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
advocacy strategies.3
Chagas disease has been described by WHO and
others as a “silent and silenced disease”,1,4 as the majority
of people with the disease will not present with
symptoms, and there is a staggering shortage of rele­vant
information, resulting in little attention from govern­
ments, researchers, health and education professionals,
institutional donors, and the general population. Chagas
disease is a chronic infectious condition that intrinsically
promotes and perpetuates poverty, and mainly
affects people with greater social vulnerability, causing
substantial physical, psychological, and socioeconomic
challenges.3,5 Combatting the disease requires an
intersectoral approach, with the inclusion of civil society
and social movements, reflecting the voices of those
affected by Chagas disease. Over the last decade, non-
governmental organisations focusing on Chagas disease
have formed an international federation representing
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
chronic phase. An estimated 30–40% of people who are
infected but untreated will develop severe and sometimes
life-threatening medical conditions, including cardiac,
digestive, and neurological or associated alterations,
which might require specific treatment. If untreated,
infection is lifelong.6 If treated, the chance of progression
might be reduced, but the effectiveness is variable and
not well defined. Symptomatic Chagas disease imposes
a substantial financial burden on health-care systems
and societies,7 with an estimated US$690 million in
health-care costs and $8 billion in annual economic
losses.8,9 Despite the high morbidity and mortality of
reduction of progression to advanced forms of the Correspondence to:
Dr Andréa Silvestre de Sousa,
disease in adults.12–18
Evandro Chagas National
Institute of Infectious Diseases,
Parasite lifecycle Oswaldo Cruz Foundation,
Replicant and infective stages of T cruzi can be identified Rio de Janeiro 21040-360, Brazil
andrea.silvestre@fiocruz.br
in the insect vector and mammalian hosts. Trypo­
mastigotes circulating in the blood of hosts are
transformed in the vector’s intestine into replicating
epimastigotes, which change into metacyclic trypo­
mastigotes in the distal portion of their intestine, and
are released in the insect’s faeces. These trypomastigotes
penetrate the damaged skin or mucous membranes of
the host, where they enter host cells and change into
replicating amastigotes, and are released into circulation
again in the form of trypomastigotes.19
The T cruzi parasite is classified into at least seven
discrete typing units (DTUs), TcI–TcVI and Tcbat
(appendix).20,21 Some DTUs have been associated with See Online for appendix
geographical distribution in epidemiological scenarios
Search strategy and selection criteria
Data for this Seminar were identified through searches of
PubMed and Embase between Oct 1, 2022, and Dec 23, 2022,
with no language restrictions, using the following search
terms: “Chagas disease”, “American trypanosomiasis”, or
“Trypanosoma cruzi”. We selected key references and seminal
papers, reviews, case reports, and relevant book chapters. We
also reviewed abstracts from pertinent scientific meetings
and publications from international organisations such as
the Pan American Health Organization, WHO, and the Special
Programme for Research and Training in Tropical Diseases
from WHO from Jan 1, 2010, to Dec 1, 2022.

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
poorly understood. Evidence is emerging that the diverse
genetic makeup of the parasite is responsible for distinct
outcomes in diagnosis and treatment of Chagas disease,
but this should be researched further.
Epidemiology
Chagas disease is mainly found in Latin America, where
the large majority of the estimated 6–8 million people
infected with the T cruzi parasite reside. In addition,
approximately 75 million people are at risk of contracting
the disease.22 An estimated 30 000 new cases and more
than 10 000 Chagas disease-related deaths are reported
annually.22–24 According to the last weekly epidemiological
report published by WHO in 2015, using data from 2010,
Argentina, Brazil, Mexico, Bolivia, and Colombia have the
highest estimated number of cases, and Bolivia,
Argentina, and Paraguay have the highest estimated
prevalence.25 Due to migratory movements associated
with political, health, environmental, and economic crises
in the endemic countries of origin, Chagas disease has
now been recorded in several non-endemic countries in
Europe, as well as in the USA, Australia, and Japan,
among other countries.26–28
In the early and mid 20th century, Chagas disease was
mainly restricted to vulnerable, rural areas in
Latin America, where vectorial transmission prevailed.
Nowadays, the epidemiological pattern of the disease
has shifted due to human dynamics, meaning it is
present in urban settings and has an international scope.
Chagas disease has become a global health problem, and
has been inserted into strategic international agendas,
such as the WHO 2030 Roadmap and the Sustainable
Development Goals.29
In the 1990s, the Pan American Health Organization
(PAHO), in partnership with endemic countries, developed
multinational initiatives to strengthen the control and
surveillance of Chagas disease.30 According to PAHO,
17 countries have achieved the interruption of intra­
domiciliary vectorial transmission by Triatoma infestans or
Rhodnius prolixus.22 This interruption, combined with
rural–urban migration, has substantially reduced the
instances of vectorial transmission; however, eradication
of vectorial T cruzi transmission in the Americas is
impossible.30 Entomological surveillance actions should,
therefore, be continuous, especially given emerging
challenges in Chagas disease epidemiology, such as
climate change combined with deforestation and the
human exposure to sylvatic scenarios; the adaptation of
secondary and non-domiciliated vectors to the human
habitat; the increasing occurrence of alternative trans­
mission routes by vectors; and the rise of insecticide
resistance. The complexity of these eco-epidemiological
factors can only be efficiently addressed from the concept
of One Health, an approach that includes collaborative
efforts to attain optimal health for people, animals, and the
environment.31–34
2 www.thelancet.com Published online December 7, 2023 https://doi.org/10.1016/S0140-6736(23)01787-7
Congenital Chagas disease has progressively gained
epidemiological relevance, and remains a crucial challenge
for both endemic and non-endemic countries; however,
due to the neglected nature of the disease and the barriers
that persist in access to diagnosis, treatment, and care,
prevalence in pregnant women and newborns might be
underestimated.24,35,36 According to the last available weekly
epidemiological report on Chagas disease, an estimated
1·12 million women of childbearing age are infected with
the T cruzi parasite,25 and the vertical transmission
prevalence approaches 5%, with higher rates in high-risk
endemic areas.35,37 The incidence of congenital Chagas
disease is an estimated 8000 to 15 000 cases per year in
Latin America.38 In the wake of progress in vector
transmission control, vertical transmission has become
proportionately more relevant, accounting for about a
third of new infections in 2010, and could perpetuate the
disease indefinitely, even in countries without vector
transmission.39 The panel describes the mechanisms of
T cruzi transmission and suggests methods for prevention
and control.
