Leishmaniasis: A Neglected Tropical Disease with Diverse Manifestations and Treatment Challenges

Leishmaniasis is a complex vector-borne disease caused by protozoan parasites of the genus Leishmania, transmitted to humans through the bite of infected female phlebotomine sandflies. The disease encompasses a spectrum of clinical manifestations, including cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), and visceral leishmaniasis (VL), also known as kala-azar. First described in the early 20th century by William Leishman and Charles Donovan, leishmaniasis has since emerged as one of the most important parasitic diseases after malaria, due to its wide geographic distribution and clinical severity (Alvar et al., 2012). Leishmaniasis is classified by the World Health Organization (WHO) as one of the neglected tropical diseases (NTDs), a group of infections that predominantly affect impoverished populations in tropical and subtropical regions. Despite affecting millions globally, leishmaniasis receives disproportionately limited attention and funding in comparison to its disease burden. The “neglect” is reflected in poor healthcare access, limited drug development, and inadequate vector control programs in endemic regions (WHO, 2023). Globally, an estimated 700,000 to 1 million new cases of leishmaniasis occur annually, with over 90 countries affected. The disease is endemic in parts of Asia, East Africa, Latin America, and the Mediterranean. According to recent WHO reports, over 1 billion people are at risk, and visceral leishmaniasis alone is responsible for 20,000 to 30,000 deaths annually (WHO, 2023). The highest burden of visceral leishmaniasis is reported from India, Bangladesh, Sudan, South Sudan, Ethiopia, and Brazil, while cutaneous leishmaniasis is most prevalent in countries such as Afghanistan, Syria, and Algeria (Burza, Croft, & Boelaert, 2018). The socioeconomic impact of leishmaniasis is profound. It primarily affects poor communities with limited access to healthcare, clean water, and sanitation. The chronic nature of cutaneous lesions and disfiguring mucosal involvement often results in stigmatization and mental health challenges. In endemic regions, the disease also hampers labor productivity and economic development, exacerbating the cycle of poverty (Reithinger et al., 2007). Given the diverse manifestations of leishmaniasis and the mounting challenges associated with its treatment—such as drug resistance, toxicity, and limited therapeutic options—there is an urgent need to reassess the clinical complexity of the disease and explore innovative therapeutic and preventive strategies. This review aims to provide a comprehensive analysis of the epidemiological landscape, clinical diversity, diagnostic methods, current treatment regimens, and emerging therapeutic avenues, with a focus on addressing the global neglect of this debilitating disease.

2. Etiology and Transmission

Leishmaniasis is caused by obligate intracellular protozoan parasites belonging to the genus Leishmania, a member of the family Trypanosomatidae. More than 20 species of Leishmania are known to cause disease in humans, with specific species associated with distinct clinical syndromes. For example, Leishmania donovani, L. infantum (also known as L. chagasi in Latin America), and L. tropica are commonly linked to visceral and cutaneous forms of the disease, while L. braziliensis and L. panamensis are primarily associated with mucocutaneous leishmaniasis (Akhoundi et al., 2016).

2.1. Causative Agents: Leishmania Species

The taxonomy of Leishmania is complex, with species distributed among two major subgenera: Leishmania (Leishmania) and Leishmania (Viannia). The subgenus Leishmania is primarily found in the Old World (Asia, Africa, Europe), whereas Viannia species are mostly found in the New World (Central and South America). Each species exhibits specific geographical distributions, vector affinities, and host preferences (WHO, 2023).

2.2. Vectors: Phlebotomine Sandflies

Transmission of Leishmania parasites occurs through the bite of infected female phlebotomine sandflies. In the Old World, vectors belong mainly to the genus Phlebotomus, whereas in the New World, Lutzomyia species are the principal vectors (Ready, 2013). These nocturnal insects thrive in warm, humid environments and breed in organic-rich soils, cracks, and crevices near human dwellings. During blood feeding, sandflies inject the infective promastigote stage of Leishmania into the host’s skin.

2.3. Reservoirs: Humans, Dogs, Rodents, and Other Mammals

Leishmaniasis exists in both anthroponotic and zoonotic forms. In anthroponotic transmission, humans are the primary reservoir (e.g., L. donovani in the Indian subcontinent), whereas in zoonotic transmission, various wild and domestic animals serve as reservoirs. Dogs are the most prominent domestic reservoir, particularly for L. infantum, contributing significantly to the maintenance and spread of zoonotic visceral leishmaniasis. Rodents, sloths, and other mammals have been identified as important sylvatic reservoirs for cutaneous forms of the disease (Dantas-Torres, 2007).

