Studies on Epidemic Influenza: Comprising Clinical and Laboratory Investigations

by University of Pittsburgh. School of Medicine

The lesion within the lymph nodes following the early serous inflammation was of a non-suppurative kind. The lymph follicles lost their outline, and the lymphocytes were diffused through the stroma so that no recognition of the germinal centers could be found. The dilated sinuses within the lymph nodes were filled with large mononuclear cells, of the type of endothelial cells, along with some lymphocytes and leucocytes. Subsequently the leucocytes increased very materially so that the lymphatic fluid became purulent. Smears obtained from larger lymphatics showed leucocytes and varieties of bacteria. This was particularly true in those cases where the pulmonary lesion had itself become purulent either localized in a patchy pneumonia or with lobar involvement. Under these circumstances focal areas of purulent infiltration were found within the tissues of the gland occupying the regions of the former follicles and leading to necrosis or abscess. Where such purulent reaction and abscess formation were found within the lymph nodes there was remarkably little reaction in the tissues of the immediate vicinity. No attempt at the development of a pyogenic membrane or granulation tissue was observed, though this probably does take place in the cases recovering.

In only one instance did we observe the development of the peculiar fibrosis along the lymphatic channels where the freshly cut section of lung reveals prominent and raised demarcation between the lobules. This response has been described by MacCallum as unique for the streptococcus inflammation of the lung. The character of the exudate within the lymphatics with many mononuclear cells and blood is not to be considered singular for the influenza pneumonia. It has been found that in ordinary lobar pneumonia, as well as in the pneumonia following measles, the early pulmonary reaction is accompanied by the dilatation of the lymphatic channels along the bronchi, containing serous fluid, mononuclear cells, blood and leucocytes, while occasionally thrombosis entangling bacteria is also encountered. It would seem, however, that the lymphatics in epidemic influenza can more readily recover their normal character when a streptococcus infection is wanting.

In the late purulent lesions of the lung we have encountered dilated lymphatic channels whose yellow contents could be recognized by the naked eye. At times this could be followed for short distances along the bronchi as narrow yellow cords, or when cut transversely appeared as small dots close to the bronchi or vessels. On pressure small droplets of pus may be evacuated, or again where fibrin has led to a coagulation of the exudate a yellow plug can be withdrawn from the channel. These small plugs resembled the thick exudate seen within the bronchi and often were misleading when first viewed. The distribution of the purulent lymphatic masses was most irregular occupying only local or patchy fields in the lung, particularly associated with the purulent confluent pneumonia. In one instance such a lymphatic appeared to be associated with the development of a small abscess lying close to the bronchus.

Too much stress cannot be placed upon the importance of the lymphatics in all forms of pneumonia. They play an important role in the drainage of the lung during inflammation. In the normal lung we hardly appreciate the lymphatic distribution except in our observations upon anthracosis. But even under these conditions when much carbon is deposited in conjunction with the lymphatic system we do not gain a true appreciation of the activity of the lymph channels and nodes during an acute process. Bacteria may be demonstrated in acute infections of the lung within the fluid and cells of the lymph channels. Less easily may we demonstrate bacteria in the lymph nodes under similar conditions, although when abscess has occurred their presence is readily recognized. The transport of bacteria is accomplished not only by a passive migration of micro-organisms in the fluid as it drains from the lung, but organisms are also found within the leucocytes as they travel with the current. Only occasionally have we demonstrated bacteria within the wandering large mononuclear cells, although we have observed them in a few instances within the cells lining the sinuses of the nodes.

Whether the inflammation of the pleura is directly related to the involvement of the pleural lymphatics we have not been able to determine. In our series of cases pleurisy has not been a prominent feature of the disease, and in many instances the grade of involvement was so slight that it was not easily recognized by the naked eye and showed only a slight reaction microscopically. That the presence of bacteria within the intricate plexus of lymphatics beneath the pleura may be responsible for the development of an inflammation of this membrane may well be the case, and in this way simulate the mode of transmission of the infection as seen in lobar pneumococcus pneumonia and in the streptococcus type of infection.

