Early treatment of high-risk hospitalized COVID-19 patients with a combination of interferon beta-1b and remdesivir: a phase 2 open-label randomized controlled trial.

BACKGROUND: Early antiviral therapy was effective in the treatment of COVID-19. We assessed the efficacy and safety of combined interferon beta-1b and remdesivir treatment in hospitalized COVID-19 patients. METHODS: We conducted a multicentre, prospective open-label, randomized-controlled trial involving high-risk adults hospitalized for COVID-19. Patients were randomly assigned to a 5-day interferon beta-1b 16 million units daily and remdesivir 200mg loading on day 1 followed by 100mg daily on day 2 to 5 (combination-group), or to remdesivir only of similar regimen (control-group) (1:1). The primary end-point was the time to complete alleviation of symptoms (NEWS2 = 0). RESULTS: Two-hundred and twelve patients were enrolled. The median days of starting treatment from symptom-onset was 3 days. The median age was 65 years and 159 patients (75%) had chronic disease. The baseline demographics were similar. There was no mortality. For the primary-endpoint, the combination-group was significantly quicker to NEWS2 = 0 (4 versus 6.5 days; hazard-ratio [HR],6.59; 95% confidence-interval [CI],6.1-7.09; p < 0.0001) when compared to the control-group. For the secondary endpoints, the combination-group was quicker to negative NPS VL (6 versus 8 days; HR,8.16; 95% CI,7.79-8.52; p < 0.0001) and develop seropositive IgG (8 versus 10 days; HR,10.78; 95% CI,9.98-11.58; p < 0.0001). All adverse events resolved upon follow-up. Combination group (HR,4.1 95%CI,1.9-8.6, p < 0.0001), was the most significant independent factor associated with NEWS2 = 0 on day 4. CONCLUSIONS: Early treatment with interferon beta-1b and remdesivir was safe and better than remdesivir only in alleviating symptoms, shorten viral shedding and hospitalization with earlier seropositivity in high-risk COVID-19 patients.

Early short course of neuromuscular blocking agents in patients with COVID-19 ARDS: a propensity score analysis.

BACKGROUND: The role of neuromuscular blocking agents (NMBAs) in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) is not fully elucidated. Therefore, we aimed to investigate in COVID-19 patients with moderate-to-severe ARDS the impact of early use of NMBAs on 90-day mortality, through propensity score (PS) matching analysis. METHODS: We analyzed a convenience sample of patients with COVID-19 and moderate-to-severe ARDS, admitted to 244 intensive care units within the COVID-19 Critical Care Consortium, from February 1, 2020, through October 31, 2021. Patients undergoing at least 2 days and up to 3 consecutive days of NMBAs (NMBA treatment), within 48 h from commencement of IMV were compared with subjects who did not receive NMBAs or only upon commencement of IMV (control). The primary objective in the PS-matched cohort was comparison between groups in 90-day in-hospital mortality, assessed through Cox proportional hazard modeling. Secondary objectives were comparisons in the numbers of ventilator-free days (VFD) between day 1 and day 28 and between day 1 and 90 through competing risk regression. RESULTS: Data from 1953 patients were included. After propensity score matching, 210 cases from each group were well matched. In the PS-matched cohort, mean (± SD) age was 60.3 ± 13.2 years and 296 (70.5%) were male and the most common comorbidities were hypertension (56.9%), obesity (41.1%), and diabetes (30.0%). The unadjusted hazard ratio (HR) for death at 90 days in the NMBA treatment vs control group was 1.12 (95% CI 0.79, 1.59, p = 0.534). After adjustment for smoking habit and critical therapeutic covariates, the HR was 1.07 (95% CI 0.72, 1.61, p = 0.729). At 28 days, VFD were 16 (IQR 0-25) and 25 (IQR 7-26) in the NMBA treatment and control groups, respectively (sub-hazard ratio 0.82, 95% CI 0.67, 1.00, p = 0.055). At 90 days, VFD were 77 (IQR 0-87) and 87 (IQR 0-88) (sub-hazard ratio 0.86 (95% CI 0.69, 1.07; p = 0.177). CONCLUSIONS: In patients with COVID-19 and moderate-to-severe ARDS, short course of NMBA treatment, applied early, did not significantly improve 90-day mortality and VFD. In the absence of definitive data from clinical trials, NMBAs should be indicated cautiously in this setting.

Assessment of 28-Day In-Hospital Mortality in Mechanically Ventilated Patients With Coronavirus Disease 2019: An International Cohort Study.

