THE PATHOLOGY OF EPIDEMIC INFLUENZA

ByOskar Klotz, M. D., C. M.

The discussion to be entered into in this report will be limited to an experience dealing with epidemic influenza as it was met with in the emergency Military Hospital in Pittsburgh. We shall largely confine our attention to the observations which came directly under our supervision, and in as much as this investigation was continued during the epidemic as it swept over this district, the intensive study was limited to a time period of about five weeks. During this period much material was collected, which since then, has taken us a considerable time to analyze. We have thought it more valuable to restrict our discussion to this material in that it illustrates the pathological lesions as they occurred during the acute stage of the disease. We have not entered upon a discussion of the sequelæ or the chronic lesions which are not uncommonly found following in the wake of an acute epidemic nor do we deal with the lesions arising in cases of sporadic influenza, such as are always with us. As is so well illustrated in the literature, there is probably no disease which has so many late complications and sequelæ as influenza. The investigations upon the protean lesions have been fully reported in numerous papers during the intervals between epidemics. A comprehensive bibliography upon influenza will be found at the end of the extensive report by Leichtenstern (1905). There is very much less accurate information available upon the actual lesions present during the acute disease when present in epidemic or pandemic form, than upon the many clinical complications in various systems and organs. In fact, our knowledge of the pathology of influenza lies more largely in the field of associated lesions such as the late events in the bronchi, the sinuses of the head, abscesses, meningitis and other conditions, rather to be viewed as complications than as portions of the disease. There are relatively few thorough pathological analyses of the influenza lesions as they are found in the acute epidemic disease.

A fair literature has already appeared upon epidemic influenza from the many countries and regions over which the present pandemic (1918) has swept. These reports by various authors are offered from different viewpoints, some investigators being impressed with certain features which they bring into marked prominence in their reports. It thus happens that up to the present there is a decided lack of uniformity in the opinions expressed upon different phases of the subject. The nature of the pathology of the past epidemic has given rise to many expressions of opinion as well as dogmatic statements, which are found to differ from those of others. It seems to us that this apparent confusion arises partly through the somewhat different characteristics of the disease as it has made its appearance in different centers. We hear it repeatedly stated that the types found in different military camps and urban communities were quite unlike those of other regions. It is evident that such differences in the clinical course actually did exist and that the epidemic though having a common foundation upon which the disease process was built differed in what might be looked upon as symbiotic complications during the early and acute stages. Differences in the nature of the findings in various communities also probably lay in the fact that the bacterial flora associated with the causative agent of influenza was quite different in different regions. We mention this here so that a full appreciation will be obtained for the differences in the pathological characters of the disease as they are found in one region or another. We appreciate, of course, that if the concomitant bacterial flora associated with the underlying cause of influenza, differs in different regions, so, too, will the bodily reactions differ within certain degrees. We are becoming more familiar with different types of bacteria, and the resulting inflammatory reaction which is often unique or at least particular, and that not uncommonly the nature of the inflammatory process suggests the type of bacterium involved. This argument, of course, must not be driven too far, for we well know that the same micro-organisms under different conditions can cause types of inflammatory reactions wholly divergent.

In as much as our observations are confined to a particular group of cases and the study of these was undertaken during the five weeks of the acute epidemic, these results are not to be compared with the collected statistics on influenza as they shallbe made over a period beginning with the onset of the epidemic and ending with the last vestiges remaining after months or it may be years of time. Our observations are to be considered only in the light of the events taking place during the height of an epidemic wave. In as much as influenza presents itself during an epidemic in different forms, we shall again mainly limit the report upon our investigations of those cases having respiratory lesions. Our acute observations were made upon the tissues of those who had died of this disease. It is impossible, or nearly so, to fully study the tissues of those with lesser lesions and who recover. Hence, if we divide the influenza cases into those (1) without pulmonary lesions and (2) those with pulmonary lesions, we must state that all of our cases coming to autopsy fall in the second group. It is true that one of these having pulmonary lesions was not brought to his fatal termination by them but by a septicæmia arising in the middle ear. He had distinct lesions in his lungs. In other words, our autopsy material represents epidemic influenza in which the lung was definitely involved in an inflammatory state. In all but one of these the pulmonary lesion was the cause of death.

No doubt, if opportunity had presented itself to follow a large epidemic through months of its progress, during which late complications in various portions of the body would make their appearance, our analysis would give a different picture and the pulmonary factor for the fatal termination would not be in such prominence.

