This intercontinental study aimed to study gram-negative rod (GNR) resistance in hematopoietic stem cell transplantation (HSCT).
GNR bacteremias occurring during 6 months post-HSCT (February 2014-May ...2015) were prospectively collected, and analyzed for rates and risk factors for resistance to fluoroquinolones, noncarbapenem anti-Pseudomonas β-lactams (noncarbapenems), carbapenems, and multidrug resistance.
Sixty-five HSCT centers from 25 countries in Europe, Australia, and Asia reported data on 655 GNR episodes and 704 pathogens in 591 patients (Enterobacteriaceae, 73%; nonfermentative rods, 24%; and 3% others). Half of GNRs were fluoroquinolone and noncarbapenem resistant; 18.5% carbapenem resistant; 35.2% multidrug resistant. The total resistance rates were higher in allogeneic HSCT (allo-HSCT) vs autologous HSCT (auto-HSCT) patients (P < .001) but similar in community-acquired infections. Noncarbapenem resistance and multidrug resistance were higher in auto-HSCT patients in centers providing vs not providing fluoroquinolone prophylaxis (P < .01). Resistance rates were higher in southeast vs northwest Europe and similar in children and adults, excluding higher fluoroquinolone- and β-lactam/β-lactamase inhibitor resistance rates in allo-HSCT adults. Non-Klebsiella Enterobacteriaceae were rarely carbapenem resistant. Multivariable analysis revealed resistance risk factors in allo-HSCT patients: fluoroquinolone resistance: adult, prolonged neutropenia, breakthrough on fluoroquinolones; noncarbapenem resistance: hospital-acquired infection, breakthrough on noncarbapenems or other antibiotics (excluding fluoroquinolones, noncarbapenems, carbapenems), donor type; carbapenem resistance: breakthrough on carbapenem, longer hospitalization, intensive care unit, previous other antibiotic therapy; multidrug resistance: longer hospitalization, breakthrough on β-lactam/β-lactamase inhibitors, and carbapenems. Inappropriate empiric therapy and mortality were significantly more common in infections caused by resistant bacteria.
Our data question the recommendation for fluoroquinolone prophylaxis and call for reassessment of local empiric antibiotic protocols. Knowledge of pathogen-specific resistance enables early appropriate empiric therapy. Monitoring of resistance is crucial.
NCT02257931.
Abstract
To describe reasons for initiation and evolution under isavuconazole (ISZ), a 2-year prospective and observational study was performed. Anonymized data collected during the first 3 months of ...treatment were indications of treatment, efficacy, overall survival (OS), evolution of toxicity markers, and ISZ trough levels. Fifty-one (26 invasive aspergillosis, 16 prophylaxis, and 9 mucormycosis) patients started on isavuconazole. Isavuconazole was initiated upfront in 12/51 cases, especially to avoid toxicities from other antifungals. As second-line therapy (39/51 patients), isavuconazole was mostly initiated after toxicities of the previous treatments (66.7%; 26/39 cases). An improvement in toxicity markers was reported in most patients. However, five patients experienced adverse events. The mean ISZ trough levels measured from 179 samples collected in 37 patients was 3.33 ± 1.64 mg/l. The mean ISZ through levels was significantly lower (P = .003) in alloHSCT recipients (3.10 ± 1.45 mg/l) than in other patients (3.76 ± 1.88 mg/l) but still within the expected range of efficacy. After 12 weeks, the OS was 69.2% (n = 18/26) in the invasive aspergillosis intention-to-treat (ITT) group and 44.4% (n = 4/9) in the mucormycosis ITT group. After 2 years, the OS was respectively 46.2% (n = 12/26) and 33.3% (n = 3/9) in these two groups.
Lay Summary
Isavuconazole is commonly prescribed as second-line therapy after the toxicity of a previous treatment. In most cases, an improvement is reported. The well tolerability of isavuconazole was associated with correct blood levels, even in alloHSCT recipients.
Summary
This 16‐month‐long multicentre retrospective study of 225 allogeneic haematopoietic stem cell transplantation (alloHSCT) recipients with COVID‐19 examines risk factors for severity and ...mortality, describing the successive waves of infections (from March to June 2020 and from August 2020 to June 2021). We confirm the negative role of low respiratory tract disease and immunosuppressive treatment. We highlight significantly lower percentages of severe forms and COVID‐19‐related mortality during the second wave. Monthly comparative evolution of cases in alloHSCT recipients and in the French population shows a higher number of cases in alloHSCT recipients during the first wave and a decrease from February 2021.
Abstract
Background
Little is known about characteristics of seasonal human coronaviruses (HCoVs) (NL63, 229E, OC43, and HKU1) after allogeneic stem cell transplantation (allo-HSCT).
Methods
This was ...a collaborative Spanish and European bone marrow transplantation retrospective multicenter study, which included allo-HSCT recipients (adults and children) with upper respiratory tract disease (URTD) and/or lower respiratory tract disease (LRTD) caused by seasonal HCoV diagnosed through multiplex polymerase chain reaction assays from January 2012 to January 2019.
Results
We included 402 allo-HSCT recipients who developed 449 HCoV URTD/LRTD episodes. Median age of recipients was 46 years (range, 0.3–73.8 years). HCoV episodes were diagnosed at a median of 222 days after transplantation. The most common HCoV subtype was OC43 (n = 170 38%). LRTD involvement occurred in 121 episodes (27%). HCoV infection frequently required hospitalization (18%), oxygen administration (13%), and intensive care unit (ICU) admission (3%). Three-month overall mortality after HCoV detection was 7% in the whole cohort and 16% in those with LRTD. We identified 3 conditions associated with higher mortality in recipients with LRTD: absolute lymphocyte count <0.1 × 109/mL, corticosteroid use, and ICU admission (hazard ratios: 10.8, 4.68, and 8.22, respectively; P < .01).
Conclusions
Seasonal HCoV after allo-HSCT may involve LRTD in many instances, leading to a significant morbidity.
Seasonal human coronavirus infection in allogeneic stem cell transplant recipients was associated with considerable morbidity, in particular in those who had radiological signs of pulmonary involvement. Three-month mortality was 7% in the whole cohort and 16% in those with pulmonary involvement.
Mobilized peripheral blood has become the predominant stem cell source for allogeneic hematopoietic cell transplantation. In this retrospective single center study of 442 patients with hematologic ...malignancies, we analyzed prognostic factors for long-term survival after peripheral blood stem cell transplantation from HLA-matched related or unrelated donors. To account for disease/status heterogeneity, patients were risk-stratified according to the Disease Risk Index. Five-year overall survival was similar after transplants with matched related and unrelated donors (45% and 46%, respectively; P=0.49). Because donor age ≥60 years impacted outcome during model building, we further considered 3 groups of donors: matched unrelated (aged <60 years by definition), matched related aged <60 years and matched related aged ≥60 years. In multivariate analysis, the donor type/age group and the graft CD34(+) and CD3(+) cell doses impacted long-term survival. Compared with matched unrelated donor transplant, transplant from matched related donor <60 years resulted in similar long-term survival (P=0.67) while transplant from matched related donor ≥60 years was associated with higher risks for late mortality (hazard ratio (HR) 4.41; P=0.006) and treatment failure (HR: 6.33; P=0.009). Lower mortality risks were observed after transplant with CD34(+) cell dose more than 4.5×10(6)/kg (HR: 0.56; P=0.002) and CD3(+) cell dose more than 3×10(8)/kg (HR: 0.61; P=0.01). The Disease Risk Index failed to predict survival. We built an "adapted Disease Risk Index" by modifying risks for myeloproliferative neoplasms and multiple myeloma that improved stratification ability for progression-free survival (P=0.04) but not for overall survival (P=0.82).
Complement activation has shown a role in murine models of graft-versus-host disease (GVHD) and in endothelial complications after allogeneic hematopoietic cell transplantation (allo-HSCT). However, ...its impact on post-transplant outcomes has not been so far fully elucidated. Here, we conducted a prospective multicentric trial (NCT01520623) performing serial measurements of complement proteins, regulators, and CH50 activity for 12 weeks after allo-HSCT in 85 patients receiving a myeloablative conditioning (MAC) regimen for various hematological malignancies. Twenty-six out of 85 patients showed an "activated" complement profile through the classical/lectin pathway, defined as a post-transplant decline of C3/C4 and CH50 activity. Time-dependent Cox regression models demonstrated that complement activation within the first weeks after allo-HSCT was associated with increased non-relapse mortality (hazard ratio HR: 3.69, 95% confident interval CI: 1.55-8.78, p = .003) and poorer overall survival (HR: 2.72, 95% CI: 1.37-5.39, p = .004) due to increased incidence of grade II-IV acute GVHD and in particular gastrointestinal (GI) GVHD (HR: 36.8, 95% CI: 12.4-109.1, p < .001), higher incidences of thrombotic microangiopathy (HR: 8.58, 95% CI: 2.16-34.08, p = .0022), capillary leak syndrome (HR: 7.36, 95% CI: 2.51-21.66, p = .00028), post-engraftment bacterial infections (HR: 2.37, 95% CI: 1.22-4.63, p = .0108), and EBV reactivation (HR: 3.33, 95% CI: 1.31-8.45, p = .0112). Through specific immune staining, we showed the correlation of deposition of C1q, C3d, C4d, and of C5b9 components on endothelial cells in GI GVHD lesions with the histological grade of GVHD. Altogether these findings define the epidemiology and the clinical impact of complement classical/lectin pathway activation after MAC regimens and provide a rational for the use of complement inhibitory therapeutics in a post-allo-HSCT setting.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients show lower humoral vaccine responsiveness than immunocompetent individuals. HLA diversity, measured by the HLA evolutionary ...divergence (HED) metrics, reflects the diversity of the antigenic repertoire presented to T cells, and has been shown to predict response to cancer immunotherapy. We retrospectively investigated the association of HED with humoral response to SARS-CoV-2 vaccine in allo-HSCT recipients. HED was calculated as pairwise genetic distance between alleles at HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 loci in recipients and their donors. Low anti-spike IgG levels (<30 BAU/mL) were associated with short time from allo-SCT and low donor DPB1-HED, mostly related to donor DPB1 homozygosity. The diversity of donor HLA-DP molecules, assessed by heterozygosity or sequence divergence, may thus impact the efficacy of donor-derived CD4 T cells to sustain vaccine-mediated antibody response in allo-HSCT recipients.
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•Hematopoietic stem cell transplant recipients have impaired response to SARS-CoV-2 vaccine•HLA-DPB1 divergence in the donor is associated with low levels of anti-spike IgG•Donor HLA-DPB1 homozygosity is associated with no SARS-CoV-2 vaccine response
Immunology; Virology Highlights Hematopoietic stem cell transplant recipients have impaired response to SARS-CoV-2 vaccine HLA-DPB1 divergence in the donor is associated with low levels of anti-spike IgG Donor HLA-DPB1 homozygosity is associated with no SARS-CoV-2 vaccine response
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