Diabetes Modifies the Clinic Presentation of Cutaneous Leishmaniasis

Abstract Background Cutaneous leishmaniasis (CL) caused by L. braziliensis is characterized by 1 or multiple well-limited ulcerated lesions. Diabetes mellitus (DM) impairs neutrophil and monocyte function, and there is a report of vegetative lesions in a patient with both diseases in Morocco. Here we evaluate the influence of DM on clinical manifestations, immune response, and in the treatment of CL. Methods The participants were 36 DM patients with CL and 36 patients with CL without DM, matched by age and gender. The diagnosis of CL was performed by documentation of DNA of L. braziliensis by polymerase chain reaction in the lesion biopsy and histopathologic findings. All patients were treated with Glucantime (Sanofi-Aventis) 20 mg/kg of weight per day for 20 days. Results There was no difference in the majority of the clinical variables between the groups, and the cure rate in patients with CL and DM (67%) was similar to that observed in CL patients (56%; P ˃ .05). The most important finding was the documentation that 36% of the patients with DM and CL had atypical cutaneous lesions characterized by large superficial ulcers without defined borders. High levels of interferon-γ, tumor necrosis facor, and interleukin-1β were detected in the supernatants of mononuclear cells stimulated with Leishmania antigen in patients with DM and atypical CL. Moreover, while cure was observed in only 33% of the patients with DM and atypical CL lesions, it was observed in 85% of patients with typical lesions (P < .05). Conclusions DM modifies the clinical presentation of CL, enhances pro-inflammatory cytokine production, and impairs response to antimony therapy.

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Influence of Obesity on Clinical Manifestations and Response to Therapy in Cutaneous Leishmaniasis caused by Leishmania braziliensis

Clinical Infectious Diseases ◽

10.1093/cid/ciab236 ◽

2021 ◽

Author(s):

Tainã Lago ◽

Lucas Carvalho ◽

Mauricio Nascimento ◽

Luiz H Guimarães ◽

Jamile Lago ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Clinical Presentation ◽

Clinical Manifestations ◽

Healing Time ◽

Response To Therapy ◽

Leishmania Braziliensis ◽

Cutaneous Lesions ◽

Cytokine Levels ◽

Cure Rates ◽

The Impact

Abstract Background Cutaneous leishmaniasis (CL) caused by L. braziliensis is characterized by a single ulcer or multiple cutaneous lesions with raised borders. Cure rates below 60% are observed in response to meglumine antimoniate therapy. We investigated the impact of obesity on CL clinical presentation and therapeutic response. Methods A total of 90 age-matched CL patients were included (30 obese, 30 overweight and 30 with normal BMI). CL was diagnosed through documentation of L. braziliensis DNA by PCR or identification of amastigotes in biopsied skin lesion samples. Serum cytokine levels were determined by chemiluminescence. Antimony therapy with Glucantime (20mg/kg/day) was administered for 20 days. Results Obese CL patients may present hypertrophic ulcers rather than typical oval, ulcerated lesions. A direct correlation between BMI and healing time was noted. After one course of Antimony, cure was achieved in 73% of patients with normal BMI, 37% of overweight subjects, yet just 18% of obese CL patients (p<0.01). Obese CL cases additionally presented higher leptin levels than overweight patients or those with normal BMI (p<0.05). Conclusions Obesity modifies the clinical presentation of CL and host immune response, and is associated with greater failure to therapy.

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Histological and immunological differences between zoonotic cutaneous leishmaniasis due to Leishmania major and sporadic cutaneous leishmaniasis due to Leishmania infantum

Parasite ◽

10.1051/parasite/2019007 ◽

2019 ◽

Vol 26 ◽

pp. 9 ◽

Cited By ~ 4

Author(s):

Thouraya Boussoffara ◽

Mohamed Samir Boubaker ◽

Melika Ben Ahmed ◽

Mourad Mokni ◽

Ikram Guizani ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Leishmania Major ◽

