Chagas disease or American trypanosomiasis is considered a neglected disease, and a public health problem, due to the high prevalence of the disease, as well as the high economic and social costs that it entails. There are different routes of transmission, the vector route being the main mechanism, although it can also be transmitted vertically, by transfusional transmission, by organ transplantation, laboratory accidents, and relatively new in its study, the oral route. This route is considered the oldest route of transmission, responsible for the preservation of the infection in a sylvatic way. Due partly to the decrease in the incidence of vector cases, and human activities, the oral route has been the mechanism that explains the acute outbreaks of Chagas' disease in different Latin American countries; together with its greater lethality, is that this via has become important. Early recognition of the disease is crucial in order to establish antiparasitic treatment as soon as possible, because it limits the evolution of the disease in most cases, so this research work has the objective of carrying out a bibliographic review of the oral route as a mechanism of transmission of Chagas' disease.
Keywords: Chagas disease; Trypanosoma cruzi; Oral route
Chagas disease, also called American trypanosomiasis, classified as a vector-borne disease, is a parasitic disease caused by the Trypanosoma cruzi parasite, which is transmitted to people through pre-infected hematophagous insects, considered as a neglected parasitic disease.1-3
Of these insects vectors of the disease, 141 species have been registered, grouped in 6 tribes and 19 triatomines genera. Mexico is considered the country with the highest population of triatomines: there are at least 32 species of 7 genera, including Rodnius prolixus, Triatoma dimidiata, Triatoma barberi, Triatoma longipennis, Triatoma phyllosoma, and Triatoma picturata.4-6
In the outbreak studies carried out in Colombia, the peridomiciliary collected specimen corresponds to R. pallescens, although there is also the report of having found in other outbreaks the peridomiciliary presence of Triatoma dimidiata, Panstrongylus geniculatus, Eratyrus cuspidatus, Sordid triatoma, as well as Rhodnius pallescens.6-8
Despite the widespread distribution of Chagas' disease vectors, it is until 1987 that a national seroepidemiological survey of the open population of Mexico is conducted, with a search for antibodies against T. cruzi, showing a large disparity in the numbers of seropositivity. In 1992, a serological survey was carried out on blood donors and rural population, demonstrating high levels of infection, mainly in the Huasteca area, which consists of the states of Hidalgo, San Luis Potosí, Veracruz and Tamaulipas.1,9
In addition to the wide geographic distribution in Mexico, Chagas disease is considered the most important parasitic disease in the country, due to the great economic cost involved: for example, only in the state of Oaxaca, it is estimated that the annual cost of therapy Support is $16,000,000 pesos (approximately $80,000 dollars), and, in adjusted life years for the disease, is $28,747,000 dollars.1
In other words, Chagas disease is a public health disease, not only in Mexico, but in Latin America, affecting 7-10 million people in 21 endemic countries, in addition to 90 million at risk of contracting it, with approximately 15,000 annual deaths. Besides, due to migratory movements, Chagas disease is considered reemergent in countries like Canada, Australia, France and Spain, where the vector is not endemic. The transmission of the disease can be carried out by contact of mucous membranes or wounded skin with feces of the infected vector (classical route), but also by transfusional and congenital transmission, organ transplantation, laboratory accident and, less frequently, by oral transmission,.10-12, 14,18
The importance of oral transmission as a mechanism to develop Chagas' disease has been neglected in many cases, since the vector or classical route causes 80% of known cases of the disease in endemic areas. However, due to the success of intradomiciliary vector control in some of these zones, as well as in rural and peri-urban areas of low endemicity, the oral route has reemerged as a transmission mechanism, besides of the important role it plays in the jungle cycle to preserve the infection in mammals and triatomines in a natural way. The oral route is even considered the oldest, natural, frequent and successful way of transmission of T. cruzi in the jungle environment, due to the chain of predators.2-4,6,11,14-16
In South American countries like Brazil, Venezuela, Bolivia and Colombia, there are different reports of outbreaks associated with foods or drinks contaminated with the parasite, with higher morbidity and mortality than the other infection routes.2, 3,7,17
Because of this, this research work has the objective of carrying out a bibliographic revision of the oral route as mechanism of transmission of Chagas' disease.
