FLI1 gene influences lesion size and skin test may predict therapeutic response in cutaneous leishmaniasis

Genes associated with wound healing have been shown to be risk factors for cutaneous leishmaniasis (CL) which is caused by Leishmania braziliensis. In this study, we examined whether the genes previously associated with CL influenced the clinical outcome. Patients were genotyped and retrospectively classified as responders, who were cured with a single course of pentavalent antimony (Sbv), or as refractories, who did not respond to Sbv. Patients characterised as responders showed a stronger response to the leishmanin skin test (LST) when compared to the refractory subjects (p = 0.0003). Furthermore, we observed an association between the FLI1 CC genotype and an increased size of ulcers (p = 0.0170). We suggest that the leishmanin skin test may be a predictive tool for therapeutic outcome and reinforce FLI1 as a potential influencer of susceptibility and lesion size in CL.

Tegumentary leishmaniasis mimicking visceralization in a cirrhotic patient: atypical cutaneous lesions and local immunological features

Abstract Tegumentary leishmaniasis (TL) diagnosis is challenging due to the lack of a gold standard diagnostic tool. The diagnosis is significantly harder in regions where visceral leishmaniasis (VL) is also prevalent since immunological tests may present cross-reactivity. A cirrhotic patient from an endemic Brazilian region for TL and VL presented with atypical cutaneous lesions, a usual clinico-laboratory feature of VL (including a positive rk39 test result), but he was diagnosed with TL histopathologically; VL was ruled out by necropsy. Physicians working in co-prevalent areas should be aware of atypical features, unusual clinical course, and unexpected laboratory findings of leishmaniasis.

American tegumentary leishmaniasis: severe side effects of pentavalent antimonial in a patient with chronic renal failure

Abstract: Pentavalent antimonials are the first-line drug treatment for American tegumentary leishmaniasis. We report on a patient with chronic renal failure on hemodialysis who presented with cutaneous lesions of leishmaniasis for four months. The patient was treated with intravenous meglumine under strict nephrological surveillance, but cardiotoxicity, acute pancreatitis, pancytopenia, and cardiogenic shock developed rapidly. Deficient renal clearance of meglumine antimoniate can result in severe toxicity, as observed in this case. These side effects are related to cumulative plasma levels of the drug. Therefore, second-line drugs like amphotericin B are a better choice for patients on dialysis.

Disseminated leishmaniasis: clinical, pathogenic, and therapeutic aspects

Abstract: Disseminated leishmaniasis is a severe and emerging form of American tegumentary leishmaniasis. Disseminated leishmaniasis is defined by the presence of more than 10 polymorphic cutaneous lesions, distributed over more than two noncontiguous parts of the body. Nasal mucosal involvement is observed in almost half of cases. Disseminated leishmaniasis patients present with a decreased production of Th1 cytokines in the peripheral blood due to the attraction of leishmania- activated T cells to the multiple cutaneous lesions. Disseminated leishmaniasis development is poorly understood and is related to a complex network involving environmental, host immune response, and parasite factors, in which L. braziliensis polymorphism plays an important role. Disseminated leishmaniasis is a challenging disease to cure, presenting a high failure rate of 75% to pentavalent antimony therapy. Despite its importance and severity, this form of American tegumentary leishmaniasis has been poorly studied and documented, deserving greater attention from professionals working in endemic areas.

Analysis of macrophage subtypes and annexin A1 expression in lesions of patients with cutaneous leishmaniasis

Abstract INTRODUCTION: Cutaneous leishmaniasis is caused by protozoa of the genus Leishmania and transmission occurs through the bite of sandflies. It is an infectious disease, which affects skin and mucosa. The aim was to quantify the macrophages M1 and M2 and the annexin A1 expression in the skin lesions of patients with cutaneous leishmaniasis. METHODS: Skin biopsies from patients (n = 50) were analyzed and classified according to the lesion type as: exudative cellular reaction, exudative granulomatous reaction, exudative necrotic reaction, exudative necrotic-granulomatous reaction. Using the immunofluorescence technique, macrophages were identified by CD163 marker, differentiated by anti-MHCII and anti-CD206 antibodies, and annexin A1 expression was determined by arbitrary unit (a.u.) densitometry. RESULTS: In M1 macrophages, a greater expression of this protein was observed in the exudative cellular reaction type lesions (136.3 ± 2.6 a.u., assuming mean and standard derivation) when compared to the expression in the lesions of exudative granulomatous reaction, exudative necrotic reaction and exudative necrotic-granulomatous reaction patients (108.0 ± 2.3, 121.6 ± 3.2 and 124.7 ± 2.4 a.u., respectively). Regarding M2 macrophages, it was observed that patients with exudative cellular reaction lesion also had a higher expression of this protein (128.8 ± 2.6 a.u.), when compared to the expression in the lesions of exudative granulomatous reaction, exudative necrotic reaction and exudative necrotic-granulomatous reaction patients (105.6 ± 2, 113.9 ± 2.8, 114.3 ± 2.1 a.u., respectively). CONCLUSIONS: These data suggest that annexin A1 is assisting macrophages in the phagocytosis process of patients with exudative cellular reaction lesion type.

