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 it is 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 1–10 μg/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, and 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
) 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. 16-1. 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.
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. 16-1, 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
Cytokines produced in the brain may account for the hyperpyrexia of CNS hemorrhage, trauma, or infection. Viral infections of the CNS induce microglial and possibly neuronal production of IL-1, TNF, and IL-6. In experimental animals, the concentration of a cytokine required to cause fever is several orders of magnitude lower with direct injection into the brain substance or brain ventricles than with systemic injection. Therefore, cytokines produced in the CNS can raise the hypothalamic set point, bypassing the circumventricular organs. CNS cytokines probably account for the hyperpyrexia of CNS hemorrhage, trauma, or infection.
Approach to the Patient: Fever or Hyperthermia
The chronology of events preceding the fever (e.g., exposure to other infected individuals or to vectors of disease) should be ascertained. Electronic devices for measuring oral, tympanic membrane, and rectal temperatures are reliable, but the same site should be used consistently to monitor a febrile disease. Moreover, physicians should be aware that newborns, elderly patients, patients with chronic hepatic or renal failure, and patients taking glucocorticoids may have infections in the absence of fever.
The workup should include a complete blood count; a differential count should be performed manually or with an instrument sensitive to the identification of juvenile or band forms, toxic granulations, and Döhle bodies, which are suggestive of bacterial infection. Neutropenia may be present with some viral diseases.
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 fever. In patients with low-grade fevers, the most valuable measurements are C-reactive protein level and erythrocyte sedimentation rate. These markers of inflammatory processes are particularly helpful in detecting the possible presence of occult disease. Acute-phase reactants are discussed in Chap. 271.
Fever in Recipients of Anticytokine Therapy
With the increasing use of anticytokines to reduce the activity of IL-1, IL-6, IL-12, or TNF in Crohn's disease, rheumatoid arthritis, or psoriasis, the potential of these therapies to blunt the febrile response must be considered. Chronic administration of anticytokines to block 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 treated with agents that neutralize TNF-α are similar to those reported in the HIV-1-infected population (e.g., new infection with or reactivation of Mycobacterium tuberculosis, with dissemination). 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 blunted in these patients remains unknown. This situation is similar to that in patients receiving high-dose glucocorticoid therapy or anti-inflammatory agents such as ibuprofen. Therefore, low-grade fever is of considerable concern in patients receiving anticytokine therapies. The physician must undertake early and rigorous diagnostic evaluation of these patients.
Treatment: Fever or Hyperthermia
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 short, routine treatment of fever and its symptoms with antipyretics does no harm and does not slow the resolution of common viral and bacterial infections.
However, with bacterial infections, withholding antipyretic therapy can be helpful in evaluating the effectiveness of a particular antibiotic, particularly in the absence of positive cultures of the infecting organism. Therefore, 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. 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 hepatic or renal failure, and patients taking glucocorticoids, fever may not be present despite infection. Hypothermia can be 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. Another relapsing fever is related to Borrelia infection, 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. However, these patterns have limited or no diagnostic value compared with specific and rapid laboratory tests.
Anticytokine Therapy to Reduce Fever in Autoimmune and Autoinflammatory Diseases
Recurrent fever is documented at some point in most autoimmune diseases but in all autoinflammatory diseases. Although fever also can be a manifestation of autoimmune diseases, recurrent fevers are characteristic of autoinflammatory diseases. The autoinflammatory diseases (Table 16-2) include adult and juvenile Still's disease, familial Mediterranean fever, and hyper-IgD syndrome. In addition to recurrent fevers, neutrophilia and serosal inflammation characterize autoinflammatory diseases. The fevers associated with these illnesses are reduced dramatically 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, these patients also respond to antipyretics.
Table 16-2 Autoinflammatory Diseases |Favorite Table|Download (.pdf)
Table 16-2 Autoinflammatory Diseases
|Adult and juvenile Still's disease|
|Cryopyrin-associated periodic syndromes (CAPS)|
|Familial Mediterranean fever|
|Macrophage activation syndrome|
|Normocomplementemic urticarial vasculitis|
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, use of acetaminophen is preferred as an antipyretic. In children, acetaminophen or oral ibuprofen 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 suppositories 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 the condition of patients with preexisting impairment of cardiac, pulmonary, or CNS function. Children with a history of febrile or nonfebrile seizure should be treated aggressively to reduce fever. However, 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 (CNS bleeding), reducing core temperature mitigates the detrimental 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. Antipyretics are of no use in treating hyperthermia. 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 sufficient cooling is not 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. 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 also may 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.