Pauline N. M. Mwinzi

Resistance to reinfection with Schistosoma mansoni in occupationally exposed adults and effect of HIV-1 co-infection on susceptibility to schistosomiasis: a longitudinal study.

BACKGROUND Previous studies have reported age-dependent development of resistance to reinfection by schistosomes and identified immunological correlates of this resistance. However, whether resistance exists that is independent of age effects has been questioned. We did a longitudinal investigation of reinfection by Schistosoma mansoni in an adult population with high occupational exposure. METHODS We monitored a cohort of 96 male car washers working along the shores of Lake Victoria, Kenya during 349.7 person-years for frequency of water contact and infection with S mansoni. Patients were treated with praziquantel upon study entry and after reinfection with S mansoni. Bivariate analyses and a multivariate proportional hazards model were used to assess the effects of water contact, previous infections, and HIV-1 on S mansoni reinfection rates. FINDINGS 13 car washers did not get reinfected or only became reinfected after an extended time (91 weeks). 47 initially had a short time to reinfection (15 weeks) but on subsequent treatments showed increased time to reinfection (29-38 weeks). 36 consistently displayed short times to reinfection (<15 weeks) despite multiple reinfection and treatment cycles. Decreased CD4 T-cell counts in HIV-1-positive individuals corresponded to increased susceptibility to S mansoni reinfection. INTERPRETATION Adults similarly exposed to schistosomiasis are either resistant to reinfection; susceptible, but develop resistance to reinfection after multiple treatments; or remain susceptible to reinfection. Thus, immunological resistance to reinfection with S mansoni exists or can develop independent of age effects. The consequence of HIV-1 co-infection suggests that CD4 T cells contribute to this resistance.

Evaluation of urine CCA assays for detection of Schistosoma mansoni infection in Western Kenya.

Although accurate assessment of the prevalence of Schistosoma mansoni is important for the design and evaluation of control programs, the most widely used tools for diagnosis are limited by suboptimal sensitivity, slow turn-around-time, or inability to distinguish current from former infections. Recently, two tests that detect circulating cathodic antigen (CCA) in urine of patients with schistosomiasis became commercially available. As part of a larger study on schistosomiasis prevalence in young children, we evaluated the performance and diagnostic accuracy of these tests—the carbon test strip designed for use in the laboratory and the cassette format test intended for field use. In comparison to 6 Kato-Katz exams, the carbon and cassette CCA tests had sensitivities of 88.4% and 94.2% and specificities of 70.9% and 59.4%, respectively. However, because of the known limitations of the Kato-Katz assay, we also utilized latent class analysis (LCA) incorporating the CCA, Kato-Katz, and schistosome-specific antibody results to determine their sensitivities and specificities. The laboratory-based CCA test had a sensitivity of 91.7% and a specificity of 89.4% by LCA while the cassette test had a sensitivity of 96.3% and a specificity of 74.7%. The intensity of the reaction in both urine CCA tests reflected stool egg burden and their performance was not affected by the presence of soil transmitted helminth infections. Our results suggest that urine-based assays for CCA may be valuable in screening for S. mansoni infections.

The effect of treatment of schistosomiasis on blood plasma HIV-1 RNA concentration in coinfected individuals.

ObjectiveTo determine whether drug treatment of Schistosomiasis mansoni infection leads to a reduction in plasma HIV-1 RNA concentration in coinfected individuals. MethodsStool and plasma samples were obtained prospectively from a cohort of HIV-infected persons (n = 30) in Kisumu, Kenya, before and after treatment of schistosomiasis with praziquantel (mean follow-up, 5.6 months; range 1–15 months). Schistosomal circulating cathodic antigen (CCA) concentrations in plasma were determined by ELISA and fecal egg counts were determined by microscopy. HIV-1 RNA concentrations were measured in pre- and post-treatment plasma samples obtained from the patients whose stool samples remained free of schistosomal eggs for the great majority of the follow-up period. ResultsComparison of pretreatment and follow-up samples revealed that mean ± SD fecal egg burden was reduced by 96.7% (481.5 ± 803.5 versus 16.1 ± 24.4 eggs/g feces) and mean plasma CCA concentration decreased by 90.1% (3.22 ± 3.26 versus 0.32 ± 0.38 μg/ml). In contrast, mean plasma HIV-1 load increased from 3.60 ± 0.90 to 3.93 ± 0.95 log10 RNA copies/ml (P < 0.001). Although no correlation was found between changes in HIV-1 load and changes in schistosomal burden, there was a significant correlation between changes in plasma HIV load and the time interval between pretreatment and follow-up samples (r = 0.41;P = 0.027). ConclusionsTreatment of schistosomiasis was not associated with a reduction in plasma HIV-1 load. This study does not, however, exclude the possibility of an adverse effect of helminthic infections on HIV-1 pathogenesis.

