Costochondritis

During January 24-March 28, 2003, smallpox vaccine was administered to 29,584 civilian health-care and public health workers in 54 jurisdictions as part of an effort to prepare the United States for a terrorist attack using smallpox virus. This report summarizes data on ten cases of cardiac adverse events reported among civilian vaccinees since the beginning of the smallpox vaccination program, including three new cardiac adverse events reported to CDC from the Vaccine Adverse Event Reporting System (VAERS) during March 24-30. Fourteen cases of myocarditis and one fatal myocardial infarction have been reported among military personnel. This report summarizes data on the three new cases of cardiac adverse events, updates data on seven previously reported cases among civilian vaccinees (Table 1) (1), summarizes selected cases of cardiac adverse events among military vaccinees, and updates information on all adverse events reported in the civilian vaccination program as of March 30.

CDC, the Food and Drug Administration, and state health departments are conducting surveillance for vaccine-associated adverse events among civilian vaccinees; the Department of Defense (DoD) is conducting surveillance for vaccine-associated adverse events among military vaccinees. In the first stage of the civilian program, active surveillance is being conducted for any adverse events after vaccination that require medical care. In the military vaccination program, military personnel receive medical care primarily in a network of linked clinics, which report adverse events to medical headquarters and VAERS.

Civilian Case Reports

The three new cases of cardiac adverse events among civilians during March 24-30 include two cases of myopericarditis and one case of myocardial infarction (Table 1).

Case 1. A man aged 56 years with a history of mild hypertension and hypertriglyceridemia was revaccinated on March 4. On March 16, he had onset of influenza-like illness (ILI), chest discomfort while lying flat, and pleuritic pain during inspiration; a clinical examination revealed tachycardia. During the next 7 days, he had chest pain, dyspnea on exertion, fever, chills, pallor, and left knee pain. All symptoms and signs had resolved 17 days after vaccination. On day 23 post vaccination, an electrocardiogram (ECG) indicated low R waves in the anterior leads, and borderline first-degree AV block (PR interval: 0.21 sec). Echocardiogram revealed widening of the pericardial space with minimal fluid collection, a normal ejection fraction, and normal ventricular wall function. Chest radiograph demonstrated left basilar atelecrasis. The patient had normal troponin I, creatine kinase myocardial band (CK-MB), C-reactive protein levels, and a normal erythrocyte sedimentation rate. These findings are consistent with mi ld myopericarditis. The patient recovered; a followup exercise cardiac perfusion scan was normal.

Case 2. A woman aged 32 years with no history of cardiac disease or major risk factors for coronary artery disease was vaccinated for the first time on January 31. On February 16, she had fever, crushing-type chest pain, and shortness of breath, which prompted a visit to the emergency department (ED). An ECG indicated nonspecific ST-T wave changes; cardiac enzymes were normal. A repeat ECG several days later was normal. After 5-6 days, her symptoms resolved completely, and she was able to resume normal activities. Six weeks after vaccination, a nuclear stress test was normal. Her clinical course and ECG findings were consistent with myopericarditis.

Case 3. An active man aged 64 years with a history of dyspnea on exertion and productive cough for 3 months and eight previous smallpox vaccinations was revaccinated on March 21. On March 23, he sought medical care for chest "fullness" and dizziness. Blood tests indicated elevated troponin I and CK-MB levels. ECG demonstrated inferior ST segment depression and T wave inversion. Echocardiography indicated moderate inferior wall hypokenesis with a normal ejection fraction. Coronary arteriography showed three-vessel atherosclerotic disease with development of some collateral circulation. The patient underwent cardiac catheterization with ballon atherotomy, and two coronary artery stents were placed. The clinical course and laboratory findings are consistent with acute myocardial infarction in a patient with chronic coronary artery disease. He returned to work on March 31.

Update on Previous Civilian Cardiac Adverse Events

On March 23, a woman aged 55 years with a history of hypertension, hypercholesterolemia, and smoking died 5 days after smallpox vaccination (1). Autopsy showed extensive atherosclerotic disease, with right coronary artery thrombosis and lateral wall softening. Preliminary testing, including real-time polymerase chain reaction (PCR) and immunohistochemistry, showed evidence of vaccinia virus only at the vaccination site; limited analyses of other tissues, including heart and other visceral tissue, were negative for vaccinia virus by real-rime PCR and immunohistochemistry.

