INTRODUCTION — 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
Range of normal temperature — Normal body temperature ranges from approximately 35.3 to 37.7°C (95.5 to 99.9°F), with an average of 36.7°C (98.0°F) when measured orally, as suggested by studies in both outpatients and hospitalized individuals:
●In a study that included 35,488 individuals who underwent 243,506 oral temperature measurements during routine outpatient visits, the mean temperature was 36.6°C (97.9°F), with a 99 percent range 35.3 to 37.7°C (95.5 to 99.9°F) [1]. The mean age of participants was 52.9 years, 64 percent were female, and 41 were percent non-White.
●In another study that included 42,622 medical inpatients without known infection, malignancy, or immunocompromising condition who underwent 495,866 oral temperature measurements during the first week of hospitalization, the mean temperature was 36.7°C (98.0°F), with a 99 percent range 35.4 to 37.7°C (95.8 to 99.9°F). The mean age of participants was 61 years, 50 percent were female, 25 were percent Black, and mean body mass index was 30 [2].
In both studies, older age was associated with lower temperatures, as was lower body mass index. Higher temperatures were recorded in females compared with males. Temperatures also vary by underlying conditions. Hypothyroidism has been associated with lower temperatures and cancer with higher temperatures [1]. Pregnancy and endocrinologic dysfunction also affect body temperature.
Individual daily variation — Normal body temperature varies over the course of the day, controlled in the thermoregulatory center located in the anterior hypothalamus. The normal early morning to late afternoon daily increase 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 (1.8°F). Studies suggest that a morning oral temperature >37.2°C (98.9°F) or an afternoon temperature of >37.7°C (99.9°F) could be considered a fever.
A detailed study of the range of oral temperature readings in 148 healthy individuals aged 18 to 40 years was reported using over 700 measurements [3]. 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 was 37.2°C (98.9°F), and the maximum level at 4 PM was 37.7°C (99.9°F), both values defining the 99th percentile for healthy subjects.
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. Although it is well established that females in the luteal (post-ovulatory) phase have higher body temperature, the amplitude of the circadian rhythm for body temperature is the same as in males [4].
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. The daily temperature variation appears to be fixed in early childhood.
During a febrile illness, the daily low early morning and high evening temperature difference is maintained but shifted upwards to higher levels.
The circadian rhythms in humans and the genes that regulate daily oscillations in body temperature have been studied. 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, when faced with environmental extremes, humans cannot maintain the narrow daily variation of body temperature without the aid of clothing and protective environments [5].
Methods of measurement — Peripheral methods of monitoring temperature (tympanic membrane, temporal artery, axillary, and oral thermometry) are not as accurate as central methods (pulmonary artery catheter, urinary bladder, esophageal, and rectal thermometry) [6], but central methods are less practical than peripheral methods.
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. Tympanic membrane temperature readings are close to core temperature.
FEVER, HYPERPYREXIA, AND HYPERTHERMIA — Fever, hyperpyrexia, and hyperthermia are not synonymous terms.
Fever — Fever is an elevation in core body temperature above the daily range for an individual. There is no universal threshold for fever, as normal body temperature varies by individual, time of day, and method of measurement. Based on studies documenting diurnal variations in normal body temperature, a morning oral temperature >37.2°C (98.9°F) or an afternoon temperature of >37.7°C (99.9°F) could be considered a fever. However, in practice, a general threshold of temperature >37.8°C (100.0°F) [7] or >38°C (100.4°F) [8] is often used. It is well established that baseline temperature in older adults is lower than in younger adults, and the ability to develop fever in older adults is impaired [9]. Thus, temperatures lower than those thresholds may still reflect fever (and potentially severe infection) in older adult patients. (See 'Normal body temperature' above.)
Fever is regulated at the level of the hypothalamus. The thermostat device, which regulates the temperature in a home, is comparable to the way the hypothalamus controls core body temperature. The thermostat setting in the hypothalamic thermoregulatory center shifts upwards during a fever, for example, from 37 to 39°C. In other words, during fever, the "set-point" in the hypothalamus shifts upward from the "normothermia" setting to febrile levels, similar to the way the home thermostat is reset to a higher level in order to raise the ambient temperature in a room. Elevated levels of prostaglandin E2 (PGE2) in the hypothalamus appear to be the trigger for raising the set-point. Once the hypothalamic set-point is raised, this activates neurons in the vasomotor center to commence vasoconstriction and warm-sensing neurons to slow their firing rate and increase heat production in the periphery.
The vasoconstriction produces a noticeable cold sensation in the hands and feet. Blood is shunted away from the periphery to the internal organs, essentially decreasing heat loss from the skin, and the patient feels cold. For most fevers, this is sufficient to raise core body temperature 1 or even 2°C.
