What is Chagas Disease?
Chagas disease, also called American trypanosomiasis, is a parasitic disease that is transmitted by infected reduviid bugs (also called triatomine, assassin, or kissing bugs). Humans contract the disease when the infected feces of the insect vector enter the body, typically by scratching the insect bite. Although Chagas disease first causes an acute infection, the majority of mortality and morbidity caused by Chagas are the result of organ damage from chronic infection.
Countries endemic for Chagas disease
Chagas disease is found primarily in Latin America. It is endemic in 21 countries with estimates of the at risk population ranging from 25-90 million.1,2 However, the increasing movement of populations from Latin and South America to North America and Europe has also raised the prevalence of Chagas disease in other regions of the world. It is estimated that 10 million people are currently infected worldwide, including 300,000 people residing in the United States. Each year there are approximately 109,000 new infections and 11,000 deaths resulting from Chagas disease.
|Prevalence (% total population)
||DALYs (in thousands)4
The economic burden of Chagas disease in Latin America is significant. In Brazil alone, worker absenteeism as the result of Chagas disease is estimated to result in US$5.2 million in losses per year and contributes to an estimated total productivity loss of US$1.2 billion per year in the seven southernmost South American countries.1
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Causative Agent and Transmission
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. Transmission of T. cruzi occurs in four ways:
- Natural transmission by reduviid bugs
- Transmission of the circulating parasite by blood transfusion or intracellular amastigotes by organ transplant
- Vertical or congenital transmission from mother to child
- Ingestion of food or liquid contaminated with T. cruzi parasites
Triatomine bugs often infest rural,
substandard housing (photo: CDC/WHO)
Chagas disease is transmitted to humans in the feces of infected reduviid bugs of the subfamily Triatominae. Reduviid bugs become infected with T. cruzi by ingesting trypomastigotes while taking a blood meal from infected people or animals. After taking a blood meal, an infected insect vector defecates. When the bite victim scratches the bite, metacyclic trypomastigotes of T. cruzi found in the insect feces gain access to the patient’s blood. Human transmission is primarily attributed to three reduviid species: Triatoma infestans, Rhodnius prolixus, and Triatoma dimidiate. Reduviid bugs also transmit T. cruzi to more than 150 species of animals creating an immense animal reservoir of disease.
Transmission of Chagas disease via blood transfusion is the greatest concern for non-endemic countries. Although the risk of infection from a blood transfusion is only 10-20% for a person transfused with blood from an infected donor, a lack of routine blood screening and poor awareness of Chagas disease in the medical community outside of endemic countries may delay diagnosis.
T. cruzi life cycle.
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The risk of transmission of Chagas disease from mother to child is relatively low; vertical transmission is estimated to occur in 1-5% of pregnancies in chronically infected women.3
Transmission by ingestion is rare but can occur by eating unwashed or uncooked foods and juices or in research laboratories that study live parasites.
When a patient becomes infected via the natural insect vector, infection begins with local inflammation, creating a hard, reddened, raised lesion known as a chagoma. A chagoma around the eye is known as “Romaña’s sign,” one of the best characterized signs of initial Chagas infection.
The first or acute phase of disease occurs 4 days to 2 weeks after infection. In adults, the majority of acute infections are asymptomatic. Symptoms are most severe in young children and infants and are generally non-specific, including chills, fever, muscle aches, exhaustion, and enlarged lymph nodes.
During the chronic phase of the disease, the trypomastigote form of the parasite transmitted by the insect vector can invade macrophages and transform into the amastigote or intracellular form. Amastigotes replicate asexually inside the cell to produce new trypomastigotes. The new trypomastigotes rupture the host cell and enter the blood stream. The circulating trypomastigotes go on to invade other cells in various parts of the body. The repeated rupture of newly replicated trypomastigotes from host cells in combination with chronic immune and inflammatory responses to the parasites leads to the slow accumulation of organ damage during the chronic phase of Chagas disease. Approximately 30-40% of chronically infected patients will develop clinical disease. The most common presentations are heart damage, megaesophagus, or megacolon.
Current Control Strategy
Control of Chagas disease is complex. There is no vaccine available for prevention of disease and, although acute infections can be treated, the lack of symptoms during the acute phase leads to delayed or missed diagnosis. Furthermore, the large animal reservoir of Chagas disease threatens to re-introduce disease in regions where control in humans has been achieved.
