Leishmaniasis is a group of tropical diseases caused by Leishmania parasites, which are tiny single-celled organisms spread to humans through the bites of infected female phlebotomine sandflies. More than 20 parasite species and over 90 sandfly species can transmit the infection.
The disease is found in about 99 countries across Africa, Asia, the Americas, and southern Europe, with an estimated 700,000 to 1 million new cases each year and roughly 12 million people currently infected worldwide.
Leishmaniasis appears in three main forms: cutaneous leishmaniasis, which causes skin sores that may leave permanent scars; mucocutaneous leishmaniasis, which damages the nose, mouth, and throat and can lead to severe facial deformities if untreated; and visceral leishmaniasis, the most dangerous form, which affects internal organs such as the spleen, liver, and bone marrow and is almost always fatal without treatment.
The disease disproportionately affects impoverished communities where malnutrition, poor housing, and limited healthcare increase vulnerability. Prevention focuses on reducing sandfly bites through insect repellents, protective clothing, insecticide-treated bed nets, and vector control.
Treatment depends on the disease form and region, with commonly used drugs including pentavalent antimonials, amphotericin B (especially in its safer liposomal form), and the oral drug miltefosine, though many treatments have drawbacks such as toxicity, long duration, and emerging drug resistance.
History and Epidemiology
Leishmaniasis is a long-recognized parasitic disease whose earliest clinical descriptions emerged in the late 19th century, although evidence of leishmanial skin lesions has been identified in ancient skeletal remains from regions such as Peru and Egypt, indicating its presence long before its formal discovery. The disease is caused by protozoan parasites of the genus Leishmania, transmitted through the bites of infected female phlebotomine sandflies. More than 20 Leishmania species are known to infect humans, and over 90 species of sandflies serve as competent vectors.
Though the disease occurs on several continents, it is especially associated with tropical and subtropical environments, including large parts of the Middle East, South Asia, East Africa, North Africa, Latin America, and the Mediterranean basin. Today, leishmaniasis remains endemic in more than 90 countries and territories. Global estimates suggest that between 700,000 and 1 million new cases occur each year, though the actual burden is likely higher due to chronic underreporting, limited surveillance systems, and the fact that many affected populations live in remote or resource-limited areas.
Factors such as deforestation, climate change, rapid urbanization, migration, and conflict have expanded the habitats of both sandflies and animal reservoirs, contributing to changes in disease distribution over recent decades.
Types of Leishmaniasis
Cutaneous leishmaniasis is the most common form, which typically produces localized skin lesions at the site of the sandfly bite. These lesions may begin as small nodules that gradually ulcerate, eventually forming open sores with raised edges. Although cutaneous leishmaniasis can resolve spontaneously over months to years, it often leaves permanent scars and may result in long-term cosmetic and psychological consequences for affected individuals.
Mucocutaneous leishmaniasis generally develops months or even years after the initial skin infection appears to have healed. It involves destructive inflammation of the mucous membranes of the nose, mouth, and throat, which can lead to progressive tissue damage, difficulties with speech and breathing, and severe facial disfigurement without timely treatment.
Visceral leishmaniasis is the most severe, also known as kala-azar, which occurs when the parasite spreads to internal organs such as the spleen, liver, and bone marrow. Visceral disease is marked by persistent fever, significant weight loss, anemia, and a dramatic enlargement of the spleen and liver. If untreated, it is almost always fatal due to complications such as overwhelming infection, severe malnutrition, or bleeding disorders. Visceral leishmaniasis is closely linked to poverty, malnutrition, weakened immunity (including HIV coinfection), and inadequate access to healthcare, and it remains a major public health problem in countries such as India, Bangladesh, Sudan, South Sudan, Ethiopia, and Brazil.
Causes and Transmission
Leishmaniasis results from infection by specific protozoan parasites. The disease spreads primarily through insects, which act as carriers between hosts.
Causative Agents
The disease is caused by various species of Leishmania, each associated with different clinical forms and geographical distributions. The Leishmania donovani complex (L. donovani and L. infantum) is responsible for visceral leishmaniasis, a severe form that affects internal organs such as the spleen, liver, and bone marrow. Cutaneous leishmaniasis, the most common form, is frequently linked to L. major, L. tropica, and L. mexicana, depending on the region. Mucocutaneous leishmaniasis, which can cause destructive lesions of the mucosal tissues, is typically associated with species in the L. braziliensis complex.
