Yves-Laurent Julien Jackson

Tolerance and safety of nifurtimox in patients with chronic chagas disease.

BACKGROUND Nifurtimox has been used to treat Chagas disease for 40 years, but tolerance and safety data in adults are scarce. We aimed to evaluate nifurtimox tolerance and safety in a cohort of Trypanosoma cruzi-infected adult patients in a country of nonendemicity. METHODS This observational study included all consecutive adults patients who were given a diagnosis of T. cruzi infection from June through December 2008. Eligible patients received nifurtimox at 10 mg/kg/day for 60 days, with regular medical and biological follow-up. Adverse events (AEs) were recorded according to Common Terminology Criteria for Adverse Events, version 3.0. RESULTS Eighty-one patients received nifurtimox. Eight were lost to follow-up during treatment, and 41 (56.2%) completed the 60-day course. All premature treatment terminations were caused by AEs; 97.5% of patients suffered from AEs, mostly expected (90.5%) and not severe. Gastrointestinal symptoms predominated. Six (7.4%) patients presented with a suspected unexpected serious adverse reaction: drug reaction with eosinophilia and systemic symptoms (n = 3), Quincke edema (n = 1), acute myocarditis (n = 1), and anaphylaxis (n = 1). Patients with 3 or more AEs had an increased risk of premature treatment termination (hazard ratio, 8.42; 95% confidence interval, 1.6-45.5). CONCLUSION Nifurtimox is poorly tolerated among adults with chronic Chagas disease, resulting in a low treatment completion rate. Considering the significant risk of serious AEs, close monitoring is required, which may be difficult to implement in poor rural areas of countries of endemicity. The safety and efficacy of nifurtimox and benznidazole should be compared to improve current therapeutic recommendations, and pharmacovigilance systems should be enhanced.

Congenital Transmission of Chagas Disease in Latin American Immigrants in Switzerland

International migration has changed the epidemiologic patterns of Chagas disease. Recently, 2 cases of Chagas disease transmitted from Latin American women to their newborns were diagnosed in Geneva, Switzerland. A retrospective study to detect Chagas disease showed a prevalence of 9.7% among 72 Latin American women tested during pregnancy in Switzerland.

Prevalence, Clinical Staging and Risk for Blood-Borne Transmission of Chagas Disease among Latin American Migrants in Geneva, Switzerland

Background Migration of Latin Americans to the USA, Canada and Europe has modified Chagas disease distribution, but data on imported cases and on risks of local transmission remain scarce. We assessed the prevalence and risk factors for Chagas disease, staged the disease and evaluated attitudes towards blood transfusion and organ transplant among Latin American migrants in Geneva, Switzerland. Methodology/Principal Findings This cross-sectional study included all consecutive Latin American migrants seeking medical care at a primary care facility or attending two Latino churches. After completing a questionnaire, they were screened for Chagas disease with two serological tests (Biomérieux ELISA cruzi; Biokit Bioelisa Chagas). Infected subjects underwent a complete medical work-up. Predictive factors for infection were assessed by univariate and multivariate logistic regression analysis.1012 persons (females: 83%; mean age: 37.2 [SD 11.3] years, Bolivians: 48% [n = 485]) were recruited. 96% had no residency permit. Chagas disease was diagnosed with two positive serological tests in 130 patients (12.8%; 95%CI 10.8%–14.9%), including 127 Bolivians (26.2%; 95%CI 22.3%–30.1%). All patients were in the chronic phase, including 11.3% with cardiac and 0.8% with digestive complications. Predictive factors for infection were Bolivian origin (OR 33.2; 95%CI 7.5–147.5), reported maternal infection with T. cruzi (OR 6.9; 95%CI 1.9–24.3), and age older than 35 years (OR 6.7; 95%CI 2.4–18.8). While 22 (16.9%) infected subjects had already donated blood, 24 (18.5%) and 34 (26.2%) considered donating blood and organs outside Latin America, respectively. Conclusions Chagas disease is highly prevalent among Bolivian migrants in Switzerland. Chronic cardiac and digestive complications were substantial. Screening of individuals at risk should be implemented in nonendemic countries and must include undocumented migrants.

