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Cutaneous leishmaniasis in the hand of a Central American adult
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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 (subfamily Phlebotominae). Although the majority of the literature mentions only one genus transmitting Leishmania to humans (Lutzomyia) in the US, a 2003 study by Galati suggested a new classification for American sand flies, elevating several subgenera to the genus level. Elsewhere in the world, the genus Phlebotomus is considered the vector of leishmaniasis.
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: the different species are morphologically indistinguishable, but they can be differentiated by isoenzyme analysis, DNA sequence analysis, or monoclonal antibodies.
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 manifest anywhere from a few months to years after infection, include fever, damage to the spleen and liver, and anemia.
In clinical medicine, leishmaniasis is considered one of the classic causes of a markedly enlarged (and therefore palpable) spleen; the organ, which is not normally felt during examination of the abdomen, may become larger even than the liver in severe cases.
Leishmaniasis may be divided into the following types::422–428
- Visceral leishmaniasis is the most serious form, and is potentially fatal if untreated.
- Cutaneous leishmaniasis is the most common form, which causes a sore at the bite site, which heals 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 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, the nose and mouth.
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 infected hosts 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).
Leishmaniasis is caused by infection with the pathogen Leishmania. The genomes of three Leishmania species (L. major, L. infantum, and L. braziliensis) have been sequenced and this has provided much information about the biology of the parasite. For example, in Leishmania, protein-coding genes are understood to be organized as large polycistronic units in a head-to-head or tail-to-tail manner; RNA polymerase II transcribes long polycistronic messages in the absence of defined RNA pol II promoters, and Leishmania has unique features with respect to the regulation of gene expression in response to changes in the environment. The new knowledge from these studies may help identify new targets for urgently needed drugs and aid the development of vaccines.
Leishmaniasis is diagnosed in the haematology laboratory by direct visualization of the amastigotes (Leishman-Donovan bodies). Buffy-coat preparations of peripheral blood or aspirates from marrow, spleen, lymph nodes, or skin lesions should be spread on a slide to make a thin smear and stained with Leishman's or Giemsa's stain (pH 7.2) for 20 minutes. Amastigotes are seen with monocytes or, less commonly in neutrophils, of peripheral blood and in macrophages in aspirates. They are small, round bodies 2–4 μm in diameter with indistinct cytoplasm, a nucleus, and a small, rod-shaped kinetoplast. Occasionally, amastigotes may be seen lying free between cells. However, the retrieval of tissue samples is often painful for the patient and it can be difficult to identify the infected cells. For these reasons, other indirect immunological methods of diagnosis are developed. These methods include the enzyme-linked immunosorbent assay (ELISA), antigen coated dipsticks, and the direct agglutination test (DAT). Although these tests are readily available, they are not the standard diagnostic tests due to their insufficient sensitivity and specificity. Over the years, several different Polymerase Chain Reaction (PCR) assays are made into use for the detection of Leishmania DNA. With the PCR assay, a specific and sensitive diagnostic procedure is finally possible.
Currently, no vaccines are in routine use. However, the genomic sequence of Leishmania has provided a rich source of vaccine candidates. Genome-based approaches have been used to screen for novel vaccine candidates. One study screened 100 randomly selected genes as DNA vaccines against L. major infection in mice. Fourteen reproducibly protective, novel vaccine candidates were identified. A separate study used a two-step procedure to identify T cell antigens. Six unique clones were identified: glutamine synthetase, a transitional endoplasmic reticulum ATPase, elongation factor 1gamma, kinesin K-39, repetitive protein A2, and a hypothetical conserved protein. The 20 antigens identified in these two studies are being further evaluated for vaccine development.
|This article is outdated. (May 2010)|
There are two common therapies containing antimony (known as pentavalent antimonials): meglumine antimoniate (Glucantime) and sodium stibogluconate (Pentostam). It is not completely understood how these drugs act against the parasite; they may disrupt its energy production or trypanothione metabolism. Unfortunately, in many parts of the world, the parasite has become resistant to antimony when treating for visceral or mucocutaneous leishmaniasis, but the level of resistance varies according to species. Amphotericin (AmBisome) is now the treatment of choice; its failure in some cases to treat visceral leishmaniasis (Leishmania donovani) has been reported in Sudan, but this may be related to host factors such as co-infection with HIV or tuberculosis rather than parasite resistance. Hypoxanthine-guanine phosphoribosyl transferase (HGPRT; EC 126.96.36.199) is a central enzyme in the purine recycling pathway. Parasitic protozoa (Leishmania donovani) cannot synthesize purines de novo and utilize the salvage pathway to produce purine bases. Thus, this enzyme is targeted in drug discovery and development. The model of the monomeric L. donovani HGPRT showed that this enzyme is an α/β type protein with a PRTase type I folding pattern. Among all of the computationally screened compounds, pentamidine, 1,3-dinitroadamantane, acyclovir and analogs of acyclovir had higher binding affinities than the real substrate (guanosine monophosphate). Amino acids of HGPRT that are frequently involved in the binding of these compounds are Lys 66, Asp 74, Arg 77, Asp 81, Val 88, Tyr 182, Arg 192 and Arg 194. It is predicted that patients suffering from both HIV and visceral leishmaniasis (VL) may benefit if they are treated with acyclovir or pentamidine in conjunction with first-line antileishmanial therapies such as miltefosine and AmBisome.
