Introduction
Body temperature is controlled by the hypothalamus. Neurons in both the preoptic anterior hypothalamus and the posterior hypothalamus receive two kinds of signals: one from peripheral nerves that transmit information from warmth/cold receptors in the skin and the other from the temperature of the blood bathing the region. These two types of signals are integrated by the thermoregulatory center of the hypothalamus to maintain normal temperature. In a neutral temperature environment, the metabolic rate of humans produces more heat than is necessary to maintain the core body temperature at 37°C.
A normal body temperature is ordinarily maintained, despite environmental variations, 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. According to studies of healthy individuals 18–40 years of age, the mean oral temperature is 36.8° ± 0.4°C (98.2° ± 0.7°F), with low levels at 6 A.M. and higher levels at 4–6 P.M. The maximum normal oral temperature is 37.2°C (98.9°F) at 6 A.M. and 37.7°C (99.9°F) at 4 P.M.; these values define the 99th percentile for healthy individuals. In light of these studies, an A.M. temperature of >37.2°C (>98.9°F) or a P.M. temperature of >37.7°C (>99.9°F) would define a fever. 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 great as 1.0°C. During a febrile illness, the diurnal variation is usually maintained but at higher, febrile levels. The daily temperature variation appears to be fixed in early childhood; in contrast, elderly individuals can exhibit a reduced ability to develop fever, with only a modest fever even in severe infections.
Rectal temperatures are generally 0.4°C (0.7°F) higher than oral readings. The lower oral readings are probably attributable to mouth breathing, which is a factor in patients with respiratory infections and rapid breathing. Lower-esophageal temperatures closely reflect core temperature. Tympanic membrane (TM) thermometers measure radiant heat from the tympanic membrane and nearby ear canal and display that absolute value (unadjusted mode) or a value automatically calculated from the absolute reading on the basis of nomograms relating the radiant temperature measured to actual core temperatures obtained in clinical studies (adjusted mode). These measurements, although convenient, may be more variable than directly determined oral or rectal values. Studies in adults show that readings are lower with unadjusted-mode than with adjusted-mode TM thermometers and that unadjusted-mode TM values are 0.8°C (1.6°F) lower than rectal temperatures.
FEVER VERSUS HYPERTHERMIA
Fever
Fever is an elevation of body temperature that exceeds the normal daily variation and occurs in conjunction with an increase in the hypothalamic set point (e.g., from 37°C to 39°C). This shift of the set point from "normothermic" to febrile levels very much resembles the resetting of the home thermostat to a higher level in order to raise the ambient temperature in a room. Once the hypothalamic set point is raised, neurons in the vasomotor center are activated and vasoconstriction commences. The individual first notices vasoconstriction in the hands and feet. Shunting of blood away from the periphery to the internal organs essentially decreases heat loss from the skin, and the person feels cold. For most fevers, body temperature increases by 1°–2°C. Shivering, which increases heat production from the muscles, may begin at this time; however, shivering is not required if heat conservation mechanisms raise blood temperature sufficiently. Nonshivering heat production from the liver also contributes to increasing core temperature. In humans, behavioral adjustments (e.g., putting on more clothing or bedding) help raise body temperature by decreasing heat loss.
The processes of heat conservation (vasoconstriction) and heat production (shivering and increased nonshivering thermogenesis) continue until the temperature of the blood bathing the hypothalamic neurons matches the new thermostat setting. Once that point is reached, the hypothalamus maintains the temperature at the febrile level by the same mechanisms of heat balance that function in the afebrile state. When the hypothalamic set point is again reset downward (in response to either a reduction in the concentration of pyrogens or the use of antipyretics), the processes of heat loss through vasodilation and sweating are initiated. Loss of heat by sweating and vasodilation continues until the blood temperature at the hypothalamic level matches the lower setting. Behavioral changes (e.g., removal of clothing) facilitate heat loss.
