Drug fever can be caused by various mechanisms, although it is ascribed most
commonly to a hypersensitivity reaction. Other mechanisms include the
pharmacologic action of the drug (e.g., cell destruction from antineoplastic agents
releases endogenous pyrogens); altered thermoregulatory function (e.g., increased
metabolic rate from thyroid hormone); decreased sweating from drugs with
anticholinergic properties (e.g., atropine, tricyclic antidepressants, and
phenothiazines); drug-administration-related fever (e.g., amphotericin B and
bleomycin); and idiosyncratic reactions (e.g., neuroleptic malignant syndrome from
haloperidol, malignant hyperthermia from inhaled anesthetics).
CASE 32-3, QUESTION 2: What agent is the most likely cause of drug fever in M.M.?
Most of the information available on drug fever is based on case reports or small
case series and reviews of the literature.
68,69 Unfortunately, the literature is
inconsistent with regard to the frequency of drug fever (e.g., very common, common,
uncommon) and such descriptions are not supported by good clinical data.
Nevertheless, some drugs are more commonly associated with drug fever than others.
These include anti-infectives as a class (especially β-lactam antibiotics),
antiepileptics, and antineoplastics. Drug fever has also been reported frequently with
amphotericin B, azathioprine, hydroxyurea, methyldopa, procainamide, quinidine,
In M.M.’s case, ceftriaxone or azithromycin is the most likely cause of her ongoing
fever, given the timing of the reaction relative to beginning the antibiotics and the
frequency of febrile reactions attributed to them, especially to β-lactam antibiotics.
Febrile reactions have not been associated with acetaminophen, and famotidine is
rarely a cause of fever without other symptoms of an allergic reaction. Although
diuretics such as hydrochlorothiazide can cause fever, M.M. was taking this
medication before admission without any ill effects, making this drug an unlikely
CASE 32-3, QUESTION 3: How should M.M.’s drug fever be treated? Can M.M. receive cephalosporins in
Because M.M. has responded clinically, her antibiotics should be discontinued
and her fever curve, WBC count, heart rate, and respiratory status followed. An oral
antibiotic from another drug class (e.g., a fluoroquinolone) should be started to
complete a 7-day to 10-day antibiotic course of therapy. Acetaminophen and other
antipyretics should be avoided unless M.M. becomes uncomfortable from the fever
because they can mask the response to the discontinuation of her antibiotics.
As with any hypersensitivity reaction, rechallenge with the offending drug can
cause a similar, or sometimes greater, response. In M.M.’s case, reexposure to
ceftriaxone (or another β-lactam antibiotic) or a macrolide might cause a febrile
reaction. It is unclear, however, how large the risk of reexposure truly is. Although
drug fever sometimes precedes more serious hypersensitivity reactions, evidence
suggests there may be little risk to reexposure. Should M.M. require ceftriaxone (or
another β-lactam or macrolide antibiotic) in the future, it would be prudent to
administer the drug in a setting where M.M. can be monitored, at least initially, to
ensure prompt treatment if an immediate hypersensitivity reaction develops.
QUESTION 1: M.G., a 26-year-old woman with cystic fibrosis, is admitted for treatment of pneumonia.
is the likely cause of M.G.’s rash and laboratory abnormalities?
M.G.’s presentation is suggestive of a diagnosis of hypersensitivity vasculitis.
Hypersensitivity vasculitis, also called cutaneous leukocytoclastic angiitis, is
characterized by inflammation of the small blood vessel walls. These reactions occur
when immune complex deposition within the small veins and arterioles activates
complement, causing the release of chemotactic factors. These factors attract
polymorphonuclear cells that cause vessel damage.
Approximately 10% of cases of cutaneous vasculitis are believed to be drugrelated.
73 Approximately 100 drugs have been identified as causing vasculitis,
including β-lactams, fluoroquinolones, NSAIDs, antiepileptics, and tumor necrosis
Interested readers are referred to more in-depth reviews.
diagnosis of hypersensitivity vasculitis is based on five clinical criteria (Table 32-
7), three of which must be present.
76 M.G. meets three of the five criteria, including
age greater than 16 years, palpable purpura, and a maculopapular rash. In addition,
minocycline, a medication that she was taking at the onset of the rash, has been
associated with serum sickness and vasculitic-type reactions. Onset of symptoms
typically occurs 7 to 10 days after initiation of drug therapy but can occur sooner on
reexposure. Purpuric papules and macular eruptions, the most commonly observed
findings, are usually symmetric and occur on the extremities (Table 32-8).
Hypersensitivity vasculitis can involve multiple organ systems. Renal damage,
ranging from microscopic hematuria to nephrotic syndrome and acute renal failure, is
common in patients with disseminated disease.
