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Drug-induced Fever

Drug Induced Fever

Drug-induced fever has been described as fever coinciding with drug administration when no other etiology for the fever can be discovered and when the fever abates after cessation of the drug. It is important to recognize the drug as the cause of the fever to avoid unnecessary laboratory tests and prolonged hospital stays.


Drug-induced fever (DIF) is the only clinical manifestation of an adverse drug reaction in 3-5% cases [1] [2]. Risk factors for DIF include administration of several drugs simultaneously, older age, and HIV infection [3] [4] [5]. Causes of DIF and examples are:

  • Pyrogen release due to pharmacologic action of the drug e.g. Jarisch-Herxheimer reaction with sudden onset of fever, myalgia, and tachycardia 6-8 hours after giving antibacterial treatment for infections like syphilis [6] [7].
  • Due to the drug acting as a direct or indirect pyrogen e.g. interferons cause "flu-like" symptoms [8]. Fever associated with Amphotericin B infusion can also be placed into this group [9].
  • Altered thermoregulation by the drug at the central or peripheral level or via a metabolic pathway. Examples are toxicity of drugs like monoamine oxidase inhibitors, anticholinergics, strychnine, phencyclidine, and amphetamine.
  • Immunosuppression: DIF in immunocompromised patients e.g. HIV patients or those on chemotherapy for malignancies.
  • Induced hypersensitivity which manifests as a low-grade DIF within the first 7 - 10 days of the drug administration [6] [10]. Features as skin rash, eosinophilia, chills, headaches, and myalgia may or may not be present.
  • Patient idiosyncrasy e.g. malignant hyperthermia is seen in susceptible patients following muscle relaxation with suxamethonium or volatile anesthesia agents or neuroleptic drugs [11]. The patient may develop a sudden and sustained increase in body temperature with tachycardia and muscle rigidity in the operating room. Neuroleptic malignant syndrome is another idiosyncratic response to antipsychotic medications like phenothiazines, butyrophenones, thioxanthenes, and risperidone. It presents with high fever, tachycardia, sweating, and labile blood pressure [12].
  • Drug-induced fever has been described as fever coinciding with drug administration when no other etiology for the fever can be discovered and when the fever abates after cessation of the drug.[symptoma.com]
  • As such, plasma concentration was measured even when the fever had subsided. On Day 9 of treatment, the dose was increased from 400 to 600 mg, but the patient had a fever of about 38 - 39 C.[ncbi.nlm.nih.gov]
  • The duration of drug administration before fever appeared was highly variable. Most patients had no history of previous drug reaction. Seven patients had fever with on other symptoms or signs that would suggest a diagnosis of drug-induced fever.[ncbi.nlm.nih.gov]
  • A 54-year-old man was receiving calcium dobesilate for retinopathy and after 8 days he presented fever of more than 39 degrees C, generalized myalgia, chills and headache. Other causes of fever were ruled out.[ncbi.nlm.nih.gov]
  • There was no obvious reason for fever, and cytotoxic-induced fever was considered. The drugs were given one at a time. When a test dose (10 mg) of procarbazine was given, she developed a high fever with severe nausea and vomiting.[ncbi.nlm.nih.gov]
  • […] fever R50.8 Other specified fever R50.81 Fever presenting with conditions classified elsewhere R50.82 Postprocedural fever R50.83 Postvaccination fever R50.84 Febrile nonhemolytic transfusion reaction R50.9 Fever, unspecified R52 Pain, unspecified R53 Malaise[icd10data.com]
  • Lung India 2013;30:61-3 Flu-like syndrome is variably defined in different countries. [1] Sudden onset fever (more than 38 C or 100.4 F), chills, malaise, dry cough, loss of appetite, body aches, and nausea are the common manifestations of flu-like syndrome[lungindia.com]
  • The most common symptoms and signs include fever, dyspnoea, cough, infiltrates on chest roentgenogram and an absolute peripheral eosinophilia. 56 Generalised rashes, malaise, a sputum eosinophilia, leukocytosis and an elevated erythrocyte sedimentation[pharmaceutical-journal.com]
  • Fever, malaise, arthritis, and rash were reported.[uspharmacist.com]
Puerperal Pyrexia
  • pyrexia NOS ( O86.4 ) Fever of other and unknown origin Approximate Synonyms Drug fever ICD-10-CM R50.2 is grouped within Diagnostic Related Group(s) (MS-DRG v 36.0): 864 Fever and inflammatory conditions Convert R50.2 to ICD-9-CM Code History 2016 ([icd10data.com]
  • Features 30 all-new topics , including Zika virus, hepatitis E, asthma-COPD overlap syndrome, drug-induced parenchymal lung disease, binge eating disorder, hereditary breast and ovarian cancer syndrome, transient global amnesia, and more.[books.google.com]


