Myopericarditis Following Smallpox Vaccination Among Vaccinia-Naive US Military Personnel

ORIGINAL CONTRIBUTION

Jeffrey S. Halsell, DO Context In the United States, the annual incidence of myocarditis is estimated at 1 James R. Riddle, DVM, MPH to 10 per 100000 population. As many as 1% to 5% of patients with acute viral in- J. Edwin Atwood, MD fections involve the myocardium. Although many viruses have been reported to cause myopericarditis, it has been a rare or unrecognized event after vaccination with the Pierce Gardner, MD currently used strain of vaccinia virus (New York City Board of Health). Robert Shope, MD Objective To describe a series of probable cases of myopericarditis following small- Gregory A. Poland, MD pox vaccination among US military service members reported since the reintroduction of vaccinia vaccine. Gregory C. Gray, MD, MPH Design, Setting, Participants Surveillance case definitions are presented. The cases Stephen Ostroff, MD were identified either through sentinel reporting to US military headquarters surveillance Robert E. Eckart, DO using the Defense Medical Surveillance System or reports to the Vaccine Adverse Event Reporting System using International Classification of Diseases, Ninth Revision. The cases Duane R. Hospenthal, MD, PhD occurred among individuals vaccinated from mid-December 2002 to March 14, 2003. Roger L. Gibson, DVM, PhD Main Outcome Measure Elevated serum levels of creatine kinase (MB isoenzyme), John D. Grabenstein, RPh, PhD troponin I, and troponin T, usually in the presence of ST-segment elevation on electrocardiogram and wall motion abnormalities on echocardiogram. Mark K. Arness, MD, MTM&H Results Among 230734 primary vaccinees, 18 cases of probable myopericarditis af- David N. Tornberg, MD, MPH ter smallpox vaccination were reported (an incidence of 7.8 per 100000 over 30 days). and the Department of Defense No cases of myopericarditis following smallpox vaccination were reported among 95622 Smallpox Vaccination Clinical vaccinees who were previously vaccinated. All cases were white men aged 21 years to Evaluation Team 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 cluster- E REPORT THE FIRST 18 ing (7-19 days; mean, 10.5 days following vaccination), wide geographic and temporal cases of probable myo- distribution, occurrence in only primary vaccinees, and lack of evidence for alternative pericarditis following etiologies or other diseases associated with myopericarditis. Additional supporting evi- smallpox vaccination dence 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 amongW otherwise healthy, young adult among personnel who were not vaccinated. The background incidence of myopericar- members of the US military who were ditis did not show statistical significance when stratified by age (20-34 years: 2.18 ex- vaccinated between mid-December pected cases per 100000; 95% confidence interval [CI], 1.90-2.34), race (whites: 1.82 2002 and March 14, 2003 (N=326356; per 100000; 95% CI, 1.50-2.01), and sex (males: 2.28 per 100000; 95% CI, 2.04-2.54). 230734 primary vaccinees and 95622 Conclusion Among US military personnel vaccinated against smallpox, myopericar- revaccinees). Despite decades as the ditis occurred at a rate of 1 per 12819 primary vaccinees. Myopericarditis should be standard vaccine for US civilian and considered an expected adverse event associated with smallpox vaccination. Clini- military populations, the New York City cians should consider myopericarditis in the differential diagnosis of patients present- Board of Health (NYCBOH) strain of ing with chest pain 4 to 30 days following smallpox vaccination and be aware of the vaccinia virus (Dryvax, Wyeth Labo- implications as well as the need to report this potential adverse advent. ratories, Marietta, Pa) has only rarely JAMA. 2003;289:3283-3289 www.jama.com

See also pp 3278, 3290, 3295, Author Affiliations are listed at the end of this article. Skyline Six, Suite 682, 5111 Leesburg Pike, Falls Church, and 3306. Corresponding Author and Reprints: James R. Riddle, VA 22041-3206 (e-mail: [email protected] DVM, MPH, Armed Forces Epidemiological Board, .army.mil).

