Association of complement pathways with COVID-19 severity and outcomes.

OBJECTIVES: Complement activation has been implicated in COVID-19 pathogenesis. This study aimed to assess the levels of complement activation products and full-length proteins in hospitalized patients with COVID-19, and evaluated whether complement pathway markers are associated with outcomes. METHODS: Longitudinal measurements of complement biomarkers from 89 hospitalized adult patients, grouped by baseline disease severity, enrolled in an adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial and treated with intravenous sarilumab (200 mg or 400 mg) or placebo (NCT04315298), were performed. These measurements were then correlated with clinical and laboratory parameters. RESULTS: All complement pathways were activated in hospitalized patients with COVID-19. Alternative pathway activation was predominant earlier in the disease course. Complement biomarkers correlated with multiple variables of multi-organ dysfunction and inflammatory injury. High plasma sC5b-9, C3a, factor Bb levels, and low mannan-binding lectin levels were associated with increased mortality. Sarilumab treatment showed a modest inhibitory effect on complement activation. Moreover, sera from patients spontaneously deposited C5b-9 complex on the endothelial surface ex vivo, suggesting a microvascular thrombotic potential. CONCLUSION: These results advance our understanding of COVID-19 disease pathophysiology and demonstrate the importance of specific complement pathway components as prognostic biomarkers in COVID-19.

Factors associated with non-invasive positive pressure ventilation failure in a COVID-19 intermediate care unit.

BACKGROUND: The use of non-invasive positive pressure ventilation (NIPPV) in COVID-19 patients with hypoxaemia is still under debate. The aim was to evaluate the efficacy of NIPPV (CPAP, HELMET-CPAP or NIV) in COVID-19 patients treated in the dedicated COVID-19 Intermediate Care Unit of Coimbra Hospital and University Centre, Portugal, and to assess factors associated with NIPPV failure. METHODS: Patients admitted from December 1st 2020 to February 28th 2021, treated with NIPPV due to COVID-19 were included. Failure was defined as orotracheal intubation (OTI) or death during hospital stay. Factors associated with NIPPV failure were included in a univariate binary logistic regression analysis; those with a significance level of p < 0.001 entered a multivariate logistic regression model. RESULTS: A total of 163 patients were included, 64.4% were males (n = 105). The median age was 66 years (IQR 56-75). NIPPV failure was observed in 66 (40.5%) patients, 26 (39.4%) were intubated and 40 (60.6%) died during their hospital stay. The highest CRP (OR 1.164; 95%CI 1.036-1.308) and morphine use (OR 24.771; 95%CI 1.809-339.241) were identified as predictors of failure after applying multivariate logistic regression. Adherence to prone positioning (OR 0.109; 95%CI 0.017-0.700) and a higher value of the lowest platelet count during hospital stay (OR 0.977; 95%CI 0.960-0.994) were associated with a favorable outcome. CONCLUSIONS: NIPPV was successful in over half of patients. Highest CRP during hospital stay and morphine use were predictors of failure. Adherence to prone positioning and a higher value of the lowest platelet count during hospital stay were associated with a favourable outcome.

Outcomes in COVID-19 Patients with Pneumonia Treated with High-Flow Oxygen Therapy and Baricitinib-Retrospective Single-Center Study.

BACKGROUND: The aim of the study was to assess the effect of baricitinib on 28-day all-cause mortality and the progression of respiratory failure in patients needing transfer to the intensive care unit (ICU) with COVID-19 pneumonia treated with high-flow oxygen therapy. METHODS: This retrospective study included hospitalized patients with COVID-19 pneumonia treated with high-flow oxygen non-invasive ventilation receiving standard of care (SOC) or SOC in addition to baricitinib. Data on patients' characteristics, pro-inflammatory markers, D dimer, and National Early Warning Score 2 (NEWS2) values were collected and compared between groups. The primary endpoint was 28-day all-cause in-hospital mortality and the secondary outcome was transfer to the ICU. RESULTS: The study included 125 patients. The primary outcome was observed in 44.8% of them: 27% in the baricitinib group vs. 62% in the SOC group, p < 0.001. Transfer to the ICU ward was significantly lower in the baricitinib group: 29% vs. 81%, p < 0.001. A significant improvement was observed when the baricitinib group was compared to SOC in procalcitonin, CRP, D-dimer, neutrophil-to-lymphocyte ratio values, and NEWS2. CONCLUSION: Treatment with baricitinib in addition to SOC was associated with reduced mortality and a lower prevalence of transfer to the ICU in hospitalized patients with COVID-19 pneumonia treated with high-flow oxygen non-invasive therapy.

Introducing helmet non-invasive ventilation during COVID-19 pandemic: Early experience of two centres.

