Cost-effectiveness study of therapeutic approaches for mucosal leishmaniasis.

This study aimed to estimate the cost-effectiveness of four therapeutic approaches available for mucosal leishmaniasis in Brazil: miltefosine, meglumine antimoniate, combined with and without pentoxifylline, and liposomal amphotericin B. The perspective adopted was that of the Brazilian Unified National Health System (SUS). The outcome of interest was "cured patient", which was analyzed using a decision tree model. Estimates of direct costs and effectiveness were obtained from the scientific literature. Meglumine antimoniate alone was the base comparator strategy; liposomal amphotericin B showed an incremental cost-effectiveness ratio (ICER) of USD 7,409.13 per cured patient, and the combination of meglumine antimoniate with pentoxifylline presented an ICER of USD 85.13. Miltefosine was absolutely dominated, with higher cost and similar effectiveness when compared to meglumine antimoniate. Sensitivity analyses, varying the cost by ±25%, did not change the results. However, when the cost of miltefosine was estimated at less than USD 171.23, this strategy was dominant over meglumine antimoniate alone. The results confirm that treatment with liposomal amphotericin B remains the option with the highest ICER among the approaches analyzed. Miltefosine may be cost-effective based on the variation in the acquisition price, which deserves attention because it is the only available oral option. The non-accounting of other aspects prevent the use of these results immediately to support decision-making, but they point out the need to negotiate the prices of drugs available for mucosal leishmaniasis and indicates the need of encouraging technology transfer or other actions aimed at expanding the performance of the Brazilian national industrial complex.

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.

Mucosal Leishmaniasis of the lip: Report of an Exuberant case in a Young man.

BACKGROUND: Leishmaniasis is a tropical disease caused by protozoan parasites of the genus Leishmania. Mucosal leishmaniasis has been described as secondary to the cutaneous form; however, isolated mucosal involvement can also occur. Specifically, mucosal leishmaniasis of the lip is poorly described and its diagnosis challenges clinicians. METHODS: We herein report a case of mucosal leishmaniasis affecting the lower lip without cutaneous involvement in a 20-year-old Venezuelan man. The patient had no relevant past medical history. Clinically, a mass-like lesion with ulcerations and crusts was observed. RESULTS: Microscopically, the lesion was composed of granulomatous inflammation along with macrophages containing intracytoplasmic inclusions similar to round-shaped Leishmania. The species Leishmania (Viannia) braziliensis was confirmed. Treatment with meglumine antimonate was effective. The lesion healed satisfactorily, and no side effects or recurrences were observed. CONCLUSION: Clinicians should be aware of isolated forms of mucosal leishmaniasis of the lip, even in cases where the cutaneous lesion is undetected or clinically manifests as self-limiting. Knowing the endemic areas in the scenario of the dynamics of the ecoepidemiology of leishmaniasis is also essential for surveillance and counselling of the population.

Directrices para el tratamiento de las leishmaniasis en la región de las américas - 2 ed / Guidelines for the treatment of leishmaniasis in the region of the Americas - 2 ed