Clinical presentation
Chagas disease infection evolves in two subsequent
phases. In general, the acute phase lasts 4–8 weeks and,
when symptomatic, tends to be perceived as an acute
illness, with persistent fever (>7 days), hepatosplenomegaly,
lymphadenopathy, subcutaneous oedema (in limbs or
face), and morbilliform rash.65,66 Romaña’s sign, a unilateral
bipalpebral inflammatory oedema, conjunctival hyper­
aemia, and preauricular adenopathy indicate the reaction
of the host to penetration of T cruzi into the ocular mucosa.
Despite the low frequency, it is considered a pathognomonic
sign of Chagas disease.67 Other inflammatory reactions
associated with the vector bite are inoculation chagomas.
They indicate the entry of T cruzi and are not present in
other forms of transmission, such as oral Chagas disease
transmission. The acute phase usually has a self-limited
evolution, and when properly diagnosed and treated, has a
high chance of cure, especially in children and newborns.6
The acute disease related to oral transmission tends to
be more intense due to the high parasite inoculum, and
some outbreaks present with high lethality.68
Haemorrhagic manifestations might be frequent,
making the differential diagnosis more complex in
the Amazonian region, where other icterohaemorrhagic
syndromes like malaria are common. The distinct clinical
presentations with massive pericardial effusions and
digestive bleeding are different from the acute phase
associated with classic vector transmission.69,70
Other severe conditions associated with elevated
parasitaemia are the reactivation syndromes of Chagas
disease, which are also associated with immuno­
suppression conditions.71 In the 1980s and 1990s, before
the effective institution of highly active antiretroviral
therapy, individuals living with HIV and a CD4 count
of less than 200 cells per µL could develop

Panel: Mechanisms of Trypanosoma cruzi transmission to humans23
Vectorial
This is the classic mechanism by which infested triatomine
(referred to as kissing bugs) defecate on the skin during or after
a bloodmeal, typically at night. The parasite present in the
triatomine’s faeces or urine might enter through abrasions on
the skin, or through the mucous membrane.40
Vectorial control is based on environmental interventions
and the fumigation of infested homes, and has proved to be
most effective if it is part of a national-level effort by
ministries of health.41,42
Transfusion
This transmission occurs when a person is infected through the
receipt of blood or blood products contaminated with T cruzi.
This mechanism was very common between the 1950s (when
it was recognised) and the 1990s, but nowadays, the
haemovigilance for Chagas disease is systematic in different
endemic and non-endemic countries.43,44 For instance, the USA,
the UK, Spain, France, Switzerland, and Portugal screen the
blood products of people that present with epidemiological risk
factors for Chagas disease.36,45–47
Organ transplantation
This transmission occurs when a person is infected through the
receipt of a T cruzi-infected organ. When presented with
epidemiological risk factors, both donor and receptor should be
screened: the donor to avoid organ transmission and the
receptor because parasite reactivation might occur due to
immunosuppression.48
Although Latin American countries have the most experience in
Chagas disease transplantation,48,49 programmes have been
implemented in endemic49,50 and non-endemic countries,47,51–53
with well established guidelines on mandatory universal
serological screening for all donors and receptors at risk;
conducting antiparasitic treatment for at least 30 days in all
infected donors and recipients with proven parasitaemia; active
searching for increased post-transplant parasitaemia by PCR,
in addition to T cruzi research in biopsy tissues of transplanted
organs and dermatological or neurological lesions in cases where
reactivation is suspected; contraindication of heart and intestine
donation for all infected donors (75% or higher risk of
transmission) and any organ in the acute phase of the disease;
and urgent antiparasitic treatment given the diagnosis of
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
(ie, chagoma), which were difficult to differentiate from
the opportunistic neurotoxoplasmosis.71,72 Fulminant
myocarditis and graft loss are also pronounced
www.thelancet.com Published online December 7, 2023 https://doi.org/10.1016/S0140-6736(23)01787-7
Seminar
Outbreaks have been reported, often within families or during
large celebrations, when food and beverages contaminated
with infected triatomines or their faeces (or both) are
consumed. This might include raw or undercooked meat from
infected wild reservoirs, food contaminated with anal gland
secretions of marsupials, and the ingestion of the triatomine
itself.55 Prevention comprises safe food handling practices.56
Vertical
The transmission occurs through an infected mother to her
newborn during pregnancy or childbirth. This mechanism is
increasing in relevance, due to the relative success of other
control efforts. Transmission rates are estimated to be
approximately 5%, with differences in relation to the parasite
diversity (eg, more frequent in TcV and TcVI lineages).35,57
Elevated parasitaemia during the acute phase or
immunosuppression conditions and genetic factors are
recognised as contributing factors to vertical transmission.58
Control efforts should focus on diagnosing and treating all girls
and women of childbearing age,39,59 as well as newborns who
contract the disease from their mothers,24,60 as the success rate
of antiparasitic treatment for children younger than 1 year is
near 100%.61
In some non-endemic countries such as the USA, there are no
programmes aimed towards pregnant women at risk, and in
others, there are programmes for specific geographical regions
(such as Spain, Italy, and Switzerland).62,63 Some of these
programmes have already achieved positive results.36
As most newborns and children remain asymptomatic,
underdiagnosis is common. Little access to specific diagnostic
tools, in addition to the poor knowledge on the part of the
population and health professionals, contribute to this under-
reporting.60
Accidental contamination
This transmission has been reported in more than 100 cases,64
and occurs when personal protective equipment is not properly
used, mainly in laboratories that work with cultures of the
parasite or animal inoculation.
