- In vitro coagulation triggers anti-Aspergillus fumigatus neutrophil response. [Journal Article]
- FMFuture Microbiol 2018 May 23
- CONCLUSIONS: These data suggest platelets could trigger coagulopathy and activate neutrophils during aspergillosis. They open up new perspectives for aspergillosis management.
- Failure of voriconazole therapy due to acquired azole resistance in Aspergillus fumigatus in a kidney transplant recipient with chronic necrotizing aspergillosis. [Case Reports]
- AJAm J Transplant 2018 May 22
- Invasive aspergillosis (IA) affects lungs and disseminates mostly in patients with neutropenia and/or receiving immunosuppressive and steroid therapies. Despite progress in diagnosis and therapy of I...
Invasive aspergillosis (IA) affects lungs and disseminates mostly in patients with neutropenia and/or receiving immunosuppressive and steroid therapies. Despite progress in diagnosis and therapy of IA, it is still characterized by a high mortality rate. Currently, voriconazole is considered as the standard therapy for invasive aspergillosis. Over the recent years, triazole resistant Aspergillus fumigatus isolates have emerged in the environment due to the use of fungicidal agricultural products with the risk of developing IA related to a resistant isolate. However, resistance may also develop in patient under long-term triazole therapy, particularly in the setting of chronic forms of pulmonary aspergillosis. We here describe a kidney transplant recipient who failed voriconazole therapy due to acquired resistance secondary to the appearance of a de novo mutation (Y121F) in the cyp51A gene during chronic necrotizing pulmonary aspergillosis. The infecting isolate acquired voriconazole resistance in eight months despite plasma concentrations within recommended range of the drug necessitating lobectomy in association with a new antifungal strategy consisting of liposomal amphotericin and caspofungin with a good outcome over 36 months. This article is protected by copyright. All rights reserved.
- Invasive Mold Disease in Hematologic Patients: Comparison between Fusariosis and Aspergillosis. [Journal Article]
- CMClin Microbiol Infect 2018 May 19
- CONCLUSIONS: IA and IF share the same epidemiologic scenario but different clinical presentations in the majority of cases, with disease in the airways in IA, and fever, metastatic skin lesions and positive blood cultures in IF. However, a substantial proportion of patients with IF present with a clinical picture similar to IA, with fever, lung infiltrates and positive serum galactomannan.
- Neuroinfections caused by fungi. [Review]
- IInfection 2018 May 21
- CONCLUSIONS: Although the number of fungal species causing CNS mycosis is increasing, only some possess well-defined treatment standards (e.g., cryptococcal meningitis and CNS aspergillosis). The early diagnosis of fungal infection, accompanied by identification of the etiological factor, is needed to allow the selection of effective therapy in patients with FIs-CNS and limit their high mortality.
- The Feared Five Fungal Infections in Kidney Transplant Recipients: A Single Center20-year Experience. [Journal Article]
- CTClin Transplant 2018 May 21; :e13289
- Invasive fungal infections are a feared complication in kidney transplant recipients (KTRs). Here we present the University of Wisconsin experience with five invasive fungal infections - aspergillosi...
Invasive fungal infections are a feared complication in kidney transplant recipients (KTRs). Here we present the University of Wisconsin experience with five invasive fungal infections - aspergillosis, cryptococcosis, histoplasmosis, blastomycosis, and coccidioidomycosis - in KTRs transplanted between 01/01/1994 and 06/30/2014. During this period there were 128 cases of fungal infections; aspergillosis was the most common (72), followed by cryptococcosis (29), histoplasmosis (14), blastomycosis (10) and coccidioidomycosis (3). The mean interval from transplant to fungal infection was 3.19 ± 3.58 years (range 5 days-15.8 years). By six months post-infection, there were 53 (41%) graft failures and 24 (19%) deaths. Graft failure occurred in 46%, 38%, 21%, 40%, and 67% of patients with aspergillosis, cryptococcosis, histoplasmosis, blastomycosis, and coccidioidomycosis, respectively. Anti-thymocyte globulin (ATG) induction (HR, 1.49; 95% CI, 1.03-2.16; P = 0.04), diabetes (HR, 1.53; 95% CI, 1.05-2.21; P = 0.03) and age (HR, 1.47; 95% CI, 1.27-1.70; P = <0.001) were associated with an increased risk for infection in univariate analysis. Multivariate adjustment retained ATG induction and older age. A large proportion of kidney transplant recipients with invasive fungal infections suffer graft failure within 3 years. Preventive, therapeutic, and monitoring strategies are needed to improve graft and patient outcomes. This article is protected by copyright. All rights reserved.
