iPsychology

Drug Fever

Many drugs can cause fever, by a variety of mechanisms. Drugs such as interferons can stimulate the production of endogenous pyrogens, and antibacterial agents such as penicillins can kill organisms and so release endotoxins, as in the Jarisch-Herxheimer reaction. Irritant drugs can produce local phlebitis. Alterations of thermoregulation by anticholinergic agents, amphetamines including Ecstasy, and serotoninergic agents are all important causes of druginduced fever. Antituberculous agents and anticonvulsants are implicated in fever due to hypersensitivity reactions; and some drugs can cause severe hyperthermia in susceptible individuals, for example anaesthetic agents in patients predisposed to malignant hyperthermia. Drugs should be suspected in any case of fever the cause of which is obscure.

The mechanism of fever Body temperature is usually controlled within a narrow range by a number of physiological processes. It rises when heat absorption or production exceeds heat loss. Heat is absorbed from the environment, and endogenous production depends on metabolic rate, muscular activity, and ‘non- shivering thermogenesis’. Heat is lost from the body by convection and radiation from the surface and evaporation from the skin and lungs. The normal physiological response to a rising temperature is dilatation of skin blood vessels and increased sweating.

The balance between heat production and heat loss is controlled by a combination of mechanisms including the behaviour of the whole organism (avoiding heat, shedding clothes, etc.) and homoeostatic mechanisms. Infection results in the introduction of exogenous pyrogens like bacterial lipopolysaccharide, and inflammation results in the production of endogenous pyrogens, such as the cytokine interleukin-lb. These act on the preoptic region of the hypo thalamus, where they lead to the production of prostaglandin E2 (PGE2) which is the neural mediator of fever, stimulating the endogenous pyrogen receptor (EP3).

In this short review we will outline a classification of the various mechanisms of drug-induced fever and give a number of examples. Classification of drug-induced fever A drug can cause fever in the following ways:

1. By acting as a direct or indirect pyrogen or by causing inflammation or tissue damage.
2. By causing pyrogen release as part of its pharmacological action.
3. By altering thermoregulation by central, peripheral, or metabolic means.
4. By causing hypersensitivity reactions.
5. By inducing immunosuppression.
6. As a result of patient idiosyncrasy.

Drugs acting as direct or indirect pyrogens Interferons commonly cause a ´flu-like illness with fever. They have a broad role in regulating the immune response, possibly through induction of interleukin-6, since low doses of corticosteroids reduce the symptoms at the onset of interferon betalb therapy in multiple sclerosis.

The immunosuppressant murumonab-CD3 (OKT3) causes a cytokine-release syndrome leading to fever, usually when the first dose is given. Cytokine release also seems to be the underlying mechanism in fever associated with amphotericin B infusion. Amphotericin B causes a shift towards preinflammatory cytokine production in human mononuclear cells9 and also stimulation of prostaglandin synthesis.Exogenous pyrogens may be administered parenterally when they contaminate a drug formulation, for example gentamicin.This is particularly seen with agents derived from microorganisms e.g. amphotericin, a mixture of antifungal polyenes produced by Streptomyces nodosus. Adverse Drug Reaction Bulletin 1999 2 Drugs that cause local inflammation or tissue damage A local chemical phlebitis that can lead to fever can occur with intravenous injections or infusions of antibiotics (e.g. erythromycin, vancomycin, or cephalosporins), cytotoxic drugs, and other drugs, for example amiodarone, barbiturates, unemulsified diazepam, and also with hypertonic fluids and solutions given for parenteral nutrition.These reactions can also become secondarily infected. Care should be taken to check all intravenous cannula sites in patients with fever. More serious local reactions such as sterile abscess formation can occur with intramuscular injections of drugs such as paraldehyde, diclofenac, and gold. Drugs that cause pyrogen release by microorganisms as part of their pharmacological action Pyrogens released by the pharmacological action of a drug can cause fever.

An example of this is the Jarisch-Herxheimer reaction, in which endotoxin is released front bacteria. There is an abrupt onset of fever, myalgia, hyperventilation, and tachycardia about 6-8 hours after starting bactericidal therapy - classically treatment with penicillin for secondary syphilis14 but also in other infections. The Jarisch- Hetxheimer reaction is associated with raised concentrations of tumour necrosis factor (TNF) alpha, interleukin-6 and interleukin-8. Treatment with anti- TNF-alpha Fab before giving penicillin seems to suppress the reaction. Drugs that interfere with thermoregulation Drugs can affect thermoregulation and lead to fever in several ways. Centrally, they can alter the ‘set point’ body emperature and alter adaptive responses to high temperature. Opioids, sedatives, and alcohol can affect the ability of a person to deal with excess heat. Peripherally, drugs can reduce the ability to lose heat by vasodilatation or sweating. Metabolism can be altered, leading to an increase in heat production. However, most drugs do not simply act at one level but have multiple effects, especially in overdosage. Anticholinergic agents, phenothiazines, tricyclic antidepressants, antihistamines and synthetic alkaloids impair hypo- thalamic function centrally and reduce sweating peripherally, leading to an anticholinergic ‘toxidrome’ of diminished sweating, coma, hyperreflexia, tachycardia, psychosis, dilated pupils, urinary retention, flushing and pyrexia.