A fever of >41.5°C (>106.7°F) is called hyperpyrexia. This extraordinarily high fever can develop in patients with severe infections but most commonly occurs in patients with central nervous system (CNS) hemorrhages. In the preantibiotic era, fever due to a variety of infectious diseases rarely exceeded 106°F, and there has been speculation that this natural "thermal ceiling" is mediated by neuropeptides functioning as central antipyretics.
In rare cases, the hypothalamic set point is elevated as a result of local trauma, hemorrhage, tumor, or intrinsic hypothalamic malfunction. The term hypothalamic fever is sometimes used to describe elevated temperature caused by abnormal hypothalamic function. However, most patients with hypothalamic damage have subnormal, not supranormal, body temperatures.
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Heat stroke in association with a warm environment may be categorized as exertional or nonexertional. Exertional heat stroke typically occurs in individuals exercising at elevated ambient temperatures and/or humidities. In a dry environment and at maximal efficiency, sweating can dissipate ~600 kcal/h, requiring the production of >1 L of sweat. Even in healthy individuals, dehydration or the use of common medications (e.g., over-the-counter antihistamines with anticholinergic side effects) may precipitate exertional heat stroke. Nonexertionalheat stroke typically occurs in either very young or elderly individuals, particularly during heat waves. According to the Centers for Disease Control and Prevention, there were 7000 deaths attributed to heat injury in the
Drug-induced hyperthermia has become increasingly common as a result of the increased use of prescription psychotropic drugs and illicit drugs. Drug-induced hyperthermia may be caused by monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, and amphetamines and by the illicit use of phencyclidine (PCP), lysergic acid diethylamide (LSD), methylenedioxymethamphetamine (MDMA, "ecstasy"), or cocaine.
Malignant hyperthermia occurs in individuals with an inherited abnormality of skeletal-muscle sarcoplasmic reticulum that causes a rapid increase in intracellular calcium levels in response to halothane and other inhalational anesthetics or to succinylcholine. Elevated temperature, increased muscle metabolism, muscle rigidity, rhabdomyolysis, acidosis, and cardiovascular instability develop within minutes. This rare condition is often fatal. The neuroleptic malignant syndrome occurs in the setting of neuroleptic agent use (antipsychotic phenothiazines, haloperidol, prochlorperazine, metoclopramide) or the withdrawal of dopaminergic drugs and is characterized by "lead-pipe" muscle rigidity, extrapyramidal side effects, autonomic dysregulation, and hyperthermia. This disorder appears to be caused by the inhibition of central dopamine receptors in the hypothalamus, which results in increased heat generation and decreased heat dissipation. The serotonin syndrome, seen with selective serotonin uptake inhibitors (SSRIs), MAOIs, and other serotonergic medications, has many overlapping features, including hyperthermia, but may be distinguished by the presence of diarrhea, tremor, and myoclonus rather than the lead-pipe rigidity of the neuroleptic malignant syndrome. Thyrotoxicosis and pheochromocytoma can also cause increased thermogenesis.
It is important to distinguish between fever and hyperthermia since hyperthermia can be rapidly fatal and characteristically does not respond to antipyretics. In an emergency situation, however, making this distinction can be difficult. For example, in systemic sepsis, fever (hyperpyrexia) can be rapid in onset, and temperatures can exceed 40.5°C. Hyperthermia is often diagnosed on the basis of the events immediately preceding the elevation of core temperature—e.g., heat exposure or treatment with drugs that interfere with thermoregulation. In patients with heat stroke syndromes and in those taking drugs that block sweating, the skin is hot but dry, whereas in fever the skin can be cold as a consequence of vasoconstriction. Antipyretics do not reduce the elevated temperature in hyperthermia, whereas in fever—and even in hyperpyrexia—adequate doses of either aspirin or acetaminophen usually result in some decrease in body temperature.
