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Leishmaniasis
Leishmaniasis
Leishmaniasis
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Leishmaniasis
Other namesLeishmaniosis
Cutaneous leishmaniasis in the hand of a Central American adult
Pronunciation
SpecialtyInfectious disease
SymptomsSkin ulcers, fever, low red blood cells, enlarged liver[2][3]
CausesLeishmania parasites spread by sandflies[2]
PreventionBug nets, insecticide[2]
Frequency4–12 million[4][5]
Deaths24,200 (2015)[6]

Leishmaniasis is a wide array of clinical manifestations caused by protozoal parasites of the Trypanosomatida genus Leishmania.[7] It is generally spread through the bite of phlebotomine sandflies, Phlebotomus and Lutzomyia, and occurs most frequently in the tropics and sub-tropics of Africa, Asia, the Americas, and southern Europe.[2][8] The disease can present in three main ways: cutaneous, mucocutaneous, or visceral.[2] The cutaneous form presents with skin ulcers, while the mucocutaneous form presents with ulcers of the skin, mouth, and nose. The visceral form starts with skin ulcers and later presents with fever, low red blood cell count, and enlarged spleen and liver.[2][3]

Infections in humans are caused by more than 20 species of Leishmania.[8][2] Risk factors include poverty, malnutrition, deforestation, and urbanization.[2] All three types can be diagnosed by seeing the parasites under microscopy.[2] Additionally, visceral disease can be diagnosed by blood tests.[3]

Leishmaniasis can be partly prevented by sleeping under nets treated with insecticide.[2] Other measures include spraying insecticides to kill sandflies and treating people with the disease early to prevent further spread.[2] The treatment needed is determined by where the disease is acquired, the species of Leishmania, and the type of infection.[2] Recent research in leishmaniasis treatment explores combination therapies, nanotechnology-based drugs, and immunotherapy.

For cutaneous disease, paromomycin, fluconazole, or pentamidine may be effective.[9]

About 4 to 12 million people are currently infected[4][5] in some 98 countries.[3] About 2 million new cases[3] and between 20 and 50 thousand deaths occur each year.[2][10] About 200 million people in Asia, Africa, South and Central America, and southern Europe live in areas where the disease is common.[3][11] The World Health Organization has obtained discounts on some medications to treat the disease.[3] It is classified as a neglected tropical disease.[12] The disease may occur in a number of other animals, including dogs and rodents.[2]

Signs and symptoms

[edit]
Cutaneous leishmaniasis ulcer

The symptoms of leishmaniasis are skin sores which erupt weeks to months after the person is bitten by infected sandflies.

Leishmaniasis may be divided into the following types:[13]

  • Cutaneous leishmaniasis is the most common form, which causes an open sore at each bite site, which heals in a few months to a year and a half, leaving an unpleasant-looking scar.[2][3]
    • Diffuse cutaneous leishmaniasis produces widespread skin lesions which resemble leprosy, and may not heal on their own.[3]

Leishmaniasis is considered one of the classic causes of a markedly enlarged (and therefore palpable) spleen; the organ, which is not normally felt during the examination of the abdomen, may even become larger than the liver in severe cases.[citation needed]

Cause

[edit]
Lifecycle of Leishmania

Leishmaniasis is transmitted by the bite of infected female phlebotomine sandflies[2] which can transmit the protozoa Leishmania.[2] The sandflies inject the infective stage, metacyclic promastigotes, during blood meals. Metacyclic promastigotes in the puncture wound are phagocytized by macrophages, and transform into amastigotes. Amastigotes multiply in infected cells and affect different tissues, depending in part on the host, and in part on which Leishmania species is involved. These differing tissue specificities cause the differing clinical manifestations of the various forms of leishmaniasis. Sandflies become infected during blood meals on infected hosts when they ingest macrophages infected with amastigotes. In the sandfly's midgut, the parasites differentiate into promastigotes, which multiply, differentiate into metacyclic promastigotes, and migrate to the proboscis.

The genomes of three Leishmania species (L. major, L. infantum, and L. braziliensis) have been sequenced, and this has provided much information about the biology of the parasite. For example, in Leishmania, protein-coding genes are understood to be organized as large polycistronic units in a head-to-head or tail-to-tail manner; RNA polymerase II transcribes long polycistronic messages in the absence of defined RNA pol II promoters, and Leishmania has unique features concerning the regulation of gene expression in response to changes in the environment. The new knowledge from these studies may help identify new targets for urgently needed drugs and aid the development of vaccines.[14]

Vector

[edit]

Although most of the literature mentions only one genus transmitting Leishmania to humans (Lutzomyia) in the New World, a 2003 study by Galati suggested a new classification for New World sand flies, elevating several subgenera to the genus level. Elsewhere in the world, the genus Phlebotomus is considered the vector of leishmaniasis.[14]

Possible non-human reservoirs

[edit]

Some cases of infection of non-human animals of human-infecting species of Leishmania have been observed. In one study, L. major was identified in twelve out of ninety-one wild western lowland gorilla fecal samples[15] and in a study of fifty-two captive non-human primates under zoo captivity in a leishmaniasis endemic area, eight (all three chimpanzees, three golden lion tamarins, a tufted capuchin, and an Angolan talapoin), were found to be infected with L. infantum and capable of infecting Lutzomyia longipalpis sand flies, although "parasite loads in infected sand flies observed in this study were considered low".[16]

Organisms

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Visceral disease is usually caused by Leishmania donovani, L. infantum, or L. chagasi,[3] but occasionally these species may cause other forms of disease.[3] The cutaneous form of the disease is caused by more than 15 species of Leishmania.[3]

Risk factors

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Risk factors include malnutrition, deforestation, lack of sanitation, suppressed immune system, and urbanization.[2]

  • Socioeconomic conditions: Poor living conditions like overcrowded housing and inadequate sanitation are associated with increased human exposure to sandflies. Poor waste management and open sewage create ideal breeding grounds for sandflies in rural and low-income urban areas. Limited access to healthcare may delay diagnosis and treatment, which can contribute to more severe disease outcomes. Poor individuals may face a financial barrier to treatment, increasing their risk of severe disease.[17]
  • Malnutrition: Deficiencies in protein, iron, vitamin A, and zinc weaken the immune system, making it harder to fight Leishmania infections. This increases the risk of both cutaneous and visceral leishmaniasis, leading to more severe illness and poor treatment outcomes.[18]
  • Population Mobility: Migration and displacement due to conflict, economic hardship, or environmental changes contribute to the spread of leishmaniasis, particularly when non-immune individuals enter endemic areas. Refugees and seasonal agricultural workers are at higher risk due to limited access to vector control measures. Human activity in previously uninhabited lands may increase exposure to infected sandflies and wildfire reservoirs.[19]
  • Environmental and Climate Change: Temperature, humidity, and rainfall changes affect the sandfly population. Rising temperatures have been linked to higher sandfly survival and breeding rates, allowing the disease to spread into higher altitudes and previously unaffected regions, such as Southern Europe and North America. Deforestation, urbanization, and dam construction disturb sandfly habitats, creating new transmission hotspots and increasing the risk of outbreaks.[20]

Diagnosis

[edit]
Bone marrow aspirate smear: visceral leishmaniasis

Leishmaniasis is diagnosed in the hematology laboratory by direct visualization of the amastigotes (Leishman–Donovan bodies). Buffy-coat preparations of peripheral blood or aspirates from marrow, spleen, lymph nodes, or skin lesions should be spread on a slide to make a thin smear and stained with Leishman stain or Giemsa stain (pH 7.2) for 20 minutes. Amastigotes are seen within blood and spleen monocytes or, less commonly, in circulating neutrophils and in aspirated tissue macrophages. They are small, round bodies 2–4 μm in diameter with indistinct cytoplasm, a nucleus, and a small, rod-shaped kinetoplast. Occasionally, amastigotes may be seen lying free between cells.[21] However, the retrieval of tissue samples is often painful for the patient and identification of the infected cells can be difficult. So, other indirect immunological methods of diagnosis are developed, including enzyme-linked immunosorbent assay, antigen-coated dipsticks, and direct agglutination test. Although these tests are readily available, they are not the standard diagnostic tests due to their insufficient sensitivity and specificity[citation needed].

Several different polymerase chain reaction (PCR) tests are available for the detection of Leishmania DNA.[3] With this assay, a specific and sensitive diagnostic procedure is finally possible. The most sensitive PCR tests use minicircle kinetoplast DNA found in the parasite. Kinetoplast DNA contains sequences for mitochondrial proteins in its maxicircles (~25–50 per parasite), and guide RNA in its minicircles (~10,000 per parasite) of the kinetoplast. With this specific method, one can still detect Leishmania even with a very low parasite load. When needing to diagnose a specific species of Leishmania, as opposed to only detection, other PCR methods have been superior.[22]

Most forms of the disease are transmitted only from nonhuman animals, but some can be spread between humans. Infections in humans are caused by about 21 of 30 species that infect mammals;[23] the different species look the same, but they can be differentiated by isoenzyme analysis, DNA sequence analysis, or monoclonal antibodies.

