Recent Advances in the Treatment of Leishmaniasis

Leishmaniases are a group of vector-borne neglected tropical diseases caused by more than 20 species of the protozoan parasite Leishmania. It presents in 3 main forms: cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL) and the systemic form visceral leishmaniasis (VL). The disease is transmitted by the bite of infected female sandflies of species Phlebotomus in the Old World and Lutzomyia in the New World. VL is caused by the Leishmania donovani complex: L. donovani, in the Indian subcontinent and Africa and Leishmania infantum (Leishmania chagasi) in the Mediterranean basin, Central and South America. Currently, an estimated 30,000 new cases of VL occur worldwide annually, most of which occur in Brazil, East Africa and India.1 However, only 25%–45% is reported to the World Health Organization.2 The Indian subcontinent has made immense efforts to eliminate VL as a public health problem, decreasing the incidence below 1 per 10,000 population in the subdistricts (Bangladesh) and blocks (India). A significant decline has been observed in Nepal as well. In 2023, World Health Organization gave Bangladesh an official validation of the elimination of VL.3 Nowadays, East Africa is the region with the highest burden of VL. CL is the most common form with an estimated one million new cases occurring worldwide annually.1 About 95% of CL cases occur in the Americas (New World), the Mediterranean basin, the Middle East and Central Asia. Over 90% of MCL cases occur in Bolivia, Brazil, Ethiopia and Peru.2 CL in the New World is caused by the Leishmania subgenera: Leishmania amazonensis, L. infantum, Leishmania mexicana and Leishmania venezuelensis; the Viannia subgenera: Leishmania braziliensis, Leishmania guyanensis, Leishmania panamensis, Leishmania peruviana and L. mexicana; the Viannia complex. In the Old World (Asia, Africa and Europe), CL is caused by Leishmania major, Leishmania tropica or Leishmania aethiopica, as well as species predominantly associated with visceral diseases, L. infantum and L. donovani. Diffuse CL is a severe form of CL caused by L. aethiopica in the Old World and L. mexicana and L. amazonensis in the New World. MCL is caused by New World Leishmania species L. braziliensis and L. panamensis. In the Old World, rare reports of L. tropica, L. major and L. infantum causing MCL have been published.4,5 New species like Leishmania martiniquensis and Leishmania siamensis have also been reported to cause VL as well as CL in Thailand and the French West Indies,6–8 while CL cases caused by Leishmania enriettii complex were reported from Ghana.9 Increasing travel and violent conflicts are important factors for spreading leishmaniasis to nonendemic regions. Transmission of VL in South Asia and the Horn of Africa is anthroponotic, where patients with kala-azar or post kala-azar dermal leishmaniasis (PKDL) act as the major reservoir. VL in the Mediterranean, the Middle East and Brazil and most CL have zoonotic transmission except those caused by L. tropica. Rarely transmission via infected needles or transfusions and in utero transmission has been reported. CLINICAL FEATURES Visceral Leishmaniasis Asymptomatic infections are known to surpass clinical disease in all endemic areas. Symptomatic disease due to L. donovani can affect all ages, while L. infantum mainly affects children. The incubation period is usually 2–3 months but may be >1 year. The visceral form commonly presents with fever with chills and rigor, malaise, weight loss, anorexia and discomfort in the left hypochondrium. On examination, there may be pallor, nontender splenomegaly (usually palpable by 2 weeks) and moderate hepatomegaly. Lymphadenopathy occurs commonly except in the Indian subcontinent. There may be blackish skin discoloration of the face, hands, feet and abdomen (hence kala-azar, meaning black fever). Malnutrition, severe anemia leading to congestive heart failure, thrombocytopenia leading to bleeding and intercurrent infection develop as the disease progresses.10 Hemophagocytic lymphohistiocytosis has also been reported, especially among children with VL.2,11 Post Kala-azar Dermal Leishmaniasis PKDL is a sequel of VL that appears as a hypopigmented macular, papular or nodular rash usually on the face, upper arms and trunk. It occurs in East Africa in up to 60% of patients concurrently with VL or within 6 months, but most cases resolve spontaneously. In the Indian subcontinent, 5%–15% of patients with kala-azar develop PKDL within 6 months to 3 years after the cure of VL, but spontaneous resolution is rare. It has also been reported in Brazil and HIV-coinfected VL cases caused by L. infantum.12,13 As patients of PKDL are reservoirs of infection and usually asymptomatic, they pose a major risk to sustained elimination in the Indian subcontinent. Cutaneous Leishmaniasis In CL, at the site of a sandfly bite a papule or nodule appears, which crusts after a few days or weeks, leading to an ulcer with a raised edge and surrounding induration that heals gradually over 2–15 months. Lymph node enlargement can also occur. Lesions due to L. major and L. mexicana heal faster compared to L. tropica and subspecies Viannia. L. tropica can cause a chronic form of CL called leishmaniasis recidivans, which lasts for many years, while L. aethiopica can give rise to oronasal leishmaniasis or diffuse CL. In the New World, 90% of CL cases present as localized, single or multiple lesions. Disseminated (mainly caused by L. braziliensis) and diffuse cutaneous (mainly L. amazonensis and L. mexicana) lesions are more difficult to treat and frequently