According to the Guidelines of the Pan American Health Organization (2009), it is considered a confirmed case when other forms of transmission are excluded and parasitological criteria are met, when there is epidemiological evidence of food or beverages as a source of infection, and when there is more than one case of acute Chagas without presence of inoculation chagoma.7 It is considered a probable case when parasitological criteria are met, when there is more than one case of acute Chagas with clinical characteristics, and when the epidemiological association has a confirmed case.7 A suspected case is one that presents signs and symptoms in more than 1 case of acute Chagas, in the presence of immunological criteria.7
The endemic area of Chagas disease is quite extensive, from Southern United States to the Southern Cone. As an epidemiological characteristic in the case reports, there is the proximity of forest area to the dwellings of those affected, that is, evidence of the proximity of the jungle cycle; without the presence of the vector in an intradomiciliary way, but present in the peridomicile, as well as greater presence of mammals of the genus Didelphis, association with rain season, the El Niño phenomenon, season of warm climate, and houses with artificial light.7,13,15 In these mammals, the life cycle of T. cruzi is carried out in the odoriferous glands, so that by expelling the contents of the anal glands (either to mark territory or in response to danger), they could transmit the disease by contaminating foods and drinks.2,3,15 The foods involved in the oral transmission of the disease are mainly juices, but also prepared foods. These foods are described in Table 1.2,4,7,14,15,17
| Table 1.- Foods reported in outbreaks of Chagas disease by oral route2,4,7,14,15,17 | |
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Besides anal secretions of mammals, the presence of feces of infected triatomines, and the incidental or deliberate presence of triatomines in the diet, may explain the development of acute outbreaks. The recorded outbreaks date back to 1968, mostly in countries such as Brazil, Venezuela, Bolivia and Colombia, and, to a lesser extent, Argentina, Ecuador and Mexico.2,3,14,15
Brazil: was the first country to record acute cases of Chagas disease by oral transmission. In the period 1968-2005, 311 cases of acute Chagas were reported in outbreak, while in the period 2000-2010, there were 776 cases of epidemics by oral transmission. The reported mortality has been variable, from 0-35%.2,3
Venezuela: After Brazil, it is the second country in number of reported acute cases of oral Chagas disease, with 4 events as of 2007, 228 cases, and a mortality of 2.63%. The first case of suspicion (2005) with high mortality is not included, since the outbreak could not be associated with an oral transmission.2,3
Colombia: Of the various outbreaks in different areas and municipalities, there are 49 confirmed cases and 31 suspected cases of Chagas disease by oral transmission, with 10 deaths.2,4
Mexico: In the 80's, there was a report in the state of Jalisco, however, it does not describe the number of cases nor deaths. Until now, there is no further information on acute outbreaks of oral transmission in the country.3,5
The incubation period is of 3 to 22 days after having ingested contaminated food. It is characterized by constant, prolonged and not very high fever, accompanied by headache, myalgia, epigastric pain, vomiting, arthralgia, hepatomegaly and splenomegaly, local or generalized lymphadenopathy, even severe gastritis, hemorrhage (epistaxis, hematemesis or melena) and diarrhea, for 4-8 weeks, in the absence of romana’s sign and inoculation chagoma. Subsequently, myocarditis, pericardial effusion, and cardiac tamponade, leading to death. Poor prognosis and mortality are directly proportional to a younger age of the patient.2,4,6,7,10, 11,15
Metacyclic trypomastigote, coming from contaminated food, invades gastric mucosal epithelium, resisting the pH of gastric acid and pepsin digestion, by expression of surface glycoproteins.2,3,14,15 Metacyclic trypomastigotes join the gastric mucin, thanks to the surface protein gp82, through a recognition site different from the host cell. Gp 82 is the main infection molecule, it binds to the gastric mucin, and induces the intracellular mobilization and increase of Ca2+, so it facilitates the internalization of the parasite. As negative regulatory proteins, or inhibitory proteins, there is the surface glycoprotein gp90 and mucin-like glycoprotein gp35/50.2-4,7,8,14,15,17 Subsequently, metacyclic trypomastigotes migrate through the mucosal layer and invade epithelial cells, favored by gp 30, in in vitro models.2,3,15
