Chagas Disease

Seminar
Chagas disease
Andréa Silvestre de Sousa, Debbie Vermeij, Alberto Novaes Ramos Jr, Alejandro O Luquetti
Chagas disease persists as a global public health problem due to the high morbidity and mortality burden. Despite the Published Online
possibility of a cure and advances in transmission control, epidemiological transformations, such as urbanisation and December 7, 2023
https://doi.org/10.1016/
globalisation, and the emerging importance of oral and vertical transmission mean that Chagas disease should be
S0140-6736(23)01787-7
considered an emerging disease, with new cases occurring worldwide. Important barriers to diagnosis, treatment,
Evandro Chagas National
and care remain, resulting in repressed numbers of reported cases, which in turn leads to inadequate public policies. Institute of Infectious Diseases,
The validation of new diagnostic tools and treatment options is needed, as existing tools pose serious limitations to Oswaldo Cruz Foundation, Rio
access to health care. Integrated models of surveillance, with community and intersectional participation, embedded de Janeiro, Brazil
(A S de Sousa MD PhD,
in the concept of One Health, are essential for control. In addition, mitigation strategies for the main social
D Vermeij MsC); Department of
determinants of health, including difficulties imposed by migration, are important to improve access to comprehensive Internal Medicine, School of
health care in a globalised scenario. Medicine, Federal University of
Rio de Janeiro, Rio de Janeiro,
Introduction Chagas disease and the significant associated economic Brazil (A S de Sousa);
Department of Community
Chagas disease, a neglected tropical disease also known burden,10 less than 10% of people with Chagas disease Health, School of Medicine,
as American trypanosomiasis, is a potentially life- have been diagnosed, and approximately 1% have Federal University of Ceará,
threatening illness caused by the protozoan parasite received antiparasitic treatment.11 Timely detection and Fortaleza, Ceará, Brazil
(A N Ramos Jr MD PhD); Center
Trypanosoma cruzi.1 It was discovered in 1909 by Brazilian treatment of Chagas disease has important benefits, of Studies for Chagas Disease,
scientist Carlos Ribeiro Justiniano Chagas in Minas including prevention of future vertical transmission in Hospital das Clínicas, Federal
Gerais, Brazil.2 In 2019, the World Health Assembly women of childbearing age who have been treated, University of Goiás, Goiânia,
recognised April 14 as World Chagas Disease Day, serological cure in infants and children, and potential Brazil (A O Luquetti MD PhD)
bringing visibility to the disease and strengthening reduction of progression to advanced forms of the Correspondence to:
Dr Andréa Silvestre de Sousa,
advocacy strategies.3 disease in adults.12–18
Evandro Chagas National
Chagas disease has been described by WHO and Institute of Infectious Diseases,
others as a “silent and silenced disease”,1,4 as the majority Parasite lifecycle Oswaldo Cruz Foundation,
of people with the disease will not present with Replicant and infective stages of T cruzi can be identified Rio de Janeiro 21040-360, Brazil
andrea.silvestre@fiocruz.br
symptoms, and there is a staggering shortage of relevant in the insect vector and mammalian hosts. Trypo
information, resulting in little attention from govern mastigotes circulating in the blood of hosts are
ments, researchers, health and education professionals, transformed in the vector’s intestine into replicating
institutional donors, and the general population. Chagas epimastigotes, which change into metacyclic trypo
disease is a chronic infectious condition that intrinsically mastigotes in the distal portion of their intestine, and
promotes and perpetuates poverty, and mainly are released in the insect’s faeces. These trypomastigotes
affects people with greater social vulnerability, causing penetrate the damaged skin or mucous membranes of
substantial physical, psychological, and socioeconomic the host, where they enter host cells and change into
challenges.3,5 Combatting the disease requires an replicating amastigotes, and are released into circulation
intersectoral approach, with the inclusion of civil society again in the form of trypomastigotes.19
and social movements, reflecting the voices of those The T cruzi parasite is classified into at least seven
affected by Chagas disease. Over the last decade, non- discrete typing units (DTUs), TcI–TcVI and Tcbat
governmental organisations focusing on Chagas disease (appendix).20,21 Some DTUs have been associated with See Online for appendix
have formed an international federation representing geographical distribution in epidemiological scenarios
endemic and non-endemic countries.3
Chagas disease has an acute phase, which generally
lasts 4–8 weeks and is often mild or asymptomatic, and a Search strategy and selection criteria
chronic phase. An estimated 30–40% of people who are Data for this Seminar were identified through searches of
infected but untreated will develop severe and sometimes PubMed and Embase between Oct 1, 2022, and Dec 23, 2022,
life-threatening medical conditions, including cardiac, with no language restrictions, using the following search
digestive, and neurological or associated alterations, terms: “Chagas disease”, “American trypanosomiasis”, or
which might require specific treatment. If untreated, “Trypanosoma cruzi”. We selected key references and seminal
infection is lifelong.6 If treated, the chance of progression papers, reviews, case reports, and relevant book chapters. We
might be reduced, but the effectiveness is variable and also reviewed abstracts from pertinent scientific meetings
not well defined. Symptomatic Chagas disease imposes and publications from international organisations such as
a substantial financial burden on health-care systems the Pan American Health Organization, WHO, and the Special
and societies,7 with an estimated US$690 million in Programme for Research and Training in Tropical Diseases
health-care costs and $8 billion in annual economic from WHO from Jan 1, 2010, to Dec 1, 2022.
losses.8,9 Despite the high morbidity and mortality of
www.thelancet.com Published online December 7, 2023 https://doi.org/10.1016/S0140-6736(23)01787-7 1