Of the first group, those cases of epidemic influenza not showing pulmonary lesions, we will have very little to say, in as much as the pathological investigations of them is impossible, or nearly so, during the height of the disease.

Such cases apparently do not die at this period. I am willing to admit that individuals without pulmonary involvement may succumb, but I question whether their death has been due to the result of the influenzal lesions, be it in nose, pharynx, larynx or trachea, or be it in the intestine, but rather that the fatal termination occurred later in the course of this complex disease, when distant vital organs became involved or incapacitated in a toxemia or secondary bacterial invasion. We must clearly distinguish these cases from the clear-cut ones of epidemic influenza, looking upon the new circumstances as complications aside fromthe original disease. Such, for example, is the case we have mentioned where a fatal streptococcus bacteriæmia followed in the wake of an otitis media. In our experience we have not had a fatal case of the acute epidemic disease in which the lung was not involved.

In types of epidemic disease such as we have just had, where the epidemic wave has passed over in a period of four or five weeks, there is always much to be regretted which has been left undone. We tried as far as possible to gain all the information available at the time of collecting our materials and of laying aside such of the work which could be accomplished at a subsequent date. The materials were collected from divergent sources in the cadaver, and the more perishable substances were analyzed immediately. During the period of the epidemic 32 autopsies were performed and as much use as possible was made of each for a thorough comprehension of the lesions.

During the period of our work 639 patients were admitted to the hospital suffering from clinical influenza. The cases varied in type from the very mild to the extremely ill. The majority of the cases were of the type of “three-day fever.” Clinically 81 cases developed pneumonia, and of these, 35 died. It would, of course, be impossible to say how many other individuals had a pulmonary involvement which could not be recognized clinically. In fact, some of the cases which did come to autopsy were only recognized as having a pulmonary involvement when the lungs were examined outside of the body. The physicians freely admitted that the physical signs were quite unusual and unlike those of the ordinary forms of pneumonia. In fact, except for the fact that we were living in the midst of an epidemic of respiratory infections, there was nothing to make the clinician suspect that many of these cases had a pulmonary involvement. Obviously, when the recognized signs of different types of pneumonia made their appearance, the clinician did not fail to make proper interpretation of the lung involvement. This, as we shall discuss later, is an event superadded to a lung condition which pathologically must be recognized as pneumonia (inflammation) and which differs so decidedly from what we know of as croupous or lobar pneumonia, as well as ordinary broncho-pneumonia thatit would be incorrect to include them under this heading, although the distribution of the lesion may have lobar, bronchial or lobular characters.

TABLE I

The individuals admitted to this hospital were obtained from the two military camps at the University of Pittsburgh and the Carnegie School of Technology. All of them were enrolled inthe army service and ranged from the ages of 18 to 30. They were vigorous individuals, who had passed their physical examinations for the army. The epidemic made its appearance in these camps on October 2, rapidly ascending from a report of two ill on October 2, four on October 3, eight on October 4, to 65 on October 5. On October 11 there were 307 cases in the hospital.

Of these cases 35 died, the day of death being indicated in the following table.

TABLE II

The time as indicated in the above table has no relation to the length of time that the patients were ill of pneumonia, but refer to the period of illness from the beginning of the influenza. The duration of the pneumonia is indicated in another table.

Of the 35 fatal cases 32 came to autopsy. Facilities were available to do the work very satisfactorily, in that the hospital was well provided with a modern post-mortem room and its accessories. The notes on the autopsies were taken immediately and fully, and the materials for subsequent study were collected in different types of preserving fluid. Portions of tissue were collected from all of the organs for microscopical study, while fluids from the chest, lungs, bronchi and heart were obtained for bacteriological investigations and for some chemical analyses.

Added to the above material we also had the opportunity of reviewing and studying the lesions of 18 autopsies performed byDr. J. W. McMeans. These cases were very similar to our own series, in that they were cases of epidemic influenza amongst soldiers who were being cared for at the St. Francis Hospital. The disease processes were quite alike in the two series, and the analyses made by Dr. McMeans are comparable in our own and serve as a means of checking our results obtained in another institution. The similarity of the lesions in the lungs and other organs serve to indicate that what is reported in this paper is an index of the nature of the lesions of epidemic influenza as it occurred in the Pittsburgh district. In a few instances the autopsies performed by Dr. McMeans revealed more advanced pulmonary lesions with abscess and gangrene than were noted in the cases autopsied at the Military Hospital. The process, however, in the two series of autopsies was identical.

