PEDIATRICS Vol. 108 No. 5 November 2001, pp. 1123-1128

Childhood Hepatitis B Virus Infections in the United States Before Hepatitis B Immunization

Gregory L. Armstrong, MD^*, Eric E. Mast, MD, MPH^*, Mary Wojczynski, MPH, and Harold S. Margolis, MD^*

From the ^* Hepatitis Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, and  Immunization Services Division, National Immunization Program, Centers for Disease Control and Prevention, Atlanta, Georgia.

	ABSTRACT

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Objective.  To estimate the number of hepatitis B virus (HBV) infections among US children younger than 10 years before implementation of routine childhood hepatitis B immunization.

Methods.  Incidence of HBV infection in children was modeled from existing prevalence data by means of regression analysis. Sources of data for the models included published and unpublished surveys that determined the prevalence of HBV infection in US-born children. The number of nonperinatal HBV infections in children younger than 10 years was estimated by applying these infection rates to 1991 population data according to maternal race, ethnicity, and birthplace.

Results.  Estimated annual rates of infection ranged from 24 per 100 000 in non-Asian children to 2580 per 100 000 in children of Southeast Asian immigrant mothers. These rates indicate that by the early 1990s, HBV was infecting 16 000 children who were younger than 10 years (8700 non-Asian children and 7300 Asian-American children) annually. The total estimate, not including perinatal infections, ranged from 12 000 (95% confidence interval: 5500-27 700) to 24 900 (95% confidence interval: 16 700-42 300) infections and depended on how the estimated rates were applied to the population data.

Conclusion.  Thousands of US children were infected each year with HBV before routine infant hepatitis B immunization, placing them at high risk of death from cirrhosis or hepatocellular carcinoma later in life.  Key words:  hepatitis B, incidence, prevalence, immunization.

Hepatitis B virus (HBV) infection in young children rarely produces symptoms that are recognizable as hepatitis^1-3 but frequently leads to a chronic infection that can progress to end-stage liver disease. Adults who have had chronic HBV infection since childhood develop hepatocellular carcinoma at a rate of 5% per decade, which is 100 to 300 times the rate observed among uninfected people in the general population.^4-6 Because the risk of chronic infection increases with decreasing age,^2,7 people who are infected in early childhood experience a disproportionately large burden of disease attributable to HBV.

HBV infection is now almost completely preventable by immunization. In populations in which the infection is highly endemic, routine childhood immunization has led to dramatic decreases in the prevalence of chronic infection^8-10 as well as declines in childhood mortality from hepatocellular carcinoma.¹¹

In the United States, the Advisory Committee on Immunization Practices first recommended hepatitis B vaccination for infants who were born to HBV-infected mothers in 1982¹² and expanded this recommendation in 1988 to include all infants in racial/ethnic groups with high rates of chronic HBV infection. By the early 1990s, accumulating data showed that many children remained at risk for HBV infection because of incomplete maternal screening¹³ and because a substantial proportion of infections occurred in children of hepatitis B surface antigen (HBsAg)-negative mothers.^14,15 Furthermore, hepatitis B surveillance data indicated that adults and adolescents who were at high risk of infection were not being vaccinated and that 30% of cases in adults were associated with no recognizable risk factors.¹⁶ With these data and a growing body of evidence that hepatitis B vaccination was safe, the Advisory Committee on Immunization Practices expanded its hepatitis B immunization recommendations in 1991 to include all infants, primarily to stop HBV transmission among children^14,1517-19 and eventually also to prevent HBV infections in adolescents and adults.²⁰

Recently, critics of routine infant immunization have asserted that HBV infection is rare and of little consequence in children.^21,22 The low priority accorded to hepatitis B immunization also contributed to a 1999 recommendation to delay the initiation of infant hepatitis B immunization until thimerosal preservative-free vaccine was available.²³ To quantify better the burden of HBV from infections acquired during childhood, we analyzed published and unpublished data to estimate the annual number of nonperinatal childhood infections that occurred in the United States before routine immunization.

	METHODS

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Incidence Model

The incidence of HBV infection was estimated from age-specific prevalence data by means of "catalytic" models,^24,25 the mathematical details of which are specified in the appendix. The model functioned much like a simple linear regression model in which the dependent variable was the prevalence of serologic markers of HBV infection and the independent variable was age. The intercept (at age = 0) was fixed at a proportion equal to the rate of perinatal HBV infection, and the slope of the line, an estimator of the incidence of infection, was determined by regression analysis. This simple linear model was used to estimate the average incidence over the lifetimes of the children in each study population because there were not enough data to apply more complicated models capable of estimating age-specific incidence. This linear model also assumed that HBV infection was not associated with increased mortality in children and that infected children retained serologic evidence of infection (HBsAg, antibody to HBsAg [anti-HBs], or antibody to hepatitis B core antigen [anti-HBc]).