On March 26, a woman aged 57 years with a history of smoking, hypertension, transient ischemic attack, and carotid endarterectomy died 22 days after smallpox vaccination (1). Autopsy showed extensive atherosclerosis of the coronary arteries, and a large healing infarct involving the posterior wall of the left ventricle and intraventricular septum. Histopathologic evaluation revealed no evidence of myocarditis or pericarditis. Preliminary analysis using real-time PCR tests showed evidence of vaccinia virus DNA at the vaccination site but not in affected myocardium and other viscera.

Military Case Reports

During March 25-31, four cases of myocarditis and/or pericarditis were identified, totaling 14 cases among approximately 250,000 personnel who received smallpox vaccination for the first time. No cases of myocarditis and/or pericarditis were identified among approximately 115,000 service members who were revaccinated. Among the approximately 365,000 vaccinated military service members, one death has been reported.

The 14 patients with myocardiris and/or pericarditis ranged in age from 21 to 33 years. Severity ranged from mild (no ECG or echocardiogram changes) to severe (congestive heart failure), with onset 7 to 19 days after vaccination. All military patients were hospitalized, and all survived. As of April 2, the patient with the most severe case has been hospitalized for 6 days. All other hospitalized patients have been discharged; they have either returned to duty or are on short-term convalescent leave. Following are two cases that represent the spectrum of clinical presentations of myopericardiris and a report of a fatal case of myocardial infarction.

Case 1. On March 18, a man aged 22 years sought medical care at a military health clinic for chest pain 12 days after primary smallpox vaccination. He was treated with nonsteroidal anti-inflammatory agents for presumed costochondritis. When laboratory tests revealed elevated cardiac enzymes levels, he was referred to a university hospital emergency department (ED) for further evaluation. Cardiac enzymes levels remained elevated, but an ECG, echocardiogram, and cardiac stress test were normal. Myopericarditis was diagnosed, and he was released that day in good condition.

Case 2. A man aged 29 years had ILI symptoms during the same week of primary smallpox vaccination. At the time of smallpox vaccination on March 8, he also received five other inactivated vaccines; 19 days after vaccination, he sought treatment at an ED for dyspnea while lying flat. On March 28, he was hospitalized and had myopericarditis diagnosed based on ECG findings and elevated troponin I and CK-MB. The next day, he had pulmonary edema with a pulmonary artery wedge pressure of 38 mmHg that responded well to several doses of intravenous diuretics. Serial echocardiograms showed ejection fractions as low as 25% that subsequently improved to 45% (normal: >55%). Endomyocardial biopsy revealed active myocarditis with a mixed infiltrate of lymphocytes and eosinophils and evidence of eosinophilic degranulation in proximity to myocyte necrosis. PCR testing of myocardial tissue was negative for vaccinia virus DNA, varicella-zoster virus DNA, and herpes simplex virus DNA; reverse transcriptase PCR was negative for e nterovirus RNA. As of April 2, he remained hospitalized but was stable and improving.

Case 3. On March 25, an Army National Guardsman aged 55 years with a history of smoking and treatment for hyperlipidemia was found unresponsive in a vehicle 5 days after receiving smallpox vaccine and two other inactivated vaccines. He was resuscitated but died the next day. Autopsy showed acute thrombosis of the right anterior descending coronary artery, three-vessel coronary artery disease with 75%-80% occlusion, left ventricular hypertrophy, and cardiomegaly. Histopathology of left ventricular myocardium revealed no evidence of myocarditis or pericarditis. Virologic testing of myocardium is pending. The cause of death was acute myocardial infarction.

