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from wikipedia http://en.wikipedia.org/wiki/Leishmaniasis http://en.wikipedia.org/wiki/Visceral_leishmaniasis
Leishmaniasis is a disease caused by protozoan parasites that belong to the genus Leishmania and is transmitted by the bite of certain species of sand fly, including flies in the genus Lutzomyia in the New World and Phlebotomus in the Old World. The disease was named in 1901 for the Scottish pathologist William Boog Leishman. This disease is also known as Leichmaniosis, Leishmaniose, leishmaniose, and formerly, Orient Boils, Baghdad Boil, kala azar, black fever, sandfly disease, Dum-Dum fever or espundia.
Most forms of the disease are transmissible only from animals (zoonosis), but some can be spread between humans. Human infection is caused by about 21 of 30 species that infect mammals. These include the L. donovani complex with three species (L. donovani, L. infantum, and L. chagasi); the L. mexicana complex with 3 main species (L. mexicana, L. amazonensis, and L. venezuelensis); L. tropica; L. major; L. aethiopica; and the subgenus Viannia with four main species (L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) panamensis, and L. (V.) peruviana). The different species are morphologically indistinguishable, but they can be differentiated by isoenzyme analysis, DNA sequence analysis, or monoclonal antibodies.
Visceral leishmaniasis is a severe form in which the parasites have migrated to the vital organs.
Geography and epidemiology
A 1917 case of Cutaneous Leishmaniasis in the Middle East, known then locally as "Jericho Buttons" for the frequency of cases near the ancient city of Jericho.
Leishmaniasis can be transmitted in many tropical and sub-tropical countries, and is found in parts of about 88 countries. Approximately 350 million people live in these areas. The settings in which leishmaniasis is found range from rainforests in Central and South America to deserts in West Asia. More than 90 percent of the world's cases of visceral leishmaniasis are in India, Bangladesh, Nepal, Sudan, and Brazil.
Leishmaniasis is commonly found in Mexico, Central America, and South America?from northern Argentina to southern Texas (not in Uruguay, Chile, or Canada), southern Europe (leishmaniasis is not common in travelers to southern Europe), Asia (not Southeast Asia), the Middle East, and Africa (particularly East and North Africa, with some cases elsewhere). It has recently been shown to be spreading to North Texas <sup id="_ref-Houston_Chronicle_0" class="reference">[1]</sup>. The disease is not found in Australia or Oceania.
Leishmaniasis is present in Iraq and was contracted by a number of the troops. The soldiers nicknamed the disease the Baghdad boil. It has been reported by Agence France-Presse that more than 650 U.S. soldiers may have experienced the disease between the start of the invasion in March 2003 and late 2004. [1] [2]
In fact, U.S. troops have experienced leishmaniasis cases in the Middle East already previously to the 2003 invasion, during the time of the previous Gulf conflict, when a large number of soldiers were stationed in Saudi Arabia. Of the 32 cases that were recorded by the U.S. military for that period (1990-1991), 20 were cutaneous, and 12 of the more severe visceral type [3].
During 2004, it is calculated that some 3,400 troops from the Colombian army, operating in the jungles near the south of the country (in particular around the Meta and Guaviare departments), were infected with Leishmaniasis. Apparently, a contributing factor was that many of the affected soldiers did not use the officially provided insect repellent, because of its allegedly disturbing odor. It is estimated that nearly 13,000 cases of the disease were recorded in all of Colombia throughout 2004, and about 360 new instances of the disease among soldiers had been reported in February 2005. [4] [5] [6]
In September 2005 the disease was contracted by at least four Dutch marines who were stationed in Mazari Sharif, Afghanistan, and subsequently repatriated for treatment.
Within Afghanistan, in particular Kabul is a town where leishmaniasis occurs commonly - partly to do with bad sanitation and waste left uncollected in streets, allowing parasite-spreading sand flies an environment they find favorable. See e.g. [7] and [8]. In Kabul the number of people infected is estimated at at least 200,000, and in three other towns (Herat, Kandahar and Mazar-i-Sharif) there may be about 70,000 more, according to WHO figures from 2002 cited e.g. here: [9].