At the same time, thermogenesis in fat contributes to increasing core temperature. This is termed "nonshivering thermogenesis." At birth, highly thermogenic brown fat is present but rapidly decreases within the neonatal period. It is unclear how much brown fat remains as a source of heat production in the adult.
Thermogenesis in either the fat or muscle takes place by uncoupling proteins, which release adenosine triphosphate (ATP) and heat. The combination of heat conservation and thermogenesis accounts for the majority of fever. There is also increased heat production from the liver.
Shivering may be initiated in order to increase heat production from the muscles, but shivering is not required for most fevers. Shivering appears to take place when there is a rapid rise to match the new febrile set-point.
In humans, behavioral instincts assist in raising body temperature with reduction of exposed surfaces. Subjects seek warm rooms, add extra clothing, and reduce activity. The processes of heat conservation (vasoconstriction), heat production (shivering, nonshivering thermogenesis, increased metabolic activity), and behavioral changes continue until the temperature of the blood bathing the hypothalamic neurons matches the new setting. When that point is reached, the hypothalamus now maintains the new setting at the febrile level temperature, just as it does at the normothermic level. In fact, studies have shown that the mechanisms of balancing heat loss and heat production in fever are the same as in the afebrile state.
When the hypothalamic set-point is reset downward, the processes of heat loss are accelerated through vasodilation and sweating. The resetting of the set-point downward can be due to either a reduction in the concentration of pyrogens or the use of antipyretics. Behavioral changes are also triggered at this time and removal of insulating clothing or bedding takes place. Loss of heat by sweating and vasodilation continue until the temperature of the blood supplying the hypothalamus matches the lower setting.
In some rare patients, the hypothalamic set-point is elevated owing to 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, the majority of patients with hypothalamic damage have hypo- not hyperthermia. These patients do not respond properly to minor environmental temperature changes; in this condition, core temperature falls upon exposure to slight drops in temperature, whereas normal hypothalamic function can maintain core temperature for a few hours. In those very few patients in whom elevated core temperature is suspected to be due to hypothalamic damage, the diagnosis depends upon the demonstration of other abnormal hypothalamic functions, such as production of hypothalamic releasing factors, abnormal response to cold, and absence of circadian temperature and hormonal rhythms.
Hyperpyrexia — Hyperpyrexia is the term for an extraordinarily high fever (>41.5°C), which can be observed in patients with severe infections but can also occur in patients with central nervous system (CNS) hemorrhages.
Hyperthermia — Although the vast majority of patients with elevated body temperature have fever, there are a few instances in which an elevated temperature represents hyperthermia. These include heat stroke syndromes, certain metabolic diseases, and the effects of pharmacologic agents that interfere with thermoregulation. In contradistinction to fever, the setting of the thermoregulatory center during hyperthermia remains unchanged (ie, at normothermic levels), while body temperature increases in an uncontrolled fashion and overrides the ability to lose heat. Exogenous heat exposure and endogenous heat production are two mechanisms by which hyperthermia can result in dangerously high internal temperatures. (See "Severe nonexertional hyperthermia (classic heat stroke) in adults".)
It is important to make the distinction between fever and hyperthermia. Hyperthermia can be rapidly fatal, and its treatment differs from that of fever. Despite physiologic and behavioral control of body temperature, excessive heat production can easily occur. As an example, overinsulating clothing can result in elevated core temperature. Hyperthermia is most often observed in persons who work or exercise in hot environments and produce heat faster than the peripheral mechanisms can lose it. Hypohydration is a major cause of hyperthermia.
Certain metabolic diseases such as hyperthyroidism can result in mild elevations of core temperature. The effects of some pharmacologic agents (atropine) that interfere with thermoregulation by blocking sweating or vasodilation can also raise core temperature. These syndromes represent hyperthermia because they take place in the presence of a normal hypothalamic set-point. The recreational drug "ecstasy" (3,4-methylenedioxymethamphetamine) produces hyperthermia, which is due to a loss in heat dissipation (vasoconstriction) and heat production via uncoupling protein 3.
A diagnosis of hyperthermia is often made because of a preceding history of heat exposure or use of certain drugs that interfere with normal thermoregulation. There is no rapid way to differentiate elevated core temperature due to fever from hyperthermia. The immediate events prior to the onset of hyperthermia usually play an important role in determining its cause. However, physical examination can assist the clinician in some forms of hyperthermia; for example, the skin is hot but dry in heat stroke syndromes and in patients taking drugs that block sweating. Antipyretics do not reduce the elevated temperature in hyperthermia whereas there is usually some decrease in body temperature in patients with fever or even "hyperpyrexia" after adequate doses of either aspirin or acetaminophen.
