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

Abstract

Tables

TABLE 1. Epidemiology and risk factors associated with CL across endemic regions.

Country/Region	Study (year)	Study design & population	Dominant Leishmania species	Key epidemiological findings	Identified risk factors
Pakistan (Balochistan, Hazara Community)	Ali et al. (2025)	Cross-sectional (N = 216)	L. tropica (presumed)	63.9% had CL; awareness high but preventive knowledge low (19%)	Female gender, low education, rural residence, poor housing, low socioeconomic status
Pakistan (Punjab, Khushab District)	Ashraf et al. (2025)	Cross-sectional molecular profiling (N = 423)	L. tropica (confirmed by ITS1-RFLP)	41.8% microscopy positive; peak in January (19.3%)	Female gender (57%), age <20 years, single facial lesions, low rainfall, 22 °C–27 °C temperature
Pakistan (Khyber Pakhtunkhwa)	Uddin et al. (2025)	Retrospective survey (2022–2023, N = 2035)	L. tropica/L. major	High prevalence (61.9%) in <20 years; 52.5% males	Outdoor activity, facial exposure, warm season (spring/summer)
Iraq (Diyala Province)	Hamad et al. (2025)	Retrospective (2011–2021, 25,474 cases)	L. major (likely)	Annual peaks: 4,425 cases in 2015; winter seasonality	Children aged 5–14 years, female gender (52%), poor housing, rural exposure
Iran (Damghan County)	Pourmohammadi et al. (2025)	Ecological time-series (2012–2021)	L. major	Incidence correlated with climate factors	Relative humidity, sunshine hours, air pressure, high temp (P < 0.05)
Colombia (Nationwide)	Tapias Rivera et al. (2025)	Bayesian ecological model (2007–2021, 121,828 cases)	L. panamensis, L. braziliensis	Median annual cases 7,605; incidence 0–16,072 per 100,000	Poverty, forest coverage, internal migration ↑; rainfall ↓ CL incidence
Algeria (Sahara Desert, Djamaa Province)	Boulal et al. (2025)	12-year retrospective analysis (2012–2023, 4,436 cases)	L. major	Mean annual incidence: 369.7; seasonality: peak in Nov & Jan	Male sex (65.2%), teenagers (10–20 years), outdoor exposure, lower limbs
Brazil (Montezuma, Minas Gerais)	Lopes et al. (2025)	Entomological survey	L. braziliensis (vector)	Intra-domiciliary sandfly vector presence confirmed	Indoor presence of Nyssomyia intermedia, domestic transmission risk
Sri Lanka (Anuradhapura District)	Gunasekara et al. (2025)	Qualitative, community-based	L. donovani (cutaneous strain)	Significant psychosocial & financial burden	Delayed diagnosis, poor access to healthcare, stigma
Iran (Isfahan Province, Military Personnel)	Saneian et al. (2025)	Interventional (ATSB trial, 2012–2022)	L. major	Decline in cases post-intervention (196 → 55/year)	Climate, sandfly density, vector exposure; reduction not statistically significant
Portugal (Imported Case)	de Carvalho et al. (2025)	Case report	L. mexicana	First imported CL case in Portugal	Travel history, imported infection risk
Uzbekistan (Pediatric HIV Case)	Dadaboev et al. (2025)	Case report	L. major	Diffuse CL as first sign of HIV infection	Immunosuppression, misdiagnosis (scabies, Kaposi’s sarcoma)
India (Rajasthan)	Aara et al. (2013)	Large case series	L. tropica	Male predominance and association with lower socioeconomic groups	Peri-domestic exposure, arid climate ecology
India (Himachal Pradesh)	Lypaczewski et al. (2024)	Case report	L. donovani	changing atypical species–disease patterns	Emergence linked to parasite diversification and ecological/vector shifts
Bangladesh	Khan et al. (2019)	Case report	L. major	Imported CL case	Travel/migration exposure

Full text

Introduction

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.

Epidemiology and risk factors

Globally, CL displays marked geographical heterogeneity. The WHO identifies high endemicity in the Middle East, Central Asia, North Africa, and Latin America (de Vries and Schallig, 2022). 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 (Tapias Rivera et al., 2025). 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 (Lypaczewski et al., 2024; Aara et al., 2013). 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) (Hamad et al., 2025). Similarly, in Pakistan reported increasing endemicity in non-traditional areas of Punjab with Leishmania tropica identified as the dominant species (Ashraf et al., 2025).

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 (Ali et al., 2025).

Climatic and environmental influences

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 (Olivera et al., 2025; De Oliveira et al., 2021). 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 (Uddin et al., 2025). These observations align with seasonal patterns documented in the Sahara Desert of Algeria, where cases peaked in November and January, reflecting vector transmission cycles (Boulal et al., 2025).

Vector and reservoir ecology

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 (Gunasekara et al., 2025). 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 (Pareyn et al., 2025). CL is transmitted by female sand flies in the genera Phlebotomus (Europe, Asia & Africa) and Lutzomyia (United States of America) (Gunasekara et al., 2025). 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 (Pareyn et al., 2025; Saliba and Oumeish, 1999). Humans may act as reservoirs in anthroponotic forms like L. tropica (Saliba and Oumeish, 1999). 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 (Lopes et al., 2025). 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.

Pathogenesis and immunological insights

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 (Scott and Novais, 2016). 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 (Gashaw et al., 2025). 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 (Mohamed et al., 2003; Blackwell et al., 2009). Together, these genetic differences modulate immune balance and determine disease progression and healing outcomes.

Symptoms & diagnostic advances

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 (Gadri et al., 2025). 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 (Povolo et al., 2025). 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.

Therapeutic developments

Clinically established therapies

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 (Azouz et al., 2025).

Preclinical and experimental approaches

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 (Santos et al., 2025). 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 (Jensen et al., 2025). De Oliveira et al. demonstrated that photoactivated hypericin nanoparticles induced apoptosis in L. amazonensis by inhibiting trypanothione reductase, offering a promising nanomedicine approach (de Oliveira et al., 2025).

Prevention and control

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 (Saneian et al., 2025). 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 (Pourmohammadi et al., 2025; Majidnia et al., 2023). Effective prevention will require integrated vector management, improved housing conditions, community engagement, and region-specific strategies.

Conclusion

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.