Characterization of Drug Fever

Definition
Drug fever is a disorder characterized by a febrile response coinciding temporally with the
administration of a drug in the absence of underlying conditions that can be responsible for
the fever.[1, 2, 4, 5] A key feature that differentiates drug fever from fever of other causes is that it
disappears once the offending drug is discontinued.[2, 3] Drug fever tends to be a diagnosis of
exclusion, often suspected in patients with otherwise unexplained fevers.[6]
It is important for clinicians to maintain an index of suspicion for the possibility of drug fever
and be aware of the most common offending agents in order to avoid expensive diagnostic
work-up for further evaluation, incorrect treatment with antibiotic therapy, possible adverse
effects, and prolonged hospital stays.[2, 7, 8] A review of 97 patients with drug fever, whose
cases had been reported in the literature between 1966 and 1986, revealed that 39 were
admitted specifically for a work-up of drug fever.[9] The same review identified 51 patients
with drug fever at two Dallas hospitals between 1959 and 1986. In hose cases, episodes of
drug fever led to a mean prolongation of hospital stay of 8.7 days. In addition, each drug
fever episode resulted in an average of 5 blood cultures, 2.85 radiologic studies, and 0.53
courses of antibiotics. Another review over a 2-year period of 36 patients with drug fever
found that delaying the diagnosis of drug fever resulted in an average cost of $493 for
diagnostic procedures for each case of drug fever.[7] It is clear that drug fever can be an
expensive complication.
A wide variety of agents can cause drug fever (Table 1).[7, 971] However, the list of drugs that
are most frequently implicated is rather short and includes antimicrobials, anticonvulsants,
antiarrhythmic agents, and other cardiac agents.[6, 9] Tables 2, 3 and 4 summarize the number
of cases reported in the literature for each incriminating agent, as well as clinical and
laboratory findings associated with each case.
Epidemiology
Drugs have been estimated to cause 1015% of adverse events in hospitalized patients in the
United States.[1, 3, 6] However, drug fever as the sole manifestation or the most prominent
clinical feature of an adverse reaction occurs in only an estimated 35% of cases.[2, 72] The
actual frequency of drug fever is unknown due to underreporting and frequent misdiagnosis.[3,
6]
Since conducting clinical trials to specifically evaluate drug fever is not practical, the
estimated rate of drug fever with individual agents is largely based on the number of reports
on the agent either in safety reports of other studies or as case series. As a result, the accuracy
of characterizations of the epidemiology of this disorder is uncertain.[8]
Physiology of Fever
The thermoregulatory center in the preoptic area of the anterior hypothalamus is responsible
for maintaining control of the temperature set point in humans.[4] During fever, there is an
upward shift in the thermoregulatory set point.[4, 73] Various exogenous pyrogens activate
phagocytic leukocytes to produce endogenous pyrogens, primarily interleukin-1.[4, 73]
Interleukin-1 excites the neurons in the anterior hypothalamus and initiates thermoregulatory
events by causing an increase in production of prostaglandins, cyclic adenosine

monophosphate, and nervous system monoamines, all leading to elevation of the

thermoregulatory set point.[4, 73, 74] The body compensates by minimizing heat loss by heat
conservation and heat production.[73, 74] Blood and core temperatures will continue to rise until
they match the thermoregulatory set point.[73, 74] Pathophysiologically, a drug might cause
fever by five principal mechanisms: interference with peripheral heat dissipation, alteration of
central temperature regulation, evocation of either a cellular or humoral immune response,
exogenous pyrogenicity, and the direct damage of tissues.[74]
Diagnosis
The key to diagnosing drug fever is to consider it in any patient in whom no other cause for
fever can be elucidated, particularly when fevers do not correspond with likely infection.[3]
The diagnosis is often difficult, and it should be made after a careful review of a patient's
clinical presentation, drug therapy, and laboratory values. Drugs should be considered in the
differential diagnosis of fever in many patients, particularly for those who are taking agents
that are highly implicated with causing drug fever.[4, 72] In practice, the first assumption of
most clinicians is to search for or treat a suspected infection, a process that is logical but can
lead to the frequent overuse of antibiotics. Fever can be a characteristic of many disease
processes other than infection, including malignancy, thromboembolic disease,
cerebrovascular accidents, collagen vascular diseases, acute gout, surgery, and trauma.[4] If
fever is unexpected, particularly in a situation when a patient is otherwise clinically well or
improving, then drug fever should be considered in the differential diagnosis.[4, 73] A definite
diagnosis can be made only when the fever resolves after discontinuing the implicating agent.
Recurrence of fever after rechallenge of the suspected agent solidifies a diagnosis of drug
fever but is a dangerous practice that should generally be avoided.
Clinical Features
Drug fever may occur at any point during a course of drug therapy, and there is significant
variation among different drug classes. The median time between initiation of the offending
agent and onset of fever is 710 days.[4, 72] In the previously discussed review article,[9] the lag
time between the initiation of the offending agent and onset of fever was found to be highly
variable and also dependent on the drug class. The shortest intervals between initiation of
therapy and onset of fever were observed with antineoplastic agents (median 0.5 days, mean
6 days) and antimicrobials (median 6 days, mean 7.8 days). A longer time interval was seen
with central nervous system agents (median 16 days, mean 18.5 days) and cardiovascular
drugs (median 10 days, mean 44.7 days). The shorter median lag time with antineoplastic
agents compared with any other agent was significant. Although variability among the
different classes of agents was apparent, this may have been biased toward longer times to
onset by the exclusion of cases of fever due to drug administration, which occur more rapidly.
Various patterns of fever occur in patients with drug fever.[9, 72, 75] Different patterns include
the following: continuous fevers; remittent fevers, in which temperatures vary but are
consistently elevated from normal; intermittent fevers, which are interrupted by daily normal
temperatures; and hectic fevers, which manifest as a combination of intermittent and
remittent fever patterns. Hectic fever is the most common pattern, particularly since the use
of antipyretic drugs and cooling blankets can change a pattern of fever from its natural
course.[1, 9] In addition, the degree of pyrexia can vary as well, ranging from a low-grade
temperature of 99F to temperatures as high as 109F, but elevated temperatures of 102
104F are most common.[3, 4, 6] No strong relationship has been noted with the severity of