A unique characteristic of Leishmania parasites is their ability to survive and multiply inside host macrophages, which are cells normally responsible for killing invading microbes. The parasite exists in two morphologically distinct forms:
- Amastigotes, the non-flagellated form found inside macrophages of the mammalian host.
- Promastigotes, the flagellated form that develops and multiplies within the sandfly vector.
Species identification is critical not only for understanding disease epidemiology but also for determining the most effective treatment, as sensitivity to medications varies across species. Molecular diagnostic techniques such as PCR and sequencing have become increasingly important for accurate detection.
Modes of Transmission
Leishmaniasis is transmitted primarily through the bite of infected female sandflies. During a blood meal, the sandfly injects promastigotes into the human skin. Once inside, the promastigotes are engulfed by macrophages but avoid destruction by subverting the host immune response. They then transform into amastigotes and begin to multiply. This intracellular multiplication leads to tissue damage and clinical symptoms.
Although vector-borne transmission is the dominant route, there are several additional, less common transmission pathways. These include blood transfusion, organ transplantation, needle-sharing among intravenous drug users, and congenital transmission from mother to child during pregnancy. However, these are rare and are usually documented in specific epidemiological contexts, such as regions with high parasite circulation or immunocompromised populations.
Direct human-to-human transmission does not occur under normal circumstances. In most endemic regions, leishmaniasis is zoonotic, meaning the parasite circulates naturally in animal populations, and humans become infected only when bitten by an infected sandfly. The presence of animal reservoirs, including domestic dogs, rodents, foxes, and other mammals, significantly influences the persistence of the disease in certain areas.
Vectors
The vectors responsible for transmitting leishmaniasis are phlebotomine sandflies, small, delicate insects belonging to the genera Phlebotomus (Old World—Asia, Africa, Europe) and Lutzomyia (New World—Americas). Only female sandflies take blood meals because they require blood proteins for egg development. These insects are typically active at night or during twilight hours, and their flight is weak, meaning they usually stay close to where they hatch.
Sandfly habitats vary depending on the species but commonly include cracks in walls, rodent burrows, tree holes, leaf litter, and the peridomestic environment such as animal shelters. Environmental factors such as humidity, temperature, and the presence of organic matter influence sandfly breeding and survival. Climate change, deforestation, and urban expansion have increasingly altered sandfly distribution, contributing to the emergence of leishmaniasis in previously non-endemic regions.
Inside the sandfly, Leishmania undergoes several developmental stages. After ingesting infected macrophages from a host, the amastigotes transform into promastigotes in the sandfly gut. They then multiply, migrate toward the proboscis, and become infective. When the sandfly takes its next blood meal, it inoculates the promastigotes into a new host, completing the cycle.
Clinical Manifestations
Leishmaniasis presents with distinct clinical forms depending on the species involved and the host’s immune response. Symptoms range from localized skin ulcers to severe systemic disease affecting internal organs and mucous membranes.
Cutaneous Leishmaniasis
Cutaneous leishmaniasis typically begins as a small papule at the bite site that enlarges into a painless ulcer with raised edges. Lesions can multiply and appear on exposed skin areas such as the face, arms, and legs.
The ulcers may heal spontaneously over months but often leave significant scarring. Secondary bacterial infections can complicate the wounds. The incubation period is usually weeks to months after the sandfly bite.
It is the most common form and generally causes localized skin damage without systemic involvement.
Visceral Leishmaniasis
Visceral leishmaniasis, also known as kala-azar, affects internal organs like the spleen, liver, and bone marrow. It causes prolonged fever, weight loss, and abdominal swelling due to liver and spleen enlargement.
Patients often develop anemia, leukopenia, and thrombocytopenia from bone marrow suppression. Without treatment, the disease is typically fatal. The incubation period ranges from weeks to months.
This form requires prompt diagnosis because of its systemic nature and potential for severe complications.
Mucocutaneous Leishmaniasis
Mucocutaneous leishmaniasis primarily affects mucous membranes of the nose, mouth, and throat. It often follows a cutaneous lesion but can appear months or years later.
The disease causes destructive inflammation leading to ulceration and disfigurement of mucosal tissues. Symptoms include nasal congestion, bleeding, and difficulty swallowing.
This form is mainly associated with Leishmania braziliensis and demands early intervention to prevent severe tissue damage.