Health personnel involved in detecting bugs and fumigating
houses should also wear proper personal protective equipment,
as should surgeons and personnel that perform necropsies.
manifestations of reactivation associated with post-
transplant immunosuppression.73 Acute panniculitis in
the arms, legs, and abdomen are dermatological
manifestations associated with reactivation in transplant
3
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cases. The isolated role of immune system senescence in
the eventual risk of Chagas disease reactivation is still not
well established.74,75 The ageing of the population with the
disease, greater access to health services,
immunosuppressive therapies (especially in non-ende­
mic countries), and additional diagnoses of malignant
neoplasms and autoimmune diseases (eg, rheumatological
diseases), might mean that reactivation episodes could
become more frequent in this population in the future.76,77
As in the acute phase, however, the response to
antiparasitic treatment in these severe cases of reactivation
is appropriate (ie, more likely to lead to survival) when
diagnosis is timely.
Congenital Chagas disease is considered a T cruzi
infection in the acute phase. The associated clinical
syndrome might vary widely, from absence of signs or
symptoms to evidence of non-specific manifestations
such as fever, anaemia, hepatosplenomegaly, myocarditis,
meningoencephalitis, or respiratory distress. There
might be progression to low birth weight, prematurity,
miscarriage, or neonatal death.78 Cases with more severe
evolution are particularly observed in contexts of
transmission in the first weeks of pregnancy or in the
presence of high parasitaemia. It is estimated that 28% of
infants who are infected with T cruzi show clinical
symptoms, and 2·2% progress to death.60
Between 60% and 70% of people who are infected with
T cruzi will never develop signs or symptoms of chronic
Chagas disease, maintaining normal electro-
cardiograms (ECGs) and gastrointestinal tract x-rays in
longitudinal follow-up appointments.70,79 This absence of
signs or symptoms and maintenance of normal ECGs
and x-rays represents the so-called chronic indeterminate
form of Chagas disease, identified only by reactive
serology (IgG), characterised by a prognosis that is
similar to non-infected populations. Although substantial
abnormalities might be found by more sophisticated
cardiovascular tests, the prognosis remains benign.79 In
this population, an annual clinical follow-up with an
ECG is essential, as the estimated annual progression
rate from indeterminate chronic Chagas disease to
Chagas heart disease is 1·9% (95% CI 1·3–3·0).80 Some
non-specific electrocardiographic alterations are not
considered clinical progression (table 1).79,85 Antiparasitic
treatment is encouraged for this clinical form, and its
success is related to sooner treatment, a low risk of
reinfection, and factors associated with genetics and the
type of parasite (eg, T cruzi DTU).
The remaining 30–40% of people with Chagas disease
will evolve to chronic symptomatic forms within
10–30 years, such as Chagas heart disease, the most
prevalent symptomatic form, and digestive forms,
characterised by megaoesophagus or megacolon (or
both). Digestive forms occur mainly in countries south of
the equator, which could be related to the genetic diversity
of the parasite, but the scientific data on this are scarce.
Cardiac-associated and digestive-associated forms might
4 www.thelancet.com Published online December 7, 2023 https://doi.org/10.1016/S0140-6736(23)01787-7
occur concurrently, increasing the chance of disability.19
Increased life expectancy in endemic countries,
coupled with new lifestyles resulting from urbanisation,
are responsible for high rates of cardiovascular risk
factors, such as metabolic syndrome, and other
associated heart diseases, such as cardiomyopathy in
older patients.86 A distinction between the differential
diagnosis of Chagas heart disease and cardiomyopathy
in older patients might not always be possible, for
instance, in cases of atrial fibrillation or even
bradyarrhythmia due to degenerative process, resulting
in the need for a pacemaker. In addition, the increase in
life expectancy has contributed to an increase in the
prevalence of chronic forms of Chagas disease,
particularly in patients with access to diagnosis and
treatment. As a result, people with the chronic cardiac
form of the disease have a greater chance of survival,
with greater recognition of the overlapping digestive
forms of the disease.87,88
Chagas heart disease can manifest through three major
syndromes; namely, sudden cardiac death, usually
associated with tachyarrhythmias, such as ventricular
arrhythmias, and often wrongly identified as a heart
attack;89 heart failure, associated with varying degrees of
ventricular systolic dysfunction and increased filling
pressures; and thromboembolism, from related
intracavitary thrombi.90,91
Although the prognosis of Chagas heart disease is
typically poorer than that of other heart diseases, there is a
heterogeneity of scenarios in this cardiomyopathy. In the
initial stages, patients with Chagas heart disease have no
symptoms nor ventricular systolic dysfunction, and the
disease can only be detected through active research of
typical electrocardiographic alterations (stage A). The
prognosis in this early stage is much more favourable than
the symptomatic clinical forms with treatable heart failure
(stage C), and even more than refractory syndrome
(stage D), where heart transplantation would be the only
therapeutic option. People in intermediate stages of Chagas
heart disease do not manifest symptoms of heart failure,
but rather present progressive degrees of ventricular
systolic dysfunction, with or without segmental contractile
changes (stage B).92 Although alternative classifications
have been used, they all seek the same objective of
differentiating the prognosis in Chagas heart disease.84
Sudden cardiac death could be the first manifestation
of Chagas disease, occurring even in the latent and silent
phase of the disease when those who are infected with
T cruzi are unaware of their status, and is identified as
the leading cause of death in Chagas heart disease.