There were no external characteristics of the bodies which were autopsied by us which were constant. Some features were more commonly present than others. Of these the cyanosis of the face, head, neck and shoulders, and in a few instances of the upper extremities, attracted our attention more than any other. This cyanosis was present in over one-half of the number of cases, and it was confined almost always to the upper part of the body. The face, ears and neck were always more affected than other parts. This cyanosis bore no relation to the length of time after death when the body was viewed, as we found that when it was present during life it maintained its prominent appearance for a long time after death.

The cyanosis differed from the bright hue or flush as it is at times observed in ordinary pneumonia, the color in these instances being of a dark purple, or better a purplish blue. The lips and ears showed the most intense color. The cyanosis was not associated with any evidence of œdema. The capillaries of the tissues were filled with blood which was of a very dark character. Cyanosis could also be seen in the finger tips about the nails. This was more marked in the upper extremities than in the lower. The skin of the body rarely showed any cyanosis, these tissues being quite pale, or at times showing a slightly yellowish tinge. In one instance the cyanosis of the head andneck was accompanied by a slight purplish rash upon the upper portion of the chest. This rash was of a petechial kind, there being slight hemorrhage into the tissues. The lesion, however, was not of the blotchy purpuric type which has been observed by others during this and past epidemics (Cole). This single case is the only one where we had evidence of superficial hemorrhages into the skin.

TABLE III

Occasionally we met with small hemorrhages lying in the upper layers of the subcutaneous tissue. These lesions were small and could not be seen from the external surface. Nevertheless,some of them seemed to have occurred in direct contact with the deep cutis and surrounded portions of the deep skin appendages. From an examination of our cases there was no reason at the time of autopsy to lay any particular stress upon the occurrence of these hemorrhages. Subsequently, it has come to mind, and since learning of the unusual frequency of boils and deep pustules making their appearance as post-influenzal sequelæ, that these minute lesions may have a bearing upon the localization of infection in the skin tissues. We must appreciate, of course, that other factors of a constitutional nature probably render the individual more susceptible to the invasion of the staphylococcus, and that such factors are all-important in allowing this organism to gain a foothold. Whether the decreased sugar-tolerance with hyperglycemia, which has been observed in the late stages of influenza, bears a relation to the increased susceptibility, as appears to be the case in diabetes mellitus, is an interesting point for further investigation. Other constitutional states are also undoubtedly involved in the increased susceptibility to the infection which the patient suffers. Elsewhere (Dr. Holman) it is shown that the natural complement content is considerably depressed during the height of the influenza. With such factors present and with the available infecting micro-organisms, it is possible that the minute deep skin hemorrhages bear a relation to the immediate localization of the infection.

In two instances slight hemorrhages were observed into the conjunctival tissues. In each case they were unilateral and occupied the tissues contiguous to the inner canthus. In one case there was well-marked icterus with yellow coloration of the scleræ and skin. In this case the icterus was associated with degenerative changes in the liver, there being no recognizable obstruction to the bile passages. The icterus had come on quite acutely and without any special clinical manifestations. In the epidemic of 1890 jaundice was present in a considerable number of cases (Medical Record, 1890, xxxvii, 473). Cole made similar observations in the epidemic of influenza amongst the Canadian soldiers. Œdema of the skin was not met with in any of our cases. This point is worthy of comment, inasmuch as some authors have been impressed with the serious damage taking place in the kidney and the resulting incapacity of these organs.Although, as we shall point out later, the kidney tissues in these cases showed a decided toxic degeneration, there was no evidence that a glomerular damage of serious degree ever occurred. The urinary excretion, as is pointed out in a report by Dr. Zeedick, varies considerably with the intensity of the disease. It is unusual to find derangement of kidney function to a degree to reflect seriously upon the general bodily state. At least this has been our experience in the present epidemic. Even where subsequently we were able to demonstrate a considerable tubular degeneration in the cortex of the kidney the change in the kidney function was not of sufficient magnitude to lead to a water-retention to be recognized in an anasarca. I wish to distinguish clearly at this point the difference in finding an œdema in certain involved tissue structures in various parts of the body and arising through an inflammatory reaction due to the presence of peculiar focal irritation, as compared with the accumulation of fluid in many and irregular situations as it occurs through retention and faulty excretion by the kidneys. Various organs as we have found—as, for instance, the lung, heart and liver—showed a condition of œdema which was not to be reconciled with an inadequate circulation because of a cardiac or renal incompetency. These œdemas, which we will discuss later, are local and are the result of damaging influences inducted in and upon the tissues where they are found.