Diagnosis of Leishmaniasis
Clinical assessment begins with noting the patient’s travel history or residence in endemic regions. The presentation varies by leishmaniasis type: cutaneous forms show skin ulcers or nodules, while visceral forms manifest as fever, weight loss, and enlarged spleen or liver.
Physical examination focuses on skin lesions for cutaneous leishmaniasis or signs of systemic involvement for visceral cases. Patient history should include duration and progression of symptoms. Visual inspection and palpation help identify characteristic features, but clinical signs alone are insufficient for definitive diagnosis.
Laboratory confirmation involves microscopic identification of Leishmania parasites in tissue samples. Skin biopsies, bone marrow aspirates, or lymph node samples are commonly examined. Staining techniques such as Giemsa stain highlight amastigotes within macrophages.
Molecular diagnostics, including polymerase chain reaction (PCR), offer higher sensitivity by detecting Leishmania DNA in clinical specimens. Serological tests, like the direct agglutination test (DAT) and rK39 antigen test, detect antibodies, mainly useful in visceral leishmaniasis but may not differentiate past from current infection.
Differential diagnosis includes other infectious diseases and skin disorders with overlapping symptoms. Cutaneous leishmaniasis must be differentiated from bacterial or fungal infections, cutaneous tuberculosis, and skin cancers.
Visceral leishmaniasis can resemble malaria, typhoid fever, lymphoma, or hematologic malignancies due to systemic symptoms like fever and organomegaly. Laboratory tests and careful patient history help exclude these conditions to avoid misdiagnosis and improper treatment.
Treatment Strategies
Effective management of leishmaniasis relies on specific medications, addressing potential drug resistance, and supportive care to enhance patient outcomes. These elements work together to control infection and reduce complications.
Medications and Therapies
Pharmacological treatment is the cornerstone of leishmaniasis-control efforts. The choice of medication depends on multiple factors, including the form of disease—cutaneous, mucocutaneous, or visceral—the infecting species, patient age, pregnancy status, coinfections, and local resistance patterns. Pentavalent antimonials, primarily sodium stibogluconate (SSG) and meglumine antimoniate, have been the standard therapy for decades and remain first-line agents in many low- and middle-income countries where newer drugs are costly or difficult to access. These agents are administered parenterally and require daily injections, which can pose logistical challenges in resource-limited settings.
For visceral leishmaniasis (VL), liposomal amphotericin B has become the preferred treatment in many regions due to its superior efficacy, shorter treatment duration, and reduced toxicity compared with conventional amphotericin B. It is especially recommended for vulnerable populations, including pregnant women, immunocompromised patients, and individuals with HIV coinfection. Although highly effective, the high cost of liposomal formulations limits widespread use in some endemic areas, prompting global health organizations to negotiate subsidized pricing.
Miltefosine, the first effective oral agent for leishmaniasis, represents a major advance in therapy. It is used for both cutaneous and visceral forms and offers the convenience of outpatient treatment. However, gastrointestinal side effects, potential teratogenicity, and emerging resistance underline the importance of careful patient selection and monitoring. Other therapeutic options—such as paromomycin and pentamidine—are used either as monotherapy or as part of combination regimens depending on regional guidelines. Combination therapies are becoming increasingly favored because they can shorten treatment durations, lower drug toxicity, and reduce the likelihood of resistance development.
Treatment duration varies according to drug type and disease form. Antimonials typically require 20–30 days of treatment, while liposomal amphotericin B may be given in shorter courses of 5–10 days depending on country guidelines. Even within the same drug category, dosing regimens differ by region due to variations in parasite species and treatment responses. Because many anti-leishmanial drugs have narrow therapeutic indices, careful clinical and laboratory monitoring is essential to detect toxicities early, such as cardiac arrhythmias from antimonials and kidney injury from amphotericin B.
Drug Resistance
Drug resistance poses one of the greatest challenges to leishmaniasis control. Resistance to pentavalent antimonials is particularly well-documented in the Indian subcontinent, where some regions of Bihar, India, report treatment-failure rates exceeding 60%. This trend has driven a shift away from antimonials in these areas and compelled national health programs to adopt alternative therapies.
Mechanistically, resistance often arises from genetic and biochemical adaptations in the parasite. These may include decreased drug uptake, increased efflux of the active compound, changes in thiol metabolism, and alterations in parasite redox balance. Such changes allow the parasite to survive drug exposure, persist in host cells, and contribute to treatment failure. Inadequate dosing, poor-quality drugs, and interrupted treatment courses, often caused by supply shortages or patient non-adherence, also accelerate resistance development.
