H.C. Kariuki

Immunity after treatment of human schistosomiasis mansoni. II. Identification of resistant individuals, and analysis of their immune responses.

Intensities of re-infection were monitored at three-monthly intervals after treatment of Schistosoma mansoni infections in a group of 119 Kenyan schoolchildren, whose levels of water contact were also observed. 22 children showed high reinfection intensities (greater than 100 eggs per gram of faeces) by 12 months after treatment, and were considered to be susceptible. Out of 70 children who showed low reinfection intensities during the same period (less than 30 eggs per gram), 35 showed high levels both of total water contact and of contact with sites containing infected snails. In these children, the relative lack of reinfection could not be attributed to a lack of exposure, and they were classified as resistant to reinfection. Comparison of the two groups, resistant and susceptible, revealed no difference in pretreatment intensities of infection. However, there was a marked difference in age, the mean age of the resistant group being two years greater than that of the susceptible group, within a restricted starting age range. These findings indicated that resistance was an acquired and age-dependent phenomenon, not obviously related to previous egg-induced pathology. Studies of immune responses revealed no clearcut correlate of resistance, but there were interesting differences between the two groups. Whereas anti-egg antigen responses declined after treatment to a greater extent in the resistant than in the susceptible group, antibodies mediating eosinophil-dependent killing of schistosomula rose markedly in both groups, strongly suggesting that the resistant children were being exposed to cercariae. Anti-adult worm antibodies rose sharply in both groups immediately after treatment, and thereafter declined to pretreatment levels. Although some individual children showed high levels of IgE anti-schistosomulum antibodies, there were no significant differences between the two groups. Since all children showed detectable levels of antibodies mediating eosinophil-dependent killing of schistosomula, the possibility was considered that such antibodies might be a necessary, but not a limiting, factor in immunity. Instead, the functional state of the effector cells mediating antibody-dependent killing might be limiting. Eosinophil levels, measured as an indirect estimate of eosinophil functional activity, did not differ between the two groups. There were, however, marked differences between different individuals in their capacity to produce eosinophil-stimulating monocyte mediators, and although this cannot yet be related to resistance, this aspect is worth further study.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunity in human schistosomiasis mansoni: prevention by blocking antibodies of the expression of immunity in young children

A total of 129 children were treated for Schistosoma mansoni infections, and followed for intensity of reinfection at 3-monthly intervals over a 21-month period. Blood samples were taken before treatment and at 5 weeks and 6, 12 and 18 months after treatment. This paper presents a statistical analysis of the relationship between various immune responses and subsequent reinfection. Responses analysed were: blood eosinophil levels; IgE antibodies against schistosomulum antigens; IgG antibodies mediating eosinophil-dependent killing of schistosomula; antibodies inhibiting the binding to schistosomulum antigens of two rat monoclonal antibodies that also recognize egg antigens; the levels of anti-adult worm and of anti-egg (total, IgM and IgG) antibodies; and IgM anti-schistosomulum antibodies. Results for each assay were well correlated for each of the five separate blood samples. None of the assays were predictive of resistance to reinfection, but susceptibility to reinfection was strongly correlated with results in the preceding blood samples for total anti-egg antibodies and the inhibition of binding of one of the two monoclonal antibodies. Further analysis also revealed a correlation between reinfection intensities and both IgM anti-schistosomulum antibodies and IgM and IgG anti-egg antibodies. These results are consistent with the hypothesis that early infections elicit the development, in response to egg antigens, of antibodies that block immune mechanisms directed against schistosomula. Blocking antibodies may be IgM, but might also be of an ineffective IgG isotype. The existence of such antibodies in young children would explain the slow development of immunity in the face of a range of detectable, potentially protective immune responses.

Comparison of different chemotherapy strategies against Schistosoma mansoni in Machakos District, Kenya : effects on human infection and morbidity

A comparison was made of the long-term impact of different methods of administration of chemotherapy (oxamniquine, 30 mg/kg in divided doses; or praziquantel, 40 mg/kg) on prevalence and intensity of Schistosoma mansoni infection in four areas in Kangundo Location, Machakos District, Kenya. In Area A, treatment was offered in October 1983 and again in April 1985 to all infected individuals. In Area H, treatment was offered in April 1985 to individuals excreting greater than or equal to 100 eggs per gram (epg) of faeces. In Area S, treatment was offered in April 1985 to all infected school children, within the framework of the primary schools. In the witness area, Area W, treatment was given in April 1985, for ethical reasons, to a small number of individuals excreting greater than or equal to 800 epg. Prevalence and intensities of infection were subsequently monitored at yearly intervals for three complete post-treatment years. In the Area S schools, clinical examination was also carried out at yearly intervals. Treatment of all infected individuals on two occasions (Area A) was the most effective and long-lasting way of reducing prevalence and intensity of infection. In this area, however, some earlier interventions had been carried out and pre-treatment intensities were lower than in the other areas. Treatment only of infected schoolchildren (Area S) also had a marked and prolonged effect, comparable to or better than treatment of individuals with heavy infections (Area H). Treatment of infected schoolchildren also caused a persistent reduction in the prevalence of hepatomegaly, and there was suggestive evidence from intensities of infection in community stool surveys (but not from incidence rates) of an effect on transmission. In all study areas, reinfection was most rapid and most intense among children. These findings are discussed in the light of theoretical considerations and of results from other studies, both on schistosomiasis and on intestinal helminths. We conclude that, in areas of low morbidity such as Kangundo, chemotherapy of schoolchildren only, at intervals of up to 3 years, is a satisfactory way of producing a long-term reduction in both intensity of infection and morbidity.