Prevalence Data Sources

The incidence of HBV infection among non-Asian Americans was modeled from prevalence data obtained in the second and third National Health and Nutrition Examination Surveys (NHANES II, 1976-1980,²⁶ and NHANES III, 1988-1994²⁷ [the "NHANES model"]). Analysis was restricted to US-born non-Asian participants who were 0 to 11 years of age. Only those who tested positive for anti-HBc and at least 1 other marker of HBV infection (anti-HBs or HBsAg) were considered to have been infected. To estimate the rate of perinatal HBV infection in this population, we assumed that the prevalence of HBsAg in mothers of these children was 0.17% on the basis of a meta-analysis of 18 studies of 26 959 pregnant, non-Asian women in the United States (M. Wojczynski, unpublished data) and that in the absence of postexposure prophylaxis 42% of children of HBsAg-positive mothers would be infected during the perinatal period,²⁸ giving an overall perinatal infection rate of 0.07%.

Four different prevalence studies were used to construct 3 incidence models for Asian-American children. The "Southeast Asian model" used data from 2 studies: a survey of US-born children of Hmong refugees living in Wisconsin¹⁵ and a survey of US-born children of Vietnamese immigrants living in Louisiana.²⁹ No perinatal HBV transmission was assumed in this model because in the studies used to derive this model, children who were born to HBsAg-positive mothers were excluded. The criteria for HBV infection were as described in the original articles (anti-HBc-positive in the Louisiana study²⁹ and anti-HBc- or HBsAg-positive in the Wisconsin study¹⁵).

The "Chinatown model" used data from a 1996 survey of students who were attending 2 public schools in New York City's Chinatown (Centers for Disease Control and Prevention, unpublished data). Students who were foreign-born or non-Asian or who had received hepatitis B vaccine were excluded from the analysis. Students were considered to be HBV-infected if they tested positive for HBsAg or for both anti-HBs and anti-HBc. Because an effective program to prevent perinatal HBV infection had been in place for this population since the mid-1980s,³⁰ we assumed no perinatal infection in unvaccinated children.

The "Honolulu model" was based on a survey of students who were attending 48 of Honolulu's 54 public schools in 1989.³¹ Only Hawaiian-born participants were included in the model, and the criteria for HBV infection were as described for the Chinatown model. However, children in this study were too old to have participated in Hawaii's perinatal hepatitis B prevention program, which began in 1985. We assumed that 1.2% of these children would have been born to HBsAg-positive mothers (P. Effler, Hawaii Department of Health, unpublished data), and 42% of these,²⁸ or 0.5%, would have been infected perinatally.

Population Estimates

The number of children who were younger than 10 years in the United States in 1991 was estimated from the Current Population Survey.³² The race, ethnicity, and birthplace of the mothers of these children were obtained by reviewing computerized natality records for the previous 10 years, in which Asian-American ethnicity was specified as Chinese, Japanese, Hawaiian, Filipino, or "other Asian, Pacific Islander." Natality data from 1997,³³ which included more categories of Asian-American ethnicity than data from previous years, was used to divide further the category of "other Asian, Pacific Islander" into Guamanian, Vietnamese, Korean, Asian Indian, and Samoan.

Calculation of Race/Ethnic-Specific Infection Rates

To determine the number of early childhood HBV infections in each racial/ethnic group, we applied the infection rates estimated from the models to the 1991 US population aged 0 to 9 years according to maternal race and birthplace (US-born vs foreign- born). The infection rate from the NHANES model was applied to children of white, black, Hispanic, and American Indian mothers, and the rate from the Honolulu model was applied to children of Hawaiian mothers. Rates of infection in other Asian-American children were assumed to vary in proportion to the prevalence of HBsAg in their mothers, and these rates were estimated from published data (Table 1).³⁴ The HBV infection rate from the Chinatown model was applied directly to children of Chinese women. For children of Filipino and Korean mothers, 50% of the Chinatown model infection rate was used and one fifth of this infection rate was applied to children of Indian and Japanese women.³⁴ The rate from the Southeast Asian model was applied to children of Vietnamese and Pacific Islander women.^34,35 The weighted average infection rate of children whose mothers were of known Asian or Pacific Island origin was applied to children whose mothers were of unspecified Asian or Pacific Island origin. The HBV infection rate was assumed to be 5 times lower for children of Asian or Pacific Island descent whose mothers had been born in the United States compared with children whose mothers were foreign-born.³⁶

Sensitivity Analysis

We considered 2 alternatives to the "base rate" scenario described above. In the "low rate" scenario, rates from the Chinatown model were applied to the population data in place of the rates from the Southeast Asian model. In the "high rate" scenario, the reverse was done (ie, rates from the Southeast Asian model were applied in place of rates from the Chinatown model).