Prevention

[edit]
  • Using insect repellent on exposed skin and under the ends of sleeves and pant legs. Follow the instructions on the label of the repellent. The most effective repellents generally are those that contain the chemical DEET (N,N-diethylmetatoluamide)[24]
  • Leishmaniasis can be partly prevented by using nets treated with insecticide or insect repellent while sleeping.[2] To provide good protection against sandflies, fine mesh sizes of 0.6 mm or less are required, but a mosquito net with 1.2mm mesh will provide a limited reduction in the number of sandfly bites.[25] Finer mesh sizes have the downside of higher cost and reduced air circulation which can cause overheating. Many Phlebotomine sandfly attacks occur at sunset rather than at night, so it may also be useful to put nets over doors and windows or to use insect repellents.[24]
  • Use of insecticide-impregnated dog collars and treatment or culling of infected dogs.[citation needed]
  • Spraying houses and animal shelters with insecticides.[25]
  • Prevention and control of leishmaniasis requires a multifaceted approach. Insecticide spraying, treated nets, and case management are commonly used strategies, while additional approaches are being explored for long-term disease control.
  • Vector Control: Integrated Vector Management (IVM) approach is key to reducing sand fly populations. Some of the latest strategies include:
    • Research is ongoing into genetically modifying sand flies to reduce their ability to transmit Leishmania parasites.[26]
    • Attractive toxic sugar baits (ATSBs) attract and kill sand flies that feed on plant sugars.[27]
    • Spatial repellents and insecticidal paint create long-term barriers against sand flies.[27]
  • Reservoir Control:
    • Canine control measures: domestic dogs are major reservoirs for Leishmania infantum in regions where visceral leishmaniasis is common. Instead of widespread dog culling, which has been proven ineffective and controversial, deltamethrin-impregnated dog collars have been introduced as a safer and more effective alternative.[28]
    • Wildlife reservoirs: Controlling wild animal reservoirs such as rodents, marsupials, sloths, and armadillos is more challenging due to conservation concerns.[29]

Vaccination: Canine vaccinations have been developed and are now being used in some regions to reduce transmission. Human vaccinations are in development, with several candidates in clinical trials assessing their potential for long-term immunity.[30]

Treatment

[edit]
Paromomycin is an inexpensive (US$10) and effective treatment for leishmaniasis.

The treatment is determined by where the disease is acquired, the species of Leishmania, and the type of infection.[2] For visceral leishmaniasis in India, South America, and the Mediterranean, liposomal amphotericin B is the recommended treatment and is often used as a single dose.[3][31] Rates of cure with a single dose of amphotericin have been reported as 95%.[3] In India, almost all infections are resistant to pentavalent antimonials.[3] In Africa, a combination of pentavalent antimonials and paromomycin is recommended.[31] These, however, can have significant side effects.[3] Miltefosine, an oral medication, is effective against both visceral and cutaneous leishmaniasis.[32] Side effects are generally mild, though it can cause birth defects if taken within three months of getting pregnant.[3][32] It does not appear to work for L. major or L. braziliensis.[9] Trifluralin, a herbicide, is shown to be effective treatment as ointment, without hemolytic or cell-toxic side-effects.[33]

Recent research in leishmaniasis treatment explores combination therapies, nanotechnology-based drugs, and immunotherapy. Combination treatments, such as liposomal amphotericin B (L-AmB) with miltefosine or paromomycin, have shown high cure rates for visceral leishmaniasis while reducing treatment time and side effects.[31] The WHO recommends miltefosine-based combination therapy for specific cases of visceral leishmaniasis.[31] Nanotechnology-based treatments, including lipid and metallic nanoparticles, improve drug delivery by targeting parasites more precisely and reducing toxicity.[31] Immune-modulating therapies, such as interferon-gamma (IFN-γ), are under investigation for their potential in enhancing immune responses against Leishmania infections.[31]

The evidence around the treatment of cutaneous leishmaniasis is poor.[3] Several topical treatments may be used for cutaneous leishmaniasis. Which treatments are effective depends on the strain, with topical paromomycin effective for L. major, L. tropica, L. mexicana, L. panamensis, and L. braziliensis.[9] Pentamidine is effective for L. guyanensis.[9] Oral fluconazole or itraconazole appears effective in L. major and L. tropica.[3][9] There is limited evidence to support the use of heat therapy in cutaneous leishmaniasis as of 2015.[34]

As of 2018, no studies have determined the effect of oral nutritional supplements on visceral leishmaniasis being treated with anti-leishmanial drug therapy.[35] For the reason, it is not known if nutritional supplements are ineffective (or effective).[35] Further research including high quality randomized controlled trials are needed to determine if supplements are helpful and if so, at what dose, to help people with VL who are undergoing treatment with anti-leishmanial medications.[35]

The Institute for OneWorld Health has reintroduced the drug paromomycin for the treatment of leishmaniasis, results which led to its approval as an orphan drug. The Drugs for Neglected Diseases Initiative is also actively facilitating the search for novel therapeutics. A treatment with paromomycin will cost about US$10. The drug had originally been identified in the 1950s but had been abandoned because it would not be profitable, as the disease mostly affects poor people.[36] The Indian government approved paromomycin for sale in August 2006.[37]

By 2012 the World Health Organization had successfully negotiated with the manufacturers to achieve a reduced cost for liposomal amphotericin B, to US$18 a vial, but several vials are needed for treatment and it must be kept at a stable, cool temperature.[3]

Epidemiology

[edit]
Cutaneous leishmaniasis in North Africa; Leishmania infantum = green, Leishmania major = blue, Leishmania tropica = red[38]
Disability-adjusted life year for leishmaniasis per 100,000 inhabitants
  no data
  less than 20
  20–30
  30–40
  40–50
  50–60
  60–70
  70–80
  80–100
  100–120
  120–150
  150–200
  more than 200

Out of 200 countries and territories reporting to WHO, 97 countries and territories are endemic for leishmaniasis.[39] The settings in which leishmaniasis is found range from rainforests in Central and South America to deserts in western Asia and the Middle East. It affects as many as 12 million people worldwide.[40] Leishmaniasis affect an estimated 700,000 to 1 million new cases annually, with over a billion people living in endemic areas at risk of infection.[41] Visceral leishmaniasis is a fatal form with the potential for outbreak, causing, 50,000 to 90,000 cases worldwide each year. However only 25-45% are reported to the WHO.[41] Cutaneous leishmaniasis is the most common form with 600,000 to 1 million new cases each year yet only 200,000 are officially reported.[41] It is most common in Afghanistan, Algeria, Brazil, Colombia, and Iran. Mucocutaneous leishmaniasis is rarer with over 90% of cases occurring in Bolivia, Brazil, and Peru.[41] The visceral form is most common in Bangladesh, Brazil, Ethiopia, India, and Sudan.[2] In 2014, more than 90% of new cases reported to WHO occurred in six countries: Brazil, Ethiopia, India, Somalia, South Sudan and Sudan.[42] As of 2010, it caused about 52,000 deaths, down from 87,000 in 1990.[10]

Leishmaniasis is found through much of the Americas from northern Argentina to South Texas, though not in Uruguay or Chile, and has recently been shown to be spreading to North Texas and Oklahoma,[43][44] and further expansion to the north may be facilitated by climate change as more habitat becomes suitable for vector and reservoir species for leishmaniasis.[45] Leishmaniasis is also known as papalomoyo, papa lo moyo, úlcera de los chicleros, and chiclera in Latin America.[46] During 2004, an estimated 3,400 troops from the Colombian army, operating in the jungles near the south of the country (in particular around the Meta and Guaviare departments), were infected with leishmaniasis. Allegedly, a contributing factor was that many of the affected soldiers did not use the officially provided insect repellent because of its disturbing odor. Nearly 13,000 cases of the disease were recorded in all of Colombia throughout 2004, and about 360 new instances of the disease among soldiers had been reported in February 2005.[47]

The disease is found across much of Asia and in the Middle East. Within Afghanistan, leishmaniasis occurs commonly in Kabul, partly due to bad sanitation and waste left uncollected in streets, allowing parasite-spreading sand flies an environment they find favorable.[48][49] In Kabul, the number of people infected was estimated to be at least 200,000, and in three other towns (Herat, Kandahar, and Mazar-i-Sharif) about 70,000 more occurred, according to WHO figures from 2002.[50][51] Kabul is estimated as the largest center of cutaneous leishmaniasis in the world, with around 67,500 cases as of 2004.[52] Africa, in particular, the East and North,[38] is also home to cases of leishmaniasis. Leishmaniasis is considered endemic also in some parts of southern parts of western Europe and has spread towards the north in recent years.[53] For example, an outbreak of cutaneous and visceral leishmaniasis was reported from Madrid, Spain, between 2010 and 2012.[54]

Leishmaniasis is mostly a disease of the developing world and is rarely known in the developed world outside a small number of cases, mostly in instances where troops are stationed away from their home countries. Leishmaniasis has been reported by U.S. troops stationed in Saudi Arabia and Iraq since the Gulf War of 1990, including visceral leishmaniasis.[55][56][57] In September 2005, the disease was contracted by at least four Dutch marines who were stationed in Mazar-i-Sharif, Afghanistan, and subsequently repatriated for treatment.[58][59]

History

[edit]
A 1917 case of cutaneous leishmaniasis in the Middle East, known then locally as "Jericho buttons" for the frequency of cases near the ancient city of Jericho

Descriptions of conspicuous lesions similar to cutaneous leishmaniasis appear on tablets from King Ashurbanipal from the seventh century BCE, some of which may have derived from even earlier texts from 1500 to 2500 BCE. Persian physicians, including Avicenna in the 10th century CE, gave detailed descriptions of what was called balkh sore.[60] In 1756, Alexander Russell, after examining a Turkish patient, gave one of the most detailed clinical descriptions of the disease. Physicians in the Indian subcontinent would describe it as kala-azar (pronounced kālā āzār, the Urdu, Hindi, and Hindustani phrase for "black fever", kālā meaning black and āzār meaning fever or disease). In the Americas, evidence of the cutaneous form of the disease in Ecuador and Peru appears in pre-Inca pottery depicting skin lesions and deformed faces dating back to the first century CE. Some 15th- and 16th-century texts from the Inca period and from Spanish colonials mention "valley sickness", "Andean sickness", or "white leprosy", which are likely to be the cutaneous form.[61]