Spatial distribution of schistosomiasis and treatment needs in sub-Saharan Africa: a systematic review and geostatistical analysis

BACKGROUND Schistosomiasis affects more than 200 million individuals, mostly in sub-Saharan Africa, but empirical estimates of the disease burden in this region are unavailable. We used geostatistical modelling to produce high-resolution risk estimates of infection with Schistosoma spp and of the number of doses of praziquantel treatment needed to prevent morbidity at different administrative levels in 44 countries. METHODS We did a systematic review to identify surveys including schistosomiasis prevalence data in sub-Saharan Africa via PubMed, ISI Web of Science, and African Journals Online, from inception to May 2, 2014, with no restriction of language, survey date, or study design. We used Bayesian geostatistical meta-analysis and rigorous variable selection to predict infection risk over a grid of 1 155 818 pixels at 5 × 5 km, on the basis of environmental and socioeconomic predictors and to calculate the number of doses of praziquantel needed for prevention of morbidity. FINDINGS The literature search identified Schistosoma haematobium and Schistosoma mansoni surveys done in, respectively, 9318 and 9140 unique locations. Infection risk decreased from 2000 onwards, yet estimates suggest that 163 million (95% Bayesian credible interval [CrI] 155 million to 172 million; 18·5%, 17·6-19·5) of the sub-Saharan African population was infected in 2012. Mozambique had the highest prevalence of schistosomiasis in school-aged children (52·8%, 95% CrI 48·7-57·8). Low-risk countries (prevalence among school-aged children lower than 10%) included Burundi, Equatorial Guinea, Eritrea, and Rwanda. The numbers of doses of praziquantel needed per year were estimated to be 123 million (95% CrI 121 million to 125 million) for school-aged children and 247 million (239 million to 256 million) for the entire population. INTERPRETATION Our results will inform policy makers about the number of treatments needed at different levels and will guide the spatial targeting of schistosomiasis control interventions. FUNDING European Research Council, China Scholarship Council, UBS Optimus Foundation, and Swiss National Science Foundation.

Spatial and temporal distribution of soil-transmitted helminth infection in sub-Saharan Africa: a systematic review and geostatistical meta-analysis

BACKGROUND Interest is growing in predictive risk mapping for neglected tropical diseases (NTDs), particularly to scale up preventive chemotherapy, surveillance, and elimination efforts. Soil-transmitted helminths (hookworm, Ascaris lumbricoides, and Trichuris trichiura) are the most widespread NTDs, but broad geographical analyses are scarce. We aimed to predict the spatial and temporal distribution of soil-transmitted helminth infections, including the number of infected people and treatment needs, across sub-Saharan Africa. METHODS We systematically searched PubMed, Web of Knowledge, and African Journal Online from inception to Dec 31, 2013, without language restrictions, to identify georeferenced surveys. We extracted data from household surveys on sources of drinking water, sanitation, and womens level of education. Bayesian geostatistical models were used to align the data in space and estimate risk of with hookworm, A lumbricoides, and T trichiura over a grid of roughly 1 million pixels at a spatial resolution of 5 × 5 km. We calculated anthelmintic treatment needs on the basis of WHO guidelines (treatment of all school-aged children once per year where prevalence in this population is 20-50% or twice per year if prevalence is greater than 50%). FINDINGS We identified 459 relevant survey reports that referenced 6040 unique locations. We estimate that the prevalence of hookworm, A lumbricoides, and T trichiura among school-aged children from 2000 onwards was 16·5%, 6·6%, and 4·4%. These estimates are between 52% and 74% lower than those in surveys done before 2000, and have become similar to values for the entire communities. We estimated that 126 million doses of anthelmintic treatments are required per year. INTERPRETATION Patterns of soil-transmitted helminth infection in sub-Saharan Africa have changed and the prevalence of infection has declined substantially in this millennium, probably due to socioeconomic development and large-scale deworming programmes. The global control strategy should be reassessed, with emphasis given also to adults to progress towards local elimination. FUNDING Swiss National Science Foundation and European Research Council.

Influence of Exposure History on the Immunology and Development of Resistance to Human Schistosomiasis Mansoni

Background Previous studies suggest that humans can acquire immunity to reinfection with schistosomes, most probably due to immunologic mechanisms acquired after exposure to dying schistosome worms. Methodology/Principal Findings We followed longitudinally two cohorts of adult males occupationally exposed to Schistosoma mansoni by washing cars (120 men) or harvesting sand (53 men) in Lake Victoria. Men were treated with praziquantel each time S. mansoni infection was detected. In car washers, a significant increase in resistance to reinfection, as measured by the number of cars washed between cure and reinfection, was observed after the car washers had experienced, on average, seven cures. In the car washers who developed resistance, the level of schistosome-specific IgE increased between baseline and the time at which development of resistance was first evidenced. In the sand harvesters, a significant increase in resistance, as measured by the number of days worked in the lake between cure and reinfection, was observed after only two cures. History of exposure to S. mansoni differed between the two cohorts, with the majority of sand harvesters being lifelong residents of a village endemic for S. mansoni and the majority of car washers having little exposure to the lake before they began washing cars. Immune responses at study entry were indicative of more recent infections in car washers and more chronic infections in sand harvesters. Conclusions/Significance Resistance to reinfection with S. mansoni can be acquired or augmented by adults after multiple rounds of reinfection and cure, but the rate at which resistance is acquired by this means depends on immunologic status and history of exposure to S. mansoni infection.

