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.

Lymphadenoid Tissues.

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.

The 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.

Spleen.

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.

Bone Marrow.

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 fatally 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.

Only 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.

Physical 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.

A 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.

Summary.

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.