It remains unclear who first discovered the organism. David Douglas Cunningham, Surgeon Major of the British Indian army, may have seen it in 1885 without being able to relate it to the disease.[62][63] Peter Borovsky, a Russian military surgeon working in Tashkent, conducted research into the etiology of "oriental sore", locally known as sart sore, and in 1898 published the first accurate description of the causative agent, correctly described the parasite's relation to host tissues and correctly referred it to the protozoa. However, because his results were published in Russian in a journal with low circulation, his results were not internationally acknowledged during his lifetime.[64] In 1901, William Boog Leishman identified certain organisms in smears taken from the spleen of a patient who had died from "dum-dum fever" (Dum Dum is an area close to Calcutta) and proposed them to be trypanosomes, found for the first time in India.[65] A few months later, Captain Charles Donovan (1863–1951) confirmed the finding of what became known as Leishman-Donovan bodies in smears taken from people in Madras in southern India.[66] But it was Ronald Ross who proposed that Leishman-Donovan bodies were the intracellular stages of a new parasite, which he named Leishmania donovani.[67] The link with the disease kala-azar was first suggested by Charles Donovan, and was conclusively demonstrated by Charles Bentley's discovery of L. donovani in patients with kala-azar.[68] Transmission by the sandfly was hypothesized by Lionel Napier and Ernest Struthers at the School of Tropical Medicine at Calcutta and later proven by his colleagues.[69][70] The disease became a major problem for Allied troops fighting in Sicily during the Second World War; research by Leonard Goodwin then showed pentostam was an effective treatment.[71]

Society and culture

[edit]
  • Stigma and Psychological Effects: The cutaneous and mucocutaneous forms of leishmaniasis can cause visible scarring and disfigurement, leading to social stigma, discrimination, and emotional distress. In some communities, individuals with visible scarring may face social challenges, including barriers to employment, social activities, education, and marriage, due to the stigma surrounding the disease. As awareness grows, mental health support and community education programs are recognized as important disease management aspects.[72]
  • Economic burden: The cost of diagnosis, treatment, and hospitalizations pose financial challenges, particularly in regions where access to free or subsidized treatment is limited. Patients may experience income loss due to illness, disability and long recovery time. In rural areas, leishmaniasis can impact livestock and working animals, contributing to economic challenges for agricultural and livestock-dependent communities.[17]
  • Cultural beliefs and traditional medicine: In some endemic areas, cultural beliefs regarding the cause of leishmaniasis, including supernatural or spiritual explanations, may influence healthcare-seeking behaviors, sometimes delaying access to medical treatment.[73]

Research

[edit]
Main article: Leishmaniasis vaccine
A parasitologist working on L. major in a biocontainment hood

As of 2017, no leishmaniasis vaccine for humans was available.[74][75] Research to produce a human vaccine is ongoing.[75]

Currently some effective leishmaniasis vaccines for dogs exist.[76] There is also the consideration that public health practices can control or eliminate leishmaniasis without a vaccine.[75] Pyrimidine–based drugs are being explored as anti-leishmanial compounds.[77]

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Leishmaniasis

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from Grokipedia

Leishmaniasis encompasses a group of vector-borne parasitic diseases caused by over 20 species of intracellular protozoan parasites belonging to the genus Leishmania, which are transmitted primarily through the bites of infected female phlebotomine sandflies of genera such as Phlebotomus and Lutzomyia. The parasites exhibit a digenetic life cycle, alternating between promastigote forms in the sandfly vector and amastigote forms within mammalian hosts, including humans and various reservoir animals like rodents and canines. Clinically, leishmaniasis manifests in three principal forms: cutaneous leishmaniasis, characterized by localized skin ulcers that typically self-heal but can cause disfigurement; mucocutaneous leishmaniasis, involving destructive lesions of mucous membranes in the nose, mouth, and throat; and visceral leishmaniasis (also known as kala-azar), the most severe form that disseminates to internal organs such as the spleen, liver, and bone marrow, leading to fever, weight loss, anemia, and high mortality rates exceeding 95% if untreated. Globally, leishmaniasis affects populations in over 90 countries across tropical and subtropical regions of Africa, Asia, the Americas, and the Mediterranean, with an estimated 700,000 to 1 million new cases annually, predominantly cutaneous, alongside 50,000 to 90,000 visceral cases, many underreported due to diagnostic challenges in resource-limited settings. Classified as a neglected tropical disease, it imposes a substantial burden on impoverished communities, exacerbated by factors like poor housing, malnutrition, and conflict, with visceral leishmaniasis responsible for 20,000 to 30,000 deaths yearly despite available treatments like antimonials and amphotericin B.

Clinical Manifestations

Cutaneous Leishmaniasis


Cutaneous leishmaniasis (CL) represents the predominant clinical manifestation of leishmaniasis, resulting from infection by dermotropic species of the protozoan genus Leishmania transmitted via phlebotomine sandfly bites. It primarily affects exposed skin areas such as the face, arms, and legs, with lesions developing at the inoculation site. The incubation period typically spans 2 weeks to several months, though it can extend longer in some cases. Globally, CL accounts for the majority of the estimated 600,000 to 1 million annual leishmaniasis cases, predominantly in endemic regions of the tropics and subtropics. Initial lesions emerge as small, erythematous papules or nodules that progressively enlarge and ulcerate over weeks to months, forming characteristic open sores with raised, indurated borders and a central often covered by a hemorrhagic crust or scab. These ulcers, sometimes described as "volcano-like," are generally painless unless secondarily infected, though regional may occur. size varies from millimeters to several centimeters, and multiple lesions can arise from repeated bites. Without intervention, ulcers persist for months to years, eventually healing spontaneously with atrophic, hypopigmented scars that may cause cosmetic . Clinical variants include localized cutaneous leishmaniasis (LCL), the most common form featuring solitary or few self-limiting ulcers; diffuse cutaneous leishmaniasis (DCL), a rare disseminated variant in immunocompromised individuals or with species like L. aethiopica, presenting as widespread nodules and plaques without ulceration; and leishmaniasis recidiva, a chronic relapsing form with persistent papules and scarring resembling lupus erythematosus. Manifestations differ by Leishmania species and geographic origin: Old World CL (e.g., L. major, L. tropica in , , Mediterranean) tends toward dry, self-resolving ulcers, while New World CL (e.g., L. mexicana, L. braziliensis in the ) often produces larger, wetter lesions with potential for satellite dissemination or secondary bacterial infection. Systemic symptoms are absent in uncomplicated CL, distinguishing it from visceral forms.

Mucocutaneous Leishmaniasis

Mucocutaneous leishmaniasis (MCL), also known as espundia, represents a severe, progressive form of leishmaniasis characterized by destructive and ulceration of the mucous membranes, particularly in the nasopharynx, oral cavity, and . It is primarily caused by protozoan parasites of the species (Viannia) braziliensis, with less frequent causation by L. guyanensis or L. panamensis. The disease arises from hematogenous or lymphatic dissemination of parasites from an initial cutaneous infection site, typically manifesting months to years after the primary skin lesion heals. Endemic to , MCL accounts for an estimated 90% of global cases, with the highest incidence in (up to 10,000 cases annually as of 2023 data), followed by and , where environmental factors such as and proximity to sylvatic reservoirs exacerbate transmission via sandfly vectors. Cases outside the are exceptional, limited to sporadic reports involving L. aethiopica or L. tropica, though these rarely progress to mucosal destruction. Risk factors include male sex, rural occupation, and poor nutritional status, which correlate with delayed immune responses permitting parasite persistence. Clinically, MCL begins insidiously with nasal symptoms such as persistent congestion, epistaxis, and serosanguinous discharge, mimicking chronic . Over time, granulomatous inflammation evolves into confluent ulcers that erode soft tissues, perforate the in up to 70% of untreated cases, and invade the or buccal mucosa, causing fetid odor, , and nutritional impairment. Laryngeal extension occurs in approximately 20-30% of advanced cases, resulting in hoarseness, , and potential asphyxiation if untreated. involvement may coexist or precede mucosal lesions, but isolated primary mucosal disease is rare, affecting less than 5% of patients. Histopathologically, lesions show amastigote-laden macrophages amid mixed inflammatory infiltrates, with Th1-mediated immunity often inadequate to clear the parasite, leading to chronic suppuration and . Complications include secondary bacterial superinfections, extensive scarring, and from facial disfigurement, which can necessitate post-treatment. Without intervention, mortality approaches 10% due to respiratory obstruction or , underscoring the need for early recognition of at-risk cutaneous cases in endemic zones.

Visceral Leishmaniasis

Visceral leishmaniasis (VL), also known as kala-azar, is the most severe clinical form of leishmaniasis, characterized by systemic infection of the , particularly the , liver, , and lymph nodes. Initial symptoms often emerge after an of 2 to 6 months, though it can extend to years, with insidious onset including prolonged irregular fever in bouts that may follow a quotidian, double-quotidian, or pattern, accompanied by chills and rigors. and are common early features, progressing to marked , anorexia, and generalized as parasitization impairs hematopoiesis and organ function. Physical examination reveals progressive , often massive and extending beyond the umbilicus, with in approximately 50-60% of cases; abdominal discomfort from organ enlargement is frequent. leads to and , while may cause petechiae or easy bruising; increases susceptibility to infections. of the skin, especially on the face, hands, knuckles, and abdomen—lending the disease its name "kala-azar" (black fever in )—occurs due to adrenal involvement or deposition. Laboratory abnormalities include , , and polyclonal hypergammaglobulinemia, reflecting chronic inflammation and immune dysregulation. Untreated VL leads to , secondary bacterial infections (e.g., , , or ), and hemorrhagic complications, with mortality approaching 100% from multiorgan failure or overwhelming . In immunocompromised individuals, such as those with co-infection, progression is accelerated, symptoms more atypical, and visceral burden higher, exacerbating and relapse risk. Post-kala-azar dermal leishmaniasis (PKDL) manifests in 5-10% of cases as hypopigmented or erythematous skin lesions during or after apparent cure, serving as a for transmission. Annual global incidence estimates range from 50,000 to 90,000 cases, predominantly in , , and , with higher lethality in malnourished children under 5 years.

