In the aphorisms of Sanctorious (Lister, 1701 in Sanctorii Sanctorii, 1701) we read ‘In febribus intermittentibus cur perspiratio insensibilis prohibetur? quia humor peccans est in ambitu corporis’ In other words ‘Why is insensible perspiration (the term then for sweating) stopped in fever? because an evil humour circulates in the body’. This may be the earliest mention, in ignorance, of what we now call an endogenous pyrogen.

We now define a pyrogen as a substance which when introduced into the circulation, or given intracerebrally, causes the symptoms and consequences of fever, namely a rise in body temperature which at its plateau behaves as though the temperature is regulated, and which is brought about by a combination of heat retention processes and increased metabolic rate. The process which we have defined as fever is now thought to be but one part of a complex host defence reaction involving not only a rise in temperature but activation of many immune responses and processes for the destruction of micro-organisms. This process is termed the acute phase response. Pyrogens as defined above must be differentiated from substances which just affect the metabolic rate such as dinitro-ortho-cresol, or which cut down heat loss such as adrenergic agonists, but which do not induce the acute phase response. The rise in temperature caused by such agents should be termed hyperthermia, not fever, and the agents should be termed hyperthermic agents not pyrogens.