Cost-effectiveness of Serotesting Compared with Universal Immunization for Varicella in Refugee Children from Six Geographic Regions

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1 ORIGINAL ARTICLES Cost-effectiveness of Serotesting Compared with Universal Immunization for Varicella in Refugee Children from Six Geographic Regions Marisol Figueira, Demian Christiansen, and Elizabeth D. Barnett Background: It is unknown whether it is more cost-effective to test for varicella antibody or to immunize without testing in immigrant populations. The reliability of history of varicella disease is also unclear. Methods: The prevalences of varicella antibody in immigrant children from six regions of the world were used in a costeffectiveness model to calculate the antibody prevalence above which it is more cost-effective to test rather than to immunize. History of varicella disease was obtained from chart review. We calculated the positive and negative predictive values of varicella history by age group and region. Results: The prevalence of varicella antibody above which it is more cost-effective to test than to immunize was 34% for children less than 13 years old and 17% for those aged 13 years and older. Overall, the positive predictive value of varicella history was % and the negative predictive value of varicella history was 28 66% among the six geographic regions. Conclusion: Immunization without serotesting was cost-effective in children 5 years of age. Testing prior to immunization was cost-effective in children 5 years of age and older. History of varicella was a good predictor of the presence of antibody to varicella, whereas a negative history was a poor predictor of the absence of antibody to varicella. Immigrant children entering the United States without immunization records, or with records that are not up-to-date by current US immunization standards, must be immunized in order to enter school and are therefore at risk of receiving duplicate or unnecessary vaccines. 1,2 Current practice is to immunize individuals Marisol Figueira, MD: Maxwell Finland Laboratory for Infectious Diseases, Boston Medical Center; Demian Christiansen, MPH: Data Coordinating Center, Boston University School of Public Health; Elizabeth D. Barnett, MD: Maxwell Finland Laboratory for Infectious Diseases, Boston Medical Center, Boston, MA, USA. This study was presented in part at the 6th Conference of the International Society of Travel Medicine, Montreal, Quebec, Canada, 1999, and at the Pediatric Academic Societies and the American Academy of Pediatrics Joint Meeting, Boston, Massachusetts, This study was funded in part by the Joel and Barbara Alpert Children of the City Endowment and the Alden Trust. Apart from this, the authors had no financial or other conflicts of interest to disclose. Correspondence: Marisol Figueira, MD, Maxwell Finland Laboratory for Infectious Diseases, Room 507, Boston Medical Center, 774 Albany Street, Boston, MA 02118, USA J Travel Med 2003; 10: without immunization records rather than test for immunity to vaccine-preventable diseases. Unnecessary immunization may result in additional cost, 3 risk of vaccine adverse events, 4 and inconvenience to families, and is a wasteful strategy in an era plagued by vaccine shortages. There are, to date, no analyses of the cost-effectiveness of serotesting versus presumptive immunization in immigrant populations. Detailed age- and region-specific data on the seroprevalence of vaccine-preventable diseases may be unavailable.in addition,formal cost-effectiveness analyses require precise clinical, epidemiologic and economic information, some or all of which may not be available for immigrant populations. 5 We were interested in determining the most costeffective approach to protecting newly arrived refugee children against varicella by finding the most appropriate strategy combining serotesting and immunization. We chose varicella because: the majority of refugee children who attended our clinic had not received varicella vaccine; we had studied the age-specific varicella seroprevalence for these refugee children; 6 and,in the United States,the only vaccine available is a relatively expensive singleantigen vaccine. We also studied the reliability of varicella history in refugee children, and the feasibility of using history alone to assess the presence or absence of antibody to varicella. 203

