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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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12 years (P = 0.03), but not to BMIZ (P = 0.52) or triceps skinfold Z-score (P = 0.11). Individuals with high-intensity S. japonicum infection were 3.5 times more likely to have occult blood in the stool. Adjustment for occult blood did not attenuate the relationship between S. japonicum and hemoglobin, suggesting other mechanisms are involved. Adjustment for SES allows more accurate assessment of the relationship between S. japonicum and both PEM and anemia. Exploration of the mechanisms of S. japonicum–associated anemia suggests that processes other than extracorporeal blood loss, such as anemia or inflammation, may be involved. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the past, the nutrition and health of school-aged children and adolescents in the developing world received little attention relative to those < 5 years of age. However, recent research has been more focused on school-age children because of growing evidence that 1) high prevalence and severity of PEM is sustained during these years,2 2) these nutritional problems can adversely affect cognition1–7 and school/work performance,1,8–10 and 3) undernutrition has a potentiating effect on infectious disease morbidity and mortality.11,12 In a cohort of 8- to 12-year-old children in Ghana, Tanzania, India, Viet Nam, and Indonesia, the Partnership for Child Development found prevalences of 50–71%, 47–81%, and 23–96% for stunting, anemia (< 120 g/L), and parasitic helminth infection, respectively.2 In most areas of the developing world, PEM and anemia from macro- and micronutrient deficient diets, respectively, is exacerbated by helminthiasis. Understanding the contribution of helminth infections to PEM and anemia is crucial for prioritization of scarce resources in the developing world.
Schistosoma japonicum has been related to both undernutrition and anemia in cross-sectional studies13,14 and a randomized controlled trial (RCT).15 In a cross-sectional study in The Philippines, S. japonicum infection was found to be negatively associated with nutritional status among 8- to 19-year-old individuals. This study was limited, however, by lack of adjustment for socioeconomic status (SES).13 In a randomized control trial in Leyte, The Philippines, McGarvey and others found that individuals ages 4–20 treated with praziquantel had significantly higher sum of skinfolds and hemoglobin levels (P < 0.001) than the placebo group after 6 months.15 Though randomized controlled trials are better able to infer causality, brief periods of follow-up do not permit observation of changes in longer term measures of nutritional status such as height-for-age.
The objectives of this study were to 1) provide more accurate estimates of the relationship between S. japonicum infection and both PEM and anemia through better adjustment for potential confounders such as SES and geo-helminth infections, 2) use a cross-sectional design to investigate the effects of long-term infection on growth and nutritional status, and 3) assess the role of occult blood loss in mediating S. japonicum–associated anemia.
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MATERIALS AND METHODS |
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Stool examination.
Parasite burden was determined by examination of three stool specimens obtained from each study participant. Each of the three stool specimens was examined in duplicate for Schistosoma japonicum, Ascaris lumbricoides, Trichuris trichuria, and hookworm by the Kato Katz method. For each of the stool specimens, the average eggs per gram (epg) of the duplicate test was determined, and the overall mean epg was derived by averaging the parasite burden of the three individual specimens. Intensity of infection for each helminth was determined using World Health Organization criteria as follows: S. japonicum, low-, moderate-, and heavy-intensity infections were defined as 1–99, 100–399 and 
400 epg, respectively; A. lumbricoides, low-, moderate-, and heavy-intensity infections were defined as 1–4999, 5000–49,999, and 50,000 epg, respectively; T. trichuria, low-, moderate-, and heavy-intensity infections were defined as 1–999, 1000–9999, and 10,000 epg, respectively; hookworm, low-, moderate-, and heavy-intensity were defined as 1–1999, 2000–3999, and 4000 epg, respectively.16,17 Ten hookworm larvae obtained by culturing stool samples18 from 203 volunteers were speciated by PCR; all were Necator americanus with no Ancylostoma species detected. One stool sample from each individual was evaluated with the Hemoccult system (Beckman-Coulter, Fullerton, CA), a screening test for the presence of fecal occult blood.
Tanner staging. Tanner stage provides an estimate of the stage of pubertal development and was calculated according to standard techniques.19 Breast/areolar development for girls and testicular and penile development for boys were scored on an ordinal scale from 1 (prepubescent) to 5 (adult). Pubic hair quantity and distribution were scored for both genders on this ordinal scale. The results of these 2 scores were averaged to produce the Tanner stage.
Nutritional assessment.