The influence of sex and age on antibody isotype responses to Schistosoma mansoni and Schistosoma japonicum in human populations in Kenya and the Philippines

We have investigated the effects of host age and sex on human antibody isotype responses to Schistosoma mansoni and Schistosoma japonicum adult worm (AW) and soluble egg (SEA) antigens, using sera from subjects in Kenya and the Philippines. Similar trends with age were observed between the two populations despite host, parasite and environmental differences between the two geographical locations. IgE to AW increased with age, whereas most isotype responses to SEA decreased with age. IgG1, IgG3 and IgG4 subclass responses to adult worm, however, did not show a broadly rising or falling pattern with age. Males were found to have higher IgG1, IgG4 and IgE to AW in both populations. This sex difference remained significant in the Kenyan population even after controlling statistically for confounding factors such as age and differences in intensity of infection. Analysis of S. mansoni and S. japonicum adult worm antigens reactive with IgE revealed a predominant 22 kDa band in both parasites. Only those individuals with relatively high IgE titres specifically reactive with S. mansoni or S. japonicum AW had detectable IgE against Sj22 or Sm22.

Spatial patterns of human water contact and Schistosoma mansoni transmission and infection in four rural areas in Machakos district Kenya.

This paper presents the results of microgeographical studies of human water contact behavior and Schistosoma mansoni transmission levels and intensity of infection in four rural areas in Machakos District, Kenya. The relationship between intensity of infection (geometric mean egg counts) in 3502 persons aggregated in 120 household clusters and eight independent variables was investigated using straight and stepwise linear regression and mapping techniques. Results indicate that the two water contact variables, mean frequency per person and mean duration per person, as well as mean number of sites used per person, a transmission index and mean distance to the most frequently used site were the strongest predictors of geometric mean egg counts. All three distance variables were usually negatively associated with infection although intensity of infection and water contact declined relatively slowly with distance from the streams. This pattern appears to be owing to a combination of the relatively short distances, a general lack of safe alternative water sources and the use of more distant water contact sites both inside and outside the study area during periods of drought. The study of snail-to-man transmission identified number of infected snails as the major transmission variable and number of contacts as the major predictor variable. Mapping of total egg counts at the household cluster level and total number of infected snails revealed spatial association with transmission sites. All results varied considerably between study areas, owing to differences in exposure levels, transmission patterns and environmental factors. Findings are discussed in relation to the epidemiology and control of schistosomiasis and suggestions are made for further spatial studies.

Differences in the rate of hepatosplenomegaly due to Schistosoma mansoni infection between two areas in machakos district. Kenya

The relationship between intensity of Schistosoma mansoni infection and the degree of related morbidity was suspected to differ locally within the Machakos district of Kenya. To test this possibility, prevalences of hepatomegaly and splenomegaly among 1483 school children were compared between 2 areas, Kangundo and Kambu, within this district. These areas, which were similar in many geographical and economic respects and populated by the same tribe (Akamba), had comparable levels of S. mansoni infection and no S. haematobium infection. A relationship was observed between the prevalence of hepatomegaly and intensity of S. mansoni infection, which showed no consistent difference between the 2 areas. In contrast, a relationship between the prevalence of splenomegaly and intensity of S. mansoni infection was observed only in the Kambu schools, and not in the Kangundo schools where the overall prevalence of splenomegaly was much lower. It was possible that part of the splenomegaly observed in Kambu was due to malaria. However, the observation that malaria and schistosomiasis in 2 Kambu schools were not positively correlated allowed approximations to be made of the relative contributions of each to the prevalence of splenomegaly. It was concluded that, in a school close to the river that formed the main transmission site of S. mansoni, schistosomiasis-related hepatosplenomegaly was present in at least 17% of children. The reason for the high prevalence in Kambu of hepatosplenic schistosomiasis remains uncertain, but it could include a synergistic interaction of schistosome infection with malaria.