2.4. Life Cycle of Leishmania Parasite

The life cycle of Leishmania involves two major stages: the extracellular promastigote stage in the sandfly vector and the intracellular amastigote stage in the mammalian host. When an infected sandfly bites a human or animal, it injects promastigotes into the skin. These promastigotes are phagocytosed by macrophages and transform into amastigotes within phagolysosomes. Amastigotes multiply and infect other macrophages, spreading the infection throughout the body. When another sandfly ingests infected macrophages during blood feeding, the amastigotes transform back into promastigotes in the sandfly midgut, completing the cycle (Kamhawi, 2006). Understanding the ecology of vectors and reservoirs, along with the parasite’s complex life cycle, is essential for designing effective control strategies aimed at interrupting transmission and minimizing outbreaks.

3. Classification and Clinical Manifestations

Leishmaniasis presents with a broad spectrum of clinical syndromes, primarily determined by the Leishmania species involved, the host immune response, and the site of infection. It is typically classified into three major clinical forms: cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), and visceral leishmaniasis (VL) or kala-azar. Atypical presentations such as diffuse cutaneous leishmaniasis (DCL) and post-kala-azar dermal leishmaniasis (PKDL) further complicate its diagnosis and management.

3.1. Cutaneous Leishmaniasis (CL)

Cutaneous leishmaniasis is the most common form of the disease, characterized by the development of localized skin lesions, typically at the site of sandfly bites. The lesions initially appear as papules or nodules, which may ulcerate over time and form painless but disfiguring sores. The incubation period ranges from weeks to months (Reithinger et al., 2007). There is a notable distinction between Old World CL—caused by L. major, L. tropica, and L. aethiopica, primarily found in parts of Asia, Africa, and the Mediterranean—and New World CL, caused predominantly by L. mexicana and species of the Viannia subgenus (e.g., L. braziliensis, L. panamensis) in Central and South America (Alvar et al., 2012). In some cases, CL may progress to diffuse cutaneous leishmaniasis (DCL), a rare and severe form associated with immunosuppression or poor cell-mediated immunity. DCL presents with widespread non-ulcerative nodules resembling lepromatous leprosy and is refractory to conventional treatments. Additionally, New World species such as L. braziliensis can metastasize to mucosal tissues, progressing to mucocutaneous leishmaniasis if not treated early (Gupta et al., 2020).

Mucocutaneous leishmaniasis is a destructive form of the disease characterized by parasitic invasion of the mucous membranes of the nose, mouth, pharynx, and occasionally the larynx. The condition usually develops months to years after the healing of a primary cutaneous lesion caused by L. braziliensis or L. panamensis (de Vries et al., 2015). MCL leads to severe inflammation and erosion of mucosal tissues, often resulting in facial disfigurement, breathing difficulty, and social stigmatization. The disease is endemic mainly in South and Central America, with significant prevalence in countries like Brazil, Peru, and Bolivia. Diagnosis and treatment are challenging due to its insidious onset and potential for relapse (Burza et al., 2018).

Figure 2: Mucocutaneous Leishmaniasis condition

3.3. Visceral Leishmaniasis (VL) or Kala-azar

Visceral leishmaniasis is the most severe and life-threatening form of the disease. It is caused predominantly by L. donovani (in Asia and East Africa) and L. infantum (in the Mediterranean and Latin America). The parasite disseminates through the bloodstream to infect vital organs including the spleen, liver, lymph nodes, and bone marrow (Singh et al., 2016). The clinical presentation includes prolonged fever, hepatosplenomegaly, pancytopenia, weight loss, and hypergammaglobulinemia. If left untreated, VL has a high fatality rate. Diagnosis is difficult in early stages due to non-specific symptoms and may require invasive procedures such as bone marrow or splenic aspirate microscopy, although rapid diagnostic tests like the rK39 immunochromatographic test are increasingly used (WHO, 2023). An important sequela of VL is Post-Kala-azar Dermal Leishmaniasis (PKDL), characterized by hypopigmented macules, papules, or nodules appearing on the skin after apparent cure of visceral disease. PKDL is especially common in Sudan and India and acts as a parasite reservoir, contributing to disease transmission (Zijlstra et al., 2003).

Figure 3: Visceral Leishmaniasis (VL) or Kala-azar condition

4. Diagnostic Approaches

Accurate and timely diagnosis of leishmaniasis is critical for effective treatment and control. However, the diversity in clinical manifestations, overlapping symptoms with other endemic diseases, and varying accessibility to diagnostic tools present substantial challenges, especially in resource-limited settings.