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dividual’s longitudinal health record, Box. Myopericarditis Following Smallpox Vaccination: which was maintained as part of the De- Adverse Event Surveillance Case Definitions fense Medical Surveillance System 25 Confirmed Myopericarditis Following Vaccination (DMSS). This system integrates data from sources worldwide in a continu- Patient with acute myocarditis* with or without pericarditis with symptom onset 4 to 30 days after vaccinia exposure and absence of another causal infection, dis- ously expanding relational database that ease or toxic agent and, virus culture or detection† of vaccinia DNA by polymer- documents the military and medical ex- ase chain reaction identification of vaccinia virus infection from myocardial tis- periences of service members through- sue or pericardial fluid (detection of viral nucleic acid in the myocardium is regarded out their careers. The DMSS allows as indicative of virus infection) nearly instantaneous assessments of the Probable Myopericarditis Following Vaccination morbidity experiences of service mem- Patient with acute myocarditis* with or without pericarditis with symptom onset bers who share common characteris- 4 to 30 days after vaccinia exposure and absence of another causal infection, dis- tics, such as vaccination. Statistical ease, or toxic agent analysis was performed using SAS ver- *Clinical diagnosis of myocarditis is confirmed by detection of elevated serum levels of cre- sion 8.02 (SAS Institute, Cary, NC). atine kinase (MB isoenzyme), troponin I, and troponin T, usually in the presence of ST- segment elevation on electrocardiogram and abnormal findings on echocardiogram. Case Identification †Whether vaccinial myopericarditis is a direct viral cytopathogenic effect or an immune- The cases presented herein were iden- mediated disease remains unclear. tified either through sentinel reporting to military headquarters and/or to the VAERS or through diagnostic sur- been associated with myopericarditis December 2002.24 To detect adverse veillance among vaccinees at military following vaccination. Only 5 cases events after vaccination, the Depart- treatment facilities using International were reported in the medical litera- ment of Defense and the US Coast Guard Classification of Diseases, Ninth Revi- ture between 1955 and 1986.1-8 require reporting to the Vaccine Ad- sion (ICD-9)26 coded diagnoses (420.90, Myocarditis and pericarditis follow- verse Event Reporting System (VAERS) 420.99, other and unspecified acute ing vaccination have been reported more using established guidelines. Addition- pericarditis; 422.90, 422.91, other and commonly with other vaccinia virus ally, the Department of Defense encour- unspecified acute myocarditis; and strains,9-17 may be associated with other ages clinicians to report all other clini- 429.0 myocarditis unspecified) ob- adverse events following vaccination,2 cally relevant adverse events after tained from the DMSS. Fifteen cases and may be asymptomatic.10,18-20 In 1968, administration of any vaccine or medi- were first identified from surveillance Price and Alpers14 noted that minor car- cation to VAERS or MedWatch (US Food of military treatment facilities, and only diac complications after smallpox vac- and Drug Administration Safety Infor- 3 cases were first identified from the cination may be more common than is mation and Adverse Event Reporting VAERS. The cases were classified based generally reported. Six years earlier, Program). To heighten awareness of po- on surveillance case definitions shown MacAdam and Whitaker21 reported 3 tential adverse events, including car- in the BOX. Clinical diagnosis of myo- cases of cardiac complications 5 to 14 diac events, clinicians were provided ex- carditis was based on detection of el- days following smallpox vaccination and tensive education and vaccinees were evated serum levels of creatine kinase suggested that cardiac complications had individually counseled and provided (MB isoenzyme), troponin I, and tro- been previously overlooked. In 1983, the educational material. An Internet site ponin T, usually in the presence of ST- incidence of myocarditis following vac- providing access to a comprehensive ar- segment elevation on electrocardio- cination among Finnish military con- ray of materials and ongoing program gram and wall motion abnormalities on