Chagas disease

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Chagas disease
Classifications and external resources
Photomicrograph of Giemsa-stained Trypanosoma cruzi crithidia (CDC)
ICD-10 B57
ICD-9 086
MedlinePlus 001372
eMedicine med/327 

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 hematophagous 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 and barbeiro. The most common insect species belong to the genera Triatoma, Rhodnius, and Panstrongylus. Other forms of transmission are possible, though, such as ingestion of food contaminated with parasites, blood transfusion and fetal transmission.

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

Contents

[edit] History

The disease was named after the Brazilian physician and infectologist Carlos Chagas, who first described it in 1909,[1][2] but the disease was not seen as a major public health problem in humans until the 1960s. 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.

Chagas named the pathogenic parasite that causes the disease Schizotrypanum cruzi (later renamed to Trypanosoma cruzi), 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. 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.

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.[3]

[edit] Epidemiology and geographical distribution

Chagas in Latin America (A:Endemic zones)
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Chagas in Latin America (A:Endemic zones)

Chagas disease currently affects 16-18 million people, with some 100 million (25% of the Latin American population) at risk of acquiring the disease,[2] killing around 50,000 people annually.[4] 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.[5] Also, T. cruzi has already been found infecting wild opossums and raccoons as far north as the state of North Carolina.[6]

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.[7]

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,[2] 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,[8] 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 areas of the Amazon region, this may occur, when the insects are searching for new prey.[9]

[edit] Clinical manifestations

This child from Panama is suffering from Chagas disease manifested as an acute infection with swelling of the right eye (Romaña's sign). Source: CDC.
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This child from Panama is suffering from Chagas disease manifested as an acute infection with swelling of the right eye (Romaña's sign). Source: CDC.

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.

[edit] 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[10] and in laboratory accidents. According to the World Health Organization infection rate in blood banks in Latin America vary between 3% and 53%, a figure higher than of HIV infection and hepatitis B and C.[2] Life cycle of Trypanosima cruzi. Source: CDC

[edit] Alternative infection mechanism

Researchers suspected since 1991 that the transmission of the trypanosome by the oral route might be possible,[11] 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 infected by drinking assai palm fruit juice probably contaminated with crushed triatomine vector insects.[12] In the beginning of 2005, a new outbreak with 27 cases was detected in Amapá.

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.[13] As of March 30, 2005, 49 cases had been confirmed in Santa Catarina, including 6 deaths.[citation needed] 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 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.

[edit] 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).
  • Diagnosis based on Molecular Biology techniques.
    • PCR, Polymerase chain reaction, most promising

[edit] 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.[14] Based on over 500 patients, this index includes clinical aspects, X-ray findings, EKG, echocardiography and Holter.

Chagas risk factors
Risk factor points
NYHA class III or IV 5
Cardiomegaly 5
Wall motion abnormalities 3
non-sustained ventricular tachycardia 3
low voltage on ECG 2
male sex 2
Total points Risk of death in 10 years
0-6 10%
7-11 40%
12-20 85%

[edit] 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[15] or nifurtimox (under an Investigational New Drug protocol from the CDC Drug Service), but resistance to these drugs has already been reported.[16] 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.[17] 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 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.[18] 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.[19] 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.[20]
  • Dermaseptins from frog species Phyllomedusa oreades and P. distincta. Anti-Trypanosoma cruzi activity without cytotoxicity to mammalian cells.[21]
  • Design of inhibitors to enzymes involved in trypanothione metabolism, which is unique to the kinetoplastid group of parasites.[22]
  • The sesquiterpene lactone dehydroleucodine (DhL) affects the growth of cultured epimastigotes of Trypanosoma cruzi[23]
  • The genome of Trypanosoma cruzi has been sequenced.[24] Proteins that are produced by the disease but not by humans have been identified as possible drug targets to defeat the disease.[25]

[edit] Prevention

Vector insect Triatoma infestans (Kissing Bug)
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Vector insect Triatoma infestans (Kissing Bug)

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. In the past, donated blood was mixed with 0,25 g/L of gentian violet successfully to kill 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."[26]
  • 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."[27]
  • Targeting the symbionts of Triatominae[28]

