Birgitte J. Vennervald

Periportal fibrosis in human Schistosoma mansoni infection is associated with low IL-10, low IFN-gamma, high TNF-alpha, or low RANTES, depending on age and gender.

Schistosoma mansoni infection is highly endemic in parts of Uganda, and periportal fibrosis is common in communities along the shore of Lake Albert. In this study, we have identified cellular immune responses associated with fibrosis. A cohort of 199 individuals aged 6–50, resident in the village for at least 10 years or since birth, were examined for evidence of periportal fibrosis by ultrasound using the Niamey protocol. Whole-blood samples were assayed for levels of nine cellular immune molecules (IL-3, IL-4, IL-5, IL-10, IL-13, TNF-α, IFN-γ, IL-1β, and RANTES) in the absence of in vitro Ag stimulation, and after stimulation with egg and worm Ags. A lack of Ag specificity allowed the number of variables in the analysis to be reduced by factor analysis. The resulting factor scores were then entered into a risk analysis using a classification tree algorithm. Children, adult males, and adult females had different factors associated with fibrosis. Most cases of fibrosis in children (eight of nine) were associated with low (<47th percentile) IL-10 factor scores. Adult females at lowest risk had relatively high IFN-γ factor scores (>83rd percentile), whereas those at highest risk had a combination of intermediate (32nd to 83rd percentile) IFN-γ and relatively high (>60th percentile) TNF-α factor scores. Adult males at lowest risk of fibrosis had moderate TNF-α factor scores (55th to 82nd percentile), and a high risk was associated with either high TNF-α factor scores (>82nd percentile), or intermediate TNF-α combined with low RANTES factor scores (<58th percentile). These results demonstrate that periportal fibrosis is associated with cytokine production profiles that vary with both age and gender.

Adult resistance to schistosomiasis mansoni: age-dependence of reinfection remains constant in communities with diverse exposure patterns.

In a fishing community on Lake Albert in Uganda the pattern of intensity of Schistosoma mansoni infection 6 months after treatment with praziquantel was found to be very similar to reinfection patterns seen in previously studied endemic communities: the profile peaks sharply at around the age of 10 years falling away rapidly to much lower levels in adults. This is in stark contrast to the patterns of water contact, which differ greatly between fishing and non-fishing communities. On Lake Albert, adults appear to be more heavily exposed than children. From these observations we conclude that adults are physiologically (perhaps immunologically) more resistant to infection after treatment than children.

Morbidity in schistosomiasis: an update.

Purpose of reviewSchistosomiasis is an important poverty-related health problem and more than 200 million people are infected. This review summarizes papers from April 2003 to June 2004 with a focus on schistosomiasis morbidity and the various factors that affect the level of morbidity in endemic po

Micro-geographical variation in exposure to Schistosoma mansoni and malaria, and exacerbation of splenomegaly in Kenyan school-aged children

BackgroundSchistosoma mansoni and Plasmodium falciparum are common infections of school aged children in Kenya. They both cause enlargement of the spleen, but their relative contribution to the condition of splenomegaly remains unknown in areas where both infections are endemic. Here, we have investigated whether relatively high exposure to both infections has a clinically measurable effect on this condition.Methods96 children aged 6–16 years living along a ten kilometre stretch and within 4 km south of a river that is a source of both S. mansoni and malaria infections were examined clinically for splenomegaly along the mid clavicular line (MCL) and mid axillary line (MAL). The survey was conducted outside the malaria transmission season. The consistency of the organ was recorded as soft, firm or hard. Mapping of the locations of houses and the course of the river was undertaken. Egg counts were mapped at the household level, as were IgG3 responses to Plasmodium falciparum schizont antigen (anti-Pfs IgG3), in order to identify areas with relatively high exposure to both infections, either infection or neither infection. ANOVA was used to test for differences in egg counts, IgG3 levels and the magnitude of spleen enlargement between these areas.Results4 contiguous sectors were identified, one where anti-Pfs IgG3 responses and S. mansoni egg counts were both high, one where only anti-Pfs IgG3 responses were high, one where only egg counts were high, and one where both anti-Pfs IgG3 responses and egg counts were low. Spleen MAL and MCL values were significantly higher amongst children from the sector with highest IgG3 levels and highest egg counts but similar amongst children from elsewhere. Both egg counts and anti-Pfs IgG3 responses were significantly higher in children with MAL values >=4 cm. Hardening of spleens was associated with proximity of domicile to the river.ConclusionsMicro-geographical variation in exposure to S. mansoni and malaria infections can be exploited to investigate the chronic impact of these two infections. These results provide firm evidence that relatively high exposure to both infections exacerbates splenomegaly even outside the malaria transmission season. Major implications include assessing the burden of infection in school age-children.

