Leishmaniasis

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 [[Scotland|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.

Life cycle

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 .

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

Diagnosis

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 minute. Amastigotes are seen with monocytes or, less commonly in neutrophil in peripheral blood and in macrophages in aspirates. They are small, round bodies 2-4um in diameter with indistinct cytoplasm, a nucleus and a small rod shaped kinetoplast. Occasionally amastigotes may be seen lying free between cells. Lewis SM; bAIN BJ and BatesI.Dacie and Lewis.PracticalHaematology.ISBN.0443066604

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 is now the treatment of choice – failure of AmBisome to treat visceral leishmaniasis (Leishmania donovani) has been reported in Sudan, but this failure 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 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|L. 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.(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 gastrointetinal 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 developed paromomycin, 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. 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 as of 2006 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 [http://news.bbc.co.uk/1/hi/health/4930528.stm]. 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. A bay area bio-tech firm is now developing a quick field test for leishmaniasis that could cut diagnosis from two-three weeks down to overnight, therefore speeding treatment. The KTVU news broadcast is [http://www.zangani.com/video/leishmaniasis available here]. In April 2008, Indian researchers identified a key protein that plays an important role in regulating the survival, infectivity and drug response of the parasite that causes visceral leishmaniasis - better known as 'kala-azar'. Jitesh P. Iyer and co-workers from the National Institute of Immunology, found that higher levels of an enzyme called cTXNPx made the L. donovani parasite more virulent at certain times in its life cycle. Laboratory tests also showed a higher parasite burden in immune cells. The full story is available http://timesofindia.indiatimes.com/HealthSci/Scientists_find_kala-azar_protein/articleshow/2987516.cms Here.

causes

Leishmaniasis is caused by infection with the pathogen [[Leishmania]]. The [[genome]]s 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.

Vaccines

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.

Public Discussion