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Leishmaniasis

By Richard D. Pearson, MD, Emeritus Professor of Medicine, University of Virginia School of Medicine

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Leishmaniasis is caused by species of Leishmania. Manifestations include cutaneous, mucosal, and visceral syndromes. Cutaneous leishmaniasis causes painless chronic skin lesions ranging from nodules to large ulcers that can persist for months to years but eventually heal. Mucosal leishmaniasis affects nasopharyngeal tissues and can cause gross mutilation of the nose and palate. Visceral leishmaniasis causes irregular fever, hepatosplenomegaly, pancytopenia, and polyclonal hypergammaglobulinemia with high mortality in untreated patients. Diagnosis is by demonstrating parasites in smears or cultures and increasingly by PCR-based assays at reference centers. Serologic testing can be helpful in diagnosing visceral but not cutaneous leishmaniasis. Treatment of visceral leishmaniasis is with liposomal amphotericin B. Alternatives include amphotericin B deoxycholate, pentavalent antimony compounds (sodium stibogluconate, meglumine antimonate), and miltefosine. A variety of topical and systemic treatments are available for cutaneous leishmaniasis depending on the causative species and clinical manifestations.

Leishmaniasis is present in scattered areas worldwide. Human infection is caused by 20 Leishmania sp that are morphologically indistinguishable but can be differentiated by laboratory analysis.

Etiology

Leishmania promastigotes are transmitted by sand flies (Phlebotomus sp, Lutzomyia sp) to vertebrate hosts. Vector sand flies are infected by biting infected humans or other animals. Animal reservoirs vary with the Leishmania sp 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

After inoculation by a sand fly, 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

  • Mucosal

  • Visceral

Cutaneous leishmaniasis is also known as oriental or tropical sore, Delhi or Aleppo boil, uta or chiclero ulcer, or forest yaws. The causative agents 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 sp. 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 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

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 usually heal spontaneously after several months but may persist for years. They leave a depressed, burn-like scar. The course depends on the infecting Leishmania sp and the host’s immune status.

Diffuse cutaneous leishmaniasis, a rare syndrome, results in widespread nodular skin lesions resembling those of lepromatous leprosy. It results from cell-mediated anergy to the organism.

Mucosal leishmaniasis starts with a primary cutaneous ulcer. This lesion heals spontaneously; 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, 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 mo of therapy and persist for a few months to a year after therapy. In patients in India and adjacent countries, the lesions develop 1 to 2 yr 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

  • Light microscopy of tissue samples, touch preparations, or aspirates; when available, PCR-based assays

  • For visceral leishmaniasis, antibody titers

  • For cutaneous and mucosal leishmaniasis, skin testing (not available in the US)

  • Culture (special media required)

A definite diagnosis of leishmaniasis is made by any of the following:

  • Demonstrating organisms in Giemsa-stained smears

  • Isolating Leishmania in cultures

  • 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

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 site 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.

The leishmanin skin test 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

  • Various drugs depending on the clinical syndrome and other factors

  • For topical treatment, sodium stibogluconate injection or topical paromomycin outside the US or heat therapy or cryotherapy

  • For systemic treatment, liposomal amphotericin IV, amphotericin B deoxycholate IV, or miltefosine po

  • Alternatively, pentavalent antimonials (sodium stibogluconate, meglumine antimoniate) only if the infecting Leishmania sp is likely to be susceptible

Treatment of leishmaniasis is complicated; which drugs are used depends on the following:

  • Clinical syndrome

  • Infecting Leishmania sp

  • Geographic location of acquisition

  • Organism's likelihood of susceptibility to treatment

  • Immune status of the host

Detailed recommendations for treatment are available (1, 2).

Cutaneous leishmaniasis

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 sp 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 miltefosine, liposomal amphotericin B, amphotericin B deoxycholate, and sodium stibogluconate (only if infection was acquired in areas where resistance to them is not prevalent). Liposomal amphotericin B and amphotericin B deoxycholate are typically given in the regimens used for visceral leishmaniasis.

Miltefosine 2.5 mg/kg (maximum, 150 mg/day) po once/day for 28 days can be effective for cutaneous leishmaniasis. 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, meglumine antimoniate) should be used only if the infecting Leishmania sp is likely to be susceptible. Sodium stibogluconate is available from the CDC (call the Emergency Operations Center at 770-488-7100). 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/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, itraconazole). Fluconazole 200 mg po once/day for 6 wk is commonly ineffective, sometimes leading to the use of higher daily doses.

Diffuse cutaneous leishmaniasis is relatively resistant to treatment.

Mucosal leishmaniasis

The optimal treatment is uncertain. Historically, pentavalent antimonials have been used.

Another option is amphotericin B deoxycholate 0.5 to 1.0 mg/kg once/day or every other day for a total daily dose of about 20 to 45 mg/kg. Recent studies suggest that liposomal amphotericin B with a cumulative dose ranging from 20 to 60 mg/kg or miltefosine 2.5 mg/kg (maximum, 150 mg/day) po once/day for 28 days is effective, but data are limited.

Reconstructive surgery may be required if mucosal leishmaniasis grossly distorts the nose or palate, but surgery should be delayed for 12 mo after successful chemotherapy to avoid losing grafts because of relapses.

Visceral leishmaniasis

Liposomal amphotericin B and miltefosine are approved by the FDA 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/day for 5 days and then once/day on days 14 and 21 (total dose of 21 mg/kg)

  • For patients with AIDS or other immunocompromising conditions:s 4 mg/kg IV once/day on days 1 to 5, 10, 17, 24, 31, and 38 (total dose of 40 mg/kg)

Miltefosine 2.5 mg/kg po once/day (maximum 150 mg/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 yr 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; they may be used in the US after consultation with the CDC. Dosage is 20 mg/kg (based on the antimony content) IV or IM once/day for 28 days.

An alternative is amphotericin B deoxycholate 1 mg/kg IV once/day for 15 to 20 days or every other day for up to 8 wk.

Relapses are common among patients with AIDS or other immunocompromising conditions. Antiretroviral drugs can help restore immune function, reducing the likelihood of relapse. Secondary prophylaxis with an antileishmanial drug may help prevent relapses in AIDS patients with CD4 counts < 200/μL.

Supportive measures (eg, adequate nutrition, transfusions, antibiotics for secondary bacterial infection) are often necessary for patients with visceral leishmaniasis.

Treatment reference

  • 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

For prevention, the following may help:

  • Treatment of leishmaniasis in a geographic area where humans are a reservoir

  • Reduction of the vector population by spraying residual insecticide (one that has prolonged duration of action) in sites of domestic transmission

  • Control of nonhuman reservoirs

Travelers to endemic areas should use insect repellents containing DEET (diethyltoluamide). Insect screens, bed nets, and clothing are more effective if treated with permethrin or pyrethrum because the small sand flies can penetrate mechanical barriers.

Vaccines are not currently available.

Key Points

  • 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 Giemsa-stained smears, cultures, or PCR-based assays; serologic tests can help diagnose visceral leishmaniasis in immunocompetent patients but are not helpful in 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 includes liposomal amphotericin B, amphotericin B deoxycholate, and miltefosine; sodium stibogluconate is an alternative if infection is acquired in areas where Leishmania spp are likely to be susceptible.

  • Drug resistance to antimonials is an increasing problem, particularly in India.

More Information

  • CDC: Resources for Health Professionals: Treatment.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • DIFLUCAN
  • ELIMITE, NIX
  • SPORANOX
  • No US brand name

* This is the Professional Version. *