What is 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 (subfamily Phlebotominae). Two genera transmit ''Leishmania'' to humans: ''Lutzomyia'' in the New World and ''Phlebotomus'' in the Old World.

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.

Cutaneous leishmaniasis is the most common form of leishmaniasis. Visceral leishmaniasis is a severe form in which the parasites have migrated to the vital organs.

Leishmaniasis Classification

Leishmaniasis may be divided into the following types:

  • Cutaneous leishmaniasis
  • Mucocutaneous leishmaniasis
  • Visceral leishmaniasis
  • Post-kala-azar dermal leishmaniasis
  • Viscerotropic leishmaniasis

Leishmaniasis 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

Leishmaniasis Mechanism

Leishmaniasis is transmitted by the bite of female phlebotomine sandflies. The sandflies inject the infective stage, metacyclic promastigotes, during blood meals. Metacyclic promastigotes that reach the puncture wound are phagocytized by macrophages and transform into amastigotes. Amastigotes multiply in infected cells and affect different tissues, depending in part on which ''Leishmania'' species is involved. 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. In the sandfly's midgut, the parasites differentiate into promastigotes, which multiply, differentiate into metacyclic promastigotes and migrate to the proboscis.

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 it is now understood that in ''Leishmania'' protein-coding genes are 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 Prevention

Currently there are no vaccines 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.

Leishmaniasis Treatment

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 and 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.

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 that it is also effective in Africa. In HIV immunosuppressed people who are coinfected with leishmaniasis it has shown that even in resistant cases 2/3 of the people responded 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,(More, ''et al.'', 2003). 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.

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.

Drug-resistant leishmaniasis may respond to immunotherapy (inoculation with parasite antigens plus an adjuvant) which aims to stimulate the body's own immune system to kill the parasite.

Several potential vaccines are being developed, under pressure from the World Health Organization, but none is 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.

The compound vasicine (peganine), found in the plant ''Peganum harmala'', has been tested ''in vitro'' against the promastigote stage of ''Leishmania donovani'', the causative agent of visceral leishmaniasis. It was shown that this compound induces apoptosis in ''Leishmania'' promastigotes. "Peganine hydrochloride dihydrate, besides being safe, was found to induce apoptosis in both the stages of L. donovani via loss of mitochondrial transmembrane potential."

Another alkaloid harmine found in ''Peganum harmala'', ". . .because of its appreciable efficacy in destroying intracellular parasites as well as non-hepatotoxic and non-nephrotoxic nature, harmine, in the vesicular forms, may be considered for clinical application in humans."

HIV Protease inhibitors have been found to be active against Leishmania species in two ''in vitro'' studies in Canada and India. The study reported that the intracellular growth of Leishmania parasites was controlled by nelfinavir and ritonavir in a human monocyte cell line and also in human primary monocyte-derived macrophages.

Leishmaniasis Epidemiology

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 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. 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.

The disease is found across much of Asia, though not Southeast 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 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.

Africa, in particular the East and North, is home to cases of Leishamaniasis. The disease is spreading to Southern Europe but is not found in Australia or Oceania.

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.

Leishmaniasis History

Descriptions of conspicuous lesions similar to cutaneous leishmaniasis (CL) has been discovered on tablets from King Ashurbanipal from the 7th century BC, some of which may have been 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). As for the new world, evidence of the cutaneous form of the disease was found in Ecuador and Peru in pre-Inca potteries depicting skin lesions and deformed faces dating back to the first century AD. 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. 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 in 1903 Captain Charles Donovan (1863–1951) described them as being new organisms. Eventually Ronald Ross established the link with the disease and named the organism ''Leishmania donovani''. The disease was a major problem for Allied troops fighting in Sicily during the Second World War, and it was then that research by Leonard Goodwin showed that Pentostam was an effective treatment.

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