In all of our cases we have been struck with the excellent physique of the individuals succumbing to this epidemic. All were youths in the best of health, of good muscular build and strong bony frame-work. Post-mortem rigidity set in fairly rapidly after death. Where this rigidity had “set” for six or more hours it required much force to change the position of the muscles. The voluntary muscles of the thorax and abdomen were always carefully observed, and in a number of instances the muscles of the thigh were also examined. It was not possible routinely to dissect the muscles of the extremities, so that we are unable to give an accurate account of the occurrence of degenerations in these structures. We have, however, observed the reactions taking place in the pectorals, psoas and muscles ofthe abdominal parietes. Changes were observed with greatest frequency in the recti of the abdomen. Degeneration occurred in these muscles in 14 instances, while the same tissues suffered rupture, in part or completely with hemorrhage, in six instances. It was not uncommon to find marked degeneration in the lower segment of the rectus muscle on one side, while degeneration and hemorrhage had occurred in its fellow on the opposite side. In four cases rupture of the entire belly of the muscle had taken place, so that a considerable space had occurred between the broken ends and a large clot of blood filled the intervening space. This degeneration, which was seen only in the voluntary muscles, was quite interesting and in its milder degrees was rather difficult to detect. All gradations of loss of muscle color were seen. In some instances the muscle simply seemed to have lost its meaty lustre, while again in the more severe instances the muscle color had changed from the bright red to an insipid yellow or clay color. The most marked degeneration occurred in the midportions, while the ends of the muscle masses at the points of attachment were less involved. Complete rupture of the rectus always occurred in the lowermost segment, a short distance above the insertion into the pubic bone. At times the distribution of the degeneration within the muscle was quite patchy, and irregular islands of yellow about 2 cm. in diameter were splashed through the muscle masses, which in themselves were paler than normal. Where the muscle degeneration was advanced the tissue was soft and at times even buttery. It resembled the character of the degeneration observed in typhoid fever, although I have no recollection amongst many enteric cases of having seen the degeneration of the muscle occur so acutely. Recklinghausen claimed that these hemorrhages were most unusual in influenza. This is contrary to our findings.

Degenerations of a similar kind as those of the abdominal recti were found in both pectorals. In the chest region, however, the degeneration was less frequent and less severe. We observed it only twice, and in neither instance had the degeneration led to a rupture and hemorrhage of the muscle bundles. Kuskow observed a single case of degeneration and hemorrhage of the pectoral muscles. In the psoas muscle we observed degeneration on two occasions, in one of which the lesion was associated with a partial separation of the muscle fibers and hemorrhages intoits substance. In one case clinically, but not coming to autopsy, a lesion, which from its character we presume to have been a degeneration, occurred in the sterno-mastoid, being accompanied by hemorrhage and the development of a firm clot the size of a hazel nut. In the subsequent history of this case the lesion passed through an aseptic process of organization with contracture so that the patient has recently been developing a “wryneck.” Kohts in 1890 reported the finding of muscle degeneration and abscesses in the arm. The condition arose as a late complication of influenza.

From our experience at the autopsy table in observing the relative frequency with which muscle degeneration occurs in the severe cases of epidemic influenza, we feel convinced that numerous cases which recover pass undiagnosed of this condition. Furthermore we have evidence, as illustrated in a case observed by Dr. McMeans, wherein a lesion which occurred in the gluteal muscles was followed by a localizing infection at this site that these muscle degenerations and hemorrhages may have serious consequences. There are a number of instances in which post-influenzal complications of the nature of deep-seated abscesses of the extremities, thorax, and abdomen may have their explanation for the localization in a primary muscle damage accompanied by hemorrhage and followed by an infection of variable type. Cole also comments upon the development of abscess in the deep muscles where degeneration had taken place. In illustrating some of our findings to Dr. J. Anderson he immediately recognized such a condition in the pectoral muscles of a patient in which he was unable to arrive at a conclusion of the pathological events which had taken place. It is one of the noteworthy features in this disease that the voluntary muscles of certain regions are apt to suffer severe damage, while the heart and the various unstriped muscular tissues are little if at all affected by a similar process. It would be interesting to know whether the lack of response and the delayed functional recovery on the part of the muscles of the extremities in so many patients who have suffered influenza is the result of the damaging influence of a peculiar intoxication present in this disease. One of the features in influenza is the prostration of the patient, and with it there is definite muscular weakness. We have been prone to lay the responsibility of this state entirely at the door of the nervoustissues. Here, however, we are able to offer evidence that quite aside from the lesions arising in the nervous tissue, there is definite muscle damage which, as we shall again discuss when describing the microscopic features, incapacitates even to the point of complete destruction the muscle elements in various fields of the body. Before, however, being able to state that the muscular weakness of the extremities is the result of such damage by toxins it is necessary to obtain more definite information regarding the frequency with which these degenerations occur in the limbs. In our own material we are unable to discuss the matter with adequate figures. We are, however, impressed with the changes observed in the muscles which were available to us. Naturally, too, a certain number of muscle degenerations have escaped our detection because of our unfamiliarity with the mildest grades. In fact, we have already discovered in our microscopic studies that certain cases, which in the macroscopic had escaped us, showed well-marked lesions under the microscope.

