Drug Fever

Ruchi A. Patel, Pharm.D.; Jason C. Gallagher, Pharm.D.

Disclosures

Pharmacotherapy. 2010;30(1):57-69. 

In This Article

Mechanisms of Drug Fever

Five mechanisms of drug fever have been identified. Fevers may arise from a drug's effects on thermoregulation, administration-related reactions, the drug's pharmacologic action, idiosyncratic response, and hypersensitivity reactions; this latter is the most common mechanism of drug fever.[1,4,72] Table 5 categorizes the drugs believed to cause fever by these mechanism.

Altered Thermoregulatory Mechanisms

A variety of drugs can disrupt thermoregulatory mechanisms by either increasing heat production or limiting heat dissipation.[1] Levothyroxine sodium is an example of a drug that increases metabolic rate, therefore directly increasing heat production.[4,72] This is due to the direct effects of the drug and can occur regardless of the patient's underlying thyroid state. Sympathomimetic agents such as cocaine, 3,4-methylene dioxymethamphetamine (MDMA, or "Ecstasy"), and amphetamine act centrally on the hypothalamus to cause fever.[1,72] Hyperthermia induced by MDMA is a result of increased serotonin release.

Serotonin appears to have temperature rising effects, and the typical clinical manifestation of MDMA-induced hyperthermia is similar to serotonin syndrome.[77] Epinephrine raises body temperature by promoting peripheral vasoconstriction.[72] Certain drugs possessing anticholinergic activity such as atropine, antihistamines, tricyclic antidepressants, phenothiazines, and butyrophenone tranquilizers all reduce heat loss through controlling sweat gland secretion, which can possibly lead to druginduced fever; however, it does not appear that drug fever occurs with all agents in each of these drug classes.[1,2,72] Marked hyperthermia can occur when phenothiazines and anticholinergics are taken in combination to decrease extrapyramidal effects, or when taken in increased doses.[3] Monoamine oxidase inhibitors can cause hyperthermia by increasing metabolism through elevating levels of tissue catecholamines and thereby increasing heat liberation.[3] Cimetidine blocks histamine2 receptors in the hypothalamus and has been reported to cause drug fever through this mechanism. Many of these agents that cause an alteration in thermoregulation result in clinically evident fever only in overdose situations.[4]

Drug Administration–Related Fever

The process of administering a drug can directly result in a febrile reaction. Fevers can be due to contamination or due to the intrinsic effect of the drug itself.[72] Pyrogens not removed during the manufacturing process may contaminate some antibiotics, chemotherapy agents, and streptokinase, although manufacturing processes have improved as they have progressed.[2] Vancomycin at one time used to contain impurities ("Mississippi mud") and was a wellknown source of drug fever; since then it has been reformulated and is now rarely a culprit of administration-related drug-induced fever.[2,3] Drugs such as amphotericin B formulations and bleomycin sulfate have intrinsic pyrogenic activity that causes elevations in temperature purportedly by causing the release of endogenous pyrogens (interleukin-1) from granulocytes.[1,72,73] Administration-related fever may also occur with injection, as a result of phlebitis from the infusion of irritating solutions such as cephalosporins and vancomycin.[3,4] Infusion-related phlebitis may lead to an inflammatory response resulting in the release of cellular pyrogens that can cause fever. A sterile abscess and fever can develop after intramuscular injection of pentazocine and paraldehyde.[1] Vaccines and allergenic extracts cause pyrexia through a similar mechanism because they contain bacterial or viral pyrogens.[3,4] Fevers from administration-related reactions can occur during or within hours of the administration of a drug.[1,3] Delayed reactions are uncommon.[1,3]

Fever Related to Pharmacologic Action of the Drug

Sometimes the pharmacologic effect of a drug is itself the cause of drug fever. The Jarisch-Herxheimer reaction is a classic example that is seen during antibiotic therapy for spirochetal diseases such as syphilis, leptospirosis, and borreliosis.[1] The hypothesis is that the release of endotoxins from killed or dying organisms leads to a febrile reaction.[1] Endotoxin, also known as lipopolysaccharide, is an integral part of the cell wall of gram-negative bacteria and is released when neutrophils digest the organisms.[78] A febrile response usually occurs 6–8 hours after initiation of therapy.[4] Another example includes fever induced by antineoplastic agents.[3,4] These agents can elicit fever when neoplastic cells damaged by the drugs release endogenous pyrogens that act on the hypothalamus and cause pyrexia.[1,73,74] Drug fever by this mechanism has been reported with cytosine arabinoside, bleomycin, chlorambucil, vincristine, asparaginase, streptozocin, and cisplatin.[2,8,17,24,25,46,66,71] Case of drug fever occurring with 6-mercaptopurine and chlorambucil have been reported in patients with lymphoproliferative disease.[9,21] It has been postulated that drug sensitivity reactions occur as part of an altered immunologic response by the lymphoproliferative disease.[21] Indirect pharmacologic actions of drugs can also result in development of fever, which has been suggested with the use of heparin and warfarin when excessive anticoagulation causes bleeding into enclosed spaces.[3]

