Systematic review Screening for Trypanosoma cruzi infection in immigrants and refugees: Systematic review and recommendations from the Spanish Society of Infectious Diseases and Clinical Microbiology María Velasco1, Luis Andrés Gimeno-Feliú2,3,4 , Israel Molina5 , Joaquín Salas-Coronas6 , Ivan Solà7,8 , Begoña Monge-Maillo9 , Diego Torrús-Tendero10 , Joan Caylà11 , Ena Niño de Guzmán⁷ , JL Pérez Arellano12,13 , Jose A Pérez-Molina9 1. Infectious and Tropical Medicine Section, Internal Medicine Department, Hospital Universitario Fundación Alcorcón, Madrid, Spain 2. San Pablo Health Centre, Zaragoza, Spain 3. Department of Medicine, Psychiatry and Dermatology, University of Zaragoza. EpiChron Research Group on Chronic Diseases, Aragón Health Sciences Institute (IACS), IIS Aragón, Hospital Universitario Miguel Servet, Zaragoza, Spain 4. Health Services Research on Chronic Patients Network (REDISSEC), Instituto de Salud Carlos III, Madrid, Spain 5. Infectious Diseases Department, Hospital Universitario Vall d’Hebron, PROSICS Barcelona, Universitat Autònoma de Barcelona, Barcelona, Spain 6. Tropical Medicine Unit. Hospital de Poniente, El Ejido, Almería, Spain 7. Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain 8. CIBER of Epidemiology and Public Health (CIBERESP), Barcelona, Spain 9. National Referral Centre for Tropical Diseases, Infectious Diseases Department, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain 10. Referral Unit for Imported Infections and International Health. Infectious Diseases Unit, Hospital General Universitario de Alicante. Parasitology Area, Miguel Hernández University, Alicante, Spain 11. Fundació de la Unitat d’Investigació en Tuberculosis (FuiTB), TB Research Unit, Barcelona, Spain 12. Infectious Diseases and Tropical Medicine Unit, Hospital Insular de Las Palmas. Las Palmas de Gran Canaria, Spain 13. Medical and Surgical Sciences Department. Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain Correspondence: José A. Pérez-Molina (jperezm@salud.madrid.org) Citation style for this article: Velasco María, Gimeno-Feliú Luis Andrés, Molina Israel , Salas-Coronas Joaquín , Solà Ivan , Monge-Maillo Begoña , Torrús-Tendero Diego , Caylà Joan , de Guzmán Ena Niño , Arellano JL Pérez , Pérez-Molina Jose A. Screening for Trypanosoma cruzi infection in immigrants and refugees: Systematic review and recommendations from the Spanish Society of Infectious Diseases and Clinical Microbiology . Euro Surveill. 2020;25(8):pii=1900393. https://doi.org/10.2807/1560-7917. ES.2020.25.8.1900393 Article submitted on 19 Jun 2019 / accepted on 22 Nov 2019 / published on 27 Feb 2020 Background: Chagas disease has spread beyond bias in the studies and considerable heterogeneity of its original borders on the American continent with the evaluated populations. The recommendations took migration. It can be transmitted from mother to into account economic studies on the value of screen- child, through organ transplantation and transfu- ing strategies and studies on acceptability of screen- sion of blood and blood products. It is necessary to ing and knowledge of the disease in the affected determine when to screen for this infection. Aim: population. Conclusions: We identified five situations Our objective was to evaluate the appropriateness in which screening for T. cruzi infection is indicated. of screening for Trypanosoma cruzi infection in Latin We recommend screening persons from endemic areas American migrants and their descendants. Methods: and children of mothers from these areas. We reviewed the literature using rigorous criteria. The quality of evidence was ranked according to the Introduction GRADE classification. An evidence to decision frame- Chagas disease is endemic in 21 countries in Latin work was adopted to provide information on the most America and is present from the south of the United relevant aspects necessary to formulate recommen- States (US) to the north of Argentina and Chile. dations. Results: The 33 studies evaluated revealed a Transmission in these countries is mainly vectorial, prevalence of T. cruzi infection among Latin American although migration to cities, vertical transmission and migrants in Europe of 6.08% (95% confidence inter- blood donations have enabled it to extend from rural to val (CI): 3.24–9.69; 28 studies). Vertical transmission urban areas. Estimations from the year 2010 show that occurred in three of 100 live births (95% CI: 1–6; 13 5,742,167 persons are infected with Trypanosoma cruzi. studies). The prevalence of cardiovascular disease was Of these, 62.4% live in the Southern Cone, with an 19% (95% CI: 13–27; nine studies), including only 1% at-risk population of 70.2 million people, 38,593 new severe cardiac events (95% CI: 0–2; 11 studies). The cases per year (8,668 congenital cases) and 12,000 overall quality of evidence was low because of risk of related deaths per year. Furthermore, Chagas disease www.eurosurveillance.org 1 Figure 1 thought to be living in Spain in 2009, and the rate of Systematic review about screening of migrants for potentially infected blood donations ranged from 0.02 Trypanosoma cruzi, study eligibility, Prisma flow diagram to 2.35 per 1,000 inhabitants, with wide variations between Autonomous Communities [10]. According to a 470 records more recent study and data from the 2011 census and identified through after applying values reported by Basile et al. [4], there database searching are 68,636 T. cruzi–infected Latin American immigrants in Spain, of whom 22,100 are women of reproductive 24 records suggested age [11]. by panel members In endemic areas, T. cruzi is vector-borne (reduviid bug). It can also be transmitted vertically, through 494 records screened 429 records excluded blood and organ donation and, more rarely, oral con- by title and abstract tact. Migration has led the disease to spread beyond its original borders, so that it can now be transmit- ted from mother to child in non-endemic countries or if blood donations and transplants are not monitored 65 full-text articles 32 articles excludeda [2,12]. assessed for eligibility Chagas disease has an