¹University of Houston, Houston, TX, USA
²Center for Clinical Studies, Webster, TX, USA
³Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX, USA

Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding sources: None.

Abstract:
Cutaneous leishmaniasis (CL) is an infection caused by the Leishmania protozoa, which are primarily transmitted through bites of infected female sandflies. This article provides a comprehensive overview of the clinical management of CL, including an in-depth analysis of its epidemiology, prevention and control measures, diagnostic modalities – particularly molecular and serological, differential diagnosis with other lesions, and treatment options. Also discussed are recent concerns regarding the endemicity of CL, with a focus on the significant rise in travel-related cases as well as locally acquired cases, providing insight into the changing epidemiological landscape.

Keywords: cutaneous leishmaniasis, neglected tropical diseases, zoonotic diseases, clinical management, differential diagnosis

Introduction

Cutaneous leishmaniasis (CL) is a form of leishmaniasis, a protozoal infection that affects the skin or internal organs. Other forms of leishmanisis are more severe but rarer. CL remains a significant public health challenge due to its widespread prevalence and potential to cause severe disfigurement and morbidity.^1,2 The prevention, diagnosis, and treatment of CL require a multifaceted approach. According to the World Health Organization (WHO), there were over 200,000 reported cases of CL in 2022, and the number of cases continues to rise, making CL one of the most common skin diseases globally.³ The WHO has classified CL and its other forms as neglected tropical diseases (NTDs), reflecting their significant impact in endemic regions.³ The impact of CL is also increasing in non-endemic areas due to factors such as international travel, migration, and the influence of climate change.^4,5 Therefore, managing CL and other NTDs has become a critical issue.

Epidemiology

The global distribution of CL encompasses tropical and subtropical regions, with endemic areas in the Central and South Americas, Mediterranean basin, Middle East, and parts of Asia and Africa.³ According to the WHO, CL affects approximately 0.7 to 1.2 million people annually.^1,3 The disease burden is particularly high in countries like Brazil, Iran, Afghanistan, and Syria.^6,7

In North America, CL is not commonly found, but there have been cases reported among travelers and military personnel returning from regions where the disease is prevalent.⁸ It is important to note that there have been cases of CL originating in Texas and Oklahoma, indicating the potential for local transmission.^2,8,9 In 2023 alone, the Texas Department of State Health Services has reported at least 9 new cases of CL (also the average number of new cases in the past decade), and new cases are recommended to be reported within a week.^10,11 These locally acquired cases are believed to be a result of climate change, which has expanded the habitable range of sandfly vectors.¹² The increasing number of reported cases in non-endemic regions emphasizes the need for heightened surveillance and awareness among healthcare providers in these areas.¹³

Prevention and Control

It is essential to implement effective prevention and control strategies to reduce the incidence of CL. One of the primary methods of prevention is vector control, which involves measures such as the use of insecticide-treated bed nets and indoor residual spraying.⁴ Personal protective measures, including wearing long-sleeved clothing and using insect repellents, are also recommended.¹⁴ It is also advisable to avoid outdoor activities during dusk and dawn when sandflies are most active.¹⁵ These comprehensive strategies collectively contribute to reducing the risk of contracting CL.

Environmental management strategies focus on reducing sandfly breeding sites by improving sanitation and housing conditions.^1,3,12 Such approaches include the removal of organic waste and rubble, which serve as breeding sites for sandflies, and improving housing structures to prevent sandfly entry.^7,16 Public health education campaigns are also essential in raising awareness about preventive measures and encouraging community participation.^17-19 These campaigns target both endemic regions and non-endemic areas at risk of CL introduction, emphasizing the importance of early diagnosis and treatment.^20,21 Additionally, the development and distribution of a vaccine for CL is an area of active research, though no effective vaccine is currently available.^8,22

Diagnosis

An accurate diagnosis of CL is crucial for effective treatment, as most species present a unique manifestation (Table 1). Clinically, CL is characterized by ulcerative skin lesions, often located on exposed areas such as the face, arms, and legs.^2,14,17-19 The lesions may vary in appearance and can be single or multiple, with a chronic course if left untreated.^4,23