Abdominal Viscera

The lesions occurring in the abdominal viscera were of less importance than those within the thorax. In none of the cases of the epidemic was the intestinal type of the disease, described in previous years, encountered. The changes found in the various viscera were concomitant with evidences of intoxication as observed clinically or at autopsy in other regions of the body. We found no evidence that the bacteria of the disease localized in the tissues of the abdominal viscera, and we were led to believe that the alterations in morphology and function were the result of diffusible toxins. The action of these toxins was either upon the parenchymatous cells of the organs, as in the liver and kidney, resulting in granular degeneration, or upon the capillaries with the development of petechial or diffuse hemorrhage as was encountered in the stomach, intestines and bladder. The absence of definite localized inflammatory processes in these distant tissues, including the abdominal lymphatics, speaks against the probability of a bacteriæmia playing an important role in the disease. That transient bacteriæmias by the influenza bacillus do occur has been repeatedly demonstrated, and that the organisms associated with this bacillus may also enter the blood stream has likewise been found. But these states are accessory to the disease, and must be viewed as complications rather than the rule. Hence the occasional observations by some, of bacterial inflammatory reactions in liver and kidney must not be considered a part of epidemic influenza, for in many cases it is wanting. The majority of lesions of the abdominal viscera probably arise through the action of the unknown toxin in the blood.

In the stomach and intestines the lesions were of two kinds, (1) hemorrhage and (2) erosions. Petechial hemorrhages were present in the stomach 15 times, in the intestines 4 times. These small dots of blood extravasation, lying in the mucosa and submucosa, differ in no way from those observed in other acute infections and intoxications, save that the tendency for the leakage of blood into the lumen of the viscera was more pronounced. Often we could observe the presence of free and more or less altered blood in the stomach and intestines, and in 12 cases the amount was considerable, sufficient to be spoken of as melena. It is probable that the oozing of blood takes place not only from the areas visible to the eye as petechial hemorrhages, but also from the more normal-looking mucosa of stomach and bowel. The tendency to hemorrhage was not necessarily accompanied by visible alterations in the epithelial layer of the mucosa, though at times erosions were found. When hemorrhage could be observed, the extravasation of blood occupied the superficial layers of stroma, causing a separation of the tissues beneath the epithelial layer. At times the submucosa was also infiltrated, and in one instance the musculature. The lesions were isolated and sporadic, but always about small capillary loops. It appeared to us that the damage was primarily upon the vascular tissues and particularly upon the endothelial walls of the fine channels. Inflammation was not present, and the hemorrhage was more or less passive—that is, a slow oozing rather than acute hemorrhage by rhexis.

The second type of lesion of the gastro-intestinal canal was erosion. This was of the nature of a defect in the mucosa, usually multiple, small and well circumscribed. The tissue loss was superficial. In their appearance these lesions were similar to those encountered in these parts in other infections, and also as described by McMeans in experimental infections of animals. The erosions appear to arise in a process of bland necrosis, limited in the periphery by healthy tissue and not tending to enlarge. It is probable that these erosions are associated in their development with the petechial hemorrhages, being a sequel to the vascular disturbance of the mucosa and subsequent digestion of the injured tissue. Multiple lesions of the stomach were found 10 times and twice in the intestine. The largest was 1.25 cm. in diameter. They are more common on the posterior than anterior wall, and usually toward the lesser curvature. It is probable that these defects are limited in their progress and heal readily.

The changes occurring in the liver were not of striking account. Cloudy swelling was observed 13 times, usually of moderate grade. The usual appearances with enlargement of the organ, bulging of the parenchyma on section and a dull gray cut surface were all that could be found. The one case with icterus was the only one in which the natural discharge of bile from the liver was interfered with through the swelling. Even in this case the obstruction to the outflow of bile in the small channels was not demonstrable in the microscopic sections, nor was there evidence of unusual bile staining of the liver-points suggesting the possible origin of the icterus in an unusual hemolysis. On no occasion did we meet with recent inflammatory reactions in the gall bladder or bile ducts, and we have no evidence that the organisms of the infection are discharged from the body by these routes. The cloudy swelling of the liver was accompanied by slight œdema of these tissues in seven cases; and in six instances focal necroses were observed. These focal necroses were similar in appearance to those seen in typhoid fever, but were much less frequent in the tissue. Only careful search revealed isolated pinhead gray dots with depressed centers. They were most commonly in the mid-zone of the lobule, and in the early stage were without inflammatory reaction. Subsequently, leucocytes infiltrated the area, but not in an amount to form pus. Bacteria were never demonstrated in the areas of focal necrosis. Four cases showed old adhesions about the gall bladder and in one a gall stone was present.