Hyperthermia can also occur when certain anesthetics produce a rapid uncoupling of oxidative phosphorylation in susceptible individuals [10]. This is known as malignant hyperthermia and is often fatal. Another form of hyperthermia results in patients taking certain neuroleptic drugs and is called "neuroleptic malignant syndrome" [11,12]. (See "Severe nonexertional hyperthermia (classic heat stroke) in adults" and "Neuroleptic malignant syndrome".)
Another possible cause of hyperthermia is the serotonin syndrome, which may result from any combination of drugs that has the net effect of increasing serotonergic neurotransmission. The syndrome is classically associated with the simultaneous administration of two serotonergic agents, but it can occur after initiation of a single serotonergic drug or increasing the dose of a serotonergic drug in individuals who are particularly sensitive to serotonin. (See "Serotonin syndrome (serotonin toxicity)".)
PATHOGENESIS OF FEVER
Pyrogens — The term pyrogen is used to describe any substance that causes fever. Pyrogens are either exogenous or endogenous. Endogenous pyrogens belong to the class of biologically active proteins called cytokines. Fever-producing cytokines are more precisely termed pyrogenic cytokines.
Exogenous pyrogens — Exogenous pyrogens, derived from outside the host, are mainly microbes or their products, such as toxins. The classic example of an exogenous pyrogen is the lipopolysaccharide endotoxin produced by all gram-negative bacteria. Endotoxins are potent substances not only as pyrogens but also as inducers of various pathologic changes observed in gram-negative infections [13]. Endotoxins belong to a classification of microbial products termed Toll-like receptor (TLR) ligands. TLR evolved with insects, and the mammalian homologues on macrophages bind microbial products from several bacteria and fungi and result in activation of the cell. Therefore, TLR recognition of bacteria explains how infections cause fever. As discussed below, the activation of macrophages via the TLR on mammalian cells results in the production of fever-producing cytokines [14].
Another group of bacterial substances that are potent pyrogens is produced by gram-positive organisms. The toxic shock syndrome toxin (TSST-1) is associated with strains of Staphylococcus aureus isolated from patients with toxic shock syndrome (TSS) [15,16]. TSST-1 and other enterotoxins from S. aureus and exotoxins from group A Streptococcus act both as direct toxins but also serve as "superantigens" [17,18]. Superantigens appear to play a role in the pathogenesis of severe gram-positive infections by interacting with the major histocompatibility complex (MHC) II and a number of T cell subsets [19,20] to release pyrogenic cytokines. Like the endotoxins from gram-negative bacteria, the toxins produced by staphylococci and streptococci produce fever in experimental animals when injected intravenously in the submicrogram/kg range. Of considerable importance is the fact that endotoxin is a highly pyrogenic molecule in humans since 2 to 3 ng/kg produces fever and generalized symptoms of malaise in volunteers [21].
Pyrogenic cytokines — Pyrogenic cytokines are specific cytokines produced upon activation of TLR that cause fever [3]. Cytokines are small proteins (molecular weight 10 to 20,000 Daltons) that regulate immune, inflammatory, and hematopoietic processes. As an example, stimulation of lymphocyte proliferation during an immune response to vaccination is the result of various cytokines including interleukin (IL)-2, IL-4, and IL-6. A cytokine called granulocyte colony-stimulating factor (G-CSF) stimulates granulocytopoiesis in the bone marrow (see "Introduction to recombinant hematopoietic growth factors"). Of the many cytokines (over 70), only few cause fever by directly acting on the hypothalamic thermoregulatory center.
From a historical point of view, the field of "cytokine biology" began with laboratory investigations into the cause of fever by products of activated leukocytes in the 1940s. These fever-producing molecules were called "endogenous pyrogens" [22]. When endogenous pyrogens were purified from activated leukocytes, they were shown to cause fever as well as possess a broad range of biological activities, affecting all organ systems. Cytokines can affect organ function during disease, but unless challenged by infection or trauma, cytokines do not seem to play a role in normal physiologic functions, including temperature regulation or endocrine functions.
There are several pyrogenic cytokines, namely IL-1, IL-6, tumor necrosis factor (TNF), and ciliary neurotrophic factor [23,24]. Others likely exist. Interferon (IFN)-alpha can also be considered a pyrogenic cytokine since it produces fever. In fact, recombinant IL-1, IL-6, or TNF have each been injected into humans and have produced fever. IL-1 is particularly pyrogenic, resulting in fever at doses as low as 10 ng/kg (either subcutaneously or intravenously) [23]. IL-6 is also pyrogenic but microgram/kg rather than nanogram/kg doses of IL-6 are needed to produce fever in humans. Nevertheless, large amounts of IL-6 circulate in nearly all febrile diseases and IL-6 induced by IL-1 or the combination of IL-1 plus TNF likely accounts for the clinical fever most often measured. Mice without the gene for IL-6 do not develop fever during bacterial infection. Thus, in most inflammatory and infectious diseases, IL-1 and TNF (even at low concentrations) induce large amounts of IL-6, and it is the IL-6 that likely triggers the hypothalamic centers for control of body temperature. Thus, in addition to exogenous pyrogens from microbial sources, endogenous pyrogenic cytokines cause fever. Each cytokine is coded by a separate gene and each pyrogenic cytokine has been shown to cause fever not only in laboratory animals but also when injected into humans.
