Context In the United States, the annual incidence of myocarditis is estimated
at 1 to 10 per 100 000 population. As many as 1% to 5% of patients with
acute viral infections involve the myocardium. Although many viruses have
been reported to cause myopericarditis, it has been a rare or unrecognized
event after vaccination with the currently used strain of vaccinia virus (New
York City Board of Health).
Objective To describe a series of probable cases of myopericarditis following
smallpox vaccination among US military service members reported since the
reintroduction of vaccinia vaccine.
Design, Setting, Participants Surveillance case definitions are presented. The cases were identified
either through sentinel reporting to US military headquarters surveillance
using the Defense Medical Surveillance System or reports to the Vaccine Adverse
Event Reporting System using International Classification
of Diseases, Ninth Revision. The cases occurred among individuals vaccinated
from mid-December 2002 to March 14, 2003.
Main Outcome Measure Elevated serum levels of creatine kinase (MB isoenzyme), troponin I,
and troponin T, usually in the presence of ST-segment elevation on electrocardiogram
and wall motion abnormalities on echocardiogram.
Results Among 230 734 primary vaccinees, 18 cases of probable myopericarditis
after smallpox vaccination were reported (an incidence of 7.8 per 100 000
over 30 days). No cases of myopericarditis following smallpox vaccination
were reported among 95 622 vaccinees who were previously vaccinated.
All cases were white men aged 21 years to 33 years (mean age, 26.5 years),
who presented with acute myopericarditis 7 to 19 days following vaccination.
A causal relationship is supported by the close temporal clustering (7-19
days; mean, 10.5 days following vaccination), wide geographic and temporal
distribution, occurrence in only primary vaccinees, and lack of evidence for
alternative etiologies or other diseases associated with myopericarditis.
Additional supporting evidence is the observation that the observed rate of
myopericarditis among primary vaccinees is 3.6-fold (95% confidence interval,
3.33-4.11) higher than the expected rate among personnel who were not vaccinated.
The background incidence of myopericarditis did not show statistical significance
when stratified by age (20-34 years: 2.18 expected cases per 100 000;
95% confidence interval [CI], 1.90-2.34), race (whites: 1.82 per 100 000;
95% CI, 1.50-2.01), and sex (males: 2.28 per 100 000; 95% CI, 2.04-2.54).
Conclusion Among US military personnel vaccinated against smallpox, myopericarditis
occurred at a rate of 1 per 12 819 primary vaccinees. Myopericarditis
should be considered an expected adverse event associated with smallpox vaccination.
Clinicians should consider myopericarditis in the differential diagnosis of
patients presenting with chest pain 4 to 30 days following smallpox vaccination
and be aware of the implications as well as the need to report this potential
adverse advent.
We report the first 18 cases of probable myopericarditis following smallpox
vaccination among otherwise healthy, young adult members of the US military
who were vaccinated between mid-December 2002 and March 14, 2003 (N = 326 356;
230 734 primary vaccinees and 95 622 revaccinees). Despite decades
as the standard vaccine for US civilian and military populations, the New
York City Board of Health (NYCBOH) strain of vaccinia virus (Dryvax, Wyeth
Laboratories, Marietta, Pa) has only rarely been associated with myopericarditis
following vaccination. Only 5 cases were reported in the medical literature
between 1955 and 1986.1-8
Myocarditis and pericarditis following vaccination have been reported
more commonly with other vaccinia virus strains,9-17 may
be associated with other adverse events following vaccination,2 and
may be asymptomatic.10,18-20 In
1968, Price and Alpers14 noted that minor cardiac
complications after smallpox vaccination may be more common than is generally
reported. Six years earlier, MacAdam and Whitaker21 reported
3 cases of cardiac complications 5 to 14 days following smallpox vaccination
and suggested that cardiac complications had been previously overlooked. In
1983, the incidence of myocarditis following vaccination among Finnish military
conscripts who were hospitalized with mild myocarditis following vaccination
with the Finnish strain of smallpox had been estimated to be as high as 1
per 10 000.22 As early as 1953, Mathieu
and Hadot23 recommended screening for cardiac
risk factors before vaccination, especially in individuals aged 50 years or
older.
Surveillance for Adverse Events
A program to vaccinate up to 500 000 US military personnel was
launched mid-December 2002.24 To detect adverse
events after vaccination, the Department of Defense and the US Coast Guard
require reporting to the Vaccine Adverse Event Reporting System (VAERS) using
established guidelines. Additionally, the Department of Defense encourages
clinicians to report all other clinically relevant adverse events after administration
of any vaccine or medication to VAERS or MedWatch (US Food and Drug Administration
Safety Information and Adverse Event Reporting Program). To heighten awareness
of potential adverse events, including cardiac events, clinicians were provided
extensive education and vaccinees were individually counseled and provided
educational material. An Internet site providing access to a comprehensive
array of materials and ongoing program status was established (http://www.smallpox.army.mil/).