- An unappreciated role for neutrophil-DC hybrids in immunity to invasive fungal infections. [Journal Article]
- PPPLoS Pathog 2018 May 21; 14(5):e1007073
- Neutrophils are classically defined as terminally differentiated, short-lived cells; however, neutrophils can be long-lived with phenotypic plasticity. During inflammation, a subset of neutrophils tr...
Neutrophils are classically defined as terminally differentiated, short-lived cells; however, neutrophils can be long-lived with phenotypic plasticity. During inflammation, a subset of neutrophils transdifferentiate into a population called neutrophil-DC hybrids (PMN-DCs) having properties of both neutrophils and dendritic cells. While these cells ubiquitously appear during inflammation, the role of PMN-DCs in disease remains poorly understood. We observed the differentiation of PMN-DCs in pre-clinical murine models of fungal infection: blastomycosis, aspergillosis and candidiasis. Using reporter strains of fungal viability, we found that PMN-DCs associate with fungal cells and kill them more efficiently than undifferentiated canonical neutrophils. During pulmonary blastomycosis, PMN-DCs comprised less than 1% of leukocytes yet contributed up to 15% of the fungal killing. PMN-DCs displayed higher expression of pattern recognition receptors, greater phagocytosis, and heightened production of reactive oxygen species compared to canonical neutrophils. PMN-DCs also displayed prominent NETosis. To further study PMN-DC function, we exploited a granulocyte/macrophage progenitor (GMP) cell line, generated PMN-DCs to over 90% purity, and used them for adoptive transfer and antigen presentation studies. Adoptively transferred PMN-DCs from the GMP line enhanced protection against systemic infection in vivo. PMN-DCs pulsed with antigen activated fungal calnexin-specific transgenic T cells in vitro and in vivo, promoting the production of interferon-γ and interleukin-17 in these CD4+ T cells. Through direct fungal killing and induction of adaptive immunity, PMN-DCs are potent effectors of antifungal immunity and thereby represent innovative cell therapeutic targets in treating life-threatening fungal infections.
- Helper T-Cell Responses and Pulmonary Fungal Infections. [Review]
- IImmunology 2018 May 20
- The mucosal surface of the respiratory tract encounters microbes, such as fungal particles, with every inhaled breath. When pathogenic fungi breach the physical barrier and innate immune system withi...
The mucosal surface of the respiratory tract encounters microbes, such as fungal particles, with every inhaled breath. When pathogenic fungi breach the physical barrier and innate immune system within the lung to establish an infection, adaptive immunity is engaged often in the form of helper CD4 T-cell responses. Type 1 responses, characterized by IFNγ production from CD4 cells, promote clearance of Histoplasma capsulatum and Cryptococcus neoformans infection. Likewise, IL-17A production from Th17 cells promotes immunity to Blastomyces dermatitidis and Coccidiodes species infection by recruiting neutrophils. In contrast the development of Th2 responses, characterized by IL-5 production from T-cells and eosinophil influx into the lungs, drives allergic bronchopulmonary aspergillosis and poor outcomes during C. neoformans infection. Experimental vaccines against several endemic mycoses, including Histoplasma capsulatum, Coccidioides, Cryptococcus, and Blastomyces dermatitidis, induce protective T-cell responses and foreshadow the development vaccines against pulmonary fungal infections for use in humans. Additionally, recent work using antifungal T-cells as immunotherapy to protect immune compromised patients from opportunist fungal infections also shows great promise. This review covers the role of T-cell responses in driving protection and pathology in response to pulmonary fungal infections, and highlight promising therapeutic applications of antifungal T-cells. This article is protected by copyright. All rights reserved.
- CARD9S12N facilitates the production of IL-5 by alveolar macrophages for the induction of type 2 immune responses. [Journal Article]
- NINat Immunol 2018; 19(6):547-560
- The adaptor CARD9 functions downstream of C-type lectin receptors (CLRs) for the sensing of microbial infection, which leads to responses by the TH1 and TH17 subsets of helper T cells. The single-nuc...