The diagnosis of DIF is based on the exclusion of other causes of fever of unknown origin (FUO) and can be difficult, especially in the presence of sepsis or in a neutropenic patient [13]. The clinician can only label a fever as DIF after noting the clinical presentation, medication history, and laboratory results of the patient [14]. Confirmation of DIF depends on demonstrating a temporal link between drug initiation, the onset of fever, and resolution of fever after cessation of the drug.

Laboratory tests like complete blood count may reveal variable white cell count or neutropenia, elevated eosinophils, while liver function tests may show elevated hepatic transaminases in patients with DIF [2] [15] [16] [17]. Tests to exclude causes of FUO like urinalysis, blood culture, urine culture, echocardiography, and chest X-ray are also performed depending on the clinical presentation.

Specific radiological investigations like magnetic resonance imaging and bone scan may be indicated to exclude osteomyelitis, while a positron emission tomography may be required to exclude occult malignancies.


  • On Day 9 of treatment, the dose was increased from 400 to 600 mg, but the patient had a fever of about 38 - 39 C. When the treatment was discontinued, it took 9 days for the fever to subside to a temperature of about 37 C.[ncbi.nlm.nih.gov]
  • All cytokines numerically increased compared to baseline already during the first week of treatment in both groups. Leptin, TNF-alpha, sTNFR-1, sTNFR-2 and sIL-2R levels correlated with the BMI.[ncbi.nlm.nih.gov]
  • Jarisch-Herxheimer reaction with sudden onset of fever, myalgia, and tachycardia 6-8 hours after giving antibacterial treatment for infections like syphilis.[symptoma.com]
  • The distinction is especially important with regard to drug discontinuation and decision regarding the initiation of corticosteroid treatment [Table 1] . [10] Financial support and sponsorship Nil.[ijdd.in]
  • Other causes of fevers include Medicines, including some antibiotics, blood pressure medicines, and anti-seizure medicines Heat illness Cancers Autoimmune diseases Some childhood immunizations Treatment depends on the cause of your fever.[icdlist.com]


  • The effect of corticosteroids on prognosis is unknown as controlled clinical trials are lacking. 2 Beware of cross-reactions and family predisposition Cross-hypersensitivity reactions are common between the three main aromatic anticonvulsants (i.e. phenytoin[medsafe.govt.nz]
  • Prognosis and Patient Counseling. Prognosis for drug-induced lupus is good. Symptoms usually will resolve with days or weeks of discontinuation of the medication. Antibodies may persist for longer periods. VI. Patient Safety and Quality Measures A.[clinicaladvisor.com]
  • The impact of eosinophilia and hepatic necrosis on prognosis in patients with drug-induced liver injury. Aliment Pharmacol Ther 2007;25:1411–1421. 36. Rochon J, Protiva P, Seeff LB et al .[gi.org]


  • Use Additional Use Additional Help Certain conditions have both an underlying etiology and multiple body system manifestations due to the underlying etiology.[icd10data.com]
  • Drug-induced fever has been described as fever coinciding with drug administration when no other etiology for the fever can be discovered and when the fever abates after cessation of the drug.[symptoma.com]
  • Practically all categories in the chapter could be designated 'not otherwise specified', 'unknown etiology' or 'transient'.[stage.nuemd.com]
  • Codes with this note are Etiology codes and must be followed by a Manifestation code or codes.[icd.codes]
  • Still's Disease : Still’s disease is a disorder of unknown etiology characterized by seronegative polyarthritis, fever and rash. The illness has a bimodal age distribution.[antimicrobe.org]


  • Several factors contribute to the difficulty in determining the epidemiology, including the lack of a standardized definition, clinical criteria, and coding using the International Classification of Diseases-9 code for the condition.[pedsinreview.aappublications.org]
  • HDS Induced Liver Injury Epidemiology HDS hepatotoxicity has received increasing attention over the past few years, in part owing to the recognition in the United States that among DILI cases HDS are the second most common cause (16).[gi.org]
Sex distribution
Age distribution


