Tissue inhibitor of matrix-metalloprotease-1 predicts risk of hepatic fibrosis in human Schistosoma japonicum infection.

BACKGROUND: Schistosomes infect 200 million individuals annually and cause significant hepatic fibrosis in up to 20%. Little is known regarding the mechanisms of schistosome-associated hepatic fibrosis in humans, and few biomarkers for risk of fibrosis have been identified. METHODS: We treated 611 Schistosoma japonicum-infected Filipinos with praziquantel (PZQ) and performed ultrasound to quantify hepatic fibrosis at baseline and 12 months after PZQ treatment. We developed a multiplexed assay (FibroPlex) that quantifies predictors and effect modifiers of fibrosis. We measured FibroPlex analytes produced by peripheral blood mononuclear cells stimulated with schistosome egg antigen 4 weeks after PZQ treatment and related these levels to risk of fibrosis 1 year after PZQ treatment. RESULTS: After adjusting for potential confounders, including baseline grade of fibrosis, individuals with detectable tissue inhibitor of matrix-metalloprotease-1 (TIMP-1) had a 3.5-fold greater risk of fibrosis 1 year after PZQ treatment, compared with individuals with undetectable levels (odds ratio, 3.48; 95% confidence interval, 1.41-8.43; P = .007). DISCUSSION: Because TIMP-1 inhibits most matrix metalloproteases, which are responsible for collagen degradation, these data suggest that schistosome-associated hepatic fibrosis results, in part, from excessive inhibition of collagen remodeling. These data further suggest that TIMP-1 is a promising biomarker for assessing risk of hepatic fibrosis in schistosomiasis and, potentially, other infectious and noninfectious causes of liver disease.

Reduction in hookworm infection after praziquantel treatment among children and young adults in Leyte, the Philippines.

One small previous study found that praziquantel reduced hookworm infection. In this study, 607 subjects were enrolled in a longitudinal study. At enrollment and every 3 months for 18 months, three stool samples were collected, and the intensity of infection with Schistosoma japonicum and soil-transmitted helminths (STHs) was quantified. All subjects were treated with 60 mg/kg praziquantel at baseline. Three months post-treatment, the percent of subjects who were hookworm-infected decreased to 46.5% from 61% at baseline. The putative cure rate was 23.7%. The 95% confidence interval around the change in hookworm egg counts from baseline to 6 and 12 months post-treatment was negative and did not include zero. The percent reduction in hookworm egg counts from baseline to 3 months post-treatment was 40.8%. Praziquantel treatment did not decrease the infection intensity of STHs. Control programs using praziquantel may have the added benefit of reducing hookworm infection and anemia in areas of coendemnicity.

Anonymous HIV workplace surveys as an advocacy tool for affordable private health insurance in Namibia.

BACKGROUND: With an estimated adult HIV prevalence of 15%, Namibia is in need of innovative health financing strategies that can alleviate the burden on the public sector. Affordable and private health insurances were recently developed in Namibia, and they include coverage for HIV/AIDS. This article reports on the efficacy of HIV workplace surveys as a tool to increase uptake of these insurances by employees in the Namibian formal business sector. In addition, the burden of HIV among this population was examined by sector. METHODS: Cross-sectional anonymous HIV prevalence surveys were conducted in 24 private companies in Namibia between November 2006 and December 2007. Non-invasive oral fluid-based HIV antibody rapid tests were used. Anonymous test results were provided to the companies in a confidential report and through presentations to their management, during which the advantages of affordable private health insurance and the available insurance products were discussed. Impact assessment was conducted in October 2008, when new health insurance uptake by these companies was evaluated. RESULTS: Of 8500 targeted employees, 6521 were screened for HIV; mean participation rate was 78.6%. Overall 15.0% (95% CI 14.2-15.9%) of employees tested HIV positive (range 3.0-23.9% across companies). The mining sector had the highest percentage of HIV-positive employees (21.0%); the information technology (IT) sector had the lowest percentage (4.0%). Out of 6205 previously uninsured employees, 61% had enrolled in private health insurance by October 2008. The majority of these new insurances (78%) covered HIV/AIDS only. CONCLUSION: The proportion of HIV-positive formal sector employees in Namibia is in line with national prevalence estimates and varies widely by employment sector. Following the surveys, there was a considerable increase in private health insurance uptake. This suggests that anonymous HIV workplace surveys can serve as a tool to motivate private companies to provide health insurance to their workforce. Health insurance taken up by those who are able to pay the fees will alleviate the burden on the public sector.

