Storage iron deficiency is a major contributor to anemia in high-intensity S. japonicum infection. A high prevalence of anemia without iron deficiency, exclusion of other mechanisms of anemia, and the evidence of low bioavailable iron suggest that anemia of inflammation contributes to S. japonicum-associated anemia at all infection intensities.

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There is a relationship between schistosomiasis and anemia, although the magnitude and exact mechanisms involved are unclear. In a cohort of 580 Schistosoma japonicum-infected 7-to 30-year-old patients from Leyte, The Philippines, we evaluated the impact of reinfection with S. japonicum after treatment with praziquantel on the mean hemoglobin level, iron-deficiency (IDA) and non-iron-deficiency anemia (NIDA), and inflammatory markers. All participants were treated at baseline and followed up every 3 months for a total of 18 months. At each follow-up, participants provided stools to quantify reinfection and venous blood samples for hemograms and measures of iron status and inflammation. After 18 months, reinfection with S. japonicum was associated with a lower mean hemoglobin level (؊0.39 g/dl; 95% confidence interval [95% CI], ؊0.63 to ؊0.16) and 1.70 (95% CI, 1.10 to 2.61) times higher odds of all-cause anemia than those without reinfection. Reinfection was associated with IDA for high reinfection intensities only. Conversely, reinfection was associated with NIDA for all infection intensities. Reinfection was associated with serum interleukin-6 responses (P < 0.01), and these responses were associated with NIDA (P ‫؍‬ 0.019) but not with IDA (P ‫؍‬ 0.29). Our results provide strong evidence for the causal relationship between S. japonicum infection and anemia. Rapidly reinfected individuals did not have the positive treatment effect on hemoglobin seen in nonreinfected individuals. The principle mechanism involved in S. japonicum-associated anemia is that of proinflammatory cytokine-mediated anemia, with iron deficiency playing a role in high-intensity infections. Based on the proposed mechanism, anemia is unlikely to be ameliorated by iron therapy alone.

Although schistosomiasis is effectively treated with Praziquantel, rapid reinfection with rebound morbidity precludes effective control based on chemotherapy alone and justifies current efforts to develop vaccines for these parasites. Using a longitudinal treatment-reinfection study design with 616 participants 7 to 30 years of age, we evaluated the relationship between cytokine responses to Schistosoma japonicum soluble adult worm extract (SWAP), Sj97, Sj22.6, and Sj67, measured 4 weeks after treatment with Praziquantel, and resistance to reinfection in a population from Leyte, The Philippines, where S. japonicum is endemic. S. japonicum transmission was high: 54.8% and 91.1% were reinfected within 6 and 18 months, respectively. A Th2 bias in the following cytokine ratios, interleukin-4 (IL-4)/IL-12, IL-5/IL-12, IL-13/IL-12, IL-4/gamma-IFN (IFN-␥), IL-5/ IFN-␥, and IL-13/IFN-␥, in response to SWAP predicted a 1.4-to 2.9-month longer time to reinfection (P < 0.05) and a 27 to 55% lower intensity of reinfection (P < 0.05). Similarly, a Th2 bias in response to Sj97 predicted a 1.6-to 2.2-month longer time to reinfection (P < 0.05) and a 30 to 41% lower intensity of reinfection (P < 0.05). Only a high IL-5/IL-10 ratio in response to Sj22.6 predicted a 3.0-month-longer time to reinfection (P ‫؍‬ 0.03). Cytokine responses to Sj67 were not associated with protection. In a large population-based treatment-reinfection study we found that Th2 responses to SWAP and Sj97 consistently predicted resistance to reinfection. These findings underscore Th2-type immune responses as central in human resistance to S. japonicum and support Sj97 as a leading vaccine candidate for this parasite.