2 204 Journal of Travel Medicine, Volume 10, Number 4 Methods Study Population Six hundred and thirty-seven refugee children, 1 to 20 years of age, from six geographic regions (former Yugoslavia, Kosovo, East Africa, Vietnam, Iraq/Kurdistan, and the Caribbean) were seen between March 1996 and January 2000 for a two-visit refugee health assessment at the International Clinic at Boston Medical Center. We recorded demographic information for each subject, including date of birth, birthplace, sex, history of varicella disease, and history of previous immunization. The Institutional Review Board at Boston Medical Center approved this study. The prevalence of varicella antibody from these refugee children was calculated and described previously. 6 We divided children into three age groups (1 to 4, 5 to 12 and 13 to 20 years) based on two factors:first,children 13 years of age and older require two doses of varicella vaccine; second, there was a notable difference in the agespecific prevalence of varicella between children less than 5 years of age and those 5 years of age and older.children less than 1 year of age were excluded because of the presence of maternal antibody to varicella and because varicella vaccine is licensed for children 1 year of age and older. We classified patients who reported an uncertain history of varicella as having a negative history. Patients for whom a history of varicella was not recorded were excluded from the calculation of positive and negative predictive value. Cost-effectiveness Analysis Cost-effectiveness analysis of serotesting versus universal immunization was performed using a model described by Plans Rubio. 5 We used this model to calculate a critical value of prevalence of antibody (p*), defined as the antibody prevalence above which it is more cost-effective to test for antibody than to immunize without testing. The equation used in the model is: S p* V [(1 PV)DAEC] where S is the screening cost for varicella antibody, V is the vaccination cost, PV is the positive predictive value of the ELISA test, C is the vaccine compliance, D is the mean cost of disease, A is the attack rate, and E is the vaccine efficacy. The screening cost for varicella antibody was $17 at Boston Medical Center, and the vaccination cost, based on the CDC contract price of varicella vaccine plus the cost of vaccine administration,was $49.78 per dose. 7 The positive predictive value (PV) of the ELISA test was 98% (Diamedix Corp., Miami, FL, USA). Vaccine compliance for the first dose was 100%; for the second dose, compliance was assumed to be equivalent to attendance at follow-up visits in our clinic (96%). We assumed a mean disease cost of varicella in children 13 years of age of $37, and for those 13 years of age, $42. 8 We assumed an attack rate of 90% in susceptible individuals, vaccine efficacy of one dose of vaccine in children 13 years of age of %, and vaccine efficacy of one dose of vaccine in children 13 years of age of 89%. 8 Statistical Methods We calculated the prevalence of antibody to varicella and 95% confidence intervals (95% CI) for each age group and region of origin using SAS v8.12 (Cary,NC,USA). We calculated the PPV and negative predictive value (NPV) of varicella history with 95% CI for each age group and region. Results Six hundred and thirty-seven refugee children were tested from six regions: 274 from former Yugoslavia, 97 from Kosovo, 155 from East Africa, 40 from Vietnam, 36 from Iraq/Kurdistan, and 35 from the Caribbean. The critical value of antibody prevalence (p*) was 34% in children < 13 years old, who required only one dose of varicella vaccine,and 17% in children 13 years old, who required two doses of varicella vaccine (Fig.). The prevalence of varicella antibody was less than 34% in children 1 to 4 years of age;it was therefore costeffective to immunize without serotesting this group of children. In children 5 to 12 years of age, the prevalence of varicella antibody by region was greater than 34%; thus, serotesting before immunizing was cost-effective. Interpretation of the data from Vietnamese children was limited by small sample size in this age group. In children 13 to 20 years of age,the prevalence of varicella antibody was greater than 17%; therefore, serotesting before immunizing was cost-effective. Sensitivity Analysis The critical value of antibody prevalence is sensitive primarily to variation in screening cost (S), vaccination cost (V) and compliance (C). It is less sensitive to variations in epidemiologic parameters. In children less than 13 years of age (who require one dose of vaccine), if the vaccine cost remains stable at $50 and the screening test cost is increased from $17 to $40, p* increases from 34% to 80%. Likewise, p* increases from 34% to 80% if the screening test cost remains constant at $17 and the vaccine cost is decreased from $50 to $ In both cases, the best strategy would be

3 Figueira et al., Cost-Effectiveness of Serotesting Compared with Universal Immunization % 95% 90% 85% 80% 75% 70% 65% 60% 55% 50% 45% 40% Serotest 35% 30% 25% Immunize 20% 15% 10% 5% 0% (n = 119) 5 12 (n = 301) (n = 217) Age group (years) Prevalence of antibody Former Yugoslavia East Africa Iraq/Kurdistan Kosovo Caribbean Vietnam Figure Prevalence of varicella antibody by age and region with the critical value of prevalence superimposed.

