Rev Soc Bras Med Trop 49:Supplement I, 2016
doi: 10.1590/0037-8682-0505-2016
Consensus
2nd Brazilian Consensus on Chagas Disease, 2015*
João Carlos Pinto Dias[1], Alberto Novaes Ramos Jr[2], Eliane Dias Gontijo[3],
Alejandro Luquetti[4], Maria Aparecida Shikanai-Yasuda[5], José Rodrigues Coura[6],
Rosália Morais Torres[3], José Renan da Cunha Melo[3], Eros Antonio de Almeida[7],
Wilson de Oliveira Junior[8], Antônio Carlos Silveira[9], Joffre Marcondes de Rezende[10],
Fabiane Scalabrini Pinto[11], Antonio Walter Ferreira[12], Anis Rassi[13],
Abílio Augusto Fragata Filho[14], Andréa Silvestre de Sousa[15], Dalmo Correia[16],
Ana Maria Jansen[6], Glaucia Manzan Queiroz Andrade[3],
Constança Felícia De Paoli de Carvalho Britto[6], Ana Yecê das Neves Pinto[17], Anis Rassi Junior[13],
Dayse Elisabeth Campos[18], Fernando Abad-Franch[1], Silvana Eloi Santos[3], Egler Chiari[19],
Alejandro Marcel Hasslocher-Moreno[15], Eliane Furtado Moreira[20], Divina Seila de Oliveira Marques[21],
Eliane Lages Silva[22], José Antonio Marin-Neto[23], Lúcia Maria da Cunha Galvão[19],
Sergio Salles Xavier[24], Sebastião Aldo da Silva Valente[17], Noêmia Barbosa Carvalho[25],
Alessandra Viana Cardoso[26], Rafaella Albuquerque e Silva[26], Veruska Maia da Costa[26],
Simone Monzani Vivaldini[26], Suelene Mamede Oliveira[27], Vera da Costa Valente[17],
Mayara Maia Lima[26] and Renato Vieira Alves[26]
[1]. Centro de Pesquisa René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brasil. [2]. Faculdade de Medicina, Universidade Federal do
Ceará, Fortaleza, Ceará, Brasil. [3]. Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brasil.
[4]. Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Goiás, Brasil. [5]. Faculdade de Medicina, Universidade de
São Paulo, São Paulo, São Paulo, Brasil. [6]. Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brasil. [7]. Faculdade de
Ciências Médicas, Universidade Estadual de Campinas, Campinas, São Paulo, Brasil. [8]. Faculdade de Ciências Médicas de Pernambuco, Universidade de
Pernambuco, Recife, Pernambuco, Brasil. [9]. Organização Pan American de Saúde, Brasília, Distrito Federal, Brasil. [10]. Hospital das Clínicas, Faculdade
de Medicina, Universidade Federal de Goiás, Goiânia, Goiás, Brasil. [11]. Hospital das Clínicas, Faculdade de Medicina, Universidade Federal de Minas
Gerais, Belo Horizonte, Minas Gerais, Brasil. [12]. Instituto de Medicina Tropical de São Paulo, Universidade de São Paulo, São Paulo, São Paulo, Brasil.
[13]. Hospital Anis Rassi, Goiânia, Goiás, Brasil. [14]. Instituto de Cardiologia Dante Pazzanese, São Paulo, São Paulo, Brasil. [15]. Instituto Nacional
de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brasil. [16]. Faculdade de Medicina, Universidade Federal do
Triângulo Mineiro, Uberaba, Minas Gerais, Brasil. [17]. Instituto Evandro Chagas, Ministério da Saúde, Belém, Pará, Brasil. [18]. Hospital das Clínicas,
Faculdade de Medicina, Universidade Federal de Goiás, Goiânia, Goiás, Brasil. [19]. Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais,
Belo Horizonte, Minas Gerais, Brasil. [20]. Fundação Ezequiel Dias, Secretaria de Estado de Saúde de Minas Gerais, Belo Horizonte, Minas Gerais, Brasil.
[21]. Faculdade de Medicina, Universidade Estadual de Londrina, Londrina, Paraná, Brasil. [22]. Departamento de Ciências Biológicas, Universidade Federal
do Triângulo Mineiro, Uberaba, Minas Gerais, Brasil. [23]. Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo,
Brasil. [24]. Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brasil. [25]. Hospital
das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brasil. [26]. Secretaria de Vigilância em Saúde, Ministério da Saúde,
Brasília, Distrito Federal, Brasil. [27]. Empresa Brasileira de Hemoderivados e Biotecnologia, Ministério da Saúde, Brasília, Distrito Federal, Brasil.
* This article was originally published in Portuguese (Brazil), under license of the Creative Commons CC BY NC for noncommercial use, according to the reference: Dias JCP, Ramos Jr. AN, Gontijo ED, Luquetti A, Shikanai-Yasuda MA, Coura
JR et al. 2nd Brazilian Consensus on Chagas Disease, 2015. Epidemiol Serv Saúde 2016; 25 (esp):7-86. Available at: http://
scielo.iec.pa.gov.br/scielo.php?script=sci_arttext&pid=S1679-49742016000500007&lng=pt. / http://dx.doi.org/10.5123/S167949742016000500002
Correspondence author: Dr. João Carlos Pinto Dias.
e-mail: jcpdias@cpqrr.fiocruz.br
Received 30 November 2016
Accepted 05 December 2016
2nd Brazilian Consensus on Chagas Disease, 2015
3
Rev Soc Bras Med Trop 49:Supplement I, 2016
Abstract
Chagas disease is a neglected chronic condition with a
high burden of morbidity and mortality. It has considerable
psychological, social, and economic impacts. The disease
represents a significant public health issue in Brazil, with
different regional patterns. This document presents the
evidence that resulted in the Brazilian Consensus on Chagas
Disease. The objective was to review and standardize
strategies for diagnosis, treatment, prevention, and control
of Chagas disease in the country, based on the available
scientific evidence. The consensus is based on the articulation
and strategic contribution of renowned Brazilian experts with
knowledge and experience on various aspects of the disease.
It is the result of a close collaboration between the Brazilian
Society of Tropical Medicine and the Ministry of Health. It
is hoped that this document will strengthen the development
of integrated actions against Chagas disease in the country,
focusing on epidemiology, management, comprehensive
care (including families and communities), communication,
information, education, and research.
Keywords: Chagas disease. Epidemiology. Control.
Diagnosis. Treatment. Health care. Consensus. Brazil.
INTRODUCTION
General aspects of Chagas disease epidemiology, with
specific focus on Brazil
Chagas disease, an infectious condition with an acute and
chronic phase, is classified as a neglected disease by the World
Health Organization (WHO)(1) (2). As a result of human poverty,
it presents high morbidity and mortality load in endemic
countries, including Brazil, with focal expression in different
epidemiological contexts(1) (2) (3) (4). The geographic distribution
of the disease is limited primarily to the American continent due
to the distribution of more than 140 species of insect vectors
(Triatominae, Hemiptera, Reduviidae); hence, it is also called
American trypanosomiasis(5). Gradually, however, the disease
has reached non-endemic countries; this as a result of an intense
process of international migration and as the mode of disease
transmission has changed(6) (7) (8) (9) (10) (11) (12) (13).
The World Health Organization (WHO) estimates that
approximately 6-7 million people are infected worldwide,
mostly in Latin America(14).Recent estimates for the 21 Latin
American countries, based on data from 2010, showed that
5,742,167 people were infected by Trypanosoma cruzi, of
which 3,581,423 (62.4%) were living in the countries of the
Southern Cone Initiative against Chagas disease, especially
Argentina (1,505,235), Brazil (1,156,821), Mexico (876,458),
and Bolivia (607,186)(5). However, these data differ from
the estimates of other research groups using other methods
to define T. cruzi infection in many countries; this hinders
accurate establishment of the prevalence of Chagas disease in
the Americas. Nevertheless, the authors agree that the number
of infected individuals is still very significant in the health and
social context of the continent, requiring priority and attention
from the countries(15) (16).
Table 1 represents changes in epidemiological parameters
specific to Latin America in the recent years(5) (17).
Thus, despite advances in vector control and quality
assurance of blood transfusions in many of these countries,
especially from intergovernmental initiatives started in the
1990s(3) (4) (10) (11) (18), Chagas disease remains a relevant public
health problem in Latin America, showing different regional
patterns of epidemiological expression. The challenges are
magnified by the lack of access to diagnosis and systematic
treatment; according to 2015 estimates >80% of individuals
affected by Chagas disease globally had no such access. This
supports the high impact of morbidity, mortality, and the social
cost of this illness.
Uncontrolled human migration, environmental degradation,
climate change, high population concentrations in urban areas,
and precarious socio-economic conditions (housing, education,
sanitation, and income, among others) are determinants and
social conditioning factors for the transmission of T. cruzi(1) (10)
(11) (19) (20) (21) (22) (23)
. Infected populations are vulnerable to varying
degrees of neglect, expressed by overlapping and increased
exposure to other diseases, conditions and injuries; lower
coverage for preventive interventions; a higher likelihood of
illness; less access to a network of health services, to secondary
and tertiary health care, and to other services; poor quality of
primary care services; lesser likelihood of receiving essential
treatments; and greater likelihood of developing severe forms
of the disease with increased risk of progression to death(24).
From this perspective, it is essential to obtain greater
knowledge concerning the epidemiological scenario of Chagas
disease and its transmission dynamics, involving people who are
TABLE 1
Changes in mortality, prevalence, and incidence of vector-borne transmission of Chagas disease in 21 endemic countries in Latin America, in the years 1990,
2000, 2006, and 2010.
Parameters – estimates
1990
2000
2006
2010
Number of deaths/year
>45,000
21,000
12,500
12,000
Number of infected individuals
30,000,000
18,000,000
15.000.000
5,742,167
New cases/year – vector transmission
700,000
200,000
41.200
29,925
Total population at risk
100,000,000
40,000,000
28,000.000
70,199,360
Source: Adapted from the Pan American Health Organization, 2006(17) (TDR/WHO, PAHO, WHO); World Health Organization, 2015(5).
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2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
infected or are at risk of infection, different parasite populations,
vector species, and T. cruzi reservoirs. This integrated
knowledge is central to the search for consistent and sustainable
management actions, monitoring, and coherent health and social
control programs that are efficient and effective(1) (10) (11) (25) (26) (27).
Despite a clear need for more evidence, more than 105
years since the discovery of the disease by Carlos Ribeiro
Justiniano Chagas (1909) there are still important gaps in
technical, scientific, and political fields that must be overcome
to effectively face this widely-neglected condition.
Brazil, with its continental dimensions, is undergoing major
and rapid demographic, social, and environmental change,
but serious socio-economic and regional inequalities persist.
Here, diseases associated with social contexts of vulnerability
and neglect still afflict a considerable part of the population(28).
Gradually, however, a consistent improvement in the overall
health status and life expectancy of the Brazilian population has
been observed. This can be attributed to changes in the social
determinants of health, advances in the control of infectious
diseases, and implementation of a more comprehensive national
health system with relevant social participation(28) (29).
Despite these social advances, it is recognized that the
persistence of large social inequalities, that result in individual,
programmatic and social vulnerabilities, is strongly related to
Chagas disease. New health problems emerge, however, as
the result of an intense urbanization process and changes in
the social and environmental field; others tend to persist and
coexist(28), requiring new healthcare response networks(30).
These demand specific actions, adjusted to new realities,
focused on an integrated approach to the different components
involved in the natural history of the disease: humans, vectors,
reservoirs, and T. cruzi(3) (6) (15). The great extent and territorial
diversity, with the specific ecologic, demographic, social,
and economic dynamics of the regions, implies multiple
epidemiological and operational clinical scenarios(3) (4) (15).
In addition to the challenges, the coming years bring
opportunities for shared, more concrete action in fighting Chagas
disease. In 2015 the 17 new Sustainable Development Goals
(SDGs) were released; these are based on the eight Millennium
Development Goals (MDGs). The agenda, which was agreed
to and consolidated in the framework document Transforming
Our World: The 2030 Agenda for Sustainable Development,
represents a historic and unprecedented opportunity for
countries to seek new global paths(31). In a broader sense, in
order to promote prosperity and well-being for all, to protect the
environment and cope with climate changes(31), these decisions
will determine the global course of action to confront and
eliminate poverty.
Chagas disease is part of the third objective of this
document, which aims to ensure a healthy life and promote
well-being for all, at all ages. The goal is to control the acquired
immunodeficiency syndrome (AIDS) epidemic, to eradicate
tuberculosis, malaria, and neglected tropical diseases and to
combat hepatitis and waterborne and other transmitted diseases
by 2030(31). The progress in specific indicator composition to
monitor neglected tropical diseases in the world is highlighted,
2nd Brazilian Consensus on Chagas Disease, 2015
from the recognition of the number of people requiring
interventions against this group of diseases. In addition, Chagas
disease and other neglected tropical diseases also interface
with the second (zero hunger and sustainable agriculture), fifth
(gender equality), and sixth (drinking water and sanitation)
objectives(31).
MORBIDITY AND MORTALITY
Trypanosoma cruzi infection
In Brazil, few population-based systematic studies have been
conducted. This hinders accurate estimation of the magnitude
of the impact Chagas disease throughout history.
Prior to the 1950s, Chagas disease was recognized as an
eminently rural endemic disease, transmitted predominantly
through vectors, occurring in areas of high social vulnerability.
With industrialization, the disease became modeled in a new,
urban epidemiological context, increased by internal migration
within the country from rural to urban areas with consequent
growth of cities(4).
Between 1975 and 1980, a national serological survey in
the rural population of Brazil (except São Paulo), estimated
the prevalence to be 4.2%, corresponding to 6.5 million people
infected by T. cruzi(20) (32) (33). In 1996, it was estimated that the
prevalence of T. cruzi infection in Brazil was at 3.1% in 1978
and 1.3% in 1995, amounting to an estimated 1.96 million
people infected(34). Subsequently, the Pan American Health
Organization (PAHO) estimated that 21.8 million people in
endemic areas in Brazil were at risk, given the estimated 1.9
million (1.019% of the population) infected individuals(17).
In 2014, the first systematic review and meta-analysis
to estimate the prevalence of Chagas disease in Brazil was
published. It included publications from the period between
1980 and 2012, and estimated the pooled prevalence of Chagas
disease at 4.2% [95% confidence interval (95% CI): 3.1–5.7],
ranging from 4.4% (95% CI: 2.3–8.3) in the 1980s to 2.4% (95%
CI: 1.5–3.8) after 2000(35). In that study, the highest prevalence
was found in women (4.2%; 95% CI: 2.6–6.8), individuals
over 60 years old (17.7%; 95% CI: 11.4–26.5), residents in the
Northeastern (5.0%; 95% CI: 3.1–8.1) and Southeastern regions
(5.0%; 95% CI: 2.4–9.9), and in mixed urban/rural areas (6.4%;
95% CI: 4.2–9.4). It was estimated that 4.6 million people (95%
CI: 2.9–7.2 million) would be infected by T. cruzi in Brazil.
Emphasizing the limitation of the findings in the literature,
the authors highlight the need for new studies, with a view to
obtaining truer estimates(35).
From this and other studies, the most recent estimates in
Brazil regarding the number of people infected by T. cruzi vary
from 1.9 million to 4.6 million people(35) (36) (37), probably closer
now to 1.0–2.4% of the population.
This epidemiological scenario brings challenges in the
coming decades for the country to support control actions
and establish a consistent plan in the Unified Health System
[Sistema Único de Saúde (SUS)] for diagnosis, treatment, and
comprehensive care of millions of people(38), combined with
epidemiological surveillance adjusted to this reality(15) (22). It is
5
Rev Soc Bras Med Trop 49:Supplement I, 2016
presumed that up to 30% of chronically infected people are likely
to develop cardiac alterations and up to 10% may experience
digestive, neurologic, or mixed alterations. Given this, there is a
heightened need to structure a comprehensive network of timely
health care for Chagas disease in the country(39).
In order to establish estimates for the number of people
infected by T. cruzi, the publication Projeção da População do
Brasil por Sexo e Idade para o Período 2000/2060 e Projeção da
População das Unidades da Federação por Sexo e Idade para o
período 2000/2030 (Projection of Brazil’s Population by Sex and
Age for the Period 2000/2060 and Projection of the Federative
Unit’s Population by Sex and Age for the Period 2000/2030)
by the Brazilian Institute of Geography and Statistics [Instituto
Brasileiro de Geografia e Estatística (IGBE)] was taken as a
population-based reference. According to the IBGE the Brazilian
population will continue to grow until 2042, when it will reach
228.4 million people, mostly concentrated in urban centers.
From there, it will gradually decrease and it will account for
approximately 218.2 million individuals in 2060(40).
Table 2 shows the relative projection to the estimates of
the number of infected people by T. cruzi and the number of
Chagas disease cases in the chronic phase with the cardiac and
digestive form of the disease in Brazil, between 2015 and 2055,
according to five-year periods. In 2015, for example, taking as
a basis an estimated population of 204,450,649, it is estimated
that between 1,426,994 and 3,357,633 of Brazilian individuals
would be infected with T. cruzi. Of these, 142,699 to 335,763
would potentially have the digestive form and 428,098 to
1,007,290 would have the cardiac form of the disease. Moreover,
an estimated 856,197 to 2,014,580 individuals would potentially
present with T. cruzi infection in the indeterminate form.
In addition to internal migration in Brazil, with the
urbanization of Chagas disease its occurrence in migrants
from endemic areas in countries not traditionally endemic has
brought about an expanded discussion on the contexts of risk
and vulnerability, with a challenge to develop control actions
for these countries(3) (6) (7) (10) (11) (12) (13) (16) (18) (37) (41) (42). Multiple
bio-ecological, socio-cultural, and political factors have been
implicated in this process(10), demanding an increased need for
human and social sciences research concerning the disease(43).
In 2005, it was estimated that there were a total of 501,036
Brazilians in the United States, with a prevalence of infection
by T. cruzi of 1.02%(17), or 5,106 cases(44). In a broader sense, it
is estimated that the total of people infected by T. cruzi in that
country could range from 300 thousand to just over 1.0 million(8)
(9)
, with different impacts on the health system. It is worth noting
that this is a non-endemic area(9) (45).
It is estimated that approximately 72,000 people infected
by T. cruzi live in Europe(12). From analysis of the aggregated
data of a systematic review and meta-analysis investigating the
prevalence of Chagas disease in Latin American people living
in Europe (Spain, France, Switzerland, Italy and Germany), it
is estimated that the prevalence of this infection in Brazilian
migrants is 0.6% (from 0.16 to 1.12%) or 4/954(13). Migrants
from Bolivia had the highest prevalence of Chagas disease
(18.1%), followed by Paraguayan migrants (5.5%). The
prevalence among migrants from Argentina was 2.2%; there
were no cases of Chagas disease detected among migrants
from Uruguay, Venezuela, Panama, Guatemala, and Mexico(13).
The occurrence of other important international migration
waves within Latin America, such as from Bolivia and Paraguay
to Argentina and Brazil or from Colombia to Venezuela, is
TABLE 2
Projection of the prevalence estimates of T. cruzi infection and chronic-phase Chagas disease, cardiac and digestive forms,
in Brazil, from 2000 to 2055.
Year
Estimate of the Brazilian
population
Estimated number of infected people
Reference age range
Estimate of cases with the digestive
form
Estimate of cases with the cardiac
form
infection 1.02%a infection 2.4%b
infection 1.02%a infection 2.4%b
age range
Population
%
infection 1.02%a
infection 2.4%b
2000 173,448,346
≥5
156,133,836
90.0
1,592,565
3,747,212
159,257
374,721
477,770
1,124,164
2005 185,150,806
≥10
150,944,641
81.5
1,539,635
3,622,671
153,964
362,267
461,891
1,086,801
2010 195,497,797
≥15
145,563,676
74.5
1,484,749
3,493,528
148,475
349,353
445,425
1,048,058
2015 204,450,649
≥20
139,901,357
68.4
1,426,994
3,357,633
142,699
335,763
428,098
1,007,290
2020 212,077,375
≥25
133,880,929
63.1
1,365,585
3,213,142
136,559
321,314
409,676
963,943
2025 218,35014
≥30
127,334,466
58.3
1,298,812
3,056,027
129,881
305,603
389,644
916,808
2030 223,126,917
≥35
120,096,221
53.8
1,224,981
2,882,309
122,498
288,231
367,494
864,693
2035 226,438,916
≥40
112,013,898
49.5
1,142,542
2,688,334
114,254
268,833
342,763
806,500
2040 228,153,204
≥45
102,983,115
45.1
1,050,428
2,471,595
105,043
247,160
315,128
741,479
2045 228,116,279
≥50
92,984,144
40.8
948,438
2,231,619
94,844
223,162
284,531
669,486
2050 226,347,688
≥55
82,097,220
36.3
837,392
1,970,333
83,739
197,033
251,218
591,100
2055 222,975,532
≥60
70,485,475
31.6
718,952
1,691,651
71,895
169,165
215,686
507,495
Source: IBGE – Overall population estimates and by age group. Coordination of the Population and Social Indicators. Studies Management and Analysis of
Demographic Dynamics(40). aParameters for estimates (minimum and maximum) of the prevalence of T. cruzi infection - PAHO, 2006(17); Martins-Melo et al.,
2014(35). bParameters for maximum estimates of the prevalence of Chagas disease in the chronic phase with cardiac form (× 30%) and digestive form (× 10%).
6
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
recognized(10). On the other hand, from the second half of the
twentieth century, it is especially emphasized the intensification
of the movement of thousands of citizens from Latin America
to countries in North America (mainly the United States, but
also Canada), Europe (particularly Spain, among other nations),
Asia (Japan), and Oceania (Australia), increasing the number of
people with Chagas disease living in non-endemic countries(2) (7)
(10) (12) (42)
. Overall, this migration process is associated with the
search for improved living conditions for people from endemic
countries living in conditions of serious social vulnerability(10).
In addition to Brazilians potentially infected by T. cruzi living
abroad, a considerable number of people have migrated to Brazil
from other endemic countries such as Bolivia; an estimated 80,000
to 200,000 Bolivian migrants live in the State of Sao Paulo(46). This
fact has prompted discussion, within the country, about public
health policies consistent with the need for greater attention to
this migrant population, including viewing the precarious life and
work conditions to which they are subjected(46) (47).
In addition to the migration context, there is a clear shift
in the prevalence of infection by T. cruzi to older age groups,
which brings new challenges for the SUS. With the prevalence
of chronic phase Chagas disease resulting largely from infection
by vectors in the past, the probability of infectious and noninfectious comorbidities has expanded. These comorbidities
consist mostly of chronic degenerative conditions (especially
diabetes mellitus, systemic arterial hypertension, and other heart
diseases), human immunodeficiency virus (HIV) co-infection
with T. cruzi, and other immunosuppressive conditions that are
acquired or induced(2) (48) (49) (50) (51). The risks are amplified by
longer survival combined with migration and the urbanization
that had occurred over the past five decades(49).
As for other infectious diseases, T. cruzi can behave
as an opportunistic microorganism in individuals with
imunosupression(2) (49) (50) (51) (52). Although the first case of T. cruzi
and HIV co-infection was reported in the 1980s, the frequency
of this co-infection and of specific reactivation; the clinical
and laboratory features associated with co-infection; specific,
adequate treatments for T. cruzi infection in the context of
co-infection with HIV; and outcomes (survival and death) of
co-infected individuals, persist as knowledge gaps at a global
level(49) (52) (53).
In Brazil, we estimated the prevalence of co-infection
to be 1.3%(48) (49) (52). Considering that in 2014 there were
approximately 734,000 people living with HIV (without
AIDS) in Brazil, corresponding to a prevalence in the general
population of 0.4%,(51) there would be an estimated 9,542
cases of T. cruzi/HIV co-infection. On the other hand, since
the beginning of the AIDS epidemic in Brazil to June 2014,
total of 757,042 AIDS cases were registered in the Brazilian
Notifiable Diseases Information System [Sistema de Informação
de Agravos de Notificação] (SINAN)(50); it is estimated that
more than 9,842 of these would be co-infected. Therefore, it
is estimated that there are 19,384 cases of T. cruzi/HIV-AIDS
co-infection in Brazil, based on data up to June 2014, stressing
that many of these cases probably died, are undiagnosed, or
unrecognized as having co-infection. In Brazil, anti-T. cruzi
2nd Brazilian Consensus on Chagas Disease, 2015
antibodies testing is recommended for HIV-infected patients,
taking into account their epidemiological risks(51). It is worth
noting that, for surveillance purposes, since 2004 reactivation
of Chagas disease has been added to the list of AIDS-defining
illnesses, and has been an important marker, from the definitive
diagnosis of Chagas myocarditis and meningoencephalitis(39) (49)
(52) (54)
. Generally, such HIV co-infection occurs through sexual
transmission in individuals previously infected with T. cruzi.
A progressive decrease in the number of co-infection cases
is expected in Brazil, since Chagas is gradually becoming
restricted to higher age groups.
In addition to the above co-infection, generally, despite the
high morbidity and mortality of Chagas disease in Brazil, data
relating to the specific epidemiological surveillance of human
cases of the disease does not allow estimation of its magnitude,
since it is only mandatory to report cases in the acute phase to
SINAN. Furthermore, it is estimated that only 10–20% of acute
Chagas disease cases are actually reported.
In the period 2000–2013 (data updated in May 2014), 1,570
cases of acute Chagas disease were reported ̶ an average of 112
cases per year. This figure was derived from records from most
Brazilian states, with the exception of Mato Grosso do Sul and
Federal District in the Central-West region and Paraná in the
South. Most of these cases (1,430; 91.1%) were concentrated
in the North, followed by the Northeast (73; 4.7%), South (28;
0.2%), Central-West (27; 1.8%) and Southeast (12; 0.8%).
It is noteworthy that the State of Pará was responsible for 75%
of all cases in the country and 82% of cases in the Northern
region(55).
With regard to the municipality of residence, there were
163 reported cases of acute Chagas disease: 97 (60%) from
the Northern region, 37 (23%) from the Northeast, 14 (9%)
from the Central-West and, in smaller proportions, 9 (6%) and
6 (4%) from municipalities of the Southern and Southeastern
regions, respectively(55). This notification pattern is quite distinct
from that of the 1990s(4) (18) (19), but still demarcates operational
contexts of epidemiological silence in some areas.
Mortality
The burden of mortality related to Chagas disease in Brazil
remains high, despite the introduction of control measures(3) (29)
(35) (56) (57)
. A study conducted to quantify the mortality pattern
of Chagas disease in the period 1981–1998 found that out of
68,936 deaths in Brazilian individuals with a known birthplace,
32,369 (32%) deaths occurred in states other than the deceased’s
birthplace, varying from 0.3% in Rio Grande do Sul to 100% in
Roraima and Amapá. Most (67%) of these deaths in migrants
occurred in individuals of Minas Gerais (51%) and Bahia (16%).
Mortality rates of residents within the period showed a consistent
decline in the Southeast, South, and Central-West, but not in
the Northern and Northeastern regions, where the median age
at death was comparatively low(58).
Later, from 1999 to 2007, Chagas disease was recorded as the
cause of death on 53,924 (0.6%) of approximately 9.0 million
death certificates from the Brazilian Mortality Information
System [Sistema de Informações sobre Mortalidade (SIM)]:
7
Rev Soc Bras Med Trop 49:Supplement I, 2016
for 44,537 (82.6%) it was recorded as the underlying cause
and for 9,387 (17.4%) as an associated cause(59). Acute Chagas
disease was recorded in the statement in 2.8% of deaths. The
average number of deaths per year was 5,992, with an average
standardized mortality rate of 3.36/100,000 inhabitants/
year, verifying a gradual reduction in the specific mortality
rate of 26.4%. It is emphasized the decreasing tendency of
a standardized mortality rate, especially in the Central-West
region (-37.9%). The proportional mortality (for numerous
reasons) was 0.6%, highest in the Central-West region (2.17%)
where there was a reduction of 19.5%, with a significant
decreasing tendency. However, in this study, there was a
considerable increase of 38.5% in the Northeast region, with
an increasing tendency. Risk factors identified in the bivariate
analysis were older age groups and residence in the Central-West
region. In the multivariate analysis, however, age over 30 years
and residence in the States of Minas Gerais and Goiás and in
the Federal District were identified as risk factors(59). It should
be noted that more than 40% of expected deaths associated
with Chagas disease in Latin America occurred in Brazil(56) (59).
Another study of the same Brazilian population base
examined 53,930 deaths, recorded between 1999 and 2007,
where Chagas disease was mentioned as a cause of death. When
analyzed as the underlying cause, Chagas disease was the fourth
leading cause of death (10.8%) among all infectious diseases and
parasites(56). Of the 53,930 recorded deaths, 37,800 (84.9%) were
related to cardiac forms and 4,208 (9.4%) to digestive forms
of Chagas disease. Acute cardiac involvement was noted in
1,097 (2.5%) deaths; other organ involvement in 1,157 (2.6%);
and finally, other clinical presentations of the disease (central
nervous system involvement and no cardiac involvement
in the acute phase) in 281 (0.6%). The associated causes of
death with Chagas disease as the underlying cause included
diseases of the digestive, circulatory, and respiratory systems.
Direct complications of heart disease, especially conduction
disturbances/arrhythmias and heart failure were identified in
more than 35% of deaths, followed by shock (15%). Among the
basic causes of death in which Chagas disease was mentioned
as an associated cause, the most common diseases were of the
circulatory and respiratory systems (59%), followed by cancer
(11.6%) and digestive system diseases (10.6%). Cerebrovascular
disease, ischemic heart disease, and hypertensive diseases
were the main underlying causes of death in cases where
Chagas disease had been identified as an associated cause.
Chronic lung diseases and, in particular, chronic obstructive
pulmonary disease also represented particularly important
causes of death(56).
In an additional study from this same database, using
different spatial analytical approaches, we identified a cluster
of high mortality risk for Chagas disease involving nine States
of Brazil’s Central-West region: Almost all municipalities from
the States of Goiás and Minas Gerais, Federal District and
some municipalities from the States of São Paulo, Mato Grosso,
Mato Grosso do Sul, Tocantins, Piauí and Bahia. This area
was indicated by the authors as a priority for integrated planning
of actions to strengthen the network of attention focused
on Chagas disease(60).
8
A study examining regional patterns and tendencies in
Brazil over a longer time period (1979–2009), found that of
27,560,043 deaths analyzed, Chagas disease was the underlying
cause in 172,066 deaths(57). The proportional mortality of
Chagas disease was 0.62% with a crude specific death rate of
3.61 deaths/100,000 inhabitants/year and a specific mortality
rate adjusted for age of 5.19 deaths/100,000 inhabitants/year.
Nationally, there was significant reduction over the period, but
with important inter-regional differences; there was significant
reduction in the Southeast, South and Central-West regions,
but significant growth in the Northeast and Northern regions(57).
Another historical series, from 1980 to 2008, found that
the proportion of deaths attributed to Chagas disease as the
underlying cause remained stable in the period(29).
In the State of São Paulo from 1985 to 2006, there were
40,002 Chagas disease-related deaths. Chagas disease was
an underlying cause in 34,917 (87.3%) and an associated
cause in 5,085 (12.7%). The mortality rate, according to the
underlying cause, declined by 56.1%, but remained stable in
terms of associated cause of death. There were 44.5% more
deaths in men than in women, and 83.5% of deaths occurred
in people over 45 years old. The main causes associated with
those who had Chagas disease as underlying cause of death
were: direct complications of cardiac impairment (conduction
disorders, arrhythmias and heart failure). For Chagas disease
as an associated cause, the most important underlying causes
were ischemic heart disease, cerebrovascular disease, and
neoplasms(61).
On the other hand, from the national database on mortality
related to Chagas disease as the underlying cause, from 2000
to 2010, it was found that most deaths (85.9%) occurred in
males older than 60 years. These deaths were mainly caused
by cardiac involvement, and the mortality rate of this clinical
form of the disease decreased in all regions except in the North,
where there was an increase of 1.6%. The Northeastern region
had the lowest reduction, while the Central-West had the largest.
It is noteworthy that the mortality rate related to the digestive
form increased in all regions(61).
A pattern of aging and an expansion of ages at highest age
ranges for the population affected by Chagas disease has been
verified, not only by previous studies of mortality, but also
by other population-based studies based on cases of cohorts
followed through long periods of time(63) (64).
Data from the Ministry of Health on deaths from acute
Chagas disease indicate that in the period 2005–2013, the
national average annual mortality rate over the 14 years was
2.7% (37.9/14). In 2005, a high (20%) mortality rate was
recorded. This coincided with an acute Chagas outbreak by
oral transmission in Santa Catarina, at which time little was
known about the etiology and management of the disease by
this form of transmission. In 2006, the mortality remained high
(5.9%), with subsequent reduction that has remained relatively
constant (average of 1.7% from 2007 to 2013), ranging from
0.5% in 2009 to 4.7% in 2011. It is worth noting that the lack
of disease suspicion and the delay in establishing the diagnosis
may worsen the clinical picture and the evolution of the disease,
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
and may affect the prognosis. For example, deaths occurred
due to lack of timely intervention(55), particularly in terms of
the cardiovascular forms of the disease.
In terms of mortality associated with co-infection of T.
cruzi/HIV, approximately 9 million deaths were studied in
the period 1999–2007. Seventy-four deaths were identified as
related to T. cruzi/HIV co-infection; in 57 (77%) the underlying
cause was AIDS, and in 13 (17.6%) the underlying cause was
Chagas disease(53). Co-infection was associated with male
sex (51.4%), Caucasian ethnicity (50%), age between 40 and
49 years (29.7%), and place of residence in the Southeastern
region (75.7%). The average age at death was significantly
lower among co-infected (47.1 years) individuals than among
those without co-infection (64.1 years)(53). These data probably
indicate a underestimation the real impact of co-infection on
mortality.
Epidemiological profile according to
transmission modes
In more recent years (SINAN, 2000–2013), with the
operational limitations as previously indicated, it was found that
oral transmission was the most frequent mode of transmission
every year (1,081; 68.9%), followed by vectorial transmission
(100; 6.4%)(55). The persistence of the latter has been observed
since 2006, the year that Brazil obtained certification for
interrupting transmission of T. cruzi by Triatoma infestans.
Transmission still occurs, albeit to a lesser extent, probably
due to reduced visibility of these cases. Comparatively, WHO
estimates, based on data from 2010, indicated that a total
of 46 cases of Chagas disease per year in Brazil originated
from vectorial transmission(5). Together, these data reinforce
the likely underestimation of cases relating to this mode of
transmission, both nationally and internationally. The mode
of transmission was not identified in 372 (23.7%) reported
cases; 93% (306 cases) of these were from the State of Pará.
In 11 (0.7%) cases other modes of transmission (transfusion or
accidental) were identified, and there were 6 (0.4%) cases of
vertical transmission(55). Underreporting is also clear in the later
mode of transmission.
This change in the epidemiological pattern of transmission
of Chagas disease is the combined result of the control
measures undertaken over the last four decades and major
environmental, demographic, economic, and social changes,
and the concentration of the population in urban areas(4) (15) (33)
(65)
. Thus, mechanisms directly related to the enzootic cycle
of infection, such as extradomiciliary vector transmission or
visitation of wild vectors to households, in addition to oral
transmission (also mediated by vectors, in most cases), have
to have relevance as main modes of T. cruzi transmission to
human populations(22) (27) (65).
Vector transmission
In 1950 and 1951, the first Prophylaxis Campaign for Chagas
disease was developed in Brazil, led by the then National Service
for Malaria, reaching 74 municipalities on the border of the
States of Minas Gerais and São Paulo with chemical vector
control activities. By 1975, control activities were conducted
2nd Brazilian Consensus on Chagas Disease, 2015
intermittently, with varying territorial scope. The area at risk
of vector transmission of Chagas disease in Brazil in the late
1970s included 18 states, with more than 2,200 municipalities,
which proved the presence of domiciled triatomine. Notably, the
Amazon region was excluded from this risk area(4) (19) (20) (22) (66).
Since then, with the intensification of control measures, the
vectorial transmission of T. cruzi in Brazil has shown marked
and systematic reduction. This was achieved by the development
of systemized actions of chemical control of domiciled vector
populations, introduced in 1975, with a range of coverage of
the endemic area in 1983(20) (22) (66). These actions have taken
place on a regular basis since then. However, their reach has
progressively declined over the past two decades due to technical
and political prioritization of changes, and due to politicalinstitutional reorganization in the country(20) (22).
This process, in an integrated manner, culminated with the
Certification of Interruption of Chagas Disease Transmission
of the main domiciled vector, T. infestans, granted in
2006 by Pan American Health Organization/World Health
Organization (PAHO/WHO) to countries of the Southern Cone
Initiative(18) (22) (39). The control of vector-borne transmission had
considerable impact in relation to congenital and transfusion
transmissions(4) (10) (18) (23) (29). Despite the advances, the risk of
vectorial transmission of Chagas disease persists. This has been
evaluated from different perspectives(22), including the existence
of indigenous species of triatomine with high potential for
colonization; the presence of T. cruzi reservoirs and increasing
proximity of human populations to these environments; and the
persistence of residual foci of T. infestans, still existing in some
municipalities of the States of Bahia and Rio Grande do Sul(22)
(23) (39) (67)
. The impacts of the certification process achieved by
Brazil in 2006 in relation to T. infestans generated concern about
the demobilization of society in general and the imprecise way
information was obtained and disclosed to society(68).