acute phase, which, if left untreated, progresses to a chronic phase during which patients can develop cardiac, digestive or neurologi- 33 studies included in the evidence synthesis cal involvement. This occurs in 30–40% of infected persons 10–30 years after the acute phase and is a major cause of morbidity and mortality. Treatment with a Reason for exclusion of full-text articles: 12 narrative review articles; nine conference abstracts; four studies in endemic antiparasitic agents is effective in the acute phase, in settings; two cost studies; two duplicates; one case report; one reactivations in immunosuppressed patients, in the study in a non-eligible setting; one registry report. chronic phase (especially before the age of 18 years) and in the prevention of vertical transmission [2,12- 14]. Although, during the late chronic phase, tryp- anocidal treatment can be indicated in adult patients with chronic T. cruzi infection and no specific organic continues to be the leading cause of cardiomyopathy damage [13], its effectiveness is highly questionable in in Latin America and is, according to the World Health cases of visceral involvement [2,12-14]. Organization (WHO), a ‘forgotten’ or ‘neglected’ dis- ease [1,2]. Given that Spain is a country with a high prevalence of T. cruzi infection and because early detection of this In Europe, Chagas disease is not monitored systemati- disease is advantageous (better response to treatment, cally, although available data suggest that prevalence prevention of materno-fetal transmission and of late rates are high in some countries. The highest numbers organ complications), the Spanish Society of Infectious of cases in Europe are found, in order of prevalence, Diseases and Clinical Microbiology (Sociedad Española in Spain, Italy, the Netherlands, the United Kingdom, de Enfermedades Infecciosas y Microbiología Clínica; Germany and France [3]. According to one study, SEIMC) decided to draft guidelines on screening for 4,290 cases of Chagas disease were registered among this parasitosis in immigrants and refugees. Here, we Latin American immigrants in nine European coun- present the methodology, results and recommenda- tries in 2009, with a prevalence of 1.3 cases per 1,000 tions of this initiative. migrants from endemic countries. In addition to poten- tial underdiagnosis, prevalence among undocumented Methods immigrants could be higher [4]. We performed a systematic review of the literature to determine whether screening had an impact on a series Spain is home to the largest number of infected per- of relevant outcomes of interest for decision making. sons from Latin America and has the highest num- We then developed a working framework to formulate ber of confirmed cases of Chagas disease in Europe explicit, reasoned recommendations. (75% of the total). Prevalence differs for each group of immigrants by country and specific region of origin. Review of the scientific literature Depending on the type of study and population ana- The Panel, which comprised the authors of the study, lysed, the highest prevalence rates are found among reviewed the scientific literature according to a protocol immigrants from Bolivia (10–40%). Rates are lower following methodological guidelines from the Cochrane in blood donors and pregnant women and higher in Collaboration [15] and reported its findings according patients at reference centres where Chagas disease is to the Preferred Reporting Items for Systematic Reviews screened for [5-9]. Some 53,000 potential carriers were and Meta-Analyses (PRISMA) statement [16]. 2 www.eurosurveillance.org Table 1 Summary of outcomes of interest, systematic review about screening of migrants for Trypanosoma cruzi Outcome Number of studies Quality of evidence Impact 1. Total pooled prevalence: 6% (95% CI: 3–10); 2. Among immigrants in general: 13% (95% 26 observational studies CI: 7–21; I2 = 98.15%) Patients with T. cruzi infection Low [5-7,9,22-43] 3. Pregnant women: 4% (95% CI: 2–7; I2 = 96.28%) 4. Blood donors: 0.42% (95% CI: 0.03– 1.08%; I2 = 82.06) 1. Pooled transmission rate: 3 per 100 live 13 observational studies births (95% CI: 1–6; I2 = 21.40%) Vertical transmission of T. Low cruzi infection [6,35-43,46,49,50] 2. Symptoms of infection in 20% (95% CI: 0–53; I2 = 32.4%) Mild to moderate organ 9 observational studies Cardiovascular disease: 19% (95% CI: involvement: cardiovascular Low 13–27%; I2 = 88.36%) symptoms [6,7,9,24,29,45-48] Mild to moderate organ 9 observational studies Gastrointestinal abnormalities: 5% (95% involvement: digestive Low CI: 2–11; I2 = 89.62%) symptoms [7,24,25,28,29,45-48] 1. Severe cardiac events: 1% (95% CI: 0–2; I2 = 57.9%) 11 observational studies Severe organ involvement Low 2. Severe gastrointestinal involvement [6,7,9,24,25,28,29,45-48] (megasyndrome): 0% (95% CI: 0–1; I2 = 41.26%) 1. Initiation of trypanocidal therapy: 81% (95% CI: 67–93; I2 = 93.25%) 11 observational studies 2. End of treatment: 78% (95% CI: 65–89; Indication for treatment Very low I2 = 88.5%) [6,29,30,35,37,39,43,45-48] 3. Treatment-related adverse effects: 47% (95% CI: 32–63; I2 = 90.45%) 2 observational studies Two reports of sudden cardiac death Mortality Low secondary to Chagas disease [6,7] CI: confidence interval. Clinical question Inclusion criteria In order to draw up the recommendations, the Panel Given the lack of clinical trials that compare the impact asked the following clinical question: Should immi- of screening for T. cruzi infection with not screening for grants and refugees be screened for T. cruzi infection? it, we considered descriptive studies on screening in which a denominator could be established for the ref- In order to answer the question, the Panel identified erence population. If this was not possible, we consid- the following outcomes of interest: (i) frequency of ered case series that described the clinical condition vertical transmission, transmission by blood/blood of patients with the disease. The population of inter- product transfusion and transmission by transplant, est comprised immigrants or refugees older than 14 (ii) mild to moderate organ involvement (defined as years from endemic areas, except in the case of neo- the presence of heart failure or left ventricular ejection natal screening where we also took into consideration fraction < 50%, electrocardiogram abnormalities or dys- minors born to mothers at risk of vertical transmission. phagia/constipation), (iii) severe organ involvement We took into account studies that reported experience (defined as hospitalisation because of heart failure, of screening for T. cruzi in non-endemic countries in need for a pacemaker or diagnosis of megasyndrome), Europe. The studies had to provide clear detail, namely, (iv) T. cruzi infection, (v) indications for a trypanocidal test used and setting in which it was performed. By def- drug, (vi) mortality, (vii) organ involvement of any type inition, the test is performed in asymptomatic patients. after diagnosis and (viii) quality of life. Literature search A search strategy was designed to obtain relevant studies from MEDLINE (accessed via PubMed) and www.eurosurveillance.org 3 Figure 2 Prevalence of Trypanosoma cruzi infection: pooled analysis from studies included in the review % Study Prevalence estimate (95% CI) ES (95% CI) Weight IMMIGRANTS Angheben 2011 [23] 11.28 (8.02, 15.64) 3.59 Frank 1997 [24] 2.02 (0.56, 7.07) 3.42 Jackson 2010 [25] 12.85 (10.92, 15.05) 3.67 Lescure 2009 [26] 23.62 (18.82, 29.21) 3.59 Muñoz 2009 [7] 41.31 (37.03, 45.72) 3.64 Navarro 2011 [27] 15.94 (12.10, 20.72) 3.59 Perez-Ayala 2010 [6] 31.15 (28.54, 33.89) 3.67 Perez-Molina 2011 [28] 11.00 (9.32, 12.95) 3.67 Ramos 2012 [29] 6.47 (3.82, 10.75) 3.56 Roca 2011 [9] 2.87 (1.90, 4.31) 3.66 Rodríguez-Guardado 2009 [30] 16.07 (8.69, 27.81) 3.24 Soriano 2009 [31] 4.31 (1.85, 9.69) 3.46 Subtotal (I2 = 98.15%, p = 0.00) 13.30 (7.30, 20.71) 42.76 BLOOD DONORS Angheben 2011 [23] 0.00 (0.00, 12.06) 2.88 Cancino 2015 [32] 1.92 (1.28, 2.86) 3.67 El Ghouzzi 2010 [33] 0.31 (0.11, 0.90) 3.67 Gabrielli 2013 [34] 0.98 (0.17, 5.35) 3.43 O’Brien 2013 [35] 0.30 (0.17, 0.54) 3.69 Pirón 2008 [5] 0.66 (0.36, 1.20) 3.68 Subtotal (I2 = 82.06%, p = 0.00) 0.42 (0.03, 1.08) 21.03 PREGNANT WOMEN Angheben 2011 [23] 1.40 (0.48, 4.04) 3.57 Avila Arzanegui 2013 [36] 12.18 (7.94, 18.24) 3.52 Barona-Vilar 2012 [37] 11.62 (10.27, 13.12) 3.68 Martínez 2009 [38] 0.00 (0.00, 1.24) 3.60 Muñoz 2009 [39] 3.41 (2.56, 4.51) 3.68 Muñoz-Vilches 2012 [40] 1.53 (0.60, 3.87) 3.59 Ortí Lucas 2009 [41] 9.69 (7.11, 13.07) 3.62 Otero 2012 [42] 3.48 (2.31, 5.21) 3.65 Paricio-Talayero 2008 [43] 4.71 (3.30, 6.68) 3.65 Ramos 2012 [44] 1.28 (0.62, 2.63) 3.65 Subtotal (I2 = 96.28%, p = 0.00) 3.93 (1.71, 6.98) 36.21 Heterogeneity between groups: p = 0.000 Overall (I2 = 98.82%, p = 0.00); 6.08 (3.24, 9.69) 100.00 0 10 20 30 40 50 Rate per 100 persons screened CI: confidence interval. EMBASE (accessed via Ovid) up to October 2018. The of interest (e.g. pregnant women). We also obtained strategy combined text words and controlled vocabu- numerical data that made it possible to calculate the lary from sources related to screening and T. cruzi, with prevalence or cumulative rate for each of the outcomes no major limits for year of publication, language or of interest, with their respective confidence intervals country (Supplement 1). The results of the search were (CI) when available. recorded in an EndNoteX2 database to coordinate the eligibility and availability of the studies. The results of Risk of bias the search were complemented with additional refer- Bias affecting the observational (cross-sectional) stud- ences provided by the Panel and based on references ies included was evaluated based on 10 items which from the key studies. The investigators of the original assessed the internal and external validity of the stud- studies were not contacted. ies [17]. The resulting classification defined the overall risk of bias as low, moderate or high. The information Data extraction obtained from the evaluation of risk of bias was incor- The Panel retrieved a series of descriptive character- porated in the process applied to classify the quality istics from each included study and recorded them on of evidence. a predefined data extraction form. In addition to the objective and study design, we defined the context, Data analysis and evidence synthesis number of participants and their origin, the test used We performed a narrative synthesis of results for to determine the disease, the criteria for positivity and each predefined outcome. When prevalence data were all relevant specific information from any subgroup available, we calculated pooled estimates with their 4 www.eurosurveillance.org Box 1.a Evidence-to-decision framework for the formulation of recommendations for screening of migrants for Trypanosoma cruzi Clinical question • Should immigrants and refugees undergo screening for T. cruzi infection? Population of interest • Migrants and refugees Intervention • Screening for T. cruzi infection Comparison • Not screening Outcomes of interest • Cases of vertical transmission resulting from transfusion or transplant • Mild to moderate organ involvement (heart failure or LVEF < 50%, ECG abnormalities or dysphagia/constipation) • Severe organ involvement (hospitalisation due to heart failure, need for a pacemaker or diagnosis of megasyndrome) • Infection • Indication for trypanocidal treatment • Mortality • Organ involvement of any type after diagnosis • Quality of life Is the problem a priority? Yes Research evidence and remarks from the Panel • High prevalence of immigrants from Latin America, especially Bolivia. • Between 50,000 and 70,000 persons in Spain are thought to have the disease. • Autochthonous transmission occurs in Spain, mainly by vertical transmission. • Early detection in children of infected mothers indicates a very high rate of cure. • Early detection improves response to treatment. Antiparasitic treatment is more effective in children and adolescents than in adults. It also makes it possible to identify women of reproductive age who have not yet had children (or who have had children and may wish to have more) and in whom treatment blocks vertical transmission. • There