cases where the marrow was studied, it was aplastic (12). Occasional, focal, hemorrhagic lesions of the marrow (47) similar to those discussed below in the skeletal and parenchymatous systems were encountered and there was an apparent increase in the number of megalokaryocytes. The usual hyperplasia of the myeloid elements of the marrow associated with pyogenic change was not present.

Here, as in the discussion of the involvement of the lymphadenoid tissue, the most outspoken changes are in the thorax. Frequently thrombi are encountered in the vessels of the lung (34, 138). This does not include the capillary thrombi associated with damage to the alveolar walls already discussed. It has not been possible to demonstrate an association between the hemorrhagic, infarct-like foci in the lung and these vascular complications (47). The thrombi, histologically, are most frequently propagated, but occasionally an indication of their etiology is found in a destructive lesion of the vessel wall (19, 47, 50, 108, 156). This arteritis or phlebitis may be embedded either in a pneumonic zone or in relatively normal lung. The vessel wall may be obscured by a cellular infiltrate throughout its circumference or only at one point. The cells, on account of karyorrhexis often difficult to identify, are, partly at least, polymorphonuclear leucocytes, and the thrombus which forms upon the inflammatory nucleus, as a rule, is fairly rich in these cells (Fig. LII).

This vascular lesion may involve either artery or vein and may be found either within the lung or at distant points. Not infrequently, pulmonary embolus terminates influenza. One instance of this is incorporated in the group of chronic influenzal cases detailed above (Fig. LIII). In this instance, the thrombus originated in the right iliac veins; and, although no attempt was made to demonstrate the primary vascular lesion, so many similar cases are recorded (7, 82), and vascular damage is so frequent in this disease, that the hypothesis attributing pulmonary embolus to a thrombus initiated by a phlebitis is strongly supported.

Parenchymatous and skeletal lesions of hemorrhagic type, although variable quantitatively, are frequent and involve the muscles, the parenchymatous organs,—the adrenal especially,—and the mucosa of the alimentary canal. They have been described already with regard to the pleural surface and they may occur in other serous membranes.

FIG. XXXII. AUTOPSY NO. 100. A HIGHER MAGNIFICATION OF THE LESION ILLUSTRATED IN FIGURE XXXI. THE ALVEOLAR WALL IS ENTIRELY NECROTIC: BACTERIA AND POLYMORPHONUCLEAR LEUCOCYTES ARE ABUNDANT.

FIG. XXXIV. AUTOPSY NO. 87. CROSS SECTION THROUGH THE AREA OF GANGRENE SHOWN IN FIGURE XXXIII.

FIG. XXXV. AUTOPSY NO. 160. MICROSCOPIC DRAWING OF THE GANGRENOUS CAVITY ILLUSTRATED IN FIGURES XXXIII AND XXXIV.

37Only two examples of hemorrhage in the recti muscles^[11] were encountered in the ninety-five autopsies. In other localities this lesion has not only been more frequent but also more extensive (2, 47, 50, 128, 140, etc.). However, it has been fortunate that the two instances in this series represent a fresh hemorrhage and the healing lesion, respectively. The fresh hemorrhage is quite characteristic of Zenker’s necrosis involving muscles. Grossly, it is a small lesion and does not involve the entire width of the rectus muscle, as may happen, with a resulting rupture of this structure (12, 162). Microscopically, many of the muscle cells have lost their striation, are irregularly swollen, and, as fractures in them indicate, are apparently brittle. Between the muscle fibers and where these are lacking, the predominating element of exudate is the red blood cell, but there is a considerable amount of fibrin and also some serum between these cells (Fig. LVI). The absence of polymorphonuclear leucocytes is noteworthy. The second example of a muscular lesion occurred in a patient who died on the twenty-fifth day of the disease. Grossly, this also was a small lesion, although the muscle fibers at its site were obviously ruptured. Histologically, the lesion is a healing one. Regeneration of the muscle fibers (47, 156), as illustrated by the formation of typical spindles, is handicapped by the rapid development of the fibrous scar (Fig. LVII). Suppuration had not occurred and this also has been true for the focal, hemorrhagic, inflammatory processes which were encountered in many different localities throughout the body.^[12]

Perhaps the focal hemorrhagic lesions were most frequent in the adrenal gland. Generally, they were located in the cortex, although medullary hemorrhages were encountered. The extent of the process varied from minute hemorrhages, associated with necrosis of only a few cells, to extensive ones involving half of the adrenal. The microscopic examination of the exudate revealed the same elements and in approximately the same proportions as described for the similar process in the muscles. Not infrequently, mitotic figures in the adrenal cells indicated an attempt at repair of a minute damage.

Hemorrhages in the mucosa of the alimentary canal, including the stomach and intestines, similar to those so common at the post-mortem table in many different types of acute infectious disease, are, of course, common in influenza; but, in one case especially, a lesion was encountered which adds significance to these hemorrhages (47). Here areas of mucosa, usually round or oval and varying from one-half to two centimeters in diameter, often with ulceration in their centers, show, microscopically, bacterial emboli in the vessels of the mucosa with a hemorrhagic effusion which obliterates the architecture of this coat and extends at some points into the submucosal and muscular layers (Fig. LVI). Here, the occurrence of bacterial emboli in association with the lesion suggests that they may be etiologically related to similar processes in other parts of the body.

The above example of hemorrhage in the mucosa of the alimentary canal has seemed of especial interest, not only for its possible value in explaining the etiology of the lesion here and elsewhere, but as an interpretation of the findings in Autopsy No. 185, an abstract of which is appended below. There a hemorrhagic lesion in the wall of the urinary bladder led to rupture and brought the patient to the surgical clinic of the hospital.

Autopsy No. 185.

A white female, aged 46 years, was admitted to the New Haven Hospital on January 4, 1919, complaining of “cough and headache.” Five days previously she had a “cold” that she was able to “break up” with quinine and aspirin. The “cold” recurred two days ago, and since then she has had “frequent chills, aches all over, and feels weak.” Her family and past histories were unimportant.

38Physical examination on admission showed congestion of the pharynx. Below the inferior angle of the scapula on the right, there was dullness, bronchovesicular breath sounds, and a few fine râles. The examination was otherwise negative. Three days later the signs in the lungs disappeared. The next day, after an attack of coughing, she complained of something having “burst” within her abdomen and of generalized abdominal pain. A diagnosis of ruptured bladder was made and 1,400 cubic centimeters of bloody urine were withdrawn by catheter. Immediate operation was decided upon and the bladder was found a hand’s breadth above the symphysis pubis; the posterior wall was very thin and presented a tear extending from the trigone upward in the mid line for 7 centimeters. Fully 500 cubic centimeters of clotted blood and urine were removed from the pelvis, but there was no marked evidence of peritonitis. A permanent mushroom catheter was placed in the urethra, and the tear was sutured. The abdomen was closed with provision for drainage. The patient was returned to the ward in doubtful condition.

Her temperature at entrance was 104°F., and it fell by lysis to 99°F. just before operation. After the operation it fell to 97°F., and in a few hours rose to 99°F. Thirty-six hours after operation she had a chill lasting ten minutes, and her temperature rose to 105°F. in eight hours, when death occurred. The respirations were thirty per minute until the rupture of the bladder when they rose to forty per minute and corresponding to the final rise in temperature rose to 60 per minute. The pulse ran a parallel curve to the temperature, ranging from 100 to 160 per minute.