Factors associated with mortality in coronavirus disease 2019 patients on invasive mechanical ventilation are still not fully elucidated. OBJECTIVES: To identify patient-level parameters, readily available at the bedside, associated with the risk of in-hospital mortality within 28 days from commencement of invasive mechanical ventilation or coronavirus disease 2019. DESIGN SETTING AND PARTICIPANTS: Prospective observational cohort study by the global Coronavirus Disease 2019 Critical Care Consortium. Patients with laboratory-confirmed coronavirus disease 2019 requiring invasive mechanical ventilation from February 2, 2020, to May 15, 2021. MAIN OUTCOMES AND MEASURES: Patient characteristics and clinical data were assessed upon ICU admission, the commencement of invasive mechanical ventilation and for 28 days thereafter. We primarily aimed to identify time-independent and time-dependent risk factors for 28-day invasive mechanical ventilation mortality. RESULTS: One-thousand five-hundred eighty-seven patients were included in the survival analysis; 588 patients died in hospital within 28 days of commencing invasive mechanical ventilation (37%). Cox-regression analysis identified associations between the hazard of 28-day invasive mechanical ventilation mortality with age (hazard ratio, 1.26 per 10-yr increase in age; 95% CI, 1.16-1.37; p < 0.001), positive end-expiratory pressure upon commencement of invasive mechanical ventilation (hazard ratio, 0.81 per 5 cm H2O increase; 95% CI, 0.67-0.97; p = 0.02). Time-dependent parameters associated with 28-day invasive mechanical ventilation mortality were serum creatinine (hazard ratio, 1.28 per doubling; 95% CI, 1.15-1.41; p < 0.001), lactate (hazard ratio, 1.22 per doubling; 95% CI, 1.11-1.34; p < 0.001), Paco2 (hazard ratio, 1.63 per doubling; 95% CI, 1.19-2.25; p < 0.001), pH (hazard ratio, 0.89 per 0.1 increase; 95% CI, 0.8-14; p = 0.041), Pao2/Fio2 (hazard ratio, 0.58 per doubling; 95% CI, 0.52-0.66; p < 0.001), and mean arterial pressure (hazard ratio, 0.92 per 10 mm Hg increase; 95% CI, 0.88-0.97; p = 0.003). CONCLUSIONS AND RELEVANCE: This international study suggests that in patients with coronavirus disease 2019 on invasive mechanical ventilation, older age and clinically relevant variables monitored at baseline or sequentially during the course of invasive mechanical ventilation are associated with 28-day invasive mechanical ventilation mortality hazard. Further investigation is warranted to validate any causative roles these parameters might play in influencing clinical outcomes.

An appraisal of respiratory system compliance in mechanically ventilated covid-19 patients.

BACKGROUND: Heterogeneous respiratory system static compliance (CRS) values and levels of hypoxemia in patients with novel coronavirus disease (COVID-19) requiring mechanical ventilation have been reported in previous small-case series or studies conducted at a national level. METHODS: We designed a retrospective observational cohort study with rapid data gathering from the international COVID-19 Critical Care Consortium study to comprehensively describe CRS-calculated as: tidal volume/[airway plateau pressure-positive end-expiratory pressure (PEEP)]-and its association with ventilatory management and outcomes of COVID-19 patients on mechanical ventilation (MV), admitted to intensive care units (ICU) worldwide. RESULTS: We studied 745 patients from 22 countries, who required admission to the ICU and MV from January 14 to December 31, 2020, and presented at least one value of CRS within the first seven days of MV. Median (IQR) age was 62 (52-71), patients were predominantly males (68%) and from Europe/North and South America (88%). CRS, within 48 h from endotracheal intubation, was available in 649 patients and was neither associated with the duration from onset of symptoms to commencement of MV (p = 0.417) nor with PaO2/FiO2 (p = 0.100). Females presented lower CRS than males (95% CI of CRS difference between females-males: - 11.8 to - 7.4 mL/cmH2O p < 0.001), and although females presented higher body mass index (BMI), association of BMI with CRS was marginal (p = 0.139). Ventilatory management varied across CRS range, resulting in a significant association between CRS and driving pressure (estimated decrease - 0.31 cmH2O/L per mL/cmH20 of CRS, 95% CI - 0.48 to - 0.14, p < 0.001). Overall, 28-day ICU mortality, accounting for the competing risk of being discharged within the period, was 35.6% (SE 1.7). Cox proportional hazard analysis demonstrated that CRS (+ 10 mL/cm H2O) was only associated with being discharge from the ICU within 28 days (HR 1.14, 95% CI 1.02-1.28, p = 0.018). CONCLUSIONS: This multicentre report provides a comprehensive account of CRS in COVID-19 patients on MV. CRS measured within 48 h from commencement of MV has marginal predictive value for 28-day mortality, but was associated with being discharged from ICU within the same period. Trial documentation: Available at https://www.covid-critical.com/study . TRIAL REGISTRATION: ACTRN12620000421932.

Olfactory Dysfunction in Coronavirus Disease 2019 Patients: Observational Cohort Study and Systematic Review.

BACKGROUND: Olfactory dysfunction (OD) has been reported in coronavirus disease 2019 (COVID-19). However, there are knowledge gaps about the severity, prevalence, etiology, and duration of OD in COVID-19 patients. METHODS: Olfactory function was assessed in all participants using questionnaires and the butanol threshold test (BTT). Patients with COVID-19 and abnormal olfaction were further evaluated using the smell identification test (SIT), sinus imaging, and nasoendoscopy. Selected patients received nasal biopsies. Systematic review was performed according to PRISMA guidelines. PubMed items from January 1, 2020 to April 23, 2020 were searched. Studies that reported clinical data on olfactory disturbances in COVID-19 patients were analyzed. RESULTS: We included 18 COVID-19 patients and 18 controls. Among COVID-19 patients, 12 of 18 (67%) reported olfactory symptoms and OD was confirmed in 6 patients by BTT and SIT. Olfactory dysfunction was the only symptom in 2 patients. Mean BTT score of patients was worse than controls (P = .004, difference in means = 1.8; 95% confidence interval, 0.6-2.9). Sinusitis and olfactory cleft obstruction were absent in most patients. Immunohistochemical analysis of nasal biopsy revealed the presence of infiltrative CD68+ macrophages harboring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen in the stroma. Olfactory dysfunction persisted in 2 patients despite clinical recovery. Systematic review showed that the prevalence of olfactory disturbances in COVID-19 ranged from 5% to 98%. Most studies did not assess olfaction quantitatively. CONCLUSIONS: Olfactory dysfunction is common in COVID-19 and may be the only symptom. Coronavirus disease 2019-related OD can be severe and prolonged. Mucosal infiltration by CD68+ macrophages expressing SARS-CoV-2 viral antigen may contribute to COVID-19-related OD.