Increases in human T helper 2 cytokine responses to Schistosoma mansoni worm and worm-tegument antigens are induced by treatment with praziquantel.

Levels of Schistosoma mansoni-induced interleukin (IL)-4 and IL-5 and posttreatment levels of immunoglobulin E recognizing the parasites tegument (Teg) correlate with human resistance to subsequent reinfection after treatment. We measured changes in whole-blood cytokine production in response to soluble egg antigen (SEA), soluble worm antigen (SWA), or Teg after treatment with praziquantel (PZQ) in a cohort of 187 individuals living near Lake Albert, Uganda. Levels of SWA-induced IL-4, IL-5, IL-10, and IL-13 increased after treatment with PZQ, and the greatest relative increases were seen in the responses to Teg. Mean levels of Teg-specific IL-5 and IL-10 increased ~10-15-fold, and mean levels of IL-13 increased ~5-fold. Correlations between the changes in cytokines suggested that their production was positively coregulated by tegumentally derived antigens. Levels of SEA-, SWA-, and Teg-induced interferon- gamma were not significantly changed by treatment, and, with the exception of IL-10, which increased slightly, responses to SEA also remained largely unchanged. The changes in cytokines were not strongly influenced by age or intensity of infection and were not accompanied by corresponding increases in the numbers of circulating eosinophils or lymphocytes.

Clinical findings in female genital schistosomiasis in Madagascar.

To assess the morbidity of S. haematobium infection in women of reproductive age (15–49 years) in the western part of Madagascar, the village of Betalatala with a prevalence of urinary schistosomiasis in women of 75.6% (95% confidence limit 69.3 to 81.9%) was compared with a neighbouring village with similar socio‐economic characteristics and a prevalence of 5.0% (95% confidence limit 0 to 11.75%). The women were questioned in Malagasy about obstetrical history and urogynecological symptoms. They were examined gynaecologically, parasitologically and by ultrasonography. Important STDs were excluded by appropiate diagnostics. In Betalatala significantly more women reported a history of spontaneous abortion (P < 0.01), complaints of irregular menstruation (P < 0.001), pelvic pain (<0.05), vaginal discharge (P < 0.0001), dysuria (P < 0.05) and haematuria (P < 0.01) than in the control village. Biopsies were obtained from the cervix of 36 women with macroscopical lesions, and in 12 cases S. haematobium eggs were found by histological sectioning (33.3%). In the control village no eggs were detected in the histological sections of biopsies taken from 14 women. (P < 0.05). Infections with Candida albicans, Trichomonas vaginalis, Gardnerella vaginalis and Treponema pallidum were found in similar frequencies in both villages. In 9.8% of the women in Betalatala abnormalities of the upper reproductive tract were revealed by ultrasonography versus none in the women from the control village (P < 0.05). Echographic abnormalities of the urinary tract were present in 24% and 3% of the women in the study village and in the control village, respectively (P < 0.0001). These findings were accompanied by an elevated frequency of haematuria (55% versus 20%) and proteinuria (70.4% versus 25%) in the study population (P < 0.0001). Our study indicates that S. haematobium infection in women may not only cause symptoms in the urinary tract, but also frequently in the lower and upper reproductive tract.

