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The term leishmaniasis encompasses multiple clinical syndromes, several of which are described here—the cutaneous, mucosal, and visceral forms, which result from infection of macrophages in the dermis, in the naso-oropharyngeal mucosa, and throughout the reticuloendothelial system, respectively. For all three forms, the infection can range from asymptomatic to severe. Cutaneous and mucosal leishmaniasis can cause substantial morbidity, whereas visceral leishmaniasis can be life threatening.
This is the most common form of leishmaniasis, both in general and in U.S. travelers. Unless otherwise specified, cutaneous leishmaniasis refers to localized cutaneous leishmaniasis, rather than to much less common forms, such as diffuse cutaneous leishmaniasis and disseminated cutaneous leishmaniasis. Different Leishmania species cause Old World versus New World (American) cutaneous leishmaniasis. In the Old World (the Eastern Hemisphere), the etiologic agents include Leishmania tropica, L. major, and L. aethiopica, as well as L. infantum and L. donovani. The main species in the New World (the Western Hemisphere) are either in the L. mexicana species complex (L. mexicana, L. amazonensis, and L. venezuelensis) or the subgenus Viannia (L. [V.] braziliensis, L. [V.] guyanensis, L. [V.] panamensis, and L. [V.] peruviana). The Viannia subgenus is also referred to as the L. (V.) braziliensis species complex.
In general, cutaneous leishmaniasis causes skin lesions, which can persist for months, sometimes years. The skin lesions usually develop within several weeks or months after the exposure but occasionally first appear years later (for example, in the context of trauma or immunosuppression). The lesions typically evolve from papules to nodular plaques to ulcerative lesions, with a raised border and central depression, which can be covered by scab or crust; some lesions persist as nodules. The lesions usually are painless but can be painful, especially if ulcerative lesions become infected with bacteria or if the lesions are near a joint. The healing process typically results in atrophic scarring.
Even patients with localized cutaneous leishmaniasis quite commonly develop more than one primary lesion (on the same or different parts of the body), satellite lesions, regional lymphadenopathy (occasionally bubonic), and/or nodular lymphangitis (sporotrichoid-like subcutaneous nodules). Sometimes lymphadenopathy is noticed first, before skin lesions develop.
Mucosal leishmaniasis (also called espundia) traditionally refers to a metastatic sequela of New World cutaneous infection, which results from dissemination of parasites from the skin to the naso-oropharyngeal mucosa. Mucosal leishmaniasis is caused by species in the Viannia subgenus (especially L. [V.] braziliensis but also L. [V.] panamensis and sometimes L. [V.] guyanensis); it also can be caused by L. (Leishmania) amazonensis. Adequate systemic treatment of cutaneous leishmaniasis caused by these species is thought to reduce the risk for mucosal disease, but some risk may remain. The magnitudes and determinants (parasite and host factors) of the risks for mucosal dissemination and for mucosal disease per se are poorly understood; even for the same species (for example, L. [V.] braziliensis), the risks appear to vary among geographic regions in the Americas.
Mucosal leishmaniasis usually becomes clinically evident within several years (sometimes as long as decades) of the original cutaneous lesions, which typically were not treated at all or were treated suboptimally. However, mucosal and skin lesions may be noted concomitantly (mucocutaneous leishmaniasis), and some patients had subclinical cutaneous infection.
The initial manifestations of mucosal leishmaniasis usually are persistent, unusual nasal symptoms (such as stuffiness or bleeding), although oral or pharyngeal symptoms sometimes are noticed first. If untreated, the disease can progress to ulcerative destruction of the naso-oropharyngeal mucosa (such as perforation of the nasal septum).
The general term visceral leishmaniasis encompasses a broad spectrum of severity and manifestations. The onset can be chronic, subacute, or acute. Although the incubation period generally ranges from weeks to months, asymptomatic infection can become clinically manifest years to decades after the exposure in people who become immunocompromised for other medical reasons (such as HIV/AIDS). Visceral leishmaniasis usually is caused by the species L. donovani and L. infantum (L. chagasi generally is considered synonymous with L. infantum) and affects internal organs (particularly, spleen, liver, and bone marrow).
The stereotypical manifestations of clinically manifest visceral infection include:
- weight loss (cachexia; wasting)
- hepatosplenomegaly (usually, the spleen is more prominent than the liver)
- pancytopenia—i.e., anemia, leukopenia, and thrombocytopenia
- a high total protein level and a low albumin level, with hypergammaglobulinemia
Lymphadenopathy may be noted, particularly in some geographic regions, such as Sudan.
