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Eukaryon

Chagas Disease

Lexi Dejneka ’21
Lake Forest College
Lake Forest, Illinois 60045

            Chagas disease is an often overlooked and neglected tropical disease that is endemic to many parts of Latin America and the southern United States. The disease is caused by the parasite Trypanosoma cruzi, which is transmitted through the feces of triatomine bugs. An estimated 8 million people are currently infected with T. cruzi in Latin America (WHO, 2017). Triatomine bugs are native to Latin America and are particularly prevalent in rural and agricultural areas. They thrive in poor housing conditions such as mud walls and thatched roofs, which means people living in these conditions have a greater likelihood of becoming infected (Delgado et al, 2011). The disease is often associated with poverty and thus overlooked by health policy makers and the media (Nunes et al, 2013). Urbanization, migration, and destruction of the bugs’ native dense-forest habitats have had the greatest contributions to the emergence of Chagas disease. Immigrants from endemic countries have caused the disease to spread to non-endemic areas such as the United States (Coura, 2013). The disease can be transmitted mother to child, or through contaminated blood in transfusion, but the most common transmission route is by vector (Nunes et al, 2013). Triatomine bugs obtain the parasite by feeding on the blood of an infected animal or person. These bugs then transmit the parasite to humans when they bite a person and then defecate near site of the bite wound. T. cruzi is only able to enter the body through mucous membranes or cracks in the skin (WHO, 2017). For instance, if a person rubs the triatomine feces into the bite wound it allows the parasite to enter the bloodstream. Once in the bloodstream, T. cruzi replicates and a large amount of the parasite is found in the blood (Info Chagas). There are two phases to Chagas disease: The acute phase, which occurs immediately after infection and the chronic phase, which can last a lifetime. Acute Chagas disease typically lasts for a few weeks to a few months and is usually asymptomatic (Manne et al, 2013). However, if symptoms do occur, they are usually mild and may include fever or swelling at the site of infection. After the acute phase, the disease progresses to the chronic phase, during which very few parasites are found in the blood. Most people with chronic Chagas disease are asymptomatic and may remain unaware of their infection for life. However, 20-30% of people may develop complications and severe symptoms over the course of their lifetimes (CDC, 2016). These symptoms may include heart rhythm abnormalities, heart dilation, and esophageal or colon dilation. If left untreated, chronic Chagas disease can cause congestive heart failure (Nunes et al, 2013).  

            Although it was first discovered in 1909, the parasite that causes Chagas disease has a long history. Trypanosoma cruzi is a protozoan flagellate that lives and multiplies within cells in various tissues of the body. Trypanosomes are thought to have evolved in early terrestrial mammals when the continents first began to split from the ancient supercontinent Gondwanaland (Lewis et al, 2011). Close relatives of T. cruzi have been found in bats, leading to hypotheses that T. cruzi evolved from a bat trypanosome and these bats possibly colonized South America millions of years ago (Steverding, 2014). There was likely inter-continental dispersal of T. cruzi clade species by bats and rats (Lewis et al, 2011). Vectors have also likely been transmitting this parasite among wild animals for millions of years (WHO, 2017). Human arrival, settlement, and agricultural activities contributed to the emergence of Chagas as a human disease. The oldest record of Chagas disease in humans was found in 9,000-year-old mummies in Chile and Peru (WHO, 2017). The Chinchorro people were one of the first to settle in these regions and begin farming and raising livestock. Agriculture and animal domestication were the largest contributors of the transmission of Chagas disease to humans. Human activities that led to new triatomine bug habitats likely led to hybridizations of T. cruzi strains because the ideal habitats and multitude of bugs and humans promoted co-infection (Lewis et al, 2011). Triatomine bugs adapted to the new peridomestic habitats and became prevalent in rural, farmland regions of Latin America. They lost their primary food source of wild animals, so the bugs adapted and began feeding on humans and domestic animals (WHO, 2017). Although Chagas disease emerged hundreds of years ago, it was not discovered until 1909 by bacteriologist Carlos Chagas. During an anti-malaria campaign, Carlos Chagas was made aware of some blood-sucking bugs near a railroad construction site. He dissected the bugs and found the trypanosome parasite, which he used to infect monkeys and discovered that the trypanosomes were a causative agent for a disease. Soon after he had a patient who had trypanosomes in her blood that were very similar to the ones found in the monkeys. He was the first to make the connection and describe the disease as Chagas (Steverding, 2014). In the last hundred years, deforestation and urbanization have had the greatest impact on the re-emergence of Chagas disease in endemic areas (Steverding, 2014). Chagas disease exhibits many of the classic emergence and re-emergence factors that come with habitat destruction, agriculture and animal domestication, urbanization, and human migration.