Life cycle
Life cycle of the Leishmaniasis parasite. Source: CDC
Leishmaniasis is transmitted by the bite of female phlebotomine sandflies. The sandflies inject the infective stage, metacyclic promastigotes, during blood meals (1). Metacyclic promastigotes that reach the puncture wound are phagocytized by macrophages (2) and transform into amastigotes (3). Amastigotes multiply in infected cells and affect different tissues, depending in part on which Leishmania species is involved (4). These differing tissue specificities cause the differing clinical manifestations of the various forms of leishmaniasis. Sandflies become infected during blood meals on an infected host when they ingest macrophages infected with amastigotes (5,6). In the sandfly's midgut, the parasites differentiate into promastigotes (7), which multiply, differentiate into metacyclic promastigotes and migrate to the proboscis (8)
Signs and symptoms
The symptoms of leishmaniasis are skin sores which erupt weeks to months after the person affected is bitten by sand flies. Other consequences, which can become manifest anywhere from a few months to years after infection, include fever, damage to the spleen and liver, and anaemia.
In the medical field, leishmaniasis is one of the famous causes of a markedly enlarged spleen, which may become larger even than the liver. There are four main forms of leishmaniasis:
Visceral leishmaniasis (VL),
also known as kala-azar and black fever, is the most severe form of leishmaniasis, a disease caused by parasites of the Leishmania genus. It is the second-largest parasitic killer in the world (after malaria), responsible for an estimated 60 000 who die from the disease each year out of half-million infections worldwide.<sup id="_ref-0" class="reference">[1]</sup> The parasite migrates to the visceral organs such as liver, spleen and bone marrow and if left untreated will almost always result in the death of the mammalian host. Signs and symptoms include fever, weight loss, anemia and substantial swelling of the liver and spleen. Of particular concern, according to the World Health Organization (WHO), is the emerging problem of HIV/VL co-infection
Several species of Leishmania are known to give rise to the visceral form of the disease. The "Old World" (Africa, Asia, Europe) species are L. donovani and L. infantum and the "New World" (South America) species is L. chagasi.
Life-cycle of the parasite
Kala-azar is spread through an insect vector, the sandfly of the Phlebotomus genus in the Old World and the Lutzomyia genus in the New World. Leishmania are tiny creatures, 3-6 micrometers long by 1.5-3 micrometers in diameter, and found in tropical or temperate regions throughout the world. Sand fly larvae grow in warm, moist organic matter, so old trees, house walls or garbage are their most common breeding centers ? making them hard to eradicate.
The adult female sand fly is a bloodsucker, usually feeding at night on sleeping prey. When the fly bites an animal infected with L. donovani, the pathogen is ingested along with the prey?s blood. At this point the protozoan is in the smaller of its two forms, called an amastigote ? round, non-motile, and only three to seven micrometers in diameter.
Taken into the stomach of the sandfly, the amastigotes quickly transform into a second L. donovani form, called the promastigote. This form is spindle-shaped, triple the size of the amastigote, and has a single flagellum that allows for motility. The promastigotes live extracellularly in the sandfly?s alimentary canal, reproducing asexually, then migrate to the proximal end of the gut where they become poised for a regurgitational transmission. This is their means of transmission back into a mammalian host, as the fly injects its saliva into prey when it bites. The promastigotes are introduced locally at the bite site along with the fly?s saliva.
Once inside the new host, promastigotes invade macrophages. Once inside, they transform back into the smaller amastigote form. As an amastigote, L. donovani can only reproduce intracellularly ? and the amastigotes replicate in the most hostile part of the macrophage cell, inside the phagolysosome, whose normal defensive response they are able to prevent. After they have reproduced to a certain extent, the L. donovani lyse their host cell by sheer pressure of mass, but there is some recent speculation that they are able to leave the cell by triggering the exocytosis response of the macrophage. The daughter cell protozoans then migrate through the bloodstream to find new macrophage hosts. In time, L. donovani becomes a systemic infection, spreading to all the host?s organs, particularly the spleen and liver.