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and clinical manifestations, but these aspects remain Congenital Chagas disease has progressively gained
poorly understood. Evidence is emerging that the diverse epidemiological relevance, and remains a crucial challenge
genetic makeup of the parasite is responsible for distinct for both endemic and non-endemic countries; however,
outcomes in diagnosis and treatment of Chagas disease, due to the neglected nature of the disease and the barriers
but this should be researched further. that persist in access to diagnosis, treatment, and care,
prevalence in pregnant women and newborns might be
Epidemiology underestimated.24,35,36 According to the last available weekly
Chagas disease is mainly found in Latin America, where epidemiological report on Chagas disease, an estimated
the large majority of the estimated 6–8 million people 1·12 million women of childbearing age are infected with
infected with the T cruzi parasite reside. In addition, the T cruzi parasite,25 and the vertical transmission
approximately 75 million people are at risk of contracting prevalence approaches 5%, with higher rates in high-risk
the disease.22 An estimated 30 000 new cases and more endemic areas.35,37 The incidence of congenital Chagas
than 10 000 Chagas disease-related deaths are reported disease is an estimated 8000 to 15 000 cases per year in
annually.22–24 According to the last weekly epidemiological Latin America.38 In the wake of progress in vector
report published by WHO in 2015, using data from 2010, transmission control, vertical transmission has become
Argentina, Brazil, Mexico, Bolivia, and Colombia have the proportionately more relevant, accounting for about a
highest estimated number of cases, and Bolivia, third of new infections in 2010, and could perpetuate the
Argentina, and Paraguay have the highest estimated disease indefinitely, even in countries without vector
prevalence.25 Due to migratory movements associated transmission.39 The panel describes the mechanisms of
with political, health, environmental, and economic crises T cruzi transmission and suggests methods for prevention
in the endemic countries of origin, Chagas disease has and control.
now been recorded in several non-endemic countries in
Europe, as well as in the USA, Australia, and Japan, Clinical presentation
among other countries.26–28 Chagas disease infection evolves in two subsequent
In the early and mid 20th century, Chagas disease was phases. In general, the acute phase lasts 4–8 weeks and,
mainly restricted to vulnerable, rural areas in when symptomatic, tends to be perceived as an acute
Latin America, where vectorial transmission prevailed. illness, with persistent fever (>7 days), hepatosplenomegaly,
Nowadays, the epidemiological pattern of the disease lymphadenopathy, subcutaneous oedema (in limbs or
has shifted due to human dynamics, meaning it is face), and morbilliform rash.65,66 Romaña’s sign, a unilateral
present in urban settings and has an international scope. bipalpebral inflammatory oedema, conjunctival hyper
Chagas disease has become a global health problem, and aemia, and preauricular adenopathy indicate the reaction
has been inserted into strategic international agendas, of the host to penetration of T cruzi into the ocular mucosa.
such as the WHO 2030 Roadmap and the Sustainable Despite the low frequency, it is considered a pathognomonic
Development Goals.29 sign of Chagas disease.67 Other inflammatory reactions
In the 1990s, the Pan American Health Organization associated with the vector bite are inoculation chagomas.
(PAHO), in partnership with endemic countries, developed They indicate the entry of T cruzi and are not present in
multinational initiatives to strengthen the control and other forms of transmission, such as oral Chagas disease
surveillance of Chagas disease.30 According to PAHO, transmission. The acute phase usually has a self-limited
17 countries have achieved the interruption of intra evolution, and when properly diagnosed and treated, has a
domiciliary vectorial transmission by Triatoma infestans or high chance of cure, especially in children and newborns.6
Rhodnius prolixus.22 This interruption, combined with The acute disease related to oral transmission tends to
rural–urban migration, has substantially reduced the be more intense due to the high parasite inoculum, and
instances of vectorial transmission; however, eradication some outbreaks present with high lethality.68
of vectorial T cruzi transmission in the Americas is Haemorrhagic manifestations might be frequent,
impossible.30 Entomological surveillance actions should, making the differential diagnosis more complex in
therefore, be continuous, especially given emerging the Amazonian region, where other icterohaemorrhagic
challenges in Chagas disease epidemiology, such as syndromes like malaria are common. The distinct clinical
climate change combined with deforestation and the presentations with massive pericardial effusions and
human exposure to sylvatic scenarios; the adaptation of digestive bleeding are different from the acute phase
secondary and non-domiciliated vectors to the human associated with classic vector transmission.69,70
habitat; the increasing occurrence of alternative trans Other severe conditions associated with elevated
mission routes by vectors; and the rise of insecticide parasitaemia are the reactivation syndromes of Chagas
resistance. The complexity of these eco-epidemiological disease, which are also associated with immuno
factors can only be efficiently addressed from the concept suppression conditions.71 In the 1980s and 1990s, before
of One Health, an approach that includes collaborative the effective institution of highly active antiretroviral
efforts to attain optimal health for people, animals, and the therapy, individuals living with HIV and a CD4 count
environment.31–34 of less than 200 cells per µL could develop
2 www.thelancet.com Published online December 7, 2023 https://doi.org/10.1016/S0140-6736(23)01787-7

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Panel: Mechanisms of Trypanosoma cruzi transmission to humans23

Vectorial Outbreaks have been reported, often within families or during
This is the classic mechanism by which infested triatomine large celebrations, when food and beverages contaminated
(referred to as kissing bugs) defecate on the skin during or after with infected triatomines or their faeces (or both) are
a bloodmeal, typically at night. The parasite present in the consumed. This might include raw or undercooked meat from
triatomine’s faeces or urine might enter through abrasions on infected wild reservoirs, food contaminated with anal gland
the skin, or through the mucous membrane.40 secretions of marsupials, and the ingestion of the triatomine
Vectorial control is based on environmental interventions itself.55 Prevention comprises safe food handling practices.56
and the fumigation of infested homes, and has proved to be Vertical
most effective if it is part of a national-level effort by The transmission occurs through an infected mother to her
ministries of health.41,42 newborn during pregnancy or childbirth. This mechanism is
Transfusion increasing in relevance, due to the relative success of other
This transmission occurs when a person is infected through the control efforts. Transmission rates are estimated to be
receipt of blood or blood products contaminated with T cruzi. approximately 5%, with differences in relation to the parasite
This mechanism was very common between the 1950s (when diversity (eg, more frequent in TcV and TcVI lineages).35,57
it was recognised) and the 1990s, but nowadays, the Elevated parasitaemia during the acute phase or
haemovigilance for Chagas disease is systematic in different immunosuppression conditions and genetic factors are
endemic and non-endemic countries.43,44 For instance, the USA, recognised as contributing factors to vertical transmission.58
the UK, Spain, France, Switzerland, and Portugal screen the Control efforts should focus on diagnosing and treating all girls
blood products of people that present with epidemiological risk and women of childbearing age,39,59 as well as newborns who
factors for Chagas disease.36,45–47 contract the disease from their mothers,24,60 as the success rate
Organ transplantation of antiparasitic treatment for children younger than 1 year is
This transmission occurs when a person is infected through the near 100%.61
receipt of a T cruzi-infected organ. When presented with In some non-endemic countries such as the USA, there are no
epidemiological risk factors, both donor and receptor should be programmes aimed towards pregnant women at risk, and in
screened: the donor to avoid organ transmission and the others, there are programmes for specific geographical regions
receptor because parasite reactivation might occur due to (such as Spain, Italy, and Switzerland).62,63 Some of these
immunosuppression.48 programmes have already achieved positive results.36
Although Latin American countries have the most experience in As most newborns and children remain asymptomatic,
Chagas disease transplantation,48,49 programmes have been underdiagnosis is common. Little access to specific diagnostic
implemented in endemic49,50 and non-endemic countries,47,51–53 tools, in addition to the poor knowledge on the part of the
with well established guidelines on mandatory universal population and health professionals, contribute to this under-
serological screening for all donors and receptors at risk; reporting.60
conducting antiparasitic treatment for at least 30 days in all
infected donors and recipients with proven parasitaemia; active Accidental contamination
searching for increased post-transplant parasitaemia by PCR, This transmission has been reported in more than 100 cases,64
in addition to T cruzi research in biopsy tissues of transplanted and occurs when personal protective equipment is not properly
organs and dermatological or neurological lesions in cases where used, mainly in laboratories that work with cultures of the
reactivation is suspected; contraindication of heart and intestine parasite or animal inoculation.
donation for all infected donors (75% or higher risk of Health personnel involved in detecting bugs and fumigating
transmission) and any organ in the acute phase of the disease; houses should also wear proper personal protective equipment,
and urgent antiparasitic treatment given the diagnosis of as should surgeons and personnel that perform necropsies.
reactivation.54
Oral
This transmission occurs when a person ingests T cruzi-
contaminated food or beverages. This is a principal
transmission mechanism in the Amazonian region.
meningoencephalitis and cerebral granuloma manifestations of reactivation associated with post-

(ie, chagoma), which were difficult to differentiate from transplant immunosuppression.73 Acute panniculitis in
the opportunistic neurotoxoplasmosis.71,72 Fulminant the arms, legs, and abdomen are dermatological
myocarditis and graft loss are also pronounced manifestations associated with reactivation in transplant