PATHOGENESIS OF FEVER
Pyrogens
The term pyrogen is used to describe any substance that causes fever. Exogenous pyrogens are derived from outside the patient; most are microbial products, microbial toxins, or whole microorganisms. The classic example of an exogenous pyrogen is the lipopolysaccharide (endotoxin) produced by all gram-negative bacteria. Pyrogenic products of gram-positive organisms include the enterotoxins of Staphylococcus aureus and the group A and B streptococcal toxins, also called superantigens. One staphylococcal toxin of clinical importance is that associated with isolates of S. aureus from patients with toxic shock syndrome. These products of staphylococci and streptococci cause fever in experimental animals when injected intravenously at concentrations of 1–10 µg/kg. Endotoxin is a highly pyrogenic molecule in humans: when injected intravenously into volunteers, a dose of 2–3 ng/kg produces fever, leukocytosis, acute-phase proteins, and generalized symptoms of malaise.
Cytokines are small proteins (molecular mass, 10,000–20,000 Da) that regulate immune, inflammatory, and hematopoietic processes. For example, the elevated leukocytosis seen in several infections with an absolute neutrophilia is the result of the cytokines interleukin (IL) 1 and IL-6. Some cytokines also cause fever; formerly referred to as endogenous pyrogens, they are now called pyrogenic cytokines. The pyrogenic cytokines include IL-1, IL-6, tumor necrosis factor (TNF), ciliary neurotropic factor (CNTF), and interferon (IFN) α. (IL-18, a member of the IL-1 family, does not appear to be a pyrogenic cytokine.) Other pyrogenic cytokines probably exist. Each cytokine is encoded by a separate gene, and each pyrogenic cytokine has been shown to cause fever in laboratory animals and in humans. When injected into humans, IL-1 and TNF produce fever at low doses (10–100 ng/kg); in contrast, for IL 6, a dose of 1–10µg/kg is required for fever production.
A wide spectrum of bacterial and fungal products induce the synthesis and release of pyrogenic cytokines, as do viruses. However, fever can be a manifestation of disease in the absence of microbial infection. For example, inflammatory processes, trauma, tissue necrosis, or antigen-antibody complexes can induce the production of IL-1, TNF, and/or IL-6, which—individually or in combination—trigger the hypothalamus to raise the set point to febrile levels.
Elevation of the Hypothalamic Set Point by Cytokines
During fever, levels of prostaglandin E2 (PGE2) are elevated in hypothalamic tissue and the third cerebral ventricle. The concentrations of PGE2 are highest near the circumventricular vascular organs (organum vasculosum of lamina terminalis)—networks of enlarged capillaries surrounding the hypothalamic regulatory centers. Destruction of these organs reduces the ability of pyrogens to produce fever. Most studies in animals have failed to show, however, that pyrogenic cytokines pass from the circulation into the brain itself. Thus, it appears that both exogenous and endogenous pyrogens interact with the endothelium of these capillaries and that this interaction is the first step in initiating fever—i.e., in raising the set point to febrile levels.
The key events in the production of fever are illustrated in Fig. 1. As has been mentioned, several cell types can produce pyrogenic cytokines. Pyrogenic cytokines such as IL-1, IL-6, and TNF are released from the cells and enter the systemic circulation. Although the systemic effects of these circulating cytokines lead to fever by inducing the synthesis of PGE2, they also induce PGE2 in peripheral tissues. The increase in PGE2 in the periphery accounts for the nonspecific myalgias and arthralgias that often accompany fever. It is thought that some systemic PGE2 escapes destruction by the lung and gains access to the hypothalamus via the internal carotid. However, it is the elevation of PGE2 in the brain that starts the process of raising the hypothalamic set point for core temperature.
Fig.1. Chronology of events required for the induction of fever. AMP, adenosine 5'-monophosphate; IFN, interferon; IL, interleukin; PGE2, prostaglandin E2; TNF, tumor necrosis factor.
