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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School of Medicine, Department of Dermatology, The University of Texas Medical Branch, Galveston, TX, USA 

Conflicts of Interest:
The authors have no conflicts to disclose.

ABSTRACT
Epidermal growth factor receptor (EGFR) inhibitors are part of an emerging class of anticancer medicines known as “targeted therapy,” which target pathways more specific to neoplastic proliferation than traditional chemotherapeutic agents. Adverse effects of such treatments are thought to be less severe, but can still be significant. Because EGFR is preferentially expressed in epithelial tissues, including the skin and hair follicle, cutaneous side effects of these agents are quite common. Not only can these toxicities severely affect patients’ quality of life, but in some specific instances, they can be associated with increased response to therapy. It is of paramount importance that clinicians familiarize themselves with and understand the basic management of the range of cutaneous adverse effects caused by these drugs. 

Key Words:
epidermal growth factor receptor, EGFR, epidermal growth factor receptor inhibitor, EGFR inhibitor, erlotinib, cetuximab, targeted therapy, antineoplastic therapy, medication toxicity, cutaneous side effects, cutaneous adverse events, acneiform eruption, paronychia

Introduction

The epidermal growth factor receptor (EGFR) is expressed in epithelial tissues as well as hair follicles. It contributes to epidermal proliferation, differentiation, and hair growth. Upregulating mutations of EGFR have been found in many solid tumors.¹ The discovery of EGFR’s role as an oncogene has led to the development of many new inhibitors for the treatment of various neoplasms of the head, neck, colon, and lung. These drugs have been shown to increase the rate of response to treatment, delaying disease progression and improving quality of life. Standard chemotherapeutic agents nonspecifically affect cells that proliferate rapidly; in contrast, EGFR inhibitors (EGFRIs) target pathways more specific to survival of neoplastic cells, thus belonging to a new class of chemotherapeutic agents – so-called “targeted therapy.” These targeted therapies are usually associated with fewer systemic side effects than standard chemotherapy.²

There are several different types of EGFRIs, including small molecule tyrosine kinase inhibitors, monoclonal antibodies, and multikinase inhibitors. Small molecule tyrosine kinase inhibitors, such as gefitinib and erlotinib, selectively bind the adenosine triphosphate (ATP)-binding site of the EGFR tyrosine kinase receptor, inhibiting the receptor’s intracellular domain via preventing phosphorylation.^3,4 Both gefitinib and erlotinib are approved for the treatment of non-small cell lung cancer, and erlotinib in combination with gemcitabine is approved for the treatment of advanced pancreatic cancer.

In contrast, monoclonal antibodies that target EGFR, such as cetuximab and panitumumab, bind to its extracellular domain and competitively inhibit endogenous ligand binding to the receptor.^3,4 These antibodies are approved for the treatment of advanced EGFR-expressing colorectal cancer, and cetuximab is also approved for treatment of squamous cell carcinoma of the head and neck. There are also combination therapies that affect multiple receptors such as lapatinib (approved for human epidermal growth factor receptor 2-positive [HER2+] breast cancer) and afatinib (approved for non-small cell lung cancer), which inhibit both the EGFR and HER2 receptors, and vandetanib (approved for advanced medullary thyroid cancer), which inhibits EGFR, vascular endothelial growth factor (VEGFR), and rearranged during transfection (RET) activities.

Although these drugs have been proven to be very effective for normally untreatable advanced neoplasms, EGFRIs cause cutaneous side effects in 50% or more of patients undergoing treatment.¹ The most common of these adverse reactions include acneiform eruptions, paronychia, xerosis, mucositis, and alopecia, and less common side effects include trichomegaly, hirsutism, and hyperpigmentation. The occurrence of some EGFRIassociated cutaneous toxicities is actually associated with clinical response to the medication. However, cutaneous side effects can result in decreased quality of life and may cause interruption or discontinuation of therapy despite effectiveness.³ Therefore, it is important to understand the cutaneous side effects of EGFRIs and their management in order to improve quality of life, increase compliance and avoid unnecessary interruption or cessation of treatment.