Laboratory confirmation of CL is achieved through several methods:

Microscopy

A direct visualization of Leishmania amastigotes in stained tissue smears is a common diagnostic method. However, its sensitivity varies depending on the parasite load and the skill of the technician.^1,15 Giemsa-stained smears of lesion material can be examined under a microscope; this method remains widely used due to its simplicity and low cost.²⁴

Culture

Culturing Leishmania parasites from lesion aspirates or biopsies in specialized media can provide a definitive diagnosis, but it is time-consuming and requires laboratory facilities.⁴ Media such as Novy-MacNeal-Nicolle (NNN) or Schneider’s Drosophila medium are commonly used for parasite cultures.^25,26

Molecular Techniques

Polymerase chain reaction (PCR) has become increasingly popular due to its high sensitivity and specificity. It can detect and identify Leishmania species, which is essential for guiding treatment decisions.^2,4 Real-time and loop-mediated isothermal amplification (LAMP) are advanced molecular techniques that can also provide rapid and accurate diagnosis.^27,28

Serological Tests

These are generally less useful for CL due to variable antibody responses but may have a role in epidemiological studies.²⁹ However, specific serological tests such as enzyme-linked immunosorbent assay (ELISA) and immunofluorescent antibody test (IFAT) can aid in diagnosis under certain conditions.^8,30,31

Other recent advancements include the development of rapid diagnostic tests (RDTs) that offer point-of-care diagnosis with minimal laboratory infrastructure.^1,30 These tests are particularly useful in resource-limited settings and for large-scale epidemiological surveys.³⁰ The combination of RDTs and clinical presentations, along with anecdotal histories, provides the best diagnosis of CL and can improve the subsequent quality of care.

Differential Diagnosis

Differentiating CL from other skin conditions is critical to avoid misdiagnosis and inappropriate treatment (Figure 1).^17-20,32 The differential diagnosis includes:

Fungal Infections

Sporotrichosis and chromoblastomycosis present with chronic skin lesions resembling CL. Sporotrichosis, caused by Sporothrix schenckii, typically presents with nodular lesions that can ulcerate, resembling CL.³⁴

Parasitic Infections

Cutaneous larva migrans (CLM) and myiasis should be considered, particularly in endemic regions. CLM, caused by hookworm larvae, presents with serpiginous tracks on the skin, which can be distinguished from CL lesions.³⁵

Non-Infectious Conditions

Skin cancers, eczema, psoriasis, and autoimmune diseases such as lupus erythematosus can present with lesions that resemble CL.² Basal cell carcinoma and squamous cell carcinoma may present as ulcerative lesions similar to CL but typically have different clinical and histopathological features.⁹

Therefore, a combination of thorough clinical evaluations and appropriate laboratory tests is necessary to establish the correct diagnosis.¹⁵ Biopsy and histopathological examination can aid in differentiating CL from other conditions, especially when combined with molecular techniques.¹⁸

Pharmaceutical Treatments

One of the difficulties in the management of CL is that its treatment varies based on the species of Leishmania, geographical region, and patient factors.^17,19 The mainstay of treatment includes antimonial compounds, amphotericin B, pentamidine, and miltefosine.^{4,7,14,15,20,24} Most of these pharmacologic agents can be effective against multiple species, but the conditions presented by each case should guide the treatment decision and may limit the choice of therapy (Table 2). Recent studies have even considered the use of multiple treatments to synergize therapeutic effects.^1,3

Pentavalent Antimonial Compounds

Meglumine antimoniate and sodium stibogluconate (SSG) have been the first-line treatments for decades. They are effective but associated with significant side effects such as cardiotoxicity and hepatotoxicity.¹⁵ These drugs require intramuscular or intravenous administration, and treatment courses typically last 20 to 28 days.²⁴

Amphotericin B

This antifungal agent is effective against various Leishmania species. Liposomal formulations have improved the safety profile but remain expensive.² Liposomal amphotericin B (AmBisome®) is administered intravenously and is preferred for its lower toxicity and shorter treatment duration compared to conventional formulations.³⁶

