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Benefits of Varicella Vaccination•CID 2002:34 (1 April)•885

MAJOR ARTICLE

Do the Benefits of Varicella

Vaccination Outweigh the Long-Term Risks?

A Decision-Analytic Model for Policymakers

and Pediatricians

Michael Rothberg,1,3

Michael L. Bennish,

2,4

Jack S. Kao,

1 and John B. Wong 1

Divisions of

1 Clinical Decision Making, Informatics and Telemedicine and 2 Geographic Medicine and Infectious Diseases, Department of Medicine, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts; 3

Center for Clinical Decision Making, Faculty

of Health Sciences, Ben Gurion University, Beer Sheva, Israel; and4 Africa Centre for Health and Population Studies, Mtubatuba, South Africa

Although varicella vaccine is recommended for infants, many physicians and parentshavewithheldvaccination

from infants because of concerns about the vaccine"s long-term efficacy. We used a decision-analytic Markov

model to examine the effects of decreasing vaccine efficacy on individuals and society. The model incorporated

published data on age-specific incidence, morbidity, and mortality rates, as well as data on shifting disease

burden from childhood to adulthood as vaccine compliance increases. The effects of 2 vaccination strate-

gies—vaccinating infants at age 12 months and waiting to vaccinate until children are 10 years of age—were

compared with the effects of no vaccination. If the efficacy of the vaccine were to decrease by 75%, then 50%

compliance with vaccination at age 12 months would save 1800 life-years and 12,800 quality-adjusted life-

years annually in the United States. The quality-adjusted life expectancy of individuals vaccinated at age 12

months would be 63 h longer than that of nonvaccinated individuals and would increase to 79 h as vaccination

compliance increases and the burden of chickenpox shifts to adulthood. Varicella vaccination of infants at

age 12 months appears to be beneficial, even if the efficacy of the vaccine declines substantially. In 1995, a safe [1, 2] and effective varicella vaccine be- came available in the United States. Although varicella vaccination is cost-effective [3-10] and has been en- dorsed by the American Academy of Pediatrics (AAP;

ElkGroveVillage,IL)[11,12]andtheCentersforDiseaseReceived 21 June 2001; revised 12 October 2001; electronically published 19

February 2002.

Presented in part: 20th Annual Meeting of the Society for Medical Decision Making, Cambridge, Massachusetts, October 1998 (abstract 96). Financial support: National Library of Medicine (grant LM 07092-07; M.R. was a National Library of Medicine Medical Informatics Research Fellow) and National Institutes of Allergy and Infectious Diseases (midcareer clinical investigatoraward

AI/HDO1671-01 [to M.L.B]).

Reprints or correspondence: Dr. John Wong, New England Medical Center, 750 Washington St., Box 302, Boston, MA 02111 (Jwong@Lifespan.org).

Clinical Infectious Diseases 2002;34:885-94

?2002 by the Infectious Diseases Society of America. All rights reserved.

1058-4838/2002/3407-0001$03.00Control and Prevention (CDC; Atlanta) [13], pediatri-

cians have been slow to embrace universal vaccination [14, 15]. As a result, only 43% of children are currently vaccinated [16]. Obstacles to vaccination include (1) the perception that varicella is a mild disease in children, and (2) the concern that the efficacy of the vaccinecould potentially wane [12, 14, 15, 17, 18] and, ultimately, could lead to an increase in the number of cases of [19-21]. Proponents of universal vaccinationhavecoun- tered these arguments by emphasizing that studies have suggested that (1) vaccine efficacy persists for at least 20 years [22], (2) most hospitalizations and deaths due to varicella occur among children and can be prevented by vaccination [17, 23, 24], and (3) vaccination may also prevent morbidity associated with herpes zoster[24-26].

In any vaccination program, what is best for theDownloaded from https://academic.oup.com/cid/article/34/7/885/315677 by guest on 11 July 2023

886•CID 2002:34 (1 April)•Rothberg et al.

