Chagas disease

Chagas disease (also called American trypanosomiasis) is a mammalian disease occurring only in the Americas. It is caused by the protozoan Trypanosoma cruzi, one of the kinetoplastid flagellates, transmitted to humans in most cases by insects of the subfamily Triatominae (Family Reduviidae) known in the different countries as assassin bug, vinchuca, kissing bug, chipo, barbeiro, etc. Common triatomine vector species for trypanosomiasis belong to the genera Triatoma, Rhodnius, and Panstrongylus. The most common transmitting species are Triatoma protracta and Triatoma infestans.

The disease causing agent is (closely but genetically distant) related to that of African sleeping sickness, although the assassin bug vector is not related to the tsetse fly, which carries African sleeping sickness.

Photomicrograph of Giemsa-stained Trypanosoma cruzi crithidia. Source: CDC

History

The disease was named after the Brazilian physician Carlos Chagas, who first described it in 1909 but the disease was not seen as a major problem in humans until the 1960s. Chagas named the pathogen after Oswaldo Cruz, the noted Brazilian physician and epidemiologist who fought successfully epidemics of yellow fever, smallpox and bubonic plague in Rio de Janeiro and other cities in the beginning of the 20th century.

It has been hypothesized that Charles Darwin might have suffered from this disease as a result of a bite of the so-called Great Black Bug of the Pampas (vinchuca) (see Illness of Charles Darwin). The episode was reported by Darwin in his diaries of the Beagle voyage. Darwin, who was young and in good health until he returned to London, soon afterward began to suffer from strange symptoms. Unsuccessful attempts were made to test Darwin's remains at the Westminster Abbey by using modern PCR techniques, but were met with a refusal by the curator.

Epidemiology and geographical distribution

Chagas disease currently affects 16-18 million people, killing around 20,000 annually and with some 100 million at risk of acquiring the disease. Chronic Chagas disease is a major health problem in many Latin American countries. With increased population movements, the possibility of transmission by blood transfusion has become more substantial in the United States [1] (http://content.nejm.org/cgi/content/extract/329/9/639).

The disease is distributed in the Americas, ranging from the southern United States to southern Argentina, mostly in poor, rural areas of Central and South America.

The disease is almost totally prevalent in the rural area, where the Triatominae can breed and feed on the natural reservoirs (the most common ones being opossums and armadillos). Poor housing, with mud walls and straw roofs offer many hiding places for the insect vector, which can then bite humans at night. As so depending on the local interactions of the vectors, also humans, cats ,dogs, rodents, monkeys, ground squirrels (Spermophilus beecheyi) and many other animals could serve as an important parasite reservoir. Also, T. cruzi has already been found infecting wild opossums and racoons as far as North Carolina [2] (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1597808).

At least some species of reduviidae are also able to fly short distances and can therefore easily invade open houses even in areas where they have not yet developed a predominant domestic behaviour. This may happen like in the amazon region, when the sylvatic habitat and its fauna is thinned of.

Clinical manifestations

The human disease occurs in two stages: the acute stage shortly after the infection. A local lesion (so called chagoma (see picture), palpebral edema) can appear at the site of inoculation. The acute phase is usually asymptomatic, but can present with manifestations that include fever, anorexia, lymphadenopathy, mild hepatosplenomegaly, and myocarditis. Most acute cases (10 to 20%) resolve over a period of 2 to 3 months into an asymptomatic chronic stage, which appears after several years.

The symptomatic chronic stage may not occur for years or even decades after initial infection. The disease affects the nervous system and heart. Chronic infections result in various neurological disorders, including dementia, damage to the heart muscle (cardiomyopathy, the most serious manifestation), and sometimes dilation of the digestive tract (megacolon and megaesophagus), as well as weight loss. Left untreated, Chagas disease can be fatal, in most cases due to the cardiomyopathy component.

Infection cycle

An infected triatomine insect vector takes a blood meal and releases trypomastigotes in its feces near the site of the bite wound. By scratching the site of the bite, the victim allows trypomastigotes to enter the host through the wound, or through intact mucosal membranes, such as the conjunctiva. Inside the host, the trypomastigotes invade cells, where they differentiate into intracellular amastigotes. The amastigotes multiply by binary fission and differentiate into trypomastigotes, and then are released into the circulation as bloodstream trypomastigotes. Trypomastigotes infect cells from a variety of biological tissues and transform into intracellular amastigotes in new infection sites. Clinical manifestations can result from this infective cycle and cell death at the target tissues. For example, it has been shown by Austrian-Brazilian pathologist Dr. Fritz Köberle in the 1950s at the Medical School of the University of São Paulo at Ribeirão Preto, Brazil (one of the excellence medical research centers on Chagas disease), that intracellular amastigotes destroy the intramural neurons of the autonomic nervous system in the intestine and heart, leading to megaintestine and heart aneurysms, respectively.