There are four receptors for PGE2, and each signals the cell in different ways. Of the four receptors, the third (EP-3) is essential for fever: when the gene for this receptor is deleted in mice, no fever follows the injection of IL-1 or endotoxin. Deletion of the other PGE2 receptor genes leaves the fever mechanism intact. Although PGE2 is essential for fever, it is not a neurotransmitter. Rather, the release of PGE2 from the brain side of the hypothalamic endothelium triggers the PGE2 receptor on glial cells, and this stimulation results in the rapid release of cyclic adenosine 5'-monophosphate (cyclic AMP), which is a neurotransmitter. As shown in Fig. 1, the release of cyclic AMP from the glial cells activates neuronal endings from the thermoregulatory center that extend into the area. The elevation of cyclic AMP is thought to account for changes in the hypothalamic set point either directly or indirectly (by inducing the release of neurotransmitters). Distinct receptors for microbial products are located on the hypothalamic endothelium. These receptors are called Toll-like receptors and are similar in many ways to IL-1 receptors. The direct activation of Toll-like receptors also results in PGE2 production and fever.
Production of Cytokines in the CNS
Several viral diseases produce active infection in the brain. Glial and possibly neuronal cells synthesize IL-1, TNF, and IL-6. CNTF is also synthesized by neural as well as neuronal cells. What role in the production of fever is played by these cytokines produced in the brain itself? In experimental animals, the concentrations of cytokine required to cause fever are several orders of magnitude lower with direct injection into the brain than with IV injection. Therefore, CNS production of these cytokines apparently can raise the hypothalamic set point, bypassing the circumventricular organs involved in fever caused by circulating cytokines. CNS cytokines may account for the hyperpyrexia of CNS hemorrhage, trauma, or infection.
APPROACH TO THE PATIENT : FEVER OR HYPERTHERMIA
Attention must be paid to the chronology of events and to other signs and symptoms preceding the fever. The temperature may be taken orally or rectally, but the site used should be consistent. Axillary temperatures are notoriously unreliable. Electronic devices for measuring tympanic membrane temperatures are reliable and preferred over oral temperature measurements in patients with pulmonary disease such as acute infection or asthma.
The workup should include a complete blood count; a differential count should be performed manually or with an instrument sensitive to the identification of eosinophils, juvenile or band forms, toxic granulations, and Döhle bodies, the last three of which are suggestive of bacterial infection. Neutropenia may be present with some viral infections.
Measurement of circulating cytokines in patients with fever is of little use since levels of pyrogenic cytokines in the circulation often are below the detection limit of the assay or do not coincide with the fever. Although some studies have shown correlations between circulating IL 6 levels and peak febrile elevations, the most valuable measurements in patients with fever are C-reactive protein level and erythrocyte sedimentation rate. These markers of pathologic processes are particularly helpful in identifying disease in patients with small elevations in body temperature.
Fever in Recipients of Anticytokine Therapy
As of this writing, more than 750,000 patients in the
The blocking of cytokine activity has the distinct clinical drawback of lowering the level of host defenses against both routine bacterial and opportunistic infections. The opportunistic infections reported in patients given neutralizing antibodies to TNF-α (infliximab or adalimumab) are similar to those reported in the HIV-1-infected population (e.g., new infection with or reactivation of Mycobacterium tuberculosis , with dissemination). A soluble receptor for TNF, etanercept, is also associated with opportunistic infections but less so than the neutralizing antibodies.
In nearly all reported cases of infection associated with anticytokine therapy, fever is among the presenting signs. However, the extent to which the febrile response is reduced in these patients remains unknown. Fever in a patient who develops an infection during anticytokine treatment is likely to be due to the direct action of microbial products on the hypothalamic thermoregulatory center, with induction of PGE2. For example, blocking the activity of IL-1 or TNF during experimental endotoxin-induced fever in volunteers does not affect the febrile response
FEVER AND HYPERTHERMIA : TREATMENT
The Decision to Treat Fever
Most fevers are associated with self-limited infections, such as common viral diseases. The use of antipyretics is not contraindicated in these infections: there is no significant clinical evidence that antipyretics delay the resolution of viral or bacterial infections, nor is there evidence that fever facilitates recovery from infection or acts as an adjuvant to the immune system. In fact, peripheral PGE2 production is a potent immunosuppressant. In short, treatment of fever and its symptoms does no harm and does not slow the resolution of common viral and bacterial infections.