Favorable responses to treatment with 5 mg Sbv/kg/day meglumine antimoniate in patients with American tegumentary leishmaniasis acquired in different Brazilian regions

Abstract INTRODUCTION: Favorable responses in American tegumentary leishmaniasis (ATL) patients to treatment with 5 mg Sbv/kg/day meglumine antimoniate (MA) has been reported in Rio de Janeiro, but little is known regarding the therapeutic response to low doses in patients from other locations. METHODS: A retrospective review of medical records was conducted to compare the therapeutic response to 5 mg Sbv/kg/day MA treatment among 36 patients who acquired ATL in Brazilian states other than Rio de Janeiro (OS group) and 72 patients from Rio de Janeiro (RJ group). RESULTS: One course of 5 mg Sbv/kg/day MA cured 72.8% of 81 cutaneous (CL) and 66.6% of 27 mucosal (ML) leishmaniasis-infected patients: 70% in the CL/RJ group, 81% in the CL/OS group, 50% in the ML/RJ group, and 80% in the ML/OS group. After up to two additional treatment courses at the same dose, 88.9% and 85.2% of the CL and ML patients were cured, respectively. Adverse events were observed in 40% of patients in the CL/RJ group, 57% of the CL/OS group, 58% of the ML/RJ group, and 80% of the ML/OS group. No significant differences were observed in the cure rates or adverse effects between the RJ and OS groups. No patients required permanent discontinuation of treatment due to adverse events. CONCLUSIONS: Patients with ATL acquired in both RJ and OS may respond to low-dose MA. While high-dose MA should remain the standard treatment for ATL, low-dose MA might be preferred when toxicity is a primary concern.

Predominance of Leishmania major and rare occurrence of Leishmania tropica with haplotype variability at the center of Iran

ABSTRACT Background Leishmania major is a causative agent of zoonotic cutaneous leishmaniasis in the center of Iran, Abarkouh district. Molecular characterization and precise incrimination of Leishmania species was carried out to perform controlling measurements and to design treatment programs for zoonotic cutaneous leishmaniasis. Methods All smears isolated from ulcers of suspected patients were examined under a light microscope and graded for amastigotes frequency. Extraction of DNA, PCR, RFLP and sequencing of ITS-rDNA genotype were done to increase the efficacy of Leishmania parasites identification at their species-specific level and to detect any Leishmania infections within. Results Humans were found to be infected with L. major with high infection frequency and also Leishmania tropica was identified with low occurrence for the first time as non-native species using molecular analyses. The rates of infections was considerable with microscopic observation (n= 65, 73%) out of 89 smears prepared from suspected patients. Molecular analyses showed that the density of L. major was significantly higher (n= 48, 53.93%) than L. tropica (n= 4, 4.49%) (Mann-Whitney U test: p< 0.05) and two samples (2.25%) remained ambiguous after several sequencing. L. major did not have diversity with two common haplotypes but L. tropica were found to exhibit high diversity with three novel haplotypes. Conclusion L. major was considered the causative agent of leishmaniasis in the region, but the identification of a non-native L. tropica revealed the importance of further isolation of Leishmania parasites following molecular analyses and confirmation, and also revealed the importance of further isolation of Leishmania parasites from patients of the field areas who do not have easily access to health care centers for specialized treatment strategies.

Treatment of cutaneous leishmaniasis with thermotherapy in Brazil: an efficacy and safety study