Etiology and Pathogenesis

Causative Protozoa

Leishmaniasis is caused by obligate intracellular protozoan parasites belonging to the genus Leishmania in the family Trypanosomatidae. More than 20 Leishmania species are pathogenic to humans, with approximately 21 of the 30 known mammal-infecting species capable of causing disease. These kinetoplastid parasites exhibit a dimorphic life cycle, alternating between flagellated promastigote forms in the insect vector and non-flagellated amastigote forms within mammalian host cells, primarily macrophages of the reticuloendothelial system. The taxonomy of Leishmania divides the genus into subgenera based on the site of promastigote development in the sand fly gut: primarily (Leishmania) for species maturing in the and , and Viannia for those restricted to the . A newer subgenus, Mundinia, includes emerging human-pathogenic species like L. (Mundinia) martiniquensis, but most human infections involve species from the and Viannia subgenera. Pathogenicity varies by species due to differences in factors, such as surface glycoproteins and enzymes that enable immune evasion and intracellular survival, though host factors also influence outcome. Key Leishmania species and their primary associations with clinical forms are summarized below; note that some species can cause multiple syndromes, and distribution overlaps Old World (Africa, Asia, Europe) and New World (Americas) regions.
Complex/SpeciesSubgenusPrimary Disease Form(s)Notes
L. donovani complex (L. donovani, L. infantum, L. chagasi)LeishmaniaVisceral leishmaniasis (kala-azar)L. infantum also causes cutaneous forms; zoonotic in dogs.
L. tropica, L. major, L. aethiopicaLeishmaniaCutaneous leishmaniasisL. tropica anthroponotic; L. major zoonotic in rodents.
L. mexicana complex (L. mexicana, L. amazonensis, L. venezuelensis)LeishmaniaCutaneous leishmaniasis (diffuse or localized)New World; rodents as reservoirs.
L. (V.) braziliensis complex (L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) panamensis, L. (V.) peruviana)VianniaMucocutaneous and cutaneous leishmaniasisHigh risk of mucosal destruction; New World.
Amastigotes, the replicative form in humans, measure 2–4 μm, lack an external , and reside in parasitophorous vacuoles within host , multiplying by binary fission until host cell lysis releases progeny to infect new cells. This intracellular strategy contributes to chronic infection and dissemination, with visceral species like L. donovani targeting , liver, and , leading to and if untreated. Species-specific , including kDNA minicircles used for identification, underlies variable and severity.

Vectors and Reservoirs

Leishmaniasis is transmitted exclusively by the bite of phlebotomine flies, belonging to the genera in the and (previously and Psychodopygus) in the . Over 90 fly species are known to transmit various species, with transmission occurring when promastigotes in the fly's are deposited into the skin during a . Certain vectors demonstrate specificity; for example, papatasi primarily transmits L. major in the , while P. argentipes is a key vector for caused by L. donovani in . In the , longipalpis serves as the principal vector for L. infantum. Reservoir hosts differ by Leishmania species, clinical form, and endemic region, sustaining the parasite in zoonotic cycles while humans often act as incidental hosts or primary reservoirs in anthroponotic transmission. For cutaneous leishmaniasis due to L. major, synanthropic rodents such as Meriones spp. (gerbils) and Rhombomys opimus (great gerbil) function as main reservoirs in and the . In visceral leishmaniasis endemic to the Mediterranean, , and , domestic dogs (Canis familiaris) are the primary reservoir for L. infantum, with infection rates in dogs reaching 67–80% in some vector-transmitted foci via or PCR detection. Emerging evidence from , , indicates dogs as potential reservoirs for L. donovani, traditionally considered anthroponotic, with DNA detected in village dogs alongside goats and cows. Wild mammals contribute as sylvatic reservoirs, including foxes (Vulpes spp.), jackals, and rodents in various cycles, while cats may serve as secondary hosts for L. infantum, facilitating transmission to humans and dogs. In the Americas, diverse synanthropic and wild hosts such as opossums, armadillos, sloths, and rodents harbor L. braziliensis and other species causing mucocutaneous forms. In anthroponotic visceral leishmaniasis foci like parts of India and Sudan, humans maintain the cycle without evident animal reservoirs, though recent studies challenge this by identifying peridomestic mammals. Reservoir competence varies, with some species like dogs exhibiting high parasitemia and infectivity to vectors, underscoring their epidemiological significance.

Transmission and Immune Evasion


Leishmania parasites are transmitted to humans and other mammals primarily via the bite of infected female phlebotomine sandflies, which inject metacyclic promastigotes—the infective stage—into the host's skin during blood meals. These vectors, belonging to over 70 species across genera such as Phlebotomus (Old World) and Lutzomyia (New World), acquire the parasite during feeding on infected hosts and support its development in their midgut over 4–25 days before transmission. Transmission efficiency depends on factors like sandfly microbiota, which promotes parasite survival and vector competence through inflammasome-mediated IL-1β production, and the parasites' ability to evade digestion in the fly's gut. Zoonotic cycles involve reservoirs such as rodents (e.g., Rhombomys opimus for cutaneous forms) and canids (e.g., dogs for L. infantum), while anthroponotic cycles rely on human reservoirs, particularly in urban visceral leishmaniasis foci. Non-vector routes, including blood transfusions, shared needles, congenital transfer, and rarely sexual contact, account for fewer than 1% of cases but pose risks in endemic areas with poor screening. Following , promastigotes are rapidly phagocytosed by host macrophages and dendritic cells but evade intracellular killing through multiple strategies that subvert phagolysosome maturation and oxidative bursts. Key surface glycoproteins like GP63 cleave complement components and inhibit (ROS) production, while lipophosphoglycan (LPG) blocks lysosomal enzyme recruitment and fusion, allowing transformation into replicative amastigotes within parasitophorous vacuoles. Parasites further manipulate host signaling by activating SHP-1, which dephosphorylates kinases like JAK2 and MAPK, thereby suppressing activation and pro-inflammatory cytokine release (e.g., IL-12, TNF-α) essential for Th1 immunity. enzymes, such as arginase and , deplete host L-arginine and neutralize ROS, respectively, promoting parasite persistence and shifting immune responses toward Th2 dominance with elevated IL-10 and TGF-β. In adaptive immunity, impairs by downregulating expression on infected and inducing regulatory T cells (Tregs) that suppress CD4+ T cell proliferation via IL-10 and CTLA-4 pathways. Parasite-derived exosomes and secreted proteins further disseminate immunosuppressive signals, inhibiting maturation and promoting exhaustion of effector T cells. These mechanisms collectively enable chronic infection, with species-specific variations—such as L. donovani's enhanced A2 protein-mediated survival in visceral sites—contributing to diverse clinical outcomes. Despite robust innate responses, evasion of in host cells via modulation of proteins prolongs the intracellular niche, underscoring the parasite's evolutionary adaptations to defenses.

Diagnosis

Clinical Evaluation

Clinical evaluation of leishmaniasis relies on a detailed history and comprehensive to identify features suggestive of cutaneous, mucocutaneous, or visceral disease, particularly in individuals with exposure history. A key element is assessing for residence or travel to endemic regions, such as parts of Asia, Africa, the Middle East, Central and South America, or the Mediterranean basin, where sandfly vectors transmit Leishmania species. Immunosuppression, including HIV coinfection, increases risk and alters presentation, often leading to atypical or disseminated forms. For , history typically reveals a slowly progressing starting as a pruritic at the bite site, evolving over 2-8 weeks into a nodule and then a painless with indurated, raised borders; lesions commonly appear on exposed areas like the face, arms, or legs and may self-resolve over 3-18 months but leave scars. confirms volcano-like ulcers with central crusting and satellite lesions in some cases, though multiple lesions suggest dissemination in immunocompromised patients. Differential considerations include bacterial or fungal infections, , cutaneous , and , necessitating exclusion via or culture in ambiguous cases. Mucocutaneous leishmaniasis evaluation focuses on persistent nasal symptoms such as stuffiness, epistaxis, or congestion emerging months to years after initial cutaneous , primarily from L. braziliensis in the . Examination may reveal mucosal , nodules, or destructive ulcers in the , , or , progressing to or if untreated. Oral or laryngeal involvement can cause hoarseness or , with differentials encompassing , , , and midline granulomas. Visceral leishmaniasis presents with insidious onset of irregular fever (often bi-phasic, peaking in evenings), profound fatigue, anorexia, and significant over weeks to months, accompanied by from . Physical findings include marked (extending >10 cm below the costal margin in advanced cases), moderate , and generalized , alongside signs of , , and hypergammaglobulinemia evident in , petechiae, or bleeding. In endemic areas, differentials include , , , , and , requiring careful history to distinguish based on and absence of response to antimicrobials. Post-kala-azar dermal leishmaniasis may follow resolved visceral infection, manifesting as hypopigmented macules or nodules on the face and trunk. While clinical features guide suspicion, definitive demands parasitological confirmation due to overlapping syndromes.

