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Drug fever

Drug fever
Authors:
Denis Spelman, MBBS, FRACP, FRCPA, MPH
Rekha Pai Mangalore, MBBS, FRACP, MPH, DTM&H
Section Editor:
Daniel J Sexton, MD
Deputy Editor:
Allyson Bloom, MD
Literature review current through: Aug 2021. | This topic last updated: Jun 23, 2021.

INTRODUCTION — Clinicians are universally aware that medications can cause fever, although reliable data on incidence are not available. Fever can be the sole manifestation in 3 to 5 percent of adverse drug reactions [1,2]. The risk of developing drug fever increases with the number of drugs prescribed, especially in older adult patients.

The recognition of drug fever is clinically important. Failure to recognize the etiologic relationship between a drug and fever often has undesired consequences including extra testing, unnecessary therapy, and longer hospital stays.

This topic reviews the clinical approach to drug fever. The general treatment of fever, approach to fever of unknown origin, and fever in specific patient populations are discussed in detail elsewhere:

(See "Pathophysiology and treatment of fever in adults".)

(See "Etiologies of fever of unknown origin in adults" and "Approach to the adult with fever of unknown origin".)

(See "Fever of unknown origin in children: Etiology" and "Fever of unknown origin in children: Evaluation".)

(See "Overview of neutropenic fever syndromes".)

(See "Fever in the intensive care unit".)

(See "Fever in the surgical patient".)

(See "Intrapartum fever".)

(See "Evaluation of fever in the returning traveler".)

DEFINITION — For the purpose of this discussion, drug fever is a disorder characterized by fever that coincides with administration of a drug and disappears after the discontinuation of the drug, when no other cause for the fever is evident after a careful clinical history, physical examination, and laboratory investigation [3].

Other definitions, such as "the febrile response to a drug without cutaneous manifestations" [4], have been used, but in our view, these are overly restrictive. Data on drug fever are largely derived from hundreds of single case reports and a few small series. There are no controlled trials on this subject, and reporting bias may significantly distort the view.

MECHANISMS — The mechanisms of drug fever are multiple and, in many cases, poorly or incompletely understood. However, most authorities classify drug-related fevers into five broad categories [1,2,4-6]:

Hypersensitivity reactions

Idiosyncratic reactions

Reactions that are direct extensions of the pharmacologic action of the drug

Altered thermoregulatory mechanisms

Reactions that are directly related to administration of the drug

Hypersensitivity — Hypersensitivity is the most common cause of drug fever [1-5,7]. Drugs or their metabolites can interact with the human immune system and elicit any of the hypersensitivity reactions through immunoglobin mediation, formation of circulating antigen-antibody complexes, or stimulation of T- and B-cell responses [8,9]. Any one episode may involve multiple antigenic determinants and mechanisms.

Clinically important drug-induced hypersensitivity reactions occur due to immediate hypersensitivity reactions (type I, IgE-mediated reactions, such as anaphylaxis) and delayed-type reactions (type IV, T cell-mediated reactions) [8]. Various hypotheses, including the hapten hypothesis and the pharmacological-interactions (p-i) hypothesis, have been proposed to explain the underlying mechanisms of delayed-type reactions. (See "Drug hypersensitivity: Classification and clinical features".)

Risk factors — Genetic predispositions to drug hypersensitivity have been described. As an example, HLA-B*57:01 is associated with abacavir hypersensitivity, and testing for this genotype is recommended prior to using abacavir [10,11] (see "Abacavir hypersensitivity reaction" and "Fever and rash in patients with HIV"). Drug fever due to genetic predisposition has been described for drugs such as carbamazepine, allopurinol (see 'Allopurinol' below), and misoprostol, a prostaglandin analog used for treatment of postpartum hemorrhage and termination of pregnancy [8,9,11]. However, pharmacogenetic tests for these and most other agents are not routinely available.

Viral infections, in particular HIV infection, can also increase the risk of drug hypersensitivities [2]. Other viral infections associated with an increased risk of drug hypersensitivity are cytomegalovirus, Epstein-Barr virus, and human herpesvirus 6 [12].

Associations with specific agents — Although virtually any drug is capable of causing fever via a hypersensitivity mechanism, the following drug classes warrant special mention.