scripts who were hospitalized with mild status was established (http://www echocardiogram. myocarditis following vaccination with .smallpox.army.mil/). the Finnish strain of smallpox had been A 3-pronged approach was imple- RESULTS estimated to be as high as 1 per 10000.22 mented for surveillance and patient Clinical and diagnostic details for the 18 As early as 1953, Mathieu and Hadot23 safety following vaccination, as de- cases of probable myopericarditis fol- recommended screening for cardiac risk scribed by Grabenstein and Winken- lowing smallpox vaccination reported factors before vaccination, especially in werder24 elsewhere in this issue of THE among 230734 primary vaccinees (71% individuals aged 50 years or older. JOURNAL. Standard documentation was of vaccines) are presented in the TABLE. used to record screening results, vac- No cases were detected among 95622 METHODS cination delivery, vaccination revaccinees who were previously vacci- Surveillance for Adverse Events sponse, and adverse event manage- nated. All cases were military person- A program to vaccinate up to 500000 US ment. Vaccination was recorded nel in active duty who received vaccina- military personnel was launched mid- electronically as a component of the in- tion with the NYCBOH strain of vaccinia

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Table. Relevant Findings Among 18 Primary Vaccinee Cases With Probable Myopericarditis Following Smallpox Vaccination Among US Military Personnel Cardiac After Smallpox and Other Enzymes Infectious Disease Vaccination, Vaccines Administered ECG ECHO Positive Peak Laboratory Evaluation Case d Within 30 d Viral Prodrome Chest Pain Findings Findings Levels* Results† 1 11 1/25/03: smallpox Myalgias, Substernal ST-segment Low normal LV CK-MB, 48.6; Serum: hepatitis panel 1/23/03: meningococcal arthralgias, elevation systolic troponin I, negative; CBC and and anthrax lymphade- function; 14.76 metabolic panel normal; 1/29/03: MMR nopathy EF, elevated liver enzymes: 50%-55% AST, 94 (normal, 5-45 IU/L); ALT, 66 (normal, 7-56 IU/L); ESR elevated: 30 (normal, 0-15 mm/h) CSF: none Other: none 2 7 1/31/03: smallpox Fever (38.5°C), Better with Normal EF, 50%; CK-MB, 8.0; Serum: coxsackie A and B chills, bending improved troponin I, virus, HIV, hepatitis A, B, headache, forward later to 59% 1.31 and C, Lyme Ab, ANA, stiff neck, RF, ASO: negative, myalgias acute, and convalescent; Adenovirus CF Ab unremarkable; DNAse B Ab unremarkable CSF: viral culture negative, Shell vial culture for Enterovirus, HSV, and CMV negative Other: nasal wash viral culture negative 3 8 2/05/03: smallpox, Fever Squeezing, ST-segment Normal CK-MB, 22.3; Serum: influenza A and B, anthrax, influenza, (subjective), pleuritic, elevation troponin I, RPR, ANA, HIV, hepatitis typhoid (parenteral) sore throat, reproduced 3.0 profile, RF, viral cultures, myalgias by touch PPD, CBC, metabolic panel normal, C-reactive protein, 1.1 (normal Ͻ1 mg/dL), ESR, 26 (normal 0-15 mm/h) CSF: none Other: none 4 11 2/08/03: smallpox Fever Radiation to ST-segment Pericardial CK-MB, 133 Serum: baseline laboratory (subjective), neck elevation effusion = 4 results (chem7, CBC, myalgias, mm LFT, and coagulation arthralgias, studies) normal; headache C-reactive protein, 42 (normal 0-1 mg/dL) CSF: none Other: normal cardiac catherization 5 10 2/13/03: smallpox Recent upper Pleuritic ST-segment Normal CK-MB, 33; Serum: CBC, ESR, and 2/07/03: anthrax respiratory elevation troponin T, metabolic panel normal; 2/26/03: anthrax tract 1.3 PCRs and cultures for symptoms enteroviruses and vaccinia negative CSF: none Other: none

6 7 2/27/03: smallpox Chills, night Worse with ST-segment Mild global CK-MB, 55; Serum: C3/C4, CH50 levels, and anthrax sweats movement elevation hypokinesis: troponin I, C1q assay, Raji cell LVEF, 97.2 assay for circulating 50%-55% immune complexes, RF, ANA, all normal; PCRs and cultures for enteroviruses and vaccinia, negative CSF: none Other: none 7 11 2/27/03: smallpox Fever Pleuritic ST-segment Small pericardial CK-MB, 46.4 Serum: hepatitis panel (subjective), elevation effusion negative except for HBs chills, Ab positive (previous sweating hepatitis B vaccine); CBC normal CSF: none Other: none 8 10 2/13/03: smallpox Myalgias, fever Pleuritic ST-segment Normal Troponin I, 7.7 Serum: C-reactive protein 2/06/03: anthrax (subjective), elevation and ANA normal, Lyme 2/20/03: anthrax arthralgias titers negative CSF: none Other: none (continued)

