Population-based, spatiotemporal modeling of social risk factors and mortality from schistosomiasis in Brazil between 1999 and 2018.

Schistosomiasis remains a significant public health concern in Brazil. To identify areas at, and social determinants of health (SDH) associated with, high-risk for schistosomiasis-related mortality from Brazil, we conducted a spatial and spatiotemporal modeling assessing all deaths confirmed in Brazil between 1999 and 2018. We used the segmented log-linear regression model to assess temporal trends, and the local empirical Bayesian estimator, the Global and Local Moran Index for spatial analysis. A total of 12,251 schistosomiasis-related deaths were reported in this period. Within the Mortality Information System (SIM) of the Brazilian Ministry of Health, the states of Alagoas (AL), Pernambuco (PE) and Sergipe (SE) recording the highest mortality rates: 2.21, 1.92 and 0.80 deaths/100,000 inhabitants, respectively. Analyses revealed an increase in the mean age of schistosomiasis-related deaths over the time assessed (APC = 0.9; p-value<0.05). Spatial analysis identified a concentration of municipalities presenting high risk of schistosomiasis-related mortality along the coastline of PE and AL. Similarly, we identified the formation of high space-time clusters in municipalities in the states of PE, AL, SE, Bahia, and Minas Gerais. Finally, mortality rates showed a significant correlation with 96.96% of SDH indices. The data reveal additional important changes in schistosomiasis-related deaths in Brazil between 1999 and 2018, such as a slow reduction among males (unlike females that displayed no change). Regardless, our analyses indicates that schistosomiasis continues to have the greatest detrimental impact in poor regions of Brazil and suggest the need for enhancement of current control measures to accelerate progress.

Use of a Tablet-Based System to Perform Abdominal Ultrasounds in a Field Investigation of Schistosomiasis-Related Morbidity in Western Kenya.

Chronic intestinal schistosomiasis can cause severe hepatosplenic disease and is a neglected tropical disease of public health importance in sub-Saharan Africa, including Kenya. Although the goal of control programs is to reduce morbidity, milestones for program performance focus on reductions in prevalence and intensity of infection, rather than actual measures of morbidity. Using ultrasound to measure hepatosplenic disease severity is an accepted method of determining schistosomiasis-related morbidity; however, ultrasound has not historically been considered a field-deployable tool because of equipment limitations and unavailability of expertise. A point-of-care tablet-based ultrasound system was used to perform abdominal ultrasounds in a field investigation of schistosomiasis-related morbidity in western Kenya; during the study, other pathologies and pregnancies were also identified via ultrasound, and participants referred to care. Recent technological advances may make it more feasible to implement ultrasound as part of a control program and can also offer important benefits to the community.

Spatiotemporal clusters of schistosomiasis mortality and association with social determinants of health in the Northeast region of Brazil (1980-2017).

The Northeast region of Brazil includes the states with the highest prevalence for schistosomiasis mansoni (SM). This study aimed to evaluate the spatiotemporal patterns of SM mortality and to analyze this association with social determinants in health. We conducted an ecological time series study (1980-2017), using spatial analysis tools. Time trend analysis was performed by joinpoint regression. Maps representing mortality rates for SM were constructed and Moran Index was calculated to analyze spatial autocorrelation. A total of 13,720 deaths from SM were reported in this period. The states of Pernambuco (PE) (50.62%) and Alagoas (AL) (22.09%) had the highest mortality percentages. The mortality rate decreased from 1.28 to 0.63 along the time. Although most states showed a stable trend, Sergipe (SE) and Bahia (BA) showed increasing trends in the latest years. Additionally, the spatial analysis showed the concentration of municipalities that presented high risk in the coastal region of the states of PE, AL, SE, and BA. Lastly, mortality rates were correlated with social and educational indicators and hospitalizations for diarrhea. Altogether, these results demonstrate that some states showed stable or increasing trends of SM mortality in the last period of the studied time interval.

Schistosomiasis mansoni in the northeast region of brazil: temporal modeling of positivity, hospitalization,and mortality rates.

