Cardiovascular Clinics

Myocarditis Related to Drug Hypersensitivity

CHARLES P. TALIERCIO, M . D . , Res/dent in Cardiology*; BYRON A. OLNEY, M . D . , Division of

Cardiovascular Diseases and Internal Medicine; J. T. LIE, M . D . , Department of Pathology

Hypersensitivity myocarditis is an inflammatory disease of the myocardium usually related to a drug allergy. The
clinical manifestations may be nonspecific, and the diagnosis is seldom suspected or established during life. We
report a case that demonstrates both typical and atypical features of this disease and review the clinicopathologic
correlations. This case illustrates the potential occurrence of both electrical conduction block and ventricular
tachyarrhythmias, either of which may account for the mechanism of sudden death in these patients. When
cardiac symptoms or electrocardiographic abnormalities (or both) occur in a setting consistent with drug allergy,
hypersensitivity myocarditis should be considered. Treatment consists of discontinuation of use of the drug
responsible for the reaction and, possibly, administration of corticosteroids and immunosuppressive therapy.

Hypersensitivity myocarditis is rarely recognized as a
clinical entity; reported cases have most often been
discovered unexpectedly at autopsy. Thus, the diagnosis
is usually retrospective and circumstantial. The initial
reports of apparent hypersensitivity myocarditis co-
incided with the introduction of sulfonamides, 1 and sub-
sequent sporadic reports have been related to the use of a
variety of drugs. Aside from sulfonamides, the most
commonly implicated agents have been penicillin and its
derivatives and methyldopa. 2
The actual incidence of hypersensitivity myocarditis
cannot be accurately estimated. In one reported series,
16 histologically confirmed cases were identified among
3,373 consecutive autopsies.3 The ratio of fatal to nonfa-
tal cases, however, remains unknown. In most cases of
hypersensitivity myocarditis identified at autopsy, the
patients have died suddenly and unexpectedly while
being treated for an unrelated and nonlethal illness.2 The
antemortem manifestations of myocarditis have rarely
been distinctive enough to lead to diagnosis and initia-
tion of treatment.
The following case report illustrates both typical and
atypical features of hypersensitivity myocarditis.
REPORT OF CASE
A 32-year-old woman was in excellent health until Janu-
ary 1981, when she began to experience episodes of
involuntary muscle spasms that were diagnosed else-
*Mayo Graduate School of Medicine, Rochester, Minnesota.
Address reprint requests to Dr. B. A. Olney.
where as "idiopathic myoclonus." In |uly 1981, therapy
with phenytoin (Dilantin), 300 mg/day, was begun, and
the symptoms resolved. Four weeks after the initiation of
this treatment, however, fever, pruritus, and a vesicular
skin rash developed. An allergy to phenytoin was sus-
pected, and discontinuation of this therapy alleviated the
symptoms. Carbamazepine (Tegretol), 600 mg/day, was
substituted; 3 weeks later, fever and a pruritic vesicular
rash recurred, and subsequently, urticaria, hepato-
megaly, and jaundice developed. A short course of eryth-
romycin and cefoxitin provided no benefit.
In September 1981, a liver biopsy showed panlobular
and portal inflammation histologically consistent with
drug-induced hepatitis, and a skin biopsy specimen had
changes characteristic of a hypersensitivity vasculitis. All
prior medications were discontinued, and corticosteroid
(prednisone) treatment was initiated. Although the hep-
atitis gradually resolved, the skin rash reappeared when
the dose of prednisone was tapered to less than 30
mg/day.
In October 1981, the patient underwent an extensive
laboratory evaluation. Except for an elevated concentra-
tion of IgE (803 lU/ml; normal range, 0 to 113 lU/ml) and
a peripheral eosinophilia of 8%, the results of other
studies were normal. When the prednisone dosage was
decreased to 40 mg/day, the eosinophilia increased to
42%. After the dosage was readjusted upward, the rash
gradually diminished but an eosinophilia of 14 to 17%
persisted. Investigations for causes of eosinophilia other
than the drug hypersensitivity showed normal findings,
as did an electrocardiogram. From November 1981 to

