S168 • CID 2008:46 (Suppl 3) • Ortega-Sanchez et al.
S U P P L E M E N T A R T I C L E
Economics of Cardiac Adverse Events after Smallpox
Vaccination: Lessons from the 2003 US Vaccination
Ismael R. Ortega-Sanchez,1Mercedes M. Sniadack,1,2and Gina T. Mootrey1
1National Immunization Program, Centers for Disease Control and Prevention, Atlanta, Georgia; and
2Logistics Health, La Crosse, Wisconsin
Of 139,000 civilian public health responders vaccinated against smallpox in 2003, 203 reported cardiovascular
adverse events (CAEs). An association exists between the US vaccinia strain and myocarditisand/orpericarditis
(“myo/pericarditis” [MP]). Other associations are inconclusive. We used surveillance and follow-up survey
data of CAE case patients to estimate the resources used during the 2003 smallpox vaccination program and
used a probabilistic model to estimate the potential costs of CAEs in a mass vaccination campaign. For every
million adult vaccinees, 3001 CAEs (including 351 MP cases) would occur, with 192% in revaccinees. CAEs
would require a median of 5934 outpatient visits, 1786 emergency department visits, 533 days in general
wards, 132 days in intensive care units, 5484 cardiac enzymes tests, 3504 electrocardiograms, 3049 chemistry
tests, 2828 complete blood counts, and 1444 transthoracic echocardiograms, among other procedures. CAEs
would reduce productivity (15,969 work days lost) and cost $11 per vaccinee. In a mass vaccination campaign,
the care of a sizable number of CAEs would be resource intensive.
In December 2002, the President of the United States
announced a national program for voluntarysmallpox
vaccination to enhance bioterrorism preparedness in
the military [1, 2] and civilian sectors . The first
phase of the voluntary civilian program began in Jan-
uary 2003 and consisted of vaccinating health care
and public health workers who volunteered to serve
as members of smallpox response teams. A smallpox
vaccine safety monitoring and response system, in-
cluding screening criteria and enhanced surveillance
systems to prevent or detect smallpox vaccine adverse
events, was developed and implemented by the Cen-
ters for Disease Control and Prevention (CDC), the
US Food and Drug Administration (FDA), and state
The findings and conclusions in this report are those of the authors and do not
necessarily represent the views of the Centers for Disease Control and Prevention
or the Department of Health and Human Services.
Reprints or correspondence: Dr. Ismael Ortega-Sanchez, Centers for Disease
Control and Prevention, 1600 Clifton Rd. NE, MS A-47, Atlanta, GA 30333
Clinical Infectious Diseases2008;46:S168–78
? 2008 by the Infectious Diseases Society of America. All rights reserved.
and local public health officials, in consultation with
medical subspecialists [4, 5].
From January to October 2003, 36,813 civilianpublic
health responders were vaccinated with smallpox vac-
cine (139,000 by December 2003) [6, 7]. Among these
vaccinees, 203 reported cardiovascular adverse events
(CAEs), including dilated cardiomyopathy (DCM),
ischemic cardiac events (ICEs), myocarditis and/orper-
icarditis (“myo/pericarditis” [MP]), and others [7–9].
The epidemiologic and clinical outcomes of these re-
ported cases have been described elsewhere [7, 10–12].
Follow-up during the 5–12 months after vaccination
demonstrated that, although death and severe adverse
were rare, ∼0.5% of vaccinees developedcardiovascular
symptoms that resulted in hospitalization and a decline
in health-related quality of life . Although an as-
sociation between the US vaccinia strain and MP was
recently described and other associations were incon-
clusive [7, 12], the risk of and costs related to reported
CAEs could be of concern, should a larger population
require preemptive immunization against smallpox in
the future. The objectives of the present study were to
estimate the resource utilization and costs associated
by guest on January 14, 2016
Costs of Cardiac Events after Smallpox Vaccine • CID 2008:46 (Suppl 3) • S169
with observed CAEs during the recent smallpox vaccination
program and to assess the risks and costs of CAEs in a hy-
pothetical mass vaccination campaign against smallpox for
Following standard protocols for the assessment of diseasebur-
den and cost of illness [13–15], we estimated the amounts and
types of resources utilized for CAEs, as well as associated costs
(see the Appendix). Data on CAE case patients reported from
January through October 2003 were obtained from the Vaccine
Adverse Event Reporting System and from a follow-up ques-
tionnaire administered to reported CAE case patients 5–12
months after immunization .
