scholarly journals Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5394-5402 ◽  
Author(s):  
Cristina Cunha ◽  
Mauro Di Ianni ◽  
Silvia Bozza ◽  
Gloria Giovannini ◽  
Silvia Zagarella ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Invasive Aspergillosis ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Mononuclear Cells ◽  
Stop Codon ◽  
Hematopoietic Stem ◽  
Antifungal Immunity

Abstract The C-type lectin receptor Dectin-1 plays a pivotal role in antifungal immunity. In this study, the recently characterized human DECTIN1 Y238X early stop codon polymorphism leading to diminished Dectin-1 receptor activity was studied in relation to invasive aspergillosis susceptibility and severity in patients receiving hematopoietic stem cell transplantation. We found that the presence of the DECTIN1 Y238X polymorphism in either donors or recipients of hematopoietic stem cell transplantation increased susceptibility to aspergillosis, with the risk being highest when the polymorphism was present simultaneously in both donors and recipients (adjusted hazard ratio = 3.9; P = .005). Functionally, the Y238X polymorphism impaired the production of interferon-γ and interleukin-10 (IL-10), in addition to IL-1β, IL-6, and IL-17A, by human peripheral mononuclear cells and Dectin-1 on human epithelial cells contributed to fungal recognition. Mechanistically, studies on preclinical models of infection in intact or bone marrow-transplanted Dectin-1 knockout mice revealed that protection from infection requires a distinct, yet complementary, role of both donor and recipient Dectin-1. This study discloses Dectin-1 deficiency as a novel susceptibility factor for aspergillosis in high-risk patients and identifies a previously unsuspected role for Dectin-1 in antifungal immunity that is the ability to control both resistance and tolerance to the fungus contingent on hematopoietic/nonhematopoietic compartmentalization.

scholarly journals Therapeutic Drug Monitoring of Posaconazole in Allogeneic Hematopoietic Stem Cell Transplantation Patients Who Develop Gastrointestinal Graft-versus-Host Disease

2012 ◽  
Vol 56 (10) ◽  
pp. 5247-5252 ◽  
Author(s):  
J. Tonini ◽  
A. Thiébaut ◽  
J. F. Jourdil ◽  
A. S. Berruyer ◽  
C. E. Bulabois ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Invasive Aspergillosis ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Interindividual Variability ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Drug Concentrations

ABSTRACTPosaconazole (PCZ) is the latest triazole antifungal agent that has been approved for prophylaxis of invasive aspergillosis in high-risk immunocompromised patients, such as allogeneic hematopoietic stem cell transplantation patients, who develop graft-versus-host disease (GVHD). PCZ has high interindividual variability with regard to its plasma drug trough concentrations (Cmin). Moreover, the concentration-efficiency relationship remains to be better characterized in prophylaxis. To determine the variability factors in plasma drug concentrations, the PCZCminand clinical parameters (localization of GVHD, presence of diarrhea, and diagnosis of invasive aspergillosis) were collected retrospectively in 29 consecutive allogeneic hematopoietic stem cell transplantation patients who developed GVHD and were receiving prophylactic PCZ (200 mg, 3 times/day, for ≥7 days). Blood samples were analyzed at steady state to determine the PCZCminby liquid chromatography-tandem mass spectrometry. The average PCZCminwas 1.28 ± 0.82 mg/liter (mean ± standard deviation;n= 292 dosages), with an intraindividual variability of 49% and an interindividual variability of 64%. Twenty percent ofCmins were below 0.7 mg/liter, which is considered the threshold of efficacy by the Food and Drug Administration. The patients who had gastrointestinal (GI) GVHD experienced a 24% reduction in the posaconazoleCmin, compared with those with other localizations of GVHD. This decrease reached 33% when patients presented with diarrhea due to GI GVHD or an infectious etiology. PCZCmins were 26% lower when invasive aspergillosis was declared. These data demonstrate that GI disturbances affect drug concentrations. Thus, therapeutic monitoring of PCZ can be used to detect low drug concentrations, possibly resulting in a lack of efficacy of invasive aspergillosis prophylaxis.

scholarly journals The importance of CD34 positive cell quantification for Hematopoietic stem cell mobilization

JBMTCT ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. p94
Author(s):  
Patricia Elkiki dos Santos
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Mononuclear Cells ◽  
Leukocyte Count ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Significant Difference

