Search

Background In the COVID-STEROID 2 trial there was suggestion of heterogeneity of treatment effects (HTE) between patients enrolled from Europe vs. India on the primary outcome. Whether there was HTE for the remaining patient-centred outcomes is unclear. Methods In this post hoc analysis of the COVID-STEROID 2 trial, which compared 12 mg vs. 6 mg dexamethasone in adults with COVID-19 and severe hypoxemia, we evaluated HTE by geographical region (Europe vs. India) for secondary outcomes with analyses adjusted for stratification variables. Results are presented as risk differences (RDs) or mean differences (MDs) with 99% confidence intervals (CIs) and P-values from interaction tests. Findings There were differences in mortality at day 28 (RD for Europe −8.3% (99% CI: −17.7 to 1.0) vs. India 0.1% (99% CI: −10.0 to 10.0)), mortality at day 90 (RD for Europe −7.4% (99% CI: −17.1 to 2.0) vs. India −1.4% (99% CI: −12.8 to 9.8)), mortality at day 180 (RD for Europe −6.7% (99% CI: −16.4 to 2.9) vs. India −1.0% (99% CI: −12.3 to 10.3)), and number of days alive without life support at day 90 (MD for Europe 6.1 days (99% CI: −1.3 to 13.4) vs. India 1.7 days (99% CI: −8.4 to 11.8)). For serious adverse reactions, the direction was reversed (RD for Europe −1.0% (99% CI: −7.1 to 5.2) vs. India −5.3% (99% CI: −16.2 to 5.0). Interpretation Our analysis suggests higher dose dexamethasone may have less beneficial effects for patients in India as compared with those in Europe; however, the evidence is weak, and this could represent a chance finding., Background: In the COVID-STEROID 2 trial there was suggestion of heterogeneity of treatment effects (HTE) between patients enrolled from Europe vs. India on the primary outcome. Whether there was HTE for the remaining patient-centred outcomes is unclear. Methods: In this post hoc analysis of the COVID-STEROID 2 trial, which compared 12 mg vs. 6 mg dexamethasone in adults with COVID-19 and severe hypoxemia, we evaluated HTE by geographical region (Europe vs. India) for secondary outcomes with analyses adjusted for stratification variables. Results are presented as risk differences (RDs) or mean differences (MDs) with 99% confidence intervals (CIs) and P-values from interaction tests. Findings: There were differences in mortality at day 28 (RD for Europe −8.3% (99% CI: −17.7 to 1.0) vs. India 0.1% (99% CI: −10.0 to 10.0)), mortality at day 90 (RD for Europe −7.4% (99% CI: −17.1 to 2.0) vs. India −1.4% (99% CI: −12.8 to 9.8)), mortality at day 180 (RD for Europe −6.7% (99% CI: −16.4 to 2.9) vs. India −1.0% (99% CI: −12.3 to 10.3)), and number of days alive without life support at day 90 (MD for Europe 6.1 days (99% CI: −1.3 to 13.4) vs. India 1.7 days (99% CI: −8.4 to 11.8)). For serious adverse reactions, the direction was reversed (RD for Europe −1.0% (99% CI: −7.1 to 5.2) vs. India −5.3% (99% CI: −16.2 to 5.0). Interpretation: Our analysis suggests higher dose dexamethasone may have less beneficial effects for patients in India as compared with those in Europe; however, the evidence is weak, and this could represent a chance finding. Funding: None for this analysis. The COVID STEROID 2 trial was funded by The Novo Nordisk Foundation and supported by Rigshospitalet's Research Council.

Immune dysfunction resulting from allogeneic haematopoietic stem cell transplantation (aHSCT) predisposes one to an elevated risk of cytomegalovirus (CMV) infection. Changes in metabolism have been associated with adverse outcomes, and in this study, we explored the associations between metabolic profiles and post-transplantation CMV infection using plasma samples collected 7-33 days after aHSCT. We included 68 aHSCT recipients from Rigshospitalet, Denmark, 50% of whom experienced CMV infection between days 34-100 post-transplantation. First, we investigated whether 12 metabolites selected based on the literature were associated with an increased risk of post-transplantation CMV infection. Second, we conducted an exploratory network-based analysis of the complete metabolic and lipidomic profiles in relation to clinical phenotypes and biological pathways. Lower levels of trimethylamine N-oxide were associated with subsequent CMV infection (multivariable logistic regression: OR = 0.63; 95% CI = [0.41; 0.87]; p = 0.01). Explorative analysis revealed 12 clusters of metabolites or lipids, among which one was predictive of CMV infection, and the others were associated with conditioning regimens, age upon aHSCT, CMV serostatus, and/or sex. Our results provide evidence for an association between the metabolome and CMV infection post-aHSCT that is independent of known risk factors.

Purpose: Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are neurotropic human alphaherpesviruses endemic worldwide. Upon primary infection, both viruses establish lifelong latency in neurons and reactivate intermittently to cause a variety of mild to severe diseases. Acute retinal necrosis (ARN) is a rare, sight-threatening eye disease induced by ocular VZV or HSV infection. The virus and host factors involved in ARN pathogenesis remain incompletely described. We hypothesize an underlying genetic defect in at least part of ARN cases. Methods: We collected blood from 17 patients with HSV-or VZV-induced ARN, isolated DNA and performed Whole Exome Sequencing by Illumina followed by analysis in Varseq with criteria of CADD score > 15 and frequency in GnomAD < 0.1% combined with biological filters. Gene modifications relative to healthy control genomes were filtered according to high quality and read-depth, low frequency, high deleteriousness predictions and biological relevance. Results: We identified a total of 50 potentially disease-causing genetic variants, including missense, frameshift and splice site variants and on in-frame deletion in 16 of the 17 patients. The vast majority of these genes are involved in innate immunity, followed by adaptive immunity, autophagy, and apoptosis; in several instances variants within a given gene or pathway was identified in several patients.Discussion: We propose that the identified variants may contribute to insufficient viral control and increased necrosis ocular disease presentation in the patients and serve as a knowledge base and starting point for the development of improved diagnostic, prophylactic, and therapeutic applications.

Background: The combined effectiveness of remdesivir and dexamethasone in subgroups of hospitalised patients with COVID-19 is poorly investigated. Methods: In this nationwide retrospective cohort study, we included 3826 patients with COVID-19 hospitalised between February 2020 and April 2021. The primary outcomes were use of invasive mechanical ventilation and 30-day mortality, comparing a cohort treated with remdesivir and dexamethasone with a previous cohort treated without remdesivir and dexamethasone. We used inverse probability of treatment weighting logistic regression to assess associations with progression to invasive mechanical ventilation and 30-day mortality between the two cohorts. The analyses were conducted overall and by subgroups based on patient characteristics. Results: Odds ratio for progression to invasive mechanical ventilation and 30-day mortality in individuals treated with remdesivir and dexamethasone compared to treatment with standard of care alone was 0.46 (95% confidence interval, 0.37–0.57) and 0.47 (95% confidence interval, 0.39–0.56), respectively. The reduced risk of mortality was observed in elderly patients, overweight patients and in patients requiring supplemental oxygen at admission, regardless of sex, comorbidities and symptom duration. Conclusions: Patients treated with remdesivir and dexamethasone had significantly improved outcomes compared to patients treated with standard of care alone. These effects were observed in most patient subgroups.

Cytomegalovirus (CMV) and invasive aspergillosis (IA) cause morbidity among lung transplant recipients (LTXr). Early diagnosis and treatment could improve outcomes. We examined rates of CMV after IA and vice versa to assess whether screening for one infection is warranted after detecting the other. All Danish LTXr, 2010–2019, were followed for IA and CMV for 2 years after transplantation. IA was defined using ISHLT criteria. Adjusted incidence rate ratios (aIRR) were estimated by Poisson regression adjusted for time after transplantation. We included 295 LTXr, among whom CMV and IA were diagnosed in 128 (43%) and 48 (16%). The risk of CMV was high the first 3 months after IA, IR 98/100 person-years of follow-up (95% CI 47–206). The risk of IA was significantly increased in the first 3 months after CMV, aIRR 2.91 (95% CI 1.32–6.44). Numbers needed to screen to diagnose one case of CMV after IA, and one case of IA after CMV was approximately seven and eight, respectively. Systematic screening for CMV following diagnosis of IA, and vice versa, may improve timeliness of diagnosis and outcomes for LTXr., Cytomegalovirus (CMV) and invasive aspergillosis (IA) cause morbidity among lung transplant recipients (LTXr). Early diagnosis and treatment could improve outcomes. We examined rates of CMV after IA and vice versa to assess whether screening for one infection is warranted after detecting the other. All Danish LTXr, 2010–2019, were followed for IA and CMV for 2 years after transplantation. IA was defined using ISHLT criteria. Adjusted incidence rate ratios (aIRR) were estimated by Poisson regression adjusted for time after transplantation. We included 295 LTXr, among whom CMV and IA were diagnosed in 128 (43%) and 48 (16%). The risk of CMV was high the first 3 months after IA, IR 98/100 person-years of follow-up (95% CI 47–206). The risk of IA was significantly increased in the first 3 months after CMV, aIRR 2.91 (95% CI 1.32–6.44). Numbers needed to screen to diagnose one case of CMV after IA, and one case of IA after CMV was approximately seven and eight, respectively. Systematic screening for CMV following diagnosis of IA, and vice versa, may improve timeliness of diagnosis and outcomes for LTXr.

