Cytomegalovirus Seroprevalence among Children 1-5 Years of Age in the United States: The National Health and Nutrition Examination Survey,

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1 CVI Accepts, published online ahead of print on 17 December 2014 Clin. Vaccine Immunol. doi: /cvi Copyright 2014, American Society for Microbiology. All Rights Reserved. 1 2 Cytomegalovirus Seroprevalence among Children 1-5 Years of Age in the United States: The National Health and Nutrition Examination Survey, Tatiana M. Lanzieri, MD, MPH a#, Deanna Kruszon-Moran, MS b, Minal M. Amin, MPH a, Stephanie R. Bialek, MD, MPH a, Michael J. Cannon, PhD c, Margaret D. Carroll, MSPH b, Sheila M. Dollard, PhD a Affiliations: a National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA; b National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, MD; c National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA. # Corresponding author: Tatiana M. Lanzieri, tmlanzieri@cdc.gov, phone: , fax: Running title: CMV seroprevalence among U.S. children Abbreviations: CMV cytomegalovirus, NHANES National Health and Nutrition Examination Survey; IgG immunoglobulin G, IgM immunoglobulin M Abstract length: 50 words Text length: 1,500 words

2 24 25 Financial Disclosure: The authors have no financial relationships relevant to this article to disclose Funding Source: No external funding was used for this study Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Downloaded from on July 26, 2018 by guest

3 ABTRACT Cytomegalovirus (CMV) seroprevalence among U.S. children 1-5 years-old was assessed in the National Health and Nutrition Examination Survey Overall seroprevalence (95% confidence interval) of IgG was 20.7% ( %), IgM 1.1% ( %), and low IgG avidity 3.6% ( %), corresponding to a 17.3% ( %) prevalence of recent infection among IgG-positive children. Keywords: cytomegalovirus, prevalence, survey, children, NHANES TEXT Congenital cytomegalovirus (CMV) infection is a major cause of sensorineural hearing loss and developmental disabilities in children in the United States (1). An estimated 0.7% of U.S. infants are born with congenital CMV infection (1). Early in life CMV infection generally results from mother-to-infant transmission through exposure to the virus in genital secretions during birth or postnatally via breast milk (2). CMV seroprevalence continues to rise throughout early childhood as infants and young children acquire CMV infection via exposure to body fluids from other infected individuals, especially from close contact with young children in household or day care settings (3, 4). Young CMV-seropositive children, who may shed virus in body fluids for months after primary CMV infection, are thought to be an important source of CMV transmission to adults (5). Population-based estimates of CMV seroprevalence among young children in the United States have not been previously reported. In this study, we describe CMV seroprevalence among U.S. children 1-5 years-old, who were sampled in the National Health and Nutrition Examination Survey (NHANES) in

4 Methods of the NHANES, a nationally representative, cross-sectional survey of the civilian non-institutionalized U.S. population have been published elsewhere (6). The NHANES oversampled non-hispanic Asians, in addition to Hispanics (including Mexican Americans), non-hispanic Blacks, and low-income non-hispanic Whites and other persons to increase sample size and obtain more statistically reliable estimates of these subgroups (6). National estimates of CMV seroprevalence for CMV IgG, IgM and low IgG avidity were calculated using the exam weights developed for the NHANES to represent the total civilian non-institutionalized U.S. population and to account for oversampling and nonresponse to the household interview and physical examination (7). Seroprevalence of CMV IgG was examined by age in years, sex, race/hispanic origin, and poverty index ratio. Race/Hispanic origin was collected by proxy and categorized as non- Hispanic White, non-hispanic black, non-hispanic Asian, Mexican American, other Hispanic, and other race (which includes multi-racial) (8). In our analysis, we combined Mexican American and other Hispanic to form the Hispanic group. The other race group (n=39) is included in overall estimates but is not shown separately due to small sample sizes and heterogeneity of participants in this group. Poverty-index ratio was calculated by dividing family income by a poverty threshold specific for family size using the U.S. Department of Health and Human Services' poverty guidelines and categorized as either below poverty [<1] or at or above poverty [ 1]) (9) Standard error estimates were calculated using Taylor Series Linearization to incorporate the complex sampling design. Estimates were considered unstable if: 1) the relative standard error around the proportion of seropositive or seronegative participants was > 30%; 2) the estimate was based on < 10 seropositive or seronegative persons; or 3) the variance estimates

