Studies on Epidemic Influenza: Comprising Clinical and Laboratory Investigations

by University of Pittsburgh. School of Medicine

This type of lesion has been discussed from the standpoint of its etiology and its possible bearing upon true arteriosclerosis. Some believe that the frequency of its finding in autopsy material suggests the non-importance of its presence. This we can hardly agree with. It is true that the presence of these lesions does not materially incapacitate the aorta in acting as the main channel for the distribution of blood. The lesions are quite superficial in the intima and cause but little elevation on the surface. The amount of roughening which the intima presents to the blood is not great. Nevertheless, the presence of these fatty streaks is an index of the disturbed metabolism of the cholesterin products of the body. Under certain conditions they make their appearance when there is a true hypercholesterinemia such as is readily produced in the animal experiments by feeding cholesterin. Under these circumstances the various tissues of the body, including the adrenal, the corpus luteum, the spleen, liver and arteries, all participate in localizing cholesterin in the form of cholesterin-ester in peculiar cells which have been termed cholesterin-ester phagocytes. It has been shown that cholesterin metabolism is quite readily altered in the human and that the blood content will vary from the normal. In chronic kidney disease, pregnancy, diabetes, chronic heart disease and arteriosclerosis the blood cholesterin rises, while in many of the acute infectious diseases the cholesterin in the blood is materially diminished. It is particularly in these latter cases where fatty streaks of the intima are prone to occur. Hence in human pathology we more often meet with the development of fatty streaks of the intima associated with a hypocholesterinemia than with a hypercholesterinemia.

The fatty streaks of the intima of the aorta to which we are referring are lesions quite aside from true endarteritis as well as atheroma. In naked eye appearance the lesion is of a fatty nature and suggests atheroma, but it differs from this well-known lesion in the fact that the fatty materials, cholesterin-esters, are contained within cells which are of uniform type and have no reaction in their immediate vicinity. True atheroma may occur in definite levels of the intima, most commonly in the deepest portion, and is characterized by the fact that we are dealing with a variety of fatty materials, neutral fat, fatty acids, soap, cholesterin-ester and free cholesterin which lie between the tissue cells forming a detritus following a process of true degeneration. It is possible that some of the superficial fatty streaks do give rise to a small atheromatous area by death of the cells which primarily contain the fatty substances. Most commonly, however, the fatty streaks do not progress directly to atheroma but may entirely disappear, as we have seen it occur in our experimental animals. At other times these fatty streaks are followed by a slight thickening of the surface of the intima so that the resemblance to early endarteritis is obtained. We do not believe that these fatty streaks in themselves lead to the chronic nodular thickening of the aorta, but that other factors giving rise to a low grade inflammatory reaction must be present.

There appears to be a relation between the development of these fatty streaks and the altered cholesterin metabolism, brought about by pathological change in the blood, adrenal cortex and it may be in the liver. It is under these conditions where these tissues are altered particularly by bacterial toxins in a process of marked cloudy swelling that these intimal fatty streaks arise. Analyses in other diseases have shown that such organic changes lead to a diminution in the cholesterin content of the blood, while at the same time there is neither an increased intake nor an excessive output. It would appear that certain types of tissues and cells are stimulated into activity to become depots for the cholesterin which is not being properly handled by the adrenal and other organs. These cells in the intima which become active in taking up cholesterin-esters are types of endothelial cells whose origin is not entirely clear. In these lesions it is observed that the most superficial cells of the intima do not show an overloading with the fatty compound, but that the cells active in absorption lie at a level slightly beneath the endothelial lining and form colonies as if arising through active division of cells which are present in these parts. Active migration on the part of these cells is not to be observed. They do not appear to wander far from the location where they are found during the acute process. The plaque may enlarge by proliferation and thus enlarge the extent of the involved area. We have failed to find, however, that these cells migrate into the lowermost portion of the intima or into the media. The possibility that these cells do arise from the endothelium lining the blood vessels has, up to the present, not been excluded. If such is the case, the cells appear to adopt a function which is not commonly observed in normal arteries nor present in the endothelial cells lying immediately above the fatty plaque.

We have searched various arterial systems in the cases of acute epidemic influenza for inflammatory lesions lying in the adventitia and media. These, up to the present, we have not discovered. Some years ago a number of French authors reported the development of acute non-suppurative influenza lesions in the outer coats of arteries which at times had aneurysm as the outcome. These cases, however, occurred during non-epidemic periods, when the type of influenza of which the patient suffered was quite different from that seen in pandemics. As far as we know none of the reported cases of arteritis and aneurysm occurring under these conditions has shown the presence of the influenza bacilli in the arterial lesion. It is possible that sporadic influenza has complicating secondary infections which are of importance in localizing in the arterial wall.

