Smallpox vaccination and adverse cardiac events.To the Editor: The Incidence of adverse cardiac events related to smallpox vaccinations administered during the National Smallpox Vaccination Program (NSVP NSVP NATO Secure Voice Program ) in 2003 has received widespread attention. From January 24 through August 8, 2003, suspected or probable myo- or pericarditis Pericarditis Definition
Pericarditis is an inflammation of the two layers of the thin, sac-like membrane that surrounds the heart. This membrane is called the pericardium, so the term pericarditis means inflammation of the pericardium. was reported in 22 of 38,257 civilian vaccinees (1); as of November 4, 2003, suspected or probable myo- or pericarditis was reported in 63 of 515,000 military vaccinees (2). Additionally, cases of coronary artery disease coronary artery disease, condition that results when the coronary arteries are narrowed or occluded, most commonly by atherosclerotic deposits of fibrous and fatty tissue. , including myocardial infarction myocardial infarction: see under infarction. and cardiac death, were reported in the weeks after vaccination although no causal link has been established.
An October 3, 2003, MMWR MMWR Morbidity & Mortality Weekly Report Epidemiology A news bulletin published by the CDC, which provides epidemiologic data–eg, statistics on the incidence of AIDS, rabies, rubella, STDs and other communicable diseases, causes of mortality–eg, article, "Cardiac deaths after a mass smallpox vaccination campaign--New York City, 1947" states that the NYC NYC
New York City
NYC New York City experience suggests "... that cardiac deaths observed in 2003 might have been unrelated to smallpox vaccination." While the causes of these cardiac or coronary deaths have not been established, the 1947 data lack the power to address whether there is a relationship to the vaccine.
Cardiac or coronary deaths after vaccination in 2003 were rare, with a total of 3 of 488 550 military and civilian vaccinees (6 per 1 million vaccinees), approximately the same as might be expected in a generally healthy population. The total number of cardiac or coronary deaths in 1947 during the 2-week estimated risk period after vaccination was 1,545. While the denominator (number vaccinated in the previous 4-17 days) was not reported, a total of 6.4 million persons were vaccinated during the 4 weeks of the vaccination program. The 4-week vaccination period would result in a 6-week period of susceptibility for cardiac death according to according to
1. As stated or indicated by; on the authority of: according to historians.
2. In keeping with: according to instructions.
3. the 4-17 day latency period latency period
In psychoanalytic theory, the fourth stage of psychosexual development, extending from about age 5 to puberty, when a child apparently represses sexual urges and prefers to associate with members of the same sex. . Thus, we extrapolate extrapolate - extrapolation that the denominator for the 2-week observation period is approximately 2.1 to 6.4 million vaccinees at risk during the study period. This would mean that approximately 240 to 720 cardiac deaths occurred per million vaccinees.
Suppose that the 1947 smallpox vaccine smallpox vaccine
A vaccine containing vaccinia virus suspensions that is inoculated subcutaneously to immunize against smallpox. indeed caused serious cardiac disease, including myopericarditis and myocardial infarctions, with 10 fatal cases per million. Viewed in perspective, this would approximate the historic rate of vaccine-induced encephalitis encephalitis (ĕnsĕf'əlī`təs), general term used to describe a diffuse inflammation of the brain and spinal cord, usually of viral origin, often transmitted by mosquitoes, in contrast to a bacterial infection of the meninges and would be well in excess of the historic rate of progressive vaccinia progressive vaccinia
A severe or even fatal form of vaccinia occurring as a complication of smallpox vaccination chiefly in persons with an immunologic deficiency or dyscrasia, characterized by progressive enlargement of the initial and secondary . In this scenario, at a hypothetical incidence of 10 per million, from 21 to 64 of the 1,545 cardiac deaths (1.4% to 4. 1%, respectively) would have been caused by the vaccine. This magnitude of effect would have been very difficult to detect in this study. Thus, the results of such investigations must be considered in the context of power limitations. Further, studying death rates sheds no light on cardiac illness such as myo- or pericarditis.
The proper interpretation of these data is important given the national policy impact that resulted from the observation of cardiac and coronary illness and death after vaccination in 2003. At this time, adverse cardiac events associated with the vaccine, particularly myo- or pericarditis, are still of concern. Whether coronary or cardiac deaths can be attributed to the vaccine remains an open question.
Table. Smallpox vaccination and estimated risk for cardiac death All cardiac Atherosclerotic deaths (a) deaths (a), (b) Estimated vaccine-associated 6.1 per million 6.1 per million death risk (deaths/vaccinees) (3/488,550) (3/488,550) based on 2003 experience (d) 1947 rate of cardiac deaths 241 per million 44 per million in 2-week risk period (1,545/6.4 million) (280/6.4 million) (deaths/vaccinees) Percent of 1947 deaths that 2.5% 14.0% would have been due to vaccination, given estimated vaccine-associated risk Sufficient power to detect? Possibly Definitely All cardiac deaths, civilians only (c) Estimated vaccine-associated 52.3 per million death risk (deaths/vaccinees) (2/38,257) based on 2003 experience (d) 1947 rate of cardiac deaths 44 per million in 2-week risk period (280/6.4 million) (deaths/vaccinees) Percent of 1947 deaths that 100% would have been due to vaccination, given estimated vaccine-associated risk Sufficient power to detect? Definitely (a) For these estimates, we used the total number of vaccinees as of November 2003, per Upfal's letter. Our original article estimated risk based on 394,584 vaccinees as of April 2003; the resulting effect size would be even larger and more easily detectable. (b) All cardiac deaths in 2003 were atherosclerotic. (c) For this calculation, we used the total number of civilian vaccinees as of August 2003, per Upfal's letter. Our original article estimated risk based on 29,584 civilian vaccinees as of April 2003; the resulting effect size would be even larger and more easily detectable. (d) Estimated risk for death caused by vaccine, if one assumes that all 2003 cardiac deaths were vaccine-related.