INTRODUCTION: We aimed to analyze trends in Schistosomiasis positivity, mortality, and hospitalization rates in Northeast Brazil. METHODS: We conducted an ecological study using data from the Brazilian Schistosomiasis Control Program, and Hospital and Mortality Information Systems. A joinpoint regression model was used for temporal analysis. RESULTS: The positivity(-4.7%;p<0.001) and hospitalization(-17.7%;p<0.001) rates declined globally, while the mortality remained stationary (-0.8%;p>0.05). However, the hospitalization in Alagoas(27.1%;p<0.001) and Pernambuco (35.1%;p<0.001), and the mortality in Bahia(2.9%;p<0.001) and Sergipe(4.1%;p<0.001), increased. CONCLUSIONS: Schistosomiasis mansoni represents an important public health problem in Pernambuco, Alagoas, Sergipe, and Bahia.

Schistosomiasis mansoni in the northeast region of brazil: temporal modeling of positivity, hospitalization,and mortality rates

Abstract INTRODUCTION We aimed to analyze trends in Schistosomiasis positivity, mortality, and hospitalization rates in Northeast Brazil. METHODS We conducted an ecological study using data from the Brazilian Schistosomiasis Control Program, and Hospital and Mortality Information Systems. A joinpoint regression model was used for temporal analysis. RESULTS The positivity(−4.7%;p<0.001) and hospitalization(−17.7%;p<0.001) rates declined globally, while the mortality remained stationary (−0.8%;p>0.05). However, the hospitalization in Alagoas(27.1%;p<0.001) and Pernambuco (35.1%;p<0.001), and the mortality in Bahia(2.9%;p<0.001) and Sergipe(4.1%;p<0.001), increased. CONCLUSIONS Schistosomiasis mansoni represents an important public health problem in Pernambuco, Alagoas, Sergipe, and Bahia.

Schistosomiasis is associated with incident HIV transmission and death in Zambia.

BACKGROUND: We examined relationships between schistosome infection, HIV transmission or acquisition, and all-cause death. METHODS: We retrospectively tested baseline sera from a heterosexual HIV-discordant couple cohort in Lusaka, Zambia with follow-up from 1994-2012 in a nested case-control design. Schistosome-specific antibody levels were measured by ELISA. Associations between baseline antibody response to schistosome antigens and incident HIV transmission, acquisition, and all-cause death stratified by gender and HIV status were assessed. In a subset of HIV- women and HIV+ men, we performed immunoblots to evaluate associations between Schistosoma haematobium or Schistosoma mansoni infection history and HIV incidence. RESULTS: Of 2,145 individuals, 59% had positive baseline schistosome-specific antibody responses. In HIV+ women and men, baseline schistosome-specific antibodies were associated with HIV transmission to partners (adjusted hazard ratio [aHR] = 1.8, p<0.005 and aHR = 1.4, p<0.05, respectively) and death in HIV+ women (aHR = 2.2, p<0.001). In 250 HIV- women, presence of S. haematobium-specific antibodies was associated with increased risk of HIV acquisition (aHR = 1.4, p<0.05). CONCLUSION: Schistosome infections were associated with increased transmission of HIV from both sexes, acquisition of HIV in women, and increased progression to death in HIV+ women. Establishing effective prevention and treatment strategies for schistosomiasis, including in urban adults, may reduce HIV incidence and death in HIV+ persons living in endemic areas.

Interleukin-4 Receptor Alpha Expressing B Cells Are Essential to Down-Modulate Host Granulomatous Inflammation During Schistosomasis.

Schistosomiasis (bilharzia) is a parasitic helminth disease that can cause severe inflammatory pathology leading to organ damage in humans. Failure of the host to regulate egg-driven granulomatous inflammation causes host morbidity during chronic infection with Schistosoma mansoni. Although the importance of B cells in regulating pathology during chronic infection has been well defined, the specific contribution of IL-4Rα-expressing B cells is still unknown. To address this, we examined B cell-specific IL-4Rα-deficient (mb1creIL-4Rα-/lox) mice in three experimental models of schistosomiasis: high-dose (100 cercariae), low dose (30 cercariae), and a synchronous egg challenge. In the high dose model, we found that mice deficient in IL-4Rα-expressing B cells were more susceptible to acute schistosomiasis than B cell-deficient (µMT) mice, succumbing to infection at the acute stage whereas µMT mice survived until the chronic stage. An S. mansoni egg challenge model demonstrated that deleting IL-4Rα expression specifically on B cells resulted in increased lung granulomatous pathology, suggesting a role for this B cell subset in controlling granulomatous pathology. In agreement with this, a low dose model of schistosomiasis-which mimics the course of clinical chronic disease-demonstrated that depleting IL-4Rα-expressing B cells in mb1creIL-4Rα-/lox mice considerably impaired the host ability to down-modulate granulomatous inflammation in the liver and gut during chronic schistosomiasis. Taken together, our findings indicate that within the B cell compartment, IL-4Rα-expressing B cells in particular down-modulate the deleterious egg-driven tissue granulomatous inflammation to enable host survival during schistosomiasis in mice.