            The pathogen that causes Chagas disease, Trypanosoma cruzi, exhibits many characteristics of a successful pathogen. The protozoan primarily lives inside vertebrate hosts, such as humans and animals, and in the gut of triatomine bugs (Manne et al, 2013). It is also able to live outside of a host for some time in the feces of triatomine bugs. It is actually quite difficult for the parasite to enter a host because it cannot easily cross anatomical barriers. However, T. cruzi is able to enter the bloodstream and infect humans through mucous membranes or cracks in the skin such as a bug bite wound (CDC, 2016). Once inside the bloodstream, the parasite invades cells near the site of infection and multiplies inside these cells, developing into an intracellular form of the parasite called an amastigote (Info Chagas). After these amastigotes multiply in the cells, they become trypomastigotes and travel through the bloodstream to infect other cells and tissues. They are able to enter any kind of body cell except for neurons (Teixera et al, 2009). The body initiates an immune response against the pathogen; however, the parasite is able to remain at undetectable levels in tissue cells for a prolonged period of time. The pathogen, T. cruzi, is also successful because it is able to incorporate host cell proteins in its cell membrane and can conceal its antigenic signal from the host’s immune system (Teixera et al, 2009). Researchers have found that there is genetic exchange between different strains of T. cruzi, which leads to recombination and new strains of the parasite (Lewis et al, 2011). This then leads to issues of drug resistance, which have already begun appearing. Trypansoma cruzi can mutate and form drug resistant clones that can cause the front-line treatment of benznidazole to fail (Campos et al, 2017). Lack of drug compliance has been a main contributor to drug resistant mutations in Chagas disease. Since Chagas disease is transmitted by vector, there are also issues of vector resistance to insecticides. There have been efforts to eliminate the triatomine bug, which is the carrier for T. cruzi. However, these efforts have not been successful in many regions because researchers found that triatomine bugs developed enhanced detoxification mechanisms that create metabolic insecticide resistance (Traverso et al, 2017). The pathogen, T. cruzi, is successful on its own, and with the increased risk of drug resistance from mutations and vector insecticide-resistance, the pathogen becomes even more dangerous and Chagas disease becomes more difficult to treat.

            Along with the success of the pathogen, environmental and socio-cultural factors also contribute tremendously to the emergence, morbidity, and mortality of Chagas disease. Urbanization, agricultural activities, and deforestation were the primary environmental factors that contributed to an increase in Chagas disease vectors in human settlements, and therefore the emergence of Chagas. Currently, the disease is more prevalent in rural, agricultural areas with poor housing conditions (Delgado et al, 2011). Researchers have found various environmental predictors of Chagas disease prevalence. In Parra-Henao et al (2016) researchers examined how different ecological systems affected the distribution of one species of triatomine bug, T. dimidiata, in Colombia, South America. Determinants of the presence of triatomine bugs include altitude, vegetation type, climate, and land use. They found that the bugs were significantly more prevalent in areas of perturbed vegetation, such as agricultural land, but also in their native habitat of high forests (Parra-Henao et al, 2016, Figure 3). Further risk factors include living in areas with warm and humid weather, living in conditions of poverty, and owning domesticated animals (Parra-Henao, 2016). Poorer living conditions are often associated with greater risk of any disease, and in South America, Chagas disease is often stigmatized because of its association with poverty. It is considered a neglected tropical disease because it primarily affects rural populations and so is overlooked by the media and health policymakers (Briceño-León & Galván, 2007). However, with increasing urbanization, Chagas has become a disease of the cities as well (Briceño-León & Galván, 2007). Also, Chagas has shifted from being simply a disease of rural South America. The migration of immigrants from endemic to non-endemic countries has contributed to Chagas spreading to areas such as the southern United States (Coura, 2013). With migrations, people who are unknowingly infected with Chagas may carry the parasite to non-endemic areas and put even more people at risk if they donate blood or organs (Briceño-León & Galván, 2007). Environmental and socio-economic factors along with migrations have contributed to the emergence and spreading of Chagas disease.