To project population-based risks and costs of reported
CAEs, we used a probabilistic model consisting of an age-rep-
resentative US population of 1 million individuals 118 years
of age  vaccinated against smallpox. Health outcomes in-
cluded the number of CAEs by type, age group, andvaccination
status and the amount of medical and nonmedical resources
used per million vaccinees. Direct costs accrued to medical
evaluation, medical care, and follow-up and indirect costs of
productivity losses were estimated, along with summary costs
per vaccinee and per million vaccinees.
For the sensitivity analysis of projected estimates,probability
distributions were specified for key parameters, by use of a
range of values (table 1), and were varied simultaneously in
Monte Carlo simulations. For each estimated health risk and
economic outcome, we used the median of simulations as the
most likely value and the 5th and 95th percentiles to approx-
imate a range.
Reported cases and incidence rates.
the incidence of CAEs by type of event (DCM, ICE, MP, and
other), age group,andvaccinationstatus,asdescribedelsewhere
[2, 7, 23]. For each type of CAE, the base-case incidence values
used in the estimations were actual rates calculated using the
number of CAEs reported in the surveillance data and the total
number of vaccinees by age group as reported elsewhere (table
1) [2, 7]. The upper incidence values are a 100% increase in
the base-case value, and the lower values were obtained using
all of the CAEs as numerator or from the literature . Al-
though no association was found between vaccinia and the 2
deaths after ICE [7, 11, 24], we assumed a worst-case scenario
and calculated potential deaths using a case-fatality ratio of
20%—that is, 2 reported deaths due to ICE over a total of 10
ICE case patients (8 included in this study) [7, 11]. On the
basis of the vaccination status (i.e., the proportions of primary
vaccinees and revaccinees) of civilians vaccinated from January
to October 2003, we assumed that the proportion of primary
vaccinees in the population of adults ?18 years of age is ∼22%
We used estimates of
(with uncertainty represented by a range of 15%–30%) (see
table 1) .
up investigation of 201 of the 203 reported CAE case patients
was conducted between November 2003 and February2004.The
clinical, health lifestyle, and economic data by type of CAE. De-
mographic characteristics of vaccinees have been described and
and clinical evaluation of CAE case patients . For the eco-
nomic-burden investigation, case patients were also asked about
number of doctor visits, days spent in the hospital, work time
missed, household expenses or income lost, and how health care
costs were financed. To complement these data, CAE case pa-
tients’ medical records were also reviewed, regardingthenumber
and type of cardiology tests and laboratory work performed for
Unitary costs for medical and indirect re-
sources utilized by CAE case patients were obtained from var-
ious sources. Most were obtained from the literature [18, 19,
25–28] and from databases from Blue Cross Blue Shield North
Carolina , the Medicare fee schedule from the Centers for
Medicare and Medicaid Services , and the Agency for
Healthcare Research and Quality  (table 1). When needed,
medical charges were adjusted using charge-to-cost ratios. The
cost of time missed from work was calculated using hourly
earnings reported by the US Bureau of Labor Statistics  for
the general population. Productivity lost because of premature
death was determined using expected age-specific foregonelife-
time earnings for the general US population . All costs were
measured in 2005 US dollars.