Volunteers were measured while wearing light clothing and no shoes, according to procedures described by Jelliffe.20 Volunteers were weighed to the nearest 0.1 kg on a Seca Model 880 Digital scale (Hanover, MD), and height was measured to the nearest 0.1 cm using a portable anthropometer. These measurements were used to determine the height-for-age Z-score (HAZ) and body mass index (BMI; wt/ht2). BMI is the index of choice for the assessment of recent undernutrition in both adults and adolescents.21–23 HAZ represents a measure of long-term growth and nutritional status. Weight for age Z-scores were not assessed, as perturbations in WAZ may be due to short stature or thinness. Z-Scores for each nutritional index (HAZ and BMIZ only calculable for individuals aged 18 and < 20 years, respectively) were calculated from Center for Disease Control (National Center for Health Statistics) [year 2000] reference values24 using EpiInfo version 2000 (Centers for Disease Control and Prevention [CDC], Atlanta, GA). Z-Scores represent a given nutritional index’s standard deviation from the age- and gender-adjusted CDC reference median from the year 2000.25 Volunteers were considered stunted or wasted if HAZ or BMIZ were < -2 standard deviations. In addition, triceps skinfold was measured in triplicate to 1 mm using a Lange skinfold caliper (Lange, Cambridge, MD) and the mean value was recorded. A Z-score for triceps skinfold was calculated using age- and gender-specific mean and standard deviations from the National Health and Nutritional Examination Surveys (NHANES I and II).26 Test-retest and inter-rater reliability assessment for weight, height, and triceps skinfold were conducted on a sample of 50 subjects from a neighboring village. Test-retest was done such that each subject was tested by each rater twice with blinding to initial measurements and multiple assessments in between ratings of a single subject. Inter-rater reliability was assessed by evaluation of the correlation between two different raters of the same subject on the same day. Test-retest and inter-rater reliability for weight, height, and triceps skinfold were excellent, ranging from 0.73 to 0.99 and 0.56 to 0.96, respectively.
Blood collection and processing. Venipuncture was performed and blood was collected into Vacutainer tubes (Becton Dickinson and Company, Franklin Lakes, NJ) containing EDTA as an anticoagulant. This venous sample was used to obtain a complete hemogram on a Serono Baker 9000 hematology analyzer (Serono Baker Diagnostics, Allentown, PA).
Socioeconomic status. SES was based on questionnaire data addressing parental and child educational status, occupational status, ownership status of home/land, and assets. The questionnaire had good internal consistency with a Cronbach’s alpha of 82.4% for all questions. A summary SES score composed of all questionnaire items was calculated using principal components analysis to appropriately weight questionnaire items as described by Filmer.27
Data management and statistical analyses. Data forms collected in the field were bar coded and entered using File-maker 5.5 software (Filemaker Inc., Santa Clara, CA). Normality diagnostics were first performed, and non-normally distributed variables, including epg, were loge transformed [ln(value+1)]. Pearson’s correlation coefficients and Student’s t test were used to assess bivariate relationships between primary outcomes of interest and primary predictors of interest or potential mediating/confounding covariates (i.e., intensity of S. japonicum infection, geohelminth infection, age, gender, socioeconomic status).
Regression models were constructed to provide uncon-founded estimates of the relationships of interest. The primary exposure of interest, S. japonicum infection intensity, was first entered into the model. Variables that were significantly related to the outcome in bivariate analyses (P < 0.10) then were sequentially entered into the model. These were retained if they were significantly related to the outcome of interest. Variables also were retained in the model if their inclusion altered the beta coefficient for the primary exposure of interest by > 10%. Interaction terms were evaluated to assess whether the relationship between S. japonicum and nutritional outcomes was modified by gender, age 12 years, and baseline stunting or wasting. The choice of age grouping for stratification was based on the fact that the median age between early adolescence (Tanner 1–2) and later adolescence/adult (Tanner 3–5) was 12. All analyses were performed in JMP version 5.1 on PC computers (SAS Institute, Cary, NC).
Ethical clearance and informed consent. This study was approved by Brown University and The Philippines Research Institute of Tropical Medicine Institutional Review Boards. Separate ethical clearance was obtained for reliability assessment of anthropometric measures, and ethical clearance for that protocol was obtained from the two aforementioned boards. All S. japonicum–infected subjects were treated at baseline and will be treated again at the end of the longitudinal study at 18 months. Individuals infected with geo-helminths will be treated at the end of the longitudinal study. Written informed consent was obtained from each adult participant or the parents of assenting children.
