Leishmania infection in patients with inflammatory bowel disease: Case series and literature review. / Infección por Leishmania en pacientes con enfermedad inflamatoria intestinal: Serie de casos y revisión de la literatura.

Infection by Leishmania spp. in patients diagnosed with inflammatory bowel disease (IBD) is rare. Considered endemic in the Mediterranean basin, its manifestations are almost exclusive of patients with impaired cellular immunity. Most of the evidence is found through case reports; without guidelines for its management in patients with IBD. In this study we present three cases of Leishmania infection in patients with IBD that lead us to carry out a review of the current literature. Immunosuppressive treatment contributes to this infection, which presents atypically, with a challenging diagnosis. Initial systemic treatment with withdrawal of the immunosuppressant drug seems to be the best therapeutic strategy. Studies are needed in endemic areas to determine its incidence in IBD patients, as well as its possible association with immunosuppressive therapy. The need for serological screening prior introduction of immunosuppressive drugs could be suggested.

Prevalence of visceral leishmaniasis among people with HIV: a systematic review and meta-analysis.

Leishmaniasis is a parasitic infection expressing different clinical phenotypes. Visceral leishmaniasis (VL) is considered an opportunistic infection among people with human immunodeficiency virus (HIV). The objective of this review was to identify published data on the prevalence of Leishmania spp. infection among PWH and to define particular determinants that affect critically the epidemiological characteristics of VL-HIV coinfection and, potentially, its burden on public health. Two independent reviewers conducted a systematic literature search until June 30, 2022. Meta-analyses were conducted using random-effects models to calculate the summary prevalence and respective 95% confidence intervals (CI) of leishmaniasis among PWH. Meta-regression analysis was performed to investigate the impact of putative effect modifiers, such as the mean CD4 cell count, on the major findings. Thirty-four studies were eligible, yielding a summary prevalence of 6% (95%CI, 4-11%) for leishmaniasis (n = 1583) among PWH (n = 85,076). Higher prevalence rates were noted in Asia (17%, 95%CI, 9-30%) and America (9%, 95%CI, 5-17%) than in Europe (4%, 95%CI, 2-8%). Prevalence rates were significantly mediated by the age, sex, and CD4 cell count of participants. Heterogeneity remained significant in all meta-analyses (p < 0.0001). In the majority of included studies, people were coinfected with HIV and Leishmania species associated with VL, as opposed to those associated with cutaneous leishmaniasis. No sign of publication bias was shown (p = 0.06). Our summary of published studies on leishmaniasis among PWH is important to provide prevalence estimates and define potential underlying factors that could guide researchers to generate and further explore specific etiologic hypotheses.

The BRCT Domain from the Homologue of the Oncogene PES1 in Leishmania major (LmjPES) Promotes Malignancy and Drug Resistance in Mammalian Cells.

Around 15% of cancer cases are attributable to infectious agents. Epidemiological studies suggest that an association between leishmaniasis and cancer does exist. Recently, the homologue of PES1 in Leishmania major (LmjPES) was described to be involved in parasite infectivity. Mammalian PES1 protein has been implicated in cellular processes like cell cycle regulation. Its BRCT domain has been identified as a key factor in DNA damage-responsive checkpoints. This work aimed to elucidate the hypothetical oncogenic implication of BRCT domain from LmjPES in host cells. We generated a lentivirus carrying this BRCT domain sequence (lentiBRCT) and a lentivirus expressing the luciferase protein (lentiLuc), as control. Then, HEK293T and NIH/3T3 mammalian cells were infected with these lentiviruses. We observed that the expression of BRCT domain from LmjPES conferred to mammal cells in vitro a greater replication rate and higher survival. In in vivo experiments, we observed faster tumor growth in mice inoculated with lentiBRCT respect to lentiLuc HEK293T infected cells. Moreover, the lentiBRCT infected cells were less sensitive to the genotoxic drugs. Accordingly, gene expression profiling analysis revealed that BRCT domain from LmjPES protein altered the expression of proliferation- (DTX3L, CPA4, BHLHE41, BMP2, DHRS2, S100A1 and PARP9), survival- (BMP2 and CARD9) and chemoresistance-related genes (DPYD, Dok3, DTX3L, PARP9 and DHRS2). Altogether, our results reinforced the idea that in eukaryotes, horizontal gene transfer might be also achieved by parasitism like Leishmania infection driving therefore to some crucial biological changes such as proliferation and drug resistance.

