Fever of Unknown Origin (FUO) is defined in human medicine as an illness of more than 3 weeks duration, with a fever 1.5 °F
above normal body temperature on multiple occasions, the cause of which remains uncertain after 1 week of in-hospital investigation.1 In veterinary medicine, the term is much more loosely applied to any patient with a sustained or episodic fever without
a readily apparent cause after routine laboratory testing. Fever of unknown origin tends to be a challenging clinical entity
in veterinary medicine, frequently necessitating diagnostic testing that is labor intensive, expensive, invasive, and time
consuming. Despite this, causes of fever may still go undiagnosed. Understanding the pathophysiology and varied causes of
fever is critical to successful management of these frustrating cases.
The febrile response is a "complex physiologic reaction to disease, involving a cytokine mediated rise in core temperature,
generation of acute phase reactants, and activation of numerous physiologic, endocrinologic, and immunologic systems." Fever
develops when exogenous or endogenous stimuli such as endotoxin, viral, bacterial rickettsial, or fungal agents, tumor antigens,
tissue necrosis, or immune-mediated diseases induce mononuclear cells to release endogenous pyrogens. The pyrogens most commonly
associated with febrile responses include interleukins (IL-1 and IL-6), tumor necrosis factor (TNF), and interferon. Exogenous
antigens taken up by Kupffer cells in the liver, or endogenous pyrogens entering the central nervous system at the anterior
hypothalamus elevate the thermoregulatory setpoint through upregulation of prostaglandin E2. Alteration of the hypothalamic
"thermostat" in this way triggers physiologic mechanisms such as shivering and vasoconstriction that increase heat production
and conservation within the body.
Animal experimental models evaluating the effect of fever on survival during infection suggest that mild to moderate fevers
benefit the host, and may improve survival during sepsis. Increased temperature is known to induce change in phagocytic cells
and lymphocytes, stimulate release of interferon, and induce the heat shock response. This heat shock response leads to the
production of heat shock proteins (HSPs) that serve to protect against cell death from a variety of stressors, including endotoxemia.
Additionally, increasing temperature may lower minimum inhibitory concentrations of antibiotics, progressively increasing
their antimicrobial activity. Severe fever (>106 °F) may become dangerous however, as a result of altered cellular metabolism
and direct thermal damage to a variety of tissues (ie. Heatstroke).
Table 1. Causes of fever, grouped according to category
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Causes of fever may be divided into 4 major categories; infectious, inflammatory, paraneoplastic, and immune-mediated (see
table 1). By far, infection is the most common cause of fever in veterinary patients, though many of these cases may be diagnosed
and/or treated successfully without the need for intensive diagnostics and care. Immune-mediated disease is the second most
common cause of fever, accounting for over one-quarter of cases presenting with persistent fevers. Of the immune-mediated
diseases, polyarthritis and vasculitis are the ones most commonly associated with fevers. Neoplastic processes are the third
most common cause, accounting for approximately 15-20% of cases. In older patients presenting with fevers, neoplasia rises
to the top of the list of differential diagnoses. A variety of miscellaneous or inflammatory conditions account for the remainder
of the fevers of unknown origin. A definitive cause may not be determined in 10-20% of cases.
