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Toxocara infection and diminished lung function in a nationally representative sample from the United States population
International Journal for Parasitology 41 (2011) 243–247
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International Journal for Parasitology journal homepage: www.elsevier.com/locate/ijpara
Toxocara infection and diminished lung function in a nationally representative sample from the United States population Michael G. Walsh ⇑ Epidemiology and Biostatistics, School of Public Health, State University of New York, Downstate 450 Clarkson Avenue, Box 43, Brooklyn, NY 11203, USA
a r t i c l e
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Article history: Received 10 August 2010 Received in revised form 7 September 2010 Accepted 9 September 2010 Available online 9 November 2010 Keywords: Asthma Helminth infection Lung function Parasites Toxocara
a b s t r a c t The relevance of parasitic infection for the increasing incidence of asthma is a topic of considerable debate. Large population-based studies examining the association between helminth infection and specific measures of lung function in humans are lacking. This report sought to examine this association by exploring the differences in forced expiratory volume in 1 s (FEV1) among participants with and without infection with Toxocara spp. using data from the Third National Health and Nutrition Examination Survey, undertaken by the United States Department of Health and Human Services, during 1988–1994. The results showed a significant association between diminished lung function and previous infection with Toxocara spp. Those with antibody evidence of Toxocara infection displayed FEV1 that was 105.3 mL less than those without previous infection. This relationship persisted while controlling for age, sex, education level, BMI, smoking status, ethnicity, immigration, rural residence and dog ownership (fully-adjusted difference = 73 mL). These findings suggest diminished lung function in the presence of Toxocara infection and illustrate the urgent need for longitudinal data to more clearly define the immunological relationship with helminth infection and its potential influence on lung function. Ó 2010 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.
1. Introduction Parasitic infection has been gaining some recognition as potentially inhibitory to atopy and asthma (Weiss, 2000). Infection with platyhelminths (flatworms) or nematodes (roundworms), the two major classes of helminths, have been shown in association with decreased atopy and asthma symptoms. The atopic mediating potential of helminth infection follows from the recruitment of inflammatory cytokines and B leukocytes to neutralize the worms and thus diminishes the likelihood of immunological hypersensitivity responses to environmental allergens. Perhaps even more important is the balance between Th1 and Th2 cells in cell-mediated immunity in early childhood. A lack of a ‘‘Th1 shift” in the absence of early infection, which is now typical in developed countries, may lead to a Th2 bias early on and thus prime the immune system for hypersensitivity (Weiss, 2000). For example, parasite infection has been suggested to prevent IgE-mediated allergic disease by blocking effector-cell IgE receptors (Godfrey and Gradidge, 1976). Another potential mediating factor in inflammatory pathways is the production of IL10 (van den Biggelaar et al., 2000). Nevertheless, infection with parasitic helminths, even the more benign species, is still systemically invasive with potential complications and may not be beneficial with respect to immunological inflam⇑ Tel.: +1 347 557 1108. E-mail address: [email protected]
matory mediation, particularly in airway reactivity. Indeed, there is some evidence from animal models that suggests the opposite may be true. Specifically, otherwise benign roundworm infection (Toxocara canis) may reduce lung function in mice (Buijs et al., 1995; Pinelli et al., 2005). Additionally, primate infection with Ascaris suum was associated with hypersensitivity in lung cells (Pritchard et al., 1983). Moreover, there has been some discussion, albeit in the absence of empirical data, regarding the link between ‘‘covert” toxocariasis and associated wheezing and pulmonary infiltrates (Sharghi et al., 2000). Unfortunately, studies in humans examining lung function in the presence of a common and relatively benign (although not without potential complications) nematode infection such as Toxocara spp. are largely non-existent. This report sought to examine the association between Toxocara spp. infection and lung function by testing differences in forced expiratory volume in 1 s (FEV1) between those with and without evidence of infection with this helminth in a nationally representative sample from the United States population.
2. Materials and methods The association of Toxocara infection and lung function was assessed using data from the Third National Health and Nutrition Examination Survey (National Center for Health Statistics, US Department of Health and Human Services (DHHS). Third National
0020-7519/$36.00 Ó 2010 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijpara.2010.09.006
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Health and Nutrition Examination Survey, 1988–1994, NHANES III Examination Data File (CD-ROM). Public Use Data File Documentation Number 76200. Hyattsville, MD, USA: Centers for Disease Control and Prevention, 1996) conducted between the years of 1988 and 1994 by the National Center for Health Statistics at the Centers for Disease Control and Prevention, USA. Methods describing this national survey have been described previously (National Center for Health Statistics, 1996). The survey was designed to obtain nationally representative information on the health and nutritional status of the population of the USA through interviews and direct physical examinations. The study had very good participation, with an 86% response rate for the questionnaire interview, and a 78% response rate for the examination component, which included blood samples subsequently stored and used for analysis of Toxocara antibodies. Self-reported health data as well as physiological measures were collected in either the Mobile Examination Center or at the participants’ homes. As described in the NHANES laboratory documentation, Toxocara antibodies were measured with an inhouse enzyme immunoassay (EIA) developed at the Centers for Disease Control and Prevention (CDC, USA). This assay utilized an excretory/secretory antigen of T. canis, absorbed to 96-well Immulon II HB Flat Bottom plates. First, serum reacts with the antigen, which is followed by the application of horseradish peroxidase labeled anti-human IgG. Tetramethylbenzidine (TMB) substrate was used to visualize the reaction. A vMax microplate reader and SOFTmax software was used to determine O.D. (Molecular Devices Corp., Menlo Park, CA, USA) (Center for Disease Control (2007) Documentation, codebook and frequencies; surplus sera laboratory component: antibody to Toxocara larva migrans. NHANES III, series 11 Data Files 26A. ftp://ftp.cdc.gov/pub/Health_Statistics/NCHS/ Datasets/NHANES/NHANESIII/26a/SSTOXO.pdf). However, the assay was not able to distinguish between T. canis and Toxocara cati antibodies (Won et al., 2008), and so this report simply refers to Toxocara spp. infection throughout the text. Spirometry was performed for all participants in this report. At least five measurements were taken to meet the then, newly updated, American Thoracic Society reliability guidelines (Hankinson and Bang, 1991). Forced exhaled volumes were measured using a dry rolling-seal spirometer. Forced expiratory volume was digitally recorded (National Center for Health Statistics, 1996). Level of education was used as a robust indicator of socioeconomic status and was recorded as the number of years of education completed. Body mass index (BMI) was recorded as the ratio of weight in kilograms to height in meters squared (kg/m2). Smoking history was represented here by three categories. Those who have never smoked more than 100 cigarettes in their lifetime were classified as never smokers, those that have smoked at least 100 cigarettes in their lifetime, but do not currently smoke were classified as past smokers, and those who currently smoke were classified as current smokers. Ethnicity was determined by self-report and was represented by three categories: African-Americans, MexicanAmericans and Whites. Immigration status reflects simply the participant’s place of nativity rather than the participant’s official administrative documentation of that status. This was determined by the answer to the question: ‘‘Were you born in the United States?”