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cases. The isolated role of immune system senescence in occur concurrently, increasing the chance of disability.19
the eventual risk of Chagas disease reactivation is still not Increased life expectancy in endemic countries,
well established.74,75 The ageing of the population with the coupled with new lifestyles resulting from urbanisation,
disease, greater access to health services, are responsible for high rates of cardiovascular risk
immunosuppressive therapies (especially in non-ende factors, such as metabolic syndrome, and other
mic countries), and additional diagnoses of malignant associated heart diseases, such as cardiomyopathy in
neoplasms and autoimmune diseases (eg, rheumatological older patients.86 A distinction between the differential
diseases), might mean that reactivation episodes could diagnosis of Chagas heart disease and cardiomyopathy
become more frequent in this population in the future.76,77 in older patients might not always be possible, for
As in the acute phase, however, the response to instance, in cases of atrial fibrillation or even
antiparasitic treatment in these severe cases of reactivation bradyarrhythmia due to degenerative process, resulting
is appropriate (ie, more likely to lead to survival) when in the need for a pacemaker. In addition, the increase in
diagnosis is timely. life expectancy has contributed to an increase in the
Congenital Chagas disease is considered a T cruzi prevalence of chronic forms of Chagas disease,
infection in the acute phase. The associated clinical particularly in patients with access to diagnosis and
syndrome might vary widely, from absence of signs or treatment. As a result, people with the chronic cardiac
symptoms to evidence of non-specific manifestations form of the disease have a greater chance of survival,
such as fever, anaemia, hepatosplenomegaly, myocarditis, with greater recognition of the overlapping digestive
meningoencephalitis, or respiratory distress. There forms of the disease.87,88
might be progression to low birth weight, prematurity, Chagas heart disease can manifest through three major
miscarriage, or neonatal death.78 Cases with more severe syndromes; namely, sudden cardiac death, usually
evolution are particularly observed in contexts of associated with tachyarrhythmias, such as ventricular
transmission in the first weeks of pregnancy or in the arrhythmias, and often wrongly identified as a heart
presence of high parasitaemia. It is estimated that 28% of attack;89 heart failure, associated with varying degrees of
infants who are infected with T cruzi show clinical ventricular systolic dysfunction and increased filling
symptoms, and 2·2% progress to death.60 pressures; and thromboembolism, from related
Between 60% and 70% of people who are infected with intracavitary thrombi.90,91
T cruzi will never develop signs or symptoms of chronic Although the prognosis of Chagas heart disease is
Chagas disease, maintaining normal electro- typically poorer than that of other heart diseases, there is a
cardiograms (ECGs) and gastrointestinal tract x-rays in heterogeneity of scenarios in this cardiomyopathy. In the
longitudinal follow-up appointments.70,79 This absence of initial stages, patients with Chagas heart disease have no
signs or symptoms and maintenance of normal ECGs symptoms nor ventricular systolic dysfunction, and the
and x-rays represents the so-called chronic indeterminate disease can only be detected through active research of
form of Chagas disease, identified only by reactive typical electrocardiographic alterations (stage A). The
serology (IgG), characterised by a prognosis that is prognosis in this early stage is much more favourable than
similar to non-infected populations. Although substantial the symptomatic clinical forms with treatable heart failure
abnormalities might be found by more sophisticated (stage C), and even more than refractory syndrome
cardiovascular tests, the prognosis remains benign.79 In (stage D), where heart transplantation would be the only
this population, an annual clinical follow-up with an therapeutic option. People in intermediate stages of Chagas
ECG is essential, as the estimated annual progression heart disease do not manifest symptoms of heart failure,
rate from indeterminate chronic Chagas disease to but rather present progressive degrees of ventricular
Chagas heart disease is 1·9% (95% CI 1·3–3·0).80 Some systolic dysfunction, with or without segmental contractile
non-specific electrocardiographic alterations are not changes (stage B).92 Although alternative classifications
considered clinical progression (table 1).79,85 Antiparasitic have been used, they all seek the same objective of
treatment is encouraged for this clinical form, and its differentiating the prognosis in Chagas heart disease.84
success is related to sooner treatment, a low risk of Sudden cardiac death could be the first manifestation
reinfection, and factors associated with genetics and the of Chagas disease, occurring even in the latent and silent
type of parasite (eg, T cruzi DTU). phase of the disease when those who are infected with
The remaining 30–40% of people with Chagas disease T cruzi are unaware of their status, and is identified as
will evolve to chronic symptomatic forms within the leading cause of death in Chagas heart disease.
10–30 years, such as Chagas heart disease, the most Predicting the risk of this event is one of the great
prevalent symptomatic form, and digestive forms, challenges in managing Chagas disease. Implantable
characterised by megaoesophagus or megacolon (or cardioverter defibrillators are indicated for the prevention
both). Digestive forms occur mainly in countries south of of malignant arrhythmic events in patients at high risk of
the equator, which could be related to the genetic diversity sudden cardiac death.90,93
of the parasite, but the scientific data on this are scarce. Although the digestive forms of Chagas disease present
Cardiac-associated and digestive-associated forms might a better prognosis in relation to heart disease, they are

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responsible for substantial reductions in the quality of life. bronchoaspiration.94 Oesophageal cancer might overlap
Oesophagopathy is manifested by progressive dysphagia, with more severe cases.95 Megacolon might result in
odynophagia, oesophageal reflux, and megaoesophagus persistent constipation (>5–7 days), with recurrent
associated with achalasia, malnutrition, and risk of faecalomas that, in addition to abdominal discomfort and
Clinical and epidemiological Diagnostic strategy Surveillance and control or prevention

situations strategies
Acute phase (with a fever >7 days)
Contact with a triatomine or its faeces (bite or Classical vectorial transmission Fresh smear (direct parasitological test); if negative, Entomological and reservoir research; and
presence of the vector in the home); or Romaña concentrations tests (microhaematocrit or Strout) of environmental surveillance actions
sign or inoculation chagoma high sensitivity; PCR upon resource availability;
IgG seroconversion (increase of ≥2 titres in blood
collections separated by 20–40 days); IgM serology
(if available); and rule out false-positive reactions,
such as rheumatoid factor
Ingestion of suspicious food or undercooked Oral transmission Fresh smear (direct parasitological test); Epidemiological investigation (of symptoms in
game meat; or symptoms of people from the concentration tests; IgG seroconversion; or PCR relatives or contacts, or both); investigate and
same family or community, with food as a might be useful if available report outbreak; and safe food handling practices
common source of infection
Newborn of a mother infected with Vertical transmission Fresh smear (direct parasitological test) from Laboratory tests for mother and other children
Trypanosoma cruzi or with clinical or newborn blood or concentration method (eg, micro- with IgG serologies; and prevention through
epidemiological suspicion haematocrit) at birth; PCR might be useful if screening, diagnosis, and treatment of all women
available before 9 months of age; or of childbearing age in endemic regions
two serologies (IgG) after 9 months
Receptor of blood or blood products within Blood transmission Fresh smear (direct parasitological test); Sanitary inspection in hospitals and blood
120 days before symptoms concentrations tests; PCR upon resource availability; centres; haemovigilance: a single test of high
or IgG seroconversion sensitivity (ie, ELISA or CMIA) must be used for
blood exclusion
Receptor of organs or tissues (any time) Organ transplantation If recipient previously infected, follow up for All organ donors and recipients at risk should be
reactivation with parasitological tests such as screened for anti-T cruzi antibodies; sanitary
quantitative PCR with high sensitivity inspection in hospitals and blood centres; and for
living donors with Chagas disease, treat before
transplantation, and for deceased donors
infected with T cruzi, heart and intestine
donations are contraindicated
Contact with T cruzi culture; or health-care Accidental transmission Take blood immediately for serology after start of Start specific treatment before any laboratory
professional in contact with blood of people with treatment to evaluate possibility of previous result if transmission is highly probable; use of
Chagas disease or professionals involved in infection; after 5 days, direct parasitological tests; personal protective equipment; and worker
detection of bugs PCR upon resource availability; and second serology health surveillance
after 20–40 days to evaluate IgG seroconversion
Immunosuppression conditions in chronic Chagas disease reactivation Serial parasitological tests; serial quantitative PCR Avoid excessive immunosuppression, if possible;
Chagas disease cases (co-infection of T cruzi and (blood); or PCR in biopsies specimens benznidazole prophylaxis in T cruzi–HIV
HIV, cancer treatment, autoimmune disease, or co-infection with CD4 count of <200 cells per µL;
post-transplantation) or Chagas disease reactivation as a condition for
AIDS-defining event to Brazilian epidemiological
surveillance81
Chronic phase
Clinical or epidemiological suspicion; and index Chronic Chagas disease First line: two conventional IgG serologies (ELISA, Search for new cases in family members and
case family and household contacts IHA, or IIF); non-conventional IgG serologies might household contacts; and annual ECG search for
accelerate and amplify the access to diagnosis typical ECG pattern* that defines progression to
(recombinant ELISA or CMIA); or rapid diagnostic Chagas heart disease
tests (immunochromatography) of proven quality
might be used for screening purposes to facilitate the
diagnose and treat principle in PHC
Prenatal care Pregnant with possibility of Rapid diagnostic tests of proven quality can be used Follow up the newborn and evaluate other
chronic Chagas disease, to avoid for screening purposes;82 confirm that the mother children from the same mother; and treat the
vertical transmission has Chagas disease, ideally through two conventional mother only after the pregnancy
IgG serologies (ELISA, IHA, or IIF); and recombinant
ELISA or CMIA can be used as a second test
Evaluating an excluded blood donor To confirm chronic Chagas Conventional serology should be used; avoid Counsel people with confirmed cases not to
disease after a first positive recombinant ELISA and CMIA that are commonly perform new blood donations; and evaluate
screening used in blood banks treatment and clinical form of confirmed cases
Seroepidemiological surveys Epidemiological studies High-sensitivity rapid diagnostic tests of proven Update information systems and guide
quality59,83 surveillance actions
(Table 1 continues on next page)