TABLE IVMUSCLE DEGENERATION

TABLE IV

MUSCLE DEGENERATION

We have convinced ourselves that the marked hemorrhage taking place in the muscle tissue follows upon a primary degeneration of this tissue and its spontaneous rupture. The amountof hemorrhage is in proportion to the degeneration and fracture of the muscle elements. The hemorrhage does not precede the muscular change, nor does it have any antecedent relation to the actual tearing of the muscle fibers.

A much better appreciation of the muscle degeneration was obtained in themicroscopicstudies of these tissues. The various gradations of tissue change could be followed, which was not possible in the naked-eye examinations. Some points respecting this degeneration were quite noteworthy. Firstly, the process of degeneration in its early stages and advancing through the acute destructive periods was not accompanied by any inflammatory reaction. Evidence of inflammatory exudate was obtained only when the degeneration had proceeded to a degree permitting of rupture with hemorrhage, or in the late stages when the areas of marked muscle dissolution were undergoing repair. We have no evidence to indicate that bacteria were present during the beginning of the degenerative process. Bacteria could not be demonstrated in section. The appearance of the tissue suggested a purely toxic process which was selective in its action, picking out voluntary striped muscle tissue and attacking certain muscle groups in preference to others. It was also interesting to observe in the early stages of the degeneration that individual fibers lying amidst healthy and unchanged muscle elements would show degeneration in many of its stages. This appearance was often unique, particularly when in the early stages of the process the involved fiber would still retain its normal position and shape though markedly altered in its staining and chemical qualities.

The degeneration as observed in these cases showed many of the characters like that of waxy degeneration seen in typhoid fever. Similar appearances to these have also been described in connection with the toxic degenerations which occur in the vicinity of infections by the gas bacillus. In fact, all the stages observed in the one can be seen in the other. They differ, however, only in the degree to which final destruction takes place and in the speed with which the degeneration is accomplished. The character of the degeneration is well studied in sections stained with hematoxylin and eosin, eosin-methylene blue, and best of all in the phosphotungstic acid hematoxylin. By the latter method one is able to follow clearly the grade of degeneration as it effects the muscle striations. On theother hand, the peculiar waxy appearance of the early degenerating fibers is best seen in sections stained with eosin or fuchsin, where the striated muscle fibers are found to be changed to a more intensely staining red body of homogeneous character and devoid of all evidence of their original internal architecture. These bland waxy fibers were often of the size and shape like the normal. On the other hand, the fibers are also not uncommonly swollen, stretching the sarcolemma to almost the bursting point. Following this primary bland degeneration the fiber takes on irregular shapes, becoming constricted and collapsed at irregular intervals, so that islands of the waxy contents lie within the sarcolemma, being separated from each other by constricted areas in which the original myoplasm has undergone decomposition and sometimes complete absorption. This irregular destruction of the muscle contents often has a granular stage in which the original muscle substance has become disintegrated. The sarcolemma follows the condition within it, stretching when the fiber is swollen and shrinking, or even becoming collapsed when the inner substance is becoming liquified and absorbed. The sarcolemma does not suffer the degenerative changes of the inner fiber, nor can one observe nuclear changes in this sheath which are significant.