Anticonvulsants — Aromatic anticonvulsants such as carbamazepine and phenytoin, phenobarbital, and primidone are important causes of drug fever [13-17]. The estimated incidence is 1 reaction per 5000 treated patients [18]. Fever usually begins five to six days after commencement of the drug and may be accompanied by an illness resembling infectious mononucleosis or even a lymphoma-like syndrome. When the drug is discontinued, resolution of fever and lymphadenopathy may be slow, taking from two to six weeks.

Anticonvulsants are also associated with the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Minocycline — Minocycline is a widely used antimicrobial agent, and it is used as long-term therapy for certain indications. Various febrile reactions with minocycline have been reported; these are often accompanied by eosinophilia and may also be associated with joint, lung, liver, and skin involvement [19-22]. In most of these reports, patients were taking minocycline for many months to years before the reaction occurred; this may result in the drug being overlooked as the cause of the fever. (See 'Timing of fever' below.)

Other antimicrobial agents — Antimicrobials, along with antipyretics, are the most common drugs to be prescribed for febrile illnesses; antimicrobial agents are also the most common cause of drug fever, accounting for approximately one-third of episodes [23]. This especially applies to beta-lactams, sulfonamides, and nitrofurantoin [23]. Patients with cystic fibrosis have a disproportionately high incidence of antibiotic-associated drug fever, in particular with piperacillin and imipenem-cilastatin [24].

Drug fever due to an antimicrobial agent can cause clinical confusion; recurrence of fever in a patient who has defervesced on antimicrobial treatment for an infection may be misinterpreted as relapse of the original infection.

Allopurinol — Allopurinol hypersensitivity is a rare but severe life-threatening complication of long-term allopurinol use. An allopurinol reaction should be considered in the differential diagnosis of fever in patients taking this drug. Reactions to allopurinol are associated with various severe cutaneous reactions that range from allopurinol hypersensitivity syndrome, DRESS, to Stevens-Johnson syndrome/toxic epidermal necrolysis. Fever is present with all these manifestations [25]. These reactions have been observed to occur up to eight to nine weeks (median of three weeks) after commencing allopurinol [26]. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Adverse effects'.)

Allopurinol should be avoided in individuals with the HLA-B*58:01 genotype, which increases the risk of allopurinol drug reaction; this association has been observed in certain East Asian ethnic groups [26,27]. Other risk factors for allopurinol reaction include high doses, drug accumulation, renal impairment, and/or concurrent use of diuretics [25,27].

Heparin — Heparins, including low-molecular-weight heparins, are a rare cause of drug fever [28,29]. Heparin-induced fever can be particularly difficult to diagnose in critically ill or postoperative patients who often receive the drug for prophylaxis against thromboembolism.

Immune checkpoint inhibitors — Immune checkpoint inhibitors, such as pembrolizumab and nivolumab, and anti-CTLA-4 antibodies, such as ipilimumab, are antibodies that target the programmed cell death receptor 1 (PD-1)/programmed cell death-ligand 1 (PDL-1) pathway and are used for treatment of certain cancers [30]. These antibodies produce a range of immune-mediated (T cell) responses that not only have antitumor effects but can also result in a range of adverse events, including fever, pneumonitis, rash, and fatigue [31]. These are discussed in detail elsewhere. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

Fever due to an idiosyncratic reaction — Idiosyncratic febrile drug reactions are a heterogeneous category of drug-induced fevers. These reactions include unpredictable syndromes and genetic disorders, and there is some overlap with hypersensitivity phenomena.

Malignant hyperthermia — Malignant hyperthermia is a rare but dramatic event characterized by the sudden appearance of fever over 40°C, muscle rigidity, metabolic acidosis, and hemodynamic instability during general anesthesia [32,33]. Most episodes of malignant hyperthermia have been triggered by muscle-depolarizing agents, such as succinylcholine, and inhaled anesthetic agents, such as halothane. It is usually observed with the third exposure to the provoking agent but can occur with the initial exposure [34]. It is critical to recognize this syndrome because early intervention and treatment may be lifesaving. (See "Malignant hyperthermia: Diagnosis and management of acute crisis".)

Predisposition to malignant hyperthermia is inherited as an autosomal-dominant trait in 50 percent of cases and can affect any ethnic group. It is more common in men than women and most common in children under the age of 15 years. The primary defect is a mutation in the gene for the skeletal muscle ryanodine receptor (RyR1), which is a calcium channel found in the sarcoplasmic reticulum. (See "Susceptibility to malignant hyperthermia: Evaluation and management".)