A hypervirulent Klebsiella pneumoniae SL218 (ST23-KL57), phylogenetically distinct from the classical hypervirulent SL23 (ST23-KL1) lineage, was transmitted between hospitalised patients in Denmark in 2021. The isolate carried a hybrid resistance and virulence plasmid containing blaNDM-1 and a plasmid containing blaOXA-48 (pOXA-48); the latter plasmid was horizontally transferred within-patient to Serratia marcescens. The convergence of drug resistance and virulence factors in single plasmids and in different lineages of K. pneumoniae is concerning and requires surveillance., A hypervirulent Klebsiella pneumoniae SL218 (ST23-KL57), phylogenetically distinct from the classical hypervirulent SL23 (ST23-KL1) lineage, was transmitted between hospitalised patients in Denmark in 2021. The isolate carried a hybrid resistance and virulence plasmid containing blaNDM-1 and a plasmid containing blaOXA-48 (pOXA-48); the latter plasmid was horizontally transferred within-patient to Serratia marcescens. The convergence of drug resistance and virulence factors in single plasmids and in different lineages of K. pneumoniae is concerning and requires surveillance.

Background Piperacillin/tazobactam or meropenem are often used to treat patients with severe bacterial infections. We aimed to compare the desirable and undesirable effects of empirical and/or definitive piperacillin/tazobactam versus carbapenems in patients with severe bacterial infections. Methods We searched PubMed, Embase, CENTRAL, Epistemonikos, and trial registers for randomised clinical trials of empirical and/or definitive piperacillin/tazobactam versus carbapenems in adult patients with severe bacterial infection (i.e., any bacterial infection requiring hospitalisation). The primary outcome was all-cause short-term mortality within 90 days. Secondary outcomes were all-cause long-term mortality, adverse events, quality of life, days alive without or duration of life support, secondary infections, selection of fungi or resistant bacteria, and days alive and out of hospital or hospital length of stay. We calculated relative risks (RRs) using random effects and fixed effect meta-analyses along with trial sequential analyses. Results We included 31 trials (n = 8790 patients) with overall high risk of bias. The RR for all-cause short-term mortality was 1.16 (95% confidence interval [CI]: 0.94–1.43, low certainty evidence), for adverse events 1.00 (98% CI: 0.96–1.04, moderate certainty evidence), for secondary infections 1.13 (98% CI: 0.76–1.68, very low certainty evidence), and for selection of fungi or resistant bacteria 1.61 (98% CI: 0.89–2.89, very low certainty evidence). There were no or limited data for the remaining outcomes. Conclusions Based on very low or low certainty evidence, piperacillin/tazobactam may be associated with less favourable outcomes in patients with severe bacterial infections as compared with carbapenems, but the information size for a robust conclusion has not been reached., Background: Piperacillin/tazobactam or meropenem are often used to treat patients with severe bacterial infections. We aimed to compare the desirable and undesirable effects of empirical and/or definitive piperacillin/tazobactam versus carbapenems in patients with severe bacterial infections. Methods: We searched PubMed, Embase, CENTRAL, Epistemonikos, and trial registers for randomised clinical trials of empirical and/or definitive piperacillin/tazobactam versus carbapenems in adult patients with severe bacterial infection (i.e., any bacterial infection requiring hospitalisation). The primary outcome was all-cause short-term mortality within 90 days. Secondary outcomes were all-cause long-term mortality, adverse events, quality of life, days alive without or duration of life support, secondary infections, selection of fungi or resistant bacteria, and days alive and out of hospital or hospital length of stay. We calculated relative risks (RRs) using random effects and fixed effect meta-analyses along with trial sequential analyses. Results: We included 31 trials (n = 8790 patients) with overall high risk of bias. The RR for all-cause short-term mortality was 1.16 (95% confidence interval [CI]: 0.94–1.43, low certainty evidence), for adverse events 1.00 (98% CI: 0.96–1.04, moderate certainty evidence), for secondary infections 1.13 (98% CI: 0.76–1.68, very low certainty evidence), and for selection of fungi or resistant bacteria 1.61 (98% CI: 0.89–2.89, very low certainty evidence). There were no or limited data for the remaining outcomes. Conclusions: Based on very low or low certainty evidence, piperacillin/tazobactam may be associated with less favourable outcomes in patients with severe bacterial infections as compared with carbapenems, but the information size for a robust conclusion has not been reached.

