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What is drug fever?

Drug fever is defined as a persistent fever in the absence of infection or other underlying condition. The fever must coincide temporally with the administration of the offending agent and disappear promptly upon its withdrawal, after which the temperature remains normal. Although a working definition exists, drug fever is not easy to diagnose. Factors such as time of onset of fever, ingestion of other medications that may mask fever, and the absence of a set range of temperatures make drug fever a diagnosis of exclusion. Due to its difficult recognition, drug fever may result in an increase in hospital stay along with the administration of unnecessary procedures and medications. It has been estimated that 3-5% of hospitalized patients experiencing adverse drug reactions experience drug fever alone or as part of multiple symptoms.

The mechanisms of drug fever are separated into different categories. The broad classifications include:

  • Drugs altering thermoregulation
  • Fevers related to pyrogen release as part of the pharmacological action of the drug
  • Drug administration related fevers
  • Hypersensitivity reactions
  • Idiosyncratic reactions

Drug fever from altered thermoregulation

Exogenous thyroid hormone can result in drug fever by increasing the metabolic rate. Drugs that cause decreased sweating and do not allow the body to properly cool also fit into this category. This is seen with drugs that have anticholinergic effects including: atropine, antihistamines, tricyclic antidepressants, phenothiazines, and butyrophenone tranquilizers. Drugs that cause vasoconstriction also create an obstacle for the body to properly lose heat. Medications that have this characteristic include sympathomimetic agents such as epinephrine, cocaine, and amphetamine. Other medications, such as monoamine oxidase inhibitors, may elevate the levels of tissue catecholamines, which would result in an increase in heat produced by the body. In rare instances, blocking the H2 receptors in the hypothalamus can cause fever.

Drug fever as a result of pyrogen release from the action of the drug

In some situations the deliberate action of a drug can be the cause of fever. In theory it is recognized that when drugs cause cell death, endogenous pyrogens are released from the cells resulting in drug fever. This is most commonly seen with chemotherapeutic agents that cause mass cell destruction. Another classic example is the Jarisch-Herxheimer reaction-a febrile reaction seen in syphilitic patients treated with antitreponemal agents such as heavy metals, immune serum, or antibiotics. Endotoxin is released from dead spirochetes, resulting in fever 6 to 8 hours after starting therapy. Often it is accompanied by rash, rigors, myalgia, and malaise. However, the debate here is if the fever is actually a direct cause of the drug or from toxins. Either way, the fever must be recognized and treated properly.

Drug-administration related fevers

If not carefully constituted, solutions can be contaminated with impurities that can act as pyrogens and cause fever. A local inflammatory response or phlebitis after an intravenous infusion or an even more serious reaction such as the development of a sterile abscess can result in fever. Inflammatory phlebitis with resultant fever can occur from hypertonic fluids, amphotericin, and a variety of antibiotics, such as erythromycin, vancomycin, and cephalosporins. Intravenous catheters can cause mechanical irritation that can result in fever. Sterile abscesses can occur following intramuscular injections of drugs such as paraldehyde, pentazocine, and aurothioglucose.

Hypersensitivity fevers

Hypersensitivity fevers are probably the most common cause of drug fevers and are immunologically mediated. A classic reaction would occur after brief exposure, is dose dependent, and always reoccurs immediately upon readministration. Often a hypersensitivity drug fever will start 7 to 10 days after initial administration and reoccur within a few hours after rechallenging the patient. The fever will last as long as the drug is being given to the patient.Gaining tolerance to this type of reaction is very rare after the body has been sensitized. Several mechanisms are responsible for hypersensitivity drug fever. One example includes metabolites acting as haptens combining with endogenous proteins to form antigens.Another possible mechanism would be the development of drug-antibody immune complexes. This would promote the release of endogenous pyrogen and cause fever in the patient. Still other reactions can be IgE-mediated, which has recently been found to be the mechanism of cimetidine-induced fever.