Furthermore, additional studies and analyses have sought to
evaluate further the operational processes involved in different
strategies to control/eliminate of indigenous vector transmission,
including the certification model and potential alternatives(69)
(70) (71) (72)
. Data from the Ministry of Health on entomological
surveillance (passive or active) specific to the period 2007–2011
(Epidemiological Bulletin of Chagas Disease 2015) indicate
a record catch of >770,000 triatomine in local homes and
peridomestic contexts. Like human cases, considering the low
coverage of entomological surveillance actions, this record
probably comprises less than 10% of triatomine in or around
residences. Also, according to data from the Ministry of
Health, among the 62 species distributed in intradomicile and
peridomicile spaces in Brazil, the following stand out as species
of epidemiological relevance: Panstrongilus geniculatus,
Panstrongilus lutzi, Panstrongilus megistus, Rhodnius nasutus,
Rhodnius neglectus, Rhodnius robustus, Rhodnius pictipes,
Triatoma infestans, Triatoma brasiliensis, Triatoma maculata,
Triatoma pseudomaculata, Triatoma rubrovaria, Triatoma
rubrofasciata, Triatoma sordida and Triatoma vitticeps.
According to the data from the Epidemiological Bulletin of
the Ministry of Health on Chagas Disease, 591,360 (76.8%)
9
Rev Soc Bras Med Trop 49:Supplement I, 2016
of the captured triatomine were examined for infection with
T. cruzi; the natural infection rate was an estimated 2.7%
(15,967 triatomine). The Triatoma vitticeps (52%), Rhodnius
robustus (33.3%), and Panstrongylus lutzi (29.4%) species had
the highest rates of natural infection. According to the data from
the Ministry of Health, T. vitticeps appears more frequently in
the Southeastern States (Minas Gerais and Espírito Santo), R.
robustus in the Northern region (Tocantins, Amazonas, Acre,
and Rondônia), and P. lutzi in the Northeastern region (Piauí,
Bahia, Sergipe, Alagoas, Paraiba, Rio Grande do Norte, Ceará
and Pernambuco)(55).
In 2012, the investigation of two cases of acute Chagas
disease recorded by vector transmission showed the involvement
of wild species with high rates of natural infection in
municipalities that were considered non-endemic for Chagas
disease. One case occurred in the city of Ibitirama (Espírito
Santo), where infected T. vitticeps adults are often found by
local residents. The other case occurred in Mangaratiba (Rio de
Janeiro), involving Triatoma tibiamaculata found to be infected
with T. cruzi. These episodes reflect a nationwide reality; that
parasite transmission cycles exist in wild environments close
to human dwellings, which favors transmission(55).
For the period 2007–2011, the persistence of Triatoma
infestans foci was identified in four municipalities of the
State of Bahia (Itaguaçu da Bahia, Ibipeba, Novo Horizonte,
and Tremedal) and 12 municipalities of Rio Grande do Sul
(Ajuricaba Alegria, Coronel Barros, Doutor Mauricio Cardoso,
Giruá, Humaitá, Ijuí, Independência, Porto Mauá, Salvador das
Missões, Santo Cristo, and São José do Inhacorá)(55). Integrated
actions of vector control mobilizing Federal, State, and Municipal
governments have advanced towards the control of this triatomine.
Currently, the risk related to the transmission of T. cruzi in
Brazil depends mainly on: I) the persistence of residual foci of T.
infestans, with episodes found in some states, such as Bahia and
Rio Grande do Sul; II) the existence of large number of species
that were confirmed as indigenous or acting as potential vectors
in the country, even though in some cases resident populations
have been greatly reduced; III) the emergence of new species at
risk of domiciliation (T. rubrovaria, P. lutzi); IV) the existence
of endemic transmission in the Amazon Region, with still poorly
characterized mechanisms of transmission such as domiciliary
vectorial without colonization, extradomiciliary vectorial, and
oral; and V) the occurrence of outbreaks and micro-epidemics
of orally transmitted of T. cruzi infection(20) (33) (65) (67).
The major change in the epidemiological situation of the
disease in the country has generated the need for a dynamic
review of the control strategies adopted(4) (20) (23) (33) (65) (67). From
this perspective, identifying areas with greater vulnerability to
the synanthropic occurrence of triatomine has been important
tool to reorient prevention, control, and surveillance actions(39)
(67)
, and to optimize the use of available program resources(20).
On the other hand, risk stratification associated with vector
transmission has been proposed as an important strategy for the
guidance and support of control measures in the country and has
been incorporated, in different ways, by the control programs
of states and municipalities(4) (20) (22) (39) (65). This stratification is
10
based on three different scenarios or eco-epidemiological spaces
of vector-borne transmission of T. cruzi(22):
• an area first considered endemic, with registered
domiciliary vectorial transmission, which was submitted
for an extended period to intensive chemical control
operations, resulting in the almost complete elimination of
the main vector (T. infestans), and the risk being currently
limited to a more or less focal transmission, mainly
by native species. This scenario includes the States of
Alagoas, Bahia, Ceará, Goiás, Mato Grosso do Sul, Minas
Gerais, Paraíba, Pernambuco, Paraná, Piauí, Rio Grande
do Norte, Rio Grande do Sul, São Paulo and Sergipe, as
well as the Federal District;
•
an area previously considered harmless for human Chagas
disease, in which the disease is now transmitted through
mechanisms that before were considered extraordinary or
improbable and are still poorly characterized but able to
maintain endemic transmission of relatively low intensity
to sustain endemic transmission (oral, extradomiciliary
and domiciliary without vector colonization). This
scenario includes the region covering the States of Acre,
Amazonas, Amapá, Rondônia, Roraima and Pará; and
•
a transition area between the two previous scenarios, in
which both coexist. This scenario includes the States of
Maranhão, Mato Grosso, and Tocantins.
As previously discussed, the States of Santa Catarina, Rio
de Janeiro, and Espírito Santo, although not covered by the
proposal of the previous risk stratification, given the historical
patterns observed from the entomological surveillance of
the states, have registered autochthonous cases of Chagas
disease(39) (55) (73) (74) (75) (76) (77).
The evaluation and systematic monitoring of this process
should incorporate the possibility of colonization of the Amazon
and other agricultural fronts (extensive cattle ranching and
soybean cultivation, among others) by domiciliated vectors, with
epidemiological importance in the areas of human migration(22) (65).
The great diversity of vector-borne transmission of
T. cruzi inherent to the aforementioned scenarios or ecoepidemiological spaces include(22) (65): I) the remote risk of
reestablishment by introduced species, such as Triatoma
infestans; II) focal transmission by native species known as
vectors, such as Panstrongilus megistus, Triatoma brasiliensis
and, less likely, Triatoma pseudomaculata and Triatoma
sordida; III) domiciliation of some species typically considered
as exclusively wild, and the risk that these then act as vectors
in some areas, as in case of Triatoma rubrovaria in the State
of Rio Grande do Sul and Panstrongilus lutzi in the States
of the Northeastern region; and IV) the possibility of extradomiciliary transmission or triatomine house visitation (basic
form of outbreak generation by oral transmission, at least in
rural areas), as already observed with Rhodnius brethesi in the
region of Alto Rio Negro, in the State of Amazonas, and with
Rhodnius pictipes in the State of Tocantins.
Given the coexistence of areas with different degrees of
risk, surveillance and vector control actions should be adjusted
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
and based on established risks(22) (65). In addition to considering
the operational capacity of municipalities, the stratification of
a large traditionally endemic area is based on a set of variables
that potentially influence the process of infestation and/or
reinfestation, and therefore of transmission or reintroduction
of vectorial transmission of Chagas disease in the house
environment(22).
It is recognized that the process of simplification of fauna is
the result of unplanned occupation of the environment, having
the following potential consequences: I) lower diversity of food
supply for triatomines in different habitats; II) a greater tendency
of displacement of triatomines in search of food (hematophagous
activity) from their original habitat, to feed on more eclectic
mammals species that remained and expanded numerically;
III) the populations of the parasite will also expand from these
species of mammals with this environmental eclecticism,
in general large reservoirs of T. cruzi(21) (78) (79) (80). As these
animals (such as marsupials and rodents) have a high degree
of synanthropy, the epidemiological risk becomes clear(79) (80).
T. cruzi is a multi-host flagellate parasite capable of infecting
tens of species of wild and domestic mammals distributed in all
phytogeographic regions in Brazil; it is found in the most diverse
ecological niches, contributing, in each type of ecotope, to form
singular modalities of natural transmission foci(21) (23) (27) (39) (78) (79) (80).
The integration of the reservoirs in the routine monitoring
process should be taken into account given that domestic animals
are not confined and can also act as a link between wild and
domestic transmission routes(80) (81). As with wild mammals, the
importance of domestic animals (for example, dogs and cats)
as reservoirs of T. cruzi varies in different places, and they can
be used as sentinel populations of transmission of T. cruzi in a
given area(21) (81). In general, they are always exposed and their
infection usually precedes human infection(78). Therefore, the
presence of domestic animals infected with T. cruzi in a given
area indicates that transmission is occurring in areas where
these animals circulate, which reinforces the need to widen
control actions(81).
The research of entomological and reservoirs must be
associated with sustained environmental surveillance actions(39).
To this end, the understanding of the processes of habitat
selection by triatomines is fundamental for the construction
of epidemiological evidence, in order to plan and develop
local systems of epidemiological surveillance and control,
thus reinforcing the role of surveillance(22) (39) (82). However,
operational failures identified in the detection of vectors can
generate critical classification errors and, therefore, prevent the
scope of the actions, hampering the composition of scenarios
and dynamics of these insects in their habitat(70) (71) (82).
Assuming that no sampling technique is perfect, some
studies in Brazil have applied methods that explicitly incorporate
the failures in the detection of infestation foci in the research of
the ecology and the surveillance of vectors of Chagas disease
in different environments, including the Amazon and Northeast
region(70) (71) (82). This approach has and will increasingly enable
future improvement of the estimates of eco-epidemiological
indicators and may significantly strengthen the strategies for
2nd Brazilian Consensus on Chagas Disease, 2015
integrated monitoring and control of vectors(70) (71) (83) (84). The
failures were observed in areas with well-established triatomine
infestation, where active searches by trained and motivated
agents usually detect approximately 40–60% of intradomiciliary
and extradomiciliary infestation outbreaks, while undetected
foci are not eliminated(70). In addition, from the analysis of the
monitoring process by means of active searches conducted by
control agents, its sensitivity is estimated at approximately 20%
for locations with low intensity infestation (few outbreaks, with
few triatominae) and at approximately 40% in locations with
more intense infestation(71).
In addition to this approach, the integrated use of spatial
analysis techniques to extend the analytical capability, with
insertion of spatial and temporal dimensions of the transmission
of Chagas disease, has shown great potential, in particular by
the significant development of portable electronic equipment
and software for data processing and analysis(70) (85) (86) (87).
In the past two decades, several studies have been published
describing the different degrees of resistance of triatomine
populations to insecticides(88). However, the actual factors behind
the emergence of these phenotypes are unknown and the impact
of this on the development of standardized strategies for vector
control are unclear(89) (90). This new context will require endemic
countries to build networks of cooperation between laboratories
for the analysis of resistance in triatomine populations in a
standardized manner, integrating this activity in the process of
epidemiological surveillance(88).
Oral transmission
In Brazil, vectorial transmission of Chagas disease by
its principal vector, T. infestans, is under control. However,
oral transmission of T. cruzi has become increasingly
epidemiologically relevant, particularly in the Amazon
Region(11) (23) (39) (76) (91) (92). Transmission by the oral route is
considered a primary mechanism, in particular in the wild
cycle(93); it will occur regardless of control actions undertaken(21)
(39)
. It presents a common feature in the early enzootic cycle of
this parasite: ingestion of vectors and reservoirs of infection by
susceptible mammals(21). In the case of humans, this transmission
occurs in a sporadic and circumstantial manner, through
food contaminated with the parasite, mainly from triatomines
or their feces, with records since the 1960s(93). Therefore, the
analysis of this epidemiological context refers indirectly to
vectors.
In Brazil, most cases of orally transmitted Chagas disease
have been reported in the Amazon as outbreaks in families or
multifamily contexts(11) (23) (91) (92). Outside the Amazon region,
few events have been investigated; most were related to sugar
cane juice, the likely food carrier in the oral transmission of
these cases(76) (93). A recent review of the subject identified
records of outbreaks or micro-outbreaks in Brazil, in the States
of Rio Grande do Sul, Pará, Paraíba, Santa Catarina, Bahia,
and Ceará. Other countries with records included Venezuela
and Colombia(76).
The Ministry of Health reported 112 outbreaks nationally
between 2005 and 2013, involving all 35 municipalities in
11
Rev Soc Bras Med Trop 49:Supplement I, 2016
the Amazon Region. The probable source of infection was
food contaminated with T. cruzi, including: açaí, bacaba, jaci
(Syagrus), sugar cane juice, and palm hearts of babaçu nuts.
Most of the outbreaks occurred in the States of Pará, 75.9% (85
outbreaks) and Amapá, 12.5% (14 outbreaks) and, to a lesser
extent, in the States of Amazonas, 4.5% (5 outbreaks), Tocantins,
1.8% (2 outbreaks), and Bahia, 1.8% (2 outbreaks)(55).
The process of surveillance of Chagas disease and acute oral
transmission was potentiated by the increased sensitivity of the
surveillance system. The first officially investigated outbreak of
orally transmitted Chagas disease in Brazil occurred in Santa
Catarina in 2005, probably linked to the intake of sugar cane juice
contaminated with T. cruzi(55). Between 2007 and 2013, it should
be emphasized that more than 50% of orally transmitted Chagas
disease cases presented with symptoms between August and
November, a period that coincides with the açaí harvest in Pará(55).
Available experimental evidence suggests that oral transmission
may occur from trypomastigote, epimastigotes, and probably
amastigotes forms of T. cruzi and cell masses, originating from
mammals or contaminated vectors, as well as, accidentally,
through artificial cultures of the parasite(21) (23) (94). Depending on the
predominance of a large group or lineage of T. cruzi transmitted,
as well as of the inoculum in question, there is a diversity in
pathogenicity, histiotropism, morbidity, and mortality(21). In
relation to the mechanism of oral transmission of T. cruzi, the
following possible scenarios have been identified(21) (39) (93) (94):
•
ingestion of triatomine feces or urine of or even infected
triatomines, on the assumption that these are processed or
carried along with food, as verified in episodes investigated
in which the infection was assigned to the consumption of
acai fruit, typical of the Brazilian Amazon Region(92);
•
intake of food or drinks contaminated with metacyclic
trypomastigote forms in the secretion of the anal gland or
in the urine of infected marsupials of the genus Didelphis;
•
intake of suspensions of T. cruzi in pipettes in the context
of research or diagnostic laboratories;
•
intake of breast milk from mothers diagnosed with: acute
Chagas disease, T. cruzi-HIV co-infection in the AIDS
stage, documented reactivation of Chagas disease, or
bleeding from fissures of the nipples.
Other speculative situations of exposure include(21) (39) (93) (94):
•
ingestion of raw or poorly cooked meat or blood from
infected mammals, especially wild animals;
•
consumption of the blood of infected animals for
therapeutic purposes, as performed by some indigenous
groups in the Amazon. This has been reported in some
regions of Colombia, where the intake of blood of
armadillos and skunks has been observed;
•
contamination of equipment used in the handling of
carcasses of infected mammals;
•
ingestion of triatomines by primitive or exotic habits.
12
It is noteworthy that the feces of infected triatomines can
retain infectious potential for a few hours in environments with
high humidity. Therefore, they can potentially contaminate food
directly or indirectly, by the feet and oral cavity of secondary
carriers, like flies and cockroaches. Experimental studies have
shown that the parasite can remain viable for ≥24 hours in foods
such as milk or sugar cane juice if stored at room temperature.
Although gastric juice is able to destroy a considerable number
of parasites, some are able to escape this through chemical
mechanisms of external protection, allowing the parasites to
penetrate the intestinal mucosa(21) (92).
Although oral transmission is generally associated with
outbreaks, it can also occur in isolated cases(21) (39). In fact, we can
identify two main profiles of outbreaks, according to the place
of occurrence: urban and rural. Urban outbreak derives from the
consumption of semi-industrialized and commercialized açaí,
reflecting an issue of sanitary surveillance, associated with food
safety and good food handling practices. In rural outbreaks, there
is the participation of various types of food prepared locally
by hand, generally by family or people of the social network/
community of a given family.
For research and surveillance purposes, food recall is a useful
tool to identify the possibility of suspect food intake. It allows
one to identify the source, place of preparation and consumption
of suspect food, and to list all the people who may have ingested
the suspect food(21) (39) (92). The focus of surveillance actions and
control should therefore include the productive chain, based on
good food handling practices(21) (39).
Transmission by blood transfusion and transplantation
of tissues/organs
The transmission of T. cruzi in blood transfusions was
amplified by the urbanization of Chagas disease in Brazil
and in other endemic countries in Latin America(3) (4) (10) (95) (96).
The risk of transmission by blood transfusion is dependent on
various factors: I) the presence of the parasite in the blood or
blood component transfused; II) type and number of infected
blood products transfused; III) immune status of the recipient;
IV) quality of the clinical-epidemiological screening; V) level
of coverage of the serologic screening of donors; and VI)
sensitivity of serologic tests used to screen blood donation
candidates(4) (23) (95) (96).
Given that the majority of potential blood donors are
aged 18–35 years—the age group with the lowest number
of candidates potentially infected with T. cruzi—and that, in
recent years, the obligation of clinical, epidemiological, and
serologic status screening has been established in most endemic
countries, the risk of transfusion transmission of Chagas disease
has been largely reduced in Latin America as a whole(4) (23) (95)
(96)
. In Brazil in the 1950s, the estimated average prevalence
of positive serology for T. cruzi among potential blood donors
was 8.3%. This decreased to 6.9% in the 1960s and 1970s,
dropping to 3.2% in the late 1980s and early 1990s(96). A Health
ministry report from January to June 1994 stated an estimated
prevalence of Chagas disease through blood transfusion, by the
public blood donation network to different geographic regions
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
of the country, of 0.75%(95). In 2006, this estimate was 0.21%,
a reduction of more than 95% compared with previous data(17).
Most recent WHO data from 2010, estimated this prevalence
to be 0.18% in Brazil(5).
In Brazil, not only the safety of blood transfusion has
improved, but also the process of hemovigilance, with the
establishment of a national system integrating blood banks and
epidemiological and sanitary surveillance(97) (98). With this, one can
classify the rare, but possible cases of Chagas disease transmitted
by blood, associated with the residual blood transfusion risk and
any failures within the process. The same applies for situations
associated with screening of candidates for donation of tissues
or organs. For both, sanitary inspection in hematology and
transplantation services (hospitals or blood banks) are instituted,
as is communication and integrated action with haemovigilance(97)
(98)
, recalling that the transfusion transmission can only be
determined if the infected person received blood or some other
component within the 120 days before the onset of symptoms(97).
A similar trend in the reduction of the risk of transmission
from blood transfusions has been observed in other endemic
countries, to a greater or lesser degree. For non-endemic
countries, in the last decade several strategies have been adopted
to prevent and control transfusion transmission of Chagas
disease. Nations like the United States, Canada, Spain, France,
the United Kingdom, Switzerland and Australia, for example,
have already introduced strategies of universal or selective
serologic screening of blood donation candidates(99).
In case of organ transplants, endemicity patterns of areas
of origin and residence should be considered, both for donors
and recipients, in order to outline the best approach possible for
each case in terms of screening and management of possible
infection by T. cruzi(100).
Vertical transmission (congenital)
Vertical transmission of Chagas disease is still relatively
important in Brazil, despite the absence of systematic preventive
measures against this type of transmission in the country. To
assess its impact and also the impact of vector control, between
2001 and 2008 a new national serologic survey was conducted,
now having as a reference population 105,000 children aged
0–5 years(101). The estimated prevalence of children infected
with T. cruzi was 0.03% (32 cases). Of these, 20 (0.02%)
had concomitant maternal positivity, suggesting congenital
transmission [coming from the States of Rio Grande do Sul
(12), Minas Gerais (3), Paraná (1), Pernambuco (1), Alagoas
(1), Bahia (1), and Acre (1)]. In the other 11 (0.01%) cases, only
the child tested positive, indicating probable vector transmission
[derived from the State of Piauí (2), Ceará (2), Paraíba (2),
Alagoas (2), Rio Grande do Norte (1), Amazon (1) and Paraná
(1)]. This study was the first to identify regional differences in
the congenital transmission of Chagas disease in Brazil, possibly
related to the existence of T. cruzi TcV and TcVI(101). Moreover,
it points to the absence of Chagas disease transmission by a
sustained domiciliary vector in the country(39) (101).
Official data from the Ministry of Health concerning
epidemiological surveillance by reporting cases of acute Chagas
2nd Brazilian Consensus on Chagas Disease, 2015
disease indicate consistency with the findings obtained in the
aforementioned survey: 50% of notifications of this form of
transmission were from the State of Rio Grande do Sul(55).
The overall estimate of the prevalence of T. cruzi infection
in pregnant women ranges from 1 to 40%(102) (103) (104), and
approximately 1.8 million women of childbearing age in Latin
America are infected(17). The latest data from WHO estimate that
1,124,930 women aged 15–44 years are infected with T. cruzi(5).
A recent meta-analysis estimated the global risk for congenital
T. cruzi infection in children born to infected mothers as being
5% (range: 0–28.6%)(101). In Latin America, more than 15,000
cases per year of congenital Chagas disease are estimated to
occur(17). More recent studies estimate that 8,668 children are
vertically infected(5). On the other hand, in non-endemic areas,
the availability of evidence to estimate incidence is even more
limited(5) (17) (104). In North America, for example, the estimate is
of 2,000 cases of congenital Chagas disease per year(45).
A systematic review with meta-analysis of studies
conducted in Brazil estimated the prevalence of infection in
pregnant women to be 1.1% with a vertical transmission rate
of 1.7%(106). According to data from the Brazilian Live Birth
Information System [Sistema de Informações sobre Nascidos
Vivos (SINASC)], 2,861,868 live births were recorded in the
country in 2010. From these data it was estimated that 34,629
pregnant women would be infected with T. cruzi this year; the
number of congenitally infected children would thus range
from 312 to 1,073 (average: 589 cases)(106). These data are
consistent with those of an epidemiological survey conducted
in the State of Minas Gerais in 1998, extrapolated to the
Brazilian population(107), and with the global estimate provided
by the WHO of 571 Brazilian children infected by vertical
transmission in 2010(5). In 2006, PAHO estimated that 5,000
Brazilian children would be vertically infected(17). Considering
the gradual reduction in fertility rates in Brazil, it is estimated
that over the next few decades, vertical transmission will be
substantially reduced, with possible elimination as public health
problem for the country in the next 10 to 20 years.
A recent retrospective study from a referral hospital of the
Federal University of Goiás [Universidade Federal de Goiás
(UFG)] analyzed 1,211 individuals born to mothers known to be
infected by T. cruzi and identified a rate of vertical transmission
of 2%, consistent with previous estimates. This suggests that
the presence of TcII in the study area may be associated with
lower rates of transmission than TcV, which predominates in the
southern regions of Brazil and other Southern Cone countries,
where the vertical transmission rates are generally known(108).
Despite existing scientific evidence, important gaps remain in
terms of the role of genetic diversity of T. cruzi in relation to
the evolution of the chronic phase of the disease, the risk of
congenital transmission or reactivation, and the occurrence of
oral outbreaks transmission(27).
In Brazil, congenital Chagas disease is considered acute
and therefore its registration is mandatory(20) (39). However,
surveillance for Chagas disease specifically in pregnant women
or exposed/infected children has not yet been established in
the country. On the other hand, it is recognized that provision
13
Rev Soc Bras Med Trop 49:Supplement I, 2016
of anti-T. cruzi treatment to non-pregnant infected women of
childbearing age may be an effective strategy to reduce vertical
transmission in future pregnancies(41) (109). It should also be noted
that vertical transmission may be repeated in every pregnancy(104).
•
to maintain the elimination of vector transmission by T.
infestans and to monitor/control other important species
involved in transmission to humans;
•
to integrate health surveillance and environmental actions
(regarding vectors and reservoirs) with epidemiological
surveillance activities.
Accidental transmission
Accidental transmission has been recorded in different
contexts: triatomine laboratories, vector capture actions in
endemic areas, experimental work with infected mammals and
cultures, aerosols of infected materials, surgical infection and
infection during collection of blood samples from people with
acute infection. In these cases, safety deficiencies are evident
in the transportation of contaminated materials, among other
factors(93). Risk factors include ignorance, inattention, lack or
misuse of personal protective equipment, inadequate facilities
and equipment, poor lighting, lack of training, non-compliance
with standard precautionary measures, and non-adoption of
routine technical protocols(93) (110).
The process of monitoring and control must include the
development of continuing education actions in health and
supervision, to check the proper use of personal protective
equipment and, if applied, the communication of work accidents
within the demarcated processes for the health surveillance of
workers(39) (93) (110).
Epidemiological surveillance
Epidemiological surveillance is a set of strategic actions that
provide knowledge, detection, or prevention of any change in
determinants and conditioning factors of individual or collective
health, in order to recommend and adopt measures for the
prevention and control of diseases and disorders(39). In the case
of Chagas disease, it includes necessarily integrated actions
involving human cases, vectors, and reservoirs, interfacing
closely with the health care network, with emphasis on primary
care or primary health(4) (15).
Systematized below are the main elements in Brazil for the
development of surveillance processes for human cases and for
entomological surveillance. Several questions related to this
process have already been presented and previously discussed.
Chagas disease cases surveillance
Epidemiological surveillance actions for Chagas disease in
Brazil have the following main objectives(20) (39):
• to detect early cases of acute Chagas disease, with the
aim to treat newly diagnosed cases timeously and to apply
preventive measures of occurrence to new cases;
• to conduct epidemiologic investigation of all acute
cases, aiming to identify the form of transmission and,
consequently, to institute appropriate control measures;
•
•
14
to monitor T. cruzi infection in humans, through periodic
serologic surveys in key populations, and by means of
adopting a national screening process of blood donation
candidates in blood donation centers;
to monitor the profile of morbidity and mortality of
Chagas disease in the country, outlining scenarios for
strengthening the healthcare network for infected people;
The change in the epidemiological patterns of the disease
in the country required structuring of Chagas Epidemiological
Surveillance in the Northern region due to oral transmission.
There is a clear need to closely interfacing with the Health
Surveillance, with the aim to improve prevention and control
measures, besides the definition of reference flows for the
diagnosis, treatment and monitoring of disease complications.
The high percentage of cases in the Health Ministry database
with an undetermined mode of transmission suggests a
weakness of the surveillance process and indicates the need
for improvement in the opportunity of surveillance activities
regarding the detection and investigation of suspect cases(55). It
also reinforces the need for quality health surveillance actions
in the SUS, potentiated through continuing education activities
and monitoring and evaluation by the health teams.
The occurrence of suspected cases of acute Chagas disease
in Brazil requires immediate notification (within 24 hours after
suspicion) using a specific instrument, the Acute Chagas Disease
Research Sheet, which is standardized throughout the national
territory. For epidemiologic surveillance purposes, the following
case definitions have been established(39):
1. Suspected case of acute Chagas disease
• Person with persistent fever (more than 7 days) with one or
more of the following clinical manifestations: swelling of
the face or limbs, rash, lymphadenopathy, hepatomegaly,
splenomegaly, acute cardiomyopathy (tachycardia and
signs of heart failure), hemorrhagic manifestations,
jaundice, Romaña’s sign, inoculation chagoma, or:
•
He/she has had a direct contact with triatomines or their
excreta; or
•
He/she has received blood/blood products or transplantation of cells/tissues/organs contaminated with T. cruzi; or
•
He/she has ingested food suspected of being contaminated
with T. cruzi; or
•
He/she is a newborn, from an infected mother.
2. Confirmed case of acute Chagas disease
Laboratory criteria
•
Parasitologic: T. cruzi circulating in the peripheral blood
identified by direct parasitologic examination.
•
Serologic: suspected case with serology reactive with anti-T.
cruzi IgM antibodies by the indirect immunofluorescent
antibody test (IFA); or serology reactive with anti-T. cruzi
immunoglobulin G (IgG) antibodies by indirect IFA, with
change in IgG concentration of at least two titers after a
minimum interval of 21 days in preferably paired samples;
or seroconversion by any of the methods [enzyme-linked
immunosorbent assay (ELISA), indirect hemagglutination
(IHA) or indirect IFA].
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
Clinical-epidemiological criteria
Cases of acute Chagas disease should always be confirmed
by laboratory diagnosis. Only in specific situations can
clinical-epidemiological criteria be used for suspected cases,
such as during an outbreak of the disease in the acute phase
by oral transmission. Such cases have initial negative or nonreactive serologic and parasitologic test results but possess an
epidemiological link to confirmed cases of acute Chagas disease
by laboratory criteria.
3. Discarded case of acute Chagas disease
This refers to a suspected case with negative or non-reactive
laboratory test results, or in whom another illness is diagnosed.
Due to the limited clinical expression presented in many cases
in the acute phase and the long, silent course of the disease, the
reported case can be discarded as being a chronic case or a case
of disease reactivation.
4. Definition of a case according possible forms of
transmission in Brazil
Reserved for confirmation of cases of acute Chagas disease
characterized according to the probable form of transmission.
Confirmed case of Chagas disease by oral transmission
Case in which other routes of transmission are excluded, with
epidemiological evidence of a food as a common source of
transmission, and usually the simultaneous occurrence of
more than one case with an epidemiological link (origin,
customs, and cultural elements).
Confirmed case of Chagas disease by vector transmission
Case in which other routes of transmission are excluded, with
clinical evidence (Romaña’s sign or inoculation chagoma)
and/or epidemiological evidence of triatomine occurrence
at the site of the infection. Typically, this is observed as an
isolated case.
Confirmed case of Chagas disease by laboratory accident
Case that had contact with T. cruzi cultures, exposure to
contaminated triatomine feces or blood (human or animal
cases) containing infective forms of the parasite. Usually,
this occurs in laboratory scientists, health professionals, or
researchers.
Confirmed case of Chagas disease by vertical transmission
Newborn from mother with positive parasitologic
examination or reactive serology with T. cruzi and
presenting:
•
Positive parasitologic examination from birth; or
•
Serologic examination reactive from 9 months of
age (before that, maternal antibodies may still be
present in the child) and no evidence of infection
by other forms of exposure to T. cruzi.
In addition to the surveillance of current outbreaks for
the specific surveillance of Chagas disease in Brazil, with the
revision of the case definition for epidemiological surveillance
of AIDS in the country, from January 2004 throughout the
national territory, reactivation Chagas disease (myocarditis and/
2nd Brazilian Consensus on Chagas Disease, 2015
or meningoencephalitis) has been introduced as indicative of
AIDS for SUS(49) (54).
Although so far, these are not the subject of epidemiologic
surveillance in Brazil(54), individuals with the chronic form of
Chagas disease should be confirmed, considering the evaluation
of people with no indicative picture of febrile illness in the last
60 days and the presence of one of the following tests(39):
• Serology: Anti-T. cruzi IgG reactive by two methods
based on different principles [ELISA, indirect fluorescent
antibody technique (IFAT) or IHA]; or
•
Xenodiagnosis (artificial or indirect): positive for T. cruzi;
or
•
Positive blood culture for T. cruzi in blood samples or
cerebrospinal fluid; or, even from postmortem samples.
It is noteworthy that the current epidemiological context
in Brazil brings to debate the expansion of the focus and
approaches of epidemiological surveillance in the human
population for Chagas disease in its chronic phase, considering,
among other factors, the possibility of increased sensitivity of
epidemiological research actions of other cases in the family,
social network and communities (in the acute phase or chronic),
as well as the design of spatial contexts of transmission (past
or recent, active or not) in a manner integrated with vectors
and reservoirs. At the same time, consideration should be
given to expanding the criteria for the specific treatment of
Chagas disease, considering that millions of infected Brazilian
citizens would clearly benefit(15) (59). Therefore, these questions
bring the need to overcome operational problems of the health
care network, which should be prepared for longitudinal
management of this chronic condition. There is also a need
to guarantee sustainable production of medicines, given the
potential increase in the demand for specific treatment, and
international agreements(38). Extensive national discussion is
therefore ongoing, to assess the inclusion of surveillance through
mandatory reporting of human cases in the chronic phase in
order to qualify the actions of both epidemiology and control,
and health care.
Entomological surveillance
Entomological surveillance for Chagas disease should
be implemented throughout the country, supported mainly
on two pillars: passive surveillance, with the participation
of the population in the notification of triatomine; and active
surveillance, carried out by entomological teams of the
municipalities in partnership with regional health states, without
necessarily being based on prior notification by the resident(39).
The entomological surveillance has been enhanced with
a community-based support, responsible for the network of
Triatomine Information Posts (TIPs), which is being slowly
consolidated in the country(22). The home research by the
institutional technical team has been recommended in a
more systematic and comprehensive form, depending on
the existing risk. However, few municipalities have adopted
this approach, and those that developed it, generally, have
low sensitivity in active search, not detecting at least half
15
Rev Soc Bras Med Trop 49:Supplement I, 2016
of infestation foci. Systematic review addressing impacts of
community participation in the entomological surveillance
process found that the development of strategies to ensure
such participation should be incorporated as a component of
entomological surveillance process. This study emphasizes that
only the standardized chemical control seems to be consistently
effective in eliminating foci of infection(85). It was strengthened,
therefore, the necessary participation of individuals, families
and communities of endemic areas in all stages of this process,
from the planning to actions evaluation, considering the social
dimensions in which they fall(18) (43) (85), and recognizing the need
for empowerment and participation of these populations.
The strategies adopted must be appropriate to the reality of
each location, since passive surveillance with the participation
of the population is a priority in Brazil and is suitable for
the vast majority of scenarios, safeguarding the necessary
and prompt response by the services to the demands of the
population(85). On the other hand, active surveillance should be
carried out obligatorily in municipalities with residual foci of
T. infestans(23) (39).
Amplification of T. cruzi transmission, registered in areas
previously considered harmless or with no risk for transmission
of Chagas disease, such as the Amazon region, required greater
attention to the epidemiologic surveillance teams(76) (91) (92). In
several Brazilian regions, environmental changes favoring the
adaptation of vectors to artificial environments, thus establishing
new spaces for the appearance of disease, have been observed(22)
(23) (39) (65) (66)
. Similarly, it has also been observed the domiciliation
of secondary species, even in a much smaller scale to that seen
previously to the control of T. infestans(22) (23) (39) (66).
The emergence or re-emergence of Chagas disease in Brazil
characterizes a new epidemiological profile that is independent
of the intradomiciliary transmission by T. infestans. Thus, the
control of transmission of T. cruzi, in the current scenario,
should be examined under a new perspective. Surveillance
attention is extremely important, especially mainly maintaining
the functioning of sensitive entomological surveillance in
the municipalities, in addition to health and environmental
educational actions.
Challenges for Brazil
In Brazil, the SUS is based on core values and principles
within society, such as universality, equity, integrity, social
participation and control, which should be the foundation for
policies and programs of public interest. The country is one
of the main endemic areas of Chagas disease in the world, in
various contexts of great complexity for prevention and control.
Due to the high morbidity and mortality burden associated with
Chagas disease and their relative invisibility in society, the
government must ensure its prioritization for public health and
mobilize necessary resources and capabilities with other state
actors or non-governmental organizations to its confrontation,
by strengthening the singular role that primary care plays for
the national health system.
National estimates of millions of people infected by T. cruzi
indicate the great responsibility of the country in the technical16
scientific and political fields, not only for the prevention of new
cases, but especially in the implementation of better decisions
and benefits for patients with disease that are both acute and
chronic. Brazil and the other Latin American countries have a
key role in conducting this process and implementing the action
commitments internationally agreed under the seals of PAHO
and WHO. The emerging social movement should be valued
and promoted, in order to seek the sustainability of actions for
coping.
The health surveillance activities for Chagas disease,
based on primary health care, should have as principles:
territorialization, intersectoriality, focus on people and not
the disease, formation of multidisciplinary teams, focus on
the needs and expectations of the population and finally,
the search quality. The qualified and ethical approach of
families affected by Chagas disease should be integrated with
promotion and prevention actions, health care for diagnosis
and timely treatment, but also to physical, psychological and
social rehabilitation. Similarly, for transversal epidemiological
surveillance activities in these territories. Therefore, new pacts
and agendas must be built, by inserting the Chagas disease as a
relevant issue, aimed at ensuring access to inputs necessary for
the diagnosis and treatment of the disease in the SUS.
Therefore, in addition to the elements presented previously,
the country must continually review the current goals and
focuses of epidemiological surveillance of Chagas disease,
considering the accumulation of scientific evidence and
successful experiences. The social and human development
must be strongly linked to promote strategic research focusing
on overcoming science, market and public health system
failures(111), with a broad popular participation and the emerging
social movement in Chagas disease. The establishment of the
International Federation of Associations of People Affected
by Chagas Disease (FINDECHAGAS), with the important
participation of various representations of Brazil and other
countries, strengthens the possibility of raising and catalyzing
discussions and decisions from a technical and political point of
view based on evidence, to reach the true control and prevention.
The Ministry of Health, in partnership with states, Federal
District and municipalities, has played a key inducer role and
should be guaranteed the strengthening and sustainability of
the National Program for Chagas Disease Control, to enable
the scientific evidence, many of which are summarized in
this Consensus, in fact be applied in the different realities of
the SUS. It is worth to reiterate its strategic role to ensure the
sustainability of research funding for control and prevention of
Chagas disease in Brazil, more adjusted to different situations
and contexts in the country(83).
The expansion of epidemiologic surveillance activities, in
addition to acute cases of Chagas disease, integrating cases of the
disease in the chronic phase, has to be incorporated strategically
in this perspective, expanding network access to health care for
diagnosis, timely infection treatment and potential complications
of the disease. The antiparasitic treatment should be guaranteed
to all cases that have indication for its use, and new safe and
effective treatment options must be continuously pursued.
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
The priority areas for the development of monitoring
programs should be designed for both current and future
epidemiological scenarios, encompassing the redefinition
of instruments and tools with innovative character for
the development of monitoring procedures, integrating
environmental aspects, reservoirs, vectors, parasites and human
population. The macroecologic and eco-geographic perspective
should be integrated into the planning of actions in the country,
in coordination with the other nations of the Southern Cone
Initiative against Chagas disease.
Considering the risk contexts outlined for Brazil, it should be
defined the role of other forms of surveillance and how these will
be integrated into existing processes of surveillance, including:
hemovigilance, technovigilance, pharmacovigilance, vertical
transmission, accidents with biologic materials, transplants,
HIV/AIDS infections, other immunosuppressive conditions,
unusual acute events, such as outbreaks and microepidemics,
among others.
It should be emphasized that the integration of Chagas
disease control program to other communicable disease
control programs (vectorial programs or not) is required and
non-communicable chronic diseases in the country - all linked
mainly to the Secretariat of Health Surveillance [Secretaria
de Vigilância em Saúde (SVS)], as well as with other areas of
the Ministry of Health: Secretariat of Science, Technology and
Strategic Inputs (SCTIE), Secretariat of Health Care (SAS),
Secretariat of Strategic and Participative Management (SGEP),
Secretariat of Labor Management and Education Health
(SGTES), and Special Secretariat of Indigenous Health (SESA),
aiming to strengthen intersectorial actions for the effective
control of Chagas disease.
Faced with such prospects, it is justified the construction of
this consensus, which, in addition to focusing on the Brazilian
reality, could be a reference tool, encouraging and mobilizing
all actors involved in the global fight against Chagas disease.
Vertical transmission of Trypanosoma cruzi
Vertical transmission (from mother to child) of T. cruzi
remains a reality, even with the favorable impact of vector
control actions and the qualification of the transfusion process
in several countries, including(104) (105) (112) (113) included in Brazil(20)
(106) (107)
. The existence of infected women in childbearing age,
in endemic countries or not, supports this risk, which tends to
be reduced over the next two decades.
In Brazil, in 2011, according to SINASC data were collected
about 3 million live births. Based on the estimated prevalence of
1% of T. cruzi infection in women between 25 and 44 years of
age(17) and a risk of vertical transmission estimated as maximum
of 1% for the State of Minas Gerais, it is estimated that up to 300
children were born infected that year(107). Detection of vertical
transmission is complicated in practice, since the vast majority of
congenital cases is totally asymptomatic(4) (10) (102) (104) (113) (114) (115) (116).
It is a complex issue, considering the existence of little
scientific evidence of population base. In Brazil, as congenital
Chagas disease is considered acute, its notification is compulsory
within the epidemiological surveillance activities.
2nd Brazilian Consensus on Chagas Disease, 2015
Diagnosis and management of Trypanosoma cruzi
infection during pregnancy
It is recommended to carry out a serologic assessment
(screening) for T. cruzi infection in all pregnant women living in
or are from endemic areas, preferably during their first prenatal
visit (20) (117). The Technical Group on Prevention and Control of
Congenital Transmission and Case Management of Congenital
Infections (IVa) of WHO Programme on Control of Chagas
disease also recommends that screening for those women who
have a history of having received blood transfusions performed
in endemic areas or who were born in these areas(104). Although
transmission depends fundamentally by maternal parasitemia,
there is no clear evidence on which women may actually be
transmitting the infection, which emphasizes the importance
of prenatal screening(112) (116) (117).
The transmission may occur at any time during pregnancy,
possibly being greater in the third quarter, with increasing
parasitemia(116) (118). On the other hand, the timely diagnosis of
infection during pregnancy allows a more qualified care to the
infected pregnant women, who should be monitored throughout
gestation.
Reports of accidental exposure to benznidazole in pregnant
women do not indicate adverse effects on the newborn.
However, given the evidence of teratogenicity demonstrated
in animals, the specific antiparasitic treatment of infection by
T. cruzi is contraindicated during pregnancy and not
recommended during breastfeeding(20) (115), and should be given
only after these periods(112). Accidental exposure to antiparasitic
drug during pregnancy is not a criterion for interrupting the
gestation(115).
Studies point to the possible benefit of antiparasitic
treatment, with better evolution of Chagas disease(116) (119) (120)
(121) (122)
and reduction of the risk of vertical transmission in
future gestations(109) (116). High maternal parasitemia is associated
with an increased risk of vertical transmission and abortion(103)
(115)
. Pregnant women who are in the acute phase of Chagas
disease should be evaluated case by case, preferably with the
participation of experts, to define the risk-benefit of indicating
the antiparasitic treatment. The pregnant women with chronic
Chagas disease must be accompanied in referral centers for
high-risk pregnancy, as they may present the need for highcomplexity care.
The evidence of T. cruzi infection does not justify the
abdominal delivery indication (Cesarean),(115) since the congenital
T. cruzi infection may result in delayed uterine growth, detected
in ultrasound, and premature delivery(102) (115) (116) (123).
The importance of carrying out all the recommended
evaluations during prenatal care, including anti-HIV testing is
emphasized. The coinfection of T. cruzi and HIV in pregnant
women increases the risk for congenital transmission of T. cruzi,
by high parasitemia, also implying an increased morbidity and
mortality(20) (116) (120) (123) (124).
After the delivery, the woman should be evaluated as to
the conduct of Chagas disease, from the clinic of this disease,
aiming at an appropriate specific treatment.
17
Rev Soc Bras Med Trop 49:Supplement I, 2016
Diagnosis and management in exposed children
The risk of vertical transmission of T. cruzi depends on
the level of parasitemia, maternal immune status, infecting
strain and placental factors, and might occur at any stage of
disease(41) (104) (113) (115) (116).
Although most cases are asymptomatic, in some cases
prolonged fever, hepatosplenomegaly, respiratory failure,
prematurity, low birth weight and stillbirth may occur. Signs
of meningoencephalitis and myocarditis were observed in
coinfection with HIV(102) (104) (113) (114) (115) (123). Therefore, they
have been recommended as routine assessments in children
with clinical signs of congenital Chagas disease: complete
blood count, serum biochemistry, urinalysis, chest X-ray,
electrocardiogram (ECG), echocardiogram, and cerebral and
abdominal ultrasonography(115).
The strategy employed for the diagnosis of T. cruzi infection
depends essentially on the child’s age. Children exposed to T. cruzi,
by vertical transmission, have circulating maternal IgG antibodies
that can be detected by routine serologic testing up to 9 months
of age, and their detection in this period, does not necessarily
characterize a congenital infection. In turn, the persistence of
unaltered titers of anti-T. cruzi antibodies in children from 9 months
old, is indicative of congenital infection, and the absence of these
antibodies removes the possibility of infection in children(104) (123).
The diagnosis in suspected cases of Chagas disease by
vertical transmission (excluding other forms of transmission),
because it is an acute infection, should be confirmed using direct
parasitological methods (fresh examination, micro-hematocrit,
leukocyte cream and/or Strout method) in cord blood or of the
newborn in the first 30 days of age (preferably in the first week
of life), with evaluation of two or three samples in the absence
of signs and symptoms to expand sensibility(20) (104) (123).
For symptomatic children or newborn from mother presenting
an acute T. cruzi infection or reactivation in the presence of
coinfection with HIV/T. cruzi, these parasitological tests should
be performed repeatedly and, if negative, parasitological methods
of enrichment and/or molecular (in research laboratories) have
been used. However, these are not accessible and standardized
for use in the routine of health services(115) (125).
In case of negative parasitological/molecular tests in the first
months or in the impossibility of using parasitological methods,
it is recommended to search for anti-T. cruzi IgG antibodies after
the ninth month in two tests(20) (104) (123) (125)). Conventional reagent
serology in children during this period is strongly indicative of
congenital transmission, especially when excluding possibilities
of vector transmission and transfusion(20).
In Brazil, the inclusion of serologic tests searching IgG for
T. cruzi in the National Newborn Screening Program (heel prick
blood test) is recommended, especially in endemic areas for T.
cruzi infection, representing an useful and low cost strategy(20) (107).
The search for anti-T. cruzi IgM antibodies has a low
sensitivity and there are still difficulties to standardize this
technique and obtain controls. The use of serological methods
employing recombinant antigens, such as the Shed Acute Phase
Antigen (SAPA), it may be used if available. There are reports
18
that anti-SAPA maternal antibodies disappear earlier than
conventional antibodies in about three months(126).
Once the diagnosis of T. cruzi infection has been established,
the child must be treated with benznidazole (10–15mg/kg/
day in two or three doses for 60 days); this is a well-tolerated
regimen(20) (104) (115). There is a clear need to develop formulations
in suspension that are more suitable for this treatment, despite
the recent advance in providing pediatric tablets (12.5mg) for
these clinical situations. Treatment is mandatory in all cases
of congenital infection, since it treatment is highly efficacious
and safe for the vast majority of children. In addition, studies
show a high cure rate (≥ 95%) when treatment is started before
1 year of age, already in the first weeks of life(104) (112) (115) (127).
Clinical and laboratory evaluation (blood count testing)
should be performed at the beginning of the treatment and 30,
60, and 90 days after the use of benznidazole. In children with
the clinical syndrome of Chagas disease, other complementary
assessments should be carried out according to the table presented.
The cure control must be performed with serologic tests every
six months with titration until the child has two consecutive nonreactive serologic test results. Persistence of positive serology or
evidence of positive parasitologic tests may indicate treatment
failure and the child must be monitored and evaluated for possible
complications of the disease. In refractory cases, benznidazole
therapy may be repeated or may be substituted with nifurtimox
(up to 15mg/kg/day in two or three doses, for 60 days).
In newborns from infected mothers and asymptomatic,
whenever possible, T. cruzi research should be performed.
Those with initial negative parasitologic examination or not
carried out must be submitted at nine months after birth, for
the research with serologic tests of anti-T. cruzi IgG antibodies
or conventional serology for infection by T. cruzi(107) (117) (127).
A reactive serologic test after this age necessarily implies the
need to initiate antiparasitic treatment. On the other hand, no
evidence of positive serology excludes infection.
It is not recommended to suspend breastfeeding of infants
whose mothers have Chagas disease in the chronic phase except in cases where there is bleeding by nipple fissure, when
the interruption of breastfeeding in the affected breast would
be appropriate - or in situations of high parasitemia, such as in
reactivation of Chagas disease or in women in the acute phase of
the pathology(112) (115). If exposed to breast milk of mother with acute
or chronic infection with the presence of nipple cracks, the infant
should be monitored for the acquisition of T. cruzi infection during
the exposure period, using the same parasitologic and/or serologic
criteria described above. In some of these cases, heat treatment
of milk prior to administration to infants can be considered(112).
In T. cruzi/HIV coinfection, it is recommended that all
infected mother is advised not to breastfeed, considering
that breastfeeding, regardless of the association with Chagas
disease, it is associated with an additional 7–22% risk of HIV
transmission. Meanwhile, in cases of acute maternal infection
by HIV, breastfeeding increases the likelihood of vertical
transmission of HIV to 29%. In Brazil, the mother is entitled
to receive infant milk formula, at least until your child reaches
6 months of age(128). Figure 1 shows the general flow diagram
for the approach of T. cruzi infection in the mother/child pair.
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
Pregnant women living in an area
endemic to Chagas disease
1st prenatal consultation
Two anti-T. cruzi serologicala tests
in the pregnant women - different
methods [ELISA / indirect IFA / IHA]
Discarded infection by T. cruzi
(according to diagnostic flowchart) a, b
At birth
Confirmed infection by T. cruzi
(according to diagnostic flowchart)a
Forward to high-risk prenatal
care - evaluate the commitment
of the pregnant woman (clinical
evaluation and ECG) b, c
Routine/normal prenatal follow-up
Refer the mother for medical
control of the disease and
therapeutic evaluation
Assess T. cruzi
infection in the
newborn
Absence of
clinical alterations
suggestive of
congenital infection
In the postpartum period
Presence of
clinical alterations
suggestive of
congenital infection
Perform anti-T. cruzi
serology in the
remaining children (if any)
Assessment of T. cruzi d
Positive
result
Negative
result
Treatment of infection
by T. cruzi
Positive result
Assess other
causes of
congenital infection
Assessment of T. cruzi
again (one week
after birth)
Negative result with
clinical alterations
Negative result
without clinical
alterations
Child serology (2 tests after
9 months age) e
Confirmed congenital infection
by T. cruzi (according to
diagnostic flowchart)a
Discarded congenital infection
by T. cruzi (according to
diagnostic flowchart a)
a Follow flowchart to confirm the diagnosis of infection by T. cruzi (see section on laboratorial diagnosis of infection by T. cruzi, in this Consensus)
b If the complementary exams do not confirm changes, o prenatal assistance can be done within the routine procedures of the Basic Health Unit (primary health care). If signs/symptoms
suggestive of Chagas disease are present, one should continue prenatal assistance in a reference care unit for high risk pregnancies.
c Evaluation of the fetus by obstetric ultrasonography, one should look for signs of restricted uterine growth and other signs common in the TORCH group (Toxoplasmosis, Other infections,
Rubella, Cytomegalovirus, and Herpes).
d Parasitological tests are recommended in the first days of life of the child.
e After the 9th
month of life use serological tests for the diagnosis of infection.
ELISA: enzyme-linked immunosorbent assay; IFA: immunofluorescent antibody test; IHA: indirect
hemagglutination; ECG: electrocardiogram
FIGURE 1. Flowchart for investigating and managing T. cruzi infection in both the mother and child.
2nd Brazilian Consensus on Chagas Disease, 2015
19
Rev Soc Bras Med Trop 49:Supplement I, 2016
LABORATORY DIAGNOSIS OF
TRYPANOSOMA CRUZI INFECTION
In Brazil, an attempt to establish the etiologic diagnosis of
Chagas disease should be made in all suspected cases, both in
the acute phase and in the chronic phase(20) (39) (129). Therefore, it
is essential to integrate epidemiologic, clinical, and laboratory
evidence, in order to increase the degree of predictive and
diagnostic accuracy. The complementary diagnosis of infection
by T. cruzi through various laboratory techniques should follow
defined criteria, depending on the stage of the disease. The
following recommendations for diagnosis include the current
Brazilian regulations.
Laboratory criteria to define the diagnosis
of Chagas disease
Acute phase
Parasitologic criterion
Parasitologic examination is the most appropriate at
this stage. This criterion is defined by the presence of T.
cruzi trypomastigotes, identified by direct examination of
the peripheral blood (with or without centrifugation) using
microscopy (with or without staining)(39) (129) (130) (131) (132).
Simultaneous performance of different modalities of
direct parasitological examinations is recommended - fresh
examination of trypanosomatids, concentration methods, or
thick smear or smear stained slide. When the results of the
fresh examination and concentration methods are negative in
the first collection, new collections must be carried until the
case definition and/or the disappearance of the symptoms of
the acute phase, or until the confirmation of another diagnostic
hypothesis(20) (39) (133).
Serologic criterion
The serologic criterion is based on indirect methods for
diagnosis that may be performed when parasitologic tests are
negative but clinical suspicion persists. Such methods have
complementary usefulness, and should always be performed
in suspected or confirmed cases of acute Chagas disease(39) (134).
When the parasite is not identified by direct observation,
verifying the presence of anti-T. cruzi IgM antibodies in the
peripheral blood is considered suggestive of the acute stage,
particularly when combined with the patient’s epidemiologic
context and clinical events(39) (135). This represents a more
complex technique and is most suitable in the late acute phase,
when repeated direct examinations are negative(129) (133) (134).
Seroconversion to T. cruzi infection is defined by an initial
non-reactive serum sample for anti-T. cruzi IgG antibodies,
followed by a reactive sample collected 2–4 weeks later, based
on an assay that includes both samples simultaneously(133) (134).
Alternately, an increase of at least two titers between two
reactive samples taken 2–4 weeks apart, in a clinical and
epidemiologic context suggestive of acute Chagas disease, may
also be considered diagnostic of acute Chagas disease(39) (132) (133) (134).
In situations where vertical transmission is possible, the
strategy used for the diagnosis of infection by T. cruzi would
20
depend on the child’s age; this is discussed in a specific part of
this document. It is noteworthy that every case of congenital
transmission means an acute case of Chagas disease and, as
such, should be reported and managed(104).
Chronic phase
Parasitologic criterion
Due to the low parasite burden in the blood in the chronic
phase of Chagas disease, parasitologic methods of enrichment/
multiplication, blood culture(136) (137) and xenodiagnosis(138) have
demonstrated low sensitivity, which implies the absence of
diagnostic value when the result is negative(20) (133) (139). When
positive, the results are useful, mainly to monitor the specific
treatment, or in unusual cases where serology presented
inconclusive results(129) (134).
Serologic criterion
In the chronic phase, the diagnosis is essentially serologic,
and must be performed using a test with high sensitivity in
conjunction with another having high specificity(20) (39) (132) (133) (134).
An individual is considered in the chronic phase of infection
if anti-T. cruzi IgG antibodies are detected by means of two
serologic tests with different principles/methods having different
antigenic preparations. Other diseases (for example, visceral
leishmaniasis, virchowian (lepromatous) hanseniasis, and
autoimmune diseases) should be considered in the differential
diagnosis(140) (141) (142).
Principles and Guidelines for the Laboratory
Diagnosis of Trypanosoma cruzi Infection
Parasitologic diagnosis in the acute phase
The parasitologic diagnosis of Chagas disease at this stage
is mainly based on the identification of the parasite, and its
sensitivity depends on the level of parasitemia. In the acute
phase, the number of parasites in the peripheral blood is high.
It is recommended that, if presented with a suspected case of
Chagas disease in the acute phase, different methods of direct
parasitologic examination be used for immediate and repeated
reading, in order to clarify the diagnosis(20) (39) (104) (132) (133) (134).
The fresh search for trypanosomatids is quick and easy to
perform, and is more sensitive than staining the smear. The
ideal situation is to collect them from a febrile patient within 30
days of symptoms onset(134). The examination can be performed
directly under the microscope with a drop of blood between
the slide and cover slip. Blood collection should be carried out
simultaneously for techniques of blood concentration.
The concentration methods are quick and inexpensive
(Strout’s method, micro-hematocrit and buffy coat). They
are recommended as the first choice of diagnostic test for
symptomatic cases with more than 30 days of evolution, due
to the decline in parasitemia with time. Blood samples should
be examined within 24 hours due to possible lysis of the
parasites(129) (134).
Direct examination of a stained thick blood drop or blood
smear can be used, but this has lower sensitivity than the
methods described above. However, in the Northern region
of Brazil, belonging to Legal Amazon, this method is widely
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
used; it is convenient and able to be integrated into malaria
diagnostic actions(20) (39). It also represents an important method
for verification and morphologic characterization, especially in
geographic areas where the infection by T. rangeli can coexist
with T. cruzi.
It is emphasized that in cases with high parasitemia ̶
as in the acute phase of the disease, but also in transfusion
transmission and in immunocompromised individuals ̶ parasites
can be incidentally found on blood smear when performing a
differential leukocyte count(20) (39) (49) (52) (100).
In cases where a strong clinical and epidemiological suspicion
of acute phase T. cruzi infection exists but direct parasitologic
examinations are negative, molecular diagnosis using
polymerase chain reaction (PCR) methods with hybridization
has shown promising results. However, these are in-house
tests, performed by only a few research/reference centers. The
methods, protocols, and operating procedures should follow the
recent recommendations for the standardization for the PCR
use(143) (144). In Brazil, due to the absence of defined protocols
and standard operating procedures, as well as of commercial
kits to be routinely used in health surveillance, PCR cannot be
considered an isolated diagnostic method to confirm or discard
cases of acute or chronic Chagas disease(39).
Performing reactions in eluates from collected blood on filter
paper is not recommended to diagnose the infection, although
these are usually used in the screening steps of epidemiological
investigations(152). The Guerreiro and Machado reaction (or
complement fixation) for Chagas disease does not meet the
standards currently required. Since it is not commercially
available, it is also not indicated(20) (129).
The chemiluminescence test also allows the identification of
IgG antibodies. While some kits are available on the market, the
technique is still not recommended by the Ministry of Health
of Brazil(133).
The recent evaluation of 11 rapid test kits used for serologic
diagnosis of Chagas disease indicates the potential of these
methods. However, further studies should be conducted in the
laboratory and in the field to confirm these data, in particular
assessing their reproducibility in the context of limited resources
or the use of whole blood in the real contexts of endemic and
non-endemic areas(153).
The following flowchart (Figure 2) summarizes the steps
for the laboratory diagnosis of T. cruzi infection in the chronic
phase of the disease.
Serologic diagnosis in the acute phase
Acute Chagas disease is becoming a less frequent event in
endemic countries, including Brazil, where control of vector
(especially by T. infestans) and transfusion transmission has
altered the epidemiological scenario(20) (39). On the other hand,
the occurrence of cases and outbreaks by oral transmission,
transmission by domiciliary vectors without colonization and
by extradomiciliary vectors, especially in Amazônia Legal,
has gained epidemiological importance(20) (21) (39) (76) (154) (155) (156).
Urbanization and globalization of Chagas disease due to
large migrations, both in endemic and non-endemic countries,
has contributed to making the epidemiological scenarios even
more complex. In addition, reactivation episodes of Chagas
disease associated with immunodeficiencies have become
emerging challenges for health systems(20) (39) (49) (157) (158) (159). In
this sense, the epidemiological investigation of the mode of
transmission of Chagas disease is of particular importance, not
only in order to determine actions to be implemented, but also
because the different routes potentially lead to specificity in the
clinical expression of the acute disease(20) (39) (76) (132).
In Brazil, there are currently difficulties in performing
serologic tests in patients in the acute phase, due to the lack of
registered commercial kits approved by the Brazilian National
Health Surveillance Agency (ANVISA) and difficulty in
obtaining positive controls for IgM(20) (39) (133). Therefore, it has
been traditionally recommended that indirect IFA methods are
performed in reference laboratories to detect IgM(145) in addition
to the conventional techniques already in use, such as indirect
IFA to detect IgG, IHA(146), and ELISA(147).
Parasitologic diagnosis in the chronic phase
Indirect conventional methods for the isolation and
identification of T. cruzi (xenodiagnosis and blood culture) have
low sensitivity; sensitivity can be increased through repetition(20)
(129) (133) (148) (149)
. A negative test does not rule out the possibility
of infection, but a positive test has an absolute diagnostic value.
The PCR at this stage, despite being limited by the lack of
standardized protocols, is indicated when serologic tests present
an indeterminate result or to determine cure after antiparasitic
treatment. PCR should be performed by laboratories with
recognized competence, carried out by experts in the field(150).
Serologic diagnosis in the chronic phase
Diagnosis in the chronic phase is essentially serologic,
and should be performed using a test with high sensitivity
(ELISA with total antigen or indirect IFA) in conjunction
with another method with high specificity (IHA)(129) (133) (134).
Known conventional tests (IHA, indirect IF, and ELISA)
(131)
can determine the diagnosis in almost 100% of cases.
Unconventional tests (with recombinant antigens, for example)
may preferably be used in parallel with another conventional
test(151).
2nd Brazilian Consensus on Chagas Disease, 2015
ACUTE PHASE OF CHAGAS DISEASE
Clinical and complementary examination aspects
Acute phase of Chagas disease by vectorial transmission
The clinical picture is characterized by the appearance of
a set of manifestations of variable intensity after an incubation
period that is inversely proportional to the load of the inoculum
and the inoculation route. There may be a lesion at the inoculation
site(20) (21) (39) (76) (91) (155) (160). The clinical picture of acute illness in
cases of vectorial transmission is polymorphic, ranging from the
classical description ̶ a sign of infection at the inoculation site,
fever, subcutaneous edema, lymphadenopathy, hepatomegaly,
splenomegaly, and evidence of myocarditis and meningoencephalitis
̶ to asymptomatic and oligosymptomatic situations(20) (76) (91)
(160)
. The incubation period may vary from 4 to 15 days.
21
Rev Soc Bras Med Trop 49:Supplement I, 2016
Plasma or serum samples
2 tests, different methods
(ELISA, indirect IFA/IHA)
Both
reactive
Positive result
1 test reactive
1 test non-reactive
Inconclusive
Both
reactive
Negative result
Collect new sample
Repeat 2 tests, different methods
(ELISA, indirect IFA/IHA)
Both
reactive
1 test reactive
1 test non-reactive
Positive result
Inconclusive result
ELISA: enzyme-linked immunosorbent assay
IFA: immunofluorescent antibody test
IHA: indirect hemagglutination
Both
non-reactive
Negative result
Forward samples to reference
laboratory
FIGURE 2. Flowchart of steps for the laboratory diagnosis of T. cruzi infection in suspected cases of chronic Chagas disease.
The portal of entry is the ocular conjunctiva (Romaña
sign) in 50% of cases and the skin (inoculation chagoma)
in 25% of cases; it is unknown in the remaining 25% of
cases(160). However, it is assumed that the ocular route is the
most frequently diagnosed as it is easy to recognize, both by
the affected individual and the healthcare team. The Romaña
sign is essentially characterized by unilateral, painless, elastic
edema of the eyelids with satellite lymph node reaction (mainly
pre-auricular). Often, the swelling spreads to the ipsilateral side
of the face; its degree is variable and can be severe enough to
cause total occlusion of the palpebral fissure. The presence of
the Romaña sign is an excellent marker for the diagnosis of the
acute phase, allowing recognition of many cases(20) (160) (161). In
terms of the skin, the inoculation chagoma presents as a hard,
erythematous, slightly painful nodule surrounded by elastic
edema. It is also accompanied by satellite lymph node reaction
and, sometimes, ulceration. It can be found on any region of
the body, especially exposed parts(20) (160).
22
Along with these signs of entry, general symptoms such as
fever, malaise, headache, asthenia, and pyrexia appear. Fever
is an initial symptom is almost all cases; it usually does not
exceed 39°C; although it can be higher, especially in children.
The thermal curve is not characteristic; the temperature record
may show a continuous or relapsing and intermittent pattern,
with significant increases in the late afternoon(160) (162).
Around the second week of the disease, generalized or
localized edema may appear (on the face or lower limbs),
regardless of the inoculation site or presence/absence of cardiac
failure(160). Its consistency can be elastic or soft; the elastic is
observed only in young children. The pathogenesis of this edema
is unclear; several hypotheses have been suggested.
Usually, lymph nodes are slightly to moderately increased
in size, isolated, mobile, smooth, painless, and firm. Of those
accessible to palpation, lymphadenopathy is most commonly
found in the cervical, axillary, and inguinal regions; this
manifestation occurs early in disease(160).
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
Hepatomegaly and splenomegaly, alone or in combination,
are often observed. In general, the increase in liver and spleen
volume is small or moderate, the consistency does not change,
the edge and the surface are smooth and, sometimes, there is
pain on palpation of the liver. These signs are an early part of
the clinical framework(160) (163).
Although less common, other features (neurologic and
cutaneous) may be present. Neurologic manifestations refer to
signs of meningoencephalitis (vomiting, agitation, convulsions,
opisthotonos, neck stiffness, etc.), which is mainly observed
in young children. Meningoencephalitis may present with
abnormal cerebrospinal fluid (CSF) findings. The characteristic
examination findings are clear CSF, increased cellularity with
mild lymphocytosis (<100 cells/mL), low glucose and slightly
increased protein levels; it is possible to see trypomastigote
forms of T. cruzi after centrifugation of CSF, using specific
staining methods(20) (160).
Cutaneous manifestations (rare in Brazil and relatively
frequent in Argentina) include rashes (morbilliform, urticariform,
and macular) called esquizotripanides and hematogenous
chagomas (usually flat formations). These affect skin and
subcutaneous tissues without changing their color; are nonadherent to the deep planes; usually painless; and of variable
size, from that of a coin to large plaques(160) and, according to
Lugones (2001), they are more palpable than visible(162).
The heart presents changes of greater or lesser severity;
with a moderate frequency. However, the clinical, radiologic,
or ECG manifestations involved are not significant, are not in
keeping with the histologic findings, and may even be absent.
On the other hand, it is necessary to bear in mind that serial
radiologic and electrocardiographic examinations are required
in the short-term, seeking signs of cardiac impairment, given
the transience of some of the manifestations(20) (21) (160) (164).
The symptoms of acute Chagas myocarditis are essentially
identical to those of acute myocarditis of other etiologies,
sometimes being masked by other clinical manifestations.
Tachycardia is often reported and, generally, not dependent on
the degree of temperature increase; in most cases this is observed
early. A systolic murmur with functional blow characteristics
can be detected in the mitral area. Excitability arrhythmias are
only occasionally found. Heart failure, when present, is global;
its symptomatology is no different from that related to other
etiologies. There may be a degree of arterial hypotension(160) (164).
Already in the first weeks of infection, radiologic and/or
electrocardiographic changes, of greater or lesser significance,
may be observed. These tests are not always simultaneously
abnormal. Practically, if one test result is abnormal it has
the same diagnostic value as both being abnormal, as both,
individually, reveal disorders with the same frequency. When
performed in combination and serially, however, these allow
more frequent demonstration of impairment(160) (164). Therefore,
the study of cardiac function by echocardiography is indicated
in cases with signs and symptoms of myocarditis.
Radiologically, the heart size can be normal or may be
mildly, moderately, or severely increased. Cardiomegaly
is global, predominantly as a result of enlargement of the
2nd Brazilian Consensus on Chagas Disease, 2015
ventricles, but in some cases, due to a dilation of only the left
ventricle. The exudate in the pericardial cavity contributes to
increase the heart shadow(160) (164).
The electrocardiographic changes most frequently
encountered are sinus tachycardia, decreased QRS complex
voltage, first-degree atrioventricular block (AVB), primary
alteration of ventricular repolarization, and increased electrical
systole. Arrhythmias, except for first-degree AVB, are only
occasionally observed(160) (164).
The chronologic asynchrony between the appearance of
echocardiography findings and the occurrence of acute phase
is not a reason not to perform this examination. In a study
conducted in Venezuela that followed 58 patients in the acute
phase, the ECG findings proved to be abnormal in 27 (52%);
the most important finding was pericardial effusion, present in
42% of the cases, ranging from mild to moderate intensity in
17 patients and severe in 5; in 11 (21%) patients earlier and/or
apical dyskinesia was demonstrated, and in 3 (6%) patients, left
ventricular dilation was observed(165). A study of 158 patients
with acute Chagas disease in the Amazon (most cases due to oral
transmission) revealed the presence of 108 changes, with more
than one alteration present in the same individual(91). The main
abnormal findings were pericardial effusion (from small to large
volume), mitral or tricuspid valve regurgitation, and symmetric
hypertrophy of the left ventricle. Occasionally, accentuation of
sinus tachycardia was observed, in contrast to the reduction in
intensity or disappearance of acute manifestations, including
fever; this was previously reported by Chagas(76) (91) (160).
The main nonspecific laboratory abnormalities found are, in
order of frequency: anemia, leukopenia, relative lymphocytosis,
and an increase, from mild to moderate, of aminotransferases.
Also described are thrombocytopenia and, more rarely,
thrombocytosis and atypical lymphocytosis(21) (76).
The complete blood count reveals that the total leukocyte
count is generally increased, although it may be normal or
slightly decreased, with intense lymphocytosis, plasmacytosis,
and related neutropenia. A high percentage of atypical
lymphocytes and leukocytoid cells appear after the second
week of the disease. As the disease evolves to chronicity, these
changes disappear, and eosinophilia emerges(20) (21) (39) (160).
Acute phase of Chagas disease by blood transmission
In the acute phase of transfusion transmitted Chagas
disease, the clinical syndrome is practically identical to that
seen when transmitted by triatomines, except for the absence
of an inoculation chagoma. Similarly, it must be assessed with
complementary examinations. The incubation period can range
from 30 to 112 days, being a little longer than that observed
in vector-borne transmission, although much shorter periods
(such as 8 days) or longer periods (such as 120 days) have been
observed(160) (166). Chagas disease must always be considered in
cases presenting with a fever of unknown origin, particularly
if the patient under investigation has received a transfusion in
a remote or hyperendemic region(166).
Fever is the most common symptom, affecting 80–100% of
cases. It is often the only symptom found. Lymphadenopathy
23
Rev Soc Bras Med Trop 49:Supplement I, 2016
and splenomegaly are also frequently observed, while anemia/
pallor, perimalleolar and periorbital edema, skin rash, and
hepatomegaly appear in <50% of cases(166).
Acute phase of Chagas disease by oral transmission
Oral transmission of Chagas disease has been reported in the
Amazon and extra-Amazon regions(76) (91) (94) (167) with peculiar
clinical characteristics when compared to vectorial transmission,
and sometimes with regional differences(21). The major clinical
differences between the descriptions of past endemic areas and
the Amazon region (in which oral transmission prevails) is the
clinical presentation of high morbidity, highlighting the regional
epidemiological characteristics regarding the occurrence of a
more efficient mode of transmission than the vectorial route(76)
(94)
. Evaluation by non-specific complementary tests is generally
similar to that previously seen.
Evidence suggestive of inoculation (Romaña sign and
inoculation chagoma) ̶ typical of the disease induced by vector
transmission ̶ is rarely described in cases of oral transmission,
emphasizing the clinical differential diagnosis between the two
forms of transmission and the low frequency of contact between
humans and non-domiciled vectors in this region(91) (94) (160).
The incubation period ranges from 3 to 22 days. The main
signs and symptoms recorded in acute Chagas disease are, in
order of frequency: prolonged fever, headache, pallor, myalgia,
skin rash, and edema of the face and lower limbs(21) (39). The
characteristic signs and symptoms of cardiac impairment
include tachycardia without fever, palpitations, dyspnea, and
chest pain(76).
Fever is the predominant manifestation in almost all cases. In
general, it is characterized by daily high temperatures, from the
morning until the late afternoon. This continues for an average
of 18 days (range: 3–25 days). In individuals manifesting
prolonged fever, the fever is initially high (38.7–39.0ºC)
and is accompanied by chills and generalized pain. After
approximately 12–15 days, it begins to settle; the temperatures
range between 37.0ºC and 37.8ºC, occur daily, and the fever
usually disappears in the afternoon(76) (91).
Pallor (anemia) occurs from the beginning of the febrile
syndrome, in particular on days 3–5, and lasts 20–25 days.
Myalgia can be intense; it is often described as an acute stabbing
pain, or similar to that experienced in dengue fever (generalized
and confused with polyarthralgia)(91) (168).
When Chagas disease is induced by oral transmission,
skin rash appears as an important sign and is associated with
abundant parasitemia. It occurs more frequently than when
Chagas disease is caused by vectorial transmission. In general,
it presents as a macular rash that is not itchy or painful. It occurs
on around days 4–8 of disease, usually affecting the chest, back,
lower limbs, and neck, and sparing the face and palmoplantar
regions. It is relatively transient and most often goes unnoticed
by the patient, found only on physical examination(91) (169) (170).
The edema of the lower limbs generally appears after
approximately 12 days of illness and lasts until day 20,
coinciding with the disappearance of fever. Invariably, it has
the characteristics of inflammatory edema, inelastic and slightly
24
painful. It affects the malleolar region or the entire lower limb.
Facial edema can occur in the same period; it has no specific
features(76) (91).
In most cases, acute myocarditis may start slightly before
the disappearance of fever, on average from day 15 to 20 of the
disease. The main signs and symptoms are dyspnea, palpitations,
tachycardia (without fever) and, possibly, precordial chest pain
simulating myocardial infarction. Myocarditis is one of the
most common complications among patients in the acute phase.
ECG and echocardiographic examinations should be performed
immediately after diagnosis(76) (160) (164).
Among patients evaluated in the Amazon, 52.3% had
altered ECG findings, consisting of diffuse changes with
ventricular repolarization abnormalities (VRA), low voltage
of the QRS complex, deviation of the electrical axis to the left,
and sinus tachycardia, demonstrating some involvement of
milder conduction system of the heart and, more often, diffuse
signs of inflammation. Cardiac electrical conduction disorders
are more evident in adults. Myopericarditis, evidenced by the
presence of VRA and pericardial effusion (seen on ECG and
echocardiography, respectively) is important in both adults and
children(154) (160) (164). In outbreaks outside the Amazon Region,
a high frequency of pericardial effusion was observed(155),
emphasizing the need for early diagnosis in view of severe
evolution if not promptly diagnosed and treated.
Pericardial and/or pleural effusion may occur in more than
50% of cases infected via the oral transmission route, suggesting
that pericarditis may be more important than involvement of the
cardiac electrical conduction system during the acute phase(154)
(160) (164)
.
Painful nodules of lower limbs may be associated with
edema, and have been invariably recorded in lower limbs of
women. The presence of erythema nodosum has been frequently
observed in cases of oral transmission. Similar descriptions
in children were also recorded in an Argentinian case series,
in which some skin and subcutaneous lesions were labeled as
hematogenous or metastatic chagomas(169) (171).
Other manifestations associated with this form of transmission
can be present, such as epigastric pain, jaundice of the skin and
mucous membranes, hepatomegaly, and lymphadenopathy.
Lymphadenopathy is common in children, affecting especially
cervical lymph nodes chains; it is not generalized. Splenomegaly
and diarrhea are rare events(91) (94).
It has been reported that 13.3% of cases are severe.
Severity is almost always related to manifestations of acute
myocarditis and severe gastrointestinal bleeding. The presence
of gastrointestinal bleeding might represent the portal of entry(94),
with the inflammatory infiltrate containing amastigotes. There
are rare reports of acute meningoencephalitis(172). Hemorrhage
represents a critical scenario of the epidemic that occurred in
the City of Navegantes, in the State of Santa Catarina (Southern
region of Brazil), providing differential diagnosis for severe
diseases that presented a jaundice-hemorrhagic condition, such
as leptospirosis, dengue and hantavirosis(76). The mortality rate
was significant among adults aged over 50 years (5.6%).
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
In just over half (54.1%) of the cases in the Amazon, the
diagnosis was confirmed by parasitologic examination(154) (156) (169).
Therefore, in cases with negative parasitologic tests, but with strong
clinical suspicion, concomitant serologic testing is recommended,
considering in particular their higher sensitivity after the first month
of clinical history.
Specific treatment
Specific and immediate treatment is indicated in the acute
phase, with long-term follow-up to identify the treatment
response serologically(76) (156) (169). For more details, see the
specific treatment part of this Consensus.
A case series was reported of 179 patients treated with
benznidazole in the acute phase of Chagas disease induced
by oral transmission who were followed-up under a research
protocol for an average period of 5.6 years. A serologic response
to treatment was found in 26.3% of patients, most evident
four years after treatment; 2.7% developed a chronic mild-tomoderate cardiomyopathy; and 73.7% had persistently reactive
serology, although with a significant decrease in the levels of
antibodies(156).
Reactivation of Chagas disease
The management of cases with reactivation of Chagas
disease, in the context of immunosuppression, is an important
and emerging public health problem in all countries where
people with chronic Chagas disease reside. In particular, the high
congenital transmission rate (>50%) in T. cruzi/HIV coinfected
pregnant women is highlighted in the literature. It is advised,
therefore, that careful follow-up with clinical assessment and
periodic direct search for the parasite be conducted in these
women(20) (173) (174) (175).
Reactivation of chronic Chagas disease in previously
infected cases is defined as positivity of the following tests,
regardless of the presence of other signs and symptoms(159):
1.
Parasite detected by direct microscopic examination
of blood or biological secretions: cerebrospinal fluid,
pleura, pericardium, ascitic fluid, among others. In terms
of sensitivity, parasite search in buffy coat or microhematocrit specimens or sediment from other materials
is more sensitive than fresh direct search in biological
material or smear. The thick blood smear is more difficult
to perform and interpret, and can only be carried out by a
trained technician.
2.
Histopathologic examination of tissue lesions (panniculitis,
myocarditis, encephalitis, enteritis, colpitis, among others),
with parasite nests within the acute inflammatory infiltrate.
Reactivation of Chagas disease was first reported in patients
immunocompromised by hematologic neoplasms(176). From the
late 1980s and early 1990s, cases of reactivation of Chagas
disease began to be reported in HIV-infected individuals(159)
(175) (177) (178) (179) (180)
. In the largest prospective study of T. cruzi/
HIV coinfection (n = 53 patients), the rate of reactivation was
20.8%(175). Considering only followed-up patients and excluding
hospitalized patients diagnosed with reactivation, this value was
approximately 10%(175).
2nd Brazilian Consensus on Chagas Disease, 2015
In kidney transplant recipients, the rates of transmission
(from infected donors) and reactivation (in chronically infected
patients submitted to transplantation) are 18.7% and 21.7%,
respectively(181). In the context of heart transplant recipients, a
reactivation rate of 26.4–40% was found(182) and, although use
of infected donor hearts is prohibited, this has been reported in
the absence of donor screening in non-endemic countries(157) (158).
In Brazil, in addition to prohibiting the use of infected donor
heart and intestine in transplants, it is recommended not to use
other transplant organs from donors with infection; exceptional
situations should be discussed on a case-by-case basis with
specialized teams(183).
The rate of reactivation in recipients of allogeneic
hematopoietic stem cell(184) and liver(185) transplants is 27.3%,
and 18.7%, respectively. The use of corticosteroids in
association with increased parasitemia and a possible effect with
immunosuppressive drugs to treat mesenchymal diseases have
been recorded, without a well-defined causal relationship(186).
Diagnosing reactivation of Chagas disease
Clinically, the most common manifestations of reactivation
are fever, panniculitis (subcutaneous nodules), myocarditis,
meningoencephalitis, stroke, and symptoms such as anorexia,
myalgia, malaise, and diarrhea. Case series studies suggest that
reactivation associated with HIV infection has a higher morbidity
and mortality than other causes of immunosuppression, such as
in transplant recipients, where the monitoring of organ recipients
is suggested, with high success rate for some groups(181) (184).
In reactivation associated with HIV infection,
meningoencephalitis (74% of the cases), myocarditis (17.1%),
and both occurrences (7.9%) have been reported(48) (49) (159) (175) (187).
Oligosymptomatic forms forms were diagnosed in mothers
who gave birth to children with severe Chagas disease and in
patients with prolonged fever in long-term follow-up, with good
therapeutic responses to benznidazole. Other rare manifestations
of reactivation in immunosuppressed patients have been observed,
such as erythema nodosum, myelitis, peritonitis, and colpitis(49) (159).
Complementary examinations, such as computed
tomography and/or magnetic resonance imaging of the brain,
are fundamental to localize lesions; to differentiate other
diagnostic possibilities, such as neurotoxoplasmosis and
primary lymphoma of the central nervous system; and to assess
whether it is possible to perform a lumbar puncture to obtain
CSF for examination to confirm the diagnosis, by recognizing
the presence of the parasite (and subsequent cultivation).
These tests are more sensitive when performed on CSF than on
peripheral blood. CSF examination reveals discrete pleocytosis
(with predominance of lymphocytes and monocytes), average or
slightly reduced glucose level, and a mild-to-moderately raised
protein level(48) (49) (159).
In reactivation disease, myocarditis is manifested as heart
failure induced by arrhythmia, cardiogenic shock, and low
response to symptomatic drugs for congestive heart failure.
Echocardiography and other complementary examinations to
assess cardiac function are indicated(49) (159) (175). Diagnosis is
facilitated when there is a concomitant increase in parasitemia
25
Rev Soc Bras Med Trop 49:Supplement I, 2016
in peripheral blood; however, reactivation can occur in the tissue
without systemic repercussions(49) (159).
The reactivated form of Chagas disease, in its manifestations
of meningoencephalitis and/or myocarditis, is officially
considered in Brazil as indicative of severe immunodeficiency
in individuals over 13 years, and have been included as AIDSdefining conditions since January 2004(54).
For epidemiological surveillance purposes, cases of
reactivation of Chagas disease are those that present a definitive
diagnosis of T. cruzi infection by parasitologic diagnosis through
direct investigation of blood or body fluids (CSF, pericardial,
or peritoneal fluid), associated with:
• Meningoencephalitis: Brain injury image with mass effect
(magnetic resonance imaging or computed tomography,
with or without injection of contrast medium, showing
ring enhancement); and/or
• Acute myocarditis: Arrhythmias and/or heart failure
diagnosed by electrocardiography and echocardiography.
Factors associated with the reactivation
of Chagas disease
A CD4+ T lymphocyte count <200 cells/mm3 is observed in
>80% of cases of reactivation(49) (159) (175). Reactivation is rarely
seen in patients with a CD4+ T lymphocyte count >350 cells per
mm3(48) (49). Available data do not suggest the importance of HIV
viral load as prognostic factor for reactivation or as factor related
to the severity of the cases. On the other hand, HIV viral load
increases have been observed in the context of reactivation(49) (159).
Regarding the role of the protozoan, prospective studies
have shown the importance of high parasitemia (observed by
quantitative methods) as a predictive factor of reactivation (50%
of cases). In addition, the participation of different subpopulations
of T. cruzi in the genesis of clinical manifestations of reactivation
is discussed; this remains controversial in the literature(48) (49) (159).
In heart transplant situations, factors associated with
reactivation are the number of rejection episodes, the presence of
neoplasms, and tangentially, the use of mycophenolate mofetil(182).
Evolution and prognosis of reactivated
Chagas disease
If early treatment is not provided, most patients with AIDS
and reactivation of Chagas disease die before or shortly after
diagnosis(159) (175). Of patients who complete at least 30 days of
treatment, about 80% survive(159). The prognosis in cases of
HIV infection and reactivation of Chagas disease was reserved
before the advent of highly active antiretroviral therapy
(HAART), with an estimated average survival of 10 days(20).
In immunocompromised patients, the severity depends on
the degree of immunosuppression, the parasite load and the
sensitivity of the isolated parasite to antiparasitic treatment.
The outcomes recorded in kidney transplant recipients were
favorable, due to monitoring, diagnosis, and early treatment. The
clinical picture is quite severe in newborn infants with congenital
infection from born to T. cruzi/HIV coinfected mothers; the
morbidity and mortality is high(173) (174) (175).
26
CHRONIC INDETERMINATE FORM OF
CHAGAS DISEASE
The indeterminate chronic form (ICF) of Chagas disease is
particularly relevant as it is the most prevalent clinical form the
disease. It has a benign nature and low evolutionary potential
in the short and medium term(19) (20) (39) (188) (189) (190) (191). With
the reduced incidence of acute Chagas disease and improved
clinical management, the duration of survival of patients with
chronic Chagas disease has increased, reflecting a tendency to
proportional reduction of ICF with advanced age(19) (189) (192) (193) (194).
On the other hand, since the last Brazilian Consensus in 2005(20),
no applicable strategy of clinical or complementary evaluation
to the classic concept of ICF has been proposed.
Diagnostic criteria
Patients are considered to have ICF if in a chronic phase
of Chagas disease with positive serology and/or positive
parasitologic examination for T. cruzi(188) (189) but no typical clinical
syndrome specific of the disease; conventional ECG results;
and normal radiologic examination of the chest, esophagus, and
colon(188). No other complementary examinations in addition to
those previously listed, are required to define ICF. The expression
indetermined chronic form was first used by Carlos Chagas and
stablished by its use(195) (196) (197) (198). The reference of this term,
mainly in the context of scientific research, was consolidated by
Brazilian researchers in 1984(20) (142) (188) (199).
In field and operational studies, for asymptomatic cases with
normal physical examination, conventional ECG, and chest and
esophagus radiography findings, the term ICF was used without
performing radiologic investigation of the colon(19) (189) (190) (191).
This conduct is justified, taking into account the low availability
and feasibility of these complementary tests in the real context
of the national health systems in endemic regions.
Treatment and clinical follow-up
Specific antiparasitic treatment is indicated for all cases
with ICF (see specific section on antiparasitic treatment in this
Consensus)(20) (39).
While the ECG finding is normal, the prognosis of cases
with ICF of Chagas disease is similar to the general population,
since serial repetition of these examinations can detect evolution
to a cardiac form of Chagas disease(20) (189) (192) (197). Based on this
key concept, is not recommended performing other routine
complementary tests while the ECG finding is normal(19) (20) (189) (190) (191).
Cases with ICF should be advised not to donate blood, and in
principle, tissues or organs(20) (39). Due to the benign nature of ICF,
the (still common) practice of requesting specific serologic exams
for Chagas disease in pre-employment assessments for labor
purposes and periodic examinations conducted by institutions
and/or public or private companies, is not justified(192) (200) (201) (202).
As for other complementary tests, these may be ordered according
to the specific labor activities that the individual will perform.
Similarly, in these cases, temporary or permanent removal from
work activity is not recommended(192) (200) (201) (202) (203).
Engaging in usual, regular physical activity is not
contraindicated in patients with ICF. For professional activities
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
involving individual and collective risk that may require high
demand of physical effort and/or psychological stress, the
adoption of a complementary specific cardiologic evaluation
is recommended. There is no restriction of sexual activity for
patients with ICF(192) (200) (201) (202).
ICF carriers must be assessed annually, preferably in the
primary healthcare services, by means of medical evaluation
and conventional ECG (20) (202). If disease evolution is observed,
these cases should be referred to more specialized healthcare
services with the aim to provide the patient with a more precise
direction (to define the appropriate investigation and treatment
interventions) for the integrated management with primary
health care teams (up- and down-referral).
Indeterminate chronic form does not interfere with the
management of associated diseases and does not justify neglecting
the follow-up and treatment of comorbidities that may possibly be
present(49) (197) (203) (204). If immunodeficiency (acquired or induced)
occurs in patients with ICF, special attention should be given to
possible reactivation of Chagas disease (see specific section on
reactivation of Chagas disease)(20) (49) (159). The surgical risk for the
patient with ICF does not differ from that observed in the general,
uninfected population(20) (194) (200) (202) (203).
Regarding pregnant women infected with T. cruzi with this
classification, attention should be paid to the possibility of
vertical transmission, and opportunities should be created for
adequate assessment of the newborn infant (see specific section
on vertical transmission)(20) (39) (202). Women with ICF should not
restrict breastfeeding, except in the presence of fissures and/or
bleeding of the nipple/areola(20) (202).
It is emphasized that health professionals should avoid the
adoption of any practice that may induce stigma or prejudice.
Health services should provide space and resources for advice,
clarification, and orientation of the population regarding
the characteristics of this form of disease. It is strongly
recommended that this approach is led by a multidisciplinary
team(20) (189) (190) (191) (193) (202).
CARDIAC FORMS OF
CHAGAS DISEASE
Chronic Chagas heart disease is the most prevalent
symptomatic clinical form, responsible for the high burden of
morbidity and mortality, with great impact on social and medical
systems(4) (19) (20). Recently, the notion has been considered that
the pathogenesis of myocardial injury in the chronic phase of
Chagas disease depends mainly on parasite persistence and
the unfavorable immune system response to this incessant
infectious stimulus(205) (206) (207) (208). Among the most peculiar
characteristics of chronic Chagas heart disease, the following
are highlighted: Its inflammatory and intensely fibrosing nature,
presence of complex ventricular arrhythmias in association with
disturbances in atrioventricular and intraventricular formation
and conduction of the electrical stimulus, high incidence of
sudden death and thromboembolic events, and right ventricular
dysfunction and ventricular aneurysms(209) (210) (211) (212) (213) (214).
Acute Chagas disease and consequently, acute Chagas
myocarditis, was previously restricted to vectorial transmission
2nd Brazilian Consensus on Chagas Disease, 2015
of Chagas disease, now rare in Brazil. However, their
epidemiological importance in Brazil and other countries,
endemic and non-endemic, has expanded due to reactivation
of the disease in immunocompromised individuals, favored
by the spread and chronicity of HIV infection, as well as by
the increased access to organ transplantation. In addition to
this scenario, there is the challenge posed by Chagas disease
in the Amazon, attributed to oral transmission. As a result of
changing the epidemiological profile of disease transmission,
cases of acute Chagas heart disease, which currently present
clinical and specific epidemiological aspects, has again
increased(76) (91) (92) (169) (170).
The importance of the composition of a resolute healthcare
network for people with Chagas disease, in particular the role
of primary care as the first contact and provider of secondary
prevention of the disease, is emphasized. From the recognition
of the context of clinical cases, this primary health care network
should be integrated into the matrix/reference network for more
complex situations.
Acute Chagas heart disease
1. Acute Chagas myocarditis associated with oral
transmission
In Amazônia Legal, especially, a systematic record exists
of cases with the acute form of Chagas disease, occurring in
sporadically, in outbreaks, or in micro epidemics, where the
main form of transmission is oral, involving food contaminated
with triatomine feces(21) (76). The clinical presentation differs from
classical acute Chagas myocarditis (vectorial) mainly by the
absence of evidence of a portal of entry (inoculation chagoma),
the involvement of community groups or families in outbreaks,
and having no identified predilection for a specific age group
or for disease severity(91) (169).
Clinical manifestations of acute disease associated with oral
transmission are variable, ranging from asymptomatic cases
up to those developing severe heart failure, cardiogenic shock,
and even death. It can also manifest as a nonspecific infectious
syndrome, with prolonged fever (usually for more than three
weeks). The manifestations of acute myocarditis are described
in Figure 3(215).
Laboratory and radiologic examinations
Chest radiography may be normal or may show varying
degrees of cardiomegaly and pleural effusion. The ECG readings
are altered in most acute cases. The main ECG findings are
non-specific changes in ventricular repolarization, followed
by prolonged QTc interval, left atrial overload, low voltage of
QRS complex, AVB, bundle branch block, sinus tachycardia,
and atrial fibrillation(216). ECG can detect pericardial effusion,
atrioventricular valve regurgitation, increase in the size of
the heart chambers, presence of thrombi, and changes in left
ventricular systolic function.
Treatment
Pharmacological management of acute Chagas myocarditis
is even recommended for the treatment of heart failure in
patients with acute myocarditis of other etiologies: Routine use
27
Rev Soc Bras Med Trop 49:Supplement I, 2016
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Dyspnea of variable intensity
Tachycardia (even without fever)
Palpitations
Chest pain
Raised jugular venous pressure
Soft heart sounds
A gallop rhythm
Heart murmurs in the apical region and tricuspid area
Pericardial effusion
Hypotension
Cardiac tamponade
Tachyarrhythmias (atrial fibrillation)
Bradyarrhythmias (atrioventricular block)
In children: tachypnea, irritability, sweating, vomiting, anorexia, hepatomegaly, and edema of the lower limbs
FIGURE 3. Key signs and symptoms of acute Chagas myocarditis
of a combination of three types of drugs [diuretics, angiotensin
converting enzyme inhibitors (ACEI) or angiotensin II AT1
receptor blockers (ARBs), and beta-blockers] is always
combined with specific treatment of T. cruzi infection (using
benznidazole or nifurtimox)(203).
The natural history of the acute phase of Chagas myocarditis,
induced by oral transmission of Chagas disease, is still not fully
known. The most severe cases, with ventricular dysfunction,
pericardial effusion, and atrial fibrillation, tend to have worse
outcomes in the acute phase, requiring treatment in an intensive
care environment.
2. Acute Chagas myocarditis in immunocompromised
individuals
Individuals infected with T. cruzi, when exposed to
immunosuppressive agents or who have other concomitant
diseases such as cancer and other infections, particularly HIV
infection, may experience reactivation of Chagas disease. The
frequency of this reactivation is not fully known. However, in
a prospective study in which cases were evaluated pre- and
post-antiretroviral therapy, the occurrence of reactivation was
observed in 20% of the cases(48).
The heart appears to be involved in approximately 30–40%
of cases of reactivation of Chagas disease in individuals
coinfected with HIV. However, the incidence of myocarditis
alone does not seem to be common. Cardiac involvement is
usually characterized by acute myocarditis, with diffuse or focal
cardiac involvement. Clinically, it is characterized by signs and
symptoms of heart failure (tachycardia, edema, hepatomegaly)
or severe arrhythmias. In some cases, only electrocardiographic
changes are observed; in others, myocarditis is confirmed
only by histopathologic examination of endomyocardial
biopsy material. Anatomopathological examination reveals
acute myocarditis with intense inflammatory infiltrate,
cardiac fiber injury with focal necrosis, and large numbers
of amastigote forms of the parasite(217). In cases where there
was previous cardiac involvement (for chronic Chagas heart
disease), there may be overlapping reactivation Chagas disease
28
cardiomyopathy and decompensation of preexisting Chagas
heart disease. Determining if the clinical picture is solely due to
reactivation of Chagas disease, myocarditis associated with HIV
itself, or the overlap of the two conditions, is complex(218). Acute
myocarditis due to the reactivation of T. cruzi infection might
be also confused with the natural progression and worsening of
chronic Chagas heart disease. The differential diagnosis between
these two conditions is important in terms of deciding whether
or not to administer the specific treatment of T. cruzi infection,
as many patients do not tolerate the medication. High levels of
parasitemia are indicative of reactivation. However, there is no
record of patients who developed low parasitemia(219).
Diagnosis
Confirmation of reactivated Chagas disease in patients
with immunosuppression is performed by parasite detection in
peripheral blood and other body fluids (cerebrospinal fluid, cavity
effusions, etc.), by direct observation methods, or in sites of organ
damage (heart, skin, etc.) in individuals with co-infection(48).
Treatment
There are no specific treatment measures for this group.
Treatment should follow evidence-based recommendations
developed for the treatment of heart failure in general.
Acute decompensated heart failure, resulting from the
hemodynamic effects of heart failure, is associated with
neurohumoral activation and symptoms of congestion and/
or low cardiac output. Early recognition of this condition and
the implementation of appropriate therapeutic measures for
heart failure, associated with the specific treatment for T. cruzi
infection, can reduce the high rate of mortality observed in
cases of myocarditis induced by reactivation of Chagas disease
in immunocompromised patients.
Chronic Chagas cardiomyopathy
Definition
Chronic Chagas cardiomyopathy (CCC) is defined as the
presence of ECG changes suggestive of cardiac involvement
typical of Chagas disease in symptomatic and asymptomatic
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
individuals. Since ECG examination is easily accessible and
has high sensitivity and specificity (around 90%), the modified
conventional ECG is used, a priori, to diagnose CCC in people
chronically infected with T. cruzi(20). Cardiac involvement in
the chronic phase of Chagas disease includes a wide spectrum
of manifestations, ranging from the presence of clinically
unapparent abnormalities to severe forms, such as end-stage
heart failure, thromboembolic complications, refractory
ventricular arrhythmias, and sudden death.
Taking as a reference only conventional 12-lead ECG, it is
possible to establish, in a simplified way, the degree of cardiac
involvement in routine evaluation of the patient with chronic
Chagas disease, as shown in the following flowchart (Figure 4)(20).
Cases with nonspecific ECG changes would not be diagnosed with
CCC, but they should be re-evaluated according to the concomitant
symptoms and changes found in additional tests.
Chronic Chagas cardiomyopathy staging
Presence of severe heart failure [functional class III and IV
of the New York Heart Association (NYHA)] and left ventricular
global systolic dysfunction are the most important prognostic
factors in CCC(220) (221) (222) (223).
Echocardiography allows evaluation of both the overall and
segmental myocardial function. It can also identify important
Altered conventional electrocardiogram
Significant non-specific changes:
Sinus bradycardia (HR> 40 bpm)
Low voltage, IRBB, LAFB, first
degree AVB, Nonspecific ST-T
changes
Changes:
RBBB (or with LAFB) isolated VES, monomorphic,
2nd degree AV block, T
Changes, HR <40 bpm
Changes:
Polymorphic or repetitive
VES, Electrically inactive
area, Sinus node
dysfunction
Changes:
NSVT, AF,
CAB, LBBB
Evaluation
LVEF on echocardiogram and
arrhythmia evaluated by Holter or
stress test
Individualized assessment
(Clinic / age / labor demand)
Echocardiogram, Stress test, Holter
Without CHF
Periodic
reassessment
A
Normal Eco
B1
Altered
Eco LVEF
≥ 45%
Without
arrhythmia
With
arrhythmia
Arrhythmia
reassessment
With CHF
B2
Altered Eco
LVEF < 45%
C
Altered Eco
Compensable
HF
Without
arrhythmia
D
Altered
Eco refractory
HF
With
arrhythmia
Periodic
treatment and
reassessment
IRBB: incomplete right bundle-branch block; LAFB: Upper anterior fascicular block; AVB: Atrioventricular block; ST-T: ST-T segment; RBBB: Complete right bundle
branch block; VES: Ventricular extrasystoles; T: T-wave; HR: Heart rate; NSVT: Non-sustained ventricular tachycardia; AF: Atrial fibrillation; CAVB: Complete
atrioventricular block; LBBB: Left bundle branch block; LVEF: Left ventricular ejection fraction; CHF: Congestive heart failure; ECO: Echocardiogram; HF: Heart failure.
FIGURE 4. Algorithm for evaluation of individuals with Chagas disease using conventional ECG.
2nd Brazilian Consensus on Chagas Disease, 2015
29
Rev Soc Bras Med Trop 49:Supplement I, 2016
Stage
Electrocardiogram
Echocardiogram
Heart failure
A
Altered
Normal
Absent
Altered
Altered, LVEFa ≥45%
Absent
B2
Altered
Altered, LVEFa <45%
Absent
C
Altered
Altered
Compensated
D
Altered
Altered
Refractory
B1
aLVEF: left ventricular ejection fraction.
Source: Adapted Xavier SS et al. 2005(223)
FIGURE 5. Initial staging of myocardial dysfunction in chronic Chagas cardiomyopathy.
markers for staging the disease, such as size of chambers,
alterations in segmental mobility, and presence of aneurysms
and mural thrombosis. For these reasons, and because it is a
noninvasive and inexpensive examination, echocardiography
is of great value for the initial staging of CCC, in association
with the functional NYHA classification. From a prognostic and
therapeutic point of view, it is possible to identify five different
subgroups of CCC, as shown in Figure 5(223) (224) (225) (226).
In addition to the impairment of myocardial function, rhythm
disturbances and electrical impulse conduction abnormalities
are significant changes in CCC; in some cases, arrhythmias may
occur alone, without global ventricular dysfunction, or only with
small regional dyskinesias(227) (228) (229) (230) (231) (232).
If possible, it is obligatory to perform a 24 hourelectrocardiogram (Holter) in all cases with suspected arrhythmia.
Less frequently, an ergometric test may be used instead of a Holter,
to show ventricular arrhythmias during standardized physical
effort. When possible, both tests should be performed, as they
are complementary in the evaluation of these cases.
There is also a group of cases in the chronic phase of
Chagas disease (not included in the classification above) that
shows normal ECG findings, but presents changes ̶ usually
discrete and not associated with an increased risk of death ̶
in other cardiac tests, such as echocardiography, myocardial
scintigraphy, and magnetic resonance imaging. However,
since the risk of progression of these cases to the cardiac form,
classically defined, appears to be higher than that of cases of
Chagas disease without these changes, they should receive
regular clinical follow-up(231) (232).
Chronic Chagas cardiomyopathy prognosis
In a systematic review of studies that used multivariate
analysis to evaluate the prognosis of patients with CCC(233), four
independent prognostic variables were identified: functional
class III/IV of NYHA, cardiomegaly on chest radiograph, left
ventricular systolic dysfunction, and non-sustained ventricular
tachycardia (NSVT) on Holter examination. By using these four
variables in an integrated manner, it was possible to develop
an algorithm capable of stratifying the prognosis of cases with
CCC (Figure 6).
30
It is important to highlight that the presence of functional
class III or IV NYHA, per se, identifies high-risk cases, since
virtually all these cases have ventricular systolic dysfunction
(evident on echocardiography) and NSVT (detected by Holter).
The combination of ventricular dysfunction with NSVT
(regardless of functional class) already identifies a group with
a risk about 15 times higher than cases without these two
variables(222) (233) (234).
Clinical manifestations of
chronic Chagas cardiomyopathy
Clinical manifestations of CCC can be grouped into three
syndromes: arrhythmic, heart failure, and thromboembolic.
These syndromes may occur alone or in combination in the
same case, and may be associated with megaesophagus and/
or megacolon(235) (236).
I - Arrhythmic syndrome
Ventricular arrhythmias
Ventricular arrhythmias are common in Chagas disease and
are of various types, including ventricular extrasystoles, isolated
and in pairs; NSVT; sustained ventricular tachycardia (SVT);
and ventricular fibrillation(237). These commonly present in
combination. Clinically, they present as palpitations, lipothymia,
syncope, and sudden death(237) (238). Syncope and other symptoms
of low output in cases with CCC should be quickly investigated,
due to the risk of complex ventricular arrhythmias and sudden
death.
Ventricular extrasystole is the most common arrhythmia.
Initially uncommon, monomorphic, and isolated, it becomes
polymorphic and repetitive with the evolution of the disease.
Holter and ergometric tests are the methods of choice for the
detection of ventricular arrhythmias and, when possible, should
be performed in all cases with CCC, regardless of the presence of
symptoms(42). Ventricular tachycardia may be sustained (duration
≥30 sec or shorter than this when interrupted electrically or
pharmacologically) or non-sustained (3 heartbeats or more and
a duration <30 sec).
NSVT relates to the degree of ventricular dysfunction,
occurring in about 40% of cases with CCC associated with
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
Patients with serological exam
reactive to T. cruzi
Normal
Conventional electrocardiogram
FC III/IV
(NYHA)
Abnormal
FC I/II
(NYHA)
Chest radiograph
Without
NSVT
Low risk
Normal
Cardiomegaly
Echocardiogram
Echocardiogram
Normal
Reduced
LVEF
Normal
Reduced
LVEF
Holter
Holter
Holter
Holter
With
NSVT
Without
NSVT
Intermediate
risk
With
NSVT
Without
NSVT
High risk
Low risk
With
NSVT
Without
NSVT
Intermediate
risk
With
NSVT
High risk
Source: Adapted from Rassi Jr. A et al., 2007(233)
FC: Functional class; NYHA: New York Heart Association; LVEF: Left ventricular ejection fraction; NSVT: Non-sustained ventricular tachycardia.
FIGURE 6. Algorithm for risk stratification in patients with chronic Chagas cardiomyopathy.
regional changes in ventricular contractility, and in 90% of
cases with left ventricular global systolic dysfunction associated
with heart failure(222) (237). This may occur in cases with normal
ventricular function(234). There is evidence that the frequency
of ventricular arrhythmias is increased in heart failure due to
Chagas disease, compared with other etiologies(239). SVT can
occur spontaneously or be reproduced by electrophysiological
study, which is indicated for cases whose history suggests this
hypothetical diagnosis but for whom non-invasive methods have
failed to confirm the diagnosis(240). Ventricular fibrillation is the
leading cause of sudden death in CCC. It occurs more frequently
in patients who have had previous episodes of ventricular
tachycardia, although it may also be the first manifestation of
2nd Brazilian Consensus on Chagas Disease, 2015
the disease or its terminal event, especially in cases with severe
ventricular dysfunction and chronic cardiac insufficiency (CCI ) (238).
Treatment of ventricular arrhythmias
Treatment of the arrhythmia has two main objectives: to
control symptoms and to prevent sudden death(238). Simple
ventricular arrhythmias (isolated and monomorphous ventricular
extrasystoles) are not associated with an increased risk of death.
Hence, they should be treated only if causing symptoms of
functional impairment. If needed, suitable treatment consists of
normal doses of amiodarone, sotalol, or beta blockers.
In cases of life-threatening arrhythmias (NSVT, SVT, and
ventricular fibrillation), the most effective antiarrhythmic,
31
Rev Soc Bras Med Trop 49:Supplement I, 2016
and the safer to use, is amiodarone(241). It is necessary to pay
attention to the side effects of this drug – that are generally
related to the cumulative dose – which can trigger serious
bradyarrhythmias. In such cases, evaluation of the need for
permanent pacemaker implantation is required. Extra-cardiac
toxicity, thyroid dysfunction, and skin abnormalities are not
uncommon, while severe pulmonary toxicity is rare(242). Periodic
assessment of the thyroid function is recommended in patients
treated with amiodarone.
In turn, cases with SVT (a relatively common condition) and
those who recover from cardiorespiratory arrest in an out-ofhospital environment (a much rarer condition) are at high risk of
death and deserve a rigorous evaluation. For these cases, there are
not only antiarrhythmic drugs, but also arrhythmic focus catheter
ablation techniques (or, rarely, surgical techniques) and, especially,
implantable cardioverter-defibrillator (ICD) devices(237).
The treatment of ventricular arrhythmias in CCC is described
briefly in Figure 7. Drug treatment and ICD recommendations
are described in Figure 8 and Figure 9, respectively.
Supraventricular arrhythmias
Atrial fibrillation is the sustained supraventricular
arrhythmia more frequently observed in CCC, found in 4–12%
of cases(229). It tends to manifests later on and is often associated
with marked cardiomegaly. Treatment consists in controlling the
ventricular rate, which can be obtained through the use of drugs
prolonging the refractory period of the atrioventricular node. If
there is an associated heart failure, preference is given to digitalis
and beta-blockers (metoprolol succinate, carvedilol, or bisoprolol).
If ventricular function is normal, the use of conventional betablockers (propranolol and atenolol) or calcium channel blockers
(verapamil and diltiazem) is recommended for the initial control
of the heart rate, with subsequent evaluation of the possible need
for electrical or pharmacologic cardioversion. Anticoagulation is
indicated when atrial fibrillation is associated with heart failure
and cardiomegaly, CHA2DS2VASc score ≥2, or when there is
evidence of intracavitary thrombosis or previous embolic episodes.
The drug of choice is warfarin, in a dose sufficient to maintain
the international normalization factor (INR) between 2 and 3(243).
Bradyarrhythmias
The treatment of bradyarrhythmias in CCC does not differ
from that recommended for other types of cardiomyopathies. It
consists of the implantation of a permanent cardiac pacemaker in
symptomatic or high-risk blockage cases. These recommendations
are well defined in the Brazilian Guidelines for Implantable
Cardiac Electronic Devices, published in 2007(244).
The association between disorders of the heart conduction
system and frequent and complex arrhythmias is common in
CCC. In these cases, the effective pharmacologic antiarrhythmic
Ventricular arrhythmias in Chagas disease
NSVT
(with frequent isolated or paired VES)
Symptoms
present
Individualized
AA drug (Amio,
sotalol, BB,
class I)
. Unstable SVT
. VF
. Syncope + induction
SVT
Stable SVT
Preserved LV
function
Impaired LV
function
Amio
(Class I a/IIa b)
Sustained / malignant
ventricular arrhythmias
Symptoms
absent
No AA drug
(except: >20%
VES on 24h
Holter)
LVEF> 35%
Amio (class I)
ICD (class IIa)
LVEF< 35%
LVEF> 35%
Amio (class I)
ICD (class I)
LVEF< 35%
Amio (class IIa)
ICD (class I)
Source: Adapted from Rassi Jr.A et al., Abordagem atual das arritmias Ventriculares na doença de Chagas. Cardios, year 16, n. 15 may - june 2013
a Symptomatic
b Assymptomatic
NSVT: Non-sustained ventricular tachycardia; VES: Ventricular extrasystoles; LVEF: Left ventricular ejection fraction; SVT: Sustained ventricular tachycardia;
Amio: Amiodarone; AA: Antiarrytmic drugs; ICD: Implantable cardioverter defibrillators; BB: Adrenergic betablockers.
FIGURE 7. Interventions for treatment of ventricular arrhythmias in Chagas disease.
32
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
Recommendation class
I
I
I
I
I
IIa
IIa
IIb
IIb
III
Indication
Individualized antiarrhythmic medication for cases of isolated or paired VESa, symptomatic
Amiodarone for cases with symptomatic NSVTb
Amiodarone for recovered cases of cardiac arrest or with stable SVTc and EFd>35%
Amiodarone for cases with stable SVTc
Amiodarone for reduction of shock in appropriate cases with ICDe
Amiodarone for cases with asymptomatic NSVTb and LVf dysfunction
Routine amiodarone for cases with symptomatic SVTc who were treated with ICDe
Amiodarone for cases with asymptomatic NSVT and normal LVf function
Amiodarone for recovered cases of cardiac arrest or with unstable SVTc and EFd ≤ 35%
Antiarrhythmic drugs for cases with asymptomatic isolated or paired VESa
Level of evidence
C
C
B
C
C
B
C
C
C
C
aVES: Ventricular extrasystole; bNSVT: Non-sustained ventricular tachycardia; cSVT: Sustained ventricular tachycardia; dEF: Ejection fraction;
eICD: Implantable cardioverter defibrillator; fLV: Left ventricle.
FIGURE 8. Recommendations and levels of evidence for the use of antiarrhythmic drugs in the treatment of ventricular arrhythmias in chronic Chagas
cardiomyopathy.
Recommendation class
I
I
IIa
IIb
Indication
ICDa for recovered cases of cardiac arrest or with unstable SVTb, regardless of EFc
ICDa for cases with stable SVTb and LVEFd ≤35%
ICDa for cases with stable SVTb and EFc >35%
ICDa for cases with NSVTe and EFc ≤35%
Level of evidence
C
B
C
C
aICD: Implantable cardioverter defibrillators; bSVT: Sustained ventricular tachycardia; cEF: Ejection fraction; dLVEF: Left ventricular ejection fraction; eNSVT: Nonsustained ventricular tachycardia.
FIGURE 9. Class of recommendation and levels of evidence for the use of CDI in the treatment of ventricular arrhythmias in chronic Chagas cardiomyopathy.
drug therapy may require permanent pacemaker implantation in
order to prevent a possible AVB or high-risk bradyarrhythmia
induced by antiarrhythmic. The choice of the pacing mode is,
to date, the subject of controversy in the literature.
II - Heart failure syndrome
In the acute phase of Chagas disease, heart failure (HF)
can occur due to severe myocarditis. Although the outcome
may be death, in most cases, it is reversible, progressing to the
indeterminate form of the disease. Approximately 30–40% of
cases with the indeterminate form will progress to the heart
form of the disease, usually after decades of evolution(42) (236).
The chronic heart form, characterized by the gradual
appearance of electrocardiographic changes, is caused by
the slow but steady destruction of myocardial fibers, caused
by a continuous chronic inflammatory process, with intense
reparative fibrosis and progressive ventricular remodeling(208).
In the early chronic stage of the cardiomyopathy, it is not
uncommon that only the ECG findings are changed; individuals
remain asymptomatic, capable of performing unrestricted,
sometimes even extreme, physical activity. Therefore, they are
included into NYHA class I(227) (230) (239). Rarely, in this group of
2nd Brazilian Consensus on Chagas Disease, 2015
cases, the first and only manifestation of CCC is sudden death(245).
In most cases, a progressive reduction in the ability to perform
physical activities is observed, followed by deterioration of
contractile function of the left ventricle, initially in the form
of regional dyskinesia and diastolic dysfunction, followed by
a drop in the global systolic function of the chamber, due to
several associated factors, such as the progressive destruction
of cardiomyocytes, microvascular changes, the breakdown of
the muscle structure and fibrosis(208) (236) (247). It is not common for
cases with Chagas disease in the chronic phase to present with
acute pulmonary edema. There are also many cases with CCC
in whom the initial manifestations of heart failure are fatigue
and edema, with minimal dyspnea(246) (247). In these cases there
is the early involvement of the right ventricle, with impaired
systolic function. In the more advanced stages of the disease,
when heart failure is completely manifested, predominant
symptoms and signs of systemic congestion may arise, but with
little significant pulmonary congestion. Chest teleradiography
shows a marked cardiomegaly, with little engorgement of
the pulmonary vasculature. It is important to identify early
signs of left ventricular systolic failure, since the treatment
at this early stage could, in theory, delay the deterioration of
contractile cardiac function(42) (227). In addition, left ventricular
33
Rev Soc Bras Med Trop 49:Supplement I, 2016
systolic dysfunction is also the most important indicator of risk in the
chronic phase of Chagas disease-induced cardiomyopathy(222) (224) (225).
Treatment of heart failure in cases with chronic Chagas
cardiomyopathy
Treatment of heart failure aims to relieve the symptoms,
slow the progression of ventricular dysfunction, and prolong
survival(20). Treatment of heart failure due to Chagas disease, as
well as other etiologies, should be comprehensive, starting with
general measures, removing the factors that contribute to worsen
heart failure, and treating the underlying syndrome(248) (249).
General measures
1.
2.
3.
4.
5.
Diet: Obesity should be corrected and the ideal weight
should be maintained, avoiding inadequate intake of
sodium chloride and, in specific cases, alleviating the
symptoms of dysphagia and constipation.
Controlling water retention: A balanced intake of salt (3–4g/
day of sodium chloride [mild to moderate disease], and ≤2g/
day [severe disease]). A simple and reliable way to evaluate
water retention is daily assessment of body weight. Variations
higher than 1kg/day are indicative of fluid retention. A gain of
rapid and constant weight (1kg/day) is an indication that heart
failure is worsening. People affected should be encouraged
to monitor their weight daily in the morning (after urinating
and fasting). In severe heart failure with hypervolemia and/
or hyponatremia, fluid restriction may be required.
Control of aggravating factors: The intake of alcohol
and the use of anti-inflammatories should be avoided.
Arterial hypertension, cardiac arrhythmias, anemia, or
thyroid function disorders should be controlled. Other
comorbidities may contribute to worsening heart failure,
such as coronary artery disease and diabetes mellitus.
Individualization of the recommendations for rest or
physical activity, in accordance with the degree of heart
failure and the patient’s age.
Vaccination against influenza (annually) and pneumococcal
23-valent (a booster after five years for those cases with
compromised immune systems, or adults over the age of
60 years who received the first dose before 65 years old)
should be provided.
Drug treatment of heart failure
caused by Chagas disease
At the time of finalization of this Consensus, the results
of the BENEFIT study were published. This was a doubleblinded, multicenter, clinical trial that tested the hypothesis
that trypanosomicide treatment with benznidazole, compared
to placebo, could modify the prognosis of patients with
Chagas disease chronic cardiomyopathy (250) (251). Overall,
2,854 patients were evaluated. They were randomly assigned
to receive benznidazole or placebo for up to 80 days, with a
mean follow-up period of 5.4 years. A reduction in the parasite
load was observed with benznidazole, but it had no effect on
the progression of heart disease (estimated by complications
occurring during clinical follow-up, such as death, ventricular
arrhythmias, need for implanted devices, thromboembolic
34
events, heart failure, or heart transplantation): 27.5% of patients
in the benznidazole group and 29.1% of patients in the placebo
group experienced complications, hazard ratio (HR) = 0.93;
95% CI, 0.81–1.07; p = 0.31)(251). This result differed from the
results of previous observational studies(252) (253). These results
shift the focus of attention to treatment (of patients with CCC)
with conventional anti-failure methods derived from other
cardiomyopathies(254).
Long-term treatment of heart failure is usually based on
a combination of the following classes of drugs: diuretics;
ACE inhibitors or ARBs; adrenergic blockers (BB); and the
aldosterone antagonists(254). Positive inotropic drugs (such
as catecholamine or milrinone) have limited applicability
in intensive care settings, and slightly prolonged cardiac
decompensation. Digitalis, however, may be administered
chronically in individuals without bradyarrhythmias to alleviate
their symptoms and prevent cardiac decompensation and
hospital admission, especially in patients with atrial fibrillation
with rapid ventricular response(255).
Loop and thiazide diuretics may be used separately or in
combination to relieve symptoms and signs of pulmonary and
systemic venous congestion. When it is imperative to use high
doses of loop diuretics, such as furosemide, one should be aware
of the higher likelihood of hypokalemia and/or hyponatremia,
which, in turn, can exacerbate or trigger serious arrhythmias(248).
In CCC with heart failure or asymptomatic systolic
dysfunction (ejection fraction <45%), the chronic administration
of ACE inhibitors is indicated to reduce the morbidity, mortality
or ARB, when patients are intolerant to ACE inhibitors(256). With
the same purpose, the use of spironolactone is recommended in
cases with heart failure, in NYHA functional classes II–IV(248).
Furthermore, it is thought that aldosterone antagonists can provide
additional benefits when used in patients with CCC because
of their antifibrotic properties (demonstrated in experimental
studies). The combination of hydralazine and nitrates is a
recommended alternative to treat cases in functional NYHA
class II–III if a contraindication to the use of ACE inhibitors or
ARBs (e.g., progressive renal failure or hyperkalemia) exists(248).
The use of adrenergic beta-blockers in addition to blockade of
the renin-angiotensin-aldosterone system (with ACE inhibitors
or ARBs) is recommended to reduce the morbidity and mortality
associated with the disease. It is assumed that these drugs can
help to prevent the worsening of the ventricular remodeling,
development of malignant arrhythmias, and sudden death(257)
(258)
. However, the use of an optimized dose of adrenergic
blockers may be hindered in CCC, given bradyarrhythmias and
frequent need of amiodarone administration for the treatment
of tachyarrhythmias. To date, there is no consensus among
experts about which drug, beta-blockers or amiodarone, should
be prioritized in the management of Chagas disease.
Complementary forms of treatment for heart failure
caused by Chagas disease
Heart transplantation is the treatment of choice for end-stage
heart failure, despite the many limitations of medical and social
nature that embargo its broader use in cases of Chagas disease.
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
Recommendation class
I
Indication
ACEIa or ARBb (intolerant to ACEIa) in cases with t reduced LVEFc, symptomatic or no
Level of evidence
C
IIb
ACEIa or ARBb (in intolerant to ACEIa) in cases with normal LVEFc
and segmental dysfunction of LVd
I
Spironolactone in cases with LVEFc <35% and FCe III/IV of the NYHA
B
IIa
Spironolactone in cases with LVEFc <35% and FCe II of the NYHA
C
I
Carvedilol, metoprolol succinate or bisoprolol in cases with reduced LVEFc,
symptomatic or not, and with HRg>55 bpm
C
I
Loop diuretics in symptomatic cases, with signs and symptoms of congestion
C
I
Combination of hydrochlorothiazide in cases resistant to loop diuretics
C
IIa
Digoxin in symptomatic cases with reduced LVEFc (<45%) and sinus rhythm or AFh,
despite optimized therapy with ACEIa and BBi
C
I
Heart transplant in cases with refractory HFj
C
C
aACEI: Angiotensin converting enzyme inhibitors; bARB: Angiotensin II AT1 receptor blockers; cLVEF: Left ventricular ejection fraction; dLV: Left ventricle;
eFC: Functional class; fNYHA: New York Heart Association; gHR: Heart rate; hAF: Atrial fibrillation; iBB: Adrenergic beta-blocker; jHF: Heart failure.
FIGURE 10. Recommendations and levels of evidence for the treatment of heart failure in patients with chronic Chagas cardiomyopathy.
The results obtained in a selected series of cases, compared with
those observed in cases with heart failure due to other etiologies,
show an even more favorable evolution in transplanted cases
with Chagas disease. Among other possible factors, this is
possibly due to the fact that, in this series, cases with Chagas
disease were younger and had fewer comorbidities(259) (260).
There is no definitive indication for prophylaxis; however,
active control is recommended for possible reactivation the
disease, especially in the first year after transplantation, when
immunosuppression is more pronounced. Benznidazole, in a
dose of 5mg/kg/day, should be promptly started and maintained
for 60 days to obtain a good clinical outcome(100).
There is no evidence to support routine indication of cardiac
resynchronization therapy (CRT). In addition to the fact that
there are no controlled studies exploring in a scientific and
valid manner this therapeutic possibility, in CCC the complete
block of the right bundle branch is frequent and, in the presence
of this condition, evidence of the benefits of CRT, even in
other etiologies of heart failure, are even more scarce and less
convincing(203) (244).
Cell implant-based therapies were recently explored in a
single study, properly controlled. The results did not show any
benefit, even on surrogate outcomes such as the left ventricular
ejection fraction(261).
The recommendation classes and levels of evidence for
treating heart failure in patients with CCC are summarized in
Figure 10.
III - Thromboembolic syndrome
Systemic and pulmonary thromboembolic events are
common in CCC. Pulmonary thromboembolism is certainly
under-diagnosed when considering the results of postmortem
2nd Brazilian Consensus on Chagas Disease, 2015
studies(262). Embolic events are favored by the combination of
several factors. The most important are venous stasis, reduction
in cardiac output, and intracardiac mural thrombus, favored
by localized ventricular dyskinesias (e.g., apical aneurysm),
dilation of the cardiac chambers, and atrial fibrillation in more
advanced stages of the cardiomyopathy.
Prevention of thromboembolic complications in chronic
Chagas cardiomyopathy
Embolic accidents in the central nervous system are the most
severe form of thromboembolism in CCC and contribute to the
high morbidity and mortality of the disease(263). The scientific
basis for antithrombotic treatment in CCC is based on findings
of a prospective cohort study of 1,043 cases, which assessed
the risk and defined prevention strategies for cardioembolic
stroke (CES)(264). In that study, the incidence of CES was 3.0%
(or 0.56% per year), and the multivariate statistical analysis
allowed the composition of a risk score for CES occurrence:
The presence of left ventricular systolic dysfunction contributed
2 points; while presence of apical aneurysm, primary alteration
of ventricular repolarization in ECG, and age over 48 years
contributed 1 point each. Warfarin may be indicated for cases
with 4–5 points (in this subgroup, the incidence of stroke is
4.4% vs. 2.0% of severe bleeding per year). In the subgroup
with a score of 3 points, embolism rates and bleeding with oral
anticoagulants are equivalent, and acetylsalicylic acid or warfarin
may be indicated. In cases with 2 points, with low incidence of
CES (1.22% per year), acetylsalicylic acid or no prophylaxis is
recommended. Cases with 0–1 point, with an event incidence
close to zero, do not require prophylaxis. Obviously, in cases
with intracavitary thrombus, atrial fibrillation associated with
CHA2DS2VASc score ≥2, and previous embolic accident, the use
35
Rev Soc Bras Med Trop 49:Supplement I, 2016
Class of recommendation
I
I
I
IIa
Indication
Atrial fibrillation with CHS2DS2VASc ≥2
Intracavitary thrombus
Previous cardioembolic stroke
Risk score with 4 or 5 points
Level of evidence
C
C
C
B
FIGURE 11. Recommendations for oral anticoagulation in chronic Chagas cardiomyopathy.
of oral anticoagulants is always advisable, maintaining the INR
between 2 and 3(264). Recommendations for oral anticoagulation
in CCC are described in Figure 11.
Pregnancy approach in
chronic Chagas cardiomyopathy
Chronic Chagas cardiomyopathy ranks second among the
cardiomyopathies present in the pregnancy-puerperal cycle, being
second only to rheumatic cardiomyopathy. Most pregnant women
with Chagas disease are asymptomatic or oligosymptomatic,
being carriers of indeterminate or initial cardiac forms.
The risks of pregnancy in women with Chagas cardiomyopathy
depend on the cardiac functional status and the presence and
severity of arrhythmias. Pregnancy should be discouraged in
cases with heart failure and/or arrhythmias. Pregnant women
with these conditions require monitoring and special care, due
to the possibility of worsening during pregnancy. In the initial
consultation of the pregnant woman with Chagas diseaseinduced cardiomyopathy, in addition to routine tests, ECG and
echocardiography (to assess cardiac dimensions and ventricular
function) and a 24-hour Holter (in order to identify conduction
disorders and arrhythmias) should be requested(265). The relative
and absolute contraindications to the use of drugs acting on the
cardiovascular system or with a teratogenic potential should
always be observed. Pregnant women with CCC must be attended
to at reference centers for high-risk pregnancy, as they may require
high-complexity care. It is worth highlighting the importance of
carrying out all recommended assessments during the prenatal
period, including HIV testing(20).
Surgical risk in patients with
chronic Chagas disease
The evaluation of surgical risk in patients with Chagas
cardiomyopathy is based on available data related to other heart
diseases. However, the unique characteristics of CCC, especially
those related to autonomic dysfunction, complex arrhythmias,
and intraventricular stimulus conduction disturbances, can cause
different responses to surgical trauma(266). Cases with more
severe myocardial damage (NYHA class IV heart failure or
LVEF <30%; moderate systolic dysfunction, but with complex
arrhythmia, atrial fibrillation, significant dilation of the left
ventricle, total AVB and sinus node dysfunction) are more likely
to have perioperative complications.
Asymptomatic sinus bradycardia in patients undergoing
surgery under general anesthesia should be monitored by
ECG during the procedure, which must be carried out where
36
there is the possibility of performing emergency pacemaker
implantation. If bradycardia is symptomatic, preventive
implantation of pacemaker should be considered.
Patients with atrial fibrillation with a high ventricular rate
(>90 beats/min), regardless of the type of anesthesia, should
be operated on under continuous ECG monitoring and prior
scanning. In patients with atrial fibrillation with a ventricular
rate <60 beats/min, the possibility of a marked decrease in
the heart rate due to anesthetic agents must be borne in mind.
In these cases, the surgical procedure should be performed
under continuous ECG monitoring and in an institution able
to perform emergency pacemaker implantation. The same care
should be taken in relation to cases with AVB associated with
bundle branch block, due to the possibility of developing full
AVB during surgery due to the action of anesthetic agents(266).
Cases with complex ventricular arrhythmias should
be evaluated by Holter and operated on after institution of
appropriate antiarrhythmic therapy. The surgical procedure
should be performed under continuous ECG monitoring and
where there are defibrillators.
Preoperative evaluation of patients with cardiac pacemaker
includes knowing the arrhythmia that lead to the implant, as
well as generator characteristics. In addition to the clinical
history, important data can be obtained from the card that
cardiac pacemaker carriers receive and identifies the main
characteristics of the device, such as the date of the implant,
programmed heart rate, operating mode, and manufacturer.
The main risks associated with the presence of a pacemaker
during surgical or diagnostic procedures consist of changing the
unit’s operating threshold (by the action of drugs, changes in serum
potassium levels, and changes in thoracic impedance for pulmonary
ventilation), ventricular fibrillation (conduction of the electrical
current from the electrocautery by the intracardiac electrode
pacemaker) and, finally, damage, inhibition or reprogramming
of the system by electrocautery, cardioversion, or magnetic
resonance imaging. Whenever possible, biphasic electrocautery
(bipolar) should be used, since the electric current remains
confined between the region of the surgery and the electrocautery,
reducing the risk of leakage and interference with the device(244) (267).
In any case, the use of electrocautery should be minimized.
It should be used in short and irregular intervals, monitoring
not only the ECG, but also the pulse by plethysmography or
pulse oximeter. In the event of severe bradycardia or tachycardia
during the use of the electrocautery, a magnet cover can be used
over the pacemaker, which makes it work in its programmed
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
magnetic response. Attention should be paid to the fact that
the placement of the magnet should be restricted to the short
periods of electrocautery use. The patient should be advised
postoperatively to return to the clinic for pacemaker follow-up
for the assessment of its operation and eventual reprogramming
of its generator(267).
In patients with a CDI, the presence of technician or specialist
in the operating room is recommended. The antitachycardia
function should be switched off, with staff prepared to treat any
possible arrhythmias, including having to perform electrical
cardioversion(244) (267).
If electrical cardioversion is required in patients with
pacemakers, the ideal would be to use adhesive pads in the
anteroposterior chest position, as remote as possible from the
generator, using as little energy as possible for resolution of the
arrhythmia. Similarly, the thresholds and the functioning of the
pacemaker should ideally be assessed after the procedure(244).
Occupational health evaluation
Chronic Chagas cardiomyopathy is an important cause of
incapacity to work in endemic areas. It should be the subject
of surveillance actions for workers’ health, included in primary
care. Careful clinical examination, with particular attention to the
cardiovascular system, is the basic component of functional and
occupational health evaluation in CCC(268). These assessments
should take into account: the degree of ventricular dysfunction;
the presence, magnitude and complexity of conduction and rhythm
disorders; and the thromboembolism risk. It is also important to
consider the characteristics of the labor activity performed by the
worker, especially the need for intense or continued physical effort
in the activity, as well as the degree of professional qualification of
the worker and his/her ability to enroll in a vocational rehabilitation
program. The age of the worker should also be considered, as the
possibility of evolution of heart disease is greater for younger
workers and vice versa. In general, the worse the LVEF and the
greater the ventricular diameter, the worse the prognosis and the
greater the inability to work(269).
The presence of cardiomegaly and significant ventricular
dysfunction implies incapacity to perform activities that require
physical effort, and, when vocational rehabilitation is not
possible, disability. In all functional assessments of prognosis
and working capacity of an individual with Chagas disease,
the great clinical variability of these cases should be taken into
account, even when in the same stage of any classification of
cardiac impairment. Often, but not always, advanced disorders
of stimulus conduction are associated with the severity of
myocardial damage, leading to the need for a complementary
evaluation of the degree of myocardial dysfunction, especially
in cases where the work requires intense physical activity and
involves personal or social risk (e.g., aviation pilots)(270).
DIGESTIVE FORM OF
CHAGAS DISEASE
The digestive form of Chagas disease can affect all organs
in the gastrointestinal tract. However, from a practical point
of view, it is manifested as involvement of the esophagus and
2nd Brazilian Consensus on Chagas Disease, 2015
large intestine, resulting in megaesophagus and megacolon,
respectively(20). The association between megaesophagus and
megacolon in cases that have an indication for surgery is
approximately 92%. The association between megaesophagus,
megacolon, and heart disease is 65%(271). A specific search for
T. cruzi infection should be undertaken in patients with clinical
syndromes consistent with those described below, who live
in at-risk contexts and/or who have increased vulnerability to
Chagas disease(20).
Diagnosis
Digestive manifestations in the acute phase of Chagas
disease
Clinical manifestations are usually nonspecific, with
practically imperceptible symptoms related to the gastrointestinal
tract. However, there are reports describing the occurrence of
gastrointestinal bleeding in cases of oral transmission and of
dysphagia in rare cases of vectorial transmission(20).
Digestive manifestations in the chronic phase of Chagas
disease
Digestive manifestations of Chagas disease are concentrated
in the esophagus and colon and are basically dysphagia
and constipation, due to chronic alterations that can lead to
megaesophagus and/or megacolon(20). However, as the disease
causes autonomic nervous system injury throughout the
gastrointestinal tract, anatomical and functional abnormalities
of the salivary glands, stomach, extra-hepatic bile ducts,
duodenum, small intestine, large intestine, and even of organs
not belonging to the gastrointestinal tract, such as the ureter,
can occur. The prevalence of Helicobacter pylori infection and
of characteristic gastric endoscopic and histologic changes
were similar in patients with and without Chagas disease.
Furthermore, studies have shown that H. pylori is the main
cause of gastritis in patients with Chagas disease(272). The most
common symptoms and signs of the digestive system, in the
chronic phase of Chagas disease, are described below.
Esophagus
Clinical diagnosis
Dysphagia is the main symptom of patients with severe
impairment of the esophagus. Other dysphagia-related
complaints occur in cases of megaesophagus, including
ptyalism, hiccups, odynophagia, regurgitation, a sense of
nocturnal choking, aspiration pneumonia, and malnutrition(20).
In the early stages of the disease, the patient reports a feeling of
obstruction at the level of the xiphoid after eating solids and, later,
after fluid intake, especially cold fluids. Dysphagia progresses
slowly and is well-tolerated for many years. Therefore, patients
with achalasia often do not seek care in health services until
the progressive dysphagia interferes with their lifestyle. It is
observed that the patients themselves spontaneously change
their eating habits to alleviate dysphagia. Patients with achalasia
feed slowly, ingest large volumes of water to assist the food
into the stomach, often bend the back, lift the chin, extend the
neck, or walk to help esophageal emptying. Regurgitation of
undigested food is common as the disease progresses, with a
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Rev Soc Bras Med Trop 49:Supplement I, 2016
risk of aspiration, which may lead to pneumonia, lung abscess,
bronchiectasis, hemoptysis, and bronchospasm. Great distension
of the dilated esophagus may lead to dyspnea, compression of
the main stem of the bronchus or lung hilum.
evident. Although there is a correlation between the degree of
megaesophagus and the severity of dysphagia, it is common to
find patients with bulky megaesophagus complaining about or not
even reporting dysphagia(273). Notably, the incidence of esophageal
cancer in patients with idiopathic achalasia is 3.3%, 15 times
higher than that of the general population without achalasia(274) (275).
Esophageal involvement occurs to varying degrees, with
great variation in morphology and differences of esophageal
motor behavior, ranging from minimal changes of esophageal
transit to advanced forms of dolicomegaesophagus with
an extremely prolonged esophagogastric transit time (20).
Considering practical and therapeutic aspects, patients with
megaesophagus can be classified into groups, depending on the
degree of expansion of the organ, as shown in Figure 12(273).
Complementary examinations
•
Plain radiography of the thorax (posterior-anterior or
lateral views): In cases of megaesophagus grade III or IV,
great dilation of the esophagus extending to the posterior
mediastinum can be observed (Figure 13 A and B).
Contrast radiography of the esophagus: This shows not
only the degree of esophageal dilation, allowing classification
of megaesophagus, but also demonstrates functional changes,
such as abnormal or missing peristaltic waves and the emptying
time of esophageal contents into the stomach. The radiologic
characteristics of megaesophagus in Chagas disease are: increased
esophageal diameter and emptying time (Figure 14); a tapered
Most cases of megaesophagus are found in groups II and III.
The degree of megaesophagus does not necessarily reflect the
duration of the disease. There are cases that rapidly progress
to advanced forms, while others remain stable in the early
stages. Lower esophageal sphincter dysfunction is greater in
cases where the motor abnormalities of the esophagus are more
A
B
C
D
A=Group I; B=Group II; C=Group III; D=Group IV
Group I – Patients in this group present esophageal diameter within normal limits, without food stasis, but with an increase in food
transit time from mouth to stomach. Functional motor disturbances predominate without corresponding dilation.
Group II – Patients present with moderate dilation of the esophagus e loss of motor control. Secondary and tertiary waves can be
seen in the esophagogram.
Group III – More accentuated dilation can be observed than in group II, transit time more prolonged and reduced motor activity. The
esophagus behaves like an inert tube.
Group IV – Consists of advanced forms with large dilation and stretching of the esophagus (dolicomegaesophagus).
Source: Rezende, 1982.(273)
FIGURE 12. Radiologic classification of megaesophagus. (A) Group I: The esophageal diameter is within normal limits, without food stasis, but with an
increase in food transit time from mouth to stomach. Functional motor disturbances predominate without corresponding dilation; (B) Group II: Moderate dilation
of the esophagus with loss of motor control. Secondary and tertiary waves can be seen in the esophagogram. (C) Group III: More accentuated dilation than in
group II, transit time more prolonged, and motor activity reduced. The esophagus behaves like an inert tube. (D) Group IV: Advanced form with massive dilation
and stretching of the esophagus.
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2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
A
B
Source: Radiographs of a patient attended at the Hospital das Clínicas, Federal University of Minas Gerais (UFMG).
FIGURE 13. Plain radiography of the thorax. (A) Posterior-anterior view and (B) lateral view, demonstrating the great dilation of the esophagus extending
to the posterior mediastinum.
A
B
Note: Images taken 2 minutes (A) and 6 hours after ingestion of contrast (B). Note the pacemaker wires implanted in this patient due
to AV block of concomitant Chagasic cardiomyopathy.
Source: Radiographs of a patient attended at the Hospital das Clínicas, Federal University of Minas Gerais (UFMG).
FIGURE 14. Contrast study of a patient with esophageal achalasia (group III ). Images taken (A) 2 minutes and (B) 6 hours after ingestion of contrast.
Note the pacemaker wires implanted in this patient due to AVB secondary to concomitant Chagas disease-associated cardiomyopathy.
2nd Brazilian Consensus on Chagas Disease, 2015
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Rev Soc Bras Med Trop 49:Supplement I, 2016
distal third; retention of food debris; esophageal/mediastinal
stretching; and reduced gastric volume.
• Esophageal electromanometry: This is a useful method
to distinguish between the differential diagnoses of other
diseases that develop due to motor dysfunction that present
with dysphagia. In patients without dilatation, or with slight
dilation of the esophagus (group I and II), uncoordinated
pressure waves can occur in the body of the esophagus and
incomplete or atypical relaxation of the lower esophageal
sphincter (LES) can be observed. These findings precede
radiologically demonstrated abnormalities(276).
• Endoscopy: Although endoscopy is not essential to confirm
the diagnosis of megaesophagus, it should be performed to
assess the degree of mucosal inflammation and to exclude
the presence of neoplastic lesions in patients with dysphagia,
varicose veins, and ulcers. This examination is useful in
cases requiring forced balloon dilatation of the gastric cardia
and in cases requiring botulinum toxin injection.
Colon
Clinical diagnosis
The main signs and symptoms of megacolon are constipation,
paradoxical diarrhea (constipation interspersed by periods of
diarrhea), dyschezia, abdominal distension, and fecaloma(20).
Anorectal manometry is useful to diagnose internal anal sphincter
achalasia. Colonic dilatation located in the rectum and sigmoid is
better observed by contrast radiography studies and can be detected
in up to 80% of cases. However, dilatation can occur only in the
rectum, only in the sigmoid, or in the entire colon(277). It should
be emphasized that the clinical picture of severe constipation in
patients with idiopathic megacolon who are not infected with
T. cruzi is indistinguishable from that induced by Chagas disease(278).
Complementary tests
• Plain radiography of the abdomen: Bulky megacolons can
be detected on plain radiographic films of the abdomen,
especially if a fecaloma is present. Plain radiography is
also useful in cases of suspected volvulus, since it can
demonstrate rotation of the sigmoid and dilation of small
bowel loops caused by obstruction (Figure 15).
• Contrast radiography of the colon (barium enema): This is
the gold standard for the diagnosis of megacolon. It shows
dilation and/or stretching of the colon, presence of fecaloma,
and anatomic abnormalities of the sigmoid (Figure 16).
• Computed tomography and magnetic resonance imaging:
These more modern imaging tests occupy a prominent
place in the evaluation of patients with Chagas disease and
are gradually replacing conventional imaging methods.
Both methods are more sensitive in evaluating pericolonic
and/or perisophageal tissues; they can detect infiltration,
not only visible masses and fecalomas detectable by
conventional radiography. These modalities also provide
greater detail than a barium enema (Figure 17 A, B and C).
• Digestive endoscopy: This is useful in cases of megacolon,
to assess the degree of mucosal inflammation, detect
ulcers, wall necrosis, perforation or bleeding, and to rule
40
out the presence of associated lesions, particularly cancer.
It is particularly important in cases of suspected sigmoid
volvulus and can be therapeutic, since it might allow
laparotomy to be avoided. If it is not possible to reduce the
sigmoid volvulus by endoscopic examination, emergency
surgery is absolute indicated.
Megaesophagus
Considering the impossibility of restoring normal physiology
due to the irreversible changes caused by denervation, the goal of
treatment is to act on the lower esophageal sphincter in a patient
with achalasia, by removing the functional barrier to the passage
of food into the stomach. The treatment, except if specific, does not
cure the disease; it seeks only improve the symptom of dysphagia.(20)
Clinical treatment
This is indicated in patients with advanced age, with no
history of complications, who are oligosymptomatic, are at
high risk for surgical treatment, who refuse to undergo invasive
treatments, or those treated in hospitals lacking adequate
infrastructure to perform this type of surgery(20). The basis for
the treatment is specified below.
Source: Radiograph of a patient attended at the Hospital das Clínicas, UFMG.
FIGURE 15. Simple radiograph of the abdomen in a case of sigmoid
volvulus. Note the anomalous position of the sigmoid caused by the dilatation
and the characteristic image of the small bowel loops secondary to the
obstruction caused by the volvulus.
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
1.
Counseling and health education related to megaesophagus,
in order to improve patient safety.
2.
Adequacy of eating habits. It is recommended that the
patient chew their food well; eat small amounts at a time;
and consume liquid foods, pastes, and solids appropriate
to their severity of dysphagia. Irritating foods, such as
very spicy or hot foods or ice cream, aggravate dysphagia
and should be avoided. Due to the risk of regurgitation
and aspiration, food intake should be avoided before
bedtime. Balanced enteral nutrition is indicated in patients
with megaesophagus in Groups III and IV, malnourished
patients, and candidates for surgical treatment. If the
passage of a nasoenteric tube is not possible, parenteral
nutrition can be administered via a central venous catheter.
In both situations, the intervention is temporary.
3.
Use of drugs: Medicines that relax smooth muscle fibers of
the lower esophageal sphincter can relieve the symptoms
of dysphagia. These drugs include:
•
Isosorbide dinitrate, at a dose from 2.5mg to 5mg,
administered sublingually, 15 minutes before each meal.
•
Nifedipine, at a dose of 10mg, administered sublingually,
30 minutes before each meal. The use of nifedipine
should be performed with caution, considering the
significant association of this condition with chronic
Chagas cardiopathy; nifedipine may induce hypotension
and shock.
A
Source: Radiograph of a patient attended at the Hospital das Clínicas, UFMG.
FIGURE 16. Radiograph of a barium enema examination revealing a
hypodense image typical of a fecaloma.
C
B
Source: Computed tomography of a patient attended at the Hospital das Clínicas, UFMG.
FIGURE 17. Abdominal computed tomography, showing a megaesophagus with an air-fluid level formed by ingested contrast (A); megacolon with a large
dilatation of the air-filled colon with a fecaloma in the rectum (B); and megacolon with a predominant image of a fecaloma in the dilated sigmoid (C).
2nd Brazilian Consensus on Chagas Disease, 2015
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Rev Soc Bras Med Trop 49:Supplement I, 2016
4.
5.
Botulinum toxin: Botulinum toxin type A, applied locally,
blocks the release of acetylcholine from pre-synaptic nerve
endings and leads to chemical denervation. The treatment
is effective in 70% of patients, and the average duration of
symptom remission is 16 months. Patients over 50 years
of age respond better to this treatment(279) (280). Botulinum
toxin treatment of megaesophagus has worse outcomes
than those of dilation or surgery (level IIB). Although
the effect is temporary, botulinum toxin injection may be
indicated in selected cases, presenting the advantage that it
can be repeated several times. The dose of botulinum toxin
is 20 units injected into each of the lower quadrants of the
esophageal sphincter. One of the limitations of this treatment
is that the procedure should be guided by endoscopy.
Balloon dilatation: Pneumatic dilation is indicated for
patients with group I megaesophagus, but can be performed
in patients in groups II and III who have a contraindication
to surgery. It can also be used preoperatively in patients in
groups II and III who are candidates for surgical treatment
of megaesophagus, aiming to improve their preoperative
nutritional status. In patients in group IV, due to the risk
of redundant esophageal perforation, dilatation is not
recommended. The procedure is performed with a balloon
coupled to gauge introduced endoscopically, which
makes it the safest method. The result of megaesophagus
treatment by balloon dilation relieves dysphagia in 71%
of patients(280). However, the effect is transient, worsening
over time with successive dilations.
Surgical treatment
1. Conventional surgery (laparotomy): This does not address
the underlying cause of the disease, but restores the
ability of the patient to swallow. Based on the knowledge
gained about the pathogenesis and pathophysiology
of megaesophagus, the cardiomyotomy known as
Heller surgery(281), associated with some kind of partial
fundoplication(282), is the most appropriate surgical
procedure for cases of megaesophagus grades I to III. The
response rate is about 90%(280), giving a more long-lasting
and effective result than that achieved by pneumatic
dilatation. For dolichomegaesophagus, there is still no
consensus among surgeons; hence, different surgical
techniques are still used.
2. Laparoscopic surgery: This technique was introduced in
Brazil in the early 1990s, with simultaneous availability
of modern surgical instruments, such as electronic
scalpels and staplers. The experience of the surgeons with
this technological innovation and its use in the treatment
of cases of megaesophagus from achalasia related to
Chagas disease, has reduced the morbidity and mortality
associated with conventional surgery for megaesophagus
induced by Chagas disease (level IA). Laparoscopic
cardiomyotomy, associated with some type of antireflux
valve, especially those made by partial fundoplication, has
become standard surgery; it is virtually the standardized
surgical procedure for patients with this condition(283).
42
3.
4.
5.
6.
Robotic surgery: Robotic surgery is probably the most
advantageous of all the surgical options. However, the
complexity of its implementation and the high associated
costs hinder its routine application in practice(20).
Megaesophagus treatment by myotomy associated with
antireflux surgery carries a risk of esophageal perforation;
this complication can be severe. Robotic surgery, by
making scheduled and precise movements, will most
certainly reduce the rate of this complication.
Endoscopic surgery: Technological advances and the
increasing expertise of professionals has allowed myotomy
to be performed as a totally endoscopic procedure. This
surgery is now known by the acronym POEM (per-oral
endoscopic myotomy). It uses the Heller technique,
performed by transluminal endoscopic surgery through
natural orifices [natural orifice transluminal endoscopic
surgery (NOTES)]. This procedure was introduced by
professionals from the Mayo Clinic Endoscopic division
and, after testing on animals, the procedure was widely
disseminated, being used in humans since 2012. The
POEM technique seems to be a safe method, and is
currently an effective alternative for the treatment of
achalasia.
The procedure is performed with the person in the
supine position under general anesthesia, and consists in
approaching the esophageal lumen with a high-definition
gastroscope with frontal view. Saline stained with indigo
carmine is injected to create a safety gap between the
mucosa and submucosa of the esophagus. Then, a 2cm
longitudinal incision of the mucosa is performed, at the two
o’clock position, 10–15cm proximal to the gastroesophageal
junction, to expose the submucosal layer. A tunnel is
dissected in the submucosa, extending from the point of
section to 2–3cm beyond the gastroesophageal junction
(GEJ)(284). Myotomy of the lower esophageal sphincter is
usually performed starting at 2cm distal to the opening of
the mucosa to below the GEJ. As a rule, myotomy should
have a minimum length of 6cm (on average, 8–10cm): 2cm
in the esophagus, 2–3cm in the lower esophageal sphincter,
and 2cm in the cardia. Dissection of the submucosal tunnel
is performed in the plane before the muscle of the mucosa,
and esophageal muscle section is performed only in the
circular layer of the muscle, there is no need for longitudinal
muscle layer section.
Data from 14 English language publications show that
of 804 patients who underwent a POEM procedure,
therapeutic success was documented in more than 80%
(level A1)(285). The technique is less invasive and the
patients do not experience gastroesophageal reflux, as
observed in cases submitted to myotomy by conventional
laparotomy or laparoscopy surgical technique. The
familiarization of the endoscopist with the method enables
secure closure of smaller perforations and adequate
hemostasis (level B1)(286). If there is a more extensive
perforation of the esophagus, or more intense bleeding,
the assistance of a surgeon may be necessary.
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
Megacolon
1.
2.
3.
4.
5.
6.
7.
Clinical treatment
Health counseling and education related to
megaesophagus, in order to improve patient safety.
Adequacy of eating habits: This should focus on a higher
degree of self-care. Patients evacuated two to three times a
week without reporting a fecaloma should be instructed to
drink more fluids, and eat more fruits and vegetables. The
use of a diet rich in fiber in these patients is controversial,
because there is the fear that excess fiber may favor fecal
impaction and the worsening of symptoms. The diet can
be the patient’s usual diet, with restriction of constipating
foods. Abundant water intake is recommended – a volume
of at least 2L/day – as well as foods that favor intestinal
functioning.
Regular defecation: It is necessary to systematically pay
attention to the urge to defecate and to create the habit to
evacuate at certain hours.
Laxatives: These are indicated for patients who do
not adequately respond to dietary measures. Osmotic
laxatives (20% mannitol or polyethylene glycol) are the
most suitable. Mineral oil is also effective.
Avoidance of potentially constipating drugs: Opioids,
diuretics, antidepressants, antihistamines, anticonvulsants,
antiparkinsonians, among others, should only be
prescribed under medical monitoring.
Removal of fecaloma: Fecalomas, located in the rectum,
can be removed manually (under anesthesia) if they do
not respond to dietary and drug measures.
Intestinal wash-out: Patients who do not respond
satisfactorily to drug and dietary treatment, or those with
significant fecalomas, should be treated with glycerin or
saline enemas. Intestinal wash-out with 500–1,000mL
twice a week is recommended for patients resistant
to medical treatment. In patients with fecalomas, the
procedure may be repeated two to three times a day,
taking care not to use more than 3.5L of solution per day.
Experience with these treatments shows that, with the
removal of the fecalomas and normalization of bowel
movements, the diameter of the colon tends to return to
normal.
2.
•
•
3.
is elective and should be well planned. The most
commonly used conventional surgical techniques are
the aforementioned rectosigmoidectomy and the surgery
originally proposed by DuHamel for the treatment of
Hirschsprung disease(287). With the advent and spread
of laparoscopic surgery, the laparoscopic DuHamel
procedure has become the gold standard for treatment of
these cases(288).
Emergency surgery: The indications for emergency
surgery to treat megacolon are:
sigmoid volvulus not resolved by endoscopy; and
ulceration, necrosis and/or perforation, due to volvulus
or endoscopy.
The surgery to be performed will depend on the patient’s
condition and anatomopathological situation. The surgical
procedure may vary from a simple colostomy to fixing
the part affected by sigmoid resection with primary or
delayed anastomosis.
ANTIPARASITIC TREATMENT OF
CHAGAS DISEASE
Although there is disagreement about the cure rates of the
antiparasitic treatment of Chagas disease, there is consistent
evidence showing its usefulness in both acute and chronic
phases of the disease and in all clinical forms of chronic
infection, as the organic lesions depend exclusively (acute
phase) or at least in part (chronic phase) on the presence of
the parasite. In addition, there is apparent suppression of the
parasitemia with the current antiparasitic treatment(289) (290).
In turn, the rates of cure and their confirmation depend on
several factors, such as the phase and the duration of disease,
the age of the patient, the tests used to evaluate therapeutic
efficacy, the duration of follow-up after treatment, associated
conditions, and the susceptibility of the specific T. cruzi strain
to antiparasitic drugs.
Treatment in the acute phase
In the acute phase, treatment should be provided to all
cases and as quickly as possible, regardless of the parasite
transmission route (Class I, level of evidence B). Studies of a
case series followed for over 20 years have shown cure rates
above 50% at this stage of the disease(291).
Treatment of congenital Chagas disease
Surgical treatment
1. Elective surgery: Surgical treatment of megacolon is
indicated for patients who have large dilatation of the
sigmoid, repeated episodes of volvulus, prolonged
retention of feces, recurrent fecalomas, and difficulties in
applying enemas at home. Similar to the surgical treatment
of megaesophagus, the goal of treating the megacolon is
to improve or normalize the intestinal rhythm, since the
predominant symptom is constipation. Except in cases
of emergency caused by volvulus, bleeding, obstruction
or perforation, in which emergency procedures must be
adopted (colonoscopy or surgery), megacolon surgery
2nd Brazilian Consensus on Chagas Disease, 2015
Patients diagnosed with congenital Chagas disease should
receive antiparasitic treatment (more details on the specific part
of vertical transmission)(20), regardless of whether the diagnosis
has been made by parasitologic methods in the first weeks of
life or by conventional serologic tests at least nine months after
birth (Class I, level of evidence B).
Treatment of chronic phase
All children aged less than 12 years with chronic phase
Chagas disease should be treated (Class I, level of evidence
A). Prospective, randomized, double-blind, controlled studies
with placebo, performed in asymptomatic school-aged children,
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Rev Soc Bras Med Trop 49:Supplement I, 2016
demonstrated therapeutic cure of T. cruzi infection in 58–62% of
cases(292) (293). In an uncontrolled study involving Latin American
countries(294), large regional differences were observed in
treatment response rates: The seroconversion rate in Honduras
was 92.7% for children aged 9 months to 12 years and 58.8%
in a quarter of the study patients younger than 15 years. There
were variations in Bolivia, from 0% in Sucre to 5.4% in Entre
Rios. In the latter region this rate was higher in children younger
than 5 years (24.4%) than in children aged 5–9 years (4.6%)(294).
For adolescents (aged 13–18 years) and adults with chronic
infection, when it can be established that the acute phase
occurred up to 12 years before (considered as recent infection)
antiparasitic treatment is usually recommended(20) (294), although
there is no consistent evidence from randomized studies
justifying this (Class IIa, level of evidence C)(295).
For individuals with Chagas disease aged 19–50 years with
no recent documented infection, antiparasitic treatment should
be considered on an individual basis, whether in ICF(120) (252)
(Class IIa, level of evidence B) or in the determined chronic
form, without advanced cardiopathy(42) (120) (252) (295) (296) (297) (298)
(Class IIb, level of evidence C). Specifically, treatment of
chronically infected women of childbearing age, when provided
before pregnancy, can reduce congenital transmission(104) (109).
Some observational studies have shown that in this age
group, antiparasitic treatment is able to prevent the onset or
delay the progression of the disease in a significant proportion
of cases(42) (120) (252) (295) (298). This would lead to a reduction in the
complications of the disease, especially those related to heart
disease. Classical experimental studies in mice have already
documented total or partial regression of early myocardial
injuries and the prevention of cardiopathy with antiparasitic
treatment(299) (300). However, regression of inflammatory and
fibrotic lesions, observed in experimental studies, has not been
verified in the clinical context(20).
A case series demonstrated cure in at least 20% of the
cases treated in the late chronic phase(301). It should be noted
that demonstrating cure depends on various factors, including
follow-up of treated cases, which should continue for more than
two decades for patients treated in the late phase. Increased
seroconversion of cases showing no acute illness and without
cardiac failure was also assessed(290).
For individuals older than 50 years, without advanced heart
disease, there are no studies justifying antiparasitic treatment.
An observational study in elderly subjects infected with T. cruzi
demonstrated that the disease is present and active – the percentage
of patients with ICF decreases but the percentage with the heart
form increases(195). Thus, these individuals should not be completely
excluded from the etiological treatment plan of Chagas disease;
treatment can be individualized (Class IIb, level of evidence C).
Antiparasitic treatment should not be given to patients with
chronic phase Chagas disease with severe heart dysfunction, since
there is no evidence of clinical benefit(251) (289) (291) (295) (296) (302) (303)
(Class III, level of evidence C).
Recently, a series results from the BENEFIT study
– a prospective, multicenter, randomized, double-blind,
44
controlled study with placebo (placebo vs. benznidazole) –
was published(251). This is the first study to evaluate the effect
of a specific treatment for up to 80 days in relation to cardiac
outcomes and T. cruzi infection. The effects of benznidazole in
reducing morbidity and mortality among 2,854 patients with
established chronic Chagas cardiopathy were evaluated(250) (251).
After 5.4 years of follow-up, the results showed no statistically
significant difference between the two groups in relation to
the primary composite outcome that included death, sustained
ventricular tachycardia, recent heart failure, implantation of a
cardioverter-defibrillator or pacemaker, cardiac transplantation,
resuscitated cardiac arrest, stroke, or other thromboembolic
event(251). These findings, at first, seem to indicate a divergence
of considerably lower rates of parasite detection by PCR in
blood in the same study after treatment with benznidazole(303).
In the BENEFIT study, the treatment with benznidazole in
the protocol used probably has no significant preventive effect
on the progression of heart disease in patients with advanced
Chagas disease(251) (Class III, level of evidence B). However,
the severity of Chagas disease is emphasized in this study, as is
the resulting need for diagnosis and timely treatment, based on
qualified management, especially of heart disease. In the study,
503 patients died within 5 years (246 the in benznidazole group
and 257 in the placebo group), and 63% of patients (in both
treatment groups) developed a left ventricular ejection fraction
<40%, one of the primary outcomes of the study(251).
The study highlighted, therefore, the urgent need to structure
a network of qualified health care to manage patients with
Chagas disease comprehensively, without loss of diagnostic
and treatment opportunities. Longitudinal clinical management
is needed in terms of the various clinical forms of the disease,
especially the advanced cardiopathy form, with protocols
adjusted to local realities. In addition, the ability to create
specific treatment opportunities for people with therapeutic
indications based on more consistent evidence, is required(303).
Furthermore, the study draws attention to the lower
frequency of serious adverse effects to benznidazole compared
with previous study findings(251) (303). This reinforces the real
possibility of including, in a more expanded form, the specific
treatment of Chagas disease in the primary healthcare network
(primary) not only in Brazil but also in other endemic countries.
The digestive form of Chagas disease is not a contraindication
for antiparasitic treatment. Moreover, megaesophagus correction
should be performed in order to ensure full transit of the drug and,
subsequently, its absorption(20) (302) (Class IIa, level of evidence C).
Treatment of immunosuppressed cases
Cases with immunodeficiency, including patients taking
immunosuppressive drugs to treat neoplasms, transplants, and
other diseases, and patients with T. cruzi/HIV co-infection,
can develop reactivation of Chagas disease(181) (184) (304). This is
discussed, in themes, below.
Transplantation
In transplants in general, it is necessary to know if the
donor or the recipient has Chagas disease, considering the risk
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
of transmission or reactivation of the disease. Thus, there are
three possible scenarios:
• donors with Chagas disease and recipient without Chagas
disease;
• donors without Chagas disease and recipient with Chagas
disease;
• donors and recipient with Chagas disease.
Donor with Chagas disease and recipient
without Chagas disease
1. Guidelines for the donor with Chagas disease:
• The candidate for organ donation who has positive
serology for T. cruzi should be treated with antiparasitic
drugs for 60 days before the procedure. In special
situations requiring transplantation before completing
treatment, the transplant can be performed, but if possible,
not before 14 days of treatment has been completed (Class
I, level of evidence C).
2. Guidelines for the recipient when the donor is treated:
a. Consider etiological treatment soon after transplantation,
maintaining treatment for 60 days by means of intense
immunosuppression (Class IIa, level of evidence C)(184).
b. Do not treat, but provide sequential clinical monitoring
or parasitologic evaluation as follows: weekly direct
search for T. cruzi in the peripheral blood, until 60 days
post-transplantation; indirect parasitologic methods
(blood and/or xenodiagnosis) of follow-up of the
recipient during the period of immunosuppression;
and serologic examination 30 and 60 days posttransplant(181) (184) (305). In cases where monitoring is not
possible, etiologic treatment is recommended. The
following clinical and serologic examinations should
be performed at 3, 6, 9, and 12 months of follow-up:
direct/indirect parasitologic tests (blood culture and/or
artificial xenodiagnosis at 3, 6, and 12 months) or PCR.
Subsequently, the evaluation is repeated every 6 months,
while there is persistent immunosuppression (Class
IIa, level of evidence B)(181) (184) (305). It is noteworthy
that, in some reference centers, PCR, but not indirect
parasitologic examination, is performed. At any time, if
an acute infection is detected through parasitologic or
serologic tests, the conventional etiological treatment
should be instituted. Out of the usual controls, any
clinical signs suspicious of infection should be
investigated through parasitologic examination, and
positive cases should receive conventional treatment
for the acute phase. Since 2009 in Brazil, organ
transplantation laws have restricted the possibility of
patients with Chagas disease being accepted as organ
donors(183). In Brazil, Ordinance number 2,600, in
2009, which approved the Technical Regulations of the
National Transplant System, states that it is mandatory
to perform serologic testing for T. cruzi infection
in the following situations(183): I) for all donations,
2nd Brazilian Consensus on Chagas Disease, 2015
following the same algorithms used for screening
blood donors; II) for registration purposes of potential
organ recipients in a Single Technical Registry; III)
for all potential deceased donor organs, tissues, cells,
or body parts before the allocation of the grafts. It also
establishes criteria for the classification of living and
deceased donors as well as for potential recipients for
the distribution of organs, tissues, cells, and captured
parts. It does indicate that the team will decide whether
the organ/tissue is acceptable for use or not regarding
kidney, kidney/pancreas, pancreas, liver, and lung
donations. In the order, the rejection of organs relates
only to the heart. For ocular tissues, hematopoietic stem
cells, musculoskeletal tissues, skin, and cardiovascular
tissue, the issues related to T. cruzi infection are not
mentioned(183).
3. Guidance for the recipient without Chagas disease:
In cases in which the donor with Chagas disease has not
been treated or has received incomplete treatment, three
possible actions may be taken in relation to the recipient:
a. Start antiparasitic treatment soon after transplantation,
for a 60-day period (class IIa, level of evidence C). This
is recommended if the sequence monitoring indicated
in item c below is not possible.
b. Start treatment immediately after surgery, for an initial
14-day period. Then, proceed to sequential monitoring
with clinical, parasitologic, and serologic evaluation
(Class IIa, level of evidence C or without evidence). If
seroconversion occurs, introduce antiparasitic treatment
for the acute phase.
c. Do not treat, but proceed to sequential clinical monitoring
and parasitologic evaluation (Class IIa level of evidence
B)(181) (184) (305). Such evaluation consists of direct search
for T. cruzi in the peripheral blood, every week, for
up to 60 days, and indirect parasitologic and serologic
examinations on days 30 and 60 after transplantation.
Thereafter, clinical, serologic, and parasitologic (direct/
indirect/PCR) examinations should be performed every
two months for up to one year of follow-up; then every
six months, for as long as immunosuppression persists
(time dependent on the mode and type of transplant). It
is worth emphasizing that in some centers PCR, rather
than indirect parasitologic examination, is performed.
d. At any time, if an acute infection is detected by
parasitologic or serologic tests (IgM or seroconversion),
conventional antiparasitic treatment should be started.
Outside of the above-stated monitoring intervals, any
clinical sign of suspected infectious condition should
be investigated through parasitologic examination, and
positive cases should receive conventional treatment for
acute stage disease(20) (302).
e. A few of cases have been reported of kidney transplant
recipients without Chagas disease who were treated with
antiparasitic prophylaxis for 14 days, as the organ donors
had Chagas disease(308). In another work, prophylaxis
45
Rev Soc Bras Med Trop 49:Supplement I, 2016
f.
was provided for 60 days to recipients (without
Chagas disease) who received livers from donors with
Chagas disease(306) as usual strategy; seroconversion
was not observed in the surviving recipients, as this
may not occur in about 20% of patients in the posttransplant period . Use of antiparasitic drugs in patients
without documented infection (no identification of the
parasite or evidence of seroconversion) is considered
prophylactic use. In this text, even when the drug was
administered for the same duration as the duration of
treatment (60 days), the term prophylaxis has been used
if the drug was used in the absence of a documented
infection in the recipient. The works cited are not
controlled and, in addition of having been carried out in
a small number of cases in kidney and liver transplant
recipients, these did not use the systematic monitoring
of parasitemia, and the final results were based on the
absence of seroconversion in patients who survived.
However, since 2009, the possibility of patients with
Chagas disease being accepted as organ donors in Brazil
has been restricted by transplant regulations(184), with
systematic serologic screening limiting this type of
donation in individuals with T. cruzi infection. However,
these same organs can function as "marginal organs" in
specific situations(184) (305) (307).
Donor without Chagas disease and recipient
with Chagas disease
In these cases, the expected complication is the reactivation
of Chagas disease in the recipient, due to the use of
immunosuppressive drugs to prevent or treat rejections. With
time, pre-transplant conventional antiparasitic treatment can
be instituted. However, it should not prevent the realization of
transplantation, as subsequent actions can be adopted (Class
IIa, level of evidence C).
1. Prophylaxis of episodes of reactivation: In heart transplant
recipients, antiparasitic treatment may fail(100) (307).
2. Clinical and parasitologic monitoring of the recipient
after transplantation should be carried out, as in the case
with a donor with Chagas disease and a recipient without
Chagas disease, and early conventional treatment of
reactivation episodes should be provided(181) (184) (305). The
monitoring during the post-transplant period in patients
receiving cardiac transplantation is mandatory and must
include monitoring of blood and tissues, due to the
greater sensitivity of the methods in the reactivation site
(myocardium).
of potential episodes of reactivation, such as in the case of a
donor with Chagas disease and a recipient without Chagas
disease. If reactivation occurs, conventional treatment for the
acute phase should be provided (class IIa, level of evidence C).
Episodes of reactivation can occur more than once and should
be treated when documented. Hence, systematic parasitologic
monitoring while immunosuppression persists, is recommended.
Coinfection Trypanosoma cruzi/HIV
Observational studies have shown that, in the presence of
T. cruzi/HIV coinfection without AIDS, the natural evolution
of both diseases occurs, and one should follow the guidelines
for antiparasitic treatment of Chagas disease in its acute and
chronic forms, or monitoring of parasitemia, quantitatively if
possible(49) (159) (175) (Class IIa, level of evidence C) (see specific
part of this Consensus). In patients with co-infection and
AIDS, reactivation of Chagas disease might occur, and the
following measures are recommended: Specific antiparasitic
treatment is indicated for reactivation with a clinical syndrome
of myocarditis, meningoencephalitis, or other; and parasitologic
examination of the blood or cerebrospinal fluid yields
positive results by direct microscopy; or characteristic lesions
are demonstrated on histologic examination of tissue specimens(20)
(49) (159)
(Class I, level of evidence C). This therapeutic approach
should also be adopted in cases without evidence of reactivation
but with the associated clinical syndrome and a high level
of parasitemia, as defined by Sartori et al. as the presence of
more than 20% of positive nymphs in the same xenodiagnostic
test (indirect parasitologic examination, quantitative PCR) or
sustained parasitemia(49) (159) (175) (308) (Class IIa, level of evidence C).
Coinfection and prophylaxis
By analogy with other opportunistic infections in AIDS,
secondary prophylaxis can be used for patients with reactivation
of Chagas disease, who were treated for and achieved clinical
and parasitologic remission, when the levels of CD4+ T
lymphocyte were less than 200 cells/mm3 (IIa class, level of
evidence C(20) (49) (159) (175). However, this recommendation needs
to be validated in prospective studies, considering the low
frequency of relapse observed in patients taking combined
antiretroviral treatment.
Immunosuppression in other diseases associated with
Chagas disease
Clinical conditions such as neoplasms and collagen vascular
disorders in carriers of Chagas disease might be associated
with reactivation. The recommendations are the same as those
for reactivation occurring in organ transplantation patients and
patients with HIV coinfection(20) (49) (159) (175).
Accidental transmission
Donor and recipient with Chagas disease
Both should be considered as carriers of the chronic form
of Chagas disease and should be evaluated for antiparasitic
treatment, as described for cases with the chronic form of the
disease. After transplantation, the recipient should be monitored
from a clinical and parasitologic point of view for the diagnosis
46
In accidents characterized as high risk for disease
transmission, such as percutaneous injury or mucosal contact
with biological material containing live parasites (samples
for the culture of T. cruzi obtained from of patients with high
parasitemia or necropsy material, vectors, and animals that
are already infected), primary prophylaxis should be given.
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
Prophylaxis should be initiated immediately after the accident
and should be continued for 10 days(309) (310) (311). (Class IIa, level
of evidence C). Serologic tests should be performed before
initiating treatment and after 20, 40, and 60 days post-treatment
to monitor possible seroconversion. In the case of positive
serologic results, conventional antiparasitic treatment should
be provided, as described previously for the acute phase.
In minimal risk situations, such as the contact with the blood of
a patient with Chagas disease in chronic phase, drug prophylaxis
is not indicated. Serologic tests should be performed immediately
after the accident, and 20, 40, and 60 days post-infection. If
seroconversion occurs, conventional treatment for acute phase of
Chagas disease should be given, and post-therapeutic monitoring
should be conducted as in the acute phase. If the serology remains
positive after treatment, the therapeutic gap should be documented
and repeat treatment provided, either with the same drug or with
an alternative drug(20).
Treatment options, dosage, and type of administration
The neglected character of Chagas disease is evidenced by
the limited therapeutic options; only two antiparasitic drugs
with established efficacy are available for specific treatment:
benznidazole (a nitroimidazole derivative agent) and nifurtimox
(a nitrofuran compound)(14) (19) (20) (38) (42) (293) (294) (296).
The drug of first choice for the antiparasitic treatment of
Chagas disease in all the situations previously discussed is
benznidazole(20) (38) (100) (294). Currently, this medicine is produced
by a Brazilian pharmaceutical company, distributed by request
to the Ministry of Health of Brazil, with no distribution to the
general pharmaceutical market(20) (39).
Benznidazole is a well-tolerated drug(20) (38) (251). Children
generally have fewer adverse effects than adults and can
tolerate higher doses (104). In April 2013, the 19 th Expert
Committee on the Selection and Use of Essential Medicines
of the WHO discussed and approved the addition of two new
formulations of benznidazole in the essential drugs list for
children(38). Benznidazole is being increasingly prescribed
for the antiparasitic treatment of Chagas disease, not only the
expansion of indications based on evidence, but also as a result
of increased demand in endemic and non-endemic countries
with better structure of their national surveillance and healthcare
systems(38) (294) (295) .
Benznidazole (Class 1, level of evidence b) is produced
as tablets of 100mg and 50mg (adults) and 12.5mg and 50mg
(children)(20) (42) (104) (109) (122) (291) (296) (299) (302) (312) (313). In Brazil, only
the 100mg and 12.5mg tablets are available in the SUS network.
•
Adults: 5mg/kg/day, orally, in two or three daily doses,
for 60 days.
• The maximum dose recommended is 300 mg/day.
The 100mg and 50mg benznidazole tablets are distributed
in Latin America by the Argentine Endocrine Laboratory
(ELEA, Maprimed) and the PAHO Revolving Fund; in
Spain, through the Spanish Agency for Medicines and Health
Products; and the rest of the world through the ELEA and the
WHO(38). In Brazil, it is acquired by the Ministry of Health,
2nd Brazilian Consensus on Chagas Disease, 2015
and distributed to State Health Secretariats (SES) upon request
in the Information Strategic Procurement System (SIES).
Benznidazole distribution flow (100mg) for regional and/or
municipalities should be established for each SES, articulating
Pharmaceutical Assistance, Epidemiological Surveillance and
Primary Care. The distribution of benznidazole in doses of
12.5mg is centralized, considering the small occurrence of
cases of the disease in the recommended age for use of the
drug. Therefore, to apply for a pediatric formulation, the Chagas
Disease Technical Group, Communicable Disease Surveillance
Coordination of the Secretariat of Health, Ministry of Health
should be contacted(49).
• Children: 10mg/kg/day orally in two or three daily doses,
for 60 days.
• In all cases, the dose should not exceed 300mg/day. When
the daily dose exceeds 300mg, it is recommended that the
treatment duration be extended to achieve the total dose
calculated for 60 days.
The main advantage of the 12.5mg tablet is that it can be
used to treat infants as young as 2 years of age, allowing proper
dosing without the need to fragment and manipulate parts of
larger tablets. In addition, the main advantage of 50 mg tablet
is that it can be used to treat the rest of the pediatric population,
including teenagers and young adults(38).
In addition to the specific treatment for T. cruzi infection,
antiparasitic drugs can be used for prophylaxis in specific
situations. Secondary prophylaxis should be considered after
conventional treatment of reactivation in patients co-infected with
HIV, and with evidence of AIDS (2.5 to 5mg/kg/day, orally, three
times per week), but there is still no consistent evidence to validate
the use of benznidazole prophylactically in this situation(49) (159) (175).
In turn, primary prophylaxis is indicated in situations where
accidental exposure to T. cruzi has occurred. The recommended
dose is 5mg/kg/day (adult) or 10mg/kg/day (child), orally, twice
a day for 10 days, not exceeding 300mg/day. In cases where the
inoculum has a high parasite load (≥107 trypomastigotes/mL),
one should use conventional treatment for acute phase of Chagas
disease for at least 60 days(310) (Class IIa, level of evidence C).
In the case of children, one should use the pediatric formulation
of benznidazole, that is now available.
The adverse effects and toxicity of benznidazole, together
with the respective actions to be taken, are shown in Figure 18.
Thus, care should be taken before and during treatment to monitor
these events. Before starting treatment, clinical examination
and laboratory tests (complete blood count, evaluation of liver
enzymes, and renal function tests) must be performed. This must
be repeated 30 and 60 days after initiating treatment(20).
In cases of intolerance to benznidazole, nifurtimox is a
potential therapeutic option(20) (42) (119) (291) (292) (296) (312) (Class 1, level
of evidence B). Nifurtimox comes as a 120mg tablet (adults)
and a 30mg tablet (children).
• Adults: 10mg/kg/day, orally in three daily doses, for 60
days.
• Children: 15mg/kg/day, orally in three daily doses, for 60
days.
47
Rev Soc Bras Med Trop 49:Supplement I, 2016
Benznidazole
Manifestations/
adverse effects
Onset/
treatment
period
Characteristics
Localization
Intensity
Intervention
Complementary
measures
Dermatitis by
hypersensitization is
most frequent. NOT
dose-dependent and
NOT related to T.
cruzi.
10th day of
treatment, may
occur earlier or
later
Non-bullous,
pruritic,
polymorphous
erythema followed
by scaling.
Focal (restricted
to part of
the skin) or
generalized
Light (normally
focal)
Continue
treatment
Moderate (focal
or generalized)
Continue
treatment with
low dose of
corticosteroid
(5 mg of
prednisone
or equivalent)
Interrupt if
worse
Specific treatment
for scaling and
cutaneous
desquamation,
guided by a
dermatologist
Rarely oncolysis
occurs
Recovery without
sequelae.
Severe
(generally
accompanied
by fever and
mphadenopathy)
Interrupt
treatment
Hospitalize
according to clinical
presentation
Use
corticosteroid
Peripheral
polyneuropathy.
Dose-dependent,
slow regression
(months)
End of
treatment
Pain and
paresthesia
Plantar (more
frequently) and
palmar regions
Light to
moderate
Interrupt
treatment
General treatment
for peripheral
polyneuropathy,
guided by a
neurologist
Ageusia
End of
treatment
Partial or total loss
of taste
-
-
Interrupt
treatment
-
Bone marrow
depression
Between
the 20th and
30th days of
treatment
Leukopenia with
varying degree
of neutropenia,
may attain
agranulocytosis
-
Interrupt treatment
General treatment
for bone marrow
suppression, guided
by a hematologist
Digestive intolerance is rare (controlled with medication usually used for gastritis and peptic ulcers). Severe liver impairment is rare. Renal
impairment has not been observed.
FIGURE 18. Adverse effects of benznidazole and recommended approaches for each situation.
The adverse effects and toxicity of nifurtimox are similar to
those of benznidazole, except for a lower digestive tolerance,
reflected in anorexia with weight loss, and psychological
disturbances(20). In case of treatment failure with benznidazole,
nifurtimox can be used, although cross-resistance between the
two drugs has been observed.
It is necessary to remember that nifurtimox is not available in
the pharmaceutical market of any country to date. In situations
where the use of nifurtimox is essential, the drug must be
requested via the PAHO and WHO offices. The Ministry of
Health of Brazil, through the SVS Chagas Disease Technical
48
Group, has the availability of nifurtimox to be dispensed under
the conditions described above of benznidazole intolerance.
Nifurtimox is acquired by the Ministry of Health via PAHO
donation and is dispensed directly by the Chagas disease
Technical Group of SVS(39). The product may be requested
through a standardized protocol directed to this technical group
by the Ministry of Health.
Other drugs, such as allopurinol and azole antifungals
(ketoconazole, itraconazole, fluconazole, posaconazole), are
recognized as suppressors of T. cruzi parasitemia and may
be useful in some specific situations, such as reactivation
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
Event
Recommendation
class
Level of
evidence
Antiparasitic treatment in the acute phase of Chagas disease
I
B
Antiparasitic treatment in congenital Chagas disease
I
B
Antiparasitic treatment in the chronic phase of Chagas disease in children aged ≤12 years
I
A
Antiparasitic treatment in the chronic phase of Chagas disease with recent infection
IIa
C
Antiparasitic treatment in the chronic phase of Chagas disease with late infection, acquired in
the indeterminate form
IIa
B
Antiparasitic treatment in the chronic phase of Chagas disease with late infection and
cardiomyopathy without advanced disease
IIb
C
Antiparasitic treatment in the chronic phase of Chagas disease with advanced cardiac form of
the disease
III
C
Digestive form does not contraindicate antiparasitic treatment of Chagas disease
IIa
C
I
C
Antiparasitic treatment in an organ recipient without Chagas disease from organ donor with
Chagas disease
IIa
C
Monitoring of clinical and parasitologic events instead of antiparasitic treatment in an organ
recipient without Chagas disease from an organ donor with Chagas disease
IIa
B
Reactivation prophylaxis in transplanted person with Chagas disease
IIa
C
Monitoring of clinical and parasitologic events and prophylactic antiparasitic treatment for
transplanted person with Chagas disease
IIa
C
Coinfection Chagas/HIV without AIDS: antiparasitic treatment according to criteria in
immunocompromised
IIa
C
Antiparasitic treatment in an organ donor with Chagas disease
Reactivation antiparasitic treatment in coinfection Chagas/HIV
I
C
Antiparasitic treatment in coinfection Chagas/HIV without clinical events and high T. cruzi
parasitemia
IIa
C
Secondary prophylactic treatment after reactivation antiparasitic treatment in coinfection
Chagas/HIV in individuals with CD4+ lymphocyte T count <200 cells/mm3
IIa
C
Primary prophylaxis in laboratory accident with high risk of transmission of Chagas disease
IIa
C
Benznidazole as first choice drug for antiparasitic treatment of Chagas disease
I
B
Nifurtimox as a therapeutic option (instead of benznidazole) for the antiparasitic treatment of
Chagas disease
I
B
Allopurinol and azole antifungals as reactivation treatment in immunosuppressed patients when
benznidazole and nifurtimox treatment are not possible.
IIa
C (or unknown)
Serology as a criterion of cure and therapeutic failure after antiparasitic treatment for Chagas
disease
IIa
B
PCR as an alternative to indirect parasitologic examination (artificial xenodiagnosis and blood
culture) as an indication of therapeutic failure after specific treatment for Chagas disease
IIa
B
FIGURE 19. Summary of treatment situations, the recommendation class and level of evidence.
in immunosuppressed patients, when it is impossible to use
benznidazole or nifurtimox (49) (159) (175) (Class IIa, level of
evidence C). However, there is undeniable clinical evidence of
proven therapeutic efficacy.
The antiparasitic treatment with benznidazole should not
be imposed on pregnant women, or women of childbearing age
who are not making a regular use of well-known contraceptive
methods(20). As discussed in the specific section on vertical
transmission of T. cruzi in this Consensus, there is evidence
indicating the benefit of the antiparasitic treatment, with better
evolution of Chagas disease(116) (119) (120) (121) (122), reduced risk of
vertical transmission in future pregnancies(109) (116), and lower risk
of vertical transmission and evolution to spontaneous abortion
by reducing the parasitemia(103) (115).
2nd Brazilian Consensus on Chagas Disease, 2015
In the case of pregnant women for whom antiparasitic
treatment is indicated, the risk-benefit ratio and available
treatment options (in particular, acute phase and co-infection)
should be considered in each case. The indication in patients
with other serious disorders, such as hepatic and renal failure,
must be carefully assessed case by case, according to the
severity, as well as prior adverse events to drug components
that may constitute relative contraindications(20) (38) (104).
Evaluation of cure of Chagas disease after antiparasitic
treatment
Demonstrating serology becoming negative is considered
the only method to determine cure following antiparasitic
treatment of Chagas disease. The time required for this to
49
Rev Soc Bras Med Trop 49:Supplement I, 2016
occur is variable and depends on the stage and duration of
disease, with one year for congenital infection, 3–5 years for
the acute phase, 5–10 years for the recent chronic phase and
>10 years (usually 20–25 years) for the chronic phase of long
duration. The reduction in serologic test titers occurs gradually.
The persistent and progressive decline above three dilutions
of the titers of the serologic tests is suggestive that these will
be negative. Parasitologic examinations are not mandatory
for evidence of cure of Chagas disease, however, at any time,
positive parasitologic tests indicate therapeutic failure. PCR is
an alternative option to indirect methods (xenodiagnosis and
blood culture) in the parasitologic evaluation as a treatment
failure criterion after completing antiparasitic treatment(104)
(313)
. However, there are still limitations on the availability and
standardization of techniques in the health networks of endemic
countries(313).
Who and where to treat
Considering the operational specificities of national health
systems, use of antiparasitic treatment for Chagas disease by
doctors working in primary care who know the peculiarities
of the drugs and Chagas disease(20) (303), is feasible, safe(20) (251)
(294) (303) (312)
, and operationally possible(294). Depending on the
severity of clinical conditions of each case, particularly cases
with acute or reactivated and decompensated chronic forms, it
may be necessary to refer certain patients to more specialized
or reference units that have greater technological capability, or
even for hospitalization.
Figure 19 provides an overview of potential situations for
specific treatment, taking as reference the recommendation of
class and the level of existing evidence. Figure 18 shows the
adverse effects of benznidazole and recommended approaches
for each given situation.
Tribute
Tribute is paid to members of the group responsible for the
Brazilian Consensus on Chagas Disease in 2005 who died in the
period between the consensuses: Ademir Rocha, Aluízio Rosa
Prata, Antonio Carlos Silveira, Guilherme Rodrigues da Silva,
Joffre Marcondes de Rezende, and Vanize de Oliveira Macedo.
Contributions
General coordination of the Consensus and final critical
reviewing: Dias JCP and Ramos Jr AN. Thematic coordination,
design, writing, critical reviewing and final approval of the
version to be published: Dias JCP, Ramos Jr AN, Correia D,
Gontijo ED, Ostermayer AL, Shikanai-Yasuda MA, Coura JR,
Torres RM, Melo JRC, Almeida EA Oliveira Jr W, Cardoso AV,
Costa VM, Lima MM and Alves RV.
Representing the Ministry of Health of Brazil - critical
reviewing and final approval of the version to be published:
Cardoso AV, Costa VM, Lima MM and Alves RV.
Group of experts who participated in the composition of
the Brazilian Consensus on Chagas Disease, 2015 - writing
and responsibility for the document in terms of accuracy and
integrity: Dias JCP, Ramos Jr AN, Gontijo ED, Ostermayer
AL, Shikanai-Yasuda MA, Coura JR, Torres RM, Melo JRC,
50
Almeida EA, Oliveira Jr W, Silveira AC, Rezende JM, Pinto FS,
Ferreira AW, Rassi A, Fragata Filho AA, Sousa AS, Correia D,
Jansen AM, Andrade GMQ, Britto C, Pinto AYN, Rassi Jr A,
Campos DE, Abad-Franch F, Santos SE, Chiari E, HasslocherMoreno AM, Moreira EF, Marques DSO, Silva EL, Marin-Neto
JA, Galvão LMC, Xavier SS, Valente SAS, Carvalho NB,
Cardoso AV, Costa VM, Vivaldini SM, Oliveira SM, Valente
VC, Lima MM and Alves RV.
Acknowledgements
We thank Dr. Jarbas Barbosa da Silva Jr., Secretary of
Surveillance in Health of the Ministry of Health in the periods
2003–2007 and 2011–2014, for supporting the construction
of two issues of the Consensus on Chagas Disease, 2005 and
2015. To Dr. Habib Fraiha Neto and Dr. Ralph Lainson (in
memoriam), for the contributions in the section dedicated to
oral transmission. To the Brazilian Network of Attention and
Studies on Trypanosoma cruzi/HIV Coinfection and other
immunosuppressive conditions. We thank Dr. Pedro AlbajarViñas (World Health Organization - HIV/AIDS, Tuberculosis,
Malaria and Neglected Diseases - Control of Neglected Tropical
Diseases - Innovative & Intensified Disease Management Chagas disease) for the support of the translation to the english
version of the Brazilian Consensus on Chagas disease.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Financial Support
Technical Surveillance Unit of Vector-Borne Diseases,
Secretariat of Health Surveillance, Ministry of Health of Brazil,
Brasília, Distrito Federal, Brazil. The English version of the original
article in Brazilian Portuguese of this Consensus was made possible
through a partnership with the World Health Organization.
REFERENCES
1. World Health Organization. Research priorities for Chagas disease,
human African trypanosomiasis and leishmaniasis. WHO: technical
report of the TDR Disease Reference Group on Chagas Disease,
Human African Trypanosomiasis and Leishmaniasis. Geneva:
World Health Organization; 2012. (WHO Technical Report Series,
975).
2. World Health Organization. Sustaining the drive to overcome the
global impact of neglected tropical diseases: second WHO report in
neglected tropical diseases. Geneva: World Health Organization; 2013.
3. Dias JC, Silveira AC, Schofield CJ. The impact of Chagas disease
control in Latin America: a review. Mem Inst Oswaldo Cruz. 2002
Jul;97(5):603-12.
4. Coura JR, Dias JC. Epidemiology, control and surveillance of
Chagas disease: 100 years after its discovery. Mem Inst Oswaldo
Cruz. 2009 Jul;104 Suppl 1:31-40.
5. World Health Organization. Chagas disease in Latin America: an
epidemiological update based on 2010 estimates. Wkly Epidemiol
Rec. 2015 Feb;90(6):33-44.
6. Moncayo A, Silveira AC. Current epidemiological trends for Chagas
disease in Latin America and future challenges in epidemiology,
surveillance and health policy. Mem Inst Oswaldo Cruz. 2009
Jul;104 Suppl 1:17-30.
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
7. Schmunis GA, Yadon ZE. Chagas disease: a Latin American health
problem becoming a world health problem. Acta Trop. 2010 JulAug;115(1-2):14-21.
8. Centers for Disease Control and Prevention. Center for Global
Health. Division of Parasitic Diseases and Malaria. Chagas disease
in the Americas: 2013. Atlanta: Centers for Disease Control and
Prevention; 2013.
9. Hotez PJ, Dumonteil E, Betancourt Cravioto M, Bottazzi ME,
Tapia-Conyer R, Meymandi S, et al. An unfolding tragedy of
Chagas disease in North America. PLoS Negl Trop Dis. 2013
Oct;7(10):e2300.
intraspecific nomenclature: second revision meeting recommends
TcI to TcVI. Mem Inst Oswaldo Cruz. 2009 Nov;104(7):1051-4.
26. Zingales B, Miles MA, Moraes CB, Luquetti A, Guhl F, Schijman
AG, et al. Drug discovery for Chagas disease should consider
Trypanosoma cruzi strain diversity. Mem Inst Oswaldo Cruz. 2014
Aug;109(6):828-33.
27. Messenger LA, Miles MA, Bern C. Between a bug and a hard place:
Trypanosoma cruzi genetic diversity and the clinical outcomes of
Chagas disease. Expert Rev Anti Infect Ther. 2015 Aug;13(8):9951029.
10. Dias JCP. Human chagas disease and migration in the context of
globalization: some particular aspects. J Trop Med. 2013:789758.
28. Victora CG, Barreto ML, Carmo Leal M, Monteiro CA, Schmidt
MI, Paim J, et al. Health conditions and health-policy innovations in
Brazil: the way forward. Lancet. 2011 Jun;377(9782):2042-53.
11. Coura JR, Viñas PA, Junqueira AC. Ecoepidemiology, short history
and control of Chagas disease in the endemic countries and the new
challenge for non-endemic countries. Mem Inst Oswaldo Cruz.
2014 Nov;109(7):856-62.
29. Barreto ML, Teixeira MG, Bastos FI, Ximenes RAA, Barata RB,
Rodrigues LC. Successes and failures in the control of infectious diseases
in Brazil: social and environmental context, policies, interventions, and
research needs. Lancet. 2011 May;377(9780):1877-89.
12. European Centre for Disease Prevention and Control. Assessing the
burden of key infectious diseases affecting migrant populations in
the EU/EEA: technical report. Stockholm: ECDC; 2014.
30. Mendes EV. O cuidado das condições crônicas na atenção primária
à saúde: o imperativo da consolidação da estratégia da saúde da
família. Brasília: Organização Pan-Americana da Saúde; 2012.
13. Requena-Méndez A, Aldasoro E, Lazzari E, Sicuri E, Brown M,
Moore DA, et al. Prevalence of Chagas disease in Latin-American
migrants living in Europe: a systematic review and meta-analysis.
PLoS Negl Trop Dis. 2015 Feb;9(2):e0003540.
31. Nações Unidas. Transformando nosso mundo: a agenda 2030 para
o desenvolvimento sustentável [Internet]. [Rio de Janeiro]: Nações
Unidas no Brasil; 2015 [citado 2015 out 4]. Disponível em: http://
nacoesunidas.org/pos2015/agenda2030/31. .
14. World Health Organization. Chagas disease (American
trypanosomiasis) [Internet]. Geneva: World Health Organization;
2015 [citado 2015 Nov 13]. Disponível em: http://www.who.int/
mediacentre/factsheets/fs340/en/
32. Camargo ME, Silva GR, Castilho EA, Silveira AC. Serological
survey of the prevalence of Chagas’ infection in Brazil, 1975/1980.
Rev Inst Med Trop São Paulo. 1984 Jul-Aug;26(4):192-204.
15. Ramos Júnior AN, Carvalho DM. Chagas’ disease: past, present and
future. Cad Saude Colet. 2009;17(4):787-94.
33. Silveira AC, Silva GR, Prata A. O Inquérito de soroprevalência da
infecção chagásica humana (1975-1980). Rev Soc Bras Med Trop.
2011;44 supl 2:33-9.
16. Strasen J, Williams T, Ertl G, Zoller T, Stich A, Ritter O.
Epidemiology of Chagas disease in Europe: many calculations, little
knowledge. Clin Res Cardiol. 2014 Jan;103(1):1-10.
34. Akhavan D. Análise de custo-efectividade do programa de controle
da doença de Chagas no Brasil: relatório final. Brasília: Organização
Pan-Americana de Saúde; 1998.
17. Pan American Health Organization. Estimación cuantitativa de la
enfermedad de Chagas en las Americas. Washington: Pan American
Health Organization; 2006.
35. Martins-Melo FR, Ramos Júnior AN, Alencar CH, Heukelbach J.
Prevalence of Chagas disease in Brazil: a systematic review and
meta-analysis. Acta Trop. 2014 Feb;130:167-74.
18. Dias JCP. Southern Cone Initiative for the elimination of domestic
populations of Triatoma infestans and the interruption of
transfusion Chagas disease: historical aspects, present situation,
and perspectives. Mem Inst Oswaldo Cruz. 2007 Oct;102 Suppl
1:11-8.
36. Hotez PJ, Fujiwara RT. Brazil’s neglected tropical diseases: an
overview and a report card. Microbes Infect. 2014 Aug;16(8):601-6.
19. Prata A. Clinical and epidemiological aspects of Chagas disease.
Lancet Infect Dis. 2001 Sep;1(2):92-100.
38. Dias JC, Coura JR, Yasuda MAS. The present situation, challenges,
and perspectives regarding the production and utilization of
effective drugs against human Chagas disease. Rev Soc Bras Med
Trop. 2014 Jan-Feb;47(1):123-5.
20. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde.
Consenso Brasileiro em Doença de Chagas. Rev Soc Bras Med
Trop. 2005;38 Supl 3:1-29.
21. Organização Pan-americana da Saúde. Guia para vigilância,
prevenção, controle e manejo clínico da doença de Chagas aguda
transmitida por alimentos. Rio de Janeiro: Organização PanAmericana da Saúde; 2009. (Série de Manuais Técnicos, 12).
37. Bern C, Kjos S, Yabsley MJ. Montgomery SP. Trypanosoma cruzi
and Chagas disease in the United States. Clin Microbiol Rev. 2011
Oct;24(4):655-81.
39. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Guia
de Vigilância em Saúde. Brasília: Ministério da Saúde; 2014.
22. Silveira AC, Dias JCP. O controle da transmissão vetorial. Rev Soc
Bras Med Trop. 2011;44 supl 2:52-63.
40. Instituto Brasileiro de Geografia e Estatística. Projeção da
população do Brasil por sexo e idade para o período 2000/2060 e
projeção da população das Unidades da Federação por sexo e idade
para o período 2000/2030. Brasília: Instituto Brasileiro de Geografia
e Estatística; 2013.
23. Coura JR. The main sceneries of Chagas disease transmission. The
vectors, blood and oral transmissions: a comprehensive review.
Mem Inst Oswaldo Cruz. 2015 May;110(3):277-82.
41. Bern C, Verastegui M, Gilman RH, Lafuente C, Galdos-Cardenas
G, Calderon M, et al. Congenital Trypanosoma cruzi transmission
in Santa Cruz, Bolivia. Clin Infect Dis. 2009 Dec 1;49(11):1667-74.
24. Victora CG, Wagstaff A, Schellenberg JA, Gwatkin D, Claeson M,
Habicht JP. Applying an equity lens to child health and mortality:
more of the same is not enough. Lancet. 2003 Jul;362(9379):233-41.
42. Rassi Júnior A, Rassi A, Marin-Neto JA. Chagas disease. Lancet.
2010 Apr;375(9723):1388-402.
25. Zingales B, Andrade SG, Briones MR, Campbell DA, Chiari
E, Fernandes O, et al. A new consensus for Trypanosoma cruzi
2nd Brazilian Consensus on Chagas Disease, 2015
43. Ventura-Garcia L, Roura M, Pell C, Posada E, Gascón J, Aldasoro E,
et al. Socio-cultural aspects of Chagas disease: a systematic review
of qualitative research. PLoS Negl Trop Dis. 2013 Sep 12;7(9):e2410.
51
Rev Soc Bras Med Trop 49:Supplement I, 2016
44. Bern C, Montgomery SP. An estimate of the burden of Chagas
disease in the United States. Clin Infect Dis. 2009 Sep 1;49(5):e52-4.
causas múltiplas de morte. Rev Panam Salud Publica. 2009
Oct;26(4):299-309.
45. Buekens P, Almendares O, Carlier Y, Dumonteil E, Eberhard M,
Gamboa-Leon R, et al. Mother-to-child transmission of Chagas’
disease in North America: why don’t we do more? Matern Child
Health J. 2008 May;12(3):283-6.
62. Nóbrega AA, Araújo WN, Vasconcelos AM. Mortality due to
Chagas disease in Brazil according to a specific cause. Am J Trop
Med Hyg. 2014 Sep;91(3):528-33.
46. Silveira C, Carneiro Junior N, Ribeiro MC, Barata RC. Living
conditions and access to health services by Bolivian immigrants
in the city of São Paulo, Brazil. Cad Saude Publica. 2013
Oct;29(10):2017-27.
47. Martes ACB, Faleiros SM. Acesso dos imigrantes bolivianos aos
serviços públicos de saúde na cidade de São Paulo. Saude Soc. 2013
abr-jun;22(2):351-64.
63. Alves RM, Thomaz RP, Almeida EA, Wanderley JS, Guariento
ME. Chagas’ disease and ageing: the coexistence of other chronic
diseases with Chagas’ disease in elderly patients. Rev Soc Bras Med
Trop. 2009 Nov-Dec;42(6):622-8.
64. Lima-Costa MF, Peixoto SV, Ribeiro AL. Chagas disease and
mortality in old age as an emerging issue: 10 year follow-up of the
Bambuí population-based cohort study (Brazil). Int J Cardiol. 2010
Nov;145(2):362-3.
48. Almeida EA, Lima JN, Lages-Silva E, Guariento ME, Aoki FH,
Torres-Morales AE, et al. Chagas’ disease and HIV co-infection in
patients without effective antiretroviral therapy: prevalence, clinical
presentation and natural history. Trans R Soc Trop Med Hyg. 2010
Jul;104(7):447-52.
65. Silveira AC. Os novos desafios e perspectivas futuras do controle.
Rev Soc Bras Med Trop. 2011;44 Supl 2:122-4.
49. Almeida EA, Ramos Júnior AN, Correia D, Shikanai-Yasuda MA.
Co-infection Trypanosoma cruzi/HIV: systematic review (19802010). Rev Soc Bras Med Trop. 2011 Nov-Dec;44(6):762-70.
67. Vinhaes MC, Oliveira SV, Reis PO, Lacerda Sousa AC, Silva
RA, Obara MT, et al. Assessing the vulnerability of Brazilian
municipalities to the vectorial transmission of Trypanosoma cruzi
using multi-criteria decision analysis. Acta Trop. 2014 Sep;137:10510.
50. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde.
Departamento de DST, Aids e Hepatites Virais. Bol Epidemiol.
2014;3(1):1-80
51. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde.
Departamento de DST, Aids e Hepatites Virais. Protocolo clínico
e diretrizes terapêuticas para manejo da infecção pelo HIV em
adultos. Brasília: Ministério da Saúde; 2014.
52. Ministério da Saúde (BR). Recomendações para diagnóstico,
tratamento e acompanhamento da co-infecção Trypanosoma cruzi:
vírus da imunodeficiência humana. Rev Soc Bras Med Trop. 2006
jul-ago;39(4):392-415.
53. Martins-Melo FR, Ramos Júnior AN, Alencar CH, Heukelbach J.
Mortality related to Chagas disease and HIV/AIDS coinfection in
Brazil. J Trop Med. 2012;2012:534649.
54. Ramos Júnior AN. Inclusão da reativação da doença de Chagas
como uma condição definidora de AIDS para fins de vigilância
epidemiológica no Brasil. Rev Soc Bras Med Trop. 2004 marabr;37(2):192-3.
55. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde.
Doença de Chagas aguda no Brasil: série histórica de 2000 a 2013.
Bol Epidemiol. 2015;46(21):1-9.
56. Martins-Melo FR, Ramos Júnior AN, Alencar CH, Heukelbach J.
Multiple causes of death related to Chagas’ disease in Brazil, 1999
to 2007. Rev Soc Bras Med Trop. 2012 Sep-Oct;45(5):591-6.
57. Martins-Melo FR, Ramos Júnior AN, Alencar CH, Heukelbach J.
Mortality due to Chagas disease in Brazil from 1979 to 2009: trends
and regional differences. J Infect Dev Ctries. 2012 Nov;6(11):817-24.
66. Passos ADC, Silveira AC. Síntese dos resultados dos inquéritos
nacionais. Rev Soc Bras Med Trop. 2011;44 supl 2:47-50.
68. Ramos Júnior AN, Carvalho DM. Os diferentes significados da
certificação conferida ao Brasil como estando livre da doença de
Chagas. Cad Saude Publica. 2001 nov-dez;17(6):1403-12.
69. Abad-Franch F, Diotaiuti L, Gurgel-Gonçalves R, Gürtler RE.
Certifying the interruption of Chagas disease transmission by native
vectors: cui bono? Mem Inst Oswaldo Cruz. 2013 Apr;108(2):251-4.
70. Valença-Barbosa C, Lima MM, Sarquis O, Bezerra CM, AbadFranch F. Modeling disease vector occurrence when detection is
imperfect II: drivers of site-occupancy by synanthropic Triatoma
brasiliensis in the Brazilian northeast. PLoS Negl Trop Dis. 2014
May;8(5):e2861.
71. Abad-Franch F, Valença-Barbosa C, Sarquis O, Lima MM. All that
glisters is not gold: sampling-process uncertainty in disease-vector
surveys with false-negative and false-positive detections. PLoS
Negl Trop Dis. 2014 Sep;8(9):e3187.
72. Salvatella R, Irabedra P, Castellanos LG. Interruption of vector
transmission by native vectors and “the art of the possible”. Mem
Inst Oswaldo Cruz. 2014 Feb;109(1):122-30.
73. Maegawa FA, Damerau EF, Beltrame-Botelho IT, Lopes A,
Emmanuelle-Machado P, Steindel M, et al. Autochthonous Chagas’
disease in Santa Catarina State, Brazil: report of the first case of
digestive tract involvement. Rev Soc Bras Med Trop. 2003 SepOct;36(5):609-12.
58. Drumond JAG, Marcopito LF. Internal migration and distribution
of Chagas disease mortality, Brazil, 1981-1998. Cad Saude Publica.
2006 Oct;22(10):2131-40.
74. Santos CB, Ferreira AL, Leite GR, Ferreira GE, Rodrigues
AA, Falqueto A. Peridomiciliary colonies of Triatoma vitticeps
(Stal, 1859) (Hemiptera, Reduviidae, Triatominae) infected with
Trypanosoma cruzi in rural areas of the State of Espírito Santo,
Brazil. Mem Inst Oswaldo Cruz. 2005 Aug;100(5):471-3.
59. Martins-Melo FR, Alencar CH, Ramos Júnior AN, Heukelbach
J. Epidemiology of mortality related to Chagas’ disease in Brazil,
1999-2007. PLoS Negl Trop Dis. 2012 Feb;6(2):e1508.
75. Lorosa ES, Santos CM, Jurberg J. Foco de doença de Chagas em São
Fidélis, no estado do Rio de Janeiro. Rev Soc Bras Med Trop. 2008
jul-ago;41(4):419-20.
60. Martins-Melo FR, Ramos Júnior AN, Alencar CH, Lange W,
Heukelbach J. Mortality of Chagas’ disease in Brazil: spatial
patterns and definition of high-risk areas. Trop Med Int Health. 2012
Sep;17(9):1066-75.
76. Shikanai-Yasuda MA, Carvalho NB. Oral transmission of Chagas
disease. Clin Infect Dis. 2012 Mar;54(6):845-52.
61. Santo AH. Tendência da mortalidade relacionada à doença de
Chagas, Estado de São Paulo, Brasil, 1985 a 2006: estudo usando
52
77. Sangenis LH, Saraiva RM, Georg I, Castro L, Santos Lima V,
Roque AL, et al. Autochthonous transmission of Chagas disease
in Rio de Janeiro State, Brazil: a clinical and eco-epidemiological
study. BMC Infect Dis. 2015 Jan;15:4.
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
78. Xavier SC, Roque AL, Lima VS, Monteiro KJ, Otaviano JC, Ferreira
da Silva LF, et al. Lower richness of small wild mammal species and
Chagas disease risk. PLoS Negl Trop Dis. 2012;6(5):e1647.
94. Dias JCP. Notas sobre o Trypanosoma cruzi e suas características
bio-ecológicas, como agente de enfermidades transmitidas por
alimentos. Rev Soc Bras Med Trop. 2006 jul-ago;39(4):370-5.
79. Xavier SC, Roque AL, Bilac D, Araújo VA, Costa Neto SF, Lorosa
ES, et al. Distantiae transmission of Trypanosoma cruzi: a new
epidemiological feature of acute Chagas disease in Brazil. PLoS
Negl Trop Dis. 2014 May;8(5):e2878.
95. Dias JCP, Schofield CJ. Controle da transmissão transfusional da
doença de Chagas na Iniciativa do Cone Sul. Rev Soc Bras Med
Trop. 1998 jul-ago;31(4):373-83.
80. Roque AL, Xavier SC, Gerhardt M, Silva MF, Lima VS, D’Andrea
PS, et al. Trypanosoma cruzi among wild and domestic mammals in
different areas of the Abaetetuba municipality (Pará State, Brazil),
an endemic Chagas disease transmission area. Vet Parasitol. 2013
Mar;193(1-3):71-7.
81. Roque AL, Xavier SC, Rocha MG, Duarte AC, D’Andrea PS,
Jansen AM. Trypanosoma cruzi transmission cycle among wild
and domestic mammals in three areas of orally transmitted Chagas
disease outbreaks. Am J Trop Med Hyg. 2008 Nov;79(5):742-9.
82. Abad-Franch F, Ferraz G, Campos C, Palomeque FS, Grijalva
MJ, Aguilar HM, et al. Modeling disease vector occurrence when
detection is imperfect: infestation of Amazonian palm trees by
triatomine bugs at three spatial scales. PLoS Negl Trop Dis. 2010
Mar;4(3):e620.
83. Abad-Franch F, Santos WS, Schofield CJ. Research needs for
Chagas disease prevention. Acta Trop. 2010 Jul-Aug;115(1-2):44-54.
84. Padilla-Torres SD, Ferraz G, Luz SL, Zamora-Perea E, AbadFranch F. Modeling dengue vector dynamics under imperfect
detection: three years of site-occupancy by Aedes aegypti and Aedes
albopictus in urban Amazonia. PLoS One. 2013;8(3):e58420.
96. Moraes-Souza H, Ferreira-Silva MM. Controle da transmissão
transfusional. Rev Soc Bras Med Trop. 2011;44 supl 2:64-7.
97. Ministério da Saúde (BR). Agência Nacional de Vigilância Sanitária.
Manual técnico para a investigação da transmissão de doenças pelo
sangue. Brasília: Ministério da Saúde; 2004. (Série A. Normas e
manuais técnicos).
98. Ministério da Saúde (BR). Agência Nacional de Vigilância
Sanitária. Manual técnico de hemovigilância. Brasília: Ministério
da Saúde; 2004. (Série A. Normas e manuais técnicos).
99. Angheben A, Boix L, Buonfrate D, Gobbi F, Bisoffi Z, Pupella S,
et al. Chagas disease and transfusion medicine: a perspective from
non-endemic countries. Blood Transfus. 2015 Oct;13(4):540-50.
100.Pinazo MJ, Miranda B, Rodríguez-Villar C, Altclas J, Brunet Serra M,
García-Otero EC, et al. Recommendations for management of Chagas
disease in organ and hematopoietic tissue transplantation programs in
nonendemic areas. Transplant Rev (Orlando). 2011 Jul;25(3):91-101.
101. Ostermayer AL, Passos ADC, Silveira AC, Ferreira AW, Macedo V,
Prata AR. O inquérito nacional de soroprevalência de avaliação do
controle da doença de Chagas no Brasil (2001-2008). Rev Soc Bras
Med Trop. 2011;44 supl 2:108-21.
85. Abad-Franch F, Vega MC, Rolón MS, Santos WS, Rojas de Arias
A. Community participation in Chagas disease vector surveillance:
systematic review. PLoS Negl Trop Dis. 2011 Jun;5(6):e1207.
102.Torrico F, Alonso-Vega C, Suarez E, Rodriguez P, Torrico MC, Dramaix
M, et al. Maternal Trypanosoma cruzi infection, pregnancy outcome,
morbidity, and mortality of congenitally infected and non-infected
newborns in Bolivia. Am J Trop Med Hyg. 2004 Feb;70(2):201-9.
86. Roux E, Fátima Venâncio A, Girres JF, Romaña CA. Spatial
patterns and eco-epidemiological systems--part II: characterising
spatial patterns of the occurrence of the insect vectors of Chagas
disease based on remote sensing and field data. Geospat Health.
2011 Nov;6(1):53-64.
103.Salas NA, Cot M, Schneider D, Mendoza B, Santalla JA, Postigo J,
et al. Risk factors and consequences of congenital Chagas disease in
Yacuiba, South Bolivia. Trop Med Int Health. 2007 Dec;12(12):1498505.
87. Roux E, Fátima Venâncio A, Girres JF, Romaña CA. Spatial
patterns and eco-epidemiological systems--part I: multi-scale
spatial modelling of the occurrence of Chagas disease insect
vectors. Geospat Health. 2011 Nov;6(1):41-51.
104.Carlier Y, Torrico F, Sosa-Estani S, Russomando G, Luquetti A, Freilij
H, et al. Congenital Chagas disease: recommendations for diagnosis,
treatment and control of newborns, siblings and pregnant women.
PLoS Negl Trop Dis. 2011 Oct;5(10):e1250.
88. Mougabure-Cueto G, Picollo MI. Insecticide resistance in vector
Chagas disease: evolution, mechanisms and management. Acta
Trop. 2015 Sep;149:70-85.
105.Howard EJ, Xiong X, Carlier Y, Sosa-Estani S, Buekens P. Frequency
of the congenital transmission of Trypanosoma cruzi: a systematic
review and meta-analysis. BJOG. 2014 Jan;121(1):22-33.
89. Pessoa GCA, Pinheiro LC, Ferraz ML, Mello BV, Diotaiuti L.
Standardization of laboratory bioassays for the study of Triatoma
sordida susceptibility to pyrethroid insecticides. Parasit Vectors.
2015 Feb;8:109.
106.Martins-Melo FR, Lima MS, Ramos Júnior AN, Alencar CH,
Heukelbach J. Prevalence of Chagas disease in pregnant women and
congenital transmission of Trypanosoma cruzi in Brazil: a systematic
review and meta-analysis. Trop Med Int Health. 2014 Aug;19(8):943-57.
90. Pessoa GCA, Trevizani NAB, Dias LS, Bezerra CM, Melo BV,
Diotaiut L. Toxicological profile of deltamethrin in Triatoma
brasiliensis (Hemiptera: Reduviidae) in State of Ceará, Northeastern
Brazil. Rev Soc Bras Med Trop. 2015 Jan-Feb;48(1):39-43.
107.Gontijo ED, Andrade GMQ, Santos SE, Galvão LMC, Moreira EF,
Pinto FS, et al. Triagem neonatal da infecção pelo Trypanosoma cruzi
em Minas Gerais, Brasil: transmissão congênita e mapeamento das
áreas endêmicas. Epidemiol Serv Saude. 2009 jul-set;18(3):243-54.
91. Pinto AYN, Valente SA, Valente VC, Ferreira Júnior AG, Coura JR.
Fase aguda da doença de Chagas na Amazônia brasileira: estudo
de 233 casos do Pará, Amapá e Maranhão observados entre 1988 e
2005. Rev Soc Bras Med Trop. 2008 nov-dec;41(6):602-14.
108.Luquetti AO, Tavares SBN, Siriano LR, Oliveira RA, Campos DE,
Morais CA, et al. Congenital transmission of Trypanosoma cruzi in
central Brazil. A study of 1,211 individuals born to infected mothers.
Mem Inst Oswaldo Cruz. 2015 May;110(3):369-76.
92. Nóbrega AA, Garcia MH, Tatto E, Obara MT, Costa E, Sobel J,
et al. Oral transmission of Chagas disease by consumption of açaí
palm fruit, Brazil. Emerg Infect Dis. 2009 Apr;15(4):653-5.
109.Sosa-Estani S, Cura E, Velazquez E, Yampotis C, Segura EL.
Etiological treatment of young women infected with Trypanosoma
cruzi, and prevention of congenital transmission. Rev Soc Bras Med
Trop. 2009 Sep-Oct;42(5):484-7.
93. Dias JCP, Amato Neto V. Prevenção referente às modalidades
alternativas de transmissão do Trypanosoma cruzi no Brasil. Rev
Soc Bras Med Trop. 2011;44 supl 2:68-72.
2nd Brazilian Consensus on Chagas Disease, 2015
110. Herwaldt BL. Laboratory-acquired parasitic infections from
accidental exposures. Clin Microbiol Rev. 2001 Oct;14(4):659-88.
53
Rev Soc Bras Med Trop 49:Supplement I, 2016
111. Mahoney RT, Morel CMA. Global Health Innovation System
(GHIS). Innovation Strategy Today. 2006;2(1):1-12.
112.Norman FF, López-Vélez R. Chagas disease and breast-feeding.
Emerg Infect Dis. 2013 Oct;19(10):1561-6.
113. Gebrekristos HT, Buekens P. Mother-to-Child transmission of
Trypanosoma cruzi. J Ped Infect Dis Soc. 2014 Sep;3 Suppl 1:S3640.
114. De Rissio AM, Riarte AR, Martin García M, Esteva MI, Quaglino
M, Ruiz AM. Congenital Trypanosoma cruzi infection. Efficacy of
its monitoring in an Urban Reference Health Center in non-endemic
area of Argentina. Am J Trop Med Hyg. 2010 May;82(5):838-45.
115. González-Tomé MI, Rivera M, Camaño I, Norman F, FloresChávez M, Rodríguez-Gómez L, et al. Recomendaciones para el
diagnóstico, seguimiento y tratamiento de la embarazada y del niño
con enfermedad de Chagas. Enferm Infecc Microbiol Clin. 2013
Oct;31(8):535-42.
116. Carlier Y, Sosa-Estani S, Luquetti AO, Buekens P. Congenital
Chagas disease: an update. Mem Inst Oswaldo Cruz. 2015
May;110(3):363-8.
117. Russomando G, Almirón M, Candia N, Franco L, Sánchez Z, Guillen
I. Implementación y evaluación de un sistema localmente sustentable
de diagnóstico prenatal que permite detectar casos de transmisión
congénita de la enfermedad de Chagas en zonas endêmicas del
Paraguay. Rev Soc Bras Med Trop. 2005;38 Supl 2:49-54.
118. Brutus L, Castillo H, Bernal C, Salas NA, Schneider D, Santalla JA,
et al. Detectable Trypanosoma cruzi parasitemia during pregnancy
and delivery as a risk factor for congenital Chagas disease. Am J
Trop Med Hyg. 2010 Nov;83(5):1044-7.
127.Chippaux JP, Clavijo AN, Santalla JA, Postigo JR, Schneider D,
Brutus L. Antibody drop in newborns congenitally infected by
Trypanosoma cruzi treated with benznidazole. Trop Med Int Health.
2010 Jan;15(1):87-93.
128.Ministério da Saúde (BR). Secretaria de Vigilância em Saúde.
Departamento de DST, Aids e Hepatites Virais. Recomendações para
profilaxia da transmissão vertical do HIV e terapia antirretroviral em
gestantes. Brasília: Ministério da Saúde; 2010. (Série Manuais, 46).
129.Luquetti AO, Rassi A. Diagnóstico laboratorial da infecção pelo
Trypanosoma cruzi. In: Brener Z, Andrade Z, Barral-Netto M,
editores. Trypanosoma cruzi e doença de Chagas. Rio de Janeiro:
Guanabara-Koogan; 2000. p. 344-78.
130.Chiari E. Parasitological diagnosis. In: Wendel S, Brener Z, Camargo
ME, Rassi A, editores. Chagas disease (American Trypanosomiasis):
its impact on transfusion and clinical medicine. São Paulo: Editora
Sociedade Brasileira de Hematologia e Hemoterapia; 1992. p. 153-64.
131. Luquetti AO, Castro AM. Diagnóstico sorológico da doença de
Chagas. In: Dias JCP, Coura JR, editores. Clínica e terapêutica da
doença de Chagas: uma abordagem prática para o clínico geral. Rio
de Janeiro: Editora Fiocruz; 1997. p. 99-113.
132.Ministério da Saúde (BR). Secretaria de Vigilância em Saúde.
Programa Nacional de Controle de Chagas. Doença de Chagas
aguda: aspectos epidemiológicos, diagnóstico e tratamento: guia de
consulta rápida para profissionais de saúde. Rev Patol Trop. 2007 SetDez;36(3):1-32 (anexo).
133.Ministério da Saúde (BR). Recomendações sobre o diagnóstico
parasitológico, sorológico e molecular para confirmação da doença
de Chagas aguda e crônica. Rev Patol Trop. 2013 out-dez;42(4):475-8.
119. Organización Panamericana de la Salud; Organización Mundial
de la Salud. Tratamiento etiológico de la enfermidad de Chagas:
conclusiones de reunión de especialistas. Rev Patol Trop.
1999;28(2):247-79.
134.Luquetti AO, Schmuñis GA. Diagnosis of Trypanosoma cruzi infection.
In: Telleria J, Tibayrenc M, editors. American Trypanosomiasis Chagas
disease: one hundred years of research. Amsterdam: Elsevier; 2010. p.
743-92.
120.Fabbro DL, Streiger ML, Arias ED, Bizai ML, Barco M, Amicone
NA. Trypanocide treatment among adults with chronic Chagas disease
living in Santa Fe City (Argentina), over a mean follow-up of 21 years:
parasitological, serological and clinical evolution. Rev Soc Bras Med
Trop. 2007 Jan-Feb;40(1):1-10.
135.Camargo ME, Amato Neto V. Anti-Trypanosoma cruzi IgM
antibodies as serological evidence of recent infection. Rev Inst Med
Trop São Paulo. 1974 Jul-Aug;16(4):200-2.
121.Lana M, Lopes LA, Martins HR, Bahia MT, Machado-de-Assis GF,
Wendling AP, et al. Clinical and laboratory status of patients with
chronic Chagas disease living in a vector-controlled area in Minas
Gerais, Brazil, before and nine years after aetiological treatment.
Mem Inst Oswaldo Cruz. 2009 Dec;104(8):1139-47.
122.Pérez-Molina JA, Pérez-Ayala A, Moreno S, Fernández-González MC,
Zamora J, López-Velez R. Use of benznidazole to treat chronic Chagas’
disease: a systematic review with a meta-analysis. J Antimicrob
Chemother. 2009 Dec;64(6):1139-47.
123.CarlierI Y, Torrico F, organizers. Congenital infection with T. cruzi:
from mechanisms of transmission to strategies for diagnosis and
control. Rev Soc Bras Med Trop. 2003 Nov-Dec;36(6):767-71.
124.Scapellato PG, Bottaro EG, Rodríguez-Brieschke MT. Motherchild transmission of Chagas disease: could infection with human
immunodeficiency virus increase the risk? Rev Soc Bras Med Trop.
2009 Mar-Apr;42(2):107-9.
125.Bua J, Volta BJ, Velazquez EB, Ruiz AM, Rissio AM, Cardoni RL.
Vertical transmission of Trypanosoma cruzi infection: quantification
of parasite burden in mothers and their children by parasite DNA
amplification. Trans R Soc Trop Med Hyg. 2012 Oct;106(10):623-8.
126.Mallimaci MC, Sosa-Estani S, Russomando G, Sanchez Z, Sijvarger C,
Alvarez IM, et al. Early diagnosis of congenital infection, using shed
scute phase antigen, in Ushuaia, Tierra del Fuego, Argentina. Am J
Trop Med Hyg. 2010 Jan;82(1):55-9.
54
136.Chiari E, Dias JC, Lana M, Chiari CA. Hemocultures for the
parasitological diagnosis of human chronic Chagas disease. Rev Soc
Bras Med Trop. 1989 Jan-Mar;22(1):19-23.
137. Chiari E, Galvão LMC. Diagnóstico parasitológico da doença de
Chagas. In: Dias JCP, Coura JR, editores. Clínica e terapêutica da
doença de Chagas: uma abordagem prática para o clínico geral. Rio
de Janeiro: Fiocruz; 1997. p. 85-97.
138.Cerisola JA, Rohwedder R, Segura EL, Del Prado CE, Alvarez M,
Martini GJW. El xenodiagnóstico. Buenos Aires: Imp Inst Nac Invest
Cardiovasc; 1974.
139.Castro AM, Luquetti AO, Rassi A, Rassi GG, Chiari E, Galvão
LMC. Blood culture and polymerase chain reaction for the diagnosis
of the chronic phase of human infection with Trypanosoma cruzi.
Parasitol Res. 2002 Oct;88(10):894-900.
140.Camargo ME. Serological diagnosis: an appraisal of Chagas disease
serodiagnosis. In: Wendel S, Brener Z, Camargo ME, Rassi A,
editors. Chagas Disease (American Trypanosomiasis), its impact on
Transfusion and Clinical Medicine. São Paulo: Sociedade Brasileira
de Hematologia e Hemoterapia; 1992. p. 165-78.
141. Ferreira AW, Ávila SLM. Doença de Chagas. In.: Ferreira AW, Ávila
SLM. Diagnóstico laboratorial das principais doenças infecciosas
e auto-imunes. 2 ed. Rio de Janeiro: Guanabara Koogan; 2001. p.
241-9.
142.World Health Organization. Control of Chagas disease. Geneva:
World Health Organization; 2002. (Technical Report Series, 905).
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
143.Hijar G, Padilla C, Balbuena J, Bisio MMC, Bailon H, Vega S, et
al. Estandarización y validación del uso clínico de la Reacción
en Cadena de la Polimerasa para la detección de infección
por Trypanosoma cruzi. In: Anales 9º Congreso Peruano de
Enfermedades Infecciosas y Tropicales “Jose Neyra Ramirez”;
2009 nov 18-21; Lima. Lima: Sociedad Peruana de Enfermedades
Infecciosas y Tropicales; 2009.
144.Schijman AG, Bisio M, Orellana L, Sued M, Duffy T, Mejia Jaramillo
AM, et al. International study to evaluate PCR methods for detection
of Trypanosoma cruzi DNA in blood samples from Chagas disease
patients. PLoS Negl Trop Dis. 2011 Jan;5(1):e931.
145.Camargo ME. Fluorescent antibody test for the diagnosis of
American trypanosomiasis. Technical modification employing
preserved culture forms of Trypanosoma cruzi in a slide test. Rev
Inst Med Trop São Paulo. 1966 Sep-Oct;8(5):227-35.
146.Cerisola JA, Chaben MF, Lazari JO. Test de hemaglutinación para
el diagnóstico de la enfermedad de Chagas. Prensa Méd Argent.
1962;49:1761-67.
147. Voller A, Draper C, Bidwell DE, Bartlett A. Microplate enzymelinked immunosorbent assay for Chagas disease. Lancet. 1975
Feb;305(7904):426-8.
148.Castro CN, Alves MT, Macedo VO. Importância da repetição do
xenodiagnóstico para avaliação da parasitemia na fase crônica da
doença de Chagas. Rev Soc Bras Med Trop. 1983 abr-jun;16(2):98-103.
149. Junqueira AC, Chiari E, Wincker P. Comparison of the polymerase
chain reaction with two classical parasitological methods for
diagnosis of Chagas disease patients in a north-eastern endemic
region of north-eastern Brazil. Trans R Soc Trop Med Hyg. 1996
Mar-Apr;90(2):129-32.
150.Britto CC. Usefulness of PCR-based assays to assess drug efficacy
in Chagas disease chemotherapy: value and limitations. Mem Inst
Oswaldo Cruz. 2009 Jul;104 Suppl 1:122-35.
151. Silveira JF, Umezawa ES, Luquetti AO. Chagas disease:
recombinant Trypanosoma cruzi antigens for serological diagnosis.
Trends Parasitol. 2001 Jun;17(6):286-91.
152.Zicker F, Smith PG, Luquetti AO, Oliveira OS. Mass screening for
Trypanosoma cruzi infections using the immunofluorescence, ELISA
and haemagglutination tests on serum samples and on blood eluates
from filter-paper. Bull World Health Organ. 1990;68(4):465-71.
153.Sánchez-Camargo CL, Albajar-Viñas P, Wilkins PP, Nieto J, Leiby
DA, Paris L, et al. Comparative evaluation of 11 commercialized
rapid diagnostic tests for detecting Trypanosoma cruzi antibodies
in serum banks in areas of endemicity and nonendemicity. J Clin
Microbiol. 2014 Jul;52(7):2506-12.
154.Pinto AYN, Valente SAS, Valente VC. Emerging acute Chagas disease
in Amazonian Brazil: case reports with serious cardiac involvement.
Braz J Infect Dis. 2004 Dec;8(6):454-60.
155.Dias JP, Bastos C, Araújo E, Mascarenhas AV, Martins Netto E,
Grassi F, et al. Acute Chagas disease outbreak associated with oral
transmission. Rev Soc Bras Med Trop. 2008 May-Jun;41(3):296-300.
156.Pinto AY, Valente VC, Coura JR, Valente SAS, Junqueira AC, Santos
LC, et al. Clinical follow-up of responses to treatment with benznidazol
in Amazon: a cohort study of acute Chagas disease. Plos One. 2013
May;8(5):e64450.
157. Centers for Disease Control and Prevention. Chagas disease after
organ transplantation: United States, 2001. MMWR Morb Mortal
Wkly Rep. 2002 Mar;51(10):210-2.
158.Centers for Disease Control and Prevention. Chagas disease after
organ transplantation: Los Angeles, California, 2006. MMWR Morb
Mortal Wkly Rep. 2006 Jul;55(29):798-800.
2nd Brazilian Consensus on Chagas Disease, 2015
159.Rocha A, Ramos Júnior AN, Sartori AM, Correia D, Gontijo
ED, Tatto E, et al. Recomendações para diagnóstico, tratamento
e acompanhamento da co-infecção Trypanosoma cruzi-vírus
da imunodeficiência humana. Rev Soc Bras Med Trop. 2006 julago;39(4):392-415.
160.Rassi A, Rassi Júnior A, Rassi GG. Fase aguda. In: Brener Z, Andrade
Z, Barral-Netto M (orgs). Trypanosoma cruzi e Doença de Chagas. 2
ed. Rio de Janeiro: Guanabara Koogan; 2000. p.231-45.
161. Romaña C. Acerca de un síntoma inicial de valor para el diagnóstico
de la forma aguda de la enfermedad de Chagas: la conjuntivitis
schizotripanosómica unilateral: hipótesis sobre la puerta de entrada
conjuntival de la enfermedad. Mision de Estudios de Patologia
Regional Argentina (MEPRA)1935;22:16-25.
162.Lugones HS. Enfermedad de Chagas. Diagnóstico de su faz aguda.
Santiago del Estero (Argentina): Universidad Católica de Santiago del
Estero; 2001.
163.Ferreira HO, Pucci H. Estudo evolutivo da doença de Chagas
com fase aguda conhecida. Rev Soc Bras Med Trop. 1982 jandez;15(1):125-30.
164.Ferreira HO, Miziara JL. Aspectos clínicos da cardiopatia chagásica
aguda. In: Cançado JR, Chuster M (editores). Cardiopatia Chagásica.
Belo Horizonte: Imprensa Oficial; 1985.
165.Parada H, Carrasco HA, Añez N, Fuenmayor C, Inglessis I. Cardiac
involvement is a constant finding in acute Chagas’ disease: a
clinical, parasitological and histopathological study. Int J Cardiol.
1997 Jun;60(1):49-54.
166.Wendell S. Doença de Chagas transfusional. In: Dias JCP, Coura JR,
editores. Clínica e terapêutica da doença de Chagas: uma abordagem
prática para o clínico geral. Rio de Janeiro: Fiocruz; 1997. p. 411-27.
167. Noya BA, Diaz- Bello Z, Colmenares C, Ruiz-Guevara R, Mauriello
L, Zavala-Jaspe R, et al. Large urban outbreak of orally acquired
acute Chagas disease at a school in Caracas, Venezuela. J Infect Dis.
2010 May;201(9):1308-15.
168.Shaw J, Lainson R, Fraiha H. Considerações sobre a epidemiologia
dos primeiros casos autóctones de doença de Chagas registrados em
Belém, Pará, Brasil. Rev Saude Publica. 1969;3(2):153-7.
169.Pinto AYN, Ferreira Júnior AG, Valente VC, Harada GS, Valente
SAS. Urban outbreak of acute Chagas disease in Amazon region of
Brazil: four-year follow-up after treatment with benznidazole. Rev
Panam Salud Publica. 2009 Jan;25(1):77-83.
