Cutaneous leishmaniasis: emerging insights in epidemiology, diagnosis, and treatment

Cutaneous leishmaniasis (CL) is a parasitic disease caused by protozoa of the genus Leishmania, transmitted by infected female sandflies (Phlebotomus and Lutzomyia species). The World Health Organization (WHO) classifies CL among the neglected tropical diseases, currently estimates 600 000 to 1 million new cases occur worldwide annually (WHO, Leishmaniasis Fact sheets, 2023). The expanding distribution of CL, atypical species-disease associations, and persistent care gaps emphasize the need for updated evidence synthesis. This review synthesizes recent epidemiological, diagnostic, and therapeutic developments across endemic and emerging regions and offers an integrated framework to guide surveillance strategies, clinical decision-making, and future research.Globally, CL displays marked geographical heterogeneity. The WHO identifies high endemicity in the Middle East, Central Asia, North Africa, and Latin America (1). Environmental change, population displacement, and urbanization have been associated with rising incidence in several regions. In Colombia, a large-scale ecological study of 121,828 cases from 2007 to 2021 identified substantial spatial variability, with standardized incidence rates between 0 and 16,072 per 100,000 population (2). Factors such as migration, forest coverage, and poverty correlated with higher CL risk, while rainfall and urbanization appeared protective. In India, CL is geographically focal and historically concentrated in the hot, arid north-western belt, especially Rajasthan (Bikaner/Thar Desert region). In recent years, India has also reported emerging or non-traditional foci, notably in Himachal Pradesh (3,4). In Diyala Province, Iraq, a 10-year retrospective analysis of 25,474 confirmed cases showed a high burden among children aged 5-14 years (33%), with seasonality peaking in winter months (November-February) (5). Similarly, in Pakistan reported increasing endemicity in non-traditional areas of Punjab with Leishmania tropica identified as the dominant species (6). Across the studies summarized in Table 1, consistent epidemiological patterns emerge, including a higher burden among children and young adults, frequent male predominance, and marked seasonality aligned with sandfly activity, typically peaking in warmer or post-rainy periods. Transmission is often peri-domestic or rural but increasing urban and intradomiciliary exposure has been documented in several settings, reflecting changing vector behaviour. In India and South Asia, these global patterns intersect with arid or ecologically suitable environments, socioeconomic vulnerability, and emerging non-traditional foci, reinforcing the contribution of CL to the regional and global disease burden. Sociodemographic factors are key determinants of CL risk and awareness. In a cross-sectional study from Quetta, Pakistan, 63.9% of individuals had experienced CL, but knowledge of preventive measures was limited (19%), particularly among women, individuals with lower education, and rural residents (7).Environmental changes, including deforestation and broader climate change, have been linked to rising transmission rates of CL in multiple regions. Deforestation alters reservoir and vector habitats, promoting closer contact between humans, sandflies, and animal hosts. For example, in the Amazon basin and parts of South America (Brazil, Colombia, Peru), rapid forest clearance for agriculture and infrastructure has been associated with increased CL incidence, as sandfly vectors and sylvatic reservoir hosts expand into disturbed landscapes (8,9). Similarly, climate warming trends have expanded the altitude and latitude of sandfly survival, contributing to the emergence of CL in previously non-endemic highland regions of Andean countries and southern Brazil. These ecological shifts illustrate how anthropogenic environmental change can disrupt endemic stability, alter vector ecology, and increase human disease risk across continents. In north-west Pakistan, Uddin et al. reported that CL incidence peaked during summer and spring, corresponding to optimal sandfly breeding conditions (10). These observations align with seasonal patterns documented in the Sahara Desert of Algeria, where cases peaked in November and January, reflecting vector transmission cycles (11).Vector ecology is central to understanding CL transmission. CL is caused by various Leishmania species. In Europe, Asia & Africa, L. major, L. tropica, L. aethiopica, L. infantum, and L. donovani are common, while in United States of America, L. mexicana and L. braziliensis predominate (Table 1). CL caused by L. donovani & L. infantum is an atypical manifestation of a parasite traditionally associated with visceral leishmaniasis. L. donovani MON-37 classically a visceralizing parasite elsewhere has emerged as a major cause of CL in some settings, highlights that visceral lineages can become established as cutaneous pathogens under certain evolutionary and ecological pressures. In certain endemic regions, particularly Sri Lanka and parts of East Africa, L. donovani causes localized cutaneous lesions instead of systemic disease (12). L. infantum is mainly found in the Mediterranean region, the Middle East, and North Africa, where transmission is zoonotic, with dogs as the primary reservoir. Transmission occurs through infected sandflies, with rodents, hyraxes, and other mammals serving as natural reservoirs (13). CL is transmitted by female sand flies in the genera Phlebotomus (Europe, Asia & Africa) and Lutzomyia (United States of America) (12). Host reservoirs of CL are primarily mammals that maintain Leishmania parasites in nature and facilitate transmission to humans through sandfly bites. Major reservoirs include rodents such as gerbils (Rhombomys opimus) and jirds (Meriones spp.) for