Las leishmaniasis son enfermedades infecciosas desatendidas de gran importancia en la Región de las Américas debido a su morbilidad, mortalidad y amplia distribución geográfica. De las tres formas clínicas principales, la cutánea es la más común y la visceral es la forma más grave, ya que puede causar la muerte de hasta 90% de las personas que no reciban tratamiento. En el 2013, la Organización Panamericana de la Salud (OPS) elaboró recomendaciones para el tratamiento de las leishmaniasis en la Región de las Américas utilizando la metodología de clasificación de la valoración, la elaboración y la evaluación de las recomendaciones (GRADE, por su sigla en inglés). No obstante, dada la evidencia acumulada desde entonces, se hizo necesario revisar esas recomendaciones. En esta segunda edición se presentan las recomendaciones actualizadas sobre el tratamiento de las leishmaniasis, y se detallan los esquemas y los criterios de indicación del tratamiento en el contexto regional. Estas directrices presentan modificaciones sustanciales con respecto a la primera edición. En el caso de la leishmaniasis cutánea, se ha eliminado el ketoconazol de las opciones terapéuticas, el número de especies de Leishmania para las que hay evidencia sólida de la eficacia de la miltefosina ha aumentado de dos a cuatro y la recomendación de administrar antimoniales intralesionales ahora es fuerte. Con respecto a la leishmaniasis mucosa, se incluye una recomendación fuerte sobre el uso de antimoniales pentavalentes con o sin pentoxifilina oral. Por lo que respecta a la leishmaniasis visceral, la recomendación fuerte sobre el uso de antimoniales pentavalentes y desoxicolato de anfotericina B ahora es condicional. También hay evidencia contundente en contra del uso de miltefosina en pacientes con leishmaniasis causada por Leishmania infantum. Otros cambios importantes son el desglose de las recomendaciones según si se trata de pacientes adultos o pediátricos, la inclusión de las especies de Leishmania y, en el caso de los pacientes inmunocomprometidos, la introducción de una recomendación fuerte contra el uso de antimoniales pentavalentes. Esta segunda edición es una versión revisada de la publicación Leishmaniasis en las Américas: recomendaciones para el tratamiento: https://iris.paho.org/handle/10665.2/7704

Estimating direct costs of the treatment for mucosal leishmaniasis in Brazil

Abstract INTRODUCTION: The objective of this study was to estimate the direct medical costs of the treatment for mucosal leishmaniasis (ML) using three therapeutic approaches in the Brazilian context. METHODS: We performed this economic assessment from the perspective of the Brazilian public healthcare system. The following therapeutic approaches were evaluated: meglumine antimoniate, liposomal amphotericin B, and miltefosine. Direct medical costs were estimated considering four treatment components: a) drug, b) combined medical products, c) procedures, and d) complementary tests. RESULTS: Treatment with meglumine antimoniate had the lowest average cost per patient (US$ 167.66), followed by miltefosine (US$ 259.92) in the outpatient treatment regimen. The average cost of treatment with liposomal amphotericin B was US$ 715.35 both in inpatient regimen. In all estimates, the drugs accounted for more than 60% of the total cost for each treatment approach. CONCLUSIONS: These results demonstrate the marked differences in costs between the therapeutic alternatives for ML. In addition to efficacy rates and costs related to adverse events, our data have the potential to support a complete cost-effectiveness study in the future. Complete analyses comparing costs and benefits for interventions will assist health managers in choosing drugs for ML treatment in Brazil as well as in establishing effective public health policies.

Leishmania donovani mucosal leishmaniasis in Malta.

We report a case of a 76-year-old British man living in Malta who presented with a 7-month history of recurrent epistaxis and an enlarging right nasal vestibular lesion. Of note, his medical history included rheumatoid arthritis for which he was on long-term methotrexate. Blood results were unremarkable other than a mild lymphopaenia. Despite the use of various antibiotics and intranasal steroids, the lesion failed to resolve. This was eventually biopsied, and the histological picture was that of mucosal leishmaniasis. Leishmania donovani complex was detected by PCR. The patient was treated with liposomal amphotericin B on alternate days for a total of 20 doses. The lesion was found to have healed well at follow-up and the patient denied any further episodes of epistaxis.

Mucocutaneous leishmaniasis: case report and literature review of a rare endonasal infection.

Leishmaniasis is a protozoal infection transmitted by a sandfly vector. In Germany, leishmaniasis of the mucous membranes is a rare condition and usually due to extension of local skin disease into the mucosal tissue via direct extension, bloodstream or lymphatics. We report a case of endonasal leishmaniasis in a female German resident who presented in a university hospital with nasal obstruction. Histology of the left nasal septum biopsy was suggestive of leishmaniasis. The molecular detection of DNA was positive for leishmania infantum. The patient was successfully treated as a case of mucocutaneous leishmaniasis receiving liposomal amphotericin follow up visits showed significant improvement with no recurrence.

Case Report: Unusual Presentation of Pharyngeal Mucosal Leishmaniasis due to Leishmania (Viannia) braziliensis.

