Comparison of the toxicity of two treatment schemes with benznidazole for chronic Chagas disease: a prospective cohort study in two Spanish referral centres.

OBJECTIVES: Chagas disease (CD) treatment is limited to two therapeutic options: benznidazole (generally the first option in Spain) and nifurtimox. Both drugs present high rates of adverse reactions and treatment discontinuation and there is no consensus regarding the most effective administration schedule for benznidazole or how to prevent and manage treatment toxicity. We aim to compare the tolerability and treatment discontinuation rate between two different treatment schemes with benznidazole. METHODS: This was a prospective observational study of adult patients with CD, enrolled from January 2014 to March 2018 in two referral centres in Madrid (Spain). Participants were treated either with benznidazole 5 mg/kg/day (full dose) over 60 days (benznidazole standard dose scheme (BSD)), or with an escalating dose lasting 5 days up to a maximum of 300 mg/day (benznidazole increasing dose scheme (BID)). RESULTS: 471 patients were analysed: 201 in the BSD group and 270 in the BID group. There were no significant differences regarding age (40.4 (SD 8.7) vs 41 (SD 8.2) years), sex (74.1% (149/201) vs 68.5% (185/270) women), weight (69.4 (SD 12.8) vs 68.9 (SD 11) kg) or nationality (97.5% (196/201) vs 96.7% (261/270) Bolivians) between groups. There were also no differences in adverse reactions rate (55.2% (111/201) vs 55.6% (150/270)), number of adverse reactions per patient, adverse reactions type (except for arthralgias and myalgias which occurred more frequently in the BID group (0% (0/111) BSD vs 8% (12/150) BID; p 0.002)) and degree and time to first adverse reactions. There was significantly more treatment discontinuation (49.8% (100/201) vs 33.0% (89/270); p <0.001) in the BSD group, but not during the first 30 days of treatment (32.3% (65/201) vs 25.6% (69/270); p 0.08). CONCLUSION: The use of increasing doses of benznidazole for 5 days and a maximum dose of 300 mg, does not significantly improve drug tolerability. However, while the treatment discontinuation rates were similar during the first 30 days of treatment, it may improve the treatment completion rate at 60 days.

Toxicity of nifurtimox as second-line treatment after benznidazole intolerance in patients with chronic Chagas disease: when available options fail.

OBJECTIVE: To describe the tolerability and rate of nifurtimox discontinuation when administered as a second-line treatment to patients with previous treatment interruptions due to adverse reactions with benznidazole. METHODS: We studied a prospective cohort study of adult patients with chronic Chagas disease in a referral centre in Spain treated from July 2007 to July 2017. We analysed the tolerability profile and treatment interruption rate due to adverse reactions (ARs) to nifurtimox in patients previously incompletely treated (less than 30 days) with benznidazole due to ARs. RESULTS: A total of 472 patients initiated treatment with benznidazole during the study period. Of these, 118 (25%) developed ARs that led to treatment discontinuation before 30 days of therapy. Fifty-three (44.9%) of 118 initiated nifurtimox as second-line treatment; most were women (79.3%), were of Bolivian origin (98.1%) and had a median age of 37.3 years (interquartile range, 29.8-43.2). The most common ARs with nifurtimox were cutaneous hypersensitivity (24.1%), digestive disorders (22.2%), fever (12.9%), neurologic disturbances (11.1%), depression, anxiety or insomnia (9.2%), dyspnoea (7.4%), myalgia (5.5%), and dizziness, asthenia or malaise (7.4%). Twenty-six (49.1%) of 53 patients discontinued nifurtimox due to ARs, all of them before the required minimal therapy duration of 60 days. There were no deaths. CONCLUSIONS: Treatment of chronic Chagas disease relies on two drugs with a poor tolerability profile. In our cohort, 12.3% of the patients who initiated benznidazole and subsequently nifurtimox in case of nontolerance developed ARs that led to permanent treatment discontinuation. Most were women of childbearing age, a group for whom therapy has the added benefit of interrupting vertical transmission.

Challenges in the management of Chagas disease in Latin-American migrants in Europe.

Chagas disease is endemic in Latin America. Due to migration the infection has crossed borders and it is estimated that 68,000-120,000 people with Chagas disease are currently living in Europe and 30% of them may develop visceral involvement. However, up to 90% of Chagas disease cases in Europe remain undiagnosed. The challenges which have to be overcome in Chagas disease in non-endemic countries are focused on related downing barriers to health care access, and related to screening, diagnostic tools and therapeutic management. The aim of this review is to highlight how healthcare management for Latin American migrants with Chagas disease in Europe may be improved. Medical literature was searched using PubMed. No limits were placed with respect to the language or date of publication although most of the articles selected were articles published in the last five years. Chosen search terms were "Chagas disease" AND ("migrants" OR "screening" OR "transmission" OR "treatment"; OR "knowledge" OR "non-endemic countries"); migrants AND ("Public health" OR "Health Service Accessibility" OR "Delivery of Health care"); and "Congenital Chagas disease". Healthcare management of migrant populations with Chagas disease in Europe has to be improved: -Surveillance programmes are needed to measure the burden of the disease; -screening programmes are needed; -administrative and cultural barriers in the access to health care for migrants should be reduced; -education programmes on Chagas disease should be performed -research on new diagnostic tools and therapeutic options are required. This review highlights the needs of profound changes in the health care of Latin American migrants with Chagas disease in Europe.

