Am. J. Trop. Med. Hyg., 77(3), 2007, pp.

405410 Copyright 2007 by The American Society of Tropical Medicine and Hygiene

Toxoplasma gondii Infection in the United States, 19992004, Decline from the Prior Decade
Jeffrey L. Jones,* Deanna Kruszon-Moran, Kolby Sanders-Lewis, and Marianna Wilson
Division of Parasitic Diseases, National Center for Zoonotic, Vectorborne, and Enteric Diseases, CCID, Centers for Disease Control and Prevention, Atlanta, Georgia; Division of Health and Nutrition Examination Statistics, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Maryland

Abstract. Toxoplasma gondii can cause congenital, neurologic, ocular, and mild or asymptomatic infection. To determine the U.S. prevalence of T. gondii infection, we tested sera collected from the National Health and Nutrition Examination Survey (NHANES) 19992004 for T. gondii immunoglobulin G antibodies in persons 649 years old and contrasted the results to those comparable in NHANES III (19881994) (ages 1249 years). Of the 17,672 persons examined in NHANES 19992004, 15,960 (90%) were tested. The age-adjusted T. gondii seroprevalence among persons 649 years old was 10.8% (95% confidence limits [CL] 9.6%, 11.9%), and among women 1544 years old, 11.0% (95% CL 9.5%, 12.4%). T. gondii seroprevalence declined from 14.1% to 9.0% (P < 0.001) from NHANES III to NHANES 19992004 among U.S.-born persons ages 1249 years. Although T. gondii infects many persons in the U.S., the prevalence has declined in the past decade. Toxoplasma gondii is a nearly ubiquitous organism that infects humans, other mammals, and birds. However, only members of the cat family (Felidae) are the definitive host and shed the environmentally resistant oocyst form of the organism in their feces. Transmission to humans usually occurs by ingestion of cysts in undercooked meat and exposure to soil and water contaminated by oocysts. In rare cases, transmission by transfusion or organ transplantation has been reported. In general, humans are thought to be infected for life with cysts forming in the muscles, brain, and other organs, and IgG antibody production is thought to be lifelong. Human infections are usually asymptomatic or cause a selflimited illness with symptoms such as fever and lymph node enlargement. However, severe neurologic and ocular disease can occur with congenital infection and in immunesuppressed persons (usually reactivated disease). In addition, ocular disease has been estimated to occur in up to 2% of persons with normal immunity that are infected with T. gondii after birth.1 It is not yet known if chronic infection with T. gondii has other significant health-related consequences. Researchers are examining the effects of chronic T. gondii infection on reaction time,2 tendency for accidents,3 behavior,47 and mental illness.811 The prevalence of T. gondii varies greatly in populations throughout the world (from < 10% to > 90%) and is thought to be affected by food-production practices, water treatment, climate, topography, soil- and cat feces-related hygiene, occupational and non-occupational soil exposure, and culinary practices.1219 In the United States, there are an estimated 4004000 congenital infections per year,20 up to 1.26 million cases of ocular disease,1 and numerous cases of encephalitis and other systemic illnesses in immune-suppressed persons. Regardless of the source of infection, a reduction in the prevalence of T. gondii infection in the population will lead to many fewer cases of debilitating disease. In this study, we sought to determine the recent prevalence of T. gondii infection in the United States and compare it with that from a prior decade.

