Mucosal leishmaniasis of the lips and cheeks: a first concomitant presentation of visceral and mucosal leishmaniasis in a patient living with HIV/AIDS in Monastir, Tunisia.

BACKGROUND: Visceral Leishmaniasis (VL) is the most severe and fatal disease if left untreated. In people living with HIV/AIDS (PLHA), VL is considered an emerging opportunistic infection. The aim of this manuscript was to report a first case in Tunisia of a concomitant presentation of visceral and oral leishmaniasis in a patient LHA. A systematic review of the literature was performed according to PRISMA guidelines, as well. CASE PRESENTATION: The patient, a 43-year-old heterosexual man, treated for HIV/AIDS was referred for macrocheilitis of the upper and lower lips. A noticeable nodular and painless swelling extending to the cheeks' mucosa was noted. The patient's poor oral hygiene was evident due to the presence of multiple dental caries. Histological analysis of the biopsied lower lip sample revealed the presence of numerous Leishmania amastigotes. The diagnosis of VL was clinically confirmed by the presence of a mild splenomegaly and pancytopenia and biologically by the identification of the parasite using PCR Lei and the species L. infantum involved using RFLP-PCR and culture. The treatment consisted of an intravenous administration of liposomal Amphotericin B (Ambisome®, 40 mg/kg/weight) for a period of 6 weeks. A favorable outcome was noted after one year with the resolution of clinical symptoms and a negative Leishmania blood PCR test. After 2 years, the patient remained asymptomatic but showed a positive Leishmania blood PCR test. Dolutegravir® was introduced in the patient's ART regimen. CONCLUSIONS: To the best of our knowledge, this is the first case report in Tunisia of atypical VL diagnosed through an uncommon oral location in an HIV/AIDS co-infected patient . Since VL is a severe and potentially fatal disease, it is essential for dentists to perform a thorough clinical examination and adopt a multidisciplinary approach in order to ensure an early diagnosis and an effective treatment outcome.

Treatment of mucocutaneous leishmaniasis - A systematic review.

Mucocutaneous leishmaniasis is a severe infectious disease, predominantly endemic in Central and South America and is characterized by granulomatous, destructive mucosal lesions in the oral, nasal, and pharyngeal cavities. It is caused by protozoa of the genus Leishmania spp. transmitted to humans by sandflies. Mucocutaneous leishmaniasis occurs after untreated or inadequately treated cutaneous leishmaniasis and is more common in immunocompromised patients. The aim of this systematic review is to summarize all reported treatment options for mucocutaneous leishmaniasis. This review is based on all English, German, French, Spanish and Portuguese articles published in the databases "PubMed" and "Lilacs" from 1995 to 2020. Most of the medical literature is limited to case reports, small case series, retrospective studies, and a few randomized controlled trials. Various treatment options include pentavalent antimonates such as meglumine antimonate or sodium stibogluconate, amphotericin B (liposomal, deoxycholate, lipid complex, colloidal dispersion), miltefosine, and pentamidine. Other therapeutic options include itraconazole, fluconazole, ketoconazole, aminosidine sulfate, and azithromycin. The choice of drug depends primarily on its availability in the endemic area and the patient's comorbidities.

Clinicopathological characteristics of cutaneous and mucocutaneous leishmaniasis in patients treated with TNF-α inhibitors.

BACKGROUND AND OBJECTIVES: The increasing use of biologics in the treatment of inflammatory diseases has led to more cases of leishmaniasis in patients subjected to iatrogenic immunosuppression. The main objective was to describe the characteristics of the patients with cutaneous (CL) or mucocutaneous (MCL) leishmaniasis who were receiving a biological therapy at the time of diagnosis. PATIENTS AND METHODS: A multicenter retrospective study was design based on a cohort of patients diagnosed with CL or MCL. All patients who were being treated with biologicals were included. For each case, two matched non-exposed patients were included for comparison. RESULTS: 38 patients were diagnosed with CL or MCL while being treated with tumor necrosis factor alpha (TNF-α) inhibitors. Leishmaniasis presented more frequently as a plaque (58.3%) with a larger median lesion size (2.5 cm), ulceration (92.1%), and required a greater median number of intralesional meglumine antimoniate infiltrations (3 doses) (P < 0.05) than in non-exposed patients. We found no systemic involvement in patients being treated with anti-TNF-α. We did not find differences regarding the treatment characteristics whether biologic therapy was modified or not. CONCLUSIONS: Although management should be individualized, maintenance of biologic therapy does not seem to interfere with treatment of CL or MCL.

