Drug Fever, Etiology And Clinical Dilemmas
Case History :
Universally doctors are aware of occurrence of fever which is caused due to drugs. Some drugs may induce fever in some patients, however reliable data is still not available. This article aims to discuss etiology and management of fever which may be due to adverse drug reaction or which can be due to some other reasons.
Recognition of drug fever requires due attention as it has critical clinical importance. Failure to recognize the etiologic relationship between a drug and fever may have undesired consequences that may include extra testing, unnecessary therapy, and longer hospital stays. In general terms “a disorder characterized by fever coinciding with administration of a drug and disappearing after the discontinuation of the drug, when no other cause for the fever is evident after a careful physical examination and laboratory investigation” is considered as the most accepted definition of drug fever. The data on the drug fever is limited to individual case reports and trial data is lacking. This is why reporting bias found to distort the views on drug fever in general. Identified Mechanisms of Drug Fever: Several mechanisms have been proposed and been verified to have an underlying causality for drug fever. These mechanisms are: Altered thermoregulatory mechanisms: A wide range of drugs can cause thermoregulatory alterations. Drugs with anticholinergic activity such as tricyclic antidepressants, atropine, antihistamines phenothiazines and butyrophenone tranquilizers can cause fever by disturbing central hypothalamic function and peripheral effector mechanisms. Hypersensitivity reactions: Hypersensitivity is the most common cause of drug fever. Various sub-mechanisms have been identified to cause fever, such as, elevated T-cell immune response due to drug or its metabolite; formation of antibody-antigen complexes. Reactions that are directly related to administration of the drug: The parenteral administration of an array of drugs can directly lead to fever. Solutions containing drugs can also get contaminated with endotoxin or other exogenous pyrogens. Fever can also accompany a chemical phlebitis caused by drug administration, and local inflammation and/or sterile abscesses can occur at sites of injection. Reactions that are direct extensions of the pharmacologic action of the drug: Chemotherapy of several solid tumors, lymphomas and leukemia with drugs can induce drug fever. As the drugs used to treat these conditions can cause cell necrosis and lysis, the pyrogenic substances released as a result of these processes can cause fever. Idiosyncratic reactions: Febrile idiosyncratic drug reactions are considered as a heterogeneous category of drug-induced fevers. These reactions comprise of unpredictable syndromes and genetic disorders. There is some overlap with hypersensitivity phenomena. Despite these difficulties, several conditions are notable such as malignant hypothermia, neuroleptic malignant syndrome, serotonin syndrome and uncoupling oxidative phosphorylation. Clinical Dilemmas And Management of Drug Fever The diagnosis of drug fever is usually a diagnosis of exclusion. Generally, the primary assumption of most clinicians is that fever is due to infection, which may not always be easy to exclude. Connective tissue diseases or malignancy, which are other causes of fever of unknown origin, are also often difficult to exclude. Rash, when present, may be a valuable clue to the presence of drug fever, however, its absence should not deter the clinician from suspecting the diagnosis. A rash may rarely be urticarial. The timing of the onset of fever in relation to beginning the drug and the pattern of fever are usually not helpful in building a diagnosis. From various cases and analyses, the median time to onset is found to be about 8 days but can vary from less than 24 hours to many months. Similarly, the pattern of fever also can vary from a lowgrade fever without other associated symptoms to a pattern with chills and rigors which is known as "hectic" pattern. The WBC count may be elevated with accompanying eosinophilia in drug fever, but these findings generally occur in less than 20% of cases. The erythrocyte sedimentation rate is found to be increased, however, this is a nonspecific finding. Unexplained disturbance of liver function and/or renal impairment may provide clues to the diagnosis. If urine microscopy reveals pyuria, a stain for eosinophils should be performed and it may be positive, especially in interstitial nephritis caused by betalactam antibiotics. In the majority of patients, the only way to deduce if a patient has a drug fever is by stopping the administration of drug or drugs. The common approach is to discontinue the most probable offending drug first. It should be sequentially followed by cessation of other drugs if fever persists. Discontinuing all medications at once should be avoided. It 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 most but not all cases, resolution of drug fever will occur within 72 to 96 hours of discontinuing the offending drug. As mentioned above, recognizing drug induced fever is clinically very critical, especially for the patients who may require longer dosage regimen. Sources: Patel RA, Gallagher JC. Drug fever. Pharmacotherapy 2010; 30:57. Ogawara D, Fukuda M, Ueno S, et al. Drug fever after cancer chemotherapy is most commonly observed on posttreatment days 3 and 4. Support Care Cancer 2016; 24:615. Lowe CM, Grube RR, Scates AC. Characterization and clinical management of clozapineinduced fever. Ann Pharmacother 2007; 41:1700.
Investigation :
What are some the drug you would associate with Drug Fever?