Chagas disease

Chagas' disease (also called American trypanosomiasis) is a human tropical parasitic disease which occurs in the Americas, particularly in South America. Its pathogenic agent is a flagellate protozoan named Trypanosoma cruzi, which is transmitted to humans and other mammals mostly by blood-sucking assassin bugs of the subfamily Triatominae (Family Reduviidae). Those insects are known by numerous common names varying by country, including benchuca, vinchuca, kissing bug, chipo, chupança, and barbeiro. The most common insect species belong to the genera Triatoma, Rhodnius, and Panstrongylus. However, other methods of transmission are possible, such as ingestion of food contaminated with parasites, blood transfusion and fetal transmission.

The symptoms of Chagas' disease vary over the course of the infection. In the early, acute stage symptoms are mild and are usually no more than local swelling at the site of infection. As the disease progresses, over as much as twenty years, the serious chronic symptoms appear, such as heart disease and malformation of the intestines. If untreated, the chronic disease is often fatal. Current drug treatments for this disease are generally unsatisfactory, with the available drugs being highly toxic and often ineffective, particularly in the chronic stage of the disease.

Trypanosoma cruzi is a member of the same genus as the infectious agent of African sleeping sickness and the same order as the infectious agent of leishmaniasis, but its clinical manifestations, geographical distribution, life cycle and insect vectors are quite different.

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History

The disease was named after the Brazilian physician and infectologist Carlos Chagas, who first described it in 1909^[1][2][3] but, the disease was not seen as a major public health problem in humans until the 1960s (the outbreak of Chagas' disease in Brazil in the 1920s went widely ignored^[4]). He discovered that the intestines of Triatomidae harbored a flagellate protozoan, a new species of the Trypanosoma genus, and was able to prove experimentally that it could be transmitted to marmoset monkeys that were bitten by the infected bug. Later studies showed that squirrel monkeys were also vulnerable to infection.^[5]

Chagas named the pathogenic parasite that causes the disease Trypanosoma cruzi ^[1] and later that year as Schizotrypanum cruzi,^[6] both honoring 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. Chagas’ work is unique in the history of medicine because he was the only researcher so far to describe completely a new infectious disease: its pathogen, vector, host, clinical manifestations, and epidemiology. Nevertheless, he at least believed falsely until 1925, that the main infection route is by the bite of the insect - and not by its feces, as was proposed by his colleague Emile Brumpt 1915 and assured by Silveira Dias 1932, Cardoso 1938 and Brumpt himself 1939. Chagas was also the first to unknowingly discover and illustrate the parasitic fungal genus Pneumocystis, later to infamously be linked to PCP (Pneumocystis pneumonia in AIDS victims).^[2] Confusion between the two pathogens' life-cycles led him to briefly recognize his genus Schizotrypanum, but following the description of Pneumocystis by others as an independent genus, Chagas returned to the use of the name Trypanosoma cruzi.

On another historical point of view, 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 Charles Darwin's illness). The episode was reported by Darwin in his diaries of the Voyage of the Beagle as occurring in March 1835 to the east of the Andes near Mendoza. Darwin was young and in general good health though six months previously he had been ill for a month near Valparaiso, but in 1837, almost a year after he returned to England, he began to suffer intermittently from a strange group of symptoms, becoming incapacitated for much of the rest of his life. Attempts to test Darwin's remains at the Westminster Abbey by using modern PCR techniques were met with a refusal by the Abbey's curator.^[7]

Epidemiology and geographical distribution

  Chagas' disease currently affects 16–18 million people, with some 100 million (25% of the Latin American population) at risk of acquiring the disease,^[3] killing around 50,000 people annually.^[8] Chronic Chagas' disease remains a major health problem in many Latin American countries, despite the effectiveness of hygienic and preventive measures, such as eliminating the transmitting insects, which have reduced to zero new infections in at least two countries of the region. With increased population movements, however, the possibility of transmission by blood transfusion has become more substantial in the United States.^[9] Approximately 500,000 infected people live in the USA, which is likely the result of immigration from Latin American countries.^[10] Also, T. cruzi has already been found infecting wild opossums and raccoons as far north as the state of North Carolina.^[11]

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.^[12]

The disease is almost exclusively found in rural areas, where the Triatominae can breed and feed on the natural reservoirs (the most common ones being opossums and armadillos) of T.cruzi. Depending on the special local interactions of the vectors and their hosts, other infected humans, domestic animals like cats, dogs, guinea pigs and wild animals like rodents, monkeys, ground squirrels (Spermophilus beecheyi) and many others could also serve as important parasite reservoirs. Though Triatominae bugs feed on birds, these seem to be immune against infection and therefore are not considered to be a T. cruzi reservoir; but there remain suspicions of them being a feeding resource for the vectors near human habitations.

The triatomine insects are known popularly in the different countries as vinchuca, barbeiro (the barber), chipo and other names,^[3] so called because it sucks the blood at night by biting the face of its victims. The insects, who develop a predominantly domiciliary and anthropophilic behaviour once they have infested a house,^[13] usually hide during the day in crevices and gaps in the walls and roofs of poorly constructed homes. More rarely, better constructed houses may harbor the insect vector, because of the use of rough materials for making roofs, such as bamboo and thatch. A mosquito net, wrapped under the mattress, will provide protection in these situations, when the adult insect might sail down from above, but one of the five nymphal stages (instars) could crawl up from the floor.