Predicting the risk of this event is one of the great
challenges in managing Chagas disease. Implantable
cardioverter defibrillators are indicated for the prevention
of malignant arrhythmic events in patients at high risk of
sudden cardiac death.90,93
Although the digestive forms of Chagas disease present
a better prognosis in relation to heart disease, they are

responsible for substantial reductions in the quality of life.
Oesophagopathy is manifested by progressive dysphagia,
odynophagia, oesophageal reflux, and megaoesophagus
associated with achalasia, malnutrition, and risk of
Acute phase (with a fever >7 days)
Contact with a triatomine or its faeces (bite or
presence of the vector in the home); or Romaña
sign or inoculation chagoma
Ingestion of suspicious food or undercooked
game meat; or symptoms of people from the
same family or community, with food as a
common source of infection
Newborn of a mother infected with
Trypanosoma cruzi or with clinical or
epidemiological suspicion
Receptor of blood or blood products within
120 days before symptoms
Receptor of organs or tissues (any time)
Contact with T cruzi culture; or health-care
professional in contact with blood of people with
Chagas disease or professionals involved in
detection of bugs
Immunosuppression conditions in chronic
Chagas disease cases (co-infection of T cruzi and
HIV, cancer treatment, autoimmune disease, or
post-transplantation)
Chronic phase
Clinical or epidemiological suspicion; and index
case family and household contacts
Prenatal care
Evaluating an excluded blood donor
Seroepidemiological surveys
www.thelancet.com Published online December 7, 2023 https://doi.org/10.1016/S0140-6736(23)01787-7
bronchoaspiration.94 Oesophageal cancer might overlap
with more severe cases.95 Megacolon might result in
persistent constipation (>5–7 days), with recurrent
faecalomas that, in addition to abdominal discomfort and
Clinical and epidemiological
situations
Classical vectorial transmission
Oral transmission
Vertical transmission
Blood transmission
Organ transplantation
Accidental transmission
Chagas disease reactivation
Chronic Chagas disease
Pregnant with possibility of
chronic Chagas disease, to avoid
vertical transmission
To confirm chronic Chagas
disease after a first positive
screening
Epidemiological studies
Diagnostic strategy
Fresh smear (direct parasitological test); if negative,
concentrations tests (microhaematocrit or Strout) of
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
Fresh smear (direct parasitological test);
concentration tests; IgG seroconversion; or PCR
might be useful if available
Fresh smear (direct parasitological test) from
newborn blood or concentration method (eg, micro-
haematocrit) at birth; PCR might be useful if
available before 9 months of age; or
two serologies (IgG) after 9 months
Fresh smear (direct parasitological test);
concentrations tests; PCR upon resource availability;
or IgG seroconversion
If recipient previously infected, follow up for
reactivation with parasitological tests such as
quantitative PCR with high sensitivity
Take blood immediately for serology after start of
treatment to evaluate possibility of previous
infection; after 5 days, direct parasitological tests;
PCR upon resource availability; and second serology
after 20–40 days to evaluate IgG seroconversion
Serial parasitological tests; serial quantitative PCR
(blood); or PCR in biopsies specimens
First line: two conventional IgG serologies (ELISA,
IHA, or IIF); non-conventional IgG serologies might
accelerate and amplify the access to diagnosis
(recombinant ELISA or CMIA); or rapid diagnostic
tests (immunochromatography) of proven quality
might be used for screening purposes to facilitate the
diagnose and treat principle in PHC
Rapid diagnostic tests of proven quality can be used Follow up the newborn and evaluate other
for screening purposes;82 confirm that the mother children from the same mother; and treat the
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
Conventional serology should be used; avoid
recombinant ELISA and CMIA that are commonly
used in blood banks
High-sensitivity rapid diagnostic tests of proven
quality59,83
Seminar
Surveillance and control or prevention
strategies
Entomological and reservoir research; and
environmental surveillance actions
Epidemiological investigation (of symptoms in
relatives or contacts, or both); investigate and
report outbreak; and safe food handling practices
Laboratory tests for mother and other children
with IgG serologies; and prevention through
screening, diagnosis, and treatment of all women
of childbearing age in endemic regions
Sanitary inspection in hospitals and blood
centres; haemovigilance: a single test of high
sensitivity (ie, ELISA or CMIA) must be used for
blood exclusion
All organ donors and recipients at risk should be
screened for anti-T cruzi antibodies; sanitary
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
Start specific treatment before any laboratory
result if transmission is highly probable; use of
personal protective equipment; and worker
health surveillance
Avoid excessive immunosuppression, if possible;
benznidazole prophylaxis in T cruzi–HIV
co-infection with CD4 count of <200 cells per µL;
or Chagas disease reactivation as a condition for
AIDS-defining event to Brazilian epidemiological
surveillance81
Search for new cases in family members and
household contacts; and annual ECG search for
typical ECG pattern* that defines progression to
Chagas heart disease
Counsel people with confirmed cases not to
perform new blood donations; and evaluate
treatment and clinical form of confirmed cases
Update information systems and guide
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
torsion (sigmoid volvulus), with intestinal obstruction and
mesenteric infarction, requiring urgent surgery. The main
clinical manifestations of chronic Chagas disease and their
economic and social effects are described in figure 1.