Colon Perforation in a 22-year-old Male with Bartter's Syndrome, Systemic Lupus Erythematosus and Leishmaniasis.

Bartter's syndrome (BS) is an inherited renal tubular disorder characterized by hypochloremia, hypokalemia, metabolic alkalosis. Prognosis of Bartter's syndrome depends on the severity of the receptor dysfunction. In many cases the prognosis is good and patients are able to have fairly normal lives. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown cause that can affect virtually any organ of the body. The prognosis of SLE is quite variable, depending on the severity of the disease, the clinical course and organs involved. The last decades, there is a marked improvement in patient survival due to earlier diagnosis and treatment. Despite these improvements, patients with SLE still have higher mortality rates ranging from two to five times higher than that of the general population. Leishmaniasis is a disease caused by an intracellular protozoan parasite transmitted by the bite of a female phlebotomine sandfly. We report herein the case of a 22-year-old man with Bartter's syndrome (BS) and Systemic lupus erythematosus (SLE), who was hospitalized in the clinic of internal medicine because of Leishmaniasis. In the third day of his hospitalization the patient underwent Hartmann's operation for perforation located on descending colon. Management of patients with many severe diseases is very difficult for medical professionals.

Sterile or nonantibiotic-responsive pustular dermatitis and canine leishmaniosis: a 14 case series description and a statistical association study on 2420 cases.

Background - No striking clinical and histopathological features of pustular dermatitis (PustD) in dogs suffering from canine leishmaniosis (CanL) have been identified; an association between CanL and PustD has not been demonstrated. Objectives - To characterize a series of dogs affected by CanL and pruritic PustD, and to evaluate a possible association between the two conditions. Conclusions - An association exists between PustD and CanL. At least in Leishmania-endemic areas, CanL should be ruled out before attempting an immunosuppressive treatment in dogs with PustD with the aforementioned characteristics. Staging of CanL through diagnostic procedures besides immunohistochemistry and PCR is recommended. Anti-leishmania treatment and short-to-medium courses of low-dose anti-inflammatory or immunomodulatory drugs are effective in controlling the clinical signs of PustD.

Computed tomographic features of destructive granulomatous rhinitis with intracranial extension secondary to leishmaniasis in a cat.

A 5-year-old castrated male Domestic Shorthair cat presented for evaluation of chronic history of nasal discharge and nasal stridor. On computed tomography (CT), a destructive ill-defined mass of soft tissue attenuation was occupying the right nasal cavity and extending into the left nasal cavity, nasopharynx, and rostral cranial cavity. Histopathology of the rhinoscopically excised samples consisted with destructive granulomatous rhinitis secondary to Leishmania spp. Chronic granulomatous rhinitis with intracranial and nasopharyneal extension secondary to Leishmania spp. infection should be included as a differential diagnosis for a destructive nasal mass of soft tissue attenuation, especially in endemic regions for leishmaniasis.

Serological Evidence of Infection by Paracoccidioides brasiliensis in Dogs with Leishmaniasis.