clinical features and maximum temperature except that higher temperatures have been noted
in patients taking antineoplastic agents, which could also be attributable to the underlying
disease.[6]
Patients with drug fever often appear "inappropriately well" for the degree of fever that they
have.[4, 72] They are also frequently unaware of their fevers.[4] Another clue aiding in detection
of drug fever is relative bradycardia, a condition that occurs when the heart rate does not
increase to the extent that typically accompanies the temperature elevation.[3, 76] To determine
the presence of relative bradycardia, a temperature of at least 102F is required, and sinoatrial
disease or drugs that affect heart rate must not be present.[3, 76] To compute the approximate
expected pulse response for a given temperature, one uses the last digit of the temperature
reading in Fahrenheit and decreases it by 1. This number is multiplied by 10, and then added
to 100. For example, for a temperature of 103F, the appropriate pulse response would be
approximately 120 beats/minute. Any value less than this would be considered relative
bradycardia and therefore may be indicative of drug fever.[3]
Cutaneous manifestations of hypersensitivity are observed in 1829% of patients with drug
fever.[6, 9, 75] A generalized maculopapular rash occurs in a minority of patients and may be
urticarial with or without petechiae.[3] Since cutaneous manifestations are not universal, their
absence does not rule out a diagnosis of drug fever. Drug fever may precede a more overt
drug reaction and may be the first clinical sign of an impending severe drug reaction.[4, 76] If a
hypersensitivity reaction causing the drug fever is allowed to continue without discontinuing
the drug, the patient may develop a drug rash or other clinical manifestations.[4, 76]
Laboratory Findings
Laboratory findings can be helpful in supporting a diagnosis of drug fever, although they are
highly variable and cannot be relied on for a definitive diagnosis.[72] A leukocyte count with a
differential should be performed for all patients with suspected drug fever. Leukocytosis with
or without a left shift may be present.[3] The finding of leukocytosis with fever should prompt
clinicians to reevaluate the possibility of infection. Eosinophil levels are frequently elevated,
but true eosinophilia is less common.[3, 4] The erythrocyte sedimentation rate may also be
slightly elevated. Erythrocyte sedimentation rates can be 100 mm/hour or greater, but values
of 4060 mm/hour are more common.[3, 4, 76] Mild elevations of hepatic transaminase levels
may also be observed; however, they are no more than 2 times the upper limit of normal in
approximately 90% of patients.[3, 4, 76] Lactic dehydrogenase levels may also be elevated.[75]
Normal values do not preclude the diagnosis of a druginduced fever. No other laboratory test
is consistently useful in diagnosis. The demonstration of antibodies to a drug by serologic or
skin test is not helpful since these often develop in asymptomatic patients lacking clinical
hypersensitivity.[72]
Although abnormal laboratory values and other clinical findings may support the diagnosis of
fever, they are not present in all drug fever cases. In the previously discussed review,[9]
relative bradycardia occurred in 11% of patients, whereas leukocytosis, eosinophilia, and skin
rash were noted in 22%, 22%, and 18% of the patients, respectively.
Risk Factors
There are disagreements in the literature about which populations are most vulnerable to drug
fever. Some publications have found that women and older populations are at increased risk

for developing drug fever, particularly due to drugs other than antibiotics.[2, 6, 72] However,
younger patients may be at increased risk for developing drug fever due to antibiotics.[6] The
previously discussed review did not support either of these suppositions.[9] That review
suggested that women and elderly patients are no more likely to experience drug fever than
are other patients. The authors also found that patients with a history of drug allergies and
atopic disease are no more likely to experience drug fever than are other patients.[2, 9] Despite
these disagreements, certain patients may be predisposed to developing drug-induced fever.
As with other types of allergic reactions, the sensitivity of a patient to one drug is often
associated with sensitivities to other agents.[4]
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