. According to NHANES convention, participants living in central counties of metropolitan areas of 1 million population or more, or fringe counties of metropolitan areas of 1 million population or more, were classified as urban. All others were classified as rural. Dog ownership was determined by self report. Only participants less than 65 years of age were used for this analysis since the elderly are much more likely to have diminished lung function due to advanced age. A total of 16,226 adult participants who were at least 17 years old at the time of examination were measured for the presence of Toxocara spp. antibody. After excluding those 65 years of age or older, we were subsequently left with a total
analytical sample of 12,174. A further 568 participants did not have spirometry measures, leaving a final analytical sample of 11,606. The prevalence of Toxocara infection was exactly the same in the sample before and after excluding those without spirometry. 2.1. Statistical methods Sample population means and proportions are presented with linearized standard errors. Bivariate associations between Toxocara infection and FEV1 were assessed using exact methods. Multiple linear regression was used to assess the independent association between Toxocara infection and FEV1 while controlling for age, sex, education level, BMI, smoking status, ethnicity, status as an immigrant, urban versus rural residence, and dog ownership. Four models were subsequently fitted. Model 1 assessed the association between Toxocara infection and FEV1, while controlling the effects of age and sex. Model 2 assessed the same relationship, but added education level and BMI to the age and sex adjustment. Model 3 examined the Toxocara–FEV1 association while adjusting for all covariates in Models 1 and 2, and additionally adjusting for ethnicity, immigrant status (US-born versus those of foreign nativity) and smoking status (current smokers, past smokers and never smokers). The final model, Model 4, adjusted the Toxocara–FEV1 association for all of the covariates in the first three models, while also controlling for urban versus rural residence and dog ownership. The svymean, svytab, and svyregress (for the linear regression models) commands in STATA were used in order to account for the NHANES weighted sampling design. STATA version 10 was the software used for all statistical analyses (StataCorp LP, College Station, TX, USA). The level of significance for these analyses was less than or equal to 0.05. 3. Results The overall prevalence of infection with Toxocara spp. among participants less than 65 years of age was 14.2% (95% confidence Table 1 Proportions for categorical variables and means for continuous variables are presented by Toxocara infection status among adults from the Third National Health and Nutrition Examination Survey (National Center for Health Statistics, US Department of Health and Human Services (DHHS). Third National Health and Nutrition Examination Survey, 1988–1994, NHANES III Examination Data File (CD-ROM). Public Use Data File Documentation Number 76200. Hyattsville, MD, USA: Centers for Disease Control and Prevention, 1996). Linearized standard errors are also presented. Risk factors
Women Men African-American Mexican-American White Immigrant Non-immigrant Age 18–29 Age 30–39 Age 40–49 Age 50–65 Education (years) BMI (kg/m2) Current smoker Past smoker Never smoked Urban resident Rural resident Dog owner No dog FEV1 (mL)
Toxocara
P-value
Positive (n = 1898)
Negative (n = 10,276)
0.13 (0.008) 0.16 (0.01) 0.21 (0.008) 0.12 (0.006) 0.12 (0.009) 0.22 (0.008) 0.13 (0.004) 0.15 (0.011) 0.15 (0.014) 0.12 (0.012) 0.14 (0.012) 11.5 (0.15) 26.7 (0.16) 0.17 (0.01) 0.12 (0.01) 0.14 (0.01) 0.13 (0.01) 0.16 (0.02) 0.14 (0.01) 0.15 (0.01) 3311.3 (37.7)
0.87 (0.008) 0.84 (0.01) 0.79 (0.008) 0.88 (0.006) 0.88 (0.009) 0.78 (0.008) 0.87 (0.004) 0.85 (0.011) 0.85 (0.014) 0.88 (0.012) 0.86 (0.012) 12.7 (0.08) 26.4 (0.12) 0.83 (0.01) 0.88 (0.01) 0.86 (0.01) 0.87 (0.01) 0.84 (0.02) 0.86 (0.01) 0.85 (0.01) 3416.6 (21.7)
BMI, body mass index and FEV1, forced expiratory volume in 1 s.
0.01 <0.0001
0.0002 0.16
<0.001 0.06 0.01
0.08 0.29 0.02
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interval (95% CI) = 12.7–15.9) in the general US population. Table 1 shows the differences in sociodemographic characteristics and lung function by the presence or absence of Toxocara spp. antibody. Men (16%; 95% CI = 13–18%) and immigrants (22%; 95% CI = 17–28%) had a higher prevalence of Toxocara spp. antibody than women (13%; 95% CI = 11–15%) or US-born persons (13%; 95% CI = 11–15%), respectively. African-Americans (21%; 95% CI = 19–22%) had significantly greater prevalence of infection than either Mexican-Americans (12%; 95% CI = 10–13%) or Whites (12%; 95% CI = 10–14%). Those participants infected with Toxocara were less educated (11.5 years versus 12.7 years, P < 0.001) and had modestly higher BMI (26.7 versus 26.4, P = 0.06) than those who were not infected. Current smokers had a higher prevalence (17%; 95% CI = 14–19%), than either past smokers (12%; 95% CI = 10–14%) or those who had never smoked (14%; 95% CI = 12–16%). Toxocara infection showed no specific distribution pattern across the four age categories (P = 0.16), and there were no substantive or significant differences between those who owned dogs and those who did not (P = 0.29) or between those who lived in rural areas and those who lived in urban areas (P = 0.08). Expiratory volume was diminished in those with Toxocara infection relative to those without infection (FEV1 = 3311 versus FEV1 = 3417, P = 0.02). Table 2 presents the four models, each examining the association between Toxocara infection and lung function, while simultaneously controlling for potential confounders. Model 1 illustrates a difference of 180 mL (95% CI = 112.6–248.1) of forced air in 1 s between those with Toxocara infection and those without even after adjusting for age and sex. The latter two factors were also associated with lung function, with each increasing year in age corresponding to an approximate decrease of 30 mL of forced air in 1 s, and with women expiring 1061 mL less forced air in 1 s than men. These latter two associations with lung function are of the expected strength and direction for both age and sex, respectively. Model 2 additionally controls for education achieved (in years) and BMI. Although attenuated, the association between Toxocara infection and diminished lung function remained (b = 125.1; 95% CI = 188.5 to 61.8), as did the expected associations with age and sex. Nevertheless, education (b = 44.5; 95% CI = 37.9– 51.2) was significantly and strongly associated with lung function,
