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Update: Cardiac-Related Events During the Civilian Smallpox Vaccination Program --- United States, 2003
During the pre-event smallpox vaccination program, the U.S. Department of Defense (DOD) and CDC have received reports of cardiac events after vaccination. A case definition for myo/pericarditis as a smallpox vaccine--associated adverse event has been developed in conjunction with DOD, the joint Smallpox Vaccine Safety Working Group of the Advisory Committee on Immunization Practices (ACIP) and the Armed Forces Epidemiology Board (AFEB), and consulting cardiologists, immunologists, and epidemiologists. The term myo/pericarditis is used for surveillance purposes to refer to patients who have myocarditis, pericarditis, or both (myopericarditis). Myo/pericarditis cases are classified into suspected, probable, and confirmed categories. Suspected cases include those that are investigated and reported, although the level of certainty for the diagnosis is lower. These definitions were used to categorize all cardiac-related reports among civilian vaccinees received through May 9, 2003; a total of 21 cases of myo/pericarditis were ascertained. All have been reported previously (1--6); however, some have been reclassified. In addition, nine cases of ischemic cardiac events (i.e., myocardial infarction [MI] or angina) among civilian vaccinees have been reported previously (1--6). This report includes the case definition of myo/pericarditis and updates information on all reports of cardiac adverse events among 36,217 civilian vaccinees since the beginning of the civilian smallpox vaccination program reported through May 9 to CDC from the Vaccine Adverse Event Reporting System (VAERS).
In reports about the civilian program published previously, cases classified as myopericarditis included those occurring in persons reported to have chest pain and electrocardiogram (ECG) changes (e.g., ST-segment and T-wave abnormalities) within 30 days of vaccination without evidence of other causes (1--5). However, because myocarditis, which indicates inflammation of the myocardium and/or the myocardial conduction system, might manifest with dysrhythmias, the myo/pericarditis case definition now includes dysrhythmias as a clinical criterion (Box. The seven cases of dysrhythmias reported included two persons with atrial fibrillation, one with atrial ectopy and paroxysmal atrial fibrillation, one with supraventricular tachycardia, and three with frequent or sustained premature ventricular contractions (PVCs).
Among the 21 myo/pericarditis cases reported through May 9, a total of 15 had presentations consistent with the myocarditis component of the case definition (12 suspected and three probable), and six had presentations consistent with the pericarditis component (three suspected and three probable). Of the 21 myo/pericarditis patients, 19 (90%) were known to be revaccinees, and 15 (71%) were female; the median age was 48 years (range: 29--61 years). The median interval from vaccination to symptom onset was 12 days (range: 1--42 days). Three cases occurred within 4 days of vaccination; 11 (52%) persons were hospitalized, and six (29%) were evaluated in an emergency department (ED) without subsequent hospitalization. Among 18 patients with known echocardiogram results, six (29%) had findings that were consistent with myo/pericarditis: three with pericardial effusion and three with focal hypokinesis, two of which resolved on follow-up echocardiogram. Among 16 patients who had cardiac enzyme levels determined, one patient had elevated creatine kinase myocardial band (CK-MB) fractions but normal troponin levels. No fatalities occurred, and all patients have since recovered. Two representative cases of patients with dysrhythmias are described below.
Case 1. On March 25, a woman aged 56 years was revaccinated; 12 days later, she had lightheadedness, fatigue, and pedal edema, and she later noted an irregular heart beat and new onset of dyspnea with exertion. She was evaluated by her primary-care physician and was found to have PVCs but an otherwise normal ECG. Ambulatory cardiac monitoring showed frequent PVCs (16% of QRS complexes) with frequent trigeminy. Symptoms worsened, and 22 days after vaccination, she was evaluated in an ED and hospitalized. She had elevated blood pressure (140/100 mm Hg). An ECG indicated nonspecific ST-segment changes. An echocardiogram revealed normal left-ventricular function (ejection fraction: 55%), and cardiac enzyme levels were normal. A thallium exercise stress test showed no evidence of ischemia or myocardial scarring. Treatment for the palpitations and hypertension was started, and the patient was discharged. As of May 27, the frequency of PVCs had decreased with no trigeminy, and the patient had returned to work.