MATERIALS AND METHODS To monitor the prevalence of T. gondii infection in the United States, we tested sera collected in the National Health and Nutrition Examination Survey (NHANES) for the 6-year period from 1999 through 2004 and compared it to data from NHANES III (conducted from 1988 through 1994). The NHANES is a cross-sectional survey conducted by the National Center for Health Statistics (NCHS) based on a stratified, multistage probability cluster design from which a sample of the civilian, noninstitutionalized U.S. population is drawn. The NHANES collects representative health statistics on a variety of health measures and conditions through household interviews, standardized physical examinations, and collection of blood samples in mobile examination centers. Data has been collected continuously since 1999 and released in 2-year cycles. Non-Hispanic blacks, Mexican Americans, adolescents of age 1219 years, low-income persons, and persons age 60 and older are over-sampled to ensure adequate sample size. For the T. gondii antibody prevalence evaluation, we tested persons of age 649 years. Descriptions of the survey design and sampling methods have been published elsewhere.21,22 NHANES III and NHANES 19992004 were reviewed by the NCHS Institutional Review Board and included written informed consent. Variables used in data analysis were categorized as follows: age was grouped as 611, 1219, 2029, 3039, and 4049 years; however, in comparisons of NHANES 19992004 to NHANES III (19881994), the 611 year age group was excluded because a representative sample of sera for this age group was not available for testing for T. gondii in NHANES III. Race/ethnicity was defined by self-report as non-Hispanic White, non-Hispanic Black, or Mexican American. Persons who did not select one of these groups were categorized as Other and were only included when all racial/ethnic groups were combined. Poverty index was calculated by dividing the total family income by the U.S. poverty threshold, adjusted for family size.

* Address correspondence to Jeffrey L. Jones, Division of Parasitic Diseases, National Center for Zoonotic, Vectorborne, and Enteric Diseases, CCID, Centers for Disease Control and Prevention, Mailstop F-22, 4770 Buford Highway NE, Atlanta, GA. E-mail: jljl@cdc.gov

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When comparing the NHANES III (19881994) prevalence to the NHANES 19992004 prevalence we examined only the U.S.-born population because this group more accurately represents transmission of T. gondii in the U.S. This is because in many countries outside the U.S., a relatively high percentage of persons are infected at an early age18,23 and therefore are already infected when immigrating to the U.S. A high prevalence of infection is found in many areas of Mexico and Latin America,18,23 and 65% of the NHANES 19992004 non-U.S.born persons ages 649 years are from Mexico. Programs designed to prevent T. gondii infection in the U.S. cannot be monitored accurately by evaluating the prevalence in foreignborn persons with the NHANES because of this high rate of infection that occurs before immigration. Laboratory testing. All serum samples were tested using the Platelia Toxo-G enzyme immunoassay kit (Bio-Rad, Hercules, California) according to the instructions provided by the manufacturer during each time period (as a result of the manufacturers testing and determination of threshold values for the kits, samples with > 6 IU were considered positive for T. gondii antibodies during the time of NHANES III,24 and samples with 10 IU were considered positive for T. gondii antibodies during the time of NHANES 19992004). To ensure that the change in threshold values did not have a large effect on our results, we recalculated the NHANES 1999 2004 prevalence values using the previous NHANES III cutoff value (see Discussion). The Platelia Toxo-G kit was evaluated at the Centers for Disease Control and Prevention (CDC) using a battery of 90 sera (23 negative and 67 positive) and found to have a sensitivity and specificity of 100% when compared with the CDC Toxoplasma immunofluorescence assay-immunoglobulin G test (with 3 discrepant samples resolved by the SabinFeldman dye test [Dr. Jack Remington, Palo Alto, CA]). Statistical analysis. All prevalence estimates were weighted to represent the total U.S. population and to account for oversampling and nonresponse to the household interview and physical examinations.25 SUDAAN, a family of statistical procedures for analysis of data from complex sample surveys, was used for data analysis.26 Prevalence estimates were ageadjusted to the 2000 U.S. population by the direct method for both the NHANES 19992004 and the NHANES III samples when seroprevalence was compared across population subgroups. Standard error estimates were calculated using the Taylor series linearization method in SUDAAN to account for the complex sample design.26,27 A t statistic with the combined standard error was used to test differences in prevalence between NHANES III and NHANES 19992004. Because multiple comparisons were performed, P values 0.01 were considered significant. The linear test for trend with age was conducted with orthogonal polynomial contrasts in SUDAAN using both the original age groupings as well as recategorizing into evenly spaced age groups across the age range 649 years. To identify independent predictors of seropositivity among U.S.-born persons from NHANES 1999 2004, a logistic modeling procedure in SUDAAN was used with a P value of < 0.05 from a Satterthwaite adjusted F statistic considered significant. Odds ratios and their 95% confidence intervals were reported for all cofactors that remained in the final model.