Since metacyclic trypomastigotes are intracellular, they differ from amastigotes, and in an approximate period of 4 days post-intake, there can be observed intracellular replication amastigote nests, that after 9 cycles of cell division, can be differentiated from metacyclic trypomastigotes present in the host’s blood, that is, parasitemia, which is high during the first 4 weeks, and decreases in the next 8 weeks.2,7,8,15 Besides, due to the edema in the inner face of the cheeks, paresthesia and lingual edema, the possible penetration of the parasite in the oral, esophageal and intestinal mucosa is under study.4,15
Experimentally, it has been observed that a response to TH2 at the level of gastric mucosa, and a systemic response to TH1 are the ones that allow protection against oral infection.7 Initially, the host will express antibodies IgM type, when parasitemia is elevated, and will gradually express IgG, until replacing the initial IgM antibodies. IgG expresses its maximum levels between 3-4 weeks after exposure, and, if not treated, these high levels are maintained.2,7,10 As an acute phase biomarker of Chagas, TGF-β can even be for patient follow-up, once antiparasitic treatment established.20
Phylogenetically, T. cruzi can be divided into 6 populations or Discrete Typification Units (DTUs), which were later named TcI-TcVI, and recently, Tcbat and Tc marinkellei have been added. These clusters are important because they guide the clinical course of the disease, as well as geographical distribution and infective vectors: TcI, with five subpopulations, is associated with the domestic cycle of infection, and chronic chagasic cardiomyopathy; TcII has been associated with the domestic cycle, clinical manifestations and megaesophagus and megacolon; TcV and VI, associated with chronic chagasic cardiomyopathy and digestive megasyndromes.2,4 In acute Chagas disease by oral transmission, it has been identified in some cases: Brazil TcI, II, IV and VI. In Venezuela, TcId subpopulations and TcIa, Ib, Id co-infections were found. In Colombia, there were mainly TcId, but also TcIV.4
The clinical picture is suggestive of the disease. Although there are no cardiac manifestations at the time of the examination, acute Chagas' disease by oral transmission should be suspected if several people have prolonged febrile syndrome without apparent cause, especially if it is accompanied by adenopathy, facial edema, lower limb edema, hepatosplenomegaly, exanthema, meningoencephalitis and hemorrhagic manifestations.2,3,5,7,11 Besides, the search for common feeding source must be done, as well as the search for triatomines in the place of preparation and storage of food. Also, mammals of the genus Didelphis should be searched in an intradomiciliary and peridomiciliary manner, since they may be approached in search of food and be contaminated with anal or urine secretions.2,3 5,11 Within laboratory and cabinet studies in cases of acute Chagas are parasitological and immunological studies:
1. Parasitological. In these, the parasite is observed in blood, although it is only useful in the acute stage of the infection (15-45 days approximately), when parasitemia is very high. However, if any of these tests is positive, it is no longer necessary to confirm the diagnosis with another test. It should be performed in combination with clinical-epidemiological characteristics.2
• Fresh drop and thick drop
• Strout
• Capillary method (microstrout)
• Hemoculture
• Xenodiagnoses
• Polymerase chain reaction (PCR) 2,3,5,7,10,11
2. Serological methods. They are used when the parasitemia is low, intermittent or null, through the identification of antibodies against antigens of T. cruzi. They should be performed in combination with clinical and epidemiological characteristics. None of these methods has a 100% specificity and sensitivity, so the confirmation diagnosis is made with the concordance of at least two techniques of different principles and antigens. In case of medical emergency, these methods are of vital importance. Among them are the ones described in Table 2.2,3,5,7,11
| Table 2.- Diagnostic methods of Chagas Disease2,3,5,7,11 | |
| Conventional | Non-conventional |
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Besides these studies, for an adequate diagnostic approach, a chest x-ray, cardiac echocardiography, should be performed. In the electrocardiographic alterations, there can be found alterations in the rhythm (atrial arrhythmia and supraventricular or ventricular extrasystoles), conduction alterations (atrioventricular block, right bundle branch block, anterosuperior block) and voltage alterations (low QRS, T wave alterations, increased PR interval). In case of a chronic case, the studies to be used will be PCR and IgG titles.7
To avoid false positives, and due to the similarity of the nonspecific picture, it is necessary to perform a differential diagnosis with pathologies such as mucocutaneous and visceral leishmaniasis, malaria, sleep disorders, meningoencephalitis, syphilis, toxoplasmosis, hepatitis, systemic lupus erythropoiesis, schistosomiasis, rheumatoid arthritis, paracoccidiomycosis, mononucleosis, hantavirus infection, dermatitis and autoimmune diseases.2,7,10
