Latent class analysis of imaging and clinical respiratory parameters from patients with COVID-19-related ARDS identifies recruitment subphenotypes

Introduction: Patients with COVID-19-related acute respiratory distress syndrome (ARDS) require respiratory support with invasive mechanical ventilation and show varying responses to recruitment manoeuvres. In patients with ARDS not related to COVID-19, two pulmonary subphenotypes that differed in recruitability were identified using latent class analysis (LCA) of imaging and clinical respiratory parameters [1]. We aimed to validate these phenotypes and evaluate if similar subphenotypes are present in patients with COVID-19-related ARDS. Method(s): This is the retrospective analysis of mechanically ventilated patients with COVID-19-related ARDS who underwent CT scans at positive end-expiratory pressure of 10 cmH2O and after a recruitment manoeuvre at 20 cmH2O. LCA was applied to quantitative CT-derived parameters, clinical respiratory parameters, blood gas analysis and routine laboratory values before recruitment to identify subphenotypes. Result(s): 99 patients were included. Using 12 variables, a two-class LCA model was identified as best fitting. Subphenotype 2 (recruitable) was characterized by a lower PaO2/ FiO2, lower normally aerated lung volume and lower compliance as opposed to a higher nonaerated lung mass and higher mechanical power when compared to subphenotype 1 (non-recruitable) (Fig. 1). Patients with subphenotype 2 had more decrease in non-aerated lung mass in response to a standardized recruitment manoeuvre (p = 0.024) and were mechanically ventilated longer until successful extubation (adjusted SHR 0.46, 95% CI 0.23-0.91, p = 0.026), while no difference in survival was found (p = 0.814). Conclusion(s): A recruitable and non-recruitable subphenotype were identified in patients with COVID-19-related ARDS. The subphenotypes are similar to non-COVID-19-related ARDS and are promising for identification of recruitable patients in future practice as they can be classified with only few clinically available parameters before the recruitment manoeuvre.

Management in the ICU

Patients hospitalised due to infection with SARS-CoV-2 frequently require admission to the ICU for organ support. Most of these admissions are due to acute respiratory failure, often fulfilling the criteria for ARDS. This chapter will review current evidence-based management of this patient population. We discuss how oxygenation can be supported via noninvasive and invasive methods, and describe how invasive ventilation should be set to provide lung protection. We discuss how there is no place for routine antiviral, antibiotic and therapeutic anticoagulation in ICU patients with COVID-19-related ARDS, but there is a place for steroids and immunomodulation via anti-IL-6. Finally, we provide an overview of the complications and long-term consequences of critical illness caused by COVID-19.Copyright © ERS 2021.

Sustained Alveolar Fibroproliferation in Patients with Non-Resolving Covid-19 Related Ards Does Not Lead to Pulmonary Fibrosis

Introduction: Impairment of lung function and radiological abnormalities are a major concern in COVID-19 survivors, but, as of yet, patients with persistent COVID-19-related ARDS have still not been fully characterized especially regarding long-term lung injury and development of pulmonary fibrosis. The aim of this observational study is to investigate whether long-term pulmonary injury is related to fibroproliferative responses during ICU stay. Method(s): Twenty-eight PCR confirmed COVID-19 patients admitted to the ICU of the Amsterdam University Medical Centers (Amsterdam UMC), location VUmc, who underwent a diagnostic bronchoscopy with broncho-alveolar lavage (BAL) because of non-resolving COVID-19 related ARDS, were included. Bronchoscopy was repeated weekly when no clinical improvement was observed. Markers for epithelial injury and fibroproliferation were measured in BALF and plasma using specific Luminex assays or ELISA. Three and 12 months after hospital discharge, chest CT and lung function parameters were obtained during outpatient visits. Result(s): Pulmonary markers for epithelial injury and fibroproliferation were measured in BALF and compared to healthy controls (HC). Epithelial injury and fibroproliferation markers were significantly increased in critically ill COVID-19 patients as compared to HC. Plasma markers for fibroproliferation were not different as compared to HC. No signs of pulmonary fibrosis were found at 3 and 12 months after hospital discharge. Conclusion(s): Patients with non-resolving COVID-19 related ARDS show a sustained alveolar fibroproliferative response, however such fibroproliferative response is not associated with pulmonary fibrosis.