The autopsy was held two hours after death, and the essential findings were as follows:—

The body was that of a moderately obese woman. Rigor mortis had not developed, but there was a distinct heliotropic hue of the face and neck. The recent surgical wound between the symphysis pubis and umbilicus was in good condition. The peritoneum was slightly dulled in the lower half of the abdomen, and there was about 100 cubic centimeters of faintly cloudy, blood-tinged, thin fluid in the pelvis. The left pleural cavity contained about 200 cubic centimeters of slightly turbid, amber fluid, but the right side was free from fluid. While the pneumonia had not been prominent clinically, both lungs were found extensively involved by a necrotizing and organizing bronchopneumonia with purulent bronchitis similar to what has already been described. As the lesion of the bladder is the distinctive one in this case, and as the other organs show nothing that has not been described elsewhere, further description will be confined to it.

The wall of the bladder was thin and soft, and grossly the sutured wound appeared in good condition. Posteriorly there was a hemorrhagic zone about 3 centimeters in width most marked beneath the mucosa, but involving all of the coats. The mucosa was superficially ulcerated along this area, and was covered by a thin, patchy, fibrinous exudate. In addition, there were scattered beneath the mucosa several smaller hemorrhagic foci, quite distinct from the larger one.

Microscopically, one striking feature was the erosion of the mucosa, with hemorrhages most marked along the line of rupture but occurring elsewhere in the subjacent tissues. This condition was found in all the sections studied. Another feature was the lack of inflammatory exudate and the very slight attempt to repair the injury, only a very rare polymorphonuclear cell and fibroblast being seen. Sections of the peritoneum showed only a patchy deposit of fibrin with a rare polymorphonuclear cell.

In this series of cases lesions elsewhere in the body are not sufficiently constant or important to merit emphasis.^[13] Hemorrhages have been found occasionally in other structures, especially the testes. The usual cloudy swelling of the parenchymatous organs is, of course, marked, and in many cases has been associated with actual cellular necrosis both in the liver and the kidney. Such necroses are usually focal, and occasionally mitotic figures in the cells of the renal convoluted tubules or in the liver may be a similar expression of previous damage. Acute nephritis was not found in our series.^[14] The swollen liver cells often show the bile canaliculi clearly, and this appearance may be associated with a variable degree of jaundice which has been found frequently, although the explanation of the jaundice is, in all probability, an hemolysis of the red cells caused by the infecting microorganisms. The only other lesion encountered and of sufficient importance to mention, has been the congestion of the membranes of the brain and a swelling of the cerebral substance, in all probability dependent upon edema. One example of purulent meningitis was encountered.^[15] The dilatation of the right side of the heart with a greater or lesser degree of splanchnic engorgement is such a common feature in acute pulmonary diseases that it is hardly worthy of detailed discussion.

FIG. XXXVI. AUTOPSY NO. 133. A SMALL ABSCESS IN AN EDEMATOUS BAND OF INTERLOBULAR CONNECTIVE TISSUE.

FIG. XXXVII. AUTOPSY NO. 114. ILLUSTRATES AN UNUSUAL ANATOMICAL PICTURE IN INFLUENZA—AN EXTENSIVE FIBRINOPURULENT PLEURISY. THE BRONCHIAL LYMPH GLANDS ARE PROMINENT ON ACCOUNT OF THE HEMORRHAGIC INFLAMMATORY PROCESS WHICH HAS INVOLVED THEM.

39A striking feature of influenza is the occurrence of abortion in cases complicated by pregnancy. Of the ninety-five cases included in this report, twenty-seven were women of whom three died undelivered (three months, six months, term), three had suffered complete abortion (one, three months, and two, six months), and one (six months) was in process of abortion. It is not our purpose to discuss the relation between pregnancy and this complication. Here it is desirable simply to point out that, although in the non-complicated cases of influenza, pregnancy does not influence the course of the disease, if pneumonia supervenes, the mortality for the mother, as well as for the child, is definitely increased (57, 148, 164).

A specific placental lesion would be difficult, indeed, to establish since hemorrhage is a part of the normal process of placental separation. However, the hemorrhagic lesion of influenza seems a plausible explanation for the frequency of abortions in this disease.

The most important extrapulmonary lesions in influenza are those of the hematopoietic and the vascular systems. The first are typical of a general non-suppurative, inflammatory process, and are characterized in the majority of cases by a picture not unlike that encountered in typhoid fever, although the hyperplasia of the lymphadenoid tissues, as seen in the latter disease, is not present. The more important lesions are associated with the vascular system; phlebitis and arteritis occur, but are not so frequent as hemorrhages in the skeletal system, in the parenchymatous organs, and in the mucous membranes of the hollow viscera. These hemorrhagic necroses may be etiologically associated with capillary bacterial thrombi.

IV. COMPARISON BETWEEN THE RESPIRATORY LESIONS OF INFLUENZA AND THOSE INITIATED BY THE INHALATION OF POISONOUS GASES — A. THE INFLAMMATORY RESPONSE VERSUS THE SYSTEMIC CAPACITY TO COMPENSATE — B. THE PRIMARY INJURY — C. THE TENDENCY TO ORGANIZATION OF BRONCHIOLAR AND ALVEOLAR EXUDATES — D. THE IMPORTANCE OF THE TRACHEA AND ITS RAMIFICATIONS AS A PROTECTIVE MECHANISM AGAINST INFECTION OF THE PULMONARY PARENCHYMA

Immediately preceding the advent of the influenza epidemic in New Haven, there had been completed in this laboratory the experimental studies of the effects of a large number of different toxic gases upon the respiratory tract. This was begun with the support of the Bureau of Mines, and subsequently, after the formation of the Chemical Warfare Service, the work received the support, not only of this branch of the Army, but also of the Surgeon General’s Office. Exceptional opportunities for animal experimentation were offered. Every stage of the inflammatory process in the respiratory tract was studied, from the most acute, a few hours after the exposure of the animal to a high concentration of gas, to the very chronic types that resulted from sublethal concentrations and led to lesions encountered at the sacrifice of the animals many months later.

The criticism will unquestionably be introduced, that with the anatomical picture of the respiratory lesions initiated by irritating gases freshly in mind, an analogy between them and those of the pulmonary lesions of influenza may not be impartially drawn. However, such fundamental and striking similarities exist between the two processes (128) that the argument is simplified.

Symmers (141) and Oberndorfer (108) have already likened the influenzal pulmonary complications to plague pneumonia, and it is quite possible that others will find fundamental similarities with other fulminating, inflammatory reactions. Inflammation, a series of processes manifested after injury by a tissue which still retains its viability, is modified by another important factor usually neglected; namely, the state of the host. As a consequence, the inflammatory reaction might readily have similar manifestations even though the primary exciting agents are diverse. This has been amply demonstrated for many different reactive processes, and still it may be considered as a challenge for those who are of the opinion that specific bacterial agents necessarily produce characteristic anatomical manifestations. Consider the state of knowledge of the various reactions to the tubercle bacillus before this microorganism was isolated; and then bear in mind that we are dealing here with a disease whose causative agent, despite the present uncertainty regarding its specific nature, produces a lesion that paves the way for the invasion of the respiratory tract by many different organisms. The extent of the reaction may depend upon the systemic capacity to compensate, as well as upon the degree of primary damage in a specific system of organs. Unquestionably, these two factors must take their places in the balance, the opposite pan of which contains the one or the other secondary bacillary invader.