A wide spectrum of exogenous pyrogens induces the synthesis and release of pyrogenic cytokines via activation of the TLRs. Most exogenous pyrogenic substances are from bacterial or fungal sources. Viruses induce pyrogenic cytokines by infecting cells. Additionally, fever can also be a symptom of a variety of noninfectious diseases. Inflammation, trauma, or antigen-antibody complexes induce the production of IL-1, TNF, and IL-6, and each or all three cytokines trigger the hypothalamus to raise the set-point to febrile levels [25]. The cellular sources of pyrogenic cytokines are primarily monocytes, neutrophils, and lymphocytes, although many different cells can synthesize these molecules when stimulated.
Elevation of the hypothalamic set-point by cytokines — During fever, hypothalamic tissue and third cerebral ventricle levels of prostaglandin E2 (PGE2) are elevated [26-28]. The highest concentrations of PGE2 are near the circumventricular vascular organs (organ vasculosum lamina terminalis, OVLT) which are networks of fenestrated capillaries surrounding the hypothalamic regulatory centers [29]. Destruction of these organs reduces the ability of pyrogens to produce fever. However, most studies in animals have not been able to show that pyrogenic cytokines pass from the circulation into the brain substance itself [23]. Thus, it appears that both exogenous and endogenous pyrogens interact with the endothelium of these capillaries, which is probably the first step in initiating fever.
The interaction of pyrogens with the hypothalamic circumventricular vascular endothelium is the first step in raising the set-point to febrile levels. The following Algorithm illustrates the key events in the production of fever. As shown, several cells have the potential to produce pyrogenic cytokines. Pyrogenic cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF) are then released from the cell and enter the systemic circulation. Although the systemic effects of these circulating cytokines initiate fever by their ability to induce the synthesis of PGE2, they also induce PGE2 in peripheral tissues [23]. The increase in PGE2 in the periphery accounts for the nonspecific myalgias and arthralgias that often accompany fever. However, it is the induction of PGE2 in the brain that starts the process of raising the hypothalamic set-point for core temperature.
There are four receptors for PGE2, and each signals the cell in different ways. Studies in mice demonstrated that the third PGE2 receptor (EP-3) is essential for the production of fever; mice deficient in the gene for this receptor do not develop fever following the injection of IL-1 or endotoxin [30]. Deletion of the other PGE2 receptor genes leaves the fever mechanism intact. Although PGE2 is essential for fever, PGE2 is not a neurotransmitter. However, release of PGE2 from the brain side of the hypothalamic endothelium triggers the PGE2 receptor on glial cells, and this results in the rapid release of cyclic adenosine monophosphate (cAMP), which is a neurotransmitter [23].
As shown in the following Algorithm, release of cAMP from the glial cells activates neuronal endings from the thermoregulatory center that extend into the area. The elevation of cAMP is thought to account for changes in the hypothalamic set-point either directly or indirectly by inducing the release of monoamine neurotransmitters. Receptors for endotoxin share many similarities to those of IL-1, and, hence, activation of endotoxin receptors on the hypothalamic endothelium also results in PGE2 production and fever [31].
Production of cytokines in the central nervous system — Several viral diseases produce active infection in the brain. Glial cells, but particularly microglia and possibly neuronal cells, synthesize IL-1, TNF, and IL-6 [32]. Ciliary neurotrophic factor (CNTF) is also synthesized by neural as well as neuronal cells. These cytokines produced within the brain itself appear to play a role in the production of fever. When a cytokine is injected directly into the brain of experimental animals, the dose required to cause fever is several orders of magnitude lower compared with intravenous injection. Thus, it appears that central nervous system (CNS) production of these cytokines can raise the hypothalamic set-point, bypassing the circumventricular organs involved in the fever that results from circulating cytokines. Local production of cytokines in the CNS may account for the hyperpyrexia of CNS hemorrhage noted above.
