Pharmac. Ther. Vol. 19, pp. 211 to 244, 1983 0163-7258/83/020211-34517.

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Printed in Great Britain. All rights reserved Copyright © 1983 Pergamon Press Ltd

Specialist Subject Editors: E. SCHONBAUMand P. LOMAX

MECHANISMS OF FEVER

RICHARD HELLON* a n d YVONNE TOWNSEND

*National Institute for Medical Research, London NW7, U.K.

Department of Medicine, St Thomas' Hospital School of Medicine, London SEI, U.K.

1. I N T R O D U C T I O N
The purpose of this chapter is to survey our present understanding of the adjustment
to thermoregulation which occurs during fever. Extensive reviews by Hensel (1973, 1981),
Boulant (1980), Simon (1974) and several contributions to appear in this publication deal
with various aspects of normal thermoregulation and its control mechanisms in the
central nervous system. We begin our review by defining fever and making clear the
distinction between fever and other hyperthermias. Next we review briefly the manifold
circumstances in which fever may arise. Most, if not all, fevers involve the production 6f
endogenous pyrogens, the source of which are cells of the reticuloendothelial system; we
aJ~o discuss the site of action of endogenous pyrogens. Particular attention will be given
to the controversial issues surrounding possible mediators of the action of endogenous
pyrogens in the brain. We then consider modifications of the fever process in pregnant
animals, the newborn and the aged. Finally, evidence for the possible survival value of
fever will be assessed. Most of our discussion will be confined to mammalian species, but
the survival value of fever has been demonstrated most clearly in lower vertebrates
(reptiles, amphibia and fishes). Unlike mammals, these species can generate a fever only
by moving to a warmer environment, a maneuver which the experimenter can foil easily.

1.1. FEVER AND HYPERTHERMIA

Fever is only one of several circumstances in which body temperature rises above its
normal range, and it is important to recognize the distinction between fever and other
hyperthermias (Stitt, 1979~).
Any imbalance in which heat production exceeds heat loss will lead to the storage of
heat and a rise of body temperature. Such an imbalance may occur in hot environments,
and in extreme conditions the body's control mechanisms may become inadequate, lead-
ing to heatstroke (Shibolet et al., 1976). Less common is the malignant hyperthermia
occasionally seen in patients and some animals under general anesthesia (Aldrete and
Britt, 1978) when, in those with a muscular biochemical defect, an explosive increase in
muscle heat production occurs. Pharmacological interference with body temperature
control mechanisms can also lead to hyperthermia. There are very many instances of
drug treatment causing an elevated body temperature, which need not be described in
detail in this context; the matter is dealt with at length in the recent reviews by Clark
(1979), Clark and Clark (1980a,b) and Townsend and Cranston (1981).
Sustained exercise provides another example of hyperthermia. In large mammals there
is a rise in body temperature which persists for at least the duration of the exercise. The
magnitude of the rise depends on the intensity of the exercise and is largely independent
of the ambient temperature over a wide range (Nielsen, 1969; Lind, 1963). At the start of
exercise, heat production increases abruptly, whereas heat loss processes take longer to
mobilize. Body temperature rises until heat loss matches the increased heat production
so that there is a sustained hyperthermia. The rise is a necessary consequence of normal
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