5 were based on < 12 degrees of freedom (7). For estimates of standard errors based on < 12 degrees of freedom, additional standard error estimates were calculated using a model-based average design effect method (10). Confidence intervals and t-statistics using the design-based method (Taylor Series Linearization) and the model-based average design effect method were compared. Because both methods yielded similar results, we report only those using the designbased method. The exact binomial method was used to calculate 95% confidence intervals (CIs) (11). Pairwise differences between seroprevalence estimates and tests for trends were evaluated using a t-statistic from an orthogonal linear contrast procedure and adjusted odds ratios and independent predictors of positivity were estimated from a logistic regression model, both in SUDAAN Version 9.0 (Research Triangle Institute, Research Triangle Park, NC); P-values < 0.05 were considered significant. Serologic testing of plasma specimens from the NHANES was conducted at the CDC CMV diagnostic laboratory. CMV IgG, IgM, and IgG avidity were all measured by VIDAS (biomerieux) (12). For measuring IgG avidity, a modified cutoff value of 0.7 that has been shown to provide improved sensitivity for detection of recent infection was used (12). A positive CMV IgG result indicates past or recent CMV infection, whereas the presence of CMV IgM is transient and can indicate a recent primary infection, reactivation, or reinfection. Low IgG avidity is typically present for 3-4 months after primary infection, after which high avidity IgG develops as a result of maturation of the humoral immune response (13) Among the 1,463 children 1-5 years-old who were sampled in NHANES , 1,203 (82.2% of those sampled) completed the home interview, 1135 (94.3% of those interviewed) completed the health examinations component, 741 (65.3% of those examined) had a blood sample successfully collected and 699 (61.6% of those examined) were tested for CMV

6 antibody. Those tested for CMV differed from those who were examined but not tested for CMV by age, poverty status, and race/hispanic origin (Table 1). Because the percent of sample persons with sufficient blood available for CMV testing out of those examined was <60% in many subgroups and differed by age, poverty status, and race/hispanic origin (Table 1) the analysis was repeated using new sample weights that accounted for the missing CMV testing data. Individual exam weights for those tested were inflated to account for those examined but not tested within all race/hispanic origin and age strata (14). Results from the reweighted analysis did not vary substantially from the original analysis so only the results using the original exam weights are reported. The overall seroprevalence of CMV IgG among children 1-5 years-old in the United States was 20.7%. IgG seroprevalence was lowest among 1 year-olds (12.3%) and highest among 5 year-olds (31.1%) (P<0.01 linear test for trend) (Table 1). There was no significant difference in IgG seroprevalence between males and females. IgG seroprevalences among non-hispanic Asians, Hispanics and non-hispanic Blacks were significantly higher than among non-hispanic Whites (P <0.05). However, the estimates for non-hispanic Whites and non-hispanic Asians were unstable. IgG seroprevalence was significantly higher among those living below the poverty line compared to those living at or above the poverty line (P <0.001). In the logistic regression model, age (5 years compared to 1 year), race/hispanic origin (non-hispanic Asian and Hispanic compared to non-hispanic White persons), and index ratio of family income (below versus at or above the poverty line) were independently associated with IgG seroprevalence (Table 1). The overall weighted seroprevalence of CMV IgM was 1.1% (95% CI, %). This estimate was based on 11 seropositive children with a relative standard error > 40% so results were considered unstable. The overall weighted prevalence of low IgG avidity

7 was 3.6% (95% CI, %), corresponding to a prevalence of recent infection among IgG- positive children of 17.3% (95% CI, %) Our study is the first to provide an estimate of CMV seroprevalence (20.7%) in a nationally representative sample of U.S. children 1-5 years-old. The only other study in healthy U.S. children that we are aware of reported 17% seroprevalence among children 1-5 years-old recruited from a single pediatric practice in Alabama in the 1980s (3). Our study did not include children <1 year-old, thus the detection of CMV IgG was not likely due to the presence of residual maternal antibody. We found that CMV IgG seroprevalence was higher in older children and in non-white and poorer children, consistent with trends reported for older children and adults in the United States using previous NHANES data (15). During , CMV seroprevalence among 6-11 year-olds was 38% overall and was higher in non-hispanic Black (~45%) and Mexican American (~ 60%) children than in non-hispanic White (~30%) children. Throughout adolescence and adulthood the prevalence differences across racial and ethnic subgroups increased with age, particularly among women (15). Wide variations in maternal seroprevalence, breastfeeding rates, and group childcare practices among racial and ethnic subgroups likely contribute to the differences in CMV seroprevalence observed across subgroups in children 1-5 years-old. We could not examine some other factors reported to be associated with CMV IgG seroprevalence in older children (4) because they either were not collected in NHANES (e.g. childcare attendance, maternal CMV serostatus) or were not yet available for analysis (family size, crowding index, household education level, history of breastfeeding). We could not assess the extent to which higher seroprevalences among non-hispanic Asian and Hispanic children reflected birth outside of the US because the number of foreign-born children was not large enough to provide reliable