Idiosyncratic Reactions

In certain patients, febrile idiosyncratic drug reactions can develop due to hereditable genetic predisposition.[8,74] The most notable example of this is malignant hyperthermia, which is a disorder characterized by marked hyperthermia (temperature > 106°F), muscular rigidity, tachycardia, arrhythmias, and hypotension in patients undergoing treatment with inhaled anesthetic agents.[73,74] The most commonly implicated agents include halothane (alone or in combination with succinylcholine), isoflurane, and enflurane. The mechanism is thought to be due to a genetic defect resulting in abnormal release of calcium ions into the muscle myoplasm, leading to catabolic reactions that produce a large amount of heat.[74] This type of hyperthermia is a medical emergency and must be reversed immediately by dantrolene to prevent tissue damage.[79]

Neuroleptic malignant syndrome (NMS) is more commonly encountered by clinicians and is characterized by hyperthermia, muscle rigidity, fluctuating consciousness, and autonomic disturbances.[4,80] It is most commonly associated with highly potent dopamine2-receptor antagonists such as the phenothiazines, haloperidol, and thiothixene.[3,4,77,80] Dopamine antagonists cause NMS in 0.02–2.4% of patients due to effects on hypothalamic heat-conserving mechanisms, which occur as a result of blockade of dopamine receptors.[77,79] The onset is often related to an increase in dosage, and the reaction occurs over 1–6 days.[77] The NMS may respond to dantrolene, to dopamine agonists such as bromocriptine, and to a discontinuation or reduction in the dose of the responsible drug.[79]

Some drugs may cause a hemolytic reaction in patients with a deficiency of glucose-6-phosphate dehydrogenase, which can be accompanied by fever.[73] Numerous drugs, such as the sulfonamides, antimalarial agents (e.g., primaquine), nitrofurantoin, quinidine, and chloramphenicol, have been associated with this reaction.[1,4] The mechanism is due to release of endogenous pyrogens by the hemolyzed red blood cells that cause an elevation in body temperature.[3]

Hypersensitivity

The most common mechanism for drug fever is due to a hypersensitivity reaction.[1–3,72,73] Several types of hypersensitivity that lead to drug fever have been proposed. The most probable mechanism is mediated by a humoral response.[4] Drugs or degradation products may act as either a complete antigen or a hapten.[4] Haptens are small molecules that can elicit an immune response only when attached to large carrier proteins to form functional antigens.[78] The formation of circulating antibody-antigen complexes in combination with complement can stimulate the release of pyrogens from granulocytes, resulting in pyrexia.[3,4] A second mechanism for the development of hypersensitivity that manifests as drug fever is through T-cell lymphocyte immune response or cellular immunity.[3,4] The mechanism of pyrexia in cellular immunity appears to be due to production of nonpyrogenic soluble factors (lymphokines) that act on blood and tissue macrophages to produce and release endogenous pyrogen to result in fever.[3,4,72]

Most hypersensitivity reactions are not limited to drug fever.[72,74] Since many other characteristics of an allergic response accompany the fever, the diagnosis of drug hypersensitivity can be made fairly easily when this is the case.[1,4,5,72–74] Conversely, when drug fever without any evidence of obvious findings of hypersensitivity occurs, the diagnosis of drug hypersensitivity is considerably more difficult. There is no consensus on the frequency in which this occurs; estimates vary depending on the definition of drug fever that is used.[3,73,74] Drugs such as methyldopa, anticonvulsants (phenytoin, carbamazepine), antimicrobial agents, procainamide, quinidine, allopurinol, and others cause drug fever through this mechanism.[4,18,19,73,74]

The presence of antibodies in the serum does not prove a hypersensitivity reaction since they can be present in patients who demonstrate no signs of a drug reaction.[3,4,74] Also, the failure to detect the presence of antidrug antibodies does not rule out hypersensitivity-induced drug fever since the antibodies formed may not be directed against the drug itself.[4]

The timing of the onset of drug fever due to hypersensitivity can be an important diagnostic clue. Elevated temperatures can appear several days to weeks after starting drug therapy. This variability in the onset of drug fever can cloud the diagnosis, particularly in patients who begin several new drugs simultaneously. In contrast with the initial fever from hypersensitivity, fever recurs within hours of a rechallenge when the offending agent is readministered whether days, months, or even years later.[2,4,73] The diagnosis of drug fever can be confirmed with careful attention to the temporal relationship in response to the offending agent and resolution of fever after discontinuation of the agent.

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