An adaptive randomized controlled trial of non-invasive respiratory strategies in acute respiratory failure patients with COVID-19

BackgroundBoth continuous positive airway pressure (CPAP) and high-flow nasal oxygenation (HFNO) have been recommended for acute respiratory failure in COVID-19. However, uncertainty exists regarding effectiveness and safety. MethodsIn the Recovery-Respiratory Support multi-center, three-arm, open-label, adaptive, randomized controlled trial, adult hospitalized patients with acute respiratory failure due to COVID-19, deemed suitable for treatment escalation, were randomly assigned to receive CPAP, HFNO, or conventional oxygen therapy. Comparisons were made between each intervention and conventional oxygen therapy. The primary outcome was a composite of tracheal intubation or mortality within 30-days. ResultsOver 13-months, 1272 participants were randomized and included in the analysis (380 (29.9%) CPAP; 417 (32.8%) HFNO; 475 (37.3%) conventional oxygen therapy). The need for tracheal intubation or mortality within 30-days was lower in the CPAP group (CPAP 137 of 377 participants (36.3%) vs conventional oxygen therapy 158 of 356 participants (44.4%); unadjusted odds ratio 0.72; 95% CI 0.53 to 0.96, P=0.03). There was no difference between HFNO and conventional oxygen therapy (HFNO 184 of 414 participants (44.4%) vs conventional oxygen therapy 166 of 368 participants (45.1%); unadjusted odds ratio 0.97; 95% CI 0.73 to 1.29, P=0.85). ConclusionsCPAP, compared with conventional oxygen therapy, reduced the composite outcome of intubation or death within 30 days of randomisation in hospitalized adults with acute respiratory failure due to COVID-19. There was no effect observed, compared with conventional oxygen therapy, with the use of HFNO. (Funded by the UK National Institute for Health Research; ISRCTN 16912075).

Relevance of prediction scores derived from the SARS-CoV-2 first wave, in the UK COVID-19 second wave, for early discharge, severity and mortality: a PREDICT COVID UK prospective observational cohort study

ObjectiveProspectively validate two prognostic scores, pre-hospitalisation (SOARS) and hospitalised mortality prediction (4C Mortality Score), derived from the coronavirus disease 2019 (COVID-19) first wave, in the evolving second wave with prevalent B.1.1.7 and parent D614 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, in two large United Kingdom (UK) cohorts. DesignProspective observational cohort study of SOARS and 4C Mortality Score in PREDICT (single site) and multi-site ISARIC (International Severe Acute Respiratory and Emerging Infections Consortium) cohorts. SettingProtocol-based data collection in UK COVID-19 second wave, between October 2020 and January 2021, from PREDICT and ISARIC cohorts. Participants1383 from single site PREDICT cohort and 20,595 from multi-site ISARIC cohort. Main outcome measuresRelevance of SOARS and 4C Mortality Score derived from the COVID-19 first wave, determining in-hospital mortality and safe discharge in the UK COVID-19 second wave. ResultsData from 1383 patients (median age 67y, IQR 52-82; mortality 24.7%) in the PREDICT and 20,595 patients from the ISARIC (mortality 19.4%) cohorts showed both SOARS and 4C Mortality Score remained relevant despite the B.1.1.7 variant and treatment advances. SOARS had AUC of 0.8 and 0.74, while 4C Mortality Score had an AUC of 0.83 and 0.91 for hospital mortality, in the PREDICT and ISARIC cohorts respectively, therefore effective in evaluating both safe discharge and in-hospital mortality. 19.3% (231/1195, PREDICT cohort) and 16.7% (2550/14992, ISARIC cohort) with a SOARS of 0-1 were potential candidates for home discharge to a virtual hospital (VH) model. SOARS score implementation resulted in low re-admission rates, 11.8% (27/229), and low mortality, 0.9% (2/229), in the VH pathway. Use is still suboptimal to prevent admission, as 8.1% in the PREDICT cohort and 9.5% in the ISARIC cohort were admitted despite SOARS score of 0-1. ConclusionSOARS and 4C Mortality Score remains valid, providing accurate prognostication despite evolving viral subtype and treatment advances, which have altered mortality. Both scores are easily implemented within urgent care pathways with a scope for admission avoidance. They remain safe and relevant to their purpose, transforming complex clinical presentations into tangible numbers, aiding objective decision making. Trial registrationNHS HRA registration and REC approval (20/HRA/2344, IRAS ID 283888).

