AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Leishmaniasis is a zoonotic infection caused by protozoa that belong to the genus Leishmania. The disease is named after Leishman, who first described it in London in May 1903. Leishmaniasis is transmitted by sandflies (Phlebotomus species). In the human host, Leishmania are intracellular parasites that infect the mononuclear phagocytes. The spectrum of human disease ranges from self-healing localized ulcers to widely disseminated progressive lesions of the skin, mucus membranes, and the entire reticuloendothelial system.

Epidemiology

The Leishmania species that infect humans are mainly Leishmania donovani, which causes visceral leishmaniasis (kala azar), and Leishmania tropica and Leishmania brasiliensis, which cause cutaneous leishmaniasis. Visceral leishmaniasis occurs worldwide but is predominantly encountered in India, South America, Central Asia, the Middle East, and Africa. Cutaneous leishmaniasis caused by L tropica is most common along the shores of the Mediterranean, throughout the Middle East, central Africa, and parts of India. Cutaneous leishmaniasis caused by L brasiliensis is mainly confined to Central America and South America.

Leishmaniasis has a long history. Designs on pre-Columbian pottery and thousand-year-old skulls with evidence of leishmaniasis prove that the disease has existed in the Americas for a long time. It has also been present in Africa and India since at least the mid eighteenth century. Geographical distribution of leishmaniasis is restricted to tropical and temperate regions (natural habitat of the sandfly). Leishmaniases are considered endemic in 88 countries (16 developed countries, 72 developing countries) on 5 continents: Africa, Asia, Europe, North America, and South America. A total of 350 million people are at risk. Geographical distribution of leishmaniasis is limited by the distribution of the sandfly, its susceptibility to cold climates, its tendency to take blood from humans or animals only, and its capacity to support the internal development of specific species of Leishmania.

The incidence of leishmaniasis is increasing, mainly because of man-made environmental changes that increase human exposure to the sandfly vector. Poverty and malnutrition play a major role in the increased susceptibility to the disease. Extracting timber, mining, building dams, widening areas under cultivation, creating new irrigation schemes, expanding road construction in primary forests such as the Amazon, continuing widespread migration from rural to urban areas, and continuing fast urbanization worldwide are among the primary causes for increased exposure to the sandfly.

Another risk factor is the movement of susceptible populations into endemic areas, including large-scale migration of populations for economic reasons. In the city of Kabul, Afghanistan, which has a population of less than 2 million, an estimated 270,000 cases of cutaneous leishmaniasis occurred in 1996. The resurgence of visceral leishmaniasis has occurred because of deficiencies in the control of the vector (sandfly), absence of a vaccine, and lack of access to medical treatment because of the cost and increasing drug resistance to first-line treatment.

Coexistence of leishmaniasis with human immunodeficiency virus (HIV) infection is a serious concern. Leishmaniasis is spreading in several areas of the world because of the rapidly spreading epidemic of acquired immunodeficiency syndrome (AIDS). The immune deficiency has lead to increased susceptibility to infections, including leishmaniasis. Thus far, co-infections have been reported in 33 countries worldwide (see Media file 3). Co-infection with HIV has lead to the spread of leishmaniasis, typically a rural disease, into urban areas. In patients infected with HIV, leishmaniasis accelerates the onset of AIDS by cumulative immunosuppression and by stimulating the replication of the virus. It may also change asymptomatic Leishmania infections into symptomatic infections. Sharing of needles by intravenous drug users can spread not only HIV but also leishmaniasis.

Although cutaneous leishmaniasis is found in many countries where L donovani is prevalent, the 2 parasites are not present in the same regions. In India, visceral leishmaniasis is confined to the eastern parts, and cutaneous leishmaniasis is limited to the dry western parts.

Pathophysiology

Leishmaniasis infections are considered zoonotic diseases because the infection is maintained in dogs, wild rodents, and other animals in endemic areas. Leishmania are obligatory intracellular parasites and are transmitted by the bite of a tiny 2- to 3-mm insect vector, the sandfly belonging to the genera Phlebotomus and Lutzomyia (see Media file 4).Only about 30 of the 500 known phlebotomine species have been positively identified as vectors of the disease.

The reservoir of infection for Indian kala azar is humans, whereas it is rodents for African kala azar, foxes in Brazil and Central Asia, and canines for the Mediterranean and Chinese kala azar.