HIV-coinfected patients may have atypical manifestations, such as involvement of the gastrointestinal tract and other organ systems.
The term kala-azar—which means black (kala) fever (azar) in Hindi—often is reserved for severe (advanced) cases of visceral leishmaniasis, although the terms kala-azar and visceral leishmaniasis sometimes are used interchangeably. If untreated, severe cases of visceral leishmaniasis typically are fatal, either directly from the disease or indirectly from complications, such as hemorrhage or secondary bacterial infection.
Some patients develop post kala-azar dermal leishmaniasis (PKDL), a syndrome characterized by skin lesions (such as erythematous or hypopigmented macules, papules, nodules, and patches), typically first noticed and most prominent on the face, that develop at variable times after therapy for visceral leishmaniasis. PKDL is best described in cases of L. donovani infection in South Asia and East Africa. In general, PKDL is more common, develops earlier, and is less chronic in patients in East Africa. For example, in Sudan, PKDL is noted in up to 60% of patients, typically from 0 to 6 months after therapy for visceral leishmaniasis, and often heals spontaneously. In contrast, in South Asia, PKDL is noted in ~5-15% of patients, on average several years after initial therapy, and usually requires additional treatment. Persons with chronic PKDL can serve as important reservoir hosts of infection.
Various laboratory methods can be used to diagnose leishmaniasis—to detect the parasite and to identify the Leishmania species. Some of the methods are available only in reference laboratories.
In the United States, CDC provides reference diagnostic services for leishmaniasis. For more details and instructions in this regard, see:
Leishmaniasis is diagnosed by detecting Leishmania parasites (or DNA) in tissue specimens—such as from skin lesions, for cutaneous leishmaniasis (see instructions), or from bone marrow, for visceral leishmaniasis (see note below)—via light-microscopic examination of stained slides, specialized culture techniques, or molecular methods.
Identification of the Leishmania species also can be important, particularly if more than one species is found where the patient lived or traveled and if they can have different clinical and prognostic implications. The species can be identified by biochemical techniques (isoenzyme analysis of cultured parasites), molecular methods, or immunologic approaches (use of monoclonal antibodies).
For visceral leishmaniasis, serologic testing can provide supportive evidence for the diagnosis. The performance of various serologic assays may vary by geographic region and by host factors (for example, the sensitivity of serologic testing generally is lower in HIV-coinfected patients, particularly if the HIV infection predated the Leishmania infection). Most serologic assays do not reliably distinguish between active and quiescent infection.
No leishmanin skin-test preparation has been approved for use in the United States.
For visceral leishmaniasis, although the sensitivity is highest for splenic aspirates (>95% vs. <90% for other organs/tissues), the procedure can be associated with life-threatening hemorrhage, even if conducted under radiologic guidance. Bone marrow aspiration is much safer. Examples of other potential sources of specimens for diagnostic testing include liver, lymph node, and whole blood or buffy coat. Among HIV-infected patients, the parasite also may be found in atypical sites (such as the gastrointestinal tract).
The information provided here does not constitute a primer on treating leishmaniasis; rather, the focus is on basic principles and perspective, geared towards clinicians treating patients in the United States. Treatment decisions should be individualized, with expert consultation. In general, all clinically manifest cases of visceral leishmaniasis and mucosal leishmaniasis should be treated, whereas not all cases of cutaneous leishmaniasis require treatment.
The treatment approach depends in part on host and parasite factors. Some therapies/regimens are effective only against certain Leishmania species/strains and only in certain areas of the world. Even data from well-conducted clinical trials are not necessarily generalizable to other settings. Of particular note, data from the many clinical trials of therapy for visceral leishmaniasis in parts of India are not necessarily directly applicable to visceral leishmaniasis caused by L. donovani in other areas, to visceral leishmaniasis caused by other species, or to treatment of cutaneous and mucosal leishmaniasis.
Special groups (such as young children, pregnant/lactating women, immunocompromised persons, and persons with other comorbidities) may need different medications or dosage regimens.
The relative merits of various treatment approaches can be discussed with CDC staff. In addition, special considerations apply in the United States. For examples:
- Pentavalent antimonial (SbV) compounds—the mainstays for treating leishmaniasis since the 1940s—are not licensed for U.S. commercial use. However, the SbV compound sodium stibogluconate (Pentostam®) is available to U.S.-licensed physicians through the CDC Drug Service (404-639-3670), under an IND (Investigational New Drug) protocol approved by the Food and Drug Administration (FDA) and by CDC's Institutional Review Board (IRB). Although Pentostam® is not new or investigational, the IND mechanism makes it possible for CDC to stock and provide the drug in the United States. CDC's IND covers intravenous (IV) and intramuscular (IM) administration (not intralesional). In the United States, the most common route of administration is IV (vs. IM), because the volume per dose is relatively high (for example, 14 mL for a 70-kg patient). Of note, Pentostam® is the only antileishmanial medication available through CDC.
- No medications have been approved by FDA for treatment of cutaneous or mucosal leishmaniasis, whereas one medication—liposomal amphotericin B (AmBisome®)—is FDA-approved for treatment of visceral leishmaniasis per se.
- Some medications that might have merit for treating selected cases of leishmaniasis are available in the United States, but the FDA-approved indications do not include leishmaniasis. Examples of such medications include amphotericin B deoxycholate, various "azoles" (ketoconazole, itraconazole, and fluconazole), and pentamidine isethionate.
- Other medications that might have merit for treating selected cases of leishmaniasis currently are not available in the United States (such as the parenteral form of the aminoglycoside paromomycin sulfate)—or—are potentially available only through special mechanisms. For example, particular topical formations of paromomycin may be available through compounding pharmacies or may be imported under a single-use treatment protocol. The oral agent miltefosine can be imported under a single-use treatment protocol.
Decisions about whether and how to treat should be individualized. The treatment approach depends in part on the Leishmania species/strain and the geographic area in which infection was acquired; the natural history of infection, the risk for mucosal dissemination, and the drug susceptibilities in the pertinent setting; and the number, size, location, evolution, and other clinical characteristics of the patient's skin lesions.
Therapy of cutaneous leishmaniasis may be indicated to:
In general, the first sign of a therapeutic response to adequate treatment is decreasing induration (lesion flattening). The healing process for large, ulcerative lesions often continues after the end of therapy. Relapse (clinical reactivation) typically is noticed first at the margin of the lesion.
Systemic therapy (parenteral)
For pentavalent antimonial (SbV) therapy, see above about CDC's IND protocol for sodium stibogluconate (Pentostam®). The standard daily dose is 20 mg of SbV per kg, administered IV or IM. The traditional duration of therapy is 20 days for cutaneous leishmaniasis (10 days may suffice in some settings) and 28 days for mucosal (and visceral) leishmaniasis. For some patients, adjustment of the daily dose or the duration of therapy may be indicated.
No controlled clinical trials of conventional or lipid formulations of amphotericin B have been conducted for cutaneous (or mucosal) leishmaniasis; standard dosage regimens have not been established. Some data suggest that conventional amphotericin B is likely to be highly and broadly effective (against a wide range of species), albeit potentially toxic. The anecdotal experience using lipid formulations of amphotericin B—which are targeted to the reticuloendothelial system—has been mixed. When used, patients with cutaneous leishmaniasis typically have been treated with 3 mg/kg daily, by IV infusion, for a total of 6 to 10 doses (sometimes even more doses).
In the United States, pentamidine isethionate is uncommonly used for treatment of cutaneous leishmaniasis. Its limitations include the potential for irreversible toxicity and variable effectiveness. For example, a parenteral dose of 2 mg/kg, every other day, for 7 doses, was ineffective in Peru against L. (V.) braziliensis.
Systemic therapy (oral)
"Azoles" (ketoconazole, itraconazole, fluconazole) have been used with mixed results, in various settings. For example:
- Ketoconazole (adult regimen: 600 mg daily for 28 days) showed modest activity against L. mexicana and L. (V.) panamensis in small studies in Guatemala and Panama, respectively. However, itraconazole (adult regimen: 200 mg twice daily for 28 days) was ineffective against L. (V.) panamensis in a clinical trial in Colombia.
- Use of fluconazole (adult regimen: 200 mg daily for 6 weeks) for treatment of L. major infection in various countries in the Old World has been associated with mixed results. Preliminary data from Iran suggest that a higher daily dose (400 vs. 200 mg) might be more effective against L. major. Preliminary, uncontrolled data from Brazil suggest that a regimen of 8 mg/kg daily for 4–6 weeks might be effective against L. (V.) braziliensis.
Miltefosine (see above about availability issues) is being evaluated for treatment of cutaneous leishmaniasis and appears promising in some settings. However, its effectiveness is species and locale dependent—for examples, it appears to be effective against L. (V.) panamensis in Colombia and against L. (V.) braziliensis in Bolivia but not against L. (V.) braziliensis and L. mexicana in Guatemala. The typical dosage regimen is 2.5 mg/kg (maximum, 150 mg), daily, for 28 days. Miltefosine is contraindicated in pregnancy; its use in women of reproductive age requires a negative pregnancy test and effective contraception during and for 3 months after therapy.
Some cases of cutaneous leishmaniasis without risk for mucosal dissemination might be candidates for local therapy, in part depending on the number, location, and characteristics of the skin lesions. Examples of local therapies that might have utility in some settings include cryotherapy (with liquid nitrogen), thermotherapy (use of localized current field radiofrequency heat), intralesional administration of SbV (not covered by CDC's protocol for Pentostam®), and topical application of paromomycin (such as an ointment containing 15% paromomycin/12% methylbenzethonium chloride in soft white paraffin; not commercially available in the United States).
The use of highly effective systemic therapy for leishmaniasis is important, as is supportive care—for example, therapy for malnutrition, anemia/bleeding, and intercurrent infections. For HIV-coinfected patients, antiretroviral therapy (ART) should be started or optimized according to standard practice; appropriate use of ART delays relapses and improves survival.
Liposomal amphotericin B is approved by FDA for treatment of visceral leishmaniasis. Although various regimens have been suggested in the published literature, the FDA-approved regimen for immunocompetent patients consists of 3 mg/kg daily, by IV infusion, on days 1–5, 14, and 21 (total dose of 21 mg/kg). The FDA-approved regimen for immunosuppressed patients consists of 4 mg/kg daily on days 1–5, 10, 17, 24, 31, and 38 (total dose of 40 mg/kg). Some immunosuppressed patients may need even higher total doses and/or secondary prophylaxis (chronic maintenance therapy), in particular, HIV-coinfected patients with CD4 counts <200 cells/mm3. However, standard approaches to antileishmanial treatment and secondary prophylaxis have not been established—for example, the optimal agent, dose, and dosing interval for maintenance therapy.
Conventional amphotericin B deoxycholate is highly effective therapy for visceral leishmaniasis but generally is more toxic than liposomal amphotericin B. Immunocompetent patients typically receive 0.5 to 1.0 mg/kg—either daily or every other day—by IV infusion—for a total dose of ~15 to 20 mg/kg. Longer courses of therapy may be indicated for some patients.
Pentavalent antimonial (SbV) therapy generally remains highly effective in most regions, with the notable exception of parts of South Asia. See above about CDC's IND protocol for sodium stibogluconate (Pentostam®). The standard dosage regimen for immunocompetent patients consists of 20 mg of SbV per kg daily, IV or IM, for 28 days. For some patients, adjustment of the daily dose or the duration of therapy may be indicated.
Other parenteral agents that have merit in some settings include paromomycin sulfate (the chemical equivalent of aminosidine), which is not available for parenteral administration in the United States—and—pentamidine isethionate, a second-line agent whose limitations include suboptimal effectiveness (most notably, in parts of South Asia) and the potential for irreversible toxicity.
Miltefosine (see above about availability issues) is considered the first highly active oral agent for visceral leishmaniasis. The typical dosage regimen is 2.5 mg/kg (maximum, 150 mg), daily, for 28 days. Miltefosine is contraindicated in pregnancy; its use in women of reproductive age requires a negative pregnancy test and effective contraception during and for 3 months after therapy.
Prevention & Control
No vaccines or drugs to prevent infection are available.
The best way for travelers to prevent infection is to protect themselves from sand fly bites. Personal protective measures include minimizing nocturnal outdoor activities, wearing protective clothing, and applying insect repellent to exposed skin.
In general, prevention and control measures must be tailored to the local setting and typically are difficult to sustain. Control measures against sand fly vectors or animal reservoir hosts might be effective in some settings.
In many geographic areas where leishmaniasis is found in people, infected people are not needed to maintain the transmission cycle of the parasite in nature; animal reservoir hosts (such as rodents or dogs), along with sand flies, maintain the cycle. For example, in L. infantum/L. chagasi-endemic regions, dogs serve as the main reservoir hosts; potential control strategies for such areas are being evaluated.
In some parts of the world, infected people are needed to maintain the cycle; this type of transmission (human—sand fly—human) is called anthroponotic. For example, in the Indian Subcontinent (South Asia), the transmission of L. donovani is anthroponotic. In such areas, early detection and effective treatment of patients can serve as a control measure; suboptimal treatment can lead to development and spread of drug resistance. Because the transmission is intra- and peridomiciliary (rather than sylvatic), spraying dwellings with residual-action insecticides and using bed nets treated with long-lasting insecticides may be protective. In 2005, India, Nepal, and Bangladesh resolved to collaborate to decrease the annual incidence of visceral leishmaniasis to <1 case per 10,000 persons by the year 2015.
More on: Travelers and Leishmaniasis
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