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Table. Relevant Findings Among 18 Primary Vaccinee Cases With Probable Myopericarditis Following Smallpox Vaccination Among US Military Personnel (cont) Cardiac After Smallpox and Other Enzymes Infectious Disease Vaccination, Vaccines Administered ECG ECHO Positive Peak Laboratory Evaluation Case d Within 30 d Viral Prodrome Chest Pain Findings Findings Levels* Results† 9 12 2/28/03: smallpox, Recent upper Pleuritic ST-segment Mild LV Troponin I, 22.5 Serum: metabolic panel, CBC, anthrax, hepatitis B, respiratory elevation dysfunction; C1q assay, C3/C4, CH50 hepatitis A, tract LVEF, 45% levels, ANA, RF, all influenza, polio (IPV), symptoms normal; C-reactive protein, meningococcal, 3 (normal, 0-1 mg/dL) typhoid (parenteral) CSF: none Other: none 10 12 3/05/03: smallpox None reported Pleuritic and ST-segment Normal Troponin T, Serum: CBC, metabolic panel, positional elevation 0.395 LFTs, TSH, all normal; ESR, 35 (normal, 0-15 mm/h) CSF: none Other: none 11 19 3/08/03: smallpox, Fever, Positional ST-segment Low EF, 37% Troponin T, 9.2 Serum: multiple heart biopsy anthrax, hepatitis B, arthralgias, elevation specimens negative by hepatitis A, dry cough PCR for vaccinia influenza, CSF: none typhoid (ViCPs) 3/24/03: anthrax Other: cardiac biopsy pathological results consistent with eosinophilic myocarditis 12 12 3/13/03: smallpox Myalgias Pleuritic ST-segment Low normal CK-MB, 76.6; Serum: acute and 1/16/03: typhoid (ViCPs) elevation LVEF, troponin I, convalescent viral titers 50%-55% 150 negative; C3/C4, C1q assay, CH50, interleukin-6, Rajii cell assay, C-reactive protein, negative CSF: none Other: none 13 14 1/30/03: smallpox Recent upper Substernal ST-segment Normal Troponin I, 30 Serum: CBC, metabolic panel, 1/17/03: anthrax respiratory elevation INR, lipid panel, protein tract electrophoresis, TSH, symptoms normal; C-reactive protein, 12 (normal, 0-1 mg/dL) CSF: none Other: none 14 7 3/06/03: smallpox None reported Left axillary Normal Normal Troponin I, 0.73 Serum: none CSF: none Other: none 15 7 3/14/03: smallpox Headache, Substernal ST-segment Low normal Troponin I, 15 Serum: CBC normal fatigue elevation LVEF, 50% CSF: none Other: none 16 8 3/14/03: smallpox Chills, Substernal with ST-segment Inferior wall Troponin I, 1.99 Serum: CBC, metabolic panel, adenopathy radiation depression hypokinesis lipid panel, drug down both assays/toxicology, normal arms CSF: none Other: none 17 12 3/04/03: smallpox None reported Substernal ST-segment Normal Troponin I, 139; Serum: CBC, metabolic panel, 2/18/03: anthrax elevation CK-MB, 93 normal 2/06/03: anthrax CSF: none 2/03/03: meningococcal Other: none 18 11 2/14/03: smallpox Muscle aches, Substernal with ST-segment Small pericardial Troponin I, 3.23 Serum: CBC, metabolic panel, and anthrax elevated radiation to elevation effusion ANA, anti-DNA, temperature right with mild anti-cardiolipin, serum scapula inferior electroimmunoelectropho- hypokinesis resis, normal; C-reactive protein, 8.03 (normal, 0-0.94 mg/dL) CSF: none Other: none Abbreviations: ALT, alanine aminotransferase; ANA, antinuclear antibody; ASO, anti-streptolysin O; AST, aspartate aminotransferase; C3/C4, complement factor 3/complement factor 4; CBC, complete blood cell count; CFS, cerebrospinal fluid; CF, complement fixation; CK-MB, creatine kinase MB isoenzyme; CH50, total hemolytic complement; ECG, electrocardiogram; ECHO, echocardiograph; EF, ejection fraction; ESR, erythrocyte sedimentation rate; HBsAg, hepatitis surface antigen; HIV, human immunode- ficiency virus; INR, international normalized ratio; IPV, injectable polio vaccine; LFT, liver function tests; LV, left ventricular; LEVF, left ventricular ejection fraction; MMR, measles- mumps-rubella; PCR, polymerase chain reaction; RF, rheumatoid factor; TSH, thyrotropin; ViCPs, Vaccine Injury Compensation Programs. *Troponin I and troponin T activity and CK-MB are reported in ng/mL. †Metabolic panel includes serum sodium, potassium, chloride, CO2, blood urea nitrogen, creatinine, glucose, and calcium concentrations. Hepatitis panel includes hepatitis B surface antigen, hepatitis C antibody, hepatitis B surface antibody, and hepatitis B core antibody. Chem 7 includes sodium, potassium, chloride, CO2, blood urea nitrogen, creatinine, and glucose.

