Cooper, Leslie T.

Gami, Appor S.

Murphy, Joseph

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Cautious interpretation of data regarding myopericarditis associated with smallpox vaccination 

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Letters to the Editor
Cautious Interpretation of
Data Regarding Myopericarditis
Associated With Smallpox Vaccination
We congratulate Cassimatis et al. (1) for their excellent review of
myopericarditis associated with smallpox vaccination. We suggest
a different interpretation of the data regarding some important
issues.
First, the true incidence of myopericarditis secondary to small-
pox vaccination with Dryvax (NYBOH strain) vaccine remains
unknown and it is likely higher than the quoted rates of one case
per 9,360 (1), 10,000 (2), or 12,819 (3) vaccinations, which
represent the recognition of overt, symptomatic myopericarditis in
a highly selected, very fit military population. We suspect myo-
pericarditis is underdiagnosed in this population because of the
wide spectrum of presenting clinical symptoms and signs that
confound accurate diagnosis, the potential for minimal or no-
symptom cases that could lead to missed cases, and the character-
istics of young, volunteer, military personnel who could conceiv-
ably overlook or minimize symptoms that do not limit their service
duties. A higher rate of myopericarditis is supported by the 2% to
3% incidence of electrocardiographic changes after smallpox vac-
cination in Swedish military personnel in the 1960s (4,5). Impor-
tantly, a higher incidence of myopericarditis would likely be
recognized if mass smallpox vaccination were applied to the
general population with higher prevalence rates of cardiovascular
and immunologic disease, in an attempt to protect citizens against
smallpox bioterrorism.
Second, the long-term sequelae of myopericarditis due to
smallpox vaccination remain unknown. Subclinical or overt abnor-
malities due to vaccinia viremia or its immunologic responses, such
as direct viral toxicity or immune-mediated myocyte necrosis,
persistent myocardial inflammatory infiltrates, or development of
myocardial fibrosis, may manifest years later, with ventricular
dysfunction, conduction system abnormalities, or sudden death.
Although almost all recently vaccinated patients with myopericar-
ditis recovered clinically, the possibility of residual low-grade
myocardial inflammation and fibrosis cannot be excluded or
prevented.
Third, endomyocardial biopsy probably is of greater than
“limited utility” after smallpox vaccination. We advocate endo-
myocardial biopsy for all patients with suspected new-onset ven-
tricular dysfunction (ejection fraction 45%) and symptoms of
heart failure after smallpox vaccination. The rationale for this
approach is the documentation of possible steroid responsive
eosinophilic myocarditis, which occurred in one recent patient
after smallpox vaccination, and the need to exclude uncontrolled
vaccinia virus replication within the myocardial that may be
responsive to immune globulin. Endomyocardial biopsy under
echocardiographic guidance is a relatively safe procedure in expe-
rienced hands and may provide a definitive actionable diagnosis in
high-risk patients (6).
It is a profound tragedy that vaccination against an eradicated
disease whose elimination marked the single greatest human
success against a communicable disease is now required for U.S.
soldiers because of the threat of biowarfare. Current smallpox
vaccine appears to carry significant risks of serious adverse events.
The true incidence and long-term sequalae of current smallpox
vaccine remain unknown.
Appor S. Gami
Joseph Murphy, MD
*Leslie T. Cooper, Jr., MD
*Mayo Clinic
Cardiovascular Division, Mayo East 16B
200 First Street SW
Rochester, MN 55905
E-mail: cooper.leslie@mayo.edu
doi:10.1016/j.jacc.2004.10.006
REFERENCES
1. Cassimatis DC, Atwood JE, Engler RM, Linz PE, Grabenstein JD,
Vernalis MN. Smallpox vaccination and myopericarditis: a clinical
review. J Am Coll Cardiol 2004;43:1503–10.
2. Karjalainen J, Heikkila J, Nieminen MS, et al. Etiology of mild acute
infectious myocarditis. Relation to clinical features. Acta Med Scand
1983;213:65–73.
3. Halsell JS, Riddle JR, Atwood JE, Myopericarditis following smallpox
vaccination among vaccinia-naive U.S. military personnel. JAMA 2003;
289:3283–9.
4. Ahlborg B, Linroth K, Nordgren B. ECG changes without subjective
symptoms after smallpox vaccination of military personnel. Acta Med
Scand Suppl 1966;464:127–34.
5. Bengtsson E, Holmgren A, Nystrom B. Smallpox outbreak and
vaccination problems in Stockholm, Sweden 1963. Circulatory studies
in patients with abnormal ECG in the course of postvaccinal compli-
cations. Acta Med Scand Suppl 1966;464:113–26.
6. Wu LA, Lapeyre AC 3rd, Cooper LT. Current role of endomyocardial
biopsy in the management of dilated cardiomyopathy and myocarditis.
Mayo Clin Proc 2001;76:1030–8.
REPLY
We appreciate the comments on our review (1) of myopericarditis
associated with smallpox vaccination. The recently published rates
of myopericarditis may indeed be underestimates, for they are
based on reporting of clinical encounters with symptomatic pa-
tients from an occupational cohort, as we noted previously (2). To
better assess the true incidence rate, we will soon enroll volunteers
in a prospective trial of smallpox vaccinees with baseline and
follow-up electrocardiography, laboratory markers, and question-
naires.
We described the need to follow patients diagnosed with
postvaccinial myopericarditis to establish whether long-term se-
quelae exist (1), and we recently have published the results of such
follow-up (3). On the basis of these data, long-term sequelae are
160 Correspondence JACC Vol. 45, No. 1, 2005
January 4, 2005:154–64


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Cautious interpretation of data regarding myopericarditis associated with smallpox vaccination

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