We conducted a prospective cohort study in Leyte, the Philippines, among 611 Schistosoma japonicum-infected participants 7-30 years old, all of whom were treated with praziquantel at baseline. To detect hepatic fibrosis, abdominal ultrasound was performed at baseline and 12 months after treatment. Stool for assessment of S. japonicum infection was collected at baseline and at 3, 6, 9, and 12 months after treatment. Cytokines (interleukin [IL]-4, IL-5, IL-10, IL-13, tumor necrosis factor- alpha , and interferon- gamma ) produced by peripheral-blood mononuclear cells in response to soluble worm antigen preparation (SWAP), soluble egg antigen (SEA), and control medium were measured once 4 weeks after treatment. IL-4 to SWAP and IL-10 to both SWAP and SEA were associated with the presence of baseline fibrosis after adjustment for potential confounding variables (P<.03, for all). In participants with fibrosis at baseline, IL-4 to SWAP and IL-5 and IL-13 to both SWAP and SEA were associated with persistent fibrosis at 12 months after treatment (P<.05, for all). Males showed consistently stronger T helper 2 (Th2) cytokine responses to both SWAP and SEA than did females (P<.02, for all). These results suggest an independent role for Th2-biased cytokine responses to S. japonicum antigens in persistent hepatic fibrosis and indicate that Th2 cytokines may contribute to the male-biased prevalence of fibrosis.

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.

Schistosomiasis is associated with undernutrition, but the mechanisms involved remain unknown. We analyzed baseline and follow-up data from a longitudinal treatment-reinfection study in N = 477 Schistosoma japonicum-infected subjects 7-20 years of age from Leyte, the Philippines. After baseline treatment with praziquantel, follow-up visits were scheduled every 3 months for 18 months; stool, venous blood, and anthropometric measurements were collected at each visit. Cytokine production by peripheral blood mononuclear cells (PBMCs) stimulated with specific S. japonicum antigens was measured once 4 weeks after treatment. After adjustment for confounders, S. japonicum intensity was associated with decreased serum albumin and Z-scores (all P < 0.05) and with increased serum C-reactive protein (CRP) and interleukin (IL)-6. CRP was associated with decreased albumin and Z-scores (all P < 0.01). Production of IL-1b and tumor necrosis factor (TNF)-alpha in response to worm antigen was associated with decreased albumin (both P < 0.005) and height-for-age Z-score (TNF-alpha only, P = 0.05). S. japonicum-associated undernutrition may, in part, result directly from inflammation.

Apoptosis is important for targeting cancer cells for destruction. Various single-nucleotide polymorphisms (SNPs) in apoptotic genes have been associated with increased risks in lung cancer, particularly FAS 21377 G>A (rs2234767), FASLG 2844 C>T (rs763110), IL1B 13954 C>T Phe105Phe (rs1143634) and BAT3 Ser625Pro (rs1052486). We studied the association of these SNPs with non-small cell lung cancer (NSCLC) in a large case-control study (N 5 4263: 2644 cases and 1619 controls). No associations with NSCLC were observed in the main effects analysis for all four SNPs, adjusting for age, gender, smoking status, pack-years and years since smoking cessation. In subjects under age 60, for FASLG 2844 C>T polymorphism, CT compared with the CC genotype, was significantly associated with increased risk of NSCLC, adjusted odds ratio (aOR) 5 1.58 (1.22, 2.05), P 5 0.0006 and TTaOR 5 1.45 (1.01, 2.04), P 5 0.04. In contrast, for those over age 60, the CT aOR 5 0.91 (0.73, 1.13), P 5 0.37 and TT aOR 5 0.86 (0.64, 1.16), P 5 0.32. The P-value for the age-genotype interaction was 0.004. For the IL1B 13954 C>T polymorphism, compared with the CC genotype, TT showed significant associations in former smokers and in men but tests of interaction were not significant (P smoking 5 0.24, P gender 5 0.17). No interactions were observed for FAS 21377 G>A and BAT3 Ser625Pro polymorphisms. Our findings indicate that age and smoking may modify the association of the FASLG 2844 and IL1B 1 3954 SNPs with the risk of NSCLC.