is the possibility of reactivation in immunosuppressed patients, with severe consequences. • Approximately 30% of persons with Chagas disease develop heart disease, with subsequent morbidity and mortality and added cost for the health system. • Chagas disease carries a risk of stigmatisation. Better knowledge and normalisation of the disease improves the negative perception that often keeps patients from being diagnosed and treated early. How substantial are the desirable anticipated effects? Large How substantial are the undesirable anticipated effects? Moderate Research evidence and remarks from the Panel See Table 1 for a summary of findings for the outcomes of interest. The prevalence of the disease in the study population, the rate of vertical transmission, and the rate of complications—mainly cardiovascular complications—justify screening. In the case of indication for treatment, treatment of chronic infection in children younger than 19 years is very useful, while in adults, it should be questioned owing to the lack of quality studies. The efficacy of treatment in chronic infection may be questionable, especially for patients with moderate to severe cardiopathy. The marginal effect of treatment for adults in this phase of the disease could be due to considerable differences between studies [51-55,68]. While the tolerability of parasiticidal treatment is good in children, it is important to highlight the poor tolerability of treatment in adults: up to 44% of patients treated with benznidazole experience adverse effects, which have an impact on discontinuation of treatment (11% of all treated patients) [56]. The adverse effects of screening are minimal, i.e. those associated with blood sampling and the potential psychological consequences of having the disease, which may lead to stigmatisation. CI: confidence interval; ECG: electrocardiogram; ICER: incremental cost-effectiveness ratio; LVEF: left ventricular ejection fraction; QALY: quality-adjusted life year. www.eurosurveillance.org 5 Box 1.b Evidence-to-decision framework for the formulation of recommendations for screening of migrants for Trypanosoma cruzi However, treatment with trypanocidal agents led to a high rate of adverse effects (on occasion up to 50%), some of which were severe. There is little evidence on the real cure rates in adult patients with chronic disease, which may be around 30% [68]. What is the overall certainty of the evidence of the effects? Low Research evidence and remarks from the Panel The studies evaluated for this question are observational (generally cross-sectional) with a prospective or retrospective design. The populations evaluated are heterogeneous. The quality of the results of these studies can be affected by selection bias. Furthermore, most of the combined analyses for the outcomes of interest revealed a very notable rate of statistical heterogeneity. However, this variability decreased when studies with well-defined populations (e.g. pregnant women) were evaluated together or when variability was attributed to estimations from few studies. Therefore, in most studies it was not considered a reason for reduced quality of evidence. Is there major uncertainty about or variability in how much people value the main outcomes? There may be major uncertainty or variability. Research evidence and remarks from the Panel A study on Bolivian women with Chagas disease in Madrid revealed relevant aspects of their knowledge of and attitudes towards the disease. Most knew that the disease was transmitted by a vector, could be asymptomatic, and could lead to severe complications such as sudden death and heart failure. While there is some confusion over treatment, the women know that it is available [69]. The study included women from a country where Chagas disease was highly prevalent. There may be major differences between people from different countries. Does the balance between desired and undesired effects favour the intervention or the comparison? The balance between desired and undesired effects favours the intervention. Research evidence and remarks from the Panel The expected benefit is centred on three basic aspects: • Intervention prevents vertical transmission, with treatment offered after serology-based diagnosis in women of reproductive age from endemic areas. Furthermore, detection of the disease in a pregnant woman enables early diagnosis and treatment of the newborn, thus ensuring cure rates close to 100% during the first year, with very few adverse effects. Early diagnosis and treatment of the disease could prevent mainly cardiovascular complications, although evidence is scarce. • The risks associated with treatment can be controlled to a large extent with appropriate follow-up at specialised clinics during the administration period. • Screening of donors to prevent transmission through blood products and organs is addressed in current Spanish legislation (Royal Decree 1088/2005, dated 16 September 2005 (BOE-A-2005–15514)) Is the intervention acceptable to key stakeholders (population, professionals)? Probably Research evidence and remarks from the Panel The participants in the study on Bolivian women living in Madrid showed a certain degree of indifference and a lack of understanding of the risk of contracting the disease [69]. Participants who presented symptoms or had relatives with symptomatic disease expressed their concern for the more severe complications of the disease and the possibility of vertical transmission. In addition, fear of rejection by their social circle because of the disease was detected. In a similar study in the US, participants also expressed their concern about the lack of knowledge of the disease by health professionals and about more logistic aspects, such as difficulties reaching health centres or having sufficient time to attend an appointment. Of note, the participants in this study were at risk of social exclusion [70]. Stigmatisation because of the disease in specific groups should be taken into consideration when screening. Education, knowledge of the disease and easy access to diagnosis and treatment are necessary