The medications used to treat the disease are beznidazole (BNZ) and nifurtimox (NFX). In the case of acute Chagas' disease, the effectiveness in children is almost 100%, and 65-80% in adults, and therapy must be given as soon as possible. In case of chronic phase, more than 80% of the therapeutics used, it does not have high trypanocidal effectiveness, but it does achieve electrocardiographic modifications, as well as low frequency of clinical deterioration.2,7,9
Beznidazole (Ragonil®, Rochagan®, Roche), used since 1971, acts on the respiratory chain of T. cruzi, producing covalent modifications of macromolecules by the introduction of intermediates. Dose: 5-7.5 mg / kg body weight for 30-60 days. Adverse effects: rash, photosensitivity, severe dermatitis with rashes, myalgia, lymphadenopathy, neuropathy, suppression of bone marrow activity (agranulocytosis and thrombocytopenic purpura). It is a first-choice treatment, since it has superior efficacy to nifurtimox, with less amount of adverse effects, and the possibility of administering it less time.2,7,9,12
Nifurtimox (Lampit®, Bayer), introduced as an antiparasitic drug in 1965, acts by generating unstable free radicals, such as nitroanion, and reactive metabolites, such as hydrogen peroxide and superoxide anion. Dose: 8-10 mg / kg body weight for 60 days. Adverse effects: in 50-75% of patients, anorexia, nausea, vomiting and abdominal discomfort. Besides, irritability, insomnia, disorientation, mood changes, paresthesia and tremors may occur.2,9,12
As a therapeutic alternative, Allopurinol, which inhibits the synthesis of proteins and purines, causing a failure in the proliferation of the parasite; Itraconazole and Posaconazole, inhibitors of ergosterol synthesis at the parasite level, get to be used.12
Preventive measures should be aimed at avoiding the contact of infected triatomines and mammals with food for human consumption, such as mosquito netting on doors and windows, regardless of whether it is a rural or urban environment, as well as adequate food handling and processing, including pasteurization or chemical treatment of food and beverages.3,4,11,15 Also, it is suggested to emphasize attention on wildlife animals, and the consumption of their meat.15 In addition, the awareness regarding the presence of triatomines, and the possible transmission of Chagas disease, as well as the importance of receiving timely medical treatment is important. Another area that requires greater awareness is the health personnel, because, due to the unusual nature of the acute Chagas disease by oral transmission, it is probable that the diagnosis and, therefore, the registry of this pathology is underestimated, in addition to the little curricular value that is given to this disease in medical schools.2,3.4,18
On the other hand, the development of a vaccine that confers immunity against T. cruzi is still under research, although it is not yet effective for prevention.9
Chagas disease has shown a decline in incidence, mainly due to the decrease in vector pathways, however, due to human activity like the invasion of vectors’ habitats, migratory changes, globalization and climate change, the oral route reemerges as a mechanism of transmission of Chagas disease. Acute Chagas disease by oral transmission has a higher lethality than that transmitted by the classical route, having to comply with clinical, epidemiological and laboratory characteristics to ensure that it is a confirmed case.
Early recognition of the disease is crucial to implement as soon as possible an antiparasitic treatment, which, despite the various adverse effects, limits the evolution of the disease in the majority of cases. It is necessary to continue studies that facilitate the development of new and more sensitive diagnostic methods, therapy with greater effectiveness in the chronic stage and with less adverse effects, as well as vaccines that effectively favor immunity to T. cruzi, without neglecting the other preventive measures.
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[17] Korales Laverde LA, Jaimes Campos MA, Estupiñan Moreno EF, González Rugeles CI. Participación de las moléculas de superficie de Trypanosoma cruzi en la enfermedad de Chagas por vía oral. Rev. Fac. Cienc. Salud UDES 2016; 3:33.
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[20] La enfermedad de Chagas (tripanosomiasis americana) [Monografía en Internet] 2016. Available in http://www.who.int/mediacentre/factsheets/fs340/es/
[a] Department of Medicine, School of Health Sciences, Universidad Autónoma del Estado de Hidalgo. Ex Hacienda la Concepción s/n, Carr. Pachuca – Tilcuautla, C.P. 42060, Tilcuautla, Hgo., México.
Corresponding Author: Oliva Castro Tenorio. E-mail: olivact@gmail.com