A trespasser from a foreign land? A case report of primary mucosal leishmaniasis.

BACKGROUND: We report a clinically challenging and unusual case of L. donovani oral mucosal leishmaniasis. CASE PRESENTATION: Israeli resident with a former travel to central and North Africa, with no documented or prior cutaneous lesions presented with oral lesions of the maxillary gingiva and the upper lip. A delay in diagnosis and treatment have led to progression of the maxillary gingival lesions towards the hard palatal and the soft palate that could have potentially compromised the upper airway. CONCLUSIONS: This case highlights the importance of early diagnosis of leishmaniasis in patients with oral lesions and the laboratory workup necessary to appropriately characterize and treat the disease.

Tilting the balance between RNA interference and replication eradicates Leishmania RNA virus 1 and mitigates the inflammatory response.

Many Leishmania (Viannia) parasites harbor the double-stranded RNA virus Leishmania RNA virus 1 (LRV1), which has been associated with increased disease severity in animal models and humans and with drug treatment failures in humans. Remarkably, LRV1 survives in the presence of an active RNAi pathway, which in many organisms controls RNA viruses. We found significant levels (0.4 to 2.5%) of small RNAs derived from LRV1 in both Leishmania braziliensis and Leishmania guyanensis, mapping across both strands and with properties consistent with Dicer-mediated cleavage of the dsRNA genome. LRV1 lacks cis- or trans-acting RNAi inhibitory activities, suggesting that virus retention must be maintained by a balance between RNAi activity and LRV1 replication. To tilt this balance toward elimination, we targeted LRV1 using long-hairpin/stem-loop constructs similar to those effective against chromosomal genes. LRV1 was completely eliminated, at high efficiency, accompanied by a massive overproduction of LRV1-specific siRNAs, representing as much as 87% of the total. For both L. braziliensis and L. guyanensis, RNAi-derived LRV1-negative lines were no longer able to induce a Toll-like receptor 3-dependent hyperinflammatory cytokine response in infected macrophages. We demonstrate in vitro a role for LRV1 in virulence of L. braziliensis, the Leishmania species responsible for the vast majority of mucocutaneous leishmaniasis cases. These findings establish a targeted method for elimination of LRV1, and potentially of other Leishmania viruses, which will facilitate mechanistic dissection of the role of LRV1-mediated virulence. Moreover, our data establish a third paradigm for RNAi-viral relationships in evolution: one of balance rather than elimination.

In vitro activity of new N-benzyl-1H-benzimidazol-2-amine derivatives against cutaneous, mucocutaneous and visceral Leishmania species.

The identification of specific therapeutic targets and the development of new drugs against leishmaniasis are urgently needed, since chemotherapy currently available for its treatment has several problems including many adverse side effects. In an effort to develop new antileishmanial drugs, in the present study a series of 28 N-benzyl-1H-benzimidazol-2-amine derivatives was synthesized and evaluated in vitro against Leishmania mexicana promastigotes. Compounds 7 and 8 with the highest antileishmanial activity (micromolar) and lower cytotoxicity than miltefosine and amphotericin B were selected to evaluate their activity against L. braziliensis 9and L. donovani, species causative of mucocutaneous and visceral leishmaniasis, respectively. Compound 7 showed significantly higher activity against L. braziliensis promastigotes than compound 8 and slightly lower than miltefosine. Compounds 7 and 8 had IC50 values in the micromolar range against the amastigote of L. mexicana and L. braziliensis. However, both compounds did not show better activity against L. donovani than miltefosine. Compound 8 showed the highest SI against both parasite stages of L. mexicana. In addition, compound 8 inhibited 68.27% the activity of recombinant L. mexicana arginase (LmARG), a therapeutic target for the treatment of leishmaniasis. Docking studies were also performed in order to establish the possible mechanism of action by which this compound exerts its inhibitory effect. Compound 8 shows promising potential for the development of more potent antileishmanial benzimidazole derivatives.

Cost-effectiveness of liposomal amphotericin B in hospitalised patients with mucocutaneous leishmaniasis.