Mucosal leishmaniasis (ML) affects predominantly the nose and occurs usually weeks or months after the cure of the primary cutaneous lesion. The pathology of ML is characterized by an exaggerated inflammatory reaction with infiltration of lymphocytes, macrophages, and plasma cells. There is also a paucity of parasites and a strong delayed-type hypersensitivity reaction. Herein, we report a case of a young man who had a large ulcer in his left leg and complained of dysphagia. In nasofibrolaryngoscopy, there were nodular lesions in the oropharynx and rhinopharynx. The skin lesion biopsy showed a chronic inflammation with amastigotes inside macrophages, and DNA of Leishmania braziliensis confirmed the diagnosis of ML in tissue biopsied from the pharynx. The leishmaniasis skin test was negative. Cytokine evaluation showed lack of production of interferon (IFN)-γ, interleukin (IL)-1ß, and IL-17 with enhancement of these cytokine levels after cure.

Case Report: Successful Treatment with Miltefosine of Severe New World Mucosal Leishmaniasis Caused by Leishmania guyanensis.

An 88-year-old man with mutilating mucosal leishmaniasis (ML) involving septal perforation, with granulomas in the pharynx and larynx, was treated with oral miltefosine, 50 mg three times/day for 28 days. Miltefosine, an antineoplastic agent, is considered an alternative option for the treatment of ML, showing efficacies of 75-92% in Bolivia, Brazil, and Argentina. The patient denied having previous cutaneous (CL) leishmaniasis, and no CL lesions were recognized by physical examination. Parasites obtained from mucosal lesions were identified by cytochrome b gene sequencing as Leishmania guyanensis. Clinical cure was observed 2 months posttreatment, and no evidence of reactivation was observed in the 3-year follow-up. Adverse effects such as nausea, loss of appetite, and epigastric pain were experienced during treatment with miltefosine. There is a need for improved access to miltefosine in leishmaniasis-endemic areas of Latin America and a greater awareness of ML and its treatment among physicians working in endemic countries.

Refractory mucocutaneous leishmaniasis resolved with combination treatment based on intravenous pentamidine, oral azole, aerosolized liposomal amphotericin B, and intralesional meglumine antimoniate.

INTRODUCTION: Mucocutaneous leishmaniasis (MCL) is a complication of tegumentary leishmaniasis, causing potentially life-threatening lesions in the ear, nose, and throat (ENT) region, and most commonly due to Leishmania (Viannia) braziliensis. We report a case of relapsing MCL in an Italian traveler returning from Argentina. CASE DESCRIPTION: A 65-year-old Italian male patient with chronic kidney disease, arterial hypertension, prostatic hypertrophy, and type-2 diabetes mellitus was referred for severe relapsing MCL acquired in Argentina. ENT examination showed severe diffuse pharyngolaryngeal edema and erythema, partially obstructing the airways. A nasopharyngeal biopsy revealed a lymphoplasmacytic inflammation and presence of Leishmania amastigotes, subsequently identified as L. (V.) braziliensis by hsp70 PCR-RFLP analysis and sequencing. Despite receiving four courses of liposomal amphotericine B (L-AmB) and two courses of miltefosine over a 2-year period, the patient presented recurrence of symptoms a few months after the end of each course. After the patient was referred to us, a combined treatment was started with intravenous pentamidine 4 mg/kg on alternate days for 10 doses, followed by one dose per week for an additional seven doses, intralesional meglumine antimoniate on the nasal lesion once per week for six doses, oral azoles for three months, and aerosolized L-AmB on alternate days for three months. The treatment led to regression of mucosal lesions and respiratory symptoms. Renal function temporarily worsened, and the addition of insulin was required to maintain glycemic compensation after pentamidine discontinuation. CONCLUSIONS: This case highlights the difficulties in managing a life-threatening refractory case of MCL in an Italian traveler with multiple comorbidities. Even though parenteral antimonial derivatives are traditionally considered the treatment of choice for MCL, they are relatively contraindicated in cases of chronic kidney disease.The required dose adjustment in cases of impaired renal function is unknown, therefore the use of alternative drugs is recommended. This case was resolved with combination treatment, including aerosolized L-AmB, which had never been used before for MCL.