Neuroleptic malignant syndrome — The neuroleptic malignant syndrome (NMS) is characterized by high fever, muscle rigidity, altered and fluctuating mental state, and dysautonomias [33,35,36]. Hyperthermia results from increased myocyte metabolic activity and altered hypothalamic thermoregulation. (See "Neuroleptic malignant syndrome".)

More than 25 different drugs have been incriminated, most prominently the major tranquilizers, such as haloperidol; all of the implicated drugs are central nervous system dopamine-depleting agents. The probability of developing NMS is directly related to the antidopaminergic potency and dose of the neuroleptic agent [34].

Abrupt withdrawal of dopaminergic agents, such as carbidopa-levodopa, and dopamine agonists, such as amantadine, bromocriptine, ropinirole, and pramipexole, can also precipitate NMS. This type of NMS is called Parkinsonism-hyperpyrexia syndrome. Reintroduction of these medications leads to resolution of this syndrome [37].

NMS is associated with significant mortality unless it is recognized and the drug withdrawn. Treatment of NMS is discussed in detail elsewhere. (See "Neuroleptic malignant syndrome", section on 'Treatment'.)

Serotonin syndrome — Serotonin syndrome is a predictable consequence of excess agonist activity of serotonin on central and peripheral 5-HT1A and 5-HT2A receptors [38]. Features include agitation, confusion, hyperthermia, and autonomic hyperactivity such as diaphoresis, tachycardia, and neuromuscular disturbances, including rigidity, clonus, and tremors. It may be precipitated by selective serotonin reuptake inhibitor (SSRI) use alone or in combination with other drugs, including L-tryptophan, lysergic acid diethylamide (LSD), lithium, L-dopa, dextromethorphan, tramadol, meperidine, and the monoamine oxidase inhibitors. (See "Serotonin syndrome (serotonin toxicity)".)

Hemolysis secondary to glucose-6-phosphate deficiency — Fever may occur in patients with glucose-6-phosphate deficiency when drugs such as primaquine, quinine sulfate, nitrofurantoin, or sulfonamides result in hemolysis and release of endogenous pyrogens [34]. Fever is a minor complication compared with the hemolytic anemia induced by these drugs. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

Fever as an extension of the pharmacologic effect of a drug

Chemotherapy – The most common example of fever as an extension of the pharmacologic effect of the drug is the fever observed following cancer chemotherapy [39]. Cell necrosis and lysis release various pyrogenic substances from damaged cells; the resulting inflammatory response is also accompanied by cytokine activation of the febrile response. Fever most commonly commences three to four days after chemotherapy [39] and may last for one week or more. This early febrile response usually can be distinguished from febrile neutropenia, which rarely develops before the second week after chemotherapy.

Drug fever can occur when BRAF inhibitors and BRAF/MEK inhibitor combinations are used for treatment of metastatic melanoma. Most notably, the combination of dabrafenib and trametinib causes fever in 40 to 60 percent of people; the mechanism is uncertain [40]. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

Jarisch-Herxheimer reaction with antimicrobial therapy – The parallel situation with antimicrobial therapy is the Jarisch-Herxheimer reaction. Fever and transient exacerbation of constitutional symptoms are thought to result from the sudden release of bacterial products from injured and/or killed bacteria [41]. Classically, this reaction was described following treatment for secondary and tertiary syphilis, brucellosis, and enteric fever. It can also occur with treatment of schistosomiasis and trypanosomiasis. (See "Syphilis: Treatment and monitoring", section on 'Jarisch-Herxheimer reaction'.)

Severe reactions of this type have been observed following treatment of borreliosis, particularly Borrelia recurrentis, with a mortality rate of approximately 5 percent. (See "Clinical features, diagnosis, and management of relapsing fever", section on 'Jarisch-Herxheimer reactions'.)

Clozapine – Patients on clozapine can develop fever due to its effects on immune modulation, which lead to increased interleukin-6 and tumor necrosis factor concentrations [34,42]. The fever is usually self-limited, and there are reports of the drug being reintroduced at a lower dose at a later date [43].

Fever due to altered thermoregulation — The thermoregulatory center of the hypothalamus sets and maintains the core body temperature at around 37°C [25]. The physiologic mechanism of thermoregulation occurs via heat loss or heat conservation by the interaction between the hypothalamus and various parts of the central and peripheral nervous system (limbic system, brain stem, spinal cord, sympathetic ganglia) with input from peripheral and central temperature-sensing receptors. Fever occurs when host cells produce "endogenous pyrogens," including the cytokines interleukin (IL)-1 alpha and -1 beta, tumor necrosis factor (TNF)-alpha and -beta, and interferon alpha [44]. These lead to elevations in cyclo-oxygenases and local prostaglandin E2 levels, which mediate thermo-conservation through increased muscle activity (shivering), increased basal metabolic rate, and vasoconstriction.

Drugs that alter or modify one or all of the above mechanisms can cause fever. Specific examples include:

Exogenous thyroid hormone – Thyroid hormone can increase the metabolic rate and directly increase heat production. This exogenous effect can occur without regard to the underlying thyroid function [6].

Drugs with anticholinergic activity – Such drugs, including tricyclic antidepressants, atropine, antihistamines, phenothiazines, and butyrophenone tranquilizers, can cause fever by disturbing central hypothalamic function and the peripheral effector mechanisms detailed above. Marked hyperthermia can ensue when these drugs are taken in combination [2,4,5]. Oligohydrosis and hyperthermia have also been reported with the antiseizure medication zonisamide [45].

Sympathomimetic agents – Drugs such as amphetamines and cocaine cause peripheral vasoconstriction as a result of disturbances in central hypothalamic function and peripheral effector mechanisms. In addition, drug-induced psychomotor agitation may lead to increased muscle activity and secondary heat production [38]. As an example, 3,4-methylene dioxymethamphetamine (MDMA or "ecstasy") has sympathomimetic properties that can cause a potentially fatal acute syndrome characterized by hyperthermia, seizures, rhabdomyolysis, acute renal failure, and coagulopathy, especially when taken prior to vigorous exercise, such as dancing. This reaction is due to serotonin release and shares clinical features of serotonin syndrome [46,47]. (See "MDMA (ecstasy) intoxication", section on 'Clinical features'.)

Drugs that uncouple oxidative phosphorylation – Toxic concentrations of salicylates and the wood preservative pentachlorophenol can short circuit the normal oxidative phosphorylation process in mitochondria and result in excess heat production and hyperthermia. Hyperthermia in patients with salicylate toxicity is a late and serious finding requiring aggressive treatment such as hemodialysis [38]. (See "Salicylate (aspirin) poisoning in adults".)

Fever associated with drug administration — The parenteral administration of certain drugs can directly lead to fever.

Solutions containing drugs and intravenous fluids can become contaminated with endotoxin or other exogenous pyrogens [23]. Such pyrogen reactions have been associated with reusable infusion sets [23,48].

Fever can also accompany a chemical phlebitis caused by drug administration (eg, as with cephalothin or potassium chloride), and local inflammation and/or sterile abscesses can occur at sites of injection [49].

Some drugs, such as amphotericin B and bleomycin, have intrinsic but poorly understood pyrogenic properties (see "Pharmacology of amphotericin B"). Fever sometimes follows injections with paraldehyde and pentazocine [48].

In the past, fever sometimes resulted from drug impurities; this was a particular problem with the older formulations of vancomycin and gentamicin [25,50].

DIAGNOSTIC EVALUATION

Evaluate for other causes of fever — Drug fever is generally a diagnosis of exclusion. The differential diagnosis is broad and includes all other causes of fever, such as infection, malignancy, autoimmune or autoinflammatory conditions, stroke, endocrine disorders, and conditions associated with substance use (eg, alcohol withdrawal). The approach to evaluation of fever varies by underlying patient characteristics (immunocompetent versus immunocompromised, critically ill versus outpatient, specific exposures or underlying medical conditions). In some cases, the possibility of drug fever is assessed as part of an evaluation for fever of unknown origin. Details on the general approach to fever in different patient populations are found elsewhere:

(See "Approach to the adult with fever of unknown origin".)

(See "Fever of unknown origin in children: Evaluation".)

(See "Overview of neutropenic fever syndromes".)

(See "Fever in the intensive care unit".)

(See "Fever in the surgical patient".)

(See "Intrapartum fever".)

(See "Evaluation of fever in the returning traveler".)

Assess for likelihood of drug fever — In hospitalized patients, drug fever can lead to prolonged hospitalization and extensive, expensive evaluation. As an example, in a large study, each episode of drug fever prolonged hospital stay by a mean of 8.7 days and was associated with average of 5 blood cultures and 2.85 radiologic studies [23]. A detailed review of the history, presenting features, and laboratory findings may reveal potential clues to the possibility of drug fever, and thus spare repeat evaluation for other potential causes of fever.