OBJECTIVE: To compare the cost-effectiveness of L-AmB with that of SbV and AmB-D, for the treatment of mucocutaneous leishmaniasis in a hospital in north-east Brazil. METHODS: We developed an economic model based on retrospective data of 73 hospitalised patients in 2006-2012, from hospital and public health system perspectives. RESULTS: In the economic model, 82.2% of patients who started treatment with L-AmB had completed it after 2 months, vs. 22.0% for the SbV and 19.9% for the AmB-D groups. After 12 months of follow-up, these proportions were 100% in the L-AmB, 77.4% in the AmB-D and 72.2% in the SbV group. Markov chain analyses showed that the group that started therapy with SbV had the lowest mean total cost (US$ 3782.38), followed by AmB-D (US$ 5211.27) and L-AmB (US$ 11 337.44). The incremental cost-effectiveness ratio for L-AmB was US$ 18 816.23 against SbV and US$ 24 504.65 against AmB-D. In the sensitivity analysis, the drug acquisition cost of L-AmB significantly influenced the results. CONCLUSIONS: In the treatment of mucocutaneous leishmaniasis, L-AmB is a cost-effective alternative to SbV and AmB-D owing to its higher effectiveness, safety and shorter course.

AIM2 inflammasome is associated with disease severity in tegumentary leishmaniasis caused by Leishmania (V.) braziliensis.

The inflammasome is a multiprotein signalling platform involved in the pathogenesis of various inflammatory skin diseases. Herein, we investigated gene and protein expression of the inflammasome molecules AIM2 and NLRP3 in active lesions from patients with L. (V.) braziliensis-associated tegumentary leishmaniasis (TL) and correlated these findings with the clinical presentations and responses to therapy. Real-time PCR assays showed a significantly higher AIM2 gene expression in mucosal leishmaniasis (ML) compared with that in cutaneous leishmaniasis (CL). Additionally, AIM2 mRNA expression was significantly higher in lesions from poor responders than in lesions from good responders. In situ protein quantification analyses revealed greater AIM2 expression in ML lesions than in CL lesions. The percentage of AIM2-producing cells was higher in poor responders than in good responders. Although not quite significant, IL-1ß+ cells were slightly more prominent in poor responders than in good responders. Similar results were observed when patients were evaluated according to clinical form. GP63 immunostaining was identified in all samples, but no significant variation between mucosal and cutaneous lesions was observed. GP63 could be associated with reduced NLRP3 inflammasome expression in CL and ML patients. Taken together, these data demonstrate that AIM2 is an important component of the inflammasome in TL patients and is directly associated with the severity of lesions.

Lip leishmaniasis: a case series with molecular identification and literature review.

BACKGROUND: Mucocutaneous leishmaniasis (MCL), a protozoan infectious disease, is very rare in Iran despite the endemicity of both cutaneous and visceral forms. It is transmitted by the Phlebotomus sand fly. The lip is considered one of the extraordinary sites. Lesions usually initiate with erythematous papules, slowly enlarges and then it ulcerates. The diagnosis of MCL encompasses epidemiological, clinical and laboratory aspects. Usually, the combination of some of these elements is necessary for the final diagnosis. So, lip leishmaniasis lesions can be challenging to diagnose. CASE PRESENTATION: We presented seven rare cases of lip leishmaniasis. Tissue impression smear, culture, PCR and phylogenetic analysis were carried out for explicit diagnosis. Skin scraping investigation showed several Leishmania spp. amastigotes in the cytoplasm of macrophages. Culture examination was positive for Leishmania spp. PCR was positive for L. major, L. tropica, and L. infantum. Differential diagnosis includes orofacial granulomatosis, basal cell carcinoma, squamous cell carcinoma, and mesenchymal tumors. The cases were treated with systemic meglumine antimoniate (Glucantime®). No relapses were observed during 1 year of follow-up. Early detection of the infection are necessary in order to start effective treatment and prevent more serious complications. CONCLUSIONS: In this paper, we reported seven rare cases of lip leishmaniasis in Iran, emphasized the importance of clinical and diagnostic features of lesions, characterized the phylogenetic kinship of isolated parasites, and reviewed the literature on lip leishmaniasis.

Nerolidol, the main constituent of Piper aduncum essential oil, has anti-Leishmania braziliensis activity.