FIG. XXXVIII. THE UPPER ILLUSTRATION, AUTOPSY NO. 116, SHOWS A FRESH, FIBRINOPURULENT PLEURAL EXUDATE. THE PLEURAL LINING CELLS ARE SWOLLEN AND CONSPICUOUS. THE LOWER ILLUSTRATION, AUTOPSY NO. 100, SHOWS ANOTHER AND LATER TYPE. THE ELEMENTS OF THE EXUDATE HAVE DISINTEGRATED TO FORM A MUCILAGINOUS MASS. COMPARE FIGURE XXXVII.

FIG. XLI. AUTOPSY NO. 140. IS A LOW POWER DRAWING OF THE CHARACTERISTIC LUNG IN THE MORE CHRONIC STAGE OF THIS DISEASE. NECROTIZING AND ORGANIZING BRONCHIOLITIS AND PERIBRONCHIOLITIS ARE ASSOCIATED WITH AN ORGANIZATION OF THE EXUDATE IN THE ALVEOLI. THE ORGANIZATION PROCESS IS SOMEWHAT OBSCURED BY THE EDEMA. COMPARE FIGURES XI, XXXIX, XI, AND XLIV.

FIG. XXXIX. AUTOPSY NO. 140. RIGHT LUNG. THE HISTOLOGY OF THE PULMONARY CHANGES IN THIS CASE IS ILLUSTRATED IN FIGURES XI, XLI, AND XLIV. THE NECROTIZING PERIBRONCHIAL FOCI STAND OUT PROMINENTLY AND THE ORGANIZATION OF THE EXUDATE IN THE SURROUNDING ALVEOLI IS ALSO DISTINCTLY SEEN IN THE ABOVE FIGURE.

41Scientific medicine has reached that evolutionary period where, in addition to the specific infecting microorganism, associated etiological factors find an important place in the interpretation of a disease. More and more attention is being directed toward the latter factors and the rôle they play in respiratory infections. Many different factors open the pulmonary portal for organisms and, in this way, terminate by a serious respiratory inflammatory complication what otherwise might have been a relatively mild disease. In the past two years this has been demonstrated for measles.

For the above reasons, not only the immediate action but the complications and sequelæ, too, of the inhalation of irritating gases by normal healthy animals, emphasize themselves as a framework for a more comprehensive interpretation of respiratory disease in general.

With few exceptions, the gases studied have their most marked effect upon the respiratory tract. They differ, however, in the localization of the lesions and in the extent of the damage. For instance, mustard gas, in high concentrations, has a necrotizing effect upon the entire respiratory tract even to the pulmonary parenchyma itself. Inhaled in a more dilute form it involves the larynx and the trachea and has spent itself before the lung is reached. With phosgene, the opposite is true. The upper respiratory tract is only slightly involved. The outspoken lesions involve the bronchioles, the ducti alveolares, and extend to the alveolar walls of the lung. Chlorine, while it produces a less severe lesion of the upper respiratory tract, extends more often through all of the ramifications of the tracheal tree to the lung.

With vital stains (trypan blue), it may be readily demonstrated that these gases kill the epithelium of the respiratory tract and extend through this superficial cellular coat to the deeper tissues of the bronchiolar wall and to the lung tissue, killing it entirely, just as a corrosive chemical destroys the wall of the stomach.

When chlorine and phosgene reach the lung, an intense reactive process follows immediately. The congestive changes, the hemorrhage into the pulmonary parenchyma both in the alveoli and in the subpleural and interstitial tissues, and the albuminous rich, serous exudates occupy the foreground of the acute picture and are associated clinically with intense cyanosis, great dyspnœa, hemorrhage, bronchorrhea, and also with pulmonary and subcutaneous interstitial emphysema. The microscope reveals a hyalinization of the walls of the bronchioles or ducti alveolares which are distended during this acute period and form a picture that is very unusual in the more frequent types of respiratory inflammation. It shows also a hyalinization of the alveolar walls, usually those in direct continuity with the larger air passages. The interstitial edema and hemorrhage, often perivascular in distribution, is only overshadowed by the thick, almost colloid-like material within the alveolus itself. Fibrin stains at this stage show this exudative element in surprisingly large amounts. Fibrin not only covers the alveolar wall, but crosses this structure and often forms intracapillary plugs. In fact, besides the red blood cells, the serum and the fibrin, one often sees, not only an excess of polymorphonuclear leucocytes in the vessels of the lung, but these appear in process of migration within a few hours after the animal has been exposed.

Animals surviving this stage often succumb later with a typical pneumonic process. Although frequently pseudolobar, the process may be lobar in extent, and as time goes on more definite lobular involvement is frequently encountered. With the localization of the 42inflammatory process, the general edema, congestion and milder reactions in other portions of the lung tend to subside, and may be entirely absent in a few days. The clinical picture, in the experimental animal at least, also assumes a more typical expression of respiratory infection,—leucocytosis, chlorine retention, etc., appear. Often the pneumonias, both lobar and lobular, are complicated, grossly, by softening, and histologically, by necrotization of the bronchiolar and alveolar walls. Recrudescence of the active pulmonary infection is not uncommon, and perhaps is associated with these focal necrotizing areas.

The sequelæ after exposure to gas may be markedly delayed. They occur, not only in animals which have exhibited characteristic acute symptoms, but also, and especially with phosgene, where no serious immediate clinical effects followed exposure to the gases. They are dependent upon the fact that the pneumonic process has a very striking tendency to undergo organization, a process which involves not only the exudate in the alveoli, but also that within the bronchioles. The organizing process may be present in both these portions of the lung or may be confined to the bronchiole alone, and lead to a progressive interference with the ingress and egress of alveolar air, so that atelectasis and emphysema become permanent, and in turn lead to narrowing of the vascular bed, ultimately producing right-sided cardiac decompensation. Bronchiectases also occur; they may be tubular, associated with organization of the pneumonic process in their vicinity, or saccular if death has not followed the destruction of the bronchiolar wall.

Compare this picture with that of influenzal pneumonia and its sequelæ; in both there is, first the acute diffuse involvement of the lung, initiated by, or occurring simultaneously with, an acute tracheobronchitis and presenting clinically dyspnœa, cyanosis, blood-stained, abundant sputum, and even interstitial emphysema; next, the tendency for the pneumonic process to localize and to necrotize; and finally, if the acute period is survived, organization of the pneumonic and bronchiolar exudates with resulting bronchiolitis and bronchiectasis. With even more minute comparison, the resemblance is sustained. The initial or early dilatation of the ducti alveolares, so characteristic in gas poisoning, also occupies the foreground of the histological picture in influenza. These dilated structures are the more prominent on account of the red, ribbon-like strands that cover the surface and often involve the walls. Similar necrotization, varying in its depth even to involve the whole of the alveolar walls, occurs in both of these conditions. Similar hemorrhages in the early stage, rupture of the alveolar wall with interstitial and subcutaneous emphysema, necrotization, gangrene, and organization in the same localities, characterize the two lesions, and are not found with the same uniformity in any other type of respiratory disease.