A 3-pronged approach was implemented for surveillance and patient safety
following vaccination, as described by Grabenstein and Winkenwerder24 elsewhere in this issue of THE JOURNAL. Standard
documentation was used to record screening results, vaccination delivery,
vaccination response, and adverse event management. Vaccination was recorded
electronically as a component of the individual's longitudinal health record,
which was maintained as part of the Defense Medical Surveillance System (DMSS).25 This system integrates data from sources worldwide
in a continuously expanding relational database that documents the military
and medical experiences of service members throughout their careers. The DMSS
allows nearly instantaneous assessments of the morbidity experiences of service
members who share common characteristics, such as vaccination. Statistical
analysis was performed using SAS version 8.02 (SAS Institute, Cary, NC).
The cases presented herein were identified either through sentinel reporting
to military headquarters and/or to the VAERS or through diagnostic surveillance
among vaccinees at military treatment facilities using International Classification of Diseases, Ninth Revision (ICD-9)26 coded diagnoses (420.90, 420.99, other and unspecified
acute pericarditis; 422.90, 422.91, other and unspecified acute myocarditis;
and 429.0 myocarditis unspecified) obtained from the DMSS. Fifteen cases were
first identified from surveillance of military treatment facilities, and only
3 cases were first identified from the VAERS. The cases were classified based
on surveillance case definitions shown in the Box. Clinical diagnosis of myocarditis was based on detection
of elevated serum levels of creatine kinase (MB isoenzyme), troponin I, and
troponin T, usually in the presence of ST-segment elevation on electrocardiogram
and wall motion abnormalities on echocardiogram.
Box Section Ref IDBox. Myopericarditis Following Smallpox Vaccination: Adverse Event
Surveillance Case Definitions
Confirmed Myopericarditis Following Vaccination
Patient with acute myocarditis* with or without pericarditis with symptom
onset 4 to 30 days after vaccinia exposure and absence of another causal infection,
disease or toxic agent and, virus culture or detection† of vaccinia
DNA by polymerase chain reaction identification of vaccinia virus infection
from myocardial tissue or pericardial fluid (detection of viral nucleic acid
in the myocardium is regarded as indicative of virus infection)
Probable Myopericarditis Following Vaccination
Patient with acute myocarditis* with or without pericarditis with symptom
onset 4 to 30 days after vaccinia exposure and absence of another causal infection,
disease, or toxic agent
*Clinical diagnosis of myocarditis is confirmed by detection of elevated
serum levels of creatine kinase (MB isoenzyme), troponin I, and troponin T,
usually in the presence of ST-segment elevation on electrocardiogram and abnormal
findings on echocardiogram.
†Whether vaccinial myopericarditis is a direct viral cytopathogenic
effect or an immune-mediated disease remains unclear.
Clinical and diagnostic details for the 18 cases of probable myopericarditis
following smallpox vaccination reported among 230 734 primary vaccinees
(71% of vaccines) are presented in Table
1. No cases were detected among 95 622 vaccinees who were previously
vaccinated. All cases were military personnel in active duty who received
vaccination with the NYCBOH strain of vaccinia virus in various regions of
the United States, Europe, and the Middle East. All cases were white (73%
of total vaccinees), men (78% of total vaccinees), aged 21 years to 33 years
(mean age, 26.5 years; 59% of total vaccinees were aged 21-35 years), with
disease onset 7 to 19 days following vaccination (mean, 10.5 days). Typical
clinical presentation involved prodromal myalgias; arthralgias; subsequent
pleuritic, precordial chest pain; and variable shortness of breath and/or
dry cough. All vaccinees had elevated serum cardiac enzyme levels; 15 of the
18 cases had ST-segment elevation changes on electrocardiogram, and 11 of
the 18 cases had abnormal echocardiogram findings (ie, wall motion abnormalities).
Biopsy of myocardial tissue was performed in only 1 case; the results revealed
histological evidence of eosinophil infiltration of the myocardium, eosinophil
degranulation, secretion of major basic protein in close apposition to myocyte
necrosis, and IL-5 generation. No cases were confirmed by viral diagnosis.
All cases had a characteristic primary vaccination response at the inoculation
site as defined by the World Health Organization.27 Results
of serologic laboratory tests, when done, did not indicate the presence of
other infectious etiologies or host conditions predisposing to myopericarditis.