The efficacy and safety of intravenous imatinib in invasively ventilated patients with COVID-19 related acute respiratory distress syndrome (InventCOVID): a multicentre, randomised, double-blinded, placebocontrolled, phase II clinical study

Background: A central hallmark of ARDS is hypoxemic respiratory failure due to increased pulmonary capillary leakage. The kinase inhibitor imatinib was shown to reverse vascular leak. This study aimed to investigate the effect of intravenous imatinib on pulmonary edema in patients with COVID-19 ARDS. Method(s): This multicentre, randomised, double-blind, placebo-controlled clinical trial (ClinicalTrial.gov identifier NCT04794088) included adult patients admitted to the ICU with moderate or severe COVID-19 ARDS. Patients were randomised 1:1 to receive 200mg intravenous imatinib or placebo twice daily for seven days or until ICU discharge. The change in extravascular lung water index between day 1 and day 4, measured using a PiCCO catheter, was chosen as the primary endpoint. Secondary outcomes included the PaO2/FiO2 ratio, number of ventilator free days, length of ICU admission and 28-day mortality rate. Study drug safety was assessed by daily screening of the patient records for adverse and serious adverse event occurrence and by performing ECGs and targeted clinical laboratory tests to monitor renal, liver and cardiac function. Result(s): Between March 2021 and 2022, 67 predominantly male (58%) patients with a mean age of 63+/-10 years were randomized to receive imatinib or placebo. No adverse events were considered to be related to study drug administration. At the moment of the submission, data cleaning is still ongoing. Conclusion(s): Thus far, intravenous imatinib administration seems safe and feasible in patients with COVID-19 related ARDS.

Impaired ventilation is not independently associated with 28-day mortality in coronavirus disease 2019 (COVID19) acute respiratory distress syndrome (ARDS)

INTRODUCTION Surrogates for impaired ventilation such as estimated dead-space fractions and the ventilatory ratio are independently associated with an increased risk of mortality in the acute respiratory distress syndrome (ARDS) and small case series of COVID-19 related ARDS. METHODS This study aimed to quantify the dynamics and determine the prognostic value of surrogate markers of impaired ventilation in patients with COVID-19 related ARDS. The present study is a secondary analysis of the PRactice Of VENTilation in COVID-19 patients (PROVENT-COVID) in 22 intensive care unit hospitals in the Netherlands. Surrogates of impaired ventilation such as the estimated dead space fraction (by Harris-Benedict-VD/VT HB and direct method-VD/VT DIR), ventilatory ratio (VR), and end-tidal-to-arterial PCO2 ratio (PETCO2/PaCO2) were used. RESULTS 927 consecutive patients admitted with COVID-19 related ARDS were included in this study. Surrogates of impaired ventilation were significantly higher in non-survivors than survivors at baseline and during the following days of mechanical ventilation (p <0.001). As ARDS severity increased, mortality increased with successive tertiles for VD/VT HB and VD/VT DIR, and VR, and decreased with successive tertiles for PETCO2/PaCO2. Mortality over the first 28 days was higher in patients in the high group of dead space fraction by VD/VT HB (16.4% vs. 12.3%;p = 0.003), but similar in the groups considering the dead space fraction by VD/VT DIR (15.4% vs. 13.3%;p = 0.100), and VR (15.5% vs. 13.2%;p = 0.080) (Figure 2). After adjustment for a base risk model that included chronic comorbidities, ventilation and oxygenation parameters, none of the surrogates of impaired ventilation measured at the start of ventilation or the following days were significantly associated with 28-day mortality. CONCLUSION Surrogate markers for impaired ventilation are abnormal at the start of invasive ventilation in patients with COVID-19 related ARDS and worsen during consequent days. Ventilation impairment seems to be more extensive in non-survivors than in survivors, but they do not yield prognostic information when added to a baseline risk model. In the absence of bedside capnography, surrogates of impaired ventilation may serve as an important tool to assess the severity of COVID-19 related ARDS along with other variables such as oxygenation abnormalities and respiratory mechanics.