RESULTS Of the 18,433 persons 649 years of age selected and interviewed for NHANES 19992004, 17,672 (96%) were examined. Of those examined, 15,960 (90%) had sera available for T. gondii antibody testing. The percent tested out of those examined varied with respect to age (lower for 6- to 11-yearolds [82%] as compared with all other age groups [9194%]), race/ethnicity (lower for non-Hispanic blacks [89%] as compared with non-Hispanic whites and Mexican Americans [both 91%]), foreign birth (lower for those U.S.-born [90%] as compared with non-U.S.-born [91%]), but not sex or poverty. The overall age-adjusted T. gondii seroprevalence among persons of age 649 years was 10.8% (95% CL: 9.6%, 11.9%; Table 1). Among women of age 1544 years, the age-adjusted seroprevalence was 11.0% (95% CL: 9.5%, 12.4%); 7.7% (95% CL: 6.1%, 9.2%) for U.S.-born women, and 28.1% (95% CL: 23.4%, 32.8%) for foreign-born women. Seroprevalence increased linearly with age (P < 0.001 linear test for trend), was higher among non-Hispanic blacks and Mexican Americans than among non-Hispanic whites (P 0.01 and P < 0.001, respectively), was higher among persons below the poverty level than those at or above the poverty level (P < 0.001), and was higher among foreign-born than U.S.born persons (P < 0.001; Table 1). To compare NHANES 19992004 to NHANES III (1988 1994), we restricted the analysis to U.S.-born persons age 1249 years (see Materials and Methods).The T. gondii antibody prevalence was significantly lower in NHANES 1999 2004 than in NHANES III overall (9.0% versus 14.1%, respectively), for all 4 of the age groups, among men and women, among all 3 racial/ethnic groups, and among persons both below and at or above the poverty index level (Table 2).
TABLE 1 Toxoplasma gondii prevalence by age group and age-standardized* by sex, race/ethnicity, poverty index, and birth origin (NHANES 19992004)
Category N Prevalence 95% CL

Age group (years) 611 1219 2029 3039 4049 Sex Male Female Race/ethnicity White, not hispanic Black, not Hispanic Mexican American Poverty index Below At or above Birth origin U.S. Other Overall

2,673 6,332 2,449 2,272 2,234 7,731 8,229 5,464 4,408 4,917 4,170 10,618 12,944 2,974 15,960

3.6 5.8 10.1 14.3 15.7 11.6 9.9 8.7 12.1 13.7 14.5 9.9 8.2 24.8 10.8

2.4, 4.9 4.7, 6.8 8.1, 12.1 12.3, 16.4 13.7, 17.7 10.1, 13.2 8.7, 11.2 7.2, 10.1 9.9, 14.4 11.4, 16.1 12.4, 16.5 8.6, 11.2 6.8, 9.5 21.2, 28.5 9.6, 11.9

* All categories except age groups are age-standardized to the 2000 U.S. Census population. CL, confidence limits. The sample size for the total population is greater than the sum for the 3 racial/ethnic groups because the total population includes individuals who classified themselves in the other racial/ethnic group. Poverty index and birth origin categories do not sum to total due to non-response.

