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==Pathophysiology==
==Pathophysiology==
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 [[amastigote]]s.  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 tissue]]s 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 [[Faculdade de Medicina de Ribeirão Preto|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 [[aneurysm]]s, respectively.
===Transmission===
*Chagas disease usually has a vector-borne transmission. Triatomine insects, the Riduvid (kissing/assassin) bugs, suck blood from an infected individual and are subsequently infected themselves.
*The insects carry the pathogen in their feces and urine. Human infection with ''T. cruzi'' occurs following exposure to feces/urine of infected insects. The pathogen typically enters the host either through a wound induced by the host's scratching following the insect bite or through the conjunctival mucus membranes.
*Other modes of transmission include organ transplantation, blood transfusions, vertical transmission, breast milk, and oral transmission following ingestion of infected foods.<ref>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</ref><ref name=WHO>WHO. [http://www.who.int/tdr/diseases/chagas/ Chagas.] Accessed 24 September 2006.</ref><ref>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</ref><ref>UK Health Protection Agency (HPA).[http://www.hpa.org.uk/cdr/archives/archive05/News/news1305.htm Chagas’ disease (American trypanosomiasis) in southern Brazil.] Accessed 24 September 2006.</ref>


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.
*The incubation period following transmission is typically 1-2 weeks.
 
''[[Trypanosoma cruzi]]'' can also be transmitted through [[blood transfusions]], organ [[transplantation]], [[placenta|transplacentally]], [[breast milk]],<ref>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</ref> and in laboratory accidents.  According to the [[World Health Organization]], the infection rate in Latin American [[blood bank]]s varies between 3% and 53%, a figure higher than of [[HIV]] infection and [[hepatitis]] B and C.<ref name=WHO>WHO. [http://www.who.int/tdr/diseases/chagas/ Chagas.] Accessed 24 September 2006.</ref>
 
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.<ref>Hudson L, Turner MJ. "Immunological Consequences of Infection and Vaccination in South American Trypanosomiasis [and Discussion]". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, Vol. 307, No. 1131, Towards the Immunological Control of Human Protozoal Diseases. (November 13, 1984), pp. 51–61. JSTOR. Accessed 2/22/07. PMID 6151688 </ref>


[[Image:Trypanosoma cruzi LifeCycle.gif|Life cycle of [[Trypanosima cruzi]]. Source: CDC]]
[[Image:Trypanosoma cruzi LifeCycle.gif|Life cycle of [[Trypanosima cruzi]]. Source: CDC]]


===Alternative infection mechanism===
===Cellular Pathogenesis===
Researchers suspected since 1991 that the transmission of the trypanosome by the oral route might be possible,<ref>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</ref> 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.<ref>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</ref>  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 <ref>[http://www1.folha.uol.com.br/fsp/cotidian/ff1808200701.htm Açaí faz 1 vítima de Chagas a cada 4 dias na Amazônia. ''Jornal Folha de São Paulo''] </ref>
====Acute infection====
 
* Following transmission, trypomastigotes invade host cells via a unique transmigration process that involves bradykinin and CCL2 chemokine.
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.<ref>UK Health Protection Agency (HPA).[http://www.hpa.org.uk/cdr/archives/archive05/News/news1305.htm Chagas’ disease (American trypanosomiasis) in southern Brazil.] Accessed 24 September 2006.</ref>  As of March 30, 2005, 49 cases had been confirmed in Santa Catarina, including 6 deaths.<!--http://aol.countrywatch.com/aol_wire.asp?vCOUNTRY=183&UID=1442449  This is not an acceptable source, it is only available on AOL - please provide general URL or information accessible to all. --> 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.
*Unlike African [[trypanosomes]], the bloodstream trypomastigotes are unable to replicate. Instead, they differentiate into intracellular [[amastigote]]s intracellularly.