Paracoccidioidomycosis is a systemic mycosis prevalent in Latin American countries, caused by the dimorphic fungi Paracoccidioides brasiliensis and P. lutzii. The habitat of these fungi in nature remains undefined, although it is believed that infection occurs by inhalation of infective propagules present in soil. Sentinel animals, such as dogs, can be valuable epidemiological markers of paracoccidioidomycosis. Taking into account that paracoccidioidomycosis and visceral leishmaniasis may occur in the same area, the objective of this study was to evaluate the occurrence of P. brasiliensis infection in dogs positive for Leishmania sp. Serum samples of dogs positive (n = 199) and negative (n = 101) for Leishmania sp. were analyzed by the immunodiffusion test using P. brasiliensis exoantigen, and 22 samples (7.3%) were positive. The serum samples positive in the immunodiffusion test were also analyzed by Western blotting using the P. brasiliensis gp43 recombinant protein, and 86% of the samples were positive. A high positive correlation (r = 0.96) between positivity for Leishmania sp. and P. brasiliensis was observed. These data suggest an association between leishmaniasis and paracoccidioidomycosis in dogs.

A retrospective study comparing histopathological and immunopathological features of nasal planum dermatitis in 20 dogs with discoid lupus erythematosus or leishmaniosis.

BACKGROUND: In areas endemic for leishmaniosis, discoid lupus erythematosus (DLE) and canine leishmaniosis (CanL) are the most common differential diagnoses for nasal planum erosive-ulcerative dermatitis in dogs. HYPOTHESIS/OBJECTIVE: To compare histopathological and immunopathological features of canine nasal planum erosive-ulcerative dermatitis with depigmentation due to DLE or CanL. ANIMALS: Nasal planum biopsies from dogs with nasal planum loss of architecture, depigmentation, swelling, erosions or ulcerations due to DLE (n = 14) or CanL (n = 6). METHODS: Sections of paraffin-embedded samples, stained with haematoxylin and eosin were reviewed. Samples were examined using antibodies targeting T cells (CD3), B cells (CD20), macrophages (Mac387) and class II major histocompatibility complex (MHC II). Histopathological and immunophenotypical findings were compared between DLE and CanL cases. RESULTS: Lichenoid and interface dermatitis were observed in both DLE and CanL cases. A nodular-to-diffuse, superficial and/or deep dermatitis with macrophages, lymphocytes and plasma cells was present only in CanL samples. CD20-positive cells predominated over CD3- and Mac387-positive cells in the two conditions. The percentage of dermal Mac387-positive cells was higher in CanL compared to DLE samples and the difference was statistically significant (P = 0.025). CONCLUSIONS/CLINICAL IMPORTANCE: In this study, similar histopathological and immunopathological findings were observed in dogs with nasal planum lesions due to DLE or CanL. Therefore, in areas endemic for leishmaniosis, the presence of the parasite should be investigated in canine nasal planum dermatitis showing clinical and histopathological features suggestive of DLE.

The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis.

Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. These patients include those with primary immunodeficiencies, in whom the pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression is contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/µL T cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower levels of soluble CD25 and higher ferritin concentrations. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus: (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies; (ii) this syndrome can develop despite severe deficiency of T and NK cells, implying that the pathophysiology is distinct and not appropriately described as "lympho"-histiocytosis in these patients; and (iii) current criteria for hemophagocytoc lymphohistiocytosis are insufficient to differentiate hemophagocytic inflammatory syndromes with different pathogeneses. This is important because of implications for therapy, in particular for protocols targeting T cells.

Α case of multiple bilateral testicular capsule mast cell tumours in a dog.

A 5-year-old intact male German Shepherd dog was referred with a diagnosis of leishmaniasis. Several testicular masses were palpated during the physical examination, while the diagnostic screening yielded no remarkable findings. Fine needle aspiration cytology of the masses revealed the presence of intermediately differentiated mast cell tumours. Scrotal ablation and orchiectomy were performed as a definitive treatment option. The pathological examination of the surgical specimens confirmed the diagnosis of grade II mast cell tumours and showed that they were all confined to the testicular capsule. At 7 months post-admission, the dog exhibited neither postsurgical complications nor metastatic foci and was, therefore, given a favourable prognosis. Despite their exceptionally rare occurrence, mast cell tumours should be considered for the differential diagnosis of testicular tumours.

Role of hemodialysis with high cut-off membranes in a patient with a non-recognized leishmaniasis.