Figure 1.Markov model representing the lifetime of a birth cohort. Circles denote “health states." Straight arrows denote events resulting in transition to a new health state. Circular arrows indicate thepossibility of maintaining the same health state. The health state of all cohort members is “unvaccinated"(Unvaccinated)at the beginning of life. De- pending on the vaccination strategy followed, the health state of some members may be changed to “vaccinated"(Vaccinated)after the first or

10th yearly cycle. Each year, nonvaccinatedindividualsmaycontractchick-

enpox and vaccinated individuals may contract breakthrough varicella. Both of these groups of individuals are then considered to be “immune" (Immune).Immune individuals can develop zoster and then can be con- sidered immune again, or, if they experience a permanent complication, they may have unilateral deafness(Deaf),monocular blindness(Blind), or both (not shown). Regardless of an individual"s health state, it is possible for an individual to die directly(Dead)as a result of either chickenpox or zoster or as a result of death as it occurs among the general population. community may not be what is best for each individual [21]. When considering mandatory vaccination, public health offi- cials attempt to maximize societal benefit [27], whereasparents and health care providers are more concerned aboutthewelfare of individual children. Varicella models published elsewhere have all viewed vaccination in terms of its societal benefit, offering no specific guidance for the individual. Some pediatricians have proposed, as an alternative to uni- versal vaccination, that vaccination be delayed until children are

10 years of age [19, 20]. This delay would result in most children

acquiring immunity after natural infection, with the remainder receiving vaccination before adulthood. To help individuals and policymakers decide whether and when to vaccinate, we devel- oped a decision-analytic model that considered possible waning vaccine efficacy. The model considered 3 vaccination strategies and weighed a postulated future risk of disease duringadulthood against the known benefit of the vaccine to children.

MATERIALS AND METHODS

Decision-Analysis Model

Using a standard computer program (Decision Maker 7.07; Pratt Medical Group), we constructed a Markov model to ex- amine the effects of 3 vaccination strategies in a birth cohort of 4 million children [28, 29]. The 3 strategies involved either (1) vaccinating all infants at age 12 months, (2) delaying vac- cination until age 10 years and then vaccinating only if a child has no history of varicella, or (3) not vaccinating at all. Markov models simulate the natural history of a disease as a cohort progresses through a finite number of "health states" (figure

1) [30]. Time is represented by yearly cycles during which the

current health state of the patients may remain unchanged or may change on the basis of "transition probabilities,"asderived from the literature. For this analysis, the entire cohort began life as unvaccinated newborns. At age 12 months, the health state of infants who received vaccination was classified as "vaccinated," whereas the as "unvaccinated." For each year assessed, an age-specific un- derlying attack rate was multiplied by the number of susceptible individuals in the population, to predict the number of chick- enpox cases and the number of major complications and deaths due to chickenpox. Natural mortality rates were based on life table statistics. Because the varicella vaccine is not 100% efficacious, some vaccinated children experience breakthrough varicella (BV), The health state of individuals who develop either chickenpox or BV is reclassified as "immune." For individuals who die of any cause, the health state classification is "dead." Both immune

and vaccinated groups of individuals are at risk for developingzoster and its complications. Zoster may result in death or per-manent disability.

The simulation ended when all cohort members had died. Totaling the amount of time that the health state of individuals was classified as "vaccinated,""unvaccinated,"or"immune"(but not"dead") yielded the life expectancy of the cohort. Subtracting a length of time proportional to the amount of time that indi- viduals were affected by short- and long-term morbidity pro- duced the quality-adjusted life expectancy (QALE; appendix A). To determine the QALE for an individual who followed a given vaccination strategy - as opposed to determining the QALE of the entire cohort, not all of whom chose the same strategy - we

reran the model with the use of age-specific attack rates thatDownloaded from https://academic.oup.com/cid/article/34/7/885/315677 by guest on 11 July 2023

Benefits of Varicella Vaccination•CID 2002:34 (1 April)•887 were generated by the cohort model for the level of compliance tested.

Data and Assumptions

Table 1 presents thebaselinevaluesforthemodelandtheranges for sensitivity analysis. When data were unknown, we always chose the most conservative estimate, thereby purposefully bi- asing the results against vaccination. Varicella incidence.Wederivedprevaccine-era,age-specific incidence of varicella from data in the Kentucky Behavioral Risk Factor Survey Study (BRFSS) [31] and the Health InterviewSur- veys (HIS) [32]. For children aged?15 years, we used age- specific rates from the BRFSS, because they were reported in 1- year intervals. For children aged