The bloodstream trypomastigotes do not replicate (different from the African trypanosomes). Replication resumes only when the parasites enter another cell or are ingested by another vector. The “kissing” bug becomes infected by feeding on human or animal blood that contains circulating parasites. The ingested trypomastigotes transform into epimastigotes in the vector’s midgut . The parasites multiply and differentiate in the midgut and differentiate into infective metacyclic trypomastigotes in the hindgut .

Trypanosoma cruzi can also be transmitted through blood transfusions, organ transplantation, transplacentally, breast milk [3] (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12751321&query_hl=1) and in laboratory accidents.

Alternative infection mechanism

Researchers suspected since 1991 [4] (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1844961&dopt=Citation) that the transmission of the trypanosome by the oral route might be possible, due to a number of micro-epidemics involving a single restricted times and places (such as a farm of a family dwelling), particularly in non-endemic areas such as the Amazonia (17 such episodes recorded between 1968 and 1997). In 1991, farm workers in the state of Paraiba, Brazil, were apparently infected by contamination of food with opossum feces; and in 1997, in Macapá, state of Amapá, 17 members of two families were infected by drinking assai palm fruit juice probably contaminated with crushed triatomine vector insects[5] (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10677763&dopt=Citation). In the beginning of 2005, a new outbreak with 27 cases was detected in Amapá.

Recently (March 2005) a new startling outbreak was recorded in the state of Santa Catarina, Brazil, that seems to confirm this alternative mechanism of transmission. Several people in Santa Catarina who had ingested sugar cane juice ("garapa", in Portuguese) by a roadside kiosk have acquired Chagas disease [6] (http://aol.countrywatch.com/aol_wire.asp?vCOUNTRY=183&UID=1442449). Until March 30th, 2005, 49 cases had been confirmed in Santa Catarina, with 6 deaths. The hypothesized mechanism, so far, is that trypanosome-bearing insects were crushed into the raw preparation. The health authorities of Santa Catarina have estimated that ca. 60,000 people might have had contact with the contaminated food in Santa Catarina and urged everyone in this situation to submit to blood tests. They have prohibited the sale of sugar cane juice in the state until the situation is clarified.

The unusual severity of the disease outbreak has been blamed on a hypothetical higher parasite load achieved by the oral route of infection. Brazilian researchers at the Instituto Oswaldo Cruz, Rio de Janeiro, were able to infect mice via a gastrointestinal tube with trypanosome-infected oral preparations.

Laboratory diagnosis

Demonstration of the causal agent is the diagnostic procedure in acute Chagas disease. It almost always yields positive results, and can be achieved by:

• Microscopic examination: a) of fresh anticoagulated blood, or its buffy coat, for motile parasites; and b) of thin and thick blood smears stained with Giemsa, for visualization of parasites.
• Isolation of the agent by: a) inoculation into mice; b) culture in specialized media (e.g. NNN, LIT); and c) xenodiagnosis, where uninfected reduviidae bugs are fed on the patient's blood, and their gut contents examined for parasites 4 weeks later.

Treatment

Medication for Chagas disease is usually effective when given during the acute stage of infection, only. The drugs of choice are azole or nitroderivatives such as benznidazole [7] (http://aac.asm.org/cgi/content/abstract/49/4/1521) or nifurtimox (under an Investigational New Drug protocol from the CDC Drug Service), but resistance to these drugs has already been reported [8] (http://aac.asm.org/cgi/content/abstract/42/12/3245). Furthermore, these agents are very toxic and have many adverse effects, and cannot be taken without medical supervision. A 10-year study of chronic administration of drugs in Brazil has revealed that these drugs are not totally effective, too, in removing parasitemia [9] (http://scholar.google.com/url?sa=U&q=http://www.ajtmh.org/cgi/reprint/63/3/111.pdf). Thus, the decision about whether to use antiparasitic therapy should be individualized in consultation with an expert.

Use of oxidosqualene cyclase inhibitors and cysteine protease inhibitors has been found to cure experimental infections in animals [10] (http://www.jem.org/cgi/content/abstract/188/4/725).

In the chronic stage, treatment involves managing the clinical manifestations of the disease, e.g., drugs and heart pacemaker for chronic heart failure and heart arryhthmias; surgery for megaintestine, etc., but the disease per se is not curable in this phase. Chronic heart disease is now a common cause for heart transplantation surgery and was first developed by Dr. Adib Jatene's group at the Heart Institute of the University of São Paulo, in São Paulo, Brazil [11] (http://ats.ctsnetjournals.org/cgi/content/abstract/61/6/1727). Recently, direct stem cell therapy of the heart muscle using bone marrow cell transplantation has been shown to improve dramatically heart failure in Chagas patients [12] (http://publicacoes.cardiol.br/abc/2004/8202/8202010i.pdf).

