ABSTRACT
Rationale 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 smallcase 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 the impact of CRS on the ventilatory management and outcomes of COVID-19 patients on mechanical ventilation (MV), admitted to intensive care units (ICU) worldwide.Results We enrolled 318 COVID-19 patients enrolled into the study from January 14th through September 31th, 2020 in 19 countries and stratified into two CRS groups. CRS was calculated as: tidal volume/[airway plateau pressure-positive endexpiratory pressure (PEEP)] and available within 48h from commencement of MV in 318 patients. Patients were mean±SD of 58.0±12.2, predominantly from Europe (54%) and males (68%). Median CRS (IQR) was 34.1 mL/cmH2O (26.5-45.5) and PaO2/FiO2 was 119 mmHg (87.1-164) and was not correlated with CRS. Female sex presented lower CRS than in males (95% CI:-13.8 to-8.5 P<0.001) and higher body mass index (34.7±10.9 vs 29.1±6.0, p<0.001). Median (IQR) PEEP was 12 cmH2O (10-15), throughout the range of CRS, while median (IQR) driving pressure was 12.3 (10-15) cmH2O and significantly decreased as CRS improved (p<0.001). No differences were found in comorbidities and clinical management between CRS strata. In addition, 28-day ICU mortality and hospital mortality did not differ between CRSgroups.Conclusions This multicentre report provides a comprehensive account of CRS in COVID-19 patients on MV-predominantly males or overweight females, in their late 50s-admitted to ICU during the first international outbreaks. Phenotypes associated with different CRS upon commencement of MV could not be identified.
ABSTRACT
Rationale: Patients with COVID-19 commonly develop severe hypoxemic respiratory failure and require invasive mechanical ventilation (MV). The disease burden and predictors of mortality in this population remain uncertain. Methods: Prospective observational cohort study from 139 intensive care units of the international COVID-19 Critical Care Consortium. Patients enrolled from January 14th through November 31st 2020 were included in the analysis. Patient's characteristics and clinical data were assessed. Multivariable Cox proportional hazards analysis was conducted to identify indipendent predictors of mortality within 28 days from commencement of MV. Results: 1578 patients on MV were included into the analysis. Mean±SD age was 59 years±13 and patients were predominantly males (66%). 542 Patients (34.4%) died within 28 days from commencement of MV. Nonsurvivors were slightly older (mean age±SD 62±13 vs. 59±13) and presented more frequently hypertension, chronic cardiac disease and diabetes. Median (IQR) PaO2/FiO2 upon commencement of MV was 96 (68-135) and 111 (81-173) in patients who did not survive vs. survivors, respectively (p=0.04). ECMO (13% vs 25%, p<0.01), inhaled nitric oxide (11% vs 15%, p=0.02) and recruitment manoeauvres (26% vs 31%, p<0.01) were used less frequently in patients who did not survive. Independent risk factors associated with 28-day mortality included age older than 70 years (hazard ratio [HR], 2.83;95% CI, 1.32-6.07), higher creatinine levels upon ICU admission (HR, 1.20;95% CI, 1.03-1.40), and lower pH within 24h from commencement of MV (HR, 0.12;95% CI, 0.02-0.62), while a shorter period (day) from early symptoms to hospitalisation reduced mortality risks (HR, 0.96;95% CI, 0.93-0.99). Conclusions: Our findings from a large international cohort of critically-ill COVID-19 patients on mechanical ventilation emphasises that elderly patients, not promptly admitted to the hospital, and who present higher creatinine levels and acidosis are at higher risk of mortality.
ABSTRACT
Background: Patients with R/M SCC have low response rates to second line therapies, including PD-1 inhibitors nivolumab and pembrolizumab, representing an area of unmet clinical need. Cetuximab has modest activity as a single agent but potentiates the activity of radiotherapy in locally advanced head & neck SCC (HNSCC) and chemotherapy in R/M HNSCC. Cetuximab initiates Natural Killer cell antibody-dependent cell-mediated cytotoxicity, resulting in an anti-tumour immune response and the potential to augment the activity of PD-1/PD-L1 inhibition. Methods: Trial entry required histologically confirmed R/M SCC of any site, unselected by PD-L1 expression, considered incurable by local therapies and no previous treatment with cetuximab for recurrent/metastatic disease. Prior therapy with anti-PD-1, anti-PD-L1 or anti-PD-L2 was excluded. Patients had avelumab 10 mg/kg + cetuximab 500 mg/m2 intravenously every 2 weeks, for up to 1 year. Primary endpoint was occurrence of dose-limiting toxicity within 42 days of treatment starting, graded using CTCAE v5. Secondary endpoints were objective response (ORR) and disease control rate (DCR) at 6 and 12 months using iRECIST. Results: 16 patients, median age 58 years (range 34 – 88), were enrolled from 2 UK hospitals between July 2018 and October 2019. The trial stopped after completing the safety run-in. 5 patients remain on treatment, 9 stopped treatment early (7 disease progression, 1 patient choice, 1 due to risk of COVID-19). 2 patients died whilst on treatment (both unrelated to trial treatment). Grade 3 AEs were seen in 4 patients and grade 5 in 1 patient. None were related to trial treatment. No patients experienced dose-limiting toxicity. Of 10 patients evaluable for response by iRECIST 2 (20%) had complete response, 3 (30%) had partial response and 4 (40%) had stable disease as their best response, representing an ORR of 50%. One patient had confirmed disease progression. In 6 patients who remained on trial for >6 months, all 6 had disease control at 6 months (2 CR, 1 PR, 3 SD). Conclusions: Avelumab + cetuximab is safe and tolerable, and demonstrates promising efficacy in R/M SCC patients. Clinical trial identification: NCT03494322;20/03/2018;Sponsor reference: UCL/17/0560. Legal entity responsible for the study: University College London. Funding: Merck KGaA. Disclosure: M. Forster: Advisory/Consultancy, Travel/Accommodation/Expenses: BMS;Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck;Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD;Advisory/Consultancy: Novartis;Advisory/Consultancy: PharmaMar;Advisory/Consultancy, Travel/Accommodation/Expenses: Roche;Advisory/Consultancy: Nanobiotix;Advisory/Consultancy, Travel/Accommodation/Expenses: Guardant Health;Advisory/Consultancy: Oxford VacMedix;Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca;Advisory/Consultancy: Takeda;Research grant/Funding (institution): Boehringer Ingelheim;Travel/Accommodation/Expenses: Celgene. J. Sacco: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS;Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: MSD;Honoraria (self), Advisory/Consultancy: Amgen;Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Immunocore;Honoraria (self), Advisory/Consultancy: Delcath;Honoraria (self): Pierre Fabre;Research grant/Funding (institution): AstraZeneca. A. Kong: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck;Honoraria (self), Speaker Bureau/Expert testimony: BMS;Advisory/Consultancy: Centauri Therapeutics;Advisory/Consultancy: Amgen;Advisory/Consultancy, Research grant/Funding (institution): Puma Biotechnology;Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: MSD;Research grant/Funding (institution): AstraZeneca. G. Wheeler: Honoraria (self): AstraZeneca. J. Hartley: Full/Part-t me employment: AstraZeneca;Advisory/Consultancy, Shareholder/Stockholder/Stock options: ADC Therapeutics. All other authors have declared no conflicts of interest.