Leishmaniasis

A parasitic infection caused by protozoa of the genus Leishmania, transmitted by the bite of infected female sandflies.

Disease manifests in three principal clinical forms, determined by the infecting species and host immune response.

• Cutaneous leishmaniasis, the commonest form, produces localised skin lesions.
• Mucocutaneous leishmaniasis causes destructive involvement of the nasopharyngeal mucosa. It is predominantly associated with specific New World species.
• Visceral leishmaniasis (kala azar) is a severe, potentially fatal systemic disease with reticuloendothelial system involvement if untreated.

Geographical distribution spans parts of Asia, Africa, the Mediterranean, and Central and South America.

Treatment is guided by both the clinical form and the infecting species, given significant variation in treatment response between species.

Pathophysiology and epidemiology

• After sandfly inoculation, promastigotes are taken up by host macrophages. They transform into amastigotes that replicate within the macrophage phagolysosome.
• The predominantly cell mediated host immune response determines clinical manifestation and severity.
• A robust, effective cell mediated response generally limits disease to a localised, self healing cutaneous lesion.
• Impaired or absent cellular immunity permits widespread parasitic dissemination throughout the reticuloendothelial system. This occurs in visceral disease, and in significantly immunocompromised hosts including advanced HIV infection.
• Visceral leishmaniasis is caused predominantly by Leishmania donovani and Leishmania infantum. Dissemination to and progressive infiltration of the bone marrow, spleen and liver produces pancytopenia, massive splenomegaly and systemic illness. It carries near universal fatality without treatment.
• Animal reservoirs maintain transmission in many endemic settings: dogs for Leishmania infantum, various rodents for several other species.
• Humans are either an accidental host (zoonotic transmission) or, for specific species and regions, the primary reservoir maintaining direct human to sandfly to human transmission (anthroponotic transmission).

• Cutaneous leishmaniasis presents with one or more painless (or minimally painful) papules at the site of the sandfly bite. Over weeks to months they evolve into a characteristic ulcerated lesion with raised, indurated borders, typically on exposed skin (face, arms).
• Natural history varies by species. Some lesions resolve spontaneously over months, leaving scarring. Others are more chronic and non healing and need specific treatment.
• Mucocutaneous leishmaniasis occurs in a proportion of patients, predominantly those infected with specific New World Leishmania braziliensis complex species. It appears months to years after apparent resolution of the original cutaneous lesion.
• It presents with progressive, destructive involvement of the nasal and oral mucosa, causing nasal obstruction and epistaxis. In advanced untreated disease there is severe destruction of nasal and oral structures.
• Prompt recognition and treatment are needed, given the potential for severe disfigurement and morbidity.
• Visceral leishmaniasis presents with progressive fever. It is often prolonged, with a characteristic but inconsistent double daily temperature spike pattern described in some regions.
• Other features are marked, often massive splenomegaly, hepatomegaly, weight loss, and progressive pancytopenia (from bone marrow infiltration and hypersplenism).
• Darkening of the skin is described particularly in the Indian subcontinent presentation. It gave rise to the historical name "kala azar", meaning black fever.
• Susceptibility to secondary bacterial infection is significant, given the profound immune dysfunction.
• Post kala azar dermal leishmaniasis is a recognised complication occurring particularly after treated visceral disease in certain endemic regions, notably East Africa and the Indian subcontinent.
• It presents with a macular, papular or nodular skin eruption developing months to years after apparently successful treatment of visceral disease. It is an important reservoir for ongoing anthroponotic transmission in affected communities.

• Cutaneous leishmaniasis is diagnosed by demonstrating amastigotes on tissue smear, biopsy or culture from the active edge of the lesion.
• Polymerase chain reaction testing is more sensitive and also identifies the species. Species directly informs treatment selection, given significant variation in treatment response and mucocutaneous risk between species.
• Visceral leishmaniasis is diagnosed by demonstrating amastigotes in bone marrow, splenic, or lymph node aspirate.
• Splenic aspiration has the highest sensitivity but carries a small, recognised risk of haemorrhage, so it needs appropriate caution and expertise.
• Serological testing has good sensitivity. In highly endemic populations with frequent prior exposure it cannot always reliably distinguish active from past infection.
• Polymerase chain reaction testing on blood or tissue is increasingly used.
• The rK39 rapid diagnostic test is a point of care serological assay. It has substantially improved access to diagnosis in resource limited endemic settings, with good sensitivity particularly for Leishmania donovani infection on the Indian subcontinent.
• Full blood count in visceral disease characteristically shows pancytopenia.
• For any suspected case, carefully establish travel or residence history in an endemic region. Establish the specific region visited, as the predominant infecting species varies regionally and bears on clinical pattern and treatment selection.

• Cutaneous leishmaniasis management is guided by the infecting species and by lesion characteristics and location.
• Observation alone suits small, low risk lesions caused by species with a favourable natural history and low mucocutaneous risk.
• Local treatment (intralesional antimonial injection, cryotherapy, or topical paromomycin) is used for uncomplicated lesions.
• Systemic treatment is used for larger, multiple, or cosmetically or functionally significant lesions, or infection with species carrying recognised mucocutaneous risk.
• Systemic options for cutaneous and mucocutaneous disease include pentavalent antimonial compounds (sodium stibogluconate or meglumine antimoniate), 20 mg per kg once daily intravenously or intramuscularly for twenty days.
• Antimonials were historically the mainstay. They have significant toxicity, including cardiac and pancreatic effects, requiring monitoring.
• Liposomal amphotericin B is another option. Miltefosine is increasingly used, given its oral administration and better tolerability.
• Mucocutaneous leishmaniasis requires systemic treatment, given the risk of progressive, destructive disease. The course is generally more prolonged and monitoring closer than for typical cutaneous disease.
• Specialist tropical medicine input is advised, given the complexity and potential severity.
• Visceral leishmaniasis is treated with liposomal amphotericin B. This is current first line treatment, with superior efficacy and safety compared with older antimonial based regimens.
• The regimen varies by region and disease severity. A commonly used regimen in the Indian subcontinent is a single dose of 10 mg per kg, reflecting excellent efficacy against the locally predominant Leishmania donovani.
• Other regions and clinical contexts, including HIV coinfected patients, generally require a more prolonged, higher cumulative dose regimen.
• Combination therapy (liposomal amphotericin B with miltefosine or paromomycin) is increasingly used in some endemic settings. It shortens treatment duration and reduces the potential for emergence of drug resistance compared with monotherapy.
• HIV coinfected patients with visceral leishmaniasis are a particularly challenging population, with increased treatment failure and relapse risk.
• They generally need more intensive or prolonged regimens, secondary prophylaxis and antiretroviral therapy optimisation, under specialist infectious disease guidance.
• Supportive care is essential alongside antiparasitic treatment in visceral disease. It includes management of secondary bacterial infection, a major cause of mortality given the profound immune dysfunction.
• It also includes nutritional support and blood product transfusion for severe cytopenia where clinically indicated.
• Prevention is through sandfly bite avoidance: insect repellent, protective clothing, and bed nets. This is particularly relevant given the typically nocturnal or crepuscular biting pattern of sandflies.
• In specific highly endemic settings, vector control measures are used. For zoonotic transmission cycles, the animal reservoir is managed, including dog related control measures where dogs are the primary reservoir.
• These are the principal preventive strategy, as no human vaccine is currently available.