Leishmaniasis is present in scattered areas worldwide. Human infection is caused by 20 Leishmania species that are morphologically indistinguishable but can be differentiated by laboratory analysis.
Etiology of Leishmaniasis
Leishmania promastigotes are transmitted by sand flies (Phlebotomus, Lutzomyia) to vertebrate hosts. Vector sand flies are infected by biting infected humans or animals. Animal reservoirs vary with the Leishmania species and geographic location and include dogs, other canines, rodents, and other animals. In the Indian subcontinent, humans are the reservoir for L. donovani.
Rarely, infection is spread by blood transfusion, shared needles, congenitally, or sexually.
Pathophysiology of Leishmaniasis
After inoculation by a sand fly, extracellular promastigotes are phagocytized by host macrophages; inside these cells, they transform into amastigotes.
The parasites may remain localized in the skin or spread to the mucosa of the nasopharynx or disseminate to bone marrow, the spleen, the liver, and occasionally other organs, resulting in 3 major clinical forms of leishmaniasis:
Cutaneous leishmaniasis is also known as oriental or tropical sore, Delhi or Aleppo boil, uta or chiclero ulcer, or forest yaws. The major causative species are
L. major and L. tropica in southern Europe, Asia, and Africa
L. mexicana and related species in Mexico and Central and South America
L. braziliensis and related species in Central and South America
Cases have occurred among US military personnel serving in Iraq and Afghanistan and among travelers to endemic areas in Central and South America, Israel, and elsewhere. Uncommonly, L. braziliensis spreads widely in the skin causing disseminated cutaneous leishmaniasis.
Mucosal leishmaniasis (espundia) is caused mainly by L. braziliensis but occasionally by other Leishmania species. The parasites are thought to spread from the initial skin lesion through the lymphatics and blood to nasopharyngeal tissues. Symptoms and signs of mucosal leishmaniasis typically develop months to years after the appearance of the skin lesion.
Visceral leishmaniasis (kala-azar, Dumdum fever) is typically caused by L. donovani or L. infantum (previously called L. chagasi in Latin America) and occurs in India, Africa (particularly the Sudan), Central Asia, the Mediterranean basin, South and Central America, and infrequently China. Most cases occur in northeastern India. Parasites disseminate from the site of the sand fly bite in the skin to regional lymph nodes, the spleen, the liver, and bone marrow and cause systemic symptoms. Subclinical infections are common; only a minority of infected patients develop progressive visceral disease. Symptomatic infection with L. infantum is more common among children than adults. Visceral leishmaniasis is an opportunistic infection in patients with AIDS or other immunocompromising conditions.
Symptoms and Signs of Leishmaniasis
In cutaneous leishmaniasis, a well-demarcated skin lesion develops at the site of a sand fly bite, usually within several weeks to months. Multiple lesions may occur after multiple infective bites or with metastatic spread. Their appearance varies. The initial lesion is often a papule that slowly enlarges, ulcerates centrally, and develops a raised, erythematous border where intracellular parasites are concentrated. Ulcers are typically painless and cause no systemic symptoms unless secondarily infected. Lesions heal spontaneously after several months but may persist for years. They leave a depressed, burn-like scar. The course depends on the infecting Leishmania species and the host’s immune status.
Diffuse cutaneous leishmaniasis, a rare syndrome, results in widespread nodular skin lesions resembling those of lepromatous leprosy Leprosy Leprosy is a chronic infection usually caused by the acid-fast bacilli Mycobacterium leprae, which has a unique tropism for peripheral nerves, skin, and mucous membranes of the upper respiratory... read more . It results from cell-mediated anergy to the organism.
Mucosal leishmaniasis due to L. braziliensis and related organisms typically starts with one or more primary cutaneous ulcers. Spread to the mucosa via lymphatics and the bloodstream probably occurs early in infection. The skin lesions heal spontaneously; but progressive mucosal lesions may not become apparent for months to years. Typically, patients have nasal stuffiness, discharge, and pain. Over time, the infection may progress, resulting in gross mutilation of the nose, palate, oral pharynx, or face.
In visceral leishmaniasis, the clinical manifestations usually develop gradually over weeks to months after inoculation of the parasite but can be acute. Irregular fever, hepatosplenomegaly, pancytopenia, and polyclonal hypergammaglobulinemia with a reversed albumin:globulin ratio occur. In some patients, there are twice-daily temperature spikes. Cutaneous skin lesions rarely occur. Emaciation and death occur within months to years in patients with progressive infections. Those with asymptomatic, self-resolving infections and survivors (after successful treatment) are resistant to further attacks unless cell-mediated immunity is impaired (eg, by AIDS). Relapse may occur years after initial infection.
Post kala-azar dermal leishmaniasis (PKDL) may develop after treatment for visceral leishmaniasis in patients in the Sudan and India. It is characterized by flat or nodular cutaneous lesions that contain many parasites. In patients in the Sudan, these lesions develop at the end of or within 6 months of therapy and spontaneously resolve a few months to a year later. In patients in India and adjacent countries, skin lesions typically develop 1 to 2 years after therapy ends and can last for many years. PKDL lesions are thought to be a reservoir for the spread of infection in these areas.
Diagnosis of Leishmaniasis
Light microscopy of Wright-Giemsa or Giemsa-stained tissue samples, touch preparations, or aspirates
Antibody titers for visceral leishmaniasis, but not for cutaneous or mucosal leishmaniasis
Culture (special media required)
Polymerase chain reaction–based assays
Parasites are usually difficult to find or isolate in culture from biopsies of mucosal lesions.
Organisms causing simple cutaneous leishmaniasis can be differentiated from those capable of causing mucosal leishmaniasis based on the geographic area of acquisition, specific DNA probes, or analysis of cultured parasites.
Serologic tests can help diagnose visceral leishmaniasis; high titers of antibodies to a recombinant leishmanial antigen (rk39) are present in most immunocompetent patients with visceral leishmaniasis. But antibodies may be absent in patients with AIDS or other immunocompromising conditions. Serologic tests for antileishmanial antibodies are not helpful in the diagnosis of cutaneous leishmaniasis.
Polymerase chain reaction (PCR)–based assays of aspirates from bone marrow, the spleen, or lymph nodes in patients with visceral leishmaniasis or of biopsy, aspirates, or touch preparations from a skin lesion help diagnose leishmaniasis.
The leishmanin skin test that detects a delayed-type hypersensitivity response to leishmanial antigens is not available in the US. It is typically positive in patients with cutaneous and mucosal leishmaniasis but negative in those with active visceral leishmaniasis.
Treatment of Leishmaniasis
Drug therapy depends on the clinical syndrome and other factors
For cutaneous infection, topical treatment, sodium stibogluconate injection or topical paromomycin outside the US or heat therapy or cryotherapy
For systemic treatment of cutaneous, mucosal, or visceral leishmaniasis, liposomal amphotericin IV or miltefosine orally
Alternatively, amphotericin B deoxycholate IV or pentavalent antimonials (sodium stibogluconate, meglumine antimoniate) IV or IM if the infecting Leishmania species is likely to be susceptible
Treatment of leishmaniasis is complicated. The therapeutic approach depends on the following:
Infecting Leishmania species
Geographic location of acquisition
Organism's likelihood of susceptibility to antileishmanial drugs
Immune status of the host
Detailed recommendations for treatment are available (1 Treatment references Leishmaniasis is caused by species of Leishmania. Manifestations include cutaneous, mucosal, and visceral syndromes. Cutaneous leishmaniasis causes painless chronic skin lesions ranging from... read more , 2 Treatment references Leishmaniasis is caused by species of Leishmania. Manifestations include cutaneous, mucosal, and visceral syndromes. Cutaneous leishmaniasis causes painless chronic skin lesions ranging from... read more ).
Treatment of cutaneous leishmaniasis may be topical or systemic, depending on the lesion and organism.
If a lesion is small, spontaneously healing, and not caused by a Leishmania species associated with mucosal leishmaniasis, it can be closely followed, rather than treated.
Topical treatment is an option for small, uncomplicated lesions. Intralesional injection of sodium stibogluconate has been used for many years for simple cutaneous leishmaniasis in Europe and Asia; it is not currently available in the US for intralesional use. Other topical options include heat therapy, which requires a specialized system for administration, and cryotherapy; both can be painful and are practical only when used to treat small lesions. In addition, topical paromomycin is used outside the US as an ointment that contains 15% paromomycin and 12% methylbenzethonium chloride in soft white paraffin.
Systemic therapy is used in patients who have the following:
Infection by L. braziliensis or related organisms associated with mucosal leishmaniasis
Complex cutaneous leishmaniasis with multiple, large, widespread, or disfiguring lesions
Compromised cell-mediated immunity
In the US, systemic options include liposomal amphotericin B, miltefosine, and amphotericin B deoxycholate. Sodium stibogluconate or meglumine antimoniate may be used if infection was acquired in areas where antimony-resistance is not prevalent. Liposomal amphotericin B and amphotericin B deoxycholate are typically given in the regimens used for visceral leishmaniasis Visceral leishmaniasis Leishmaniasis is caused by species of Leishmania. Manifestations include cutaneous, mucosal, and visceral syndromes. Cutaneous leishmaniasis causes painless chronic skin lesions ranging from... read more .
Miltefosine, which has the advantage of oral administration, can be effective for cutaneous leishmaniasis, particularly when caused by Leishmania braziliensis, Leishmania guyanensis, and Leishmania panamensis. Miltefosine is dosed by body weight: patients 30 to 44 kg, 50 mg orally twice a day for 28 days; ≥ 45 kg, 50 mg orally 3 times a day for 28 days. Adverse effects include nausea, vomiting, transient elevations in aminotransferases, and dizziness. Miltefosine is contraindicated during pregnancy; women of childbearing age who are taking this drug must use effective birth control measures.
Pentavalent antimonials (sodium stibogluconate or meglumine antimoniate) should be used only if the infecting Leishmania species is likely to be susceptible. Sodium stibogluconate is available from the Centers for Disease Control and Prevention (CDC) (CDC Drug Service at 404 639-3670). Meglumine antimoniate (a pentavalent antimonial) is used in Latin America. Doses of both are based on their pentavalent antimony content—20 mg/kg IV (slow infusion required) or IM once a day for 20 days. Adverse effects include nausea, vomiting, malaise, elevated amylase and/or liver enzymes, and cardiotoxicity (arrhythmias, myocardial depression, heart failure, ECG changes, cardiac arrest). The incidence of adverse effects increases with age. The drug is stopped if patients develop cardiotoxicity.
Alternatives include azoles (eg, fluconazole). Fluconazole 200 mg orally once a day for 6 weeks is commonly ineffective, but success has been reported with higher daily doses in some areas.
Diffuse cutaneous leishmaniasis is relatively resistant to treatment.
The optimal treatment is uncertain.
Recent studies suggest that liposomal amphotericin B with a cumulative dose ranging from 20 to 60 mg/kg or miltefosine dosed by body-weight: patients 30 to 44 kg, 50 mg orally twice a day for 28 days; ≥ 45 kg, 50 mg orally 3 times a day for 28 days are often effective, but data are limited. Adverse effects of miltefosine include nausea, vomiting, transient elevations in aminotransferases, and dizziness; the drug is contraindicated during pregnancy so women of childbearing age who are taking this drug must use effective birth control measures. Historically, pentavalent antimonials have been used in Latin America. Another alternative is amphotericin B deoxycholate 0.5 to 1.0 mg/kg IV once a day or every other day for a total dose of 20 to 45 mg/kg.
Reconstructive surgery may be required if mucosal leishmaniasis grossly distorts the nose or palate, but surgery should be delayed for 12 months after successful chemotherapy to avoid losing grafts because of relapses.
Liposomal amphotericin B and miltefosine are approved by the US Food and Drug Administration for treatment of visceral leishmaniasis; other lipid-associated amphotericin preparations may be effective but have been less well-studied.
Dosage of liposomal amphotericin B is
For immunocompetent patients: 3 mg/kg IV once a day for 5 days and then once a day on days 14 and 21 (total dose of 21 mg/kg)
For patients with AIDS or other immunocompromising conditions: 4 mg/kg IV once a day on days 1 to 5, 10, 17, 24, 31, and 38 (total dose of 40 mg/kg)
Miltefosine orally, dosed by body-weight: patients 30 to 44 kg, 50 mg twice a day for 28 days or for patients ≥ 45 kg, 50 mg 3 times a day for 28 days can be used to treat immunocompetent patients who acquired L. donovani in India or adjacent areas of South Asia, who are > 12 years of age, who weigh > 30 kg, and who are not pregnant or breastfeeding.
Pentavalent antimonials can be used to treat visceral leishmaniasis acquired in Latin America or other areas of the world where the infection is not resistant to these drugs; sodium stibogluconate may be obtained in the US from the CDC Drug Service (404-639-3670). Dosage is 20 mg/kg (based on the antimony content) IV or IM once a day for 28 days.
An alternative is amphotericin B deoxycholate 1 mg/kg IV once a day for 15 to 20 days or every other day for up to 8 weeks.
Relapses are common among patients with AIDS or other immunocompromising conditions. Antiretroviral drugs can help restore immune function in those with AIDS, reducing the likelihood of relapse. Secondary prophylaxis with an antileishmanial drug may help prevent relapses in AIDS patients with CD4 counts < 200/mcL.
Supportive measures (eg, adequate nutrition, transfusions, antibiotics for secondary bacterial infection) are often necessary for patients with visceral leishmaniasis.
1. Aronson N, Herwaldt BL, Libman M, et al: Diagnosis and treatment of leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Clin Infect Dis 63 (12):e202-e264, 2016. doi: 10.1093/cid/ciw670
2. CDC: Resources for Health Professionals: Treatment.
Prevention of Leishmaniasis
For prevention of leishmaniasis, the following may help:
Treatment of leishmaniasis in a geographic area where humans are the reservoir
Reduction of the vector population by spraying residual insecticide (one that has prolonged duration of action) in sites of domestic transmission
Personal protective measures including insect repellants on exposed skin and protective clothing
Control of nonhuman reservoirs
Travelers to endemic areas should use insect repellents containing DEET (diethyltoluamide) on exposed skin. Insect screens, bed nets, and clothing are more effective if treated with permethrin because the small sand flies can penetrate mechanical barriers.
Vaccines are not currently available.
Leishmaniasis is present in scattered areas worldwide and is transmitted by bites of sand flies.
The parasites may remain localized in the skin (cutaneous leishmaniasis), spread to the mucosa (mucosal leishmaniasis), or disseminate to the liver, the spleen, and bone marrow (visceral leishmaniasis).
Diagnose using Wright-Giemsa or Giemsa-stained smears, cultures, or polymerase chain reaction-based assays; serologic tests can help diagnose visceral leishmaniasis in immunocompetent patients but are not helpful in many patients with AIDS or with cutaneous or mucosal leishmaniasis.
Treat small, uncomplicated skin lesions with locally applied heat or cryotherapy or, outside the US, with topical paromomycin or intralesional sodium stibogluconate.
Systemic treatment options for complex cutaneous leishmaniasis, mucosal leishmaniasis, and visceral leishmaniasis include liposomal amphotericin B, miltefosine, and amphotericin B deoxycholate; sodium stibogluconate or meglumine antimoniate may be used if infection is acquired in areas where the infecting Leishmania species is likely to be susceptible.
Drug resistance to antimonials is common in India and adjacent countries and is emerging in other areas.