Studies on the Pathogenesis of Fever

Abstract

Evidence has been previously presented that an endogenous pyrogen is demonstrable in the circulation of rabbits with fever caused by the intravenous injection of typhoid vaccine (1, 2). The endogenous factor is readily differentiated from the pyrogenic component of the vaccine and reaches a maximum concentration well after the latter has been cleared from the blood stream. Its presence in the circulation is closely correlated with the fever. These observations have recently been confirmed in analogous studies made with dogs (3).The biological properties of the newly identified pyrogen were originally found to be identical with those of the heat-labile pyrogenic substance which is extractable from polymorphonuclear leucocytes (1, 2). Further evidence as to the identity of the two factors has subsequently been reported (4, 5). Because the endogenous factor makes its appearance in the blood stream shortly after the leucopenia which follows the injection of vaccine, the hypothesis has been advanced that the febrile response is caused by the action of endogenous pyrogen released from injured leucocytes (2).Although an endogenous pyrogen can be readily extracted from polymorphonuclear leucocytes (6--8), and a similar pyrogen can be demonstrated in the fluid portion of acute inflammatory exudates (8), doubt has arisen as to whether the pyrogen in the exudates is actually derived from the leucocytes. The doubt has been engendered primarily by two observations. First, a pyrogenic substance, with properties similar to those of leucocytic pyrogen, has been demon= strated in the fluid portion of acute infl~trnmatory exudates in agranulocytic rabbits, despite the virtual absence of polymorphonuclear leucocytes in the exudate (8). Secondly, rabbits and dogs made leucopenic with nitrogen mustard have been shown to exhibit the usual febrile response to bacterial pyrogens (9, lO).

Studies on the Pathogenesis of Fever

“…The basic procedures used (a) in eliminating extraneous pyrogens from reagents and glassware, (b) in assaying the activity of endogenous pyrogen by intravenous injection of rabbits, and (¢) in measuring the febrile response to pyrogen in arbitrary fever index units have been described in previous publications (9,10). All of the fever indices recorded in this study were calculated from 2 hour fever curves, since the febrile response to leucocytic pyrogen rarely extends beyond the 2nd hour, except when massive doses of pyrogen are employed (13).…”

Studies on the Pathogenesis of Fever

“…The method finally adopted revealed that endogenous pyrogen, as it exists both in leucocytic exudates (3,18) and in 2 hour serum (5, 6) causes a more rapid and a more pronounced fever when introduced ~a the carotid artery than when injected intravenously. The exogenous pyrogen in 5 minute serum (5, 6), on the other hand, caused a relatively slow response which was uninfluenced by the route of injection.…”

“…The approximate position of an intracarotid catheter, however, can be deter-I The method of calculatiag the fever indices was the same as in the preceding study (18) except that a cut-off point of 240 minutes was arbitrarily used because of the consistently longer responses produced by exogenous pyrogen.…”

“…Leucocytic Pyrogen.--Leucocytic exudates were produced by the same technique as previously described (18), except for minor modifications. Physiologic saline, administered intraperitoneally by constant injection over a 3~ hour period, was given in 300 mi.…”

“…IV of handling the rabbits and recording their temperatures, s and the precautions taken to avoid contamination of solutions and glassware with extraneous bacterial pyrogens have been described in the preceding paper (18).…”