Histological Analysis ◽

Quantitative Polymerase Chain Reaction ◽

Immunohistochemical Analysis ◽

Interferon Γ ◽

Mrna Levels ◽

Zoonotic Cutaneous Leishmaniasis ◽

Chemotactic Protein ◽

Polymerase Chain

Lesion features in cutaneous leishmaniasis (CL) depend on the infecting Leishmania species as well as on host immune reponse. In this study, we evaluated the histological and immunological differences between two forms of CL described in Tunisia: zoonotic cutaneous leishmaniasis (ZCL) caused by L. major and sporadic cutaneous leishmaniasis (SCL) caused by L. infantum. Histological analysis showed a mild to moderate infiltrate within ZCL lesions. In contrast, massive infiltration of the dermis was observed within SCL lesions. Contrary to ZCL, infiltrates within SCL lesions were organized and showed granuloma composed of macrophages and lymphocytes. In addition, immunohistochemical analysis showed a predominance of CD4+ T cells within both CL forms. Furthermore, expression of interferon-γ, interleukin (IL)-10, IL-8, IL-13 and monocyte chemotactic protein (MCP)-1 was evaluated using real-time quantitative polymerase chain reaction (RT-qPCR). MCP-1 and IL-10 were expressed at comparable levels in ZCL and SCL lesions. Interestingly, IL-8 mRNA levels were significantly higher in ZCL lesions compared to SCL lesions, but interferon-γ was significantly higher in SCL lesions than in ZCL lesions.

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Subcutaneous immunization against Leishmania major - infection in mice: efficacy of formalin-killed promastigotes combined with adjuvants

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652010000200006 ◽

2010 ◽

Vol 52 (2) ◽

pp. 95-100 ◽

Cited By ~ 10

Author(s):

Joshua M. Mutiso ◽

John C. Macharia ◽

Rosemary M. Mutisya ◽

Evans Taracha

Keyword(s):

Cutaneous Leishmaniasis ◽

Leishmania Major ◽

Immune Status ◽

Parasite Burden ◽

Interferon Γ ◽

Cutaneous Lesions ◽

Ifn Γ ◽

Efficacious Vaccine ◽

Subcutaneous Immunization ◽

Murine Cutaneous Leishmaniasis

Formalin-killed promastigotes (FKP) of Leishmania major, in combination with Montanide ISA 720 (MISA), BCG or alum were used in vaccination of an inbred murine model against cutaneous leishmaniasis (CL). Significant and specific increases in anti-FKP IgG responses were detected for both alum-FKP and BCG-FKP compared to MISA-FKP (p < 0.001). Significant increases in splenic lymphocyte recall proliferation was obtained in the MISA-FKP vaccinated mice compared to alum-FKP or BCG-FKP vaccinated groups (p < 0.01). The highest interferon-γ responses were observed in the BCG-FKP group followed by the MISA-FKP while the alum-FKP gave the least responses. Significantly reduced lesion sizes were obtained in the MISA-FKP group compared to the BCG/alum adjuvants-FKP vaccinated groups. Although the BCG-FKP group showed the highest IFN-γ responses, it failed to control cutaneous lesions. Significant reductions in parasite numbers were observed in the MISA-FKP and BCG-FKP vaccinated groups (p < 0.001). There was a good correlation between parasite burden and IFN-γ level indicating IFN-γ response as a sensitive parameter of the immune status. In conclusion, MISA-FKP is the most efficacious vaccine formulation against murine cutaneous leishmaniasis.

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Variants of MIRNA146A rs2910164 and MIRNA499 rs3746444 are associated with the development of cutaneous leishmaniasis caused by Leishmania guyanensis and with plasma chemokine IL-8

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0009795 ◽

2021 ◽

Vol 15 (9) ◽

pp. e0009795

Author(s):

Tirza Gabrielle Ramos de Mesquita ◽

José do Espírito Santo Junior ◽

Thais Carneiro de Lacerda ◽

Krys Layane Guimarães Duarte Queiroz ◽

Cláudio Marcello da Silveira Júnior ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Wide Spectrum ◽

