35-03: Leishmaniasis

Leishmaniasis is a zoonosis transmitted by bites of sand flies of the genus Lutzomyia in the Americas and Phlebotomus elsewhere. When sand flies feed on an infected host, the parasitized cells are ingested with the blood meal (eFigure 35–7). Leishmaniasis is caused by about 20 species of Leishmania; taxonomy is complex. Clinical syndromes are generally dictated by the infecting species, but some species can cause more than one syndrome.

The estimated annual incidence of disease has been decreasing, with current estimates of 700,000 to 1 million annual cases of cutaneous disease and 50,000–90,000 cases of visceral disease. Progress against visceral disease has been greatest on the Indian subcontinent.

Visceral leishmaniasis (kala azar) is caused mainly by Leishmania donovani in the Indian subcontinent and East Africa; Leishmania infantum in the Mediterranean, Middle East, China, parts of Asia, and Horn of Africa; and Leishmania chagasi in South and Central America. Other species may occasionally cause visceral disease. Over 90% of cases occur in six countries: India, Bangladesh, Nepal, Sudan, South Sudan, and Brazil. In each locale, the disease has particular clinical and epidemiologic features. The incubation period is usually 4–6 months (range: 10 days to 24 months). Without treatment, the fatality rate reaches 90%. Early diagnosis and treatment reduce mortality to 2–5%.

About 90% of cases of cutaneous leishmaniasis occur in Afghanistan, Pakistan, Syria, Saudi Arabia, Algeria, Iran, Brazil, and Peru. Old World cutaneous leishmaniasis is caused mainly by Leishmania tropica, Leishmania major, and Leishmania aethiopica in the Mediterranean, Middle East, Africa, Central Asia, and Indian subcontinent. New World cutaneous leishmaniasis is caused by Leishmania mexicana, Leishmania amazonensis, and the species listed below for mucocutaneous disease in Central and South America. Mucocutaneous leishmaniasis (espundia) occurs in lowland forest areas of the Americas and is caused by Leishmania braziliensis, Leishmania panamensis, and Leishmania peruviana.

A. Symptoms and Signs

1. Visceral leishmaniasis (kala azar)

Most infections are subclinical, but a small number progress to full-blown disease. A local nonulcerating nodule at the site of the sand fly bite may precede systemic manifestations but usually is inapparent. The onset of illness may be acute, within 2 weeks of infection, or insidious. Symptoms and signs include fever, chills, sweats, weakness, anorexia, weight loss, cough, and diarrhea. The spleen progressively becomes greatly enlarged, firm, and nontender. The liver is somewhat enlarged, and generalized lymphadenopathy may occur. Hyperpigmentation of skin can be seen, leading to the name kala azar (“black fever”). Other signs include skin lesions, petechiae, gingival bleeding, jaundice, edema, and ascites. As the disease progresses, severe wasting and malnutrition are seen; death eventually occurs, often due to secondary infections, within months to a few years. Post–kala azar dermal leishmaniasis may appear after apparent cure in the Indian subcontinent and Sudan. It may simulate leprosy, with hypopigmented macules or nodules developing on preexisting lesions. Viscerotropic leishmaniasis has been reported in small numbers of American military personnel in the Middle East, with mild systemic febrile illnesses after L tropica infections.

2. Old World and New World cutaneous leishmaniasis

Cutaneous swellings appears 1 week to several months after sand fly bites and can be single or multiple. Characteristics of lesions and courses of disease vary depending on the leishmanial species and host immune response. Lesions begin as small papules and develop into nonulcerated dry plaques or large encrusted ulcers with well-demarcated raised and indurated margins (Figure 35–1). Satellite lesions may be present. The lesions are painless unless secondarily infected. Local lymph nodes may be enlarged. Systemic symptoms are uncommon, but fever, constitutional symptoms, and regional lymphadenopathy may be seen. For most species, healing occurs spontaneously in months to a few years, but scarring is common.

Leishmaniasis recidivans is a relapsing form of L tropica infection associated with hypersensitivity, in which the primary lesion heals centrally, but spreads laterally, with extensive scarring. Diffuse cutaneous leishmaniasis involves spread from a primary lesion, with local dissemination of nodules and a protracted course. Disseminated cutaneous leishmaniasis involves multiple nodular or ulcerated lesions, often with mucosal involvement.

3. Mucocutaneous leishmaniasis (espundia)

In Latin America, mucosal lesions develop in a small percentage of persons infected with L braziliensis and some other species, usually months to years after resolution of a cutaneous lesion. Nasal congestion is followed by ulceration of the nasal mucosa and septum, progressing to involvement of the mouth, lips, palate, pharynx, and larynx. Extensive destruction can occur, and secondary bacterial infection is common.

4. Infections in patients with AIDS

Leishmaniasis is an opportunistic infection in persons with AIDS. Visceral leishmaniasis can present late in the course of HIV infection, with fever, hepatosplenomegaly, and pancytopenia. The gastrointestinal tract, respiratory tract, and skin may also be involved.

B. Laboratory Findings

Identifying amastigotes within macrophages in tissue samples provides a definitive diagnosis. In visceral leishmaniasis, fine-needle aspiration of the spleen for culture and tissue evaluation is generally safe, and yields a diagnosis in over 95% of cases. Bone marrow aspiration is less sensitive but safer and diagnostic in most cases, and Giemsa-stained buffy coat of peripheral blood may occasionally show organisms. Cultures with media available from the CDC will grow promastigotes within a few days to weeks. Molecular assays can also be diagnostic. Serologic tests may facilitate diagnosis, but none are sufficiently sensitive or specific to be used alone. Numerous antibody-based rapid diagnostic tests are available; these have shown good specificity but limitations in sensitivity outside of India. Antigen-based rapid diagnostic tests may offer improved sensitivity. For cutaneous lesions, biopsies should be taken from the raised border of a skin lesion, with samples for histopathology, touch preparation, and culture. The histopathology shows inflammation with mononuclear cells. Macrophages filled with amastigotes may be present, especially early in infection. An intradermal leishmanin (Montenegro) skin test is positive in most individuals with cutaneous disease but negative in those with progressive visceral or diffuse cutaneous disease; this test is not approved in the United States. In mucocutaneous leishmaniasis, diagnosis is established by detecting amastigotes in scrapings, biopsy preparations, or aspirated tissue fluid, but organisms may be rare. Cultures from these samples may grow organisms. Serologic studies are often negative, but the leishmanin skin test is usually positive.

A. Visceral Leishmaniasis

The treatment of choice for visceral leishmaniasis on the Indian subcontinent is liposomal amphotericin B (approved by the FDA), which is generally effective and well tolerated but expensive. Standard dosing is 3 mg/kg/day intravenously on days 1–5, 14, and 21. Simpler regimens that have shown good efficacy in India include four doses of 5 mg/kg over 4–10 days and a single dose of 15 mg/kg, but efficacies of shorter regimens have been lower outside India. A single infusion of an amphotericin B lipid emulsion, which is more affordable than liposomal preparations, showed excellent efficacy, albeit lower than that of the liposomal formulation. Conventional amphotericin B deoxycholate, which is much less expensive, is also highly effective but with more toxicity. It is administered as a slow intravenous infusion of 1 mg/kg/day for 15–20 days or 0.5–1 mg/kg every second day for up to 8 weeks. Infusion-related side effects with conventional or liposomal amphotericin B include gastrointestinal symptoms, fever, chills, dyspnea, hypotension, and hepatic and renal toxicity.

Pentavalent antimonials remain the most commonly used drugs to treat leishmaniasis in most areas. Response rates are good outside India, but in India, resistance is a major problem. Two preparations are available, sodium stibogluconate in the United States and many other areas and meglumine antimonate in Latin America and francophone countries; the compounds appear to have comparable activities. In the United States, sodium stibogluconate can be obtained from the CDC Drug Service (www.cdc.gov/laboratory/drugservice). Standard dosing for either antimonial is 20 mg/kg once daily intravenously (preferred) or intramuscularly for 20 days for cutaneous leishmaniasis and 28 days for visceral or mucocutaneous disease. Toxicity increases over time, with development of gastrointestinal symptoms, fever, headache, myalgias, arthralgias, pancreatitis, and rash. Intramuscular injections can cause sterile abscesses. Monitoring should include serial ECGs, and changes are indications for discontinuation to avoid progression to serious arrhythmias.

The efficacy of amphotericin B is lower in East Africa than in Asia, and the standard treatment is a combination of sodium stibogluconate (20 mg/kg/day intravenously) plus paromomycin (15 mg/kg/day intramuscularly) for 17 days, with demonstrated excellent efficacy; liposomal amphotericin B may be considered in elderly or pregnant patients due to toxicity concerns.

Miltefosine is the first oral drug for the treatment of leishmaniasis, and it is registered in India for this indication. It initially demonstrated excellent results in India, but efficacy is decreasing due to drug resistance. It can be administered at a daily oral dose of 2.5 mg/kg in two divided doses for 28 days. A 28-day course of miltefosine (2.5 mg/kg/day) is also effective for the treatment of New World cutaneous leishmaniasis. Vomiting, diarrhea, and elevations in transaminases and kidney function studies are common, but generally short-lived, side effects.

Pentamidine isethionate is an alternative therapy for visceral leishmaniasis, given daily or on alternate days for 15 doses of 2–4 mg/kg intramuscularly or intravenously, but it is no longer widely used. Side effects are as described for the treatment of African trypanosomiasis.

The aminoglycoside paromomycin (11 mg/kg/day intramuscularly for 21 days) was shown to be similarly efficacious to amphotericin B for the treatment of visceral disease in India, where it is approved for this indication. It is much less expensive than liposomal amphotericin B or miltefosine. The drug is well tolerated; side effects include ototoxicity and reversible elevations in liver enzymes.

The use of drug combinations to improve treatment efficacy, shorten treatment courses, and reduce the selection of resistant parasites has been actively studied. In India, compared to a standard 30-day (treatment on alternate days) course of amphotericin, noninferior efficacy and decreased adverse events were seen with a single dose of liposomal amphotericin plus a 7-day course of miltefosine, a single dose of liposomal amphotericin plus a 10-day course of paromomycin, or a 10-day course of miltefosine plus paromomycin. A combination of sodium stibogluconate and paromomycin is the standard treatment in East Africa.

B. Cutaneous Leishmaniasis

In the Old World, cutaneous leishmaniasis is generally self-healing over some months and does not metastasize to the mucosa, so it may be justified to withhold treatment in regions without mucocutaneous disease if lesions are small and cosmetically unimportant. Lesions on the face or hands are generally treated. New World leishmaniasis has a greater risk of progression to mucocutaneous disease, so treatment is more often warranted. Standard therapy is with pentavalent antimonials for 20 days, as described above. Other treatments include those discussed above for visceral disease, azole antifungals, and allopurinol. In studies in South America, a 28-day course of miltefosine was superior to a 20-day course of meglumine antimoniate, and oral fluconazole also showed good efficacy. Topical therapy has included intralesional antimony, intralesional pentamidine, paromomycin ointment, cryotherapy, local heat, and surgical removal. Diffuse cutaneous leishmaniasis and related chronic skin processes generally respond poorly to therapy.

C. Mucocutaneous Leishmaniasis

Cutaneous infections from regions where parasites include those that cause mucocutaneous disease (eg, L braziliensis in parts of Latin America) should all be treated to help prevent disease progression. Treatment of mucocutaneous disease with antimonials is disappointing, with responses in only about 60% in Brazil. Other therapies listed above for visceral leishmaniasis may also be used, although they have not been well studied for this indication.

Personal protection measures for avoidance of sand fly bites include use of insect repellants, fine-mesh insect netting, long sleeves and pants, and avoidance of warm shaded areas where flies are common. Disease control measures include destruction of animal reservoir hosts, mass treatment of humans in disease-prevalent areas, residual insecticide spraying in dwellings, limiting contact with dogs and other domesticated animals, and use of permethrin-impregnated collars for dogs.