However, in bacterial infections, withholding antipyretic therapy can be helpful in evaluating the effectiveness of a particular antibiotic therapy, particularly in the absence of cultural identification of the infecting organism. The routine use of antipyretics can mask an inadequately treated bacterial infection. Withholding antipyretics in some cases may facilitate the diagnosis of an unusual febrile disease. For example, the usual times of peak and trough temperatures may be reversed in typhoid fever and disseminated tuberculosis. Temperature-pulse dissociation (relative bradycardia) occurs in typhoid fever, brucellosis, leptospirosis, some drug-induced fevers, and factitious fever. In newborns, the elderly, patients with chronic renal failure, and patients taking glucocorticoids, fever may not be present despite infection, or core temperature may be hypothermic. Hypothermia is often observed in patients with septic shock.
Some infections have characteristic patterns in which febrile episodes are separated by intervals of normal temperature. For example, Plasmodium vivax causes fever every third day, whereas fever occurs every fourth day with P. malariae. Other relapsing fevers are related to Borrelia infections, with days of fever followed by a several-day afebrile period and then a relapse of days of fever. In the Pel-Ebstein pattern, fever lasting 3–10 days is followed by afebrile periods of 3–10 days; this pattern can be classic for Hodgkin's disease and other lymphomas. In cyclic neutropenia, fevers occur every 21 days and accompany the neutropenia. There is no periodicity of fever in patients with familial Mediterranean fever.
Recurrent fever is documented at some point in most autoimmune diseases and all autoinflammatory diseases. The autoinflammatory diseases include adult and juvenile Still's disease, familial Mediterranean fever, hyper-IgD syndrome, familial cold-induced autoinflammatory syndrome, neonatal-onset multisystem autoinflammatory disease, Blau syndrome, Schnitzler syndrome, Muckle-Wells syndrome, and TNF receptor–associated periodic syndrome. Besides recurrent fevers, neutrophilia and serosal inflammation characterize these diseases. The fevers associated with these illnesses are dramatically reduced by blocking of IL-1β activity. Anticytokines therefore reduce fever in autoimmune and autoinflammatory diseases. Although fevers in autoinflammatory diseases are mediated by IL-1β, patients also respond to antipyretics.
Mechanisms of Antipyretic Agents
The reduction of fever by lowering of the elevated hypothalamic set point is a direct function of reducing the level of PGE2 in the thermoregulatory center. The synthesis of PGE2 depends on the constitutively expressed enzyme cyclooxygenase. The substrate for cyclooxygenase is arachidonic acid released from the cell membrane, and this release is the rate-limiting step in the synthesis of PGE2. Therefore, inhibitors of cyclooxygenase are potent antipyretics. The antipyretic potency of various drugs is directly correlated with the inhibition of brain cyclooxygenase. Acetaminophen is a poor cyclooxygenase inhibitor in peripheral tissue and lacks noteworthy anti-inflammatory activity; in the brain, however, acetaminophen is oxidized by the p450 cytochrome system, and the oxidized form inhibits cyclooxygenase activity. Moreover, in the brain, the inhibition of another enzyme, COX-3, by acetaminophen may account for the antipyretic effect of this agent. However, COX-3 is not found outside the CNS.
Oral aspirin and acetaminophen are equally effective in reducing fever in humans. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and specific inhibitors of COX-2 are also excellent antipyretics. Chronic, high-dose therapy with antipyretics such as aspirin or any NSAID does not reduce normal core body temperature. Thus, PGE2 appears to play no role in normal thermoregulation.
As effective antipyretics, glucocorticoids act at two levels. First, similar to the cyclooxygenase inhibitors, glucocorticoids reduce PGE2 synthesis by inhibiting the activity of phospholipase A2, which is needed to release arachidonic acid from the cell membrane. Second, glucocorticoids block the transcription of the mRNA for the pyrogenic cytokines. Limited experimental evidence indicates that ibuprofen and COX-2 inhibitors reduce IL-1-induced IL-6 production and may contribute to the antipyretic activity of NSAIDs.