Chagas disease in Australia and New Zealand: risks and needs for public health interventions.

International migration has changed the global distribution of Chagas disease, with the emerging importance of non‐endemic regions. We aimed at better documenting the Australia and New Zealand risk of Chagas disease and needs for interventions.

Serum biomarkers predictive of cure in Chagas disease patients after nifurtimox treatment

BackgroundChagas disease (CD), caused by the protozoan Trypanosoma cruzi, remains an important public health issue in many Central and South American countries, as well as non-endemic areas with high rates of immigration from these countries. Existing treatment options for CD are limited and often unsatisfactory. Moreover the lack of post-treatment tests of cure limits the development of new drugs. To address this issue, we sought to identify serum biomarkers following nifurtimox (Nfx) treatment that could be used as an early test of cure and/or markers of a therapeutic response.MethodsHuman sera from Chagas patients pre- and post-treatment with Nfx (n = 37) were compared to samples from healthy subjects (n = 37) using a range of proteomic and immunologic techniques. Biomarker peaks with the best discriminatory power were further characterized.ResultsUsing serum samples (n = 111), we validated the presence of five key biomarkers identified in our previous study, namely human apolipoprotein A-I (APOA1) and specific fragments thereof and one fragment of human fibronectin (FN1). In chagasic serum samples all biomarkers except full-length APOA1 were upregulated. These five biomarkers returned to normal in 43% (16/37) of the patients treated with Nfx at three years after treatment.ConclusionsThe normalization of biomarker patterns strongly associated with CD suggests that these markers can be used to identify patients in whom Nfx treatment is successful. We believe that these are the first biomarkers predictive of cure in CD patients.

Serological and parasitological response in chronic Chagas patients 3 years after nifurtimox treatment

BackgroundWith declining vectorial transmission, Chagas disease predominantly affects adults nowadays. The efficacy of nifurtimox in the chronic phase in adult patients is poorly known, particularly in regions where there is no risk of reinfection. Recommendations for treatment outcome assessment rely on serological follow-up. We evaluated the serological and parasitological response to nifurtimox in a cohort of adult patients three years post-treatment in Switzerland.MethodsPatients treated with nifurtimox in 2008 during a cross-sectional study in Geneva, Switzerland, were contacted for follow-up in 2011. Two ELISAs and a rapid immunochromatographic test were used to test 2008 and 2011 serum samples simultaneously. In addition, conventional and real-time PCR were performed on 2011 samples.ResultsThirty-seven (84.1%) of 44 eligible patients, predominantly female, middle-aged, Bolivians at the indeterminate stage, were enrolled. All 2011 ELISA and immunochromatographic tests were positive. Twenty-eight (75.7%) patients presented a lower optical density (OD) in 2011 compared to 2008. This OD difference was significant in both commercial (P < 0.001) and in-house (P = 0.002) ELISAs. Agreement between the two ELISAs was low (Kappa = 0.469). All patients had negative conventional PCR results but one (2.7%) was positive with real-time PCR.ConclusionOur results highlight the inadequacy of serology for assessing response in adults, three years after treatment. In our cohort, 97.3% had results that could either indicate treatment failure or persistant humoral response despite treatment. The lack of accurate early post-treatment tests of cure prevents appropriate patients information and councelling. New follow-up tests are needed to assess treatments efficacy given the large adult population in need of antiparasitic therapy.

Cost-effectiveness of Chagas disease screening in Latin American migrants at primary health-care centres in Europe: a Markov model analysis

