Part 32

More or less cloudy swelling or granular degeneration of the muscle elements of the heart was not uncommon. It was sufficiently pronounced in 12 cases to be readily detected by the naked eye. A lesser amount was also observed in other cases on microscopical examination. In only one instances was the myocardial degeneration of such extent to lead to a definite and recognizable weakening of the musculature. In this instance the autopsy showed a flabby myocardium which was relatively soft and easily broken and in which all the chambers of the heart were decidedly dilated. This was the only case in which we were convinced of a sufficient influence of the toxic effects upon the musculature to permit a stretching of the walls, with failure of function.

In a number of other instances, however, in which there was more or less granular degeneration and cloudy swelling we found that the right ventricle ceased in diastole without, however, the capacity of the chamber being enlarged. We would make this differentiation in speaking of dilatation of the heart. We have met with 11 cases in which the right heart died in diastole, but in which there was no evidence that the right ventricle had been unduly expanded. In four cases there was evidence of an old compensatory hypertrophy of the left ventricle in which the cavity of this chamber was also slightly larger than normal. The lesions in these four cases, however, bore no direct relation to the results from the influenza infection. The appearance of the musculature with moderate grade of cloudy swelling suggested some œdema of the tissues. In the myocardium, œdema is difficult to recognize, and we would not place great stress upon its presence in mild degree.

The microscopic examination of the myocardium showing cloudy swelling gave the usual picture as is seen with a variety of infections. The muscle fibers showed a fine granular deposit in their cytoplasm and the staining quality of the tissue was somewhat altered. The transverse striæ were less distinct than normal, while not uncommonly the longitudinal fibrils became more evident. Fatty degeneration was not encountered.

In the single case showing a definite and acute dilatation of the ventricles the cause of the myocardial lesion could not be placed at the door of the influenzal infection. This was the case suffering from a secondary streptococcal bacteriæmia arising in the middle ear. It is more than probable that the streptococcus was the immediate cause of the acute muscle change and weakening. In a number of cases we have studied the tissues of the bundle of His, but we were unable to note any definite change.

It is interesting that the intoxication associated with acute influenza is selective in localizing in certain muscle tissues. We have previously indicated the intensity of muscle degenerations occurring in the abdominal recti. Even in these cases where these striped voluntary muscles were markedly affected the myocardium showed nothing more than a mild or moderate grade of cloudy swelling. We can only account for this in a difference in the constitution of these muscular structures, some being of such composition permitting of the localizing and damage by the unknown intoxicant. It does not appear that the reason for localization in certain tissues is in any way related to the character of the blood supply, nor is it related to the activity of the part.

In three cases we have found an inflammatory lesion of the endocardial tissues. In all of them this consisted of a slight acute verrucose mitral endocarditis. The lesions were very small, consisting only of a fine granular deposit looking like grains of sand localized along the border of the mitral leaflets. In no instance was the leaflet injured or incapacitated. Unfortunately the lesion not being suspected was encountered after the heart had been removed and opened and when it was too late to make bacteriological analyses. This point is greatly to be regretted, in as much as it is of great importance to know whether some distant lesions are induced through the influenza bacillus or its symbiotic flora.

The majority of authors report but little upon the heart lesions in influenza. Many deny that a heart involvement is to be found, a few report an occasional endocarditis. Wallis and Kuskow found more or less myocardial change similar to what is usually described as cloudy swelling. This reaction they point out differs in no way from the degenerations arising from other types of intoxications. Keegan in a series of about 23 autopsies found only a single case with acute dilatation.

Abrahams, Hallows and French had an opportunity of observing over 400 autopsies upon the influenza patients, and they comment upon the infrequency of cardiac dilatation. A slight dilatation of the right ventricle was seen in a few cases, and in no instance did they find pericarditis or endocarditis. They comment upon the heart condition as follows: “The most remarkable feature about the heart is the general absence of dilatation. In quite a large proportion of cases there has been no trace of dilatation; in a fair number of others there has been some dilatation of the right side, but this has seldom been extreme, perhaps enough to cause the apex of the heart to be formed about equally by right and left ventricles. Most often the heart has appeared of normal dimensions and the apex has been formed entirely by the left ventricle. This absence of dilatation accounts for the clinical absence of orthopnœa.” In direct contradiction to the above findings, the Advisory Board to the D. G. M. S., France, report the findings in 30 autopsies of clinical influenza. Twenty-nine of these 30 cases showed dilatation of the heart, chiefly of the right side, but very commonly of the left side as well. Twenty-one showed myocarditis and two endocarditis. In this report it is stated that these patients showed evidence of obsolete tuberculosis. It is possible that the condition of the patients and the presence of an unusual complicating infection led to the high incidence of cardiac involvement. The figures in this last series are much too high when compared with the frequency of heart involvement as found by the majority of other investigators.

A number of heart lesions not resulting from influenza were observed. For none of them was there an antecedent history, but in some cases the condition may have had an influence in causing accessory cardiac embarrassment. One case had a chronic interstitial myocarditis of the rheumatic type, three had mild grades of chronic sclerotic mitral endocarditis, one a bicuspid pulmonary valve and three showed old pericardial adhesions, one of them having a complete obliteration of the sac. The foramen ovale was patent in six of the hearts.

_Arteries_

The arteries in these young adults were remarkably healthy, and in none of them did we observe the characters of arteriosclerosis or leutic lesions. On the other hand, evidence of superficial fatty streaks lying in the intima of the aorta and some of its large branches were not uncommon and are believed to have had a relation to the acute infection of which they died. In only four cases in the series of 32 autopsies was evidence of these fatty streaks wanting. In about one-half of the remaining number these fatty streaks were only slight or moderate in extent, while in the rest of them these lesions were particularly prominent and striking. They formed linear markings on the posterior wall of the aorta, aggregating with particular prominence about the intercostal arteries. The anterior wall was quite free from them. The greater extent of these lesions lay in the descending thoracic and was less marked in the arch and the abdominal aorta. At times these fatty streaks were found to extend into the large vessels of the neck and into the intercostal arteries, and they were also found in the coronaries of the heart. It was uncommon to observe their presence in the arteries of the abdominal viscera.

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.

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.