Chapter XIII: Part 13

During the acute epidemic and while the disease was at its height it was remarkable how few cases showed involvement of the heart. It was the common observation that even during intense illness the heart action remained fairly stable and did not indicate an effect by intoxication as might be expected from the severity of the illness. In as much as the majority of deaths occurred within relatively few days of the onset of the severe infection, the type of lesion that would be looked for in the heart would be either bacterial inflammatory products within the pericardium, myocardium or endocardium or toxic lesions of musculature alone.

In our series we have encountered no cases of pericarditis. This lesion in the experience of others has also been unusual, and it would appear that bacterial invasion of this sac is accomplished mainly in the presence of secondary infections localizing in the neighboring pleura. It was not uncommon to find a slight increase in the serous fluid in the sac, but this on no occasion amounted to a hydropericardium. The fluid was always clear and with no evidence of fibrin or cellular exudate. Petechial hemorrhages scattered over the epicardium were noted in seven cases. In the majority of instances these minute hemorrhages were scattered in small numbers over the ventricular walls. In one instance these petechial hemorrhages were also present through the myocardium, suggesting the influence of an intoxication not upon the tissues of the heart as much as upon the finer structures of the vascular channels. This is furthermore borne out in the presence of petechial hemorrhages confined not to one organ, but to various tissues and structures in the body.

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.

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.

Lesions of the _pancreas_ were not encountered. In a few cases the lymph glands about the head of the pancreas were slightly enlarged.

The _spleen_ showed relatively little reaction and in only two cases was it enlarged. Fourteen times a diagnosis of acute splenitis was made on examination of the gross specimen. This diagnosis rested upon the finding of a swollen spleen with tense capsule and with a dark bulging pulp. The Malpighian bodies were usually in part or completely obliterated, though in a few instances these grayish nodules seemed even larger than normal. These spleens contained an excess of blood within the pulp. In one case several isolated areas appeared hemorrhagic as if a local rupture of the tissues had occurred. The microscopic examination of these specimens showed mainly a marked congestion of the sinusoids, a diminution in the size of the lymphoid corpuscles and some increase in the number of leucocytes within the blood spaces and reticulum. Only occasionally did we observe a proliferative reaction of the large mononuclear cells lying in the reticulum. This proliferation was not sufficiently marked nor uniformly present to be considered as characteristic. We did not find abnormal deposition of blood pigment indicating an unusual destruction of red blood cells within the spleen. It is interesting to note that 5 of the 32 cases showed obsolete miliary tubercles in the spleen.

Our analysis of the changes occurring in the _kidney_ bore out the clinical findings observed in the wards. Like in so many acute infectious diseases urinary changes were commonly present. These are in part dependent upon systemic changes in the metabolism of tissues and not entirely the result of renal lesions. In acute epidemic influenza there was no common characteristic in the urinary output. The amount excreted in 24 hours was usually diminished to a small extent, the color was darker, the specific gravity slightly increased, as well as the total solids. There was no marked change in the total quantity of output of any one of the constituents as far as they were analyzed by us. Albumin was present in the urine in variable amounts and in the more severe cases casts were also present. There was only one case in which the quantitative output was much diminished and where some fear was entertained of development of acute uremic manifestations. This individual, however, died before these made their appearance and before there was any evidence that the retention of waste products was causing definite clinical symptoms.

In 30 cases coming to autopsy more or less cloudy swelling was to be observed in the kidney. This reaction varied from a very mild swelling and granular degeneration of the tubules of the cortex to a decided parenchymatous degeneration with loss of nuclear structure and erosion of some of the cells lining the tubules. The convoluted tubules were always most markedly involved. Occasionally this tubular degeneration was accompanied by a desquamation of the lining cells of the glomerular capsules. We were, however, unable to recognize an acute inflammatory reaction in the interstitial tissue or in the glomeruli in any of the cases, except the one which had developed a streptococcus bacteriæmia as a sequel to an otitis media. The kidney lesion reminded one very much of the toxic lesion which is observed in the kidney in typhoid fever. Differing, however, from the latter there was a variable congestion of the fine vessels associated with the cyanosis which was present in a certain percentage of these cases. At times the kidneys were quite wet with blood from the venous engorgement.

The lesions in the kidney were of a toxic type and did not resemble reactions following the presence of the bacteria in the stroma of the organ. In the majority of instances in other diseases where bacteria themselves locate in tissues we are able to recognize focal lesions of acute necrosis or inflammation. In epidemic influenza where a variety of micro-organisms within the lung are able to reach distant structures in a bacteriæmia, we would, because of their type, expect to find inflammatory reactions of a definite kind. The absence of such reactions is very suggestive that the bacteria do not commonly localize in the kidney, but that their toxins alone affect it during its elimination. We have also entirely missed the finding of any vascular lesions in the renal system. Neither degeneration nor inflammatory reactions of any of the coats of the blood vessels could be distinguished.