Medication history — All of the patient’s current medications as well as their doses and durations of use should be detailed. These include over-the-counter medications, herbal medications, supplements, and recreational substances.

Although any medication can be associated with fever, review of the medication list should focus on agents or drug classes that are more frequently implicated. These include:

Anticonvulsants (see 'Anticonvulsants' above)

Antibiotics (especially minocycline, beta-lactams, sulfonamides, nitrofurantoin) (see 'Minocycline' above and 'Other antimicrobial agents' above)

Allopurinol (see 'Allopurinol' above)

Cancer therapy, including chemotherapy and immunotherapy (see 'Fever as an extension of the pharmacologic effect of a drug' above and 'Immune checkpoint inhibitors' above)

Thyroid hormone (see 'Fever due to altered thermoregulation' above)

Agents with anticholinergic effect (see 'Fever due to altered thermoregulation' above)

Sympathomimetic agents (eg, amphetamines, cocaine) (see 'Fever due to altered thermoregulation' above)

Neuroleptics (including clozapine) (see 'Fever as an extension of the pharmacologic effect of a drug' above and 'Neuroleptic malignant syndrome' above)

Selective serotonin reuptake inhibitors (SSRIs) (see 'Serotonin syndrome' above)

A previous history of drug fever, particularly with a medication related to one the patient is currently taking, should increase suspicion for drug fever.

Timing of fever — The time to onset of drug fever can vary from a few hours to a few months following initiation of the offending agent. While most cases occur within the first few weeks of drug initiation, clinicians should be aware that even medications that the patient has been using chronically can be potential causes of drug fever.

The median reported time to onset of drug fever is about eight days after starting the medication [23]. However, typical time to onset varies widely by drug (table 1) [6,23,25,39,51-67]. Additionally, most estimated times are informed by limited data from isolated case reports or series.

Pattern of fever — The fever pattern and severity of temperature rise in cases of drug fever are variable. Some features may raise the possibility of drug fever, but they are not specific to it.

Hectic fever (ie, continuous but fluctuating fever that is characterized by wide swings that do not return to baseline temperature) is the most common fever pattern observed; however, continuous, intermittent (spiking temperatures returning to normal in between), and remitting (spiking temperatures that do not return to normal in between) fevers can also occur [3,39]. The degree of pyrexia can vary from low grade to high grade and generally has no bearing on prognosis [4,39].

Relative bradycardia, in which the pulse rate does not rise as expected with the temperature, is seen in about 10 percent of cases and can occasionally be a useful clue to the presence of drug fever [3].

Associated clinical features — Certain clinical features should raise suspicion of drug fever:

General appearance – Drug fever should be suspected in a patient who appears and feels well and is unaware of fever. However, this presentation is not specific to drug fever, and patients with drug fever can also be ill-appearing, particularly if they have serious systemic complications.

Rash – Rash or other cutaneous manifestations of hypersensitivity have been reported in up to 30 percent of patients with drug fever [6]. However, the absence of rash should not deter the clinician from pursuing the diagnosis of drug fever. In one review of 148 episodes of drug fever, rash occurred in only 18 percent of cases [3].

The type of rash varies and includes erythema, morbilliform eruptions, urticaria/hives, as well as severe cutaneous reactions such as nonfollicular pustules, rash with lymphadenopathy, and mucosal involvement with epidermal detachment. Fever is an important prodromal symptom of severe cutaneous reactions [68,69]. (See "Acute generalized exanthematous pustulosis (AGEP)" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

Neurologic, neuromuscular, and autonomic abnormalities – Muscle rigidity, dysautonomia, agitation, and confusion are clues to the presence of an idiosyncratic reaction, such as neuroleptic malignant syndrome or serotonin syndrome. (See 'Fever due to an idiosyncratic reaction' above.)

Underlying conditions associated with drug fever – Drug fever occurs more frequently in certain patient populations, such as people with HIV or cystic fibrosis. Other comorbidities, such as psychiatric illnesses, active malignancy, gout, liver, and renal impairment, are associated with treatment with medications that are commonly implicated in drug fever.

Suggestive laboratory abnormalities

The white blood cell count can be elevated with accompanying eosinophilia in drug fever, but these findings occur in fewer than 20 percent of cases [3].