Control of Chagas disease therefore focuses on two activities:
- Reduction in transmission through vector control and blood screening
- Identification and treatment of acute disease with currently available medications
The primary focus of Chagas disease control efforts is on reducing transmission through vector control and blood supply monitoring. The majority of natural T. cruzi transmission occurs in households at night. Reduviid bugs live in the walls of poorly constructed housing and tend to bite household residents while they sleep. Through a combination of insecticide spraying, use of bednets, and improvements in housing construction, a significant reduction in domestic transmission of Chagas disease has been achieved in the Southern Cone (Argentina, Brazil, Chile, Paraguay, the Plurinational State of Bolivia, and Uruguay). Uraguay, Chile, and Brazil were reported to have stopped transmission via the main domiciliary vector species T. infestans in 1997, 1999, and 2006, respectively.3 Screening of blood donations is also increasing throughout Latin America. These efforts helped reduce the incidence of new Chagas infections from 700,000 infection per year in 1990 to 41,200 per year in 2006.3
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The standard treatment for acute Chagas disease is nifurtimox (60-90 day course) or benznidazole (preferred treatment; 60 day course). Both medications are expensive, have high risks of side effects, and cannot be used in pregnant women or people with renal or hepatic insufficiency. There is currently no approved treatment for chronic Chagas disease. A pediatric formulation of benznidazole was approved in Brazil in December 2011.
There are currently no vaccines in use for Chagas disease.
Diagnosis of Chagas disease most commonly involves visualization of parasites in blood samples by microscopy. However, the number of circulating parasites can be extremely low, especially in adults and in patients with chronic disease.
The more definitive diagnosis and current gold standard for diagnosis is a method of xenodiagnoses that involves allowing a laboratory-reared reduviid bug to bite the person with suspected infection. The reduviid bug is then dissected to look for the presence of parasites.
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- WHO (2010) First WHO report on neglected tropical diseases 2010: working to overcome the global impact of neglected tropical diseases.
- Hotez PJ et al. (2008) “The neglected tropical diseases of Latin America and the Caribbean: a review of the disease burden and distribution and a roadmap for control and elimination.” PLoS Neglected Tropical Diseases 2: e300.
- Rassi A et al. (2010) “Chagas disease.” The Lancet 375: 1388-1402.
- WHO (2002) Global Burden of Disease.
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There is a great need for new treatments for Chagas disease to replace the long treatment regimens and toxic side effects of current drugs.1,2 The latest stage product is a new evaluation of an on market drug, benznidazole, for chronic disease. This large scale trial, known as the BENEFIT trial, is underway to evaluate the effects of benznidazole on the progression of cardiac symptoms in patients with chronic disease.
The other products in clinical development for Chagas disease with known mechanisms of actioninclude inhibitors of an enzyme called CYP51 that is involved in lipid biosynthesis and a cysteine protease inhibitor. The most advanced CYP51 inhibitor, posaconazole, is currently on market for the treatment of fungal infections and is being repurposed by Merck for the treatment of Chagas disease in a phase II trial.
|Benznidazole (DNA damage)
|Most advanced program: Benznidazole, on market (Treatment of chronic infection, Phase III)
||Already on market and in use for treatment of acute disease
||60 day course of treatment
Toxic side effects
Cannot be used in pregnant women or people with renal or hepatic insufficiency
Drug resistance exists
|Anecdotal clinical evidence treatment will have a positive effect on cardiac outcomes in chronic infection
||Lack of diagnostics to measure effect on parasitemia in chronic disease
Cardiac endpoints have not been validated for chronic disease
|Most advanced program: Posaconazole and E1224, Phase II (Additional products in phase I)
||Inhibitors of this enzyme class are on market and in use as antifungals
Anecdotal evidence of efficacy in Chagas
|No clinical efficacy data is available yet
Combination with therapy with benznidazole
|Lack of diagnostics to measure effect on parasitemia in chronic disease makes it difficult to determine efficacy
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A preventative vaccine for Chagas disease is considered unlikely. Instead, a more concerted effort has been made by the scientific community to develop therapeutic vaccines that help boost the body’s immune response to fight chronic infection.
Currently there is one therapeutic vaccine under development to prevent the onset of Chagastic cardiomyopahty in patients with indeterminate Chagas disease or in patients with early-stage evidence of Chagas disease.
There is currently no diagnostic test available to evaluate the effects of drugs or vaccines on chronic Chagas disease. In chronic disease, parasitemia is generally too low to evaluate the infection by microscopy, and immune-based assays cannot distinguish between new and old infections due to the persistence of antibodies. A diagnostic that can accurately detect chronic infection as well as clearance of chronic infections will be essential before new treatments or therapeutic vaccines for chronic disease can be brought to market.
- Riberio I et al. (2009) “New, improved treatments for Chagas disease: from the R&D pipeline to the patients.” PLoS Neglected Tropical Diseases 3: e484.
- Clayton J (2010) “Chagas disease: pushing through the pipeline.” Nature 465: S4-S5.
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