which was also to be expected, while BMI (b = 3.7; 95% CI = 7.5 to 0.04) was only modestly associated with lung function, albeit in the expected direction. Model 3 added ethnicity, immigrant status and smoking status to the previous adjustment. This adjustment further attenuated the association between Toxocara and FEV1, but the relationship between the two nevertheless remained strong and significant (b = 76.7; 95% CI = 130.9 to 22.6), while simultaneously showing that there was a substantive difference in FEV1 between African-Americans (b = 432.2; 95% CI = 470.2 to 394.1) and Whites, although not between immigrants (b = 71.5; 95% CI = 175.8 to 32.8) and US-born participants. Finally, Model 4, which added urban/rural residence and dog ownership to the final model, had only a small effect on the Toxocara–FEV1 association (b = 73; 95% CI = 128.1 to 17.9), which continued to show a 73 mL deficit in the volume of air forcibly expired in 1 s. 4. Discussion This is believed to be the first report to describe the association between Toxocara infection and lung function in a nationally representative population-based sample in the United States. The findings show an association between diminished lung function and infection with Toxocara spp., such that a fully-adjusted estimated difference of 73 mL of forced air in 1 s was observed between those with antibody evidence of Toxocara spp. infection versus those with no such evidence of infection. This relationship existed after controlling for age, sex, education level, BMI, ethnicity, smoking status, whether the person was born in the USA or immigrated there, rural residence and dog ownership. All but the last three of these potential confounders were also significantly associated with FEV1 in the expected directions. The relationship between reduced atopy or asthma and microbial colonization seems to extend to a broad variety of gastrointestinal infections with bacterial, viral and protozoan microbes implicated in reduced disease (Matricardi et al., 2000). In one study, participants with exposures to either the protozoan Toxoplasma gondii or hepatitis A virus showed significantly reduced atopy, while additionally, a very strong statistical trend in reduced atopy appeared for those exposed to one, two or three gastrointestinal organisms. However, this study also showed no association between
Table 2 Multiple linear regression models showing the adjusted associations between previous Toxocara infection and forced expiratory volume in 1 s (FEV1) among adults from the Third National Health and Nutrition Examination Survey (National Center for Health Statistics, US Department of Health and Human Services (DHHS). Third National Health and Nutrition Examination Survey, 1988–1994, NHANES III Examination Data File (CD-ROM). Public Use Data File Documentation Number 76200. Hyattsville, MD, USA: Centers for Disease Control and Prevention, 1996). The regression coefficients (b) and 95% confidence intervals (95% CIs) are presented for Toxocara spp. antibody and all of the confounder covariates. b Model 1a 95% CI
Risk factors Toxocara infection (versus non-infected) Age (years) Female (versus male)
180.3
248.1 to
29.5 1061.4
30.8 to 28.1 1093.9 to 1028.9
Education (years) BMI (kg/m2) Past smoker (versus never) Current smoker (versus never) Immigrant (yes versus no) African-American (versus White) Mexican-America (versus White) Urban (versus rural) resident Dog owner (yes versus no) a b c d
Toxocara–FEV1 Toxocara–FEV1 Toxocara–FEV1 Toxocara–FEV1
association association association association
is is is is
b Model 2b 95% CI 112.6
125.1 29 1056.2 44.5 3.7
188.5 to
b Model 3c 95% CI 61.8
30.2 to 27.7 1088.8 to 1023.7 37.9–51.2 7.5 to 0.04
76.7 30.5 1068.1 37.3 5.4 31.5 135.9
130.9 to
b Model 4d 95% CI 22.6
31.9 to 29.1 1099.7 to 1036.6 29.8–44.7 9.1 to 1.6 22.4 to 85.3 179.5 to 92.4
73 30.5 1067.9 35.9 5.2 31.7 135.6
for for for for
17.9
31.9 to 29.1 1099.2 to 1036.5 28.4–43.4 9.0 to 1.4 22.4 to 85.9 178.4 to 92.8
71.5 432.2
175.8 to 32.8 470.2 to 394.1
81.3 436.3
188.2 to 25.5 476.2 to 396.3
45.3
108.6 to 18.1
51
115.7 to 13.7
50.1 22.8 adjusted adjusted adjusted adjusted
128.1 to
age and sex. Model 1 covariates, plus education and body mass index (BMI). Models 1 and 2 covariates plus ethnicity, immigrant status and smoking status. Models 1, 2 and 3 covariates plus urban residence and dog ownership.
2.6 to 102.5 25.0 to 70.5
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concentration of IgE antibody and any of those infections (Matricardi et al., 2000). Interestingly, those infections are typically responsible for a Th1 shift in the balance of immune response, whereas helminth infections are not. In contrast, helminths typically promote a Th2 immune response and are usually associated with a preponderance of IgE production. From an evolutionary perspective, a potential association between parasitic infection and atopic dysfunction is plausible in the context of an IgE-mediated hypersensitivity that is highly evolved to target a tremendous presence, in both quantity and diversity, of parasites in the environment (Weiss, 2000). Parasitic antigens, by way of T cell mediation, stimulate B cell production of IgE antibodies. Mast cell binding sites are the primary target for IgE binding, which cause the degranulation of those cells and allow them to perform their inflammatory function. Moreover, helminth infections stimulate very high levels of IgE production (Turner et al., 1979). This concert with the mast cell is clear given there are over 100,000 IgE binding sites per cell. Therefore, in the absence of helminth infections, this highly specific immune mechanism is without its target and may default to aeroallergens, which would otherwise induce weak antigenicity (Turner et al., 1979). Nevertheless, the greater consistency with this relationship is between clearly defined atopy and helminth infection. The relationship between clinically designated asthma, or lung function in general, and helminth infection is not as consistent. Our results, in particular, question whether a more specific relationship between lung function and infection with Toxocara is likely. Indeed, infection with helminths may actually lead to the presentation of asthmatic symptoms. It was shown almost 30 years ago that primate infection with A. suum was associated with hypersensitivity in lung cells (Pritchard et al., 1983). More recent rodent models have also demonstrated challenged lung function in roundworminfected mice (Buijs et al., 1995; Pinelli et al., 2005). This relationship is equally plausible given that the extreme up-regulation of both IgE antibodies and eosinophils is clearly associated with pulmonary infiltrates, wheezing and airflow obstruction (Weiss, 2000). As such, this report adds further important evidence to the complex relationship between parasitic infection and lung function. As expected, we found a higher level of educational attainment associated with decreased presence of Toxocara spp. antibodies, and an increased level of lung function. As with most parasitic infections, helminths are typically associated with poorer socioeconomic conditions and this report provides further evidence for this established finding (Hotez, 2007; Hotez and Wilkins, 2009). Similarly, we also found that increased BMI was associated with decreased lung function in the full model (Table 2), with every unit increase in BMI corresponding to a 5 mL decrease in FEV1. This is believed to be the first study to consider the potential moderation of BMI on the relationship between lung function and Toxocara infection, however, the association between BMI and Toxocara infection was quite modest. This study further examined whether the association between Toxocara infection and lung function could be accounted for by ethnicity or immigration status. African-Americans had significantly higher Toxocara infection than either Mexican-Americans or Whites in this population, and further demonstrated an adjusted FEV1 deficit of 430 mL. These results corroborate what has been shown in previous reports of both Toxocara infection and lung function (Won et al., 2008; Harik-Khan et al., 2001). Indeed, ethnicity demonstrated the strongest association with Toxocara infection of any sociodemographic variable other than sex. Nevertheless, the relationship between Toxocara infection and lung function, while attenuated, remained after adjusting for ethnicity. Interestingly, this study found a significantly higher prevalence of Toxocara infection among individuals born outside the US. Many people who