Neutropenia or agranulocytosis can uncommonly occur in the context of drug fever, including fever associated with antimicrobial agents (eg, penicillin or cephalosporin) [70]. (See "Drug-induced neutropenia and agranulocytosis", section on 'Drug-induced neutropenia/agranulocytosis'.)

Unexplained disturbance of liver function can also be a manifestation of a drug reaction. (See "Drug-induced liver injury".)

If urine microscopy reveals pyuria, a stain for eosinophils can be performed. Eosinophiluria could suggest interstitial nephritis, and in turn, drug fever. (See "Clinical manifestations and diagnosis of acute interstitial nephritis".)

Elevated creatinine kinase and myoglobinuria can suggest neuroleptic malignant syndrome. (See 'Neuroleptic malignant syndrome' above.)

Inflammatory markers, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), are not particularly useful as they are nonspecific and can be normal or increased in drug fever.

Establishing the diagnosis

Drug cessation — Stopping the offending agent can both establish a presumptive diagnosis of drug fever and treat it. In most cases, this is the only way to establish the diagnosis. In most but not all cases, resolution of drug fever will occur within 72 to 96 hours of discontinuing the offending drug.

The usual approach is to discontinue the most probable offending drug first. Identifying the most probable offending agent entails reviewing the medication history for drugs that are more frequently associated with drug fever and synthesizing other information, including timing of drug initiation relative to fever onset (table 1), associated clinical features, whether the patient has received the drug before, and suggestive laboratory abnormalities, as discussed above. (See 'Assess for likelihood of drug fever' above.)

After cessation of that drug, if the fever subsides within a few half-lives, it is reasonable to presume that medication is the cause of the fever. If not, we proceed with sequential cessation of other drugs. The first drug can be restarted, if necessary and drugs from alternate classes are not appropriate.

Discontinuing all medications at once may eliminate the fever but may also put the patient at some risk from the underlying disease and prevent identification of the causative drug.

In cases of suspected antimicrobial-induced drug fever when ongoing antimicrobial therapy is warranted, alternate agents from a different class of antimicrobials should be used. However, there is insufficient evidence to determine whether there is cross-reactivity for drug fever amongst medications within the same antimicrobial class.

Rechallenge to confirm or exonerate a putative offending agent — If the diagnosis of fever due to a particular agent is uncertain and it is important to confirm or reject the diagnosis (eg, because use of that agent is preferred over alternatives or it may be needed in the future), cautious rechallenge may be able to clarify the diagnosis. Rechallenge should only be performed when the following conditions are met:

It is a planned, prospective experiment in a controlled environment where the patient can be monitored frequently for symptoms, changes in vital signs, and, in some cases, laboratory parameters [71]. This may be in a hospital or outpatient (eg, allergy consultation), depending on the presumed reaction. The duration of monitoring depends on the initial reaction and how long after initial dosing the fever occurred. If the fever was thought to be secondary to a hypersensitivity reaction, the procedure for rechallenge is discussed in detail elsewhere. (See "An approach to the patient with drug allergy", section on 'Graded challenge'.)

The original drug reaction was not associated with organ damage or other severe signs and symptoms, such as blistering skin reactions or reactions that involve mucous membranes [72,73].

There are no specific contraindications to rechallenge, such as HLA-B*57:01 genotype with abacavir, HLA-B*58:01 genotype with allopurinol, and known G6PD deficiency with hemolysis-inducing medications. (See "Abacavir hypersensitivity reaction" and 'Allopurinol' above and 'Hemolysis secondary to glucose-6-phosphate deficiency' above.)

If fever recurs with rechallenge of the agent, the diagnosis of drug fever and the offending agent are confirmed. If so, the drug is generally avoided.

In one study, rechallenge with the putative offending agent was undertaken in 63 of 167 cases of drug fever [74]. Fever recurred in all cases, at a median of two days, and outcomes were favorable after drug discontinuation in 97 percent of patients undergoing rechallenge.

SUMMARY AND RECOMMENDATIONS

Definition – Drug fever is a disorder characterized by fever that coincides with administration of a drug and disappears after the discontinuation of the drug, when no other cause for the fever is evident after a careful clinical history, physical examination, and laboratory investigation. (See 'Definition' above.)