in order to overcome this problem. CI: confidence interval; ECG: electrocardiogram; ICER: incremental cost-effectiveness ratio; LVEF: left ventricular ejection fraction; QALY: quality-adjusted life year. 6 www.eurosurveillance.org Box 1.c Evidence-to-decision framework for the formulation of recommendations for screening of migrants for Trypanosoma cruzi Does the cost-effectiveness of the intervention favour the intervention or the comparison? They probably favour the intervention. Research evidence and remarks from the Panel An economic evaluation [11] evaluated the most efficient strategy for controlling Chagas disease among Latin American immigrants living in Spain. The study showed that not screening was more expensive and less effective and was dominated by other strategies from the societal perspective and from the perspective of the Spanish National Health System (SNHS). One of the most efficient strategies from both perspectives was screening of pregnant women, their newborns and first- and second- degree relatives of disease-positive mothers. From the SNHS perspective, moving from the strategy of screening ‘mother and newborn’ to the strategy of including ‘relatives of a disease-positive mother’ would involve a mean increase of EUR 301 per patient and QALY gained. In addition, moving from a strategy of ‘relatives of a disease-positive mother’ to ‘relatives of a disease-negative mother’ would involve a mean increase of EUR: 30,844 per patient and QALY gained. The parameters whose modification had the greatest effect on the results were efficacy of treatment of chronic disease and disease prevalence. We observed that it could prove efficient to extend a programme of this type to relatives of disease- negative mothers if the efficacy of treatment increased or the programme targeted the population at greatest risk. Results were recently published for an economic evaluation of systematic screening for Chagas disease in the Latin American population receiving primary care in Europe [71]. The evaluation consisted of a decision-making approach based on a Markov model in which the impact of systematic screening (all asymptomatic Latin Americans seen at primary care setting, treatment and follow-up of positive cases) was compared with screening and treatment of symptomatic persons. The model was based on a simulation in a cohort of 100,000 Latin American citizens, with a T. cruzi infection rate of 4.2% (95% CI: 2.2–6.8) and a maximum of 5 years of treatment in positive cases. The results of the analysis according to the probabilistic models revealed a total cost of systematic screening of EUR 32,163,649 (95% CI: 31,263,705–33,063,593) compared with EUR 6,904,764 (95%: CI: 6,703,258–7,106,270) for screening of symptomatic persons. The difference in QALY gained was 4,758.62 (95% CI: 4,618.42– 4,898.82) for systematic screening compared with testing only symptomatic patients, with an incremental cost (ICER) of EUR 6,840.75 (95% CI: 6,255.75–7,425.75) for each QALY gained, treatment efficacy of 20% and EUR 4,243 for each QALY gained when efficacy was estimated to be 50%. Therefore, systematic screening in primary care would prove cost-effective, even in scenarios with a very low disease prevalence (0.05%). Another economic evaluation compared a decision-making model for screening the newborn or the mother against the alternative of no screening [72]. All of the models revealed screening to be the dominant (clinically superior and cost saving) situation compared with not screening. The ICER for the screening in the newborn was EUR 22 per QALY gained compared with EUR 125 per QALY gained in the case of not screening. In the case of mothers, the ICER was EUR 96 per QALY gained compared with EUR 1,675 per QALY gained for not screening. Screening strategies were cost-effective, even in settings with a higher prevalence of Chagas disease (0.9%) and lower risk of vertical transmission (2.2%), where the ICER increased by only EUR 37.50 per QALY gained for both strategies. It would be necessary to perform studies on the costs for the health system of a patient with symptomatic Chagas disease, especially when this involved heart disease. CI: confidence interval; ECG: electrocardiogram; ICER: incremental cost-effectiveness ratio; LVEF: left ventricular ejection fraction; QALY: quality-adjusted life year. respective 95% CI using the Freeman-Tukey double arc- blood donors and pregnant women). The analyses were sine transformation [18]. All tests were two-tailed. We performed using the Metaprop command of Stata 12.0 used the random effects model of DerSimonian and (Stata Statistical Software: Release 12. College Station: Laird to evaluate heterogeneity between studies based StataCorp LP). on an indicator of variation between studies attributed to heterogeneity rather than to chance (I2) [15]. We con- The quality of evidence was classified as high, moder- structed forest plots showing the point prevalence and ate, low or very low in accordance with the methodo- the 95% CI of the individual studies, as well as pooled logical guidelines of the Grading of Recommendations, estimates with the 95% CI, both for the total population Assessment, Development and Evaluation (GRADE) and for subgroups of interest (e.g. participants’ origin, working group [19]. The process for evaluating the www.eurosurveillance.org 7 Box 2 Recommendations on the screening of migrants for Trypanosoma cruzi Should immigrants and refugees be screened for T. cruzi infection? 1. Screening for Chagas disease is recommended in pregnant women (from endemic areas or daughters of women from these areas). Strong recommendation. 2. Screening for Chagas disease is recommended in women of reproductive age from endemic areas who wish to become pregnant and daughters of women from these areas. Strong recommendation. 3. Screening for Chagas disease is recommended in blood and organ donors (from endemic areas or children of mothers from these areas). Strong recommendation. 