Congenital Chagas disease: alert of research negligence

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 areas^2-3. 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 higher^8-9. 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 cases^10-13. 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 transmission^3,14.

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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• ²
  Bern C. Chagas’ Disease. New Engl J Med. 2015; 373(5):456-66.
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  De Rissio AM, Riarte AR, García MM, Esteva MI, Ruiz AM, Quaglino M. Congenital Trypanosoma cruzi infection. Efficacy of its monitoring in an urban reference health center in a non-endemic area of Argentina. Am J Trop Med Hyg. 2010;82(5):838-45.
• ¹¹
  Flores-Chavez M, Merino F, Garcia-Bujalance S, Martin-Rabadan P, Merino P, Garcia-Bermejo I, et al. Surveillance of Chagas disease in pregnant women in Madrid (Spain), 2008-2010. Trop Med Int Heal. 2011;16:368.
• ¹²
  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 Heal . 2007;12(12):1498-505.
• ¹³
  Salas NA, Postigo JR, Schneider D, Santalla JA, Brutus L, Chippaux JP. Prevalence of Chagas disease in pregnant women and incidence of congenital transmission in Santa Cruz de la Sierra, Bolivia. Acta Trop . 2012;124(1):87-91.
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  Angheben A, Anselmi M, Gobbi F, Marocco S, Monteiro G, Buonfrate D, et al. Chagas disease in Italy: Breaking an epidemiological silence. Eurosurveillance. 2011;16(37):1.
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  Dias JCP, Novaes Ramos A, Dias Gontijo E, Luquetti A, Aparecida Shikanai-Yasuda M, Rodrigues Coura J, et al. II Consenso Brasileiro em Doença de Chagas, 2015. Epidemiol e Serviços Saúde. 2016;25(21):1-10.

Publication Dates

• Publication in this collection
  21 Feb 2019
• Date of issue
  2019

History

• Received
  28 Feb 2018
• Accepted
  06 July 2018