Disease progression
In human hosts, response to infection by L. donovani varies a great deal, not only by the strength but also by the type of the patient?s immune reaction. Patients whose immune systems produce large numbers of TH1-type T-Cells, which strengthen cell defenses but do not encourage antibody formation, often recover easily from infection on their own, and after recovery are immune to reinfection. Patients whose systems produce more TH2-type cells, which prompt antibody formation but do nothing for cellular health, are likely to quickly succumb to leishmaniasis. Sadly, some of the stronger strains of L. donovani appear to be able to force a switch in the host from a TH1 to a TH2-type immune response as the infection progresses.
When a human patient does develop visceral leishmaniasis, the most typical symptoms are fever and the enlargement of the spleen, or splenomegaly, with enlargement of the liver ? hepatomegaly ? sometimes being seen as well. The blackening of the skin that gave the disease its common name in India does not appear in most strains of the disease, and the other symptoms are very easy to mistake for those of malaria. Mis-diagnosis is dangerous, as without proper treatment the mortality rate for kala-azar is close to 100%. L. donovani itself is not usually the direct cause of death in kala-azar sufferers, however. Pneumonia, tuberculosis and dysentery are omnipresent in the depressed regions where leishmaniasis thrives, and, as with AIDS, it is these opportunistic infections that are more likely to kill, flaring up in a host whose immune system has been weakened by the L. donovani infection. Progress of the disease is extremely variable, taking anywhere from one to twenty weeks, but a typical duration for the Sudanese strain of the disease is narrower, between twelve and sixteen weeks.
Even with recovery, kala-azar does not always leave its hosts unmarked. Some time after successful treatment?generally a few months with African kala-azar, or as much as several years with the Indian strain?a secondary form of the disease may set in, called post kala-azar dermal leishmaniasis, or PKDL. This condition manifests first as small, measle-like skin lesions on the face, which gradually increase in size and spread over the body. Eventually the lesions may coalesce to form disfiguring, swollen structures resembling leprosy, and occasionally causing blindness if they spread to the eyes. (This disease is not the same as cutaneous leishmaniasis, a milder disease caused by another protozoan of the Leishmania genus which also causes skin lesions).
Diagnosis
The gold standard for diagnosis is visualisation of the amastigotes in splenic aspirate or bone marrow aspirate. This is a technically challenging procedure that is frequently unavailable in areas of the world where visceral leishmaniasis is endemic.
Serological testing is much more frequently used in areas where leishmaniasis is endemic. The K39 dipstick test is easy to perform, and village health workers can be easily trained to use it. The kit may be stored at ambient temperature and no additional equipment needs to be carried to remote areas. The DAT anti-leishmania antigen test is standard within MSF is much more cumbersome to use and appears not to have any advantages over the K39 test.<sup id="_ref-1" class="reference">[2]</sup>
There are a number of problems with serological testing: in highly endemic areas, not everyone who becomes infected will actually develop clinical disease or require treatment. Indeed, up to 32% of the healthy population may test positive, but not require treatment.<sup id="_ref-2" class="reference">[3]</sup><sup id="_ref-3" class="reference">[4]</sup> Conversely, because serological tests look for an immune response and not for the organism itself, the test does not become negative after the patient is cured, it cannot be used as a check for cure, or to check for re-infection or relapse.<sup id="_ref-Lockwood_0" class="reference">[5]</sup> Likewise, patients with abnormal immune systems (e.g., HIV infection) will have false-negative tests.<sup id="_ref-4" class="reference">[6]</sup>
Other tests being developed include a latex agglutination test (KAtex), which is currently being tested in Asia and Africa. Another potential test detects erythrosalicylic acid.<sup id="_ref-Lockwood_1" class="reference">[5]</sup>
Leishmaniasis is a disease caused by protozoan parasites that belong to the genus Leishmania and is transmitted by the bite of certain species of sand fly, including flies in the genus Lutzomyia in the New World and Phlebotomus in the Old World. The disease was named in 1901 for the Scottish pathologist William Boog Leishman. This disease is also known as Leichmaniosis, Leishmaniose, leishmaniose, and formerly, Orient Boils, Baghdad Boil, kala azar, black fever, sandfly disease, Dum-Dum fever or espundia.
