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.

Early prognostication of COVID-19 to guide hospitalisation versus outpatient monitoring using a point-of-test risk prediction score

IntroductionRisk factors of adverse outcomes in COVID-19 are defined but stratification of mortality using non-laboratory measured scores, particularly at the time of pre-hospital SARS-CoV-2 testing, is lacking. MethodsMultivariate regression with bootstrapping was used to identify independent mortality predictors in a derivation cohort of COVID-19 patients. Predictions were externally validated in a large random sample of the ISARIC cohort (N=14,231) and a smaller cohort from Aintree (N=290). Results983 patients (median age 70, IQR 53-83; in-hospital mortality 29.9%) were recruited over an 11-week study period. Through sequential modelling, a 5-predictor score termed SOARS (SpO2, Obesity, Age, Respiratory rate, Stroke history) was developed to correlate COVID-19 severity across low, moderate and high strata of mortality risk. The score discriminated well for in-hospital death, with area under the receiver operating characteristic values of 0.82, 0.80 and 0.74 in the derivation, Aintree and ISARIC validation cohorts respectively. Its predictive accuracy (calibration) in both external cohorts was consistently higher in patients with milder disease (SOARS 0-1), the same individuals who could be identified for safe outpatient monitoring. Prediction of a non-fatal outcome in this group was accompanied by high score sensitivity (99.2%) and negative predictive value (95.9%). ConclusionThe SOARS score uses constitutive and readily assessed individual characteristics to predict the risk of COVID-19 death. Deployment of the score could potentially inform clinical triage in pre-admission settings where expedient and reliable decision-making is key. The resurgence of SARS-CoV-2 transmission provides an opportunity to further validate and update its performance.

Outcome of hospitalisation for COVID-19 in patients with Interstitial Lung Disease: An international multicentre study.

RationaleThe impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established. ObjectivesTo assess outcomes following COVID-19 in patients with ILD versus those without in a contemporaneous age, sex and comorbidity matched population. MethodsAn international multicentre audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death. Measurements and Main ResultsData from 349 patients with ILD across Europe were included, of whom 161 were admitted to hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity-score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching ILD patients with COVID-19 had higher mortality (HR 1.60, Confidence Intervals 1.17-2.18 p=0.003) compared with age, sex and comorbidity matched controls without ILD. Patients with a Forced Vital Capacity (FVC) of <80% had an increased risk of death versus patients with FVC [≥]80% (HR 1.72, 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR 1.98, 1.13-3.46). ConclusionsPatients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.