	RESULTS

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The incidence of childhood HBV infection varied considerably among the different population models (Table 2 and Fig 1). Among non-Asians (the NHANES model), the incidence estimate with the most conservative criteria for HBV infection (anti-HBc positive and either anti-HBs or HBsAg positive) was 23.7 per 100 000 (95% confidence interval [CI]: 9.0-62.3). Using a less conservative definition of HBV infection (the presence of any of the 3 HBV infection markers), the estimated incidence rate was 102.7 per 100 000 (95% CI: 65.7-160.5).

View larger version (24K): [in this window] [in a new window]   Fig. 1.   In each of the 4 graphs, the circles represent the data points used to model incidence. The areas of the circles are proportional to the number of observations at each point (the scale is different in each graph). The solid line represents the modeled incidence, and the dotted lines represent the 95% CIs. Note that the scale of the y axis is different in each graph.

When modeled separately, the data from Hurie et al¹⁵ and Mahoney et al²⁹ produced incidence estimates of 3280 (95% CI: 2420-4460) and 2290 per 100 000 (95% CI: 1810-2900), respectively. Because these rates were not different statistically, the 2 studies were combined into a single model, the Southeast Asian model (Table 2). Rates in the Chinatown and Honolulu models were approximately one fifth and one seventeenth that of the Southeast Asian model, respectively (Table 2).

By application of the HBV infection rates from the respective models to the 1991 US population data, it is estimated that 15 950 (95% CI: 8980-32 190, Tables 3 and 4) children who were younger than 10 years were infected annually. In the sensitivity analysis, the estimated number of infections per year depended on how the rates from the Chinatown and Southeast Asian models were applied to the racial/ethnic distribution of children in the United States (Table 4).

	DISCUSSION

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On the basis of prevalence of markers of HBV infection in US children, we estimated that 16 000 children who were younger than 10 years were infected in 1991, with the number of infections almost equally divided between Asian American and non-Asian children. Most of these infections would have been clinically silent and unrecognized, because infection at a young age rarely results in symptoms that are suggestive of hepatitis.^1,2 This estimate is consistent with a previous, less refined estimate of early childhood infection in the United States³⁷ and does not include perinatal infections in the approximately 15 000 children who were born to HBsAg-positive mothers in 1991 (M. Wojczynski, unpublished data).

Since 1991, the number of US children who are born to HBsAg-positive women has increased substantially attributable in large part to increases in foreign-born Asian-American women of childbearing age. Applying the estimated maternal prevalence of HBsAg (M. Wojczynski, unpublished data) and the rates of childhood infection from our model to 1998 births,³⁸ there would have been 6800 perinatal infections and an additional 18 700 infections in the first 10 years of life among this birth cohort had no vaccination taken place. Chronic infection would occur in 90% of those infected in the perinatal period, 60% of those infected before 2 years of age, and 25% of those infected between ages 2 and 9 years.^2,7 Thus, 12 100 children would have been chronically infected, half in the perinatal period and the other half after birth but before their 10th birthday. Many of the chronically infected children would develop chronic liver disease later in life, and approximately 25%,^4,5 or 3000, would eventually die from cirrhosis or hepatocellular carcinoma. However, according to the most recent National Immunization Survey, approximately 90% of children are now fully immunized with 3 doses of the hepatitis B vaccine by their second birthday. Thus, as a direct effect of vaccination, the 1998 birth cohort can expect at least 2700 fewer deaths from chronic liver disease as it grows to adulthood.