In gas poisoning it has been demonstrated that the initial damage to the epithelium of the larger air passages is followed by an invasion of the pulmonary parenchyma by the bacteria of the mouth. Repeated cultures from the mouth before the exposure of the animal to gas have been followed by the recovery of the same organisms, including the pneumococci, the streptococci, the staphylococci, and a gram-negative, hemoglobinophilic, small bacillus from the pneumonic lung. They find their way into the lung after the destruction or incapacitation of the protective mechanism (70) of the upper respiratory tract,—into a lung which has been so damaged by the irritative gas that bacteria innocuous in the normal pharynx now find a favorable medium for their development. The inflammatory reaction which develops into pneumonia, perhaps necrotizing, perhaps later organizing, can only be explained by the combined action of the corrosive gas and the organisms saprophytic in the normal mouth, but now pathogenic in varying degrees in the lung whose vital reactions have either been inhibited or impaired by the gas.

FIG. XL. AUTOPSY NO. 140. LEFT LUNG. THE HISTOLOGY OF THE PULMONARY CHANGES IN THIS CASE IS ILLUSTRATED IN FIGURES XI, XLI, AND XLIV. THESE PROCESSES, ILLUSTRATED IN FIGURE XXXIX, ARE ACCENTUATED AND THERE IS ALSO AN ORGANIZATION OF THE EXTENSIVE PURULENT PLEURISY TO BE MADE OUT IN THE ABOVE FIGURE.

43There is no reason why this analogy should not be drawn, no reason why we should not consider that the unknown etiological agent in influenza produces a similar injury to, or even destruction of, the protective mechanism of the respiratory tract. Similarly, gas and influenza damage the pulmonary parenchyma itself, so that the bacteria of the air and of the mouth which find their way into the damaged lung^[16] initiate processes and produce complications which may not be distinguished.

V. PECULIARITIES OF THE HISTOLOGY OF INFLUENZAL PNEUMONIA — A. THE EXTENT OF THE INITIAL PULMONARY LESION — B. THE HEMORRHAGIC EXUDATE — C. THE APLASTIC EXUDATE — D. THE HYALINE NECROSIS OF THE PULMONARY TISSUE — E. THE ORGANIZATION PROCESS

One of the features differentiating the pneumonic process in influenza from the usual types of inflammation of the lung, is diffuseness (90). In the early cases especially, or in cases which terminate fatally at an early period, both lungs are often involved, and, on histological examination, only a small portion of the pulmonary parenchyma is found unaffected. The exudate, largely acellular, presents serum as its most conspicuous feature. The picture is one of a patchy pneumonia with intermediary areas of what might be called edema, although fibrin is often demonstrable in the coagulated, albuminous material. So little attention has been paid to earlier stages of the usual types of pneumonia, for example lobar, that it is impossible to say whether or not diffuse involvement of the pulmonary parenchyma initiates the process which later becomes localized in one or more lobes. The initial edema of influenzal pneumonia is the expression of a widespread irritation. If the injury has not extended deeply, the edema may disappear within a relatively short time, and exfoliated lining cells fill the alveoli; those remaining in their normal position are frequently in process of division (Fig. XLVII). It is conceivable—and the view has already been announced—that this edema is a disseminating factor and perhaps responsible for the diffuseness of the pneumonic process which may follow. If the fluid is simply a serous exudate, it may play no essential rôle in the severe acute symptoms manifested by these patients, for it has been shown, both in the experimental lesions induced by pulmonary irritating gases and by pulmonary irrigation through which extensive artificial edema of the lungs may be attained, that the presence of fluid in the lung in itself is not harmful (161).

Another striking feature of the inflammatory process in this disease is the extensive hemorrhagic exudate expressed clinically in the fresh, red blood of the abundant sputum. In the tissues the blood is always fairly well preserved. It may be scattered diffusely through the cellular exudate (Fig. XXIV) or so abundantly that the area resembles an infarct (Fig. XXV). These hemorrhagic foci, which vary considerably in size, are found not only in the cases that terminate fatally within a few days, but may occur at any time during the acute manifestation of the disease. They are an exaggerated form of red hepatization and it is difficult to see how such red foci could ever change to areas of grey pneumonia. It is a widely accepted statement, in textbooks of Pathology at least, that the stage of red hepatization in pneumonia follows the period of engorgement and precedes the grey form. This interpretation is open to question concerning the lesions that are encountered in influenza, as well as in those that are seen after gas inhalation. Unquestionably, in the stage of engorgement the lung has a red appearance, enhanced by the acellular, serofibrinous exudate in the alveoli through which the greatly congested vessels are seen. At this stage, the lung has a translucency on gross examination, which is not the case when the cellular content of the alveoli is increased. This picture is not the one spoken of most commonly as red hepatization; for, although it appears as a relatively red lung in the gross, difficulty is encountered in its histological correlation, for the exudate is composed, not of red cells, but largely of serum and fibrin. The red color may persist even when numerous polymorphonuclear leucocytes and desquamated alveolar wall cells are within the alveoli, the walls of which are markedly engorged. Later, as the circulation in the pneumonic zone is impaired, the alveolar exudate determines the tone of the gross color, and a considerable number of red blood cells may be overshadowed by the larger percentage of white ones.

FIG. XLII. AUTOPSY NO. 133. IS A MUCH LATER STAGE OF THE PROCESS SHOWN IN FIGURE XXXI. ASSOCIATED WITH THE ENCAPSULATED BRONCHIOLAR AND PERIBRONCHIOLAR ABSCESS, THERE IS A DIFFUSE ORGANIZATION OF THE EXUDATE IN THE SURROUNDING ALVEOLI.

FIG. XLIII. THE ALVEOLAR WALLS ARE THIN AND THE EXUDATE OF RED BLOOD CELLS AND DESQUAMATED EPITHELIUM IS IN PART HYALINIZED.

45The advent of red blood cells where grossly the exudate is red can hardly be explained by the simple process of diapedesis. Indeed, there is ample evidence that they escape by rhexis through lesions of the vascular wall. This phenomenon cannot be demonstrated in areas where a compact mass of red cells obliterates the alveolar space (Fig. XXV), but in the less firmly consolidated alveoli where red blood cells predominate (Fig. XXVI) the picture of the alveolar wall is very instructive. The capillaries may be prominent and contain red cells almost exclusively. Often the epithelium of the air space is exfoliated so that there is nothing to minimize the prominence of the engorged vessels. These capillaries, covered by such a delicate wall that rupture seems imminent, may protrude like saccular aneurysms (101) into the alveolar space (Fig. XXVI). In all probability, these sacs do rupture and this result would be one explanation for the escape of large numbers of red blood cells. In several instances such a picture was encountered, where with little reaction at the point of rupture, red cells within the vessel were continuous with an accumulation of similar cells in the alveolus. Further evidence for such rupture is offered where the vessel is collapsed. Here there is accumulation of polymorphonuclear leucocytes in the area of destruction in contrast to the well preserved red corpuscles in the remainder of the vessel (Fig. XXVI). The above pictures may be utilized in the interpretation of the outspoken foci of red hepatization which may assume infarct-like proportions. As has been said, it is impossible to conceive that these hemorrhagic areas where the alveoli are packed with red cells ever change to a grey type of consolidation. Consequently, it seems more probable that the color of red hepatization in the usual types of pneumonia depends upon the marked engorgement of the vessels seen through a relatively acellular, transparent, serofibrinous, alveolar mass and not upon the number of red cells in the exudate.