8 estimates and parental country of origin was not collected. Our study lacked power to provide stable national seroprevalence estimates of IgG, low IgG avidity, or IgM for all subgroups. The seroprevalence data described in our study will be useful for modeling the potential impact of interventions. A better understanding of immune correlates of protection against CMV in young children and adults will be critical for the development of an effective CMV vaccine. Young children have been identified as a potential target population for CMV vaccination with the ultimate goal of prevention of congenital CMV infection. Because young children often shed CMV in urine and saliva for many months, a vaccine that provides protection against CMV infection in infants and toddlers could prevent congenital CMV infections by reducing CMV transmission from young children to women during pregnancy. REFERENCES 1. Dollard SC, Grosse SD, Ross DS New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection. Reviews in medical virology 17: Stagno S, Reynolds DW, Pass RF, Alford CA Breast milk and the risk of cytomegalovirus infection. The New England journal of medicine 302: Pass RF, Hutto SC, Reynolds DW, Polhill RB Increased frequency of cytomegalovirus infection in children in group day care. Pediatrics 74: Staras SA, Flanders WD, Dollard SC, Pass RF, McGowan JE, Jr., Cannon MJ Cytomegalovirus seroprevalence and childhood sources of infection: A population-

9 based study among pre-adolescents in the United States. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology 43: Hyde TB, Schmid DS, Cannon MJ Cytomegalovirus seroconversion rates and risk factors: implications for congenital CMV. Reviews in medical virology 20: Johnson CL, Dohrmann SM, Burt VL, Mohadjer LK National Health and Nutrition Examination Survey: Sample design, National Center for Health Statistics. Vital Health Statistics Centers for Disease Control and Prevention. National Center for Health Statistics. Division of Health and Nutrition Examination Surveys. National Health and Nutrition Examination Survey: Analytic Guidelines, [Available at: 8. Centers for Disease Control and Prevention. National Center for Health Statistics. Division of Health and Nutrition Examination Surveys. National Health and Nutrition Examination Survey, : Data Documentation, Codebook, and Frequencies. [Available at: 9. U.S. Department of Health and Human Services. Poverty Guidelines, Research, and Measurement. [Available at: Kovar MG, Johnson C Design effects from the Mexican American portion of the Hispanic Health and Nutrition Examination Survey: a strategy for analysis.. Proceedings of the American Statistical Association - Section on Survey Research Methods:

10 Korn EL, Graubard BI Confidence Intervals for Proportions with small expected number of positive counts estimated from survey data. Survey Methodology 24: Dollard SC, Staras SA, Amin MM, Schmid DS, Cannon MJ National prevalence estimates for cytomegalovirus IgM and IgG avidity and association between high IgM antibody titer and low IgG avidity. Clinical and vaccine immunology : CVI 18: Lazzarotto T, Guerra B, Lanari M, Gabrielli L, Landini MP New advances in the diagnosis of congenital cytomegalovirus infection. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology 41: Lohr S Sampling Design and Analysis. Duxbury Press, Albany, NY. 15. Bate SL, Dollard SC, Cannon MJ Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 50:

11 Table 1. Cytomegalovirus (CMV) IgG Seroprevalence in U.S. Children 1-5 Years of Age by Selected Demographic Factors, NHANES, Number of Children Examined Tested for CMV IgG among Examined CMV IgG Positive CMV IgG weighted a Seroprevalence Demographic factor n n % n % (95% CI) aor (95% CI) Total ( ) Age (years) ( ) Ref ( ) 1.7 ( ) ( ) b 2.0 ( ) ( ) 1.6 ( ) ( ) c 3.6 ( ) d Sex Male ( ) Ref. Female ( ) 1.2 ( )

12 Race/Hispanic origin d Non-Hispanic White ( ) f Ref. Non-Hispanic Black ( ) c 2.5 ( ) All Hispanic ( ) c 3.0 ( ) d Non-Hispanic Asian ( ) c,g 14.9 ( ) d Index ratio of family income to poverty line Below poverty line ( ) c 2.1 ( ) d At or above poverty line ( ) Ref. aor= adjusted odds ratio from logistic regression model Ref.=reference group a Estimated seroprevalence based on original exam weights from NHANES b Estimate considered unstable because the relative standard error was 32.4%. c P < 0.05 from t-statistic comparing subgroup to reference group within demographic characteristic, univariate analysis. d P < 0.05 from Satterthwaite-adjusted F statistic comparing subgroup to reference group adjusting for other demographic characteristics (gender, age, race/hispanic origin, index ratio of family income to poverty line), logistic regression model. e Children of other races are included in total estimates but are not shown separately.

13 f Estimate considered unstable because the relative standard error of the estimate was 44.3% and the degrees of freedom for the estimate of the standard error was < 12. g Estimate considered unstable because the degrees of freedom for the estimate of the standard error was < 12 and the sample size for the estimate was based on < 100 sample persons. Downloaded from on July 26, 2018 by guest