Laboratory Confirmation

Laboratory confirmation of leishmaniasis primarily relies on direct parasitological methods, which detect the intracellular form of parasites in clinical specimens. For , specimens include lesion scrapings, punch biopsies, or aspirates stained with Giemsa or to visualize amastigotes within macrophages; sensitivity ranges from 50% to 80%, depending on lesion chronicity and parasite load. In , aspirates or splenic punctures yield higher detection rates, up to 95% for bone marrow microscopy, though splenic sampling is riskier due to potential hemorrhage. Histopathological examination of biopsies reveals amastigotes alongside inflammatory responses like granulomas, but requires expertise to distinguish from other intracellular pathogens. Culture isolation remains a reference standard for viable parasite confirmation and species identification, using media such as Novy-MacNeal-Nicolle (NNN) or Schneider's medium incubated at 26–28°C for 4–21 days. Success rates vary: 70–90% for fresh cutaneous specimens but lower for older lesions or frozen samples, with limitations including slow growth, overgrowth by contaminants, and 2 requirements. Molecular methods, particularly (PCR) targeting kinetoplast DNA or ITS regions, offer superior sensitivity (90–100%) and specificity (>95%), enabling detection in low-parasite-load cases and rapid species typing via sequencing or probes. Real-time PCR assays, validated for tissue, , and buffy coat, reduce contamination risks and provide quantitative data on parasite burden. Serological tests, such as direct agglutination test (DAT) or rK39 rapid diagnostic tests, support diagnosis with sensitivities of 85–95% in endemic areas but are less reliable for cutaneous forms due to inconsistent antibody responses. Cross-reactivity with other infections like limits specificity in co-endemic regions, necessitating parasitological corroboration. Emerging techniques like (LAMP) provide field-applicable alternatives to PCR, with comparable sensitivity in resource-limited settings. Overall, combining with PCR enhances diagnostic accuracy, particularly for atypical presentations, though access to specialized labs remains a barrier in endemic areas.

Diagnostic Challenges

Diagnosis of leishmaniasis is complicated by its nonspecific clinical features, which frequently overlap with bacterial, fungal, or other parasitic infections, resulting in presumptive diagnoses that delay confirmatory testing. In resource-limited endemic areas, where the disease burdens over 90% of cases, shortages of trained microscopists and infrastructure further impede accurate detection. Parasitological confirmation via microscopy of lesion aspirates or biopsies remains the frontline method but yields sensitivities of 50-90% for cutaneous leishmaniasis, dropping below 70% in chronic lesions or visceral forms due to sparse parasite loads and operator-dependent visualization of amastigotes. This approach also fails to differentiate Leishmania species, essential for tailoring antimonial versus miltefosine therapy in regions with varying drug responsiveness. Culture enhances specificity but demands specialized media like Novy-MacNeal-Nicolle, with growth taking 1-6 weeks and overall sensitivity under 60-70%, rendering it impractical for rapid diagnosis. Serological tests, including indirect immunofluorescence or ELISA for anti-Leishmania antibodies, achieve 80-95% sensitivity in but perform poorly (60-80%) in cutaneous forms and exhibit with or other pathogens, complicating interpretation in co-endemic zones. These assays cannot distinguish active from resolved or subclinical cases, limiting their value for treatment monitoring or epidemiological surveys. Molecular diagnostics, particularly real-time PCR targeting ITS1 or kDNA minicircles, offer superior sensitivity (>95%) and species identification but require thermocyclers, trained technicians, and kits, with costs prohibitive for peripheral health centers in low-income countries. Field-deployable shows promise for point-of-care use yet lacks widespread validation and standardization across taxa. In , gold-standard parasitological diagnosis necessitates invasive splenic or aspirations, associated with complication risks up to 0.5-5%, particularly in pediatric or HIV-co-infected patients where parasite burdens vary. , atypical presentations, and co-infections further erode test accuracies, contributing to diagnostic delays averaging 4.5 years from symptom onset in systematic reviews of imported cases.
Diagnostic MethodTypical Sensitivity RangeKey Limitations
50-90% (cutaneous); <70% (visceral)Operator-dependent; low yield in low-parasite cases; no speciation
Culture50-70%Slow (weeks); requires expertise and media; contamination risk
Serology70-95%Cross-reactivity; cannot confirm active disease
PCR>95%Infrastructure needs; cost; limited field access

Prevention

Vector Management

Vector management for leishmaniasis primarily targets phlebotomine sandflies ( spp. in the and spp. in the ), which serve as the biological vectors transmitting parasites through bites. The (WHO) endorses indoor residual spraying (IRS) with insecticides such as pyrethroids or organophosphates for endophilic sandflies that rest indoors after feeding, as this method kills vectors upon contact and can reduce sandfly density by up to 90% in treated areas when applied correctly. However, IRS efficacy varies; in , DDT-based IRS has shown suboptimal coverage and persistence, failing to interrupt transmission in some (VL) hotspots due to poor application quality and sandfly behavior. Long-lasting insecticidal nets (LLINs) and insecticide-treated nets (ITNs) provide personal protection by killing or repelling sandflies during host-seeking at night, with WHO recommending their use in endemic areas where sandflies are anthropophilic. Systematic reviews indicate ITNs reduce sandfly biting rates, but community-level impact on VL incidence is limited; a 2022 analysis across trials found only a 1% risk reduction, often statistically insignificant, attributed to inconsistent usage and exophilic sandfly activity outside net-protected hours. Integrated approaches combining IRS and LLINs, as piloted in regions like Brazil and Morocco, have demonstrated higher efficacy, with reductions in sandfly abundance exceeding 70% in household settings. Emerging methods include attractive toxic sugar baits (ATSBs), which lure sandflies to insecticide-laced sugar sources and have reduced populations by 50-80% in field trials in Israel and Morocco, offering promise for exophilic species resistant to IRS. Environmental management, such as clearing rodent burrows or vegetation near dwellings to eliminate breeding sites, complements chemical controls but lacks standalone efficacy data exceeding 30% vector reduction without insecticides. Insecticide resistance, documented in over 20 sandfly species since 2010, undermines pyrethroid-based IRS and ITNs, necessitating rotation of chemical classes and surveillance via WHO-guided bioassays. Biological controls, including sterile insect techniques or paratransgenesis, remain experimental, with no large-scale deployment as of 2023 due to scalability challenges. Effective vector management requires integrated vector management (IVM) frameworks, emphasizing surveillance of sandfly density and behavior to adapt strategies regionally.

Personal and Community Measures

Personal protective measures against Leishmania-transmitting bites form the cornerstone of prevention, as no vaccines or prophylactic drugs are currently available. Individuals in endemic areas or travelers to such regions should minimize exposure during peak activity from dusk to dawn by remaining indoors in well-screened or air-conditioned accommodations when feasible. Wearing long-sleeved shirts, long pants tucked into socks, and closed shoes reduces exposure, while treating , gear, and bed nets with provides additional repellent efficacy lasting through multiple washes. Application of EPA-registered repellents containing 20–50% (or picaridin or IR3535 as alternatives) to exposed and edges offers further , with reapplication every 4–8 hours depending on concentration and activity level. These measures have demonstrated effectiveness in field studies, such as among U.S. in endemic zones where combined use reduced bite incidence significantly. At the level, campaigns promote widespread adoption of personal protections and early case detection to interrupt anthroponotic transmission cycles, particularly in foci where humans serve as reservoirs. -based interventions, including training local health workers for active and prompt treatment of suspected cases, have reduced incidence by up to 58% in hotspots when paired with behavioral change messaging. In zoonotic settings, communities may collaborate on reservoir animal management, such as or treating infected dogs, though efficacy varies by and implementation adherence. Social mobilization efforts, as recommended by WHO, enhance participation but require sustained funding and monitoring to overcome barriers like low awareness in rural populations.

Limitations of Current Strategies

Current prevention strategies for leishmaniasis, which primarily rely on , personal protective measures, and reservoir reduction, face significant constraints that limit their effectiveness in reducing transmission. No are licensed for use against any form of leishmaniasis as of 2025, despite ongoing into candidates like live-attenuated strains and recombinant proteins, leaving populations without a tool for inducing long-term immunity. This gap is particularly acute in endemic regions, where repeated exposure does not confer reliable protection due to the parasite's ability to evade host immunity across diverse strains. Vector management, often centered on spraying and environmental modifications, is undermined by widespread resistance in sand fly populations to pyrethroids and organophosphates, which reduces the longevity and efficacy of indoor residual spraying programs. Sand flies' exophilic and crepuscular behaviors further complicate control, as adults do not breed indoors and larval habitats in diverse ecosystems like burrows are difficult to target systematically. In regions such as and the Mediterranean, these factors have contributed to persistent transmission despite elimination efforts, with vector densities rebounding post-intervention. Personal and community measures, including insecticide-treated nets and repellents, provide only partial protection because sand flies bite during early evening hours when people are active outdoors, and adherence is low in resource-poor settings due to cost, discomfort, and cultural practices. Studies in endemic areas show that while bed nets reduce bites by up to 50% in controlled trials, real-world usage drops below 30% in some communities owing to , issues, and limited awareness. Reservoir control in zoonotic cycles, such as infected dogs or , yields inconsistent results due to high animal turnover rates and ethical barriers, failing to interrupt transmission chains effectively. Broader implementation challenges exacerbate these issues, including inadequate for early detection of outbreaks, fragmented health infrastructure in conflict zones, and insufficient , which result in coverage gaps affecting over 90% of cases in high-burden countries like and . These limitations highlight the need for integrated approaches incorporating novel tools, as current strategies alone have not achieved sustained reductions in incidence below elimination thresholds in most foci.