BACKGROUND: We report here a case of a woman affected by fever, weight loss, splenomegaly, and leucopenia associated with trombocytopenia, transferred to the intensive care unit with acute kidney injury and septic shock. METHODS: Patient was treated with high cut-off continuous veno-venous hemodialysis (HCO-CVVHD). RESULTS: During treatment, the patient experienced a stable improvement in the hemodynamic, pulmonary function and tissue perfusion parameters. After 48 h of treatment, significant reductions in SOFA score (from 12, before starting the procedure, to 6) and in serum inflammatory mediators (as IL-6, from 599-568 pg/ml) were observed. Leishmania infection was identified as responsible of the septic condition only 48 h after removing hemodialysis. Antiprotozoal therapy was begun and the patient discharged. CONCLUSIONS: By supporting the renal function and reducing systemic inflammation, HCO-CVVHD could be a useful bridge therapy. This procedure allowed the medical team to gain sufficient time to diagnose the type of infection and begin an etiological therapy.

Diagnostic utility of bone marrow examination for the assessment of patients with fever of unknown origin: a 10-year single-centre experience.

Bone marrow (BM) examination is included in the diagnostic algorithm of fever of unknown origin (FUO), although its role is not clearly determined. The purpose of this study was to assess the role of BM studies in patients with FUO. We retrospectively reviewed 45 consecutive patients (25% human immunodeficiency virus-positive) with FUO who underwent a BM study in the University Hospital of Salamanca from 2000 to 2010. We analysed the diagnostic role of BM smears, multiparameter flow cytometry analysis, histology and microbiological cultures. Five patients (11%) were finally diagnosed by BM study (three had an infectious disease and two were found to have haematological malignancies), all of whom were immunocompetent patients. Histology was the most useful study (diagnosis was obtained in 4/5 patients), while BM cultures did not establish the final diagnosis in any patient. Flow cytometry established the diagnosis in one patient, although this patient was also diagnosed by histology. In conclusion, BM study is useful for establishing the aetiology of FUO. BM biopsy for histological examination should be always mandatory if a BM examination is performed.

Leishmania amazonensis infection regulates oxidate stress in hyperglycemia and diabetes impairing macrophage's function and immune response.

Leishmaniasis is a group of infectious diseases caused by protozoa of the Leishmania genus and its immunopathogenesis results from an unbalanced immune response during the infection. Diabetes is a chronic disease resulting from dysfunction of the body's production of insulin or the ability to use it properly, leading to hyperglycemia causing tissue damage and impairing the immune system. AIMS: The objective of this work was to evaluate the effects of hyperglycemia and diabetes during Leishmania amazonensis infection and how these conditions alter the immune response to the parasite. METHODS: An in vitro hyperglycemic stimulus model using THP-1-derived macrophages and an in vivo experimental diabetes with streptozotocin (STZ) in C57BL/6 mice was employed to investigate the impact of diabetes and hyperglicemia in Leishmania amazonensis infection. RESULTS: We observed that hyperglycemia impair the leishmanicidal capacity of macrophages derived from THP-1 cells and reverse the resistance profile that C57BL/6 mice have against infection by L. amazonensis, inducing more exacerbated lesions compared to non-diabetic animals. In addition, the hyperglycemic stimulus favored the increase of markers related to the phenotype of M2 macrophages. The induction of experimental diabetes in C57BL/6 mice resulted in a failure in the production of nitric oxide (NO) in the face of infection and macrophages from diabetic animals failed to process and present Leishmania antigens, being unable to activate and induce proliferation of antigen-specific lymphocytes. CONCLUSION: Together, these data demonstrate that diabetes and hyperglycemia can impair the cellular immune response, mainly of macrophages, against infection by parasites of the genus Leishmania.

Light and electron microscopic analysis of consecutive renal biopsy specimens from leishmania-seropositive dogs.