4.1. Clinical Diagnosis

Clinical suspicion of leishmaniasis arises from characteristic signs such as chronic skin ulcers (cutaneous leishmaniasis), mucosal disfigurement (mucocutaneous leishmaniasis), or prolonged fever with hepatosplenomegaly (visceral leishmaniasis), particularly in patients from endemic regions. However, these features are not pathognomonic and can mimic other infectious or inflammatory diseases, making clinical diagnosis alone insufficient (Reithinger et al., 2007).

4.2. Laboratory Tests

Microscopy

Direct microscopic examination of Giemsa-stained smears from skin lesions (for CL and MCL), bone marrow, splenic, or lymph node aspirates (for VL) remains a cornerstone of diagnosis. It enables identification of amastigote forms (Leishman-Donovan bodies). Although highly specific, sensitivity varies from 50–70% and depends heavily on sample quality and operator expertise (Singh et al., 2016).

Serological Tests

Serological assays such as the direct agglutination test (DAT) and rK39-based immunochromatographic tests are widely used for VL diagnosis. The rK39 test is particularly valuable due to its simplicity and high sensitivity (>90%) in South Asia, although its performance is less reliable in East Africa (Boelaert et al., 2014). Serology is less useful for CL and MCL due to the limited systemic immune response.

Molecular Diagnostics

Polymerase Chain Reaction (PCR)-based assays targeting kinetoplast DNA or ribosomal RNA are highly sensitive and specific, capable of detecting low parasite loads. PCR is valuable for species identification and confirming diagnosis in atypical or relapse cases. However, its application is limited in endemic areas due to the need for infrastructure and technical expertise (Cruz et al., 2013).

4.3. Point-of-Care Diagnostics in Endemic Areas

Rapid diagnostic tests (RDTs) like the rK39 strip test offer significant advantages in remote settings—being fast, user-friendly, and cost-effective. These tests enable prompt field-level screening and have become integral to kala-azar control programs in South Asia (WHO, 2023). Nevertheless, regional variability in test performance and cross-reactivity with other diseases remain limitations.

4.4. Limitations and Needs for Improved Diagnostics

Current diagnostic tools for leishmaniasis have several limitations:

50. Variable sensitivity and specificity across geographic regions and disease forms
50. Limited reliability of serology in immunocompromised patients
50. Invasive procedures (e.g., splenic aspiration) carry risks
50. High costs and infrastructure requirements for PCR in low-income settings

There is an urgent need for non-invasive, highly sensitive, affordable, and field-adaptable diagnostic tools. Innovations like loop-mediated isothermal amplification (LAMP) and CRISPR-based diagnostics show promise but require further validation (Adams et al., 2021). An ideal diagnostic strategy would integrate clinical, serological, and molecular tools in a tiered approach tailored to regional needs.

5. Treatment Strategies and Challenges

The treatment of leishmaniasis is complex due to the diversity of its clinical forms, variability in drug response by region and parasite species, toxicity profiles, and increasing drug resistance. The development of effective and accessible therapies is essential to reduce disease burden and improve outcomes in endemic populations.

5.1. Current Treatment Options

Several antileishmanial drugs are currently in use, with selection depending on the type of leishmaniasis, species involved, patient status, and regional guidelines.

Table 1. Overview of Current Antileishmanial Drugs

(Source: Sundar & Singh, 2018; WHO, 2023)

5.2. Treatment Limitations and Challenges

Despite available treatments, several challenges limit the success of current therapeutic strategies.

5.2.1. Drug Resistance and Relapse

Resistance to pentavalent antimonials is a major concern, particularly in regions like Bihar, India, where cure rates have declined significantly (Singh et al., 2012). Miltefosine resistance is also emerging due to widespread monotherapy use and long half-life.

5.2.2. Toxicity and Side Effects

Many antileishmanial drugs are associated with severe adverse effects. Amphotericin B (conventional) is nephrotoxic, while miltefosine can cause gastrointestinal disturbances and hepatotoxicity. Parenteral drugs can also cause injection site reactions and systemic effects (Croft et al., 2006).

5.2.3. High Treatment Cost

Liposomal amphotericin B, although safer and effective, is prohibitively expensive in many endemic regions. This restricts its widespread use despite being a preferred option (WHO, 2023).

5.2.4. Lengthy Treatment Duration

Traditional regimens often require prolonged hospitalization or repeated injections over weeks. This leads to poor patient compliance and increased risk of relapse or incomplete treatment (Olliaro et al., 2005).

5.2.5. Regional Variation in Drug Efficacy

Drug efficacy varies with Leishmania species and geographical location. For example, miltefosine shows high efficacy in India but reduced success rates in South America and East Africa due to parasite variability (Ponte-Sucre et al., 2017).