4. Screening for Chagas disease is suggested in immunosuppressed patients or those at risk of immunosuppression (persons from endemic areas or children of mothers from these areas), ideally before immunosuppression or at diagnosis of HIV infection. Conditional recommendation. 5. It has been suggested that asymptomatic adults from endemic areas should receive help in making a joint decision on the possibility of screening for Chagas disease. They should be informed about the characteristics and consequences of the disease, the advantages and disadvantages of treatment and the limited benefit of treatment in the case of a latent infection. Conditional recommendation. HIV: human immunodeficiency virus. quality of the evidence was included in the summary out in Spain (n=23) and the rest of Europe (n=10). of findings Tables [20], which also included the main Almost half of the studies focussed on the general effect estimates for the outcomes of interest. migrant population (n=16), while the remainder evalu- ated vertical transmission (n=13) or included blood Evidence to decision framework donors (n=6). Follow-up varied from a mean of 32 In order to formulate the recommendations in an months in prospective studies (range: 12–72 months) explicit and reasoned manner, we used an evidence to 87 months in retrospective studies (range: 13–148 to decision (EtD) framework to inform the Panel of the months). The screening tests varied depending on the most relevant aspects necessary for taking decisions study, although they generally involved a combination and thus making them easy to justify [21]. of an ELISA-based approach and indirect immunofluo- rescence; the studies also used other, confirmatory In addition to the information from the literature review tests. The criterion for a positive screening result on the outcomes defined in the clinical question, we was generally consistent with the recommendations assessed economic evaluations and studies on percep- of the WHO, according to which a case of chronic T. tions and experiences of the population of interest in cruzi infection is defined by two positive results in dif- order to gather relevant information to inform recom- ferent serology tests [12]. mendations on use of resources, values and prefer- ences and acceptability of screening. Impact of screening for Trypanosoma cruzi Table 1 summarises the findings of the literature review Results for the outcomes of interest. We summarise the main findings from the scientific lit- erature review and the discussion of the Panel for for- Patients with Trypanosoma cruzi infection mulating the recommendations. A complete report can We collected data from 28 observational studies cover- be consulted online (Supplement 2). ing 1,441 cases in a population of 19,735 immigrants from endemic areas. The total pooled prevalence The search yielded 470 references. Based on the eligi- of T. cruzi infection was 6.08% (95% CI: 3.24–9.69%; bility criteria, we identified 65 references for which the I2 = 98.82%). Of the total number of cases where it was complete text was reviewed. Of these, we selected 33 possible to identify the country of origin (n = 986; from studies that fulfilled the inclusion criteria [5-7,9,22-50]. 17 countries), 90% (n = 884) were from Bolivia, fol- A PRISMA flow diagram (Figure 1) details the eligibility lowed by Argentina (n = 32; 3.3%), Paraguay (n = 25; process. 2.5%) and Ecuador (n = 12; 1.22%). Prevalence was systematically higher in Bolivian immigrants than in all More than half of the studies were prospective (n=20) other groups. Considerable differences were found in with a cross-sectional design (n=8) and were carried 8 www.eurosurveillance.org population subgroups according to the setting where trials investigating these regimens is to improve toler- screening was performed (Table 1, Figure 2). ability while maintaining treatment efficacy (Multibenz NCT03191162; BENDITA NCT03378661; BETTY Vertical transmission of Trypanosoma NCT03672487). Preliminary results have demonstrated cruzi infection reductions in the frequency of adverse events, with Vertical transmission was recorded in 27 cases from 13 equivalent percentages of undetectable T. cruzi in PCR observational studies covering a total of 502 children at 12 months [57]. born to mothers with chronic T. cruzi infection [6,35- 43,46,49,50]. The pooled transmission rate was three Mortality per 100 live births (95% CI: 1–6). Two studies reported one case each of sudden death from cardiac causes secondary to Chagas disease [6,7]. Organ involvement We recorded 343 cases of mild to moderate cardiovas- Quality of evidence cular disease in 1,946 seropositive patients (nine stud- The Panel rated the overall quality of evidence for the ies), a cumulative prevalence of 19% (95% CI: 13–27%) evaluated outcomes as low. Given the absence of clini- [6,7,9,24,29,45-48]. Furthermore, nine studies yielded cal trials that evaluated the efficacy of screening in the 180 cases with a mild to moderate digestive tract disor- population of interest, the included studies were obser- der from 1,862 patients (pooled prevalence: 5%; 95% vational (generally cross-sectional), with a prospective CI: 2–11%) [7,24,25,28,29,45-48]. or retrospective design and, therefore, a risk of selec- tion bias that could affect confidence in the reported Nine observational studies yielded a cumulative preva- results. The study populations were heterogeneous, lence of severe cardiac events of 1% (95% CI: 0–2%; 39 resulting in marked statistical heterogeneity for the events in 1,946 patients) [6,7,9,24,29,45-48]. The esti- outcomes of interest in most analyses. However, this mated cumulative prevalence of megasyndrome was variability diminished when studies with well-defined lower (0%; 95% CI: 0–1%; 45 events in 1,935 patients) populations (e.g. pregnant women) were evaluated [6,7,9,24,25,28,29,45-48]. together as a subgroup (Figure 2). Indication for treatment Recommendations Data from 11 observational studies showed that in 81% Box 1 shows an adaptation of the EtD framework based of detected cases, treatment was started with a trypan- on which the Panel discussed and formulated the rec- ocidal drug (95% CI 67–93%) [6,29,30,35,37,39,43,45- ommendations. The complete EtD