Life cycle

The parasite has 2 forms: the amastigote form and the promastigote form. The amastigote form occurs in humans, whereas the promastigote form occurs in the sandfly and in artificial culture (see Media file 5). Only the female sandfly transmits the protozoan, infecting itself with the Leishmania parasites contained in the blood it sucks from its human or mammalian host. Over 4-25 days, the parasite continues its development inside the sandfly, where it undergoes a major transformation into the promastigote form. A large number of flagellate forms (promastigotes) are produced by binary fission. Multiplication proceeds in the mid gut of the sandfly, and the flagellates tend to migrate to the pharynx and buccal cavity of the sandfly. A heavy pharyngeal infection is observed between the sixth and ninth day of an infected blood meal. A bite during this period results in the spread of leishmaniasis.

Following the bite, some of the flagellates that enter the circulation are destroyed, whereas others enter the cells of the reticuloendothelial system, where they change into the amastigote form. The amastigote forms also multiply by binary fission, with multiplication continuing until the host cell is packed with the parasites and ruptures, liberating the amastigotes into the circulation. The free amastigotes then invade fresh cells, thus repeating the cycle and, in the process, infecting the entire reticuloendothelial system. Some of the free amastigotes are drawn by the sandfly during its blood meal, thus completing the cycle.

Cutaneous leishmaniasis is caused by L tropica. Morphologically, it is indistinguishable from L donovani. The life cycle is exactly the same as that of L donovani except that the amastigote form resides in the large mononuclear cells of the skin.

Methods of transmission

The predominant mode of transmission is a sandfly bite. Different species of sandfly act as vectors in different parts of the world (see Media file 1). Uncommon modes of transmission include congenital transmission, blood transfusion, and, rarely, inoculation of cultures.

Pathogenesis

After inoculation by sandflies, the flagellates (promastigote form) bind to macrophages in the skin. Two of the parasite surface molecules appear to play a prominent role in parasite-phagocyte interactions. The outcome of Leishmania infection appears to depend on the complex interaction between the parasite's virulence and the immune response of the host. Promastigotes activate complement through the alternate pathway and are opsonized. The most important immunological feature is a marked suppression of the cell-mediated immunity to leishmanial antigens. In persons with asymptomatic self-resolving infection, T-helper cells predominate, although immune suppression years later can result in disease. An overproduction of both specific immunoglobulins and nonspecific immunoglobulins also occurs. The increase in gamma globulin leads to a reversal of the albumin-globulin ratio commonly associated with this disease.

Leishmaniasis is a disease that involves the reticuloendothelial system. Parasitized macrophages disseminate infection to all parts of the body but more so to the spleen, liver, and bone marrow. The spleen is enlarged, with a thickening of the capsule, and is soft and fragile; its vascular spaces are dilated and engorged with blood. The reticular cells of Billroth are markedly increased and packed with the amastigote forms of the parasite. However, no evidence of fibrosis is present. In the liver, the Kupffer cells are increased in size and number and infected with amastigote forms of Leishmania. Bone marrow turns hyperplastic, and parasitized macrophages replace the normal hemopoietic tissue.

Genetic susceptibility to visceral leishmaniasis has been described in parts of Sudan. Susceptibility genes in chromosome 22q12 have been found in an ethnic group in Sudan that has a high prevalence rate of visceral leishmaniasis.

Frequency

International

An estimated 12 million cases of leishmaniasis currently exist worldwide, with an estimated 1.5-2 million new cases occurring annually. Approximately 1-1.5 million cases of cutaneous leishmaniasis and 500,000 cases of visceral leishmaniasis occur each year.

Of the 500,000 new cases of visceral leishmaniasis that occur annually, 90% are in Bangladesh, Brazil, India, Nepal, and Sudan (see Media file 1). Mucocutaneous leishmaniasis mainly occurs in South America, with Bolivia, Brazil, and Peru accounting for 90% of the cases (see Media file 2). Nearly 90% of all cases of cutaneous leishmaniasis occur in Afghanistan, Brazil, Iran, Peru, Saudi Arabia, Sri Lanka, and Syria, with 1-1.5 million new cases reported annually worldwide.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
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• Follow-up
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History

Visceral leishmaniasis is caused by L donovani. The spectrum of illness ranges from asymptomatic infection to severe life-threatening infection. The disease is also known as kala azar, Dumdum fever, Assam fever, and infantile splenomegaly in various parts of the world. It is the most severe form of leishmaniasis and is usually fatal within 2 years if left untreated. The incubation period is usually 3-6 months but can be months or years. Young malnourished children are most susceptible to developing progressive infection.