The partial incapacity on the part of the kidneys must, therefore, be viewed as a complication resulting from the effect of a diffusible toxin reaching them by the blood stream. The damage performed in this manner may be quite extensive upon the secreting tissues of the tubules leading to an increased or decreased output of the urinary constituents. Because of the nature of the lesion, it is probable that the kidney damage incurred during the acute epidemic influenza is only temporary and not permanent. Tubular degeneration is readily repaired, and in the absence of an inflammatory reaction in the interstitial tissue or the glomeruli avoids the development of a permanent mark or derangement in the system. This is as we find it in typhoid fever.

In two cases we observed very interesting lesions in the _bladder_. These two individuals during life had been excreting markedly blood-stained urine for some days preceding death. In the one case the hemorrhage was so marked that on standing, about one-tenth of the urine was composed of sedimented red blood cells. It was assumed that the hemorrhage was of kidney origin until the autopsy revealed a simple cloudy swelling of the kidney associated with a hemorrhagic state of the submucosa of the bladder. In both cases the posterior wall of the bladder was heavily infiltrated with blood so that the mucosa was raised from the surface and the prominent folds showed a superficial erosion with small points of greenish necrosis. This bladder hemorrhage was concomitant with hemorrhagic foci elsewhere in the body, pericardium, pleura, stomach and intestine. Alone in the bladder however, the hemorrhage formed a distinct mass and allowed a considerable escape from the lesions on the surface. These areas of hemorrhage were not infected and showed no local inflammatory reaction. They also appeared to be toxic in origin and resembled the hemorrhages occurring in the muscles of the abdomen.

Changes in the _adrenal_ gland were noted in 14 instances. In all of these there was the picture of what is commonly known as cloudy swelling of the cortex and, in addition to this, in three cases small petechial hemorrhages were observed. The so-called cloudy swelling of the adrenal consists largely in a loss of the bright golden appearance of the cortical tissues accompanied by soft œdematous swelling. The tissues change color to a brown or clay color, and it is not uncommon to observe that the inner zone of pigmentation is more diffuse. There is no sharp demarcation between the layers of the cortex. With this alteration in the outer structure of the adrenal, the medulla not uncommonly appears smaller. This change is more apparent than real, and we have not been able to observe any definite lesion in the nervous portion. At times we believed that the inner tissue appeared more cellular, but it was not possible to determine any specific alteration in the cells.

The changes in the adrenal cortex are comparable to those observed in typhoid fever. The analyses of these tissues showed that the cells were almost devoid of cholesterin bodies and few doubly refractile globules could be demonstrated. This change in the adrenal is by no means specific for any acute disease, it being found in many of the severe infections. We regret that systematic analysis of the blood serum in these cases was not made to determine the cholesterin content. If the comparison bears out with typhoid fever, we would expect to find that the quantitative cholesterin of the blood is diminished. Some importance attaches itself to the study of the cholesterin metabolism, particularly in regard to the development of the peculiar fatty streaks which develop in the aorta and other arteries during these acute infections. It has been claimed that in the human these streaks bear an analogy to those produced in the experimental animals and that the arterial lesions are associated with an altered activity on the part of the adrenal cortex in handling the cholesterin compounds. In influenza there is evidence that the adrenal does not function in a normal fashion and that the storage of cholesterin-esters does not take place. From this, however, we cannot conclude that the blood content is increased, and, in fact, it is more than probable in comparing the other reactions of the disease that it follows the changes as seen in typhoid fever where the blood content of cholesterin is lowered. In this way comparison with the experimentally produced arterial lesions in animals is not clear, in as much as in the experimental work a true hypercholesterinemia was induced. Nevertheless it is possible that with the abnormal function on the part of the adrenal the cholesterin materials are made more available for absorption by other tissues and that a true hypercholesterinemia is not necessarily a constant factor, even with the abnormal accumulation of these substances in the intima. It may well be that the normal activity of the adrenal is related to the presence of toxins in the circulation and an attempt by mobilizing cholesterin to diminish the activity of these harmful substances.