5.2.6. Access Issues in Endemic and Rural Settings

Health infrastructure in endemic areas is often inadequate. Lack of access to diagnostic and therapeutic facilities delays treatment initiation and contributes to morbidity and transmission (Alvar et al., 2006).

Table 2. Summary of Treatment Challenges in Leishmaniasis

6. Emerging Therapeutic Approaches

Due to the limitations of conventional treatments—such as toxicity, resistance, and high cost—research is shifting toward innovative therapies for leishmaniasis. These include novel drug candidates, advanced drug delivery systems, immunotherapies, vaccines, and natural remedies. These emerging approaches aim to improve efficacy, reduce side effects, and target resistant strains.

6.1. New Drug Candidates and Clinical Trials

Several novel compounds are currently in preclinical and clinical development to address resistance and improve pharmacokinetic properties.

50. Fexinidazole, a nitroimidazole originally developed for Trypanosoma infections, has shown promise for visceral leishmaniasis (VL) and is under evaluation in East Africa (Wasunna et al., 2022).
50. Oleyl phosphocholine, a new oral alkyl phosphocholine compound, has demonstrated efficacy in preclinical models of cutaneous leishmaniasis (Wijnant et al., 2018)
50. Leishman lysin (Gp63) inhibitors and proteasome inhibitors are other promising molecular targets under investigation (Sundar & Singh, 2018).

6.2. Nanotechnology and Targeted Drug Delivery

Nanotechnology offers precise drug delivery, improved bioavailability, and targeted accumulation at infected macrophages:

50. Liposomal amphotericin B, already in clinical use, exemplifies nanocarrier-based therapy with reduced toxicity (Croft et al., 2016).
50. Solid lipid nanoparticles (SLNs) and polymeric nanoparticles are being designed to carry miltefosine, paromomycin, and natural compounds for sustained release (Bhardwaj et al., 2020).
50. Surface-functionalized nanoparticles are tailored to target macrophage receptors, enhancing uptake and efficacy.

6.3. Immunotherapy and Host-Directed Therapy

Immunomodulatory strategies aim to boost host responses to enhance parasite clearance and prevent relapse:

50. Checkpoint inhibitors and interleukin-12 (IL-12) therapy have shown efficacy in experimental models of cutaneous and visceral leishmaniasis (Khare et al., 2021).
50. CpG oligodeoxynucleotides (TLR9 agonists) combined with chemotherapy significantly enhance treatment response by activating innate immunity (Liese et al., 2008).

6.4. Vaccines Under Development

Despite decades of research, no human vaccine is commercially available, but several candidates are in the pipeline:

50. LEISH-F3+GLA-SE, a recombinant protein vaccine, has entered Phase I trials with promising immunogenicity (Duthie et al., 2017).
50. Live-attenuated vaccines, such as genetically modified Leishmania donovani, are being tested in animal models (Trigo et al., 2019).
50. DNA vaccines, targeting parasite antigens like A2 and KMP-11, show strong protective responses in preclinical studies (Basu et al., 2005).

6.5. Role of Traditional and Herbal Medicines

Ethnomedicine remains an underutilized area in anti-leishmanial therapy. Several plant-derived compounds exhibit antiparasitic activity:

50. Quinonoids, alkaloids, and flavonoids from plants like Azadirachta indica, Withania somnifera, and Nigella sativa have shown leishmanicidal effects in vitro and in vivo (Mendonça-Filho et al., 2004).
50. Essential oils from Ocimum gratissimum and Artemisia annua have demonstrated promising immunomodulatory and antileishmanial properties (Machado et al., 2020).
50. These agents offer accessible and potentially less toxic alternatives for low-resource settings but require further pharmacological validation.

7. Prevention and Control Strategies

Preventing and controlling leishmaniasis is a multifaceted challenge that requires a comprehensive and integrated approach. Strategies span vector control, reservoir management, public education, surveillance, and community-based interventions.

7.1 Vector Control

Controlling the sandfly population is the cornerstone of leishmaniasis prevention. Effective methods include:

50. Indoor residual spraying (IRS) with insecticides (e.g., DDT, pyrethroids).
50. Use of insecticide-treated bed nets (ITNs) and curtains.
50. Environmental management, such as improving sanitation and reducing breeding sites.

Table 3. Common Vector Control Strategies and Their Effectiveness

     Insecticide resistance is a growing concern, especially in endemic areas in India, Brazil, and Sudan (Killick-Kendrick, 1999; WHO, 2022).