come to the US to work leave impoverished rural areas in their native countries. As helminth infections in general, and Toxocara spp. in particular, are more common in rural settings, immigrant communities may collectively experience greater exposure to these helminths in their early childhood before migrating and thus may be over-represented in Toxocara prevalence. Most studies indicate that being foreign-born is associated with reduced risk for asthma, or asthma-related symptoms (Rottem et al., 2005). Nevertheless, our data showed that being born outside the US was associated with diminished lung function relative to those born within the US. Even so, immigrant status itself was not significantly associated with FEV1 when ethnicity was also controlled. Finally, given the possibility of greater Toxocara infection among rural residents and dog owners, and given the possibility that these same groups may also demonstrate diminished lung function, this study further assessed urban versus rural residence and dog ownership with respect to the Toxocara–FEV1 relationship. There was only a moderate difference (non-significant) in Toxocara prevalence across these groups, and they failed to show an association with lung function. This is not entirely surprising since a previous report showed that, while there was no significant difference in Toxocara prevalence by rural residence or dog ownership, there were ethnicity-specific significant differences in prevalence by both. However, the authors of that report point out that their crude ethnicity stratum-specific rate estimates were unstable (Won et al., 2008), which makes multivariable modeling of these variables questionable. In this current report, there is likely no association because the model controls for ethnicity. This study has strengths and limitations that warrant discussion. An important strength of this study was the ability to directly examine measured lung function in the context of known infection with Toxocara spp. in a diverse, nationally representative population-based survey. This is believed to be the first study to explore the relationship between spirometry-measured pulmonary function and infection with Toxocara in humans. It is also believed to be the first study to test the association between lung function and parasitic infection of any kind in a population-based study of this scale and with the compliment of covariate measurements to control for potential confounding. While infection with this helminth in the US is more common than perhaps would have been expected (over 14% overall), only a study of this scale would allow for a thorough investigation of this relationship by providing sufficient power to include confounder adjustment. Thus the sample size is a major strength of this study, allowing for multiple layers of stratification. The most obvious limitation is the cross-sectional nature of these data, which precludes, more than anything else, direct causal interpretation of the observed association. Two points are worth noting, however. First, the association between lung function and Toxocara infection is unlikely to be due to reverse causality, which can be one of the most problematic characteristics underlying an observed cross-sectional association. The question under current investigation is whether or not Toxocara infection has an effect on lung function as has been hypothesized (largely by inference from ecological data). We cannot, of course, measure the effect directly and are therefore constrained to measure the association, which can go in either direction with respect to a cause–effect relationship. Nevertheless, in this instance, it is biologically more plausible that infection with this parasite lends the host to pulmonary involvement given the nature of the immunological response to the organism, rather than diminished lung function predisposing the pulmonologically less fit individual to infection with the parasitic organism. There is a possible exception, however, and this serves as the second notable point. If Toxocara infection is itself a proxy for poorer socioeconomic status, then we might expect to see an increased occurrence of infection associated with decreased lung function, just as we observed in this
M.G. Walsh / International Journal for Parasitology 41 (2011) 243–247
study, because both may be associated with lower socioeconomic conditions. However, we did adjust for the level of education attained. As such, we would expect this to capture the reverse causality that could have explained the observed association if Toxocara infection did indeed represent low socioeconomic status rather than a potential effector of lung function. Nevertheless, no claim of causality can be made for Toxocara infection given that these data are observational and cross-sectional. In conclusion, this report demonstrates a strong association between infection with Toxocara spp. and current lung function as measured by FEV1. The diminished lung function among individuals with Toxocara infection is an important finding in the ongoing debate over the rising asthma epidemic in the absence of parasitic infection in Western countries. While more concrete evidence has been presented to show a general parasitic protective effect against atopic disease, the relationship between parasites and lung function, specifically, may be far more complex. Further longitudinal data examining these relationships should be sought and captured quickly to shed further light on this important relationship between the human environment and immunology. References Buijs, J., Egbers, M.W., Lokhorst, W.H., Savelkoul, H.F., Nijkamp, F.P., 1995. Toxocarainduced eosinophilic inflammation. Airway function and effect of anti-IL-5. Am. J. Respir. Crit. Care Med. 151, 873–878. Godfrey, R.C., Gradidge, C.F., 1976. Allergic sensitization of human lung fragments prevented by saturation of IgE binding sites. Nature 259, 484–486. Hankinson, J.L., Bang, K.M., 1991. Acceptability and reproducibility criteria of the American Thoracic Society as observed in a sample of the general population. Am. Rev. Respir. Dis. 143, 516–521.
247
Harik-Khan, R.I., Fleg, J.L., Muller, D.C., Wise, R.A., 2001. The effect of anthropometric and socioeconomic factors on the racial difference in lung function. Am. J. Respir. Crit. Care Med. 164, 1647–1654. Hotez, P.J., 2007. Neglected diseases and poverty in ‘‘The Other America”: the greatest health disparity in the United States? PLoS Negl. Trop. Dis. 1, e149. Hotez, P.J., Wilkins, P.P., 2009. Toxocariasis: America’s most common neglected infection of poverty and a helminthiasis of global importance? PLoS Negl. Trop. Dis. 3, e400 [Epub 2009 March 31]. Matricardi, P.M., Rosmini, F., Riondino, S., Fortini, M., Ferrigno, L., Rapicetta, M., Bonini, S., 2000. Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma: epidemiological study. BMJ 320, 412–417. Pinelli, E., Withagen, C., Fonville, M., Verlaan, A., Dormans, J., van Loveren, H., Nicoll, G., Maizels, R.M., van der Giessen, J., 2005. Persistent airway hyperresponsiveness and inflammation in Toxocara canis-infected BALB/c mice. Clin. Exp. Allergy 35, 826–832. Pritchard, D.I., Eady, R.P., Harper, S.T., Jackson, D.M., Orr, T.S.C., Richards, I.M., Trigg, S., Wells, E., 1983. Laboratory infection of primates with Ascaris suum to provide a model of allergic bronchoconstriction. Clin. Exp. Immunol. 54, 469–476. Rottem, M., Szyper-Kravitz, M., Shoenfeld, Y., 2005. Atopy and asthma in migrants. Int. Arch. Allergy Immunol. 36, 198–204. Sharghi, N., Schantz, P., Hotez, P.J., 2000. Toxocariasis: an occult cause of childhood neuropsychological deficits and asthma? Sem. Ped. Infect. Dis. 11, 257–260. Turner, K.J., Feddema, L., Quinn, E.H., 1979. Nonspecific potentiation of IgE parasitic infections in man. Int. Arch. Allergy Appl. Immunol. 58, 232–236. van den Biggelaar, A.H., van Ree, R., Rodrigues, L.C., Lell, B., Deelder, A.M., Kremsner, P.G., Yazdanbakhsh, M., 2000. Decreased atopy in children infected with Schistosoma haematobium: a role for parasite-induced interleukin-10. Lancet 356, 1723–1727. Weiss, S.T., 2000. Parasites and asthma/allergy: what is the relationship? J. Allergy Clin. Immunol. 105, 205–210. Won, K.Y., Kruszon-Moran, D., Schantz, P.M., Jones, J.L., 2008. National seroprevalence and risk factors for zoonotic Toxocara spp. infection. Am. J. Trop. Med. Hyg. 79, 552–557.
