Definition

Fever is defined as a rectal temperature ≥38°C, and a value >40°C is called hyperpyrexia. Body temperature fluctuates in a defined normal range (36.6°C-37.9°C rectally), so that the highest point is reached in early evening and the lowest point is reached in the morning. Any abnormal rise in body temperature should be considered a symptom of an underlying condition.

Pathogenesis

Body temperature is regulated by thermosensitive neurons located in the preoptic or anterior hypothalamus that respond to changes in blood temperature as well as cold and warm receptors located in skin and muscles. Thermoregulatory responses include redirecting blood to or from cutaneous vascular beds, increased or decreased sweating, regulation of extracellular fluid volume via arginine vasopressin, and behavioral responses, such as seeking a warmer or cooler environmental temperature.

Three different mechanisms can produce fever: pyrogens, heat production exceeding loss, and defective heat loss.

The first mechanism involves endogeneous and exogenous pyrogens that raise the hypothalamic temperature set point. Endogenous pyrogens include the cytokines interleukin 1 (IL)-1 and IL-6, tumor necrosis factor-α (TNF-α), and interferon (IFN)-β and IFN-γ. Stimulated leukocytes and other cells produce lipids that also serve as endogenous pyrogens. The best-studied lipid mediator is prostaglandin (PG)E_2, which attaches to the prostaglandin receptors in the hypothalamus to produce the new temperature set point. Exogenous pyrogens or substances that come from outside the body include mainly infectious pathogens and drugs. Microbes, microbial toxins, or other products of microbes are the most common exogenous pyrogens and stimulate macrophages and other cells to produce endogenous pyrogens.

Some substances produced within the body are not pyrogens but are capable of stimulating endogenous pyrogens. Such substances include antigen-antibody complexes in the presence of complement, complement components, lymphocyte products, bile acids, and androgenic steroid metabolites. Endotoxin is one of the few substances that can directly affect thermoregulation in the hypothalamus as well as stimulate endogenous pyrogen release. Many drugs cause fever, and the mechanism for increasing body temperature varies with the class of drugs. Drugs that are known to cause fever include vancomycin, amphotericin B, and allopurinol. Along with infectious diseases and drugs, malignancy and inflammatory diseases can cause fever through the production of endogenous pyrogens.

Heat production exceeding heat loss is the second mechanism that leads to fever, with examples including salicylate poisoning and malignant hyperthermia. Defective heat loss is the third mechanism of fever genesis, for example, in children with ectodermal dysplasia or victims of severe heat exposure.

Etiology

The causes of fever can be organized into 4 main categories: infectious, inflammatory, neoplastic, and miscellaneous. Self-limited viral infections (common cold, gastroenteritis) and uncomplicated bacterial infections (otitis media, pharyngitis, sinusitis) are the most common causes of acute fever and hyperpyrexia. The body temperature should not rise above potentially lethal levels (41.7°C) in the neurologically intact child unless extreme hyperthermic environmental conditions are present or other extenuating circumstances exist, such as underlying malignant hyperthermia or thyrotoxicosis.

The pattern of the fever can provide clues to the underlying etiology. Viral infections typically are associated with a slow decline of fever over a week, whereas bacterial infections are associated with a prompt resolution of fever after effective antimicrobial treatment is employed. Although administration of antimicrobial agents can result in a very rapid elimination of bacteria, if tissue injury has been extensive, the inflammatory response and fever can continue for days after all microbes have been eradicated.

Intermittent fever is an exaggerated circadian rhythm that includes a period of normal temperatures on most days; extremely wide fluctuations may be termed septic or hectic fever. Sustained fever is persistent and does not vary by more than 0.5°C/day. Remittent fever is persistent and varies by more than 0.5°C/day. Relapsing fever is characterized by febrile periods that are separated by intervals of normal temperature; tertian fever occurs on the first and third days (malaria caused by Plasmodium vivax), and quartan fever occurs on the first and fourth days (malaria caused by Plasmodium malariae). Diseases characterized by relapsing fevers (Table 169-1) should be distinguished from infectious diseases that have a tendency to relapse. Biphasic fever indicates a single illness with 2 distinct periods (camelback fever pattern); poliomyelitis is the classic example. A biphasic course is also characteristic of other enteroviral infections, leptospirosis, dengue fever, yellow fever, Colorado tick fever, spirillary rat-bite fever (Spirillum minus), and the African hemorrhagic fevers (Marburg, Ebola, and Lassa fevers). The term periodic fever is used narrowly to describe fever syndromes with a regular periodicity (cyclic neutropenia and PFAPA [periodic fever, aphthous stomatitis, pharyngitis, and adenopathy]) or more broadly to include disorders characterized by recurrent episodes of fever that do not follow a strictly periodic pattern (familial Mediterranean fever, Hibernian fever, TNF-receptor–associated periodic syndrome [TRAPS], hyper-IgD syndrome, the Muckle-Wells syndrome). Factitious fever, or self-induced fever, may be caused by intentional manipulation of the thermometer or injection of pyrogenic material.