Pentamidine

Used primarily for L. guyanensis infections, pentamidine is an alternative when antimonies are contraindicated or ineffective.³⁷ It is administered intramuscularly or intravenously, and common side effects include nephrotoxicity, hypotension, and hyperglycemia.²⁰

Miltefosine

As the first oral drug approved for CL, miltefosine is effective against several species and has a more favorable safety profile, though it is teratogenic and requires monitoring for gastrointestinal side effects.³⁸ Treatment with miltefosine typically lasts 28 days and is even effective against visceral leishmaniasis.^24,39

Recent research has focused on combination therapies to improve efficacy and reduce the duration of treatment.⁴ Combination therapy using miltefosine with other drugs such as paromomycin or liposomal amphotericin B has shown promise in clinical trials.²⁴

Drug Resistance

The emergence of drug resistance in CL is influenced by various factors, including parasite genetics, host immune responses, and treatment regimens.⁴⁰ Studies have highlighted the role of genetic mutations in mediating resistance to antimonies, amphotericin B, and miltefosine.^39,41 For instance, mutations in genes encoding proteins involved in drug transport and metabolism, such as aquaglyceroporin 1 (AQP1) and multidrug resistance protein 1 (MRP1), have been associated with decreased drug susceptibility in Leishmania parasites.^42,43

AQP1 is a transmembrane channel protein that facilitates the passage of water, glycerol, and certain small solutes across the cell membrane of Leishmania parasites.^42,44 Importantly, the channel also serves as a conduit for the uptake of antimonial drugs like SSG. Therefore, mutations in the AQP1 gene can lead to structural alterations in the protein, resulting in reduced drug uptake and diminished susceptibility to antimonials.⁴⁵ Similarly, MRP1 belongs to the ATP-binding cassette (ABC) transporter family and is involved in the efflux of a broad range of substrates, including chemotherapeutic agents.⁴¹ Overexpression or mutations of MRP1 can confer resistance to multiple antileishmanial drugs by actively reducing their intracellular concentrations and, consequently, their therapeutic efficacy.⁴³ Therefore, an understanding of the molecular basis of drug resistance is essential for the development of effective therapeutic strategies and the identification of novel drug targets to combat CL.

Moreover, environmental factors, including drug pressure and host immune status, play a crucial role in shaping the dynamics of drug resistance in CL. Prolonged exposure to suboptimal drug concentrations can select for resistant parasite strains.^40,42 Additionally, immunocompromised individuals, such as those co-infected with human immunodeficiency virus (HIV), are more susceptible to treatment failure and the development of drug resistance due to impaired immune responses.³³

Non-Pharmaceutical Treatments

Non-pharmaceutical treatments are often used in conjunction with pharmaceutical therapies or when drug treatment is contraindicated.^2,46 These methods provide alternative patient options and can be tailored to individual needs and preferences. Current treatments include cryotherapy, photodynamic therapy, and surgical excision.^19,20,46

Cryotherapy

Cryotherarpy involves the application of liquid nitrogen to freeze and destroy the lesion. It is effective for localized lesions but may require multiple sessions.⁴⁷ Cryotherapy is a simple, low-cost option that can be performed in outpatient settings and is particularly useful for lesions in accessible areas.⁴⁸

Photodynamic Therapy

Photodynamic therapy utilizes light-activated compounds to selectively target and destroy Leishmania parasites. The application of a photosensitizing agent followed by exposure to a specific wavelength of light, leads to the generation of reactive oxygen species that kill the parasites.⁴⁹ For patients who cannot tolerate systemic treatments, photodynamic therapy is a promising solution.⁵⁰

Surgical Excision

Surgical excision can be considered for single, well-defined lesions that are resistant to other treatments.^23,51 It carries the risk of scarring and should be performed by experienced clinicians.^2,52

Conclusion

Managing CL involves a comprehensive approach that includes prevention, accurate diagnosis, and effective treatment. Recent advancements in diagnostic tools and treatment options have improved the management of CL. However, challenges remain, particularly in non-endemic regions like North America, where awareness and expertise may be limited.^4,8 Increased travel and climate change could lead to a rise in cases, highlighting the need for continued research and international collaboration to address these challenges and reduce the burden of CL globally.³

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