Control of Chagas disease is an important issue since there is no cure for the disease and no acquired immunity. The goal of current treatments is to kill the parasite that causes Chagas disease. Benznidazole and nifurtimox are the current front-line medications for Chagas, and are the only drugs proven effective for the acute stage of Chagas disease (CDC, 2016). They treat Chagas by eliminating the parasite from the tissue cells of the patient. However, since most people experience very mild or no symptoms during the acute stage or they little or no access to healthcare, most people are not treated in time (Beaumier, 2016). Once the disease reaches the chronic stage after a few weeks to a few months, it becomes very difficult to treat (Beaumier, 2016). There are no specific treatments for the chronic form of the disease and since the chronic form affects each individual differently, treatments vary. For instance, cardiomyopathy is a common complication of chronic Chagas and can be treated with a pacemaker or surgery (CDC, 2016). Although the current front-line drugs for acute Chagas disease are effective, they need to be taken for a long period of 30-60 days and are often associated with frequent side effects, which makes the patient drop-out rate very high (Campos et al, 2017). Early treatment cessation results in T. cruzi remaining in the body and possibly developing drug-resistant mutations. In Campos et al., (2017), researchers found a total of 26,495 single nucleotide polymorphisms across three drug resistant clones, which indicates a genome-wide accumulation of mutations (Figure 1). Since there are so few effective treatments, the possibility of drug resistance becomes a greater issue and could contribute to higher morbidity and mortality from Chagas disease. Much of the current research on Chagas involves investigating better treatment possibilities and the potential for a vaccine. Francisco et al (2016) found, using mice and experimental Trypanosoma cruzi infections, that the front-line drugs for the acute phase of Chagas disease were actually more effective in curing the chronic form of the disease. These results were surprising because medications have long been considered ineffective against the chronic form of the disease. Yet, in this study, the cure rate for chronic phase mice was higher than that for acute stage mice given benznidazole, and acute stage infections required longer treatment durations (Francisco, 2016, Figure 5). These findings indicate the possibility of effective chronic phase Chagas treatments. Further research is also being done on a potential vaccine against Chagas, but the current vaccine developments are still only being tested on mice and dogs (Quijano-Hernandez, 2011). A successful vaccine would need to induce a strong cellular immune response and activate CD8 cytotoxic T-cells to attack the parasite (Beaumier, 2016). There is potential for a preventative or therapeutic vaccine; however, there are still many questions of whether a vaccine would be truly effective or necessary (Quijano-Hernandez, 2011). There is also a concern that the vaccine could stimulate the autoimmune response Chagas causes instead of providing protection against the disease (Quijano-Hernandez, 2011). Overall, there are treatments that are successful in treating the acute phase of Chagas disease. However, since it is usually asymptomatic, and diagnosis is often overlooked or difficult to obtain, many people progress to the chronic form of the disease, which is considerably more difficult to treat. Research is still being done for better treatments and a possible vaccine.

The most common and effective control method against Chagas is prevention of the transmission of the disease through vector control. Common vector control methods include spraying of insecticides in endemic areas, along with housing improvements because triatomine bugs thrive in poorly made households (Delgado et al, 2011). Working outside puts people at the greatest risk for being bitten by triatomines, therefore, better vector control strategies need to be applied to known Chagas endemic areas (Coura, 2013). There have been vector control campaigns, but since Chagas is a neglected disease they are often not sustained or not extensive enough (Delgado et al, 2011). Researchers looked at an urbanizing rural region of Peru to investigate the history of Chagas in a peri-rural environment. They found that the area has long had high levels of T. cruzi transmission, which were shortly interrupted by an efficacious vector control campaign in 1995. However, the campaign was not sustained and high levels of T. cruzi re-emerged in the area. They also found that migrations from peri-rural areas to more urban areas contribute to the increased prevalence of Chagas disease in cities (Delgado et al, 2011). In terms of individual vector control, researchers analyzed the current vector awareness and control practices of three rural villages in Mexico and found that most people used insecticide sprays and cleaned their backyards in order to prevent triatomine bugs (Rosecrans et al, 2014, Figure 2). However, they found a lack of association of triatomine bugs with Chagas disease. Most villagers were aware of the immediate effects of a triatomine bite, such as itching and swelling, but only 8% of survey participants reported that triatomine bugs can specifically cause Chagas disease (Rosecrans et al, 2014). This indicates a clear need for education about the risks of these vectors and a need to stress the value of vector control strategies. In order for vector control to be effective, it is vital to determine the areas with the highest prevalence of triatomine bugs and to target those areas first. Cohen et al (2017) examined the abundance of four insect vectors of Chagas disease in different areas of the Gran Chaco region of Argentina before and after insecticide spraying. They investigated whether Taylor’s law, which is an ecological pattern that relates the variance of a species in a habitat to the mean species number with a power function, applied to the vectors of Chagas disease. Taylor’s law identifies areas with high average vector infestation, which allows for identification of the areas that need the most insecticide spraying and can help in vector control measures. They found that areas of high infestation variance before or after insecticide spraying were more likely to have a high likelihood of a vector outbreak (Cohen et al, 2017). Since vector control is the most effective method of preventing Chagas disease, various methods must be introduced for sustained periods of time in order for it to be effective. On a larger scale, extensive insecticide spraying for a prolonged period of time could be extremely effective in eradicating Chagas disease, but it is difficult to sustain (Delgado et al, 2011). Further research and improvements must be made to truly effectively control Chagas disease through elimination of the vector.