Resource utilization by CAE case patients.
selected summary statistics of medicalandnonmedicalresource
utilization by 201 reported CAE case patients, stratified by type
of CAE. For each event, the proportion of those using specific
resources is provided, along with the mean and SD of the
Although clinical outcomes of MP, DCM, ICE, and other
types of CAEs were generally mild at follow-up , sizable
amounts of medical and nonmedical resources were used by a
relatively high proportions of CAE case patients (table 2). With
the exception of chemistry tests (
count tests (), statistical analyses performed across CAEs
P ! .45
showed significant differences in the amount of each medical
and nonmedical resource used by case patients (table 2). Dif-
ferences in resource utilization among CAE case patients re-
mained invariant to age, sex, and heart-diseaseriskfactors(data
Higher proportions of resource utilization were observed for
Table 2 presents
) and complete blood
P ! .15
by guest on January 14, 2016
S178 • CID 2008:46 (Suppl 3) • Ortega-Sanchez et al.
pensation survey: occupational wages in the United States, June 2005.
Available at: http://stats.bls.gov/ncs/ocs/sp/ncbl0832.pdf.AccessedDe-
22. Grosse SD. Appendix I: productivity loss tables. In: HaddixAE,Teutsch
SM, Corso PS, eds. Prevention effectiveness: aguidetodecisionanalysis
and economic evaluation. New York: Oxford University Press, 2003:
23. Cassimatis DC, Atwood JE, Engler RM, Linz PE, Grabenstein JD, Ver-
nalis MN. Smallpox vaccination and myopericarditis: a clinical review.
J Am Coll Cardiol 2004;43:1503–10.
24. 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.
25. Garber AM, Solomon NA. Cost-effectiveness of alternative test strat-
egies for the diagnosis of coronary artery disease. Ann Intern Med
26. Kuntz KM, Fleischmann KE, Hunink MGM, Douglas PS. Cost-effec-
tiveness of diagnostic strategies for patients with chest pain.AnnIntern
27. Pronovost PJ, Needham DM, Waters H, et al. Intensive care unit phy-
sician staffing: financial modeling of the Leapfrog standard. Crit Care
28. Safdar N, Dezfulian C, Collard HR, Saint S. Clinical and economic
consequences of ventilator-associated pneumonia: a systematic review.
Crit Care Med 2005;33:2184–93.
29. US Department of Health and Human Services, Agency for Healthcare
Research and Quality (AHRQ). Outcomes by patientandhospitalchar-
acteristics for myocarditis: DX1(s) 391.2, 390. HCUP Nationwide In-
patient Sample (NIS), 2003. Available at: http://hcupnet.ahrq.gov/.Ac-
cessed December 2006.
30. Centers for Disease Control and Prevention. Supplemental recom-
mendations on adverse events following smallpox vaccine in the pre-
event vaccination program: recommendations of the Advisory Com-
mittee on Immunization Practices. MMWR Morb Mortal Wkly Rep
31. Halsell JS, Riddle JR, Atwood JE, et al. Myopericarditisfollowingsmall-
pox vaccination among vaccinia-naı ¨ve US military personnel. JAMA
32. Hilleman DE, Mohiuddin SM, Lucas BD, Stading JA, Stoysich AM,
Ryschon K. Cost-minimization analysis of initial antihypertensivether-
apy in patients with mild-to-moderate essential diastolichypertension.
Clin Ther 1994;16:88–102.
33. Pitt B, O’Neill B, Feldman R, et al. The QUinapril Ischemic Event Trial
(QUIET): evaluation of chronic ACE inhibitor therapy in patientswith
ischemic heart disease and preserved left ventricular function. Am J
34. Treating high blood pressure and heart disease: the ACE inhibitors.
Comparing effectiveness, safety, and price. Consumer ReportsBestBuy
Drugs. Consumers Union, 2005. Available at: http://consumerreports
valuedrug.com/drugreport_DR_ACEI.shtml. Accessed 17 December
35. Strongin RJ, Salinsky E. Who will pay for the adverse events resulting
from smallpox vaccination? Liability and compensation issues. NHPF
Issue Brief 2003;(788):1–15.
by guest on January 14, 2016