Schistosoma japonicum-associated morbidity and its mechanisms among children and young adults in the Philippines

Abstract

This thesis presents results from a longitudinal study in Schistosoma japonicum infected children, adolescents and young adults, carried out in the Philippines. The aim of this thesis was to describe nutritional morbidity and hepatic fibrosis in the context of S. japonicum infection and reinfection following treatment with praziquantel, and to evaluate potential immunological mechanisms involved in these morbidities. In addition, the potential immunomodulatory role of the puberty-associated hormone dehydroepiandrosterone sulphate (DHEAS) in the age-related decline of nutritional morbidity was evaluated. Following treatment with praziquantel, nutritional status as measured by Z-scores and hemoglobin levels improved, whereas S. japonicum reinfection had an overall negative impact on nutritional status. Reinfection was associated with iron deficiency anemia in the high reinfection intensities only. Conversely, reinfection was associated with non-iron deficiency anemia in all reinfection intensities. Serum C-reactive protein (CRP) and interleukin (IL)-6 showed a dose-dependent positive association with intensity of S. japonicum infection and reinfection, suggesting that schistosomiasis induces systemic inflammation. Taken together, these results 1) strengthen the causal relationship between S. japonicum infection and undernutrition and anemia, 2) suggest this is mediated, in part, by proinflammatory cytokines, in particular IL-6, and 3) suggest that anemia of inflammation is the central mechanism responsible for anemia associated with S. japonicum infection. Based on these findings, treatment intervals in highly endemic areas should not exceed one year in order to prevent rebound morbidity due to reinfection. Furthermore, dietary supplementation should be combined with schistosomiasis control strategies in order to reduce nutritional morbidity in these areas. Independent of age and intensity of helminth infections, increased levels of DHEAS were associated with a reduction in inflammation-associated undernutrition and anemia, as well as with reduced serum levels of CRP, IL-1 and IL-6. These findings support the hypothesis that with increasing age, the anti-inflammatory effects of increased levels of DHEAS during pubertal development result in decreased proinflammatory cytokine-mediated nutritional morbidity. Both presence and severity of S. japonicum-associated hepatic fibrosis were associated with reduced nutritional status, and with increased serum levels of CRP, IL-1 and IL-6. These findings support the hypothesis that hepatic fibrosis induces systemic inflammation and thereby leads to undernutrition and anemia. Even individuals with mild fibrosis, which is generally considered clinically insignificant, had reduced nutritional status compared to those without fibrosis. This finding stresses the importance of early recognition and treatment of fibrosis. Persistent hepatic fibrosis, i.e. fibrosis that was diagnosed at baseline and remained present one year following treatment, was associated with increased levels of S. japonicum-specific IL-4, IL-5 and IL-13. This finding suggests that these pro-fibrotic T-helper 2 (Th2) cytokine responses, which may also protect against S. japonicum reinfection, play a role in the progression of hepatic fibrosis. Therefore, with development of a Th2-boosting vaccine against S. japonicum reinfection, worsening of hepatic fibrosis should be investigated as a potential adverse effect. Males experienced a higher prevalence and greater severity of both nutritional and hepatic morbidity than females. The increased risk of fibrosis among males may result directly from greater production of Th2 cytokines.