Chagas disease in non-endemic countries: Experience from Geneva, Switzerland
Thesis summary
Introduction:
Chagas disease is considered one of the most neglected tropical diseases. This chronic protozoan infection with Trypanosoma cruzi affects 8-10 million persons mostly in Latin America, where it is endemic in 21 countries. Major routes of transmission include vector-borne, transplacental, through infected blood transfusion or organ transplant and oral. Its burden derives from the potentially fatal cardiomyopathy and digestive tract motility disorder affecting 20-40% and 10-20% of infected individual, respectively.
The clinical management of Chagas disease in adults is hampered by the limited therapeutic options available, the complexity of the diagnostic procedures and the difficulty in assessing cure. Nifurtimox and benznidazole, marketed in the early 1970’s, are the only available drugs but their accessibility remains insufficient. Moreover, data regarding their safety and effectiveness in adults are scarce. Diagnosis requires using different strategies and methods at the different stages of the infection and cure is assessed by decades-long serological follow-up. There are also uncertainties regarding the optimal methods to assess cure in adults.
Chagas disease has traditionally been restricted to areas where triatomine vectors were endemic (from the Southern United States of America to Chile). In recent years, enhanced population movements both within and between endemic countries and towards other continents have transformed the distribution of the infection. Indeed, more than 15 million people at risk moved to North America, Western Europe, Japan and Australia since mid-1990. The lack of clinical and public health workforce awareness, of strategies to identify and manage people at risks, of programs aiming at preventing transmission and the peculiar socioeconomic conditions of Latino immigrants constitute a favourable terrain for the emergence and transmission of Chagas disease in non-endemic regions.
In Geneva, Switzerland, the identification of an increasing number of sporadic cases and of congenital transmission represented new clinical and public health challenges. Most cases occurred in hard-to-reach immigrants’ community with poor access to health care. This called for epidemiological and clinical investigations to better understand and tackle this phenomenon. More specifically, there was a need for defining diagnostic/treatment algorithms that fitted with the new circumstances around this emerging infection.
Objectives:
We aimed at investigating the distribution of the disease, its clinical presentation, the risks of local transmission, the performance of a rapid diagnostic test, the tolerance to treatment, the immunological response following treatment and the use of proteomics biomarkers to assess cure.
Methods:
We conducted three successive studies from 2007 to 2011. The first, a retrospective serological survey among pregnant Latino women delivering at the Geneva University Hospitals aimed at identifying the prevalence and the transmission risk. The second, a cross-sectional study in the community, evaluated the prevalence among the Latino immigrants community in Geneva, described the clinical presentation, compared the performance of an immunochromatographic rapid diagnostic test (Stat-Pak®, ChemBio, USA) to two commercial ELISA assays (Biomérieux ELISA cruzi®; Biokit Bioelisa Chagas®) and recorded the tolerance to nifurtimox. The third study assessed the serological response to treatment and the evolution of circulating T.cruzi proteomics biomarkers in a cohort of patients and healthy controls.
Results:
T. cruzi infection was found in 7 (9.7%) of 72 pregnant Latina women and in 130 (12.8%; 95% confidence interval: 10.8%-14.9%) of 1012 Latino immigrants. The main factors associated with 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). Maternal infection, ongoing blood donation and willingness to donate organs by infected individuals accounted for the risk of local transmission. All infected individuals were in the chronic phase, including 11.3% with cardiac and 0.8% with digestive complications.
The rapid diagnostic test showed a sensitivity and a specificity on blood samples of 95.2% (95% CI: 89.2%-97.9%) and 99.9% (95% CI: 99.3%-100%), respectively. When the test was performed on serum samples, the sensitivity was 96% (95% CI: 91%-98.3%), and the specificity was 99.8% (95% CI: 99.2%-99.9%). The concordance of test results for blood and serum samples was 99.7%. Both negative and positive predictive values were above 98%.
Tolerance to nifurtimox was assessed in 81 patients. Eight were lost to follow-up during treatment and 41 (56.2%) completed the recommended 60-day course. All premature treatment terminations were caused by adverse events (AE); 97.5% of patients suffered from AE, mostly expected (90.5%) and not severe. Gastrointestinal symptoms predominated. Six (7.4%) patients presented with a suspected unexpected serious adverse reaction (SUSAR): drug reaction with eosinophilia and systemic symptoms (n=3), Quincke oedema (n=1), myocarditis (n=1), and anaphylaxis (n=1). Patients with 3 or more AE had an increased risk of premature treatment termination (hazard ratio, 8.42; 95% CI: 1.6-45.5).
Three years after treatment, none of 37 patients had negative serology results indicating cure after testing with two ELISA assays and the rapid diagnostic test. Yet, twenty-eight (75.7%) presented declining optical densities as compared to pre-treatment status. All patients had negative conventional PCR results but one (2.7%) was positive with real-time PCR. Conversely, an algorithm with five proteomic biomarkers indicated possible cure in 17 (46%) patients with circulating biomarkers levels returning to normality following treatment.
Discussion and conclusion:
These studies provide strong evidences about the emergence of Chagas disease in Switzerland and about a consequent risk of transmission in absence of measures of prevention. These findings can be extended to other Western European countries with similar context. Indeed, Spain, Italy and other neighbouring countries have reported similar findings. Most cases affect middle-aged Latino immigrants but emerging evidences show that children are affected as well. This calls for multi-pronged and comprehensive public health interventions aiming at identifying cases early and avoiding its transmission.
The detection of T. cruzi infection in chronic carriers can be facilitated by the use of the Stat-Pack® rapid diagnostic test as a screening tool in hard-to-reach communities. Moreover, multi-steps diagnostic procedures to identify congenital transmission allow for early and effective interventions. Yet, major clinical challenges remain. Poor tolerance and effectiveness of both nifurtimox and benznidazole hamper effective interventions in adults at the chronic stage that represent the major reservoir of infection, thus placing them at subsequent risk of complications and failing to eliminate the potential of subsequent transmission. More effective and safer drugs, including formulations for children are urgently needed. The use of new serum biomarkers as tests of cure opens new avenues towards solving the complex issue pertaining to the lack of an accurate, early post-treatment, test of cure that hinders appropriate patient monitoring, information and counselling in addition to drug development. Our data confirm that serology is of no value to assess cure in patients in the chronic stage.
In conclusion, Chagas disease emergence in Switzerland and in Europe deserves enhanced clinical and public health attention given the consequent burden of disease and the need to further investigate optimal management strategies.