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TABLE 2 Toxoplasma gondii prevalence in U.S.-born persons by age groups (age, 1249 years) and age-standardized* by gender, race/ethnicity, and poverty index (NHANES III 19881994 and NHANES 19992004)
NHANES III 19881994 Category n Prevalence 95% CL n NHANES 19992004 Prevalence 95% CL P value

Age group (year) 1219 2029 3039 4049 Sex Male Female Race/ethnicity White, not Hispanic Black, not Hispanic Mexican American Poverty index Below At or above Overall

2,348 2,223 2,222 1,813 3,865 4,741 3,178 3,406 1,879 2,031 6,024 8,606

7.6 12.4 13.8 20.7 14.8 13.4 14.2 16.1 10.2 20.1 13.4 14.1

5.5, 9.7 9.4, 15.5 12.3, 15.3 17.9 23.4 12.9, 16.7 11.6, 15.1 12.4, 16.0 14.3, 17.8 8.3, 12.1 16.9, 23.4 11.8, 15.1 12.7, 15.5

5,360 1,812 1,648 1,657 4,962 5,515 4,525 3,222 2,212 2,375 7,405 10,477

4.5 6.7 10.5 12.7 9.8 8.2 8.8 11.5 5.1 11.3 8.4 9.0

3.4, 5.6 4.6, 8.8 8.4, 12.6 10.4, 14.9 8.0, 11.6 6.6, 9.8 7.2, 10.5 8.8, 14.3 3.4, 6.7 8.6, 14.1 7.0, 9.8 7.5, 10.4

0.01 < 0.01 0.01 < 0.001 < 0.001 < 0.001 < 0.001 < 0.01 < 0.001 < 0.001 < 0.001 < 0.001

* All categories except age groups are age-standardized to the 2000 U.S. Census population. CL, confidence limits. Poverty index does not sum to total due to non-response.

In other words, the reduction in prevalence from NHANES III to NHANES 19992004 among 12- to 49-year-old U.S.born persons was significant for the combined subpopulation (P < 0.001) and all the demographic subgroups (P 0.01). In a multivariate logistic model comparing NHANES 1999 2004 to NHANES III among U.S.-born persons of age 1249 years, controlling for age, sex, race/ethnicity, and poverty index, the odds ratio for the survey cycle was 0.57 (95% CL: 0.46, 0.72; P < 0.001; model not shown in tables), indicating a significant drop in T. gondii prevalence over this 10-year period. It is interesting to note that the T. gondii antibody prevalence in NHANES 19992004 among U.S.-born Mexican Americans age 12 49 years was lower than that of U.S.-born non-Hispanic white persons (Table 2). This finding is in direct contrast to the relationship between these two racial/ethnic groups seen in Table 1 (ages 649 years), which included both U.S.-born and foreign-born persons,

because the age-adjusted seroprevalence was much lower among U.S.-born Mexican Americans (ages 649 years) 4.6% (95% CL: 3.2%, 6.0%) than foreign-born Mexican Americans 21.4% (95% CL: 18.5%, 24.4%; data not shown in tables). T. gondii antibody prevalence for the NHANES 19992004 U.S.-born population increased linearly with age for each of the three racial/ethnic groups (P < 0.001, linear test for trend; Figure 1). All age groups from 6 to 49 years were used in this figure because no comparison to NHANES III was being made. In a multivariate logistic model for the NHANES 1999 2004 U.S.-born population that included age group, sex, race/ ethnicity, and poverty index, T. gondii antibody prevalence increased with age group (P < 0.001), was lower in Mexican Americans than in non-Hispanic white persons (P 0.001), and was higher in persons below the poverty index than in those at or above it (P < 0.01; Table 3).

FIGURE 1. Toxoplasma gondii IgG antibody prevalence by age and race/ethnicity, U.S.-born persons, NHANES 19992004, N 12,274 (racial/ethnic groups combined).

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TABLE 3 Multivariate logistic model for Toxoplasma gondii infection, U.S.born persons from NHANES 19992004 (ages, 649 years, N 11,445 for logistic analysis)
Category OR (95% CL)* P value

Age group (years) 611 1219 2029 3039 4049 Sex Male Female Race/ethnicity White, not Hispanic Black, not Hispanic Mexican American Poverty index Below At or above

Ref. 1.3 (0.9, 1.9) 2.0 (1.5, 2.9) 3.8 (2.7, 5.3) 4.3 (2.9, 6.4) 1.3 (1.0, 1.6) Ref. Ref. 1.3 (0.9, 1.7) 0.55 (0.4, 0.8) 1.4 (1.1, 1.8) Ref.