The disease has an insidious onset with pyrexia, which is continuous or remittent and becomes intermittent at a later stage. It is characteristically described as a double rise in 24 hours. Waves of pyrexia may be followed by a period without fever. The disease occasionally presents with an acute onset. Children presenting later in the course of the disease may present with edema caused by hypoalbuminemia, hemorrhage caused by thrombocytopenia, or growth failure caused by features of chronic infection.

Although the patient has high fever, malaise is not reported, and usual accompaniments such as anorexia and coated tongue are unusual.

Fulminant forms of visceral leishmaniasis, which mainly affect children, have been reported in India, with manifestations that include pancytopenia and hepatic failure.

Physical

Splenic enlargement is another striking feature that is often considerable. The abdomen is protuberant because of the splenomegaly and the accompanying hepatomegaly. With progress of the disease, the spleen extends to well below the costal margin. The spleen is usually firm to hard, but soft spleen can be seen in acute disease.

Jaundice with mildly elevated enzyme levels is rarely seen and is considered a bad prognostic sign.

Lymphadenopathy is observed in the African and Chinese forms but is rarely observed in the Indian form.

Anemia is almost always present and is usually severe. It is normochromic and normocytic and caused by various factors, including replacement of marrow by the parasites, splenic sequestration, hemorrhage, hemodilution, and hemolysis. Leukopenia is also observed and may contribute to secondary infections. Thrombocytopenia contributes to the hemorrhagic tendency observed in some cases.

The skin is dry, thin, and scaly, and hair is lost. As the disease progresses, the skin on the hands, feet, abdomen and face may become darkened, which is why the disease is also termed kala azar or black fever. Petechiae and ecchymosis may be seen in the extremities. Pedal edema is more common in children. Skin lesions that contain parasites and appear as diffuse, warty, nonulcerative lesions may occur in visceral leishmaniasis, especially in Africa. Mucosal lesions in the mouth and nose, which appear as nodules or ulcers and may lead to perforation of the nasal septum, have been described in Sudan but are rare elsewhere.

Hypergammaglobinemia, circulating immune complexes, and rheumatoid factors are present in sera of most patients with visceral leishmaniasis. Rarely, immunocomplex deposition in the kidneys may lead to mild glomerulonephritis. However, renal failure is not a feature of visceral leishmaniasis.

Unusual clinical presentations include pancytopenia without splenomegaly, immune-mediated hemolysis, generalized lymphadenopathy without hepatosplenomegaly, massive hepatic necrosis, and retinal hemorrhages. If untreated, death occurs within 2 years and is often caused by bacterial pneumonia, septicemia, dysentery, tuberculosis, cancrum oris, and uncontrolled hemorrhage or its sequelae.

A variant of visceral leishmaniasis has been described in US soldiers who participated in the gulf war. This is associated with light parasitic burden and mild symptoms including fever, malaise, and nausea.

Post–kala azar dermal leishmaniasis follows the treatment of visceral leishmaniasis in approximately 10% of cases in India and 2% of cases in Africa. Lesions in India develop 1-2 years after treatment of the original disease and may persist for as long as 20 years. In Africa, they usually appear during or shortly after treatment and persist only for a few months. Recurrence of kala azar that is resistant to antimonials has been reported in dermal leishmanoid, with an incidence rate of 1 in 700 cases.

Dermal lesions are categorized into 3 types, as follows:

• Depigmented macules are the earliest lesions and are present on the trunk and extremities. 
• Erythematous patches appear early in the course of disease and are seen on the nose, cheeks, and chin with a butterfly distribution. They are photosensitive and become prominent toward the middle of the day.
• Yellowish pink nodules appear mostly on the face and replace the earlier lesions. The absence of ulceration distinguishes these nodules from those of cutaneous leishmaniasis (oriental sore).

Cutaneous leishmaniasis mainly occurs in 2 forms: an oriental sore caused by L tropica and American cutaneous leishmaniasis caused by L brasiliensis. The pathologies of the lesions caused by L tropica and L brasiliensis are the same. Cutaneous leishmaniasis produces skin lesions mainly on the face, arms, and legs. Although this form is often self-healing, it can create serious disability and permanent scars. After recovery or successful treatment, cutaneous leishmaniasis induces immunity to reinfection by the species of Leishmania that caused the disease. 

Urban cutaneous leishmaniasis, caused by a subspecies of L tropica, causes a dry cutaneous ulcer on the face and has an urban distribution. The incubation period is approximately 2 months. It is common in Western India, North Africa, the Mediterranean region, and Middle East. A similar disease in Mexico, Honduras, and Guatemala is known as the bay sore or chiclero ulcer. It is a chronic lesion that occurs at the site of a sand fly bite.

Rural cutaneous leishmaniasis is caused by L tropica major and has a rural distribution. Multiple moist cutaneous lesions appear on the extremities and are associated with marked local subcutaneous infiltration and regional lymphadenitis. Both lesions are common in Central Asia. 

Diffuse cutaneous leishmaniasis is associated with a deficient cell-mediated immunity that enables the parasite to disseminate in the subcutaneous tissues. It starts as a single lesion and slowly spreads over the face, ears, extremities, and buttocks until the whole body is affected. The lesions are neither destructive nor erosive but are disfiguring. The lesions are often misdiagnosed as leprosy and are resistant to treatment.

Mucocutaneous leishmaniasis, also called espundia in South America, causes disfiguring lesions on the face and destroys the mucous membranes of the nose, mouth, and throat. The lesions commonly arise at the mucocutaneous junction around the nose and may spread inward, destroying tissues and leading to deformity. The lesions heal with scarring, causing the typical tapir or camel nose. Mucocutaneous leishmaniasis is associated with a significant mortality rate. Children are rarely affected.

Causes

Leishmaniasis is a zoonotic infection caused by protozoa that belong to the genus Leishmania. Leishmaniasis is transmitted by sandflies (phlebotomus species). In the human host, Leishmania are intracellular parasites that infect the mononuclear phagocytes. Visceral leishmaniasis is caused by L donovani.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Differential diagnosis

Visceral leishmaniasis - Includes other conditions associated with massive splenomegaly, including malaria, tropical splenomegaly syndrome, typhoid, miliary tuberculosis, portal hypertension, leukemias and lymphomas, hemolytic anemia

Post–kala azar dermal leishmaniasis - Yaws, syphilis, leprosy

Cutaneous leishmaniasis - Traumatic ulcers, stasis ulcers

Mucocutaneous leishmaniasis - Sarcoidosis, midline granuloma, histoplasmosis, syphilis, tertiary yaws

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Direct evidence of infection: The parasite can be detected through direct evidence from peripheral blood, bone marrow, or splenic aspirates, as explained below. The smears are stained in Leishman, Giemsa, or Wright stains and examined under oil immersion microscope.
• • Peripheral blood smear: Amastigotes are revealed inside the circulating monocytes and neutrophils. However, they are often difficult to locate because of the small numbers. L donovani is best detected using the following methods: (1) creating thick film by producing a single straight leukocyte edge when making a peripheral smear or (2) centrifuging citrated blood and withdrawing the sediment, which is then smeared, dried, and stained.
  • Culture: Obtaining a culture is time consuming, and findings take approximately a month. Cultures are made using a Novy-McNeal-Nicolle medium. The medium is a rabbit-blood agar that has an overlay of Locke solution with added antibiotics. Two mL of blood is aseptically obtained from a vein and is diluted with 10 mL of citrated saline solution. This is centrifuged and the cellular deposit is inoculated into the water of condensation of nitrosonornicotine (NNN) medium and incubated at 22°C for 1-4 weeks. At the end of each week, a drop of condensation fluid is examined for promastigote forms.
  • Animal inoculation: This is a sensitive method but can take several weeks. The sample is inoculated intraperitoneally or intradermally into skin on the nose and feet. The parasites can be demonstrated from the ulcers and nodules that develop from the sites of inoculation.
• Indirect evidence of infection
• • Detection of hypergammaglobinemia
  • • The aldehyde test and the antimony test were the initial tests used to diagnose kala azar.
    • Aldehyde test results reveal increased gamma globulin levels. Obtain approximately 1 mL of blood in a small glass tube and add 1-2 drops of 40% formalin. The formation of milky white–like opacity and jellification indicates a positive result. Aldehyde test findings are not positive unless the disease has been present for at least 3 months.
    • Antimony test findings also depend on a rise in serum gamma globulin levels. Positive findings are indicated by a white flocculent precipitate observed when a urea stibamine solution comes in contact with serum.
  • Immunological tests: Before the use of specific leishmanial antigens, nonspecific antigens were used. These include the Witebsky, Klingenstein, Kuhn (WKK) antigen from the tubercle bacilli and an antigen from the Kedrowsky acid-fast bacillus. False-positive results occur in patients with tuberculosis, leprosy, and tropical Eosinophilia infection. The direct agglutination test, which detects the specific immunoglobulin M (IgM) antibody at an early stage, has been found to be useful in the detection of both clinical and subclinical infections. Because this test is easy to perform and the results are available in 24 hours, it can be used as a rapid test in primary care settings.
  • Nonspecific tests
  • • Specific leishmanial antigens prepared from cultures have been used in a number of tests. The direct agglutination test, immunofluorescent antibody test, complement fixation, and counterimmunoelectrophoresis are the various tests used in diagnosis of kala azar. Cross-reactions can occur with leprosy, Chagas disease, malaria, and schistosomiasis. Polymerase chain reaction (PCR) has also been used in the diagnosis of leishmaniasis using sequences from the variable region of kinetoplast DNA. A negative serological test result does not exclude the possibility of a leishmanial infection.
    • An immunochromatographic test for detection of anti–rK-39 antibodies has been reported with high sensitivity and specificity in diagnosis of visceral leishmaniasis and post–kala azar dermal leishmaniasis.
    • Leishmanin skin test (Montenegro test) is a delayed hypersensitivity reaction introduced in Montenegro, South America. It is performed by intradermally injecting 0.1 mL of killed promastigote antigen. The test results are available after 72 hours. The leishmanin skin test results are negative during active visceral leishmaniasis and usually become positive only after successful therapy. The test results are also positive in patients with dermal leishmaniasis. This test is useful only for epidemiological purposes, indicating prior exposure to infection.
• Supportive tests: Hematological parameters include the following: blood examination findings reveal a normochromic normocytic anemia, leukopenia, neutropenia, thrombocytopenia, elevated gamma globulin levels, and a reversal of the albumin-globulin ratio.

Procedures

• Bone marrow aspiration is the most common sample obtained. Samples are obtained from the sternum or the iliac crest. Amastigote forms are revealed in plain film, and the promastigote forms are revealed in culture. Although safer than splenic puncture, the parasites are scant and may give a false-negative test result. Positivity rates ranging from 54-86% have been obtained using bone marrow.
• When the spleen is enlarged considerably, splenic aspiration is one of the valuable methods for obtaining a positive result. As many as 98% of positive results have been obtained using splenic aspiration. Amastigote forms are revealed in stained specimens, and the promastigote forms are revealed in culture. Splenic puncture is associated with the risk of uncontrolled hemorrhage and, therefore, should be carried out only when bone marrow examination findings are inconclusive. Platelet counts and prothrombin times should be checked before the procedure.
• Lymph node aspiration or biopsy may be helpful in the presence of enlarged lymph nodes. In cutaneous disease, tissue can be obtained with a 3-mm punch biopsy, lesion scrapings, or needle aspiration of the nonnecrotic edge of the lesion.

Histologic Findings

Leishmaniasis is a disease that involves the reticuloendothelial system. The parasitized macrophages disseminate infection to all parts of the body, especially to the spleen, liver, and bone marrow. The spleen is enlarged, with a thickening of the capsule, it is soft and fragile, its vascular spaces are dilated and engorged with blood, and the reticular cells of Billroth are markedly increased and packed with amastigote forms of the parasite. However, no evidence of fibrosis is present. In the liver, the Kupffer cells are increased in size and number and infected with amastigote forms of Leishmania. The bone marrow is hyperplastic, and parasitized macrophages replace the normal hemopoietic tissue.

TREATMENT

Section 6 of 11  

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• Introduction
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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Sodium stibogluconate, a pentavalent antimonial compound (Sb^v), is the drug of choice in the treatment of visceral leishmaniasis, except for in Europe and Sb^v-unresponsive regions of India. However, resistance is on the rise. Resistance is as high as 43% in the Bihar province of India, where visceral leishmaniasis is endemic. Amphotericin B deoxycholate is the drug of choice in India, whereas the lipid formulation liposomal amphotericin is used in Europe. Miltefosine will have an important role to play in the future, preferably as a combination for first-line treatment of visceral leishmaniasis, because of its efficacy and convenient oral administration.