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RESULTS |
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. There were 1,701 individuals aged 7–30 in the study area, of whom 36.0% were S. japonicum infected. Overall, 656 individuals were eligible to participate, in addition to 111 S. japonicum–uninfected control subjects. Of these, 38 did not come to the laboratory for baseline data collection, giving a participation rate of 95%. The study sample, therefore, consists of 729 individuals, of which, 449 were male and 280 were female. The mean age (95% CI) among the volunteers was 14.9 (14.5–15.3) years. The overall nutritional status of the cohort was poor, with mean HAZ and BMIZ scores of –2.42 and –1.07, respectively. Infection with more than one helminth was common as the prevalence of each of three geo-helminth infections assessed was greater than 50%.
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, top). For the whole cohort, HAZ was inversely related to S. japonicum infection, after adjusting for other covariates, although this did not reach statistical significance (ß = –0.035; P = 0.11).
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12" revealed that the negative relationship between S. japonicum infection and HAZ was strongest among those 12 years of age (ß = –0.064; P = 0.03). Therefore, stratified results for study participants on the basis of age are shown (Table 2
, bottom). There was no significant relationship between S. japonicum infection and HAZ among those > 12 years of age (ß = 0.001; P = 0.96) or Tanner 4 (ß = 0.066; P = 0.32; data not shown). When the cohort was stratified by gender, the strongest relationship between S. japonicum infection and HAZ was observed among males (ß = –0.057; P = 0.05; data not shown). We evaluated the interaction between baseline nutritional status and S. japonicum to assess whether the effect modification by gender was explained by baseline nutritional status, which was worse among boys. The interaction term between baseline nutritional status (stunted or wasted) and S. japonicum was not significant. Of note, SES was significantly and positively related to HAZ in the whole cohort (ß = 0.318; P = < 0.0001) and remained so in all stratified models. Its inclusion greatly attenuated the relationship between S. japonicum and HAZ (with SES: S. japonicum ß = –0.035; P = 0.11; without SES: S. japonicum ß = –0.047; P = 0.03). BMIZ and S. japonicum burden. For the whole cohort, BMIZ was not significantly related to S. japonicum infection (ß = –0.013, NS; data not shown) after adjusting for confounders. Of note, a significant increase in the magnitude of the S. japonicum infection ß coefficient (> 10%) is observed when SES is removed from the model, implying that SES is a confounder of this relationship. We additionally observed no significant relationship between triceps-skinfold Z-score and S. japonicum infection (ß = 0.021; P = 0.11; data not shown).
Hemoglobin and S. japonicum burden.
A multivariate linear regression model was made to assess the relationship between burden of S. japonicum infection and hemoglobin (Table 3, top). For the whole cohort, hemoglobin was inversely and significantly related to the intensity of S. japonicum infection, after adjusting for other covariates (ß = –0.194; P = < 0.0001). Occult blood status is retained in the model, despite the fact that its inclusion does not alter the S. japonicum ß-coefficient significantly, suggesting that occult blood loss is not the only mechanism through which S. japonicum causes anemia. We then repeated this analysis, excluding individuals with high-intensity S. japonicum infection, and found that S. japonicum infection was still negatively related to hemoglobin after adjusting for other covariates. (ß = –0.201; P = < 0.0001; data not shown). Of note, strong negative relationships with hemoglobin were observed only for heavy- and moderate-intensity hookworm (ß = –1.012; P = < 0.0001) and heavy-intensity T. trichuria infections (ß = –0.2401; P = < 0.08).
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, bottom). When the cohort was stratified by age, strong inverse relationships between S. japonicum infection and hemoglobin were observed across all age groups (Age 12: ß = –0.206; P < 0.0001; Age > 12: ß = –0.165; P = 0.009; data not shown).
A least squares means analysis was conducted to determine the adjusted relationship between mean hemoglobin and intensity of S. japonicum infection as defined by WHO criteria. There was a dose-response relationship between mean hemoglobin and S. japonicum WHO infection intensity category (Figure 1), with significant differences across groups (P < 0.0001).
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DISCUSSION |
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After adjusting for SES and geo-helminths, there was no significant relationship between S. japonicum infection status and HAZ across all ages. There was, however, a significant negative relationship between S. japonicum and HAZ among children 12 years of age. Subgroup analyses by Tanner stage suggest that the lack of relationship among older adolescents is not simply due to increased variance in HAZ, which is expected based on variability in pubertal growth spurt timing. This is evidenced by a lack of relationship between HAZ and S. japonicum among adolescents Tanner 4. This finding differs from a previous cross-sectional study conducted in The Philippines in 1989, where the greatest effect on stature was observed among older adolescents.13 Such differences may be due to varying frequency of treatment and thus chronicity of infection, differences in infection intensities, which may or may not delay pubertal growth, or temporal and ecologic changes that may place younger children at risk for a longer duration of exposure.