Supportive Care
For patients with visceral leishmaniasis, supportive care often includes nutritional rehabilitation, hydration, management of anemia, and monitoring for secondary bacterial infections. Malnutrition is both a risk factor and a complication of VL, making dietary support particularly important to restore immune function and improve recovery. Severe anemia may require blood transfusion in controlled clinical settings, especially in children and immunocompromised patients.
In cutaneous leishmaniasis, wound care is essential. Proper cleaning, topical antiseptics, and protection from trauma help prevent secondary bacterial infection, which can worsen lesions and delay healing. In some cases, adjunct therapies such as thermotherapy or cryotherapy may be employed as local treatment options.
Patients with visceral leishmaniasis remain at risk for post-kala-azar dermal leishmaniasis (PKDL), a skin condition that can develop months to years after treatment and may serve as a reservoir for ongoing transmission.
Prevention and Control
Vector Control Methods
Vector control remains the cornerstone of leishmaniasis prevention because female phlebotomine sand flies are the primary means by which the parasite spreads to humans. Indoor residual spraying (IRS) with insecticides, particularly pyrethroids, is widely implemented in endemic regions. These insecticides are applied to walls, ceilings, and other indoor surfaces where sand flies rest after feeding. IRS can significantly reduce vector density when coverage is high and applications are repeated seasonally. However, the success of IRS depends on the behavior of local sand fly species. Species that rest outdoors or in animal shelters may be less affected, requiring complementary strategies.
Environmental management is equally important. Sand fly breeding and resting sites are typically associated with humid, shaded environments containing organic matter. Clearing brush and excess vegetation around homes, improving drainage, managing animal shelters, and disposing of waste properly reduce the availability of suitable habitats. Repairing cracks in walls and floors, particularly in mud or brick houses, removes common sheltering sites for adult sand flies. Because sand flies have short flight ranges, even small improvements in the immediate living environment can substantially reduce exposure.
Insecticide-treated nets (ITNs) and long-lasting insecticidal nets (LLINs) provide personal protection during sleeping hours. Although sand flies are smaller than mosquitoes and may pass through standard meshes, nets with fine-weave material or those treated with insecticide remain effective. Nets are especially useful in areas where people sleep outdoors or where housing structures are not fully enclosed.
Personal Protective Measures
Personal protection strategies complement community-level interventions and empower individuals to reduce their own exposure to sand flies. Because sand flies are most active during the hours between dusk and dawn, minimizing outdoor activities during these periods is a highly effective behavioral intervention. When outside, wearing long-sleeved shirts, long pants, and socks creates a physical barrier that decreases the amount of exposed skin available for biting.
Topical insect repellents are an important additional layer of defense. Products containing DEET, picaridin, or IR3535 have been shown to repel sand flies effectively when applied to exposed skin. Their efficiency varies with concentration, formulation, and sweating rate, so reapplication may be necessary in hot climates. For those living in or traveling to high-risk areas, combining repellents with protective clothing maximizes protection.
Improving the structural integrity of housing also plays a major role. Sand flies can pass through gaps smaller than those used in mosquito studies; therefore, sealing wall cracks, repairing damaged plaster, and installing fine-mesh screens on windows and doors significantly reduces indoor entry. The addition of insecticide-treated curtains, which are increasingly used in some endemic regions, can further limit vector penetration.
Vaccination Research
Although significant progress has been made, no licensed human vaccine currently exists for leishmaniasis. Vaccine development has been challenging due to the parasite’s complex life cycle, antigenic variability among species, and its ability to manipulate the host immune system. Historically, some regions practiced “leishmanization,” a method that involved deliberate inoculation with live parasites to induce protective immunity; however, this practice was discontinued due to safety concerns, including the risk of severe or persistent lesions.
Modern research is advancing through several promising pathways. Killed-parasite, attenuated-parasite, recombinant protein, DNA, and peptide-based vaccines are all under investigation. Many experimental vaccines aim to trigger a strong cellular immune response, particularly a Th1-type response, since this type of immunity is critical for controlling intracellular pathogens like Leishmania. Several candidates have shown protective effects in animal models and early human trials, but none yet meet the requirements for widespread use in endemic regions.