Mayo Clin Proc 60:463-468, 1985 463

464 DRUG-INDUCED MYOCARDITIS
June 1982, the prednisone dosage was adjusted to 50 mg
every other day; trials of lower dosages caused exacer-
bation of the rash.
On June 7, 1982, the patient was referred to our
institution and was admitted to an affiliated hospital. A
physical examination revealed normal findings except
for a diffuse erythroderma and changes in body habitus
consistent with hypercortisolism. She had a leukocyte
count of 6,900/mm 3 with 5% eosinophils and a markedly
elevated IgE concentration (2,628 lU/ml). A skin biopsy
specimen showed changes consistent with a "lichenoid
drug reaction." Normal results were found on the rest of
the studies, i n c l u d i n g chest roentgenography and
electrocardiography.
Prednisone therapy was discontinued at the time of the
current admission, and a regimen of hydroxyzine pamo-
ate (Vistaril) and topical corticosteroids was instituted.
After an initial period of improvement, the rash flared,
and on June 26, 1982, administration of adrenocortico-
tropic hormone, 40 U twice a day, was begun. On July 3,
prednisone, 30 mg every other day, was substituted for
the adrenocorticotropic hormone.
On the evening of July 6, 1982, the patient noted mild
central anterior chest discomfort. Although results of a
cardiopulmonary examination were normal, this symp-
|^v-4rv-AJUvy
Fig. 1. Electrocardiogram on July 7, 1982, showing pattern of right bundle-branch block and diffuse ST segment elevation.
Mayo Clin Proc, July 1985, Vol 60
tom persisted and intensified during the next 24 hours.
An electrocardiogram (Fig. 1) disclosed a new right
bundle-branch block with diffuse ST segment elevation,
and a chest roentgenogram showed cardiomegaly. Other
pertinent laboratory data included a leukocyte count of
11,600/mm 3 with 10% eosinophils and mildly elevated
serial measurements of creatine kinase with substantially
elevated MB isoenzyme fractions (Table 1).
On July 8, 1982, an echocardiogram showed a dilated
and poorly functioning left ventricle with an estimated
ejection fraction of 35%. Concurrently, progressive sinus
tachycardia (130 to 140 beats/min), hypotension (90/60
mm Hg), and intermittent episodes of ventricular tachy-
cardia developed. Central hemodynamic monitoring
was initiated (Table 2). With the presumptive diagnosis of
fulminant myocarditis, she was given prednisone, 100
mg/day, and azathioprine (Imuran), 600 mg/day. Subse-
quently, hydrocortisone sodium succinate (Solu-Cortef)
was administered intravenously. Her course remained
stable for the next 24 hours with the additional use of
dopamine, nitroprusside, and lidocaine.
On July 10, 1982, progressive impairment of the con-
duction system (Fig. 2) and increasingly refractory ven-
tricular tachycardia became evident. These arrhythmias
were unresponsive to several measures: temporary trans-
Mayo Clin Proc, July 1985, Vol 60 DRUG-INDUCED MYOCARDITIS 465

Table 1 .—Results of Serial Measurements of Creatine Kinase in Table 2.—Hemodynamic Data in Patient With
Patient With Hypersensitivity Myocarditis Hypersensitivity Myocarditis
Total creatine kinase MB isoenzyme Factor Value
Date (U/L)· (%)t
Pressure measurements (mm Hg)
1982: July 7 133 28 Systemic arterial* 110/70
8 130 31 Mean right atrial 20
8 174 30 Right ventricular 40/22
9 154 30 Pulmonary artery 40/22
10 140 37 Mean pulmonary artery wedge 24
»Normal range, 15-57 U/L. Heart rate (beats/min) 125
tNormal value, 0%. Cardiac index (L/min/m2) 1.4
Stroke volume index (ml/beat/m2) 11
»Patient was taking dopamine.