(1.) Centers for Disease Control and Prevention Centers for Disease Control and Prevention (CDC), agency of the U.S. Public Health Service since 1973, with headquarters in Atlanta; it was established in 1946 as the Communicable Disease Center. . Update: adverse events following civilian smallpox vaccination United States, 2003. MMWR Morb Mortal Wkly Rep 2003; 52;819-0.
(2.) U.S. Army. Smallpox vaccine-cardiac related reactions. 2003 Nov [Accessed Mar 9, 2004]. Available from: http://www.smallpox.army.mil/media/pdf/spQAshort.pdf
(3.) Centers for Disease Control and Prevention. Cardiac deaths after a mass smallpox vaccination campaign--New York City, 1947. MMWR Morb Mortal Wkly Rep 2003;52;933-6.
Address for correspondence: Mark Upfal, Corporate Medical Director, Detroit Medical Center The Detroit Medical Center is a Detroit-based non-profit corporation that owns and operates nine general and specialty hospitals in southeast Michigan. Detroit Medical Center hospitals include:
Mark J. Upfal, * and Sandro Cinti ([dagger])
* Detroit Medical Center, Detroit, Michigan, USA; and ([dagger]) University of Michigan (body, education) University of Michigan - A large cosmopolitan university in the Midwest USA. Over 50000 students are enrolled at the University of Michigan's three campuses. The students come from 50 states and over 100 foreign countries. , Ann Arbor, Michigan
“Ann Arbor” redirects here. For other uses, see Ann Arbor (disambiguation).
Ann Arbor is a city in the U.S. state of Michigan and the county seat of Washtenaw County. , USA
In Reply: We have reviewed the letter submitted by Upfal and his colleagues (1), and we applaud their careful examination of our previously published data (2). Their aim was to assess whether the study was adequately powered to detect a small but potentially relevant effect in cardiac death rates. This question is important, and their message regarding the difficulty of measuring small effects is certainly true. We address these problems in the discussion section of our article published in this edition of Emerging Infectious Diseases; however, we would also like to clarify some points that were misleading in their letter.
While the methods Upfal et al. employ to assess statistical power are generally correct, they base their argument on estimates derived from 2003 deaths in both the civilian and military population. We remind readers that the military is a unique group, more physically fit and potentially younger than the general population, today and in 1947. A more appropriate estimate of potential risk for the general population (i.e., what we would have seen in 1947 if a vaccine-associated risk for cardiac death existed) would be to use risk estimates derived from deaths among civilians. If observed civilian deaths in 2003 were indeed vaccine-associated, our study certainly had the power to detect such an effect in 1947.
Also, when calculating the rate of cardiac deaths among 2003 vaccinees, Upfal et al. refer to additional 2003 vaccinations in the military that have occurred since the time our article was published. Since no additional deaths occurred, these additional vaccinations further dilute the risk. However, this larger number of vaccinees modestly affects the estimated risk size. In the Table below, we show that our study had sufficient power to detect effects of a relevant size.
We agree with Upfal's basic premise that our study lacks the statistical power to detect very small risks (such as 1% increases), but most studies struggle with the same limitation. Our study does provide useful and convincing evidence that neither moderate nor large increases in cardiac mortality occurred in 1947 as a result of smallpox vaccination.
(1.) Upfal MJ, Cinti S. Smallpox vaccination and adverse cardiac events. Emerg Infect Dis 2004;10:971-2.
(2.) Centers for Disease Control and Prevention. Cardiac deaths after a mass smallpox vaccination campaign--New York City, 1947. MMWR Morb Mortal Wkly Rep 2003;52:933-6.
Address for correspondence: Lorna E. Thorpe, NYC DOHMH DOHMH Department of Health and Mental Hygiene (New York City) , 125 Worth St. Rm. 315 (CN6), New York New York, state, United States
New York, Middle Atlantic state of the United States. It is bordered by Vermont, Massachusetts, Connecticut, and the Atlantic Ocean (E), New Jersey and Pennsylvania (S), Lakes Erie and Ontario and the Canadian province of , NY 10013, USA; fax: 212-788-4473; email: email@example.com
Lorna E. Thorpe, * ([dagger]) Farzad Mostashari, * Adam M. Karpati, * Steven P. Schwartz, * Susan E. Manning, ([dagger]) Melissa A. Marx, * ([dagger]) and Thomas R. Frieden *
* New York City New York City: see New York, city.
New York City
City (pop., 2000: 8,008,278), southeastern New York, at the mouth of the Hudson River. The largest city in the U.S. Department of Health and Mental Hygiene mental hygiene, the science of promoting mental health and preventing mental illness through the application of psychiatry and psychology. A more commonly used term today is mental health. , New York, New York, USA; and ([dagger]) Centers for Disease Control and Prevention, Atlanta, Georgia, USA