Wound Management Strategy for Treatment of Localized Cutaneous Leishmaniasis Using the TIME Framework

Leishmaniasis is a disease caused by intracellular protozoan parasites belonging to the Leishmania genus. The disease is the result of the bite of a female sand fly (phlebotomine), which transmits the Leishmania parasites to the vertebrate host. Clinical manifestations vary, from simple self-healing skin ulcers to severe chronic mucocutaneous infections and life-threatening visceral diseases.¹ The severity of symptoms depends on both the parasitic species and the immune system of the infected host.²

The most common forms of leishmaniasis in people are cutaneous leishmaniasis (CL) and visceral leishmaniasis. Cutaneous leishmaniasis is the most prevalent clinical type of the disease and affects between 1 million and 1.5 million people globally.¹ Cutaneous leishmaniasis is characterized by an effective Th1 response activated by dendritic cells that uptake and process antigens (pattern recognition receptors–pathogen-associated molecular patterns interaction), migrate to the lymphoid organs, and activate the maturation of naive T cells.¹ The pivotal cytokines involved in this immune response are IL-12, IFN-g, and IL-17, which trigger a strong inflammatory response of macrophages against parasites. The progression of the disease may be related to the activation of a Th2 response that leads to the production of IL-4 and IL-10.¹ In addition, the Th1/Th2 interaction is not completely understood. Reports have suggested the involvement of CD8+ T cells, natural killer cells, and T regulatory cells with complex interactions modulated by the parasite.^1,3 Histopathological examination, immunohistochemistry, immunofluorescence, and electron microscopy have revealed the immunology of CL in vivo.⁴ A correct diagnosis is usually obtained with medical and travel history, clinical findings (papules, plaques, ulcers, and/or  nodules), and histological features.⁵ In particular, histological examinations of amastigotes and Leishman-Donovan bodies have a sensitivity of 50% to 70%.⁵ Cultural examination is difficult to perform, has a low sensitivity (30%), and is considered a second-level diagnostic test.⁵ Additional diagnostic tests include isoenzyme analysis, monoclonal antibody analysis, and polymerase chain reaction studies. While the polymerase chain reaction study has a high sensitivity (97%), it is expensive and does not have a well-defined specificity.⁵

There are currently few drugs to treat CL, and several adverse events as well as poor evidence of efficacy have limited their use in treatment.⁶ First-line treatments include simple wound care (with unspecified strategies) or topical treatments (paromomycin-containing ointments, imiquimod, local infiltration with antimonials, and physical treatment such as cryotherapy or local heat therapy).⁶ Systemic treatments include pentavalent antimonials as first-line treatment and amphotericin B, allopurinol, ketoconazole, and miltefosine as second-line treatments.^5,6

The authors report a clinical case of ulcerated CL to propose a specific wound care approach based on wound bed preparation (WBP) strategy realized through the tissue debridement, infection/inflammation management, moisture balance, and edge assessment (TIME) model. This systematic approach may simplify the local management of ulcerated CL, thereby potentially improving both the healing process and cosmetic outcome as well as limiting the risk of complications and need for systemic therapy.

A 32-year-old female with no history of disease presented to the emergency department with nonpainful ulcerated nodules, each on the right arm, neck, and right thigh (Figure A). No treatment was administered in the emergency department; the patient was referred to the dermatology unit for outpatient care. The patient was immediately sent (ie, within the hour) to the authors’ department. The lesions developed 15 days after incurring insect bites during a trip to Colombia. Past medical history was negative for systemic and local diseases. Clinical suspicion of CL was confirmed by clinical and epidemiological criteria. A punch biopsy was performed on the border of the wound on the right arm (including affected and non-affected tissue), which confirmed etiologic diagnosis. The histological examination revealed a dense dermal infiltrate and amastigotes within phagolysosome vacuoles. These findings, combined with localized skin lesions, suggested an adequate immune response. The serology tests for HIV and Leishmania, performed to exclude immunosuppression and hematic spreading of the parasite, were negative. No regional lymphadenopathy or clinical signs of visceral involvement were detected.

Wound cleansing was performed once daily with application of a specific solution containing propyl betaine and polyhexanide ([PHMB] Prontosan Wound Irrigation Solution; B. Braun Medical Inc.) until clinical resolution. Wound cleaning occured until clinical resolution, performed twice a week by medical staff and the other days by a professional nursing home service.

After applying a lidocaine 5% anesthetic cream (Ortodermina; SOFAR), the ulcerated nodules were treated with local surgical debridement using a sterile curette. Following debridement, silver-impregnated dressing composed of ionic silver, carboxymethyl cellulose (CMC), and alginate (AQUACEL Ag; ConvaTec) and secondary polyurethane foam with gentle silicone layer self-adhesive dressings (Suprasorb P; L&R USA, Inc.) were used twice a week until clinical resolution (ie, 15 days in total). Clinical improvement indicated by epithelial advancement was observed after 10 days (Figure B), satisfactory clinical resolution after 15 days (Figure C), and complete remission after 30 days from the beginning of treatment with post-inflammatory hyperpigmentation and in the absence of scars (Figure D).