115 years, we used the most

recent HIS rates [32, 33]. To calculate the age-specific annual varicella attack rates, we divided the number of expected cases in a given year by the number of susceptible individuals at the beginning of that year [3]. Vaccination and subsequent induction of herd immunity may cause the incidence of varicella to be redistributed according to age [34]. With decreased numbers of susceptible children and increased numbers of susceptible adults (as a result of waning immunity), the varicella attack rate might decrease among chil- dren and increase among adults. To capture this effect of herd immunity, we converted age-specific attack rates into suscepti- bility-specific attack rates. Furthermore, because BV probably is less infectious than natural varicella, we decreased the over- all attack rate by use of the following formula: attack ratep , wherefis the susceptibility-specific attackf[n? v7(1?e)7i] rate function,nis the percentage of nonimmune, nonvaccinated individuals in the population,vis the percentage of vaccinated individuals,eis the efficacy of the vaccine, andiis the relative infectivity of BV [6]. Complications due to chickenpox.Major complications associated with chickenpox include encephalitis, pneumonia, and superinfection of the skin [35]. In the United States,before introduction of the varicella vaccine, the estimated number of annual hospital admissions of patients with complications due to chickenpox ranged from 3837 [36] to 9300 admissions [37], with almost one-half of the admissions involving children aged !5 years [37]. We used age-specific hospitalization rates from the Commission on Professional and Hospital Activities (CPHA) National Sample File to estimate the likelihood of complications [32]. Lin and Hadler [38, 39] recently reported similar hospitalization rates in Connecticut. Deaths due to chickenpox.We based our age-specificdeath rates on the most recent CDC data for the period 1985-1994 [35]. These data show an increasing case-fatality rate among adults, which will magnify the effect of any vaccine-induced up- ward shift in incidence with age [40].

Incidences of zoster and its complications.Two popula-tion-based studies have examined the age-specific incidences of

zoster [41, 42] and complications associated with zoster [42, 43]. We relied on the findings of the more recent studies [41, 43], although all 3 studies found similar rates for specific compli- cations as well as increasing complication rates with advancing age. The average duration of postherpetic neuralgia was based on its observed age-specific natural history [44]. More recent studies have reported themedian,ratherthanthemean,duration of pain; in addition, they have not beenage-specificandgenerally have been limited to 6 months of follow-up [45-47]. Hospitalizations due to zoster.Recently published data have shown that rates of hospitalization due to zoster are 4- fold greater than those due to chickenpox [39]. The majority of individuals admitted to the hospital were elderly persons with no underlying medical conditions. HIV infection was an underlying condition in 11% of hospitalizations for zoster.

Deaths due to zoster.According to CDC data for

1979-1995, more deaths occur annually as a result of zoster

[48] than as a result of chickenpox [35]. Deaths due to zoster occur predominantlyamongelderlyindividuals,whereasdeaths due to chickenpox can occur among individuals of all ages. Vaccine efficacy in the prevention of chickenpox.We de- fined vaccine efficacy as the reduction in the observed number of cases of chickenpox versus the expected number of cases of chickenpox. We calculated the efficacy of the varicella vaccine, as reported from trials in the United States, for each of the first 7 years after administration [49, 50]. Although one vaccine trial in Japan reported a 20-year follow-up with an efficacy of

100% after the first year that vaccine was administered, the

study was small and relied on self-reporting of vaccine failure, a reporting method that tends to overestimate efficacy [22]. Other analyses have assumed that efficacy either did not wane [4, 7, 9, 10] or decreased by 15% during a lifetime [3, 6]. For our analysis, we assumed a 75% decrease in efficacy during a lifetime (appendix A) [50]. Risk of complications due to varicella in vaccinated indi- viduals.BV generally has been less severe than natural var- icella [51-56]. A recent case-control study reported that the varicella vaccine was 97% effective against moderately severe and severe disease [57]. Our estimate of an 89% reduction in the risk of complications, which was based on the relative re- duction in the number of lesions, was lower than the risk reduction estimates of 95%-99% that were used in previous analyses [3, 4, 6, 7, 9, 10]. Vaccine efficacy in the prevention of herpes zoster.Studies of children with leukemia and studies of healthy children and adults have demonstrated that vaccination reduces the incidence of herpes zoster by 75%-82% [58-62]. This reduction may stem from the vaccine strain's reduced propensity to cause zoster; if so, once an individual contracts BV with wild-type varicella, the

protective effect may not persist. Furthermore, no study hasDownloaded from https://academic.oup.com/cid/article/34/7/885/315677 by guest on 11 July 2023

Table 1. Baseline values for the Markov model and ranges for sensitivity analysis used in the assessment of varicella vaccination strategies in a birth cohort of 4 million individuals.