The adaptor CARD9 functions downstream of C-type lectin receptors (CLRs) for the sensing of microbial infection, which leads to responses by the TH1 and TH17 subsets of helper T cells. The single-nucleotide polymorphism rs4077515 at CARD9 in the human genome, which results in the substitution S12N (CARD9S12N), is associated with several autoimmune diseases. However, the function of CARD9S12N has remained unknown. Here we generated CARD9S12N knock-in mice and found that CARD9S12N facilitated the induction of type 2 immune responses after engagement of CLRs. Mechanistically, CARD9S12N mediated CLR-induced activation of the non-canonical transcription factor NF-κB subunit RelB, which initiated production of the cytokine IL-5 in alveolar macrophages for the recruitment of eosinophils to drive TH2 cell-mediated allergic responses. We identified the homozygous CARD9 mutation encoding S12N in patients with allergic bronchopulmonary aspergillosis and revealed activation of RelB and production of IL-5 in peripheral blood mononuclear cells from these patients. Our study provides genetic and functional evidence demonstrating that CARD9S12N can turn alveolar macrophages into IL-5-producing cells and facilitates TH2 cell-mediated pathologic responses.
- Feasibility of CXCR4-directed radioligand therapy in advanced diffuse large B cell lymphoma. [Journal Article]
- JNJ Nucl Med 2018 May 18
- We have recently reported on our experience with C-X-C-motif chemokine receptor 4- (CXCR4-) directed radioligand therapy (RLT) in multiple myeloma and acute leukemia. Methods: Six patients with heav...
We have recently reported on our experience with C-X-C-motif chemokine receptor 4- (CXCR4-) directed radioligand therapy (RLT) in multiple myeloma and acute leukemia. Methods: Six patients with heavily pre-treated relapsed diffuse large B cell lymphoma (DLBCL) (3 males, 3 females; aged, 54±8 years) underwent CXCR4-directed RLT in combination with conditioning chemotherapy and allogeneic stem cell transplantation (SCT). In 2 patients, radioimmunotherapy (RIT) targeting CD20 or CD66 was added to enhance anti-lymphoma activity. Endpoints were incidence and severity of adverse events, progression-free and overall survival. Results: RLT as well as additional RIT were well-tolerated without any acute adverse events or changes in vital signs. Successful engraftment was recorded after a median of 11 days (range, 9-13 d). In the 4 patients who were available for follow-up (one patient died of CNS aspergillosis 29 days, another of sepsis in aplasia 34 days after after RLT), CXCR4-directed RLT resulted in partial response in 2/4 cases (both treated with additional RIT) and mixed response in the remaining 2 subjects. Response duration was rather short-lived with median progression-free survival of 62 days (range, 29-110 d) and median overall survival of 76 days (range, 29-313 d). Conclusion: CXCR4-directed RLT (in combination with additional RIT) as a conditioning regimen prior to allogeneic SCT in DLBCL is feasible.
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- Risk factors for lung disease progression in children with cystic fibrosis. [Journal Article]
- EREur Respir J 2018 May 17
- To identify potential risk factors for lung disease progression in children with cystic fibrosis (CF), we studied the longitudinal data of all children with CF (aged ≥5 years) registered in the Dutch...
To identify potential risk factors for lung disease progression in children with cystic fibrosis (CF), we studied the longitudinal data of all children with CF (aged ≥5 years) registered in the Dutch CF Registry (2009-2014). Lung disease progression was expressed as a decline in lung function (FEV1%pred) and the pulmonary exacerbation rate (PEx). Potential risk factors at baseline included: sex, age, best FEV1%pred, best forced vital capacity (FVC)%pred, genotype, BMI z-score, pancreatic insufficiency, medication use (proton pump inhibitors [PPI], prophylactic antibiotics, and inhaled corticosteroids), CF-related diabetes, allergic bronchopulmonary aspergillosis, and colonisation with Pseudomonas aeruginosaThe data of 545 children were analysed. PPI use was associated with both annual decline of FEV1%pred (p=0.017) and future PEx (p=0.006). Moreover, lower FEV1%pred at baseline (p=0.007), prophylactic inhaled antibiotics use (p=0.006), and PEx in the baseline year (p=0.002) were related to PEx in subsequent years.In a cohort of Dutch children with CF followed for five years, we were able to identify several risk factors for future exacerbations. Especially the association between PPI use and lung disease progression definitely requires further investigation.