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International Journal for Parasitology journal homepage: www.elsevier.com/locate/ijpara
Toxocara infection and diminished lung function in a nationally representative sample from the United States population Michael G. Walsh ⇑ Epidemiology and Biostatistics, School of Public Health, State University of New York, Downstate 450 Clarkson Avenue, Box 43, Brooklyn, NY 11203, USA
a r t i c l e
i n f o
Article history: Received 10 August 2010 Received in revised form 7 September 2010 Accepted 9 September 2010 Available online 9 November 2010 Keywords: Asthma Helminth infection Lung function Parasites Toxocara
a b s t r a c t The relevance of parasitic infection for the increasing incidence of asthma is a topic of considerable debate. Large population-based studies examining the association between helminth infection and specific measures of lung function in humans are lacking. This report sought to examine this association by exploring the differences in forced expiratory volume in 1 s (FEV1) among participants with and without infection with Toxocara spp. using data from the Third National Health and Nutrition Examination Survey, undertaken by the United States Department of Health and Human Services, during 1988–1994. The results showed a significant association between diminished lung function and previous infection with Toxocara spp. Those with antibody evidence of Toxocara infection displayed FEV1 that was 105.3 mL less than those without previous infection. This relationship persisted while controlling for age, sex, education level, BMI, smoking status, ethnicity, immigration, rural residence and dog ownership (fully-adjusted difference = 73 mL). These findings suggest diminished lung function in the presence of Toxocara infection and illustrate the urgent need for longitudinal data to more clearly define the immunological relationship with helminth infection and its potential influence on lung function. Ó 2010 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.
1. Introduction Parasitic infection has been gaining some recognition as potentially inhibitory to atopy and asthma (Weiss, 2000). Infection with platyhelminths (flatworms) or nematodes (roundworms), the two major classes of helminths, have been shown in association with decreased atopy and asthma symptoms. The atopic mediating potential of helminth infection follows from the recruitment of inflammatory cytokines and B leukocytes to neutralize the worms and thus diminishes the likelihood of immunological hypersensitivity responses to environmental allergens. Perhaps even more important is the balance between Th1 and Th2 cells in cell-mediated immunity in early childhood. A lack of a ‘‘Th1 shift” in the absence of early infection, which is now typical in developed countries, may lead to a Th2 bias early on and thus prime the immune system for hypersensitivity (Weiss, 2000). For example, parasite infection has been suggested to prevent IgE-mediated allergic disease by blocking effector-cell IgE receptors (Godfrey and Gradidge, 1976). Another potential mediating factor in inflammatory pathways is the production of IL10 (van den Biggelaar et al., 2000). Nevertheless, infection with parasitic helminths, even the more benign species, is still systemically invasive with potential complications and may not be beneficial with respect to immunological inflam⇑ Tel.: +1 347 557 1108. E-mail address: [email protected]
matory mediation, particularly in airway reactivity. Indeed, there is some evidence from animal models that suggests the opposite may be true. Specifically, otherwise benign roundworm infection (Toxocara canis) may reduce lung function in mice (Buijs et al., 1995; Pinelli et al., 2005). Additionally, primate infection with Ascaris suum was associated with hypersensitivity in lung cells (Pritchard et al., 1983). Moreover, there has been some discussion, albeit in the absence of empirical data, regarding the link between ‘‘covert” toxocariasis and associated wheezing and pulmonary infiltrates (Sharghi et al., 2000). Unfortunately, studies in humans examining lung function in the presence of a common and relatively benign (although not without potential complications) nematode infection such as Toxocara spp. are largely non-existent. This report sought to examine the association between Toxocara spp. infection and lung function by testing differences in forced expiratory volume in 1 s (FEV1) between those with and without evidence of infection with this helminth in a nationally representative sample from the United States population.
2. Materials and methods The association of Toxocara infection and lung function was assessed using data from the Third National Health and Nutrition Examination Survey (National Center for Health Statistics, US Department of Health and Human Services (DHHS). Third National
0020-7519/$36.00 Ó 2010 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijpara.2010.09.006
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Health and Nutrition Examination Survey, 1988–1994, NHANES III Examination Data File (CD-ROM). Public Use Data File Documentation Number 76200. Hyattsville, MD, USA: Centers for Disease Control and Prevention, 1996) conducted between the years of 1988 and 1994 by the National Center for Health Statistics at the Centers for Disease Control and Prevention, USA. Methods describing this national survey have been described previously (National Center for Health Statistics, 1996). The survey was designed to obtain nationally representative information on the health and nutritional status of the population of the USA through interviews and direct physical examinations. The study had very good participation, with an 86% response rate for the questionnaire interview, and a 78% response rate for the examination component, which included blood samples subsequently stored and used for analysis of Toxocara antibodies. Self-reported health data as well as physiological measures were collected in either the Mobile Examination Center or at the participants’ homes. As described in the NHANES laboratory documentation, Toxocara antibodies were measured with an inhouse enzyme immunoassay (EIA) developed at the Centers for Disease Control and Prevention (CDC, USA). This assay utilized an excretory/secretory antigen of T. canis, absorbed to 96-well Immulon II HB Flat Bottom plates. First, serum reacts with the antigen, which is followed by the application of horseradish peroxidase labeled anti-human IgG. Tetramethylbenzidine (TMB) substrate was used to visualize the reaction. A vMax microplate reader and SOFTmax software was used to determine O.D. (Molecular Devices Corp., Menlo Park, CA, USA) (Center for Disease Control (2007) Documentation, codebook and frequencies; surplus sera laboratory component: antibody to Toxocara larva migrans. NHANES III, series 11 Data Files 26A. ftp://ftp.cdc.gov/pub/Health_Statistics/NCHS/ Datasets/NHANES/NHANESIII/26a/SSTOXO.pdf). However, the assay was not able to distinguish between T. canis and Toxocara cati antibodies (Won et al., 2008), and so this report simply refers to Toxocara spp. infection throughout the text. Spirometry was performed for all participants in this report. At least five measurements were taken to meet the then, newly updated, American Thoracic Society reliability guidelines (Hankinson and Bang, 1991). Forced exhaled volumes were measured using a dry rolling-seal spirometer. Forced expiratory volume was digitally recorded (National Center for Health Statistics, 1996). Level of education was used as a robust indicator of socioeconomic status and was recorded as the number of years of education completed. Body mass index (BMI) was recorded as the ratio of weight in kilograms to height in meters squared (kg/m2). Smoking history was represented here by three categories. Those who have never smoked more than 100 cigarettes in their lifetime were classified as never smokers, those that have smoked at least 100 cigarettes in their lifetime, but do not currently smoke were classified as past smokers, and those who currently smoke were classified as current smokers. Ethnicity was determined by self-report and was represented by three categories: African-Americans, MexicanAmericans and Whites. Immigration status reflects simply the participant’s place of nativity rather than the participant’s official administrative documentation of that status. This was determined by the answer to the question: ‘‘Were you born in the United States?”. According to NHANES convention, participants living in central counties of metropolitan areas of 1 million population or more, or fringe counties of metropolitan areas of 1 million population or more, were classified as urban. All others were classified as rural. Dog ownership was determined by self report. Only participants less than 65 years of age were used for this analysis since the elderly are much more likely to have diminished lung function due to advanced age. A total of 16,226 adult participants who were at least 17 years old at the time of examination were measured for the presence of Toxocara spp. antibody. After excluding those 65 years of age or older, we were subsequently left with a total
