TREATMENT Fever 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: no significant clinical evidence indicates either that antipyretics delay the resolution of viral or bacterial infections or that fever facilitates recovery from infection or acts as an adjuvant to the immune system. In short, treatment of fever and its symptoms with routine antipyretics does no harm and does not slow the resolution of common viral and bacterial infections.
However, in bacterial infections, the withholding of antipyretic therapy can be helpful in evaluating the effectiveness of a particular antibiotic, especially in the absence of positive cultures of the infecting organism, and 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. As stated earlier, in newborns, elderly patients, patients with chronic liver or kidney failure, and patients taking glucocorticoids, fever may not be present despite infection. Hypothermia can develop 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 into additional 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 and nearly all autoinflammatory diseases. Although fever can be a manifestation of autoimmune diseases, recurrent fevers are characteristic of autoinflammatory diseases (Table 23-1), including 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 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 reduction of the PGE2 level 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 also are 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 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 aggressively treated 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.
For a discussion of treatment for hyperthermia, see Chap. 479e.