Purpose: The helmet is a novel interface for delivering non-invasive ventilation (NIV). We conducted a case series to characterize introduction of the helmet interface in both COVID and non-COVID patients at two-centres. Methods: We enrolled all patients with respiratory failure admitted to the Juravinski Hospital (Hamilton, Canada) and St. Joseph's Health Center (Syracuse, New York) between November 1, 2020 and June 30, 2021 who used the helmet interface (Intersurgical StarMed) as part of this introduction into clinical practice. We collected patient demographics, reason for respiratory failure, NIV settings, device-related complications and outcomes. We report respiratory therapist's initial experiences with the helmet using descriptive results. Results: We included 16 patients with a mean age of 64.3 ± 10.9 years. The most common etiology for respiratory failure was pneumonia (81.3%). The median duration of NIV during the ICU admission was 67.5 (15.3, 80.8) hours, with a mean maximum PS of 13.9 ± 6.6 cm H2O and a mean maximum PEEP of 10.4 ± 5.1 cm H20. Three patients (18.7%) did not tolerate the helmet. Ten (62.5%) patients ultimately required intubation, and 7 (43.4%) patients died while in the ICU. The most common reason for intubation was worsening hypoxia (70%). No adverse events related to the helmet were recorded. Conclusion: Over the 8-month period of this study, we found that the helmet was well tolerated in over 80% of patients, although, more than half ultimately required intubation. Randomized controlled trials with this device are required to fully assess the efficacy of this interface.

Extracorporeal Membrane Oxygenation for COVID-19: Comparison of Outcomes to Non-COVID-19-Related Viral Acute Respiratory Distress Syndrome From the Extracorporeal Life Support Organization Registry.

To compare complications and mortality between patients that required extracorporeal membrane oxygenation (ECMO) support for acute respiratory distress syndrome (ARDS) due to COVID-19 and non-COVID-19 viral pathogens. DESIGN: Retrospective observational cohort study. SETTING: Adult patients in the Extracorporeal Life Support Organization registry. PATIENTS: Nine-thousand two-hundred ninety-one patients that required ECMO for viral mediated ARDS between January 2017 and December 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcomes of interest were mortality during ECMO support and prior to hospital discharge. Time-to-event analysis and logistic regression were used to compare outcomes between the groups. Among 9,291 included patients, 1,155 required ECMO for non-COVID-19 viral ARDS and 8,136 required ECMO for ARDS due to COVID-19. Patients with COVID-19 had longer duration of ECMO (19.6 d [interquartile range (IQR), 10.1-34.0 d] vs 10.7 d [IQR, 6.3-19.7 d]; p < 0.001), higher mortality during ECMO support (44.4% vs 27.5%; p < 0.001), and higher in-hospital mortality (50.2% vs 34.5%; p < 0.001). Further, patients with COVID-19 were more likely to experience mechanical and clinical complications (membrane lung failure, pneumothorax, intracranial hemorrhage, and superimposed infection). After adjusting for pre-ECMO disease severity, patients with COVID-19 were more than two times as likely to die in the hospital compared with patients with non-COVID-19 viral ARDS. CONCLUSIONS: Patients with COVID-19 that require ECMO have longer duration of ECMO, more complications, and higher in-hospital mortality compared with patients with non-COVID-19-related viral ARDS. Further study in patients with COVID-19 is critical to identify the patient phenotype most likely to benefit from ECMO and to better define the role of ECMO in the management of this disease process.

Intensive Care and Organ Support Related Mortality in Patients With COVID-19: A Systematic Review and Meta-Analysis.

To perform a systematic review and meta-analysis to generate estimates of mortality in patients with COVID-19 that required hospitalization, ICU admission, and organ support. DATA SOURCES: A systematic search of PubMed, Embase, and the Cochrane databases was conducted up to December 31, 2021. STUDY SELECTION: Previously peer-reviewed observational studies that reported ICU, mechanical ventilation (MV), renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO)-related mortality among greater than or equal to 100 individual patients. DATA EXTRACTION: Random-effects meta-analysis was used to generate pooled estimates of case fatality rates (CFRs) for in-hospital, ICU, MV, RRT, and ECMO-related mortality. ICU-related mortality was additionally analyzed by the study country of origin. Sensitivity analyses of CFR were assessed based on completeness of follow-up data, by year, and when only studies judged to be of high quality were included. DATA SYNTHESIS: One hundred fifty-seven studies evaluating 948,309 patients were included. The CFR for in-hospital mortality, ICU mortality, MV, RRT, and ECMO were 25.9% (95% CI: 24.0-27.8%), 37.3% (95% CI: 34.6-40.1%), 51.6% (95% CI: 46.1-57.0%), 66.1% (95% CI: 59.7-72.2%), and 58.0% (95% CI: 46.9-68.9%), respectively. MV (52.7%, 95% CI: 47.5-58.0% vs 31.3%, 95% CI: 16.1-48.9%; p = 0.023) and RRT-related mortality (66.7%, 95% CI: 60.1-73.0% vs 50.3%, 95% CI: 42.4-58.2%; p = 0.003) decreased from 2020 to 2021. CONCLUSIONS: We present updated estimates of CFR for patients hospitalized and requiring intensive care for the management of COVID-19. Although mortality remain high and varies considerably worldwide, we found the CFR in patients supported with MV significantly improved since 2020.

Mechanical power and 30-day mortality in mechanically ventilated, critically ill patients with and without Coronavirus Disease-2019: a hospital registry study.

BACKGROUND: Previous studies linked a high intensity of ventilation, measured as mechanical power, to mortality in patients suffering from "classic" ARDS. By contrast, mechanically ventilated patients with a diagnosis of COVID-19 may present with intact pulmonary mechanics while undergoing mechanical ventilation for longer periods of time. We investigated whether an association between higher mechanical power and mortality is modified by a diagnosis of COVID-19. METHODS: This retrospective study included critically ill, adult patients who were mechanically ventilated for at least 24 h between March 2020 and December 2021 at a tertiary healthcare facility in Boston, Massachusetts. The primary exposure was median mechanical power during the first 24 h of mechanical ventilation, calculated using a previously validated formula. The primary outcome was 30-day mortality. As co-primary analysis, we investigated whether a diagnosis of COVID-19 modified the primary association. We further investigated the association between mechanical power and days being alive and ventilator free and effect modification of this by a diagnosis of COVID-19. Multivariable logistic regression, effect modification and negative binomial regression analyses adjusted for baseline patient characteristics, severity of disease and in-hospital factors, were applied. RESULTS: 1,737 mechanically ventilated patients were included, 411 (23.7%) suffered from COVID-19. 509 (29.3%) died within 30 days. The median mechanical power during the first 24 h of ventilation was 19.3 [14.6-24.0] J/min in patients with and 13.2 [10.2-18.0] J/min in patients without COVID-19. A higher mechanical power was associated with 30-day mortality (ORadj 1.26 per 1-SD, 7.1J/min increase; 95% CI 1.09-1.46; p = 0.002). Effect modification and interaction analysis did not support that this association was modified by a diagnosis of COVID-19 (95% CI, 0.81-1.38; p-for-interaction = 0.68). A higher mechanical power was associated with a lower number of days alive and ventilator free until day 28 (IRRadj 0.83 per 7.1 J/min increase; 95% CI 0.75-0.91; p < 0.001, adjusted risk difference - 2.7 days per 7.1J/min increase; 95% CI - 4.1 to - 1.3). CONCLUSION: A higher mechanical power is associated with elevated 30-day mortality. While patients with COVID-19 received mechanical ventilation with higher mechanical power, this association was independent of a concomitant diagnosis of COVID-19.

Report of the first seven agents in the I-SPY COVID trial: a phase 2, open label, adaptive platform randomised controlled trial.