Do anticytokine therapies mask infection by preventing fever? — An increasing number of patients with autoimmune or autoinflammatory diseases are being treated with biologic agents. These are mostly anticytokine therapies, such as IL-1 receptor antagonists (eg, anakinra), TNF-alpha inhibitors, IL-6 receptor inhibitors, anti-IL-12 antibodies, or anti-IL-23 antibodies. Anticytokine therapies have the distinct drawback of lowering host defense against infection [33]. In the case of neutralizing antibodies to TNF-alpha by infliximab or adalimumab, opportunistic infections such as Mycobacterium tuberculosis with dissemination have been reported [34,35]. The soluble receptor for TNF-alpha, etanercept, is also associated with opportunistic infections, but less so compared with the neutralizing antibodies [35,36]. In nearly all reports of infections associated with the use of anticytokine therapies, fever is one of the presenting signs. However, it is likely that fever in these patients is blunted in much the same way as with high-dose glucocorticoids. (See "Tumor necrosis factor-alpha inhibitors and mycobacterial infections" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)
The ability of a patient to present with fever despite being treated with an anticytokine agent can be due to the other cytokines that can cause fever (eg, IL-1, TNF-alpha, IL-6, interferons, and others) that are not affected by a specific anticytokine agent [14]. For example, in a patient with staphylococcal skin infection being treated with anti-TNF-alpha for rheumatoid arthritis, the three pyrogenic cytokines, TNF-alpha, IL-1, and IL-6, are produced, but only TNF-alpha is blocked by the anti-TNF-alpha antibody. In that case, the patient may manifest a low-grade fever or no fever, which confounds the diagnosis of an active infection. Another explanation is that microbial products are capable of inducing brain PGE2 directly via hypothalamic toll-like receptors. In the case of the patient with staphylococcal skin infection being treated with anti-TNF-alpha for rheumatoid arthritis, staphylococcal products may reach the TLRs of the hypothalamic endothelium and trigger COX-2 expression.
Anticytokine agents dramatically reduce fever in autoimmune and autoinflammatory diseases. Some autoimmune diseases and most autoinflammatory diseases have recurrent fever as a prominent presenting sign. The autoinflammatory diseases are diseases in which the monocyte rather than the lymphocyte plays a pathological role. 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's syndrome, Schnitzler's syndrome, Muckle-Wells syndrome, and TNF receptor-associated periodic syndrome. They are characterized by recurrent fevers, neutrophilia, and serosal inflammation. The fever associated with these diseases is dramatically reduced by blocking IL-1 with the IL-1 receptor antagonist, caspase-1 inhibitors, or anti-IL-1beta neutralizing antibodies [37-42]. The febrile course of a patient with spiking daily fevers due to adult onset Still's disease are unaffected by daily prednisone but rapidly falls with a single dose of the IL-1 receptor antagonist [37]. Although the fever in autoinflammatory diseases is mediated by IL-1beta, patients also respond to antipyretics.
MECHANISMS OF ANTIPYRETIC AGENTS — Nonsteroidal antiinflammatory drugs (NSAIDs) are potent antipyretics because they inhibit cyclooxygenases (COX-1 or COX-2), an enzyme that promotes the synthesis of prostaglandin E2 (PGE2) [43]. 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. There is a direct correlation between the antipyretic potency of various drugs and their ability to inhibit brain cyclooxygenase [44]. There appears to be no role for PGE2 in normal thermoregulation based upon observations that chronic use of aspirin or NSAIDs in arthritis does not reduce normal core body temperature. More information regarding the mechanism of action of NSAIDs is found elsewhere. (See "NSAIDs: Pharmacology and mechanism of action".)
Acetaminophen is a poor cyclooxygenase inhibitor in peripheral tissue and does not display noteworthy antiinflammatory activity; however, acetaminophen is oxidized in the brain by the p450 cytochrome system, and the oxidized form inhibits cyclooxygenase activity.
Glucocorticoids are also effective antipyretics, which act at two levels [45,46]:
●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 membrane.
●Glucocorticoids block the transcription of the mRNA for the pyrogenic cytokines.
Drugs that interfere with vasoconstriction (eg, phenothiazines) can also act as antipyretics as can drugs that block muscle contractions. However, these are not true antipyretics since they can also reduce core temperature independently of hypothalamic control.
TREATMENT OF FEVER AND HYPERPYREXIA
Deciding whether to treat — We suggest treating fever to reduce symptoms of headache, myalgia, and arthralgias, or to prevent complications of fever in children (eg, febrile seizures) or in individuals with underlying cardiac or pulmonary disease. We suggest treating hyperpyrexia in individuals with advanced age, heart or pulmonary disease, or chemotherapy or checkpoint inhibitor therapy; we also treat hyperpyrexia due to CNS disease (eg, intracerebral hemorrhage) to reduce adverse effects of high temperature on the brain. Dosing of specific agents, and further discussion of the potential benefits of treatment, are found below and elsewhere. (See 'Selection of antipyretic' below.)