Chemotherapy for Schistosomiasis in Ugandan Fishermen: Treatment Can Cause a Rapid Increase in Interleukin-5 Levels in Plasma but Decreased Levels of Eosinophilia and Worm-Specific Immunoglobulin E

ABSTRACT Chemotherapy for blood-dwelling schistosomes kills the worms and exposes parasite antigen to the circulation. In many people from areas of endemicity, this treatment increases parasite-specific immunoglobulin E (IgE) and other Th2 responses in the months following therapy, responses that have been associated with subsequent resistance to reinfection. Here we investigate much earlier changes in immune reactions after praziquantel therapy in Schistosoma mansoni-infected fishermen working in an area of high transmission in Uganda. The subjects gave blood before treatment and at 1 and 21 days posttreatment. Blood cultures were incubated with schistosome soluble worm antigen (SWA) or soluble egg antigen (SEA). Interleukin-4 (IL-4), IL-5, IL-10, IL-13, gamma interferon, and transforming growth factor β levels were measured in the cultures and in plasma. A marked transient increase in plasma IL-5 levels was observed in 75% of the subjects (n = 48) by 1 day posttreatment. This response was dependent on pretreatment intensity of infection and was accompanied by a transient decrease in eosinophil numbers. One day posttreatment, blood cultures from the 16 subjects with the greatest increase in plasma IL-5 level (>100 pg/ml) displayed reduced IL-5, IL-13, and IL-10 responses to SWA, and in contrast to the rest of the cohort, these high-IL-5 subjects displayed reduced levels of SWA-specific IgE in plasma 21 days posttreatment. Twenty months after treatment, the intensity of reinfection was positively correlated with the increase in plasma IL-5 level seen 1 day posttreatment. These studies describe the heterogeneity in early immune reactions to treatment, identifying subgroups who have different patterns of reaction and who may have different capacities to mount the responses that have been associated with resistance to reinfection.

Evidence for predisposition of individual patients to reinfection with Schistosoma mansoni after treatment

Statistical analysis of the relationship between intensities of infection before treatment and during reinfection after treatment in a sample of 119 Kenyan schoolchildren demonstrated a positive association, indicating that the individuals differed consistently in their tendency to become infected. This association was stronger in young children but the trend was detectable in older individuals. Possible reasons for this variation and for its apparently greater influence in younger age groups are discussed.

Immunity after treatment of human schistosomiasis mansoni. III. Long-term effects of treatment and retreatment

Group mean Schistosoma mansoni reinfection patterns are presented for 2 years after treatment with oxamniquine in 1981 of over 100 9- to 16-year-old Kenyan schoolchildren, and for one year after retreatment in 1983 with either oxamniquine or praziquantel when most (nearly 700) infected people in the whole community were treated. Quality control confirmed comparable Kato egg counts throughout the study. Continuing transmission after 1981 raised prevalence to nearly its original level within 6 months, but intensity remained suppressed throughout the 2 year follow-up and very few children reacquired heavy infections (greater than 400 eggs/g). Age and sex had significant effects: reinfection diminished with age, especially among boys--a pattern not apparently attributable to differential water contact. Children with heavy pretreatment infections tended to develop heavy reinfections but this trend was not statistically significant on a group basis, nor were similar trends during the period of less pronounced transmission following the 1983 community treatment. Oxamniquine was equally effective in children receiving it in both 1981 and 1983, and the efficacy of praziquantel resembled that of oxamniquine. In this area of Kenya, repeated chemotherapy will be needed to contain transmission, probably annually or biennially, unless supplemented with other, effective control measures. These findings confirm the beneficial effects of treating even a limited segment of a community at intervals of a year or more without necessarily stopping transmission. They are also compatible with recent findings on potential immune mechanisms in man.

Exposure to malaria affects the regression of hepatosplenomegaly after treatment for Schistosoma mansoni infection in Kenyan children.

BackgroundSchistosoma mansoni and malaria infections are often endemic in the same communities in sub-Saharan Africa, and both have pathological effects on the liver and the spleen. Hepatosplenomegaly associated with S. mansoni is exacerbated in children with relatively high exposure to malaria. Treatment with praziquantel reduces the degree of hepatosplenomegaly, but the condition does not completely resolve in some cases. The present analysis focused on the possibility that exposure to malaria infection may have limited the resolution of hepatosplenomegaly in a cohort of Kenyan schoolchildren.MethodsNinety-six children aged 6–16, from one community in Makueni district, Kenya, were treated with praziquantel. At baseline, all children had hepatomegaly and most had splenomegaly. The source of S. mansoni infection, a river, was molluscicided regularly over the following three years to limit S. mansoni re-infection, whereas malaria exposure was uninterrupted. Hepatic and splenic enlargement was assessed annually outside the malaria transmission season.ResultsChildren living in an area of relatively high exposure to both infections presented with the largest spleens before treatment and at each follow-up. Spleens of firm consistency were associated with proximity to the river. The regression of hepatomegaly was also affected by location, being minimal in an area with relatively low S. mansoni exposure but high exposure to malaria, and maximal in an area with relatively low exposure to both infections.ConclusionsThe outcome of treating cases of hepatosplenomegaly with praziquantel in this cohort of Kenyan children depended strongly on their level of exposure to malaria infection. Furthermore, a residual burden of hepatosplenic morbidity was observed, which was possibly attributable to the level of exposure to malaria. The results suggest that exposure to malaria infection may be a significant factor affecting the outcome of praziquantel treatment to reduce the level of hepatosplenic morbidity.