Increased prevalence and clinical impact of hypocalcaemia in severe COVID-19 distinguishes it from other forms of infective pneumonia

BackgroundHypocalcaemia has been reported in the context of acute COVID-19, where it has been associated with an increased risk of hospitalisation and disease severity. Calcium is an important intracellular messenger that controls diverse cellular processes. Two other clinically important coronaviruses, SARS-CoV-1 and Middle East respiratory syndrome (MERS)-CoV, can use calcium ions to enter and replicate within host cells. Calcium may therefore be important in the pathophysiology of COVID-19 infection. We sought to investigate whether calcium derangement was a specific feature of COVID-19 that distinguishes it from other infective pneumonias, and its association with disease severity. MethodsWe conducted a single centre retrospective study of albumin-corrected serum calcium on adult patients with COVID-19 who presented between March 1st and May 16th 2020. The primary outcome was maximal level of care based on the World Health Organization Clinical Progression Scale for COVID-19. Cases with community acquired pneumonia (CAP) and viral pneumonia (VP) were identified through a clinical database over three intervals (January to February 2018, January to February 2019 and September to December 2019). ResultsWe analysed data from 506 patients with COVID-19, 95 patients with CAP and 152 patients with VP. Hypocalcaemia (serum calcium <2.2mmol/L) was a specific and common clinical finding in patients with COVID-19 that was not present in other respiratory infections. Calcium levels were significantly lower in those with severe disease. Ordinal regression of risk estimates for categorised care levels showed that baseline hypocalcaemia was incrementally associated with odds ratio of 2.33 for higher level of care, superior to other variables that have previously been shown to predict worse COVID-19 outcome. Serial calcium levels showed improvement by day 7-9 of admission, only in in survivors of COVID-19. ConclusionHypocalcaemia may independently predict not only more severe but more progressive disease and warrants detailed prognostic investigation. The fact that decreased serum calcium is observed at the time of clinical presentation in COVID-19, but not other infective pneumonias, suggests that its early derangement is pathophysiological and may influence the deleterious evolution of this disease. If calcium is ultimately shown to be critical to the entry and replication of SARS-CoV-2 in host cells, unravelling how this mechanism could be therapeutically targeted deserves more intensive examination. Trial registration HRA20/HRA/2344.

Evaluation of the ROX index in SARS-CoV-2 Acute Respiratory failure treated with both High-Flow Nasal Oxygen (HFNO) and Continuous Positive Airway Pressure (CPAP)

BackgroundNon-invasive respiratory support including high-flow nasal oxygen (HFNO), and continuous positive airway pressure (CPAP) have been used to provide therapy in selected SARS-CoV-2 patients with acute respiratory failure (ARF). The value of the ROX index, a validated benchmark for outcomes in HFNO is unknown in CPAP. ObjectiveCan the ROX, a validated benchmark in HFNO be used for measuring treatment outcomes of CPAP in SARS-COV-2 ARF? Study Design and MethodsA non-randomised prospective protocol driven observational non-intensive care unit study in 130 SARS-COV-2 patients with ARF treated with non-invasive therapy from March 2020 to January 2021. The primary end point was failure of therapy (death or escalation). Secondary outcomes included time to failure including invasive mechanical ventilation (IMV) or death, the effect of escalation to CPAP from HFNO and the utility of ROX in ARF. ResultsHFNO was better than CPAP in treating SARS-COV-2 ARF: 17/35 (48.5%) with successful HFNO therapy versus 24/95 (25.2%) with CPAP. The ROX index was more sensitive to outcomes with CPAP compared to HFNO and distinguished treatment failure early at 1, 4, 6, 12, and 24 hours with the highest sensitivity at 24 hours (ROX-24h). The AUC for the ROX-24h was 0.77 for HFNO (P<0.0001), and 0.84 for CPAP (P<0.0001). The ROX-24h cut-points predicted failure with HFNO when < 3.9 (PPV 71%, NPV 75%) and CPAP < 4.3 (PPV 75%, NPV 91%). For success, ROX-24h cut-points of 7.6 for HFNO (PPV 85%, NPV 48%) and 6.1 for CPAP (PPV 88%, NPV 62%) were observed. Escalation from HFNO to CPAP was mostly not successful. ConclusionARF in SARS-COV-2 can be successfully managed by non-invasive support. The ROX index, validated for HFNO, provides a timely, low resource measure for both HFNO and CPAP avoiding delayed intubation. Trial registrationStudy approved by NHS HRAREC (20/HRA/2344;ethics 283888) KEY MESSAGEO_ST_ABSWhat is the key question?C_ST_ABSCan the ROX, a validated benchmark in high-flow nasal oxygen (HFNO) be used for measuring treatment outcomes of continuous positive airway pressure (CPAP) in SARS-COV-2 ARF? What is the bottom line?The ROX index, validated for HFNO, provides a timely, low resource measure for both HFNO and CPAP support avoiding delayed intubation. Why read on?The present study compares the efficacy of HFNO and CPAP, two common globally used modalities of treatment for SARS-CoV-2 and notes the superior utility of the ROX-24h in CPAP to predict outcome, enabling timely escalation decisions.