Even when the colonies of insects are eradicated from a house and surrounding domestic animal shelters, they can arrive again (e.g., by flying) from plants or animals that are part of the ancient, natural sylvatic infection cycle. This can happen especially in zones with mixed open savannah, clumps of trees, etc., interspersed by human habitation.

Dense vegetation, like in tropical rain forests, and urban habitats, are not ideal for the establishment of the human transmission cycle. However, in regions where the sylvatic habitat and its fauna are thinned out by economical exploitation and human habitation, such as in newly deforested, piassava palm (Leopoldinia piassaba) culture areas, and some parts of the Amazon region, this may occur, when the insects are searching for new prey.^[14]

Clinical manifestations

  The human disease occurs in two stages: the acute stage shortly after the infection, and the chronic stage that may develop over 10 years.

In the acute phase, a local skin nodule called a chagoma can appear at the site of inoculation. When the inoculation site is the conjunctival mucous membranes, the patient may develop unilateral periorbital edema, conjunctivitis, and preauricular lymphadenitis. This constellation of symptoms is referred to as Romaña's sign. The acute phase is usually asymptomatic, but may present symptoms of fever, anorexia, lymphadenopathy, mild hepatosplenomegaly, and myocarditis. Some acute cases (10 to 20%) resolve over a period of 2 to 3 months into an asymptomatic chronic stage, only to reappear after several years.

The symptomatic chronic stage may not occur for years or even decades after initial infection. The disease affects the nervous system, digestive 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. Swallowing difficulties may be the first symptom of digestive disturbances and may lead to malnutrition. After several years of an asymptomatic period, 27% of those infected develop cardiac damage, 6% develop digestive damage, and 3% present peripheral nervous involvement. Left untreated, Chagas' disease can be fatal, in most cases due to the cardiomyopathy component.

Infection cycle

An infected triatomine insect vector feeds on blood and releases trypomastigotes in its feces near the site of the bite wound. The victim, by scratching the site of the bite, causes trypomastigotes to enter the host through the wound, or through intact mucosal membranes, such as the conjunctiva. Then, inside the host, the trypomastigotes invade cells, where they differentiate into intracellular amastigotes. The amastigotes multiply by binary fission and differentiate into trypomastigotes, then are released into the circulation as bloodstream trypomastigotes. These trypomastigotes infect cells from a variety of biological tissues and transform into intracellular amastigotes in new infection sites. Clinical manifestations and cell death at the target tissues can occur because of this infective cycle. 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, 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 (unlike 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. Moreover the bugs might be able to spread the infection to each other through their cannibalistic predatory behaviour. 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,^[15] and in laboratory accidents. According to the World Health Organization, the infection rate in Latin American blood banks varies between 3% and 53%, a figure higher than of HIV infection and hepatitis B and C.^[3]

Children can also acquire Chagas' Disease while still in the womb. Chagas' disease accounts for approximately 13% of stillborn deaths in parts of Brazil. It is recommended that pregnant women be tested for the disease.^[16]

Alternative infection mechanism

Researchers suspected since 1991 that the transmission of the trypanosome by the oral route might be possible,^[17] due to a number of micro-epidemics restricted to particular times and places (such as a farm or 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 Paraíba, 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 probably infected by drinking acai palm fruit juice contaminated with crushed triatomine vector insects.^[18] In the beginning of 2005, a new outbreak with 27 cases was detected in Amapá. Despite many warnings in the press and by health authorities, this source of infection continues unabated. In August 2007 the Ministry of Health released the information that in the previous one year and half 15 clusters of Chagas infection in 116 people via ingestion of assai have been detected in the Amazon region ^[19]

In March 2005, a new startling outbreak was recorded in the state of Santa Catarina, Brazil, that seemed 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 acquired Chagas' disease.^[20] Between February 30 and March 30, 2005, 31 cases had been confirmed in Santa Catarina, including 5 deaths and 64 suspected cases.^[21] 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 around 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 rectified.

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; it can be confused with the 50% longer Trypanosoma rangeli, which has not shown any pathogenicity in humans yet.
• 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.
• Various Immunodiagnostic tests; (also trying to distinguish strains (zymodemes) of T.cruzi with divergent pathogenicities).
  • Complement fixation
  • indirect hemagglutination
  • IFA, Indirect fluorescent assay
  • RIA, Radio-immunoassay
  • ELISA, Enzyme-Linked Immunosorbent Assay
• Diagnosis based on Molecular Biology techniques.
  • PCR, Polymerase chain reaction, most promising

Prognosis

An index for classification of patients who have Chagas' disease was published in the August 24, 2006 edition of the New England Journal of Medicine.^[22] Based on over 500 patients, this index includes clinical aspects, X-ray findings, EKG, echocardiography and Holter.