The future of Chagas disease depends on the control of disease transmission, elimination of diagnosis barriers, improvements in treatment, and education about the disease and its risks. Since an estimated 8 million people are infected with Chagas disease in Latin America, new research has shifted the focus from vector control and transmission prevention to improvements in treatments and treatment access. Manne et al (2013) identified potential solutions to factors that act as barriers to treatment access in Mexico. Implementing disease-specific education programs for healthcare providers and people at risk for Chagas is one of the best ways to promote treatment and educate people about the dangers of Chagas disease (Manne et al, 2013). Also, improving importation processes for Chagas medications would increase access to these drugs in Mexico and other Latin American countries (Manne et al, 2013). The future of Chagas disease treatment itself depends on the furthering of research about antitrypanosomal medications and finding better treatments for the chronic form of the disease or preventing Chagas from progressing to the chronic form by more effectively treating the acute phase (Nunes et al, 2013). There are also still many barriers to diagnosis access for people living in rural areas. Olivera et al (2018) examined possible obstacles to Chagas disease screening and diagnosis for people in Colombia. The researchers found the main barriers to be lack of physician awareness of Chagas and limited government infrastructure for Chagas diagnosis. There are also few laboratories with the capacity to perform parasitological tests to diagnose Chagas and they are not equally distributed throughout the country (Olivera et al, 2018, figure 3). Not only are there very few laboratories, but an average of six months elapse between the request of the test and the confirmation of the disease (Olivera et al, 2018). This means that by the time people are diagnosed with Chagas, it has already progressed to the chronic form and is much more difficult to treat. Reducing barriers to early diagnosis of Chagas disease is an important goal in the fight against Chagas disease. Vector control must also continue to be a top priority in the reduction of Chagas disease. There must be ongoing epidemiological surveillance of the disease and continued vector elimination efforts. With increases in migration and urbanization, countries need to be concerned with locating and treating infected migrants so that Chagas is not spread through blood transfusions to non-endemic countries (Coura, 2013). Overall, more attention must be given to Chagas disease by the media and health policymakers to promote disease control, prevent transmission, and educate people about the disease. Chagas is no longer just a disease of poor, rural South American populations and the future depends on integrated disease management through vector control, access to treatment and diagnosis, education, and further research about all aspects of Chagas disease.

 

Works Cited

 

Beaumier, Coreen M., et al. “Status of vaccine research and development of vaccines for Chagas disease.” Vaccine, vol. 34, 2016, pp. 2996-3000.

Briceño-León, Roberto, and Jorge Méndez Galván. “The social determinants of Chagas disease and the transformations of Latin America.” Memórias do Instituto Oswaldo Cruz 102 (2007): 109-112.

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Nunes, Maria Carmo Pereira, et al. “Chagas disease: an overview of clinical and epidemiological aspects.” Journal of the American College of Cardiology, vol. 62, no. 9, 2013, pp. 767-776.

Olivera, Mario et al. “Barriers to Diagnosis Access for Chagas Disease in Colombia.” Journal of Parasitology Research, 2018, pp. 1-14.

Parra-Henao, Gabriel et al. “Environmental Determinants of the Distribution of Chagas Disease Vector Triatoma dimidiata in Colombia.” The American Society of Tropical Medicine and Hygiene, vol. 94, no. 4, 2016, pp. 767-774.

Quijano-Hernandez, Israel, and Eric Dumonteil. “Advances and challenges towards a vaccine against Chagas disease.” Human vaccines, vol. 7, no. 11, 2011, 1184-1191.

Rosecrans, Kathryn, et al. “Opportunities for Improved Chagas Disease Vector Control Based on Knowledge, Attitudes and Practices of Communities in the Yucatan Peninsula, Mexico.” PLoS Neglected Tropical Diseases, vol. 8, 2014, pp. 1-10

Steverding, Dietmar. “The History of Chagas Disease.” Parasites & Vectors, vol. 7, 2014, pp. 1-8.

Traverso, Lucila et al. “Comparative and functional triatomine genomics reveals reductions and expansions in insecticide resistance-related gene families.” PLoS Neglected Tropical Diseases, vol. 11, 2017, pp. 1-25.

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