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Clinical and epidemiological Diagnostic strategy Surveillance and control or prevention

situations strategies
(Continued from previous page)
Antiparasitic treatment follow-up Evaluate cure (ideally compare a To evaluate a cure, serial serology before and after For treatment failure: evaluate longer periods of
well preserved serum, collected treatment (ideally comparison evaluate at same day treatment or change to another drug
before the treatment, with a and reaction, by the same technician); for newborns, (eg, nifurtimox if benznidazole failure is
serum collected post- antibody concentrations absent at 1 year; for others, suspected)
treatment); or evaluate sustained decay >2 titres IHA or IIF; diminution
treatment failure of 1 at the index of reactivity ELISA; time to
evaluation serial serology is 6 months if acute or
newborn, 1 year if children or recent chronic phase,
2–5 years if adult or no recent infection; and to
evaluate a treatment failure, PCR (or other
parasitological test) positive post-treatment
Confirmed Chagas heart disease (serological Assess the degree of cardiac Active search for signs or symptoms of heart failure, If systolic ventricular dysfunction or heart failure
diagnosis and abnormal ECG) impairment palpitation, low cardiac output (syncope), and (or both), prescribe ACEIs or angiotensin receptor
neurological complications (cardioembolic events); blockers, β-blockers, and diuretics; if
perform echocardiogram for presence of systolic bradyarrhythmia with symptoms, recommend
dysfunction, aneurysms, or thrombi; perform 24 h pacemaker; if tachyarrhythmias or syncope,
Holter monitoring to evaluate bradyarrythmia and prescribe amiodarone and ICD; if
tachyarrhythmia thromboembolic events or thrombus, prescribe
anticoagulation
Confirmed chronic Chagas disease and digestive Assess the degree of For oesophagopathy, if dysphagia and oesophageal For oesophagopathy, assess nutritional status
symptoms oesophagopathy and megacolon reflux, take contrast-enhanced oesophagus x-ray, and risk of bronchoaspiration, avoid dry food,
upper digestive endoscopy, and (eventually) chew food well, and ingest liquids and semi-
manometry; or for megacolon, if constipation >5–7 solids; prescribe nitrate or nifedipine if
days, perform barium enema or colonoscopy and hypertonia of the cardia; if symptoms persist,
(eventually) manometry evaluate dilation with pneumatic balloon,
sphincteric botulinum toxin A injection, or
myectomy; for megacolon, recommend an anti-
constipation diet and good hydration (if no
contraindication); prescribe osmotic laxatives or
mineral oil, evaluate use of enema with
glycerinate solution, and evaluate necessity of
faecaloma removal; or surgical treatment
(colectomy) for refractory cases and intestinal
obstruction
Diagnosis of acute-phase Chagas disease should be followed by notification of all suspected cases, according to national surveillance guidelines, and immediate treatment of all confirmed cases (benznidazole or
nifurtimox). Diagnosis of chronic-phase Chagas disease should be followed by notification of all confirmed cases, according to national surveillance guidelines; antiparasitic treatment according to indications
(benznidazole or nifurtimox), excluding pregnancy, liver or renal failure, and advanced chronic forms of Chagas disease; and history, physical examination, and ECG to define clinical form and prognosis. Non-
specific ECG changes that alone do not define Chagas heart disease: sinus bradycardia 40 beats per minute or more, isolated ventricular premature beat, incomplete right bundle branch block, non-specific ST-T
changes, first degree atrioventricular block, first degree left bundle branch block, electrical axis deviation to the left, sinus arrhythmia, sinus tachycardia, left anterior superior divisional block, low QRS voltage,
and migratory pacemaker rhythm. Access to symptomatic comprehensive care (eg, physical, nutritional, and psychological support or rehabilitation) should be ensured. ACEIs=angiotensin-converting enzyme
inhibitors. CMIA=chemiluminescent microparticle immunoassay. ELISA=enzyme-linked immunosorbent assay. ICD=implantable cardioverter defibrillator. IHA=indirect haemagglutination assay. IIF=indirect
immunofluorescence. PHC=primary health care. *The typical ECG pattern84 defining progression to Chagas heart disease is sinus bradycardia of less than 40 beats per minute, polymorphic ventricular premature
beat, complete right bundle branch block, primary alterations ST-T segment, second-degree and third-degree atrioventricular block, complete left bundle branch block, electrically inactive zone, sinus node
dysfunction, non-sustained ventricular tachycardia, and atrial fibrillation.
Table 1: Diagnostic strategies for Chagas disease by history and physical examination
functional limitation, might progress to intestinal loop and more affordable test than other techniques such as
torsion (sigmoid volvulus), with intestinal obstruction and PCR is the fresh smear, where very rapid movements of
mesenteric infarction, requiring urgent surgery. The main the parasite (thereby displacing red blood cells) might be
clinical manifestations of chronic Chagas disease and their observed, confirming the diagnosis. This technique
economic and social effects are described in figure 1. requires an experienced technician. As parasitaemia
declines over time, the sensitivities of the parasitological
Laboratory diagnosis tests reduce 20–30 days after the first symptoms, and
For diagnostic purposes, it is important to distinguish concentration tests, such as microhaematocrit or Strout
between the two Chagas disease phases, acute and techniques, can be used.44,92,96 Serial exams are
chronic, due to the difference in parasitaemia and the recommended to obtain higher positivity in a non-
techniques necessary for a successful diagnosis. congenital scenario of acute Chagas disease.
Chagas disease antibodies in the acute phase, as for any
Acute phase infectious disease, are primarily of IgM class and might be
In the acute phase, T cruzi parasites are detectable in found after the first 10–15 days of symptoms. Nevertheless,
peripheral blood, which should be investigated. An easier there are no commercially available kits and positive

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Parasite Trypanosoma cruzi
Heart Oesophagus Colon
Affected organs Myocardial contractile Autonomic nervous Heart conduction

and tissues cells system system
Systolic dysfunction Segmental changes Sympathetic Heart conduction Motility changes Constipation
(fibrosis) denervation disorders dysphagia megacolon
megaoesophagus intestinal volvulus
Atrial Electrical Bradyarrhythmias