Most forms of the disease are transmissible only from animals (zoonosis), but some can be spread between humans. Human infection is caused by about 21 of 30 species that infect mammals. These include the L. donovani complex with three species (L. donovani, L. infantum, and L. chagasi); the L. mexicana complex with 3 main species (L. mexicana, L. amazonensis, and L. venezuelensis); L. tropica; L. major; L. aethiopica; and the subgenus Viannia with four main species (L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) panamensis, and L. (V.) peruviana). The different species are morphologically indistinguishable, but they can be differentiated by isoenzyme analysis, DNA sequence analysis, or monoclonal antibodies.
Visceral leishmaniasis is a severe form in which the parasites have migrated to the vital organs.
Geography and epidemiology
A 1917 case of Cutaneous Leishmaniasis in the Middle East, known then locally as "Jericho Buttons" for the frequency of cases near the ancient city of Jericho.
Leishmaniasis can be transmitted in many tropical and sub-tropical countries, and is found in parts of about 88 countries. Approximately 350 million people live in these areas. The settings in which leishmaniasis is found range from rainforests in Central and South America to deserts in West Asia. More than 90 percent of the world's cases of visceral leishmaniasis are in India, Bangladesh, Nepal, Sudan, and Brazil.
Leishmaniasis is commonly found in Mexico, Central America, and South America?from northern Argentina to southern Texas (not in Uruguay, Chile, or Canada), southern Europe (leishmaniasis is not common in travelers to southern Europe), Asia (not Southeast Asia), the Middle East, and Africa (particularly East and North Africa, with some cases elsewhere). It has recently been shown to be spreading to North Texas <sup id="_ref-Houston_Chronicle_0" class="reference">[1]</sup>. The disease is not found in Australia or Oceania.
Leishmaniasis is present in Iraq and was contracted by a number of the troops. The soldiers nicknamed the disease the Baghdad boil. It has been reported by Agence France-Presse that more than 650 U.S. soldiers may have experienced the disease between the start of the invasion in March 2003 and late 2004. [1] [2]
In fact, U.S. troops have experienced leishmaniasis cases in the Middle East already previously to the 2003 invasion, during the time of the previous Gulf conflict, when a large number of soldiers were stationed in Saudi Arabia. Of the 32 cases that were recorded by the U.S. military for that period (1990-1991), 20 were cutaneous, and 12 of the more severe visceral type [3].
During 2004, it is calculated that some 3,400 troops from the Colombian army, operating in the jungles near the south of the country (in particular around the Meta and Guaviare departments), were infected with Leishmaniasis. Apparently, a contributing factor was that many of the affected soldiers did not use the officially provided insect repellent, because of its allegedly disturbing odor. It is estimated that nearly 13,000 cases of the disease were recorded in all of Colombia throughout 2004, and about 360 new instances of the disease among soldiers had been reported in February 2005. [4] [5] [6]
In September 2005 the disease was contracted by at least four Dutch marines who were stationed in Mazari Sharif, Afghanistan, and subsequently repatriated for treatment.
Within Afghanistan, in particular Kabul is a town where leishmaniasis occurs commonly - partly to do with bad sanitation and waste left uncollected in streets, allowing parasite-spreading sand flies an environment they find favorable. See e.g. [7] and [8]. In Kabul the number of people infected is estimated at at least 200,000, and in three other towns (Herat, Kandahar and Mazar-i-Sharif) there may be about 70,000 more, according to WHO figures from 2002 cited e.g. here: [9].
Life cycle
Life cycle of the Leishmaniasis parasite. Source: CDC
Leishmaniasis is transmitted by the bite of female phlebotomine sandflies. The sandflies inject the infective stage, metacyclic promastigotes, during blood meals (1). Metacyclic promastigotes that reach the puncture wound are phagocytized by macrophages (2) and transform into amastigotes (3). Amastigotes multiply in infected cells and affect different tissues, depending in part on which Leishmania species is involved (4). These differing tissue specificities cause the differing clinical manifestations of the various forms of leishmaniasis. Sandflies become infected during blood meals on an infected host when they ingest macrophages infected with amastigotes (5,6). In the sandfly's midgut, the parasites differentiate into promastigotes (7), which multiply, differentiate into metacyclic promastigotes and migrate to the proboscis (8)
Signs and symptoms
The symptoms of leishmaniasis are skin sores which erupt weeks to months after the person affected is bitten by sand flies. Other consequences, which can become manifest anywhere from a few months to years after infection, include fever, damage to the spleen and liver, and anaemia.
In the medical field, leishmaniasis is one of the famous causes of a markedly enlarged spleen, which may become larger even than the liver. There are four main forms of leishmaniasis:
- Visceral leishmaniasis - the most serious form and potentially fatal if untreated.
- Cutaneous leishmaniasis - the most common form which causes a sore at the bite site, which heal in a few months to a year, leaving an unpleasant looking scar. This form can progress to any of the other three forms.
- Diffuse cutaneous leishmaniasis - this form produces widespread skin lesions which resemble leprosy and is particularly difficult to treat.
- Mucocutaneous leishmaniasis - commences with skin ulcers which spread causing tissue damage to (particularly) nose and mouth
Visceral leishmaniasis (VL),
also known as kala-azar and black fever, is the most severe form of leishmaniasis, a disease caused by parasites of the Leishmania genus. It is the second-largest parasitic killer in the world (after malaria), responsible for an estimated 60 000 who die from the disease each year out of half-million infections worldwide.<sup id="_ref-0" class="reference">[1]</sup> The parasite migrates to the visceral organs such as liver, spleen and bone marrow and if left untreated will almost always result in the death of the mammalian host. Signs and symptoms include fever, weight loss, anemia and substantial swelling of the liver and spleen. Of particular concern, according to the World Health Organization (WHO), is the emerging problem of HIV/VL co-infection
Several species of Leishmania are known to give rise to the visceral form of the disease. The "Old World" (Africa, Asia, Europe) species are L. donovani and L. infantum and the "New World" (South America) species is L. chagasi.
Life-cycle of the parasite
Kala-azar is spread through an insect vector, the sandfly of the Phlebotomus genus in the Old World and the Lutzomyia genus in the New World. Leishmania are tiny creatures, 3-6 micrometers long by 1.5-3 micrometers in diameter, and found in tropical or temperate regions throughout the world. Sand fly larvae grow in warm, moist organic matter, so old trees, house walls or garbage are their most common breeding centers ? making them hard to eradicate.
The adult female sand fly is a bloodsucker, usually feeding at night on sleeping prey. When the fly bites an animal infected with L. donovani, the pathogen is ingested along with the prey?s blood. At this point the protozoan is in the smaller of its two forms, called an amastigote ? round, non-motile, and only three to seven micrometers in diameter.
Taken into the stomach of the sandfly, the amastigotes quickly transform into a second L. donovani form, called the promastigote. This form is spindle-shaped, triple the size of the amastigote, and has a single flagellum that allows for motility. The promastigotes live extracellularly in the sandfly?s alimentary canal, reproducing asexually, then migrate to the proximal end of the gut where they become poised for a regurgitational transmission. This is their means of transmission back into a mammalian host, as the fly injects its saliva into prey when it bites. The promastigotes are introduced locally at the bite site along with the fly?s saliva.
Once inside the new host, promastigotes invade macrophages. Once inside, they transform back into the smaller amastigote form. As an amastigote, L. donovani can only reproduce intracellularly ? and the amastigotes replicate in the most hostile part of the macrophage cell, inside the phagolysosome, whose normal defensive response they are able to prevent. After they have reproduced to a certain extent, the L. donovani lyse their host cell by sheer pressure of mass, but there is some recent speculation that they are able to leave the cell by triggering the exocytosis response of the macrophage. The daughter cell protozoans then migrate through the bloodstream to find new macrophage hosts. In time, L. donovani becomes a systemic infection, spreading to all the host?s organs, particularly the spleen and liver.
