Chagas disease

doi:10.1016/S0140-6736(17)31612-4

The Lancet

Volume 391, Issue 10115, 6–12 January 2018, Pages 82-94

https://doi.org/10.1016/S0140-6736(17)31612-4 Get rights and content

Summary

Chagas disease is an anthropozoonosis from the American continent that has spread from its original boundaries through migration. It is caused by the protozoan Trypanosoma cruzi, which was identified in the first decade of the 20th century. Once acute infection resolves, patients can develop chronic disease, which in up to 30–40% of cases is characterised by cardiomyopathy, arrhythmias, megaviscera, and, more rarely, polyneuropathy and stroke. Even after more than a century, many challenges remain unresolved, since epidemiological control and diagnostic, therapeutic, and prognostic methods must be improved. In particular, the efficacy and tolerability profile of therapeutic agents is far from ideal. Furthermore, the population affected is older and more complex (eg, immunosuppressed patients and patients with cancer). Nevertheless, in recent years, our knowledge of Chagas disease has expanded, and the international networking needed to change the course of this deadly disease during the 21st century has begun.

Introduction

More than 100 years ago, Trypanosoma cruzi was identified as the causative agent of Chagas disease, yet the condition remains a major social and public health problem in Latin America and is regarded as a neglected tropical disease by WHO. According to WHO, and in common with other neglected tropical diseases, “Chagas disease is a proxy for poverty and disadvantage: it affects populations with low visibility and little political voice, causes stigma and discrimination, is relatively neglected by researchers, and has a considerable impact on morbidity and mortality”.¹ In addition, stigma often precludes prompt detection and control of the disease since many patients do not want to know about the condition.² In the seven southernmost American countries, the disease causes the loss of about 752 000 working days because of premature deaths and US$1·2 billion in productivity.³ The estimated annual global burden of disease is $627·46 million in health-care costs and 806 170 disability-adjusted life-years; 10% of this burden affects non-endemic countries.⁴ Migration and specific modes of transmission have led to Chagas disease spreading beyond its natural geographical boundaries and becoming a global issue.5, 6, 7 Furthermore, the typical patient profile has changed owing to increasing age and associated comorbidities.

Section snippets

Life cycle of T cruzi

T cruzi takes two forms in human beings. The trypomastigote, with a flagellum extending along the outer edge of an undulating membrane, does not divide in blood, but carries the infection throughout the body. The amastigote, which has no flagellum, multiplies within various types of cell, preferring those of mesenchymal origin (figure 1).

T cruzi is a heterogeneous species with high genetic and phenotypic diversity. It circulates between insect vectors and mammalian hosts, and has been

Epidemiology

Chagas disease is endemic in 21 continental Latin American countries, from southern USA to the north of Argentina and Chile. It has traditionally been confined to poor, rural areas of Central and South America, where vectorial transmission is the main route of contagion. Residents of infested houses are continuously exposed to vector bites, and the incidence of infection by T cruzi is less than 0·1% to 4% per year in hyperendemic regions such as the Bolivian Chaco.26, 27 Recent internal

Clinical manifestations

The clinical course of Chagas disease usually comprises an acute phase and a chronic phase (table 2). Acute infection can occur at any age, though usually during the first years of life, and is asymptomatic in most cases. Acute phase symptoms include fever, inflammation at the inoculation site (inoculation chancre), unilateral palpebral oedema (Romaña sign; when the conjunctiva is the portal of entry), lymphadenopathy, and hepatosplenomegaly. The acute phase lasts 4–8 weeks, and parasitaemia

Pathogenesis

In the acute phase of the disease, organ damage is secondary to the direct action of the parasite and the acute inflammatory response. Nests of T cruzi amastigotes are found in tissues (mainly cardiac, skeletal, and smooth muscle) and elsewhere (CNS, gonads, and mononuclear phagocyte system).35, 40 In this phase, highly efficient control of the parasite is the result of an intense inflammatory response with active antibody production and activation of the innate immune response (natural killer

Parasitological diagnosis

Diagnosis of acute and congenital disease is made by direct microscopic visualisation of trypomastigotes in blood and, occasionally, other body fluids such as cerebrospinal fluid.¹⁰ In congenital infection, diagnosis can also be based on positive serology results beyond 8 months. Parasites can be observed through a simple fresh blood examination or in Giemsa-stained thin and thick blood smears (sensitivity 34–85%)⁶⁹ (table 2). Concentration methods such as microhaematocrit and the Strout method

Treatment

Treatment with antitrypanosomal drugs is always recommended for acute and congenital Chagas disease, reactivated infections, and chronic disease in children younger than 18 years. Since persistence of parasitosis and concomitant chronic inflammation underlie chronic chagasic cardiomyopathy, parasiticidal treatment is generally offered to patients with chronic Chagas disease in the indeterminate phase and patients with mild-to-moderate disease (table 3).10, 79, 82 However, opinions differ about

Prevention

Prevention of infection requires control of vectorial transmission and screening of blood and organs for donation. Travellers should avoid sleeping in hovels or mud dwellings potentially infested with triatomines, use insect repellent and bednets, and avoid potentially contaminated fruit or cane juices such as those from street vendors. In the laboratory, personnel should use protective equipment suitable for risk group 2 organisms.¹²¹ No vaccine is available for prevention of transmission of T

Pregnant and lactating women

Pregnant women potentially exposed to the parasite should be screened for T cruzi infection. For a woman with a new diagnosis, the appropriate protocol for assessment of visceral involvement and treatment after delivery should be followed. The infection itself does not justify caesarean section. ¹²⁴

Although there is no definite evidence of teratogenicity,¹²⁵ treatment with benznidazole or nifurtimox is not recommended during pregnancy because of the lack of data on fetal safety. Parasiticidal

Immunosuppressed patients

Organ and bone marrow recipients never exposed to T cruzi can be infected through graft tissue, bone marrow, or blood products. Acute infection has a prolonged incubation period (mean ∼112 days) and severe and sometimes atypical clinical manifestations such as long-lasting fever, panniculitis, and meningoencephalitis.22, 133 Diagnosis relies on the detection of circulating trypomastigotes using parasitological or molecular tests (table 2). Treatment with benznidazole should be initiated as soon

Future challenges and opportunities

Prevention of new infections and end organ disease is a major challenge, which can be addressed by making diagnosis and treatment readily available, especially in children, young adults, and women of childbearing age. Thus, the frequency of secondary transmission would decrease, and the effectiveness of current drugs, which are far from ideal, would be maximised. Such measures must be undertaken within a global strategy that includes improving the socioeconomic conditions of the less fortunate

Search strategy and selection criteria

We undertook a search of PubMed and Embase from inception to Aug 1, 2016, with no language restrictions, using the following search terms: “Chagas disease”, “American trypanosomiasis”, or “Trypanosoma cruzi”, and “epidemiology or pathogenesis or symptoms or diagnosis or treatment or outcome”. We selected key references and seminal papers, review articles, patient reports, and book chapters. We also reviewed abstracts from pertinent scientific meetings and publications from international

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Mapping the transporter-substrate interactions of the Trypanosoma cruzi NB1 nucleobase transporter reveals the basis for its high affinity and selectivity for hypoxanthine and guanine and lack of nucleoside uptake
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Trypanosoma cruzi is a protozoan parasite and the etiological agent of Chagas disease, a debilitating and sometimes fatal disease that continues to spread to new areas. Yet, Chagas disease is still only treated with two related nitro compounds that are insufficiently effective and cause severe side effects. Nucleotide metabolism is one of the known vulnerabilities of T. cruzi, as they are auxotrophic for purines, and nucleoside analogues have been shown to have genuine promise against this parasite in vitro and in vivo. Since purine antimetabolites require efficient uptake through transporters, we here report a detailed characterisation of the T. cruzi NB1 nucleobase transporter with the aim of elucidating the interactions between TcrNB1 and its substrates and finding the positions that can be altered in the design of novel antimetabolites without losing transportability. Systematically determining the inhibition constants (K_i) of purine analogues for TcrNB1 yielded their Gibbs free energy of interaction, ΔG⁰. Pairwise comparisons of substrate (hypoxanthine, guanine, adenine) and analogues allowed us to determine that optimal binding affinity by TcrNB1 requires interactions with all four nitrogen residues of the purine ring, with N1 and N9, in protonation state, functioning as presumed hydrogen bond donors and unprotonated N3 and N7 as hydrogen bond acceptors. This is the same interaction pattern as we previously described for the main nucleobase transporters of Trypanosoma brucei spp. and Leishmania major and makes it the first of the ENT-family genes that is functionally as well as genetically conserved between the three main kinetoplast pathogens.
TRPA5 encodes a thermosensitive ankyrin ion channel receptor in a triatomine insect
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As ectotherms, insects need heat-sensitive receptors to monitor environmental temperatures and facilitate thermoregulation. We show that TRPA5, a class of ankyrin transient receptor potential (TRP) channels absent in dipteran genomes, may function as insect heat receptors. In the triatomine bug Rhodnius prolixus (order: Hemiptera), a vector of Chagas disease, the channel RpTRPA5B displays a uniquely high thermosensitivity, with biophysical determinants including a large channel activation enthalpy change (72 kcal/mol), a high temperature coefficient (Q₁₀ = 25), and in vitro temperature-induced currents from 53°C to 68°C (T_0.5 = 58.6°C), similar to noxious TRPV receptors in mammals. Monomeric and tetrameric ion channel structure predictions show reliable parallels with fruit fly dTRPA1, with structural uniqueness in ankyrin repeat domains, the channel selectivity filter, and potential TRP functional modulator regions. Overall, the finding of a member of TRPA5 as a temperature-activated receptor illustrates the diversity of insect molecular heat detectors.
Selenosugars targeting the infective stage of Trypanosoma brucei with high selectivity
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Earlier evidences showed that diglycosyl diselenides are active against the infective stage of African trypanosomes (top hits IC₅₀ 0.5 and 1.5 μM) but poorly selective (selectivity index <10). Here we extended the study to 33 new seleno-glycoconjugates with the aim to improve potency and selectivity. Three selenoglycosides and three glycosyl selenenylsulfides displayed IC₅₀ against bloodstream Trypanosoma brucei in the sub-μM range (IC₅₀ 0.35–0.77 μM) and four of them showed an improved selectivity (selectivity index >38-folds vs. murine and human macrohages). For the glycosyl selenylsulfides, the anti-trypanosomal activity was not significantly influenced by the nature of the moiety attached to the sulfur atom. Except for a quinoline-, and to a minor extent a nitro-derivative, the most selective hits induced a rapid (within 60 min) and marked perturbation of the LMWT-redox homeostasis. The formation of selenenylsulfide glycoconjugates with free thiols has been identified as a potential mechanism involved in this process.
RNA interference of NADPH[sbnd]cytochrome P450 increased deltamethrin susceptibility in a resistant strain of the Chagas disease vector Triatoma infestans
2024, Acta Tropica
The enzyme NADPH-cytochrome P450 reductase (CPR) plays a central role in cytochromes P450 activity. Gene expression analysis of cytochromes P450 and CPR in deltamethrin-resistant and susceptible populations revealed that P450s genes are involved in the development of insecticide resistance in Triatoma infestans. To clarify the role of cytochromes P450 in insecticide resistance, it was proposed to investigate the effect of CPR gene silencing by RNA interference (RNAi) in a pyrethroid resistant population of T. infestans. Silencing of the CPR gene showed a significant increase in susceptibility to deltamethrin in the population analysed. This result support the hypothesis that the metabolic process of detoxification mediated by cytochromes P450 contributes to the decreased deltamethrin susceptibility observed in the resistant strain of T. infestans.
