Alveolar cytokines and interferon autoantibodies in COVID-19 ARDS.

Background: Type I interferon (IFN-I) and IFN autoantibodies play a crucial role in controlling SARS-CoV-2 infection. The levels of these mediators have only rarely been studied in the alveolar compartment in patients with COVID-19 acute respiratory distress syndrome (CARDS) but have not been compared across different ARDS etiologies, and the potential effect of dexamethasone (DXM) on these mediators is not known. Methods: We assessed the integrity of the alveolo-capillary membrane, interleukins, type I, II, and III IFNs, and IFN autoantibodies by studying the epithelial lining fluid (ELF) volumes, alveolar concentration of protein, and ELF-corrected concentrations of cytokines in two patient subgroups and controls. Results: A total of 16 patients with CARDS (four without and 12 with DXM treatment), eight with non-CARDS, and 15 healthy controls were included. The highest ELF volumes and protein levels were observed in CARDS. Systemic and ELF-corrected alveolar concentrations of interleukin (IL)-6 appeared to be particularly low in patients with CARDS receiving DXM, whereas alveolar levels of IL-8 were high regardless of DXM treatment. Alveolar levels of IFNs were similar between CARDS and non-CARDS patients, and IFNα and IFNω autoantibody levels were higher in patients with CARDS and non-CARDS than in healthy controls. Conclusions: Patients with CARDS exhibited greater alveolo-capillary barrier disruption with compartmentalization of IL-8, regardless of DXM treatment, whereas systemic and alveolar levels of IL-6 were lower in the DXM-treated subgroup. IFN-I autoantibodies were higher in the BALF of CARDS patients, independent of DXM, whereas IFN autoantibodies in plasma were similar to those in controls.

Long-term outcomes in COVID-19 patients admitted to intensive care in Denmark: A nationwide observational study.

BACKGROUND: Among ICU patients with COVID-19, it is largely unknown how the overall outcome and resource use have changed with time, different genetic variants, and vaccination status. METHODS: For all Danish ICU patients with COVID-19 from March 10, 2020 to March 31, 2022, we manually retrieved data on demographics, comorbidities, vaccination status, use of life support, length of stay, and vital status from medical records. We compared patients based on the period of admittance and vaccination status and described changes in epidemiology related to the Omicron variant. RESULTS: Among all 2167 ICU patients with COVID-19, 327 were admitted during the first (March 10-19, 2020), 1053 during the second (May 20, 2020 to June 30, 2021) and 787 during the third wave (July 1, 2021 to March 31, 2022). We observed changes over the three waves in age (median 72 vs. 68 vs. 65 years), use of invasive mechanical ventilation (81% vs. 58% vs. 51%), renal replacement therapy (26% vs. 13% vs. 12%), extracorporeal membrane oxygenation (7% vs. 3% vs. 2%), duration of invasive mechanical ventilation (median 13 vs. 13 vs. 9 days) and ICU length of stay (median 13 vs. 10 vs. 7 days). Despite these changes, 90-day mortality remained constant (36% vs. 35% vs. 33%). Vaccination rates among ICU patients were 42% as compared to 80% in society. Unvaccinated versus vaccinated patients were younger (median 57 vs. 73 years), had less comorbidity (50% vs. 78%), and had lower 90-day mortality (29% vs. 51%). Patient characteristics changed significantly after the Omicron variant became dominant including a decrease in the use of COVID-specific pharmacological agents from 95% to 69%. CONCLUSIONS: In Danish ICUs, the use of life support declined, while mortality seemed unchanged throughout the three waves of COVID-19. Vaccination rates were lower among ICU patients than in society, but the selected group of vaccinated patients admitted to the ICU still had very severe disease courses. When the Omicron variant became dominant a lower fraction of SARS-CoV-2 positive patients received COVID treatment indicating other causes for ICU admission.

PaCO2 trajectories in mechanically ventilated patients with COVID-19: A population-based cohort study.