76 An enlarged liver with elevated
enzymes is indicative of hepatocellular involvement. Although the lungs and ears can
be involved as well, clinical manifestations are usually mild.
commonly observed. Laboratory examinations usually show nonspecific
abnormalities of inflammation such as an elevated ESR and leukocytosis. In patients
with cystic fibrosis experiencing acute pneumonia, these laboratory abnormalities
could already be present and, therefore, will not be helpful in establishing the
diagnosis of hypersensitivity vasculitis in M.G.
Criteria for the Classification of Hypersensitivity Vasculitis
Development of symptoms after age 16
Medication at disease onset that may have been a precipitating factor
pressure and is not related to thrombocytopenia
Maculopapular rash over one or more areas of the skin
Biopsy showing granulocytes around an arteriole or venule
hypersensitivity vasculitis. Arthritis Rheum. 1990;33:1108.
Hypersensitivity Reactions to Drugs: Clinical Manifestations of Drug-Induced
Multiple organ systems may be involved:
Renal: microscopic hematuria to nephrotic syndrome and acute renal failure
Liver: enlarged liver, elevated enzymes
Gastrointestinal: abdominal pain
Onset typically 7–21 days after initiation of therapy
In addition to the previous workup, other laboratory and diagnostic procedures
might demonstrate peripheral eosinophilia and low serum complement
concentrations. A biopsy, which typically reveals granulocytes in the wall of a
venule or arteriole and eosinophils at any location, would provide more definitive
CASE 32-4, QUESTION 3: How should M.G.’s hypersensitivity vasculitis be treated?
The first step is to discontinue the minocycline therapy. Drug-induced vasculitic
reactions typically resolve on their own without additional interventions. If the
reaction is severe, corticosteroids can be used.
Some drugs can induce an autoimmune process characterized by the presence of
autoantibodies and, in some instances, clinical features of an autoimmune disorder. A
drug-induced syndrome resembling SLE is usually characterized by myalgias,
arthralgias, positive ANA titers, and an elevated ESR (see Chapter 33, Systemic
Lupus Erythematosus). All of these characteristics are manifested by R.F.
The first case of drug-induced lupus erythematosus (DILE) was recognized more
than 60 years ago and was associated with sulfadiazine.
drugs have been associated with DILE including isoniazid, chlorpromazine,
quinidine, methyldopa, and minocycline; however, hydralazine and procainamide are
the drugs most frequently associated with this syndrome.
DILE can be separated into systemic, subacute cutaneous, and chronic cutaneous
lupus. An exact incidence of DILE is difficult to ascertain because of changing
CASE 32-5, QUESTION 2: How can the diagnosis of drug-induced lupus be differentiated from SLE in
In contrast to idiopathic SLE, DILE is less likely to affect women and black
79 On average, patients with DILE are twice as old as those with idiopathic
SLE at the time of diagnosis. Individuals with a slow acetylator phenotype have a
greater tendency to exhibit DILE; ANA after exposure to lupus-inducing drugs also
In general, DILE is a milder disease than idiopathic SLE.
Many patients with DILE, however, could fulfill the diagnostic criteria for SLE
according to the American Rheumatism Association.
accompanied by a positive ANA test can be the only clinical features for some
patients with drug-induced lupus. Symptoms usually appear abruptly after several
months to years of continuous therapy with the offending drug. Common complaints
include fever, malaise, arthralgias, myalgias, pleurisy, and slight weight loss. Mild
splenomegaly and lymphadenopathy have been reported occasionally. The skin is
affected in about 25% of cases manifesting as photosensitivity on light exposed
surfaces. The classic butterfly malar rash, discoid lesions, oral mucosal ulcers,
Raynaud’s phenomenon, and alopecia are unusual features in DILE in contrast to
idiopathic SLE. In addition, the central nervous system and kidneys rarely are
84 Laboratory abnormalities commonly include anemia and an elevated ESR.
The evidence supporting a diagnosis of drug-induced lupus in R.F. includes white
male predominance, abrupt onset and relatively mild symptomatology, and lack of the
classic butterfly malar rash. More definitive tests include determining whether
antibodies to single-stranded (indicative of drug-induced lupus) or double-stranded
DNA (indicative of SLE) are present.
earlier stage in this patient?
No. Although all patients with symptomatic drug-induced lupus test positive for
ANA (which consist predominantly of single-stranded DNA and antihistone
84 many patients taking lupus-inducing drugs become ANA positive
without going on to experience lupus. In patients treated with procainamide, about
50% to 75% are positive for ANA after 12 months and 90% after 2 years or more of
continuous therapy; only 10% to 20% of those patients actually experience lupus
84–86 Similarly, up to 44% of patients are ANA positive after 3 years of
hydralazine therapy, but DILE occurs in only 6.7% of patients after 3 years of
It is not necessary to discontinue therapy in asymptomatic patients with
positive ANA because most of them will never exhibit clinical symptoms.