  • […] is unknown The underlying mechanisms causing DHS are poorly understood. 1 Defective detoxification of reactive oxidative metabolites 1 and a genetic predisposition 4 have been implicated in the pathophysiology of this syndrome, as has slow acetylator[medsafe.govt.nz]
  • Pathophysiologically, drug-induced hypersensitivity syndrome (DHS) is an immune-mediated reaction involving macrophage and T-lymphocyte activation and cytokine release, although no consensus has been reached as to its etiology ( 1 ).[jpediatricsreview.com]


  • These data indicate that in these lizards the prevention of fever by use of an antipyretic drug such as sodium salicylate increases the mortality rate from bacterial infection.[science.sciencemag.org]
  • It is also important to drink enough liquids, to prevent dehydration. Familial Mediterranean fever (Medical Encyclopedia) Fever (Medical Encyclopedia) When your baby or infant has a fever (Medical Encyclopedia) [ Read More ][icdlist.com]
  • Drug-induced Diseases: Prevention, Detection, and Management. Bethesda, MD: American Society of Health-Systems Pharmacists; 2005. 7. Mackowiak PA, LeMaistre CF. Drug fever: A critical appraisal of conventional concepts.[ijdd.in]
  • Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea. Aliment Pharmacol Ther. 2015 Oct;42(7):793-801. doi: 10.1111/apt.13344. Accessed online 3/6/2017 at .[drugs.com]
  • If you have a drug allergy, the best prevention is to avoid the problem drug.[mayoclinic.org]



  1. Roush MK, Nelson KM. Understanding drug-induced febrile reactions. Am Pharm.1993;NS33(10):39.
  2. Tabor PA. Drug-induced fever. Drug Intell Clin Pharm. 1986;20(6):413.
  3. Bayard PJ, Berger TG, Jacobson MA. Drug hypersensitivity reactions and human immunodeficiency virus disease.J Acquir Immune Defic Syndr.1992;5(12):1237.
  4. Mijch AM, Hoy JF. Unexplained fever and drug reactions as clues to HIV infection.Med J Aust.1993;158(3):188.
  5. Ryan C, Madalon M, Wortham DW, Graziano FM. Sulfa hypersensitivity in patients with HIV infection: onset, treatment, critical review of the literature.WMJ.1998;97(5):23.
  6. Woodhouse KW. Disorders of temperature regulation. In: Davies DM, Ferner RE, de Glanville H (eds). Davies’s Textbook of Adverse Drug Reactions. London: Chapman and Hall.1998;857-864.
  7. Gelfand JA, Elin RJ, Berry FW Jr, Frank MM. Endotoxaemia associated with the Jarisch-Herxheimer reaction. New England Journal of Medicine.1976;295(4):211-213.
  8. Borden EC. Interferons – expanding therapeutic roles. New England Journal of Medicine 1992;326(22):1491-1492.
  9. Vonk AG, Netea MG, Denecker NE, Verschueren IC, van der Meer JW, Kullberg BJ. Modulation of pro and anti-inflammatory cytokine balance by amphotericin B. Journal of Antimicrobial Chemotherapy 1998;42(4):469-474.
  10. Mackowiak PA, LeMaistre CF. Drug fever: a critical appraisal of conventional concepts. An analysis of 51 episodes in two Dallas hospitals and 97 episodes reported in the English literature.Ann Intern Med.1987;106(5):728.
  11. Denborough M. Malignant Hyperthermia. Lancet 1998;352: 1131-1136.
  12. Guzé BH, Baxter LR. Neuroleptic Malignant Syndrome. New England Journal of Medicine.1985;313(3):163-166
  13. Linares T, Fernandez A, Soto MT, et al. Drug fever caused by piperacillin-tazobactam. J Investig Allergol Clin Immunol 2011; 21:250–251.
  14. Vodovar D, LeBeller C, Megarbane B, et al. Drug fever: a descriptive cohort study from the French national pharmacovigilance database. Drug Saf.2012;35:759–767.
  15. Johnson DH, Cunha BA. Drug fever. Infect Dis Clin North Am. 1996;10(1):85.
  16. Cunha BA. Clinical approach to fever in the neurosurgical intensive care unit: focus on drug fever. Surg Neurol Int.2013;4 (Suppl 5): S318-S322.
  17. Patel RA, Gallagher JC. Drug fever. Pharmacotherapy 2010;30:57–69.

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Last updated: 2018-06-22 05:20