The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group IMPORTANCE Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.OBJECTIVE To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.DATA SOURCES Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.STUDY SELECTION Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. DATA EXTRACTION AND SYNTHESISIn this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I 2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. MAIN OUTCOMES AND MEASURESThe primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.RESULTS A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). CONCLUSIONS AND RELEVANCEIn this prospective meta-analysis of clinical trials of patients hosp...

Background Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. Methods The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. Results The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March–May 2020) and the second wave (October–December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases. Conclusions This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases.

No abstract

© F e r r a t a S t o r t i F o u n d a t i o norder to decrease the lag time for CTL transfer. Among other things, interferon-gamma capture of virus-specific CTL and allogeneic CTL banks containing CTL against the most common HLA haplotypes have been used with some success. 16,22,23 Our group has tried separation of peptide-specific T cells with the help of magnetic beads and MHC multimers. 17,18 Even though this has shown promising results, none of these strategies is yet part of standard clinical practice.In this retrospective analysis we analyzed possible risk factors associated with the development of PTLD after SCT at our center. The earlier part of the cohort of patients was previously included in the studies by Sundin et al. and Omar et al. 1,24 We found several factors that were independently associated with an increased risk of PTLD. Some of the factors seem to act synergistically, which adds additional risk of PTLD in the patients. Moreover, in spite of improved prophylaxis and rituximab use, the long-term survival of affected patients is poor. Methods PatientsIn total 1021 patients who underwent SCT at Karolinska University Hospital in Huddinge, Stockholm, between 1996 and 2011 were included in this retrospective analysis of risk factors for and clinical outcome of PTLD. This study was approved by the regional ethical committee in Stockholm (n. 425/97). A review of patients' charts and the clinical database identified 40 cases of verified PTLD. The characteristics of patients with and without PTLD are displayed in Table 1. Diagnosis and treatment of Epstein-Barr virus-associated post-transplant lymphoproliferative diseaseThe diagnosis of PTLD was made according to the histological criteria reported for B-cell lymphoproliferative states following transplantation. 25 After July 2005 (total of 446 individuals) all patients considered to be at high risk of developing PTLD were screened weekly or biweekly for EBV during the first 3 months post-SCT. In patients at low risk, quantitative polymerase chain reaction (PCR) analysis was performed if EBV reactivation was suspected. From July 2005 all patients were treated with rituximab if the EBV load was >10 000 copies/mL. Thirty-five of the patients were treated with rituximab. More details are available in the Online Supplementary Methods section.Conditioning regimen, graft-versus-host disease prophylaxis and stem-cell source RIC was used in 402 patients, while myeloablative conditioning was given to 619 patients. Antithymocyte globulin (ATG) was given to 705 patients as part of the conditioning with the last dose on day -1. ATG was used in all patients with an unrelated or mismatched donor and in all patients with a non-malignant disease, independently of the type of donor. A few patients with a sibling donor treated with RIC (n=44) were also given ATG. The graft source was bone marrow in 361 cases, peripheral blood in 608 and umbilical cord blood in 52. For more details regarding conditioning regimens, GVHD prophylaxis and stem-cell source see th...

We analyzed the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) over the past 2 decades. Between 1992 and 2009, 953 patients were treated with HSCT, mainly for a hematologic malignancy. They were divided according to 4 different time periods of treatment: 1992 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2009. Over the years, many factors have changed considerably regarding patient age, diagnosis, disease stage, type of donor, stem cell source, genomic HLA typing, cell dose, type of conditioning, treatment of infections, use of granulocyte-colony stimulating factor (G-CSF), use of mesenchymal stem cells, use of cytotoxic T cells, and home care. When we compared the last period (2006-2009) with earlier periods, we found slower neutrophil engraftment, a higher incidence of acute graft-versus-host disease (aGVHD) of grades II-IV, and less chronic GVHD (cGHVD). The incidence of relapse was unchanged over the 4 periods (22%-25%). Overall survival (OS) and transplant-related mortality (TRM) improved significantly in the more recent periods, with the best results during the last period (2006-2009) and a 100-day TRM of 5.5%. This improvement was also apparent in a multivariate analysis. When correcting for differences between the 4 groups, the hazard ratio for mortality in the last period was 0.59 (95% confidence interval [CI]: 0.44-0.79; P < .001) and for TRM it was 0.63 (CI: 0.43-0.92; P = .02). This study shows that the combined efforts to improve outcome after HSCT have been very effective. Even though we now treat older patients with more advanced disease and use more alternative HLA nonidentical donors, OS and TRM have improved. The problem of relapse still has to be remedied. Thus, several different developments together have resulted in significantly lower TRM and improved survival after HSCT over the last few years.

Background Bloodstream infection (BSI) after allogeneic hematopoietic stem cell transplantation (HSCT) is a well‐known complication during the pre‐engraftment phase. Knowledge of trends in etiology and antibiotic susceptibility of BSI is important as the time to effective antibiotic treatment is closely associated with survival in bacteremic patients with septic shock. Methods BSI during the pre‐engraftment phase was studied retrospectively in 521 patients undergoing HSCT at our center in 2001–2008. Incidence, risk factors, outcome, and microbiology findings were investigated and compared with BSI in a cohort transplanted during 1975–1996. Results The incidence of at least 1 episode of BSI was 21%, the total attributable mortality of BSI was 3.3%, and crude mortality at day 120 after transplantation was 21%. The rate of gram‐positive and gram‐negative BSI was 80% and 13%, respectively. Gram‐negative BSI was more frequent both in 2001–2004 and in 2005–2008 compared with 1986–1996 (P = 0.023 for 2001–2004, P = 0.001 for 2005–2008), with fluoroquinolone‐resistant Escherichia coli as the predominant finding. BSI with viridans streptococci and E. coli occurred significantly earlier after HSCT than BSI with Enterococcus species, with median time of 4, 8, and 11 days, respectively (P < 0.01 both for viridians streptococci vs. Enterococcus species, and E. coli vs. Enterococcus species). Risk factors for BSI in multivariate analysis were transplantation from unrelated donor and cord blood as stem cell source, whereas peripheral blood as stem cell source was protective. Conclusions Despite low attributable mortality of BSI, crude mortality at day 120 after transplantation was 21%, indicating an association between BSI and other risk factors for death. The risk of gram‐negative BSI increased over time in parallel with an increased rate of quinolone resistance. However, the incidence and attributable mortality of gram‐negative BSI remained low. Thus, prophylaxis with ciprofloxacin is still deemed appropriate, but continued assessments of the risk and benefits of fluoroquinolone prophylaxis must be performed.

We performed a retrospective cohort study to find out whether the use of reduced-intensity conditioning (RIC) might reduce the risk of early death from pneumonia. Pneumonia-associated deaths were evaluated in 691 hematopoietic stem cell transplantation (HSCT) patients. The majority had a hematological malignancy (n = 504) and an HLA-matched donor (n = 584). RIC was given to 336 patients and myeloablative conditioning (MAC) to 355. Data concerning radiology, culture and autopsy results were evaluated together with risk factors for death related to pneumonia within or after 100 d after HSCT (early and overall pneumonia). In 60 patients, pneumonia contributed to death (early n = 17). The cumulative incidence of early pneumonia-related death was 2.8% and 2.1% in MAC and RIC patients, respectively. The cumulative incidence of overall pneumonia-related death was 8.2% and 10.5%, respectively. In 40 patients, (67%) an etiology could be established, with 19 patients having proven or probable mold infection. In the multivariate analyses, acute graft-versus-host disease (GVHD) grades II-IV, cytomegalovirus (CMV) infection and having received mesenchymal stromal cells (MSCs) were factors associated with overall pneumonia-related death. Bacteremia and a previous HSCT were associated with early pneumonia-related death. RIC did not reduce the incidence of early death associated with pneumonia. Acute GVHD II-IV, CMV infection and MSC treatment were factors associated with pneumonia-related death. Mold infection was the most common contributor to pneumonia-related death in HSCT patients.

Vitamin D has emerged as a central player in the immune system, with its deficiency being implicated in the pathogenesis of several autoimmune diseases, including chronic GvHD. This is a retrospective cohort analysis of 166 patients, who underwent allogeneic hematopoietic stem cell transplantation (HSCT) at the Karolinska University Hospital, evaluating GvHD, graft failure, infectious complications and survival after HSCT in relation to pre-transplantation vitamin D levels. Most of the patients were deficient in vitamin D before HSCT (median 42 nmol/L). In multivariate analysis, vitamin D level before HSCT was identified as a significant independent risk factor for development of cGvHD. The increased incidence of cGvHD was not coupled to better disease-free survival; instead there was a trend towards lower overall survival in the vitamin D-deficient patients. In addition, we found a significant correlation between vitamin D deficiency and incidence of CMV disease, with no case of CMV disease occurring in patients with sufficient levels of vitamin D before HSCT. Our results support a role of vitamin D in immune tolerance following HSCT. These findings could be highly relevant for the care of HSCT patients, and prospective, randomized studies on the effect of vitamin D supplementation are therefore needed.