Abstract: BACKGROUND: Pentavalent antimonials remain as the standard drugs in the treatment of cutaneous leishmaniosis. The high cost, difficult administration, long treatment time, toxicity and increasing morbidity are factors that limit the use of these drugs. OBJECTIVES: To describe the response to radiofrequency thermotherapy in the treatment of localized cutaneous leishmaniasis in Brazil, and to evaluate its safety and tolerability. METHODS: We conducted a non-comparative open trial with a total of 15 patients confirmed to have cutaneous leishmaniasis on parasitological examination. A single radiofrequency thermotherapy session at 50ºC for 30 seconds was applied to the lesion and its edges. In patients with more than one lesion, only the largest one was treated initially. If after 30 days there was no evidence of healing, the smaller lesion was also treated with thermotherapy. Clinical cure was defined as visible healing for three months after treatment. The patients were followed-up for six months and there was no follow-up loss. RESULTS: Of all 23 lesions, only two evolved to complete healing without the need of treatment. Of 21 lesions, 18 (85.7%) achieved full healing. The main observed side effects were itching, burning sensation, pain and blisters. STUDY LIMITATIONS: Sample with a small number of patients and short follow-up. CONCLUSION: Thermotherapy can be considered a therapeutic alternative in localized cutaneous leishmaniasis, especially in cases of single cutaneous lesions and with formal contraindications to conventional treatment with pentavalent antimonials.

Dermatoscopic signs in cutaneous leishmaniasis

Abstract: Dermoscopy is a non-invasive technique widely used to aid in the characterization and diagnosis of pigmented skin lesions. Recently, it has also been employed for the evaluation of non-pigmented skin tumours, and inflammatory and infectious cutaneous diseases. Although the diagnosis of cutaneous leishmaniasis is confirmed by the demonstration of amastigotes in infected skin or by the growth of promastigotes in culture medium, dermoscopy could be useful as a further diagnostic test. We report a patient with a nodular lesion located on the right cheek for almost two years. The lesion was clinically suggestive of cutaneous leishmaniasis. Dermoscopy showed yellow tears, erythema and vascular structures. The diagnosis was confirmed by the demonstration of amastigotes in a skin scraping sample.

Cytotoxic activity in cutaneous leishmaniasis

Cutaneous leishmaniasis (CL) is a chronic disease caused by species of the protozoan Leishmania and characterised by the presence of ulcerated skin lesions. Both parasite and host factors affect the clinical presentation of the disease. The development of skin ulcers in CL is associated with an inflammatory response mediated by cells that control parasite growth but also contribute to pathogenesis. CD8+ T cells contribute to deleterious inflammatory responses in patients with CL through cytotoxic mechanisms. In addition, natural killer cells also limit Leishmania infections by production of interferon-γ and cytotoxicity. In this review, we focus on studies of cytotoxicity in CL and its contribution to the pathogenesis of this disease.

Final diagnosis of 86 cases included in differential diagnosis of American tegumentary leishmaniasis in a Brazilian sample: a retrospective cross-sectional study

Abstract: Background: Cutaneous leishmaniasis is distributed worldwide, including Brazil. Its several clinical forms need to be distinguished from other dermatoses. Clinical similarities and lack of a gold standard diagnostic tool make leishmaniasis-like lesions a challenging diagnosis. Objectives. To report the final diagnosis of patients primarily suspected of having American tegumentary leishmaniasis (ATL). Methods. A retrospective cross-sectional study was conducted on the basis of medical records of 437 patients with clinical suspicion of ATL, registered in electronic hospital system between 1980 and 2013. Demographic, clinical, and laboratory data were compiled. Results. Analysis of 86 cases (19.7%) registered as ATL in one of the hypothesis revealed a different final diagnosis; 55 (63.9%) and 31 cases (36.1%) had skin and mucosal lesions, respectively. In 58 cases (67.4%), the requested PCR did not identify Leishmania sp. In 28 cases (32.5%), biopsies established the diagnosis and confirmed tumors, mycobacteriosis, and subcutaneous or systemic mycosis. Overall, 27% of the cases had inflammatory etiology, mainly nasal nonspecific inflammatory processes; 27% had infectious etiology, especially paracoccidioidomycosis and leprosy; 20% had neoplastic etiology, mainly basal and squamous cell carcinoma; 15% had miscellaneous etiology, including neuropathic ulcer, traumatic ulcers, idiopathic ulcer; 11% missed the follow-up. Study limitations: Some cases had no final diagnosis due to loss of follow-up. Conclusion. ATL can be confused with several differential diagnoses, especially inflammatory and infectious granulomatous diseases as well as non-melanoma skin cancers. Clinicians working in tropical areas should be aware of the main differential diagnosis of leishmaniasis-like lesions.

Periungual tegumentary leishmaniasis: a diagnostic challenge

Abstract: Periungual and paronychia-like skin lesions can mimic various diseases, setting up a diagnostic challenge that invariably requires correlation with complementary tests. We report a case of an ulcerated tumor of the nailfold diagnosed as leishmaniasis. Although paronychia-like cutaneous leishmaniasis is a rare variant, its epidemiological relevance in Brazil should prompt dermatologists to include it as a plausible diagnosis thus leading to correct work up and treatment.