Idiosyncratic drug fever

Idiosyncratic causes of drug fever cannot be explained by any of these previous mechanisms. Some classic examples include the neuroleptic malignant syndrome from haloperidol, thiothixene, and phenothiazines and malignant hyperthermia from inhaled anesthetics such as halothane, isoflurane, and enflurane. In addition to these disorders, another serious but rare genetic cause of drug fever is glucose 6-phosphate dehydrogenase deficiency.

Which drugs have been associated with drug fever?

In general almost all drugs can cause drug fever, but there are some that are associated with a higher incidence. The following table is a list of current drugs that have had an incidence of fever.

Table 1. Drugs associated with an incidence of drug fever.

Allopurinol

Aminoglycosides

Amphetamine

Amphotericin B

Anesthetics (inhaled)

Antacids

Anticholinergics

Antihistamines

Antilymphocyte globulin

Antineoplastics

Azathioprine

Barbituates

Bleomycin

Carbamazepine

Cephalosporins

Chloramphenicol

Cimetidine

Clofibrate

Cocaine

Corticosteroids

Cyclosporine

Diazoxide

Digoxin

Epinephrine

Folate

Griseofulvin

Heparin

Hydralazine

Hydroxyurea

Ibuprofen

Imipenem

Iodides

Isoniazid

Iron dextran

Macrolides

Mebendazole

Metoclopramide

Methyldopa

Monamine oxidase inhibitors

Muromonab-CD3

Mycophenolate mofetil

Neuroleptics

Nifedipine

Nitrofurantoin

Oral contraceptives

Para-aminosalicylate

Penicillins

Phenytoin

Procainamide

Propylthiouracil

Quinidine

Ranitidine

Salicylates

Streptokinase

Streptomycin

Sulfonamides

Sulindac

Tacrolimus

Tetracyclines

Tolmetin

Triamterene

Trimethoprim

Vancomycin

Vitamins

   

How should drug fever be managed?

Diagnosing drug fever correctly is the most vital part of managing the condition. It should be suspected when the patient is clinically improving but still has a fever. Drug fever can be easily overlooked because the amount of medications that can cause fever is extensive. One possible clue to drug fever is the presence of relative bradycardia with an accompanying elevated temperature. Relative bradycardia should be taken into account only after the body temperature reaches 102F and it has been concluded that the patient has not received any medications, or has any disease states, that would affect heart rate. To clarify if an on-board drug is causing drug fever, it should be discontinued to see if resolution of fever occurs within 72 hours. It is not recommended to rechallenge the patient with the same drug at a later time because the patient may have an even worse response, including a more severe hypersensitivity reaction. When treating drug fever, unless infectious in nature, antipyretics and cooling measures may help to accelerate recovery but there is no specific treatment protocol that currently exists. Corticosteroids are generally not used unless there is a severe cutaneous reaction. In conclusion, drug fever should be suspected when obvious reasons for fever are not present and the patient should be treated within a timely matter to avoid unnecessary costs and improve a patient's quality of care.

References:

1. Abate B, Barriere S. Antimicrobial regimen selection. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: a pathophysiologic approach. 5th ed. New York: McGraw-Hill; 2002. p. 1817.

2. Beringer P, Middleton R. Anaphylaxis and drug allergies. In: Koda-Kimble Young. Applied Therapeutics: The clinical use of drugs. 7th ed. Philadelphia: Lippincott Williams and Wilkins; 2001. p. 4-7 - 4-10.

3. Mackowiak, PA. Drug fever: mechanisms, maxims, and misconceptions. Am J Med Sci 1987 Oct;294:275-86.

4. Davies DM, Ferner RE, Glanville HD, editors. Davies's textbook of adverse drug reactions. Philadelphia: Lippincott-Raven Publishers; 1998. p. 858-862.

5. Johnson DH, Cunha BA. Fever: drug fever. Infect Dis Clin North Am 1996 March;10:85-90.

6. Hiraide A, Yoshioka T, Ohshima S. IgE-mediated drug fever due to histamine H2-receptor blockers. Drug Saf 1990;5:455-7.

 

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