Pathophysiology and treatment of fever in adults
- Reuven Porat, MD
Reuven Porat, MD
- Professor of Medicine
- Tel Aviv University School of Medicine
- Charles A Dinarello, MD
Charles A Dinarello, MD
- Professor of Medicine
- University of Colorado School of Medicine
Fever, an elevation in core body temperature above the daily range for an individual, is a characteristic feature of most infections but is also found in a number of noninfectious diseases such as autoimmune and autoinflammatory diseases. Definitions of normal body temperature, the pathophysiology of fever, the role of cytokines, and the treatment of fever in adults will be reviewed here. Fever of unknown origin in adults, drug fever, and the treatment of fever in infants and children are discussed separately. (See "Approach to the adult with fever of unknown origin" and "Etiologies of fever of unknown origin in adults" and "Drug fever" and "Fever in infants and children: Pathophysiology and management".)
NORMAL BODY TEMPERATURE
Normal body temperature varies over the course of the day, controlled in the thermoregulatory center located in the anterior hypothalamus. The body is normally able to maintain a fairly steady temperature because the hypothalamic thermoregulatory center balances the excess heat production, derived from metabolic activity in muscle and the liver, with heat dissipation from the skin and lungs. However, faced with environmental extremes, humans cannot maintain the narrow daily variation of body temperature without the aid of clothing and protective environments .
In 1992, a detailed study of the range of oral temperature readings in 148 healthy men and women aged 18 to 40 was reported using over 700 measurements . Oral temperatures in the cohort ranged from 35.6°C (96.0°F) to 38.2°C (100.8°F) with a mean of 36.8 ± 0.4°C (98.2 ± 0.7°F). Low levels occurred at 6 AM and higher levels at 4 to 6 PM. The maximum normal oral temperature at 6 AM is 37.2°C (98.9°F), and the maximum level at 4 PM is 37.7°C (99.9°F), both values defining the 99th percentile for healthy subjects. From these studies, a morning reading >37.2°C (98.9°F) or an afternoon temperature of >37.7°C (99.9°F) would be considered a fever. Rectal temperatures are generally 0.6°C (1.0°F) higher than oral readings. Oral readings are lower probably because of mouth breathing, which is particularly important in patients with respiratory infections and rapid breathing. Temperature measurements from the lower esophagus reflect core temperature, and tympanic membrane temperature readings are also close to core temperature.
The normal daily temperature variation is typically 0.5°C (0.9°F). However, in some individuals recovering from a febrile illness, this daily variation can be as high as 1.0°C. During a febrile illness, daily low and high temperature readings are maintained but at higher levels.
In menstruating women, the morning temperature is generally lower during the two weeks prior to ovulation, rising by about 0.6°C (1.0°F) with ovulation and remaining at that level until menses occur. Seasonal variation in body temperature has been described, but this may reflect a metabolic change and is not a common observation. Elevation in body temperature occurs during the postprandial state, but this is not fever. Pregnancy and endocrinologic dysfunction also affect body temperature. The daily temperature variation appears to be fixed in early childhood. On the other hand, it is well established that the ability to develop fever in older adults is impaired and that baseline temperature in older adults is lower than in younger adults . Thus, older adult patients with severe infections may only display a modest fever.
- Lee-Chiong TL Jr, Stitt JT. Disorders of temperature regulation. Compr Ther 1995; 21:697.
- Mackowiak PA, Wasserman SS, Levine MM. A critical appraisal of 98.6 degrees F, the upper limit of the normal body temperature, and other legacies of Carl Reinhold August Wunderlich. JAMA 1992; 268:1578.
- Roghmann MC, Warner J, Mackowiak PA. The relationship between age and fever magnitude. Am J Med Sci 2001; 322:68.
- Jurkat-Rott K, McCarthy T, Lehmann-Horn F. Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve 2000; 23:4.
- Karagianis JL, Phillips LC, Hogan KP, LeDrew KK. Clozapine-associated neuroleptic malignant syndrome: two new cases and a review of the literature. Ann Pharmacother 1999; 33:623.
- Gurrera RJ. Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome. Am J Psychiatry 1999; 156:169.
- Bone RC. Gram-negative sepsis: a dilemma of modern medicine. Clin Microbiol Rev 1993; 6:57.
- Dinarello CA. Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed. J Endotoxin Res 2004; 10:201.
- Schlievert PM, Shands KN, Dan BB, et al. Identification and characterization of an exotoxin from Staphylococcus aureus associated with toxic-shock syndrome. J Infect Dis 1981; 143:509.
- Parsonnet J, Gillis ZA, Pier GB. Induction of interleukin-1 by strains of Staphylococcus aureus from patients with nonmenstrual toxic shock syndrome. J Infect Dis 1986; 154:55.