4 206 Journal of Travel Medicine, Volume 10, Number 4 to immunize for varicella rather than to serotest children less than 13 years of age. For children older than 13 years, if the vaccine cost remains stable at $100 ($50 each for two doses of vaccine) and the screening test cost is increased from $17 to $40, p* increases from 17% to 40%.The vaccine cost must be decreased from $100 to $21.50 for two doses of vaccine in order for p* to increase from 17% to 40% when the screening test cost remains constant at $17. The best strategy remains serotesting children older than 13 years of age rather than universally immunizing. For immunization without testing for antibody to be cost-effective in children 13 years of age and older, either the vaccine cost must be very low or the screening test cost very high.for example,to arrive at a critical value of prevalence of 95% or greater, at a vaccine cost of $50 per dose, the screening test cost would have to rise from $17 to $95 or more. Similarly, if the screening test cost remained $17, the vaccine cost would have to decrease from $50 to $9.10 per dose. PPV and NPV of History of Varicella History of varicella was available for 361/637 (56%) charts reviewed. One hundred and sixty-three (45%) reported a positive history of varicella, 166 (46%) reported a negative history of varicella, and 32 (9%) reported an uncertain history of varicella (classified as negative history). The Table shows the PPV (probability of positive serology when history is positive) and NPV (probability of negative serology when history is negative) of varicella history with 95% CI by age group and region of origin. The PPV of a positive history was high among children in all regions except Vietnam. The NPV of a negative history was a poor indicator of the absence of varicella antibodies. Discussion Ideally, policy decisions about new health programs should be based not only on clinical effectiveness, but also on cost-effectiveness. 9 We were interested in developing a policy for varicella immunization for refugee and immigrant children that would limit the number of unnecessary immunizations in a cost-effective way. Our results showed that the most cost-effective strategy for protecting children against varicella is to immunize children under 5 years of age without serotesting, and to serotest children 5 years of age and older prior to immunizing. The diverse geographic, climatic and socioeconomic situations from which our patients come suggest that generalizing to other immigrant populations may be possible. This strategy has the disadvantage that susceptible children will remain susceptible while awaiting results of serotesting, although this will become of less importance as the prevalence of varicella in the United States decreases. Finally, this strategy will be less desirable if children are unlikely to return for a second visit. A negative or uncertain history of varicella is a poor predictor of absence of immunity to varicella in refugee children. The NPV of varicella history ranged between 28% and 66% among children from the six geographic regions studied, similar to results of studies in US populations. Lieu et al found that varicella antibody prevalence in US children 7 to 12 years of age with negative and uncertain histories of varicella ranged from 9% in 7-year-olds to 68% in 11-year-olds. They concluded that serotesting of patients with negative or uncertain histories of varicella would be more costeffective than presumptive vaccination in children 9 to 12 years old, where varicella seroprevalence was greater than 48%. 10 Others have reported that up to 80% of adolescents with negative and uncertain histories of varicella have positive varicella serology, which supports serotesting for previously unknown exposure to varicella, rather than presumptive vaccination. 11 Our study showed similar results, with the NPV of varicella history lower among refugee adolescents than among younger children in all regions (Table). The large number of records with missing information about varicella history was a potential source of bias. Among these patients, the prevalence of antibody was approximately the same as for patients included in the analysis. If we had assumed an uncertain or missing history of varicella to be negative, as is standard clinical practice, and had included them in the analysis, neither PPV nor NPV would change.the increase in the number of subjects with a negative history would result in narrower confidence intervals around values of NPV. The accuracy of histories of varicella was a potential limitation of our study. Possible explanations for difficulty in obtaining accurate varicella history in refugee children could be language barriers, translation problems, lack of knowledge of the disease, and no caregivers present during the health assessment. In general, history of varicella is correlated with immunity in both children and adults. 