The use of benztropine in combination with antipsychotic drugs which also have anticholinergic adverse effects has been associated with fatal heat stroke when the ambient temperature is above 29ºC. It may be safer to treat agitation and psychosis in anticholinergic toxicity with benzodiazepines rather than benztropine.

Profuse sweating, hyperreflexia, pyrexia, hypertonia, and restlessness may be seen in toxicity with monoamine oxidase inhibitors, anticholinergic drugs, phencyclidine (‘Angel dust’) and amphetamine and its derivatives (such as Ecstasy).

The serotonin syndrome, characterised by fever, autonomic disturbance (tachycardia), neuromuscular disorders (hyperreflexia, bizarre movements, myoclonus) and altered mental state (agitation or confusion), is caused by drugs that increase central nervous system serotonin transmission, including selective serotonin reuptake inhibitors (SSRIs). It is differentiated from the neuroleptic malignant syndrome by the drug history, and by the absence of coma, Parkinsonian features, or autonomic instability. in most cases, two or more types of medications known to increase the activity of serotonin at the 5HT1A receptor, or a specific interaction (an SSRI with lithium, or an SSRI with sumatriptan), or an overdose, are required to produce the syndrome. As SSRls replace tricyclic antidepressants, the incidence of serotonin syndrome is likely to increase. Exertional heat stroke has been reported with amphetamine analogues such as Ecstasy methylenedioxymethamphetamine [MDMA]). Extreme physical activity induced by the stimulant effects of Ecstasy, together with high ambient temperatures and reduced water consumption, can lead to severe hyperpyrexia. Dantrolene has been used in the acute management of such cases.

Deaths from a single dose of Ecstasy may have been due to the serotonin syndrome in susceptible individuals. Epidural analgesia during labour, especially when prolonged, can cause fever in the mother and the fetus. The cause of the fever is uncertain but it may, in part, be related to the alteration of thermoregulation by the associated sympathetic blockade in epidural analgesia, which would reduce sweating.

Drugs that cause hypersensitivity reactions Hypersensitivity reactions to drugs can include fever, as well as other features of hypersensitivity such as anaphylaxis (Type 1) or immune-complex disease (Type 3). Drug-induced fever due to Type 3 hypersensitivity typically presents as a low-grade fever that subsequently rises. It usually starts in the first 7-10 days of drug administration, particularly with anti- microbials, although it can occur at any Adverse Drug Reaction Bulletin 1999. The fever subsides rapidly with drug withdrawal hut recurs within hours of re-challenge. Antimicrobials can cause fever, and of course this can lead to diagnostic difficulty when there is the possibility of under-treated sepsis, requiring further antimicrobial treatment. Antituberculous drugs, in particular, are associated with drug fever. Rifampicin causes a ‘flu-like syndrome of fever, rigors, hone pain, and malaise lasting about 12 hours after each dose when given intermittently- in keeping with a hyper- sensitivity reaction. Other antituberculous drugs - isoniazid, pyrazinamide and, rarely, ethambutol can also cause fever. Piperacillin has been implicated in drug fever especially in the treatment of patients with cystic fibrosis, who are often taking multiple drug regimens. Drug-induced fever is seen in up to 5 per cent of patients treated with vancomycin, and not uncommonly with sulphamethoxazole, trimethoprim, or co-trimoxazole.

Other antibiotics implicated in drug fever include tetracyclines, erythromycin (in association with hepatotoxicity), imipenem, topical neornycin, and nitrofurantoin. Other drugs are also particularly associated with fever. Cardiovascular drugs implicated in hypersensitivity reactions with fever include methyldopa, captopril, acetazolamide, hydralazine (in association with drug-associated lupus erythematosus), procainamide, labetalol, and nifedipine. Anticonvulsants can cause fever. Carbamazepine sometimes produces a reaction with lymphadenopathy, fever, rash, hepatosplenomegaly, and eosinophilia. Most cases occur within the first 30 days of starting therapy. Anticarbarnazepine antibodies have also been described. Phenobarbitone causes a fever with intensely pruritic rash.