All cases survived and all returned to duty or are on short-term convalescent
leave. Longer-term follow-up to detect possible sequelae is underway.
The 18 cases among 230 734 primary vaccinees represent an incidence
of 7.80 per 100 000 over a 30-day observation window. The background
incidence of myopericarditis in all service members on active duty is 2.16
cases (95% confidence interval, [CI], 1.90-2.34; Poisson distribution) per
100 000 over any 30-day period. This incidence was calculated using 2002
calendar year DMSS data for all services for the above described 5 myopericarditis ICD-9 diagnoses among a population of 1 399 739
persons. When stratified by age, race, and sex, the background incidence rates
in all service members of myopericarditis were not statistically significant,
with 2.18 expected cases per 100 000 for ages 20 years to 34 years (95%
CI, 1.90-2.34); 1.82 expected cases per 100 000 for whites (95% CI, 1.50-2.01),
and 2.28 expected cases per 100 000 for males (95% CI, 2.04-2.54).
The expected number of myopericarditis cases in the population of 230 734
primary vaccinees was calculated by applying the background rate estimate
of 2.16 to this population, which yielded 4.98 expected cases (95% CI, 4.38-5.40).
The 18 cases reported herein represent an unadjusted estimate of relative
risk (RR) of 3.61 (95% CI, 3.33-4.11; Poisson distribution) over the expected
incidence of myopericarditis.
Etiologic Summary of Cases
The lack of clinical suspicion for myopericarditis following vaccination,
no standard evaluation protocol, and the varied capability of the medical
sites where these cases presented resulted in variable diagnostic workup for
etiologic causes. In none of the cases was infection of myocardial tissue
or pericardial fluid with the vaccinia virus confirmed using virus culture
or by detection of vaccinia DNA by polymerase chain reaction. Among this case
series, when serologic testing was done, findings have been negative for coxsackie
A and B viruses, as well as hepatitis B and C, HIV, Borrelia
burgdorferi, and Streptococcus pyogenes (by
antistreptolysin O and anti-DNAse B). Viral cultures of nasal wash from 1
patient recovered no adenovirus or influenza viruses. Results of cerebrospinal
fluid viral cultures from the same patient were negative, including a shell
viral culture that tests specifically for enteroviruses, herpes simplex viruses,
and cytomegalovirus. Results of serum antinuclear antibody from 6 patients
and rheumatoid factor from 4 patients also were negative. To address the variability
in etiologic diagnosis given the unexpected occurrence of these probable cases
of myopericarditis following vaccination, the Department of Defense Vaccine
Healthcare Center Network is developing clinical guidelines for evaluating
patients and clinical policy to increase clinician awareness.
Viral myocarditis is an inflammatory disorder of the myocardium characterized
by injury of myocytes with associated inflammatory infiltrate.28 Often
pericarditis and myocarditis are observed in tandem, hence the term myopericarditis.29 Clinical
diagnosis is suggested by detection of elevated serum levels of myocardial
enzymes (creatine kinase-MB isoenzyme, troponin I, and troponin T), usually
in the presence of nonspecific electrocardiographic changes and/or focal or
generalized wall motion abnormalities on echocardiography.18,30 In
most cases, an etiology is not determined, but in cases in which a causative
infectious agent has been identified, viral agents are most common, particularly
the enterovirus group (predominantly coxsackie B virus), adenoviruses, and
influenza A.31 Diagnosis may be confirmed using
histopathological and/or viral identification by polymerase chain reaction
from endomyocardial biopsy or autopsy specimens.28,30 Whether
myopericarditis following smallpox vaccination is a direct viral cytopathic
effect or an immune-mediated phenomenon remains unclear.
Association of Myopericarditis With Vaccinia Virus
Vaccinia virus has long been associated with myopericarditis.28,29,32 However, only 1 previous
report has described the pathological characteristics of myopericarditis following
smallpox vaccination; the histological changes included a mixed mononuclear
infiltrate.33 This case series of probable
myopericarditis associated with the New York City Board of Health strain of
vaccinia virus serves to establish an expected baseline rate for myopericarditis
following vaccination in primary vaccinees. The cases reported herein occurred
only in otherwise healthy, young, white adult men who were carefully screened
for conditions that might preclude vaccination. The cases reported were moderate
to severe in clinical presentation, and our observed incidence of myopericarditis
likely represents a minimum, with milder cases unrecognized.