Interleukin 1 ◽

Clinical Manifestations ◽

Cellular Functions ◽

Pcr Rflp ◽

Plasma Cytokines ◽

Polymerase Chain ◽

Leishmania Guyanensis ◽

Necrosis Factor

Leishmania are intracellular protozoan parasites that cause a wide spectrum of clinical manifestations in genetically susceptible individuals with an insufficient or balanced Th1 immune response to eliminate the parasite. MiRNAs play important regulatory role in numerous biological processes including essential cellular functions. miR146-a acts as an inhibitor of interleukin 1 receptor associated kinase 1 (IRAK1) and tumour necrosis factor (TNF) receptor associated factor 6 (TRAF6) present in the toll-like receptors pathway while miR499a modulates TGF-β and TNF signalling pathways. Here, we investigated whether MIRNA146A rs2910164 and MIRNA499 rs3746444 variants are associated with the development of L. guyanensis (Lg)-cutaneous leishmaniasis (CL). The variants MIR146A rs2910164 and MIR499A rs3746444 were assessed in 850 patients with Lg-CL and 891 healthy controls by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Plasma cytokines were measured using the BioPlex assay. Carriers of rs2910164 CC genotype have 30% higher odds of developing CL (ORadjage/sex = 1.3 [95%CI 0.9–1.8]; Padjage/sex 0.14) compared to individuals with the genotype GG (ORadjage/sex = 0.77 [95%CI 0.56–1.0]; Padjage/sex 0.14) if exposed to Lg-infection. Heterozygous GC individuals also showed lower odds of developing CL (ORadjage/sex = 0.77 [95%CI 0.5–1.1]; Padjage/sex 0.09). Homozygosity for the allele C is suggestive of an association with the development of Lg-CL among exposed individuals to Lg-infection. However, the odds of developing CL associated with the CC genotype was evident only in male individuals (ORadjage = 1.3 [95% CI = 0.9–2.0]; Padjage = 0.06). Individuals homozygous for the G allele tend to have higher plasma IL-8 and CCL5. Similarly, for the MIR499A rs3746444, an association with the G allele was only observed among male individuals (OR = 1.4 [1.0–1.9]; P = 0.009). In a dominant model, individuals with the G allele (GG-GA) when compared to the AA genotype reveals that carriers of the G allele have 40% elevated odds of developing Lg-CL (ORadjage = 1.4 [1.1–1.9]). Individuals with the GG genotype have higher odds of developing Lg-CL (ORadjage/sex = 2.0 [95%CI 0.83–5.0]; Padjage = 0.01. Individuals homozygous for the G allele have higher plasma IL-8. Genetic combinations of both variants revealed that male individuals exposed to Lg bearing three or four susceptible alleles have higher odds of developing Lg-CL (OR = 2.3 [95% CI 1.0–4.7]; p = 0.017). Both MIR146A rs2910164 and MIR499A rs3746444 are associated with the development of Lg-CL and this association is prevalent in male individuals.

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Influence of Intestinal Helminth Burden on Clinical Manifestations, Therapeutic Response, and Leishmania braziliensis Load in Patients with New World Cutaneous Leishmaniasis

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.20-1664 ◽

2021 ◽

Author(s):

Brady Page ◽

Alex Lago ◽

Juliana Almeida Silva ◽

Albert Schriefer ◽

Jamile Lago ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Therapeutic Response ◽

Helminth Infection ◽

Clinical Manifestations ◽

Response To Treatment ◽

Stool Examination ◽

Clinical Aspects ◽

Intestinal Helminth ◽

Leishmania Braziliensis ◽

Cure Rate

Leishmania braziliensis is the most important cause of cutaneous leishmaniasis (CL) in the Americas. A Th1-type immune response is required to control Leishmania infection, but an exaggerated inflammatory response leads to the development of ulcers seen in CL. Infection with intestinal helminths has the potential to inhibit the Th1 response in a manner that depends both on the species of helminth present as well as the burden of helminthiasis. We conducted a prospective cohort study of CL patients from an endemic area between January and December 2017 with either negative or high intestinal helminth burden to characterize relationships between helminth burden, L. braziliensis quantification within CL lesions, clinical aspects of CL, and therapeutic response. Of 234 participants with leishmaniasis who underwent stool examination at the time of diagnosis, 45% had detectable helminth infection. The overall cure rate after 90 days was 66%, with a median time to resolution of disease of 40 days (interquartile range: 30–65 days). There was no significant association between the type of helminth infection or the magnitude of intestinal helminth burden at the time of diagnosis and L. braziliensis genomic DNA (gDNA) detected in biopsies from CL lesions. Likewise, there was no association between helminth burden and response to treatment after 90 days. Considering quantification of parasite DNA in CL lesions, participants who were cured at 90 days had a median of 0.017 ng/mg gDNA, and participants who failed therapy had a median of 0.091 ng/mg gDNA (P = 0.03). The results indicate that cutaneous Leishmania load may influence therapeutic response in CL.

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Evaluation of the Ability of Miltefosine Associated with Topical GM-CSF in Modulating the Immune Response of Patients with Cutaneous Leishmaniasis

Journal of Immunology Research ◽

10.1155/2020/2789859 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Fábio Peixoto ◽

Maurício T. Nascimento ◽

Rúbia Costa ◽

Juliana Silva ◽

Gaby Renard ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Cutaneous Leishmaniasis ◽

Oxidative Burst ◽

Mononuclear Cells ◽

Cure Rate ◽

Gm Csf ◽

Pentavalent Antimony ◽

Cytokine Levels ◽

Infected Cells

Cutaneous leishmaniasis (CL) due to L. braziliensis is associated with an exaggerated inflammatory response and tissue damage. Miltefosine is more effective than pentavalent antimony (Sbv) in the treatment of CL, and here, we evaluate the ability of Sbv, 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 Sbv. 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.

