Rationale: Supplemental oxygen is widely administered to ICU patients, but appropriate oxygenation targets remain unclear.Objectives: This study aimed to determine whether a low-oxygenation... Show moreRationale: Supplemental oxygen is widely administered to ICU patients, but appropriate oxygenation targets remain unclear.Objectives: This study aimed to determine whether a low-oxygenation strategy would lower 28-day mortality compared with a high-oxygenation strategy.Methods: This randomized multicenter trial included mechanically ventilated ICU patients with an expected ventilation duration of at least 24 hours. Patients were randomized 1:1 to a low-oxygenation (Pa-O2, 55-80mmHg; or oxygen saturation as measured by pulse oximetry, 91-94%) or high-oxygenation (Pa-O2, 110-150mmHg; or oxygen saturation as measured by pulse oximetry, 96-100%) target until ICU discharge or 28 days after randomization, whichever came first. The primary outcome was 28-day mortality. The study was stopped prematurely because of the COVID-19 pandemic when 664 of the planned 1,512 patients were included.Measurements and Main Results: Between November 2018 and November 2021, a total of 664 patients were included in the trial: 335 in the low-oxygenation group and 329 in the high-oxygenation group. The median achieved Pa-O2 was 75mmHg (interquartile range, 70-84) and 115mmHg (interquartile range, 100-129) in the low- and high-oxygenation groups, respectively. At Day 28, 129 (38.5%) and 114 (34.7%) patients had died in the low- and high-oxygenation groups, respectively (risk ratio, 1.11; 95% confidence interval, 0.9-1.4; P = 0.30). At least one serious adverse event was reported in 12 (3.6%) and 17 (5.2%) patients in the low- and high-oxygenation groups, respectively.Conclusions: Among mechanically ventilated ICU patients with an expected mechanical ventilation duration of at least 24 hours, using a low-oxygenation strategy did not result in a reduction of 28-day mortality compared with a high-oxygenation strategy. Show less
Heiden, P.L.J. van der; Arbous, M.S.; Beers, E.J. van; Bergh, W.M. van den; Cessie, S. le; Demandt, A.M.P.; ... ; HEMA-ICU Study Grp 2019
Following allogeneic stem cell transplantation (alloSCT), most patients experience a period of profound and prolonged T cell deficiency due to the immune suppression and/or T cell depletion (TCD... Show moreFollowing allogeneic stem cell transplantation (alloSCT), most patients experience a period of profound and prolonged T cell deficiency due to the immune suppression and/or T cell depletion (TCD). In this period the patients are at risk for developing infectious complications by reactivation of endogenous herpes like viruses cytomegalovirus (CMV), Epstein-Barr virus (EBV) and varicella zoster virus (VZV). Reactivation of endogenous CMV is the most frequently occurring herpes virus reactivation following alloSCT. Approximately 60% of alloSCT recipients are seropositive for CMV and are therefore at risk for endogenous reactivation of latent CMV. CMV reactivation can lead to potentially fatal CMV disease, comprising CMV pneumonitis, CMV colitis or CMV encephalitis. The aim of this thesis was to evaluate factors that influence the incidence of CMV disease after TCD alloSCT. These factors include the conditioning regimen, serostatus of the donor, pharmacological intervention following alloSCT and adoptive T cell transfer for treatment of refractory CMV reactivation or CMV disease. Show less
Heiden, P.L.J. van der; Egmond, H.M. van; Veld, S.A.J.; Meent, M. van de; Eefting, M.; Wreede, L.C. de; ... ; Jedema, I. 2018
BACKGROUND Persistent infections with herpesviruses such as human cytomegalovirus (HCMV) frequently occur after solid organ or stem cell transplantation, and are due to either failure of the host... Show moreBACKGROUND Persistent infections with herpesviruses such as human cytomegalovirus (HCMV) frequently occur after solid organ or stem cell transplantation, and are due to either failure of the host to immunologically control the virus or emerging resistance of the virus to the antiviral drug(s) used. Antiviral therapy can be guided by viral drug susceptibility testing based on screening for known resistance-inducing mutations in the viral genome. Mass spectrometry-based comparative sequence analysis (MSCSA) might be advantageous for this purpose because of its suitability for semi-automation. OBJECTIVES The applicability of MSCSA to detect sequence polymorphisms and drug resistance-inducing mutations in the HCMV genome was investigated. STUDY DESIGN We analyzed the 3' part of the HCMV UL97 gene, which encodes the kinase that is activated by the commonly used anti-HCMV drug ganciclovir. Sequences obtained by MSCSA of material from HCMV-infected patients (43 samples) and the HCMV type strain were compared to conventional cycle sequencing results. RESULTS In 94.1% of all samples the results obtained by MSCSA of the UL97 gene were identical to those from conventional cycle sequencing. The threshold to detect mutant sequences in a mixture with wild-type material was 20% using either technique. Furthermore, MSCSA was successfully applied to study the development of drug resistance in a patient who developed encephalitis due to ganciclovir-resistant HCMV. CONCLUSIONS MSCSA was found to be equally accurate compared to conventional cycle sequencing in the analysis of UL97 of HCMV. Show less
The innate immune system plays a pivotal role in the primary defence against invasive fungal infection. Genetic variation in genes that regulate this response, initiated by pulmonary macrophages,... Show moreThe innate immune system plays a pivotal role in the primary defence against invasive fungal infection. Genetic variation in genes that regulate this response, initiated by pulmonary macrophages, may influence susceptibility to invasive aspergillosis in patients at risk. We investigated in a clinical setting whether common polymorphisms in Toll-like receptor (TLR) and cytokine genes involved in macrophage regulation are associated with susceptibility to invasive aspergillosis. Forty-four allogeneic stem cell transplantation recipients diagnosed with probable or proven IA according to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group, were enrolled. The control group consisted of 64 allogeneic stem cell transplantation recipients without invasive aspergillosis. The TLR4 1063A>G single nucleotide polymorphism was associated with invasive aspergillosis when present in donors of allogeneic stem cell transplantation recipients (unadjusted OR 3.77 95% CI 1.08-13.2, p=0.03). In a multivariate analysis, adjusted for occurrence of graft-versus-host-disease, Cytomegalovirus serostatus and duration of neutropenia, paired presence of the TLR4 1063A>G and IFNG 874T>A single nucleotide polymorphisms showed a trend towards increased susceptibility to invasive aspergillosis (p=0.04). These findings point to the relevant immunological pathway involved in resistance to invasive aspergillosis and warrant further study of the effects of TLR and cytokine polymorphisms and their interaction, which may occur on different levels of the complex biological interplay between the immunocompromised host and Aspergillus sp. Show less