We additionally noted no significant relationship between S. japonicum infection and BMIZ. This is not unexpected given BMIZ is a measures of recent nutritional well-being. Given the chronicity of S. japonicum infection in communities where it is endemic, we would expect long-term linear growth faltering as reflected by HAZ, with relative "protection" of weight-for-height indices. We also found no significant differences in triceps skinfold Z-scores, a measure of adipose stores and recent nutritional status. In the aforementioned cross-sectional study from Leyte, S. japonicum infection was found to be negatively associated with sum of skinfolds.13 It is possible that this difference lies in lack of control for confounders such as SES, which may place children who are more likely to be S. japonicum–infected at increased risk of recent nutritional deprivation
Fecal occult blood was relatively rare in this study sample (4.8%). There was a significant trend toward increased odds of occult blood positivity only among those with high-intensity schistosomiasis infection versus all other intensities of schistosomiasis. Other studies of occult blood loss in the context of schistosomiasis have provided varied results. One cross-sectional study in the Anhui Province, China, did not observe any relationship between occult blood and S. japonicum presence or intensity of infection. However, their study sample harbored a low prevalence and intensity (only 1–3% with high intensity) of S. japonicum infection, potentially due to ready availability of drug therapy.28 In cross-sectional and case-control studies in the context of Schistosoma mansoni, investigators have found strong evidence for a relationship between fecal occult blood and intensity of schistosomiasis infection.29–31 In one such study, individuals with moderate-or high-intensity S. mansoni had increased prevalence of occult blood; however, uninfected individuals had a 23.1% prevalence of occult positivity, and no adjustment was made for the presence of hookworm infection, which was endemic.30 In another study, high- versus low-intensity infection with S. mansoni increased the risk for occult positivity by approximately 4-fold.31 Given the lack of control for hookworm and trichuris infections, which have been associated with occult blood loss at high intensities,16,32 it is difficult to interpret the studies in S. mansoni. This study suggests that occult blood loss may be relevant only at high-intensity infection in S. japonicum.
With respect to hemoglobin, there was a strong inverse relationship with S. japonicum. This effect was noted even when the analysis excluded those with high-intensity infection, suggesting a generalized phenomenon not limited to those most intensely infected. This analysis was adjusted for other helminth infections, most importantly hookworm and trichuris, which, as supported by this data, have been associated with decreased hemoglobin at high intensity of infection.17,33,34 Notably, the relationship between S. japonicum infection and hemoglobin remained even when occult blood loss was retained in the multivariate model. This suggests that some other mechanism, such as anemia of inflammation/ chronic disease, may be mediating S. japonicum–associated anemia. To our knowledge, no studies have examined the relationship between tumor necrosis factor (TNF) -
, a known mediator of anemia of inflammation, and S. japonicum–associated anemia. It is possible that changes in iron bioavailability, mediated through proinflammatory cytokines,35 could contribute to schistosomiasis-attributable anemia. In a rabbit model of S. japonicum, investigators suggested that the anemia observed was due to anemia of chronic disease, as no occult blood loss was observed in the stool, the anemia was normocytic, and there were no changes in serum iron levels during the course of infection.36
One surprising finding was that hookworm infection was positively associated with both HAZ and BMIZ. Of note, this was limited to older adolescent males for BMIZ and older adolescent females for HAZ, but not younger children. This was not explained by differences in hookworm prevalence across villages, or neighborhoods within villages, which may have had different baseline nutritional status. Relatively few studies have addressed the relationship between hookworm and anthropometric nutritional status.37 Further, most studies that have addressed this have treated with albendazole in populations that also harbor trichuris and ascaris infections.38–40 Thus, it is unclear whether growth and nutritional improvements are due to treatment of hookworm, specifically, or the other geo-helminths. Future work should address this question in other populations.
We found that the relationship between S. japonicum infection and undernutrition (both HAZ and hemoglobin) was modified by gender, with infection having a greater negative impact on males. This was not explained by poorer baseline nutritional status of boys, based on evaluation of stunted (and wasted) * (* = multiply) S. japonicum interaction terms. Previous work has demonstrated a gender-dependent immune response to schistosomiasis with males suffering higher morbidity.41,42 One study found significantly increased production of proinflammatory cytokines TNF- and interferon (IFN)-gamma coupled with decreased production of transforming growth factor (TGF)- ß and interleukin (IL)-10 in response to Schistosoma haematobium for males as compared with females.42 Proinflammatory cytokines, such as TNF-, have been implicated in the pathogenesis of cachexia and may contribute to malnutrition through appetite suppression and lean body wasting.43–49 They have also been implicated in anemia of inflammation and may explain some of the gender differences in S. japonicum’s effect on hemoglobin.