Cutaneous Toxicities

Mechanism

EGFR is expressed in undifferentiated keratinocytes in the basal layer of the epidermis and the outer layers of the hair follicle, and plays a key role in normal differentiation and proliferation in these tissues. EGFR is activated by ligands such as EGF and transforming growth factor-alpha (TGF-α), and its effects are mediated via downstream pathways including the MAPK (mitogen-activated protein kinase) and PI3K (phosphatidylinositol 3-kinase)-Akt pathways. Downstream effects include growth stimulation, protection from apoptosis, inhibition of differentiation, loss of intercellular attachments, and increased migration. EGFR expression is lost as keratinocytes leave the basal layer and terminally differentiate towards corneocytes.^3-6

Inhibition of EGFR signaling leads to apoptosis of normal keratinocytes, but not of melanocytes or fibroblasts. EGFR inhibition also induces terminal differentiation, and has been shown to inhibit formation of the cornified cell envelope and cause premature hair keratinization and maturation of the inner root sheath. Migration of cells is also decreased and attachment is promoted, interfering with normal movement of cells towards the layers of the epidermis and follicle as they mature. These effects are reflected in findings of decreased epidermal thickness and decreased stratum corneum found in skin specimens of patients treated with EGFRIs. Downregluation of EGFR-signaling also seems to result in increased recruitment of inflammatory cells, contributing to the inflammatory nature of several EGFRI-related cutaneous toxicities.^3-6

The culmination of all of these effects of EGFR blockade results in overall disruption of the integrity of the skin and follicle with associated inflammation. The high incidence of mucocutaneous side effects reflects the importance of EGFR and its function in the epidermis, hair follicle and periungual tissue.

Acneiform Eruptions

Acneiform eruptions are the most common skin reaction found in those undergoing EGFRI therapy, with 43-85% of patients affected. It is the most common side effect of cetuximab and panitumumab, reported in up to 90% of patients. It is also the earliest side effect, presenting only 7-10 days after initiation of drug therapy. The pathological mechanism underlying EGFRIassociated acneiform eruptions differs than that of traditional acne, lying mainly in the follicular instability caused by disruption of EGFR-related normal growth, induction of apoptosis and early differentiation, as opposed to follicular occlusion.²

The acneiform eruption manifests as a papulopustular eruption that affects mainly the head, neck, and upper trunk, normally sparing sites undergoing radiation therapy. It can, however, affect areas spared by traditional acne, such as the lower legs and dorsal arms.² Acneiform eruptions due to EGFRI therapy are characterized by a lack of comedones and often display crusting and confluence. Pruritus is more frequent than in traditional acne.² This eruption is associated with treatment efficacy, showing an increased survival rate when present.^3,4 The effects are dose dependent and improvement in the eruption can be seen within 1-2 weeks of discontinuation of therapy.

Treatment focuses more on reducing inflammation than relieving follicular occlusion, and current treatment guidelines are based on the severity of the eruption. A grading scale from 1-4 is used to determine severity (Table 1). For grade 1 eruptions, sun protection, emollients, topical clindamycin, and topical hydrocortisone 1-2.5% are recommended. For grade 2 eruptions, oral tetracyclines such as doxycycline or minocycline 100 mg twice daily should be added. Progression to grade 3 calls for EGFRI dose reduction, oral corticosteroids, and delay in the interval of treatment.^5,7,8 Patients will rarely present with grade 4 lesions, but should immediately discontinue EGFRI therapy and be seen by a burn care specialist. It is important to note that, in contrast to traditional acne, retinoids are not effective. Retinoids do not improve the follicular instability caused by EGFRIs and can even exacerbate it. They can also aggravate the concomitant xerosis that is seen with EGFRI therapy. Prophylactic treatment is controversial, as the eruption aids in determining treatment efficacy; however, oncologists will often recommend emollients and may prescribe hydrocortisone or topical clindamycin in anticipation of at least a mild eruption.

Paronychia

Nail changes are a common cutaneous side effect in those undergoing EGFRI therapy and are seen in up to 17% of patients.^9,10 Patients present with painful inflammation and suppuration of the periungual skin 4-6 weeks after initiation of therapy. EGFRI-induced paronychia is characterized by abnormal periungal desquamation that results in friable pyogenic granuloma-like changes of the lateral nail folds, as well as pain of the distal finger tufts.^11,12 Disruption and fragility of the epidermis caused by EGFRIs may lead to increased susceptibility of skin to penetration by nail fragments, which may be more brittle with EGFR inhibition, a mechanism similar to that seen in retinoidinduced periungual inflammation.²