CASE 32-5, QUESTION 4: How should R.F.’s drug-induced lupus be treated?
Musculoskeletal complaints can be treated with aspirin or an NSAID. More severe
symptoms from pleuropulmonary or pericardial involvement may require the use of
corticosteroids. Clinical features of DILE usually subside and disappear in days to
weeks with discontinuation of the offending drug. Occasionally, these symptoms
linger or recur over a course of several months before eventually disappearing.
Serologic tests tend to resolve more slowly: ANA may persist for a year or
79,87 Drug-induced lupus does not predispose patients to the subsequent
development of idiopathic SLE.
In most instances, lupus-inducing drugs do not
increase the risk of exacerbation of idiopathic SLE
; however, long-term treatment
with isoniazid may worsen preexisting SLE.
90 Since R.F. has not yet completed his 6-
to 9-month course of isoniazid therapy, an alternative agent should be prescribed for
R.F. with appropriate monitoring (see Chapter 68, Tuberculosis).
The drug allergies in this chapter have been grouped into categories of generalized
reactions, organ-specific reactions, and pseudoallergic reactions. The generalized
reactions have been described first, the organ-specific hypersensitivity drug
reactions affecting the blood, liver, lung, kidney, and skin are described next, and
pseudoallergic reactions follow.
Drug-induced immune cytopenias (e.g., granulocytopenia, thrombocytopenia, and
hemolytic anemia) result from type II–mediated allergic reactions (Table 32-1). A
drug or drug metabolite binds to the surface of blood elements such as granulocytes,
platelets, and red blood cells. IgG or IgM antibodies are formed and are directed
against the drug or drug metabolite bound to the cell (i.e., hapten–cell reaction).
Typical symptoms associated with immune thrombocytopenia include chills, fever,
petechiae, and mucous membrane bleeding. Granulocytopenia generally manifests
with chills, fever, arthralgias, and a precipitous drop in the leukocyte count.
Symptoms of hemolytic anemia can be subacute or acute and can be sufficiently
severe to cause renal failure. The Coombs test is useful in identifying antibodies
bound to red cells or circulating immune complexes directed against red cells.
Antibiotics are the most commonly implicated class of drugs causing either
neutropenia or hemolytic anemia.
Hypersensitivity reactions involving the liver can be classified as cholestatic or
cytotoxic. Jaundice is usually the first sign of a cholestatic reaction, in addition to
pruritus, pale stools, and dark urine. Cholestatic reactions usually are reversible on
discontinuation of the offending agent. Cytotoxic reactions can involve hepatocellular
necrosis or steatosis and can result in irreversible damage if not recognized early.
Pulmonary manifestations of drug hypersensitivity include asthma and infiltrative
reactions. Asthma typically occurs as part of a generalized systemic reaction. Most
reactions to drugs that involve asthma alone represent a pharmacologic side effect
rather than a true allergic reaction.
Infiltrative reactions typically develop 2 to 10 days after exposure and manifest
with cough, dyspnea, fever, chills, and malaise.
Infiltrative reactions vary in
presentation from eosinophilic pneumonitis to acute pulmonary edema.
The most common hypersensitivity reaction involving the kidney is interstitial
nephritis. Typical findings include fever, rash, and eosinophilia. Methicillin is the
drug most commonly associated with interstitial nephritis, although penicillins,
sulfonamides, and cimetidine also have been implicated in renal hypersensitivity
(See Chapter 29, Acute Kidney Injury, for hypersensitivity reactions to
specific drugs that adversely affect the kidney.)
Adverse reactions involving the skin are the most common clinical manifestation of
drug allergy. Although several different types of cutaneous reactions are possible,
most drug-induced skin eruptions can be classified as erythematous, morbilliform, or
In a surveillance study of drug-induced skin
reactions, amoxicillin was the most common cause, followed by trimethoprim–
sulfamethoxazole and ampicillin. Overall, allergic skin reactions were identified in
Treatment of skin reactions includes discontinuation of the offending drug and
general supportive care (see Chapter 39, Dermatotherapy and Drug-Induced Skin
minutes after the new dose of vancomycin is begun, C.C. experienced hypotension (100/70 mm Hg),
pseudoallergic reaction to vancomycin. What subjective and objective data in C.C. are important in
differentiating vancomycin pseudoallergic reaction from a true allergic reaction?
Pseudoallergic reactions (also called nonallergic hypersensitivity reactions) are
drug reactions that exhibit clinical signs and symptoms of an allergic response but are
91 They can manifest as relatively benign symptoms or
as severe, life-threatening events indistinguishable from anaphylaxis (Table 32-9).
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