Treatment

Standard Therapies

Liposomal amphotericin B is the first-line therapy for visceral leishmaniasis in many non-endemic settings, including the , due to its high efficacy rates exceeding 95% and lower toxicity profile compared to older agents. Typical regimens involve total doses of 21-30 mg/kg body weight, administered as 3-5 mg/kg intravenously on alternate days for 6-10 doses, with adjustments for immunocompromised patients requiring higher cumulative doses up to 40 mg/kg. In endemic regions like and , shorter courses such as single-dose 7 mg/kg or three doses of 5 mg/kg on days 1, 3, and 7 achieve cure rates over 90% in immunocompetent individuals. Pentavalent antimonials, including sodium stibogluconate and meglumine antimoniate at 20 mg SbV/kg/day intravenously or intramuscularly for 20-28 days, serve as standard systemic treatment for cutaneous, mucocutaneous, and visceral leishmaniasis in much of the Old World and parts of Latin America, with initial cure rates of 80-95% for cutaneous forms but higher relapse risks in visceral cases. These agents target parasite amastigotes by disrupting bioenergetics, though efficacy varies by species—effective against most but less so against Leishmania aethiopica—and they are associated with dose-dependent toxicities such as QT prolongation, pancreatitis, and arthralgias in up to 10-20% of patients. For uncomplicated , local therapies predominate, including topical ointment (15% with soft paraffin) applied twice daily for 10-20 days, yielding cure rates of 70-80% for Old World species like L. major, or intralesional antimonial injections every 1-2 weeks until flattening, with success rates up to 85%. Systemic (2.5 mg/kg/day orally for 28 days) is recommended for complex cutaneous or lesions, achieving 80-95% efficacy across species but limited by in 20-40% of recipients and strict contraception requirements due to embryotoxicity. In regions with high antimonial resistance, such as , , combination regimens for —such as liposomal followed by or (15 mg/kg/day intramuscularly for 21 days)—are standard to enhance cure rates above 95% and mitigate relapse. For mucocutaneous disease, prolonged antimonial courses or are used, though disfiguring outcomes persist in 10-20% despite treatment. Regional WHO guidelines emphasize species-specific dosing and monitoring for toxicities, with no universal oral monotherapy due to emerging resistances.

Treatment Outcomes and Toxicities

Treatment outcomes for visceral leishmaniasis (VL) vary by drug and region, with liposomal (L-AmB) achieving cure rates of 80-90% in observational studies, often comparable to or exceeding other antileishmanial agents. monotherapy yields initial cure rates around 94% in phase III trials for Indian VL, though late treatment failures occur at higher rates, necessitating allometric dosing adjustments for optimal exposure. Pentavalent antimonials (SbV), historically first-line, show of 30-90% but face declining success due to resistance and higher toxicity profiles, including and , prompting their replacement by in some endemic areas. Toxicities associated with VL treatments include and infusion-related reactions with conventional , though L-AmB mitigates these via reduced dosage and lipid formulation, enabling shorter courses with lower overall adverse event rates. , often used in combination, exhibits low systemic toxicity but carries risks of and potential resistance development. Relapse rates for VL post-treatment range from 5-10% across regimens, influenced by host immunity, co-infection, and incomplete parasite clearance, with combination therapies showing promise in reducing these but requiring further validation. For (CL), systemic SbV achieves initial cure rates of approximately 74% (95% CI: 61-84%) at day 90-100, with overall cure accumulating to higher rates upon retreatment, though outcomes depend on species like L. tropica showing lower responsiveness. Topical demonstrates efficacy against L. major and L. mexicana, with cure rates up to 95% in some trials when combined with gentamicin, but local reactions such as , vesicles, and injection-site pain are common, alongside rare systemic absorption risks. L-AmB for Old World CL yields 85% cure in immunocompetent patients, but high dosing variability and cost limit broader use. Mucocutaneous leishmaniasis (MCL) treatments mirror CL but with lower cure rates, estimated at 70-90% for SbV, compounded by risks of disfiguring relapse and antimonial toxicities like . , used for refractory cases, shows variable success (e.g., parasite reduction in diffuse CL) but incurs potential irreversible and cardiac effects, restricting its application. Across forms, adverse events lead to discontinuation in 10-20% of SbV cases, underscoring the need for monitoring and alternative regimens in resource-limited settings.

Drug Resistance Issues

Drug resistance in Leishmania parasites poses a significant barrier to effective treatment of leishmaniasis, particularly (VL), by reducing efficacy of first-line therapies and necessitating shifts to more toxic or expensive alternatives. Pentavalent antimonials (SbV), such as , were historically the mainstay for VL but experienced failure rates exceeding 60% in , , by the early 2000s due to the emergence of resistant L. donovani strains. This resistance, linked to genomic adaptations including overexpression of genes like AQP1 (aquaglyceroporin 1) mutations and efflux pumps, prompted the Indian government's 2005 policy to abandon SbV monotherapy in favor of liposomal or . Miltefosine, an oral alkylphosphocholine introduced as an alternative in the , has shown emerging resistance since 2010, with laboratory-confirmed cases in relapsed VL patients from exhibiting IC50 values over 30-fold higher than susceptible strains. Resistance mechanisms involve downregulation of the LdMT/LdRos3 influx transporter and upregulation of ABC transporters like LdABCC2 for drug efflux, alongside suppression of responses that enhance parasite survival. Field isolates from treatment failures demonstrate natural resistance variants, contributing to relapse rates of 10-20% in single-drug regimens, though with mitigates this to some extent. Resistance to , an used in combinations, has been documented in L. donovani isolates from , involving mitochondrial dysfunction and altered ribosomal binding, with prevalence increasing in regions of prior antimonial overuse. Liposomal remains highly effective with minimal reported resistance globally, attributed to its polyene mechanism disrupting in parasite membranes, though sporadic failures in suggest potential fitness costs in resistant strains that reduce overall . Multidrug resistance patterns, including co-resistance to SbV and , are prevalent in up to 38% of human VL isolates in endemic areas, driven by epistatic interactions in genomic plasticity such as copy number variations and . These issues exacerbate treatment failures, elevate mortality risks in resource-limited settings, and underscore the need for genomic surveillance and novel therapies targeting efflux or metabolic pathways.

Epidemiology

Global Distribution and Burden

Leishmaniasis occurs in over 97 countries and three territories, spanning tropical, subtropical, and temperate zones across the , , , the Mediterranean basin, the , and parts of . The parasite thrives in environments with suitable vectors, often linked to , conflict zones, and migration, with over 1 billion people at risk of exposure. Endemic foci include the highlands of and for visceral forms, arid regions of and for cutaneous variants, and forested areas of for both zoonotic and anthroponotic cycles. Emerging cases in non-endemic areas, such as , reflect climate shifts and travel, though autochthonous transmission remains limited outside traditional hotspots. The global burden manifests unevenly, with an estimated 700,000 to 1 million new cases annually, predominantly , though underreporting—especially in remote or unstable regions—suggests true incidence exceeds 1.5 million. drives mortality, causing 20,000–30,000 deaths yearly, equivalent to the second deadliest parasitic disease after , with 95% of cases concentrated in ten countries: , , , , , , , , , and . , , , and alone account for 60% of VL incidence, exacerbated by co-infection in over 42 countries. Reported CL cases in 2023 totaled nearly 272,000 across 55 countries, but Global Burden of Disease estimates indicate 6.2 million prevalent CL cases as of 2021, reflecting chronic scarring and . Overall , measured in disability-adjusted life years (DALYs), underscores leishmaniasis as a neglected , with VL contributing most to years of life lost due to premature death and CL to years lived with from disfiguring lesions. High-burden areas overlap with , , and weak , amplifying socioeconomic costs estimated at billions in lost productivity, though precise global figures remain elusive due to diagnostic gaps and stigma-driven undernotification. Progress toward WHO targets, such as reducing VL mortality by 75% from 2010–2020 baselines, shows mixed results, with data up to 2023 indicating persistent hotspots in and the .

Zoonotic and Anthroponotic Cycles

Leishmania transmission occurs primarily through the bite of infected female phlebotomine sand flies, with cycles classified as zoonotic—where animal reservoirs maintain the parasite—or anthroponotic, where humans serve as the primary reservoir. Zoonotic cycles predominate for many species, including , which causes zoonotic (ZVL) in regions like the Mediterranean Basin, , and parts of , with domestic dogs as the principal reservoir host; studies confirm dogs' infectiousness to sand flies is higher in symptomatic cases, with seroprevalence in endemic areas reaching up to 20-30% in some canine populations. For , zoonotic transmission involves as key reservoirs; Leishmania major, prevalent in the , , and , is maintained by species such as Meriones libycus (), with infection rates in these averaging 17.9% in endemic foci of . Sylvatic cycles in the feature wild mammals like for L. mexicana and L. amazonensis, or marsupials for certain species. Anthroponotic cycles, in contrast, rely on human reservoirs and are characteristic of Leishmania donovani in anthroponotic visceral leishmaniasis (AVL) on the and in , where transmission is human-sand fly-human without significant animal involvement; early case detection is emphasized to interrupt these cycles. Leishmania tropica, causing urban cutaneous leishmaniasis in parts of the , is predominantly anthroponotic, though evidence of zoonotic potential via like gerbils exists in some rural Moroccan settings. Emerging research challenges strict dichotomies, with phylogenetic studies indicating unrecognized wildlife hosts for zoonotic and potential spillover events; for instance, dogs have been identified as reservoirs for L. donovani in , , from 2018-2022, suggesting hybrid cycles in areas previously deemed purely anthroponotic. Most human-infective Leishmania species have zoonotic origins or ongoing zoonotic components, underscoring the evolutionary predominance of animal-hosted cycles.