Occasional reports have been made upon the occurrence of thrombosis immediately following an attack of influenza. These thromboses have occurred in diverse regions, the brachial, femoral, the mesenteric, and other arteries. It is possible that the development of the deep hemorrhagic lesions of muscles in the extremities are associated with thrombosis. It is impossible, however, to demonstrate within such blood masses the presence of thrombosed vessels which had preceded the hemorrhagic state. It was, however, possible to demonstrate capillary thromboses through the lung and in the submucosa of bronchi and trachea. In these instances the damage to the vascular walls was brought about by the action of the infection immediately surrounding them, and was not associated with a process beginning within the lumen of the channel. The type of thrombosis within the lung to which we have referred in a previous discussion is interesting in that it does not show the usual type of fibrin clotting, but in place of fibrin threads a gummy homogeneous material is deposited upon the vessel walls within which the red blood cells soon undergo dissolution. It would appear that these thromboses within the lung are dependent upon a toxic action on the vessel wall and its plasma content.

Thromboses within venous channels are met with more often than in arteries. The veins of the lower extremities are most frequently affected, and yet amidst the many cases of influenza it is an unusual occurrence. The various thromboses of larger vessels usually occur as post-influenzal complications rather than as accompaniments of the acute disease. It is possible that factors other than those present during the acute stage play an important part, and that the virus of influenza is not directly the cause of the thrombosis.

Lymphatics of Lung and Mediastinum

One of the prominent reactions which was almost constantly present as the inflammatory reaction involving the lymphatic system of the chest. The lymph glands within the chest responded to a marked degree in hyperplasia and commonly showed enlargement quite out of proportion to what is usually observed in lobar pneumonia. These reactions were in direct relation to the inflammatory processes of the lung and appeared to be involved in proportion to the inflammation occupying the tissues drained by them. Elsewhere in the body the lymph glands responded but slightly, and often no change was observed in the lymphatics of the abdomen, axilla and lower extremities. The systemic intoxication thus had no effect upon distant lymph glands, and even the presence of micro-organisms in the circulation did not appear to cause responses in these tissues other than in the neighborhood of the chest. Within the chest the lymphatic system became involved through the presence of the various bacteria migrating along the lymphatic channels as well as through its activity in removing products of inflammation.

The response of the thoracic lymphatics, including those within the lung and mediastinum, is observed in all stages of pneumonia. But in epidemic influenza the reaction was much more prompt, appearing in the early stages and rapidly developing tissue changes along the channels and in the lymph nodes. The lymph channels during the period of the early serous pneumonia became dilated and filled with fluid with relatively few cells. The stroma immediately surrounding became œdematous, so that in the gross specimen the connective tissue between the lobules of lung were sometimes easily seen as gray strands. At this time this tissue was not increased in quantity and did not project above the level of the cut lung. The fibrous tissue remained soft and pliable, but formed quite wide strands. When the pulmonary reaction became hemorrhagic, red blood cells, leucocytes and large mononuclears were found mixed with the fluid in the lymphatics. We had no way of determining the direction of the lymph flow from the pulmonary tissues, but it was assumed that as there was no excessive loss of serous fluid from the lung and the lymphatics beneath pleura into the chest cavities that the fluid was draining through the channels lying about the bronchi and vessels. The further evidence of the direction of flow was seen in the rapid and comparable responses which occurred in the lymph glands along these routes. The glands about the bronchi and at the hilus became enlarged, red and succulent. The glands were often two and one-half centimeters in diameter. Their capsule was thin and stretched and the gland was quite soft. Many of them when cut open were almost diffluent.

This acute lymph hyperplasia occurred in 30 of our cases. It is impossible to indicate any particular type of infection as being responsible for these lymphatic lesions. The nature of the bacteria present in these 30 cases differed quite considerably: 25 showed influenza bacilli, 15 pneumococci, 18 streptococci, 8 M. catarrhalis and 17 staphylococci. In as much as the pulmonary reaction was fairly constant in certain characteristics in all of our cases, and as we believe that the influenza bacilli were the very important factor in these reactions, it would appear that the lymphatic responses are only a part of the general inflammation of the respiratory organs. Comparison can also be made of the character of the lymphatic changes with that occurring within the pulmonary tissues. The lymphatics were filled with fluid which dilated all the available sinuses; the lymph nodes were œdematous and within them the reaction often had numerous small hemorrhages.