Leishmaniasis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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 America, 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.^[1]

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 migrate to the vital organs.

In the medical field, leishmaniasis is one of the famous causes of a markedly enlarged spleen, which may become larger even than the liver. The four main forms of leishmaniasis include visceral leishmaniasis, cutaneous leishmaniasis, diffuse cutaneous leishmaniasis and mucocutaneous leishmaniasis.

Leishmaniasis is spread by the bite of some types of phlebotomine sand flies. Sand flies become infected by biting an infected animal (for example, a rodent or dog) or person. Since sand flies do not make noise when they fly, people may not realize they are present. Sand flies are very small and may be hard to see; they are only about one-third the size of typical mosquitoes. Sand flies usually are most active in twilight, evening, and night-time hours (from dusk to dawn). Sand flies are less active during the hottest time of the day. However, they will bite if they are disturbed, such as when a person brushes up against the trunk of a tree where sand flies are resting. Rarely, leishmaniasis is spread from a pregnant woman to her baby. Leishmaniasis also can be spread by blood transfusions or contaminated needles.

The number of new cases of cutaneous leishmaniasis each year in the world is thought to be about 1.5 million. The number of new cases of visceral leishmaniasis is thought to be about 500,000.

People of all ages are at risk for leishmaniasis if they live or travel where leishmaniasis is found. Leishmaniasis usually is more common in rural than urban areas; but it is found in the outskirts of some cities. The risk for leishmaniasis is highest from dusk to dawn because this is when sand flies are the most active. All it takes to get infected is to be bitten by one infected sand fly. This is more likely to happen the more people are bitten, that is, the more time they spend outside in rural areas from dusk to dawn. Adventure travelers, Peace Corps volunteers, missionaries, ornithologists (people who study birds), other people who do research outdoors at night, and soldiers are examples of people who may have an increased risk for leishmaniasis (especially cutaneous leishmaniasis).

Human leishmanial infections can result in 2 main forms of disease, cutaneous leishmaniasis and visceral leishmaniasis (kala-azar). The factors determining the form of disease include leishmanial species, geographic location, and immune response of the host.

A physical exam may show signs of an enlarged spleen, liver, and lymph nodes. The patient may have been bitten by sandflies, or was in an area known for leishmaniasis.

Diagnosis of visceral leishmaniasis may require taking a blood sample and/or taking a biopsy from the bone marrow to show the parasite. Diagnosis of cutaneous leishmaniasis will require a small biopsy or scraping of the ulcer. Diagnosis of mucocutaneous leishmaniasis requires a biopsy of the affected tissues.

Biopsy samples are examined by microscopy, culture and other methods to look for the parasite and identify the specific kind of Leishmania causing the ulcer. Some of these methods will give results within a few days, but culture may take 2-4 weeks to demonstrate the parasite.

Examination of Giemsa stained slides of the relevant tissue is still the technique most commonly used to detect the parasite.

Medicines called antimony-containing compounds are the main drugs used to treat leishmaniasis. These include meglumine antimoniate and sodium stibogluconate. Other drugs that may be used include amphotericin B, fluconazole and pentamidine.

Plastic surgery may be needed to correct the disfigurement caused by sores on the face (cutaneous leishmaniasis). Patients with drug-resistant viral leishmaniasis may need to have their spleen removed.

The best way for travelers to prevent leishmaniasis is by protecting themselves from sand fly bites. Vaccines and drugs for preventing infection are not yet available.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Description of conspicuous lesions similar to cutaneous Leishmaniasis (CL) has been discovered on tablets from King Ashurbanipal from the 7th century BCE, some of which may have been derived from even earlier texts from 1500 to 2500 BCE. Arab physicians including Avicenna in the 10th century gave detailed description of what was called Balkh sore^[1]. In 1756, Alexander Russell, after examining a Turkish patient, gave one of the most detailed clinical description 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 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 CE. 15th and 16th century texts from Inca period and from spanish colonials mention “valley sickness”, “Andean sickness” or “white leprosy” which are likely to be CL^[2].