Paronychia rarely leads to the cessation of therapy; however it does have a significant impact on the patient’s quality of life.¹ Although the lesions are sterile, secondary infection with Staphylococcus aureus or Candida albicans has been documented.^1,3,13 Treatment is dependent on the severity of the reaction. Local care consists of using petrolatum emollients, as well as antiseptic soaks and cushioning of the soles. For reactions that are mild-tomoderate, disinfectants, topical antibiotic ointments, and mid to high potency topical corticosteroids under occlusion are recommended. Although rare, certain cases may be severe enough to require surgical debridement, electrodessication, or cessation of therapy.^3,14

Alopecia

Both non-scarring and scarring alopecia has been documented as a side effect of long-term EGFRI therapy. EGFR seems to play a role in maintaining the immune privilege of the hair follicle, and the resultant inflammation leads to hair loss, with eventual follicular destruction.² Patients usually present with fine, brittle hair with frontal balding about 2-3 months after drug initiation. At this non-scarring stage, alopecia typically resolves after discontinuation of therapy, although hair quality may be affected.¹³ With time, scarring alopecia can occur and lead to permanent hair loss. Management usually consists of topical steroids to reduce inflammation and prevent scarring.^13,15

Xerosis

Xerosis is a common side effect of EGFRI therapy due to the deteriorated stratum corneum, which results in increased transepidermal water loss. This can lead to inflammation and xerotic dermatitis. Patients present 1-2 months after initiation of therapy. Pruritus is also a frequently occurring symptom. Xerosis can accompany or follow the acneiform eruption associated with therapy. Treatment for EGFRI-induced xerosis follows a strategy similar to atopic dermatitis, which includes avoidance of hot baths and extreme temperatures, and using moisturizing soaps that are free of fragrances and thick moisturizing creams or emollients. Preventative measures, consisting of education on dry skin care and bathing techniques, are recommended.¹³ If the xerosis is severe, topical steroids may be required.¹³

Other Cutaneous Toxicities

There have been other rare side effects reported with the use of EGFRIs, including trichomegaly and facial hirsutism. Patients may present 1-2 months after initiation of therapy, and the abnormal hair growth lasts for the duration of therapy with the EGFRI. Patients with trichomegaly may experience discomfort and corneal abrasions due to abnormal eyelash growth. Management consists of eye lash clipping every 2-4 weeks and referral to an ophthalmologist for complications. Patients with hirsutism can be managed with laser hair removal as well as topical eflornithine.^16,17 Oral complications are uncommonly reported in patients receiving EGFRI therapy. The most common oral side effect observed is mucositis. Patients present with broad areas of erythema and aphthous-like stomatitis.¹³ Localized measures for symptom relief such as ice chips and thorough oral care are normally sufficient; pain management with analgesics may be necessary.

Although eventually fading over several months, hyperpigmentation has also been reported in a few cases, which is believed to be due to post inflammatory changes secondary to EGFR-induced acneiform eruptions and dermatitis. Management guidelines for this hyperpigmentation focuses on treating the acneiform eruption and eczema. It is also recommended for these patients to limit sun exposure in order to prevent exacerbation of existing hyperpigmentation. There has been no efficacy shown in the use of bleaching creams.⁷

Conclusion

The use of EGFRIs for chemotherapy is on the rise due to their observed efficacy and decreased rate of nonspecific and hematopoietic side effects. However, due to EGFR’s important role in the skin and hair follicle, EGFRIs are associated with frequent mucocutaneous toxicities. It is important to understand these adverse effects and their management in order to avoid unnecessary interruption of therapy and decreased quality of life. The most common dermatologic toxicities include acneiform eruptions, paronychia, alopecia, and xerosis. Many of these side effects can be managed, which can increase compliance and help reduce the physical and emotional burden that patients face.

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Section of Infectious Diseases, Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

ABSTRACT

Cutaneous leishmaniasis is a vector-borne protozoal infection of the skin. Several species of Leishmania cause this disease in the Old World. It is manifested as chronic nodular to ulcerative lesions of the skin, which last for many months and may be disfiguring. They eventually heal leaving a scar. Local care of the lesion and treatment of secondary bacterial infection are essential for healing. Antileishmania therapy is indicated in immunocompromised hosts, patients with progressive, multiple, or critically located lesions. Pentavalent antimony compounds remain the main therapeutic option for all species. They are given intravenously (IV), intramuscularly (IM), or intralesionally. Cryotherapy, and some systemic antifungal agents have been used successfully. Oral azoles are promising new treatments for lesions caused L. major. Several other alternatives and their evidence are also presented.