OBSERVATIONS UPON THE PATHOLOGY OF EIGHTEEN CASES OF INFLUENZA

By J. W. MCMEANS

The recent epidemic of influenza has afforded a series of interesting autopsies in view of the very extensive and peculiar involvement that occurred in the lungs of the cases examined. Ordinary lobar pneumonia, as we know it, was not observed, although it must be said that the lungs many times exhibited a consolidation of a lobar distribution. The usual dry granular lung of the more common pneumonia was absent, and in its stead a most unusual series of pictures was observed in the several cases. A common feature of all cases was the œdema of the lung tissue, which in the majority of instances contained such an amount of fluid that it ran freely from the cut surface in almost unlimited quantity. This fluid varied in its color and consistence depending upon the age of the process. In the very early cases the lungs were boggy, very congested, and a thin serosanguinous fluid poured forth from the cut surface. It actually appeared as though the fluid within the tissue was under considerable pressure. At times blotchy deep red hemorrhages occurred in the lung substance, and hemorrhages of a bright red color were not infrequent in the pleura. That the circulation of the lungs was much embarrassed was often prettily demonstrated by the dilatation of the fine capillaries and lymphatics beneath the pleura. These small vessels stood out prominently as a meshwork more or less outlining the areas supplied by them. Not only was the peculiar consolidation in lobar arrangement, but also in many cases was there evidence of a lobular distribution. Even in some cases where the entire lobe was consolidated the cut surface presented a peculiar lobulation with patches of lung tissue projecting above the general surface. The wet trabeculated structure of the lung in this stage did not give the impression of true red hepatization, but rather a structure resembling spleen and at times a meaty, compact, glassy picture not unlike thyroid.

As the process advanced the appearance of the lung changed from deep red to yellowish red and finally to a quite yellowish gray color, still retaining, however, the very moist characters. The fluid found in the lung changed its consistency from the thin red type to a sticky, glairy variety which could be pulled out in long strings. It was noted that the change in the character of the fluid was accompanied by similar changes in the lung structure, advancing in two cases to abscess formation of a grape-bunch type. Here there was a rather extensive necrosis and cavitation of lung substance in communication with the bronchioles. However, there was also marked softening and necrosis of lung in a number of cases where abscesses did not develop, but the lesion was so advanced that the lung substance was almost diffluent. An accompaniment of these advanced cases were irregular yellow islands which appeared beneath the pleura. At times they reached the size of a circle 2 cm. in diameter and were slightly raised above the surrounding pleural surface. When these were opened they were found to be areas of softened lung substance. This reaction was so extensive in some lungs that it resembled to a degree the appearance of a caseous pneumonia. However, the former process appeared to be brought about by the interference with the lymphatic drainage, as it was not uncommon to see engorged yellow channels beneath the pleura as well as enlarged lymph nodes at some distance from the hilus. Another feature of the advanced cases were the plugs of ropy yellow material which were contained within the bronchioles, while in the early cases the bronchi and bronchioles showed intense congestion of the mucosa with blood-stained fluid in their lumina.

Of the more unusual reactions observed in the lungs an infarct was found occupying a considerable part of the lower left lobe in one case. There was a marked softening of the lung tissue with reddish, mucky-looking lung substance arranged about small irregular cavities. This reaction extended into the lung for a distance of 4.5 cm. Bordering close on these softened areas there was a dry mottled yellowish gray and deep red lung tissue. Surrounding this area again were noted a number of small blood vessels in which there were found yellowish granular plugs. One plug in a vessel was found at a distance of 3 cm. from the base of the lobe, and another was found at a distance of 8 cm. from the apex of the lobe. On further examination it was observed that the base of this softened area was situated on the pleural surface and that the apex was directed inward about a distance of 6 cm. from the pleura. Bathing the cut surface there was a glairy and very sticky material of a reddish yellow color. Near the apex of this softened area in the lung there was found a vessel about the size of a goose-quill in which there was a grayish yellow granular plug. This plug was adherent to the vessel. Within the small bronchioles there were plugs of a soft yellowish brown material. The striking feature in addition to the softening of the lung in a number of places was the glairy material of a sticky nature which bathed the cut surface. A white infarct was present in the spleen. The lung described above as well as another showed gangrenous change. In the second of these two abscesses had formed, and there was a communication between the lung and pleural cavity in which there was a large amount of sanguino-purulent fluid and a pyopneumothorax.

In a description of these reactions it must be added that the early and late changes were not always observed independently, but in most cases occurred together, giving the lung a peculiar mottled red and yellow glassy appearance. More frequently the congested œdematous reaction was observed singly, while the purulent alteration usually was in combination with the former type. The acute serous pneumonia was noted 13 times, 6 times in combination with the purulent reaction and 7 times alone, while the acute purulent pneumonia was found in 9 cases, 3 times alone and 6 times with an acute serous process. In all but 3 of 18 cases there was evidence of a bronchial distribution. Two of these three cases showed a massive œdematous lung with in one case an extensive hemorrhage, while the third presented an advanced purulent reaction with marked necrosis and softening. An acute bronchitis which varied in character from a hemorrhagic to a purulent one was present in all the cases. The reaction observed within the bronchi in the individual cases corresponded closely to the picture found in the lungs.