Clinical fibrillation re-entry
manifestations
Aneurysms Broncoaspiration Intestinal obstruction
Heart failure Stroke Sudden death Malnutrition Mesenteric ischaemia
Economic and Heart Oral Implantable Pacemaker Gastrointestinal

social burden transplantation anticoagulation cardioverter surgical procedures
defibrillator
Figure 1: Clinical manifestations, and economic and social burden of chronic Chagas disease
controls are difficult to find. The single finding of high parasites has been the loop-mediated isothermal
titres of IgM cannot be deemed conclusive, as they can be amplification, which is easier to perform than PCR for
detected in some infected individuals in the chronic phase amplification of DNA, and is able to detect T cruzi in
of the disease. Rheumatoid factor might give false-positive samples from newborns and immuno suppressed
reactions (frequently high in the acute phase of infectious patients.101,102
diseases), and IgM is absent in most newborns infected Reactivation can be diagnosed by direct detection of
with T cruzi.44 Faced with these difficulties, seroconversion parasites in blood, cerebrospinal fluid, biopsy samples
(an increase of 2 or more titres of IgG antibodies) is taken from any transplanted organ, and other tissue
considered a more useful tool in suspect acute Chagas samples (such as subcutaneous nodules). Specific signs of
disease (excluding congenital transmission), when blood acute Chagas disease, including fever, lymphadenopathy,
collections are performed at intervals of 20–40 days. jaundice, skin rash, and liver changes, might occur with
A diagnosis of congenital Chagas disease can only be clinical features of myocarditis, panniculitis,
ruled out if, in addition to the negative parasitological meningoencephalitis, and brain abscess. Alternatively,
examination close to birth, no anti-T cruzi antibodies of reactivation might be asymptomatic, and in post-transplant
the IgG class are detected from 9 months of age, when cases, the differential diagnosis with cellular rejection
the presence of circulating maternal antibodies is no might be difficult, as the clinical picture and
longer expected.38,97 histopathological findings are similar. The identification of
There are other tools that might be used to detect amastigote nests in tissue samples by direct visualisation
parasites, such as animal inoculation, xenodiagnosis, or PCR, or detection of antigens by immunohistochemistry,
haemoculture, and PCR.44,92,96 Real-time PCR (rtPCR) is allow for a diagnosis. Furthermore, transplant rejection
an automated technique developed to detect and amplify often precedes reactivation. Positive qualitative results
T cruzi DNA, which might quantify the parasite load. from parasitological exams (eg, PCR, blood culture, or
Because there are different techniques and protocols, the xenodiagnosis) from blood of people chronically infected
commercial kits currently available must follow with T cruzi do not confirm the diagnosis, but quantitative
harmonisation and standardisation criteria validated by analyses that show a gradual increase in parasitaemia do,
specialists. Due to the presence of high and consistent beyond direct parasitological tests. Serology might be
parasitaemia in the acute phase, rtPCR has been useful only in cases of seronegative recipients receiving
identified as a promising technique to be validated for organs from seropositive donors.103
the diagnosis of vertical transmission.98 The usefulness
of rtPCR has also been described in immunosuppressed Chronic phase
cases and recipients of solid organs or bone marrow During the chronic phase, direct parasitological diagnosis
transplants,99 allowing the identification of a gradual is compromised due to the usual low parasitaemia.
increase in parasitaemia as an early and sensitive marker Therefore, most of the tests that are used for laboratorial
of reactivations.100 Another promising tool for detecting diagnosis look for anti-T cruzi antibodies, from IgG class

Seminar
(mainly IgG1 and IgG3 subclasses) detected for life in the treatment of Chagas disease; namely, nifurtimox and
people who are untreated. Although most individuals benznidazole, which were both discovered between
with T cruzi infection (around 75–80%) have high the 1960s and 1970s. Both drugs are effective in reducing
concentrations of antibodies, approximately 15% have the duration and clinical severity of Chagas disease by
intermediate concentrations, and a minority (5%) have enabling parasite elimination when cases are treated
low antibody concentrations, which makes the follow-up early in the natural history of the disease (in acute,
of treated individuals more difficult.44 Spontaneous cure congenital, and some chronic Chagas disease cases, in
has been exceptionally described,104 but additional studies addition to cases of reactivation in immunosuppressed
estimate this possibility to be less than 1%.105 hosts), with potential gains in terms of quality of life by
WHO106 and PAHO59 strongly recommend the use of at overcoming eventual physical limitations; however, the
least two serological tests that represent different available therapeutic regimens can lead to unwanted
methodological principles or different sorts of antigens: adverse reactions and treatment discontinuation.17,59 As
one being of high sensitivity (eg, indirect immuno an infectious disease with a chronic course comprising
fluorescence or the immunoenzymatic test referred to as several disabling clinical syndromes, the treatment of
enzyme-linked immunosorbent assay), and one of high Chagas disease should adopt the concept of
specificity (eg, indirect haemagglutination). If both tests comprehensive care, with different objectives: to promote
are reactive, the serum is positive and belongs to an the clearance of parasites using antiparasitic drugs,
individual infected with T cruzi. If both are non-reactive, aiming at cure or at least reducing parasitaemia, thereby
the individual is not infected. Should one test be reactive preventing clinical progression and vertical trans
and the other non-reactive, a third test should be used. mission;18 to manage and provide symptomatic treatment
Through the proper use of serological tests, it is possible for the chronic cardiac or digestive forms of Chagas
to correctly diagnose up to 98% of the sera tested; disease (or both); and to provide psychosocial support to
however, cross reactions might occur, mainly in Chagas people with Chagas disease and their families. Treatment
disease-endemic regions that are also endemic for is expected to prevent or at least decrease morbidity,
leishmaniasis (in most cases, visceral leishmaniasis). disability, and mortality associated with Chagas disease.65
A substantial improvement to the diagnostic process of
chronic Chagas disease includes the use of rapid Effectiveness
diagnostic tests as a point-of-care screening tool.107 Many The effectiveness of both benznidazole and nifurtimox
kits are available with different behaviours83 and an array depends on the phase of the disease. For congenital
of specific antigens. Advantages are clear, as no laboratory transmission, both drugs are very effective when used in
personnel is necessary, and the result can be read the first year of life.61,108 At the recent chronic phase, when
immediately, facilitating the diagnose and treat principle. parasites have been circulating for a short time (<10 years,
Disadvantages are mainly due to a lower sensitivity when for instance in children <12 years) the percentage of cure is
compared with other serological methods, so a rapid around 60%;14,109 however, in chronic cases where the
diagnostic test should not be used as a single test for parasite has been present for at least two decades, the rate
diagnosis. Positive results obtained through rapid of cure is around 20–40%, but this can only be established
diagnostic tests should be confirmed through serologies, after a significant period of follow-up.110 Age cannot be
to certify that the individual is infected. used as a cutoff point for treatment if the transmission
The use of parasitological tests in the chronic phase is mechanism is not evaluated, considering that recent cases
not encouraged for diagnostic purposes, as parasites are of oral transmission can occur in any age group
scarce or absent in blood; however, they might be applied (eg, an individual aged 50 years might be in the acute or
with immunosuppressed patients to monitor reactivation. recent chronic phase of Chagas disease, with a high chance
PCR is usually used due to a high sensitivity and of cure).111
quantification capacity, which means it is able to measure In an international controlled clinical trial,
the parasitic load. PCR is also useful after treatment with benznidazole was shown to not be able to reduce
parasiticidal drugs, when a positive result detects mortality in patients with advanced Chagas heart
treatment failure.102 disease,112 which is why it is very important that diagnosis
A clinician might be faced with different real-life occurs in the early stages of the Chagas disease, when
situations, with each requiring a different demand for treatment is not contraindicated and is associated with
laboratory tests to exclude or confirm a T cruzi infection. clinical benefits. Table 2 describes the indications,
Table 1 describes different diagnostic strategies, as well contraindications, objectives, doses, and main adverse
as necessary clinical and surveillance actions. events of the available antiparasitic drugs.
A new variable that should be considered when it
Antiparasitic treatment comes to the effectiveness of treatment is the T cruzi
Ensuring access to effective, efficient, and safe DTU. Remarkable differences were seen in a study of
antiparasitic treatment for T cruzi infection remains a children younger than 12 who were treated in Honduras
challenge. There are only two effective drugs available for (DTU TcI), children younger than 15 who were treated in