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Cutaneous and Systemic Necrotizing Vasculitis in Swine

Veterinary Pathology ◽

10.1177/030098589803500204 ◽

1998 ◽

Vol 35 (2) ◽

pp. 108-116 ◽

Cited By ~ 47

Author(s):

S. Thibault ◽

R. Drolet ◽

M.-C. Germain ◽

S. D'Allaire ◽

R. Larochelle ◽

...

Keyword(s):

Mononuclear Cells ◽

Systemic Vasculitis ◽

Skin Lesions ◽

Cutaneous Lesions ◽

Prrs Virus ◽

Skin Biopsies ◽

Polymerase Chain ◽

Generalized Lymphadenopathy ◽

Synovial Membranes ◽

Epidemiologic Characteristics

A systemic vasculitis involving particularly the skin and kidneys has been recently described in swine under the name dermatitis/nephropathy syndrome. Twelve pigs with gross cutaneous lesions typical of this condition were necropsied, and morphologic, immunohistochemical, microbiologic, and epidemiologic characteristics were studied. The pigs were divided into three groups comprising eight pigs with acute lesions, two with chronic lesions, and two with acute lesions kept for sequential skin biopsies. Acute skin lesions consisted of round to irregular, red to purple macules and papules that often coalesced to form large, irregular patches and plaques. With time, the lesions became covered by crusts and faded gradually, sometimes leaving scars. Characteristic distribution included the perineal area of the hindquarters, limbs, dependent parts of the abdomen and thorax, and margins of the ears. In the acute phase of the disease, necrotizing and leucocytoclastic vasculitis of small-caliber blood vessels were observed within the dermis and panniculus and in various extracutaneous locations such as the renal pelvis and synovial membranes. All pigs had macroscopic evidence of pneumonia and generalized lymphadenopathy. Microscopically, they had interstitial pneumonia and perivascular cuffing of mononuclear cells in various tissues including skin. The presence of immunoglobulins and complement was demonstrated by immunofluorescence in and around necrotic vessels of the skin in the early stages. Porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV) antigens were detected by immunohistochemistry in macrophages located around vessels of the tissues examined (skin and kidneys) in acute and chronic cases. PRRSV RNA was demonstrated by reverse transcription-polymerase chain reaction in lung and spleen homogenates from all pigs. The PRRSV was isolated in cell culture from 11 of the pigs. These findings suggest that PRRSV infection may play a role in the pathogenesis of this systemic vascular disease of swine.

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Evaluation of the lymphoproliferation of mononuclear cells in cutaneous leishmaniasis patients treated with Libidibia ferrea

Acta Brasiliensis ◽

10.22571/2526-4338560 ◽

2021 ◽

Vol 5 (3) ◽

pp. 97

Author(s):

Erika Oliveira Da Silva ◽

Paula Figliuolo da Cruz Borges ◽

Rafaela Benício Santana ◽

Heriederson Sávio Dias Moura ◽

José Fernando Marques Barcellos ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Mononuclear Cells ◽

Clinical Manifestations ◽

Immunomodulatory Activity ◽

Parasitic Diseases ◽

Healthy Individuals ◽

Lymphoproliferative Response ◽

Peripheral Blood Mononuclear ◽

Significant Difference ◽

Before And After

American integumentary leishmaniasis (ATL) is a neglected disease that mostly affects vulnerable populations. Its broad spectrum of clinical manifestations is related to the type of immune response produced by the host and the species of Leishmania involved. In recent years, the use of medicinal plants has become a therapeutic alternative in the treatment of infectious parasitic diseases. This research aimed to evaluate the lymphoproliferative responses of peripheral blood mononuclear cells (PBMCs) of patients with cutaneous leishmaniasis (CL) before and after treatment, and healthy individuals. The lymphoproliferative response was evaluated in cell culture using stimuli of the dichloromethane fraction (DCM) obtained from Libidibia ferrea, Glucantime® and phytohemagglutinin - PHA using a BrdU Cell Proliferation after 72 h of incubation. In cultures treated with the DCM fraction, intense induction of lymphoproliferation was observed (p<0.0001), as was also observed in response to the PHA mitogen, and there was a significant difference when compared with the conventional treatment (p<0.0135). In the post-treatment and healthy groups, although the compound induced lymphoproliferation, there was no statistical difference. These results suggest that the organic compound played an important inducing role in lymphoproliferation, which highlights the importance of continuity involving new studies in order to evaluate its immunomodulatory activity.

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