Investigação sobre os casos e óbitos por esquistossomose na cidade do Recife, Pernambuco, Brasil, 2005-2013 / Investigación sobre los casos y los óbitos por esquistosomiasis en la ciudad de Recife, Pernambuco, Brasil, 2005-2013 / Investigation of schistosomiasis cases and deaths in the city of Recife, Pernambuco, Brazil, 2005-2013

Objetivo: descrever os casos e óbitos por esquistossomose em residentes na cidade de Recife, Pernambuco, Brasil, no período 2005-2013. Métodos: estudo epidemiológico descritivo com dados do Sistema de Informações sobre Mortalidade (SIM) (2005-2013) e do Sistema de Informação de Agravos de Notificação (Sinan) (2007-2013); realizou-se a busca ativa dos familiares dos óbitos e o relacionamento probabilístico das bases de dados (2007-2013) pelo aplicativo Reclink. Resultados: no SIM, registraram-se 297 óbitos por esquistossomose no período estudado; pela busca ativa, 130 familiares foram contatados, identificando-se 20,8% de autoctonia; no Sinan, 388 casos foram registrados para residentes no Recife; pelo relacionamento probabilístico, identificaram-se 23 registros pareados entre SIM e Sinan. Conclusão: a investigação dos óbitos demonstrou que alguns indivíduos nunca viajaram para fora do Recife e evoluíram para a fase crônica da doença; 23,8% dos casos notificados no Sinan tiveram como município de infecção o Recife.

Objetivo: describir casos y óbitos por esquistosomiasis en residentes de la ciudad de Recife, Pernambuco, Brasil, en el período de 2005 a 2013. Métodos: estudio epidemiológico descriptivo con datos del Sistema Información sobre Mortalidad (SIM) (2005-2013) y del Sistema de Información de Agravamientos de Notificación (Sinan) (2007-2013); se realizó la búsqueda activa de los familiares de los fallecidos y la relación probabilística de los datos (2007-2013) en el aplicativo Reclink. Resultados: en el SIM, hubo 297 óbitos por esquistosomiasis; en la búsqueda activa, se identificaron 130 familiares y un 20,8% de autoctonía; en Sinan, 388 casos fueron registrados para residentes en Recife; en la relación probabilística, 23 registros pareados fueron identificados en el SIM y el Sinan. Conclusión: la investigación de los óbitos mostró que algunas personas nunca viajaron fuera de Recife y evolucionaron a la fase crónica de la enfermedad; 23,8% de los casos registrados en el Sinan tuvieron a Recife como municipio de la infección.

Objective: to describe schistosomiasis cases and deaths among residents of the city of Recife, Pernambuco, Brazil, from 2005 to 2013. Methods: this was a descriptive epidemiological study using data from the Mortality Information System (SIM) (2005-2013) and the Notifiable Diseases Information System (SINAN) (2007-2013); active tracing of the relatives of the dead was undertaken and probabilistic linkage of the databases (2007-2013) was performed using the Reclink program. Results: 297 schistosomiasis deaths were recorded on the SIM system; through active tracing, 130 relatives were contacted and 20.8% autochthony was identified; 388 cases resident in Recife were registered on the SINAN system; through probabilistic linkage, 23 matching records were identified on SIM and SINAN. Conclusion: investigation of deaths showed that some individuals had never traveled outside Recife and progressed to the chronic stage of the disease; 23.8% of the cases registered on SINAN had Recife as the municipality in which infection occurred.

Morbidity of mansoni schistosomiasis in Pernambuco-Brazil: Analysis on the temporal evolution of deaths, hospital admissions and severe clinical forms (1999-2014).