In all cases except one there was an exudate in one or both pleural cavities. A serofibrinous pleurisy was noted in 11 cases with, in 2 of this number, a fibrino-purulent reaction present in the opposite pleural cavity, while fibrino-purulent pleurisy occurred alone in 6. In 6 cases pleurisy occurred on one side only with the incidence equally divided in each cavity. Both pleurae were involved in 9 cases. Seventeen of the 18 cases showed both lungs involved. One case was an individual who had had clinical influenza and during convalescence developed gangrenous colitis and acute ascending myelitis which terminated fatally. B. influenzæ was isolated from the bronchioles in the lung of this individual.

The reaction of the body generally was evidenced by a widespread distribution of petechial hemorrhages over serosal and mucosal surfaces. However, certain other important lesions were noted such as one acute vegetative mitral endocarditis, two acute serofibrinous pericarditis, three cases in which focal necroses were prominent in the liver and two examples of infarct of spleen. Further, there were four cases of slight dilatation of the right heart. The liver was usually swollen and œdematous and the spleen presented evidence of an acute reaction, softening and reddening of its pulp with at times slight enlargement.

As evidence of the virulent character of the infection from which these patients suffered, there was not only present in the lung a peculiar hemorrhage and purulent process, but also a more or less widespread distribution of hemorrhages in other parts of the body. The gastro-intestinal tract was most affected with the stomach showing petechial hemorrhages in 17 of 18 cases and the small intestine in 15 of the same number. In the gastric mucosa of three cases there were definite erosions, while in two instances the duodenum presented an intense œdematous and hemorrhagic appearance of its mucosa. Further hemorrhages were observed on one occasion each in the mesentery and in the mesenteric and retroperitoneal lymph nodes. In the latter the mesenteric glands were so distended with hemorrhages that a soft pulp spurted out when the glands were sectioned. Next in order of frequency, hemorrhages were noted 9 times in the pleura, 8 in the pelvis of the kidney, 6 in heart muscle and 3 each in pericardium and bladder. In one case of widespread distribution of petechial hemorrhages there was a massive loose hemorrhage into the lower recti abdominis. Further another case showed a large amount of a blood-stained fluid in the peritoneal cavity.

_Summary_

In the analysis of the cases of acute epidemic influenza two important features of the disease present themselves, (1) a marked systemic intoxication with localized manifestations in certain organs, and (2) inflammatory lesions of the respiratory tract. These manifestations present themselves both to the clinician and to the pathologist, and to each they have demonstrated their importance in the disease. The pathologist not in touch with the clinical manifestations of the toxæmia has more closely linked the occurrence of these two factors with the actual findings in the cadaver. But there are those who look upon these factors as separate and distinct, viewing the toxæmia as an individual process and as illustrating the uninvolved influenza, while the inflammatory reaction of the respiratory tract is taken to be a complication arising through the activity of secondary invading organisms. This is the view held by MacCallum, who compares influenza with the acute exanthemata wherein the respiratory lesions are but secondary to the production of a lowered resistance and an invasion by a variety of bacteria. Such confusion presupposes an undetermined virus for influenza. In confirmation to such views we have the reports upon a filterable virus. Up to the present, however, the latter has been on insecure grounds.

It would appear to us that, as has been discussed by Dr. Holman, the case against the B. influenzæ not being the important causative agent has not been proved. The demonstration by others of a potent toxin from the B. influenzæ cannot be overlooked, and although the actual disease has not been reproduced in animals, there is evidence that this toxin will induce acute degenerations in various tissues. Furthermore, the in vitro symbiotic relation demonstrated for the B. influenzæ with other organisms, as the pneumococcus, streptococcus, staphylococcus pyogenes aureus and M. catarrhalis, gives ample support to the claim for a similar symbiosis in the human tissues. The evidence for the important primary relation of the B. influenzæ to epidemic influenza is such that we cannot disregard it—at least, not before we can produce some definite positive evidence that another demonstrable virus precedes it and produces those constitutional effects which initiate the remaining sequelæ.

We must agree with Christian in the statement that all cases dying during the acute stage of epidemic influenza have inflammatory lesions in the respiratory tract and largely in the lung (pneumonia). It is difficult to conceive of a disease comparable to the acute exanthemata, which beginning as a separate and distinct process ends fatally within 48 hours with a pneumonia which is claimed to be secondary.