Canine visceral leishmaniasis frequently causes renal damage that leads to chronic kidney disease. Fifteen dogs seropositive for Leishmania were selected and biopsied before (T0) and 60 days later after (T1) treatment with a specific anti-Leishmania pharmacological agent. Various parameters were selected for evaluating the glomerular and tubulointerstitial damage. At T0, mesangioproliferative and membranoproliferative glomerulonephritis were observed in 6 dogs, chronic glomerulosclerosis in 5, and end-stage kidney in 3; renal tissue from 1 dog was within normal histologic limits. The most frequently observed ultrastructural changes were foot-process effacement, thickening of the basement membranes, and immune deposits. One dog had mesangial immune deposits at T1 that had not been present at T0, so the diagnosis was changed to mesangioproliferative glomerulonephritis. In dogs with end-stage kidney, the number of obsolescent glomeruli and cystic atrophied glomeruli was increased at T1. However, progression of the glomerular lesions was minimal in most dogs. Worsening of tubulointerstitial scores was evident in the dogs with the most severe lesions at the first biopsy. Progression of the tubulointerstitial damage was minimal in the mildly affected dogs, and the interstitial inflammation was abated. In conclusion, renal lesions can progress over a 60-day period in canine leishmaniasis. A longer period between the renal biopsies would be necessary to demonstrate more severe changes. In addition a specific anti-Leishmania treatment could have a significant effect in the early stages of the disease.

Renal leishmaniasis as unusual cause of nephrotic syndrome in an HIV patient.

Renal involvement is a rare complication in HIV-1-infected patients leading to various pathologies and clinical symptoms. In addition to the classic HIV-1-associated nephropathy with collapsing-type focal segmental glomerulosclerosis and characteristic tubulocystic changes, which is more common in Afro-American than in Caucasian HIV-1 patients, immune complex GNs such as membranous GN and membranoproliferative GN are particularly common renal manifestations. Besides HIV-1 itself, a number of opportunistic infections may cause renal disease in HIV-1-infected patients. In this study, we report an unusual case of HIV-1 infection with a severe renal manifestation of systemic leishmaniasis that developed years after repeated visits to Mediterranean countries. The case presents several remarkable clinical, pathologic, and therapeutic aspects that may be important for daily clinical practice.

Variation of proteinuria in dogs with leishmaniasis treated with meglumine antimoniate and allopurinol: a retrospective study.

A retrospective study was performed using 53 client owned dogs with leishmaniasis to determine whether the degree of proteinuria, evaluated by the urine protein/creatinine ratio (UP/C), changes following treatment with meglumine antimoniate and allopurinol. Medical records of dogs with leishmaniasis in clinical stage C (according to the Canine Leishmaniasis Working Group staging system) and either proteinuric or borderline proteinuric (according to the International Renal Interest Society [IRIS] staging system) were reviewed. All dogs were treated with meglumine antimoniate and allopurinol for 4-8 wk. After treatment, UP/C, total protein, and total globulin significantly decreased and albumin and the albumin/globulin ratio (A/G) increased. After treatment, 7 of the 53 dogs (13.4%) became nonproteinuric following either a proteinuric or borderline proteinuric stage. Moreover, 12 of the 53 proteinuric dogs (22.6%) changed their stage to borderline proteinuric. The antileishmaniasis treatment with meglumine antimoniate in combination with allopurinol in dogs significantly reduced the degree of proteinuria in a short period of time. The results of the current study may be useful to the veterinary practitioner in the clinical management of canine leishmaniasis (CanL) in dogs with proteinuric chronic kidney disease.

Undifferentiated febrile illnesses in military personnel.

Undifferentiated febrile illnesses (UFIs) present with acute symptoms, objective fever and no specific organ focus on clinical assessment. The term is mostly used in developing and tropical countries where a wide range of infections may be responsible. Laboratory diagnosis often requires specialist microbiology investigations that are not widely available, and serology tests that only become positive during convalescence. Optimal clinical management requires a good travel history, awareness of local endemic diseases, an understanding of the features that may help distinguish different causes and appropriate use of empirical antibiotics. This review describes the most common examples of UFI in military personnel on overseas deployments, and provides a practical approach to their initial management.