Key Words: Leishmania, cutaneous leishmaniasis, therapy, review

Cutaneous leishmaniasis of the Old World is wide-spread in the Middle East, Mediterranean littoral, Arabian Peninsula, Africa, Near Asia, Indian Subcontinent and other areas. According to WHO, leishmaniasis is endemic in 66 countries in the Old World, 16 of which are in Europe, and the population at risk is more than 350 million. The infected sand fly transmits promastigotes to humans. The parasites are engulfed by tissue macrophages where they multiply as amastigotes. There are at least five species causing cutaneous leishmaniasis in the Old World (see Table 1). L. major and L. tropica cause the majority of cases. Some species are well known for their visceral involvement, but have also been noted to cause cutaneous lesions. L. donovani causes post kala-azar dermal leishmaniasis.^1,2 L. tropica was found to cause visceral disease among American solders serving in the Arabian Peninsula.³ It is apparent that the extent of disease manifestation is a combination of the parasite pathogenesis and the immune host response. A series of complex and not fully understood interactions occur between the species-specific virulence factors and genetically determined cell-mediated immunity. Parasitemacrophage binding triggers a series of cellular and cytokine responses that have been investigated in animal models, but remains less clear in humans.^4-7

Table 1: Leishmania species causing cutaneous disease in the Old World.⁸

Skin lesions develop at the site of inoculation of promastigotes. Therefore, they are rarely seen in covered areas, as in cases of diffuse cutaneous leishmaniasis where lesions may even be nonulcerative papules. The lesion starts as a small nodule that slowly enlarges and then ulcerates. Depending on the age of the lesion and host response, the lesion may be papular, acneform, or nodular with minimal ulceration. The patient may develop a secondary bacterial infection especially on the feet. Small nodules that could ulcerate may appear in the line of the lymphatics draining the area of the primary lesion akin to sporotrichoid presentation. Lesions of leishmaniasis recidivans enlarge slowly while healing in the center, and may last or recur for decades. Diffuse cutaneous leishmaniasis is uncommon. It is related to L. aethiopica in Africa. Mucosal involvement is rare in the Old World. Depending on travel history, differential diagnosis may include fungal or mycobacterial skin infections, cutaneous neoplasms, and sarcoidosis.

Diagnosis is usually suspected in the endemic regions for typical lesions. Confirmation is achieved by obtaining skin scrapings or a biopsy from the lesion edge. A touch preparation using Wright-Giemsa stain reveals the leishmania amastigotes in macrophages or extracellular areas. Leishmania amastigotes are similar in size to Histoplasma capsulatum and can be differentiated by the presence of kinetoplast. The parasite can be grown using one of several culture media. Culturing leishmania will assist in speciating the parasite through isoenzyme analysis⁹ or monoclonal antibody.¹⁰ Serology for cutaneous leishmaniasis is not helpful because of variable antibody elevation.

Treatment

Natural History
Cutaneous leishmaniasis of the Old World eventually heals. The rate of spontaneous healing depends on several factors, including: parasite load and virulence, host immune response, location of the lesion, and the presence or absence of secondary bacterial infection. Lesions caused by L. major heal spontaneously after about 18 weeks.¹¹ L. tropica lesions, on the other hand, typically last for one or two years, but may last for decades. There is no ideal therapy for cutaneous leishmaniasis (topical, effective, inexpensive, and safe). The majority of lesions may best be dealt with using local care and patience. As mucosal leishmaniasis is rare in the Old World, only large, multiple, or diffuse lesions of the face, head and neck need to be considered for therapeutic intervention. Immunocompromised patients should be treated immediately. An important part of therapy for cutaneous leishmaniasis is local care along with antileishmania therapy. Treatment of secondary bacterial infection is essential for healing.

Cryotherapy
Cryotherapy using liquid nitrogen has been used to treat individual lesions. Uncontrolled studies showed enhanced healing either alone or in combination with intralesional antimony.^12-14 This modality is labor intensive and not suitable for multiple or complicated lesions. Applying the same principle, nomads of Arabia use cauterization of leishmania skin lesions. It is effective in eliminating the parasites, but the ensuing scar may be larger than that of leishmania.

Intralesional Antimony
This therapy involves injecting antimony compound in the lesion, and requires multiple doses. The doses, number of injections, and intervals vary widely in reported studies. It has been effective alone¹⁵ or in combination with cryotherapy.^12,14 It is not a practical method in endemic areas because of the high numbers of patients and lesions.

