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Disseminated leishmaniasis (DL) is an emergent severe disease manifesting with multiple lesions. To determine the relationship between immune response and clinical and therapeutic outcomes, we studied 101 DL and 101 cutaneous leishmaniasis (CL) cases and determined cytokines and chemokines in supernatants of mononuclear cells stimulated with leishmania antigen. Patients were treated with meglumine antimoniate (20 mg/kg) for 20 days (CL) or 30 days (DL); 19 DL patients were instead treated with amphotericin B, miltefosine, or miltefosine and meglumine antimoniate. High levels of chemokine ligand 9 were associated with more severe DL. The cure rate for meglumine antimoniate was low for both DL (44%) and CL (60%), but healing time was longer in DL (p = 0.003). The lowest cure rate (22%) was found in DL patients with >100 lesions. However, meglumine antimoniate/miltefosine treatment cured all DL patients who received it; therefore, that combination should be considered as first choice therapy.

Background: Mucosal Leishmaniasis (ML), a neglected tropical disease caused by Leishmania parasites, impairs the quality of life of under-resourced populations in South America. If not treated promptly, this disease progresses to facial deformities and death. The low sensitivity of microscopy results and the unavailability of other accurate tests hamper the diagnosis. As clinical criteria are readily available in any setting, these may be combined in a syndromic algorithm, which in turn can be used as a diagnostic tool. We explore potential clinical criteria for a syndromic diagnostic algorithm for ML in rural healthcare settings in South America., Methodology/principal Findings: The protocol for this systematic review was pre-registered in PROSPERO with the number: CRD42017074148. In patients with ML, described in case series identified through a systematic retrieval process, we explored the cumulative ML detection rates of clinical criteria. Participants: all patients with active mucosal disease from an endemic area in South America. Any original, non-treatment study was eligible, and case reports were excluded. PUBMED, EMBASE, Web of Science, SCIELO, and LILACS databases were searched without restrictions. The risk of bias was assessed with the JBI checklist for case series. We included 10 full texts describing 192 ML patients. Male gender had the highest detection rate (88%), followed by ulcer of the nasal mucosa (77%), age >15 (69%), and symptom duration >4 months (63%)., Significance: Within this selection of patients, we found that the male gender, ulcer of the nasal mucosa, age >15, and symptom duration >4 months lead to the highest detection rates. However, higher detection comes -naturally- with a higher rate of false positives as well. As we only included ML patients, this could not be verified. Therefore, the criteria that we found to be most promising should be validated in a well-designed prospective study., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JB is a volunteer for Latin Link Nederland and receives a monthly volunteer allowance from this organization. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS NTD policies on sharing data.

Cutaneous leishmaniasis (CL) due to L. braziliensis is associated with an exaggerated inflammatory response and tissue damage. Miltefosine is more effective than pentavalent antimony (Sb v ) in the treatment of CL, and here, we evaluate the ability of Sb v , miltefosine, and GM-CSF administered intravenously, orally, or topically, respectively, to modify the immune response. Patients were treated with miltefosine plus GM-CSF, miltefosine plus placebo, or Sb v . Mononuclear cells were stimulated with soluble Leishmania antigen (SLA) on day 0 and day 15 of therapy, and cytokine levels were determined in supernatants by ELISA. The lymphocyte proliferation and oxidative burst were evaluated by flow cytometry, and the degree of infection and Leishmania killing by optical microscopy. Proliferation of CD4 + T cells were enhanced in patients using miltefosine and in CD8 + T cells when GM-CSF was associated. Enhancement in the oxidative burst occurred in the miltefosine plus GM-CSF group on day 15 of therapy. Moreover, the number of L. braziliensis in infected monocytes on day 15 as well as the percentage of infected cells was lower after 48- and 72-hour culture in cells from patients treated with miltefosine plus GM-CSF. In addition to the ability of miltefosine to kill Leishmania , the changes in the immune response caused by miltefosine and GM-CSF may increase the cure rate of CL patients using these drugs., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Fábio Peixoto et al.)

Cutaneous leishmaniasis (CL), caused by Leishmania braziliensis, in recent decades has shown decreasing cure rates after treatment with meglumine antimoniate (MA). Granulocyte colony-stimulating factor (G-CSF) is a cytokine associated with epithelialization and healing processes. Methods: This study compares the effectiveness of G-CSF associated with MA in the treatment of CL. A total of 32 patients aged between 18 and 50 years with CL confirmed for L. braziliensis were included in this study. G-CSF or placebo (0.9% saline) was applied by intralesional infiltration at four equidistant points on the edges of the largest ulcer on days 0 and 15 of treatment associated with intravenous MA. Results: Males predominated in the G-CSF group (59%), while females predominated in the control group (53%). Injuries to the lower limbs predominated in both study groups. The cure rate in the G-CSF group was 65% and in the control group it was 47%, 90 days after initiation of therapy. Conclusions: Our data indicate that the association of G-CSF with MA is not superior to MA monotherapy. Although not significant, the potential benefit of this combination deserves further investigation. The use of higher doses or other routes of application of G-CSF in a greater number of patients should contribute to a definitive response. [ABSTRACT FROM AUTHOR]