venous pacing; intravenously administered lidocaine, external direct-current cardioversion. The patient died of
procainamide hydrochloride, and bretylium tosylate intractable ventricular tachycardia and hypotension.
given singly and in combination; overdrive suppression Diffuse acute myocarditis was the most striking patho-
by means of the temporary pacemaker; and repeated logic finding at autopsy. The heart was edematous and

Fig. 2. Electrocardiographic tracings on July 10, 1982. A, Note evidence of progression of conduction system disease with features suggesting
delay in both right and left bundle branches ("masquerading bundle-branch block"). B, Rhythm strips, showing intermittent 2:1 atrioventricular
block.
466 DRUG-INDUCED MYOCARDITIS
Fig. 3. A, Photograph of gross specimen of heart, opened in left ventricular outflow view, showing generalized mottled appearance of
myocardium. B, Representative photomicrograph, showing diffuse acute myocarditis with numerous mature eosinophils in inflammatory cell
infiltrate and necrosis of scattered individual cardiac myocytes. (Hematoxylin and eosin; x 160.)
had a generalized mottled appearance grossly. The myo-
carditis affected all four chambers of the heart (Fig. 3 A).
The inflammatory cell infiltrate showed a preponderance
of eosinophils, admixed with lymphocytes, plasma cells,
and histiocytes, and surrounded foci of individual car-
diac myocyte necrosis (Fig. 3 ß). Histologie sections from
the atrioventricular conduction tissue also showed myo-
carditis involving the His bundle and bundle branches
(Fig. 4). No vasculitis was observed. In the organs other
than the heart, no eosinophilic infiltrate or other type of
inflammatory process was noted. The liver was normal
histologically except for moderate centrilobular sinu-
soidal dilatation. Cardiac mural thrombi were detected
only microscopically, in the right ventricular cavity. A
few fibrin-platelet thromboemboli were seen in the pul-
monary microvasculature.
DISCUSSION
With few exceptions, hypersensitivity myocarditis has
been a postmortem diagnosis, and, as in our reported
case, the diagnosis has been circumstantial. None-
theless, on retrospective review, more than 90% of the
patients described in published reports have had clini-
cally recognizable cardiac abnormalities before death. 2
Typically, however, the findings have been considered
relatively minor and nonspecific, and death has been
Mayo Clin Proc, July 1985, Vol 60
sudden, unexpected, and presumed to be caused by
arrhythmia. Inappropriate sinus tachycardia, conduction
delays, and ST-T abnormalities are common findings,
whereas pseudoinfarct patterns are less frequently seen.
Approximately 75% of patients in whom cardiac muscle
enzymes are measured have mildly elevated levels
(rarely more than twice the normal value), 2 a finding in
accordance with the infrequent occurrence of massive
myocardial cell necrosis. Mild cardiomegaly is common.
The spectrum of initial clinical manifestations may also
include sudden hemodynamic collapse 4 or, as in the
patient described herein, fulminant acute myocarditis.
Several features of the current case warrant further brief
comment. In our patient, progressive conduction system
disease corresponded with the histologic finding of in-
volvement of the His bundle and bundle branches by the
eosinophilic myocarditis. Such a correlation has been
reported previously. 5 Our patient had both heart block
and ventricular tachycardia, either of which might ex-
plain why sudden death is the common mode of death in
those patients with drug-related myocarditis who die.
The presence of conduction block or a complex ventricu-
lar arrhythmia should be viewed as a worrisome finding.
The elevated levels of creatine kinase were modest (2 to 3
times the normal value) but greater than those usually
reported, and the MB isoenzyme fraction was particu-
Mayo Clin Proc, July 1985, Vol 60 DRUG-INDUCED MYOCARDITIS 467

Fig. 4. A, Low-power view of ventricular septum (VS), showing diffuse myocarditis with involvement of atrioventricular bundle {open arrows) and
left bundle branch {black arrows). (Hematoxylin and eosin; x 16.) B, Close-up view of myocarditis in boxed-in area of atrioventricular bundle
shown in A. (Hematoxylin and eosin; x 160.)

