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].

• 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. [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]

• Fever of Unknown Origin

  R50 Fever of other and unknown origin Excludes1 chills without fever ( R68.83 ) febrile convulsions ( R56.0 -) fever of unknown origin during labor ( O75.2 ) fever of unknown origin in newborn ( P81.9 ) hypothermia due to illness ( R68.0 ) malignant hyperthermia [icd10coded.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. [symptoma.com]

  […] of unknown origin during labor ( O75.2 ) fever of unknown origin in newborn ( P81.9 ) hypothermia due to illness ( R68.0 ) malignant hyperthermia due to anesthesia ( T88.3 ) puerperal pyrexia NOS ( O86.4 ) Fever of other and unknown origin Approximate [icd10data.com]

  Educational Gap Pediatricians often confuse fever without a source and fever of unknown origin. [pedsinreview.aappublications.org]

  […] of unknown origin Fever w chills Fever with chills Pyrexia of unknown origin 780.60 Excludes Applies To Chills with fever Fever NOS Fever of unknown origin (FUO) Hyperpyrexia NOS Pyrexia NOS Pyrexia of unknown origin ICD-9-CM Volume 2 Index entries containing [icd9data.com]

• Malaise

  […] 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

  Excludes1 chills without fever ( R68.83 ) febrile convulsions ( R56.0 -) fever of unknown origin during labor ( O75.2 ) fever of unknown origin in newborn ( P81.9 ) hypothermia due to illness ( R68.0 ) malignant hyperthermia due to anesthesia ( T88.3 ) puerperal [icd10coded.com]

  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]

• Muscle Rigidity

  The patient may develop a sudden and sustained increase in body temperature with tachycardia and muscle rigidity in the operating room. [symptoma.com]

  However, a small subset of patients can present in extremis with high core temperatures, muscle rigidity, cardiovascular instability and coma. These patients are critically unwell and require urgent management. [stemlynsblog.org]

• Liver Dysfunction

  The previous case report from the Fukushima Medical University School of Medicine described a 16-year old boy hospitalized with liver dysfunction, high fever, and abdominal pain but no rash. [hhv-6foundation.org]

  Anti-tuberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology 2000;31:201–206. 95. Sembera S, Lammert C, Talwalkar JA et al. [gi.org]

• Maculopapular Rash

  On the 16th day of therapy, however, relative eosinophilia developed, and 2 days later a pruritic maculopapular rash appeared. Diltiazem therapy was discontinued, leading to resolution of fever within 48 hours. [ncbi.nlm.nih.gov]

  Cephalexin has also been reported to cause pulmonary eosinophilia. 17 A patient developed a diffuse maculopapular rash seven days after commencing cephalexin therapy (500mg three times a day). [pharmaceutical-journal.com]

• Foot Ulcer

  A 67-year-old man was admitted for management of a diabetic foot ulcer. His hospital course was complicated by a non-Q-wave myocardial infarction, for which diltiazem was prescribed. [ncbi.nlm.nih.gov]

• Pruritic Rash

  Enalapril has been reported to cause a pruritic rash associated with eosinophilia. 34 The rash resolved seven days after enalapril was discontinued. [pharmaceutical-journal.com]

• Amnesia

  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]

• Nystagmus

  […] serum sickness, vaginal candidiasis Cross-hypersensitivity may occur in patients with documented penicillin allergy List of Aminoglycosides Gentamicin, tobramycin, amikacin Renal (kidney) toxicity, ototoxicity (hearing loss), dizziness, nausea/vomiting, nystagmus [drugs.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.

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