relapse. Children typically have a shorter duration of illness, more lesions on the head and smaller ulcers.14 MCL is rare in children and can occur simultaneously with cutaneous lesions or present years later. It involves the mucosal tissues of the mouth and upper respiratory tract by lymphatic or hematogenous dissemination and is associated with lymphadenopathy.4,5,10 DIAGNOSIS Visceral Leishmaniasis Parasite Detection The gold standard for the diagnosis of VL is the demonstration of the amastigote form of the parasite by microscopic examination of aspirates from bone marrow, spleen or lymph node. The sensitivity of microscopy is highest for the spleen (93%–99%) followed by bone (53%–86%) marrow and lymph nodes (50%). However, splenic aspiration can cause life-threatening hemorrhage and requires considerable technical expertise. Culture of tissue aspirates further increases sensitivity. Serologic Tests A meta-analysis demonstrated that the direct agglutination test (DAT) performs well compared to other diagnostic methods in most scenarios. It demonstrated high pooled sensitivity (95%) and specificity of DAT (95%) for diagnosing VL with a drop of finger-prick blood. The lack of standardization of DAT methods and preparations is its major drawback. Results are similar for freeze-dried DAT antigen and liquid DAT antigen.14 The most used test for leishmaniasis is the rK39-based immunochromatographic test, which detects the presence of antibodies against the rK39 antigen and has very high sensitivity and specificity for VL. However, it has lower sensitivity in East Africa, Latin America and the Mediterranean region.15 Recent studies among pediatric VL in endemic areas of Europe have shown high sensitivity of this rapid test.16 In the Indian subcontinent, rK39 immunochromatographic test has been widely adopted as it is easy to perform with a drop of finger-prick blood in difficult field conditions, is rapid, cheap and yields reproducible results. Indirect fluorescent antibody test and TruQuick immunochromatographic test perform well in the Mediterranean region,17 while DAT is commonly used in East Africa. Antibody-based tests have some drawbacks, as serum antibody levels remain detectable up to several years after cure, and therefore, they cannot be used to diagnose VL relapse. Also, they may be false-negative in HIV-positive patients. Owing to asymptomatic infections, up to 32% of healthy individuals living in endemic areas with no history of VL may be positive for antileishmanial antibodies.18 Thus antibody-based tests must always be used in combination with standardized clinical case definitions for the diagnosis of VL. Molecular Diagnosis The detection of parasite DNA by polymerase chain reaction in blood or bone marrow aspirates is very sensitive but is currently restricted to referral hospitals and research centers only. Recently a loop-mediated isothermal amplification with visual read-out has been developed, which can be used in field conditions.19 It is considered a point of care test capable of monitoring the cure and relapses of the disease.20 Ultrasonography In pediatric patients, focal subcentimetric hypoechoic splenic lesions are frequently seen in ultrasound and are characteristic of VL in the Mediterranean region.21 Cutaneous and Mucocutaneous Leishmaniasis Demonstration of amastigotes from slit skin smears, aspirates and biopsies is the gold standard. Culture from a biopsy sample can be done but has lower sensitivity. The CL Detect a rapid test, initially developed to detect the peroxidoxin antigen of L. major in the Old World, has shown variable results in different geographical regions.22–24 However, recently it has been observed that using the standard method of lancet scraping and increasing the extraction time and the volume of the sample added to the test strip can improve sensitivity even in species of the New World.25 A recent meta-analysis confirmed that polymerase chain reaction is the most accurate diagnostic approach for CL.26 It not only improves the diagnostic sensitivity but also allows the identification of the Leishmania species. Quantitative polymerase chain reaction may be used to monitor treatment responses and predict treatment failures.26 Newer, simpler techniques like loop-mediated isothermal amplification and recombinase polymerase amplification with a lateral flow strip with a visual read-out are promising developments.5,27 Speciation is particularly important in regions where several Leishmania species coexist as there is species-specific variation in clinical outcomes and responses to treatment. TREATMENT The choice of treatment for leishmaniasis depends on many factors, such as clinical form, toxicity, cost and patient acceptability. Visceral Leishmaniasis Single-dose Liposomal amphotericin B (L-AmB; 10 mg/kg body weight) is the treatment of choice for VL in the Indian subcontinent. Other options are combination therapy of a single dose of L-AmB (5 mg/Kg) with either miltefosine (MF) for 7 days or paromomycin (PM) for 10 days or a combination regimen of MF plus PM for 10 days.10 For the Mediterranean Basin, Middle East, Central Asia and South America, L-AmB at a total dose of 18–21 mg/kg is recommended. A combination of sodium stibogluconate with paromomycin for 17 days is the treatment of choice in East Africa and Yemen.10 Recently in Africa, a combination therapy of MF plus PM for 14 days has shown similar efficacy as the above regimen with shorter duration, one less injection daily and no risk of cardiotoxicity making it a more children-friendly regimen for this region.28 Recent studies in children with