framework can be 48]. These studies revealed treatment-related adverse consulted in Supplement 2. The Panel subsequently effects in 47% of cases (95% CI: 32–63%). formulated the recommendations included in Box 2. The usefulness of trypanocidal treatment in adults with Justification Chagas disease is questionable. A 2009 meta-analysis Recommendations have been formulated in favour showed limited benefit of treatment with benznidazole of screening owing to the high prevalence of T. in chronic disease, with a marginal effect compared with cruzi infection among immigrants from Latin America, placebo [51]. The only randomised clinical trial compar- especially Bolivia. Furthermore, the possibility ing benznidazole with placebo revealed no benefit of of autochthonous transmission, mainly vertical benznidazole in clinical outcomes (heart disease or transmission, is notable in Spain. Given that the death); it reported that T. cruzi remained undetectable response to trypanocidal treatment is greater than in PCR in more patients treated with benznidazole than 90% during the first year of life, early detection in the in those who received placebo, although no associa- children of affected mothers provides huge benefits. tion with clinical outcomes was observed [52]. Since A strong recommendation has been formulated for the study patients had moderate to severe heart dis- women of reproductive age who wish to become preg- ease, we do not know whether benznidazole controls nant, since this situation is considered to be an oppor- disease in patients with mild or no organ involvement. tunity for preventing transmission to future children, Furthermore, recent clinical trials on the use of imida- taking into account the rate of maternofetal transmis- zoles (posaconazole or ravuconazole) alone [53,54] or sion of Chagas disease (3–7%) [2,13]. Transmission is in combination with benznidazole [55] showed these more frequent when PCR in blood is positive than when to be less efficacious than benznidazole based on it is negative. microbiological response markers (PCR for T. cruzi). A systematic review on safety of treatment showed that The Panel also considered that blood or organ dona- benznidazole was poorly tolerated, with a frequency of tion is a situation where identification of people with adverse effects of 44% and discontinuation of treat- infection could be particularly relevant for preventing ment in 11% of patients [56]. transmission and providing appropriate treatment for positive cases. Nevertheless, promising alternative regimens based on different doses and durations of treatment with Immunosuppressed patients are at risk of reactivation benznidazole are being developed. The objective of of disease and progressing to a more severe clinical www.eurosurveillance.org 9 condition; therefore, the potential benefit of treat- recommendations are in place [58,59]. Likewise, most ment is greater in this subgroup of patients. Ideally, countries in the European Union do not have legisla- screening should be performed before immunosup- tion regulating screening for Chagas disease in preg- pression is detected, although it is not always possi- nant women from endemic areas [60]. Furthermore, ble to know this in advance. Therefore, screening can the prevalence of T. cruzi infection is clearly higher in also be performed once immunosuppression has been populations that may also be infected by HIV, hepa- confirmed. However, in the case of patients from non- titis B virus and syphilis and that do in fact undergo endemic countries, it is not recommended to repeat regular screening [61,62]. This disease burden has serology when the result is negative. The following been observed in studies on the seroprevalence of T. patient groups are considered as immunosuppressed: cruzi and on the serological profile of pregnant women, patients taking immunosuppressants (e.g., cytostatic with a prevalence of 1.75–5% [42,63,64]. The results of agents, corticosteroids) at doses > 1 mg/kg for more our review show a pooled vertical transmission rate of than 1 month, biological drugs with potent immunosup- three per 100 live births, which is lower than reported pressive action or other types of immunosuppressive in another systematic review (4.7 per 100 live births) antineoplastic chemotherapy, transplant recipients, [65]. Similarly, screening should be included in health HIV-infected patients and patients with haematological programmes aimed at immigrant children or children of cancer. immigrants from endemic areas [11,42]. In the case of asymptomatic adults, a conditional The Panel used a systematic and explicit methodol- recommendation was formulated on shared decision ogy to formulate the recommendations. While we were making with the patient, given the beneficial effect of unable to identify a clinical trial that could provide data treatment and the low quality of evidence in this patient on the relevance of screening for T. cruzi infection, we group. However, the Panel considered the option of evaluated a large number of studies from which we were screening involving the patient in diagnosis and treat- able to retrieve data on the outcomes of interest based ment for several reasons: (i) poor visibility and knowl- on the experience of other authors. Using data from the edge of the disease, (ii) the major psychological impact literature review, the Panel created an EtD framework of the disease on the potentially affected population that enabled an explicit and reasoned assessment of and (iii) the fact that the benefit of treatment in this the main criteria for formulating recommendations [21]. group of patients would be strictly on an individual When it comes to implementing the recommendations, basis. In non-endemic countries, patients are screened this process makes it possible for users to evaluate all only once since there is no risk unless they return to the aspects and opinions that the Panel took into con- an endemic country for long periods. Therefore, a sideration during the formulation process. pregnant woman with a negative result for T. cruzi in serology testing does not require