White starburst-like pattern as a dermoscopic clue in Old World cutaneous leishmaniasis

Abstract: A 70-year-old woman was referred to our dermatological unit by her general practitioner last summer, with a history of a two-month ulcerated purplish lesion on her left arm that spread centrifugally and that unsuccessfully treated with topical corticosteroids. The dermoscopic evaluation revealed an erythematous macula with central ulceration that showed the characteristic called "white starburst-like pattern" and some vascular structures (dotted vessels, polymorphous⁄ atypical vessels). The diagnosis of cutaneous leishmaniasis was made after histopathologic analysis and polymerase chain reaction essay.

N-acetyl-cysteine inhibits liver oxidative stress markers in BALB/c mice infected with Leishmania amazonensis

BACKGROUND Leishmaniasis is a parasitosis caused by several species of the genus Leishmania. These parasites present high resistance against oxidative stress generated by inflammatory cells. OBJECTIVES To investigate oxidative stress and molecular inflammatory markers in BALB/c mice infected with L. amazonensis and the effect of antioxidant treatment on these parameters. METHODS Four months after infection, oxidative and inflammatory parameters of liver, kidneys, spleen, heart and lungs from BALB/c mice were assessed. FINDINGS In liver, L. amazonensis caused thiol oxidation and nitrotyrosine formation; SOD activity and SOD2 protein content were increased while SOD1 protein content decreased. The content of the cytokines IL-1β, IL-6, TNF-α, and the receptor of advanced glycation endproducts (RAGE) increased in liver. Treatment with the antioxidant N-acetyl-cysteine (20 mg/kg b.w) for five days inhibited oxidative stress parameters. MAIN CONCLUSIONS L. amazonensis induces significant alterations in the redox status of liver but not in other organs. Acute antioxidant treatment alleviates oxidative stress in liver, but it had no effect on pro-inflammatory markers. These results indicate that the pathobiology of leishmaniasis is not restricted to the cutaneous manifestations and open perspectives for the development of new therapeutic approaches to the disease, especially for liver function.

Sporotrichoid leishmaniasis: a cross-sectional clinical, epidemiological and laboratory study in Rio de Janeiro State, Brazil

ABSTRACT Background Atypical presentations of cutaneous leishmaniasis include sporotrichoid leishmaniasis (SL), which is clinically described as a primary ulcer combined with lymphangitis and nodules and/or ulcerated lesions along its pathway. Aims To assess the differences between patients with sporotrichoid leishmaniasis and typical cutaneous leishmaniasis (CL). Methods From January 2004 to December 2010, 23 cases of SL (4.7%) were detected among 494 CL patients diagnosed at a reference center for the disease in Rio de Janeiro State, Brazil. These 23 cases were compared with the remaining 471 patients presenting CL. Results SL predominated in female patients (60.9%, p = 0.024), with older age (p = 0.032) and with lesions in upper limbs (52.2%, p = 0.028). CL affected more men (64.5%), at younger age, and with a higher number of lesions exclusively in lower limbs (34.8%). Conclusions Differences in clinical and epidemiological presentation were found between SL patients as compared to CL ones, in a region with a known predominance of Leishmania (Viannia) braziliensis. The results are similar to the features of most of the sporotrichosis patients as described in literature, making the differential diagnosis between ATL and sporotrichosis more important in overlapping areas for both diseases, like in Rio de Janeiro State.

Intralesional meglumine antimoniate for the treatment of localised cutaneous leishmaniasis: a retrospective review of a Brazilian referral centre

Although intralesional meglumine antimoniate (MA) infiltration is considered an option for cutaneous leishmaniasis (CL) therapy and is widely used in the Old World, there have been few studies supporting this therapeutic approach in the Americas. This study aims to describe outcomes and adverse events associated with intralesional therapy for CL. This retrospective study reviewed the experience of a Brazilian leishmaniasis reference centre using intralesional MA to treat 31 patients over five years (2008 and 2013). The median age was 63 years (22-86) and the median duration time of the lesions up to treatment was 16 weeks. In 22 patients (71%), intralesional therapy was indicated due to the presence of contraindications or previous serious adverse events with systemic MA. Other indications were failure of systemic therapy or ease of administration. Intralesional treatment consisted of one-six infiltrations (median three) for a period of up to 12 weeks. The initial (three months) and definitive (six months) cure rates were 70.9% and 67.7%, respectively. Most patients reported mild discomfort during infiltration and no serious adverse events were observed. In conclusion, these results show that the intralesional MA efficacy rate was very similar to that of systemic MA treatment, and reinforce the need for further studies with adequate design to establish the efficacy and safety of this therapeutic approach.