Travelers visiting friends and relatives (VFR) and imported infectious disease: travelers, immigrants or both? A comparative analysis.

INTRODUCTION: Immigrants are increasingly traveling back to their countries of origin to visit friends and relatives (VFRs). They account for an important proportion of all international travelers and have a high risk for certain travel-related infectious diseases. METHODS: We describe the spectrum of infectious diseases diagnosed in a cohort of 351 VFRs and compare them with two previously published cohorts: of immigrants and travelers attended at our centre. RESULTS: The most frequent diagnoses observed among VFRs were typical travel-associated infections such as malaria (75 [21.4%]), traveler's diarrhea 17 [4.8%]), intestinal parasites (16 [4.6%]) and dengue (11 [3.1%]). Asymptomatic chronic infectious diseases, such as latent tuberculosis (56 [16%]), chronic viral hepatitis (18 [5.1%]) and filariasis (18 [5.1%]), probably acquired before migration, were also observed. CONCLUSIONS: VFRs should thus be approached from two perspectives as concerns imported infectious diseases: as travelers and as immigrants. Etiological studies focusing on the presenting complaint as well as systematic screening for other latent infectious diseases should be performed.

Gastro-intestinal Chagas disease in migrants to Spain: prevalence and methods for early diagnosis.

Each year in Spain, the number of Latin American immigrants who present with chronic Trypanosoma cruzi infection increases. Although gastro-intestinal abnormalities are not as common as cardiomyopathy in such infection, they can still lead to an impaired quality of life. In a recent study based in Madrid, the frequencies of gastro-intestinal involvement in a cohort of Latin American immigrants infected with T. cruzi, and the role of early diagnostic techniques in the detection of such involvement, were explored. Between January 2003 and April 2009, all Latin Americans who attended the Tropical Medicine Unit of the Hospital Universitario Ramón y Cajal were tested for T. cruzi infection, in IFAT and ELISA. Each subject found both IFAT- and ELISA-positive was considered to be infected (chronically) and checked for symptoms indicative of Chagas disease. Each infected subject giving informed consent was investigated further, using an electrocardiogram, an echocardiogram and oesophageal manometry. Between January 2003 and June 2008, every infected subject who consented was also explored using a barium swallow and barium enema. After July 2008, however, only subjects showing oesophageal and/or colonic symptoms were investigated in this manner. Of the 248 patients found infected with T. cruzi, 118 underwent oesophageal manometry, 75 a barium enema and 48 a barium swallow. Thirteen (11%) showed evidence of oesophageal involvement (incomplete relaxation of the lower oesophageal sphincter; three cases) or bowel involvement (five cases of dolichosigma, three of dolichocolon and two of megacolon). Only six of these 13 had any gastro-intestinal symptoms (all six were suffering from constipation). None of the barium swallows revealed any pathology. It appears that oesophageal manometry can reveal mild abnormalities not detected by barium swallow, even in asymptomatic patients, while barium enemas are useful in the detection of colonic involvement.

Chagas disease in Latin American migrants: a Spanish challenge.

Chagas' disease affects millions in Latin America and is the leading cause of cardiomyopathy and death due to cardiovascular disease in patients aged 30-50 years. As a consequence of immigration it has settled in several European countries, where besides imported cases, autochthonous infections arise through vertical transmission and blood/organ donation. All Latin American immigrants who attended our Unit were screened for T. cruzi infection (ELISA and IFAT ± PCR). An ECG and echocardiogram were requested for all positive patients, and oesophageal manometry, barium swallow and barium enema were requested according to patient symptoms. All patients under 50 years without severe cardiac involvement and who had not received correct treatment previously were treated with benznidazole 5 mg/kg/day for 60 days. Patients were followed-up with serology and PCR 1 month after treatment ended and every 6 months thereafter. A total of 1146 Latin Americans were screened for T. cruzi (357 positive serology results). The typical patient profile was a Bolivian female, of rural origin, in her fourth decade of life, without evidence of visceral involvement. Treatment tolerance was poor, with 29.7% discontinuing treatment due to adverse reactions. Among those with adverse reactions (52%), the most frequent were cutaneous hypersensitivity (68.7%), gastrointestinal upset (20%) and nervous system disturbances (16.2%). T. cruzi infection is no longer limited to Latin America. Poor treatment tolerance can limit current treatment options. More epidemiological data are necessary to estimate the magnitude of a problem of great relevance for public health and health resource planning.