The close temporal clustering following vaccination (7 to 19 days; mean
10.5 days), the wide geographic and temporal distribution during the vaccination
program, and the lack of alternative diagnoses, provide epidemiologic evidence
for an association between smallpox vaccination and myopericarditis. Additional
supporting evidence is the absence of myopericarditis in revaccinees and the
observation that the observed rate of myopericarditis among primary vaccinees
is 3.6-fold higher than the expected rate among personnel on active duty who
were not vaccinated. However, some covariates could confound this rate comparison,
and a multivariate statistical model in a case-control study design is needed.
Myopericarditis due to a synergistic inflammatory effect of multiple vaccines
cannot be excluded. Exertion may have predisposed these military personnel
to viral myocarditis, as exertion has been associated with increased viral
titer and inflammation of the heart in experimental animal models.34,35 It is possible that the occurrence
of myopericarditis following vaccination may represent coincidental outcomes;
however, the data linking myopericarditis with smallpox vaccine seem the most
likely explanation.
Clinicians should be alert to the potential occurrence and implications
of myopericarditis among adult primary vaccinees after receiving smallpox
vaccination, and they should report these adverse events to the VAERS. Patients
with a clinical suspicion of myopericarditis based on decreased ventricular
function on echocardiography, a markedly elevated troponin levels suggestive
of significant myocyte injury or a cardiac magnetic resonance imaging positive
scan for myocarditis may be indicated to undergo endomyocardial biopsy. Biopsy
specimens should be tested for the presence of vaccinia virus.
Potential bias exists for both underreporting and overreporting of cases.
Although extensive efforts have been made to identify all cases, underreporting
bias may result from incomplete ascertainment of cases with myopericarditis
following smallpox vaccination, considering the reported mild-to-moderate
acute presentation and clinical course,10 and
the necessity of an index of suspicion to pursue an association. The generalized
lack of clinical suspicion, exemplified by only 3 cases initially being reported
through the VAERS, argues against overreporting of myopericarditis among vaccinees
resulting from a case-ascertainment bias of clinicians. Ascertainment bias
among vaccinees that resulted in overreporting (eg, the inference that individuals
with chest pain after smallpox vaccination may be more likely to seek care)
also is unlikely, given the moderate-to-severe clinical presentation of the
reported cases. The absence of cases in this study among revaccinees, females,
and nonwhite males is difficult to explain from a purely epidemiologic perspective.
The Centers for Disease Control and Prevention (CDC) has reported myopericarditis
following smallpox vaccination in females, although the CDC case definition
differed from that used to classify the cases reported herein.36 Although
revaccinees might be expected to be more aware of the potential adverse effects
from this vaccine and thus be less likely to seek care, given the extended
time (decades) from their initial vaccination, and the acutely ill presentation
of the reported cases, this seems to be an unlikely explanation.
These cases were diagnosed prior to the press release from the CDC on
March 25, 2003, which changed the vaccine eligible screening criteria and
highlighted the concerns for potential cardiac adverse effects after smallpox
vaccination.37 Recognition of potential cardiac
adverse events led to development of a case definition for myocarditis and
pericarditis and increased awareness by clinicians of this potential adverse
event following smallpox vaccination.38 Future
reports will include additional cases recognized subsequent to the change
in case definition along with follow-up of these cases and a case-control
study examining risk factors among the cases reported herein.
The generalizability of these findings from young adult military vaccinees
to the general US population is limited. Similar populations, such as police,
firefighters, or other first-responders, are prescreened and periodically
evaluated for good overall health and therefore may be the most appropriate
comparison group. Further investigation is ongoing to better define the occurrence
of myopericarditis following smallpox vaccination. It also will be important
to closely monitor the longer-term health of these cases, as studies have
indicated that viral myocarditis may result in long-term or permanent damage
to the heart.29,30
Implications of these findings for older individuals, or individuals
with preexisting cardiac morbidity, are unclear.39 Clinicians
treating patients with other complications from smallpox vaccination (eg,
encephalitis, generalized vaccinia, or eczema vaccinatum) may want to evaluate
patients for occult myopericarditis.2 Based
on reports of cardiac events following smallpox vaccination among military
and civilian vaccinees, the CDC has recommended additional exemptions based
on known cardiac disease or potential risk factors for cardiac disease.40
These findings are relevant to current policies and guidelines for vaccinating
military and civilian populations against smallpox. Although these cases all
recovered clinically from their acute illness, the potential long-term consequences
must be evaluated to know the true significance of myopericarditis following
vaccination. Furthermore, these findings suggest that myopericarditis following
smallpox vaccination is an expected adverse event. We project a morbidity
estimate of at least 78 cases of clinical myopericarditis per million primary
vaccinees in comparable adult populations. Myopericarditis following vaccination
should be considered in the differential diagnosis of patients with chest
pain 4 to 30 days following smallpox vaccination.
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