Higher serum concentrations of DHEAS predict improved nutritional status in helminth-infected children, adolescents, and young adults in Leyte, the Philippines.

Pubertal development and associated downmodulation of proinflammatory cytokines may predict improved nutritional status, independent of chronic parasite infections, in developing countries. We enrolled 731 individuals, aged 7-30 y, from Leyte, the Philippines, where helminth infections and nutritional morbidity are highly prevalent. The following data were collected: venous blood hemoglobin and serum concentrations of ferritin, dehydroepiandrosterone sulfate (DHEAS), C-reactive protein and proinflammatory cytokines (IL-1, IL-6, TNF-alpha, and soluble TNF receptor I); anthropometric measurements to calculate upper arm muscle area Z-score and sum of triceps and subscapular skinfolds Z-score; stool samples to determine Schistosoma japonicum and geohelminth egg counts; and responses to questionnaires assessing socio-economic status. In cross-sectional multilevel linear and logistic regression analyses adjusted for confounders, relations were assessed between 1) DHEAS and nutritional status, 2) DHEAS and proinflammatory cytokines, and 3) nutritional status and proinflammatory cytokines. Independent of age, socio-economic status, and helminth infections, increased levels of DHEAS were associated with improved nutritional status and decreased prevalence of non-iron deficiency anemia in both males and females. DHEAS showed dose-dependent inverse associations with C-reactive protein (P=0.08) and the production of IL-6 (P<0.0001). These inflammatory markers, in turn, were consistently associated with undernutrition and anemia. The results suggest that the puberty-associated rise in DHEAS downmodulates proinflammatory immune responses and thereby reduces undernutrition and anemia in a population experiencing a high burden of chronic helminth infections. This novel regulatory mechanism of inflammation-related nutritional morbidity emphasizes the importance of treating prepubescent children for helminth infections.

Pro-inflammatory cytokines and C-reactive protein are associated with undernutrition in the context of Schistosoma japonicum infection.

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.

Schistosoma japonicum reinfection after praziquantel treatment causes anemia associated with inflammation.

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.

Nutritional status improves after treatment of schistosoma japonicum-infected children and adolescents.

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.

Nutritional status and serum cytokine profiles in children, adolescents, and young adults with Schistosoma japonicum-associated hepatic fibrosis, in Leyte, Philippines.

In a cross-sectional study of 641 Schistosoma japonicum-infected individuals in Leyte, Philippines, who were 7-30 years old, we determined the grade of hepatic fibrosis (HF) by ultrasound and used anthropometric measurements and hemoglobin levels to assess nutritional status. Serum levels of interleukin (IL)-1, IL-6, and IL-10; tumor-necrosis factor (TNF)-alpha; soluble TNF- alpha receptor I; and C-reactive protein (CRP) were measured to examine the association between these markers of inflammation and HF grade. HF was present in 8.9% of the cohort; the majority of cases were mild (grade I), and severe (grade II or grade III) cases occurred only in male individuals. Compared with individuals without HF, those with severe HF--and, to a lesser degree, those with mild HF--had a significantly lower body-mass index (BMI) and BMI z-score, a higher prevalence of anemia, and a higher level of CRP and were more likely to produce IL-6; furthermore, those with severe HF had a significantly higher level of IL-1, compared with those either without HF or with mild HF. These findings suggest that even mild HF is associated with nutritional morbidity and underscore the importance of early recognition and treatment. In addition, our data are consistent with the hypothesis that, by systemically increasing the levels of the proinflammatory cytokines IL-1 and IL-6, HF causes undernutrition and anemia.