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Community and International Nutrition

Nutritional Status Improves after Treatment of Schistosoma japonicum–Infected Children and Adolescents¹

Hannah M. Coutinho^*,2, Luz P. Acosta, Stephen T. McGarvey, Blanca Jarilla, Mario Jiz, Archie Pablo, Li Su^**, Daria L. Manalo, Remigio M. Olveda, Jonathan D. Kurtis and Jennifer F. Friedman^**

^* Center for International Health Research (CIHR), Department of Pathology and Laboratory Medicine, and ^** Department of Pediatrics, Rhode Island Hospital, Brown University Medical School, Providence, RI; Research Institute of Tropical Medicine, Manila, the Philippines; International Health Institute and Center for Statistical Sciences, Brown University, Providence, RI

² To whom correspondence should be addressed. E-mail: hannah_coutinho{at}Brown.edu.

ABSTRACT

Studies addressing the relation between chronic schistosomiasis japonica and nutritional status are limited. We conducted a longitudinal treatment-reinfection study in Leyte, the Philippines, among 477 Schistosoma japonicum–infected subjects aged 7–20 y, to evaluate changes in nutritional status after treatment with praziquantel. Stool, Tanner stage, anthropometric indices, and hemoglobin (Hb) were evaluated at baseline, 4 wk post-treatment, and every 3 mo for 18 mo. Height-for-age Z-score (HAZ) and BMI Z-score (BMIZ) were calculated. Change scores relative to baseline were created for all outcome measures. Multilevel repeated-measures analyses were used to adjust for socioeconomic status, sex, either pubertal status or age, and household-level clustering. Z-scores improved modestly but significantly over time. BMIZ in children wasted at baseline improved the most [0.41 (0.26–0.56) Z-score unit] and HAZ improved only in children stunted at baseline [0.17 (0.l2–0.21) Z-score unit]. Hb improvement peaked at 15 mo and occurred only in subjects that were anemic at baseline [peak improvement: 8.3 (6.0–10.6) g/L] and in males [peak improvement 4.7 (2.9–6.6) g/L]. Reinfection, evaluated as egg count over time and egg count 3 mo earlier to assess a delay in effect, was inversely associated with improvement in Hb (P = 0.06 and 0.004, respectively). High-intensity reinfection at 18 mo was associated with significantly less absolute growth from baseline compared with lower-intensity and no reinfection. Based on the peak Hb improvement at 15 mo post-treatment, annual treatment intervals are recommended to reduce schistosomiasis-associated nutritional morbidity.

KEY WORDS: • Schistosoma japonicum • praziquantel • nutritional status • longitudinal

Schistosomiasis currently affects >200 million people worldwide, yet the burden of this chronic disease has long been underestimated (1,2). Serious health consequences such as undernutrition and anemia are now recognized as major contributors to the disability adjusted life year estimate for schistosomiasis. This estimate, which is an attempt to quantify the burden of disease, was recently upgraded by a factor of 4 to 30 compared with earlier WHO estimates (1). Schistosoma japonicum is a major public health problem in the Philippines, with an estimated national prevalence of 3%, i.e., 200,000 infected individuals. Because this prevalence is based on 1 stool sample, it is likely underestimated (personal communication, Dr. R. Olveda, Director, Research Institute of Tropical Medicine, Manila, the Philippines). Children have the highest prevalence and intensity of infection, but the consequences of chronic schistosomiasis, such as growth stunting, anemia, hepatic fibrosis, and impaired cognitive development, continue to have an effect throughout adulthood (3–6).

Relations between chronic schistosomiasis japonica and both undernutrition and anemia in children and adolescents were documented in several studies (7–11). However, these studies were either cross-sectional or the follow-up period was relatively short (6–12 mo); except for the randomized controlled trial by Olds et al. (10), assessment of infection with S. japonicum was based on 1 stool sample.

Treatment of S. japonicum with praziquantel (PZQ)³ is very effective, with approximate cure rates of 90% (10,12). If cure is not achieved, reduction of egg excretion occurs in the majority of individuals (9,10). Furthermore, treatment can reduce schistosomiasis-associated morbidity, even in supposedly uninfected individuals (9,10), which is likely due to misclassification of individuals with low-intensity infection. The optimal interval for treatment with PZQ to address these morbidities is unknown. This knowledge is especially important in areas of high transmission, where reinfection may quickly attenuate the benefit of treatment.

Two main strategies are currently used to control schistosomiasis in endemic populations, i.e., mass treatment with PZQ, which makes no use of diagnostic tests, and case finding and treatment with PZQ, requiring pretreatment screening. In the Philippines, the latter may be a more successful strategy, due to the high refusal rate observed in the absence of stool screening (13). These 2 strategies have not been formally compared for cost effectiveness or efficacy.