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virus in various regions of the United with 2.18 expected cases per 100000 for guidelines for evaluating patients and States, Europe, and the Middle East. All ages 20 years to 34 years (95% CI, 1.90- clinical policy to increase clinician cases were white (73% of total vaccinees), 2.34); 1.82 expected cases per 100000 awareness. men (78% of total vaccinees), aged 21 for whites (95% CI, 1.50-2.01), and 2.28 years to 33 years (mean age, 26.5 years; expected cases per 100000 for males COMMENT 59% of total vaccinees were aged 21-35 (95% CI, 2.04-2.54). Viral myocarditis is an inflammatory years), with disease onset 7 to 19 days The expected number of myoperi- disorder of the myocardium character- following vaccination (mean, 10.5 days). carditis cases in the population of ized by injury of myocytes with asso- Typical clinical presentation involved 230734 primary vaccinees was calcu- ciated inflammatory infiltrate.28 Often prodromal myalgias; arthralgias; subse- lated by applying the background rate pericarditis and myocarditis are ob- quent pleuritic, precordial chest pain; and estimate of 2.16 to this population, served in tandem, hence the term myo- variable shortness of breath and/or dry which yielded 4.98 expected cases (95% pericarditis.29 Clinical diagnosis is sug- cough. All vaccinees had elevated se- CI, 4.38-5.40). The 18 cases reported gested by detection of elevated serum rum cardiac enzyme levels; 15 of the 18 herein represent an unadjusted esti- levels of myocardial enzymes (cre- cases had ST-segment elevation changes mate of relative risk (RR) of 3.61 (95% atine kinase-MB isoenzyme, troponin on electrocardiogram, and 11 of the 18 CI, 3.33-4.11; Poisson distribution) I, and troponin T), usually in the pres- cases had abnormal echocardiogram over the expected incidence of myo- ence of nonspecific electrocardio- findings (ie, wall motion abnormalities). pericarditis. graphic changes and/or focal or gener- Biopsy of myocardial tissue was per- alized wall motion abnormalities on formed in only 1 case; the results re- Etiologic Summary of Cases echocardiography.18,30 In most cases, an vealed histological evidence of eosino- The lack of clinical suspicion for myo- etiology is not determined, but in cases phil infiltration of the myocardium, pericarditis following vaccination, no in which a causative infectious agent has eosinophil degranulation, secretion of standard evaluation protocol, and the been identified, viral agents are most major basic protein in close apposition varied capability of the medical sites common, particularly the enterovirus to myocyte necrosis, and IL-5 genera- where these cases presented resulted group (predominantly coxsackie B tion. No cases were confirmed by viral in variable diagnostic workup for etio- virus), adenoviruses, and influenza A.31 diagnosis. All cases had a characteristic logic causes. In none of the cases was Diagnosis may be confirmed using his- primary vaccination response at the in- infection of myocardial tissue or peri- topathological and/or viral identifica- oculation site as defined by the World cardial fluid with the vaccinia virus tion by polymerase chain reaction from Health Organization.27 Results of sero- confirmed using virus culture or by endomyocardial biopsy or autopsy logic laboratory tests, when done, did not detection of vaccinia DNA by poly- specimens.28,30 Whether myopericardi- indicate the presence of other infec- merase chain reaction. Among this tis following smallpox vaccination is a tious etiologies or host conditions pre- case series, when serologic testing was direct viral cytopathic effect or an im- disposing to myopericarditis. All cases done, findings have been negative for mune-mediated phenomenon re- survived and all returned to duty or are coxsackie A and B viruses, as well as mains unclear. on short-term convalescent leave. hepatitis B and C, HIV, Borrelia burg- Longer-term follow-up to detect pos- dorferi, and Streptococcus pyogenes (by Association of Myopericarditis sible sequelae is underway. antistreptolysin O and anti-DNAse B). With Vaccinia Virus The 18 cases among 230734 pri- Viral cultures of nasal wash from 1 Vaccinia virus has long been associ- mary vaccinees represent an incidence patient recovered no adenovirus or ated with myopericarditis.28,29,32 How- of 7.80 per 100000 over a 30-day ob- influenza viruses. Results of cerebro- ever, only 1 previous report has de- servation window. The background in- spinal fluid viral cultures from the scribed the pathological characteristics cidence of myopericarditis in all ser- same patient were negative, including of myopericarditis following smallpox vice members on active duty is 2.16 cases a shell viral culture that tests