Background: An urgent need exists to rapidly screen potential therapeutics for severe COVID-19 or other emerging pathogens associated with high morbidity and mortality. Methods: Using an adaptive platform design created to rapidly evaluate investigational agents, hospitalised patients with severe COVID-19 requiring ≥6 L/min oxygen were randomised to either a backbone regimen of dexamethasone and remdesivir alone (controls) or backbone plus one open-label investigational agent. Patients were enrolled to the arms described between July 30, 2020 and June 11, 2021 in 20 medical centres in the United States. The platform contained up to four potentially available investigational agents and controls available for randomisation during a single time-period. The two primary endpoints were time-to-recovery (<6 L/min oxygen for two consecutive days) and mortality. Data were evaluated biweekly in comparison to pre-specified criteria for graduation (i.e., likely efficacy), futility, and safety, with an adaptive sample size of 40-125 individuals per agent and a Bayesian analytical approach. Criteria were designed to achieve rapid screening of agents and to identify large benefit signals. Concurrently enrolled controls were used for all analyses. https://clinicaltrials.gov/ct2/show/NCT04488081. Findings: The first 7 agents evaluated were cenicriviroc (CCR2/5 antagonist; n = 92), icatibant (bradykinin antagonist; n = 96), apremilast (PDE4 inhibitor; n = 67), celecoxib/famotidine (COX2/histamine blockade; n = 30), IC14 (anti-CD14; n = 67), dornase alfa (inhaled DNase; n = 39) and razuprotafib (Tie2 agonist; n = 22). Razuprotafib was dropped from the trial due to feasibility issues. In the modified intention-to-treat analyses, no agent met pre-specified efficacy/graduation endpoints with posterior probabilities for the hazard ratios [HRs] for recovery ≤1.5 between 0.99 and 1.00. The data monitoring committee stopped Celecoxib/Famotidine for potential harm (median posterior HR for recovery 0.5, 95% credible interval [CrI] 0.28-0.90; median posterior HR for death 1.67, 95% CrI 0.79-3.58). Interpretation: None of the first 7 agents to enter the trial met the prespecified criteria for a large efficacy signal. Celecoxib/Famotidine was stopped early for potential harm. Adaptive platform trials may provide a useful approach to rapidly screen multiple agents during a pandemic. Funding: Quantum Leap Healthcare Collaborative is the trial sponsor. Funding for this trial has come from: the COVID R&D Consortium, Allergan, Amgen Inc., Takeda Pharmaceutical Company, Implicit Bioscience, Johnson & Johnson, Pfizer Inc., Roche/Genentech, Apotex Inc., FAST Grant from Emergent Venture George Mason University, The DoD Defense Threat Reduction Agency (DTRA), The Department of Health and Human ServicesBiomedical Advanced Research and Development Authority (BARDA), and The Grove Foundation. Effort sponsored by the U.S. Government under Other Transaction number W15QKN-16-9-1002 between the MCDC, and the Government.

Unexpected Aggravation of COVID-19 After Recovery in Three Adolescents With Chronic Neurologic Conditions: A Case Series

The clinical severity of coronavirus disease 2019 (COVID-19) in children is usually mild. Most of the affected patients completely recovered from COVID-19 before being released from approximately 7-day quarantine. However, children with comorbidities are at risk of more severe disease and adverse outcomes. We report three cases of COVID-19-affected adolescents with underlying chronic respiratory difficulty due to neurologic diseases who showed sudden clinical aggravations at the time of discharge, even after full clinical improvement. Patient 1 is a 17-year-old boy with Ullrich congenital muscular dystrophy who had cardiopulmonary arrest 9 days after the initial COVID-19 symptoms. Patient 2 is a 17-year-old girl with intracerebral hemorrhage with infarction in bed-ridden status who had cardiopulmonary arrest 11 days after the initial symptoms. Patient 3 is a 12-year-old boy with intraventricular hemorrhage with hydrocephalus in bed-ridden status who showed multiorgan failure 10 days after the initial symptoms. Remdesivir, dexamethasone, and empirical antibiotics were administered with mechanical ventilation and intensive unit care. Among the three patients, two (patients 1 and 3) were alive, and one (patient 2) expired. Clinicians caring for adolescents with chronic neurologic and/or pulmonary disease should keep in mind that these patients could have sudden deterioration after recovery from the acute phase of COVID-19 around or after the time of discharge. © 2022 The Korean Society of Pediatric Infectious Diseases.

Severe viral respiratory infections in the pre-COVID era: A 5-year experience in two pediatric intensive care units in Italy.

BACKGROUND: Viral respiratory infections are one of the main causes of hospitalization in children. Even if mortality rate is low, 2% to 3% of the hospitalized children need mechanical ventilation. Risk factors for admission to the pediatric intensive care unit (PICU) are well known, while few studies have described risk factors for invasive ventilator support and prolonged hospitalization. METHODS: A retrospective study including all patients aged between 2 and 18 months with a confirmed viral respiratory infection, requiring admission to PICU from September to March between 2015 and 2019, was conducted at Bambino Gesù Children's Hospital in Rome, Italy. RESULTS: One hundred ninety patients were enrolled, with a median age of 2.7 months; 32.1% had at least one comorbidity, mainly prematurity. The most frequent isolated viruses were RSV-B, rhinovirus, and RSV-A; 38.4% needed mechanical ventilation. This subgroup of patients had lower median birth weight compared with patients not requiring mechanical ventilation (2800 g vs. 3180 g, p = 0.02); moreover, comorbidities were present in 43.8% of intubated patients and in 24.8% of patients treated with non-invasive ventilation (p = 0.006). Viral coinfection did not result to be a risk factor for mechanical support, while virus-bacteria coinfection was significantly associated with mechanical ventilation (p < 0.001). Similar risk factors were identified for prolonged hospitalization. CONCLUSIONS: Early identification of patients who could have a sudden respiratory deterioration and need of mechanical ventilation is crucial to reduce complications due to orotracheal intubation and prolonged hospitalization in PICU. Further studies are needed to define high-risk group of patients and to design targeted interventions.