analytical sample of 12,174. A further 568 participants did not have spirometry measures, leaving a final analytical sample of 11,606. The prevalence of Toxocara infection was exactly the same in the sample before and after excluding those without spirometry. 2.1. Statistical methods Sample population means and proportions are presented with linearized standard errors. Bivariate associations between Toxocara infection and FEV1 were assessed using exact methods. Multiple linear regression was used to assess the independent association between Toxocara infection and FEV1 while controlling for age, sex, education level, BMI, smoking status, ethnicity, status as an immigrant, urban versus rural residence, and dog ownership. Four models were subsequently fitted. Model 1 assessed the association between Toxocara infection and FEV1, while controlling the effects of age and sex. Model 2 assessed the same relationship, but added education level and BMI to the age and sex adjustment. Model 3 examined the Toxocara–FEV1 association while adjusting for all covariates in Models 1 and 2, and additionally adjusting for ethnicity, immigrant status (US-born versus those of foreign nativity) and smoking status (current smokers, past smokers and never smokers). The final model, Model 4, adjusted the Toxocara–FEV1 association for all of the covariates in the first three models, while also controlling for urban versus rural residence and dog ownership. The svymean, svytab, and svyregress (for the linear regression models) commands in STATA were used in order to account for the NHANES weighted sampling design. STATA version 10 was the software used for all statistical analyses (StataCorp LP, College Station, TX, USA). The level of significance for these analyses was less than or equal to 0.05. 3. Results The overall prevalence of infection with Toxocara spp. among participants less than 65 years of age was 14.2% (95% confidence Table 1 Proportions for categorical variables and means for continuous variables are presented by Toxocara infection status among adults from the Third National Health and Nutrition Examination Survey (National Center for Health Statistics, US Department of Health and Human Services (DHHS). Third National Health and Nutrition Examination Survey, 1988–1994, NHANES III Examination Data File (CD-ROM). Public Use Data File Documentation Number 76200. Hyattsville, MD, USA: Centers for Disease Control and Prevention, 1996). Linearized standard errors are also presented. Risk factors
Women Men African-American Mexican-American White Immigrant Non-immigrant Age 18–29 Age 30–39 Age 40–49 Age 50–65 Education (years) BMI (kg/m2) Current smoker Past smoker Never smoked Urban resident Rural resident Dog owner No dog FEV1 (mL)
Toxocara
P-value
Positive (n = 1898)
Negative (n = 10,276)
0.13 (0.008) 0.16 (0.01) 0.21 (0.008) 0.12 (0.006) 0.12 (0.009) 0.22 (0.008) 0.13 (0.004) 0.15 (0.011) 0.15 (0.014) 0.12 (0.012) 0.14 (0.012) 11.5 (0.15) 26.7 (0.16) 0.17 (0.01) 0.12 (0.01) 0.14 (0.01) 0.13 (0.01) 0.16 (0.02) 0.14 (0.01) 0.15 (0.01) 3311.3 (37.7)
0.87 (0.008) 0.84 (0.01) 0.79 (0.008) 0.88 (0.006) 0.88 (0.009) 0.78 (0.008) 0.87 (0.004) 0.85 (0.011) 0.85 (0.014) 0.88 (0.012) 0.86 (0.012) 12.7 (0.08) 26.4 (0.12) 0.83 (0.01) 0.88 (0.01) 0.86 (0.01) 0.87 (0.01) 0.84 (0.02) 0.86 (0.01) 0.85 (0.01) 3416.6 (21.7)
BMI, body mass index and FEV1, forced expiratory volume in 1 s.
0.01 <0.0001
0.0002 0.16
<0.001 0.06 0.01
0.08 0.29 0.02
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interval (95% CI) = 12.7–15.9) in the general US population. Table 1 shows the differences in sociodemographic characteristics and lung function by the presence or absence of Toxocara spp. antibody. Men (16%; 95% CI = 13–18%) and immigrants (22%; 95% CI = 17–28%) had a higher prevalence of Toxocara spp. antibody than women (13%; 95% CI = 11–15%) or US-born persons (13%; 95% CI = 11–15%), respectively. African-Americans (21%; 95% CI = 19–22%) had significantly greater prevalence of infection than either Mexican-Americans (12%; 95% CI = 10–13%) or Whites (12%; 95% CI = 10–14%). Those participants infected with Toxocara were less educated (11.5 years versus 12.7 years, P < 0.001) and had modestly higher BMI (26.7 versus 26.4, P = 0.06) than those who were not infected. Current smokers had a higher prevalence (17%; 95% CI = 14–19%), than either past smokers (12%; 95% CI = 10–14%) or those who had never smoked (14%; 95% CI = 12–16%). Toxocara infection showed no specific distribution pattern across the four age categories (P = 0.16), and there were no substantive or significant differences between those who owned dogs and those who did not (P = 0.29) or between those who lived in rural areas and those who lived in urban areas (P = 0.08). Expiratory volume was diminished in those with Toxocara infection relative to those without infection (FEV1 = 3311 versus FEV1 = 3417, P = 0.02). Table 2 presents the four models, each examining the association between Toxocara infection and lung function, while simultaneously controlling for potential confounders. Model 1 illustrates a difference of 180 mL (95% CI = 112.6–248.1) of forced air in 1 s between those with Toxocara infection and those without even after adjusting for age and sex. The latter two factors were also associated with lung function, with each increasing year in age corresponding to an approximate decrease of 30 mL of forced air in 1 s, and with women expiring 1061 mL less forced air in 1 s than men. These latter two associations with lung function are of the expected strength and direction for both age and sex, respectively. Model 2 additionally controls for education achieved (in years) and BMI. Although attenuated, the association between Toxocara infection and diminished lung function remained (b = 125.1; 95% CI = 188.5 to 61.8), as did the expected associations with age and sex. Nevertheless, education (b = 44.5; 95% CI = 37.9– 51.2) was significantly and strongly associated with lung function,