The objectives of this longitudinal treatment-reinfection study were to evaluate the magnitude of improvement in nutritional status after treatment with PZQ and to identify the approximate timing of peak improvement and subsequent decline to inform ideal treatment intervals to minimize morbidity. Secondary objectives included identification of individuals who may be expected to have the greatest improvements in nutritional status after chemotherapy, and evaluation of the modifying effects of reinfection on nutritional improvement.

SUBJECTS AND METHODS

    Study site and population. This longitudinal treatment-reinfection study was conducted in 3 S. japonicum–endemic rice-farming villages in Leyte, the Philippines (Macanip, Buri, and Pitogo), where transmission of schistosomiasis is holoendemic. Malaria is not endemic in this area. Treatment in this study area is provided by the Schistosomiasis Control Program, which conducts annual mass treatment campaigns. Participation in this program is low due to absence of pretreatment screening for the presence of infection (personal communication, Dr. Antonio Ida, Director, Schistosomiasis Control Program, Leyte, the Philippines). For the current study, participants were enrolled during 2 periods, in October 2002 and April 2003. The main study enrolled subjects aged 7–30 y, but the analyses in this manuscript were limited to subjects aged 7–20 y, who are still growing and represent a more homogeneous study population. In total 77.6% (n = 982/1265) of individuals aged 7–20 y residing in the 3 study villages were screened for the presence of S. japonicum infection by duplicate examination of 3 stool samples before enrolment. The prevalence of infection with S. japonicum in this age range was 61.6%. Subjects were eligible if they were infected with S. japonicum, lived primarily in a study village, were between ages 7 and 20 y, were not pregnant or lactating, had no chronic medical condition or severe anemia, and provided informed consent. This resulted in the inclusion of 477 individuals. At the start of the study (baseline), all participants were treated with PZQ (60 mg/kg in a split dose). Data were collected at baseline, after 4 wk and every 3 mo from baseline for a total of 18 mo, resulting in 8 time points of data collection. Participants who did not come to the study laboratory at any time point after baseline and missed all subsequent time points were considered lost to follow-up.

    Stool examination. The parasite burden was determined by duplicate examination of 3 consecutive stool specimens obtained from each participant. Each of these specimens was evaluated for S. japonicum, Ascaris lumbricoides, Trichuris trichuria and hookworm egg counts by the Kato Katz method as described in detail elsewhere (14). Due to logistic constraints, only 1 stool sample was collected 4 wk post-treatment. Intensity of infection for S. japonicum was determined by use of WHO criteria as follows: low-, moderate-, and high-intensity infections were defined as 1–99, 100–399 and 400 eggs per gram (epg), respectively (15). The species of 10 hookworm larvae obtained by culturing stool samples (16) from 203 volunteers were determined by PCR; all were Necator americanus.

    Pubertal assessment. Tanner staging of pubertal development (breasts in girls and genitalia in boys) was performed by 2 trained physicians according to standard criteria (17). Pre-/early puberty was defined as Tanner score 1, 2, or 3.

    Nutritional assessment. Volunteers were measured while wearing light clothing and no shoes, according to procedures described by Gibson (18). Participants were weighed to the nearest 0.1 kg on a Seca Model 880 Digital scale, 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), BMI [kg/m²] and BMI Z-score (BMIZ). The new CDC reference curves (year 2000) were used to calculate these Z-scores (19) with EpiInfo software (version 2000). BMI is the index of choice for the assessment of recent undernutrition in adolescents (18,20). HAZ represents long-term growth and nutritional status (18). Although an effect of treatment on HAZ would be expected to take more time than an effect on BMIZ, we did evaluate this outcome because of its importance as a nutritional variable. Stunting and wasting were defined as HAZ and BMIZ > 2 SD below the mean, respectively. Furthermore, absolute growth from baseline was assessed through change scores for height and weight at 18 mo post-treatment. In addition, triceps skinfold thickness, a measure of subcutaneous fat stores, was measured at the midpoint of the left upper arm, between the acromion process and the tip of the olecranon in triplicate to 1 mm using a Lange skinfold caliper, and the mean value was recorded (18). Subscapular skinfold was measured similarly. Changes in these 2 skinfolds represent recent changes in nutritional status (18). Sum of skinfold Z-scores (SSFZ) were calculated based on the sum of subscapular and triceps skinfolds, using the reference population of Frisancho et al. (21). Test-retest and inter-rater reliability for weight, height, and skinfolds were excellent, ranging from 0.73 to 0.99 and 0.56 to 0.96, respectively.