Factors Influencing Incidence

The incidence of leishmaniasis is modulated by environmental conditions that influence the distribution and activity of phlebotomine sandfly vectors, such as temperature, humidity, and precipitation, which affect vector survival, reproduction, and biting rates. Studies in endemic regions like Iran and Montenegro have shown positive correlations between higher temperatures (above 20–25°C) and increased cutaneous leishmaniasis cases, as warmer conditions enhance sandfly longevity and parasite development within the vector. Precipitation and humidity further support vector breeding in moist microhabitats, with seasonal peaks in transmission often aligning with rainy periods that boost sandfly populations. Climate change exacerbates these dynamics by expanding suitable vector habitats northward and into higher altitudes; for instance, projections indicate a potential 43% increase in climatically suitable areas for visceral leishmaniasis under high-emission scenarios by the 2050s and 2070s. Anthropogenic land use changes, including , , and agricultural expansion, drive human-vector contact by altering ecosystems and bringing populations into proximity with sylvatic reservoirs. In urbanizing areas of and the Mediterranean, peri-urban sprawl has facilitated zoonotic cycles, with inadequate and correlating with higher incidence due to favorable sandfly resting sites. , , and flooding—often compounded by —prompt into high-transmission zones, amplifying outbreaks as seen in historical East African kala-azar epidemics. Socioeconomic determinants play a causal by heightening exposure and susceptibility; correlates with elevated odds of through substandard lacking screens or proper waste disposal, which harbors vectors indoors. and poor weaken immune responses, increasing severity, while occupational factors like outdoor labor in endemic areas raise bite exposure risks, particularly among males in rural settings. Conflict and civil unrest further elevate incidence by displacing populations, interrupting , and overwhelming health systems, as evidenced by surges in and where environmental stressors interact with instability. These factors underscore that incidence is not merely vector-driven but emerges from intertwined ecological and human pressures, with empirical models emphasizing targeted interventions over generalized assumptions.

History

Early Observations and Discovery

Descriptions of lesions resembling appear in ancient texts, including Assyrian tablets from the 7th century BCE and the around 1500 BCE, which mentions "Nile Pimple" as a potentially linked to the disease. In the , Persian physician (980–1037 CE) provided a detailed account of "Balkh sore," characterized by dry, persistent ulcers likely caused by L. tropica, observed in northern . By the 18th century, Alexander Russell documented the "Aleppo evil" in in 1756, describing self-healing skin ulcers transmitted in arid regions. Visceral leishmaniasis, known as kala-azar, was first clinically described during outbreaks in in the 1820s, with William Twining reporting symptoms including irregular fever, progressive , and massive in patients in 1827. Cutaneous forms were noted earlier in the , but etiological clarity emerged later; David Douglas observed protozoan-like bodies in Delhi boil lesions in 1885, though not fully characterized. The causative parasite was identified microscopically in 1898 by Piotr Borovsky, who detected protozoans in biopsies from Oriental sore patients in , marking the first recognition of amastigotes in cutaneous lesions. For visceral disease, William Boog Leishman discovered ovoid bodies measuring 2–3 µm in smears from a deceased in 1900, publishing his findings in the British Medical Journal on May 11, 1903, and proposing they were degenerated trypanosomes linked to "Dum-dum fever." Independently, Charles Donovan identified similar intracellular bodies in splenic aspirates from Indian patients with fever and organ enlargement in 1903, confirming the protozoan nature. subsequently named the organism in 1903, establishing it as the agent of kala-azar distinct from trypanosomes.

Twentieth-Century Advances

The identification of as the causative agent of marked a pivotal early 20th-century advance, with British pathologist William Boog Leishman observing the protozoan in splenic smears from a soldier in 1900 (published 1903), independently confirmed by Charles Donovan in the same year. This discovery shifted understanding from empirical folk remedies to a protozoal etiology, enabling targeted diagnostics like splenic aspiration. Subsequent species delineations followed, including L. infantum by Charles Nicolle in in 1908 for infantile visceral cases, L. tropica formalized in 1906 for cutaneous leishmaniasis, and L. braziliensis by Gaspar Vianna in in 1911 for mucocutaneous forms. Elucidation of the parasite's life cycle progressed through vector studies, with the Sergent brothers demonstrating sand fly transmission via skin scarification in 1921 using Phlebotomus species. Confirmation of bite-mediated transmission came in 1941 by Saul Adler, who infected humans via P. papatasi bites, and in 1942 by Swaminath et al. for , establishing the digenetic cycle between vertebrate macrophages (amastigotes) and sand fly midguts (promastigotes). These findings underpinned strategies, such as use post-World War II, which reduced incidence in endemic foci like through spraying against sand flies. Therapeutic breakthroughs centered on antimony compounds, transitioning from toxic trivalent forms used experimentally since to less cardiotoxic pentavalent antimonials. Upendranath Brahmachari's 1922 synthesis of urea stibamine, a pentavalent , dramatically lowered mortality in from near 95% to under 10% by targeting intracellular amastigotes with reduced host toxicity. Standardized formulations emerged in –, including (Pentostam) in 1945 and meglumine antimoniate (Glucantime), becoming first-line therapies administered intramuscularly or intravenously for 20–28 days. Mid-century alternatives included , repurposed from treatment in the for cutaneous and visceral cases, and , a polyene first reported effective against leishmaniasis in the 1950s for refractory visceral disease via membrane disruption of promastigotes and amastigotes. Epidemiological advances revealed zoonotic reservoirs, with dogs identified as key for L. infantum in the Mediterranean by the and L. chagasi (now synonymous with L. infantum) in in the , informing canine trials and programs. By the 1960s, integrated control in regions like southern eliminated autochthonous visceral cases through case detection, treatment, and vector/reservoir management, with no new infections reported since 1983. These efforts highlighted environmental factors like and migration in amplifying anthroponotic cycles, particularly for L. donovani in .

Recent Elimination Efforts

In South-East Asia, concerted efforts under the WHO-supported Kala-azar Elimination Programme have yielded significant progress toward eliminating (VL) as a problem, defined as fewer than one case per 10,000 population at the sub-district level. became the first country certified by WHO for this milestone on October 31, 2023, following a 95% reduction in new cases across the region over the prior decade, achieved through enhanced case detection, treatment with single-dose liposomal amphotericin B, active surveillance for post-kala-azar dermal leishmaniasis (PKDL), and vector control measures targeting Phlebotomus argentipes sandflies. reported just 520 VL cases in 2023, down from 9,241 in , positioning it near validation pending sustained surveillance and management of residual foci, including 324 PKDL cases and declining VL-HIV coinfections. met the elimination target in 2023, though vigilance against re-emergence in new areas remains essential. In Eastern Africa, where VL incidence remains high due to Leishmania donovani transmission involving human reservoirs and canine amplifiers, WHO launched a strategic framework on June 12, 2024, to guide elimination by 2030. This framework emphasizes five pillars: early diagnosis and prompt treatment to reduce mortality (targeting 100% decline in child deaths); integrated vector management, including insecticide-treated nets and environmental modifications; management of animal reservoirs; enhanced surveillance systems; and community engagement for cross-border coordination, given the disease's spread across porous borders in endemic zones like , , and . On May 22, 2025, six African nations—, , , , , and —signed a Memorandum of Understanding to foster regional collaboration, endorsing a Call for Action that builds on prior reductions, such as Kenya's ongoing progress amid challenges like conflict-disrupted services and diagnostic gaps. In the Americas, the (PAHO) has prioritized leishmaniasis elimination by 2030 as part of its 30-target initiative, focusing on visceral forms in and other endemic areas through improved access to and , alongside vector surveillance for species; however, progress lags behind due to persistent zoonotic cycles and urban expansion, with showing slower incidence declines compared to India's gains from 1990–2023. Globally, WHO's 2023 surveillance data indicate a need for sustained investment to meet NTD roadmap goals, as VL deaths persist at around 20,000 annually despite treatment advances, underscoring risks of resurgence from untreated PKDL reservoirs and antimonial resistance.

Societal and Economic Dimensions

Public Health Impacts

Leishmaniasis represents a major public health challenge as a neglected tropical disease, disproportionately affecting impoverished populations in 90+ countries across tropical, subtropical, and Mediterranean regions, with an estimated 600,000 to 1 million new cases annually, though only about 200,000 are reported to the World Health Organization due to diagnostic limitations and underreporting in remote areas. Cutaneous leishmaniasis accounts for the majority of cases, causing chronic skin ulcers that lead to scarring, disability, and social isolation, while visceral leishmaniasis inflicts severe systemic effects including prolonged fever, hepatosplenomegaly, anemia, and immunosuppression, resulting in high morbidity even among survivors. Visceral leishmaniasis carries the highest mortality risk, proving fatal in over 95% of untreated cases and contributing around 20,000 deaths yearly, with children under age 5 facing elevated vulnerability due to immature immune responses and synergies. Global Burden of Disease analyses indicate persistent trends in disability-adjusted life years (DALYs) from , reflecting combined years of life lost to premature death and lived with , though exact 2021 figures underscore regional hotspots in , , and the where incidence and prevalence have shown limited decline despite interventions.![Leishmaniasis DALYs map][center] The disease perpetuates cycles of and strains healthcare systems in endemic low-resource settings, where treatment for —requiring prolonged hospitalization and drugs like liposomal —imposes median household costs of US$214 per episode, equivalent to 18% of annual income in affected communities, often forcing asset sales, loans, or delayed care that worsens outcomes. Associated factors such as population displacement, poor sanitation, and weakened immunity from HIV co-infection amplify transmission and complicate control, diverting resources from other priorities and entrenching socioeconomic disparities without targeted vector management or surveillance.