Correlation between Eosinophils and Protection against Reinfection with Schistosoma mansoni and the Effect of Human Immunodeficiency Virus Type 1 Coinfection in Humans

ABSTRACT Longitudinal investigations of an adult male population of Kenyan car washers who have heavy and quantifiable occupational exposure to Schistosoma mansoni cercariae revealed that some individuals develop resistance to reinfection while others remain highly susceptible. We sought to characterize immune correlates associated with host protection in this population. Previous studies have demonstrated an association of peripheral eosinophilia with resistance to reinfection with schistosomes. Thus, we investigated the relationship between the percentage of circulating eosinophils and the effect of human immunodeficiency virus type 1 (HIV-1) coinfection on the susceptibility of the car washers to reinfection with schistosomes. Elevated percentages of circulating eosinophils were associated with resistance to reinfection by S. mansoni in HIV-1-seronegative persons. In the HIV-1-seropositive cohort, low CD4+-T-cell counts were associated with a less intense eosinophilia. Moreover, eosinophils from the car washers expressed high levels of FcεRI β chain, a molecule important in immunoglobulin E (IgE)-mediated immunity. Levels of FcεRI β chain expression correlated with serum levels of total and antigen-specific IgE for HIV-1-negative car washers, but this was not the case for individuals coinfected with HIV-1. Overall, these data further implicate eosinophils as having a potential role in development of protective immunity against schistosomes and suggest that changes associated with HIV-1 coinfection increase susceptibility to reinfection.

Cellular Immune Responses of Schistosomiasis Patients Are Altered by Human Immunodeficiency Virus Type 1 Coinfection

In vitro studies suggest that CD4(+) cells with a T helper 2 (Th2) phenotype better support human immunodeficiency virus type 1 (HIV-1) replication than do cells of the Th1 phenotype. As a result, Th2-type immune responses may be substantially affected by HIV-1 coinfection. To test this hypothesis, a comparison was done of proliferation and cytokine production by peripheral blood mononuclear cells from patients with schistosomiasis who were positive or negative for HIV-1. Patients with schistosomiasis with HIV-1 coinfections had significantly lower interleukin (IL)-4 and IL-10 production than did HIV-1-negative individuals. In contrast, interferon-gamma production levels were similar between the 2 groups. Furthermore, in patients with HIV-1, a decrease in CD4(+) T cells was correlated with an increased Th1:Th2 cytokine production ratio. The effect of praziquantel treatment on proliferation and cytokine responses also differed between HIV-1 infection groups. Thus, HIV-1 infection affects immune response patterns of patients with schistosomiasis.

Impact of intense, longitudinal retreatment with praziquantel on cure rates of schistosomiasis mansoni in a cohort of occupationally exposed adults in western Kenya

Objective  To investigate trends in the efficacy of praziquantel (PZQ) suggestive of the emergence of drug resistance against Schistosoma mansoni infection after 12.5 years of intense, repeated use in a small geographic area along the shores of Lake Victoria.

Increases in Levels of Schistosome-Specific Immunoglobulin E and CD23+ B Cells in a Cohort of Kenyan Children Undergoing Repeated Treatment and Reinfection with Schistosoma mansoni

BACKGROUND Age prevalence curves for areas in which schistosomiasis is endemic suggest that humans develop partial immunity to reinfection beginning in early adolescence. We conducted a 2-year longitudinal study to determine whether children infected with Schistosoma mansoni develop protection-related immune responses after treatment with praziquantel and whether the development of these immune responses is accelerated by frequent treatment after reinfection. METHODS Children (8-10 years old) were tested for S. mansoni every 4 months and treated with praziquantel when positive (arm A; n=68) or were tested and treated at the end of the 2-year follow-up period (arm B; n=49). RESULTS Children in arm A who remained free of infection during follow-up had significantly higher baseline levels of schistosome-specific immunoglobulin E (IgE) than did children with > or =2 repeat diagnoses of S. mansoni infection. Children with > or =2 repeat diagnoses of S. mansoni infection had significantly increased levels of anti-schistosome IgE and CD23(+) B cells after receiving > or =3 praziquantel treatments over the course of follow-up. No increase in either parameter was seen in children who received only the baseline praziquantel treatment. CONCLUSIONS B cell activation and anti-schistosome IgE are associated with resistance to S. mansoni in children, and these immunological parameters can be increased by multiple rounds of infections and praziquantel-induced cures.