The absence of cellular elements in the alveolar exudate is frequently observed in influenzal pneumonia (Figs. XXI, XXII, XXIII). This picture has been reproduced experimentally in animals which have been rendered aplastic with benzol, especially with reference to their myeloid elements (160). Pneumonia produced by intratracheal insufflation is more rapidly fatal in aplastic animals, and it is conceivable that the absence of cellular reaction is an explanation for the lack of resistance demonstrated by the high mortality of influenzal pneumonia. Frequently the fibrinoserous mass scattered diffusely throughout the lung is rich in bacteria. In the absence of cells of the polymorphonuclear series, the bacterial development seems to be unrestricted. The aplastic exudate is associated 46clinically with an absence of a myeloid reaction in the peripheral circulation. The leucocytic count may be definitely decreased, even though the tissues have been invaded by pyogenic organisms to which the usual response is a definite leucocytosis. The only explanation is that the myeloid structures have been injured, probably by the unknown virus of the disease.

The hyalinization of the epithelium lining the ducti alveolares (47, 48) also merits special attention (Figs. V, XV, XVI). This process may extend through the wall of the duct and is often seen in the alveolar walls throughout the involved lung. The entire alveolar wall may be homogeneous in appearance, but, occasionally, the thrombus alone, which has formed in its vessels (41), presents this change (Fig. XVII). The alveolar as well as the bronchiolar wall is thickened by a homogeneous material in which cell-body and exudate cannot be differentiated. This acute necrosis, as has been mentioned, is encountered in gas poisoning but is unusual in other known types of respiratory infection. Doubtless, it is a precursor to the more destructive lesions commonly found in later stages of the disease—abscesses which extend through the bronchiolar walls (Fig. XXXI), necrotizing areas of pneumonia in which huge clumps of bacteria are found (Fig. XXXII), and true gangrene (Figs. XXXIII, XXXIV, XXXV). The destruction of the alveolar wall in the early stages of the disease plays a causal rôle in the production of subcutaneous emphysema (Figs. XVIII and XIX). This important phase of the histological change in influenzal pneumonia has received but little attention and, with one or two exceptions, is not mentioned in the literature (8, 162).

In the interpretation of this necrotization, the only helpful analogy is offered by the acute respiratory lesions following the inhalation of poisonous gases. With the aid of vital stains, it has been demonstrated that chlorine quickly initiates necrosis due to the direct action of the gas. Since necrosis also occurs with phosgene,—in the decomposition of which hydrochloric acid is probably liberated,—there is presumptive evidence that the halogen is responsible for the process. Studies are now in progress to determine the relation of the acid-producing properties of the different strains of organisms to the type and fate of the pneumonic exudate.

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

FIG. XLIV. THE ALVEOLAR WALLS ARE IN PART OBLITERATED. THE ALVEOLAR EXUDATE IS ORGANIZED BUT THE FIBROUS TISSUE STRANDS ARE SPREAD APART BY EDEMA.

FIG. XLV. AUTOPSY NO. 163. ORGANIZATION OF THE ALVEOLAR EXUDATE AFTER THE SUBSIDENCE OF THE ACUTE PROCESS. COMPARE FIGURE XLIV.

47Resolution of the exudate in pneumonia, with the restoration of the tissue to normal, is a result at such variance with the usual fate of an inflammatory exudate, that it has attracted a great deal of attention. Perhaps the most striking results of the study of this subject have been published recently by Kline (69). Arguing from previous experiments (70) in which it was demonstrated that the circulation of the pneumonic lung is impaired, and that for this reason sufficient serum cannot reach the exudate to inhibit the proteolytic action of leucocytic ferments, Kline introduced normal serum into the consolidated lung by the tracheal route, and showed conclusively that this resulted in an organization of the alveolar exudate. This, of course, might explain resolution, but it is difficult to see without further study how serum can reach the exudate to inhibit autolysis, and in this way stimulate organization, in one case of pneumonia and not in another.

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

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

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

FIG. XLVI. AUTOPSY NO. 128. THE ORGANIZATION IS HERE LARGELY CONFINED TO THE INTERSTITIAL TISSUE. THE ALVEOLI ARE DISTORTED AND COMPRESSED, AND THEIR EPITHELIUM HAS ASSUMED A CUBICAL FORM.

FIG. XLVIII. AUTOPSY NO. 183. THIS DRAWING SHOWS A DILATED BRONCHUS UNDERGOING OBLITERATIVE BRONCHIOLITIS. THE EXUDATE IN THE SURROUNDING LUNG TISSUE IS BEING ORGANIZED. THE EPITHELIUM OF THE BRONCHUS IS MANY LAYERS THICK AND HAS INVADED THE SURROUNDING LUNG TISSUE. IT HAS THE APPEARANCE OF AN INFILTRATING EPITHELIAL NEOPLASM. COMPARE FIGURES XI AND XLI.

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

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

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

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

50Only the eighty-two cases at the New Haven Hospital are included in the following report. Routine post-mortem cultures were taken from blood, lung, serous fluid wherever present, and exudates from the trachea and bronchi in the later cases. Blood and serous fluids were cultured into neutral infusion broth and plated on blood agar after twelve to thirty-six hours’ incubation. Lung and bronchial cultures were streaked on blood agar plates and for the last third of the series on Avery’s oleate media. Cultures were examined on each successive day and were discarded only after one week. Undoubtedly, we have failed to find B. influenzæ in many of the earlier cases because of lack of familiarity with the organism, of variations in its morphology (33), and of unsuitable culture media. The organisms tabulated below include only those determined by cultural methods; those found by direct smears or in histopathological preparations are not considered. (See Table No. I.)

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

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

FIG. XLVII. AUTOPSY NO. 100. PROLIFERATION OF THE ALVEOLAR EPITHELIUM IN A PORTION OF THE LUNG ONLY SLIGHTLY INVOLVED BY THE ACUTE INFLAMMATORY PROCESS. COMPARE FIGURES IV, XI, XLVIII, AND XLIX.

HELIOTYPE CO. BOSTON

FIG. XLIX. AUTOPSY NO. 122. HIGHER POWER ILLUSTRATION OF EPITHELIAL PROLIFERATION AS ILLUSTRATED IN FIGURE XLVIII.

FIG. LII. AUTOPSY NO. 107. THROMBUS ASSOCIATED WITH AN ACUTE INFLAMMATION IN THE WALL OF A PULMONARY ARTERIOLE.

FIG. L. AUTOPSY NO. 209. BRONCHIECTATIC CAVITIES AT THE BASE OF A LUNG. THE HISTOLOGY OF THIS LESION IS ILLUSTRATED IN FIGURE XII.

54The type of the pneumonic process, as well as the invading organism, has varied widely in different localities. From the foregoing brief survey, it will be seen that before the associations suggested above can be proven, much more definite evidence must be presented.

An attempt has been made to correlate the bacteriological findings in this series with the distribution and type of pneumonic process. These are tabulated in Table III. It will be seen at a glance that no relationship is demonstrable between the type of single or associated organisms and the distribution of the pneumonia, whether it is lobar, pseudolobar, peribronchial or lobular and whether acute fulminating, necrotizing or organizing. (See Table No. III.)

The confusion which exists in associating different bacterial types with well defined and characteristic anatomical lesions is true, not only for the disease as it occurs spontaneously in man, but also for its reproduction in experimental animals. A review of the literature teaches that not all of the factors concerned in producing the different anatomical types are known.