Stigma and Misconceptions

Stigma associated with leishmaniasis, particularly its cutaneous form, arises primarily from visible skin lesions and scarring that alter physical appearance, leading to social exclusion and psychological distress in endemic areas. Affected individuals often experience discrimination, with women facing heightened barriers to marriage and employment due to cultural emphases on aesthetics and purity. In regions like South Asia and the Middle East, scars are perceived as markers of impurity or moral failing, resulting in self-isolation and reduced quality of life. This psychosocial burden includes elevated rates of anxiety, depression, and suicidal ideation, amplified by self-stigma where patients internalize negative societal views. Misconceptions about transmission and fuel much of this stigma, as many in affected communities erroneously believe leishmaniasis spreads through direct human contact, shared items, or poor rather than exclusively via sandfly bites. For instance, surveys in endemic zones reveal that only a minority correctly identify the vector, with prevailing myths linking the disease to , divine punishment, or ancestral curses, which discourage biomedical treatment and perpetuate avoidance behaviors. Such errors contribute to delayed , as patients may first seek traditional healers, viewing clinical interventions as ineffective or exacerbating the condition. Visceral leishmaniasis carries less visible stigma due to its internal symptoms, though associations with and fatality in untreated cases can lead to community-wide fear and marginalization of households. Efforts to mitigate these issues through have shown promise in reducing misbeliefs, but cultural drivers like fear of and treatment burdens persist, hindering responses.

Resource Allocation Debates

Leishmaniasis garners limited global funding relative to its burden, with research and development (R&D) investment for neglected tropical diseases (NTDs), including leishmaniasis, totaling around $400 million annually in the 2007–2011 period, of which 37.1% targeted kinetoplastids like leishmaniasis, human African trypanosomiasis, and Chagas disease. This contrasts sharply with billions allocated yearly to HIV/AIDS, tuberculosis, and malaria, which together receive over 40% of overseas development assistance for health R&D despite NTDs affecting over 1 billion people, primarily in low-income settings. Critics attribute this disparity to low commercial viability, as endemic areas lack affluent markets to incentivize pharmaceutical innovation, resulting in reliance on public donors like the WHO and foundations such as Wellcome, which provided €5.7 million for leishmaniasis drug development in 2022. In the U.S., NTD funding remained level at approximately $100 million in 2016, underscoring systemic underprioritization amid competing global health agendas. Proponents for reallocating resources toward leishmaniasis emphasize its exceptional cost-effectiveness, with treatment in averting a (DALY) for $18.40 (range: $13.53–$27.63), positioning it among the most efficient health interventions globally. Similar analyses for in yield $1,200 per DALY averted, still favorable compared to many programs in high-income countries. Such efficiency, coupled with leishmaniasis's role in perpetuating through and economic loss—estimated at over $1,300 per household case in —argues for viewing control as an investment in rather than charity. Yet, debates persist over opportunity costs, as leishmaniasis's 20,000–30,000 annual deaths pale against malaria's hundreds of thousands, prompting questions on whether NTDs warrant diversion from "big three" diseases with stronger evidence bases and political lobbies. In endemic countries, resource competition exacerbates neglect, with elimination efforts in hampered by prioritization of other infectious diseases, limiting dedicated programmatic management despite WHO targets for <1% mortality by 2030. Organizations like Médecins Sans Frontières have called for urgent increases in funding for NTD programmatic activities, warning that official development assistance cuts strain surveillance and access to diagnostics in high-burden regions like East Africa and . Recent declines in NTD R&D investment threaten progress, highlighting tensions between short-term humanitarian relief and long-term elimination strategies amid finite budgets.

Research Frontiers

Vaccine Prospects

No licensed vaccine exists for human leishmaniasis, despite extensive research spanning decades, due to the parasite's antigenic diversity across over 20 Leishmania species and the requirement for robust cell-mediated immunity, particularly Th1 responses, to confer protection. Early attempts with first-generation killed vaccines, such as autoclaved Leishmania major (ALM) combined with BCG adjuvant, demonstrated limited efficacy in field trials in regions like Iran, Pakistan, and Sudan, often failing to prevent infection or disease progression without additional cytokines like IL-12. Second-generation subunit vaccines targeting recombinant antigens like HASPB, KMP11, or Leish-111f have shown promise in preclinical models but struggled in human trials due to insufficient immunogenicity without potent adjuvants. Third-generation approaches, including viral-vectored and live-attenuated s, represent the most advanced prospects. The chimpanzee adenovirus 63 encoding kinesin-related H2A and hydrophilic acylated surface protein B (ChAd63-KH) has progressed to phase 2b trials in Sudan, proving safe and eliciting strong CD4+ and CD8+ T-cell responses in patients with post-kala-azar dermal leishmaniasis, though long-term efficacy against visceral forms remains under evaluation as of 2024. CRISPR-engineered live-attenuated strains, such as centrin-deleted L. major (LmCen-/-), have protected mice and hamsters against both cutaneous and visceral challenges by inducing durable immunity without causing disease, highlighting potential for single-dose regimens. Non-pathogenic platforms like Leishmania tarentolae expressing antigens offer scalable production for low-cost candidates, addressing logistical barriers in endemic areas. Veterinary vaccines provide indirect insights; for instance, a 2025 trial of a L. infantum demonstrated and comparable to commercial products in preventing canine clinical leishmaniosis, suggesting translational potential if correlates of protection are validated. Key challenges persist, including strain-specific immunity risks, potential for vaccine-induced exacerbation in immunocompromised individuals, and regulatory hurdles for live vaccines requiring stringent . Recent innovations, such as controlled infection models using low-dose L. major challenge, enable faster testing and have accelerated prioritization as of 2024. Overall, while no vaccine is approved, multi-antigen, heterologous prime-boost strategies informed by genomic data hold promise for achieving sterilizing immunity in high-burden regions like and .

Novel Drug Development

DNDi and partners have advanced several novel chemical entities targeting , focusing on oral agents with novel mechanisms to overcome resistance and achieve sterile cure. DNDI-6174, a bc1 complex inhibitor, exhibits potent activity ( values of 7-31 nM across strains) and efficacy in mouse models, reducing parasite burdens by over 99% at 30 mg/kg doses, with favorable supporting once-daily oral dosing. completed in 2024 confirmed its safety profile, positioning it for Phase I trials in 2025. DNDI-6899, nominated as a clinical candidate in 2024 through collaboration with GSK, targets undisclosed pathways and demonstrated superior efficacy in preclinical rodent models compared to , earning recognition as DNDi's pre-clinical project of the year for bolstering the pipeline against drug-resistant strains. Aminopyrazole series compounds, originating from , inhibit intracellular amastigotes with EC50 values below 1 μM and show minimal resistance emergence after (less than 4-fold shift in IC50 over 20 cycles), attributed to multi-target engagement rather than single-gene mutations. GSK's DDD01305143 (also GSK3494245 or GSK245), a proteasome chymotrypsin-like activity inhibitor, achieved over 95% parasite clearance in vivo at low doses and completed Phase I safety evaluation in healthy volunteers in the UK during 2024, confirming tolerability for potential advancement to efficacy trials in endemic regions. Recent structural elucidation of Leishmania's ergosterol biosynthesis pathway, distinct from fungal homologs, has identified vulnerabilities for selective inhibitors, potentially yielding drugs with reduced host toxicity; prototypes disrupted sterol production by 80-90% in parasites without affecting mammalian cells. Challenges persist, including ensuring activity across Leishmania species and genotypes, as cytochrome bc1 mutations (e.g., G31A) confer resistance to DNDI-6174 , underscoring the need for regimens. Dual-target strategies, such as inhibitors hitting trypanothione and pathways, have yielded preclinical hits with synergistic effects, reducing required doses by 50% in models. These efforts prioritize compounds with defined mechanisms to mitigate resistance risks observed in field isolates.

Genomic and Resistance Studies

The genome of Leishmania major Friedlin strain, the first fully sequenced representative of the , comprises a 32.8-megabase haploid distributed across 36 , with predictions of 911 RNA , 39 pseudogenes, and approximately 9,110 protein-coding . This sequencing, completed in , revealed unusual features such as polycistronic transcription units and a reliance on post-transcriptional mechanisms for , lacking the typical promoter-driven expression seen in higher eukaryotes. Subsequent assemblies, including those for L. donovani and L. infantum, confirmed genome sizes around 32-35 Mb and highlighted mosaic , where individual cells exhibit varying copy numbers, contributing to phenotypic heterogeneity and adaptive potential. Comparative genomics across species has uncovered high plasticity, including frequent gene copy-number variations (CNVs) and segmental aneuploidies that enable rapid environmental adaptation without reliance on sexual recombination, as Leishmania reproduces predominantly clonally. Studies from 2020 onward, using whole-genome sequencing (WGS) of clinical isolates, have quantified this instability: for instance, analysis of 205 Leishmania (Viannia) samples revealed extensive structural variants and single-nucleotide polymorphisms (SNPs) correlating with geographic distribution and host adaptation. In L. tropica, direct sequencing from skin lesions in emerging foci identified novel recombination events and loss-of-heterozygosity patterns, challenging prior assumptions of strict clonality. Single-cell genomics further demonstrated that aneuploidy is not uniform, with some cells exhibiting nullisomy for entire chromosomes, facilitating survival under stress. Drug resistance in Leishmania is genomically underpinned by mechanisms exploiting this plasticity, including amplification of efflux pumps like ABC transporters (e.g., LdMDR1 for miltefosine resistance) and mutations in target genes such as aquaglyceroporin-1 (AQP1) for antimonial unresponsiveness. Chromosomal rearrangements and CNVs, observed via WGS in resistant field isolates, alter drug uptake and metabolism; for example, increased copies of MRPA (a glutathione conjugate pump) correlate with sodium stibogluconate failure in L. infantum. Recent nanopore-based sequencing of L. infantum lines identified aneuploidy and CNVs as biomarkers for resistance to first-line drugs, with translational reprogramming—via altered ribosome occupancy—emerging as a non-genomic amplifier of these changes. Parasites also horizontally transfer resistance loci through extracellular vesicles containing DNA, accelerating spread in populations, as evidenced in lab-evolved strains. These findings underscore genomic instability as a primary driver of treatment failure, with implications for surveillance via WGS in endemic regions.

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