Miltefosine (Impavido), is a new drug for visceral and cutaneous leishmaniasis. The cure rate of miltefosine in phase III clinical trials is 95%; studies in Ethiopia show it is also effective in Africa. In an observational study of 34 Dutch soldiers with Leishmania major infection who had failed to respond to intralesional antimony, 30 responded to miltefosine. In HIV-immunosuppressed people who are coinfected with leishmaniasis, even in resistant cases, 2/3 of the people have been shown to respond to this new treatment. Clinical trials in Colombia showed a high efficacy for cutaneous leishmaniasis. In mucocutaneous cases caused by L. brasiliensis, it has shown to be more effective than other drugs.
Miltefosine received approval by the Indian regulatory authorities in 2002 and in Germany in 2004. In 2005, it received the first approval for cutaneous leishmaniasis in Colombia. Miltefosine is also currently being investigated as treatment for mucocutaneous leishmaniasis caused by Leishmania braziliensis in Colombia, and preliminary results are very promising. It is now registered in many countries and is the first orally administered breakthrough therapy for visceral and cutaneous leishmaniasis. In October 2006, it received orphan drug status from the US Food and Drug Administration. The drug is generally better tolerated than other drugs. Main side effects are gastrointestinal disturbance in the 1–2 days of treatment, which does not affect the efficacy. Because it is available as an oral formulation, the expense and inconvenience of hospitalisation is avoided, which makes it an attractive alternative. However, there are problems associated with the use of miltefosine that arise from its teratogenicity and pharmacokinetics: In a Dutch study by Thomas P.C. Dorlo in 2008, miltefosine was shown to be much slower eliminated from the body than previously thought and was therefore still detectable in human plasma samples taken five months after the end of treatment. The presence of subtherapeutic miltefosine concentrations in the blood beyond five months after treatment might contribute to the selection of resistant parasites and, moreover, the measures for preventing the teratogenic risks of miltefosine must be reconsidered. This led to some reluctance to taking Miltefosine by affected populations.
The antifungal drug, fluconazole 200 mg daily, has been shown to be significantly more effective in the treatment of cutaneous leishmaniasis compared to the placebo in a trial done in Saudi Arabia. In another randomized clinical trial from Iran, fluconazole 400 mg daily was shown to be significantly more effective than fluconazole 200 mg daily in the treatment of cutaneous leishmaniasis.
The Institute for OneWorld Health has reintroduced the drug paromomycin for treatment of leishmaniasis, results with which led to its approval as an orphan drug. The Drugs for Neglected Diseases Initiative is also actively facilitating the search for novel therapeutics. A treatment with paromomycin will cost about $10. The drug had originally been identified in 1960s, but had been abandoned because it would not be profitable, as the disease mostly affects poor people. The Indian government approved paromomycin for sale in August 2006. A 21-day course of paromomycin produces a definitive cure in >90% of patients with visceral leishmaniasis.
Leishmaniasis can be transmitted in many tropical and subtropical 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 and the Middle East. It affects as many as 12 million people worldwide, with 1.5–2 million new cases each year. The visceral form of leishmaniasis has an estimated incidence of 500,000 new cases and 60,000 deaths each year. More than 90 percent of the world's cases of visceral leishmaniasis are in India, Bangladesh, Nepal, Sudan, and Brazil.
Leishmaniasis is found through much of the Americas from northern Argentina to southern Texas, though not in Uruguay or Chile, and has recently been shown to be spreading to North Texas. Leishmaniasis is also known as papalomoyo, papa lo moyo and ulcero de los chicleros in Latin America. During 2004, an estimated 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. 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.
The disease is found across much of Asia, and in the Middle East. Within Afghanistan, leishmaniasis occurs commonly in Kabul, partly due to bad sanitation and waste left uncollected in streets, allowing parasite-spreading sand flies an environment they find favorable. In Kabul, the number of people infected was estimated to be at least 200,000, and in three other towns (Herat, Kandahar and Mazar-i-Sharif) there were about 70,000 more, according to WHO figures from 2002.[verification needed] Kabul is estimated as the largest center of cutaneous leishmaniasis in the world, with approximately 67,500 cases as of 2004.
Leishmaniasis is mostly a disease of the developing world, and is rarely known in the developed world outside a small number of cases, mostly in instances where troops are stationed away from their home countries. Leishmaniasis has been reported by U.S. troops stationed in Saudi Arabia and Iraq since the Gulf War of 1990, including visceral leishmaniasis. 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.
Descriptions of conspicuous lesions similar to cutaneous leishmaniasis (CL) appear on tablets from King Ashurbanipal from the seventh century BC, some of which may have derived from even earlier texts from 1500 to 2500 BC. Muslim physicians, including Avicenna in the 10th century AD, gave detailed descriptions of what was called Balkh sore. In 1756, Alexander Russell, after examining a Turkish patient, gave one of the most detailed clinical descriptions of the disease. Physicians in the Indian subcontinent would describe it as kala-azar (pronounced kālā āzār, the Urdu, Hindi and Hindustani phrase for "black fever", kālā meaning black and āzār meaning fever or disease). In the Americas, evidence of the cutaneous form of the disease in Ecuador and Peru appears in pre-Inca potteries depicting skin lesions and deformed faces dating back to the first century AD. Some 15th and 16th century texts from the Inca period and from Spanish colonials mention "valley sickness", "Andean sickness", or "white leprosy", which are likely to be CL.
It remains unclear who first discovered the organism. Surgeon Major Cunningham of the British Indian army possibly saw it first in 1885 without being able to relate it to the disease. Peter Borovsky, a Russian military surgeon working in Tashkent, conducted research into the etiology of oriental sore, locally known as "Sart sore", and in 1898 published the first accurate description of the causative agent, correctly described the parasite's relation to host tissues and correctly referred it to Protozoa. However, because his results were published in Russian in a journal with low circulation, his priority was not internationally acknowledged during his lifetime. In 1901, Leishman identified certain organisms in smears taken from the spleen of a patient who had died from "dum-dum fever" (Dum Dum is an area close to Calcutta) and proposed them to be trypanosomes, found for the first time in India. A few months later, Captain Charles Donovan (1863–1951) confirmed the finding of what became known as Leishman-Donovan bodies in smears taken from patients in Madras in southern India. But it was Ronald Ross who proposed that Leishman-Donovan bodies were the intracellular stages of a new parasite, which he named Leishmania donovani. The link with the disease kala-azar was first suggested by Charles Donovan, but was conclusively demonstrated by Charles Bentley's discovery of Leishmania donovani in patients with kala-azar. The disease became a major problem for Allied troops fighting in Sicily during the Second World War; research by Leonard Goodwin then showed pentostam was an effective treatment.
Several potential vaccines are being developed, under pressure from the World Health Organization, but as of 2010[update] none are available. The team at the Laboratory for Organic Chemistry at the Swiss Federal Institute of Technology (ETH) in Zürich are trying to design a carbohydrate-based vaccine. The genome of the parasite Leishmania major has been sequenced, possibly allowing for identification of proteins that are used by the pathogen but not by humans; these proteins are potential targets for drug treatments.
On February 2012, the nonprofit Infectious Disease Research Institute launched the world’s first human clinical trial of the visceral leishmaniasis vaccine. The vaccine is a recombinant form of two fused Leishmania parasite proteins with an adjuvant. Two phase 1 clinical trials with healthy volunteers are to be conducted. The first one takes place in Washington (state) and is followed by a trial in India.
In 2009, the Hebrew University of Jerusalem Kuvin Center for the Study of Infectious and Tropical Diseases, in a collaborative effort with Addis Ababa University, was awarded a grant by the Bill & Melinda Gates Foundation for research into visceral leishmaniasis in Ethiopia. The project will gather data to be analyzed to identify the weak links in the transmission cycle, and devise methods for control of the disease.
HIV protease inhibitors have been found to be active against Leishmania species in two in vitro studies in Canada and India. The studies reported the intracellular growth of parasites was controlled by nelfinavir and ritonavir in a human monocyte cell line and also in human primary monocyte-derived macrophages.
Notable cases 
While filming the latest series of Extreme Dreams in Peru, UK television presenter Ben Fogle caught the disease. He was left bedridden for three weeks on his return home. Fogle was treated at London's Hospital for Tropical Diseases.
During his two and a half year walk through the Amazon Ed Stafford tested positive for cutaneous leishmaniasis in Oriximiná, Para, Brazil. He convinced the local doctor that he could not stay in one place for treatment due to his undertaking and was prescribed with 20 days of intravenous injections that he self administered in the jungle.
See also 
- CVBD Canine vector-borne diseases
- Canine leishmaniasis
- Cutaneous leishmaniasis
- List of cutaneous conditions
- List of parasites (human)
- Tropical disease
- Visceral leishmaniasis (kala-azar)
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- Fogle catches a flesh-eating bug
- Doctors Without Borders' leishmaniasis information page
- Drugs for Neglected Diseases Initiative
- International Leishmania Network
- Leish-L discussion list
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