Seminar
Guatemala (DTU TcI), and children younger than 18 who

Objective of treatment and contraindications
were treated in Bolivia (DTU TcV).115 This study showed
that most children in Honduras (87%) and Guatemala Acute Chagas disease (all age groups)
(58%) were seronegative 1 year after treatment, but only a Patients with congenital Chagas disease Cure, success rate approximately 100%
few (0–5·4%) had the same results in Bolivia, with Patients with other acute Chagas disease Cure, success rate approximately 60–80%
identical protocols being followed. Patients with reactivation (immunosuppression) Reduce parasitaemia and mortality
Therapeutic effect is measured by a decline in antibody Pregnant women Treat the mother only after pregnancy, except in
life-threatening conditions
response, which might take some years given the strong
Chronic indeterminate Chagas disease
antibody response to an array of different antigens of
Children aged <12 years Cure, success rate approximately 60%
T cruzi. In recent clinical trials, PCR has been used for
Adolescents and adults aged <50 years Cure, success rate 20–40%; reduce organ damage
post-treatment follow-up, with therapeutic failure detected
in the presence of positive results; however, the clinical Adults ≥50 years old Shared decision on treatment; rule out other
clinical conditions (eg, hepatic or renal failure) to
relevance of this result still requires further evaluation.116 reduce organ damage; if recent infection is
Although regional guidelines suggest comparability of suspected, which is more frequent in cases of
efficacy between benznidazole and nifurtimox based on oral transmission, age alone should not be a
limiting factor for treatment
observational studies,59 there are no randomised protocols
Girls and women of childbearing age (rule out pregnancy Reduce vertical transmission rate
in the context of acute T cruzi infection, and currently and recommend contraception during the treatment of
there are two ongoing clinical trials comparing the women of childbearing age)
two drugs in the chronic phase of Chagas disease.113,114 The Pregnant women Treat the mother only after pregnancy; lactation
efficacy of new imidazoles such as posaconazole and is not a contraindication
ravuconazole has been evaluated in randomised clinical Mild cardiac chronic Chagas disease*
trials, with negative results, although dose and treatment All age groups Shared decision on treatment, possible benefit if
durations differed from those indicated by preclinical there is no contraindication
studies and pharmacodynamic models.117–120 Advanced chronic Chagas disease
On the basis of results of combined evaluations of All age groups Do not treat
these new drugs with shorter or reduced doses of Benznidazole and nifurtimox have similar benefits according to observational studies (randomised trials comparing
benznidazole, especially by the BENDITA study,119 it is benznidazole and nifurtimox are in progress).113,114 According to guidelines, the choice depends on acceptability and
availability in each country. *Without systolic dysfunction or heart failure.
postulated that lower doses of drugs than currently
recommended could maintain efficacy, with fewer Table 2: Indications, contraindications, and objectives for benznidazole and nifurtimox
adverse events and less treatment discontinuation. In
this respect, studies evaluating redosing regimens of nifurtimox) and similar for adults (5–31% with
benznidazole and nifurtimox for adults are in benznidazole and 14·3% with nifurtimox).125,126
progress.113,114,121–123 In a recent prospective, historically
controlled study, the 60-day treatment regimen of Treatment follow-up
nifurtimox was more effective than the same dosing for A positive parasitological result after treatment indicates
30 days in children aged 0–17 years, but the 60-day and treatment failure. Reintroduction of the same drug for a
30-day nifurtimox regimens appeared to be equally new 60-day treatment could be an alternative, as well as
efficacious in children younger than 2 years.61 the use of the other drug (ie, nifurtimox if benznidazole
Recent studies show the dormancy capacity of appears to have failed). Serological cure, defined by the
intracellular amastigotes, which can resist treatment absence of antibodies, is more easily attainable in treated
while remaining metabolically inactive, with the ability to infants aged up to 1 year, due to the limited circulation
later transform into trypomastigotes. Therefore, the time of the parasite. When T cruzi has been present for
search for compounds capable of overcoming dormancy years, the total absence of antibodies becomes more
might be the key to more effective treatment.124 difficult, due to strong immunological memory. A new
approach based on the enzymatic effect of the parasite to
Tolerance cleave apo-lipoprotein has been suggested to ascertain
Both nifurtimox and benznidazole might cause adverse cure in children treated with nifurtimox.127
reactions, with better tolerance among children aged
under 12 years (table 3). Nifurtimox is mainly associated Chagas disease comprehensive care
with weight loss and psychiatric adverse effects, and The approach to Chagas disease has changed substantially
benznidazole with cutaneous and neurological reactions. over the years, alongside the concept of integral health
With both drugs, adults have almost twice the frequency (encompassing promotion, prevention, care, and
of adverse reactions (55% with benznidazole and rehabilitation actions), defining health as physical, mental,
60·9% with nifurtimox) compared with children and social wellbeing. This concept has led to a shift from
(25% with benznidazole and 29·3% with nifurtimox). disease-centred care to person-centred care (figure 2).
The discontinuation rate is slightly higher for nifurtimox The identification of asymptomatic people in the latent
in children (4% with benznidazole and 7·4% with period of infection is one of the great challenges related

Seminar
with clear and comparable definition criteria among

Occurrence time and response
endemic and non-endemic countries.
Benznidazole Ethics-based counselling should be a central practice in
Skin: local itching, localised macules, and papules Occurs around day 10 of treatment; response is to start screening, diagnosis, and treatment, with the goal of
(light); generalised macules, papules, hives, antihistamines or corticosteroids (or both), avoid
erythema, itchy skin erosion or signs of secondary exposure to the sun and consumption of alcoholic greater patient and family adherence and a reduction in
infection (or both), and fever (moderate); drinks, and if severe, suspend benznidazole and refer anxiety, depression, and fear. The false ideas that most
Stevens-Johnson syndrome (severe) patient to a higher level of health care people with Chagas disease will become disabled or die
Digestive: abdominal pain, nausea, and vomiting Occurs within the first 2 weeks of treatment; response should be dismissed; instead, it should be remembered
(light); ageusia (total or partial loss of taste), is to administer symptomatic treatment, counselling
occurrence after 50 days of treatment (rare); on food (fractionation of diet), and administration of
that around 60% of patients can remain in the chronic
choluria, hepatomegaly, and jaundice (severe) benznidazole after the meals; if severe, suspend indeterminate form of Chagas disease their entire lives
benznidazole and refer patient to a higher level of and must be monitored and treated in primary health
health care care. After confirming diagnosis, counselling on
Neurological adverse reactions (occurring in 5% of Occurs after 50 days treatment; response is to prognosis is recommended and an ECG is crucial to
patients84): headache, peripheral neuropathy, and administer symptomatic treatment; if severe, suspend
sensitivity change (hyperesthesia or hypoesthesia, benznidazole and refer patient to a higher level of guide specific interventions, even if the patient has no
or areas that lack sensation); dose dependent; health care cardiac symptoms. In addition, annual assessments with
slow recovery over months an active search for symptoms and an ECG are necessary
Bone marrow aplasia (rare, occurring in Occurs between days 20 and 30 of treatment (it is to identify possible clinical progressions.
1 of 2000 patients84): leukopenia, neutropenia, important to evaluate a blood count in the third week
In table 4, the recommended actions at each level of
and agranulocytosis with fever. Not dose of treatment); response is immediate and permanent
dependent; recovery without sequelae interruption of benznidazole care, foreseen objectives, and sectors responsible for
Nifurtimox their performance are described, defining the ideal
Digestive (occurring in 60% of patients84): Occurs within the first 2–3 weeks of treatment, and is patient journey. Primary health care is central in the
anorexia, nausea, and weight loss maintained throughout the treatment; response is to Chagas disease comprehensive care approach and,
maintain nifurtimox, recommend counselling on food, whenever possible, a decentralised model of care,
and recommend administration of nifurtimox after the
meal
including access to diagnosis and treatment at the
Psychiatric (occurring in 22% of patients84): Occurs within the first 2–3 weeks of treatment;
primary care level, should be encouraged. Health
depression, panic attack, and psychomotor response is to suspend nifurtimox for a few days (or professionals and managers should include community
agitation until the symptoms reduce) leaders in initiatives that encourage surveillance,
Neurological (occurring in 18% of patients84): Occurs between days 2 and 10 of treatment; response environmental education, and vector control, thereby
headache, irritability, and dizziness or vertigo is to administer symptomatic treatment, and if severe, promoting health, prevention, and control of the disease.
(light); peripheral neuropathy and paraesthesia in suspend nifurtimox and refer to a higher level of health
soles and palms; dose dependent; slow recovery care In addition, the multiprofessional primary health-care
over months team has an important role in Chagas disease education,
Recommended benznidazole doses are 5–10 mg/kg per day for 60 days (12·5 mg or 25 mg dispersible tablets) for using clear and comprehensive communication,
children with a high tolerance, 5 mg/kg per day for 60 days (100 mg tablets) for adults with acute or chronic Chagas promoting self care, improving quality of life, and
disease, and 7–10 mg/kg per day for 10 days in cases of accidental transmission. Other general side-effects associated identifying a need for psychosocial support. Community
with benznidazole include asthenia and somnolence (occurring frequently), fever (occurring less frequently), joint and
muscle pain (occurring in approximately 8% of patients84), anxiety, insomnia, and altered liver enzymes. If these side-
involvement should be encouraged to promote and
effects occur, maintain benznidazole and evaluate symptomatic treatment. Recommended nifurtimox doses are demand prevention and care actions. At the quaternary
15 mg/kg per day for 60–90 days (30 mg tablets) for children with high tolerance, 10 mg/kg per day for 60–90 days care level, all sectors must be committed to offering a
(120 mg tablets) for adults with acute or chronic Chagas disease, and 10 mg/kg per day for 10 days in cases of
multidisciplinary approach and appropriate support to
accidental transmission. Other general side-effects associated with nifurtimox include fever, asthenia, rash,
eosinophilia, leukopenia, and thrombocytopenia. If these side-effects occur, maintain nifurtimox and evaluate patients and their families.65
symptomatic treatment.
Table 3: Adverse reactions associated with benznidazole and nifurtimox