Regimens for the Treatment of Fever
The objectives in treating fever are first to reduce the elevated hypothalamic set point and second to facilitate heat loss. Reducing fever with antipyretics also reduces systemic symptoms of headache, myalgias, and arthralgias.
Oral aspirin and NSAIDs effectively reduce fever but can adversely affect platelets and the gastrointestinal tract. Therefore, acetaminophen is preferred to all of these agents as an antipyretic. In children, acetaminophen must be used because aspirin increases the risk of Reye's syndrome. If the patient cannot take oral antipyretics, parenteral preparations of NSAIDs and rectal suppository preparations of various antipyretics can be used.
Treatment of fever in some patients is highly recommended. Fever increases the demand for oxygen (i.e., for every increase of 1°C over 37°C, there is a 13% increase in oxygen consumption) and can aggravate preexisting cardiac, cerebrovascular, or pulmonary insufficiency. Elevated temperature can induce mental changes in patients with organic brain disease. Children with a history of febrile or nonfebrile seizure should be aggressively treated to reduce fever, although it is unclear what triggers the febrile seizure and there is no correlation between absolute temperature elevation and onset of a febrile seizure in susceptible children.
In hyperpyrexia, the use of cooling blankets facilitates the reduction of temperature; however, cooling blankets should not be used without oral antipyretics. In hyperpyretic patients with CNS disease or trauma, reducing core temperature mitigates the ill effects of high temperature on the brain.
A high core temperature in a patient with an appropriate history (e.g., environmental heat exposure or treatment with anticholinergic or neuroleptic drugs, tricyclic antidepressants, succinylcholine, or halothane) along with appropriate clinical findings (dry skin, hallucinations, delirium, pupil dilation, muscle rigidity, and/or elevated levels of creatine phosphokinase) suggests hyperthermia. Attempts to lower the already normal hypothalamic set point are of little use. Physical cooling with sponging, fans, cooling blankets, and even ice baths should be initiated immediately in conjunction with the administration of IV fluids and appropriate pharmacologic agents (see below). If insufficient cooling is achieved by external means, internal cooling can be achieved by gastric or peritoneal lavage with iced saline. In extreme circumstances, hemodialysis or even cardiopulmonary bypass with cooling of blood may be performed.
Malignant hyperthermia should be treated immediately with cessation of anesthesia and IV administration of dantrolene sodium. The recommended dose of dantrolene is 1–2.5 mg/kg given intravenously every 6 h for at least 24–48 h—until oral dantrolene can be administered, if needed. Procainamide should also be administered to patients with malignant hyperthermia because of the likelihood of ventricular fibrillation in this syndrome. Dantrolene at similar doses is indicated in the neuroleptic malignant syndrome and in drug-induced hyperthermia and may even be useful in the hyperthermia of the serotonin syndrome and thyrotoxicosis. The neuroleptic malignant syndrome may also be treated with bromocriptine, levodopa, amantadine, or nifedipine or by induction of muscle paralysis with curare and pancuronium. Tricyclic antidepressant overdose may be treated with physostigmine.
FURTHER READINGS
| De Koning HD et al: Beneficial response to anakinra and thalidomide in Schnitzler's syndrome. Ann Rheum Dis 65:542, 2006 |
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| Hawkins PN et al: Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum 50:607, 2004 [PMID: 14872505] |
| Hoffman HM et al: Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 364:1779, 2004 [PMID: 15541451] |
| Keane J et al: Tuberculosis associated with infliximab, a tumor necrosis factor--neutralizing agent. N Engl J Med 345:1098, 2001 [PMID: 11596589] |
| Pascual V 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 201:1479, 2005 [PMID: 15851489] |
| Simon A, van der Meer JW: Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes. Am J Physiol Regul Integr Comp Physiol 292:R86, 2007 |
| ——— et al: Beneficial response to interleukin-1 receptor antagonist in TRAPS. Am J Med 117:208, 2004 |
| Wallis RS et al: Differential effects of TNF blockers on TB immunity. Ann Rheum Dis 64(Suppl3):132, 2005 |
| ——— et al: Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 38:1261, 2004 |
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