NS < 0.001 < 0.001 < 0.001 NS

NS 0.001 < 0.01

* OR, odds ratio; CL, confidence limits. Ref., reference group. NS, not statistically significant (P > 0.01). Other race/ethnicity group not included in model.

DISCUSSION In NHANES 19992004, we found an overall age-adjusted prevalence of 10.8% among persons in the U.S. age 649 years. In addition, we saw a 36% reduction in T. gondii prevalence from 14.1% to 9.0% among 12- to 49-year-old U.S.-born persons since the NHANES III was conducted in 19881994. This reduction in prevalence is likely to be partially due to a reduction of T. gondii in cysts in meat through the efforts of meat producers.13,28 In addition, the reduction could be due in part to the intensified education of physicians and the public since the 1990s by CDC and other federal agencies about how to prevent T. gondii infection through the proper cooking of meat, proper cat feces/soil-related hygiene, not feeding cats raw meat, and keeping cats indoors. The reduction in T. gondii seroprevalence is not due to fewer cats in the U.S. because the number of cats per capita has increased.29,30 Other food-related factors that could influence trends in T. gondii exposure include growth in the frozen pre-prepared meal and frozen meat markets31 (because T. gondii cysts are usually inactivated by deep freezing)32,33 and use of enhancement solutions in pork containing 2% sodium chloride or 1.4% potassium or sodium lactate that suppress T. gondii.34 Future meat surveys would be useful to monitor T. gondii contamination in meat. In addition, water-related factors could influence T. gondii exposure.35 Regulations in the 1990s for enhanced filtering and treatment of drinking water to reduce Giardia intestinalis and Cryptosporidium spp. would reduce the likelihood of T. gondii contamination as well.36,37 Home water filtering and ingestion of bottled water could also reduce the possibility of T. gondii ingestion. One interesting finding in the survey is that the overall T. gondii antibody prevalence was markedly higher among Mexican Americans than non-Hispanic whites (13.7% versus 8.7%, 649 years, age-adjusted; Table 1), but when the data were restricted to the U.S.-born population, Mexican Americans had a markedly lower prevalence than non-Hispanic whites (4.6% [95% CL: 3.2%, 6.0%] versus 8.1% [95% CL: 6.5%, 9.7%], respectively, 649 years, age-adjusted; data not

shown in tables for U.S.-born population in this age range). As would be expected from the findings above, the T. gondii antibody prevalence was much lower among U.S.-born Mexican Americans than among foreign-born Mexican Americans (4.6% [95% CL: 3.2%, 6.0%] versus 21.4% [95% CL: 18.5%, 24.4%], 649 years age-adjusted; data not shown in tables). The reason that U.S.-born Mexican Americans have the lowest T. gondii infection rate of the three major racial/ethnic groups examined is not known but may be due to culinary practices, such as thoroughly cooking meat, and a reduced ability of T. gondii to survive in the environment in the regions of the country where Mexican Americans primarily live. Of the 4 regions of the U.S., over half (55.3%) of Mexican Americans reside in the more arid Western United States,38 a region where T. gondii may not survive as well in the soil. Regardless of the source of infection, it is notable that T. gondii prevalence increased in the childbearing years (Figure 1), a finding that is of concern because it is new T. gondii infections in pregnant women that lead to congenital toxoplasmosis. This finding remains when controlling for demographic factors and poverty level in multivariate analysis. To prevent congenital toxoplasmosis, prevention of T. gondii infection is important in the childbearing years. Because the manufacturer of the Toxoplasma IgG serologic testing kit changed the cutoff value for a positive test between NHANES III and NHANES 19992004 (from > 6 IU to 10 IU), we used their recommended cutoff values for each survey when doing the analysis for this paper. However, to be certain that a change in the cutoff value for a positive test would not markedly affect the results, we recalculated the prevalence values for NHANES 19992004 using the previous NHANES III cutoff value (i.e., we used > 6 IU instead of 10 IU). Using the > 6-IU cutoff in the comparison of NHANES 19992004 to NHANES III, only 106 out of all 15,960 NHANES 19992004 samples and only 62 out of the 10,477 U.S.-born 12- to 49-year-old persons samples were affected, the T. gondii seropositivity rate only changed from 9.0% to 9.6% (age-adjusted, 1249 years old U.S. born), and the reduction in T. gondii seropositivity from NHANES III to NHANES 19992004 remained significant at the P < 0.001 level. Therefore, the manufactures change in the cutoff value for a positive test had little affect on our results. The strengths of our study include the utilization of a representative sample of the U.S. population collected through well-standardized methods and the use of the same T. gondii antibody-detection kit for both surveys, allowing a direct comparison of the results. Because the NHANES sample was designed to provide national estimates, it was not statistically possible to stratify the data by states or localities to obtain prevalence rates for specific areas. Estimates by census region also were unstable because of the sampling frame of the survey. In addition, race/ethnicity, birth origin, and socioeconomic data were self-reported and not verified by independent methods. Some of the overall reduction in T. gondii prevalence among U.S.-born persons from NHANES III to NHANES 19992004 can be attributed to a change in demographics, for example, non-Hispanic black persons had the highest T. gondii antibody prevalence of the U.S.-born racial/ ethnic groups, and the proportion of U.S.-born non-Hispanic blacks decreased from 39.6% in NHANES III to 30.8% in NHANES 19992004. However, a significant reduction occurred in each racial ethnic group from NHANES III to