specifi- vaccination; the histological changes in- (95% confidence interval, [CI], 1.90- cally for enteroviruses, herpes simplex cluded a mixed mononuclear infil- 2.34; Poisson distribution) per 100000 viruses, and cytomegalovirus. Results trate.33 This case series of probable myo- over any 30-day period. This incidence of serum antinuclear antibody from 6 pericarditis associated with the New was calculated using 2002 calendar year patients and rheumatoid factor from 4 York City Board of Health strain of vac- DMSS data for all services for the above patients also were negative. To address cinia virus serves to establish an ex- described 5 myopericarditis ICD-9 di- the variability in etiologic diagnosis pected baseline rate for myopericardi- agnoses among a population of 1399739 given the unexpected occurrence of tis following vaccination in primary persons. When stratified by age, race, these probable cases of myopericardi- vaccinees. The cases reported herein oc- and sex, the background incidence rates tis following vaccination, the Depart- curred only in otherwise healthy, in all service members of myopericar- ment of Defense Vaccine Healthcare young, white adult men who were care- ditis were not statistically significant, Center Network is developing clinical fully screened for conditions that might

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preclude vaccination. The cases re- Study Limitations reports will include additional cases rec- ported were moderate to severe in clini- Potential bias exists for both underre- ognized subsequent to the change in case cal presentation, and our observed in- porting and overreporting of cases. Al- definition along with follow-up of these cidence of myopericarditis likely though extensive efforts have been made cases and a case-control study examin- represents a minimum, with milder to identify all cases, underreporting bias ing risk factors among the cases re- cases unrecognized. may result from incomplete ascertain- ported herein. The close temporal clustering follow- ment of cases with myopericarditis fol- The generalizability of these find- ing vaccination (7 to 19 days; mean 10.5 lowing smallpox vaccination, consider- ings from young adult military vaccin- days), the wide geographic and tempo- ing the reported mild-to-moderate acute ees to the general US population is lim- ral distribution during the vaccination presentation and clinical course,10 and ited. Similar populations, such as police, program, and the lack of alternative di- the necessity of an index of suspicion to firefighters, or other first-responders, agnoses, provide epidemiologic evi- pursue an association. The generalized are prescreened and periodically evalu- dence for an association between small- lack of clinical suspicion, exemplified by ated for good overall health and there- pox vaccination and myopericarditis. only 3 cases initially being reported fore may be the most appropriate com- Additional supporting evidence is the ab- through the VAERS, argues against over- parison group. Further investigation is sence of myopericarditis in revaccinees reporting of myopericarditis among vac- ongoing to better define the occur- and the observation that the observed cinees resulting from a case-ascertain- rence of myopericarditis following rate of myopericarditis among primary ment bias of clinicians. Ascertainment smallpox vaccination. It also will be im- vaccinees is 3.6-fold higher than the ex- bias among vaccinees that resulted in portant to closely monitor the longer- pected rate among personnel on active overreporting (eg, the inference that in- term health of these cases, as studies duty who were not vaccinated. How- dividuals with chest pain after small- have indicated that viral myocarditis ever, some covariates could confound pox vaccination may be more likely to may result in long-term or permanent this rate comparison, and a multivari- seek care) also is unlikely, given the damage to the heart.29,30 ate statistical model in a case-control moderate-to-severe clinical presenta- study design is needed. Myopericardi- tion of the reported cases. The absence Implications tis due to a synergistic inflammatory of cases in this study among revaccin- Implications of these findings for older effect of multiple vaccines cannot be ex- ees, females, and nonwhite males is dif- individuals, or individuals with preex- cluded. Exertion may have predisposed ficult to explain from a purely epide- isting cardiac morbidity, are un- these military personnel to viral myo- miologic perspective. The Centers for clear.39 Clinicians treating patients with carditis, as exertion has been associated Disease Control and Prevention (CDC) other complications from smallpox vac- with increased viral titer and inflamma- has reported