Cutaneous leishmaniasis is a neglected global public health problem. There is little consistent evidence of treatment efficacy for CL, and potential adverse events for several therapies are reported in the literature.⁷ The balance between the pathogen, the host’s immune system, and the risk of complications should be evaluated in the risk-benefit assessment of the treatment. Current treatment recommendations are based on data from areas endemic for leishmaniasis and are not always perfectly applicable, especially in cases of imported CL. Thus, treatment decisions should reflect the circumstances of each individual case.^6,7

Systemic treatments should only be recommended in patients with clinical or laboratory indication of visceral leishmaniasis; in travelers from Bolivia; in patients with more than 4 lesions (each larger than 4 cm²–6 cm² that have persisted for more than 4 months), are associated with immunosuppression, and are located above the belt, on the face, or near small joints; and in all patients whose previous therapy failed and local lymphadenopathy and lymphangitis are present.⁷ In all other cases, overdiagnosis and overtreatment should be avoided.^5-7

Data on CL in the United States published between 2000 and 2015 (ie, 13 studies with 352 patients involved) showed rare spontaneous healing in patients treated with placebo and varying frequency between spontaneous healing trend for species.⁸ Due to the unlikely chance of spontaneous healing, it is essential to establish a correct and shared local therapeutic approach.

The World Health Organization Expert Committee on the Control of Leishmaniasis recommends cleaning lesions to avoid secondary infections, which may often complicate CL.⁸

The authors propose a local therapeutic approach for ulcerated CL based on WBP that takes into account 4 steps of the TIME framework: 1) tissue debridement, 2) infection/inflammation management, 3) moisture balance through the selection of appropriate dressings, and 4) edge assessment. Tissue debridement removes nonviable or necrotic tissue. Infection/inflammation management balances inflammatory cells, cytokines, chemokines, growth factors and proteases, and/or reduces bacterial concentration, thus avoiding colonizing and the consequent development of infection. The management of wound fluid/exudate avoids maceration and biofilm formation and promotes wound healing processes, thus reducing the levels of cytokines, free oxygen radicals, and proteases. The best strategy to manage wound fluid/exudate is selecting an appropriate dressing that is easy to apply and remove. Edge assessment is an important indication of wound healing; appropriate therapies need to be used to promote the progression of the epidermal margins.⁹ In cases of ulcerated CL, every phase of this framework should be tailored to optimize wound healing.

The TIME approach to ulcerated CL is summarized in the Table and can be applied to all patients with confirmed or strongly suspected infection with Leishmania major; less than 4 lesions with a diameter less than 5 cm; with no risk of disfigure or disability (exclude lesions of face, joints, toes, fingers); and in those who are not immunosuppressed with a possibility for follow-up.⁶

In the current case, the ulcerated nodules were treated with local surgical debridement (T) in order to remove the devitalized and hypergranulation tissue; subsequently, an alginate silver antimicrobial was applied as the primary dressing and polyurethane foam as the secondary dressing (I, M) in order to control the bacterial load and exudation. The dressings were changed twice a week. In the present case, the aim was to prevent secondary infection; as such, the authors suggest removing any fibrin and necrotic tissue, which are possible reservoirs of infection. The debridement was performed using a curette to ensure gentle tissue removal considering the location of the lesion localization (the neck) and pain. Bacterial proliferation was controlled using an antiseptic dressing, thus promoting the healing process and improving the cosmetic outcome. The lesion was also cleaned with an antimicrobial cleanser (PHMB). To improve the aesthetic outcomes, a silicone dressing was applied to all sites for 3 months after the wound had healed (E).

The main limitation of the report is that it is a single case that was not placebo-controlled. In addition, nodules were not measured as the clinical improvement was clearly visible.

Cutaneous leishmaniasis clinical practice guidelines cannot be standardized, and therapeutic management should be based on many risk factors. Systemic treatments should be recommended only in selected cases. In all other cases, overdiagnosis and overtreatment should be avoided. The TIME framework can simplify the local management of ulcerated CL and can be tailored to each case, optimizing the risk-benefit ratio. Further studies with placebo-controlled groups are necessary to confirm the data and to establish a shared local therapeutic approach.

Authors: Michela Iannone, MD; Teresa Oranges, MD, PhD; Valentina Dini, MD, PhD; Marco Romanelli, MD, PhD; and Agata Janowska, MD

Affiliation: Department of Dermatology, University of Pisa, Pisa, Italy

Correspondence: Michela Iannone, MD, Department of Dermatology, University of Pisa, Via Roma, 67, 56126, Pisa, Italy; drmichelaiannone@gmail.com

Disclosure: The authors disclose no financial or other conflicts of interest.