Background The treatment of cutaneous leishmaniasis (CL) in Brazil using pentavalent antimony (Sbv) is associated with a high rate of failure. Miltefosine has proven efficacy for CL caused by L. braziliensis, with a cure rate (CR) of 75%. A combined treatment with granulocyte macrophage colony-stimulating factor (GM-CSF) and miltefosine could increase CR and decrease healing time. Methods A randomized, double-blind clinical trial to evaluate the efficacy of miltefosine combined with topical GM-CSF (M + GM) vs miltefosine and placebo (M + P) vs Sbv in 133 patients with CL caused by L. braziliensis in Bahia, Brazil. Results The final CR at 180 days after the initiation of treatment was 44.4% in the Sbv group, 76.6% in the M + P group (P =.003 vs Sbv), and 75.6% in the M + GM group (P =.004 vs Sbv). The median healing time for cure was 102 days for the Sbv group and 60 days for both miltefosine groups (P =.0009). During the 6-month follow-up period, 4 relapses were documented: 1 in the Sbv group, 1 in the M + P group, and 2 in the M + GM group. Mild adverse events occurred in 65% of patients from the Sbv group, 76% and 79% from the M + P and M + GM groups respectively. Conclusions Miltefosine is more effective than Sbv for the treatment of CL caused by L. braziliensis in Brazil and accelerates the healing time. Association with GM-CSF does not improve therapeutic outcome. Clinical Trials Registration NCT03023111. [ABSTRACT FROM AUTHOR]

Disseminated Leishmaniasis (DL) is an emerging and severe form of Leishmania (Viannia) braziliensis infection defined by the presence of 10 and up to more than 1,000 skin lesions. The mechanisms underlying parasite dissemination remain unknown. Genotypic differences among species of L. braziliensis have been associated with different clinical forms of disease. The present work compared the function of monocytes obtained from patients with cutaneous leishmaniasis (CL) and DL in response to infection with L. braziliensis isolates of both these two clinical forms of disease. Mononuclear cells obtained from DL and CL patients were infected with different L. braziliensis isolates, and numbers of infected cells, parasite load, respiratory burst, TLR2 and TLR4 expression and cytokine production were evaluated. DL isolates infected more monocytes, induced greater respiratory burst, and more cytokine production compared to isolates from CL patients regardless of the origin of monocytes (DL or CL). However, greater parasite multiplication and higher TLR2 and TLR4 expression were seen in monocytes from DL patients compared to CL following infection with DL isolates. Our results indicate the participation of both parasite genotype and host factors in the pathogenesis of DL. [ABSTRACT FROM AUTHOR]

Background: Mucosal leishmaniasis (ML), the most inflammatory form of tegumentary leishmaniasis, is predominantly caused by Leishmania braziliensis. The disease is characterized by the development of lesions, mainly in the nasal mucosa. An exacerbated inflammatory response has been associated with the presence of destructive and disfiguring lesions, with stages of severity ranging from small nodulations to the complete destruction of the nasal pyramid architecture. As Leishmania is an intracellular parasite, most immunological studies have emphasized the cell-mediated immune response, while relatively few studies aimed to investigate the role antibodies in protection against, or the pathology of ML. Methods: Patients with a confirmed diagnosis of ML were classified according to clinical staging criteria. Serum levels of Leishmania -specific IgG, IgG1 and IgG2 antibodies were determined by ELISA before and after treatment with antimony or antimony plus pentoxifylline. Results: Patients in stages IV and V produced higher concentrations of IgG and IgG1 antibodies when compared to those in stage I and II. Significant reductions were seen in the concentrations of IgG and IgG2 antibodies in most patients who responded well to treatment. Conclusions: Our data demonstrate an association between IgG antibody titers and the severity of mucosal disease. The observed reduction in antibody production after successful treatment in most patients preliminarily indicates that these tests can be used to aid in the assessment of therapeutic response. [ABSTRACT FROM AUTHOR]