For the whole cohort, SES was a strong predictor of each nutritional outcome. The inclusion of SES in all of the models greatly attenuated the relationship between S. japonicum infection and the outcome variable. The S. japonicum beta coefficient diminished significantly (>10%) in each of the three main models (whole cohort HAZ, BMIZ, and hemoglobin) when SES was included. Confounding by SES is expected based on the independent relationship between poverty and both parasitic disease exposure and undernutrition. Our results highlight the importance of controlling for socioeconomic factors to more accurately quantify the relationship between parasitic diseases and nutritional status. It is likely that this adjustment captures the relationship between infection intensity and morbidity more accurately than previous studies where SES was not taken into account.13,14
The main limitation of this study is the cross-sectional design, which limits causal inferences that can be made and raises concerns about reverse causality. It is, however, unlikely that these findings reflect an increased risk for S. japonicum infection among those with PEM or lower hemoglobin, given an RCT has established the direction of causality from S. japonicum to both PEM and decreased hemoglobin.15 It should also be noted that cross-sectional data is important as it may better capture the accrued morbidity of chronic helminth infection, which may be difficult in RCTs or longitudinal studies with brief periods of follow-up. A second limitation is that no data were available with respect to food and iron availability. There may be residual confounding based on risk of exposure to helminth infection and decreased access to macro- and micronutrients, which is not captured by our SES covariate. Given the strength of the relationship between SES and nutritional outcomes in this cohort, however, residual confounding is unlikely to substantively alter these results. Finally, only one fecal occult blood examination was performed. It is possible that occult blood loss from egg translocation across the large bowel and/or polyps is too sporadic to sensitively capture with a single test. Thus, occult blood loss may still play a role in the decreased hemoglobin observed even in those without high-intensity infections. Ongoing studies of the relationship between S. japonicum–associated inflammation and anemia in this cohort should shed light on this question.
Understanding contributors to PEM and anemia among children in the developing world is crucial, as undernutrition and anemia adversely affects cognitive performance,1,3–7 potentiates mortality risk from infectious diseases,11,12 and likely contributes to adult short stature, which, in turn, decreases work capacity10,50 and increases the risk for adverse birth outcomes such as dystocia.1,51,52 Better adjusted estimates of the relationship between parasitic diseases and both PEM and anemia are important to provide an accurate estimate of the global burden of these diseases. In this study, we found that refinement of these estimates still suggests a strong relationship between both PEM and anemia and S. japonicum. Deworming programs in parts of Asia where S. japonicum is endemic should include treatment with prazi-quantel.
Received April 14, 2004. Accepted for publication August 13, 2004.
Acknowledgments: The authors thank our field staff for their diligence and energy: Blanca Jarilla, Mario Jiz, Archie Pablo, Raquel Pacheco, Patrick Sebial, Mary Paz Urbina, and Jemaima Yu. The authors thank the study participants from Macanip, Buri, and Pitogo in Leyte, The Philippines.
Financial support: This work was funded by NIH RO1AI48123 and K23AI52125.
* These authors contributed equally to this work. 
Authors’ addresses: Jennifer F. Friedman, Hemal K. Kanzaria, Gretchen C. Langdon, Haiwei Wu, Stephen T. McGarvey, and Jonathan D. Kurtis. International Health Institute, Brown University, Box G-B495, Providence, RI 02912. E-mails: jennifer_friedman{at}brown.edu, hemal.kanzaria{at}alumni.brown.edu, haiwei_wu{at}brown.edu, gretchen_langdon{at}brown.edu, stephen_mcgarvey{at}brown.edu, and jonathan_kurtis{at}brown.edu.;Luz P. Acosta, Daria L. Manalo, and Remigio M. Olveda, Research Institute of Tropical Medicine, FICC, Alabang, Muntinlupa City 1770, Metro Manila, The Philippines, E-mails: lacosta{at}ritm.gov.ph and dmanalo{at}ritm.gov.ph.
Reprint requests: Jennifer F. Friedman, Brown University, International Health Institute, Box G-B495, Providence, RI 02912, E-mail: Jennifer_Friedman{at}Brown.edu.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