OBJECTIVE: To identify PaCO2 trajectories and assess their associations with mortality in critically ill patients with coronavirus disease 2019 (COVID-19) during the first and second waves of the pandemic in Denmark. DESIGN: A population-based cohort study with retrospective data collection. PATIENTS: All COVID-19 patients were treated in eight intensive care units (ICUs) in the Capital Region of Copenhagen, Denmark, between March 1, 2020 and March 31, 2021. MEASUREMENTS: Data from the electronic health records were extracted, and latent class analyses were computed based on up to the first 3 weeks of mechanical ventilation to depict trajectories of PaCO2 levels. Multivariable Cox regression analyses were used to calculate adjusted hazard ratios (aHRs) for Simplified Acute Physiology Score 3, sex and age with 95% confidence intervals (CIs) for death according to PaCO2 trajectories. MAIN RESULTS: In latent class trajectory models, including 25,318 PaCO2 measurements from 244 patients, three PaCO2 latent class trajectories were identified: a low isocapnic (Class I; n = 130), a high isocapnic (Class II; n = 80), as well as a progressively hypercapnic (Class III; n = 34) trajectory. Mortality was higher in Class II [aHR: 2.16 {1.26-3.68}] and Class III [aHR: 2.97 {1.63-5.40}]) compared to Class I (reference). CONCLUSION: Latent class analysis of arterial blood gases in mechanically ventilated COVID-19 patients identified distinct PaCO2 trajectories, which were independently associated with mortality.

Changes over time in characteristics, resource use and outcomes among ICU patients with COVID-19-A nationwide, observational study in Denmark.

BACKGROUND: Characteristics and care of intensive care unit (ICU) patients with COVID-19 may have changed during the pandemic, but longitudinal data assessing this are limited. We compared patients with COVID-19 admitted to Danish ICUs in the first wave with those admitted later. METHODS: Among all Danish ICU patients with COVID-19, we compared demographics, chronic comorbidities, use of organ support, length of stay and vital status of those admitted 10 March to 19 May 2020 (first wave) versus 20 May 2020 to 30 June 2021. We analysed risk factors for death by adjusted logistic regression analysis. RESULTS: Among all hospitalised patients with COVID-19, a lower proportion was admitted to ICU after the first wave (13% vs. 8%). Among all 1374 ICU patients with COVID-19, 326 were admitted during the first wave. There were no major differences in patient's characteristics or mortality between the two periods, but use of invasive mechanical ventilation (81% vs. 58% of patients), renal replacement therapy (26% vs. 13%) and ECMO (8% vs. 3%) and median length of stay in ICU (13 vs. 10 days) and in hospital (20 vs. 17 days) were all significantly lower after the first wave. Risk factors for death were higher age, larger burden of comorbidities (heart failure, pulmonary disease and kidney disease) and active cancer, but not admission during or after the first wave. CONCLUSIONS: After the first wave of COVID-19 in Denmark, a lower proportion of hospitalised patients with COVID-19 were admitted to ICU. Among ICU patients, use of organ support was lower and length of stay was reduced, but mortality rates remained at a relatively high level.

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: The COVID STEROID randomised, placebo-controlled trial.

BACKGROUND: In the early phase of the pandemic, some guidelines recommended the use of corticosteroids for critically ill patients with COVID-19, whereas others recommended against the use despite lack of firm evidence of either benefit or harm. In the COVID STEROID trial, we aimed to assess the effects of low-dose hydrocortisone on patient-centred outcomes in adults with COVID-19 and severe hypoxia. METHODS: In this multicentre, parallel-group, placebo-controlled, blinded, centrally randomised, stratified clinical trial, we randomly assigned adults with confirmed COVID-19 and severe hypoxia (use of mechanical ventilation or supplementary oxygen with a flow of at least 10 L/min) to either hydrocortisone (200 mg/d) vs a matching placebo for 7 days or until hospital discharge. The primary outcome was the number of days alive without life support at day 28 after randomisation. RESULTS: The trial was terminated early when 30 out of 1000 participants had been enrolled because of external evidence indicating benefit from corticosteroids in severe COVID-19. At day 28, the median number of days alive without life support in the hydrocortisone vs placebo group were 7 vs 10 (adjusted mean difference: -1.1 days, 95% CI -9.5 to 7.3, P = .79); mortality was 6/16 vs 2/14; and the number of serious adverse reactions 1/16 vs 0/14. CONCLUSIONS: In this trial of adults with COVID-19 and severe hypoxia, we were unable to provide precise estimates of the benefits and harms of hydrocortisone as compared with placebo as only 3% of the planned sample size were enrolled. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04348305. European Union Drug Regulation Authorities Clinical Trials (EudraCT) Database: 2020-001395-15.