Pertinent experimental studies were reported recently by Blake and Cecil from the Army Medical School in Washington. One cubic centimeter of a very virulent pneumococcus (M. L. D. for a mouse in forty-eight hours equals one-millionth of 1 cubic centimeter) inoculated in monkeys through the skin of the neck into the trachea just beneath the larynx has uniformly produced a lobar pneumonia, clinically as well as anatomically the nearest experimental approach to spontaneous lobar pneumonia of man. This work indicates, not only the possible importance the species may play, but also points to the rôle of the infecting organism which, when sufficiently virulent, incites a characteristic reaction even when inoculated in a minimal quantity into the trachea as distinct from the bronchioles or lung tissue.

Pneumonia unassociated with a simultaneous or preliminary incapacitation of the mechanism of the upper respiratory tract, differs from the pulmonary lesions encountered after measles, gas poisoning, influenza, etc., and those experimentally produced by intrabronchial insufflations. In the lobar type the virulence of the infecting organism, combined perhaps with species variation,—implying as this does different capacities for reaction on the part of the host,—seems to be the fundamental principle. It remains to be determined whether other organisms of equal virulence with that of the pneumococcus are capable of producing characteristic anatomical reactions when inoculated in a similar manner.

In the other group, where there is not only a free ingress to the pulmonary parenchyma by the bacteria of the mouth, but where there is, in all probability, also a simultaneous or preliminary pulmonary damage furnishing a proper medium for relatively innocuous organisms, the lesion of response will surely depend upon other factors as much as upon the infecting organism. Among these obscure factors, the most important, unquestionably, is the extent of the damage to the lung tissue before the entry of the organisms, or simultaneously with it, into this area. The systemic capacity to compensate also must be considered.

FIG. LI. AUTOPSY NO. 194. A LUNG IN WHICH INFLUENZAL PNEUMONIA AND PULMONARY TUBERCULOSIS ARE ASSOCIATED. THERE IS A CIRCUMSCRIBED, OLD, TUBERCULOUS FOCUS IN THE UPPER LOBE. COMPARE FIGURES XXXIX AND XL.

VIII. CONCLUSIONS

The etiology of influenza is unknown.

The portal of entry of the inciting cause is likewise undetermined.

The respiratory lesions, whether primary or secondary, are responsible for the high mortality of the disease.

The lesions of the respiratory tract peculiar to this disease and most frequently encountered are:

An acute tracheobronchitis associated with diffuse involvement of the pulmonary parenchyma.

Hyalinization of the epithelium of the air passages, and necrosis of the alveolar walls with extensive interstitial emphysema and occasionally with pneumothorax.

Dilatation of the terminal bronchioles.

Aplastic serofibrinous, and hemorrhagic, pneumonic exudates.

Necrotizing and organizing bronchiolitis, and pneumonia: lobar, lobular, peribronchial, interstitial.

The sequelæ—obliterating bronchiolitis and bronchiolectasis.

Proliferation of alveolar and bronchiolar epithelium.

The extrarespiratory lesions of influenza are neither constant nor characteristic. Irrespective of localization, they have the same fundamental pathology characterized by:

Vascular damage.

Hemorrhage.

Organization with or without infection.

A basis for the interpretation of the respiratory lesions of influenza is offered by the analogous changes in the respiratory tract initiated by the inhalation of poisonous gases.

The respiratory lesions are dependent primarily upon the damage produced by the true etiological agent and the systemic capacity to compensate, and only secondarily upon invasion by the bacterial flora of the mouth and inspired air.

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FIG. LIII. AUTOPSY NO. 163. PULMONARY EMBOLUS.

FIG. LIV. (AUTOPSY NO. 20. U. S. GENERAL HOSPITAL.) ILLUSTRATES THE CHANGE IN THE BRONCHIAL LYMPH GLANDS. NOTE THE PHAGOCYTOSIS WITHIN THE SINUSOIDS AS WELL AS THE MEGALOKARYOCYTES AND THE MITOTIC FIGURES IN THE CELLS LINING THE CHANNELS.

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44. French, H.: “Influenza” (Clinical Lecture);—Guys Hospital Gazette, 1919, 33, 118.

45. Friedlander, McCord, Sladen, and Wheeler: The Epidemic of Influenza at Camp Sherman;—J. A. M. A., 1918, 71, 1652.

46. Gibson, Bowman, and Connor: A Filterable Virus as the Cause of the Early Stage of the Present Epidemic of Influenza; Prelim. Rep.—Brit. Med. J., 1918, 2, 645.

47. Glaus and Fritzsche: Über den Sektion befund bei der Gegenwärtigen Grippe Epidemie unter besonderer Berücksichtigung der Mikroskopischen Befund;—Corr. Blatt f. Schweizer Aerzte, 1919, 49, 72.

48. Goodpasture: Bronchopneumonia due to Hemolytic Streptococci following Influenza;—J. A. M. A., 1919, 72, 724.

49. Gotch and Whittingham: A Report of the Influenza Epidemic of 1918;—Brit. Med. J., 1918, 2, 82.

50. Gruber and Schädel: Zur pathologischen Anatomie und zur Bakteriologie der influenzaartigen Epidemie im Juli, 1918;—Mün. med. Wchnschr., 1918, 65, 905.

51. Hall and Dyas: Appendicitis at Camp Logan as a Sequel to Influenza and Pneumonia;—J. A. M. A., 1918, 72, 726.

52. Hall, Stone and Simpson: Epidemic of Pneumonia following Influenza at Camp Logan;—J. A. M. A., 1918, 71, 1986.

53. Hamilton and Leonard: Acquired Immunity to Influenza;—J. A. M. A., 1919, 72, 854.

5854. Hamman, L. V.: Discussion on Influenza;—Bull. Johns Hopk. Hosp., 1919, 30, 112.

55. Hammond, Rolland, and Shore: Purulent Bronchitis;—Lancet, 1917, 193, 41.

56. Harris, D. T.: Some Observations on the Recent Influenza Epidemic;—Lancet, 1918, 195, 877.

57. Harris, J.: Influenza Occurring in Pregnant Women;—J. A. M. A., 1919, 72, 978.

58. Hedinger, E.: Zur Pathologie und Bacteriologie der Grippe;—Corr. Blatt f. Schweizer Aerzte, 1919, 49, 554.

59. Hewlett and Alberty: Influenza at a Navy Base Hospital in France;—J. A. M. A., 1918, 71, 1056.

60. Hirsch and McKinney: Epidemic of Bronchopneumonia at Camp Grant, Prel. Bact. Rep.;—J. A. M. A., 1918, 71, 1735.

61. Hirschbruch: Ueber die Ansteckende Lungenentzündung;—Deut. med. Wchnschr., 1918, 44, 935.

62. Howard, S. E.: Bacteriological Findings in Epidemic Influenza;—Bull. Johns Hopk. Hosp., 1919, 30, 13.

63. Howard, Wm. T.: Bull. Johns Hopk. Hosp., 1919, 30, 111.

64. Hunt: Notes on Symptomatology and Morbid Anatomy of so-called Influenza with Special Reference to the Diagnosis;—Lancet, 1918, 195, 419.

65. Influenza Committee of the Advisory Board to the D. G. M. S., France; The Influenza Epidemic in the British Armies in France;—Brit. Med. J., 1918, 2, 505.