12 Currently, the standard is to not immunize children with a positive history. 13 We chose to test all individuals, even those with a positive history of varicella, because we were uncertain of the accuracy of varicella history in this refugee population. A positive history of varicella is an acceptable alternative to serotesting children over 5 years of age, and will be even more cost-effective than serotesting all these children,but it will leave a small number of susceptible individuals. If a prevalence of immunity to varicella in the population of 97% is required to prevent the spread of outbreaks, accepting a history of varicella as a surrogate for protection may be inadequate to eliminate varicella in the United States. 14

5 Figueira et al., Cost-Effectiveness of Serotesting Compared with Universal Immunization 207 Table Positive and Negative Predictive Values of History of Varicella Stratified by Age Group and Region of Origin Former Age group (years) Yugoslavia East Africa Iraq/Kurdistan Caribbean Vietnam Kosovo 1 4 n PPV% (95% CI) 100 ( ) * 100 ( ) * 0 ( ) 100 ( ) NPV% (95% CI) 96 (89 100) 100 ( ) 100 ( ) 0 ( ) 100 ( ) 80 (56 100) 5 12 n PPV% (95% CI) 94 (89 99) 100 ( ) 100 ( ) 100 ( ) 40 (10 70) 100 ( ) NPV% (95% CI) 54 (43 65) 35 (5 55) 100 ( ) 57 (29 85) 40 (10 70) 72 (58 86) n PPV% (95% CI) 91 (83 99) 100 ( ) 100 ( ) 100 ( ) 66 (43 89) 100 ( ) NPV% (95% CI) 35 (22 49) 25 (6 44) 0 ( ) 20 (0 50) 50 (26 75) 8 (0 17) Overall n PPV% (95% CI) 93 (89 97) 100 ( ) 100 ( ) 100 ( ) 50 (33 67) 100 ( ) NPV% (95% CI) 66 (59 73) 43 (29 57) 60 (37 83) 46 (24 68) 37 (20 54) 28 (18 38) *Infinity indicates that we had no individuals with a positive history and a positive test (resulting in division by 0). Conclusions Varicella immunization without serotesting was costeffective in children less than 5 years of age. In children 5 years of age and older, testing for varicella prior to immunization was cost-effective. A negative history of varicella was a poor indicator of the absence of varicella immunity. Immunizing all patients with a negative history is not cost-effective. A history of varicella was a good indicator of the presence of varicella antibody. Accepting a history of varicella in adolescents is cost-effective, but may result in a small number of susceptible individuals. References 1. American Academy of Pediatrics, Committee on Infectious Diseases. Recommended childhood immunization schedule United States, January December Pediatrics 2003; 111: American Academy of Pediatrics. Immunization in special clinical circumstances. In: Pickering LK, ed Red Book: Report of the Committee on Infectious Diseases, 26th edn. Elk Grove Village, IL: American Academy of Pediatrics, 2003: Feikema SM, Klevens RM, Washington ML, Barker L. Extra immunization among US children. JAMA 2000; 283: American Academy of Pediatrics. Vaccine safety and contraindications. In: Pickering LK, ed Red Book: Report of the Committee on Infectious Diseases, 26th edn. Elk Grove Village, IL: American Academy of Pediatrics, 2003:37 49, Plans Rubio P. Critical value of prevalence for vaccination programmes. The case of hepatitis A vaccination in Spain. Vaccine 1997; 15: Barnett ED, Christiansen D, Figueira M. Seroprevalence of measles, rubella and varicella in refugee children. Clin Infect Dis 2002; 35: Centers for Disease Control and Prevention. Vaccine price list: 8. Lieu TA, Finkler LJ, Sorel ME, Black SB, Shinefield HR. Cost-effectiveness of varicella serotesting versus presumptive vaccination of school-age children and adolescents. Pediatrics 1995; 95: Lieu TA, Cochi SL, Black SB, et al. Cost-effectiveness of a routine varicella vaccination program for US children. JAMA 1994; 271(5): Lieu TA, Black SB, Takahashi H, et al. Varicella serology among school age children with a negative or uncertain history of chickenpox. Pediatr Infect Dis J 1998; 17: Harel Z, Ipp L, Riggs S, et al. Serotesting versus presumptive varicella vaccination of adolescents with a negative and uncertain history of chickenpox. J Adolesc Health 2001; 28: Ross AH,Lencher E,Reittman G.Modification of chickenpox in family contacts by administration of gamma globulin. N Engl J Med 1962; 267: American Academy of Pediatrics. Serologic testing before and after immunization. In: Pickering LK, ed Red Book: Report of the Committee on Infectious Diseases, 26th edn. Elk Grove Village, IL: American Academy of Pediatrics, 2003: Gershon A, Takahashi M, White CJ. Varicella vaccine. In: Plotkin S, Orenstein WA, eds. Vaccines, 3rd edn. Philadelphia: WB Saunders Company, 1999: