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Congenital Chagas disease: alert of research negligence

Nayra Dias, Bruna de Carvalho, Nadjar Nitz, Luciana Hagström, Tamires Vital, Mariana Hecht

1Laboratório Interdisciplinar de Biociências, Faculdade de Medicina, Universidade de Brasília, Brasília, DF, Brasil.

DOI: 10.1590/0037-8682-0069-2018

ABSTRACT

INTRODUCTION:

Chagas disease (CD), a neglected endemic disease in Latin America, has acquired new epidemiological characteristics with an increase in the importance of alternative transmission routes such as congenital transmission. We evaluated the scientific research on this subject.

METHODS:

We searched the Scielo, BVS, and PubMed databases from 2006 to 2017.

RESULTS:

We identified a small number of published articles, mostly in journals with an impact factor less than 3.0. Studies on human congenital transmission of CD were carried out in only seven different countries.

CONCLUSIONS:

Our data highlight the lack of research on congenital CD.

Keywords: Congenital Chagas disease; Publications; Negligence

Chagas disease (CD), or American trypanosomiasis, is an endemic disease in Latin America classified as a neglected tropical disease by the World Health Organization (WHO). Approximately seven million people are infected with Trypanosoma cruzi worldwide, with the main concentration in Brazil, Mexico, and Argentina1. Globalization and the intense flow of people through countries, especially Latino immigrants, contribute to the spread of infection to non-endemic areas23. In the acute phase of the disease, patients may present several clinical manifestations, among them fever, hepatomegaly, splenomegaly, swelling at the inoculation site (chagoma of inoculation), and edema of the eyelid (Romana sign)2. Most infected patients, however, are asymptomatic. In approximately one-third of patients, the disease evolves into a symptomatic chronic phase, with clinical manifestations related specifically to the cardiovascular and digestive system4.

Infected hematophagous Hemiptera of the subfamily Triatominae can transmit the protozoa T. cruzi naturally to man and other animals. Alternative transmission routes are blood transfusion, organ transplantation, and sexual, oral, and congenital routes. Since classical forms of CD transmission such as vector and blood transfusion are being controlled, other less frequent forms of transmission such as congenital transmission have been showing increasing epidemiological importance.

Mother-to-child T. cruzi transmission may result in premature births, low-weight newborns, and stillbirths5. Since its description by Carlos Chagas in 19116, several authors have reported the importance of CD congenital transmission, not only experimentally, but mainly in man4. Currently, the congenital transmission rate varies greatly depending on the location, being approximately 1% in Brazil and reaching 12% in other Latin American countries7. It is estimated that, in endemic regions, approximately two million women of childbearing age have the chronic form of the disease, with an estimated incidence of 15,000 cases per year in Latin America8.

Data on congenital transmission of CD are heterogeneous, being influenced by the form of control and diagnostic and screening programs, which reinforces the need to intensify the studies and research of patients suspected to have the disease. Despite generating more work and costs, these actions would have the benefit of decreasing the number of infected children and if the child is treated up to 1 year of age, the chance of a cure is higher89. In this respect, the quality of the tests used for diagnosis is of great importance and may be fundamental to guarantee the early detection of congenital CD transmission. Unfortunately, from a political point of view, CD is considered a Latin American problem and has not attracted the attention of major world research centers.

In this context, the objective of this work was to evaluate the scientific research on this subject by identifying the number of published articles, the impact factors of the journals in which the articles were published, and the countries where the research was carried out.

A systematic review on congenital transmission of CD was carried out using the Virtual Health Library (BVS), the Scientific Electronic Library Online (Scielo), and Public Medline (PubMed), on February 23, March 3, and February 13 in 2017 and on January 24 in 2018. The study period was from 2006 to 2017 and the descriptors used were “Chagas disease,” “congenital transmission,” “Trypanosoma cruzi,” and “pregnancy.”

We established the following inclusion criteria: (1) studies involving congenital transmission of CD, (2) studies conducted in humans, and (3) articles written in English. The following types of study were excluded: case reports, review studies, dissertations and theses, studies without epidemiological and diagnostic aspects, and studies performed in animals or in vitro. Within the established study period, 97 articles were found in PubMed, 91 in the BVS database, excluding those in duplicate, result in 100 articles, and no articles on Scielo. After a thorough analysis of the found articles, 32 were eligible for the study proposal, as shown in Figure 1.

FIGURE 1: Flowchart of bibliographic review articles. 

The following bibliometric indicators were evaluated: number of papers published, names of journals and their respective impact factors, year of publication, countries where surveys were conducted, sample size, congenital transmission incidence, and diagnosis methods.

After analyzing all the inclusive and exclusive criteria of the articles, the selected publications were organized and arranged in chronological order, as shown in Table 1, from the most recent (2017) to the oldest (2007). Despite the search for articles from 2006, no article fit within the inclusion criteria in the first year. The 32 selected articles were distributed in 12 different journals with impact factors varying between 1.631 and 8.736. The journals with the most published articles Acta Tropica and The American Journal of Tropical Medicine and Hygiene, with six articles in each journal. There were few articles between the years 2006 and 2009, but more in the years 2012 and 2015 (five and seven articles, respectively).

Another aspect evaluated was the distribution of the research by country (Table 1). Studies on congenital transmission of CD were carried out in only seven different countries, with predominance in Argentina (10 studies), Bolivia (eight studies), and Spain (five studies). Of interest, a single study was conducted in Brazil. In relation to the research time span, short-term and long-term studies were identified, the largest being a retrospective 20-year study (Table 1). Of the 30 studies, only one did not report the coverage period.

TABLE 1: Bibliometric indicators of the reviewed articles on congenital Chagas disease.  

Reference Article Journal/impact factor Country Research time span
Murcia et al., 2017 Treatment of Infected Women of Childbearing Age Prevents The Journal of Spain 2013-2015
Congenital Trypanosoma cruzi Infection by Eliminating the Infectious
Parasitemia Detected by PCR Diseases/6.723
Buekens et al., 2017 Congenital Transmission of Trypanosoma cruzi in Argentina, The American Journal Mexico, Honduras, 2011-2014
Honduras, and Mexico: An Observational Prospective Study of Tropical Medicine and Hygiene/2.456 and Argentina
Montes- Rincón et al., 2016 Trypanosoma cruzi seroprevalence in pregnant women and Journal Acta Mexico 2014-2015
screening by PCR and microhaematocrit in newborns from Tropica/2.380
Guanajuato, Mexico
Vargas et al., 2015 Seroprevalence of Trypanosoma cruzi Infection in The American Journal Ecuador 2012
Schoolchildren and in Pregnant Women from an Amazonian of Tropical Medicine
Region in Orellana Province, Ecuador and Hygiene/2.456
Kaplinski et al., 2015 Sustained Domestic Vector Exposure Is Associated with Clinical Infectious Bolivia 2010-2013
Increased Chagas Cardiomyopathy Risk but Decreased Diseases/8.736
Parasitemia and Congenital Transmission Risk Among Young
Women in Bolivia
Volta et al., 2015 Diagnosis of congenital Trypanosoma cruzi infection: A Journal Acta Argentina (Buenos 2008-2011
serologic test using Shed Acute Phase Antigen (SAPA) in Tropica/2.380 Aires)
mother-child binomial samples
Luquetti et al., 2015 Congenital transmission of Trypanosoma cruzi Memórias do Instituto Brazil 1994-2014
in central Brazil. A study of 1,211 individuals born to infected mothers Oswaldo Cruz/1.789
Rendell et al., 2015 Trypanosoma cruzi-Infected Pregnant Women without Vector Exposure Have Higher PLOS One/4.411 Bolivia 2010-2011
Parasitemia Levels: Implications for Congenital Transmission Risk
Moscatelli et al., 2015 Urban Chagas disease in children and women in primary care Memórias do Instituto Argentina (Buenos 2005-2007
centres in Buenos Aires, Argentina Oswaldo Cruz/1.789 Aires)
Soriano-Arandes et al., 2014 Controlling congenital and paediatric Chagas disease through BMC Public Spain 2011
a community health approach with active surveillance and Health/2.209
promotion of paediatric awareness
Fabbro et al., 2014 Trypanocide treatment of women infected with Trypanosoma PLOS Neglected Argentina 2012-2013
cruzi and its effect on preventing congenital Chagas Tropical Disease/4.446
Velázquez et al., 2014 Predictive role of polymerase chain reaction in the early Journal Acta Argentina (Buenos 2004-2009
diagnosis of congenital Trypanosoma cruzi infection Tropica/2.380 Aires)
Bua et al., 2013 How to improve the early diagnosis of Trypanosoma cruzi PLOS Neglected Argentina 2008-2011
infection: relationship between validated conventional Tropical Disease/4.446
diagnosis and quantitative DNA amplification in congenitally
infected children
Murcia et al., 2013 Risk factors and primary prevention of congenital Chagas Clinical Infectious Spain 2007-2011
disease in a nonendemic country Diseases/8.736
Apt et al., 2013 Congenital infection by Trypanosoma cruzi in an endemic Transactions of the Chile 2006-2009
area of Chile: a multidisciplinary study Royal Society of
Tropical Medicine and Hygiene/1.631
Duffy et al., 2013 Analytical Performance of a Multiplex Real-Time PCR Assay PLOS Neglected Argentina 2011-2012
Using TaqMan Probes for Quantification of Trypanosoma Tropical Disease/4.446
cruzi Satellite DNA in Blood Samples
Ortiz et al., 2012 Presence of Trypanosoma cruzi in pregnant women and Journal Acta Chile 2006-2010
typing of lineages in congenital cases Tropica/2.380
Otero et al., 2012 Congenital transmission of Trypanosoma cruzi in non- The American Journal Spain 2008-2010
endemic areas: evaluation of a screening program of Tropical Medicine and Hygiene/2.456
in a tertiary care hospital in Barcelona, Spain
Clavijo et al., 2012 Prevalence of Chagas disease in pregnant women and Journal Acta Bolivia 2006-2008
incidence of congenital transmission in Santa Cruz de la Tropica/2.380
Sierra, Bolivia
Barona-Vilar et al., 2012 Prevalence of Trypanosoma cruzi infection in pregnant Latin Epidemiology and Spain 2009-2010
American women and congenital transmission rate in a non- Infection/2.515
endemic area: the experience of the Valencian Health Programme (Spain)
Cardoso et al., 2012 Maternal fetal transmission of Trypanosoma cruzi: a problem Experimental Mexico 2006-2008
of public health little studied in Mexico Parasitology/1.623
Bisio et al., 2011 Urbanization of congenital transmission of Trypanosoma cruzi: Transactions of the Argentina (Buenos 2002-2007
Prospective polymerase chain reaction study in Royal Society of Aires)
pregnancy Tropical Medicine and Hygiene/1.631
Flores-Chavez et al., 2011 Surveillance of Chagas disease in pregnant women in Eurosurveillance/5.98 Spain 2008-2010
Madrid, Spain, from 2008 to 2010
Romero et al., 2011 Door-to-door screening as a strategy for the detection of TM & IH. Tropical Bolivia 2004-2007
congenital Chagas disease in rural Bolivia Medicine and International
Health/2.519
Brutus et al., 2010 Detectable Trypanosoma cruzi Parasitemia during Pregnancy The American Journal Bolivia 2004-2005
and Delivery as a Risk Factor for Congenital Chagas of Tropical Medicine
Disease and Hygiene/2.453
Rissio et al., 2010 Congenital Trypanosoma cruzi Infection. Efficacy of Its The American Journal Argentina 1994-2004
Monitoring in an Urban Reference Health Center in a Non- of Tropical Medicine
Endemic Area of Argentina and Hygiene/2.453
Mallimaci et al., 2010 Early diagnosis of congenital Trypanosoma cruzi infection, The American Journal Argentina 2001-2002
using shed acute phase antigen, in Ushuaia, Tierra del of Tropical Medicine
Fuego, Argentina and Hygiene/2.453
Apt et al., 2010 Vertical transmission of Trypanosoma cruzi in the Province of Biological Chile 2006-2008
Choapa, IV Region, Chile. Preliminary Report (2005-2008) Research/1.328
Bern et al., 2009 Congenital Trypanosoma cruzi Transmission in Santa Cruz, Clinical Infectious Bolivia 2006-2007
Bolivia Diseases/8.736
Diez et al., 2008 The Value of Molecular Studies for the Diagnosis of The American Journal Argentina ND
Congenital Chagas Disease in Northeastern Argentina of Tropical Medicine and Hygiene/2.453
Brutus et al., 2008 Congenital Chagas disease: Diagnostic and clinical aspects Journal Acta Bolivia 2002-2004
in an area without vectorial transmission, Bermejo, Bolivia Tropica/2.380
Salas et al., 2007 Risk factors and consequences of congenital Chagas disease TM & IH. Tropical Bolivia 2003-2005
in Yacuiba, south Bolivia medicine and International Health/2.519

ND: not determined.

As noted in Table 2, there was a large variation in the sample size among the articles, ranging from 19 to 4355 children. The incidence of CD congenital transmission also differed among the studies, independently of the study area endemicity. In the nine studies conducted in non-endemic areas (four in Buenos Aires and five in Spain), the congenital transmission rate ranged from 2.6% in Spain to 23% in Buenos Aires. In these areas, 55.5% of studies had a transmission rate ≥5%. Of interest, the majority of these mothers came from endemic areas of Latin America (Table 2). The congenital transmission rate in the endemic areas varied from 1.98% to 20% in studies carried out, respectively, in Brazil and in Mexico.

TABLE 2: Epidemiological aspects of congenital Chagas disease in selected articles. 

Reference Sample size (child) Incidence of congenital Endemic area? Maternal nationality
transmission
Murcia et al., 2017 160 10% No Bolivia
Buekens et al., 2017 503 0% Honduras, 6.6% Yes Honduras, Argentina, Mexico
Argentina, and 6.3%
Mexico
Montes-Rincón et al., 2016 20 20% Yes Mexico
Vargas et al., 2015 1649 ND Yes Ecuador
Kaplinski et al., 2015 1000 6.8% Yes Bolivia
Volta et al., 2015 91 23% No 69.23% Argentina; 18.68% Bolivia;
12% Paraguay
Luquetti et al., 2015 1212 1.98% Yes Brazil
Rendell et al., 2015 135 11.7% Yes Bolivia
Moscatelli et al., 2015 19 Varied Yes 58.7% Argentina; 17% Bolivia;
12.4% Peru; 10% Paraguay
Soriano-Arandes et al., 2014 42 6.9% No 90.5% Bolivia
Fabbro et al., 2014 354 15.3% No 85% Argentina; 10% Bolivia;
4% Paraguay
Velázquez et al., 2014 468 10.47% No 63.5% Argentina; 26.8% Bolivia;
8.2% Paraguay
Bua et al., 2013 843 11.27% No 60% Argentina; 35% Bolivia;
5% Paraguay
Murcia et al., 2013 65 13.8% No 96.6% Bolivia; 3.4% Paraguay
Apt et al., 2013 4280 4.7% Yes Chile
Duffy et al., 2013 74 4.05% Yes Argentina
Ortiz et al., 2012 100 3% Yes Chile
Otero et al., 2012 20 5% No 34% Equador; 18% Bolivia; 13% Peru
Clavijo et al., 2012 3579 3.4% Yes ND
Barona-Vilar et al., 2012 217 14.15% No 30% Equador; 21.7% Bolivia,
17.8% Colombia; 6.4% Argentina
Cardoso et al., 2012 106 4.7% Yes ND
Bisio et al., 2011 83 2.6% No 37.5% Argentina; 24% Bolivia; 23.1%
Paraguay; 1% Peru;
14.4% indeterminate
Flores-Chavez et al., 2011 152 5% No 44.4% Bolivia
Romero et al., 2011 299 7.48% Yes Bolivia
Brutus et al., 2010 147 6.1% Yes Bolivia
Rissio et al., 2010 4355 4.4% Yes Argentina
Mallimaci et al., 2010 68 2.5% Yes Argentina
Apt et al., 2010 80 2.5% Yes Chile
Bern et al., 2009 138 6.4% Yes Bolivia
Diez et al., 2008 121 9.9% Yes Argentina
Brutus et al., 2008 231 5.2% Yes Bolivia
Salas et al., 2007 2742 5.1% Yes Bolivia

ND: not determined.

The articles we analyzed demonstrated a gamut of methodologies used for the diagnosis of congenital transmission of CD. Indeed, 90% (27/30) of the articles used more than one methodology: parasitological, serological, or molecular, according to WHO recommendations.

For the present study, we conducted a literature review to identify articles published in the last 10 years on CD congenital transmission, using predetermined inclusion and exclusion criteria. At the end of the analysis, 32 articles were selected for content evaluation. Most articles (21/32) were published in the last 5 years; but in 2016, only one article was selected within the pre-established criteria. In this respect, it should be emphasized that continuous research is extremely important for an understanding of the biological and clinical aspects of a disease and is dependent on the interest of development agencies and the scientific community. Regarding CD, one of the most widespread diseases in the Americas, significant advances in different areas are still lacking, such as the knowledge of its pathogenesis, the development of new treatments, and the follow-up of congenital transmission cases1013. Such limitations are associated with the fact that CD presents important sociocultural and political-economic aspects that do not attract investments.

Few are the well-qualified journals that currently contribute significantly to the dissemination of scientific research on CD. Our review identified articles in 12 different journals with impact factors between 1.631 and 8.736, suggesting a lack of interest of the scientific community in the topic. Only 10% of the articles were published in journals with an impact factor greater than 5.0. As trypanosomiasis occurs mainly in one of the poorest parts of the world, it does not have the same repercussion as other more widely distributed protozoa, such as malaria. Therefore, it represents a regional problem, naturally generating greater interest only in Latin America. This, in turn, explains why most of the studies were conducted in Argentina and Bolivia. Nevertheless, there was some interest in the subject in Spain, the only European country with identified articles (five). The increased interest in non-endemic areas may be associated with a greater occurrence of CD congenital transmission in these localities owing to extensive migration, reaching European and Asian countries as well as cities and states without vector transmission3,14.

Among the endemic localities, Bolivia was the country with the most studies performed as well as the country with the greatest impact on congenital transmission in non-endemic areas, which corroborates the fact that the largest number of immigrants in Europe with CD are Bolivians3. Strangely enough, only one study fulfilling the pre-defined criterion was carried out in Brazil. According to the 2nd Brazilian Consensus on CD, although Brazil has advanced in vector and blood bank control, over the years, Brazil has had few published studies on CD, making it difficult to systematize data on this topic15. Despite being considered a compulsory notification disease, according to the Brazilian Consensus, Brazil does not provide any specific surveillance of pregnant women or children.

On the other hand, even though CD does not receive the desired attention, it has an important role in the maturing Latin American scientific community, which has been responsible for the main findings of this disease, including its discovery. Thus, we expect CD to continue to be a driving force in Latin American research, helping to solve social problems and contributing to expand the knowledge about this endemic disease.

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Received: February 28, 2018; Accepted: July 06, 2018

Corresponding author: Mariana Hecht. E-mail:marianahecht@gmail.comOrcid: 0000-0003-3512-7696

Conflicts of Interest: The authors declare that there is no conflict of interest.