Mechanisms – Although the mechanisms of drug fever are incompletely understood, they can be classified into five broad categories (see 'Mechanisms' above):

Hypersensitivity – This is the most common cause of drug fever; in some cases, fever is a feature of a severe cutaneous reaction. Drugs commonly associated with fever because of hypersensitivity include anticonvulsants, antimicrobials, and allopurinol. (See 'Hypersensitivity' above.)

Idiosyncratic reactions – This is a heterogeneous category and includes malignant hyperthermia, neuroleptic malignant syndrome, and serotonin syndrome. (See 'Fever due to an idiosyncratic reaction' above.)

Direct result of the pharmacologic action of the drug – The most common example is fever following chemotherapy, which results in cell damage and release of pyrogenic substances. (See 'Fever as an extension of the pharmacologic effect of a drug' above.)

Altered thermoregulation – Drugs such as thyroid hormone, anticholinergic agents, and sympathomimetic agents can modify thermoregulation pathways to result in fever. (See 'Fever due to altered thermoregulation' above.)

Reactions directly related to administration of the drug – These include contamination of parenteral fluids with endotoxin or other exogenous pyrogens, phlebitis, and intrinsic pyrogenic properties of some injectable agents, such as amphotericin or bleomycin. (See 'Fever associated with drug administration' above.)

Evaluation – Drug fever is a diagnosis of exclusion. After ruling out other serious causes of fever, a detailed review of the history, presenting features, and laboratory findings may reveal potential clues to the possibility of drug fever. (See 'Diagnostic evaluation' above.)

A detailed medical history should include all current medications, including over-the-counter medications, herbal medications, supplements, and recreational substances, with a focus on drugs or drug classes that are more frequently associated with fever (eg, anticonvulsants, antibiotics, allopurinol, cancer therapy, thyroid hormone, anticholinergic or sympathomimetic agents, neuroleptics, and serotonin reuptake inhibitors).

The median time to onset of drug fever is about eight days after initiation of the offending agent but can range from a few hours to a few months (table 1). Even chronic medications can be potential causes of drug fever.

Fever and rash should raise suspicion for a hypersensitivity reaction, including a serious cutaneous reaction. Fever with confusion, muscle rigidity, and/or dysautonomia should raise suspicion for a severe idiosyncratic reaction. (See 'Associated clinical features' above.)

Drug cessation – Stopping the offending agent can both establish a presumptive diagnosis of drug fever and treat it. The usual approach is to sequentially discontinue drugs, beginning with the most probable offending agent. Resolution of drug fever usually occurs within 72 to 96 hours of discontinuing the culprit drug. (See 'Drug cessation' above.)

Rechallenge – If the diagnosis of fever due to a particular agent is uncertain and use of that agent rather than alternatives is preferred, cautious rechallenge may be able to clarify the diagnosis. Rechallenge should only be performed in a planned, controlled environment if the original drug reaction was not severe. (See 'Rechallenge to confirm or exonerate a putative offending agent' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Malcolm McDonald, PhD, FRACP, FRCPA, who contributed to an earlier version of this topic review.

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  30. Shivaji UN, Jeffery L, Gui X, et al. Immune checkpoint inhibitor-associated gastrointestinal and hepatic adverse events and their management. Therap Adv Gastroenterol 2019; 12:1756284819884196.
  31. Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol 2016; 27:1362.
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  37. Hocker S, Kenney DL, Ramar K. Parkinsonism-hyperpyrexia syndrome: Broadening our differential diagnosis in the ICU. Neurol Clin Pract 2013; 3:535.
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Topic 2738 Version 24.0

References

1 : Understanding drug-induced febrile reactions.

2 : Drug-induced fever.

3 : 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.

4 : Drug fever.

5 : Drug fever. Remember to consider it in diagnosis.

6 : Drug fever.

7 : Drug hypersensitivity reactions and human immunodeficiency virus disease.

8 : Immunological Mechanisms of Drug Hypersensitivity.

9 : Drug allergy.

10 : Cost-effectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity.

11 : Misoprostol-induced fever and genetic polymorphisms in drug transporters SLCO1B1 and ABCC4 in women of Latin American and European ancestry.

12 : A complex interaction between drug allergy and viral infection.

13 : Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 26-1996. A seven-year-old boy with fever, lymphadenopathy, hepatosplenomegaly, and prominent eosinophilia.

14 : Carbamazepine hypersensitivity syndrome: report of 4 cases and review of the literature.

15 : Anticonvulsant hypersensitivity syndrome.

16 : Toxic pustuloderma. A drug induced pustulating glandular fever-like syndrome.