- Dinges MM, Orwin PM, Schlievert PM. Exotoxins of Staphylococcus aureus. Clin Microbiol Rev 2000; 13:16.
- Proft T, Moffatt SL, Berkahn CJ, Fraser JD. Identification and characterization of novel superantigens from Streptococcus pyogenes. J Exp Med 1999; 189:89.
- Kum WW, Laupland KB, Chow AW. Defining a novel domain of staphylococcal toxic shock syndrome toxin-1 critical for major histocompatibility complex class II binding, superantigenic activity, and lethality. Can J Microbiol 2000; 46:171.
- Bannan J, Visvanathan K, Zabriskie JB. Structure and function of streptococcal and staphylococcal superantigens in septic shock. Infect Dis Clin North Am 1999; 13:387.
- Wolff SM. Biological effects of bacterial endotoxins in man. J Infect Dis 1973; 128:733.
- ATKINS E. Pathogenesis of fever. Physiol Rev 1960; 40:580.
- Dinarello CA. Cytokines as endogenous pyrogens. J Infect Dis 1999; 179 Suppl 2:S294.
- Shapiro L, Zhang XX, Rupp RG, et al. Ciliary neurotrophic factor is an endogenous pyrogen. Proc Natl Acad Sci U S A 1993; 90:8614.
- Dinarello CA. Thermoregulation and the pathogenesis of fever. Infect Dis Clin North Am 1996; 10:433.
- Coceani F, Bishai I, Lees J, Sirko S. Prostaglandin E2 and fever: a continuing debate. Yale J Biol Med 1986; 59:169.
- Dinarello CA, Gatti S, Bartfai T. Fever: links with an ancient receptor. Curr Biol 1999; 9:R147.
- Coceani F, Akarsu ES. Prostaglandin E2 in the pathogenesis of fever. An update. Ann N Y Acad Sci 1998; 856:76.
- Stitt JT. Evidence for the involvement of the organum vasculosum laminae terminalis in the febrile response of rabbits and rats. J Physiol 1985; 368:501.
- Ushikubi F, Segi E, Sugimoto Y, et al. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 1998; 395:281.
- Yang RB, Mark MR, Gray A, et al. Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling. Nature 1998; 395:284.
- Breder CD, Dinarello CA, Saper CB. Interleukin-1 immunoreactive innervation of the human hypothalamus. Science 1988; 240:321.
- Dinarello CA. Differences between anti-tumor necrosis factor-alpha monoclonal antibodies and soluble TNF receptors in host defense impairment. J Rheumatol Suppl 2005; 74:40.
- Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345:1098.
- Wallis RS, Broder MS, Wong JY, et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004; 38:1261.
- Wallis RS, Saliu OY, Sofer C, et al. Differential effects of TNF blockers on TB immunity. Ann Rheumat Dis 2005; 64:132.
- Fitzgerald AA, Leclercq SA, Yan A, et al. Rapid responses to anakinra in patients with refractory adult-onset Still's disease. Arthritis Rheum 2005; 52:1794.
- Pascual V, Allantaz F, Arce E, et al. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med 2005; 201:1479.
- Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum 2004; 50:607.
- Hoffman HM, Rosengren S, Boyle DL, et al. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 2004; 364:1779.
- Simon A, Bodar EJ, van der Hilst JC, et al. Beneficial response to interleukin 1 receptor antagonist in traps. Am J Med 2004; 117:208.
- de Koning HD, Bodar EJ, Simon A, et al. Beneficial response to anakinra and thalidomide in Schnitzler's syndrome. Ann Rheum Dis 2006; 65:542.
- Vane, JR. Inhibition of prostaglandin synthesis as a mechanisms of action for the aspirin-like drugs. Nature 1971; 231:232.
- Flower RJ, Vane JR. Inhibition of prostaglandin synthetase in brain explains the anti-pyretic activity of paracetamol (4-acetamidophenol). Nature 1972; 240:410.
- Bailey JM. New mechanisms for effects of anti-inflammatory glucocorticoids. Biofactors 1991; 3:97.
- Knudsen PJ, Dinarello CA, Strom TB. Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin 1 in U937 cells. J Immunol 1987; 139:4129.
- Greisman LA, Mackowiak PA. Fever: beneficial and detrimental effects of antipyretics. Curr Opin Infect Dis 2002; 15:241.
- NORMAL BODY TEMPERATURE
- FEVER, HYPERTHERMIA, AND HYPERPYREXIA
- Exogenous pyrogens
- Pyrogenic cytokines
- ELEVATION OF THE HYPOTHALAMIC SET-POINT BY CYTOKINES
- Production of cytokines in the central nervous system
- Does anticytokine therapy mask infection by preventing fever?
- MECHANISMS OF ANTIPYRETIC AGENTS
- TREATMENT OF FEVER AND HYPERTHERMIA
- Decision to treat fever
- Treating fever
- Treating hyperthermia
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS