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. 2013 Jun 5;107(1):7–14. doi: 10.1093/qjmed/hct116

Leishmaniasis: clinical syndromes and treatment

BS McGwire 1,✉, AR Satoskar 2
PMCID: PMC3869292  PMID: 23744570

Abstract

Leishmaniasis is a global term for cutaneous and visceral anthroponotic and zoonotic diseases caused by the vector-borne parasites of the genus Leishmania. These diseases afflict at least 2 million people each year with more than 350 million at risk in 98 countries worldwide. These are diseases mostly of the impoverished making prevention, diagnosis and treatment difficult. Therapy of leishmaniasis ranges from local treatment of cutaneous lesions to systemic, often toxic, therapy for disseminated cutaneous, mucocutaneous and deadly visceral disease. This review is a summary of the clinical syndromes caused by Leishmania and treatment regimens currently used for various forms of leishmaniasis.

Introduction

The protozoans of the genus Leishmania are a diverse group of parasites which are transmitted between mammalian hosts by blood-sucking sandflies. Leishmania alternately infect female sandflies, which suck blood for nutritional support for egg laying, and various mammalian species including humans. A variety of animals serve as natural reservoirs and include both domestic and feral dogs, rodents, foxes, jackals, wolves, raccoons, and hyraxes, sloths, aardvarks, opossums and rodents such as rats and mice. Humans are thought to constitute the main reservoir in India. Human infection by pathogenic leishmanial species causes diverse chronic infections of the skin and viscera and is present in both the Old (in regions of the Far and Middle East, Central Western and Eastern Europe and Africa) and New (in regions of Central and South America) Worlds and are mainly found in rural impoverished areas. Overall, there are more than 20 species of Leishmania worldwide and the subtype of disease relates to the species of infecting Leishmania and the interplay of the genetic background and immune status of the host. Worldwide there is an estimated annual incidence of 2 million cases across 98 countries with an additional 350 million at risk of infection.1

Leishmania life cycle

Leishmania have two main lifecycle stages: the motile flagellated promastigote, which is present in the sandfly vector, and intracellular non-flagellated amastigote, which is present within mammalian host cells (Figure 1). Leishmania are parasites of professional phagocytes (macrophages and dendritic cells) which initiate infection through receptor-mediated binding of infective promastigotes delivered into host tissue during the feeding of infected sandflies.2 Parasites housed in parasitophorous vacuoles fuse with lysosomes to form phagolysosomes wherein promastigotes transform into and replicate as amastigotes.3 Eventually, the parasite burden increases physically disrupting infected host macrophages delivering extracellular amastigotes into surrounding tissue where they are engulfed by uninfected macrophages. Parasites and infected macrophages can metastasize within the skin and visceral organs. Host control of infection is a complex interplay of innate and adaptive immune factors which are incompletely understood.4,5

Figure 1.

Figure 1.

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Leishmania life cycle and clinical syndromes. (A) Diagrammatic depiction of life cycle of Leishmania. (B) Giemsa stained preparation of L. donovani promastigotes, (C) Giemsa staining of touch preparation of a cutaneous lesion showing presence of intracellular parasites inside macrophages, (D) CL lesion on the hand, (E) mucocutaneous lesion (MCL) of the mouth and nose, (F) facial lesions in a case of PKDL, (G) emerging lesions within the old CL scar in LR and (H) lesions throughout in DCL. Credit for pictures: Panels: A, obtained from NIAID; B, www.lookfordiagnosis.com; C, Centers for Disease Control, www.CDC.gov; D, www.Dermnet.com; E, www.Drugline.org; F, www.WHO.int, G, www.globalskinatlas.com and H, Medical Books Online, www.cixip.com.

Clinical syndromes

Leishmanial disease causes three main human syndromes, and some lesser prevalent clinical entities (Figure 1). The outcome of each is determined by the species of infecting parasite and the genetic susceptibility of the host.

Cutaneous disease

Cutaneous leishmaniasis (CL) is the least severe form of disease and is caused by several species such as Leishmania major and Leishmania tropica in the Old World and Leishmania mexicana, Leishmania amazonensis, Leishmania guyanensis, Leishmania panamensis and Leishmania braziliensis in various regions of Central and South America.6 Simple cutaneous disease presents as singular ulcerative or nodular lesions at or near the site of insect exposure. These are usually found on uncovered areas of the body such as the face, forearms and lower legs and evolve over weeks to months. In diffuse cutaneous disease, such as that caused by L. amazonensis, nodular lesions of variable size erupt at various locations often, distant from the site of inciting insect exposure. Simple cutaneous lesions are most often self-healing but in some cases, such as those caused by L. panamensis and L. braziliensis, can progress to involve mucocutaneous tissue. The resolution of cutaneous lesions can often be hastened by treatment.7

Mucocutaneous disease

Mucocutaneous leishmaniasis (MCL) is caused by L. braziliensis which can be due to extension of, or parasite metastasis from, local skin disease into the mucocutaneous tissue. MCL can present months to years after resolution of primary lesions. This is often a horribly disfiguring infection resulting from the chronic local destruction of tissue of the nose, mouth oro- and naso-pharynx and eyelids and can progress to affect respiratory function and hamper nutrition. The underlying pathogenesis resulting in MCL is not well understood and is probably a result of a complex interplay of host and parasite factors.8 The disease is often refractory to chemotherapy and patients usually die from secondary super-infections and malnutrition. MCL found in countries in South America, with the majority of disease found in Brazil, Peru and Bolivia but is also found in lesser degrees in Colombia, Ecuador, Paraguay and Venezuela. In Ecuador, most cases are found in the Amazonian lowlands, with lesser incidence in the inter-Andean and Pacific coastal regions.9

Visceral disease

Visceral leishmaniasis (VL, also known as kala-azar) results from the infection of phagocytes within the reticuloendothelial system due to metastasis of parasites and parasite-infected macrophages from the initial site of cutaneous infection. In the Old world, VL is caused by Leishmania donovani (in regions of India, Pakistan, China and Africa) and Leishmania infantum (in the Mediterranean region). In the New World, VL is also caused by L. infantum (also known as Leishmania chagasi or L. infantum chagasi), which is found primarily in Brazil. Visceral disease has been reported in the Middle East caused by viscerotropic strains of L. tropica,10 which has been classically thought of as an agent of CL. The proliferation of parasites in macrophages in the liver, spleen and bone marrow of patients with VL gives rise to progressive hepatosplenomegaly and bone marrow suppression. Unless treated, patients develop pancytopenia and immunosuppression and are prone to super-infections with other microbes. Without therapy patients with VL will eventually succumb their disease. Individuals co-infected with HIV have a particular susceptibility to developing atypical presentations, and increased severity, of VL and the development of VL in HIV patients is an AIDS-defining illness.11 This is probably due to the dysregulation effects of both agents on the immune system of the host.12

Leishmaniasis recidivans

This is characterized by a relapse of cutaneous disease within the sites of previous healed CL lesions.13 This can occur decades after resolution of the primary lesions and often form within the edge of the previous scar.14 The lesions in leishmaniasis recidivans (LR) are reminiscent of those in discoid lupus or lupoid leishmaniasis and require treatment often with dual therapy.

Post-kala-azar dermal leishmaniasis

In a subset of patients successfully treated for VL, and who remain asymptomatic for months to years, develop a fulminant and progressive proliferation of parasites within the skin which give rise to diffuse macular, maculo-papular or nodular lesions. Post-kala-azar dermal leishmaniasis (PKDL) occurs mainly in India and Sudan in patients infected with L. donovani.15 In Sudan, PDKL can arise in up to 50% of patients and occurs sooner (in up to 6 months) than in patients in India where it has an incidence of ∼5–10% within 2–3 years after clearance of VL. The pathogenesis of PKDL is not fully understood but appears related to an aggressive interferon γ driven host immune response generated against lingering dermal parasites. Biopsy of lesions shows macrophages heavily laden with amastigotes which are the genotypically identical to the parasites generating the inciting VL. The development of PKDL seen in HIV/AIDs undergoing HAART may be a manifestation of immune reconstitution syndrome.16

Treatment

There are number of therapies for various forms of leishmaniasis and the preferences for first-line and second-line treatment vary on the type of disease and are often guided by regional practice. Pentavalent antimony has been considered the mainstay of therapy in leishmaniasis for decades, however, this agent has multiple toxicities and is increasing ineffective due to development of parasite resistance. Other alternative agents are utilized in different clinical situations and guided by availability and effectiveness in different localities. The following is general description of the drugs used now in clinical practice.1 See Table 1 for summary.

Table 1.

Leishmanial diseases, parasites and treatment regimens by regions

Species Disease Geographic locationa Treatmentb
Old World
 L. major CL Middle East, Africa Local: t-paro, il-Sb, il-Sb + CT, HT, CT
Systemic: Flu, s-Sb, s-Sb + ptxf
 L. tropica and L. infantum CL Middle East, Mediterranean, Africa Local: t-paro, il-Sb, il-Sb + CT, HT, CT Systemic: s-Sb, s-Sb + Allo
LR
    L. aethiopica CL Africa s-SB + im-paro
 L. donovani VL Far East L-AmB, L-AmB + Mil, L-AmB + im-paro, Mil + im-paro, AmB, Mil, im-paro, s-Sb
Africa s-Sb + im-paro, s-Sb, L-AmB, AmB, Mil
PKDL Far East AmB, Mil
PKDL African L-AmB, s-Sb
    L. infantum VL Mediterranean, Eastern Europe, Far East L-AmB, AmB, s-Sb
New World
    L. infantum/chagasi VL Central and South America L-AmB, AmB, s-Sb
    L. mexicana CL North, Central and South America Local: t-paro, HT, il-Sb Systemic: Ket, Mil
    L. amazonensis CL, DCL South America Local: t-paro, HT, il-Sb Systemic: s-Sb
    L. panamensis CL Central and South America Local: t-paro, HT, il-Sb Systemic: Pent, s-Sb, Mil
    L. brazilienensis CL, MCL Central and South America Local: t-paro, HT, il-Sb Systemic: AmB, L-AmB, s-Sb
    L. guyanensis CL South America Local: t-paro, HT, il-Sb Systemic: Pent, s-Sb, Mil
    Leishmania peruviana and Leishmania venezuelensis CL South America Local: t-paro, HT, il-Sb Systemic: s-Sb
All species Relapsed CL, DCL or MCL AmB, L-AmB, s-Sb + t-imi or immunotherapy
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aCountries in regional designation where disease has been found: Middle East (Afghanistan, Cyprus, Iran, Iraq, Jordan, Israel, Kuwait, Lebanon, Macedonia, Montenegro, Palastine, Saudi Arabia, Syria and Yemen), Africa (Cameroon, Central African Republic, Egypt, Gambia, Ghana, Guinea, Guinea-Bissau, Kenya, Libya, Mali, Mauritania, Morocco, Namibia, Niger, Nigeria, Oman, Senegal, Somalia, Sudan, Tunisia and Uganda), Far East (Bangladesh, China, India, Pakistan, Nepal and Sri Lanka), Eastern Europe (Albania, Algeria, Armenia, Azerbijan, Bulgaria, Bosnia and Herzegovina, Croatia, Georgia, Kazakstan, Kyrgystan, Romania, Slovenia, Ukraine, Uzbekistan and Turkmenistan), Western Europe/Mediterrenan (Greece, France, Italy, Malta, Monaco, Portugal, Spain and Turkey), Central America (Costa Rica, Dominican Republic, Guatemala, Honduras, Mexico, Nicaragua and Panama), North America (United States), South America (Argentina, Belize, Bolivia, Brazil, Columbia, Ecuador, French Guiana, Guyana, Paraguay, Peru, Suriname and Venezuela). Not included are countries where leishmanial disease is found without definitive speciation.

bTreatment options used for these disease syndromes: il-Sb, intra-lesional stibogluconate (Sb); s-Sb, systemic Sb; Ket, ketoconazole; Flu, fluconazole; Mil, Miltefosine; t-paro, topical paromomycin; im-paro, intramuscular paromomycin; L-AmB, liposomal amphotericin B; AmB, amphotericin deoxycholate; CT, cryotherapy; HT, heat therapy; Pent, pentamidine; Ptxf, pentoxyfylline; Allo, allopurinol; t-imi, topical imiquimod.

Pentavalent antimony

An agent of choice for most forms of leishmaniasis is systemic use of pentavalent antimony (Sb), which is present in meglumine antimonate (tradename ‘Glucantime’ or ‘Glucantim’) or sodium stibogluconate (tradename ‘Pentostam’). The precise mechanism of action of Sb in leishmaniasis is not well understood but is probably multi-factorial acting directly on molecular processes of the parasite as well as influencing macrophage parasiticidal activity.17 For systemic use, these compounds can be administered intravenously (iv) or intramuscularly (im), and are also be used intralesionally (il) for CL. For VL and LR, 20 mg Sb/kg body weight per day is given daily for 28–30 days and is used as a first-line agent for up to 60 days in East African PKDL. When used as systemic therapy for CL, the treatment length is shorter, from between 10 and 20 days, and when used for MCL, the length of therapy is extended up to 30 days. Systemic therapy is used in combination with other agents in some cases, including East African VL where it is combined with paromomycin (15 mg/kg/day im) to shorten the overall all course of therapy to 17 days, and in CL and diffuse cutaneous leishmaniasis (DCL) caused by Leishmania aethiopica. It has been used together with pentoxifylline, a TNF-α inhibitor (400 mg orally/day), for treatment of CL caused by L. major and in MCL where it has been shown to be more effective than antimony alone in leading to complete cure and for shortening the time to cure.18 Allopurinol (20 mg orally/kg/day for 30 days) has also been used as an adjunct with systemic antimony in CL and LR caused by L. tropica.19 Side effects are common in the use of systemic antimony therapy, the most serious of which is cardiotoxicity (arrhythmias, Q-T prolongation and sudden death) but multiple others occur (elevation of liver and pancreatic enzymes, pancytopenia and electrolyte abnormalities) requiring careful monitoring of patients during the course of therapy.

Amphotericin B

The polyene amphotericin B is an effective anti-leishmanial which works by binding to membrane ergosterol causing membrane instability. The deoxycholate and the liposomally encapsulated formulations of amphotericin B (tradename ‘AmBisome’) have been used clinically in leishmaniasis.20 Amphotericin B deoxycholate is used iv at a dose of 0.75–1 mg/kg/day for 15–20 doses for VL caused by L. donovani or up to 30 days for VL caused by L. infantum. Dosing in PKDL is daily or on alternate days for up to 4 months of therapy. For CL caused by L. braziliensis the length of therapy is 25–30 days, and for MCL is up to 45 days. Liposomal amphotericin B is typically used at a dose of 2.5–5 mg/kg/day and this formulation reduces the overall length of therapy to one-half that of the non-liposomal form. Single dose liposomal amphotericin B at a dose of 10 mg/kg in VL caused by L. donovani or at 5 mg/kg in combination with miltefosine for daily for 10 days or paromomycin has been shown to be effective in treatment (see sections below).21 Common side effects of amphotericin B are renal insufficiency and electrolyte abnormalities, which are both less with the liposomal form, however this formulation is more costly which limits its widespread use.

Paromomycin

Paromomycin is an aminoglycoside antibiotic which works by blocking protein synthesis by binding to 16S ribosomal RNA. In leishmaniasis it is used im for systemic use (at 15 mg/kg) alone for up to 21 days in Indian VL or in combination with liposomal amphotericin B for Indian or East African VL.21 Paromomycin can be used topically in New and Old World CL in a 15% ointment together with 12% methyl benzothonium chloride daily for 20 days22,23 and recently topical paromomycin with and without gentamicin has been shown to be efficacious in speeding resolution of lesions caused by L. major.24 Topical therapy is not indicated in cases of MCL. The side effects of systemic use of paromomycin are similar to other aminoglycosides such as ototoxicity, vestibular instability and nephrotoxicity.

Pentamidine

The precise anti-microbial mechanisms of pentamidine (tradenames ‘Pentacrinat’ and ‘Pentam’) are unknown but the drug interferes with the biosynthesis of macromolecules such as DNA, RNA, phospholipids and proteins. It has been used (iv doses every other day for 3–5 days with 4 mg/kg of body weight) for the treatment of South American CL caused by L. guyanensis and L. panamensis, and there is some data to show that it is also effective in Old World CL caused by L. tropica and L. major as well as cutaneous lesions of L. infantum.25 A wide array of adverse reactions have been reported with pentamidine use, most notable are hypoglycemia and/or worsening of diabetes, liver enzyme abnormalities, bone marrow effects such as leukopenia and anemia, nephrotoxicity and cardiotoxicity such as arrhythmias and heart failure and hypotension. Patients on this drug require careful observation.

Miltefosine

Originally investigated as an anti-neoplastic agent, the alkylphosphocholine miltefosine (tradenames ‘Impavido’ and ‘Miltex’) is the only oral agent in use for Indian and East African VL both in children and adults where the dose is incrementally weight-based (ages ≤12 years old at 2.5 mg/kg daily; in those >12 years of age and <25 kg of weight, the dose is 50 mg/kg; in those with weights of 25–50 kg dosing is 100 mg/kg and in those >50 kg dosing is 150 mg/kg for a total of 28 days).26,27 Miltefosine has also been used in combination with paromomycin for Indian VL (see above).21 Recently, it was shown that miltefosine is effective in PKDL and the length of therapy extended up to 12 weeks.28 In New World CL caused by L. mexicana, L. guyanensis and L. panamensis miltefosine can be effective at a dose of 2.5 mg/kg for 28 days29 but is not of benefit for L. braziliensis cutaneous infection. However, Bolivian MCL responds to miltefosine therapy for 4–6 weeks with cure rates of up to 75%.30–32 This drug is very well-tolerated, and the main adverse effects are non-specific nausea and vomiting. This agent is teratogenic and contraindicated in pregnancy.

Imiquimod

Imiquimod (tradenames ‘Aldara’ or ‘Zyclara’) is a topical imidazole quinolone which induces macrophage activation through production of pro-inflammatory cytokines such as IL-2, IFN-γ and TNF-α. It can be used in conjunction with pentavalent antimony in relapsed New World CL33,34 and may be effective in antimony-refractory cases.35 Imiquimod has not proven effective in cases of L. tropica36 but a recent report suggests response in a case of Old World CL caused by L. chagasi.37 This agent is generally well tolerated with the main adverse effect being irritation at the site of application.

Azoles

While azoles (ergosterol synthesis inhibitors) have in vitro parasitistatic activity against a variety of leishmanial species they have not been shown to be as effective as other agents for clinical use. Oral ketoconazole (tradename ‘Nizoral’) (600 mg orally daily for 28–30 days) and fluconazole (tradename ‘Diflucan’) (a daily dose of 200 mg orally for 6 weeks) have been shown to hasten healing of CL lesions caused by L. mexicana38 and L. major,23,39 respectively. Patients on long-term azole therapy require routine blood tests for liver function abnormalities.

Cryotherapy

Liquid nitrogen application directly to CL lesions either once to multiple times, up to five times, every 3–7 days has been used in Old World CL caused by L. tropica, L. aethiopica and L. infantum or in combination with intra-lesional antimony for L. major.40–42

Heat therapy

Heating lesions to 50°C for 30 s up to three times can be used to hasten resolution of Old and New World CL lesions and is comparable to intra-lesional or systemic antimony therapy.43,44 This treatment has also been found to be effective against CL in HIV infected patients who do not respond to antimonial therapy.45

Immunotherapy

Vaccines consisting of heat-killed Leishmania plus BCG or defined recombinant antigens together with granulocyte-macrophage colony-stimulating factor have been used in small numbers of patients with refractory MCL or DCL.46–50

Conclusions

The diseases caused by the intracellular protozoan parasite Leishmania represent a major global health problem and a WHO classified neglected tropical disease. Nearly 10% of the world’s population is at risk of acquiring a form of leishmaniasis. Worldwide it is estimated that there are 12 million active cases of leishmaniasis, with ∼2 million new cases occurring each year. Among parasitic infections, this disease is responsible for the highest number of disability adjusted life years (a measure of health burden) after malaria. Several treatments including systemic antimonials, liposomal amphotericin B and miltefosine are currently available for leishmaniasis. However, these chemotherapeutic interventions are toxic and have poor patient compliance because many of them require daily systemic (iv or im) administration for periods ranging from 3 to 5 weeks. Furthermore, the emergence of drug-resistant strains is rapidly increasing worldwide and these treatments fail to induce a sterile cure because they do not eliminate persistent parasites from the host. Therefore, there is a continued need for new therapies against leishmaniasis that are safe, effective in inducing long-term cure and that are easier to administer.

Funding

This work was supported by NIH grant no. RC4 AI 092624 to A.R.S.

Conflict of interest: None declared.

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