Pathogenesis of Fever

Abstract

Investigations during the past 10 years support the recently revived hypothesis that fever is caused by pyrogenic materials released from injured cells in the host. All of the febrile response to gram-positive infections, and to intravenous inoculation of influenza virus or of specific antigen in hypersensitivity, and much of the pyrogenic effect of bacterial endotoxins seems to be mediated by endogenous pyrogen (EP), which appears to act directly on the thermoregulatory center. Little is known, however, about the mechanisms which activate EP and therefore cause the variable latent periods in different types of fever and in different species given the same pyrogenic agent. Serum pyrogens induced by endotoxin inoculation and present in acute bacterial infections are similar to, or identical with, a pyrogen extracted from granulocytes. Studies have also linked polymor-phonuclear (PMN) leukocytes to fevers which occur in certain immu-nologic reactions in man. No comparable information is available about the etiology of fever in tumors, infarctions, viral infections, granulomatous, hematologic and collagen diseases and certain metabolic disorders. In some of these instances it seems possible that an associated inflammatory reaction may release an EP similar to those present in fevers. The high febrile responses seen in agranu-locytosis, together with evidence of a pyrogen in agranulocytic fluids, suggest that there may be tissue sources of pyrogen other than the PMN leukocyte. Although production of a circulating pyrogen of apparently endogenous origin suggests a ''final common pathway'' for the pathogenesis of fever, no such substance was detected in a number of drug-induced fevers. The stimuli which initiate fever in these instances appear to be different and may in some cases act peripherally rather than centrally. The recent discovery of certain pyrogenic metabolites may explain a variety of clinical fevers of hitherto unknown origin. Their mechanism of action has not been determined but it seems unlikely that they act directly on the thermoregulatory center. Nothing is known about the way in which circulating EP activates the thermoregulatory center to increase body temperature. Whether cells in the central nervous system responsible for initiating heat conservation react to this stimulus as they presumably do to cooling of arterial blood or to afferent nervous stimuli is conjectural. Biochemical identification of EP has been hindered by the necessity of using bio-assay and by the technical problems of working with pyrogen-free materials.