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Background: The poor correlation between allergen-specific immunoglobulin E (asIgE) and clinical signs of allergy in helminth infected populations suggests that helminth infections could protect against allergy by uncoupling asIgE from its effector mechanisms. We investigated this hypothesis in Ugandan schoolchildren coinfected with Schistosoma mansoni and hookworm., Methods: Skin prick test (SPT) sensitivity to house dust mite allergen (HDM) and current wheeze were assessed pre-anthelmintic treatment. Nonspecific (anti-IgE), helminth-specific, and HDM-allergen-specific basophil histamine release (HR), plus helminth- and HDM-specific IgE and IgG4 responses were measured pre- and post-treatment., Results: Nonspecific- and helminth-specific-HR, and associations between helminth-specific IgE and helminth-specific HR increased post-treatment. Hookworm infection appeared to modify the relationship between circulating levels of HDM-IgE and HR: a significant positive association was observed among children without detectable hookworm infection, but no association was observed among infected children. In addition, hookworm infection was associated with a significantly reduced risk of wheeze, and IgG4 to somatic adult hookworm antigen with a reduced risk of HDM-SPT sensitivity. There was no evidence for S. mansoni infection having a similar suppressive effect on HDM-HR or symptoms of allergy., Conclusions: Basophil responsiveness appears suppressed during chronic helminth infection; at least in hookworm infection, this suppression may protect against allergy., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Background: Human type 2 cytokine responsiveness to schistosome antigens increases after treatment; due either to removal of the immunosuppressive effects of active infection or immunological boosting by antigens released from dying parasites. We determined the responsiveness to Schistosoma mansoni over a 2-year period, when reinfection was restricted by interrupting transmission., Methods: The proinflammatory and type 2 responses of Kenyan schoolchildren were measured before, and 1 year and 2 years posttreatment in whole blood cultures stimulated with soluble egg antigen (SEA) or soluble worm antigen (SWA). The site of S. mansoni transmission was molluscicided throughout., Results: Pretreatment proinflammatory responses to SEA were high but reduced 1 and 2 years posttreatment, whereas type 2 responses were low pretreatment and increased 1 and 2 years posttreatment. Type 2 responses to SWA were high pretreatment and increased at 1 year, with no further increases at 2 years posttreatment. Children infected at follow-up had lower SEA, but not SWA, posttreatment type 2 responsiveness. Increases at 1 year in type 2 SWA, but not SEA, responsiveness correlated with pretreatment egg counts., Conclusions: Removal of immunosuppressive effects of active infection increases SEA type 2 responsiveness; long-term SWA type 2 responsiveness is due to treatment-induced immunological boosting. Dissociation of type 2 responses potentially protects against severe egg-associated immunopathology during infection, while allowing worm-antigen derived immunity to develop.

Background: Schistosoma mansoni infection is a persistent public health problem in many Kenyan communities. Although praziquantel is available, re-infection after chemotherapy treatment is inevitable, especially among children. Chemotherapy followed by intermittent mollusciciding of habitats of Biomphalaria pfeifferi, the intermediate host snail, may have longer term benefits, especially if timed to coincide with natural fluctuations in snail populations., Methods: In this cohort study, the Kambu River (Intervention area) was molluscicided intermittently for 4 years, after mass chemotherapy with praziquantel in the adjacent community of Darajani in January 1997. The nearby Thange River was selected as a control (Non-intervention area), and its adjacent community of Ulilinzi was treated with praziquantel in December 1996. Snail numbers were recorded monthly at 9-10 sites along each river, while rainfall data were collected monthly, and annual parasitological surveys were undertaken in each village. The mollusciciding protocol was adapted to local conditions, and simplified to improve prospects for widespread application., Results: After the initial reduction in prevalence attributable to chemotherapy, there was a gradual increase in the prevalence and intensity of infection in the non-intervention area, and significantly lower levels of re-infection amongst inhabitants of the intervention area. Incidence ratio between areas adjusted for age and gender at the first follow-up survey, 5 weeks after treatment in the non-intervention area and 4 months after treatment in the intervention area was not significant (few people turned positive), while during the following 4 annual surveys these ratios were 0.58 (0.39-0.85), 0.33 (0.18-0.60), 0.14 (0.09-0.21) and 0.45 (0.26-0.75), respectively. Snail numbers were consistently low in the intervention area as a result of the mollusciciding. Following termination of the mollusciciding at the end of 2000, snail populations and infections in snails increased again in the intervention area., Conclusion: The results of this study demonstrate that in the Kenyan setting a combination of chemotherapy followed by intermittent mollusciciding can have longer term benefits than chemotherapy alone.