Cutaneous leishmaniasis (CL) caused by infection with Leishmania braziliensis is characterized by an exaggerated inflammatory response that controls the parasite burden, but also contributes to pathology. While myeloid cells are required to eliminate the parasite, recent studies indicate that they may also participate in the inflammatory response driving disease progression. The innate immune response to leishmania is driven in part by the Toll-like receptors (TLRs) TLR2, TLR4, and TLR9. In this study, we used flow cytometric analysis to compare TLR2 and TLR4 expression in monocyte subsets (classical, intermediate, and non-classical) from CL patients and healthy subjects (HS). We also determined if there was an association of either the pro-inflammatory cytokine TNF or the anti-inflammatory cytokine IL-10 with TLR2 or TLR4 expression levels after L. braziliensis infection. In vitro infection with L. braziliensis caused CL monocytes to up-regulate TLR2 and TLR4 expression. We also found that intermediate monocytes expressed the highest levels of TLR2 and TLR4 and that infected monocytes produced more TNF and IL-10 than uninfected monocytes. Finally, while classical and intermediate monocytes were mainly responsible for TNF production, classical monocytes were the main source of IL-10. Collectively, our studies revealed that up-regulated TLR2/4 expression and TNF production by intermediate/inflammatory subsets of monocytes from patients correlates with detrimental outcome of cutaneous leishmaniasis. [ABSTRACT FROM AUTHOR]

Background. The treatment of cutaneous leishmaniasis (CL) caused by Leishmania braziliensis in Brazil with pentavalent antimony (Sbv) is associated with a high rate of failure, up to 45% of cases. In addition, Sbv can only administered parenterally and has important toxic effect. An effective, safe, and oral treatment for CL is required. Methods. A randomized controlled clinical trial was conducted to compare the efficacy and safety of high-dosage oral fluconazole (6.5-8.0 mg/kg/d for 28 days) versus a standard Sbv protocol (20 mg/kg/d for 20 days) for the treatment of CL in Bahia, Brazil. Results. A total of 53 subjects were included in the trial; 26 were treated with Sbv, and 27 with fluconazole. Intention-to-treat analysis showed initial cure rates (2 months after treatment) of 22.2% (6 of 27) in the fluconazole and 53.8% (14 of 26) in the Sbv group (P = .04). Six months after treatment, the final cure rate remained the same in both groups, without any relapses. The frequencies of adverse effects in the Sbv and fluconazole groups were similar, 34.6% versus 37% respectively. One patient treated with fluconazole discontinued treatment owing to malaise, headache, and moderate dizziness (Common Terminology Criteria for Adverse Events grade 2). Conclusions. Oral fluconazole at a dosage of 6.5-8 mg/kg/d for 28 days should not be considered an effective treatment for CL caused by L. braziliensis. [ABSTRACT FROM AUTHOR]

Background: Disseminated leishmaniasis (DL) is a severe and emerging form of American tegumentary leishmaniasis, associated primarily with infection by Leishmania brasiliensis. DL is defined by the presence of ≥10 mixedtype lesions such as inflammatory papules and ulcers, located in ≥2 body parts. Most patients have hundreds of lesions all over the body, and mucosal involvement is detected in up to 44% of cases. DL is a difficult to cure disease and pentavalent antimony (Sbv) is used as standard treatment, its highest dosage being 20 mg/kg/day, for 30 days. However, less than 25% of DL cases will be cured after standard therapy, and the majority of cases will require more than one course of Sbv for a cure. In this context, new therapies are needed that offer a higher cure rate and a better safety profile, with convenience in drug administration. Methods: We have evaluated liposomal amphotericin B in 20 patients with DL in an open clinical trial. The total dose ranged from 17 to 37 mg/kg, used in 7 to 14 days of treatment. Results: Cure rate at 3 months after therapy was 70%. One relapse was documented 4 months after treatment, producing a final cure rate of 65%. Although liposomal amphotericin B was considered well tolerated, mild adverse events were documented in 75% of the patients. Conclusions: Liposomal amphotericin B is an effective therapy for DL, with a higher final cure rate of 75% observed when used in a total dose above 30 mg/kg. [ABSTRACT FROM AUTHOR]

Ulcer development in patients with cutaneous leishmaniasis (CL) caused by Leishmania braziliensis is associated with high levels of tumor necrosis factor (TNF). We found that early after infection, before ulcer development, the frequency of CD16(+) (both intermediate [CD14(+)CD16(+)] and nonclassical [CD14(dim)CD16(+)]) monocytes was increased in the peripheral blood of patients with L. braziliensis, compared with uninfected controls. These results suggest that CD16(+) monocytes might promote disease. Also, we found that intermediate monocytes expressed CCR2 and that increased levels of CCL2 protein were present in lesions from patients, suggesting that intermediate monocytes are more likely than nonclassical monocytes to migrate to the lesion site. Finally, we found that the intermediate monocytes produced TNF. Our results show that intermediate monocytes are increased in frequency soon after infection; express CCR2, which would promote their migration into the lesions; and, owing to their production of TNF, can enhance the inflammatory response. [ABSTRACT FROM AUTHOR]