66. Jaffé: Zur pathologische Anatomie der Influenza 1918;—Wien. klin. Wchnschr., 1918, 31, 1203.

67. Keegan: The Prevailing Pandemic of Influenza;—J. A. M. A., 1918, 71, 1051.

68. Kinsella: Bacteriology of Epidemic Influenza and Pneumonia;—J. A. M. A., 1919, 72, 717.

69. Kline, B. S.: Experimental Study of Organization in Lobar Pneumonia;—J. Exp. Med., 1917, 26, 239.

70. Kline, B. S., and Winternitz, M. C.: Studies upon Experimental Pneumonia in Rabbits;—J. Exp. Med., 1915, 21, 311.

71. Knack: Das Verhalten der Nieren bei der Grippe;—Med. Klin., 1918, 14, 902.

72. Kosmak: Occurrence of Epidemic Influenza in Pregnancy;—Am. J. Obs., 1919, 79, 238.

73. Krumbhaar, E. B.: The Bacteriology of the Prevailing Epidemic;—Lancet, 1918, 195, 123.

74. Lacy: B. influenzæ in Sinusitis and Meningitis;—J. Lab. & Clin. Med., 1918, 4, 55.

75. Lamar, R. V., and Meltzer, S. J.: Experimental Pneumonia by Intrabronchial Insufflation;—J. Exp. Med., 1912, 15, 133.

76. Lamb: Primary and Post-Influenzal Pneumonia;—J. A. M. A., 1919, 72, 1133.

77. Lamb and Brannin: The Epidemic Respiratory Infection at Camp Cody;—J. A. M. A., 1919, 72, 1056.

78. LeCount: The Pathologic Anatomy of Influenzal Bronchopneumonia;—J. A. M. A., 1919, 72, 650.

79. LeCount: Disseminated Necrosis of the Pulmonary Capillaries in Influenzal Pneumonia;—J. A. M. A., 1919, 72, 1519.

80. Leslie, R. M.: Discussion on Influenza;—Proc. Royal Soc. Med., 1919, 12, 67.

81. Levy: Hämatologisches zur Grippe-Epidemie;—Deut. med. Wchnschr., 1918, 44, 972.

82. Leichtenstern: Influenza;—Nothnagel’s Specielle Pathologie, 1896.

83. Little, Garofalo, and Williams: Absence of B. influenzæ from the Upper Air Passages in the Present Epidemic;—Lancet, 1918, 2, 34.

84. Locke, Rönne, and Lande: Clinical Aspects of the Recent Influenzal Epidemic;—Boston Med. & Surg. J., 1919, 180, 124.

85. Lord: The Etiology of an Epidemic of Influenza;—J. Med. Res., 1908, 19, 295.

86. Lord: Influenza;—Osler and McCrae, Modern Medicine, Vol. 1.

87. Lord: Eleven Acute and Eighteen Chronic Cases of Influenza;—Boston Med. & Surg. J., 1902, 147, 662.

FIG. LVI. AUTOPSY NO. 135. ACUTE HEMORRHAGIC MYOSITIS (ZENKER’S NECROSIS).

COMPARE FIG. LVII.

HELIOTYPE CO. BOSTON

5988. Lord, Scott, and Nye: Relation of the Influenza Bacillus to the Recent Epidemic of Influenza;—J. A. M. A., 1919, 72, 188.

89. Löwenfeld: Pathologisch-anatomische und bacteriologische Befund bei der Spanischer Grippe;—Wien. klin. Wchnschr., 1918, 31, 1274.

90. Lyon: Gross Pathology of Epidemic Influenza at the Walter Reed General Hospital;—J. A. M. A., 1919, 72, 924.

91. Lyon, I. P., Tenney, and Szerlip: Some Clinical Observations on the Influenza Epidemic at Camp Upton;—J. A. M. A., 1919, 72, 1726.

92. MacCallum: Pathology of the Pneumonia following Influenza;—J. A. M. A., 1919, 72, 720.

93. MacCallum: The Pathology of the Pneumonia in the United States Army Camps during the Winter of 1917–1918;—Monograph of the Rockefeller Institute, No. 10.

94. MacKenzie: Influenza as Affecting the Respiratory System;—Practitioner, 1919, 102, 53.

95. Malloch: Discussion on Influenza;—Proc. Roy. Soc. Med., 1919, 12, 45.

96. Manges, M.: Symptomatology of the Prevailing Epidemic “Influenza”;—N. Y. Med. J., 1918, 108, 722.

97. Matthews: Preparing Medium for the Culture of Pfeiffer’s Influenza Bacillus;—Lancet, 1918, 195, 104.

98. McIntosh: The Incidence of B. influenzæ in the Present Influenza Epidemic;—Lancet, 1918, 195, 695.

99. McMeekin: The Present Epidemic of Influenza;—Med. J. Australia, 1919, 1, 209.

100. Medalia and Major: Influenza Epidemic at Camp McArthur: Etiol., Bact., Path., and Sp. Ther.;—Boston Med. & Surg. J., 1919, 180, 323.

101. Menetrier, M. P.: Bronchopneumonia à B. de Pfeiffer; Bull. de l’Acad. de Med., 1919, 81, 99.

102. Mix, C. L.: Spanish Influenza in the Army;—N. Y. Med. J., 1918, 108, 709.

103. Moore, Sir John: Influenza from a Clinical Standpoint;—Practitioner, 1919, 102, 26.

104. Nammack, C. E.: Clinical Features of the Recent Influenza Epidemic;—Med. Rec., 1918, 94, 1103.

105. Netter, M. A: L’Epidemie d’Influenza de 1918;—Presse Med., 1918, 26, 511.

106. Nicolle and Lebailly: Le Microbe de la Grippe; Communication à l’Academie des Sciences par l’intermediare de M. le Professeur Roux;—Presse Med., 1918, 26, 537.

107. Nuzum, Pilot, Stangl, and Bonar: Pandemic Influenza and Pneumonia in a Large Civil Hospital;—J. A. M. A., 1918, 71, 1562.

108. Oberndorfer: Ueber die pathologische Anatomie der Influenza-artigen Epidemie;—Mün. med. Wchnschr., 1918, 65, 811.

109. Opie, Freeman, Blake, Small, and Rivers: Pneumonia at Camp Funston:—J. A. M. A., 1919, 72, 108.

110. Opie, Freeman, Blake, Small, and Rivers: Pneumonia following Influenza;—J. A. M. A., 1919, 72, 556.

111. Orteconi, Barbie, et LeClerc: Contribution à l’Etude de la Flore Microbienne de la Grippe;—Presse Med., 1918, 26, 508.

112. Orth: Thrombosen bei der Spanischen Krankheit;—Deut. med. Wchnschr., 1918, 44, 1298.

113. Park, Wm. H.: Bacteriology and Possibility of Influenzal Vaccine as a Prophylactic;—N. Y. Med. J., 1918, 108, 621.

114. Park, Wm. H., and Williams, A. W., et al: Studies on the Etiology of the Pandemic of 1918;—Am. J. Pub. Health, 1919, 9, 45.

115. Parker, J.: A Filterable Poison Produced by B. influenzæ;—J. A. M. A., 1919, 72, 476.

116. Peacock: Influenza;—Boston Med. & Surg. J., 1919, 180, 185.

117. Peacock, T. B: Review of the Influenza or Epidemic Catarrhal Fever of 1847–1848;—The British and Foreign Medico Chirurgical Review, 1849, 7, 90.