Naturally occurring human immunity to both schistosomiasis and hookworm infection has been associated with IgE responses against parasite allergen-like proteins. Since the two helminths frequently coinfect the same individuals, there is growing advocacy for their concurrent treatment. However, both helminths are known to exert strong immunomodulatory effects; therefore, coinfected individuals could have immune responses different from those characteristically seen in monoinfected individuals. In this study, we measured changes in IgE, IgG1, and IgG4 responses to schistosome and hookworm antigens, including the allergen-like proteins Schistosoma mansoni tegumental-allergen-like 1 protein (SmTAL1), SmTAL2, and Necator americanus Ancylostoma-secreted protein-2 (Na-ASP-2), following concurrent treatment of schoolchildren coinfected with Schistosoma mansoni and hookworm. Antibody responses to schistosome egg (soluble egg antigen and SmTAL2) or somatic adult hookworm (AHW) antigens either decreased after treatment or were unchanged, whereas those to schistosome worm antigens (soluble worm antigen and SmTAL1) increased. The observed different effects of treatment likely reflect the different modes of drug action and sites of infection for these two helminths. Importantly, there was no evidence that the simultaneous treatment of coinfected children with praziquantel and albendazole affected schistosome- and hookworm-specific humoral responses differently from those characteristic of populations in which only one organism is endemic; schistosome- and hookworm-specific responses were not associated, and there was no evidence for cross-regulation. Posttreatment increases in the levels of IgE to schistosome worm antigens were associated with lower Schistosoma mansoni reinfection intensity, while no associations between humoral responses to AHW antigen and protection from hookworm reinfection were observed in this sample of school-aged children.

Patterns of disease may take on irregular geographic shapes, especially when features of the physical environment influence risk. Identifying these patterns can be important for planning, and also identifying new environmental or social factors associated with high or low risk of illness. Until recently, cluster detection methods were limited in their ability to detect irregular spatial patterns, and limited to finding clusters that were roughly circular in shape. This approach has less power to detect irregularly-shaped, yet important spatial anomalies, particularly at high spatial resolutions. We employ a new method of finding irregularly-shaped spatial clusters at micro-geographical scales using both simulated and real data on Schistosoma mansoni and hookworm infection intensities. This method, which we refer to as the "greedy growth scan", is a modification of the spatial scan method for cluster detection. Real data are based on samples of hookworm and S. mansoni from Kitengei, Makueni district, Kenya. Our analysis of simulated data shows how methods able to find irregular shapes are more likely to identify clusters along rivers than methods constrained to fixed geometries. Our analysis of infection intensity identifies two small areas within the study region in which infection intensity is elevated, possibly due to local features of the physical or social environment. Collectively, our results show that the "greedy growth scan" is a suitable method for exploratory geographical analysis of infection intensity data when irregular shapes are suspected, especially at micro-geographical scales.

Hepatosplenomegaly among school-aged children in sub-Saharan Africa is highly prevalent. Two of the more common aetiological agents of hepatosplenomegaly, namely chronic exposure to malaria and Schistosoma mansoni infection, can result in similar clinical presentation, with the liver and spleen being chronically enlarged and of a firm consistency. Where co-endemic, the two parasites are thought to synergistically exacerbate hepatosplenomegaly. Here, two potential health consequences, i.e. dilation of the portal vein (indicative of increased portal pressure) and stunting of growth, were investigated in a study area where children were chronically exposed to malaria throughout while S. mansoni transmission was geographically restricted. Hepatosplenomegaly was associated with increased portal vein diameters, with enlargement of the spleen rather than the liver being more closely associated with dilation. Dilation of the portal vein was exacerbated by S. mansoni infection in an intensity-dependent manner. The prevalence of growth stunting was not associated with either relative exposure rates to malarial infection or with S. mansoni infection status but was significantly associated with hepatosplenomegaly. Children who presented with hepatosplenomegaly had the lowest height-for-age Z-scores. This study shows that hepatosplenomegaly associated with chronic exposure to malaria and schistosomiasis is not a benign symptom amongst school-aged children but has potential long-term health consequences., (Copyright 2009 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.)

In sub-Saharan Africa, chronic hepatosplenomegaly, with palpable firm/hard organ consistency, is common, particularly among school-aged children. This morbidity can be caused by long-term exposure to malaria, or by Schistosoma mansoni, and it is exacerbated when these two occur together. Although immunological mechanisms probably underlie the pathogenic process, these mechanisms have not been identified, nor is it known whether the two parasites augment the same mechanisms or induce unrelated processes that nonetheless have additive or synergistic effects. Kenyan primary schoolchildren, living in a malaria/schistosomiasis co-transmission area, participated in cross-sectional parasitological and clinical studies in which circulating immune modulator levels were also measured. Plasma IL-12p70, sTNF-RII, IL-10 and IL-13 levels correlated with relative exposure to malaria, and with hepatosplenomegaly. Soluble-TNF-RII and IL-10 were higher in children infected with S. mansoni. Hepatosplenomegaly caused by chronic exposure to malaria was clearly associated with increased circulating levels of pro-inflammatory mediators, with higher levels of regulatory modulators, and with tissue repair cytokines, perhaps being required to control the inflammatory response. The higher levels of regulatory modulators amongst S. mansoni infected children, compared to those without detectable S. mansoni and malarial infections, but exposed to malaria, suggest that S. mansoni infection may augment the underlying inflammatory reaction.

Objectives: Chronic exposure to malaria exacerbates Schistosoma mansoni-associated hepatosplenomegaly in school-aged children. However, residual hepatosplenomegaly after treatment of S. mansoni with concurrent mollusciciding suggests malaria could be an underlying cause of hepatosplenomegaly. We investigated the role of chronic malaria in childhood hepatosplenomegaly in the presence and absence of concurrent S. mansoni infection., Methods: Cross-sectional study of children in an study area where transmission of S. mansoni, but not malaria, is restricted to the eastern end. Clinical and ultrasound examinations were conducted, and parasitological and serological tests used to determine S. mansoni infection intensities and comparative exposure levels to malaria., Results: Chronic exposure to malaria, as determined by Pfs-IgG3 levels, was associated with hepatosplenomegaly even in the absence of S. mansoni infection. Children infected with S. mansoni mostly had light to moderate infection intensities but greater enlargement of the liver and spleen than children who did not have schistosomiasis, and for the left liver lobe this was S. mansoni infection intensity dependent., Conclusions: Children chronically exposed to malaria but without S. mansoni infection can have hepatosplenomegaly, which even light S. mansoni infections can exacerbate in an intensity-dependent manner. Thus, concurrent chronic exposure to S. mansoni and Plasmodium falciparum can have an additive or synergistic effect on childhood morbidity.

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., (Copyright 2007 S. Karger AG, Basel.)