BACKGROUND: Current scientific information reported that due to successive treatments of schistosomiasis cases in endemic areas of Brazil in the last 30 years, there has been a decrease in severe clinical form (hepatosplenic) and mortality from upper gastrointestinal bleeding due to this disease. Against this information, literature data show that the state of Pernambuco presents significant percentage of deaths and hospitalizations due to schistosomiasis, and occurrence of severe clinical forms as schistosomiasis myeloradiculopathy and persistence of localities with high parasite loads. This scenario justified this research which seeking to update the morbidity and mortality of schistosomiasis in Pernambuco. OBJECTIVE: To conduct a temporal analysis on the evolution of deaths, hospital admissions and severe forms of Manson's schistosomiasis over the last 16 years in Pernambuco, Brazil. METHODS: It was performed a gathering secondary data on schistosomiasis, from healthcare information systems and from the records of Hospital das Clínicas, Federal University of Pernambuco (HC-UFPE), covering the period from 1999 to 2014. RESULTS: From 1999 to 2013 were registred 2578 deaths due to schistosomiasis and between 2008 and 2014 were recorded 473 hospitalizations for this disease. Among 1999-2014 were identified 1943 cases of schistosomiasis treated at the Hospital das Clínicas of Pernambuco. Among these cases, 72.6% (n. 1411) of the individuals presented the hepatosplenic clinical form (HE), 60.8% (n. 858) were at the age group 30-59 years (adults) and 58% were female. Among the HE cases, 4.6% (n. 58) had ascites, 43.2% (n. 556) had upper gastrointestinal bleeding and 39.1% (n. 489) had collateral circulation. The pattern of fibrosis in the liver E/EC (advanced fibrosis) and F/FC (very advanced fibrosis) occurred in 65.5% (n. 793) of cases. Between 1999-2014 the evolution curve of severe clinical forms of schistosomiasis remained stable, showing a tendency to decline from 2012. CONCLUSION: When compared to other states of Brazil, Pernambuco shows high numbers of deaths and hospital admissions due to schistosomiasis. The actions of the Schistosomiasis Control Program (PCE) have been developed in a disintegrated, disjointed and discontinuous way, which may explain the magnitude of deaths, hospitalizations and severe forms of the disease in Pernambuco, showing a lack of control and the maintenance of severe frame morbidity of schistosomiasis in this state.

Evaluation of a method for induction of praziquantel resistance in Schistosoma mansoni.

CONTEXT: Praziquantel (PZQ) is a highly efficacious anthelmintic against many flatworms including schistosomes. PZQ has been in use for more than 25 years, and concern is increasing that resistance has emerged in human schistosomes in Egypt and other endemic countries. OBJECTIVE: The current study was designed to evaluate a recently described method for induction of PZQ resistance in Schistosoma mansoni. MATERIALS AND METHODS: Successive subcurative drug treatments of Biomphalaria alexandrina snails infected with an Egyptian strain of S. mansoni were undertaken. Cercariae shed from snails exposed and unexposed to PZQ were used to infect mice. Forty-five days after infection, mice were treated with a single oral dose of PZQ in 2% aqueous solution of Cremophor-EL®. The concentration of PZQ was 0, 200, 400, or 800 mg/kg. Thirty-three days after treatment, all groups of mice were dissected to collect the S. mansoni worms by the perfusion technique. In addition, the oogram pattern was examined to study the production, maturity, and death of S. mansoni eggs in the different groups of mice. RESULTS: The present study has shown that the sublethal dose for induction of PZQ resistance in the intra-molluscan S. mansoni stages was 500 mg/kg. The worm count and the percentage of immature eggs in different groups of mice were significantly affected by the intra-molluscan exposure to PZQ and the drug concentration used to treat infected mice. DISCUSSION AND CONCLUSION: The results obtained herein confirm the possibility of using successive drug treatments of infected B. alexandrina to induce PZO resistance in S. mansoni.

Trends in schistosomiasis-related mortality in Brazil, 2000-2011.

Schistosomiasis is an important public health problem, with high morbidity and mortality in endemic countries. We analysed the epidemiological characteristics and time trends of schistosomiasis-related mortality in Brazil. We performed a nationwide study based on official mortality data obtained from the Brazilian Mortality Information System. We included all deaths in Brazil between 2000 and 2011, in which schistosomiasis was mentioned on the death certificate as an underlying or associated cause of death (multiple causes of death). We calculated crude and age-adjusted mortality rates (per 100,000 inhabitants), and proportional mortality rates. Trends over time were assessed using joinpoint regression models. Over the 12-year study period, 12,491,280 deaths were recorded in Brazil. Schistosomiasis was mentioned in 8,756 deaths, including in 6,319 (72.2%) as an underlying cause and in 2,437 (27.8%) as an associated cause. The average annual age-adjusted mortality rate was 0.49 deaths/100,000 inhabitants (95% confidence interval: 0.46-0.52) and proportional mortality rate was 0.070% (95% confidence interval: 0.069-0.072). Males (0.53 deaths/100,000 inhabitants), those aged ⩾70years (3.41 deaths/100,000 inhabitants), those of brown race/colour (0.44 deaths/100,000 inhabitants), and residents in the Northeast region of Brazil (1.19 deaths/100,000 inhabitants) had the highest schistosomiasis-related death rates. Age-adjusted mortality rates showed a significant decrease at a national level (Annual Percent Change: -2.8%; 95% confidence interval: -4.2 to -2.4) during the studied period. We observed decreasing mortality rates in the Northeast (Annual Percent Change: -2.5%; 95% confidence interval: -4.2 to -0.8), Southeast (Annual Percent Change: -2.2%; 95% confidence interval: -3.6 to -0.9), and Central-West (Annual Percent Change: -7.9%; 95% confidence interval: -11.3 to -4.3) regions, while the rates remained stable in the North and South regions. Despite the reduced mortality, schistosomiasis is still a neglected cause of death in Brazil, with considerable regional differences. Sustainable control measures should focus on increased coverage, and intensified and tailored control measures, to prevent the occurrence of severe forms of schistosomiasis and associated deaths.

The use of microencapsulated hepatocytes transplantation reduces mortality and liver alterations in Schistosoma mansoni infected hamsters.

Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotropic liver transplantation. The goal of this work was to study the adequacy of intrasplenic hepatocyte transplantation (HCTx) in fresh and microencapsulated forms, in a hamster model of liver fibrosis by Schistosoma mansoni infected hamsters were divided into 6 groups; untreated for 11 weeks (GI) and for 15 weeks (GII), treated with praziquantel (PZQ) 7 weeks PI, and killed 4 weeks (GIII) and 8 weeks (GIV) post-treatment. Treated with PZQ 7 weeks PI, and then treated orally with immunosuppressive drug "cyclosporine (4 weeks post PZQ treatment), 24 hr. before interasplenic injection with fresh hepatocytes (V). Treated with PZQ 7 weeks PI, and then injected interasplenically (4 weeks post-treatment) with microencapsulated hepatocytes (GVI). GI & GIII were killed 11 weeks PI for assessment the anti-schistosomal efficacy of PZQ. The other four groups were killed 15 weeks PI for investigation of liver and spleen histology, serum liver enzymes and hepatic oxidative markers before and after HCTx. Freshly isolated hepatocytes with a mean viability 92.97 +/- 1.2% were used for microencapsulation and transplantation. Histological study showed the presence of transplanted hepatocytes in spleen of recipient. PZQ accelerated healing of hepatic granulomatous lesions as evidenced parasitologically by the increase in the percentage of dead eggs and histologically showing more granuloma circumscription with more ova degeneration and less inflammatory cells. The 25-day survival rates in GII, GIV, GV& GVI were 5/15 (33.3%), 8/15 (53.3%), 10/15 (66.7%) and 9/15 (60%) respectively. In addition, there were significantly better outcomes in serum biochemical indexes such as ALT, AST, gamma-GT, ALP, and hepatic SOD and MDA in the fresh and microencapsulated groups than in PZQ-treated group, without great differences between the microencapsulated and the fresh transplanted groups. Liver pathological staining supported these findings.

Ameliorative effect of bone marrow-derived stem cells on injured liver of mice infected with Schistosoma mansoni.

The technique of stem cells or hepatocytes transplantation has recently improved in order to bridge the time before whole-organ liver transplantation. In the present study, unfractionated bone marrow stem cells (BMSCs) were harvested from the tibial and femoral marrow compartments of male mice, which were cultured in Dulbecco's modified Eagle's medium (DMEM) with and without hepatocyte growth factor (HGF), and then transplanted into Schistosoma mansoni-infected female mice on their 8th week post-infection. Mice were sacrificed monthly until the third month of bone marrow transplantation, serum was collected, and albumin concentration, ALT, AST, and alkaline phosphatase (ALP) activities were assayed. On the other hand, immunohistopathological and immunohistochemical changes of granuloma size and number, collagen content, and cells expressing OV-6 were detected for identification of liver fibrosis. BMSCs were shown to differentiate into hepatocyte-like cells. Serum ALT, AST, and ALP were markedly reduced in the group of mice treated with BMSCs than in the untreated control group. Also, granuloma showed a marked decrease in size and number as compared to the BMSCs untreated group. Collagen content showed marked decrease after the third month of treatment with BMSCs. On the other hand, the expression of OV-6 increased detecting the presence of newly formed hepatocytes after BMSCs treatment. BMSCs with or without HGF infusion significantly enhanced hepatic regeneration in S. mansoni-induced fibrotic liver model and have pathologic and immunohistopathologic therapeutic effects. Also, this new therapeutic trend could generate new hepatocytes to improve the overall liver functions.

Ameliorative Effect of Bone Marrow-Derived Stem Cells on Injured Liver of Mice Infected with Schistosoma mansoni

The technique of stem cells or hepatocytes transplantation has recently improved in order to bridge the time before whole-organ liver transplantation. In the present study, unfractionated bone marrow stem cells (BMSCs) were harvested from the tibial and femoral marrow compartments of male mice, which were cultured in Dulbecco's modified Eagle's medium (DMEM) with and without hepatocyte growth factor (HGF), and then transplanted into Schistosoma mansoni-infected female mice on their 8th week post-infection. Mice were sacrificed monthly until the third month of bone marrow transplantation, serum was collected, and albumin concentration, ALT, AST, and alkaline phosphatase (ALP) activities were assayed. On the other hand, immunohistopathological and immunohistochemical changes of granuloma size and number, collagen content, and cells expressing OV-6 were detected for identification of liver fibrosis. BMSCs were shown to differentiate into hepatocyte-like cells. Serum ALT, AST, and ALP were markedly reduced in the group of mice treated with BMSCs than in the untreated control group. Also, granuloma showed a marked decrease in size and number as compared to the BMSCs untreated group. Collagen content showed marked decrease after the third month of treatment with BMSCs. On the other hand, the expression of OV-6 increased detecting the presence of newly formed hepatocytes after BMSCs treatment. BMSCs with or without HGF infusion significantly enhanced hepatic regeneration in S. mansoni-induced fibrotic liver model and have pathologic and immunohistopathologic therapeutic effects. Also, this new therapeutic trend could generate new hepatocytes to improve the overall liver functions.

Aspectos ultrassonográficos associados à morbidade de formas clínicas crônicas de esquistossomose mansônica, utilizando-se protocolo proposto pela Organização Mundial da Saúde / Sonographic features associated with morbidity of chronic clinical presentations of schistosomiasis mansoni using the protocol proposed by the World Health Organization

OBJECTIVE: To evaluate sonographic features associated with morbidity in patients with chronic clinical presentations of schistosomiasis mansoni, according to the protocol proposed by the World Health Organization (WHO). MATERIALS AND METHODS: Two distinctive populations were evaluated: a) patients from an endemic area, and b) patients from a tertiary institution, with histopathologically confirmed periportal fibrosis. Inclusion criteria: diagnosis confirmed by parasitological stool examination for Schistosoma mansoni (Kato-Katz method). Exclusion criteria: positive serology for HIV, HTLV-1, HBV or HCV. The Niamey protocol on ultrasonography proposed by the WHO was utilized. RESULTS: As the measures of periportal spaces were isolatedly evaluated, no alteration was observed in 21% of the tertiary institution patients with advanced disease. As all parameters of the Niamey protocol were considered, 100% of patients from the tertiary institution, with severe disease, presented advanced periportal fibrosis. In hepatosplenic patients from endemic areas, fibrosis was not identified at ultrasonography. CONCLUSION: The sonographic protocol proposed by the WHO can detect advanced periportal fibrosis in patients with severe form of disease with higher sensitivity than the isolated measurement of periportal space. The complexity involved in the sonographic identification of early stages of periportal fibrosis in endemic areas may give rise to the field of diagnostic supplementation and to a continued improvement of sonographic protocols in these areas.

OBJETIVO: Avaliar aspectos ultrassonográficos associados à morbidade em pacientes com formas clínicas crônicas de esquistossomose mansônica, utilizando-se protocolo proposto pela Organização Mundial da Saúde (OMS). MATERIAIS E MÉTODOS: Foram avaliadas duas populações distintas: a) área endêmica e b) institucional terciária, com histopatológico confirmando fibrose. Critérios de inclusão: diagnóstico confirmado por parasitológico de fezes para Schistosoma mansoni (método Kato-Katz). Critérios de exclusão: sorologia positiva para HIV, HTLV-1, VHB ou VHC. Foi utilizado protocolo ultrassonográfico de Niamey, proposto pela OMS. RESULTADOS: Avaliando-se isoladamente as medidas dos espaços periportais, estas se mostraram sem alterações em 21% dos indivíduos com doença avançada da instituição terciária. Utilizando-se todos os parâmetros do protocolo, 100% dos indivíduos da instituição terciária, com forma grave da doença, apresentaram fibrose periportal avançada. Em pacientes hepatoesplênicos da área endêmica não se identificou fibrose à ultrassonografia. CONCLUSÃO: O protocolo ultrassonográfico proposto pela OMS detecta fibrose periportal avançada nos pacientes com forma grave da doença, com maior sensibilidade do que a medida do espaço periportal isoladamente. A complexidade de identificação das fases iniciais da fibrose periportal, em áreas endêmicas, pela ultrassonografia, pode suscitar o campo da complementação diagnóstica e a continuidade do aprimoramento dos protocolos ultrassonográficos nestas áreas.

Accelerated and progressive and lethal liver fibrosis in mice that lack interleukin (IL)-10, IL-12p40, and IL-13Rα2.

BACKGROUND & AIMS: Progressive fibrosis contributes to the morbidity of several chronic diseases; it typically develops slowly, so the mechanisms that control its progression and resolution have been difficult to model. The proteins interleukin (IL)-10, IL-12p40, and IL-13Rα2 regulate hepatic fibrosis following infection with the helminth parasite Schistosoma mansoni. We examined whether these mediators interact to slow the progression of hepatic fibrosis in mice with schistosomiasis. METHODS: IL-10(-/-), IL-12/23(p40)(-/-), and IL-13Rα2(-/-) mice were crossed to generate triple knockout (TKO) mice. We studied these mice to determine whether the simultaneous deletion of these 3 negative regulators of the immune response accelerated mortality from liver fibrosis following infection with S mansoni. RESULTS: Induction of inflammation by S mansoni, liver fibrosis, and mortality increased greatly in TKO mice compared with wild-type mice; 100% of the TKO mice died by 10 weeks after infection. Morbidity and mortality were associated with the development of portal hypertension, hepatosplenomegaly, gastrointestinal bleeding, ascites, thrombocytopenia, esophageal and gastric varices, anemia, and increased levels of liver enzymes, all features of advanced liver disease. IL-10, IL-12p40, and IL-13Rα2 reduced the production and activity of the profibrotic cytokine IL-13. A neutralizing antibody against IL-13 reduced the morbidity and mortality of the TKO mice following S mansoni infection. CONCLUSIONS: IL-10, IL-12p40, and IL-13Rα2 act cooperatively to suppress liver fibrosis in mice following infection with S mansoni. This model rapidly reproduces many of the complications observed in patients with advanced cirrhosis, so it might be used to evaluate the efficacy of antifibrotic reagents being developed for schistosomiasis or other fibrotic diseases associated with a T-helper 2 cell-mediated immune response.

Schistosoma co-infection protects against brain pathology but does not prevent severe disease and death in a murine model of cerebral malaria.

Co-infections of helminths and malaria parasites are common in human populations in most endemic areas. It has been suggested that concomitant helminth infections inhibit the control of malaria parasitemia but down-modulate severe malarial disease. We tested this hypothesis using a murine co-infection model of schistosomiasis and cerebral malaria. C57BL/6 mice were infected with Schistosoma mansoni and 8-9 weeks later, when Schistosoma infection was patent, mice were co-infected with Plasmodium berghei ANKA strain. We found that a concomitant Schistosoma infection increased parasitemia at the beginning of the P. berghei infection. It did not protect against P. berghei-induced weight loss and hypothermia, and P. berghei-mono-infected as well as S. mansoni-P. berghei-co-infected animals showed a high case fatality between days 6 and 8 of malarial infection. However, co-infection significantly reduced P. berghei-induced brain pathology. Over 40% of the S. mansoni-P. berghei-co-infected animals that died during this period were completely protected against haemorrhaging, plugging of blood vessels and infiltration, indicating that mortality in these animals was not related to cerebral disease. Schistosoma mansoni-P. berghei-co-infected mice had elevated plasma concentrations of IL-5 and IL-13 and on day 6 lower levels of IFN-γ, IL-10, monocyte chemoattractant protein-1 (MCP-1) and monokine induced by IFN-γ (MIG) than P. berghei-mono-infected mice. We conclude that in P. berghei infections, disease and early death are caused by distinct pathogenic mechanisms, which develop in parallel and are differentially influenced by the immune response to S. mansoni. This might explain why, in co-infected mice, death could be induced in the absence of brain pathology.

