Leishmaniasis comprises a complex of vector-borne diseases, caused by more than 20 species of the protozoan genus Leishmania, and ranging from localized skin ulcers to lethal systemic disease. The most common syndrome is localized cutaneous leishmaniasis. Less common syndromes caused by parasite species usually associated with cutaneous leishmaniasis include mucocutaneous leishmaniasis, disseminated cutaneous leishmaniasis, and leishmaniasis recidivans.   Visceral leishmaniasis is a systemic disease whose typical features include fever, wasting, splenomegaly, hepatomegaly, and bone marrow suppression. Fully manifest clinical visceral leishmaniasis (sometimes called kala-azar) is lethal in nearly all untreated cases.

Disease

The most common syndrome is localized cutaneous leishmaniasis, most frequently caused by L. major and L. tropica in the Old World, and L. braziliensis, L. mexicana, and related species in the New World. The incubation period ranges from a few weeks to several years. The lesion may start as a nodule but eventually ulcerates in most cases. Growth is usually fairly gradual, but continues over a period of months. In the absence of secondary bacterial infection, the lesions are usually non-painful. Local lymphadenopathy can occur, especially with species of the L. braziliensis complex. Spontaneous healing is common, but requires months to years. The proportion that heals without treatment and length of time required for healing vary by species.

Mucocutaneous leishmaniasis usually occurs months or years after healing of primary cutaneous leishmaniasis, most commonly due to parasites of the L. braziliensis complex, and can cause destruction of the nasal septum, palate and other mucosal structures, leading to devastating facial mutilation and, rarely, death from airway involvement.  Factors associated with higher risk of mucocutaneous leishmaniasis include malnutrition and delays in treatment of the antecedent localized cutaneous lesion. Other complicated forms include disseminated cutaneous leishmaniasis (diffuse nodular non-ulcerating disease) and leishmaniasis recidivans (localized slowly progressive non-healing or relapsing lesions). These forms of the disease are rare, difficult to treat, and can be severe.

Visceral leishmaniasis is usually caused by L. donovani and L. infantum (L. chagasi is synonymous with L. infantum). The time from an infective sand fly bite to the onset of visceral leishmaniasis is typically 2 to 6 months but can range from 2 weeks to more than 2 years. The onset is usually insidious, with worsening symptoms over a period of weeks to months. The typical patient presents with fever lasting at least 2 weeks, malaise, and weight loss, and may complain of abdominal fullness related to organomegaly. Common clinical features include fever, wasting, splenomegaly, hepatomegaly, hypergammaglobulinemia, and pancytopenia. Hepatomegaly is usually less prominent than splenomegaly. The course is complicated by immunosuppression and secondary bacterial infections, hemorrhage, anemia, and, when kala-azar occurs during pregnancy, fetal wastage or congenital leishmaniasis. Kala-azar is lethal in nearly all untreated cases. Even in treated patients, case-fatality rates are often 10% or higher. Jaundice, wasting, severe anemia and HIV co-infection are associated with increased risk of mortality.

Post-kala-azar dermal leishmaniasis (PKDL) is a chronic rash seen in apparently cured kala-azar patients in the Indian subcontinent and East Africa. PKDL patients present with erythematous or hypopigmented macules, sometimes progressing to plaques or nodules. In Sudan, PKDL is reported to resolve without treatment in most mild cases, while the condition is said to require universal treatment in the Indian subcontinent. However, recent data from Bangladesh suggest that a proportion of PKDL cases self-resolve in South Asia as well. Up to 60% of kala-azar patients develop PKDL in Sudan. In South Asia, the cumulative incidence is currently thought to be in the range of 5-10%.

HIV-visceral leishmaniasis co-infection poses a growing problem in developing countries. In HIV-infected individuals without severe immunosuppression, manifestations are similar to those in immunocompetent persons. Among those with CD4+ T lymphocyte counts <200 cells/µL, manifestations of leishmaniasis may be more severe or affect unusual sites such as the gastrointestinal tract. In the absence of highly active antiretroviral therapy, the relapse rate after treatment approaches 100%.

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Diagnosis

The diagnosis of cutaneous leishmaniasis relies on the demonstration of Leishmania in tissue biopsy, scraping or impression preparations by microscopy and/or culture in a specialized medium. Species identification is recommended because management may vary depending on the infecting species. Recently, assays based on the use of polymerase chain reaction (PCR), including multiplex assays that can distinguish among several species simultaneously, have become more widely available.

For visceral leishmaniasis, definitive diagnosis requires the demonstration of the parasite by smear or culture in tissue, usually bone marrow or spleen, and thus entails an invasive procedure. Splenic aspirate has the highest sensitivity of available tissue sampling techniques, but carries a risk of serious hemorrhage. Bone marrow aspirates are safer, but have substantially lower sensitivity. Parasites can be detected in tissue samples by light microscopy of stained slides, culture in a specialized medium, or by specific PCR assays. Serological tests (for example, immunofluorescent antibody tests or enzyme linked immunosorbent assays) can be used to demonstrate anti-leishmanial antibodies. These assays have high sensitivity for visceral leishmaniasis in patients without HIV infection, but may show positive results due to subclinical infection or cross-reactions, and are therefore less specific than tissue sampling. Among patients with HIV-visceral leishmaniasis coinfection, the sensitivity of serology was low; parasitological diagnosis is advisable. The introduction of point-of-use antibody-detection tests has improved prospects for diagnosis in remote settings, but the sensitivity of available tests appears to vary by geographic region.

Detailed instructions for the collection and handling of specimens can be requested from the the Division of Parasitic Diseases (404-718-4745 or email parasites@cdc.gov). CDC will also provide specialized culture medium in advance of a planned biopsy.

More on: Diagnostic Procedures

More on: Practical Guide for Laboratory Diagnosis of Leishmaniasis [PDF, 84 KB, 4 pages]

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Treatment

Cutaneous leishmaniasis

Localized cutaneous leishmaniasis is not a life-threatening condition. Treatment decisions should take into account the degree of morbidity balanced against the potential side effects of therapy options. The choice of treatment is dependent on Leishmania species (especially for New World cutaneous leishmaniasis), number, size and location of lesions, and the availability of specific treatment modalities.

Cutaneous leishmaniasis ulcers from several Leishmania species may heal without treatment, although healing usually takes months and will leave a scar. For one or a few small lesions not on the face or over a joint, careful follow-up without drug treatment may be appropriate. The exceptions are ulcers due to L. braziliensis and L. panamensis, which tend not to heal spontaneously and are associated with a small risk (<5%) of subsequent mucocutaneous leishmaniasis.

• The pentavalent antimonial drugs, sodium stibogluconate and meglumine antimoniate, remain the most widely used antileishmanial agents, but are increasingly being replaced by safer drugs. The standard dosing regimen for cutaneous leishmaniasis consists of 20 mg/kg/day of antimony IV or IM for 20 days. Pentostam (sodium stibogluconate) is not approved by the FDA, but is available under investigational new drug (IND) protocol from CDC.
• Oral antifungal drugs (fluconazole, ketoconazole, itraconazole) have been used to treat cutaneous leishmaniasis with variable results depending on the Leishmania species and geographic location. Clinical trials have demonstrated efficacy of the following regimens: fluconazole 200 mg daily for 6 weeks for cutaneous leishmaniasis due to L. major, and ketoconazole 600 mg daily for 28 - 30 days for cutaneous leishmaniasis due to L. mexicana, L. panamensis and L. major. Limited data suggest that a higher dose of fluconazole (8 mg/kg for 4-6 weeks) may have efficacy against L. braziliensis.
• Pentamidine isethionate is used as the first line treatment for L. guyanensis in French Guyana, but is less effective for L. braziliensis than pentavalent antimonial drugs.
• Liposomal amphotericin B appears to have efficacy against several cutaneous leishmanial species, but data are limited and the optimal dose regimen has not been established. This indication is not currently approved by FDA.
• Other treatment modalities that have shown some efficacy for cutaneous leishmaniasis due to some Leishmania species include topical paromomycin ointment, oral miltefosine, thermotherapy, and intralesional pentavalent antimonial drugs. Efficacy data are limited and these treatments are not readily available in the United States.

Visceral leishmaniasis

Specific treatment consists of antileishmanial therapy; the main constraints on the choice of antileishmanial drug are cost and availability. Drug resistance must also be considered, especially for visceral leishmaniasis (VL) originating in the Indian subcontinent.

Patients with VL should be evaluated for HIV co-infection; if found, HIV should be treated aggressively. In the absence of effective immune reconstitution, treatment response is poor in HIV-VL-coinfected patients.

In the absence of treatment, the case-fatality rate of visceral leishmaniasis (kala-azar) is >90 percent. Mortality is often due to hemorrhagic or infectious complications. Supportive therapy to address nutritional status, concomitant anemia, hemorrhagic complications, and secondary infections is therefore essential to optimize treatment outcomes and maximize survival.

• Liposomal amphotericin B is the drug with the highest therapeutic efficacy and the most favorable safety profile. The FDA-approved regimen consists of 3 mg/kg QD on days 1-5, 14 and 21 (total dose 21 mg/kg); other shorter regimens with similar total dose also have high efficacy. A higher total dose (e.g., 40-60 mg/kg total dose) over a longer course is usually recommended for HIV-VL-coinfected patients and post-treatment secondary prophylaxis is generally also indicated.
• The pentavalent antimonial drugs, sodium stibogluconate and meglumine antimoniate, remain the most widely used antileishmanial agents, but are increasingly being replaced by safer drugs. The standard dosing regimen consists of 20 mg/kg/day of antimony IV or IM for 28 to 30 days. Pentostam (sodium stibogluconate) is not approved by the FDA, but is available under IND protocol from CDC.
• Conventional amphotericin B deoxycholate has high antileishmanial efficacy but is associated with high risk of renal toxicity and other side effects. Effective regimens include 0.75 to 1.0 mg/kg daily for 15 to 20 days or 0.75 to 1.0 mg/kg every other day for 30 to 40 days. Alternate day dosing and pretreatment saline loading may decrease risk of renal toxicity and other adverse effects.
• In the past decade two new drugs have been added to the armamentarium: parenteral paromomycin and miltefosine; neither is readily available in the United States.
• Pentamidine isethionate was previously a second-line alternative treatment but is rarely used due to suboptimal efficacy and toxicity (with particular risk of irreversible insulin-dependent diabetes mellitus).

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Prevention & Control

Prevention and control of leishmaniasis is based on two major modalities: measures to decrease human exposure to sand fly bites and interventions to decrease the infection reservoir.   However, the strategy for a given location must be tailored to the local epidemiology and ecology. Specifically, the best control modalities depend on the ecology of transmission (sylvatic or domestic), local sand fly behavior (sylvatic versus peridomestic; resting in houses versus resting in outdoor niches); and the local reservoir hosts (wild animal, domestic animal or human).

Decreasing the Infection Reservoir

For anthroponotic leishmaniasis, rapid diagnosis and effective treatment of patients decreases the infection reservoir.  Theoretically, canine reservoir reduction should decrease transmission of zoonotic VL, but programs that focused on the culling of infected dogs have not proved highly effective, possibly due to inadequate sensitivity of diagnostic testing to detect infectious dogs, and time delays between diagnosis and culling. For sylvatic foci of cutaneous leishmaniasis, eliminating rodent reservoir hosts in a buffer zone around human dwellings may decrease transmission.

Vector Control

For sand fly vector species that rest inside human dwellings, indoor residual insecticide spraying may be an effective intervention. Spraying usually needs to be repeated every 6 months. Use of insecticide-treated nets and other materials can be highly effective when the peak period of vector activity is late in the evening. Long-lasting insecticide-treated nets avoid the need for re-treatment, but the duration of their effect against sand flies under field conditions in endemic areas has not been evaluated. In areas of zoonotic leishmaniasis with a canine reservoir (L. infantum), treated dog collars and other modalities to decrease sand fly biting show promise as interventions to decrease infection exposure for humans.

The use of insect repellent and insecticide treated clothing is advisable for travelers, but is usually not feasible for the populations at highest risk.

More on: Travelers and Leishmaniasis

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