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.
* The amastigotes multiply by [[binary fission]] and re-transform into trypomastigotes, which are released again into the blood and lymphatic circulations. These newly formed trypomastigotes are then able to infect new host tissues (macrophages, fibroblasts, skeletal and cardiac myocytes, and endothelial cells), which often accounts for the high grade parasitemia and the multisystem complications associated with Chagas disease.
* Inflammation is the hallmark of Chagas disease. Early host immune responses include the activation of B-cell and T-cell (CD4+ and CD8+) lymphocytes that result in the production of anti-trypanosoma antibodies and direct cytotoxicity. It is thought that host immune mechanisms simultaneously contribute to the elimination of the parasite and host tissue damage. The early response causes a state of systemic inflammation reaction that either subsides and resolves or persists as a low-grade silent inflammation and manifests as a chronic disease.<ref name="pmid24312535">{{cite journal| author=Coates BM, Sullivan DP, Makanji MY, Du NY, Olson CL, Muller WA et al.| title=Endothelial transmigration by Trypanosoma cruzi. | journal=PLoS One | year= 2013 | volume= 8 | issue= 12 | pages= e81187 | pmid=24312535 | doi=10.1371/journal.pone.0081187 | pmc=PMC3846899 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24312535 }} </ref><ref name="pmid1549177">{{cite journal| author=Tarleton RL, Koller BH, Latour A, Postan M| title=Susceptibility of beta 2-microglobulin-deficient mice to Trypanosoma cruzi infection. | journal=Nature | year= 1992 | volume= 356 | issue= 6367 | pages= 338-40 | pmid=1549177 | doi=10.1038/356338a0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1549177  }} </ref>


People also can become infected through:
====Chronic infection====
*The true mechanism that result in chronic manifestations of the disease are poorly understood, but it is thought that chronic Chagas disease may be caused by either pathogenic inflammatory responses against residual and persistent ''T. cruzi'' pathogens or autoimmune mechanisms.<ref name="pmid15275290">{{cite journal| author=Kalil J, Cunha-Neto E| title=Autoimmunity in chagas disease cardiomyopathy: Fulfilling the criteria at last? | journal=Parasitol Today | year= 1996 | volume= 12 | issue= 10 | pages= 396-9 | pmid=15275290 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15275290  }} </ref><ref name="pmid11334941">{{cite journal| author=Tarleton RL| title=Parasite persistence in the aetiology of Chagas disease. | journal=Int J Parasitol | year= 2001 | volume= 31 | issue= 5-6 | pages= 550-4 | pmid=11334941 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11334941  }} </ref><ref name="pmid10194457">{{cite journal| author=Kierszenbaum F| title=Chagas' disease and the autoimmunity hypothesis. | journal=Clin Microbiol Rev | year= 1999 | volume= 12 | issue= 2 | pages= 210-23 | pmid=10194457 | doi= | pmc=PMC88915 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10194457  }} </ref>


* Consumption of uncooked food contaminated with feces from infected bugs.  
*Host immune cells, namely mononuclear cells, play an important role in the chronic host tissue destruction. Other involved immune cells include activated neutrophils and eosinophils.
* [[Congenital]] transmission (from a pregnant woman to her baby).
*Chronic inflammation typically results in end-organ damage by inducing local and diffuse tissue necrosis and fibrosis.
* [[Blood transfusion]]
*[[Denervation]] is characteristic of Chagas disease, whereby host organs lose [[sympathetic nervous system|sympathethic]] and [[parasympathetic nervous system|parasympathetic]] nerve endings (neuronolysis) within the walls of infected tissue. The denervation process results in clinical manifestations (e.g. GI [[hypomotility]]).<ref name="pmid17148699">{{cite journal| author=Teixeira AR, Nitz N, Guimaro MC, Gomes C, Santos-Buch CA| title=Chagas disease. | journal=Postgrad Med J | year= 2006 | volume= 82 | issue= 974 | pages= 788-98 | pmid=17148699 | doi=10.1136/pgmj.2006.047357 | pmc=PMC2653922 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17148699  }} </ref>
* [[Organ transplantation]]  
* Accidental laboratory exposure.  


It is generally considered safe to breastfeed even if the mother has Chagas disease.  However, if the mother has cracked nipples or blood in the breast milk, she should pump and discard the milk until the nipples heal and the bleeding resolves.  
===Gross Pathology===
*On goss pathology, infected organs, such as the heart, the colon, lymph nodes, or the esophagus, demonstrate the following characteristic features<ref name="pmid17148699">{{cite journal| author=Teixeira AR, Nitz N, Guimaro MC, Gomes C, Santos-Buch CA| title=Chagas disease. | journal=Postgrad Med J | year= 2006 | volume= 82 | issue= 974 | pages= 788-98 | pmid=17148699 | doi=10.1136/pgmj.2006.047357 | pmc=PMC2653922 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17148699 }} </ref>:
:*Expansion in size
:*Dilation with flabby-appearing tissue
:*Tissue congestion and engorgement
:*Tissue effacement and [[aneurysm]] formation (e.g. left ventricle apical effacement in Chagas cardiomyopathy) typically followed by life-threatening thrombus formation
:*Whitish "soldier's" patches (early) and diffuse fibrosis (late) suggestive of tissue fibrosis in chronic states