When first studying this process of degeneration it appeared to us that the earliest change was a loss of the transverse striations and the subsequent disappearance of the longitudinal fibrillæ. We have subsequently found that this is incorrect and that the changes observed in the markings of the fibers were not constant. At times the muscle substance would progress through stages of degeneration up to the point of disintegration and dissolution while the transverse striæ were still discernible in the altered fiber. The one constant change that we have observed in the degenerating fibers was the early loss of staining qualities as obtained by the phosphotungstic acid hematoxylin. In such preparations the earliest effect of the intoxication upon the muscle fiber was a change in reaction to this stain. Sometimes within a given fiber small irregular and poorly staining blotches could be observed, while the remaining portion of the fiber was normal in its appearance. Later these poorly staining areas became larger, occupying the entire width of the fiber and being distributed at irregular intervals in its length. Finally the characteristicstaining quality was entirely lost, although in the poorly colored cell transverse striations were still discernible and a true waxy stage had not yet taken place.

At times the waxy degeneration advanced into the stage of disintegration by an irregular destruction within the fiber. When this occurred the fragments of waxy substance took on curious coiled and grotesque shapes, while a granular destruction was taking place in their periphery. Neither inflammation, œdema nor a vascular reaction could be determined in these tissues of mild or severe change. The reaction as is indicated in the table occurred quite acutely and was not accompanied by fatty products commonly seen in the slower forms of degeneration.

Gradually the debris of the degenerated fibers is absorbed and the sarcolemma shrinks and collapses upon itself. During this stage a reaction occurs in the sarcolemma with nuclear proliferation. At times the last vestiges of the muscle fiber are seen to be surrounded by a crown of nuclei and cells reminding one of the appearance of the degenerating nerve cells in the Gasserian ganglion in hydrophobia. The involved area becomes active in appearance, showing proliferation of fibroblasts and the appearance of occasional lymphocytes and plasma cells. Scar tissue continues to develop in proportion to the amount of damage done. In areas where hemorrhage had taken place the amount of scar tissue is exaggerated, owing to a process of organization which is taking place quite apart from the muscle degeneration. Thus not a few scars scattered through the voluntary striped muscles are the final outcome of this toxic degeneration occurring in epidemic influenza. Some of these lesions may account for the indefinite pains and symptoms of which the patient complains for so many months after his acute illness. I refer particularly to lesions occurring in the psoas and muscles of the back as possible explanations for the partial invaliding of some individuals.

In a certain number of cases of acute influenza the patients complain of severe abdominal pain, in the absence of any localizing symptoms or evidence of intestinal derangement. Such was the case with a number of the above cases coming to autopsy, and the sole evidence we could offer was muscle degeneration with or without massive hemorrhage. The abdominal pains complained of were more of the nature of dull aches with occasional exacerbations and shooting or lancinating “stitches.” Rarely was thepatient able to define the position of the pain, not being able to state whether it was within the abdomen or in the parietes. Most frequently they claimed it was internal. We have on no occasion demonstrated an intra-abdominal lesion which could account for such pains. None of our cases was of the type of “intestinal influenza.” We are, therefore, led to the conclusion that the muscle degenerations of the various degrees, from the slight with few muscle elements involved to the severe with rupture and hemorrhage, account for a proportion of the clinical symptoms of (muscle) pains and aches as well as weakness. We cannot claim that coughing was a necessary factor in inducing rupture of the abdominal recti. In some of the cases with rupture severe coughing had not been observed during the illness.

The pathological changes found in the nose, pharynx and larynx were of relatively slight importance and most variable in their severity and incidence. The majority of individuals had few clinical manifestations of disease in these parts. Some, however, complained of dryness of the pharynx with slight feeling of fullness. An examination of these parts revealed some congestion, varying from a red injected mucosa to a bluish cyanosis. In the nose the reaction was rarely as acute as is seen in infectious coryza, but even where relatively little change was to be seen in the tissues hemorrhage from the erectile tissue was not uncommon during the acute stages. No particular lesion was to be found associated with nose bleed. There was an unusual absence of excessive secretion from nose and pharynx in the majority of cases. One was also struck with the infrequency with which the larynx was involved. A certain number of individuals complained of hoarseness, and in them injection of the vocal cords with some swelling was found. In many others, however, even where an intense infectious process was present in the lower respiratory tract the larynx was almost without change. It was from the level below the larynx that the acute reaction in the respiratory system was found.