Case 2. On March 11, a woman aged 52 years was vaccinated; 22 days after vaccination, she had a slight cough, malaise, weakness, and palpitations, and vomited twice. She had no other abdominal symptoms and reported no chest pain, shortness of breath, or diaphoresis. Medical history was positive for hypertension and hyperlipidemia controlled with amlodipine, hydrochlorothiazide, and pravastatin. On examination in the ED, her pulse was 120 beats per minute and irregular; other vital signs and the physical examination were normal. An ECG indicated atrial fibrillation and nonspecific ST-segment and T-wave changes; the patient's rhythm converted spontaneously to normal sinus rhythm while in the ED. Routine blood count and blood chemistries, including thyroid-stimulating hormone, were within normal limits; cholesterol level was slightly elevated. Total creatine kinase and troponin levels were normal; however, CK-MB fraction was elevated on three occasions. ECG indicated normal sinus rhythm and an echocardiogram showed normal left-ventricular chamber size and function with mild left-ventricular hypertrophy. No wall-motion abnormalities or effusion were noted; heart valves were normal, and the ejection fraction was 55%--60%. The patient had a diagnosis of new-onset atrial fibrillation and suspected myocarditis. After 3 weeks, the patient returned to work, complaining of persistent fatigue but without recurrence of palpitations.
Ischemic Cardiac Events
As of May 9, nine cases of ischemic events had been reported; six persons had evidence of MI, and three had angina. All persons for whom information was available were revaccinees (n = eight). Three were female, and the median age was 57 years (range: 46--65 years). Two female patients with MI, aged 55 and 57 years, died; both patients had been reported previously (1--2). The median interval between vaccination and symptom onset was 10 days (range: 0--26 days); seven events occurred within 3 weeks of vaccination. Six (67%) persons had histories of MI, angina, or exertional chest pain before vaccination and probably would not have been vaccinated if the exclusionary guidelines approved by the ACIP (published March 28 and revised April 4) (1,7) had been in place at the time of their vaccinations. One of the remaining three patients had a history of diabetes mellitus and hypertension, one had hypertension, and one had no known cardiac risk factors. As of May 9, no ischemic cardiac events had been reported among persons vaccinated since the new exclusionary criteria were established.
Background rates of cardiac ischemic events were used to determine if ischemic cases occurred at higher-than-expected rates. Data from three population-based cohort studies were used: the Framingham Offspring Cohort study, the Atherosclerosis Risk in Communities study, and the Coronary Artery Disease Risk Development in Young Adults study. The expected numbers of ischemic events were determined for a 3-week period, considered to be the perivaccination interval, and were based on the age and sex distributions of civilian vaccinees as of May 12. Patients who had ischemic events >3 weeks after vaccination (n = two) and persons with angina who had pre-existing chest pain (n = one) were excluded. Preliminary analysis indicates that the number of observed MIs (n = five) was higher than the two that would be expected (95% predictive interval [PI] = 0.6--5.4) but not greater than the upper 95% PI, and that the number of patients (n = one) with angina within the time interval was fewer than the 10 that would be expected (95% PI = 3.5--15.7).
Reported by: Smallpox vaccine adverse events coordinators. Military Vaccine Agency, Army Medical Command, U.S. Dept of Defense. National Immunization Program, CDC.
The case definition for myo/pericarditis presented in this report is intended for surveillance purposes and not for use in individual diagnosis or treatment decisions. A total of 21 cases were reported by using this definition. Myo/pericarditis following smallpox vaccination is consistent with previous reports describing a likely causal association between vaccination and myo/pericarditis (1,2,8--10). The association between ischemic cardiac events and smallpox vaccination is unclear.
Reports now categorized as myo/pericarditis include patients with dysrhythmias, which have been reported previously in association with smallpox vaccination (9,10). Although the majority of patients in general clinical practice who have dysrhythmias do not have underlying myo/pericarditis, dysrhythmias can be a manifestation of myo/pericarditis and are therefore included. Among smallpox vaccinees, only cases of dysrhythmia for which alternative causes are excluded are categorized as myo/pericarditis.
The rate of myo/pericarditis reported in the civilian program, including suspected and probable cases (approximately 1:1,700 vaccinees), is higher than that reported in the military program (approximately 1:12,000 vaccinees) on the basis of one suspected case, 35 probable cases, and one confirmed case among 449,198 military vaccinees. Of the 37 cases in the military program, 36 identified by DOD manifested elevated cardiac enzymes (DOD, unpublished data, 2003). Only one of the patients with myo/pericarditis reported in the civilian program had elevated cardiac enzymes, yielding a rate of 1:36,000 vaccinees, which is closer to the rate among military vaccinees.
An investigation is in progress to determine if the ischemic cases in the civilian program are associated with vaccination. Surveillance for adverse cardiac events continues. Guidelines for evaluation and follow-up of patients with myo/pericarditis have been drafted, and studies to evaluate possible biologic mechanisms for cardiac adverse events following smallpox vaccination are being considered.
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