Chagas disease is not transmitted from person-to-person like a cold or the flu or through casual contact.
===Microscopic Pathology===
Microscopic histopathological analysis of organs infected with Chagas disease often demonstrate the following characteristic features<ref name="pmid17148699">{{cite journal| author=Teixeira AR, Nitz N, Guimaro MC, Gomes C, Santos-Buch CA| title=Chagas disease. | journal=Postgrad Med J | year= 2006 | volume= 82 | issue= 974 | pages= 788-98 | pmid=17148699 | doi=10.1136/pgmj.2006.047357 | pmc=PMC2653922 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17148699  }} </ref>:
====Acute Phase====
*[[Pseudocyst]] formation in muscle fibers and histiocytes
*[[Mononuclear]] and [[lymphocyte|lymphocytic]] cellular infiltrate
*Host cell lysis (eg. [myocyte]]s, [[neuron]]s, [[endothelial cell]]s, brain [[astrocytes]]) with or without any evidence of parasite presence (especially in acute phase)
*Evidence of ''T. cruzi'' parasite in the [[cytoplasm]] of host cells, such as cardiac myocytes or neurons. The parasite typically appear to be adhering to cellular [[microfilament]]s.
*Palisading mononuclear cells around meningeal blood vessels (in Virchow-Robin spaces)
====Indeterminate Phase====
*Low-grade inflammation in host tissue
====Chronic Phase====
*Evidence of mononuclear and lymphocytic cellular infiltrate and host cell lysis
*Replacement of destroyed tissue by [[fibrous scar]]s, which typically appear locally then become more diffuse


==Gallery==
==Gallery==

Revision as of 15:50, 5 August 2015

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]

Overview

Chagas disease is caused by the protozoan Trypanosoma cruzi. T. cruzi is commonly transmitted to humans and other mammals by the blood-sucking "kissing bugs" of the subfamily Triatominae (family Reduviidae) most commonly species belonging to the Triatoma, Rhodnius, and Panstrongylus genera. It can also be transmitted through blood transfusions, organ transplantation, transplacentally, breast milk,[1] and in laboratory accidents.

Pathophysiology

Transmission

  • Chagas disease usually has a vector-borne transmission. Triatomine insects, the Riduvid (kissing/assassin) bugs, suck blood from an infected individual and are subsequently infected themselves.
  • The insects carry the pathogen in their feces and urine. Human infection with T. cruzi occurs following exposure to feces/urine of infected insects. The pathogen typically enters the host either through a wound induced by the host's scratching following the insect bite or through the conjunctival mucus membranes.
  • Other modes of transmission include organ transplantation, blood transfusions, vertical transmission, breast milk, and oral transmission following ingestion of infected foods.[2][3][4][5]
  • The incubation period following transmission is typically 1-2 weeks.

Life cycle of Trypanosima cruzi. Source: CDC

Cellular Pathogenesis

Acute infection

  • Following transmission, trypomastigotes invade host cells via a unique transmigration process that involves bradykinin and CCL2 chemokine.
  • Unlike African trypanosomes, the bloodstream trypomastigotes are unable to replicate. Instead, they differentiate into intracellular amastigotes intracellularly.
  • The amastigotes multiply by binary fission and re-transform into trypomastigotes, which are released again into the blood and lymphatic circulations. These newly formed trypomastigotes are then able to infect new host tissues (macrophages, fibroblasts, skeletal and cardiac myocytes, and endothelial cells), which often accounts for the high grade parasitemia and the multisystem complications associated with Chagas disease.
  • Inflammation is the hallmark of Chagas disease. Early host immune responses include the activation of B-cell and T-cell (CD4+ and CD8+) lymphocytes that result in the production of anti-trypanosoma antibodies and direct cytotoxicity. It is thought that host immune mechanisms simultaneously contribute to the elimination of the parasite and host tissue damage. The early response causes a state of systemic inflammation reaction that either subsides and resolves or persists as a low-grade silent inflammation and manifests as a chronic disease.[6][7]