17 : Anticarbamazepine antibody induced by carbamazepine in a patient with severe serum sickness.

18 : Severe adverse cutaneous reactions to drugs.

19 : Minocycline induced arthritis associated with fever, livedo reticularis, and pANCA.

20 : Fever, lymphadenopathy, eosinophilia, lymphocytosis, hepatitis, and dermatitis: a severe adverse reaction to minocycline.

21 : Late-onset drug fever associated with minocycline.

22 : Minocycline pneumonitis and eosinophilia. A report on eight patients.

23 : Drug fever: mechanisms, maxims and misconceptions.

24 : Allergic reactions to parenteral beta-lactam antibiotics in patients with cystic fibrosis.

25 : How to prevent allopurinol hypersensitivity reactions?

26 : Allopurinol hypersensitivity: a systematic review of all published cases, 1950-2012.

27 : Allopurinol hypersensitivity syndrome: a review.

28 : Drug fever induced by heparin.

29 : Enoxaparin: A cause of postoperative fever?

30 : Immune checkpoint inhibitor-associated gastrointestinal and hepatic adverse events and their management.

31 : Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies.

32 : Drug-induced hyperthermia.

33 : Neuroleptic malignant syndrome and malignant hyperthermia. Important issues for the medical consultant.

34 : Neuroleptic malignant syndrome and malignant hyperthermia. Important issues for the medical consultant.

35 : Neuroleptic malignant syndrome.

36 : Neuroleptic malignant syndrome.

37 : Parkinsonism-hyperpyrexia syndrome: Broadening our differential diagnosis in the ICU.

38 : Bench-to-bedside review: mechanisms and management of hyperthermia due to toxicity.

39 : Drug fever after cancer chemotherapy is most commonly observed on posttreatment days 3 and 4.

40 : Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in a phase I/II clinical trial.

41 : Tumor necrosis factor and the Jarisch-Herxheimer reaction.

42 : Role of cytokine changes in clozapine-induced fever: A cohort prospective study.

43 : Clozapine and Fever: A Case of Continued Therapy With Clozapine.

44 : The neurologic basis of fever.

45 : Oligohydrosis and fever in pediatric patients treated with zonisamide.

46 : MDMA induced hyperthermia: report of a fatality and review of current therapy.

47 : The role of the sympathetic nervous system and uncoupling proteins in the thermogenesis induced by 3,4-methylenedioxymethamphetamine.

48 : Pyrogen reaction and conversion of sustained ventricular tachycardia to sinus rhythm: two case reports.

49 : The effects of drugs on thermoregulation.

50 : Vancomycin.

51 : Sulphasalazine induced three-week syndrome.

52 : Anticonvulsant hypersensitivity syndrome after phenytoin administration in an adolescent patient: a case report and review of literature.

53 : Drug fever.

54 : Febrile reactions to INH.

55 : Spiking fever from isoniazid simulating a septic process.

56 : Isoniazid-induced fever.

57 : Double quotidian fever caused by carbamazepine.

58 : Fever as an adverse reaction to carbamazepine.

59 : Letter: fever as a toxic reaction to quinidine.

60 : Drug fever caused by quinine and quinidine.

61 : Quinidine fever: an unusual manifestation of quinidine allergy.

62 : Methyldopa fever.

63 : Late-onset drug fever associated with minocycline: case report and review of the literature.

64 : Azathioprine-induced fever in autoimmune hepatitis.

65 : Azathioprine induced fever, chills, rash, and hepatotoxicity in rheumatoid arthritis.

66 : Fever caused by hydroxyurea: a report of three cases and review of the literature.

67 : An unwanted side effect of hydroxyurea in a patient with idiopathic myelofibrosis.

68 : Acute Generalized Exanthematous Pustulosis: Pathogenesis, Genetic Background, Clinical Variants and Therapy.

69 : Comparison of the causes and clinical features of drug rash with eosinophilia and systemic symptoms and stevens-johnson syndrome.

70 : Incidence of beta-lactam-induced delayed hypersensitivity and neutropenia during treatment of infective endocarditis.

71 : Evaluating drug fever to beta-lactam antibiotics.

72 : Intentional rechallenge and the clinical management of drug-related problems.

73 : Drug-induced severe cutaneous adverse reactions: Determine the cause and prevention.

74 : Drug Fever: a descriptive cohort study from the French national pharmacovigilance database.