Although the estimates of infection incidence for Asian-American children of foreign-born mothers were the most robust, they also highlight the limitations of the prevalence studies conducted before introduction of routine childhood hepatitis B immunization in the United States. These included small sample size and, for some, lack of information about maternal HBsAg status as a surrogate for risk of perinatal infection. In addition, because of the lack of data, precise estimates of HBV infection rates could not be made for the respective Asian-American ethnic groups. However, the 17-fold difference in incidence estimates most likely reflects the true heterogeneity in HBV infection incidence found among Asian immigrant communities.³⁴

Estimates of childhood HBV infection in black, Hispanic, and white children are less precise than those derived from Asian Americans for 2 reasons. First, because HBV infection rates were lower among non-Asian children, the 2 NHANES surveys, although large, did not have serologic data from enough children to yield age-specific prevalence or incidence estimates that were as precise as those obtained from studies of Asian children. Second, the true rate of perinatal infection was unknown and had to be estimated from external sources of data. However, if the rate of perinatal HBV infection were lower than the assumed 0.07%, then the true rate of early childhood infection would have been higher than that estimated by the NHANES model.

We were not able to estimate directly the proportion of childhood HBV infections that occurred among children who were born to HBsAg-positive mothers and among children who were born to HBsAg-negative mothers because maternal HBsAg status was not available for all studies. However, in 2 population-based studies conducted among Asian-Pacific Islander children who were born before perinatal hepatitis B prevention programs were widely implemented in the United States, 61% to 66% of chronic HBV infections were among children who were born to HBsAg-negative mothers.^15,29 Many of these chronic infections among children who were born to HBsAg-negative mothers would not be prevented by identification and immunization of infants who were born to HBsAg-positive mothers. Thus, both prevention of perinatal hepatitis B and routine infant hepatitis B immunization are required to prevent all early childhood HBV infections.⁸

Horizontal HBV transmission between children in households has been well documented in the United States^14,15,29 as well as transmission from adults to children.^1439-41 In addition, transmission may occur outside the household setting. For example, studies in Louisiana,²⁹ Wisconsin,¹⁵ and Georgia¹⁴ found that approximately one third of HBV infections among children who were born to HBsAg-negative mothers occurred in households where no other chronically infected household member was identified. The mechanisms of horizontal HBV transmission are not completely defined but presumably involve inapparent percutaneous or permucosal exposure to blood or body fluids that contain HBV. In addition to blood, HBV has been found in impetiginous exudates and saliva, albeit at concentrations lower than in blood.⁴² HBV also survives in the environment for at least 7 days, and HBsAg has been detected on environmental surfaces of households of chronically infected individuals.^43,44 Risk factors for horizontal HBV transmission in household settings include contact with dermatologic lesions,⁴⁵ premastication of food, and sharing washcloths or other articles contaminated with blood or body secretions.^43,46

The need for infant hepatitis B immunization in the United States has been questioned in the past⁴⁷ and again more recently^21,22 because of misconceptions about the importance of childhood HBV infection in United States. The lack of appreciation that HBV infection occurs among infants who are born to HBsAg-negative mothers contributed to a recent recommendation that, until thimerosal preservative-free hepatitis B vaccine became available, immunization be delayed until after 6 months of age.^23,48 This recommendation, although intended to be temporary, has had a lasting effect on immunization rates despite the current availability of preservative-free vaccine.⁴⁹

A recent study of teenage, first-time blood donors showed that of 2061 HBsAg-positive people identified, half were Asian American and 13% of the Asian Americans had been born in the United States.⁵⁰ Continued childhood HBV infection has implications both for personal health outcomes and for public health, including the adequacy of the nation's blood supply. If hepatitis B immunization were to have ceased in the 1990s, then thousands of children would have become chronically infected each year, which in the long-term would lead to a large number of deaths from end-stage liver disease.²⁸ Our analysis of widely available data support the need for universal infant immunization to prevent chronic hepatitis B and the substantial burden of hepatitis B-related chronic liver disease that would be acquired during infancy and early childhood.²⁰

	APPENDIX

The incidence of HBV infection was assumed to be constant with respect to time and age such that P(A), the prevalence of HBV infection in a cohort of age A, is given by: where P₀ is the rate of perinatal infection and  is the incidence in the susceptible population. Lambda and its standard error were estimated by maximum likelihood methods, except for analyses involving the NHANES surveys, in which standard errors were estimated by means of the balanced repeat replicate method.⁵¹ Ninety-five percent CIs were calculated assuming that the logarithm of incidence was normally distributed.

	FOOTNOTES

Received for publication Feb 28, 2001; accepted May 8, 2001.

Reprint requests (G.L.A.) Mailstop G-37, 1600 Clifton Rd, NE, Atlanta, GA 30333. E-mail: garmstrong{at}cdc.gov.

	ABBREVIATIONS

HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; anti-HBs, antibody to hepatitis B surface antigen; anti-HBc, antibody to hepatitis B core antigen; NHANES, National Health and Nutrition Examination Survey; CI, confidence intervals.

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