Single-cell gene profiling of human regulatory T cell subsets in human graft-versus-host disease

International audiencen.

Upper and/or lower respiratory tract infection caused by human metapneumovirus after allogeneic hematopoietic stem cell transplantation.

peer reviewed[en] PATIENTS AND METHODS: This retrospective multicenter cohort study examined the epidemiology, clinical characteristics, and risk factors for poor outcomes associated with human metapneumovirus (hMPV) infections in recipients of allogeneic stem cell transplantation (allo-HCT). RESULTS: We included 428 allo-HCT recipients who developed 438 hMPV infection episodes between January 2012 and January 2019. Most recipients were adults (93%). hMPV infections were diagnosed at a median of 373 days after allo-HCT. The infections were categorized as upper respiratory tract disease (URTD) or lower respiratory tract disease (LRTD), with 60% and 40% of cases, respectively. Patients with hMPV LRTD experienced the infection earlier in the transplant course and had higher rates of lymphopenia, neutropenia, corticosteroid use, and ribavirin therapy. Multivariate analysis identified lymphopenia and corticosteroid use (>30 mg/d) as independent risk factors for LRTD occurrence. The overall mortality at day 30 after hMPV detection was 2% for URTD, 12% for possible LRTD, and 21% for proven LRTD. Lymphopenia was the only independent risk factor associated with day 30 mortality in LRTD cases. CONCLUSIONS: These findings highlight the significance of lymphopenia and corticosteroid use in the development and severity of hMPV infections after allo-HCT, with lymphopenia being a predictor of higher mortality in LRTD cases

Outcomes in critically ill chronic lymphocytic leukemia patients

International audienceBACKGROUND:Although recent studies have demonstrated an improvement in the prognosis of critically ill cancer patients, little is known regarding the prognosis of patients with non-aggressive underlying malignancies. The aims of this study were to assess the prognosis of critically ill patients with chronic lymphocytic leukemia (CLL) and to evaluate risk factors for hospital mortality.METHODS:In retrospective mono-center cohort study, consecutive adult patients with CLL requiring ICU admission from 1997 to 2008 were included.RESULTS:Sixty-two patients of 67 years (62-75) were included. Median time interval between CLL diagnosis and ICU admission was 6.7 years (2.6-10.8). Nine patients (15 %) had stage C disease at the time of ICU admission, and seven patients (11 %) had Richter syndrome. Most ICU admissions were related to bacterial or fungal pulmonary infections (n = 47; 76 %). ICU, in-hospital, and 90-day mortality were 35 % (n = 22), 42 % (n = 26), and 58 % (n = 36), respectively. Only three factors were independently associated with in-hospital mortality: oxygen saturation lower than 95 % when breathing room air (odds ratio (OR) 5.80; 95 % confidence interval (CI) 1.23-27.33), need for vasopressors (OR 27.94; 95 % CI 5.37-145.4), and past history of infection (OR 6.62; 95 % CI 1.34-32.68). The final model did not change when disease-related variables (Binet classification, Richter syndrome, long-term steroids) or treatment-related variables (fludarabine, rituximab, or alemtuzumab) were included.CONCLUSION:Acute pulmonary infections remain the leading cause of ICU admission in patients with CLL. The severity at ICU admission and past history of infection were the only factors associated with hospital mortality. Neither disease characteristics nor previous cancer treatments were associated with outcome

Pre-transplant prognostic factors of long-term survival after allogeneic peripheral blood stem cell transplantation with matched related/unrelated donors

Mobilized peripheral blood has become the predominant stem cell source for allogeneic hematopoietic cell transplantation. Few studies have compared outcome of HLA-matched related and HLA-matched unrelated donor peripheral blood stem cell transplants. We conducted a retrospectivesingle-center analysis of 442 patients with hematologic malignancies who underwent peripheral blood stem cell transplantationfrom matched related or matched unrelated donorand we analyzed prognostic factors for long-term survival.To account for disease/status heterogeneity, patients were risk-stratified according to theDisease Risk Index.Five-year overall survival was similar aftertransplants with matched related and unrelated donor. Because donor age ≥60 years impacted outcome during model building, we further considered 3 groups of donors: matched unrelated donor (aged 4.5 x 106/kgand CD3+ cell dose > 3 x 108/kg. The Disease Risk Index failed to predictsurvival. We builtan “Adapted Disease Risk Index” by modifying risks for myeloproliferative neoplasms and multiple myeloma, thatimproved stratification ability for progression-free survivalbut not for overall survival

GLCCI1 and Glucocorticoid Receptor Genetic Diversity and Response to Glucocorticoid-Based Treatment of Graft-versus-Host Disease

AbstractThe genetic diversity of loci implicated in glucocorticoid (GC) response has been associated with interindividual variations in responsiveness to GC in various diseases, such as asthma and inflammatory bowel disorders. In acute graft-versus-host disease (aGVHD), similar differences of first-line therapy responsiveness are also observed, with approximately 40% of patients failing to respond to GC. Here, the distribution of functionally relevant single nucleotide polymorphisms (SNP) belonging to the GC-induced transcript 1 GLCCI1 (rs37972) and the glucocorticoid receptor (rs41423247, rs6195 and rs6198) gene loci were analyzed alongside clinical factors for their association with the response to corticosteroids in aGVHD. The frequencies of variant alleles did not differ significantly between corticoresistant patients, their donors, and their corticosensitive peers (P = .10 to 1.00). Severe and early onset of aGVHD, bone marrow as the stem cell source, and an HLA mismatch were associated with the failure to respond to GC in logistic regression. After including the single SNPs to the model, carriers of the rs41423247 polymorphism had a higher probability of responding to GC, whereas all other polymorphisms did not affect the likelihood of response

Hepatitis E and Allogeneic Hematopoietic Stem Cell Transplantation: A French Nationwide SFGM-TC Retrospective Study

International audienceUsually self-limited, hepatitis E virus (HEV) infection may evolve to chronicity and cirrhosis in immunosuppressed patients. HEV infection has been described in solid-organ transplantation and hematology patients, but for allogeneic hematopoietic stem cell transplant (alloHSCT) recipients, only small cohorts are available. This retrospective nationwide multi-center series aimed to describe HEV diagnostic practices in alloHSCT French centers, and the course of infection in the context of alloHSCT. Twenty-nine out of 37 centers participated. HEV search in case of liver function tests (LFT) abnormalities was never performed in 24% of centers, occasionally in 55%, and systematically in 21%. Twenty-five cases of active HEV infection were diagnosed in seven centers, all because of LFT abnormalities, by blood nucleic acid testing. HEV infection was diagnosed in three patients before alloHSCT; HEV infection did not influence transplantation planning, and resolved spontaneously before or after alloHSCT. Twenty-two patients were diagnosed a median of 283 days after alloHSCT. Nine patients (41%) had spontaneous viral clearance, mostly after immunosuppressive treatment decrease. Thirteen patients (59%) received ribavirin, with sustained viral clearance in 11/12 evaluable patients. We observed three HEV recurrences but no HEV-related death or liver failure, nor evolution to cirrhosis

Long term Immune Reconstitution and infection burden after Mismatched Hematopoietic Stem Cell Transplantation

Mismatched unrelated donor (MMUD) or umbilical cord blood (UCB) can be chosen as alternative donors for allogeneic stem cell transplantation but might be associated with long lasting immune deficiency. Sixty-six patients who underwent a first transplantation from either UCB or 9/10 MMUD (n= 36) and who survived beyond 3 months were evaluated. Immune reconstitution was prospectively assessed at sequential time points after transplantation. NK, B, CD4+ and CD8+T cells and their subsets as well as regulatory T cells (Treg) were studied. Detailed analyses on infections occurring after 3 months were also assessed. The 18-month cumulative incidences of infection-related death were 8 and 3%, and of infections were 72 and 57% after MMUD and UCB transplantation, respectively. Rates of infection per 12 patient-month were roughly 2 overall (1 for bacterial, 0.9 for viral and 0.3 for fungal infections). Memory, naïve CD4+ and CD8+T cells, naïve B cells and Treg cells reconstitution between the 2 sources was roughly similar. Absolute CD4+T cells hardly reached 500 per μL by one year posttransplantation and most B cells were of naïve phenotype. Correlations between immune reconstitution and infection were then performed by multivariate analyses. Low CD4+ and high CD8+T cells absolute counts at 3 months were linked to increased risks of overall and viral (but not bacterial) infections. When assessing for the naïve/memory phenotypes at 3 months among the CD4+ T cell compartment, higher percentages of memory subsets were protective against late infections: central memory CD4+T cells protected against overall and bacterial infections; late effector memory CD4+T cells protected against overall, bacterial and viral infections. At the opposite, high percentage of effector- and late effector-memory subsets at 3 months among the CD8+ T cell compartment predicted higher risks for viral infections. Patients transplanted from alternative donors represent a population with very high risk of infection. Detailed phenotypic analysis of immune reconstitution may help to evaluate infection risk and to adjust infection prophylaxis