which was also to be expected, while BMI (b = 3.7; 95% CI = 7.5 to 0.04) was only modestly associated with lung function, albeit in the expected direction. Model 3 added ethnicity, immigrant status and smoking status to the previous adjustment. This adjustment further attenuated the association between Toxocara and FEV1, but the relationship between the two nevertheless remained strong and significant (b = 76.7; 95% CI = 130.9 to 22.6), while simultaneously showing that there was a substantive difference in FEV1 between African-Americans (b = 432.2; 95% CI = 470.2 to 394.1) and Whites, although not between immigrants (b = 71.5; 95% CI = 175.8 to 32.8) and US-born participants. Finally, Model 4, which added urban/rural residence and dog ownership to the final model, had only a small effect on the Toxocara–FEV1 association (b = 73; 95% CI = 128.1 to 17.9), which continued to show a 73 mL deficit in the volume of air forcibly expired in 1 s. 4. Discussion This is believed to be the first report to describe the association between Toxocara infection and lung function in a nationally representative population-based sample in the United States. The findings show an association between diminished lung function and infection with Toxocara spp., such that a fully-adjusted estimated difference of 73 mL of forced air in 1 s was observed between those with antibody evidence of Toxocara spp. infection versus those with no such evidence of infection. This relationship existed after controlling for age, sex, education level, BMI, ethnicity, smoking status, whether the person was born in the USA or immigrated there, rural residence and dog ownership. All but the last three of these potential confounders were also significantly associated with FEV1 in the expected directions. The relationship between reduced atopy or asthma and microbial colonization seems to extend to a broad variety of gastrointestinal infections with bacterial, viral and protozoan microbes implicated in reduced disease (Matricardi et al., 2000). In one study, participants with exposures to either the protozoan Toxoplasma gondii or hepatitis A virus showed significantly reduced atopy, while additionally, a very strong statistical trend in reduced atopy appeared for those exposed to one, two or three gastrointestinal organisms. However, this study also showed no association between
Table 2 Multiple linear regression models showing the adjusted associations between previous Toxocara infection and forced expiratory volume in 1 s (FEV1) among adults from the Third National Health and Nutrition Examination Survey (National Center for Health Statistics, US Department of Health and Human Services (DHHS). Third National Health and Nutrition Examination Survey, 1988–1994, NHANES III Examination Data File (CD-ROM). Public Use Data File Documentation Number 76200. Hyattsville, MD, USA: Centers for Disease Control and Prevention, 1996). The regression coefficients (b) and 95% confidence intervals (95% CIs) are presented for Toxocara spp. antibody and all of the confounder covariates. b Model 1a 95% CI
Risk factors Toxocara infection (versus non-infected) Age (years) Female (versus male)
180.3
248.1 to
29.5 1061.4
30.8 to 28.1 1093.9 to 1028.9
Education (years) BMI (kg/m2) Past smoker (versus never) Current smoker (versus never) Immigrant (yes versus no) African-American (versus White) Mexican-America (versus White) Urban (versus rural) resident Dog owner (yes versus no) a b c d
Toxocara–FEV1 Toxocara–FEV1 Toxocara–FEV1 Toxocara–FEV1
association association association association
is is is is
b Model 2b 95% CI 112.6
125.1 29 1056.2 44.5 3.7
188.5 to
b Model 3c 95% CI 61.8
30.2 to 27.7 1088.8 to 1023.7 37.9–51.2 7.5 to 0.04
76.7 30.5 1068.1 37.3 5.4 31.5 135.9
130.9 to
b Model 4d 95% CI 22.6
31.9 to 29.1 1099.7 to 1036.6 29.8–44.7 9.1 to 1.6 22.4 to 85.3 179.5 to 92.4
73 30.5 1067.9 35.9 5.2 31.7 135.6
for for for for
17.9
31.9 to 29.1 1099.2 to 1036.5 28.4–43.4 9.0 to 1.4 22.4 to 85.9 178.4 to 92.8
71.5 432.2
175.8 to 32.8 470.2 to 394.1
81.3 436.3
188.2 to 25.5 476.2 to 396.3
45.3
108.6 to 18.1
51
115.7 to 13.7
50.1 22.8 adjusted adjusted adjusted adjusted
128.1 to
age and sex. Model 1 covariates, plus education and body mass index (BMI). Models 1 and 2 covariates plus ethnicity, immigrant status and smoking status. Models 1, 2 and 3 covariates plus urban residence and dog ownership.
2.6 to 102.5 25.0 to 70.5
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concentration of IgE antibody and any of those infections (Matricardi et al., 2000). Interestingly, those infections are typically responsible for a Th1 shift in the balance of immune response, whereas helminth infections are not. In contrast, helminths typically promote a Th2 immune response and are usually associated with a preponderance of IgE production. From an evolutionary perspective, a potential association between parasitic infection and atopic dysfunction is plausible in the context of an IgE-mediated hypersensitivity that is highly evolved to target a tremendous presence, in both quantity and diversity, of parasites in the environment (Weiss, 2000). Parasitic antigens, by way of T cell mediation, stimulate B cell production of IgE antibodies. Mast cell binding sites are the primary target for IgE binding, which cause the degranulation of those cells and allow them to perform their inflammatory function. Moreover, helminth infections stimulate very high levels of IgE production (Turner et al., 1979). This concert with the mast cell is clear given there are over 100,000 IgE binding sites per cell. Therefore, in the absence of helminth infections, this highly specific immune mechanism is without its target and may default to aeroallergens, which would otherwise induce weak antigenicity (Turner et al., 1979). Nevertheless, the greater consistency with this relationship is between clearly defined atopy and helminth infection. The relationship between clinically designated asthma, or lung function in general, and helminth infection is not as consistent. Our results, in particular, question whether a more specific relationship between lung function and infection with Toxocara is likely. Indeed, infection with helminths may actually lead to the presentation of asthmatic symptoms. It was shown almost 30 years ago that primate infection with A. suum was associated with hypersensitivity in lung cells (Pritchard et al., 1983). More recent rodent models have also demonstrated challenged lung function in roundworminfected mice (Buijs et al., 1995; Pinelli et al., 2005). This relationship is equally plausible given that the extreme up-regulation of both IgE antibodies and eosinophils is clearly associated with pulmonary infiltrates, wheezing and airflow obstruction (Weiss, 2000). As such, this report adds further important evidence to the complex relationship between parasitic infection and lung function. As expected, we found a higher level of educational attainment associated with decreased presence of Toxocara spp. antibodies, and an increased level of lung function. As with most parasitic infections, helminths are typically associated with poorer socioeconomic conditions and this report provides further evidence for this established finding (Hotez, 2007; Hotez and Wilkins, 2009). Similarly, we also found that increased BMI was associated with decreased lung function in the full model (Table 2), with every unit increase in BMI corresponding to a 5 mL decrease in FEV1. This is believed to be the first study to consider the potential moderation of BMI on the relationship between lung function and Toxocara infection, however, the association between BMI and Toxocara infection was quite modest. This study further examined whether the association between Toxocara infection and lung function could be accounted for by ethnicity or immigration status. African-Americans had significantly higher Toxocara infection than either Mexican-Americans or Whites in this population, and further demonstrated an adjusted FEV1 deficit of 430 mL. These results corroborate what has been shown in previous reports of both Toxocara infection and lung function (Won et al., 2008; Harik-Khan et al., 2001). Indeed, ethnicity demonstrated the strongest association with Toxocara infection of any sociodemographic variable other than sex. Nevertheless, the relationship between Toxocara infection and lung function, while attenuated, remained after adjusting for ethnicity. Interestingly, this study found a significantly higher prevalence of Toxocara infection among individuals born outside the US. Many people who