However, for patients at increased risk of side effects from antipyretics, we may avoid treatment or favor one class of antipyretic over the others. Such side effects include liver toxicity from acetaminophen and renal dysfunction, bleeding, and peptic ulcer disease from NSAIDs. Rarely, we avoid treatment of fever so we can follow a patient's pattern of fever (ie, "fever curve") to aid in clinical diagnosis of the underlying syndrome. Potential harms of treatment are further discussed below.
Whether to treat fever and hyperpyrexia is often debated [47]. Unlike fever and hyperpyrexia, there is no debate that hyperthermia should always be treated to rapidly reduce core temperature. (See 'Hyperthermia' above and 'Treatment of hyperthermia' below.)
●Potential benefits of treatment – Reducing fever with antipyretics reduces systemic symptoms, such as headache, myalgias, and arthralgias.
Additionally, providers often elect to treat to prevent adverse physiologic consequences of fever. However, there are no data that definitively suggest benefit from treatment. In a systematic review and meta-analysis of 16 randomized controlled trials that included over 2400 hospitalized patients with fever, there was no difference in mortality between those who received treatment for fever and those who did not (23 percent mortality rate in both groups; RR 1.04, 95% CI 0.91-1.19) [47]. There was also no difference in serious adverse events (24 percent rate of serious adverse events in both groups; RR 1.02, 95% CI 0.89-1.17).
Physiologic effects of elevated core temperature, whether fever or hyperthermia, include increased demand for oxygen and aggravation of pre-existing cardiac or pulmonary disease. In healthy subjects, the temperature-pulse relationship is linear with an increase in heart rate of eight beats/minute for each 1°C (4.4 beats/minute for each 1°F) rise in core temperature, although the amount of increase varies based on age and body mass index (BMI) [14,48]. For every increase of one degree above 37°C, there is a 13 percent increase in O2 consumption. In addition, elevated temperature can induce mental changes in patients with organic brain disease.
Furthermore, limited available data provide conflicting information on the immune effects of treatment of fever. During influenza vaccination, treatment with a nonsteroidal antiinflammatory agent (NSAID) increases the anti-influenza antibody level, possibly because peripheral prostaglandin E2 (PGE2) production is a potent immunosuppressant and NSAIDs inhibit PGE2 production [49]. Potentially harmful immune effects are discussed elsewhere. (See 'Treatment of fever and hyperpyrexia' above.)
In patients with hyperpyrexia due to CNS disease or trauma, reducing core temperature helps to reduce the ill effect of high temperature on the brain.
Some patient-populations exhibit lack of fever during infections, especially newborns, older adults, patients with chronic renal failure, and in patients taking corticosteroids. In fact, hypothermia may occur instead of fever, particularly in the setting of septic shock. For such patients, antipyretics do not reset the normal temperature set-point and offer no benefit.
●Potential harms of treatment – There are no definitive clinical data that suggest treatment of fever harms patients [47].
Theoretically, treating fever may reduce any physiologic benefits of fever. In animal studies, there are reports that temperatures in the febrile range may be beneficial during infectious challenges [50]. In addition, in vitro cultures of animal or human cells at elevated temperature suggest a heightened immune response as well as increased bactericidal killing of microorganisms during infection. However, there are no studies demonstrating that fever itself facilitates the recovery from infection or acts as an adjuvant to the immune system.
When deciding whether to treat patients with fever, consideration of the adverse effects of pharmacologic and nonpharmacologic treatments must also be considered, as well as the possibility of masking temperature fluctuations that may provide valuable diagnostic or treatment-related information.
•Adverse effects of antipyretics – Like all medications, antipyretics have associated side effects.
Aspirin and NSAIDs have excellent antipyretic capabilities. However, they can cause gastrointestinal (eg, gastritis, peptic ulcer disease), renal, and anti-platelet effects and have been associated with increased cardiovascular events (eg, myocardial infarction, stroke). More details regarding adverse effects of NSAIDs are found elsewhere. (See "Nonselective NSAIDs: Overview of adverse effects".)
Acetaminophen (paracetamol) is known to cause hepatotoxicity, especially in individuals with chronic liver disease, older age, or malnutrition and in those taking medications or herbal products that interfere with metabolism of acetaminophen. Care must be taken to ensure that dosages are within the recommended range. More information about acetaminophen is provided elsewhere. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Clinical factors that may influence toxicity'.)
Other medications used to reduce fever in individuals with a noninfectious etiology, such as corticosteroids, also have adverse effects that should be taken into consideration prior to prescribing. (See "Pharmacologic use of glucocorticoids", section on 'Complications of chronic use' and "Glucocorticoid effects on the immune system", section on 'Infection risk'.)
•Adverse effects of physical cooling methods – Nonpharmacologic methods of temperature reduction include use of cooling blankets and cool bathing. These methods can be counterproductive if used without concomitant use of antipyretics because they cause vasoconstriction in the skin which can inhibit heat loss from the skin's surface. Submersion should be avoided so that body heat loss by evaporation can occur.