Paromomycin sulphate ointment
An ointment preparation is fairly attractive as therapy for cutaneous leishmaniasis. Paromomycin has been tried for L. major. Results were encouraging at first. However, subsequent randomized trials in four countries for L. major failed to demonstrate the initial success.^16-19 Up to 25% of patients who tried this preparation reported side-effects.²⁰

Systemic Therapy

Antimony Compounds
Pentavalent antimonials were used against leishmania as early as 1912.²¹ Currently, there are two preparations. Sodium stibogluconate (Pentostam®, Wellcome) and
meglumine antimoniate (Glucantime®, Rhone Poulenc) remain the mainstay of therapy for the leishmaniases. For cutaneous leishmaniasis they can be given systematically (IV or IM) or as intralesional injection. Systemic antimonials are associated with many toxicities that limit their use in cutaneous leishmaniasis. They include myalgias, arthralgias, abdominal symptoms, liver enzyme elevation, pancreatitis, bone marrow suppression, neuropathy, cardiac toxicity, and sudden death.²² However, they remain the effective therapy for all species causing cutaneous leishmaniasis in the Old World.

Pentamidine
Pentamidine was tried for leishmania in an attempt to limit side-effects of systemic antimony. The drug had high cure rates in the New World, but was used in only one study in the Old World.²³ Eight out of 11 patients (73%) experienced quick healing after three IM injections of 4mg/kg. Further studies are awaited to support its use. For cutaneous leishmaniasis of the Old World, pentamidine can be used as an alternative to an ineffective antimony course.

Amphotericin B
Liposomal amphotericin B lipid formulation is the only US FDA approved agent for visceral leishmaniasis. The experience of amphotericin B for cutaneous leishmaniasis is limited. Because of its adverse effects, which include nephrotoxicity (15%), electrolyte disturbances, fever, rigors and, rarely, hemodynamic collapse, it may only be used as an alternative therapy to antimony. It has been successfully used in antimony resistant post kala azar dermal leishmaniasis.²⁴

Azoles
Azoles inhibit ergosterol biosynthesis of Leishmania parasites.²⁵ Ketoconazole failed to cure any of 14 patients infected with L. tropica who took it for 10 weeks.²⁶ In a randomized study, none of 32 patients receiving ketoconazole healed.¹⁹ L. major however, may respond better. In a single arm study in Kuwait, 80% of patients “responded”.²⁷ In a similar study from Saudi Arabia, 85% “responded” to 4-18 weeks of ketoconazole.²⁸ It was also “successful” as a treatment for peace keepers in the Sinai.²⁹ Topical ketoconazole was not as successful.³⁰ The lack of blinding and clear definition of cure make the findings subject to bias.

Because it is better tolerated, itraconazole became another option and has been studied more. Although its in vitro results are better than other azoles³¹, this agent was not superior to placebo in one randomized study in Iran.³² However, while open label³³ or non-comparative studies had a healing rate of around 75%.^34,35

The third agent used for cutaneous leishmania is fluconazole. It has the advantage of excellent bioavailability, a favorable adverse events profile, and high skin concentration. A six-week course of 200mg of fluconazole was found to be safe and doubled the chance of healing in a shorter time interval in a randomized, placebocontrolled study in Saudi Arabia.¹¹ The parasites treated were L. major. Other species may not be as responsive.

Other oral agents
Allopurinol was used for leishmania in many areas. Controlled studies in the New World had conflicting results.^36,37 Parasites of the Old World may be more susceptible^38,39 but randomized studies are lacking. Rifampin has also been used for cutaneous leishmaniasis with promising results. In a placebo-controlled study in India, patients had better chances of healing if they received rifampin.⁴⁰

Table 2: Therapies of cutaneous leishmaniasis of the Old World*
* If antileishmania therapy is indicated. The evidence for using many of these therapies is not satisfactory. See text for details.

Conclusion

Cutaneous leishmaniasis of the Old World is endemic in many countries. It poses a risk to the local population, travelers, military personnel, and aid workers. The chronic and sometimes disfiguring lesions eventually heal leaving a scar. Antileishmania therapy is indicated in selected situations, as the disease is self-limiting. When therapy is indicated, antimony compounds are the mainstay of therapy. Other alternatives include parenteral antifungal agents, oral azoles, cryotherapy, and topical paromomycin. Local lesion care and management of secondary bacterial infection are essential. The choice of antileishmania therapy should be based on the patient’s immune status, geographic location, available resources and physician expertise.

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