Prevention

A reasonably effective vaccine was developed in Ribeirão Preto in the 1970s, using cellular and subcellular fractions of the parasite, but it was found economically unfeasible. More recently, the potential of DNA vaccines for immunotherapy of acute and chronic Chagas disease is being tested by several research groups.

Prevention is centered on fighting the vector (Triatoma) by using insecticides sprays and paints, and improving housing and sanitary conditions in the rural area. For urban dwellers, spending vacations and camping out in the wilderness or sleeping at hostels or mud houses in endemic areas can be dangerous, a mosquito net is recommended. If the traveller intends to travel to the area of prevalence, he/she should get information on endemic rural areas for Chagas disease in traveller advisories, such as the CDC.

In most countries where Chagas disease is endemic, testing for blood donors is already mandatory, since this can be an important route of transmission.

Bibliography

• Adler D. Darwin's illness. Isr J Med Sci. 1989 Apr;25(4):218-21. (Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2496051))
• Kirchhoff, LV. American Trypanosomiasis (Chagas' Disease) -- A Tropical Disease Now in the United States. N Engl J Med. 329 (9):639-644, August 26, 1993 (Abstract (http://content.nejm.org/cgi/content/extract/329/9/639))
• Garcia, S., Ramos, C. O., Senra, J. F. V., Vilas-Boas, F., Rodrigues, M. M., Campos-de-Carvalho, A. C., Ribeiro-dos-Santos, R., Soares, M. B. P. (2005). Treatment with Benznidazole during the Chronic Phase of Experimental Chagas' Disease Decreases Cardiac Alterations. Antimicrob. Agents Chemother. 49: 1521-1528 (Abstract (http://aac.asm.org/cgi/content/abstract/49/4/1521))
• Buckner, F. S., Wilson, A. J., White, T. C., Van Voorhis, W. C. (1998). Induction of Resistance to Azole Drugs in Trypanosoma cruzi. Antimicrob. Agents Chemother. 42: 3245-3250 (Abstract (http://aac.asm.org/cgi/content/abstract/42/12/3245))
• Engel, J. C., Doyle, P. S., Hsieh, I., McKerrow, J. H. (1998). Cysteine Protease Inhibitors Cure an Experimental Trypanosoma cruzi Infection. J. Exp. Med. 188: 725-734 (Abstract (http://www.jem.org/cgi/content/abstract/188/4/725))
• Bocchi, E. A., Bellotti, G., Mocelin, A. O., Uip, D., Bacal, F., Higuchi, M. L., Amato-Neto, V., Fiorelli, A., Stolf, N. A. G., Jatene, A. D., Pileggi, F. (1996). Heart Transplantation for Chronic Chagas' Heart Disease. Ann. Thorac. Surg. 61: 1727-1733 (Abstract (http://ats.ctsnetjournals.org/cgi/content/abstract/61/6/1727))
• Dumonteil E, Escobedo-Ortegon J, Reyes-Rodriguez N, Arjona-Torres A, Ramirez-Sierra MJ. Immunotherapy of Trypanosoma cruzi infection with DNA vaccines in mice. Infect Immun. 2004 Jan;72(1):46-53. (Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14688079))
• Vilas-Boas F., Feitosa G.S., Soares M. B. P., Pinho Filho J.A., Almeida A., Mota A., Carvalho H. G., Oliveira A. D. D. Ribeiro-dos-Santos R. Bone marrow cell transplantation to the myocardium of a patient with heart failure due to Chagas cardiomyopathy. A case report. Arquivos Brasileiros de Cardiologia, 82(2):185-7, 2004. (Full text (http://publicacoes.cardiol.br/abc/2004/8202/8202010i.pdf))
• Valente SAS, Valente VC, Fraiha-Neto H. Considerations on the epidemiology and transmission of Chagas disease in the Brazilian amazon. Mem. Inst. Oswaldo Cruz, Sept. 1999, vol.94 suppl.1, p.395-398. (Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10677763&dopt=Citation))
• Shikanai-Yasuda MA, Marcondes CB, Guedes LA, Siqueira GS, Barone AA, Dias JC, Amato Neto V, Tolezano JE, Peres BA, Arruda Junior ER, et al. Possible oral transmission of acute Chagas' disease in Brazil. Rev Inst Med Trop Sao Paulo. 1991 Sep-Oct;33(5):351-7. (Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1844961&dopt=Citation))

Sources

• American Trypanosomyasis (http://www.dpd.cdc.gov/dpdx/HTML/TrypanosomiasisAmerican.htm). CDC Disease Information (US Federal Government public domain).
• Genome Sequencing Project: http://cruzi.unsam.edu.ar/de:Chagas

es:Enfermedad de Chagas fr:Trypanosomiase pt:Doença de Chagas