Chronic infection

  • The true mechanism that result in chronic manifestations of the disease are poorly understood, but it is thought that chronic Chagas disease may be caused by either pathogenic inflammatory responses against residual and persistent T. cruzi pathogens or autoimmune mechanisms.[8][9][10]
  • Host immune cells, namely mononuclear cells, play an important role in the chronic host tissue destruction. Other involved immune cells include activated neutrophils and eosinophils.
  • Chronic inflammation typically results in end-organ damage by inducing local and diffuse tissue necrosis and fibrosis.
  • Denervation is characteristic of Chagas disease, whereby host organs lose sympathethic and parasympathetic nerve endings (neuronolysis) within the walls of infected tissue. The denervation process results in clinical manifestations (e.g. GI hypomotility).[11]

Gross Pathology

  • On goss pathology, infected organs, such as the heart, the colon, lymph nodes, or the esophagus, demonstrate the following characteristic features[11]:
  • Expansion in size
  • Dilation with flabby-appearing tissue
  • Tissue congestion and engorgement
  • Tissue effacement and aneurysm formation (e.g. left ventricle apical effacement in Chagas cardiomyopathy) typically followed by life-threatening thrombus formation
  • Whitish "soldier's" patches (early) and diffuse fibrosis (late) suggestive of tissue fibrosis in chronic states

Microscopic Pathology

Microscopic histopathological analysis of organs infected with Chagas disease often demonstrate the following characteristic features[11]:

Acute Phase

  • Pseudocyst formation in muscle fibers and histiocytes
  • Mononuclear and lymphocytic cellular infiltrate
  • Host cell lysis (eg. [myocyte]]s, neurons, endothelial cells, brain astrocytes) with or without any evidence of parasite presence (especially in acute phase)
  • Evidence of T. cruzi parasite in the cytoplasm of host cells, such as cardiac myocytes or neurons. The parasite typically appear to be adhering to cellular microfilaments.
  • Palisading mononuclear cells around meningeal blood vessels (in Virchow-Robin spaces)

Indeterminate Phase

  • Low-grade inflammation in host tissue

Chronic Phase

  • Evidence of mononuclear and lymphocytic cellular infiltrate and host cell lysis
  • Replacement of destroyed tissue by fibrous scars, which typically appear locally then become more diffuse

Gallery

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ WHO. Chagas. Accessed 24 September 2006.
  4. ↑ 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
  5. ↑ UK Health Protection Agency (HPA).Chagas’ disease (American trypanosomiasis) in southern Brazil. Accessed 24 September 2006.
  6. ↑ Coates BM, Sullivan DP, Makanji MY, Du NY, Olson CL, Muller WA; et al. (2013). "Endothelial transmigration by Trypanosoma cruzi". PLoS One. 8 (12): e81187. doi:10.1371/journal.pone.0081187. PMC 3846899. PMID 24312535.
  7. ↑ Tarleton RL, Koller BH, Latour A, Postan M (1992). "Susceptibility of beta 2-microglobulin-deficient mice to Trypanosoma cruzi infection". Nature. 356 (6367): 338–40. doi:10.1038/356338a0. PMID 1549177.
  8. ↑ Kalil J, Cunha-Neto E (1996). "Autoimmunity in chagas disease cardiomyopathy: Fulfilling the criteria at last?". Parasitol Today. 12 (10): 396–9. PMID 15275290.
  9. ↑ Tarleton RL (2001). "Parasite persistence in the aetiology of Chagas disease". Int J Parasitol. 31 (5–6): 550–4. PMID 11334941.
  10. ↑ Kierszenbaum F (1999). "Chagas' disease and the autoimmunity hypothesis". Clin Microbiol Rev. 12 (2): 210–23. PMC 88915. PMID 10194457.
  11. ↑ 11.0 11.1 11.2 Teixeira AR, Nitz N, Guimaro MC, Gomes C, Santos-Buch CA (2006). "Chagas disease". Postgrad Med J. 82 (974): 788–98. doi:10.1136/pgmj.2006.047357. PMC 2653922. PMID 17148699.
  12. ↑ "Public Health Image Library (PHIL)".

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