larly high. This slightly exaggerated response was as- ditis, 2,8,9 and many others undoubtedly have the potential
sumed to be an indication of the intensity of the myocar- for such a reaction. Methyldopa, sulfonamides, and
dial damage in this patient. penicillin and its derivatives have been incriminated in
The diagnosis of hypersensitivity myocarditis should 75% or more of the reported cases.2 Phenytoin most
be considered when new electrocardiographic changes,
mildly elevated enzyme levels, cardiomegaly, or unex-
Table 3.—Drugs Reported To Be Associated With
plained tachycardia is noted in a patient who has an
Hypersensitivity Myocarditis
ongoing allergic reaction to a drug, usually with evidence
Acetazolamide Para-aminosalicylic acid
of eosinophilia. Other causes of eosinophilia should be
Amitriptyline hydrochloride Penicillin
excluded. Confirmation of the diagnosis of hyper- Amphotericin B Phenindione
sensitivity myocarditis may necessitate histologic dem- Ampicillin Phenylbutazone
onstration of the typical constellation of a diffuse inter- Carbamazepine Phenytoin
stitial infiltrate rich in eosinophils, with or without cellu- Chloramphenicol Spironolactone
lar necrosis. Percutaneous transvenous biopsy of the Chlorthalidone Streptomycin
Hydrochlorothiazide Sulfadiazine
endomyocardium may be a potentially useful method of
Indomethacin Sulfisoxazole
obtaining tissue for examination. 6,7 Isoniazid Sulfonylureas
More than 20 drugs (Table 3) have been reported as Methyldopa Tetracycline
possible etiologic agents in hypersensitivity myocar- Oxyphenbutazone
468 DRUG-INDUCED MYOCARDITIS
likely initiated the hypersensitivity reaction in our patient
and has been implicated in previously reported cases as
well. 2 Carbamazepine may also have been a contributing
factor, but the other two medications—erythromycin and
cefoxitin—were used only after the hypersensitivity reac-
tion was well established.
The time from initial drug exposure to the development
of hypersensitivity myocarditis varies from hours 4 to
many months. The patient is usually still taking the medi-
cation at the time of onset of cardiac problems, and the
allergic phenomenon seldom persists for an extended
period after discontinuation of the regimen. The mecha-
nism of the cardiac reaction has been postulated to be a
delayed hypersensitivity reaction.
Cellular necrosis is relatively less prominent in hyper-
sensitivity myocarditis than in other forms of myocarditis;
therefore, the patient may have minimal permanent dam-
age if the hypersensitivity reaction is halted. 1,2 ' 9 Discon-
tinuing the use of the offending medication is essential,
and in most patients, the general allergic reaction will
subside within several days or weeks. Aggressive treat-
ment with an anti-inflammatory agent may be necessary
during this recovery period if severe cardiac complica-
tions develop. 2 The prolonged reaction in our patient was
atypical. The hypersensitivity phenomenon persisted
long after use of the offending drugs had been discon-
tinued and despite long-term administration of cor-
ticosteroids. Furthermore, the myocarditis progressed
relentlessly despite an increase in the dose of the cor-
ticosteroids and, finally, the addition of azathioprine.
Nonetheless, in typical cases of hypersensitivity myo-
carditis, the use of corticosteroid or immunosuppressive
therapy (or both) seems l o g i c a l and is u s u a l l y
recommended.
It has been estimated that the average hospitalized
patient receives 10 different medications. 10 Adverse reac-
tions, including true drug allergies, are correspondingly
frequent. Autopsy-proven cases of hypersensitivity myo-
carditis probably represent only a minor portion of the
Mayo Clin Proc, July 1985, Vol 60
actual incidence, and the number of unrecognized, non-
fatal, and presumably self-limited cases is undoubtedly
much greater. Other forms of eosinophilic myocardiop-
athy are well recognized and have been described,' 1 1 2
wherein an initial eosinophilic myocarditis may lead to
chronic tissue changes and permanent impairment of
cardiac function. Whether the eosinophilic myocarditis
associated with hypersensitivity may behave similarly
and have analogous long-term functional consequences
has not been established.
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