Background The risk of superinfections and associations with mortality among patients with corona virus disease 2019 (COVID-19) receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO) is poorly elucidated. Method We identified all patients with COVID-19 treated with VV-ECMO >24 h at Rigshospitalet, Denmark from March 2020 to December 2021. Data were obtained by review of medical files. Associations between superinfections and mortality were assessed by logistic regression analyses adjusted for sex and age. Results Fifty patients, median age 53 years (interquartile range [IQR] 45–59), 66% male, were included. Median time on VV-ECMO was 14.5 days (IQR 6.3–23.5), 42% were discharged from hospital alive. Bacteremia, ventilator associated pneumonia (VAP), invasive candidiasis, pulmonary aspergillosis, herpes simplex virus, and cytomegalovirus (CMV) were detected in 38%, 42%, 12%, 12%, 14%, and 20% of patients, respectively. No patients with pulmonary aspergillosis survived. CMV was associated with increased risk of death, odds ratio 12.6 (95% confidence interval 1.9–257, p = .05), whereas we found no associations between other superinfections and risk of death. Conclusion Bacteremia and VAP are common but does not seem to affect mortality, whereas pulmonary aspergillosis and CMV are associated with poor prognosis among COVID-19 patients treated with VV-ECMO., Background: The risk of superinfections and associations with mortality among patients with corona virus disease 2019 (COVID-19) receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO) is poorly elucidated. Method: We identified all patients with COVID-19 treated with VV-ECMO >24 h at Rigshospitalet, Denmark from March 2020 to December 2021. Data were obtained by review of medical files. Associations between superinfections and mortality were assessed by logistic regression analyses adjusted for sex and age. Results: Fifty patients, median age 53 years (interquartile range [IQR] 45–59), 66% male, were included. Median time on VV-ECMO was 14.5 days (IQR 6.3–23.5), 42% were discharged from hospital alive. Bacteremia, ventilator associated pneumonia (VAP), invasive candidiasis, pulmonary aspergillosis, herpes simplex virus, and cytomegalovirus (CMV) were detected in 38%, 42%, 12%, 12%, 14%, and 20% of patients, respectively. No patients with pulmonary aspergillosis survived. CMV was associated with increased risk of death, odds ratio 12.6 (95% confidence interval 1.9–257, p =.05), whereas we found no associations between other superinfections and risk of death. Conclusion: Bacteremia and VAP are common but does not seem to affect mortality, whereas pulmonary aspergillosis and CMV are associated with poor prognosis among COVID-19 patients treated with VV-ECMO.

Introduction:Identifying genetic factors that influence HIV-pathogenesis is critical for understanding disease pathways. Previous studies have suggested a role for the human gene ten-eleven methylcytosine dioxygenase 2 (TET2) in modulating HIV-pathogenesis.Methods:We assessed whether genetic variation in TET2 was associated with markers of HIV-pathogenesis using both gene level and single nucleotide polymorphism (SNP) level association in 8512 HIV-positive persons across five clinical trial cohorts.Results:Variation at both the gene and SNP-level of TET2 was found to be associated with levels of HIV viral load (HIV-VL) consistently in the two cohorts that recruited antiretroviral-naïve participants. The SNPs occurred in two clusters of high linkage disequilibrium (LD), one associated with high HIV-VL and the other low HIV-VL, and were predominantly found in Black participants.Conclusion:Genetic variation in TET2 was associated with HIV-VL in two large antiretroviral therapy (ART)-naive clinical trial cohorts. The role of TET2 in HIV-pathogenesis warrants further investigation.

Aims: To evaluate the experience with use of sotrovimab following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in high-risk groups. Methods: In a nationwide, population-based cohort study, we identified all individuals treated with sotrovimab (N = 2933) and stratified them by 4 high-risk groups: (A) malignant haematological disease, (B) solid organ transplantation, (C) anti-CD20 therapy ≤1 year and (D) other risks. Cox regression analysis was used to calculate hazard ratios for hospitalization, death and associated prognostic factors. Results: Of 2933 sotrovimab-treated individuals, 83% belonged to high-risk groups (37.6% haematological malignancy, 27.4% solid organ transplantation and 17.5% treatment with anti-CD20 ≤1 year). Only 17.8% had other risks (11.8% were pregnant, 10.7% primary immunodeficiency, 21.2% other malignancy, 4.3% received anti-CD20 >1 year and 52.0% other/unknown causes). Within 90 days of infusion, 30.2% were hospitalized and 5.3% died. The main prognostic factors were the predefined high-risk groups, mainly malignant haematological disease and age ≥65 years. Number of COVID-19 vaccines (≥3) was associated with a decreased risk of hospitalization. The Delta but not the Omicron BA.2 variant was associated with a higher risk of death compared to the BA.1 variant. Conclusion: More than 90% of the patients treated with sotrovimab belonged to the very high-risk groups as described in the Danish guidelines. Sotrovimab-treated individuals remained at a high risk of hospitalization and death which was strongly associated with the underlying immunocompromised state and age. Having received >3 COVID-19 vaccines was association with decreased risk of death and hospitalization.

Background: Cancer treatments suppress immune function and are associated with increased risk of infections, but the overall burden of serious infectious diseases in treated patients has not been clearly elucidated. Methods: All patients treated for solid malignant tumours with radiotherapy (RT) and/or standard first-line chemotherapy (C) at the Department of Oncology at Rigshospitalet between 01/1/2010 and 31/12/2016 were included. Patients were followed from treatment initiation until the first of new cancer treatment, 1 year after treatment initiation, end of follow-up or death. Incidence rates (IR) of positive blood culture (PBC) per 1000 person-years follow-up (PYFU) were calculated. Findings: 12,433 individuals were included, 3582 (29%), 6349 (51%), and 2502 (20%) treated with RT, C, or both RT & C, respectively, contributing 8182 PYFU. 429 (3%) individuals experienced 502 unique episodes of PBC, incidence rate (95% CI) 52.43 (47.7, 57.6) per 1000 PYFU. The 30-day mortality rate after PBC was 24% independent of treatment modality. Adjusted incidence rate ratios in the first 3 months (95% CI) after PBC significantly varied by treatment: 2.89 (1.83, 4.55) and 2.52 (1.53, 4.14) for C and RT & C compared to RT. Escherichia coli (n = 127, 25%) was the top microorganism identified. Interpretation: PBCs are not common, but when they occur, mortality is high.

The optimal prevention strategy for invasive aspergillosis (IA) in lung transplant recipients (LTXr) is unknown. In 2016, the Danish guidelines were changed from universal to targeted IA prophylaxis. Previously, we found higher rates of adverse events in the universal prophylaxis period. In a Danish nationwide study including LTXr, for 2010–2019, we compared IA rates in time periods with universal vs. targeted prophylaxis and during person-time with vs. person-time without antifungal prophylaxis. IA hazard rates were analyzed in multivariable Cox models with adjustment for time after LTX. Among 295 LTXr, antifungal prophylaxis was initiated in 183/193 and 6/102 during the universal and targeted period, respectively. During the universal period, 62% discontinued prophylaxis prematurely. The median time on prophylaxis was 37 days (IQR 11–84). IA was diagnosed in 27/193 (14%) vs. 15/102 (15%) LTXr in the universal vs. targeted period, with an adjusted hazard ratio (aHR) of 0.94 (95% CI 0.49–1.82). The aHR of IA during person-time with vs. person-time without antifungal prophylaxis was 0.36 (95% CI 0.12–1.02). No difference in IA was found during periods with universal vs. targeted prophylaxis. Prophylaxis was protective of IA when taken. Targeted prophylaxis may be preferred over universal due to comparable IA rates and lower rates of adverse events. Keywords: aspergillosis; invasive aspergillosis; transplantation; lung transplantation; prophylaxis; triazoles; antifungal agents; voriconazole, The optimal prevention strategy for invasive aspergillosis (IA) in lung transplant recipients (LTXr) is unknown. In 2016, the Danish guidelines were changed from universal to targeted IA prophylaxis. Previously, we found higher rates of adverse events in the universal prophylaxis period. In a Danish nationwide study including LTXr, for 2010–2019, we compared IA rates in time periods with universal vs. targeted prophylaxis and during person-time with vs. person-time without antifungal prophylaxis. IA hazard rates were analyzed in multivariable Cox models with adjustment for time after LTX. Among 295 LTXr, antifungal prophylaxis was initiated in 183/193 and 6/102 during the universal and targeted period, respectively. During the universal period, 62% discontinued prophylaxis prematurely. The median time on prophylaxis was 37 days (IQR 11–84). IA was diagnosed in 27/193 (14%) vs. 15/102 (15%) LTXr in the universal vs. targeted period, with an adjusted hazard ratio (aHR) of 0.94 (95% CI 0.49–1.82). The aHR of IA during person-time with vs. person-time without antifungal prophylaxis was 0.36 (95% CI 0.12–1.02). No difference in IA was found during periods with universal vs. targeted prophylaxis. Prophylaxis was protective of IA when taken. Targeted prophylaxis may be preferred over universal due to comparable IA rates and lower rates of adverse events.

A man aged 60 years was admitted to Copenhagen University Hospital, with high grade fever (41°C), headache, and joint pain 7 days after returning from a two-week hunting safari in Zambia in Munyamadzi Game Ranch and Kazumba Game Ranch (Nyimba district), Luangwa Valley. He had contracted several tsetse fly bites. Physical examination showed a chancre on the right leg (figure 1A). Blood biochemistry revealed severe lymphopenia (0·2 × 109/L), low platelets (32 × 109/L), and elevated D-dimer (39 FEU/L). A loop-mediated isothermal amplification test for malaria was negative. A Giemsa-stained blood smear showed Trypanosoma spp (figure 1B) and metagenome sequencing determined the species as Trypanosoma brucei rhodesiense. Treatment with intravenous pentamidine was initiated and showed clinical improvement. After 5 days of treatment, platelets had increased to greater than 40 × 109/L and a lumbar puncture was performed. The cerebrospinal fluid cell count was 70 × 106/L, indicating second stage disease. Microscopy, metagenome sequencing, and specific TaqMan (Thermo Fisher Scientific, US) PCR, targeting a 103bp sequence of the 18S gene of T. brucei, were negative. The available treatment for second stage Tb rhodesiense is melarsoprol, which is toxic with a high frequency of severe, and sometimes fatal, adverse drug reactions (3–10% treatment-related fatality rate). Considering the potential risks associated with melarsoprol treatment and based on informal results of a clinical trial (NCT03974178), we decided to pursue off-label treatment with fexinidazole. The drug was procured through WHO, and the patient received 10 days of oral treatment. The patient received 1800 mg once a day for 4 days, followed by 1200 mg once a day for 6 days. He experienced no side-effects and showed no sign of relapse during a 6-month follow-up. The patient is still being regularly monitored.

BACKGROUND: Many interventional in-patient coronavirus disease 2019 (COVID-19) trials assess primary outcomes through day 28 post-randomization. Since a proportion of patients experience protracted disease or relapse, such follow-up period may not fully capture the course of the disease, even when randomization occurs a few days after hospitalization.METHODS: Among adults hospitalized with COVID-19 in eastern Denmark from 18 March 2020-12 January 2021 we assessed all-cause mortality, recovery, and sustained recovery 90 days after admission, and readmission and all-cause mortality 90 days after discharge. Recovery was defined as hospital discharge and sustained recovery as recovery and alive without readmissions for 14 consecutive days.RESULTS: Among 3386 patients included in the study, 2796 (82.6%) reached recovery and 2600 (77.0%) achieved sustained recovery. Of those discharged from hospital, 556 (19.9%) were readmitted and 289 (10.3%) died. Overall, the median time to recovery was 6 days (interquartile range [IQR]: 3-10), and 19 days (IQR: 11-33) among patients in intensive care in the first 2 days of admission.CONCLUSIONS: Postdischarge readmission and mortality rates were substantial. Therefore, sustained recovery should be favored to recovery outcomes in clinical COVID-19 trials. A 28-day follow-up period may be too short for the critically ill.

Background: Knowledge of the genetic variation underlying Primary Immune Deficiency (PID) is increasing. Reanalysis of genome-wide sequencing data from undiagnosed patients with suspected PID may improve the diagnostic rate. Methods: We included patients monitored at the Department of Infectious Diseases or the Child and Adolescent Department, Rigshospitalet, Denmark, for a suspected PID, who had been analysed previously using a targeted PID gene panel (457 PID-related genes) on whole exome- (WES) or whole genome sequencing (WGS) data. A literature review was performed to extend the PID gene panel used for reanalysis of single nucleotide variation (SNV) and small indels. Structural variant (SV) calling was added on WGS data. Results: Genetic data from 94 patients (86 adults) including 36 WES and 58 WGS was reanalysed a median of 23 months after the initial analysis. The extended gene panel included 208 additional PID-related genes. Genetic reanalysis led to a small increase in the proportion of patients with new suspicious PID related variants of uncertain significance (VUS). The proportion of patients with a causal genetic diagnosis was constant. In total, five patients (5%, including three WES and two WGS) had a new suspicious PID VUS identified due to reanalysis. Among these, two patients had a variant added due to the expansion of the PID gene panel, and three patients had a variant reclassified to a VUS in a gene included in the initial PID gene panel. The total proportion of patients with PID related VUS, likely pathogenic, and pathogenic variants increased from 43 (46%) to 47 (50%), as one patient had a VUS detected in both initial- and reanalysis. In addition, we detected new suspicious SNVs and SVs of uncertain significance in PID candidate genes with unknown inheritance and/or as heterozygous variants in genes with autosomal recessive inheritance in 8 patients. Conclusion: These data indicate a possible diagnostic gain of reassessing WES/WGS data from p

Background: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. Methods: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978. Findings: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184)

Background: Invasive fungal infections in lung transplant (LTX) recipients cause substantial morbidity, but the best strategy for prevention has not yet been determined. We evaluated adherence to and rates of adverse events of universal versus targeted prophylaxis. Methods: All LTX recipients in the Danish National LTX Centre (2010–2019) were included. Before July 2016, universal voriconazole prophylaxis was used. After July 2016, only high-risk patients received targeted prophylaxis with posaconazole and inhaled amphotericin B. Proportions of triazole discontinuation, side-effects, off-target calcineurin-inhibitor (CNI) levels, and acute rejection were compared between the two periods. Results: Universal and targeted prophylaxis was initiated in 183/193 and 6/102 patients, respectively. Only 37% completed > 9 of the intended 12 weeks of voriconazole; 72% of discontinuations were due to hepatotoxicity. In the universal vs. targeted prophylaxis period, 89% vs. 72% (p < 0.001) patients had low CNI episodes, and 37% vs. 1% (p < 0.001) of these were associated with discontinuation of triazole; 40% vs. 14% (p < 0.001) had acute rejection; and 23% vs. 3% (p < 0.001) had acute rejection associated with low CNI episodes. Conclusions: Universal voriconazole prophylaxis was associated with high rates of discontinuation, mainly caused by hepatotoxicity. In comparison to the targeted posaconazole period, more patients had low CNI levels and acute rejection in the universal voriconazole period.

Spatial resolution in existing chest x-ray (CXR)-based scoring systems for coronavirus disease 2019 (COVID-19) pneumonia is low, and should be increased for better representation of anatomy, and severity of lung involvement. An existing CXR-based system, the Brixia score, was modified to increase the spatial resolution, creating the MBrixia score. The MBrixia score is the sum, of a rule-based quantification of CXR severity on a scale of 0 to 3 in 12 anatomical zones in the lungs. The MBrixia score was applied to CXR images from COVID-19 patients at a single tertiary hospital in the period May 4th–June 5th, 2020. The relationship between MBrixia score, and level of respiratory support at the time of performed CXR imaging was investigated. 37 hospitalized COVID-19 patients with 290 CXRs were identified, 22 (59.5%) were admitted to the intensive care unit and 10 (27%) died during follow-up. In a Poisson regression using all 290 MBrixia scored CXRs, a higher MBrixia score was associated with a higher level of respiratory support at the time of performed CXR. The MBrixia score could potentially be valuable as a quantitative surrogate measurement of COVID-19 pneumonia severity, and future studies should investigate the score’s validity and capabilities of predicting clinical outcomes.

Background: Several studies have shown an association between abacavir (ABC) and increased risk of myocardial infarction (MI), but the causative mechanism has not been established. Both vascular endothelial inflammation and platelet activation have been proposed as contributing factors. Objective: The study aims to investigate the effects of ABC relative to tenofovir disoproxil (TDF) on functional assays of primary and secondary hemostasis and a comprehensible range of relevant biomarkers. Methods: In an investigator-initiated, open-labeled, crossover trial, we included HIV-infected males receiving either ABC or TDF and switched treatment to the alternate drug. At inclusion and after three months on the new regimen, we performed Multiplate® and thromboelastography (TEG® ) and measured biomarkers of coagulation, inflammation, platelet reactivity, endothelial disruption and activation, and fibrinolysis, lipids, HIV RNA, CD4, CD8, and creatinine. Treatment effects were assessed by comparing intraindividual differences between the two treatment orders by the Wilcoxon Rank Sum test. Results: In total, 43 individuals completed the study. No intraindividual differences were observed for Multiplate® or TEG® when switching between regimens. We observed a significant treatment effect on coagulation factors II-VII-X (p<0.0001), sCD40L (a biomarker of platelet reactivity, p=0.04), thrombomodulin (biomarker of endothelial damage, p=0.04), lipids, and CD8 cell counts (p=0.04), with higher values during ABC treatment compared to TDF. Conclusion: Compared to TDF, ABC treatment affected several outcome measures in a pro-coagulant direction. Suggesting that the risk of MI associated with ABC may be caused by the sum of multiple, discrete disturbances in the hemostatic system and endothelium. Study Registration: The trial was registered at clinicaltrials.gov (NCT02093585).

Purpose: The incidence, etiology, and association of infections with radiation therapy (RT)–induced lymphopenia in patients with solid tumors is not well elucidated. Methods and Materials: We identified possible, probable, and definite infections caused by bacteria, fungi, and viruses, combining data on medication, microbiology, and diagnoses. Definite infections had either a diagnosis or a positive microbiological isolation. We analyzed the incidence and adjusted incidence-rate ratio of infections in the year after the start of RT among patients who received RT plus chemotherapy and RT monotherapy, by type of infection and according to the degree of RT-induced lymphopenia. Results: A total of 4450 of 6334 (70.3%) patients experienced 11264 infections overall; 1424 (22.5%) patients developed 2104 definite infections in the first year after RT. Infections were more frequent among patients who received RT plus chemotherapy (2590 of 3469; incidence: 16.5 [95% confidence interval {CI}, 16.1-17.0], per 100 patient-years) compared with patients who received RT monotherapy (1860 of 2865; incidence: 12.7 [95% CI, 12.3-13.2]). The incidence of infection was highest in the first 3 months overall (28.2 vs 18.0 in patients who received RT plus chemotherapy compared with those who received RT monotherapy) and for definite infections (4.7 vs 3.8). The proportion of specific bacterial infections were similar among patients who received RT plus chemotherapy versus those who received RT monotherapy. Urinary tract infections were the most frequent (51.2% vs 56.2%), followed by pneumonias (24.1% vs 22.4%). Viral and fungal infections were more frequent among patients who received RT plus chemotherapy, but they were uncommon. In multivariable analyses, patients who received RT plus chemotherapy with a lymphopenia grade of 1-2 or ≥3 versus no lymphopenia at end of RT had an increased risk of bacterial infections 0 to 3 months after RT (incidence rate ratio, 1.45 [95% CI, 1.06-1.97] a