    Socioeconomic status. SES is an important determinant of undernutrition (22). SES scores were collected once at baseline using questionnaires that addressed parental and child educational status, occupational status, ownership status of home/land, and assets. The questionnaire had good internal consistency with a Cronbach's of 82.4% for all questions. For all participants, a summary SES score comprised of all questionnaire items was calculated. For 84 individuals, imputation of missing values was performed based on an individual from the same household.

    Blood collection and processing. Venipuncture was performed and blood was collected into Vacutainer tubes (Becton Dickinson). This venous sample was used to obtain a complete hemogram on a hematology analyzer (Serono-Baker Diagnostics). Anemia was defined according to the age- and sex-specific criteria as described by WHO (23).

    Statistical analysis. S. japonicum egg counts were not normally distributed and therefore were log_e transformed [ln(n+1)]. To evaluate whether changes in nutritional status over time were significant, raw change scores were created for all outcome measures per time point of measurement relative to baseline, resulting in 7 change scores. Interaction terms (baseline characteristic x time point) were evaluated for significance (P < 0.05) to assess whether specific subgroups with baseline morbidity experienced greater improvements longitudinally.

All analyses were performed using Proc Mixed in SAS version 8.02 (SAS Institute), which can handle intermittent missing data without loss of available data. P-values < 0.05 were considered significant.

Because outcomes were measured repeatedly within subjects, random effects models were used to account for within-person correlation. In all models, random intercepts and slopes for individuals were specified; thus, no assumptions were made regarding baseline correlation and trends over time. In addition, random intercepts were specified for household, adjusting for clustering at the household level. We used an unstructured correlation matrix, which imposes no restrictions on the within-person covariance, and utilized empirical standard errors, which are robust against misspecification of the covariance structure.

Adjusted least-square means were calculated for each time point, and are reported with 95% CI. All analyses were adjusted for SES, sex, and either pubertal status or age. Z-scores represent nutritional status in relation to a healthy U.S. reference population with earlier onset of puberty. Thus, Z-score models were adjusted for pubertal status to capture the differences in timing of onset of puberty between our study population and the reference population. Hb models were adjusted for age instead. Multivariate linear regression analyses for absolute linear growth and weight gain from baseline were also adjusted for baseline height and weight, respectively. Potential confounding of hookworm egg count was evaluated in all Hb models and no significant effect was found. Thus, results are presented without hookworm as a covariate.

    Ethical clearance and informed consent. This study was approved by the institutional review boards of Brown University and The Philippines Research Institute of Tropical Medicine. All S. japonicum–reinfected subjects as well as subjects infected with geohelminths were treated at the end of the study. Written informed consent was obtained from each participant > 18 y old or from the parents of participating children.

RESULTS

    Baseline nutritional status, treatment effect and loss to follow-up. Baseline characteristics of the whole cohort and by intensity of S. japonicum infection are shown in Table 1. Overall 449/477 (94.1%) individuals were successfully treated. Because of our interest in the health efficacy of treatment, we did not consider treatment failure a reason for exclusion from analyses; thus results are reported for all 477 individuals. At the 6- mo follow-up, 41.6% of individuals had higher egg counts compared with the 3-mo follow-up, indicating a high rate of reinfection. Of the 477 subjects, 71 (14.9%) were lost to follow-up. These subjects were significantly older, more likely to be female, had lower baseline S. japonicum egg counts, and better baseline BMIZ. They did not differ in Hb level and prevalence of anemia, stunting, and wasting.

View larger version (15K): [in this window] [in a new window]   FIGURE 1  Mean change in BMIZ at each time point after treatment with PZQ, stratified by the presence of wasting in subjects aged 7–20 y and infected with S. japonicum at baseline. Least-square means of change in BMIZ are presented, adjusted for SES, sex, Tanner stage, and clustering at the household level. Multilevel repeated-measures analyses were used. Error bars represent 95% CI. Wasted at baseline, n = 67/477; not wasted at baseline, n = 410/477.

View larger version (14K): [in this window] [in a new window]   FIGURE 2  Mean change in hemoglobin at each time point after treatment with PZQ, stratified by the presence of anemia in subjects aged 7–20 y and infected with S. japonicum at baseline. Least-square means of change in Hb are presented, adjusted for SES, sex, age, and clustering at the household level. Multilevel repeated-measures analyses were used. Error bars represent 95% CI. Anemia at baseline, n = 182/477; no anemia at baseline, n = 295/477.