[edit] See also

[edit] Notes

  1. ^ Chagas, C. Nova trypanozomíaze humana. Estudos sobre a morfologia e cíclo evolutivo do Schizotripanum cruzi n. gen. n. sp., agente etiològico de nova entidade mórbida do homem. Mem Inst Oswaldo Cruz, 1909, 1 (2): 159-218 (New human trypanosomiasis. Studies about the morphology and evolutive cycle of Schizotripanum cruzi, etiological agent of a new morbid entity of man).
  2. ^ a b c d WHO. Chagas. Accessed 24 September 2006.
  3. ^ Adler D (1989). "Darwin's Illness". Isr J Med Sci 25 (4): 218-21. PMID 2496051.
  4. ^ Carlier, Yves. Chagas Disease (American Trypanosomiasis). eMedicine (27 February 2003).
  5. ^ Kirchhoff LV. "American trypanosomiasis (Chagas disease)--a tropical disease now in the United States." N Engl J Med. 1993 Aug 26;329(9):639-44. PMID 8341339 Online.
  6. ^ Karsten V, Davis C, Kuhn R. "Trypanosoma cruzi in wild raccoons and opossums in North Carolina." J Parasitol. 1992 Jun;78(3):547-9. PMID 1597808
  7. ^ Centers for Disease Control (CDC). American Trypanosomyasis Fact Sheet. Accessed 24 September 2006.
  8. ^ Grijalva MJ, Palomeque-Rodriguez FS, Costales JA, et al. "High household infestation rates by synanthropic vectors of Chagas disease in southern Ecuador." J Med Entomol. 2005 Jan;42(1):68-74. PMID 15691011
  9. ^ Teixeira AR, Monteiro PS, Rebelo JM, et al. "Emerging Chagas Disease: Trophic Network and Cycle of Transmission of Trypanosoma cruzi from Palm Trees in the Amazon." Emerg Infect Dis. 2001 Jan-Feb;7(1):100-12. PMID 11266300. PDF full text.
  10. ^ Santos Ferreira C, Amato Neto V, Gakiya E, et al. "Microwave treatment of human milk to prevent transmission of Chagas disease." Rev Inst Med Trop São Paulo. 2003 Jan-Feb;45(1):41-2. PMID 12751321
  11. ^ Shikanai-Yasuda MA, Marcondes CB, Guedes LA, et al. "Possible oral transmission of acute Chagas disease in Brazil." Rev Inst Med Trop São Paulo. 1991 Sep-Oct;33(5):351-7. PMID 1844961
  12. ^ da Silva Valente S, de Costa Valente V, Neto H. "Considerations on the epidemiology and transmission of Chagas disease in the Brazilian Amazon." Mem Inst Oswaldo Cruz 94 Suppl 1: 395-8. PMID 10677763
  13. ^ UK Health Protection Agency (HPA).Chagas’ disease (American trypanosomiasis) in southern Brazil. Accessed 24 September 2006.
  14. ^ Rassi A Jr, Rassi A, Little W, Xavier S, Rassi S, Rassi A, Rassi G, Hasslocher-Moreno A, Sousa A, Scanavacca M (2006). "Development and validation of a risk score for predicting death in Chagas' heart disease". N Engl J Med 355 (8): 799–808. PMID 16928995.
  15. ^ Garcia S, Ramos CO, Senra JF, et al. "Treatment with benznidazole during the chronic phase of experimental Chagas disease decreases cardiac alterations." Antimicrob Agents Chemother. 2005 Apr;49(4):1521-8. PMID 15793134 Online
  16. ^ Buckner FS, Wilson AJ, White TC, Van Voorhis WC. "Induction of resistance to azole drugs in Trypanosoma cruzi." Antimicrob Agents Chemother. 1998 Dec;42(12):3245-50. PMID 9835521 Online
  17. ^ Lauria-Pires L, Braga MS, Vexenat AC, et al. "Progressive chronic Chagas heart disease ten years after treatment with anti-Trypanosoma cruzi nitroderivatives." Am J Trop Med Hyg. 2000 Sep-Oct;63(3-4):111-8. PMID 11388500 PDF Full text
  18. ^ Bocchi EA, Bellotti G, Mocelin AO, Uip D, et al. "Heart transplantation for chronic Chagas' heart disease." Ann Thorac Surg. 1996 Jun;61(6):1727-33. PMID 8651775Online
  19. ^ Vilas-Boas F, Feitosa GS, Soares MB, Mota A, et al. "[Early results of bone marrow cell transplantation to the myocardium of patients with heart failure due to Chagas disease]." Arq Bras Cardiol. 2006 Aug;87(2):159-66. PMID 16951834 PDF Full text. Also available here.
  20. ^ Engel JC, Doyle PS, Hsieh I, McKerrow JH. "Cysteine protease inhibitors cure an experimental Trypanosoma cruzi infection." J Exp Med. 1998 Aug 17;188(4):725-34. PMID 9705954Online.
  21. ^ PMID 12379643
  22. ^ Fairlamb AH, Cerami A. "Metabolism and functions of trypanothione in the Kinetoplastida." Annu Rev Microbiol. 1992;46:695-729. PMID 1444271
  23. ^ Brengio SD, Belmonte SA, Guerreiro E, et al. "The sesquiterpene lactone dehydroleucodine (DhL) affects the growth of cultured epimastigotes of Trypanosoma cruzi." J Parasitol. 2000 Apr;86(2):407-12. PMID 10780563
  24. ^ El-Sayed NM, Myler PJ, Bartholomeu DC, et al. (2005). "The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease". Science 309 (5733): 409-15. PMID 16020725
  25. ^ El-Sayed, et al., 2005
  26. ^ Pires HH, Lazzari CR, Diotaiuti L, Lorenzo MG. "Performance of yeast-baited traps with Triatoma sordida, Triatoma brasiliensis, Triatoma pseudomaculata, and Panstrongylus megistus in laboratory assays." Rev Panam Salud Publica. 2000 Jun;7(6):384-8. PMID 10949899
  27. ^ Luz C, Rocha LF, Nery GV, Magalhaes BP, Tigano MS. "Activity of oil-formulated Beauveria bassiana against Triatoma sordida in peridomestic areas in Central Brazil." Mem Inst Oswaldo Cruz. 2004 Mar;99(2):211-8. PMID 15250478 Online.
  28. ^ PubMed Search on Triatominae symbiosis

[edit] 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.

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