Factors Affecting Human IgE and IgG Responses to Allergen-Like Schistosoma mansoni Antigens: Molecular Structure and Patterns of in vivo Exposure

Background: The human IgE response is associated with allergy and with host defence against parasitic worms. A response to Sm22.6, the dominant IgE antigen in adult Schistosoma mansoni worms, correlates with resistance to re-infection after treatment. Sm22.6 is one of a family of EF-hand containing parasite proteins with sequence similarity to dynein light chain (DLC) and with major non-parasite allergens. Here we compare human IgE and IgG responses to other family members, Sm20.8 and Sm21.7, as well as to SmDLC1, relating these to antigen structure and expression in parasite life stages. Methods: Recombinant antigens were used in ELISA to measure antibody isotype responses in 177 cases from an endemic area, before and 7 weeks after treatment. Parasite antigen expression was assessed by RT-PCR and Western blotting. Results: Levels of antibodies to Sm22.6 and Sm20.8 (but not to Sm21.7 or SmDLC1) showed posttreatment increases in all but young children. Many produced IgE to Sm22.6 and Sm20.8 (2 EF-hands), few to Sm21.7 (1 EF-hand) or SmDLC1 (no EF-hands). Sm21.7 was expressed in cercariae, adults and eggs, Sm22.6 and Sm20.8 were concentrated in the adult. Conclusions: These studies suggest that IgE antigens Sm22.6 and Sm20.8 are only released to boost antibodies when adult worms die, whilst Sm21.7 and SmDLC1 are released constantly from eggs dying in host tissue. IgE responses to these allergen-like molecules may be influenced by patterns of exposure and the number of EF-hand motifs.

Detailed clinical and ultrasound examination of children and adolescents in a Schistosoma mansoni endemic area in Kenya: hepatosplenic disease in the absence of portal fibrosis.

Hepatosplenic schistosomiasis involving organomegaly, portal fibrosis and portal hypertension has been observed in autopsy studies. Here, we have tested the hypothesis that hepatosplenic disease including organomegaly and markers of increased portal pressure can occur in school aged children in the absence of fibrosis. A case‐only study of 96 children aged 7–20 years defined by ultrasound detectable hepatomegaly was undertaken in Makueni district, Kenya. A novel method of clinical examination that involved a consensus scoring by three or four examiners was used to classify children as presenting with severe or moderate hepatosplenic disease after palpation of livers and spleens. Ultrasound examination of livers and spleens was based on the Niamey protocol. Clinical measurements included spleen enlargement along the mid‐clavicular and mid‐axillary lines, liver enlargement along the mid‐sternal (MSL) and mid‐clavicular lines, as well as organ consistency. The clinical examination indicated that 9% and 60% of the children had severe or moderate hepatosplenomegaly, respectively. Amongst egg‐positive children, all clinical measurements, except MSL liver enlargement, correlated with egg count, as did portal vein diameter, spleen length and liver length measured by ultrasound. Peri‐portal fibrosis was not observed in any child, whereas 28% of the children were classified as having increased portal pressure according to World Health Organization criteria. There was no effect of malaria parasitaemia or hepatitis seropositvity on any of the observed parameters. These results indicate that hepatosplenic disease in school‐aged children attributable to S. mansoni infection, involving hepatosplenomegaly and increased portal vein diameter, can occur in the absence of peri‐portal fibrosis.

Serological Responses among Individuals in Areas Where Both Schistosomiasis and Malaria Are Endemic: Cross-Reactivity between Schistosoma mansoni and Plasmodium falciparum

We examined specific immunoglobulin G1 (IgG1) and IgG3 responses to Plasmodium falciparum schizont and Schistosoma mansoni egg and worm antigens in individuals from Kenya, Uganda, and the Sudan who had been exposed to malaria and schistosomiasis. A strong correlation between malaria- and schistosome-specific IgG3 responses was observed. This association appears to result from the presence of cross-reactive components of the 2 parasites that bind IgG3 antibodies, rather than to be mediated by immunological cross-regulation or specific regulatory mechanisms induced by either parasite. Cross-reactivity of IgG3 antibodies was confirmed in a Brazilian cohort of individuals living in an area where schistosomiasis is endemic but no malaria occurs and in a Pakistani cohort from an area where malaria is endemic but no schistosomiasis occurs. An IgG3 interaction with antigens from both parasites was observed in individuals from both cohorts, but not in uninfected European control subjects. The immunological and biological implications of this observation require further exploration.

Community-based study of genital schistosomiasis in men from Madagascar

Detection of Schistosoma haematoblum eggs in 43% of semen samples with Increased levels of eosinophil cationic protein suggests that the genital organs of men are frequently affected with schistosomiasis.