Further information regarding use of physical cooling methods is found elsewhere. (See 'Treatment of hyperthermia' below.)
•Suppression of valuable clinical information – The decision to reduce fever assumes that there is no diagnostic benefit of allowing the fever to persist. The vast majority of fevers are associated with self-limited infections, most commonly of a viral origin, where the cause of the fever is easily identified. However, there are rare clinical situations in which observation of the pattern of fever can be helpful diagnostically:
-The daily highs and lows of normal temperature are exaggerated in most patients with fever, but this is not always the case. For example, the daily high temperatures from typhoid fever are often lower than for other infections, whereas the daily high temperatures are often higher for disseminated tuberculosis than for other infections.
-Temperature-pulse dissociation (relative bradycardia) can be a diagnostic clue for some conditions, including typhoid fever, brucellosis, leptospirosis, some drug-induced fevers, and factitious fever. Relative bradycardia is present when the heart rate does not increase at the rate expected with fever [14,48].
-Some febrile diseases have characteristic fever patterns. Among these are malaria and cyclic neutropenia. However, most of the febrile illnesses that are thought to exhibit a specific time-related pattern (eg, Hodgkin lymphoma) are in fact, upon close examination, not reliable indicators or are of no diagnostic value. As an example, there is no periodicity of fever in patients with familial Mediterranean fever. (See "Clinical manifestations and diagnosis of familial Mediterranean fever".)
In some cases, treatment of fever may eliminate the ability to follow a patient's clinical response to treatment of their underlying infection or illness.
Selection of antipyretic — We suggest acetaminophen as the primary antipyretic. NSAIDs are highly effective but are associated with a higher risk of adverse events. If better fever control is needed than achieved with monotherapy, combination therapy with acetaminophen and an NSAID may be more effective. There are no randomized trials comparing acetaminophen with NSAIDs, or specific NSAIDS to each other, for fever reduction.
When treating fever, it is often prudent to treat only when the temperature reaches a predesignated threshold. Continuous fever suppression may impair the ability to monitor the response to treatment of the underlying disease process.
●Dosing acetaminophen – Due to the side effects of NSAIDs, acetaminophen is generally the preferred antipyretic. In individuals who have no risk factors for hepatotoxicity, the typical dose of acetaminophen in adults is 325 to 650 mg orally or rectally every four to six hours (the maximum total daily dose is 4 g per day); rectal dosing may have less reliable absorption than oral. A parenteral formulation can be used for patients in whom immediate fever reduction is desired or when oral and rectal routes are not options (parenteral dosage for an individual over 50 kg is 650 mg every four hours or 1 g every six hours, with a maximal daily dose of 4 g per day).
The dosage is often lowered to a total maximum daily dose of 2g per day for patients with risk factors such as heavy alcohol use, malnutrition, fasting, low body weight, advanced age, select liver disease, and use of medications that alter acetaminophen metabolism. More details regarding dosing of acetaminophen are found elsewhere. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Clinical factors that may influence toxicity'.)
●Dosing NSAIDs – Commonly used NSAIDs include ibuprofen (200 to 400 mg orally every four to six hours in adults; maximum total daily dose of 3.2 g per day) and naproxen (200 mg orally every 8 to 12 hours in adults). Some NSAIDs, such as ibuprofen, have a parenteral form for patients in whom oral therapy is not an option.
In general, NSAIDs are often avoided in patients with significant renal dysfunction (ie, CrCl ≤30 mL/minute) due to increased risk of acute kidney injury. Other side effects include peptic ulcer disease and bleeding. More details regarding side effects of NSAIDs are found elsewhere. (See 'Deciding whether to treat' above and "Nonselective NSAIDs: Overview of adverse effects".)
Additional interventions for hyperpyrexia — For hyperpyrexia, in addition to administering antipyretics to reduce the elevated set-point of the hypothalamus, physical cooling methods (with cooling blankets and cool water sponging) are often used to facilitate peripheral heat loss.
If the patient cannot take oral antipyretics, parenteral or rectal preparations of various antipyretics can be used, as described above. (See 'Selection of antipyretic' above.)
Cooling blankets and cool-water sponging should not be used without antipyretics because cooling blankets trigger reactive vasoconstriction in the skin which reduces heat loss.
TREATMENT OF HYPERTHERMIA — Antipyretics are of no use in reducing body temperature due to hyperthermia. The treatment of hyperthermia is primarily targeted at rapid reduction of body temperature by physical means. It is also crucial to identify the underlying cause of the hyperthermia, since management varies depending on the etiology.