View larger version (13K): [in this window] [in a new window]   FIGURE 3  Mean change in hemoglobin at each time point after treatment with PZQ, stratified by sex in subjects aged 7–20 y and infected with S. japonicum at baseline. Least-square means of change in Hb are presented, adjusted for SES, age, and clustering at the household level. Multilevel repeated-measures analyses were used. Error bars represent 95% CI. Females, n = 200/477; males, n = 277/477.

    Modification of nutritional improvement by S. japonicum reinfection. We evaluated the hypothesis that reinfection attenuates improvement in nutritional status after baseline treatment to strengthen the presumed causal relation between schistosome infection and undernutrition. S. japonicum egg count at follow-up, assessed longitudinally, was negatively associated with improvement in Hb over time (P = 0.06). To test the hypothesis that this negative effect was stronger once infection was chronic, a 3-mo lag-variable was created for S. japonicum egg count. This variable, representing the egg count 3 mo earlier, showed a stronger negative association with Hb improvement (P = 0.004).

To evaluate whether early reinfection had a negative effect on nutritional improvement, we assessed the effect of infection with S. japonicum at 6 mo post-treatment. Subjects who were reinfected (n = 222) had less improvement in Hb than uninfected subjects, and the mean level of Hb decreased at 18 mo [–1.8 (–3.7–0) g/L] (interaction term presence of infection x time point, P < 0.0001; Fig. 4). Mean HAZ improved less in subjects who were reinfected 6 mo post-treatment compared with those who were not [mean change at 18 mo: 0.09 (0.04–0.14) and 0.15 (0.10–0.20) Z-score unit, respectively]. However, the interaction term presence of infection x time point was not significant, indicating that changes over time were parallel between the 2 groups. There was no significant association between S. japonicum reinfection and change in BMIZ and SSFZ.

View larger version (13K): [in this window] [in a new window]   FIGURE 4  Mean change in hemoglobin at each time point after treatment with PZQ, stratified by the presence of S. japonicum reinfection at 6 mo in subjects aged 7–20 y and infected with S. japonicum at baseline. Least-square means of change in Hb are presented, adjusted for SES, sex, age, and clustering at the household level. Multilevel repeated-measures analyses were used. Error bars represent 95% CI. Reinfected at 6 mo follow-up, n = 222/477; not reinfected at 6 mo follow-up, n = 255/477.

DISCUSSION

The current data, derived from a longitudinal treatment-reinfection study, demonstrate that nutritional status improves after treatment in S. japonicum–infected children and adolescents, independently of SES, sex, and either pubertal status (for change in Z-scores) or age (for change in Hb). This improvement occurred even though the majority of the cohort (71.3%) had only low-intensity infection at baseline. Our study adds important information to the growing body of evidence that S. japonicum has a negative effect on nutritional status (7–11), and indicates that regular treatment may reduce nutritional morbidity. During our extended follow-up period, we identified the magnitude and duration of improvement in nutritional status after treatment with PZQ, which should guide treatment intervals in endemic areas. Improved nutritional status may lead to increased physical work capacity and improved cognitive function and reproductive health (3,24).

We observed a small but significant improvement in HAZ in subjects stunted at baseline, suggesting modest catch-up growth. A previous observational study demonstrated potential for catch-up growth in Filipino children who were stunted before the age of 2 y (25). Increase in SES was a significant predictor for recovery from stunting in that study. Other studies in which children remained in the same impoverished setting demonstrated that children experience a progression of stunting (26–28). This suggests that without treatment, mean HAZ may have decreased further in our population, adding relevance to the small improvement we observed.

Hb improvement peaked 15 mo post-treatment and declined thereafter. Furthermore, reinfection dampened this improvement, and did so even more once established for 3 mo. This finding has important public health implications, suggesting that annual treatment is necessary to reduce schistosomiasis-associated anemia. The rapid reinfection of this population only strengthens this conclusion. Olds et al. (10) concluded that yearly mass treatment with PZQ should have an important effect on schistosomiasis prevalence and intensity. However, mass treatment has proven to be less accepted among people in endemic areas in the Philippines compared with annual case finding and treatment, leading to low participation rates in mass treatment campaigns (13). The results of our study are more generalizable to the case-finding-and-treatment intervention because all participants were infected at baseline.