myopericarditis following cination (eg, encephalitis, generalized tion of the heart in experimental ani- smallpox vaccination in females, al- vaccinia, or eczema vaccinatum) may mal models.34,35 It is possible that the oc- though the CDC case definition dif- want to evaluate patients for occult currence of myopericarditis following fered from that used to classify the cases myopericarditis.2 Based on reports of vaccination may represent coincidental reported herein.36 Although revaccin- cardiac events following smallpox outcomes; however, the data linking ees might be expected to be more aware vaccination among military and civil- myopericarditis with smallpox vaccine of the potential adverse effects from this ian vaccinees, the CDC has recom- seem the most likely explanation. vaccine and thus be less likely to seek mended additional exemptions based Clinicians should be alert to the care, given the extended time (de- on known cardiac disease or potential potential occurrence and implications cades) from their initial vaccination, and risk factors for cardiac disease.40 of myopericarditis among adult pri- the acutely ill presentation of the re- These findings are relevant to cur- mary vaccinees after receiving small- ported cases, this seems to be an un- rent policies and guidelines for vacci- pox vaccination, and they should likely explanation. nating military and civilian popula- report these adverse events to the These cases were diagnosed prior to tions against smallpox. Although these VAERS. Patients with a clinical suspi- the press release from the CDC on March cases all recovered clinically from their cion of myopericarditis based on 25, 2003, which changed the vaccine eli- acute illness, the potential long-term decreased ventricular function on ech- gible screening criteria and highlighted consequences must be evaluated to ocardiography, a markedly elevated the concerns for potential cardiac ad- know the true significance of myoperi- troponin levels suggestive of signifi- verse effects after smallpox vaccina- carditis following vaccination. Further- cant myocyte injury or a cardiac mag- tion.37 Recognition of potential cardiac more, these findings suggest that myo- netic resonance imaging positive scan adverse events led to development of a pericarditis following smallpox for myocarditis may be indicated to case definition for myocarditis and peri- vaccination is an expected adverse event. undergo endomyocardial biopsy. carditis and increased awareness by cli- We project a morbidity estimate of at Biopsy specimens should be tested for nicians of this potential adverse event fol- least 78 cases of clinical myopericardi- the presence of vaccinia virus. lowing smallpox vaccination.38 Future tis per million primary vaccinees in com-

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parable adult populations. Myopericar- Jeffrey L. Lange, PhD (Army Medical Surveillance Ac- without subjective symptoms after smallpox vaccina- tivity, Washington, DC). tion of military personnel. Acta Med Scand Suppl. 1966; ditis following vaccination should be Funding/Support: This study was supported by the 464:127-134. considered in the differential diagnosis Department of Defense, Defense Health Program. 20. Heikkila J, Karjalainen J. Evaluation of mild acute Disclaimer: The views expressed in this article are those infectious myocarditis. Br Heart J. 1982;47:381-391. of patients with chest pain 4 to 30 days of the authors and do not reflect the official policy or 21. MacAdam D, Whitaker W. Cardiac complica- following smallpox vaccination. position of the Department of the Defense or the US tions after vaccination for smallpox. BMJ. 1962;2: Government. This work is approved for public release. 1099-1100. Author Affiliations: The University of Virginia, Char- Acknowledgment: We are indebted to the astute cli- 22. Karjalainen J, Heikkila J, Nieminen MS, et al. Eti- lottesville (Dr Halsell); Office of the Assistant Secre- nicians for diligent assistance in case investigations, ology of mild acute infectious myocarditis: relation to tary of Defense for Health Affairs, Falls Church, Va to their patients who are represented in this case se- clinical features. Acta Med Scand. 1983;213:65-73. (Drs Riddle, Gibson, and Tornberg); Walter Reed Army ries, the Walter Reed Army Medical Center Vaccine 23. Mathieu L, Hadot S. Vaccination antivariolique et Medical Center, Washington, DC (Dr Atwood); Mili- Healthcare Center Network, and to Kim S. Zabel for thromboses coronarienne aigue. Arch Mal Coeur Vaiss. tary Vaccine Agency, US Army Medical Command, assistance with manuscript preparation. 1953;48:802-806. Falls Church, Va (Dr Grabenstein); National Insti- 24. Grabenstein JD, Winkenwerder W. 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