Update on Adverse Events in the Civilian Vaccination Program

As of March 30, no cases of several potentially life-threatening adverse events associated historically with smallpox vaccination (i.e., progressive vaccinia, eczema vaccinatum, post-vaccinial encephalitis, or encephalomyelitis) have been reported among civilians. In addition, no cases of vaccinia transmission from civilians have been reported. This includes no transmission from 18,344 members of health-care teams, 6,655 of whom have been followed for >1 month.

During March 11-30, six cases of generalized vaccinia, 14 cases of inadvertent inoculation (nonocular), and four cases of myopericarditis were reported (Table 2). During the same period, 12 other serious adverse events were reported. Of these, four were myocardial infarctions, and two were cases of angina (Table 3). The remaining six other new serious adverse events had hospital discharge diagnoses of pancreatic cancer, urinary tract infection, herpes zoster virus infection, headache, and facial paralysis with paresthesias (Table 3). Among the 192 vaccinees with reported other nonserious adverse events during January 24--March 30 (Table 3), the most common signs and symptoms were fever (n = 42), rash (n = 39), headache (n = 34), and pruritus (n = 32). All of these commonly reported events are consistent with mild expected reactions after receipt of smallpox vaccine. Some reported multiple signs and symptoms. During March 11-30, no vaccinia immune globulin was released for civilian vaccinees (Table 4).

Surveillance for adverse events during the civilian and military smallpox vaccination programs is ongoing; regular surveillance reports will be published in MMWR.

Reported by: Smallpox vaccine adverse events coordinators. Military Vaccine Agency, Army Medical Command, U.S. Dept of Defense. National Center for Infectious Diseases. National Immunization Program.

Editorial Note: New reports of myopericarditis following smallpox vaccination are consistent with previous reports describing a potential causal association between vaccination and myopericarditis (1). One new case of myocardial infarction among civilian vaccinees and one death from myocardial infarction among military vaccinees have been reported, but any association between smallpox vaccine and ischemic heart disease remains unclear.

Myopericarditis is often asymptomatic or mild, but can be severe. Symptomatic patients report chest pain, fatigue, fever, palpitations, and dyspnea on exertion. The patient with myopericarditis and congestive heart failure reported by DoD illustrates the potential severity of the condition, which can lead to severe cardiac dysfunction or dysrhythmia. In addition, rare fatal cases of myocarditis after smallpox vaccination have been reported in Europe and Australia (2,3). Evaluation and follow-up guidelines are being developed by CDC to assist health-care providers in managing vaccinees with cardiac adverse events.

Preliminary autopsy findings for the three patients with myocardial infarction who died showed no evidence of disseminated vaccinia infection or myopericarditis. Although virologic testing of myocardial tissue is pending for one patient and is limited for the other two, these findings suggest the ischemic events in these patients did not result from vaccinia-associated myocarditis. The number of reported deaths from cardiac disease among civilians and military personnel is consistent with expected background rates (1). However, it is not known whether smallpox vaccination could contribute to these events through another mechanism.

On the basis of the civilian and military cases, and guidance from the Advisory Committee on Immunization Practices (4) and an independent group of cardiology consultants, CDC revised its recommendations for screening and exclusion of potential smallpox vaccine recipients. Persons should be excluded from the pre-event smallpox vaccination program if they have had heart disease or any type of ischemic cardiovascular disease diagnosed, with or without symptoms (e.g., previous myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, or other heart conditions under the care of a doctor). Persons also should be excluded if they have three or more risk factors: hypertension, diabetes, hypercholesterolemia, smoking, or an immediate family member who had onset of a heart condition before age 50. To date, five of the six vaccinated civilians with cardiac adverse events indicative of ischemic heart disease met these exclusion criteria.

References

(1.) CDC. Cardiac adverse events following smallpox vaccination-United States, 2003. MMWR 2003;52:248-50.

(2.) Feery BJ. Adverse reactions after smallpox vaccination. Med J Aust 1997;2:180-3.

(3.) Dalgaard JB. Fatal myocarditis following smallpox vaccination. Am Heart J 1957;54:156-7.

(4.) CDC. Supplemental recommendations of adverse events following smallpox vaccine in the pre-event vaccination program: recommendations of the Advisory Committee on Immunization Practices. MMWR 2003;52:282-4.

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