The role of endotoxin during typhoid fever and tularemia in man

Abstract

A B S T R A C T Volunteers infected with Salmonella ty-phosa develop a remarkable hyperreactivity to the pyrogenic and subjective toxic activities of homologous (S. typhosa) and heterologous (Pseudomonas) endotoxins. The present studies quantitate this augmented reactivity and demonstrate by three differing approaches that significant tolerance to these endotoxins can be readily induced within the framework of the hyperreactive state. Thus, (a) tolerance induced before illness by repeated daily intravenous injections of the endotoxins remained demonstrable during overt illness, (b) daily intravenous injections of the endotoxins begun during overt illness evoked progressively increasing tolerance, and (c) continuous intravenous infusions of S. typhosa endotoxin during illness rapidly induced a pyrogenic refractory state. Despite unequivocal activation of the endotoxin tolerance mechanisms by any of the above methods, the febrile and toxic course of typhoid fever proceeded unabated. Similarly, in other volunteers with Pasteurella tularensis infection, continuous intravenous infusions of S. typhosa endotoxin evoked initial hyperreactive febrile and subjective toxic responses followed by rapid appearance of a pyrogenic refractory state without modification of the underlying clinical illness. These observations suggest that circulating endotoxin plays no major role in pathogenesis of the sustained fever and toxemia during typhoid fever and tularemia in man. The mechanisms responsible for the systemic hyperreactivity to endotoxin during typhoid fever and tularemia were further investigated. Low grade endotoxemia, nonspecific effects of tissue injury, impaired ability of the reticuloendothelial system to clear circulating endotoxin, and production of cytophilic antibodies capable of sensitizing leukocytes to endotoxin did not appear responsible. Inflammatory reactions to intradermal S. typhosa endotoxin increased significantly during typhoid fever. However, since no such dermal hyperreactivity developed to Pseudomonas endotoxin during typhoid fever nor to S. typhosa endotoxin during tularemia, the systemic hyperreactivity to bacterial endotoxins during typhoid fever and tularemia could not presently be ascribed to enhanced levels of acquired hypersensitivity.

Endotoxin tolerance: is there a clinical relevance?

“…3 In human volunteers, it was shown that inoculation of live Salmonella typhosa led to a reduced fever in response to endotoxin or killed bacteria as compared to before infection. 4 Interestingly, a similar observation was reported with volunteers inoculated with Plasmodium cynomolgi by mosquito bites, 5 suggesting that cross-tolerization between different stimuli could occur Beeson (1946) first defined endotoxin tolerance as a reduced endotoxin-induced fever following repeated injections of typhoid vaccine. Freudenberg and Galanos (1988) demonstrated that endotoxin tolerance that can protect against a lethal challenge of lipopolysaccharide (LPS) involves the participation of macrophages.…”

Mechanisms of Endotoxin Tolerance. IX. Effect of Exchange Transfusion

“…The initial clearance phase is rapid, with a slower phase generally becoming evident within 30 min (1)(2)(3). The major contribution of the reticuloendothelial system (RES) to such endotoxin clearance has been documented previously (1,2).…”

“…When tolerance to the toxic activities of endotoxin is induced by prior injections of toxin, the rate? as well as total RES uptake of the injected endotoxin becomes markedly enhanced (2)(3)(4)(5). The role of this enhanced blood clearance in the development of endotoxin tolerance remains controversial.…”

Haemostatic Abnormalities in Multidrug-Resistant Enteric Fever

“…Endotoxin has been suggested to mediate the patholog ical sequelae of typhoid fever [17,18], it being capable of activating the coagulation cascade by release of the pro teolytic enzymes and tissue-factor-like material from leu cocytes [19,20]. It has been shown to activate factor XII in vitro [21], which in turn can activate prekallikrein [22], The administration of endotoxin also causes an increase in the levels of tissue plasminogen activator which is rap idly counterbalanced by the release of plasminogen acti vator inhibitor [23].…”

“…However, Nossel [24] suggested that an endotoxin-mediated fall in factor XII concentration may be a result rather than a cause of thrombin genera tion. Tolerance to endotoxin does not protect animals from lethal gram-negative bacillary infection [25], nor does it protect humans from typhoid fever [17]. Clinical studies have also shown that micro-organisms devoid of endotoxin can cause septic shock [26] and bacterial prod ucts other than endotoxin may contribute to the mortality from gram-negative infections [27].…”