Case Report: Cutaneous Leishmaniasis Misdiagnosed as Pyoderma Gangrenosum

CASE REPORT

A 29-year-old man with a 4-year history of Crohn’s disease ¹ was referred because of persistent multiple painful ulcers of 2 years’ duration. The cutaneous lesions, initially arisen on the left arm and later involving the neck, chest, right ear, and lower limbs, had appeared during systemic therapy with infliximab 400 mg iv every 8 weeks and azathioprine 50 mg/day, in the absence of significant laboratory and instrumental alterations. After 6 and 10 months, respectively, two skin biopsies had been performed in two different sites, with a subsequent worsening of the cutaneous lesions interpreted as pathergy phenomenon. Although both histological findings resulted suggestive of pyoderma gangrenosum (PG) and slow-tapered systemic steroid therapy was undertaken and repeated several times, the patient did not report any relief. Eighteen months after the ulcers’ outbreak, infliximab and azathioprine were suspended and replaced with adalimumab 40 mg every 2 weeks and cyclosporine 200 mg/day. After a further 3 months, in the absence of clinical improvement, intralesional infiltrations of triamcinolone acetonide were performed once a week for 2 months, without any benefit. When the patient came to our observation, skin examination showed well-defined multiple lesions with erythematous rolled indurated margins and necrotic-purulent slough at the base (Figure 1A). The lesions were disseminated, involving the upper limbs, neck, chest, right ear, and lower limbs. The patient lived in an endemic area of leishmaniasis and had no dogs. No previous history of insect bites was reported. Biopsy of the lesion of the left arm showed ulceration of the epidermis, edema, dilated vessels, and a dense nodular, multicellular, granulomatous infiltrate in the dermis and fatty tissue at full thickness (Figure 1B). Taken together, we suspected a diagnosis of disseminated cutaneous leishmaniasis (CL). The diagnosis was further confirmed by serological antibodies and PCR for Leishmania DNA on the tissue, revealing Leishmania infantum. Instrumental examinations (full abdomen ultrasound scan and chest X-ray) and blood tests (complete blood count, coagulation screening, serum proteins, liver function, kidney function, iron, ferritin, C-reactive protein, erythrocyte sedimentation rate, total proteins, protein electrophoresis, beta two microglobulin, and quantiferon) were all normal. Given the extent of the cutaneous disease and the immunosuppression of the patient, to exclude a visceral involvement of the disease, we also performed a PCR for Leishmania DNA on peripheral blood which tested negative. Adalimumab and cyclosporine were withdrawn, and systemic therapy with intravenous liposomal amphotericin B 3 mg/kg/day at days 1–5, 14, and 21 following international guidelines was started with a prompt clinical response. The systemic therapy was followed by three monthly intralesional infiltrations of pentavalent antimonials, leading to the complete resolution of the clinical picture and only residual scars. Because no flare of Crohn’s disease occurred, also considering the risks of leishmaniasis reactivation, treatment with adalimumab was not restarted. Twelve months later, no recurrences were observed, and the Crohn’s disease was stable.

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(A) Well-defined ulcers with rolled indurated margins on the left hand. (B) Edema, dilated vessels, and a dense diffuse infiltrate of lymphocytes, plasma cells, histiocytes, and some neutrophils in the papillary dermis (H&E, 25X).

Citation: The American Journal of Tropical Medicine and Hygiene 104, 2; 10.4269/ajtmh.20-0735

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DISCUSSION

Cutaneous leishmaniasis, a chronic protozoan skin infection of the mononuclear phagocytic system caused by more than 20 species of Leishmania and transmitted by female sandflies, is endemic in the European Mediterranean basin. ² Because of the clinical pleomorphism depending particularly on the host immune response rather than on the parasite species, CL in immunosuppressed patients can be challenging to diagnose and can be easily misdiagnosed with inflammatory and malignant conditions, as well as with other infectious diseases. ^3,4 The therapeutic use of immunosuppressive drugs is one of the main risk factors for overt clinical disease. ⁵ Although effective for several immune-mediated conditions by blocking a pro-inflammatory cytokine involved in the host defense against granulomatous diseases, antitumor necrosis factor (TNF)-alpha drugs have been linked to a higher susceptibility for infections and an increased risk of reactivation of latent infections, including leishmaniasis, even several years after exposure to the parasite. ² Screening for the presence of Leishmania and tests to detect the cell-mediated immune response may be indicated for asymptomatic subjects in areas with endemic leishmaniasis before prescribing TNF inhibitors, especially for patients who need to be kept in an immunosuppressed state. ^6–8 Italian authors recently published the first survey on Leishmania subclinical infection in rheumatological patients receiving biological drugs, in an Italian region not traditionally considered endemic but now switched as focally endemic for visceral leishmaniasis. According to them, a screening with molecular methods and monitoring Leishmania DNA during such therapies would be mandatory to prevent delay in diagnosis. ⁹ However, there is controversy about their usefulness in such patients. Actually, the first asymptomatic Leishmania infection survey in inflammatory bowel disease (IBD) patients receiving biological drugs showed that the prevalence of Leishmania asymptomatic infection detected in our IBD cohort was similar to that found in healthy population in close endemic areas. ¹⁰ Moreover, a positive serology in endemic regions might not be enough to indicate a treatment.

Differently from Mycobacterium tuberculosis infection, current guidelines for anti–TNF-alpha therapy do not advise on preventing leishmaniasis. ⁸ To date, several cases of opportunistic leishmaniasis have been reported in patients treated with anti–TNF-alpha agents, mostly with infliximab and adalimumab, mainly between 1 and 3 years after the start of treatment. ^8,11 Data from a retrospective observational study including patients with confirmed leishmaniasis acquired in the Mediterranean basin that were under TNF-α blockers therapy at the moment of the diagnosis supported the assumption that the blockage of TNF-α causes atypical clinical expression of leishmaniasis in endemic population. ¹² In these patients also, histological diagnosis can be tricky: on the one hand, a small number of protozoa can induce atypical large and multifocal lesions; on the other, chronic ulcers have fewer amastigotes than newer ones; therefore, detecting amastigotes and peripheral nuclei within macrophages microscopically can be hard. Although obtaining multiple specimens from different lesions or different portions of the same lesion may increase detection sensitivity, the definitive diagnosis is often achieved through PCR of skin samples, serology testing, and response to treatment. ^4,8 In these cases, a systemic therapy and the discontinuation of the TNF-α blockers therapy until clinical resolution could be a proper treatment strategy. ¹²

In our patient, despite the misleading histological diagnosis, the failure to respond to well-known and effective treatment options such as intralesional triamcinolone, oral steroid therapy, and cyclosporine should have called the diagnosis into question. An altered host immune response caused by immunomodulant drugs and Leishmania parasites themselves may have played a role in both the persistence of the lesions and the development of an unusual type of CL, resembling PG. The choice of a systemic therapy for CL was made considering the patient’s immunosuppression and the presence of multiple large lesions with face involvement. Significantly, adalimumab and cyclosporine were discontinued after the diagnosis of leishmaniasis, without a relapse of Crohn’s disease.

With the widespread use of TNF-alpha blocking agents in countries with a high incidence of leishmaniasis, routine serological screening before prescribing anti–TNF-alpha therapy should be performed to detect a possible latent infection and prevent reactivation. Atypical CL should be ruled out in these patients in the case of unresponsive skin ulcerations. Early diagnosis requires increased awareness among physicians across various disciplines, and the wide availability of or access to accurate diagnostic tools.