In all of our cases the trachea showed definite inflammatory reaction. Of the 32 cases there were 26 having an acute tracheitis, 5 with an acute mucopurulent inflammation and 1 with areaction in the subacute stage. In the majority of the cases with acute tracheitis there was a thin layer of exudate lying upon the mucosal surface. At times the trachea was filled with a frothy serous fluid, the greater part of which had its origin in the lung. Nevertheless, as we shall point out later, we did obtain microscopical evidence indicating that during the early acute stage of the tracheitis a considerable serous exudate escapes from its mucosa. This serous inflammatory reaction is an important one for all of the mucosal structures upon which the virus of influenza obtains a footing. This we have found true for the trachea, bronchi and alveoli of the lungs. In some cases the exudate was grey and lay in close contact with the injected tissues. At first sight this grey exudate suggested necrosis, but it was readily wiped from the underlying structure. Some leucocytes and cell debris with many bacteria made up the content of this grey exudate.

The macroscopic appearance of the trachea was that of an intensely injected structure which had largely lost its normal lustre. The naked eye could distinguish that anatomical change had occurred in the surface tissue of the trachea and that there was unusual evidence of intensely injected vessels lying in the submucosa. In only one instance was there an appearance of a true necrotic membrane lying upon the surface of this intensely inflamed layer. This apparent membrane was found to consist of a wide patch of desquamated epithelial cells which was lying as a delicate necrotic plate upon the surface. This thin layer was devoid of a meshwork of fibrin threads as usually accompanies a true false membrane of other sources.

The early intense inflammatory reaction of the surface membrane of the trachea was characteristic, and in our experience was never exceeded in intensity by other infections. A desquamation of the lining membrane was also a common finding. Naturally this intense reaction so commonly found in the trachea extended without interruption into the main bronchi and their divisions. The finding of this continuous surface inflammation is good evidence of the mode of spread of the infectious process along these membranes, beginning in the upper portions and by direct continuity involving more and more of the respiratory tubes toward the lung.

The varying grades in the intensity of the inflammatory reaction upon the inner surface of the trachea was well illustrated in the microscopic sections. Even with the different degrees of the reaction there was a fairly constant character to the inflammation. In this way the response was found to differ from that commonly observed in ordinary infections of the respiratory tract. The first striking feature is the marked response of the vascular channels, both blood and lymphatic. The vessels lying in the submucosa were found intensely engorged so that their walls were stretched to the point of bursting. In fact, not a few vessels were seen whose walls, probably under the stress of intoxication and dilatation, had given way leading to a flooding of the neighboring tissue with their contents. Where such vessels lay close underneath the surface the hemorrhage escaped into the lumen of the trachea. Accompanying this early vascular response there was found a marked serous exudate leading to a stretching of the submucosal tissues by distention of the interstitial spaces. This reaction resembled an acute inflammatory œdema and occupied the area between the mucosa and the inner border of the cartilage rings. Beyond this region no response was found. Thus in the earliest stages, and where the mucosa was still intact, the main reaction was of the nature of an intense serous inflammation with congestion of the blood vessels and frequent interstitial hemorrhages.

Shortly following the development of the serous exudate in the submucosal tissues, the epithelial lining is found to suffer from the reaction. The serous exudate does not remain confined to the interstitial tissues, but is poured out through the mucosa into the trachea. It would appear that the amount of this clear exudate may become greater than can be dealt with by the mucosa, with the result that an accumulation of this serous fluid takes place between this epithelial layer and its basement membrane. We have repeatedly seen considerable stretches of the mucosa lifted from the basement membrane and shed in large plaques into the lumen. These mucosal cells at the time of their desquamation retain fairly well their morphological characters, and do not show evidence of necrosis prior to their removal. Disintegration of these cells naturally occurs while lying in the secretion of the trachea, and a variable cellular mass in stages of disintegration may often be found both in smears and sections.When the epithelial cells are lifted in wide plates, a type of bleb develops which is easily broken and then disintegrates.