Laboratory diagnosis
For diagnostic purposes, it is important to distinguish
between the two Chagas disease phases, acute and
chronic, due to the difference in parasitaemia and the
techniques necessary for a successful diagnosis.
Acute phase
In the acute phase, T cruzi parasites are detectable in
peripheral blood, which should be investigated. An easier
and more affordable test than other techniques such as
PCR is the fresh smear, where very rapid movements of
the parasite (thereby displacing red blood cells) might be
observed, confirming the diagnosis. This technique
requires an experienced technician. As parasitaemia
declines over time, the sensitivities of the parasitological
tests reduce 20–30 days after the first symptoms, and
concentration tests, such as microhaematocrit or Strout
techniques, can be used.44,92,96 Serial exams are
recommended to obtain higher positivity in a non-
congenital scenario of acute Chagas disease.
Chagas disease antibodies in the acute phase, as for any
infectious disease, are primarily of IgM class and might be
found after the first 10–15 days of symptoms. Nevertheless,
there are no commercially available kits and positive

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 Seminar

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

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 Seminar
(mainly IgG1 and IgG3 subclasses) detected for life in
people who are untreated. Although most individuals
with T cruzi infection (around 75–80%) have high
concentrations of antibodies, approximately 15% have
intermediate concentrations, and a minority (5%) have
low antibody concentrations, which makes the follow-up
of treated individuals more difficult.44 Spontaneous cure
has been exceptionally described,104 but additional studies
estimate this possibility to be less than 1%.105
WHO106 and PAHO59 strongly recommend the use of at
least two serological tests that represent different
methodological principles or different sorts of antigens:
one being of high sensitivity (eg, indirect immuno­
fluorescence or the immunoenzymatic test referred to as
enzyme-linked immunosorbent assay), and one of high
specificity (eg, indirect haemagglutination). If both tests
are reactive, the serum is positive and belongs to an
individual infected with T cruzi. If both are non-reactive,
the individual is not infected. Should one test be reactive
and the other non-reactive, a third test should be used.
Through the proper use of serological tests, it is possible
to correctly diagnose up to 98% of the sera tested;
however, cross reactions might occur, mainly in Chagas
disease-endemic regions that are also endemic for
leishmaniasis (in most cases, visceral leishmaniasis).
A substantial improvement to the diagnostic process of
chronic Chagas disease includes the use of rapid
diagnostic tests as a point-of-care screening tool.107 Many
kits are available with different behaviours83 and an array
of specific antigens. Advantages are clear, as no laboratory
personnel is necessary, and the result can be read
immediately, facilitating the diagnose and treat principle.
Disadvantages are mainly due to a lower sensitivity when
compared with other serological methods, so a rapid
diagnostic test should not be used as a single test for
diagnosis. Positive results obtained through rapid
diagnostic tests should be confirmed through serologies,
to certify that the individual is infected.
The use of parasitological tests in the chronic phase is
not encouraged for diagnostic purposes, as parasites are
scarce or absent in blood; however, they might be applied
with immunosuppressed patients to monitor reactivation.
PCR is usually used due to a high sensitivity and
quantification capacity, which means it is able to measure
the parasitic load. PCR is also useful after treatment with
parasiticidal drugs, when a positive result detects
treatment failure.102
A clinician might be faced with different real-life
situations, with each requiring a different demand for
laboratory tests to exclude or confirm a T cruzi infection.
Table 1 describes different diagnostic strategies, as well
as necessary clinical and surveillance actions.
Antiparasitic treatment
Ensuring access to effective, efficient, and safe
antiparasitic treatment for T cruzi infection remains a
challenge. There are only two effective drugs available for
8 www.thelancet.com Published online December 7, 2023 https://doi.org/10.1016/S0140-6736(23)01787-7
the treatment of Chagas disease; namely, nifurtimox and
benznidazole, which were both discovered between
the 1960s and 1970s. Both drugs are effective in reducing
the duration and clinical severity of Chagas disease by
enabling parasite elimination when cases are treated
early in the natural history of the disease (in acute,
congenital, and some chronic Chagas disease cases, in
addition to cases of reactivation in immunosuppressed
hosts), with potential gains in terms of quality of life by
overcoming eventual physical limitations; however, the
available therapeutic regimens can lead to unwanted
adverse reactions and treatment discontinuation.17,59 As
an infectious disease with a chronic course comprising
several disabling clinical syndromes, the treatment of
Chagas disease should adopt the concept of
comprehensive care, with different objectives: to promote
the clearance of parasites using antiparasitic drugs,
aiming at cure or at least reducing parasitaemia, thereby
preventing clinical progression and vertical trans­
mission;18 to manage and provide symptomatic treatment
for the chronic cardiac or digestive forms of Chagas
disease (or both); and to provide psychosocial support to
people with Chagas disease and their families. Treatment
is expected to prevent or at least decrease morbidity,
disability, and mortality associated with Chagas disease.65
Effectiveness
The effectiveness of both benznidazole and nifurtimox
depends on the phase of the disease. For congenital
transmission, both drugs are very effective when used in
the first year of life.61,108 At the recent chronic phase, when
parasites have been circulating for a short time (<10 years,
for instance in children <12 years) the percentage of cure is
around 60%;14,109 however, in chronic cases where the
parasite has been present for at least two decades, the rate
of cure is around 20–40%, but this can only be established
after a significant period of follow-up.110 Age cannot be
used as a cutoff point for treatment if the transmission
mechanism is not evaluated, considering that recent cases
of oral transmission can occur in any age group
(eg, an individual aged 50 years might be in the acute or
recent chronic phase of Chagas disease, with a high chance
of cure).111
In an international controlled clinical trial,
benznidazole was shown to not be able to reduce
mortality in patients with advanced Chagas heart
disease,112 which is why it is very important that diagnosis
occurs in the early stages of the Chagas disease, when
treatment is not contraindicated and is associated with
clinical benefits. Table 2 describes the indications,
contraindications, objectives, doses, and main adverse
events of the available antiparasitic drugs.
A new variable that should be considered when it
comes to the effectiveness of treatment is the T cruzi
DTU. Remarkable differences were seen in a study of
children younger than 12 who were treated in Honduras
(DTU TcI), children younger than 15 who were treated in

Guatemala (DTU TcI), and children younger than 18 who
were treated in Bolivia (DTU TcV).115 This study showed
that most children in Honduras (87%) and Guatemala
(58%) were seronegative 1 year after treatment, but only a
few (0–5·4%) had the same results in Bolivia, with
identical protocols being followed.
Therapeutic effect is measured by a decline in antibody
response, which might take some years given the strong
antibody response to an array of different antigens of
T cruzi. In recent clinical trials, PCR has been used for
post-treatment follow-up, with therapeutic failure detected
in the presence of positive results; however, the clinical
relevance of this result still requires further evaluation.116
Although regional guidelines suggest comparability of
efficacy between benznidazole and nifurtimox based on
observational studies,59 there are no randomised protocols
in the context of acute T cruzi infection, and currently
there are two ongoing clinical trials comparing the
two drugs in the chronic phase of Chagas disease.113,114 The
efficacy of new imidazoles such as posaconazole and
ravuconazole has been evaluated in randomised clinical
trials, with negative results, although dose and treatment
durations differed from those indicated by preclinical
studies and pharmacodynamic models.117–120
On the basis of results of combined evaluations of
these new drugs with shorter or reduced doses of
benznidazole, especially by the BENDITA study,119 it is
postulated that lower doses of drugs than currently
recommended could maintain efficacy, with fewer
adverse events and less treatment discontinuation. In
this respect, studies evaluating redosing regimens of
benznidazole and nifurtimox for adults are in
progress.113,114,121–123 In a recent prospective, historically
controlled study, the 60-day treatment regimen of
nifurtimox was more effective than the same dosing for
30 days in children aged 0–17 years, but the 60-day and
30-day nifurtimox regimens appeared to be equally
efficacious in children younger than 2 years.61
Recent studies show the dormancy capacity of
intracellular amastigotes, which can resist treatment
while remaining metabolically inactive, with the ability to
later transform into trypomastigotes. Therefore, the
search for compounds capable of overcoming dormancy
might be the key to more effective treatment.124
Tolerance
Both nifurtimox and benznidazole might cause adverse
reactions, with better tolerance among children aged
under 12 years (table 3). Nifurtimox is mainly associated
with weight loss and psychiatric adverse effects, and
benznidazole with cutaneous and neurological reactions.
With both drugs, adults have almost twice the frequency
of adverse reactions (55% with benznidazole and
60·9% with nifurtimox) compared with children
(25% with benznidazole and 29·3% with nifurtimox).
The discontinuation rate is slightly higher for nifurtimox
in children (4% with benznidazole and 7·4% with
www.thelancet.com Published online December 7, 2023 https://doi.org/10.1016/S0140-6736(23)01787-7
Seminar
Objective of treatment and contraindications
Acute Chagas disease (all age groups)
Patients with congenital Chagas disease Cure, success rate approximately 100%
Patients with other acute Chagas disease Cure, success rate approximately 60–80%
Patients with reactivation (immunosuppression) Reduce parasitaemia and mortality
Pregnant women Treat the mother only after pregnancy, except in
life-threatening conditions
Chronic indeterminate Chagas disease
Children aged <12 years Cure, success rate approximately 60%
Adolescents and adults aged <50 years Cure, success rate 20–40%; reduce organ damage
Adults ≥50 years old Shared decision on treatment; rule out other
clinical conditions (eg, hepatic or renal failure) to
reduce organ damage; if recent infection is
suspected, which is more frequent in cases of
oral transmission, age alone should not be a
limiting factor for treatment
Girls and women of childbearing age (rule out pregnancy Reduce vertical transmission rate
and recommend contraception during the treatment of
women of childbearing age)
Pregnant women Treat the mother only after pregnancy; lactation
is not a contraindication
Mild cardiac chronic Chagas disease*
All age groups Shared decision on treatment, possible benefit if
there is no contraindication
Advanced chronic Chagas disease
All age groups Do not treat
Benznidazole and nifurtimox have similar benefits according to observational studies (randomised trials comparing
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.
