Congenital Chagas disease: alert of research 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.

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.

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.

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.