Clinico-pathological effects of Schistosoma mansoni infection associated with simultaneous exposure to malathion in Swiss outbred albino mice.

To investigate whether infection of Swiss outbred mice with the digenetic fluke Schistosoma mansoni is influenced by exposure to environmental pollutants, experimentally infected mice were exposed to 200 and 400 mg/kg of malathion. Pathology of liver and spleen, worm burden and levels of key hematological, biochemical and liver enzymes parameters of these mice were evaluated and were compared with data from infected, unexposed mice, uninfected, exposed mice as well as with data from uninfected, unexposed mice. Oral administration of malathion to mice infected with 20, 40 or 60 S. mansoni cercariae adversely affect architecture of liver and spleen and critically alter hematological, biochemical, histological and hepatic enzymes parameters significantly more than the controls. Alterations observed in infected, exposed mice included (i) higher mortality rate; (ii) severe pathologies in liver and spleen; (iii) increased serum level of bilirubin and alanine aminotransferase/aspartate aminotransferase (ALT/AST) enzymes; (iv) decreased serum level of albumin and total proteins; and (v) decreased red blood cell count (RBC), lymphocytes, leucocytic count, and hemoglobin content. The number of recovered adult worms of S. mansoni or their oviposition capacity did not seem to be affected with malathion treatment. Statistical analysis revealed that the increase alteration in hepatic functions is correlated with increasing the number of S. mansoni cercariae and malathion doses. Such alterations were more significant in mice treated with the higher dose of malathion or infected with the largest numbers of S. mansoni cercariae. These data indicate that schistosomiasis can be exacerbated by simultaneous malathion exposure, which in turn adversely impact the clinical and pathological outcome of the disease.

IL-23 is required for the development of severe egg-induced immunopathology in schistosomiasis and for lesional expression of IL-17.

In infection with the trematode helminth Schistosoma mansoni, the severity of CD4 T cell-mediated hepatic granulomatous and fibrosing inflammation against parasite eggs varies considerably in humans and among mouse strains. In mice, either the natural high pathology, or high pathology induced by concomitant immunization with schistosome egg Ags (SEA) in CFA (SEA/CFA), results from a failure to contain a net proinflammatory cytokine environment. We previously demonstrated that the induction of severe immunopathology was dependent on the IL-12/IL-23 common p40 subunit, and correlated with an increase in IL-17, thus implying IL-23 in the pathogenesis. We now show that mice lacking the IL-23-specific subunit p19 are impaired in developing severe immunopathology following immunization with SEA/CFA, which is associated with a marked drop of IL-17 in the granulomas, but not in the draining mesenteric lymph nodes, and with a markedly suppressed SEA-specific IFN-gamma response regulated by a striking increase in IL-10. The granulomas are characterized by a significant reduction in Gr-1(+) cell recruitment and by alternative macrophage activation. Taken together, these results demonstrate that IL-23 per se is not necessary for the generation of IL-17-producing T cells, but is essential for the development of severe schistosome egg-induced immunopathology, and its absence cannot be overcome with other possible compensatory mechanisms.

Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor alpha1 chain.

The interleukin 4 receptor (IL-4R) is a central mediator of T helper type 2 (T(H)2)-mediated disease and associates with either the common gamma-chain to form the type I IL-4R or with the IL-13R alpha1 chain (IL-13Ralpha1) to form the type II IL-4R. Here we used Il13ra1-/- mice to characterize the distinct functions of type I and type II IL-4 receptors in vivo. In contrast to Il4ra-/- mice, which have weak T(H)2 responses, Il13ra1-/- mice had exacerbated T(H)2 responses. Il13ra1-/- mice showed much less mortality after infection with Schistosoma mansoni and much more susceptibility to Nippostrongylus brasiliensis. IL-13Ralpha1 was essential for allergen-induced airway hyperreactivity and mucus hypersecretion but not for fibroblast or alternative macrophage activation. Thus, type I and II IL-4 receptors exert distinct effects on immune responses.