Mucocutaneous leishmaniasis in a cocaine user: diagnostic and therapeutic knowledge

Abstract Mucocutaneous leishmaniasis (MCL) is a chronic infection that can affect the skin and mucous membranes. We report a case of oral, nasopharyngeal, and penile lesions in a 35-year-old cocaine user. The patient presented with ulcerated lesions in 2014. Histopathologic analysis revealed amastigotes, and serological test results were positive for leishmaniasis. Systemic therapy with meglumine antimoniate was administered; however, the patient failed to present for follow-up. In 2018, he returned with nasal collapse, and another histopathologic test confirmed MCL. This case illustrates the importance of careful differential diagnosis of skin and mucous ulcers to identify the particular pathology.

Case Report: Mucocutaneous Leishmaniasis Masquerading as Idiopathic Midline Granulomatous Disease.

Mucocutaneous leishmaniasis (MCL) is a rare infection caused by several species within the genus Leishmania. We present a patient with multifocal MCL masquerading as idiopathic midline granulomatous disease, featuring the unusual complication of ocular leishmaniasis, as a result of prolonged immunosuppressive therapy. We review clinical features, diagnosis, and treatment of this syndrome.

In Situ Cellular Response Underlying Successful Treatment of Mucosal Leishmaniasis with a Combination of Pentavalent Antimonial and Pentoxifylline.

Mucosal leishmaniasis (ML) is characterized by high production of inflammatory cytokines. Administration of pentoxifylline (PTX), an inhibitor of TNF-alpha, with pentavalent antimony (Sbv), has been successfully used as alternative treatment for refractory ML. Our study aims to investigate the in situ cellular response underlying the effectiveness of this therapy, by evaluating the intensity of the inflammatory infiltrate, cellular composition, and expression of cytokines and granzyme A in lesions from ML before and after treatment with Sbv alone or in combination with PTX. Our data showed no differences in the intensity of inflammatory infiltrate comparing before and after treatment, and comparing between different treatments. However, although the number and frequency of CD4+ and CD8+ cells were not different before and after treatments or comparing different treatments, frequency of CD68+ cells decreased after treatment with Sbv + PTX, but not with Sbv. This was due to a reduction in CD68+ TNF-alpha+ and not in CD68+ IL-10+ cells. The frequency of TNF-alpha+ cells was correlated with the intensity of the inflammatory infiltrate before treatment, but this correlation was lost after treatment with Sbv + PTX. Although the total expression of granzyme A did not significantly change after treatments, a clear trend of decrease was observed after treatment with Sbv + PTX. Interestingly, patients who took longer to heal, regardless of the treatment, displayed a higher frequency of granzyme A+ cells. Our data suggest that treatment with Sbv + PTX acts in CD68+ cells reducing the expression of TNF-alpha but not IL-10, resulting in more efficient modulation of the inflammatory response, accelerating the healing process.

Good response to pentamidine isethionate in a case of Mucosal Leishmaniasis caused by Leishmania (Viannia) braziliensis that was difficult to treat: Case Report

Abstract In Brazil, meglumine antimoniate is the first drug of choice for mucosal leishmaniasis treatment followed by amphotericin B and pentamidine isethionate. We report the case of a patient with severe mucosal lesions caused by Leishmania (Viannia) braziliensis that were difficult to treat. Over a 14-year period, the patient showed low adherence and three treatment attempts with meglumine antimoniate failed. Additionally, there was an unsatisfactory response to liposomal amphotericin B and nephrotoxicity when using amphotericin B deoxycholate that persisted after new treatment attempt with liposomal amphotericin B. Finally, healing was achieved with pentamidine isethionate and maintained during nine months of monitoring.