Who first discovered the organism is somewhat disputed. Surgeon Major Cunningham of the British Indian army possibly saw it first in 1885 without being able to relate it to the disease.^[3][4] 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.^[5] 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.^[6] 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, India.^[7] But it was Ronald Ross who proposed that Leishman-Donovan bodies were the intracellular stages of a new parasite, which he named Leishmania donovani.^[8] 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.^[9] The disease was 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.^[10]

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

Leishmaniasis is classified according to the clinical manifestation. The most common forms are cutaneous leishmaniasis, which causes skin sores, and visceral leishmaniasis, which affects several internal organs (usually spleen, liver, and bone marrow). Mucosal leishmaniasis is a form of the disease that affects the mucous membranes of the mouth, nose and throat.

Leishmaniasis is classified in 3 different presentation forms: cutaneous, mucosal, and visceral leishmaniasis. ^[1]

• The most common form is cutaneous leishmaniasis, which causes skin lesions.
• The lesions typically develop within a few weeks or months of the sand fly bite.
• These lesions can change in size and appearance over time.
• They may start out as papules (bumps) or nodules (lumps) and may end up as ulcers; skin ulcers might be covered by scab or crust.
• The sores usually are painless but can be painful.
• Some people have swollen glands near the sores.

• Mucosal or mucocutaneous leishmaniasis is an example of one of the less common forms of leishmaniasis.
• This form can be a sequela of infection with some of the species (types) of the parasite that cause cutaneous leishmaniasis in parts of Latin America.
• Certain types of the parasite might spread from the skin and cause sores in the mucous membranes of the nose (most common location), mouth, or throat.

Visceral leishmaniasis affects several internal organs (usually spleen, liver, and bone marrow) and can be life threatening.

• The illness typically develops within months (sometimes as long as years) of the sand fly bite.
• Affected people usually have fever, weight loss, hepatosplenomegaly, and low blood counts (anemia, leukopenia, and thrombocytopenia).

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Leishmaniasis is spread by the bite of some types of phlebotomine sand flies. Sand flies become infected by biting an infected animal (for example, a rodent or dog) or person. Since sand flies do not make noise when they fly, people may not realize they are present. Sand flies are very small and may be hard to see; they are only about one-third the size of typical mosquitoes. Sand flies usually are most active in twilight, evening, and night-time hours (from dusk to dawn). Sand flies are less active during the hottest time of the day. However, they will bite if they are disturbed, such as when a person brushes up against the trunk of a tree where sand flies are resting. Rarely, leishmaniasis is spread from a pregnant woman to her baby. Leishmaniasis also can be spread by blood transfusions or contaminated needles.

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.^[1]

• 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).

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

Leishmaniasis is a vector-borne disease that is transmitted by sandflies and caused by obligate intracellular protozoa of the genus Leishmania. Human infection is caused by about 21 of 30 species that infect mammals. These include the L. donovani complex with 2 species (L. donovani,L. infantum [also known as L. chagasi in the New World]); 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 4 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, molecular methods, or monoclonal antibodies.

cellular organisms; Eukaryota; Euglenozoa; Kinetoplastida; Trypanosomatidae; Leishmaniinae; Leishmania^[1]

• Different Leishmania species cause Old World versus New World (American) cutaneous leishmaniasis.
• In the Old World (the Eastern Hemisphere), the etiologic agents include

• Leishmania tropica
• L. major
• L. aethiopica
• L. infantum
• L. donovani

• The main species in the New World (the Western Hemisphere) are either in the L. mexicana species complex (L. mexicana, L. amazonensis, and L. venezuelensis) or the subgenus Viannia (L. [V.] braziliensis, L. [V.] guyanensis, L. [V.] panamensis, and L. [V.] peruviana).
• The Viannia subgenus is also referred to as the L. (V.) braziliensis species complex.

• Mucosal leishmaniasis is caused by species in the Viannia subgenus, which includes:

• L. [V.] braziliensis
• L. [V.] panamensis
• L. [V.] guyanensis
• L. amazonensis

• Visceral leishmaniasis usually is caused by the following species:

• L. donovani
• L. infantum (L. chagasi generally is considered synonymous with L. infantum)

This form of disease affects internal organs (particularly, spleen, liver, and bone marrow).

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

Cutaneous leishmaniasis must be differentiated from other diseases that cause ulcerative skin lesions, such as: bacterial skin infections, blastomycosis, fungal skin infections, eczema, leprosy, sarcoidosis, syphilis, skin neoplasm, and tuberculosis. Visceral leishmaniasis must be differentiated from other diseases that cause fever, weight loss, hepatosplenomegaly, and pancytopenia, such as: brucellosis, bacterial endocarditis, schistosomiasis, leukemia, lymphomas, miliary tuberculosis, hemolytic anemia, and HIV.

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

Leishmaniasis is found in parts of about 90 countries. Approximately 350 million people live in these areas. Most of the affected countries are in the tropics and subtropics. The settings in which leishmaniasis is found range from rain forests 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 found in Mexico, Central America, and South America—from northern Argentina to 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).

• Leishmaniasis is found in people in focal areas of more than 90 countries in the tropics, subtropics, and southern Europe. ^[1]

• The ecologic settings range from rain forests to deserts. Leishmaniasis usually is more common in rural than in urban areas, but it is found in the outskirts of some cities.

• Climate and other environmental changes have the potential to expand the geographic range of the sand fly vectors and the areas in the world where leishmaniasis is found.
• Leishmaniasis is found on every continent except Australia and Antarctica.
• In the Old World (the Eastern Hemisphere), leishmaniasis is found in some parts of Asia, the Middle East, Africa (particularly in the tropical region and North Africa, with some cases elsewhere), and southern Europe. It is not found in Australia or the Pacific islands.
• In the New World (the Western Hemisphere), it is found in some parts of Mexico, Central America, and South America. It is not found in Chile or Uruguay. Occasional cases of cutaneous leishmaniasis have been acquired in Texas and Oklahoma.
• The number of new cases per year is not known with certainty.

• For cutaneous leishmaniasis, estimates of the number of cases range from approximately 0.7 million (700,000) to 1.2 million (1,200,000).

• For visceral leishmaniasis, estimates of the number of cases range from approximately 0.2 million (200,000) to 0.4 million (400,000).

• The cases of leishmaniasis evaluated in the United States reflect travel and immigration patterns.

• For example, many of the cases ofcutaneous leishmaniasis in U.S. civilian travelers have been acquired in common tourist destinations in Latin America, such as in Costa Rica.
• Overall, infection in people is caused by more than 20 species (types) of Leishmania parasites, which are spread by about 30 species of phlebotomine sand flies; particular species of the parasite are spread by particular sand flies.

• The sand fly vectors generally are the most active during twilight, evening, and night-time hours (from dusk to dawn).
• In many geographic areas where leishmaniasis is found in people, infected people are not needed to maintain the transmission cycle of the parasite in nature; infected animals (such as rodents or dogs), along with sand flies, maintain the cycle.

• However, in some parts of the world, infected people are needed to maintain the cycle; this type of transmission (human—sand fly—human) is called anthroponotic.

• In areas with anthroponotic transmission, effective treatment of individual patients can help control the spread of the parasite.

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

People of all ages are at risk for leishmaniasis if they live or travel where leishmaniasis is found. Leishmaniasis usually is more common in rural than urban areas; but it is found in the outskirts of some cities. The risk for leishmaniasis is highest from dusk to dawn because this is when sand flies are the most active. All it takes to get infected is to be bitten by one infected sand fly. This is more likely to happen the more people are bitten, that is, the more time they spend outside in rural areas from dusk to dawn. Adventure travelers, Peace Corps volunteers, missionaries, ornithologists (people who study birds), other people who do research outdoors at night, and soldiers are examples of people who may have an increased risk for leishmaniasis (especially cutaneous leishmaniasis).

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

The term leishmaniasis encompasses multiple clinical syndromes (cutaneous, mucosal, and visceral forms), which result from infection of macrophages in the dermis, in the naso-oropharyngeal mucosa, and throughout the reticuloendothelial system, respectively. For all three forms, the infection can range from asymptomatic to severe. Cutaneous and mucosal leishmaniasis can cause substantial morbidity, whereas visceral leishmaniasis can be life threatening.

• This is the most common form of leishmaniasis, both in general and in U.S. travelers.
• Unless otherwise specified, cutaneous leishmaniasis refers to localized cutaneous leishmaniasis, rather than to much less common forms, such as diffuse cutaneous leishmaniasis and disseminated cutaneous leishmaniasis.
• In general, cutaneous leishmaniasis causes skin lesions, which can persist for months, sometimes years.
• The skin lesions usually develop within several weeks or months after the exposure but occasionally first appear years later (for example, in the context of trauma or immunosuppression).
• The lesions typically evolve from papules to nodular plaques to ulcerative lesions, with a raised border and central depression, which can be covered by scab or crust; some lesions persist as nodules.
• The lesions usually are painless but can be painful, especially if ulcerative lesions become infected with bacteria or if the lesions are near a joint.
• The healing process typically results in atrophic scarring.
• Even patients with localized cutaneous leishmaniasis quite commonly develop more than one primary lesion (on the same or different parts of the body), satellite lesions, regional lymphadenopathy (occasionally bubonic), and/or nodular lymphangitis (sporotrichoid-like subcutaneous nodules).
• Sometimes lymphadenopathy is noticed first, before skin lesions develop.

• Mucosal leishmaniasis (also called espundia) traditionally refers to a metastatic sequela of New World cutaneous infection, which results from dissemination of parasites from the skin to the naso-oropharyngeal mucosa.
• Adequate systemic treatment of cutaneous leishmaniasis caused by these species is thought to reduce the risk for mucosal disease, but some risk may remain.
• The magnitudes and determinants (parasite and host factors) of the risks for mucosal dissemination and for mucosal disease per se are poorly understood; even for the same species (for example, L. [V.] braziliensis), the risks appear to vary among geographic regions in the Americas.
• Mucosal leishmaniasis usually becomes clinically evident within several years (sometimes as long as decades) of the original cutaneous lesions, which typically were not treated at all or were treated suboptimally. However, mucosal and skin lesions may be noted concomitantly (mucocutaneous leishmaniasis), and some patients had subclinical cutaneous infection.
• The initial manifestations of mucosal leishmaniasis usually are persistent, unusual nasal symptoms (such as stuffiness or bleeding), although oral or pharyngeal symptoms sometimes are noticed first.
• If untreated, the disease can progress to ulcerative destruction of the naso-oropharyngeal mucosa (such as perforation of the nasal septum).

• The general term visceral leishmaniasis encompasses a broad spectrum of severity and manifestations.
• The onset can be chronic, subacute, or acute.
• Although the incubation period generally ranges from weeks to months, asymptomatic infection can become clinically manifest years to decades after the exposure in people who become immunocompromised for other medical reasons (such as HIV/AIDS).
• The stereotypical manifestations of clinically manifest visceral infection include: fever, weight loss (cachexia; wasting), hepatosplenomegaly (usually, the spleen is more prominent than the liver), pancytopenia (anemia, leukopenia, and thrombocytopenia), a high total protein level and a low albumin level, with hypergammaglobulinemia
• Lymphadenopathy may be noted, particularly in some geographic regions, such as Sudan.
• HIV-coinfected patients may have atypical manifestations, such as involvement of the gastrointestinal tract and other organ systems.

• The term kala-azar—which means black (kala) fever (azar) in Hindi—often is reserved for severe (advanced) cases of visceral leishmaniasis, although the terms kala-azar and visceral leishmaniasis sometimes are used interchangeably.
• If untreated, severe cases of visceral leishmaniasis typically are fatal, either directly from the disease or indirectly from complications, such as secondary (myco)bacterial infection or hemorrhage.
• Some patients develop post kala-azar dermal leishmaniasis (PKDL), a syndrome characterized by skin lesions (such as erythematous or hypopigmented macules, papules, nodules, and patches), typically first noticed and most prominent on the face, that develop at variable intervals after (or during) therapy for visceral leishmaniasis.
• PKDL is best described in cases of L. donovani infection in South Asia and East Africa.
• In general, PKDL is more common, develops earlier, and is less chronic in patients in East Africa.
• For example, in Sudan, PKDL is noted in up to 60% of patients, typically from 0 to 6 months after therapy for visceral leishmaniasis, and often heals spontaneously. *In contrast, in South Asia, PKDL is noted in ~5-15% of patients, on average several years after initial therapy, and usually requires additional treatment. Persons with chronic PKDL can serve as important reservoir hosts of infection.

• Deadly infections due to immune system damage
• Disfigurement of the face
• Bleeding (hemorrhage)

• The skin lesions of cutaneous leishmaniasis usually heal on their own, even without treatment. ^[2]

• But this can take months or even years, and the lesions can leave scars. Another potential concern applies to some (not all) types of the parasite found in parts of Latin America: certain types might spread from the skin and cause sores in the mucous membranes of the nose (most common location), mouth, or throat (mucosal leishmaniasis).

• Mucosal leishmaniasis might not be noticed until years after the original sores healed.

• The best way to prevent mucosal leishmaniasis is to ensure adequate treatment of the cutaneous infection.

• If not treated, severe (advanced) cases of visceral leishmaniasis typically are fatal.

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