Abstract Objective: The success of autologus hematopoietic stem cell transplantation relies on CD34+ cells' availability in peripheral blood (PB),  which is affected by several factors as age, sex, type of the disease, treatments, and others. In that regard, this prospective study aimed to evaluate the influence of these factors, correlating them with the pre-apheresis CD34+ cell count. Method: Before autologous hematopoietic stem cell transplantation, CD34+ cells were quantified in the pre-apheresis PB and the final product. Then, after the determination of minimum CD34+ value, clinical and laboratory parameters were compared between patients with higher and lower CD34+ cells count. Results: Out of the 34 patients, 29 presented more than 20,000 leukocytes/μl. Patients who failed in the mobilization presented <20,000 leukocytes/μl. There was a significant difference between the groups with different pre-apheresis CD34+ cells status regarding age (p=0.025), leukocyte count (p<0.001) and mononuclear cells (p=0.001) in PB. In addition, the pre-apheresis CD34+ ≥14 cells/μl group was related to a better yield of these cells in the final product and with the requirement of a single collection to obtain the minimum yield, of 2x106 CD34+/kg. Conclusion: This study demonstrates age and leukocyte count relate to CD34+ count in PB, and that CD34+ cells yield in the collection, can be predicted by  CD34+ cells frequency in PB.

Micafungin Versus Fluconazole Or Itraconazole For Prophylaxis Against Invasive Fungal Infections During Neutropenia In Patients Undergoing Haplo-Identical Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4564-4564
Author(s):  
el-Cheikh Jean ◽  
Crocchiolo Roberto ◽  
Fürst Sabine ◽  
Bramanti Stefania ◽  
Sarina Barbara ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Invasive Aspergillosis ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Fungal Infections ◽  
Conditioning Regimen ◽  
Invasive Fungal Infections ◽  
Hematopoietic Stem

Objectives Over the past decade, invasive fungal infections (IFI) have remained an important problem in patients undergoing hematopoietic stem cell transplantation (HSCT). The optimal approach for prophylactic antifungal therapy has yet to be determined. Patients and Methods we conducted a retrospective, bi-institutional comparative clinical study, (Institut Paoli-Calmettes at Marseille France and Humanitas cancer center at Rozzano, Italy), and we compared the efficacy and safety of Micafungin 50mg/day (iv) with those of fluconazole (400mg/day) or itraconazole 200mg/day (iv) as prophylaxis for adult patients with various haematological diseases receiving haplo-identical allogeneic stem cell transplantation (haplo-SCT). Patients received prophylaxis with the beginning of the transplant conditioning regimen until the hospital discharge, or until occurrence of an IFI. We compared the incidence of proven or probable IFI (the primary end point) between the micafungin and fluconazole or itraconazole groups; death from any cause and time to death was secondary end points. Patients were followed for 100 days after haplo-SCT and for 30 days after the last dose of the prophylaxis drug administrated. Results From January 2009 to May 2013, a total of 99 patients were identified; 30 patients received micafungin, and 69 patients received fluconazole or itraconazole. 81 patients (82%) received a non myeloabaltive conditioning regimen (NMA), with Fludarabine, Cyclophosphamide and Total body irradiation (TBI) 2 Gy based , or Fludarabine, Busulfan, and Cyclophosphamide based (3%) or other (9%), while five patients (5%) received a thiotepa-based conditioning regimen. The patients and transplant details are shown in the table 1. Proven or probable invasive fungal infections were reported in 2 patients (7%) in the micafungin group and 8 patients (12%) in the fluconazole or itraconazole group (absolute reduction in the micafungin group, −5%; 95% confidence interval, 0.0565-3.1395, P=0.72). Fewer patients in the micafungin group had invasive aspergillosis (1 [3%] vs. 5 [7%], P=0.6). A total of 4 (13%) patients in the micafungin group and 23 (33%) patients in the fluconazole or itraconazole group received empirical antifungal therapy (P = 0.14). No serious adverse events related to treatment were reported by patients and there was no treatment discontinuation because of drug related adverse event in both groups. Overall Survival and disease free survival were similar among the two groups (P = 0.97). 6 patients (20%) in the micafungin group died within 100 days, as did 10 patients (14%) in the fluconazole or itraconazole group (P = 0.57). Interestingly the transplant related mortality (TRM) at 100 days was 0% in the micafungin group vs 13% in the second group [CI 95% (0-22)] (p=0,06), whereas the relapse or progression rate at 100 days was 27% vs. 8% respectively [CI 95% (14-44)] (p=0,14). Conclusions In patients undergoing to haplo-SCT, antifungal prophylaxis with micafungin is well tolerated and effective to prevent IFI. Furthermore, the incidence of IFI and invasive aspergillosis seems lower even if this did not attend statistical power, probably due to low number of patients. Disclosures: No relevant conflicts of interest to declare.

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