Eosinophil activity in vivo and in vitro was studied in relation to infection intensities and plasma cytokine profiles of 51 Schistosoma mansoni-infected Ugandan fishermen before treatment and 24 h and 3 weeks posttreatment. Blood eosinophil numbers significantly declined 24 h posttreatment, but significant eosinophilia had developed by 3 weeks posttreatment. Cellular eosinophil cationic protein (ECP) content increased significantly during the transient eosinopenia but was significantly reduced 3 weeks later. No similar reduction in cellular eosinophil protein X (EPX) content was seen. Before treatment, S. mansoni infection intensity was positively correlated with 24-h boosts in plasma interleukin-5 (IL-5) and IL-6 levels, which were in turn negatively correlated with the posttreatment fall in eosinophil numbers. Significant correlations were observed between pretreatment infection intensities and plasma IL-10 and eotaxin levels. Treatment induced significant fluctuations in plasma IL-5, IL-6, IL-10, tumor necrosis factor alpha (TNF-alpha), and eotaxin levels. Optimal relative release of ECP and EPX in vitro was detected in S. mansoni soluble egg antigen-stimulated cultures during transient eosinopenia. Our data suggest that blood eosinophils are activated during S. mansoni infection and that treatment induces a burst in released antigens, causing increased production of IL-5, IL-6, IL-10, and eotaxin; a drop in TNF-alpha levels; and a transient sequestration of eosinophils, which leaves fewer degranulated eosinophils in the circulation 24 h posttreatment, followed by the development of eosinophilia 3 weeks later. During these events, it appears that preferential release of ECP occurs in vivo. Moreover, it is possible that infection intensity-dependent levels of plasma IL-10 may be involved in the prevention of treatment-induced anaphylactic reactions.

We report multidisciplinary studies on schistosomiasis which have been ongoing in the fishing communities of Piida, Booma, Bugoigo and Walakuba, on Lake Albert, Uganda, since 1996. Schistosomiasis is the major health problem in this area, with high infection intensities and prevalence. In addition to generating basic data on the epidemiology, morbidity and immunology of human schistosomiasis, this research programme is providing important descriptive and methodological information, and has contributed to the increase in operational capacity within Uganda in recent years. Such information and operational capacity are needed to facilitate much needed schistosomiasis control programmes, such as the Schistosomiasis Control Initiative that was launched in Uganda in 2003.

Background: Schistosoma 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., Methods: Ninety-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., Results: Children 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., Conclusions: The 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.

Background: Schistosoma 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., Methods: 96 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., Results: 4 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 > or =4 cm. Hardening of spleens was associated with proximity of domicile to the river., Conclusions: Micro-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.

Background: Parasite-specific IgE levels correlate with human resistance to reinfection with Schistosoma spp. after chemotherapy. Although the role of eosinophils in schistosomiasis has been the focus of a great deal of important research, the involvement of other Fcepsilon receptor-bearing cells, such as mast cells and basophils, has not been investigated in relation to human immunity to schistosomes. Chemotherapy with praziquantel (PZQ) kills schistosomes living in an in vivo blood environment rich in IgE, eosinophils and basophils. This releases parasite Ags that have the potential to cross-link cell-bound IgE. However, systemic hypersensitivity reactions are not induced by treatment. Here, we describe the effects of schistosomiasis, and its treatment, on human basophil function by following changes in total cellular histamine and in vitro histamine-release induced by schistosome Ags or anti-IgE, in blood samples from infected Ugandan fishermen, who are continuously exposed to S. mansoni infection, before and 1-day and 21-days after PZQ treatment., Results: There was a significant increase in the total cellular histamine in blood samples at 1-day post-treatment, followed by a very significant further increase by 21-days post-treatment. In vitro histamine-release induced by S. mansoni egg (SEA) or worm (SWA) Ags or anti-IgE antibody, was significantly reduced 1-day post-treatment. The degree of this reduction correlated with pre-treatment infection intensity. Twenty-1-days post-treatment, SEA-induced histamine-release was still significantly lower than at pretreatment. Histamine-release was not correlated to plasma concentrations of total or parasite-specific IgE, nor to specific IgG4 plasma concentrations., Conclusion: The biology of human blood basophils is modulated by S. mansoni infection and praziquantel treatment. Infection intensity-dependent suppression of basophil histamine-release, histamine-dependent resistance to infection, and similarities with allergen desensitisation are discussed as possible explanations of these observations.