Three months post-treatment, a significant decrease in mean Hb occurred in the whole cohort, in boys as well as in girls. Two phenomena may explain this. First, because treatment may affect Hb with a certain delay, this could represent ongoing deterioration of Hb levels. However, the magnitude of this decrease in only 3 mo makes this explanation in isolation unlikely. Second, treatment with PZQ causes exposure of previously masked worm antigens to immune cells (29). This may initially lead to an upregulation of proinflammatory cytokines, in particular IL-6 and tumor necrosis factor-, causing a decrease in Hb due to anemia of inflammation (30). Further analysis of our data, including assessment of changes in proinflammatory cytokines, will investigate this observation.

Our finding that Hb increased only in boys may result in part from the physiological increase in Hb that occurs during puberty in boys, but not in girls, due to the increase in testosterone levels (31,32). In a study of healthy adolescent boys, an average increase in Hb of 21 g/L occurred over a period of 5 y, the majority of which took place during late puberty (31). However, in our study, the decline after the peak improvement at 15 mo post-treatment cannot be attributed to a physiological process and likely is related to reinfection. This differential effect of treatment on Hb improvement in boys compared with girls may suggest that schistosomiasis-associated anemia, resulting from a combination of iron deficiency and anemia of inflammation, is more significant among boys. This hypothesis is supported by the higher baseline prevalence of anemia and intensity of infection in boys compared girls. Cross-sectional studies from this cohort, which included a broader age range of 7–30 y, demonstrated that the negative relation between S. japonicum infection and Hb was stronger among males (14), and that S. japonicum contributes to iron deficiency anemia (IDA) mainly at high intensity levels of infection (unpublished data), the majority of which occur in males. In females, who generally experience less schistosomiasis-related morbidity (33), IDA due to a combination of increased nutritional demands during puberty and blood loss during menstruation is likely a more important cause of anemia.

Limitations of this study should be addressed. First was the lack of an untreated control group. However, our findings that BMIZ and Hb improved more after treatment in subjects with higher baseline S. japonicum egg count and that reinfection attenuated improvement in nutritional status suggest a causal relation between this chronic infection and both undernutrition and anemia. Furthermore, in randomized controlled trials, nutritional status at follow-up remained unchanged (10) or decreased significantly (9) in children who received placebo instead of PZQ. This suggests that, without intervention, improvement in nutritional status would have been very unlikely in our population. Second, the significantly greater improvement in nutritional status in subjects with severe baseline morbidity may be caused in part by a phenomenon called "regression toward the mean" (RTM). This occurs when a nonrandom sample is selected from a population and implies that individuals with extreme values will have less extreme values at a second measurement (34,35). This can be due to the following: 1) measurement error on initial evaluation that then "corrects" in follow-up; 2) biological within-person variation; or 3) the likely increased potential for growth among those most impaired. We believe the latter is more likely given our good test-retest reliability assessment for anthropometric measurements, indicating a small amount of measurement error. Furthermore, the treatment intervention that took place is likely to have the greatest effect on those most affected by schistosomiasis nutritionally. Nonetheless, because RTM will be greater among individuals with more severe baseline morbidity, it is difficult to disentangle the presumed effects of RTM and treatment without a proper control group (36). A third limitation was that subjects with severe anemia at baseline (<70 g/L) were excluded from the study. Our data show that Hb-improvement was highest among individuals who were anemic at baseline, suggesting that this limitation leads to an underestimation of overall Hb improvement. Finally, lower baseline S. japonicum egg counts among those lost to follow-up may have resulted in an overestimation of the treatment effect. Because mean egg count was only 14.7 epg lower in this group, this potential overestimation is likely to be small.

In conclusion, treatment of S. japonicum–infected children and adolescents results in improved nutritional status. A plateau improvement in BMIZ and a peak improvement in Hb 15 mo post-treatment, in addition to a negative effect of S. japonicum reinfection on Hb-improvement, were observed. Combined with our finding of a significant reduction in absolute growth due to high-intensity infection at the 18-mo follow-up, these data suggest that annual treatment intervals are necessary to reduce schistosomiasis-associated nutritional morbidity in this population.

ACKNOWLEDGMENTS

We thank our field staff for their diligence and energy: Raquel Pacheco, Patrick Sebial, Mary Paz Urbina, and Jemaima Yu. We thank Tjalling Leenstra for his critical review of this manuscript.

FOOTNOTES

¹ Funded by National Institutes of Health grants RO1AI48123 and K23AI52125.

³ Abbreviations used: BMIZ, BMI Z-score; epg, eggs per gram; HAZ, height-for-age Z-score; Hb, hemoglobin; IDA, iron deficiency anemia; PZQ, praziquantel; SES, socioeconomic status; SSFZ, sum of skinfold Z-score; RTM, regression toward the mean.

Manuscript received 25 August 2005. Initial review completed 7 September 2005. Revision accepted 12 October 2005.

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