BACKGROUND Chagas disease is currently prevalent in European countries hosting large communities from Latin America. Whether asymptomatic individuals at risk of Chagas disease living in Europe should be screened and treated accordingly is unclear. We performed an economic evaluation of systematic Chagas disease screening of the Latin American population attending primary care centres in Europe. METHODS We constructed a decision tree model that compared the test option (screening of asymptomatic individuals, treatment, and follow-up of positive cases) with the no-test option (screening, treating, and follow-up of symptomatic individuals). The decision tree included a Markov model with five states, related to the chronic stage of the disease: indeterminate, cardiomyopathy, gastrointestinal, response to treatment, and death. The model started with a target population of 100 000 individuals, of which 4·2% (95% CI 2·2-6·8) were estimated to be infected by Trypanosoma cruzi. The primary outcome was the incremental cost-effectiveness ratio (ICER) between test and no-test options. Deterministic and probabilistic analyses (Monte Carlo simulations) were performed. FINDINGS In the deterministic analysis, total costs referred to 100 000 individuals in the test and no-test option were €30 903 406 and €6 597 403 respectively, with a difference of €24 306 003. The respective number of quality-adjusted life-years (QALYs) gained in the test and no-test option were 61 820·82 and 57 354·42. The ICER was €5442. In the probabilistic analysis, total costs for the test and no-test option were €32 163 649 (95% CI 31 263 705-33 063 593) and €6 904 764 (6 703 258-7 106 270), respectively. The respective number of QALYs gained was 64 634·35 (95% CI 62 809·6-66 459·1) and 59 875·73 (58 191·18-61 560·28). The difference in QALYs gained between the test and no test options was 4758·62 (95% CI 4618·42-4898·82). The incremental cost-effectiveness ratio (ICER) was €6840·75 (95% CI 2545-2759) per QALY gained for a treatment efficacy of 20% and €4243 per QALY gained for treatment efficacy of 50%. Even with a reduction in Chagas disease prevalence to 0·05% and with large variations in all the parameters, the test option would still be more cost-effective than the no-test option (less than €30000 per QALY). INTERPRETATION Screening for Chagas disease in asymptomatic Latin American adults living in Europe is a cost-effective strategy. Findings of our model provide an important element to support the implementation of T cruzi screening programmes at primary health centres in European countries hosting Latin American migrants. FUNDING European Commission 7th Framework Program.

Economic crisis and increased immigrant mobility: new challenges in managing Chagas disease in Europe

There are little data on the extent to which communicable diseases are affected by the economic crisis in developed countries. However, a meta-analysis suggests worse health outcomes affecting the whole population, with infants, elderly, poor and/or homeless people, prisoners and immigrants car-rying the main burden.

Control and management of congenital Chagas disease in Europe and other non-endemic countries: current policies and practices.

Identifying pregnant women infected with Trypanosoma cruzi is one of the major challenges for preventing and controlling Chagas disease (CD) in non‐endemic countries. The aim of this paper was to perform a policy evaluation of the current practices of congenital Chagas disease (CCD) control in non‐endemic countries and to propose specific targets for enhanced interventions to tackle this emerging health problem outside the endemic areas of Latin America.

Pediatric Chagas disease in Europe: 45 cases from Spain and Switzerland.

Background: Chagas disease, a potentially fatal parasitic infection, is emerging in Europe in the context of international migration but there is little public health attention and frequent lack of clinicians’ awareness. To date, there is no published information about clinical characteristics in children. Methods: We reviewed the medical files of all children (<18 years) with Chagas disease managed in 2 hospitals in Barcelona, Spain and Geneva, Switzerland between January 2004 and July 2012. Results: Forty-five cases were identified. Two children (4.4%) were diagnosed during the acute phase and the remaining 43 (95.6%) were in the chronic phase of the infection. All but 1 were asymptomatic. Of the 41 treated children, 40 (97.6%) completed 60 days of treatment. Thirty-five (85.4%) received benznidazole, 5 (12.2%) nifurtimox and 1 (2.4%) both drugs consecutively. There were 2 (4.9%) treatment interruptions due to adverse events. The most frequent adverse events were rash (24.4%), anorexia or insufficient weight gain (14.6%) and anemia (2.4%). Twenty-nine (64.4%) children were followed up by serology after 2 years. Five (17.2%) were cured. Conclusions: Pediatric Chagas disease is an emerging health issue in Europe that requires enhanced attention. Greater emphasis should be put on screening pregnant women at risk and their newborns in case of infection along with older children and relatives. Pediatricians have a central role to play in providing families with information and offering testing in situations of risk.