Leishmania (Viannia) braziliensis is a protozoan that causes mucocutaneous leishmaniasis, which is an infectious disease that affects more than 12 million people worldwide. The available treatment is limited, has side-effects or is inefficient. In a search for alternative compounds of natural origin, we tested the microbicidal activity of Piper aduncum essential oil (PaEO) on this parasite. Our data showed that PaEO had an inhibitory effect on the growth of L. braziliensis promastigotes with an IC50/24 h=77·9 µg mL-1. The main constituent (nerolidol: 25·22%) presented a similar inhibitory effect (IC50/24 h = 74·3 µg mL-1). Ultrastructural observation of nerolidol-treated parasites by scanning and transmission electron microscopies revealed cell shrinkage and morphological alterations in the mitochondrion, nuclear chromatin and flagellar pocket. Flow cytometry analysis showed a reduction in the cell size, loss of mitochondrial membrane potential, phosphatidylserine exposure and DNA degradation, which when associated with the morphological changes indicated that nerolidol induced incidental cell death in the L. braziliensis promastigotes. The results presented here indicate that nerolidol derivatives are promising compounds for further evaluation against Leishmania parasites.

Ornithine decarboxylase or gamma-glutamylcysteine synthetase overexpression protects Leishmania (Vianna) guyanensis against antimony.

Trypanosomatids present a unique mechanism for detoxification of peroxides that is dependent on trypanothione (bisglutathionylspermidine). Ornithine decarboxylase (ODC) and γ-glutamylcysteine synthetase (GSH1) produce molecules that are direct precursors of trypanothione. In this study, Leishmania guyanensis odc and gsh1 overexpressor cell lines were generated to investigate the contribution of these genes to the trivalent antimony (SbIII)-resistance phenotype. The ODC- or GSH1-overexpressors parasites presented an increase of two and four-fold in SbIII-resistance index, respectively, when compared with the wild-type line. Pharmacological inhibition of ODC and GSH1 with the specific inhibitors α-difluoromethylornithine (DFMO) and buthionine sulfoximine (BSO), respectively, increased the antileishmanial effect of SbIII in all cell lines. However, the ODC- and GSH1-overexpressor were still more resistant to SbIII than the parental cell line. Together, our data shows that modulation of ODC and GSH1 levels and activity is sufficient to affect L. guyanensis susceptibility to SbIII, and confirms a role of these genes in the SbIII-resistance phenotype.

Association of the Endobiont Double-Stranded RNA Virus LRV1 With Treatment Failure for Human Leishmaniasis Caused by Leishmania braziliensis in Peru and Bolivia.

Cutaneous and mucosal leishmaniasis, caused in South America by Leishmania braziliensis, is difficult to cure by chemotherapy (primarily pentavalent antimonials [Sb(V)]). Treatment failure does not correlate well with resistance in vitro, and the factors responsible for treatment failure in patients are not well understood. Many isolates of L. braziliensis (>25%) contain a double-stranded RNA virus named Leishmaniavirus 1 (LRV1), which has also been reported in Leishmania guyanensis, for which an association with increased pathology, metastasis, and parasite replication was found in murine models. Here we probed the relationship of LRV1 to drug treatment success and disease in 97 L. braziliensis-infected patients from Peru and Bolivia. In vitro cultures were established, parasites were typed as L. braziliensis, and the presence of LRV1 was determined by reverse transcription-polymerase chain reaction, followed by sequence analysis. LRV1 was associated significantly with an increased risk of treatment failure (odds ratio, 3.99; P = .04). There was no significant association with intrinsic Sb(V) resistance among parasites, suggesting that treatment failure arises from LRV1-mediated effects on host metabolism and/or parasite survival. The association of LRV1 with clinical drug treatment failure could serve to guide more-effective treatment of tegumentary disease caused by L. braziliensis.

Differential Expression of the Eicosanoid Pathway in Patients With Localized or Mucosal Cutaneous Leishmaniasis.

Unfettered inflammation is thought to play critical role in the development of different clinical forms of tegumentary leishmaniasis. Eicosanoids are potent mediators of inflammation and tightly associated with modulation of immune responses. In this cross-sectional exploratory study, we addressed whether targets from the eicosanoid biosynthetic pathway, assessed by multiplexed expression assays in lesion biopsy and plasma specimens, could highlight a distinct biosignature in patients with mucocutaneous leishmaniasis (MCL) or localized cutaneous leishmaniasis (LCL). Differences in immunopathogenesis between MCL and LCL may result from an imbalance between prostaglandins and leukotrienes, which may serve as targets for future host-directed therapies.