come to the US to work leave impoverished rural areas in their native countries. As helminth infections in general, and Toxocara spp. in particular, are more common in rural settings, immigrant communities may collectively experience greater exposure to these helminths in their early childhood before migrating and thus may be over-represented in Toxocara prevalence. Most studies indicate that being foreign-born is associated with reduced risk for asthma, or asthma-related symptoms (Rottem et al., 2005). Nevertheless, our data showed that being born outside the US was associated with diminished lung function relative to those born within the US. Even so, immigrant status itself was not significantly associated with FEV1 when ethnicity was also controlled. Finally, given the possibility of greater Toxocara infection among rural residents and dog owners, and given the possibility that these same groups may also demonstrate diminished lung function, this study further assessed urban versus rural residence and dog ownership with respect to the Toxocara–FEV1 relationship. There was only a moderate difference (non-significant) in Toxocara prevalence across these groups, and they failed to show an association with lung function. This is not entirely surprising since a previous report showed that, while there was no significant difference in Toxocara prevalence by rural residence or dog ownership, there were ethnicity-specific significant differences in prevalence by both. However, the authors of that report point out that their crude ethnicity stratum-specific rate estimates were unstable (Won et al., 2008), which makes multivariable modeling of these variables questionable. In this current report, there is likely no association because the model controls for ethnicity. This study has strengths and limitations that warrant discussion. An important strength of this study was the ability to directly examine measured lung function in the context of known infection with Toxocara spp. in a diverse, nationally representative population-based survey. This is believed to be the first study to explore the relationship between spirometry-measured pulmonary function and infection with Toxocara in humans. It is also believed to be the first study to test the association between lung function and parasitic infection of any kind in a population-based study of this scale and with the compliment of covariate measurements to control for potential confounding. While infection with this helminth in the US is more common than perhaps would have been expected (over 14% overall), only a study of this scale would allow for a thorough investigation of this relationship by providing sufficient power to include confounder adjustment. Thus the sample size is a major strength of this study, allowing for multiple layers of stratification. The most obvious limitation is the cross-sectional nature of these data, which precludes, more than anything else, direct causal interpretation of the observed association. Two points are worth noting, however. First, the association between lung function and Toxocara infection is unlikely to be due to reverse causality, which can be one of the most problematic characteristics underlying an observed cross-sectional association. The question under current investigation is whether or not Toxocara infection has an effect on lung function as has been hypothesized (largely by inference from ecological data). We cannot, of course, measure the effect directly and are therefore constrained to measure the association, which can go in either direction with respect to a cause–effect relationship. Nevertheless, in this instance, it is biologically more plausible that infection with this parasite lends the host to pulmonary involvement given the nature of the immunological response to the organism, rather than diminished lung function predisposing the pulmonologically less fit individual to infection with the parasitic organism. There is a possible exception, however, and this serves as the second notable point. If Toxocara infection is itself a proxy for poorer socioeconomic status, then we might expect to see an increased occurrence of infection associated with decreased lung function, just as we observed in this
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study, because both may be associated with lower socioeconomic conditions. However, we did adjust for the level of education attained. As such, we would expect this to capture the reverse causality that could have explained the observed association if Toxocara infection did indeed represent low socioeconomic status rather than a potential effector of lung function. Nevertheless, no claim of causality can be made for Toxocara infection given that these data are observational and cross-sectional. In conclusion, this report demonstrates a strong association between infection with Toxocara spp. and current lung function as measured by FEV1. The diminished lung function among individuals with Toxocara infection is an important finding in the ongoing debate over the rising asthma epidemic in the absence of parasitic infection in Western countries. While more concrete evidence has been presented to show a general parasitic protective effect against atopic disease, the relationship between parasites and lung function, specifically, may be far more complex. Further longitudinal data examining these relationships should be sought and captured quickly to shed further light on this important relationship between the human environment and immunology. References Buijs, J., Egbers, M.W., Lokhorst, W.H., Savelkoul, H.F., Nijkamp, F.P., 1995. Toxocarainduced eosinophilic inflammation. Airway function and effect of anti-IL-5. Am. J. Respir. Crit. Care Med. 151, 873–878. Godfrey, R.C., Gradidge, C.F., 1976. Allergic sensitization of human lung fragments prevented by saturation of IgE binding sites. Nature 259, 484–486. Hankinson, J.L., Bang, K.M., 1991. Acceptability and reproducibility criteria of the American Thoracic Society as observed in a sample of the general population. Am. Rev. Respir. Dis. 143, 516–521.
247
Harik-Khan, R.I., Fleg, J.L., Muller, D.C., Wise, R.A., 2001. The effect of anthropometric and socioeconomic factors on the racial difference in lung function. Am. J. Respir. Crit. Care Med. 164, 1647–1654. Hotez, P.J., 2007. Neglected diseases and poverty in ‘‘The Other America”: the greatest health disparity in the United States? PLoS Negl. Trop. Dis. 1, e149. Hotez, P.J., Wilkins, P.P., 2009. Toxocariasis: America’s most common neglected infection of poverty and a helminthiasis of global importance? PLoS Negl. Trop. Dis. 3, e400 [Epub 2009 March 31]. Matricardi, P.M., Rosmini, F., Riondino, S., Fortini, M., Ferrigno, L., Rapicetta, M., Bonini, S., 2000. Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma: epidemiological study. BMJ 320, 412–417. Pinelli, E., Withagen, C., Fonville, M., Verlaan, A., Dormans, J., van Loveren, H., Nicoll, G., Maizels, R.M., van der Giessen, J., 2005. Persistent airway hyperresponsiveness and inflammation in Toxocara canis-infected BALB/c mice. Clin. Exp. Allergy 35, 826–832. Pritchard, D.I., Eady, R.P., Harper, S.T., Jackson, D.M., Orr, T.S.C., Richards, I.M., Trigg, S., Wells, E., 1983. Laboratory infection of primates with Ascaris suum to provide a model of allergic bronchoconstriction. Clin. Exp. Immunol. 54, 469–476. Rottem, M., Szyper-Kravitz, M., Shoenfeld, Y., 2005. Atopy and asthma in migrants. Int. Arch. Allergy Immunol. 36, 198–204. Sharghi, N., Schantz, P., Hotez, P.J., 2000. Toxocariasis: an occult cause of childhood neuropsychological deficits and asthma? Sem. Ped. Infect. Dis. 11, 257–260. Turner, K.J., Feddema, L., Quinn, E.H., 1979. Nonspecific potentiation of IgE parasitic infections in man. Int. Arch. Allergy Appl. Immunol. 58, 232–236. van den Biggelaar, A.H., van Ree, R., Rodrigues, L.C., Lell, B., Deelder, A.M., Kremsner, P.G., Yazdanbakhsh, M., 2000. Decreased atopy in children infected with Schistosoma haematobium: a role for parasite-induced interleukin-10. Lancet 356, 1723–1727. Weiss, S.T., 2000. Parasites and asthma/allergy: what is the relationship? J. Allergy Clin. Immunol. 105, 205–210. Won, K.Y., Kruszon-Moran, D., Schantz, P.M., Jones, J.L., 2008. National seroprevalence and risk factors for zoonotic Toxocara spp. infection. Am. J. Trop. Med. Hyg. 79, 552–557.