The desquamation of the lining membrane is a fairly constant occurrence in the cases coming to autopsy. In the majority of those which we have examined the greater portion of the trachea was completely denuded, save for small islands lying in the recesses near the mouths of the mucous ducts. In one case this lesion was accompanied by a process of ulceration, due in all probability to the invasion by other micro-organisms. The denuded tracheal surface usually shows a further inflammatory reaction in which a cellular exudate then makes its appearance. This reaction is mainly one in which lymphocytes and plasma cells infiltrate the spaces previously occupied by the serous fluid. The reaction is limited to the submucosa and does not extend into the tissues beyond the cartilages. We have found only occasional polymorphonuclear leucocytes lying close below the surface. During this period, however, varying grades of degeneration may occupy the upper layers. The basement membrane particularly seems to suffer by losing its characteristic outline and staining qualities. This membrane becomes swollen, softened and indefinite. At times a homogeneous precipitate occurs along its free surface giving rise to an appearance resembling a false membrane. This deposit is, however, distinctively different from the diphtheritic membrane of other infections. It is interesting, however, that where such deposits and degeneration occur in the basement membrane more or less degeneration and necrosis also occur in the connective tissues immediately neighboring to it. These tissues show a peculiar granular destruction and alter their staining qualities. Moreover, and what is more important, under these conditions the dilated blood vessels are found to suffer from the injuries taking place in their neighborhood. We have repeatedly found partially or completely thrombosed capillaries, arterioles and venules in these surface layers. These thromboses took place while the vessel was in its distended state and thus produced a mold of the dilated vessel. This observation is of importance in indicating the severity of the effect of the virus and toxin upon the tissues of the trachea, and it is also of importance to appreciate that this damaging influence is very different from that which we encounter in pneumococcus infections, and we shall point out in our discussion on lung a reactionvery similar to that which takes place very superficially in the trachea may also occur in the alveolar walls of the lung.

Having referred to the intensity of the responses of the blood vascular system, we must also indicate the part played by the lymphatics. Simultaneously with the reactions taking place about the blood vessels of the trachea we observed similar responses in the lymphatic channels. At first these dilated structures contained only fluid. Later the migration of the lymphocytes took place along these routes, and rarely micro-organisms could be demonstrated either free or within an occasional leucocyte. The sharp response of the lymphatics during the serous inflammation is noteworthy, inasmuch as we have found that the lymph glands lying about the respiratory tubes and lungs were early in their response to the irritating virus.

Bacteria were demonstrated in the secretions lying upon the surface of the trachea. In those specimens in which the mucous membrane was still intact we attempted to demonstrate the clustering of the micro-organisms about the ciliated cells as was described by Mallory in whooping cough. Although the organisms, and particularly small Gram negative bacilli, could be demonstrated lying about these cells no characteristic arrangement was found. Furthermore where the mucosa was still attached to its basement membrane we were never able to demonstrate organisms below the surface of the epithelial layer. In several cases where the mucosa was lifted in bleb-like structures a number of organisms were detected below the epithelial layer and in contact with the basement membrane of the submucosa. We have rarely demonstrated bacteria in the interstitial spaces of the submucosa, even where large numbers of organisms were lying upon the inner denuded surface.

The distinction which was made by the gross examination of the trachea between the acute tracheitis with serous exudate, subacute tracheitis and mucopurulent tracheitis was not so readily distinguished in the microscopic sections. In the gross the character of the exudate lying upon the surface was the main guide suggesting the nature and intensity of the inflammatory reaction. In the microscopic sections this exudate was largely wanting, or was not sufficiently characteristic to confirm the gross findings. On the other hand, differences in the nature of the injury were to be found mainly in the reaction of the submucosa.As we have indicated above, the early inflammatory reaction of the trachea is mainly evident in an intense congestion accompanied by an inflammatory œdema of the submucosal tissues, hemorrhage sometimes accompanying this response. In the later stages of the reaction a cellular deposit takes the place of the inflammatory œdema and usually consists of lymphocytes and plasma cells. It is only in those cases where the intensity of the irritant continues to act over a longer period of time that a superficial necrosis with leucocytic infiltration makes its appearance. The epithelial layer of the trachea is desquamated early in the acute reaction, and hence a denudation of the surface is to be found in all stages of the acute lesion. The mucous glands have not been found to show any particular involvement in the inflammatory process, and in the majority of instances they were found to have escaped entirely the damaging effect of the virus. Their response in an over-secretion of mucus may be the outcome of a stimulation by toxins or soluble irritants; but on the other hand, may also probably be a reflex response to the injury of the mucosal surface, which being bared of its covering is highly sensitive. The increased discharge of mucus from the deep glands may well be a protective response to such injury.

The lesions in the bronchi were in every way comparable to those in the trachea. The main bronchial tubes differ in no material way from the structure of the trachea, and the extension of the inflammatory process from above downwards leads to a reaction in their walls similar to what has been above described. As we follow the subdivisions of the bronchi we gradually lose some of the characteristics contained in the larger tubes. The mucous glands gradually become fewer and eventually disappear. The cartilage rings become smaller and no longer completely encircle the bronchus, and with the further diminution in the size of these structures disappear entirely. A relatively greater amount of muscle tissues takes the place of the cartilage rings. This change in the anatomy of these structures has a certain influence in modifying the character and distribution of the inflammation.

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