Presence of Leishmania RNA Virus 1 in Leishmania guyanensis Increases the Risk of First-Line Treatment Failure and Symptomatic Relapse.

Treatment failure and symptomatic relapse are major concerns in American tegumentary leishmaniasis (TL). Such complications are seen frequently in Leishmania guyanensis infections, in which patients respond variously to first-line antileishmanials and are more prone to develop chronic cutaneous leishmaniasis. The factors underlying this pathology, however, are unknown. Recently, we reported that a double-stranded RNA virus, Leishmania RNA virus 1 (LRV1), nested within L. guyanensis parasites is able to exacerbate experimental murine leishmaniasis by inducing a hyperinflammatory response. This report investigates the prevalence of LRV1 in human L. guyanensis infection and its effect on treatment efficacy, as well as its correlation to symptomatic relapses after the completion of first-line treatment. In our cohort of 75 patients with a diagnosis of primary localized American TL, the prevalence of LRV1-positive L. guyanensis infection was elevated to 58%. All patients infected with LRV1-negative L. guyanensis were cured after 1 dose (22 of 31 [71%]) or 2 doses (31 of 31 [100%]) of pentamidine. In contrast, 12 of 44 LRV1-positive patients (27%) presented with persistent infection and symptomatic relapse that required extended therapy and the use of second-line drugs. Finally, LRV1 presence was associated with a significant increase in levels of intra-lesional inflammatory markers. In conclusion, LRV1 status in L. guyanensis infection is significantly predictive (P = .0009) of first-line treatment failure and symptomatic relapse and has the potential to guide therapeutic choices in American TL.

Miltefosine for visceral and cutaneous leishmaniasis: drug characteristics and evidence-based treatment recommendations.

Miltefosine is the only recognized oral agent with potential to treat leishmaniasis. Miltefosine had demonstrated very good cure rates for visceral leishmaniasis (VL) in India, Nepal, and Bangladesh, but high rates of clinical failures have been recently reported. Moderate efficacy has been observed for VL in East Africa, whereas data from Mediterranean countries and Latin America are scarce. Results have not been very promising for patients coinfected with VL and human immunodeficiency virus. However, miltefosine's long half-life and its oral administration could make it a good option for maintenance prophylaxis. Good evidence of efficacy has been documented in Old World cutaneous leishmaniasis (CL), and different cure rates among New World CL have been obtained depending on the geographical areas and species involved. Appropriate regimens for New World mucocutaneous leishmaniasis need to be established, although longer treatment duration seems to confer better results. Strategies to prevent the development and spread of miltefosine resistance are urgently needed.

Cutaneous and mucocutaneous leishmaniasis: Clinical perspectives.

Leishmaniasis is endemic in 98 countries and territories, with 1.2 million new cases per year, making it a worldwide concern. The deadly visceral form is a leading cause of death from tropical parasitic infections, second only to malaria. Leishmaniasis appears to be increasing in many countries because of extended urbanization. The disease reservoir includes small mammals; parasite transmission occurs via bite of the female phlebotomine sandfly. Disease manifestations vary and largely depend upon the Leishmania species acquired. It may be first evident with a range of findings-from a localized cutaneous ulcer to diffuse painless dermal nodules-or, in the mucocutaneous form, ulceration of the oropharynx. In the potentially deadly visceral form, the internal organs and bone marrow are affected.

Cutaneous and mucocutaneous leishmaniasis: Differential diagnosis, diagnosis, histopathology, and management.

The diagnosis of leishmaniasis can be challenging because it mimics both infectious and malignant conditions. A misdiagnosis may lead to an unfavorable outcome. Using culture, histologic, and/or polymerase chain reaction study results, a diagnosis of leishmaniasis can be established and treatment initiated. Appropriate management requires an accurate diagnosis, which often includes identification of the specific etiologic species. Different endemic areas have varying sensitivities to the same medication, even within individual species. Species identification may be of practical value, because infections with select species have a substantial risk of visceral involvement. In addition, HIV and otherwise immunocompromised patients with leishmaniasis have a propensity for diffuse cutaneous leishmaniasis. For most New World Leishmania species, parenteral antimonial drugs remain the first line of therapy, while Old World species are easily treated with physical modalities. Historically, live organism vaccination has been used and is effective in preventing leishmaniasis, but results in an inoculation scar and an incubation period that may last for years. A more effective method of vaccination would be welcome.