VL from the Mediterranean region have shown that short-course therapy with two 10 mg/kg doses of L-AmB is safe and effective.29,30 Post Kala-azar Dermal Leishmaniasis In India, MF for 12 weeks or amphotericin B deoxycholate 60–80 doses over 4 months are the recommended regimens for PKDL. However, ocular complications such as ulcerative keratitis, leukocoria, blurred vision, ocular hyperemia, photophobia, eye pain and rarely unilateral or bilateral blindness have been reported from India after intake of MF, mainly in PKDL patients.31 Thus, World Health Organization has recommended regular ocular examinations during MF treatment and cessation of treatment if ocular disorders occur.32 Recently the phase II trial of PKDL treatment with 20 mg/kg L-AmB alone or combined with MF for 3 weeks in India and Bangladesh has shown promising results, potentially helping to decrease therapy duration and toxicity in PKDL cases.33 In East Africa, PKDL is not routinely treated, as most cases (85%) heal spontaneously within 1 year. Only patients with severe or disfiguring disease, those with persistent lesions (>6 months) or concomitant anterior uveitis and young children with oral lesions that interfere with feeding are treated. Sodium stibogluconate (20 mg/kg/d) for up to 2 months or a 20-day course of L-AmB at 2.5 mg/kg/d is used. In a recent phase 2 trial in Sudan in which most patients were children, the combination therapy with MF + PM showed excellent efficacy, potentially helping to decrease therapy duration with one injection less.34 Cutaneous Leishmaniasis Treatment recommendations for CL vary according to the geographical region and causative species. For Old World CL, local wound care with careful follow-up is indicated as spontaneous healing occurs in most patients. However, in persistent lesions, local therapy like intralesional antimony or cryotherapy combination and thermotherapy can be used. Local treatment options are challenging in children with CL due to the pain induced. In patients with multiple lesions, large ulcers (≥5 cm in diameter), lesions on the face, joints, toes and fingers, disfiguring lesions and in children who cannot tolerate local therapy, systemic therapy (pentavalent antimonials alone or in combination with pentoxifylline, allopurinol, paromomycin; or fluconazole alone for L. major) is given. Recently MF has been found to be a safe and effective alternative in children with Old World CL (caused by L. tropica or L. major) including complicated CL and ML.35,36 In the New World CL, spontaneous resolution is less common and some patients may develop diffuse disease. Therefore, systemic treatment is indicated with pentavalent antimonials or miltefosine. The recent Pan American Health Organization guidelines recommend intralesional pentavalent antimonials in patients with localized CL caused by L. braziliensis and L. amazonensis and MF in CL caused by L. panamensis, L. mexicana, L. guyanensis and L. braziliensis in adults and in pediatric patients. MF is recommended for the treatment of CL due to L. panamensis, L. guyanensis and L. braziliensis. If the species cannot be identified, treatment should be given for the most prevalent species in the region.4 Recently a new combination of thermotherapy and MF among adults demonstrated better results than thermotherapy alone for New World CL.37 In disseminated CL, use of L-AmB, MF, or pentavalent antimonials, and in diffuse CL, pentavalent antimonials, pentamidine isethionate, or MF is advocated. Treatment with pentavalent antimonials with or without oral pentoxifylline is recommended for MCL. However, a recent systematic review found MF to have a cure rate similar to antimonials at standard doses for MCL in the Americas.38 With a better toxicity profile, L-AmB can also be used for the treatment of ML and CL.39 CONCLUSIONS Leishmaniasis remains a neglected disease of poverty. However, great strides have been made recently in managing this disease. Overall, there has been a shift to shorter and safer regimens for the treatment of VL starting with the adoption of the single dose of L-AmB (10 mg/kg) regimen. The success of 14 days of combination therapy of MF plus PM in Africa is a step in the development of shorter and more patient-friendly treatment for VL in Africa. In 2022, the Pan American Health Organization shifted from toxic antimonials to a 7-day regimen of L-AmB for the first-line treatment of VL in the Americas. Even Europe is shifting to short-course therapy with two 10 mg/kg doses of L-AmB for children with VL in the Mediterranean region.29 Oral antileishmanial drugs are of great interest to pediatricians due to their ease of use. LXE408 is a novel class of inhibitors of the kinetoplastid proteasome,40 which showed good efficacy in experimental models of VL and CL by inhibiting chymotrypsin activity in a noncompetitive manner. The drug has undergone a phase I trial and is currently in a phase II clinical trial in India. In the field of CL, much needs to be done. New molecular techniques have emerged that enable relatively easy diagnosis and Leishmania species determination, yet they are not available in resource-limited settings. The major advancement in the treatment of CL has been the strong recommendation for oral miltefosine for New World CL due to L. panamensis, L. mexicana, L. guyanensis and L. braziliensis, both in adults and children. Overall, there has been a shift toward the use of miltefosine in CL and ML instead of antimonials both in the New and Old Worlds. New treatment approaches for L. aethiopica CL are emerging to make the treatment less painful and more child-friendly.