Identified gaps
From a global agenda perspective, Chagas disease is
included into the third of the Sustainable Development
to Chagas disease diagnosis. As shown, early diagnosis Goals: “ensure healthy lives and promote well-being for
not only increases the chances of cure, but also reduces all at all ages”, with the aim to “end the epidemics of
the rate of vertical transmission (in the case of girls and AIDS, tuberculosis, malaria and neglected tropical
women of childbearing age), and potentially prevents diseases, and combat hepatitis, waterborne and other
progression to chronic forms of the disease that are communicable diseases” by 2030.33,129 However, the
costly for patients, their families, and health systems.18 persistence of Chagas disease in endemic and non-
Recognition of vulnerable territories by health managers, endemic countries results from a succession of so-called
active searches for cases by well trained health failures in scientific, market, and public health spheres.130
professionals in areas that are at risk, and empowered Insufficient knowledge of the disease and the people it
communities demanding health care are mitigation affects, costly and scarce diagnostic and therapeutic tools,
strategies for this access barrier to diagnosis. National and policy limitations regarding the management and
programmes should integrate health care and planning of comprehensive care for Chagas disease in
surveillance actions and implement compulsory national health systems all pose significant barriers to
notification of acute and chronic Chagas disease cases, the elimination of the disease.

Seminar
2022
Chagas disease globalisation 2011 Paediatric formulations of benznidazole
• Migration as a social determinant of health 2011 PCR to substitute haemoculture and xenodiagnosis
• Chronic cases and urban disease 2011 International reference sera (Tc I and Tc II)
Ageing population with Chagas disease 2009 6 DTUs (Tc I–TcVI) and TCBat
• Increased access to health care 2009 FINDECHAGAS consolidating social movements
International security 2006 Sequencing of the whole genome of Trypanosoma cruzi
challenges, climate Interdisciplinary strategies
(CL Brener)
change, and increased • IEC, SBCC, community engagement, and intersectionality
2002 Intergovernmental Initiatives of the Amazonian Countries
global migration PHC as priority and person centred care—comprehensive care
• Chagas disease in urban contexts and high-risk groups
• Treatment not only aimed at cure, but also to reduce morbidity
Increase of oral transmission in the Amazon
• Climate change and vector dispersal
One Health approach
2001
Chronic cases and urban disease 1990s Cooperation between PAHO and national governments
• Sedentary lifestyle—associated comorbidities on strategies, mainly related to vector control
• Migration from Latin America to USA (INCOSUR, IPCAM, and IPA)
Treatment only for acute and early cases aimed at cure 1987 First social movement on Chagas disease in Pernambuco,
• First report on drug susceptibility T cruzi strains Brazil
Immunosuppression 1986 Importance of zymodemes for the identification of strains
conditions and Chagas disease reactivation in HIV co-infection
of T cruzi
regional migratio Transmission from transplantation 1985 First heart transplantation, reducing immunosuppression
1980s HIV epidemic and Chagas disease co-infection
1975 Echocardiogram
1975 Conventional serology
1973 Holter
1972 Development of benznidazole
1970s Chagas disease as a contraindication to heart transplantation
1970
Urbanisation of Chagas disease 1970s Start of intergovernmental initiatives
Illness-centred care 1968 Development of nifurtimox
Industrialisation and Accidental transmission 1949 Identification of vertical transmission
internal migration Chronic cases 1940s Start of vector control activities
• Mainly CHD 1940s Identification of blood transmission
• Megaoesophagus recognised as Chagas disease
• Distancing in the doctor–patient relationship
1940
Predominantly rural disease 1935 Romaña sign
• Focus on vector-borne transmission 1926 Anatomical–clinical stages (Salvador Mazza128)
Initial discoveries • First epidemiological evidences (serology and 12-lead ECG) 1922 Description of the cardiac form (Chagas and Villela128)
• Chest x-ray: cardiomegaly 1914 Xenodiagnosis
Acute cases focus 1913 Serological diagnosis–complement fixation
• Children affected in large numbers (Guerreiro-Machado128)
1909
Discovery of Chagas disease (Carlos Chagas)
Figure 2: Timeline Chagas disease: epidemiological, clinical, and public policy changes
CHD=Chagas heart disease. DTUs=discrete typing units. ECG=electrocardiogram. FINDECHAGAS=International Federation of Associations of People Affected by
Chagas Disease. IEC=information, education, and communication. INCOSUR=Initiative of the Southern Cone Countries. IPA=Initiative of the Andean Countries.
IPCAM=Initiative of the Central American Countries and Mexico. MCH=mother and children health. PAHO=Pan American Health Organization. PHC=primary health
care. SBCC=social and behaviour change communication.
There are specific scientific knowledge gaps that can hypothetically mean a lower probability of clinical
be identified when it comes to Chagas disease, which progression.131,132
are outlined below. First, the absence of a short-term Second is the scarcity of studies specific to Chagas
biomarker capable of assessing the therapeutic heart disease that evaluate the effectiveness and security
response. Potential serological negativity might take up of symptomatic treatment. The risk of concomitant
to two decades in the chronic phase, which is unfeasible bradyarrythmia and tachyarrhythmia in the same
for clinical studies. PCR, which has been used as a individual, the high risk of sudden death even in early
surrogate endpoint, might not be adequate as the stages of the disease, and the high number of cardio
absence of sustained parasitological clearance for embolic events even using prophylaxis strategies
12–24 months does not necessarily mean the absence of recommended for other heart diseases make Chagas
clinical benefit. It is postulated that the reduction of heart disease a distinct pathophysiological model,
parasitaemia, maintained at a low steady state, could with hard clinical management. The ongoing

Seminar
Primary prevention* Secondary prevention† Tertiary prevention‡ Quaternary prevention§