170.Shikanai-Yasuda MA, Marcondes CB, Guedes LA, Siqueira GS,
Barone AA, Dias JC, et al. Possible oral transmission of acute
Chagas disease in Brasil. Rev Inst Med Trop Sao Paulo. 1991 SepOct;33(5):351-7.
171. Jörg ME, Freire RS. Lipochagomata genii or lipochagomata of the
cheeks, characteristic lesions of acute trypanosomiasis cruzi in
children under three years of age. Acta Trop. 1961;18:318-50.
172.Medeiros MB, Guerra JAO, Lacerda MVG. Meningoencephalitis in a
patient with acute Chagas disease in the Brazilian Amazon. Rev Soc
Bras Med Trop. 2008 Sep-Oct; 41(5):520-1.
173.Freilij H, Altcheh J, Muchinik G. Perinatal human immunodeficiency
virus infection and congenital Chagas’ disease. Pediatr Infect Dis J.
1995 Feb;14(2):161-2.
174.Nisida IV, Amato Neto V, Braz LM, Duarte MI, Umezawa ES. A
survey of congenital Chagas’ disease, carried out at three health
institutions in São Paulo City, Brazil. Rev Inst Med Trop Sao Paulo.
1999 Sep-Oct;41(5):305-11.
175. Sartori AM, Ibrahim KY, Nunes Westphalen EV, Braz LM, Oliveira
Junior OC, Gakiya E, et al. Manifestations of Chagas disease
(American trypanosomiasis) in patients with HIV/AIDS. Ann Trop
Med Parasitol. 2007 Jan;101(1):31-50.
55
Rev Soc Bras Med Trop 49:Supplement I, 2016
176.França LCM, Lemos S, Fleury RN, Melaragno Filho R, Ramos
Júnior HA, Pasternak J. Moléstia de Chagas crônica associada à
leucemia linfática: ocorrência de encefalite aguda como alteração
do estado imunitário. Arq Neuro-Psiquiatr. 1969 mar;27(1):59-66.
193.Dias JCP, Machado EMM, Borges ÉC, Moreira EF, Gontijo C,
Azeredo BVM. Doença de Chagas em Lassance, MG. Reavaliação
clínico-epidemiológica 90 anos após a descoberta de Carlos Chagas.
Rev Soc Bras Med Trop. 2002 mar-apr;35(2):167-76.
177. Spina-França A, Livramento JA, Machado LR, Yasuda N. Anticorpos
a Trypanosoma cruzi no líquido cefalorraqueano: pesquisa pelas
reações de fixação do complemento e de imunofluorescência. Arq
Neuro-Psiquiatr. 1988 dez;46(4):374-8.
194.Almeida EA, Barbosa Neto RM, Guariento ME, Wanderley JS, Souza
ML. Apresentação clínica da doença de Chagas crônica em indivíduos
idosos. Rev Soc Bras Med Trop. 2007 mai-jun;40(3):311-5.
178.Livramento JA, Machado LR, Spina-França A. Anormalidades do
líquido cefalorraqueano em 170 casos de AIDS. Arq Neuro-Psiquiatr.
1989 set;47(3):326-31.
179. Del Castilho M, Mendoza G, Oviedo J, Perez Bianco PR, Anselmo
AE, Silva M. AIDS and Chagas’ disease with central nervous
system tumor-like lesion. Am J Med. 1990 Jun;88(6):693-4.
180.Ferreira MS, Nishioka SA, Rocha A, Silva AM, Ferreira RG, Olivier
W, et al. Acute fatal Trypanosoma cruzi meningoencephalitis in a
human immunodeficiency virus-positive hemophiliac patient. Am J
Trop Med Hyg. 1991 Dec;45(6):723-7.
181. Riarte A, Luna C, Sabatiello R, Sinagra A, Schiavelli R, De Rissio
A, et al. Chagas’ disease in patients with kidney transplants: 7 years
of experience 1989-1996. Clin Infect Dis. 1999 Sep;29(3):561-7.
182.Campos SV, Strabelli TM, Amato Neto V, Silva CP, Bacal F,
Bocchi EA, et al. Risk factors for Chagas’ disease reactivation after
heart transplantation. J Heart Lung Transplant. 2008 Jun;27(6):597602.
195.Villela E. Moléstia de Chagas: descrição clínica, 5ª parte. Folha
Médica. 1923; 4:65-6.
196.Dias E, Laranja FS, Miranda A, Nóbrega G. Chagas’ disease: a clinical,
epidemiologic and pathologic study. Circulation. 1956 Dec;14(6):103560.
197.Prata A, Macedo V. Morbidity of Chagas’ heart disease. Mem Inst
Oswaldo Cruz. 1984;79 Suppl:93-6.
198.Organización Mundial de la Salud; Organización Panamericana de
la Salud. Aspectos clínicos de la enfermedad de Chagas. Informe de
una reunión conjunta OMS/OPAS de investigadores. Bol Oficina Sanit
Panam. 1974;76:141-58.
199.Conselho Nacional de Pesquisa. Epidemiologia da doença de Chagas:
objetivos e metodologia dos estudos longitudinais. Rio de Janeiro:
Conselho Nacional de Pesquisa; 1974. 46 p. Relatório Técnico nº 1.
200.Oliveira Júnior W. Forma indeterminada da doença de Chagas:
implicações médico-trabalhistas. Arq Bras Cardiol. 1990 fev;54(2):
89-91.
183.Ministério da Saúde (BR). Portaria nº 2.600, de 21 de outubro de
2009. Aprova o Regulamento Técnico do Sistema Nacional de
Transplantes. Diário Oficial da República Federativa do Brasil,
Brasília (DF), 2009 out 21;Seção 1:77.
201.Guariento ME, Camilo MVF, Camargo AMA. Working conditions of
Chagas’ disease patients in a large Brazilian city. Cad Saude Publica.
1999 Apr-Jun;15(2):381-6.
184.Altclas J, Sinagra A, Dictar M, Luna C, Verón MT, De Rissio AM,
et al. Chagas disease in bone marrow transplantation: an approach to
preemptive therapy. Bone Marrow Transplant. 2005 Jul;36(2):123-9.
202.Dias JCP, Siqueira IOC, Dias RB. Doença de Chagas: diagnóstico e
manejo na atenção primária à saúde. In: Gusso G, Lopes JMC. Tratado
de Medicina de Família e Comunidade: 2 Volumes: Princípios, Formação
e Prática. Porto Alegre: Artmed; 2012. p. 2067-80.
185.Barcán L, Luna C, Clara L, Sinagra A, Valledor A, De Rissio AM,
et al. Transmission of T. cruzi infection via liver transplantation to
a nonreactive recipient for Chagas’ disease. Liver Transpl. 2005
Sep;11(9):1112-6.
186.Rassi A, Amato Neto V, Siqueira AF, Ferriolli Filho F, Amato VS,
Rassi Júnior A. Protective effect of benznidazole against parasite
reactivation in patients chronically infected with Trypanosoma cruzi
and treated with corticoids for associated diseases. Rev Soc Bras Med
Trop. 1999 Sep-Oct;32(5):475-82.
187. Cordova E, Boschi A, Ambrosioni J, Cudos C, Corti M. Reactivation
of Chagas disease with central nervous system involvement in HIVinfected patients in Argentina, 1992-2007. Int J Infect Dis. 2008
Nov;12(6):587-92.
188.Validade do conceito de forma indeterminada de doença de Chagas.
Rev Soc Bras Med Trop. 1985 jan-mar;18(1):46.
189.Dias JC. The indeterminate form of human chronic Chagas’ disease:
a clinical epidemiological review. Rev Soc Bras Med Trop. 1989 JulSep;22(3):147-56.
190.Macêdo VO. Forma indeterminada da doença de Chagas. In: Dias JCP,
Coura JR, editores. Clínica e Terapêutica da doença de Chagas: uma
abordagem prática para o clínico geral. Rio de Janeiro: Editora Fiocruz;
1997. p.135-51.
191. Macêdo VO. Indeterminate form of Chagas disease. Mem Inst
Oswaldo Cruz. 1999 Sep;94 Suppl 1:311-6.
192.Ianni BM, Arteaga E, Frimm CC, Pereira Barretto AC, Mady C.
Chagas’ heart disease: evolutive evaluation of electrocardiographic and
echocardiographic parameters in patients with the indeterminate form.
Arq Bras Cardiol. 2001 Jul;77(1):59-62.
56
203.Castro I, Andrade JP, Paola AAV, Vilas-Boas F, Oliveira GMM, MarinNeto JA, et al. Sociedade Brasileira de Cardiologia. I Diretriz LatinoAmericana para o diagnóstico e tratamento da cardiopatia chagásica.
Arq Bras Cardiol. 2011 Aug;97(2 Suppl 3):1-48.
204.Ozaki Y, Guariento ME, Almeida EA. Quality of life and depressive
symptoms in Chagas disease patients. Qual Life Res. 2011 Feb;20(1):
133-8.
205.Higuchi ML, Benvenuti LA, Reis MR, Metzger M. Pathophysiology
of the heart in Chagas’ disease: current status and new developments.
Cardiovasc Res. 2003 Oct;60(1):96-107.
206.Higuchi ML. Chagas disease: importance of the parasite in the
pathogenesis of the cardiac chronic disease. Arq Bras Cardiol. 1995
Mar;64(3):251-4.
207.Higuchi ML. Chronic chagasic cardiopathy: the product of a turbulent
host-parasite relationship. Rev Inst Med Trop Sao Paulo. 1997 JanFeb;39(1):53-60.
208.Marin-Neto JA, Cunha-Neto E, Maciel BC, Simões MV. Pathogenesis
of chronic Chagas heart disease. Circulation. 2007 Mar;115(9):1109-23.
209.Chagas C, Villela E. Forma cardíaca da Trypanosomíase americana.
Mem Inst Oswaldo Cruz. 1922;14(1):5-61.
210.Coura JR, Abreu LL, Pereira JB, Willcox HP. Morbidity in
Chagas’ disease. IV. longitudinal study of 10 years in Pains and
Iguatama, Minas Gerais, Brazil. Mem Inst Oswaldo Cruz. 1985
Jan-Mar;80(1):73-80.
211. Pereira Barretto AC, Mady C, Arteaga-Fernandez E, Stolf N, Lopes
EA, Higuchi ML, et al. Right ventricular endomyocardial biopsy in
chronic Chagas’ disease. Am Heart J. 1986 Feb;111(2):307-12.
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
212.Prata A, Lopes ER, Chapadeiro E. Characteristics of unexpected
sudden death in Chagas disease. Rev Soc Bras Med Trop. 1986 JanMar;19(1):9-12.
213.Dias JC, Kloetzel K. The prognostic value of the electrocardiographic
features of chronic Chagas’ disease. Rev Inst Med Trop Sao Paulo.
1968 May-Jun;10(3):158-62.
214.Bestetti RB, Muccillo G. Clinical course of Chagas’ heart disease:
a comparison with dilated cardiomyopathy. Int J Cardiol. 1997
Jul;60(2):187-93.
215.Pinto AY, Harada GS, Valente VD, Abud JE, Gomes FD, Souza
GC, et al. Cardiac attacks in patients with acute Chagas disease in a
family micro-outbreak, in Abaetetuba, Brazilian Amazon. Rev Soc
Bras Med Trop. 2001 Sep-Oct;34(5):413-9.
216.Souza DSM, Almeida AJB, Costa FA, Costa EG, Figueiredo
MTS, Póvoa RMS. O eletrocardiograma na fase aguda da Doença
de Chagas por transmissão oral. Rev Bras Cardiol. 2013 marabr;26(2):127-30.
217. Nishioka SA, Ferreira MS, Rocha A, Burgarelli MK, Silva AM,
Duarte MI, et al. Reactivation of Chagas’ disease successfully treated
with benznidazole in a patient with acquired immunodeficiency
syndrome. Mem Inst Oswaldo Cruz. 1993 Jul-Sep;88(3):493-6
218.Almeida EA, Silva EL, Guariento ME, Souza ML, Aoki FH,
Pedro RJ. Fatal evolution of Chagas’ disease/Aids co-infection:
diagnostic difficulties between myocarditis reactivation and chronic
chagasic myocardiopathy. Rev Soc Bras Med Trop. 2009 MarApr;42(2):199-202.
219. Perez-Ramirez L, Barnabé C, Sartori AM, Ferreira MS, Tolezano
JE, Nunes EV, et al. Clinical analysis and parasite genetic diversity
in human immunodeficiency virus/Chagas’ disease coinfections in
Brazil. Am J Trop Med Hyg. 1999 Aug;61(2):198-206.
220.Bestetti RB, Dalbo CM, Freitas OC, Teno LA, Castilho OT, Oliveira
JS. Noninvasive predictors of mortality for patients with Chagas’ heart
disease: a multivariate stepwise logistic regression study. Cardiology.
1994;84(4-5):261-7.
221.Mady C, Cardoso RH, Barretto AC, Luz PL, Bellotti G, Pileggi
F. Survival and predictors of survival in patients with congestive
heart failure due to Chagas’ cardiomyopathy. Circulation. 1994
Dec;90(6):3098-102.
222.Rassi Júnior A, Rassi A, Little WC, Xavier SS, Rassi SG, Rassi AG, et
al. Development and validation of a risk score for predicting mortality
in Chagas’ heart disease. N Engl J Med. 2006 Aug 24;355(8):799-808.
223.Xavier SS, Sousa AS, Hasslocher-Moreno A. Application of the new
classification of cardiac insufficiency (ACC/AHA) in chronic Chagas
cardiopathy: a critical analysis of the survival curves. Rev SOCERJ.
2005 mai-jun;18(3):227-32.
224.Rodriguez-Salas LA, Klein E, Acquatella H, Catalioti F, Davalos V,
Gomez-Mancebo JR, et al. Echocardiographic and clinical predictors
of mortality in chronic Chagas’ disease. Echocardiography. 1998
Apr;15(3):271-278.
225.Viotti RJ, Vigliano C, Laucella S, Lococo B, Petti M, Bertocchi G, et
al. Value of echocardiography for diagnosis and prognosis of chronic
Chagas’ disease cardiomyopathy without heart failure. Heart. 2004
Jun;90(6):655-60.
226.Acquatella H, Schiller NB, Puigbó JJ, Giordano H, Suárez JA, Casal
H, et al. M-mode and two-dimensional echocardiography in chronic
Chagas’ heart disease: a clinical and pathologic study. Circulation. 1980
Oct;62(4):787-99.
227.Dias JCP. História natural da cardiopatia chagásica. In: Cançado JR,
Chuster M. Cardiopatia chagásica. Belo Horizonte: Fundação Carlos
Chagas; 1985. p. 99-110.
2nd Brazilian Consensus on Chagas Disease, 2015
228.Carrasco HA, Parada H, Guerrero L, Duque M, Durán D, Molina
C. Prognostic implications of clinical, electrocardiographic and
hemodynamic findings in chronic Chagas’ disease. Int J Cardiol. 1994
Jan;43(1):27-38.
229.Garzon SA, Lorga AM, Nicolau JC. Electrocardiography in Chagas’
heart disease. Sao Paulo Med J. 1995 Mar-Apr;113(2):802-13.
230.Marin-Neto JA, Simões MV, Sarabanda AV. Chagas’ heart disease.
Arq Bras Cardiol. 1999;72(3):247-80.
231.Almeida-Filho OC, Maciel BC, Schmidt A, Pazin-Filho A, MarinNeto JA. Minor segmental dyssynergy reflects extensive myocardial
damage and global left ventricle dysfunction in chronic Chagas
disease. J Am Soc Echocardiogr. 2002 Jun;15(6):610-6.
232.Pazin-Filho A, Romano MM, Gomes Furtado R, Almeida Filho OC,
Schmidt A, Marin-Neto JA, et al. Left ventricular global performance
and diastolic function in indeterminate and cardiac forms of Chagas’
disease. J Am Soc Echocardiogr. 2007 Dec;20(12):1338-43.
233.Rassi A Júnior, Rassi A, Rassi SG. Predictors of mortality in chronic
Chagas disease: a systematic review of observational studies.
Circulation. 2007 Mar;115(9):1101-8
234.Xavier SS, Sousa AS, Brasil PEAA, Gabriel FG, Holanda MT,
Hasslocher-Moreno A, et al. Incidência e preditores de morte súbita
na cardiopatia chagásica crônica com função sistólica preservada. Rev
SOCERJ. 2005 set-out;18(5):457-63.
235.Cunha GP. Síndromes clínicas na cardiomiopatia chagásica crônica.
Hospital. 1960;57:71-95.
236.Rassi Jr A, Marin-Neto JA. Estado da Arte. Cardiopatia chagásica
crônica. Rev Soc Cardiol Est São Paulo. 2000;10(4):6-12.
237.Rassi Júnior A, Rassi AG, Rassi SG, Rassi Júnior L, Rassi A.
Arritmias ventriculares na doença de Chagas. Particularidades
diagnósticas, prognósticas e terapêuticas. Arq Bras Cardiol. 1995
out;65(4):377-87.
238.Rassi Júnior A, Rassi SG, Rassi A. Morte súbita na Doença de Chagas.
Arq Bras Cardiol. 2001 jan;76(1):75-85.
239.Rassi Júnior A, Rassi AG, Rassi SG, Rassi Júnior L, Las Casas AA,
Rassi A. Arritmia ventricular na insuficiência cardíaca de etiologia
chagásica e não chagásica. Arq Bras Cardiol. 1993;61 supl II:11-9.
240.Scanavacca M, Sosa E. Electrophysiologic study in chronic Chagas’
heart disease. Sao Paulo Med J. 1995 Mar-Apr;113(2):841-50.
241.Chiale PA, Halpern MS, Nau GJ, Tambussi AM, Przybylski
J, Lázzari JO, et al. Efficacy of amiodarone during long-term
treatment of malignant ventricular arrhythmias in patients with
chronic chagasic myocarditis. Am Heart J. 1984 Apr;107(4):656-65.
242.Silva CP, Bacal F, Pires PV, Drager LF, Souza GEC, Fajardo GM, et
al. Importance of amiodarone pulmonary toxicity in the differential
diagnosis of a patient with dyspnea awaiting a heart transplant. Arq Bras
Cardiol. 2006 Sep;86(3):e4-7.
243.Zimerman LI, Fenelon G, Martinelli Filho M, Grupi C, Atié J,
Lorga Filho A, et al; Sociedade Brasileira de Cardiologia. Diretrizes
brasileiras de fibrilação atrial. Arq Bras Cardiol. 2009;92(6 supl 1):1-39.
244.Martinelli Filho M, Zimerman LI, Lorga AM, Vasconcelos JTM, Rassi
Júnior A; Sociedade Brasileira de Cardiologia. Diretrizes brasileiras de
dispositivos eletrônicos implantáveis (DCEI). Arq Bras Cardiol. 2007;
89(6):e210-e238.
245.Baroldi G, Oliveira SJ, Silver MD. Sudden and unexpected death in
clinically ‘silent’ Chagas’ disease. A hypothesis. Int J Cardiol. 1997
Feb;58(3):263-8.
246.Marin-Neto JA, Simões MV, Maciel BC. Aspectos peculiares da
fisiopatologia da insuficiência cardíaca na doença de Chagas. Rev Soc
Cardiol Est São Paulo. 1998;8(2):243-52.
57
Rev Soc Bras Med Trop 49:Supplement I, 2016
247.Simões MV, Almeida Filho OC, Pazin Filho A, Castro RBP,
Schmidt A, Maciel BC, et al. Insuficiência cardíaca na doença de
Chagas. Rev Soc Cardiol Est São Paulo. 2000 Jan-Fev;10(1):50-64.
264.Sousa AS, Xavier SS, Freitas GR, Hasslocher-Moreno A. Prevention
strategies of cardioembolic ischemic stroke in Chagas’ disease. Arq Bras
Cardiol. 2008 Nov;91(5):306-10.
248.Bocchi EA, Marcondes-Braga FG, Bacal F, Ferraz AS, Albuquerque D,
Rodrigues D, et al; Sociedade Brasileira de Cardiologia. Atualização da
Diretriz Brasileira de Insuficiência Cardíaca Crônica: 2012. Arq Bras
Cardiol. 2012 jan;98(1 supl 1):1-33.
265.Oliveira Júnior W. O cardiopata chagásico em situações especiais.
In: Pinto JC, Rodrigues J (Orgs). Clínica e terapêutica da doença de
Chagas. 2 ed. Rio de Janeiro: Fiocruz; 1997. p. 293-322.
249.Rocha MOC, Ribeiro AL, Teixeira MM. Clinical management of
chronic Chagas cardiomyopathy. Front Biosci. 2003 Jan;8:e44-54.
250.Marin-Neto JA, Rassi A Júnior, Morillo CA, Avezum A, Connolly SJ,
Sosa-Estani S, et al; BENEFIT Investigators. BENEFIT Investigators.
Rationale and design of a randomized placebo-controlled trial
assessing the effects of etiologic treatment in Chagas’ cardiomyopathy:
the BENznidazole Evaluation For Interrupting Trypanosomiasis
(BENEFIT). Am Heart J. 2008 Jul;156(1):37-43.
251.Morillo CA, Marin-Neto JA, Avezum A, Sosa-Estani S, Rassi
Júnior A, Rosas F, et al; BENEFIT Investigators. Randomized Trial
of Benznidazole for Chronic Chagas’ Cardiomyopathy. N Engl J
Med. 2015 Oct;373(14):1295-306.
252.Viotti R, Vigliano C, Lococo B, Bertocchi G, Petti M, Alvarez MG,
et al. Long-term cardiac outcomes of treating chronic Chagas disease
with benznidazole versus no treatment: a nonrandomized trial. Ann
Intern Med. 2006 May;144(10):724-34.
266.Bestetti RB. Avaliação do risco cirúrgico em pacientes portadores de
cardiopatia chagásica crônica em cirurgias não cardíacas. In: Pinto JC,
Rodrigues J (Orgs). Clínica e terapêutica da doença de Chagas. 2 ed. Rio
de Janeiro: Fiocruz; 1997. p. 281-91.
267.Ramos G, Ramos Filho J, Rassi Júnior A, Pereira E, Gabriel Neto S,
Chaves E. Marcapasso cardíaco artificial: considerações pré e peroperatórias. Rev Bras Anestesiol. 2003 nov-dez;53(6):854-62.
268.Prata A. Implicações epidemiológicas e sócio-econômicas da doença de
Chagas. Brasilia Med. 1973;9:69-71.
269.Porto CC, Rassi A, Faria GHDC. Aspectos sócio-econômicos
e médico-trabalhistas. In: Cançado JR, Chuster M (editores).
Cardiopatia Chagásica. Belo Horizonte: Fundação Carlos Chagas;
1985. p. 362-6.
270.Dias JCP. Aspectos clínicos, sociais e trabalhistas da doença de Chagas
em área endêmica sob controle do estado de Minas Gerais, Brasil. Rev
Soc Bras Med Trop. 1999 apr-jun;26(2):93-9.
253.Viotti R, Vigliano C, Lococo B, Petti M, Bertocchi G, Alvarez MG,
et al. Clinical predictors of chronic chagasic myocarditis progression.
Rev Esp Cardiol. 2005 Sep;58(9):1037-44.
271.Morais BB, Martins P, Maiolini DD, Silva AL, Melo JRC.
Concomitant lesions in Chagas’ disease. Eur J Gastroenterol
Hepatol. 1991;3(7):523-6.
254.Marin-Neto JA, Rassi Júnior A, Sousa AS, Dias JCP, Rassi A. Doença
de Chagas: moléstia negligenciada. In: Andrade JP, Arnett DK, Pinto FJ
(editores). Tratado de Prevenção Cardiovascular. Um Desafio Global.
São Paulo: Atheneu; 2014. p. 117-27.
272.Fonseca FM, Etchebehere RM, Queiroz DM, Rocha AM, Junqueira IS,
Fonseca DN, et al. Histological and endoscopic features of the stomachs
of patients with Chagas disease in the era of Helicobacter pylori. Rev
Soc Bras Med Trop. 2014 Nov-Dec;47(6):739-46.
255.Montera MW, Pereira SB, Colafranceschi AS, Almeida DR, Tinoco
EM, Rocha RM, et al. Sumário de Atualização da II Diretriz
Brasileira de Insuficiência Cardíaca Aguda: 2009/2011. Arq Bras
Cardiol. 2012;98(5):375-83.
273.Rezende JM. Classificação radiológica do megaesôfago. Rev Goiana
Med. 1982 jul-dez;28(3/4):187-91.
256.Roberti RR, Martinez EE, Andrade JL, Araujo VL, Brito FS, Portugal
OP, et al. Chagas cardiomyopathy and captopril. Eur Heart J. 1992
Jul;13(7):966-70.
257.Davila DF, Angel F, Arata de Bellabarba G, Donis JH. Effects of
metoprolol in chagasic patients with severe congestive heart failure.
Int J Cardiol. 2002 Oct;85(2-3):255-60.
274.Brücher BL, Stein HJ, Bartels H, Feussner H, Siewert JR. Achalasia
and esophageal cancer: incidence, prevalence, and prognosis. World J
Surg. 2001 Jun;25(6):745-9.
275.Leeuwenburgh I, Scholten P, Alderliesten J, Tilanus HW, Looman CW,
Steijerberg EW, et al. Long-term esophageal cancer risk in patients
with primary achalasia: a prospective study. Am J Gastroenterol.
2010 Oct;105(10):2144-9.
258.Freitas H, Salaltino G, Chizzola P, Costa J, Mansur A, Ramires JF, et
al. Betablockers for Chagas’ heart disease. J Am Coll Cardiol. 1999;33
Suppl A:184.
276.Pérez-Ayala A, Pérez-Molina JA, Norman F, Monge-Maillo B, Faro
MV, López-Vélez R. Gastro-intestinal Chagas disease in migrants to
Spain: prevalence and methods for early diagnosis. Ann Trop Med
Parasitol. 2011 Jan;105(1):25-9.
259.Bocchi EA, Bellotti G, Uip D, Kalil J, Lourdes Higuchi M, Fiorelli
A, et al. Long-term follow-up after heart transplantation in Chagas’
disease. Transplant Proc. 1993 Feb;25(1 Pt 2):1329-30.
277.Oliveira RB, Troncon LEA, Dantas RO, Meneghelli UG.
Gastrointestinal manifestations of Chagas disease. Am J
Gastroenterol. 1998 Jun;93(6):884-9.
260.Carvalho VB, Sousa EF, Vila JH, Silva JP, Caiado MR, Araujo SR, et
al. Heart transplantation in Chagas’ disease. 10 Years after the initial
experience. Circulation. 1996 Oct;94(8):1815-7.
278.Meier-Ruge WA, Müller-Lobeck H, Stoss F, Bruder E. The
pathogenesis of idiopathic megacolon. Eur J Gastroenterol Hepatol.
2006 Nov;18(11):1209-15.
261.Ribeiro dos Santos R, Rassi S, Feitosa G, Grecco OT, Rassi
Júnior A, Cunha AB, et al; Chagas Arm of the MiHeart Study
Investigators. Cell therapy in Chagas cardiomyopathy (Chagas arm
of the multicenter randomized trial of cell therapy in cardiopathies
study): a multicenter randomized trial. Circulation. 2012
May;125(20):2454-61.
279.Pasricha PJ, Rai R, Ravich WJ, Hendrix TR, Kalloo AN. Botulinum
toxin for achalasia: long-term outcome and predictors of response.
Gastroenterology. 1996 May;110(5):1410-5.
262.Samuel J, Oliveira M, Correa De Araujo RR, Navarro MA, Muccillo
G. Cardiac thrombosis and thromboembolism in chronic Chagas’ heart
disease. Am J Cardiol. 1983 Jul;52(1):147-51.
281.Heller E. Extramukose Cardiaplastik beim chronischen
Cardiospasmus mit Dilatation des Oesophagus. Mitt Grenzgeb Med
Chir. 1913;27(1):141-49.
263.Lopes ER, Marquez JO, Costa Neto B, Menezes AAC, Chapadeiro E.
Associação entre acidentes vasculares encefálicos e doença de Chagas.
Rev Soc Bras Med Trop. 1991 Apr-Jun;24(2):101-4.
282.Pinotti HW, Habr-Gama A, Cecconello I, Felix VN, Zilbertein B. The
surgical treatment of megaesophagus and megacolon. Dig Dis. 1993 JulOct;11(4-5):206-15.
58
280.Ferguson MK. Achalasia: current evaluation and therapy. Ann Thorac
Surg. 1991 Aug;52(2):336-42.
2nd Brazilian Consensus on Chagas Disease, 2015
Rev Soc Bras Med Trop 49:Supplement I, 2016
283.Spiess AE, Kahrilas PJ. Treating achalasia: from whalebone to
laparoscope. JAMA. 1998 Aug;280(7):638-42.
284.NOSCAR POEM White Paper Committee; Stavropoulos SN, Desilets
DJ, Fuchs KH, Gostout CJ, Haber G, Inoue H, et al. Per-oral endoscopic
myotomy white paper summary. Gastrointest Endosc. 2014 Jul;80(1):115.
297.Bitto C, Silveira C, Cardoso MA, Marques P, Luquetti A, Macedo
V, et al. Parasite persistence in treated chagasic patients revealed by
xenodiagnosis and polymerase chain reaction. Mem Inst Oswaldo
Cruz. 2001 Aug;96(6):823-6.
298.Gallerano RH, Sosa RR. Resultados de un estúdio a largo plazo con
drogas antiparasitárias en infectados chagásicos crónicos. Rev Fed Arg
Cardiol. 2001;30:289-96.
285.Inoue H, Tianle KM, Ikeda H, Hosoya T, Onimaru M, Yoshida A, et
al. Peroral endoscopic myotomy for esophageal achalasia: technique,
indication, and outcomes. Thorac Surg Clin. 2011 Nov;21(4):519-25.
299.Fragata Filho AA. Tratamento antiparasitário da doença de Chagas.
Rev Soc Cardiol Estado de São Paulo. 2009;19:2-5.
286.Swanstrom LL, Kurian A, Dunst CM, Sharata A, Bhayani N, Rieder
E. Long-term outcomes of an endoscopic myotomy for achalasia: the
POEM procedure. Ann Surg. 2012 Oct;256(4):659-67.
300.Andrade SG, Magalhães JB, Pontes AL. Terapêutica da fase crônica da
infecção experimental pelo Trypanosoma cruzi com o benzonidazol e o
nifurtimox. Rev Soc Bras Med Trop. 1989 Jul-Sep;22(3):113-8.
287.Duhamel B. Une nouvelle opération pour le mégacolon cologénital:
l’abaissement rétro-rectal et transanal du côlon et son application
possible au traitement de quelques autres malformations. Nouv Presse
Med. 1956; 64(95):2249-50.
301.Garcia S, Ramos CO, Senra JFV, Vilas-Boas F, Rodrigues MM,
Campos-de-Carvalho AC, et al. Treatment with benznidazole
during the chronic phase of experimental Chagas’ disease
decreases cardiac alterations. Antimicrob Agents Chemother. 2005
Apr;49(4):1521-8.
288.Reis-Neto JA, Pedroso MA, Lupinacci RA, Reis Júnior JA, Ciquini SA,
Lupinacci RM, et al. Megacolo adquirido: perspectivas fisiopatológicas
para o tratamento laparoscópico. Rev Bras Colo-proctol. 2004 janmar;24(1):49-62.
289.Coura JR, Borges-Pereira J. Chronic phase of Chagas disease: why
should it be treated? A comprehensive review. Mem Inst Oswaldo
Cruz. 2011 Sep;106(6):641-5.
290.Molina I, Gómez i Prat J, Salvador F, Treviño B, Sulleiro E, Serre N,
et al. Randomized trial of posaconazole and benznidazole for chronic
Chagas’ disease. N Engl J Med. 2014 May;370:1899-908.
291.Cançado JR. Terapêutica específica. In: Dias JCP, Coura JR, editores.
Clínica e Terapêutica da Doença de Chagas: uma abordagem prática
para o clínico geral. Rio de Janeiro: Fiocruz; 1997. p. 323-51.
292.Sosa Estani S, Segura EL, Ruiz AM, Velazquez E, Porcel BM, Yampotis
C. Efficacy of chemotherapy with benznidazole in children in the
indeterminate phase of Chagas’ disease. Am J Trop Med Hyg. 1988
Oct;59(4):526-9.
293.Andrade AL, Zicker F, Oliveira RM, Silva SA, Luquetti A, Travassos
LR, et al. Randomised trial of efficacy of benznidazole in treatment of
early Trypanosoma cruzi infection. Lancet. 1996 Nov;348(9039):140713.
294.Yun O, Lima MA, Ellman T, Chambi W, Castillo S, Flevaud L, et
al. Feasibility, drug safety, and effectiveness of etiological treatment
programs for Chagas disease in Honduras, Guatemala, and Bolivia:
10-year experience of Médecins Sans Frontières. PLoS Negl Trop Dis.
2009 Jul;3(7):e488.
295.Bern C, Montgomery SP, Herwaldt BL, Rassi Júnior A, Marin-Neto
JA, Dantas RO, et al. Evaluation and treatment of Chagas disease in the
United States: a systematic review. JAMA. 2007 Nov;298(18):2171-81.
296.Coura JR, Abreu LL, Willcox HP, Petana W. Comparative controlled
study on the use of benznidazole, nifurtimox and placebo, in the
chronic form of Chagas’ disease, in a field area with interrupted
transmission. I. Preliminary evaluation. Rev Soc Bras Med Trop. 1997
Mar-Apr;30(2):139-44.
2nd Brazilian Consensus on Chagas Disease, 2015
302.Coura JR, Castro SL. A critical review on Chagas disease chemotherapy.
Mem Inst Oswaldo Cruz. 2002 Jan;97(1):3-24.
303.Maguire JH. Treatment of Chagas’ disease: time is running out. N Engl
J Med. 2015 Oct;373(14):1369-70.
304.D’Albuquerque LA, Gonzalez AM, Filho HL, Copstein JL, Larrea
FI, Mansero JM, et al. Liver transplantation from deceased donors
serologically positive for Chagas disease. Am J Transplant. 2007
Mar;7(3):680-4.
305.Altclas JD, Barcan L, Nagel C, Lattes R, Riarte A. Organ transplantation
and Chagas disease. JAMA. 2008 Mar;299(10):1134.
306.Sousa AA, Lobo MC, Barbosa RA, Bello V. Chagas seropositive donors
in kidney transplantation. Transplant Proc. 2004 May;36(4):868-9.
307.Bocchi EA, Belloti G, Mocelin AO, Uip D, Bacal F, Higuchi ML, et
al. Heart transplantation for chronic Chagas’ disease. Ann Thorac
Surg. 1996 Jun;61(6):1727-33.
308.Freitas VL, Silva SC, Sartori AM, Bezerra RC, Westphalen EV, Molina
TD, et al. Real-time PCR in HIV/Trypanosoma cruzi coinfection with
and without Chagas disease reactivation: association with HIV viral load
and CD4 level. PLoS Negl Trop Dis. 2011 Aug;5(8):e1277.
309.Brener Z. Laboratory-acquired Chagas’ disease: an endemic disease
among parasitologists? In: Morel M, editor. Genes and antigens of
parasites: a laboratory manual. 2 ed. Rio de Janeiro: Editora Fiocruz;
1984. p. 3-9.
310. Brener Z. Laboratory-acquired Chagas disease: comment. Trans R
Soc Trop Med Hyg. 1987;81(3):527.
311. Shikanai-Yasuda MA, Umezawa ES, Tolezano JE, Matsubara
L. Doença de Chagas aguda após uso profilático de benznidazol
(Acidente de laboratório). Rev Soc Bras Med Tropical. 1993;26 supl
II:127-8.
312.Bern C. Chagas’ Disease. N Engl J Med. 2015 Nov;373(19):1881-2.
313. Portela-Lindoso AAB, Shikanai-Yasuda MA. Doença de Chagas
crônica: do xenodiagnóstico e hemocultura à reação em cadeia da
polimerase. Rev Saude Publica. 2003 fev;37(1):107-15.
59
Rev Soc Bras Med Trop 49:Supplement I, 2016
ATTACHMENTS
Definitions of grades or classes of recommendations and
levels of evidence1
Classes of recommendations
• Class I: conditions for which there is conclusive evidence,
or, in its absence, general agreement that the procedure or
treatment is useful and/or effective.
• Class II: conditions for which there is conflicting evidence
and/or divergence of views on the utility/effectiveness and
safety of the procedure or treatment:
• Class IIa: evidence and opinions favor the indication for
the procedure or treatment; most professionals involved
in specific management approve;
• Class IIb: utility/effectiveness and safety is less well
established by evidence, with opinion divided; procedure
or treatment is considered optional.
• Class III: conditions for which there is conclusive
evidence and/or general agreement that the procedure/
treatment is not useful and/or effective, and may even be
harmful in some circumstances.
60
•
•
•
Levels of Evidence
Level A: data from several consistent and good quality
randomized trials or robust meta-analysis of randomized
clinical trials.
Level B: data obtained from a single randomized clinical
trial or from several non-randomized clinical studies,
observational (less robust meta-analysis).
Level C: data obtained from consensual opinions of
specialists on the subject.
1
Based on international publications and particularly endorsed in the First
Latin American Guidelines for the Diagnosis and Treatment of Chagas Heart
Disease.203
Evidence levels ranked as B or C cannot be interpreted as weak recommendations.
There are many consensus-based recommendations, so with the recommendation
of class I, level of evidence C (expert opinions). On the other hand, some
indications considered controversial (recommendation grade II) may be
grounded in randomized controlled trials (level of evidence A).
2nd Brazilian Consensus on Chagas Disease, 2015
Erratum
Revista da Sociedade Brasileira de Medicina Tropical/Journal of the Brazilian Society of Tropical Medicine
49(Supplement I): 2016 - doi: 10.1590/0037-8682-0505-2016 - Page 22 - Figure 2
Should read: