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Respiratory distress syndrome (RDS) care pathways evolve slowly as new evidence emerges. We report the sixth version of “European Guidelines for the Management of RDS” by a panel of experienced European neonatologists and an expert perinatal obstetrician based on available literature up to end of 2022. Optimising outcome for babies with RDS includes prediction of risk of preterm delivery, appropriate maternal transfer to a perinatal centre, and appropriate and timely use of antenatal steroids. Evidence-based lung-protective management includes initiation of non-invasive respiratory support from birth, judicious use of oxygen, early surfactant administration, caffeine therapy, and avoidance of intubation and mechanical ventilation where possible. Methods of ongoing non-invasive respiratory support have been further refined and may help reduce chronic lung disease. As technology for delivering mechanical ventilation improves, the risk of causing lung injury should decrease, although minimising time spent on mechanical ventilation by targeted use of postnatal corticosteroids remains essential. The general care of infants with RDS is also reviewed, including emphasis on appropriate cardiovascular support and judicious use of antibiotics as being important determinants of best outcome. We would like to dedicate this guideline to the memory of Professor Henry Halliday who died on November 12, 2022.These updated guidelines contain evidence from recent Cochrane reviews and medical literature since 2019. Strength of evidence supporting recommendations has been evaluated using the GRADE system. There are changes to some of the previous recommendations as well as some changes to the strength of evidence supporting recommendations that have not changed. This guideline has been endorsed by the European Society for Paediatric Research (ESPR) and the Union of European Neonatal and Perinatal Societies (UENPS).

Introduction: donor-derived modified immune cells (MIC) induced long-term specific immunosuppression against the allogeneic donor in preclinical models of transplantation. In a phase I clinical trial (TOL-1 Study), MIC treatment resulted in a cellular phenotype that was directly and indirectly suppressive to the recipient's immune system allowing for reduction of conventional immunosuppressive therapy. Here, we describe a protocol for a randomised controlled, multicentre phase-IIb clinical trial of individualised immunosuppression with intravenously administered donor MIC compared with standard-of-care (SoC) in living donor kidney transplantation (TOL-2 Study). Methods and analysis: sixty-three living donor kidney transplant recipients from six German transplant centres are randomised 2:1 to treatment with MIC (MIC group, N=42) or no treatment with MIC (control arm, N=21). MIC are manufactured from donor peripheral blood mononuclear cells under Good Manufacturing Practice conditions. The primary objective of this trial is to determine the efficacy of MIC treatment together with reduced conventional immunosuppressive therapy in terms of achieving an operational tolerance-like phenotype compared with SoC 12 months after MIC administration. Key secondary endpoints are the number of patient-relevant infections as well as a composite of biopsy-proven acute rejection, graft loss, graft dysfunction or death. Immunosuppressive therapy of MIC-treated patients is reduced during follow-up under an extended immunological monitoring including human leucocyte antigen-antibody testing, and determination of lymphocyte subsets, for example, regulatory B lymphocytes (Breg) and antidonor T cell response. A Data Safety Monitoring Board has been established to allow an independent assessment of safety and efficacy. Ethics and dissemination: ethical approval has been provided by the Ethics Committee of the Medical Faculty of the University of Heidelberg, Heidelberg, Germany (AFmu-580/202, Preparation of the study was funded by the Federal Ministry of Education and Research, Berlin, Germany (FKZ 161B0560A, 161B0560B, and FKZ 031B0560A, 031B0560B), and TolerogenixX GmbH, Heidelberg, Germany (N/A). Conduct of the study is funded by TolerogenixX GmbH (N/A).

Objectives: humoral immunity wanes over time after two-dose BNT162b2 vaccination. Emerging variants of concern, such as the B.1.617.2 (delta) variant, are increasingly responsible for breakthrough infections owing to their higher transmissibility and partial immune escape. Longitudinal data on neutralization against the B.1.617.2 (delta) variant are urgently needed to guide vaccination strategies. Methods: in this prospective longitudinal observational study, anti-S1 IgG and surrogate neutralizing antibodies were measured in 234 collected samples from 60 health care workers after two-dose vaccination with BNT162b2 at five different time points over an 8-month period. In addition, antibodies against various severe acute respiratory syndrome coronavirus 2 epitopes, neutralization against wild-type, and cross-neutralization against the B.1.617.2 (delta) variant using a live virus assay were measured 6 weeks (second time point) and 8 months (last time point) after first vaccine dose. Results: median (interquartile range) anti-S1 IgG, surrogate neutralizing, and receptor-binding domain antibodies decreased significantly from a maximum level of 147 (102–298), 97 (96–98), and 20 159 (19 023–21 628) to 8 (4–13), 92 (80–96), and 15 324 (13 055–17 288) at the 8-month follow-up, respectively (p < 0.001 for all). Neutralization against the B.1.617.2 (delta) variant was detectable in all 36 (100%) participants at 6 weeks and in 50 of 53 (94%) participants 8 months after first vaccine dose. Median (interquartile) ID50 as determined by a live virus assay decreased from 160 (80–320) to 40 (20–40) (p < 0.001). Discussion: although humoral immunity wanes over time after two-dose BNT162b2 vaccination in healthy individuals, most individuals still had detectable neutralizing activity against the B.1.617.2 (delta) variant after 8 months., Dietmar Hopp Stiftung; Heidelberg Faculty of Medicine Rahel Goitein-Strauss Program; Heidelberg Faculty of Medicine Physician Scientist Program; German Federal Research Network Applied Surveillance and Testing (BFAST); Network University Medicine; DKFZ@fightCOVID; Helmholtz Association Initiative and Networking Fund Project Virological and Immunological Determinants of COVID-19 Pathogenesis

Hemodialysis patients are at high risk for severe COVID-19, and impaired seroconversion rates have been demonstrated after COVID-19 vaccination. Humoral immunity wanes over time and variants of concern with immune escape are posing an increasing threat. Little is known about protection against the B.1.617.2 (delta) variant of concern in hemodialysis patients before and after third vaccination. We determined anti-S1 IgG, surrogate neutralizing, and IgG antibodies against different SARS-CoV-2 epitopes in 84 hemodialysis patients directly before and three weeks after a third vaccine dose with BNT162b2. Third vaccination was performed after a median (IQR) of 119 (109-165) days after second vaccination. In addition, neutralizing activity against the B.1.617.2 (delta) variant was assessed in 31 seroconverted hemodialysis patients before and after third vaccination. Triple seropositivity for anti-S1 IgG, surrogate neutralizing, and anti-RBD antibodies increased from 31/84 (37%) dialysis patients after second to 80/84 (95%) after third vaccination. Neutralizing activity against the B.1.617.2 (delta) variant was significantly higher after third vaccination with a median (IQR) ID50 of 1:320 (1:160-1:1280) compared with 1:20 (0-1:40) before a third vaccine dose (P<0.001). The anti-S1 IgG index showed the strongest correlation with the ID50 against the B.1.617.2 (delta) variant determined by live virus neutralization (r=0.91). We demonstrate low neutralizing activity against the B.1.617.2 (delta) variant in dialysis patients four months after standard two-dose vaccination but a substantial increase after a third vaccine dose. Booster vaccination(s) should be considered earlier than 6 months after the second vaccine dose in immunocompromised individuals., Dietmar Hopp Stiftung; Heidelberg Faculty of Medicine Rahel Goitein-Strauss Program