L. major in the Old World, and hyraxes for L. aethiopica in East Africa. In the New World, forest rodents, opossums, and sloths serve as reservoirs for L. mexicana and L. braziliensis complexes (13,14). Humans may act as reservoirs in anthroponotic forms like L. tropica (14). Reservoir ecology depends on species, geography, and environment, influencing disease persistence and transmission patterns. After ingesting amastigotes from an infected host, parasites develop as promastigotes in the fly gut and are inoculated at the next blood meal; vector competence is species-specific. In Brazil, Nyssomyia intermedia was identified as a potential intradomiciliary vector in Montezuma, capturing 96.7% of sandflies within residential areas (15). This highlights a growing trend toward domestic transmission in regions traditionally associated with sylvatic cycles. Integrated entomological surveillance and housing improvements are therefore essential for prevention. CL occurs when infected sandflies inoculate Leishmania promastigotes into the skin, where they are phagocytosed by macrophages and differentiate into amastigotes. Through immune evasion strategies, including modulation of phagolysosomal function and cytokine responses, parasites persist. A Th1-dominant response is associated with parasite clearance and healing, whereas Th2-skewed immunity promotes chronic disease and persistent ulcerative lesions (21). Host immunity plays a key role in disease outcome. Gashaw et al. demonstrated significantly lower CD4+ T-cell counts among Ethiopian CL patients compared with controls, suggesting immunosuppression as a factor in disease severity (22). Genetic polymorphisms in cytokine genes (IL10, IL4, IFNG, TNFA), HLA class II loci, and NRAMP1 (SLC11A1) influence immune regulation, antigen presentation, and macrophage microbicidal activity, thereby affecting susceptibility, lesion severity, and clinical outcome in CL (23,24). Together, these genetic differences modulate immune balance and determine disease progression and healing outcomes.CL typically begins as a painless papule that gradually enlarges into a nodule and may ulcerate, forming a well-demarcated lesion with raised margins and a central crust. CL caused by L. infantum has been increasingly reported in the Americas, where this species traditionally associated with visceral disease can present as strictly cutaneous infection in immunocompetent and immunocompromised individuals.Beyond conventional microscopy and culture, newer diagnostic approaches are under active investigation. Artificial intelligence based microscopy systems, such as the YOLOv8 model described by Gadri et al., demonstrated high diagnostic accuracy in a laboratory-based validation study, but their use in field settings remains limited by infrastructure and equipment requirements (25). Molecular diagnostics, particularly PCR performed on non-invasive cutaneous swabs, have shown high sensitivity in case-based studies and small clinical series, including among immunocompromised patients (26). Rapid antigen detection tests and isothermal DNA amplification techniques such as loop-mediated isothermal amplification (LAMP) or recombinase polymerase amplification (RPA) have demonstrated promising sensitivity and specificity in pilot studies for CL. These assays enable field-applicable detection of Leishmania DNA without the need for thermocyclers.Pentavalent antimonials continue to be widely used but are limited by toxicity and emerging resistance. Liposomal amphotericin B has an established clinical role, particularly in older patients and those with contraindications to antimonials. Clinical trial data indicate that cumulative doses of 24 mg/kg achieve high cure rates with acceptable safety profiles (27).Several novel therapies are still at a preclinical stage, with amphotericin B-retinoic acid liposomal formulations demonstrating promising immunomodulatory and anti-lesional effects in animal models but lacking clinical evaluation (28). Topical microemulsions with Libidibia ferrea phenolics and photoactivated hypericin nanoparticles show experimental efficacy, but additional pharmacokinetic, safety, and clinical studies are needed prior to clinical application (29). De Oliveira et al. demonstrated that photoactivated hypericin nanoparticles induced apoptosis in L. amazonensis by inhibiting trypanothione reductase, offering a promising nanomedicine approach (30).Vector control and environmental management are the cornerstone of CL prevention but are increasingly challenged by insecticide resistance, sandfly adaptation, urbanization, and climate variability. While Attractive Toxic Sugar Baits have shown promise, their scalability and long-term impact remain unclear (17). Further challenges include weak surveillance, underreporting, limited incorporation of CL into national programs, and low community awareness. Climatic forecasting models offer early-warning potential, but their impact relies on consistent data availability and public-health action (16,31). Effective prevention will require integrated vector management, improved housing conditions, community engagement, and region-specific strategies.CL remains a significant and evolving public-health challenge, shaped by ecological change, socioeconomic vulnerability, and parasite diversity. Although advances in diagnostics, therapeutics, and predictive modeling have expanded the available tools for control, their impact is constrained by health-system limitations and inequitable access. The emergence of atypical disease patterns, particularly in South Asia, underscores the need for strengthened surveillance and species-specific approaches. Future progress will depend on multidisciplinary strategies that integrate molecular epidemiology, vector ecology, patient-centered care, and sustainable prevention programs to reduce the global burden of CL.