Efficacy of three benznidazole dosing strategies for adults living with chronic Chagas disease (MULTIBENZ): an international, randomised, double-blind, phase 2b trial
2024, The Lancet Infectious Diseases
Treatment with benznidazole for chronic Chagas disease is associated with low cure rates and substantial toxicity. We aimed to compare the parasitological efficacy and safety of 3 different benznidazole regimens in adult patients with chronic Chagas disease.
The MULTIBENZ trial was an international, randomised, double-blind, phase 2b trial performed in Argentina, Brazil, Colombia, and Spain. We included participants aged 18 years and older diagnosed with Chagas disease with two different serological tests and detectable T cruzi DNA by qPCR in blood. Previously treated people, pregnant women, and people with severe cardiac forms were excluded. Participants were randomly assigned 1:1:1, using a balanced block randomisation scheme stratified by country, to receive benznidazole at three different doses: 300 mg/day for 60 days (control group), 150 mg/day for 60 days (low dose group), or 400 mg/day for 15 days (short treatment group). The primary outcome was the proportion of patients with a sustained parasitological negativity by qPCR during a follow-up period of 12 months. The primary safety outcome was the proportion of people who permanently discontinued the treatment. Both primary efficacy analysis and primary safety analysis were done in the intention-to-treat population. The trial is registered with EudraCT, 2016-003789-21, and ClinicalTrials.gov, NCT03191162, and is completed.
From April 20, 2017, to Sept 20, 2020, 245 people were enrolled, and 234 were randomly assigned: 78 to the control group, 77 to the low dose group, and 79 to the short treatment group. Sustained parasitological negativity was observed in 42 (54%) of 78 participants in the control group, 47 (61%) of 77 in the low dose group, and 46 (58%) of 79 in the short treatment group. Odds ratios were 1·41 (95% CI 0·69–2·88; p=0·34) when comparing the low dose and control groups and 1·23 (0·61–2·50; p=0·55) when comparing short treatment and control groups. 177 participants (76%) had an adverse event: 62 (79%) in the control group, 56 (73%) in the low dose group, and 59 (77%) in the short treatment group. However, discontinuations were less frequent in the short treatment group compared with the control group (2 [2%] vs 11 [14%]; OR 0·20, 95% CI 0·04–0·95; p=0·044).
Participants had a similar parasitological responses. However, reducing the usual treatment from 8 weeks to 2 weeks might maintain the same response while facilitating adherence and increasing treatment coverage. These findings should be confirmed in a phase 3 clinical trial.
European Community's 7th Framework Programme.
Cellphone picture-based, genus-level automated identification of Chagas disease vectors: Effects of picture orientation on the performance of five machine-learning algorithms
2024, Ecological Informatics
Chagas disease (CD) is a public-health concern across Latin America. It is caused by Trypanosoma cruzi, a parasite transmitted by blood-sucking triatomine bugs. Automated identification of triatomine bugs is a potential means to strengthen CD vector surveillance. To be broadly useful, however, automated systems must draw on algorithms capable of correctly identifying bugs from images taken with ordinary cellphone cameras at varying angles or positions. Here, we assess the performance of five machine-learning algorithms at identifying the main CD vector genera (Triatoma, Panstrongylus, and Rhodnius) based on bugs photographed at different angles/positions with a 72-dpi cellphone camera. Each bug (N = 730; 13 species) was photographed at nine angles representing three positions: dorsal-flat, dorsal-oblique, and front/back-oblique. We randomly split the 6570-picture database into training (80%) and testing sets (20%), and then trained and tested a convolutional neural network (AlexNet, AN); three boosting-based classifiers (AdaBoost, AB; Gradient Boosting, GB; and Histogram-based Gradient Boosting, HB); and a linear discriminant model (LD). We assessed identification accuracy and specificity with logit-binomial generalized linear mixed models fit in a Bayesian framework. Differences in performance across algorithms were mainly driven by AN's essentially perfect accuracy and specificity, irrespective of picture angle or bug position. HB predicted accuracies ranged from ∼0.987 (Panstrongylus, dorsal-oblique) to >0.999 (Triatoma, dorsal-flat). AB accuracy was poor for Rhodnius (∼0.224–0.282) and Panstrongylus (∼0.664–0.729), but high for Triatoma (∼0.988–0.991). For Panstrongylus, LD and GB had predicted accuracies in the ∼0.970–0.984 range. AB misclassified ∼57% of Rhodnius and Panstrongylus as Triatoma, whereas specificity ranged from ∼0.92 to ∼1.0 for the remaining algorithm-genus combinations. Dorsal-flat pictures appeared to improve algorithm performance slightly, but angle/position effects were overall weak-to-negligible. We conclude that, when high-performance algorithms such as AN are used, the angles or positions at which bugs are photographed seem unlikely to hinder cellphone picture-based automated identification of CD vectors, at least at the genus level. Future research should focus on combining mixed-quality pictures and state-of-the-art algorithms to (i) identify triatomine adults to the species level and (ii) distinguish triatomine nymphs (i.e., immature stages) from adults and from other insects.