Table 2: Indications, contraindications, and objectives for benznidazole and nifurtimox
nifurtimox) and similar for adults (5–31% with
benznidazole and 14·3% with nifurtimox).125,126
Treatment follow-up
A positive parasitological result after treatment indicates
treatment failure. Reintroduction of the same drug for a
new 60-day treatment could be an alternative, as well as
the use of the other drug (ie, nifurtimox if benznidazole
appears to have failed). Serological cure, defined by the
absence of antibodies, is more easily attainable in treated
infants aged up to 1 year, due to the limited circulation
time of the parasite. When T cruzi has been present for
years, the total absence of antibodies becomes more
difficult, due to strong immunological memory. A new
approach based on the enzymatic effect of the parasite to
cleave apo-lipoprotein has been suggested to ascertain
cure in children treated with nifurtimox.127
Chagas disease comprehensive care
The approach to Chagas disease has changed substantially
over the years, alongside the concept of integral health
(encompassing promotion, prevention, care, and
rehabilitation actions), defining health as physical, mental,
and social wellbeing. This concept has led to a shift from
disease-centred care to person-centred care (figure 2).
The identification of asymptomatic people in the latent
period of infection is one of the great challenges related
9
 Seminar
Occurrence time and response
Benznidazole
Skin: local itching, localised macules, and papules Occurs around day 10 of treatment; response is to start
(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
infection (or both), and fever (moderate); drinks, and if severe, suspend benznidazole and refer
Stevens-Johnson syndrome (severe) patient to a higher level of health care
Digestive: abdominal pain, nausea, and vomiting Occurs within the first 2 weeks of treatment; response
(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
choluria, hepatomegaly, and jaundice (severe) benznidazole after the meals; if severe, suspend
benznidazole and refer patient to a higher level of
health care
Neurological adverse reactions (occurring in 5% of Occurs after 50 days treatment; response is 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
or areas that lack sensation); dose dependent; health care
slow recovery over months
Bone marrow aplasia (rare, occurring in Occurs between days 20 and 30 of treatment (it is
1 of 2000 patients84): leukopenia, neutropenia, important to evaluate a blood count in the third week
and agranulocytosis with fever. Not dose of treatment); response is immediate and permanent
dependent; recovery without sequelae interruption of benznidazole
Nifurtimox
Digestive (occurring in 60% of patients84): Occurs within the first 2–3 weeks of treatment, and is
anorexia, nausea, and weight loss maintained throughout the treatment; response is to
maintain nifurtimox, recommend counselling on food,
and recommend administration of nifurtimox after the
meal
Psychiatric (occurring in 22% of patients84): Occurs within the first 2–3 weeks of treatment;
depression, panic attack, and psychomotor response is to suspend nifurtimox for a few days (or
agitation until the symptoms reduce)
Neurological (occurring in 18% of patients84): Occurs between days 2 and 10 of treatment; response
headache, irritability, and dizziness or vertigo is to administer symptomatic treatment, and if severe,
(light); peripheral neuropathy and paraesthesia in suspend nifurtimox and refer to a higher level of health
soles and palms; dose dependent; slow recovery care
over months
Recommended benznidazole doses are 5–10 mg/kg per day for 60 days (12·5 mg or 25 mg dispersible tablets) for
children with a high tolerance, 5 mg/kg per day for 60 days (100 mg tablets) for adults with acute or chronic Chagas
disease, and 7–10 mg/kg per day for 10 days in cases of accidental transmission. Other general side-effects associated
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-
effects occur, maintain benznidazole and evaluate symptomatic treatment. Recommended nifurtimox doses are
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
(120 mg tablets) for adults with acute or chronic Chagas disease, and 10 mg/kg per day for 10 days in cases of
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
symptomatic treatment.
Table 3: Adverse reactions associated with benznidazole and nifurtimox
to Chagas disease diagnosis. As shown, early diagnosis
not only increases the chances of cure, but also reduces
the rate of vertical transmission (in the case of girls and
women of childbearing age), and potentially prevents
progression to chronic forms of the disease that are
costly for patients, their families, and health systems.18
Recognition of vulnerable territories by health managers,
active searches for cases by well trained health
professionals in areas that are at risk, and empowered
communities demanding health care are mitigation
strategies for this access barrier to diagnosis. National
programmes should integrate health care and
surveillance actions and implement compulsory
notification of acute and chronic Chagas disease cases,
10 www.thelancet.com Published online December 7, 2023 https://doi.org/10.1016/S0140-6736(23)01787-7
with clear and comparable definition criteria among
endemic and non-endemic countries.
Ethics-based counselling should be a central practice in
screening, diagnosis, and treatment, with the goal of
greater patient and family adherence and a reduction in
anxiety, depression, and fear. The false ideas that most
people with Chagas disease will become disabled or die
should be dismissed; instead, it should be remembered
that around 60% of patients can remain in the chronic
indeterminate form of Chagas disease their entire lives
and must be monitored and treated in primary health
care. After confirming diagnosis, counselling on
prognosis is recommended and an ECG is crucial to
guide specific interventions, even if the patient has no
cardiac symptoms. In addition, annual assessments with
an active search for symptoms and an ECG are necessary
to identify possible clinical progressions.