(1) Environmental monitoring, entomological Serological diagnosis (chronic Chagas Antiparasitic treatment for early cardiac and Minimise complications
surveillance, and health promotion and disease)¶; evaluation in PHC (including digestive forms¶; PHC, acting through (overmedicalisation, polypharmacy):
education¶; governmental and reception of people detected from blood shared decision making|| stimulate adhesion to symptomatic
community-led participative initiatives|| banks)|| treatment, identify adverse events¶
(2) Housing improvement policies¶; and Congenital Chagas disease diagnosis: Cardiac symptomatic treatment: heart Ensure access to quaternary care when
governmental initiatives|| access to molecular tests or quality direct failure (ACEIs and ARBs, β blockers, and needed for Chagas heart disease:
parasitological exams; follow up diuretics), arrhythmias (amiodarone; pacemakers or implantable cardioverter
serological tests until the ninth month pacemaker or implantable cardioverter defibrillator, ablation of arrhythmias,
and treatment¶; evaluation in MCH and defibrillator), and thromboembolic events heart transplantation¶
PHC; exams in central laboratories|| (anticoagulation)¶; primary, secondary, or
tertiary level, depending on severity of
clinical forms||
(3) Screen blood donors¶; haemovigilance Acute Chagas disease diagnosis (in Digestive symptomatic treatment¶; Ensure access to quaternary care when
and central laboratories|| outbreaks or immunosuppression primary, secondary, or tertiary level, needed to chronic digestive forms:
conditions)¶; primary, secondary, or depending on severity of clinical forms|| oesophageal dilation or surgery, surgery
tertiary level, depending on severity of for megacolon or intestinal obstruction¶
clinical forms||
(4) Screen organ and tissue donations¶; Detection strategy: search for family Counsel on treatment and management of Promote cardiac, digestive, and
central laboratories|| members and household contacts¶; PHC, the longitudinal care¶; primary, secondary, socioeconomic rehabilitation¶
apply screening and counselling|| or tertiary level, depending on severity of
clinical forms||
(5) Universal screening of pregnant women in Antiparasitic treatment for chronic and Promote cardiac, digestive, and Provide nutritional guidance to heart
prenatal care¶; MCH and PHC (to treat and acute Chagas disease (including socioeconomic rehabilitation¶; primary, failure cases (limiting hydric ingest), and
cure the positive newborn)|| congenital Chagas disease)¶; PHC and secondary, or tertiary level, depending on digestive forms (pasty foods and
evaluate referral to other levels in case of severity of clinical forms|| laxatives)¶
severe acute cases||
(6) Universal screening of girls and women of Identify the chronic cardiac form of Provide psychological support for fears, Promotion of health: control or treat
childbearing age in endemic countries¶; Chagas disease (anamnesis to cardiac anxiety, and depression related to disease cardiovascular risk factors and encourage
MCH and PHC (to treat girls and positive symptoms), ECG (annually)¶; PHC|| and prognosis¶; health services with healthy lifestyle habits¶
women of childbearing age before community-led initiatives||
pregnancy)||
(7) Safe practices for food production¶; Identify the chronic digestive form of Provide social support: labor rights, Provide psychosocial support to affected
governmental and community-led Chagas disease (anamnesis to digestive retirement, universal access to health¶; people, caregivers, and families¶
participative initiatives|| symptoms; annually)¶; PHC|| primary, secondary, or tertiary level,
depending on severity of clinical forms||
(8) Safe laboratory practices¶; researchers: Counsel about treatment and Self-care groups: promote independence in Counsel on palliative and end-of-life care¶
proper use of personal protective management of the longitudinal care¶; activities of daily living and improve quality
equipment|| PHC|| of life¶; health services with community-led
participative initiatives||
(9) Health education, IEC activities and Provide psychological support—fears, Promotion of health: control and treat ··
campaigns¶; governmental and anxiety and depression related to disease cardiovascular risk factors, encourage
community-led initiatives, PHC (including and prognosis¶; PHC|| healthy lifestyle habits¶; health services
CHWs)|| with community-led participative
initiatives||
(10) Screen chronic Chagas disease using rapid Provide social support: labor rights, ·· ··
diagnostic tests (point of care tools)¶; universal access to health¶; PHC with
PHC|| community-led initiatives||
(11) Counsel about screening and diagnosis¶; Self-care groups: know the benefits of a ·· ··
PHC|| specific treatment and recognise its
adverse events¶; PHC with community-
led initiatives||
(12) Provide psychosocial support for fears and Promotion of health: control and treat ·· ··
anxiety about diagnosis¶; PHC and cardiovascular risk factors, encourage
community-led initiatives|| healthy lifestyle habits¶; PHC with
community-led initiatives||
ACEIs=angiotensin-converting enzyme inhibitors. ARBs=angiotensin receptor blockers. CHW=community health worker. IEC=information, education, and communication. MCH=maternal and child health.
PHC=primary health care. QoL=quality of life. *Target population: people in conditions of risk or vulnerability; objectives: prevent transmission. †Target population: chronic Chagas disease (indeterminate form)
and acute Chagas disease (including congenital); objectives: early diagnosis aiming at cure or prevention of progression to symptomatic forms. ‡Target population: early cardiac and digestive forms; objectives:
minimise morbidity and decrease mortality; prevent or improve disabilities; ensure quality of life and promote rehabilitation. §Target population: late cardiac and digestive forms; older infected people with
comorbidities; objectives: prevent overmedicalisation; ensure comfort and quality of life; prevent complications and promote rehabilitation. ¶Actions. ||Involved sectors.
Table 4: Preventive actions and involved sectors in Chagas disease

Seminar
PARACHUTE-HF trial (NCT04023227) is a study to Acknowledgments

specifically evaluate the benefits of a drug (sacubitril– We thank Valentina Carranza Weihmüller (CUIDA Chagas Project) for
preparing the original figures. ASdS declares grants from the Research
valsartan) for heart failure in the pathophysiological Support Foundation of the State of Rio de Janeiro (Scientist of Our State
model of Chagas heart disease. number E-26/201.120.2021); ANR declares grants from the Brazilian
Third, other investments in research and development National Council for Scientific and Technological Development
are essential for better clinical management of Chagas (Scientific Productivity Scholarship number 311799/2019-1). The funding
sources had no role in the writing of the Seminar or the decision to
disease and the reduction of its burden. These submit for publication.
investments include research to optimise antiparasitic
References
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ANR and AOL reviewed and edited the Seminar. All authors have seen 18 Hasslocher-Moreno AM, Saraiva RM, Sangenis LHC, et al.
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Declaration of interests EClinicalMedicine 2020; 31: 100694.
We declare no competing interests.

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www.thelancet.com Published online December 7, 2023 https://doi.org/10.1016/S0140-6736(23)01787-7 1

2 www.thelancet.com Published online December 7, 2023 https://doi.org/10.1016/S0140-6736(23)01787-7

Panel: Mechanisms of Trypanosoma cruzi transmission to humans23

meningoencephalitis and cerebral granuloma manifestations of reactivation associated with post-

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Clinical and epidemiological Diagnostic strategy Surveillance and control or prevention

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Clinical and epidemiological Diagnostic strategy Surveillance and control or prevention

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Parasite Trypanosoma cruzi

Heart Oesophagus Colon

Affected organs Myocardial contractile Autonomic nervous Heart conduction

Atrial Electrical Bradyarrhythmias

Heart failure Stroke Sudden death Malnutrition Mesenteric ischaemia

Economic and Heart Oral Implantable Pacemaker Gastrointestinal

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Guatemala (DTU TcI), and children younger than 18 who

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with clear and comparable definition criteria among

Table 3: Adverse reactions associated with benznidazole and nifurtimox

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Primary prevention* Secondary prevention† Tertiary prevention‡ Quaternary prevention§

Table 4: Preventive actions and involved sectors in Chagas disease

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PARACHUTE-HF trial (NCT04023227) is a study to Acknowledgments

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