Studies on Epidemic Influenza: Comprising Clinical and Laboratory Investigations

by University of Pittsburgh. School of Medicine

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 reaction very 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.

Bronchi

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.

TABLE V

BRONCHITIS AND TRACHEITIS