In table 4, the recommended actions at each level of
care, foreseen objectives, and sectors responsible for
their performance are described, defining the ideal
patient journey. Primary health care is central in the
Chagas disease comprehensive care approach and,
whenever possible, a decentralised model of care,
including access to diagnosis and treatment at the
primary care level, should be encouraged. Health
professionals and managers should include community
leaders in initiatives that encourage surveillance,
environmental education, and vector control, thereby
promoting health, prevention, and control of the disease.
In addition, the multiprofessional primary health-care
team has an important role in Chagas disease education,
using clear and comprehensive communication,
promoting self care, improving quality of life, and
identifying a need for psychosocial support. Community
involvement should be encouraged to promote and
demand prevention and care actions. At the quaternary
care level, all sectors must be committed to offering a
multidisciplinary approach and appropriate support to
patients and their families.65
Identified gaps
From a global agenda perspective, Chagas disease is
included into the third of the Sustainable Development
Goals: “ensure healthy lives and promote well-being for
all at all ages”, with the aim to “end the epidemics of
AIDS, tuberculosis, malaria and neglected tropical
diseases, and combat hepatitis, waterborne and other
communicable diseases” by 2030.33,129 However, the
persistence of Chagas disease in endemic and non-
endemic countries results from a succession of so-called
failures in scientific, market, and public health spheres.130
Insufficient knowledge of the disease and the people it
affects, costly and scarce diagnostic and therapeutic tools,
and policy limitations regarding the management and
planning of comprehensive care for Chagas disease in
national health systems all pose significant barriers to
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
be identified when it comes to Chagas disease, which
are outlined below. First, the absence of a short-term
biomarker capable of assessing the therapeutic
response. Potential serological negativity might take up
to two decades in the chronic phase, which is unfeasible
for clinical studies. PCR, which has been used as a
surrogate endpoint, might not be adequate as the
absence of sustained parasitological clearance for
12–24 months does not necessarily mean the absence of
clinical benefit. It is postulated that the reduction of
parasitaemia, maintained at a low steady state, could
hypothetically mean a lower probability of clinical
progression.131,132
Second is the scarcity of studies specific to Chagas
heart disease that evaluate the effectiveness and security
of symptomatic treatment. The risk of concomitant
bradyarrythmia and tachyarrhythmia in the same
individual, the high risk of sudden death even in early
stages of the disease, and the high number of cardio­
embolic events even using prophylaxis strategies
recommended for other heart diseases make Chagas
heart disease a distinct pathophysiological model,
with hard clinical management. The ongoing

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 Seminar

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

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

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

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


PARACHUTE-HF trial (NCT04023227) is a study to
specifically evaluate the benefits of a drug (sacubitril–
valsartan) for heart failure in the pathophysiological
model of Chagas heart disease.
Third, other investments in research and development
are essential for better clinical management of Chagas
disease and the reduction of its burden. These
investments include research to optimise antiparasitic
treatment options that use new chemical molecules in
monotherapy or in combination, formulations for use in
children and newborns, safer drugs for use in pregnant
women, vaccines as a preventive measure, and the
identification of a biomarker of disease progression.
Identification of this biomarker would allow the targeting
of early symptomatic treatments, avoiding progression to
more severe cases with risk of death or disabilities, and
the resulting high costs for health systems.133–135
Many other structural roadblocks need to be overcome
for the 2030 agenda challenge on Chagas disease to be
met. These roadblocks include the economic difficulties of
people with Chagas disease in endemic low-income
countries; the weaknesses of health systems in these
countries that need to provide specialised and expensive
treatments (eg, cardiac implantable electronic devices); the
time-consuming and difficult referral system for tertiary
care, which is often concentrated in large urban centres,
far away from people affected by the disease; the political,
legal, and linguistic issues restricting health access of
migrants in non-Chagas disease-endemic countries;136 the
scarcity of knowledge among health professionals
regarding Chagas disease; and the power dynamics
between health professionals and patients.66 New strategies
are needed, including implementation research; updated
public policies; increased community participation;
improved information, education, and communication
materials that contribute to breaking down stigma and
eliminating fear and advocacy actions.5,137,138
More than 100 years after its discovery, Chagas disease
persists as a crucial global public health problem, with an
unacceptably high morbimortality burden. The availability
of effective and comprehensive prevention, diagnosis,
treatment, and care actions through health systems has
been poor. Moreover, new challenges are posed by the
ageing of the affected population and the coexistence of
immunosuppressive conditions. Therefore, implemen­
tation research on diagnosis and treatment, contextualised
and nested in a One Health perspective and that
incorporates civil society and the scientific community,
should be increasingly valued, in addition to the generation
of basic evidence for a disease that now has a global reach.
Contributors
ASdS, DV, ANR, and AOL performed the scientific literature search and
reviewed the most relevant articles. ASdS, DV, and AOL wrote the first
draft of the Seminar. ASdS prepared the original tables and figures.
ANR and AOL reviewed and edited the Seminar. All authors have seen
and approved the final text.
Declaration of interests
We declare no competing interests.
www.thelancet.com Published online December 7, 2023 https://doi.org/10.1016/S0140-6736(23)01787-7
Seminar
Acknowledgments
We thank Valentina Carranza Weihmüller (CUIDA Chagas Project) for
preparing the original figures. ASdS declares grants from the Research
Support Foundation of the State of Rio de Janeiro (Scientist of Our State
number E-26/201.120.2021); ANR declares grants from the Brazilian
National Council for Scientific and Technological Development
(Scientific Productivity Scholarship number 311799/2019-1). The funding
sources had no role in the writing of the Seminar or the decision to
submit for publication.
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