7.2 Reservoir Control

Animal reservoirs, particularly domestic dogs, play a significant role in transmission, especially for zoonotic species like Leishmania infantum.

50. Canine vaccination with Leish-Tec and CaniLeish shows partial protection (Palatnik-de-Sousa & Day, 2011).
50. Culling of infected dogs has been controversial due to ethical and efficacy concerns.
50. Use of insecticide-impregnated collars has proven effective in reducing dog-to-human transmission.

Table 4. Reservoir Control Interventions

7.3 Community Awareness and Health Education

Health education and community participation are crucial in sustaining prevention efforts:

50. Awareness programs on personal protective behaviors, such as avoiding outdoor exposure at dusk.
50. Training local health workers for early detection and management.
50. Involving schools and local NGOs to foster community ownership.

Studies have shown that communities informed about leishmaniasis are more likely to adopt preventive behaviors (Alvar et al., 2012).

7.4 Surveillance and Outbreak Management

Effective surveillance ensures timely identification of cases and outbreaks:

50. Case notification systems, including mobile reporting platforms.
50. Sentinel surveillance in endemic areas for real-time trend monitoring.
50. Outbreak response teams for rapid intervention and focal spraying.

WHO's Global Leishmaniasis Surveillance system collects standardized data from over 90 countries, yet underreporting remains a challenge (WHO, 2022).

7.5 Integrated Disease Management Approaches

Integrated approaches combine multiple strategies for more effective and sustainable control:

50. The One Health approach, linking human, animal, and environmental health.
50. Community-based interventions, integrating vector control, health education, and diagnosis.
50. Public–private partnerships, such as those supporting access to diagnostics and drugs (e.g., DNDi).

8. Global Initiatives and Policy Frameworks

The global response to leishmaniasis as a neglected tropical disease (NTD) has gained momentum through coordinated strategies, frameworks, and policy initiatives led by international and national organizations. These efforts aim to reduce disease burden, improve access to diagnostics and treatment, and prioritize research for innovative interventions.

8.1 WHO Roadmap for NTDs

The World Health Organization (WHO) launched its "Ending the neglect to attain the Sustainable Development Goals: A roadmap for neglected tropical diseases 2021–2030", which prioritizes leishmaniasis control and elimination efforts. The roadmap emphasizes integrated approaches, country ownership, and innovation in diagnostics and treatment.

Key targets for leishmaniasis by 2030 include:

50. Reducing incidence of visceral leishmaniasis (VL) to less than 1 per 10,000 population at the sub-district level in endemic countries.
50. Achieving elimination of cutaneous leishmaniasis (CL) as a public health problem in targeted regions.
50. Strengthening surveillance systems and access to affordable medicines (WHO, 2020).

8.2 Sustainable Development Goals (SDGs) and Leishmaniasis

Leishmaniasis control is embedded within SDG 3: Good Health and Well-being, specifically Target 3.3, which aims to end the epidemics of AIDS, tuberculosis, malaria, and neglected tropical diseases by 2030.

The disease also intersects with:

50. SDG 1 (No Poverty): Leishmaniasis disproportionately affects low-income communities.
50. SDG 10 (Reduced Inequalities): Elimination strategies promote equitable healthcare access.
50. SDG 17 (Partnerships for the Goals): Supports collaborations for research and development.

Meeting SDG targets requires sustained political commitment, financial resources, and innovation in public health strategies (United Nations, 2015).

8.3 National and International Programs

Several global and regional programs support leishmaniasis elimination:

50. Drugs for Neglected Diseases initiative (DNDi): A not-for-profit R&D organization that has advanced affordable therapies like Liposomal Amphotericin B and supports ongoing trials for oral treatments such as DNDi-0690.
50. G-FINDER (Global Funding for Innovation for Neglected Diseases): Tracks global investments in R&D for NTDs. In 2022, over $61 million was invested in leishmaniasis-related research, with notable contributions from the USA, the UK, and the Bill & Melinda Gates Foundation (Policy Cures Research, 2023).
50. National control programs: Countries like India, Bangladesh, and Brazil have launched national kala-azar elimination programs, often in collaboration with WHO and donor agencies, to expand access to diagnosis, treatment, and vector control.

8.4 Funding and Research Priorities

Despite advancements, leishmaniasis remains underfunded. WHO and partners have highlighted priority areas including:

50. Development of short-course, oral, non-toxic therapies.
50. Better diagnostics suitable for field use.
50. Enhanced surveillance and pharmacovigilance systems.
50. Research on vaccine development, which is still in early clinical stages.

Table 5. Key Global Actors in Leishmaniasis Policy and Research