The human host is continuously exposed to the egg and the adult worm developmental stages of Schistosoma mansoni during chronic infections with the parasite. To assess the cytokine responses induced by these different costimulating stages and how they are influenced by host age and infection intensity, whole blood samples from a cross-sectional cohort of 226 members of a Ugandan fishing community who had been resident in an area with high transmission of S. mansoni for the previous 10 years or from birth were stimulated with S. mansoni egg antigen (SEA) or worm antigen (SWA). SWA-specific gamma interferon (IFN-gamma) production increased with age, and the levels of SWA- and SEA-specific interleukin 3 (IL-3) were weakly correlated with schistosome infection intensity. The production of most cytokines was little affected by age or infection intensity but was either SEA or SWA specific. One hundred thirty-two members of the cohort coproduced IL-5 and IL-13 specifically in response to SWA, whereas only 15 produced these cytokines, and at much lower levels, in response to SEA. IL-10, IL-4, and IFN-gamma were also produced in response to SWA, whereas the response to SEA consisted almost exclusively of IL-10. Our results suggest that, in contrast to what has been described for the murine model of S. mansoni and during acute human infections, chronic intense exposure to and infection with S. mansoni in this cohort resulted in very low levels of response to SEA in vitro in the presence of a vigorous and mixed Th1-Th2 response to SWA.

Peri-portal fibrosis can be a serious sequelae of Schistosoma mansoni infection. Age or duration of exposure have been identified as important risk factors, but their relative importance cannot be easily separated. Here, we have compared two cohorts, aged 6-50 years and resident for ten years or since birth, from two neighbouring villages (Booma and Bugoigo) on the eastern shore of Lake Albert, Uganda. Parasitological measurements were similar, whereas the prevalence of peri-portal fibrosis was 5-fold higher in Booma. Data from the cohorts were pooled to assess the relative contribution of age and duration of residency on the risk of disease. Amongst adults, duration of residency was the critical risk factor--individuals aged 17-31 years resident for more 22 years had an almost 12-fold increased risk of fibrosis than those resident for less than 15 years. Height-standardised Splenic Vein Diameter (SVD), Portal Vein Diameter (PVD), Para-sternal Liver Length (PLL) and Spleen Length (SL) values were all higher in Booma, and each organometric parameter except PLL increased with the severity of fibrosis. Our results clearly demonstrate that duration of exposure is a critical risk factor for the development of peri-portal fibrosis and its sequelae in adults. This parameter should therefore be a routine measurement during epidemiological surveys of S. mansoni.

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-alpha, IFN-gamma, IL-1beta, 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-gamma factor scores (>83rd percentile), whereas those at highest risk had a combination of intermediate (32nd to 83rd percentile) IFN-gamma and relatively high (>60th percentile) TNF-alpha factor scores. Adult males at lowest risk of fibrosis had moderate TNF-alpha factor scores (55th to 82nd percentile), and a high risk was associated with either high TNF-alpha factor scores (>82nd percentile), or intermediate TNF-alpha 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.

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.

In a case-control study based in two areas of Kenya, hepatosplenic schistosomiasis mansoni was shown to be linked with low levels of IL-5 and with correspondingly high IFN-gamma, TNF, and circulating soluble TNF receptor I (sTNFR-I), sTNFR-II, and sICAM-1. PBMC from the hepatosplenic cases responded to in vitro Ag stimulation with significantly higher levels of IFN-gamma and TNF, but lower levels of IL-5, compared with nonhepatosplenic controls matched for age and infection intensity. Most of these correlations were confounded by differences between geographical areas. However, principle component analysis identified a high IFN-gamma and TNF, and low IL-5 axis in the data as the first principle component; this was significantly associated with hepatosplenomegaly (p < 0.0005) even after controlling for area. High plasma levels of sTNFR-I (p < 0.001), sTNFR-II, (p < 0.0001), and sICAM-1 (p < 0.009) were also significantly associated with hepatosplenomegaly, independently of area, in the case of the soluble forms of both TNF receptors. These parameters were negatively related to IL-5. These results suggest that proinflammatory cytokines are involved in the hepatosplenic disease process in infected individuals who have low anti-inflammatory Th2 responses and that sTNFR may be a useful circulating marker for this disease process, perhaps reflecting the level of TNF activity in hepatic tissues.