Phenytoin causes a fever with skin eruptions, lymph adenopathy and hepatitis. Drugs that cause Immunosuppression Patients who are immunocompromised by cancer chemotherapy, immune sup pressants (such as azathioprine), or idiosyncratic reactions, are at risk of opportunistic infections. Cytotoxic drugs, phenothiazines, many antibiotics, NSAIDs, antithyroid agents, and psychotropic drugs are among those that cause neutropenia. Fever in such patients is a common haematological emergency and management depends on rational antimicrobial use, thorough investigation, and measures to reduce exposure to infection. Idiosyncratic drug fever Some individuals are especially prone to the effects of a drug, and drug-induced fever is one manifestation of this. Malignant hyperthermia is a dangerous hypermetabotic state after anaesthesia with suxamethonium and/or volatile halogenated anaesthetic agents. It is also seen, in susceptible individuals, after severe exercise in high ambient temperatures, in infections, in overheated infants, and during treatment with neuroleptic drugs. It is characterised by a sustained rise in body temperature (without shivering), tachycardia, cyanosis, and generalized muscle rigidity during or soon after the anaesthetic. To the non-anaesthetist, it can be mistaken for heat stroke, rhabdomyolysis, muscle pains, neuroleptic malignant syndrome, or sudden infant death syndrome. Treatment consists of supportive measures, reversal of acidosis, and dantrolene. The genetics of malignant hyperthermia are well recognised. It is autosomal dominant but is a genetically heterogeneous condition with a variable number of genes implicated in different families. Everyone who is susceptible to malignant hyperthermia has a disorder of muscle membrane that can be demonstrated by the sensitivity of muscle biopsy strips to agents such as halothane, caffeine, potassium and temperature changes. In vitro tests can be performed to confirm susceptibility to malignant hyperthermia. Three clinical myopathies have been identified: Evans myopathy, which is usually subclinical but may have wasting of the lower thigh muscle and chronically raised creatine kinase activity; king-Denborough syndrome, which is rare and seen in young boys, small for age, with undescended testes, lordosis, kyphosis, and facial abnormalities; and central-core disease. Members of families affected by central core disease should all be assumed to be susceptitble to malignant hyperthermia, and there are striking microscopic changes in muscle. Neuroleptic malignant syndrome is an idiosyncratic reaction to antipsychotic drugs such as phenothiazines, butyrophenones, thioxanthenes and risperidone, but has also been seen after abrupt withdrawal of antiparkinsonian agents and treatment with dopamine-depleting agents or lithium. It is characterized by fever, hypertonia, fluctuating consciousness, and autonomic disturbances such as tachycardia, sweating, and labile blood pressure.

It has been argued that the syndrome may not be a rare idiosyncratic condition with a high mortality but the extreme end of a continuum of effects induced by neuroleptics, such as Parkinsonism and dystonia. Early mild cases may be far more common than previously thought. Adverse Drug Reaction Bulletin 1999 The condition is thought to be due to a profound reduction in dopaminergic function in the brain. Loss of dopamine activity in the nigrostriatal system explains the extrapyramidal effects of rigidity and Parkinsonian tremor. The sustained muscle activity then causes fever and rhabdomyolysis. Predisposing factors include physical exertion, dehydration, organic brain disease and the use of neuroleptic drugs. Lately, acquired immune deficiency syndrome (AIDS) has been suggested as another risk factor. In AIDS, there may be structural brain damage from opportunistic infections, and sufferers may be more likely to suffer dehydration and to be taking many drugs. Treatment consists of withdrawal of drugs (although they may be introduced again later), supportive measures, dantrolene and dopamine receptor agonists such as bromocriptine. Diagnosis of drug-induced fever Drugs are an important, though sometimes overlooked, cause of fever, and should be suspected in any case whose cause is obscure. Patients with drug-induced fever tend to have been extensively investigated for bacterial infections and often treated with broad-spectrum antibiotics. In patients with fever of unknown origin, drug-related fever was the underlying cause in 5 per cent of inpatients aged over 65 years and in 3per cent of general medical inpatients.

Drug-induced fever tends to be a difficult diagnosis since it is only confirmed after the elimination of other causes, the demonstration of the link between initiation of the drug and the start of the fever, and the resolution of fever within a few days of stopping the causative agent. Conclusion Any pattern of fever may be seen in drug- induced fever; the mechanisms by which it occurs are numerous; and many drugs have been implicated. Drugs should always be considered in the differential diagnosis of fever of obscure origin.