Rapid reduction in body temperature can be accomplished by cool or tepid (20°C), not cold, bathing, preferably using damp sponges; alcohol adds nothing to tepid or cool water sponging. Submersion should be avoided so that body heat loss by evaporation can occur. Cooling blankets are of potential danger because of excess vasoconstriction preventing heat loss from the skin's surface. Intravenous fluids should be administered for dehydration, but if cool fluids are administered through a central line, the central line should not terminate close to the heart.
Detailed management recommendations for hyperthermia, specific to the underlying cause, are found elsewhere. (See "Severe nonexertional hyperthermia (classic heat stroke) in adults" and "Malignant hyperthermia: Diagnosis and management of acute crisis" and "Neuroleptic malignant syndrome" and "Serotonin syndrome (serotonin toxicity)" and "MDMA (ecstasy) intoxication".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topic (see "Patient education: When to worry about a fever in adults (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Normal body temperature ranges from approximately 35.3 to 37.7°C (95.5 to 99.9°F). Body temperature is low in the early morning and high in evening, varying 0.5°C (0.9°F) over the course of the day. Demographic factors, body mass, certain diseases, and physiologic factors also affect body temperature. (See 'Normal body temperature' above.)
●Fever is an elevation in core body temperature above the daily range for an individual. There is no universal threshold for fever; however, in practice, a general threshold of temperature >37.8°C (100.0°F) or >38°C (100.4°F) is often used. During a febrile illness, daily low and high temperature readings are maintained but at higher levels. (See 'Fever' above.)
●Baseline temperature in older adults is lower than in younger adults, and the ability to develop fever in older adults is impaired. Thus, temperatures lower than commonly used thresholds may still reflect fever (and potentially severe infection) in older adult patients. (See 'Normal body temperature' above.)
●Although the vast majority of patients with elevated body temperature have fever, there are a few instances in which an elevated temperature represents hyperthermia. These include heat stroke syndromes, certain metabolic diseases, and the effects of pharmacologic agents that interfere with thermoregulation. It is important to make the distinction between fever and hyperthermia. Hyperthermia can be rapidly fatal, and its treatment differs from that of fever. (See 'Hyperthermia' above.)
●Hyperpyrexia is the term for an extraordinarily high fever (>41.5°C), which can be observed in patients with severe infections but most commonly occurs in patients with central nervous system hemorrhages. (See 'Hyperpyrexia' above.)
●Patients with autoimmune diseases being treated with biologic agents, such as tumor necrosis factor-alpha inhibitors, are at increased risk for routine as well as opportunistic infections. In these patients, a low-grade fever may serve as an early warning sign of a serious infection. (See 'Do anticytokine therapies mask infection by preventing fever?' above.)
●Inhibitors of cyclooxygenases, such as aspirin and nonsteroidal antiinflammatory agents (NSAIDs), are potent antipyretics. Although acetaminophen is a poor cyclooxygenase inhibitor in peripheral tissue and does not display noteworthy antiinflammatory activity, acetaminophen is an excellent antipyretic. Acetaminophen is oxidized in the brain by the p450 cytochrome system, and the oxidized form inhibits cyclooxygenase activity. There is no difference between aspirin and acetaminophen in reducing fever. (See 'Mechanisms of antipyretic agents' above.)
●Reducing fever with aspirin or NSAIDs reduces systemic and local symptoms of headache, myalgias, and arthralgias but causes unwanted side effects on platelets and the gastrointestinal tract. Thus, acetaminophen is generally the preferred antipyretic. (See 'Deciding whether to treat' above.)
●Elevated core temperature, whether fever or hyperthermia, increases the demand for oxygen and can aggravate preexisting cardiac or pulmonary insufficiency. (See 'Deciding whether to treat' above.)
●The vast majority of fevers are associated with self-limited infections, most commonly of a viral origin, where the cause of the fever is easily identified. The decision to reduce fever with antipyretics assumes that there is no diagnostic benefit of allowing the fever to persist. However, there are rare clinical situations in which observation of the pattern of fever can be helpful diagnostically. (See 'Deciding whether to treat' above.)
●In patients with no contraindications to antipyretics, we suggest treating fever and hyperpyrexia to reduce symptoms of headache, myalgia, and arthralgias or to prevent complications of fever in children (eg, febrile seizures) or in individuals with underlying cardiac or pulmonary disease (Grade 2C). We also suggest treating patients with hyperpyrexia who have advanced age, are on chemotherapy or checkpoint inhibitors, or have related CNS disease (eg, intracerebral hemorrhage) (Grade 2C). (See 'Deciding whether to treat' above and 'Selection of antipyretic' above.)
●For hyperthermia, the goal of treating of hyperthermia is primarily to rapidly reduce body temperature by physical means. It is also crucial to identify the underlying cause of the hyperthermia, since management varies depending on the etiology. Antipyretics are of no use for hyperthermia. (See 'Treatment of hyperthermia' above.)