A randomized, open-label clinical trial comparing the long-term effects of miltefosine and meglumine antimoniate for mucosal leishmaniasis

Abstract INTRODUCTION: The treatment of mucosal leishmaniasis (ML) is difficult due to the toxicity and route of administration of standard drugs. Miltefosine is an oral agent used for leishmaniasis treatment; however, no data exist regarding its use for ML in Brazil. In this study, we aimed to evaluate the efficacy of miltefosine for ML treatment compared to that of pentavalent antimonial in a pilot study. METHODS: We performed a randomized clinical trial with two parallel groups. The tested intervention consisted of miltefosine 1.3-2 mg/kg/day (two capsules) for 28 days or intravenous 20 mg SbV/kg/day of meglumine antimoniate (N-MA) for 30 days. The final endpoint was defined as complete healing of the lesion four years after treatment. We also analyzed an early endpoint at 90 days after treatment. RESULTS: Forty patients were included in this study: each experimental group comprised 20 patients. Applying a multivariate model in an intention-to-treat analysis, we observed that patients treated with miltefosine had a cure probability 2.08 times greater (95% confidence interval [CI] = 1.03-4.18) than those treated with N-MA at 90 days after treatment. At the final endpoint, we observed no differences in cure probability between miltefosine and N-MA (relative risk = 0.66; 95% CI = 0.33-1.32). With respect to adverse reactions, significant differences between groups were related to gastrointestinal effects, which were more frequent in the miltefosine group. CONCLUSIONS: Miltefosine may be an interesting alternative for treating ML because of its oral administration and cure rate after long-term follow-up.

Formulation and Characterization of a Self-Emulsifying Drug Delivery System (SEDDS) of Curcumin for the Topical Application in Cutaneous and Mucocutaneous Leishmaniasis.

BACKGROUND: Leishmaniasis, which is classified by the World Health Organization (WHO) as one of the Neglected Tropical Diseases (NTDs) faces several challenges in terms of successful chemotherapy and novel drug developments. OBJECTIVE: The aim of the present study was to develop a Self-Emulsifying Drug Delivery System (SEDDS) for the hydrophobic polyphenol pigment curcumin to enable it for its potential use in cutaneous and mucocutaneous leishmaniasis. METHODS: Two Curcumin-loaded formulations SNEDD-A and B, were developed. Both were characterized by the droplet size, PDI and zeta potential and evaluated for the cytotoxicity on Caco-2 cell lines and through hemolysis test on red blood cells. The spreading potential of the formulations was checked over buccal mucosa and damaged skin model. Antileishmanial activities were performed against promastigote, axenic amastigote and macrophage harbored amastigotes of Leishmania tropica parasite. RESULTS: SNEDDS-A and B had minor differences in physical characteristics. In the toxicological assay, the viability of the Caco-2 cells was 87.5 % for SNEDDS-A and 88.9% for SNEDDS-B while both caused 1-2% hemolysis. Both had remarkable spreading potential, covering 8cm2 of buccal mucosa and damaged the skin for less than 45 minutes. The Antileishmanial activities of the SNEDDS-A in terms of IC50 were 0.13 µg/ml and 0.25 µg/ml against promastigote and amastigote, respectively while IC50 values of SNEDDS-B were 0.18 µg/ml and 0.27 µg/ml against promastigote and amastigote, respectively. Both the formulations killed 100% of the macrophage harbored Leishmania tropica parasites at a concentration of 4.4 µg/ml. CONCLUSION: Our results demonstrate that both the SEDDS formulations of curcumin have the potential to provide a promising tool for curcumin for its use through topical routes in the treatment of cutaneous and mucocutaneous leishmaniasis.

[Atypical mycocutaneous manifestation of Leishmania tropica in a refugee].

In this case report a male 19-year-old Syrian refugee presented with a sore throat. A biopsy from larynx detected Leishmania tropica compatible with leishmaniasis, although L. tropica does not normally cause mucosal leishmaniasis (CL). An immunodeficiency was detected, and the patient was treated for hypogammaglobulinaemia and CL three times, before the symptoms disappeared. Leishmaniasis is a disease, which should be taken into consideration, when refugees present with atypical clinical manifestations, especially in immunosuppressed patients.