Treatment

Medication for Chagas' disease is usually only effective when given during the acute stage of infection. The drugs of choice are azole or nitroderivatives such as benznidazole^[23] or nifurtimox (under an Investigational New Drug protocol from the CDC Drug Service), but resistance to these drugs has already been reported.^[24] Furthermore, these agents are very toxic and have many adverse effects, and cannot be taken without medical supervision. The antifungal agent Amphotericin B has been proposed as a second-line drug, but cost and this drug's relatively high toxicity have limited its use. Moreover, 10-year study of chronic administration of drugs in Brazil has revealed that current chemotherapy does not totally remove parasitemia.^[25] Thus, the decision about whether to use antiparasitic therapy should be individualized in consultation with an expert.

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 caused by Chagas' disease is now a common reason for heart transplantation surgery. Until recently, however, Chagas' disease was considered a contraindication for the procedure, since the heart damage could recur as the parasite was expected to seize the opportunity provided by the immunosuppression that follows surgery. The research that changed the indication of the transplant procedure for Chagas' disease patients was conducted by Dr. Adib Jatene's group at the Heart Institute of the University of São Paulo, in São Paulo, Brazil.^[26] The research noted that survival rates in Chagas' patients can be significantly improved by using lower dosages of the immunosuppressant drug cyclosporin. Recently, direct stem cell therapy of the heart muscle using bone marrow cell transplantation has been shown to dramatically reduce risks of heart failure in Chagas patients.^[27] Patients have also been shown to benefit from the strict prevention of reinfection, though the reason for this is not yet clearly understood.

Some examples for the struggle for advances:

• Use of oxidosqualene cyclase inhibitors and cysteine protease inhibitors has been found to cure experimental infections in animals.^[28]
• Dermaseptins from frog species Phyllomedusa oreades and P. distincta. Anti-Trypanosoma cruzi activity without cytotoxicity to mammalian cells.^[29]
• Design of inhibitors to enzymes involved in trypanothione metabolism, which is unique to the kinetoplastid group of parasites.^[30]
• The sesquiterpene lactone dehydroleucodine (DhL) affects the growth of cultured epimastigotes of Trypanosoma cruzi^[31]
• The genome of Trypanosoma cruzi has been sequenced.^[32] Proteins that are produced by the disease but not by humans have been identified as possible drug targets to defeat the disease.^[33]

In November, 2007, the Olive View-UCLA Medical Center in Sylmar in the San Fernando Valley area of Los Angeles county, California has opened the first clinic in the nation that studies and treats Chagas disease gratis for LA county residents^[34][35].

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 sprays and paints containing insecticides (synthetic pyrethroids), 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 of blood donors is already mandatory, since this can be an important route of transmission. The United States FDA has recently licensed a test for antibodies against T. cruzi for use on blood donors but has not yet mandated its use. The AABB recommends that past recipients of blood components from donors found to be infected be notified and themselves tested. In the past, donated blood was mixed with 0,25 g/L of gentian violet successfully to kill the parasites.

With all these measures, some landmarks were achieved in the fight against Chagas' disease in Latin America: a reduction by 72% of the incidence of human infection in children and young adults in the countries of the Initiative of the Southern Cone, and at least two countries (Uruguay, in 1997, and Chile, in 1999), were certified free of vectorial and transfusional transmission. In Brazil, with the largest population at risk, 10 out of the 12 endemic states were also certified free.

Some stepstones of vector control:

• A yeast trap has been tested for monitoring infestations of certain species of the bugs:"Performance of yeast-baited traps with Triatoma sordida, Triatoma brasiliensis, Triatoma pseudomaculata, and Panstrongylus megistus in laboratory assays."^[36]
• Promising results were gained with the treatment of vector habitats with the fungus Beauveria bassiana, (which is also in discussion for malaria- prevention):"Activity of oil-formulated Beauveria bassiana against Triatoma sordida in peridomestic areas in Central Brazil."^[37]
• Targeting the symbionts of Triatominae through paratransgenesis.^[38]

See also

• Tropical disease
• Drugs for Neglected Diseases Initiative
• Distinguish from: Chaga mushroom

Notes

References

• CDC, Division of Parasitic Diseases. Chagas Disease Fact Sheet. (23 September 2004). Accessed 24 September 2006.
• Dumonteil E, Escobedo-Ortegon J, Reyes-Rodriguez N, Arjona-Torres A, Ramirez-Sierra M (2004). "Immunotherapy of Trypanosoma cruzi infection with DNA vaccines in mice.". Infect Immun 72 (1): 46–53. PMID 14688079.

Further reading

Recent news and events

• Chagas' disease parasite found in desert blood samples
• Chagas Control in the Southern Cone Countries: History of an International Initiative, 1991/2001, PAHO. (Full text e-book)
• Genome Sequencing Project
• Parasites' genetic code 'cracked' From BBC
• Catholic Relief Services. Housing Improvement and Chagas' Disease Prevention Project
• 2006: Nature.com / Scott M. Landfear: Flagella are whip-like structures that power the movement of certain cells. Analysis of a single-cell parasite, the African trypanosome, reveals that flagella are also essential for viability in this organism. (restricted commercial access now)
• Science Magazine Search Results: Chagas