VariableValue

at baselineSensitivity range Reference(s)

Annual attack rate per 1000 susceptible persons

Of chickenpox

Among infants and children?15 years of age Variable 44-305 [31]

Among children

115 years of ageVariable 20-55 [32, 33]

Of herpes zosterVariable 1.1-15.8 [41]

Efficacy in the prevention of

Modified varicella-like syndrome

Natural infection0.999[74]

Vaccine (initial efficacy)0.98 0.80-1.00 [49, 50, 75, 76]

Annual decline0.010-0.01 [50]

Herpes zoster

Natural infection0.00

Vaccine0.75 0.55-0.86 [11, 62]

Varicella-associated complications

a

After natural infection0.999

After vaccination0.890-1 [51-56]

Probability of complications after

Chickenpox

a Hospitalization (per 10,000 cases)Age-specific 9-140 [33, 36, 37] Death (per 100,000 cases)Age-specific 0.7-20.4 [35]

Herpes zoster

b Hospitalization (per 10,000 cases)Age-specific 200-1100 [39] Death (per 100,000 cases)Age-specific 2.7-48.2 [48]

Monocular blindness, given ocular

complication0.056 0-0.1 [77] Unilateral deafness, given herpes oticus0.059 0-0.24 [78, 79]

Postherpetic neuralgia0.079 0.040-0.200 [42, 43]

Neuropathy0.009 0.004-0.026 [42, 43]

Ocular complications0.016 0.007-0.054 [42, 43]

Herpes oticus0.002 0.001-0.006 [42, 43]

Meningitis0.005 0.002-0.015 [42, 43]

Skin superinfection0.023 0.010-0.064 [43]

Vaccination

Fever0.028 0.024-0.032 [80]

Rash0.017 0.014-0.020 [80]

Local reaction0.032 0.028-0.036 [80]

Morbidity

Short-term, in days

Fever0.250-2 [73]

Rash0.480-3 [73]

Local reaction0.580-3 [73]

Herpes oticus1.210-30 [73]

Ocular complications1.660-30 [73]

Herpes zoster1.990-14 [73]

Uncomplicated chickenpox2.340-12 [53, 55, 63]

BV varicella-like syndrome

c

1.160-6 [55, 63]

(continued)Downloaded from https://academic.oup.com/cid/article/34/7/885/315677 by guest on 11 July 2023

Benefits of Varicella Vaccination•CID 2002:34 (1 April)•889

Table 1.(Continued.)

VariableValue

at baselineSensitivity range Reference(s)

Hospitalization

For chickenpox 5.74 0-6 [39, 63]

For herpes zoster (meningitis or superinfection) 11.00 0-11.5 [39, 63]

Neuropathy 54.05 0-462 [42, 63]

Postherpetic neuralgia Age-specific 31-235 [44, 63]

Long-term quality-adjustment factor

Monocular blindness 0.76 [63]

Unilateral deafness 0.83 [73]

NOTE.BV, breakthrough varicella.

a

The probability of complications after BV equals the age-specific rate of complications multipliedby thequantity

1 minus the efficacy of the vaccine in preventing complications associated with BV.

b

The probabilities of all herpes zoster complications are age-adjusted by use of age-specific ORs. The baseline

probabilities shown in the table are the averages for all age groups. c The severity of BV is calculated as a fraction (0.5) of the severity of natural chickenpox. compared the severity of wild-type zoster with that of thevaccine strain. To be conservative, we assumed that the risk and severity of zoster after BV would be identical to those seen after wild- type varicella - that is, the vaccine would have no future pro- tective effect against zoster. Quality adjustments.We used a validated utility instru- ment, the Index of Well-Being, to determine quality of life for individuals with chickenpox, zoster, complications of chick- enpox and zoster, or vaccine side effects (appendix B) [63].

RESULTS

Validation of Model

In the absence of vaccination, the model accuratelyreproduced the age-specific incidence ofchickenpoxreportedbytheBRFSS. Furthermore, the model predicted that 7% of 18-year-old in- dividuals would be susceptible, a finding similar to estimates of 6%-8% reported elsewhere [37, 64]. The predicted cumu- lative number of hospitalizations (7700) and deaths (81) due to varicella was also similar to data reported by the CPHA (9300 hospitalizations) [37], the CDC (71 deaths) [37], and the Halloran model (9900 hospitalizations and 56 deaths) [6].

Population Decision

Life expectancy.Without vaccination, the life expectancy for the population is 74.8 years. Achievement of 50% and 97% com- pliance with vaccination at age 12 months increases life expec- tancy by 4 h and 8 h, respectively, and increases QALE by 28 h and 54 h, respectively, compared with no vaccination. A strategy that involves vaccination of nonimmune children at age 10 yearsquotesdbs_dbs17.pdfusesText_23