Early Detection of Deterioration in COVID-19 Patients by Continuous Ward Respiratory Rate Monitoring: A Pilot Prospective Cohort Study (preprint)

Background Tachypnea is among the earliest signs of pulmonary decompensation. Contactless continuously respiratory rate monitoring might beuseful in isolated COVID-19 patients admitted in wards. We aim to determine whether continuous untethered ward respiratory rate patterns in hospitalized COVID-19 identify patients who require escalation of pulmonary management 24 hours ahead of time.Methods Single-center pilot prospective cohort study in COVID-19 patients who were cared for in routine wards. COVID-19 patients who has at least one escalation of pulmonary management were matched to 3 non-escalated patients. Contactless Breathing Monitoring was instituted after patients enrolled, and continued for 15 days unless hospital discharge, initiation of invasive mechanical ventilation, or death occurred. Respiratory rate data from the continuous monitor was not available to clinicians. The exposures were respiratory features over rolling periods of 30 min, 24 hours, and 72 hours before respiratory care escalation. The primary outcome was escalation in the pulmonary care beyond Venturi-mask.Results Among 125 included patients, 13 exhibited at least one escalation and were each matched to 3 non-escalated patients. A total of 28 escalation events were matched to 84 non-escalation episodes. The 30-min mean respiratory rate in escalated patients was 23 breaths per minute (bpm) ranging from 13 to 40 bpm, similar to the 22 bpm in non-escalated patients, although with less variability (range 14 to 31 bpm). However, higher respiratory rate variability, especially skewness over 1 day, was associated with higher incidence of an escalation event. Our overall model, based on continuous data, had a moderate accuracy with an AUC 0.81 (95%CI:0.73,0.88) and a good specificity 0.93 (95%CI:0.87,0.99).Conclusions Our pilot observational study suggests that continuous respiratory monitoring and respiratory rate variability are associated with the need for care escalation 24 hours in advance. ur results suggest that continuous respiratory monitoring is a valuable increment over intermittent monitoring.

Clinician perceptions of the impact of ICU family visiting restrictions during the COVID-19 pandemic: an international investigation (preprint)

Background: To guarantee the safety of the public, clinicians and patients during the COVID-19 pandemic, hospital visits were severely restricted internationally. There is limited data on the precise impact of these visiting restrictions on Intensive Care Unit clinicians. Our objectives therefore were, to explore the impact of family visitation restrictions on clinicians and care and describe innovation and areas for potential improvement. Methods: A qualitative approach, using focus groups was employed. We recruited members of the multi-disciplinary team from Spain, France and the UK. Framework analysis was used to synthesize and interpret data. Results: In total, 28 staff from multiple international sites contributed to data across six focus groups: 12 from the UK, 9 from France and 7 from Spain. In relation to the key aims, we derived four themes: the emergence of new technologies; relationships and rapport establishment, communication challenges and end of life care provision. Across each theme, the overarching concepts of clinician emotional exhaustion and emotional distress emerged alongside the negative impact on job satisfaction. Conclusion: The impact of COVID-19 family visitation restrictions is far reaching. Future research should examine the wider impact of family presence in the ICU.

New susceptibility loci for severe COVID-19 by detailed GWAS analysis in European populations (preprint)

Due to the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), deepening the host genetic contribution to severe COVID-19 may further improve our understanding about underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany, as well as hypothesis-driven targeted analysis of the human leukocyte antigen (HLA) region and chromosome Y haplotypes. We include detailed stratified analyses based on age, sex and disease severity. In addition to already established risk loci, our data identify and replicate two genome-wide significant loci at 17q21.31 and 19q13.33 associated with severe COVID-19 with respiratory failure. These associations implicate a highly pleiotropic ~0.9-Mb 17q21.31 inversion polymorphism, which affects lung function and immune and blood cell counts, and the NAPSA gene, involved in lung surfactant protein production, in COVID-19 pathogenesis.

Timing of elective tracheotomy and duration of mechanical ventilation amongst patients admitted to intensive care with severe COVID-19: a multicentre prospective cohort study (preprint)

Background: The COVID-19 pandemic has strained intensive care unit (ICU) resources. Tracheotomy is the most common surgery performed on ICU patients and can affect the duration of ICU care. We studied the association between when tracheotomy occurs and ICU stay length, mortality, and intraoperative and postoperative complications. Methods: Multicentre prospective cohort including all COVID-19 patients admitted to ICUs in 36 hospitals in Spain who received invasive mechanical ventilation and tracheotomy between 11 March and 20 July 2020. We used a target emulation trial framework to study the causal effects of early (7 to 10 days post-intubation) versus late (>10 days) tracheotomy on time from tracheotomy to weaning, postoperative mortality, and tracheotomy complications. Cause-specific Cox models were used for the first two outcomes and Poisson regression for the third, all adjusted for potential confounders. Findings: We included 696 patients, of whom 142 (20.4%) received early tracheotomy. Using late tracheotomy as the reference group, multivariable cause-specific analysis showed that early tracheotomy was associated with faster post-tracheotomy weaning (hazard ratio (HR) [95% confidence interval (CI)]: 1.28 [1.01 to 1.61]) without differences in mortality (HR [95% CI]: 0.94 [0.65 to 1.36]) or intraoperative or postoperative complications (adjusted rate ratio [95% CI]: 0.56 [0.23 to 1.38] and 1.31 [0.89 to 1.93], respectively). Interpretation: Early tracheotomy reduced post-tracheotomy weaning time, resulting in fewer mechanical ventilation days and shorter ICU stays, without changing complication or mortality rates. These results support early tracheotomy for COVID-19 patients when clinically indicated.

Early Corticosteroids Decrease Mortality in Critically Ill Patients with COVID-19: A Cohort Study (preprint)

Background: Critically ill patients with coronavirus disease 19 (COVID-19) have a high fatality rate likely due to a dysregulated immune response. Corticosteroids could attenuate this inappropriate response, although there are still some concerns regarding its use, timing, and dose. Methods: : This is a nationwide, prospective, multicenter, observational, cohort study in critically ill adult patients with COVID-19 admitted into Intensive Care Units (ICU) in Spain from March 12 th to June 29 th , 2020. Using a multivariable Cox model with inverse probability weighting, we compared relevant outcomes between patients treated with early corticosteroids (before or within the first 48h of ICU admission) with those who did not receive early corticosteroids or any corticosteroids at all. Primary endpoint was ICU mortality. Secondary endpoints included 7-day mortality, ventilator-free days, and complications. Results: : A total of 691 patients out of 882 (78.3%) received corticosteroid during their hospital stay. Patients treated with early-corticosteroids (n=485) had a lower ICU mortality (30.3% vs 40.6%, HR 0.71, 95% CI 0.57-0.89) and higher number of ventilator-free days (mean difference 2.5 days, 95% CI 1.3-3.8) compared to non-early treated patients. There were no differences in 7-day mortality (HR 0.76, 95% CI 0.48-1.2), medical complications (OR 2.18, 95% CI 0.91-5.25) or secondary infections (OR 0.88, 95% CI 0.67-1.15) between both groups. Of note, early use of moderate-to-high doses was associated with better outcomes than low dose regimens. Conclusion: Early use of corticosteroids in critically ill patients with COVID-19 is associated with lower mortality (10.3% absolute risk reduction) and shorter duration of mechanical ventilation.

Tocilizumab is associated with reduction of the risk of ICU admission and mortality in patients with SARS-CoV-2 infection (preprint)

Background In some patients the immune response triggered by SARS-CoV-2 is unbalanced, presenting an acute respiratory distress syndrome which in many cases requires intensive care unit (ICU) admission. The limitation of ICU beds has been one of the major burdens in the management around the world, therefore, clinical strategies to avoid ICU admission are needed. Objective We aimed to describe the influence of tocilizumab on the need of transfer to ICU or death in non-critically ill patients. Methods A retrospective study of 171 patients with SARS-CoV-2 infection that did not qualify as requiring transfer to ICU during the first 24h after admission to a conventional ward, were included. The criteria to receive tocilizumab was radiological impairment, oxygen demand or an increasing of inflammatory parameters, however, the ultimate decision was left to the attending physician judgement. The primary outcome was the need of ICU admission or death whichever came first. Results 77 patients received tocilizumab and 94 did not. The tocilizumab group had less ICU admissions (10.3% vs. 27.6%, P= 0.005) and need of invasive ventilation (0 vs 13.8%, P=0.001). In the multivariable analysis, tocilizumab remained as a protective variable (OR: 0.03, CI 95%: 0.007-0*1, P=0.0001) of ICU admission or death. Conclusions Tocilizumab in the early stages of the inflammatory flare, could avoid an important number of ICU admissions and mechanical ventilation use. The mortality rate of 10.3% among patients receiving tocilizumab appears to be lower than other reports.

The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis (preprint)

Background. Respiratory failure is a key feature of severe Covid-19 and a critical driver of mortality, but for reasons poorly defined affects less than 10% of SARS-CoV-2 infected patients. Methods. We included 1,980 patients with Covid-19 respiratory failure at seven centers in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe (Milan, Monza, Madrid, San Sebastian and Barcelona) for a genome-wide association analysis. After quality control and exclusion of population outliers, 835 patients and 1,255 population-derived controls from Italy, and 775 patients and 950 controls from Spain were included in the final analysis. In total we analyzed 8,582,968 single-nucleotide polymorphisms (SNPs) and conducted a meta-analysis of both case-control panels. Results. We detected cross-replicating associations with rs11385942 at chromosome 3p21.31 and rs657152 at 9q34, which were genome-wide significant (P<5x10-8) in the meta-analysis of both study panels, odds ratio [OR], 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.14x10-10 and OR 1.32 (95% CI, 1.20 to 1.47; P=4.95x10-8), respectively. Among six genes at 3p21.31, SLC6A20 encodes a known interaction partner with angiotensin converting enzyme 2 (ACE2). The association signal at 9q34 was located at the ABO blood group locus and a blood-group-specific analysis showed higher risk for A-positive individuals (OR=1.45, 95% CI, 1.20 to 1.75, P=1.48x10-4) and a protective effect for blood group O (OR=0.65, 95% CI, 0.53 to 0.79, P=1.06x10-5). Conclusions. We herein report the first robust genetic susceptibility loci for the development of respiratory failure in Covid-19. Identified variants may help guide targeted exploration of severe Covid-19 pathophysiology.

COVID-19 is an emergent disease of aging (preprint)

COVID-19 is an ongoing pandemic caused by the SARS-CoV-2 coronavirus that poses one of the greatest challenges to public health in recent years. SARS-CoV-2 is highly contagious and often leads to severe viral pneumonia with respiratory failure and death in the elderly and subjects with pre-existing conditions, but the reason for this age dependence is unclear. Here, we found that the case fatality rate for COVID-19 grows exponentially with age in Italy, Spain, South Korea, and China, with the doubling time approaching that of all-cause human mortality. In addition, men and those with multiple age-related diseases are characterized by increased mortality. Moreover, similar mortality patterns were found for all-cause pneumonia. We further report that the gene expression of ACE2, the SARS-CoV-2 receptor, grows in the lung with age, except for subjects on a ventilator. Together, our findings establish COVID-19 as an emergent disease of aging, and age and age-related diseases as its major risk factors. In turn, this suggests that COVID-19, and deadly respiratory diseases in general, may be targeted, in addition to therapeutic approaches that affect specific pathways, by approaches that target the aging process.