Disease progression
In human hosts, response to infection by L. donovani varies a great deal, not only by the strength but also by the type of the patient?s immune reaction. Patients whose immune systems produce large numbers of TH1-type T-Cells, which strengthen cell defenses but do not encourage antibody formation, often recover easily from infection on their own, and after recovery are immune to reinfection. Patients whose systems produce more TH2-type cells, which prompt antibody formation but do nothing for cellular health, are likely to quickly succumb to leishmaniasis. Sadly, some of the stronger strains of L. donovani appear to be able to force a switch in the host from a TH1 to a TH2-type immune response as the infection progresses.
When a human patient does develop visceral leishmaniasis, the most typical symptoms are fever and the enlargement of the spleen, or splenomegaly, with enlargement of the liver ? hepatomegaly ? sometimes being seen as well. The blackening of the skin that gave the disease its common name in India does not appear in most strains of the disease, and the other symptoms are very easy to mistake for those of malaria. Mis-diagnosis is dangerous, as without proper treatment the mortality rate for kala-azar is close to 100%. L. donovani itself is not usually the direct cause of death in kala-azar sufferers, however. Pneumonia, tuberculosis and dysentery are omnipresent in the depressed regions where leishmaniasis thrives, and, as with AIDS, it is these opportunistic infections that are more likely to kill, flaring up in a host whose immune system has been weakened by the L. donovani infection. Progress of the disease is extremely variable, taking anywhere from one to twenty weeks, but a typical duration for the Sudanese strain of the disease is narrower, between twelve and sixteen weeks.
Even with recovery, kala-azar does not always leave its hosts unmarked. Some time after successful treatment?generally a few months with African kala-azar, or as much as several years with the Indian strain?a secondary form of the disease may set in, called post kala-azar dermal leishmaniasis, or PKDL. This condition manifests first as small, measle-like skin lesions on the face, which gradually increase in size and spread over the body. Eventually the lesions may coalesce to form disfiguring, swollen structures resembling leprosy, and occasionally causing blindness if they spread to the eyes. (This disease is not the same as cutaneous leishmaniasis, a milder disease caused by another protozoan of the Leishmania genus which also causes skin lesions).
Diagnosis
The gold standard for diagnosis is visualisation of the amastigotes in splenic aspirate or bone marrow aspirate. This is a technically challenging procedure that is frequently unavailable in areas of the world where visceral leishmaniasis is endemic.
Serological testing is much more frequently used in areas where leishmaniasis is endemic. The K39 dipstick test is easy to perform, and village health workers can be easily trained to use it. The kit may be stored at ambient temperature and no additional equipment needs to be carried to remote areas. The DAT anti-leishmania antigen test is standard within MSF is much more cumbersome to use and appears not to have any advantages over the K39 test.<sup id="_ref-1" class="reference">[2]</sup>
There are a number of problems with serological testing: in highly endemic areas, not everyone who becomes infected will actually develop clinical disease or require treatment. Indeed, up to 32% of the healthy population may test positive, but not require treatment.<sup id="_ref-2" class="reference">[3]</sup><sup id="_ref-3" class="reference">[4]</sup> Conversely, because serological tests look for an immune response and not for the organism itself, the test does not become negative after the patient is cured, it cannot be used as a check for cure, or to check for re-infection or relapse.<sup id="_ref-Lockwood_0" class="reference">[5]</sup> Likewise, patients with abnormal immune systems (e.g., HIV infection) will have false-negative tests.<sup id="_ref-4" class="reference">[6]</sup>
Other tests being developed include a latex agglutination test (KAtex), which is currently being tested in Asia and Africa. Another potential test detects erythrosalicylic acid.<sup id="_ref-Lockwood_1" class="reference">[5]</sup>