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NHANES 19992004, including non-Hispanic blacks (Table 2). In spite of these limitations, our data were collected by one of the most representative surveys ever conducted in the U.S. and provide the best available estimates of T. gondii seroprevalence trends. The NHANES has made it possible to determine how often one of the most intriguing protozoan parasites infects persons in the U.S. There are still many questions about the implications of T. gondii infection. For example, specific genetic types may be more likely to cause ocular or congenital disease.39,40 Much more research into these areas is required before we fully understand the molecular and pathophysiologic effects of this highly successful parasite on those infected in the population.
Received April 10, 2007. Accepted for publication June 7, 2007. Acknowledgments: The authors thank Erica Christian and Christopher Burns for their technical assistance with T. gondii serologic testing. Disclaimer: The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the Department of Health and Human Services or the Centers for Disease Control and Prevention Authors addresses: Jeffrey L. Jones, Division of Parasitic Diseases, National Center for Zoonotic, Vectorborne, and Enteric Diseases, CCID, Centers for Disease Control and Prevention, Mailstop F-22, 4770 Buford Highway NE, Atlanta, GA 30341-3724, Telephone: +1 (770) 488-7771, Fax: +1 (770) 488-7761, E-mail: jlj1@cdc.gov. Deanna Kruszon-Moran, Division of Health and Nutrition Examination Statistics, National Center for Health Statistics, Centers for Disease Control and Prevention, HYAT Bldg. IV, Rm. 4308, MS P08, Hyattsville, MD 20782, Telephone: +1 (301) 458-4328, Fax: +1 (301) 4584029, E-mail: ddk0@cdc.gov. Kolby Sanders-Lewis and Marianna Wilson, Division of Parasitic Diseases, National Center for Zoonotic, Vectorborne, and Enteric Diseases, CCID, Centers for Disease Control and Prevention, Mailstop F-36, 4770 Buford Highway NE, Atlanta, GA 30341-3724, Phone: +1 (770) 488-4431, Fax: +1 (770) 4883115, E-mail: myw1@cdc.gov. Reprint requests: Jeffrey L. Jones, Division of Parasitic Diseases National Center for Zoonotic, Vectorborne, and Enteric Diseases, CCID, Centers for Disease Control and Prevention, Mailstop F-22, 4770 Buford Highway NE, Atlanta, GA 30341-3724, Telephone: +1 (770) 488-7771, Fax: +1 (770) 488-7761, E-mail: jlj1@cdc.gov.

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