The earliest sign of improvement is an improvement in symptoms. Regression of splenomegaly takes a few months.

Supportive treatment includes rest, high-calorie diet, blood transfusions, and treatment of secondary infections.

• Resistant visceral leishmaniasis
• • Drug resistance can be primary or secondary. Resistance can be caused by delayed diagnosis (prolonged duration of illness), interrupted and low-dose treatment, immunological failure, emergence of resistant strains of parasites, and leishmaniasis associated with AIDS. Visceral leishmaniasis is an important opportunistic infection associated with AIDS. Leishmaniasis in AIDS, mainly reported in southern Europe, is now observed in other parts of the world, including South America, Asia, and North Africa. Patients co-infected with HIV can develop unusual manifestations of leishmaniasis. Parasitologic diagnosis using peripheral blood smear and buffy coat smear is easier in patients with HIV co-infection because parasites are more commonly found in the circulating monocytes of these patients. 
  • Patients resistant to stibogluconate should be treated with alternative agents, such as liposomal amphotericin (0.5-3 mg/kg) on alternate days until a dose of 20 mg/kg or pentamidine (2-4 mg/kg) on alternate days for 15 doses. Pentamidine is available in 2 preparations: pentamidine isethionate (Pentam 300) and pentamidine dimethane sulphonate (Lomidine). However, the effectiveness of pentamidine has recently declined. Other alternatives include miltefosine, the first oral antileishmanial agent licensed for use in India.
  • Liposomal amphotericin is a lipid complex with amphotericin that is more active than amphotericin B. The 3 preparations formulated include amphotericin B lipid complex, liposomal amphotericin B, and amphotericin B colloidal dispersion. Cure rates of more than 90% have been observed in various studies. The high cost of this drug is a disadvantage to its use in areas where visceral leishmaniasis is prevalent.
  • Combination of stibogluconate with drugs, such as aminosidine and interferon gamma, has also produced good results in patients who with a poor response to stibogluconate therapy alone. Other alternatives include miltefosine, the first oral antileishmanial drug that has been licensed for use in India. Aminosidine, an aminoglycoside identical to paromomycin, has also been found to be effective in trials in India. A shift from monotherapy to multidrug combinations in short courses delivered at no or affordable cost, through directly observed therapy, appears to be the only way to effectively treat and prevent drug resistance.
• Cutaneous leishmaniasis: Treatment essentially remains the same; sodium antimony gluconate and pentamidine are the drugs of choice, although some authors have indicated that a shorter course of pentamidine for 4 days has been effective in Colombia.¹ Oral drugs such as ketoconazole, itraconazole, and allopurinol are also effective but only in combination with the first-line drugs. Other approaches include local application of paromomycin and intralesional stibogluconate, but these are of limited value only.
• Mucocutaneous leishmaniasis: This responds to a 20-day course of sodium antimony gluconate (ie, sodium stibogluconate); resistant cases are treated with amphotericin.

Diet

A high-protein and high-calorie diet is required during the course of treatment.

MEDICATION

Section 7 of 11  

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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Drug Category: Pentavalent antimony compounds

These compounds are the drugs of choice in patients with visceral leishmaniasis. Sodium stibogluconate is a compound available in English-speaking countries, and meglumine antimonate is a compound available in Latin American countries.

Drug Name	Aminosidine (Gabbromicina)
Description	PO product Humatin (called paromomycin [Humantin] in United States) available in United States as an orphan drug. IV and topical products are not available in the United States. Amebicidal and antibacterial aminoglycoside obtained from a strain of Streptomyces rimosus, active in intestinal amebiasis.
Pediatric Dose	16-20 mg/kg/d IV/IM divided tid for 21 d
Contraindications	Documented hypersensitivity; intestinal obstruction
Interactions	Concurrent administration of other nephrotoxic drugs (eg, other aminoglycosides, penicillins, cephalosporins, amphotericin B, loop diuretics) may increase toxicity
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Not recommended for long-term therapy because of narrow therapeutic index and toxic hazards associated with extended administration; caution in renal failure, hypocalcemia, myasthenia gravis, and conditions that depress neuromuscular transmission; adjust dose in renal impairment

Drug Category: Antiprotozoal agent

Parasite biochemical pathways are different from the human host; thus, drug treatment is directed to the life cycle and may affect the parasite, egg, or larvae.

Drug Category: Systemic antifungal agents

These agents are used in resistant leishmaniasis. Mechanisms of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Drug Name	Ketoconazole (Nizoral)
Description	Imidazole broad-spectrum antifungal agent; inhibits synthesis of ergosterol, which causes cellular components to leak, resulting in fungal cell death.
Adult Dose	600 mg/d PO divided tid for 28 d
Pediatric Dose	10 mg/kg/d PO qd or divided q12h
Contraindications	Documented hypersensitivity; fungal meningitis
Interactions	Isoniazid may decrease bioavailability of ketoconazole; coadministration decreases effects of rifampin or ketoconazole; potent inhibitor of CYP450 3A4 isoenzyme, may increase effect of anticoagulants; may increase toxicity of corticosteroids and cyclosporine (cyclosporine dosage can be adjusted); may decrease theophylline levels
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Hepatotoxicity may occur; may decrease corticosteroid serum levels reversibly (adverse effects avoided with dose of 200-400 mg/d); administer antacid, anticholinergics, or H2 blockers at least 2 h after ketoconazole

Drug Name	Itraconazole (Sporanox)
Description	Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.
Adult Dose	200 mg PO qd for 28 d
Pediatric Dose	3-5 mg/kg/d PO
Contraindications	Documented hypersensitivity; coadministration with cisapride may cause adverse cardiovascular effects (possibly death)
Interactions	Antacids may reduce absorption of itraconazole; inhibits CYP450 3A4 isoenzymes; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may increase tacrolimus and cyclosporine plasma concentrations when high doses are used; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (lovastatin, simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death; may increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce itraconazole levels (phenytoin metabolism may be altered)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in hepatic insufficiencies

Drug Category: Xanthine oxidase inhibitor

These agents may be added to first-line drugs.

Drug Category: Antibiotic agents

Available preparations include pentamidine isethionate (Pentam) and pentamidine dimethanesulfonate (Lomidine). Pentamidine dimethane sulphonate administered in the same dose schedule is more effective than pentamidine isethionate.

Drug Category: Immunomodulatory agents

Interferons are naturally occurring cytokines that possess various biological functions, which include immunosuppressive action. They are produced by cells in response to virus, double-stranded RNA, antigen, or mitogen, and are classified in relation to biochemical properties and cell of origin. They are commercially produced with recombinant DNA technology.

FOLLOW-UP

Section 8 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Monitor patients following treatment for relapse or recrudescence. Prescribe hematinics until hemoglobin levels return to within the reference range.

Deterrence/Prevention

• Personal protection using repellants and nets is an important aspect. In endemic areas, spraying with dichlorodiphenyltrichloroethane (DDT) and other residual insecticides is effective in sandfly control.

Complications

• Bacterial pneumonia, septicemia, dysentery, tuberculosis, cancrum oris, and uncontrolled hemorrhage or its sequelae can occur as complications of leishmaniasis. These complications occur as a consequence of anemia, leucopenia, and thrombocytopenia.

Prognosis

• If untreated, death occurs within 2 years and is often caused by bacterial pneumonia, septicemia, dysentery, tuberculosis, cancrum oris, and uncontrolled hemorrhage or its sequelae.

Patient Education

• Education regarding preventing sandfly bites is the most important measure.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Leishmaniasis should be considered in patients with fever of undetermined origin (FUO) who originate from or have spent time in developing countries.

Special Concerns

• Prevention: Until a safe and effective vaccine is developed for leishmaniasis, control of the sandfly vector, detecting and exterminating the animal vectors, and early diagnosis and treatment are the main measures for controlling the disease. In endemic areas, spraying with DDT and other residual insecticides are effective in sandfly control. Personal protection using insect repellants and nets is effective to prevent the sandfly bite.
• Isolation: Because the disease is mainly transmitted through sandfly bites, standard precautions are recommended.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Distribution map of visceral leishmaniasis.
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Media file 2:  Distribution map of cutaneous leishmaniasis.
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Media file 3:  Distribution map of human immunodeficiency virus (HIV) and leishmaniasis co-infection.
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Media file 4:  The predominant mode of transmission is the sandfly's bite.
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Media file 5:  Leishmania donovani is one of the main Leishmania species that infects humans.
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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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Article Last Updated: Aug 23, 2007