60118. Pfeiffer, R.: Vorlaufige Mittheilungen über die Erreger der Influenza;—Deut. med. Wchnschr., 1892, 18, 28.

119. Pfeiffer, R.: Die Aetiologie der Influenza;—Zeit. f. Hyg., 1893, 13, 357.

120. Pfeiffer, R., and Beck, M.: Weitere Mittheilungen über den Erreger der Influenza;—Deut. med. Wchnschr., 1892, 18, 465.

121. Pritchett and Stillman: Occurrence of B. influenzæ in Throats and Saliva;—J. Exp. Med., 1919, 29, 259.

122. Rapoport: The Complement Fixation Test in Influenzal Pneumonia;—J. A. M. A., 1919, 72, 633.

123. Review of War Surgery and Medicine, Washington;—2, No. 1, 49.

124. Robertson and Elkins: Report on an Epidemic of Influenza Occurring at the Royal Asylum, Morningside, Edinburgh;—Brit. Med. J., 1890, 1, 228.

125. Rosenow: Prophylactic Inoculation against Respiratory Infection;—J. A. M. A., 1919, 72, 31.

126. Rosenow: Studies in Influenza and Pneumonia;—J. A. M. A., 1919, 72, 1604.

127. Schinz: Die Influenza Epidemie bei der Guiden-Abteilung 5;—Corr. Blatt f. Schweizer Aerzte, 1918, 48, 1329.

128. Schmorl: Pathologische-anatomische Beobachtungen bei der jetzt herrschenden Influenza Epidemie;—Deut. med. Wchnschr., 1918, 44, 937.

129. Schorer, E. H.: Influenza at the Port of Embarkation (Bacteriology);—N. Y. Med. J., 1918, 108, 641.

130. Shera: Influenza Epidemic of Spring of 1915;—Lancet, 1917, 192, 450.

131. Simmonds, M.: Zur Pathologie der diesjährigen Grippe;—Mün. med. Wchnschr., 1918, 65, 873.

132. Slye, Holmes, and Wells: Primary Spontaneous Tumors of the Lung in Mice;—J. Med. Res., 1914, 30, 417.

133. Smith: Influenzal Intra-abdominal Catastrophies;—Lancet, 1919, 196, 421.

134. Soper: Pandemic in the Army Camps;—J. A. M. A., 1918, 71, 1899.

135. Speares: Influenza;—Boston Med. & Surg. J., 1919, 180, 212.

136. Spooner, Scott, and Heath: Bacteriological Study of the Influenza Epidemic at Camp Devens;—J. A. M. A., 1919, 72, 155.

137. Spooner, Sellards, and Wyman: Serum Treatment of Type I Pneumonia;—J. A. M. A., 1918, 71, 1310.

138. Stone and Swift: Influenza and Bronchopneumonia at Fort Riley;—J. A. M. A., 1919, 72, 487.

139. Strouse and Bloch: Notes on Present Epidemic of Respiratory Disease;—J. A. M. A., 1918, 71, 1568.

140. Symmers: A Note on the Pathology of the Prevailing Pandemic Influenza;—N. Y. Med. J., 1918, 108, 621.

141. Symmers: Pathologic Similarity between Pneumonia of Bubonic Plague and of Pandemic Influenza;—J. A. M. A., 1918, 71, 1482.

142. Symmonds, C. P.: Nephritis in Relation to the Recent Epidemic of Influenza;—Lancet, 1918, 195, 664.

143. Synnot and Clark: The Influenza Epidemic at Camp Dix;—J. A. M. A., 1918, 71, 1816.

144. Talbot: Influenza among Children;—Boston Med. & Surg. J., 1918, 179, 779.

145. Thayer: Discussion on Influenza;—Proc. Roy. Soc. Med., 1919, 12, 28 & 61.

146. Thomas, H. M., Jr.: Rupture of Encapsulated Empyema into Pleural Cavity;—J. A. M. A., 1919, 72, 29.

147. Thompson: Influenza as it Affects the Air Passages;—Practitioner, 1919, 102, 12.

148. Titus and Jamison: Pregnancy Complicated by Epidemic Influenza;—J. A. M. A., 1919, 72, 1665.

FIG. LVII. AUTOPSY NO. 150. ORGANIZATION OF THE INFLAMMATORY EXUDATE AND REGENERATION OF THE MUSCLE FIBERS AFTER AN ACUTE HEMORRHAGIC MYOSITIS. COMPARE FIGURE LVI.

HELIOTYPE CO. BOSTON

61149. Torry and Grosch: Acute Pulmonary Emphysema Observed during the Epidemic of Influenzal Pneumonia at Camp Hancock;—Am. J. Med. Sci., 1919, 157, 170.

150. Uhlenhuth: Zur Bacteriologie der Influenza;—Med. Klin., 1918, 14, 777.

151. U. S. Pub. Health Reports, 1919, 34, 1.

152. Valentine: Study of Agglutination Reactions of B. influenzæ;—Bureau of Lab., N. Y. Board of Health Report, 1918.

153. Vaughan: The Bacteriology of Influenza (Editorial);—J. Lab. & Clin. Med., 1918, 4, 83.

154. Wadsworth, A. B.: A Study of Experimental Organizing Pneumonia;—J. Med. Res., 1918, 39, 147.

155. Wanner, F.: La Grippe à l’Hôpital d’isolement de Vevey en Juillet-Août, 1918;—Corr. Blatt f. Schweizer Aerzte, 1918, 48, 1729.

156. Wegelin: Pathologische-anatomische Beobachtungen bei der Grippe Epidemie von 1918;—Corr. Blatt f. Schweizer Aerzte, 1919, 49, 65.

157. Whittingham and Sims: Bacteriology and Pathology of Influenza;—Lancet, 1918, 195, 865.

158. Winternitz, M. C.: Anatomical Changes in the Respiratory Tract Initiated by the Inhalation of Irritating Gases;—Military Surg., 1919, 44, 476.

159. Winternitz, M. C.: Collected Studies in the Pathology of War Gas Poisoning;—Yale University Press, 1919.

160. Winternitz, M. C., and Hirschfelder, A. D.: Studies upon Experimental Pneumonia in Rabbits;—J. Exp. Med., 1913, 17, 657.

161. Winternitz, M. C., and Smith, G. H.: Intrapulmonary Irrigation;—Proceed. Soc. Exp. Biology & Med., 1919, 16, 55.

162. Wolbach, S. B.: Comments on the Pathology and Bacteriology of Fatal Influenza Cases Observed at Camp Devens, Massachusetts;—Bull. Johns Hopk. Hosp., 1919, 30, 104.

163. Wollstein, Martha: An Immunological Study of Bacillus influenzæ;—J. Exp. Med., 1915, 22, 445.

164. Wollstein and Goldbloom: Epidemic Influenza in Infants;—Am. J. Dis. Children, 1919, 17, 165.

165. Woolston and Conley: Epidemic Pneumonia (Spanish Influenza) in Pregnancy;—J. A. M. A., 1918, 71, 1898.

166. Yanagisawa: Experimental Study on the Mixed Injection of Bacillus influenzæ and Various Species of Cocci;—Kitasato Arch. Exp. Med., 1919, 3, 85.

FIG. LV. AUTOPSY NO. 146. ACUTE HEMORRHAGIC ENTERITIS ASSOCIATED WITH MULTIPLE BACTERIAL EMBOLI IN THE CAPILLARIES OF THE INTESTINAL MUCOSA.

TRANSCRIBER’S NOTES