further screening in The paucity of relevant literature and its limited quality subsequent pregnancies if she remains in Spain. with respect to the decision-making process in some cases (e.g. asymptomatic adults) could limit the pro- Discussion posal for recommendations in these specific situations The Panel of the SEIMC reviewed the literature to or open a debate on their relevance. In any case, the determine the appropriateness of screening for T. process for using the available information and justi- cruzi infection in immigrants and refugees and used fying the different opinions of the Panel validates the explicit criteria to formulate a series of reasoned recommendations, since these explicitly reflect all the recommendations for this purpose. Following this considerations taken into account, even those that rigorous and systematic methodology, we identified were more subjective. five situations where screening for T. cruzi infection is indicated. The recommendations are justified by Another potential limitation of this study is that we the high prevalence of this problem in immigrants did not include studies conducted explicitly in chil- from Latin America and a notable rate of autochtho- dren younger than 14 years. Most of the studies in nous transmission in Spain, mainly owing to vertical non-endemic countries are performed in migrants transmission. and refugees older than 14 years (younger people are rarely included because of difficulties with informed Trypanosoma cruzi infection is the most common consent). Nevertheless, and given that Chagas dis- imported parasitic disease in Spain. Nevertheless, ease can be transmitted vertically, studies including there remains much room for improvement with screening of neonates and of minors born to mothers respect to diagnosis. A Royal Decree from 2005 set out at risk of vertical transmission, were also taken into the minimum conditions and technical requirements consideration. for blood donation (RD 1088/2005). This law covered screening for T. cruzi infection. Similarly, screening for While Latin American immigrants in Spain account the infection has been part of transplant programmes for 24.9% of all foreigners (Bolivians for 1.9%) and for several years. However, it is not yet part of routine the greatest increases in non-EU foreign nationals in practice in protocols for pregnant women in most 2018 were recorded among citizens of endemic coun- Autonomous Communities, despite the fact that tries such as Venezuela and Colombia [66], there are 10 www.eurosurveillance.org 2011;16(37):1-10. https://doi.org/10.2807/ese.16.37.19968-en no protocols for screening for T. cruzi infection in most PMID: 21944556 Spanish Autonomous Communities. Despite agreement 5. Piron M, Vergés M, Muñoz J, Casamitjana N, Sanz S, Maymó in Europe on the need for screening to control RM, et al. Seroprevalence of Trypanosoma cruzi infection in at-risk blood donors in Catalonia (Spain). Transfusion. transmission in blood banks and in the transplantation 2008;48(9):1862-8. https://doi.org/10.1111/j.1537- setting, there is considerable uncertainty with regard 2995.2008.01789.x PMID: 18522707 6. Pérez-Ayala A, Pérez-Molina JA, Norman F, Navarro M, to congenital transmission and the provision of care Monge-Maillo B, Díaz-Menéndez M, et al. Chagas disease in to Latin American immigrants. In fact, this uncertainty Latin American migrants: a Spanish challenge. Clin Microbiol Infect. 2011;17(7):1108-13. https://doi.org/10.1111/j.1469- is so widespread that other similar guidelines (e.g. 0691.2010.03423.x PMID: 21073628 guidelines from the European Centre for Disease 7. Muñoz J, Gómez i Prat J, Gállego M, Gimeno F, Treviño B, López- Prevention and Control on screening and vaccination Chejade P, et al. Clinical profile of Trypanosoma cruzi infection in a non-endemic setting: immigration and Chagas disease for infectious diseases in newly arrived migrants within in Barcelona (Spain). Acta Trop. 2009;111(1):51-5. https://doi. the European Union and European Economic Area) have org/10.1016/j.actatropica.2009.02.005 PMID: 19426663 not addressed this issue [67]. 8. Pérez-Molina JA, López-Polín A, Treviño B, Molina I, Goikoetxea J, Díaz-Menéndez M, et al. 6-year review of +Redivi: a prospective registry of imported infectious diseases in Spain. J The recommendations made by the SEIMC can serve Travel Med. 2017;24(5):24. https://doi.org/10.1093/jtm/tax035 PMID: 28931128 as a guide for the development of protocols and help 9. Roca C, Pinazo M-J, López-Chejade P, Bayó J, Posada E, López- health professionals make decisions on screening for Solana J, et al. Chagas disease among the Latin American adult this disease in clinical practice in other countries. population attending in a primary care center in Barcelona, Spain. PLoS Negl Trop Dis. 2011;5(4):e1135-5. https://doi. org/10.1371/journal.pntd.0001135 PMID: 21572511 Conclusions 10. Grupo de Trabajo Donación de Sangre e Inmigración. [Blood Donation and Immigration Working Group]. Enfermedad de The use of a rigorous methodology enabled us to for- Chagas y donación de sangre. [Chagas disease and blood mulate recommendations in an explicit and reasoned donation]. Madrid: Dirección General de Salud Pública y Sanidad Exterior, Ministerio de Sanidad y Política Social. way by ensuring that during the formulation process, 2009. Spanish. Available from: https://www.mscbs.gob. the Panel had information on the most important crite- es/en/profesionales/saludPublica/medicinaTransfusional/ publicaciones/docs/informeChagasJulio09.pdf ria for decision making. 11. Imaz-Iglesia I, Miguel LG-S, Ayala-Morillas LE, García- Pérez L, González-Enríquez J, Blasco-Hernández T, et al. As for the usefulness of screening immigrants and refu- Economic evaluation of Chagas disease screening in Spain. Acta Trop. 2015;148:77-88. https://doi.org/10.1016/j. gees for T. cruzi, the Panel of the SEIMC identified a actatropica.2015.04.014 PMID: 25917718 series of situations in which screening would be indi- 12. World Health Organization (WHO). Control of Chagas disease: cated. 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