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SeminarChagas disease

Summary

Introduction

Section snippets

Life cycle of T cruzi

Epidemiology

Clinical manifestations

Pathogenesis

Parasitological diagnosis

Treatment

Prevention

Pregnant and lactating women

Immunosuppressed patients

Future challenges and opportunities

Search strategy and selection criteria

Lancet

Lancet Infect Dis

Acta Trop

Infect Genet Evol

Adv Parasitol

Trans R Soc Trop Med Hyg

Am J Transplant

Am J Transplant

Trends Parasitol

J Am College Cardiol

Int J Cardiol

Clin Microbiol Infect

Clin Microbiol Infect

Am J Gastroenterol

J Card Fail

J Neurol Sci

Int J Parasitol

Enferm Infecc Microbiol Clin

Acta Trop

First WHO report on neglected tropical diseases: working to overcome the global impact of neglected tropical diseases. WHO/HTM/NTD/2010

Socio-cultural aspects of Chagas disease: a systematic review of qualitative research

PLoS Negl Trop Dis

Prevalence of Chagas disease in Latin-American migrants living in Europe: a systematic review and meta-analysis

PLoS Negl Trop Dis

An estimate of the burden of Chagas disease in the United States

Clin Infect Dis

Control of Chagas disease: second report of the WHO expert Committee. WHO technical report series, 905

Frequency of the congenital transmission of Trypanosoma cruzi: a systematic review and meta-analysis

BJOG

Congenital transmission of Trypanosoma cruzi in central Brazil. A study of 1,211 individuals born to infected mothers

Mem Inst Oswaldo Cruz

Risk factors and primary prevention of congenital Chagas disease in a nonendemic country

Clin Infect Dis

Congenital Trypanosoma cruzi transmission in Santa Cruz, Bolivia

Clin Infect Dis

Sustained domestic vector exposure is associated with increased Chagas cardiomyopathy risk but decreased parasitemia and congenital transmission risk among young women in Bolivia

Clin Infect Dis

Chagas disease and the US blood supply

Curr Opin Infect Dis

Evidence of meaningful levels of Trypanosoma cruzi in platelet concentrates from seropositive blood donors

Transfusion

Chagas' disease in patients with kidney transplants: 7 years of experience 1989–1996

Clin Infect Dis

Use of kidneys from Trypanosoma Cruzi-infected donors in naive transplant recipients without prophylactic therapy

Transplantation

Transmission of Trypanosoma cruzi by heart transplantation

Clin Infect Dis

Large urban outbreak of orally acquired acute Chagas disease at a school in Caracas, Venezuela

J Infect Dis

Laboratory-acquired parasitic infections from accidental exposures

Clin Microbiol Rev

Epidemiology of and impact of insecticide spraying on Chagas disease in communities in the Bolivian Chaco

PLoS Negl Trop Dis

Chagas disease transmission in periurban communities of Arequipa, Peru

Clin Infect Dis

Chagas disease in Latin America: an epidemiological update based on 2010 estimates

Wkly Epidemiol Rec

Trypanosoma cruzi and Chagas' disease in the United States

Clin Microbiol Rev

Brief Report: Autochthonous Transmission of Trypanosoma cruzi in Southern California

Open Forum Infect Dis

Current epidemiological trends for Chagas disease in Latin America and future challenges in epidemiology, surveillance and health policy

Mem Inst Oswaldo Cruz

Estimación cuantitativa de la enfermedad de Chagas en las Américas. OP5/HDM/CD/425-0G

Interruption of vector transmission by native vectors and the art of the possible

Seminar
Chagas disease