Early proximal tubular injury in COVID-19 related ARDS: the URICOV study (preprint)

Background: During COVID-19, renal impairment is the most frequent after lung impairment and is associated with a poor prognosis particularly in intensive care unit (ICU). In this work we aimed to assess the existence and incidence of early renal dysfunction and its prognostic value in patients with COVID-19-related acute respiratory distress syndrome (ARDS) and to compare them with patients with non-COVID-19-related ARDS. Methods: This prospective multicenter study was conducted in 3 ICUs. Patients aged 18 years and older with invasive mechanical ventilation for ARDS were enrolled. Precise evaluation of renal dysfunction markers including urinary proteins electrophoresis (UPE) and quantification, was performed within 24 hours after mechanical ventilation onset. Results: From March 2020 to December 2021, 135 patients in ICU for ARDS were enrolled: 100 COVID-19 ARDS and 35 non-COVID-19 ARDS. UPE found more tubular dysfunction in COVID-19 patients (68% vs. 21.4%, p<0.0001) and more normal profiles in non-COVID-19 patients (65.0% vs. 11.2%, p=0.0003). COVID-19 patients significantly displayed early urinary leakage of tubular proteins like beta-2-microglobulin and free-light chains, tended to display more frequently acute kidney injury (AKI) (51.0% vs 34.3%, p=0.088), and had longer mechanical ventilation (20 vs. 9 days, p<0.0001) and longer ICU length of stay (26 vs. 15 days, p<0.0001). In COVID-19 ARDS, leakage of free lambda light chain was significantly associated with the onset of KDIGO ≥2 AKI (OR: 1.014, 95%CI [1.003-1.025], p=0.011). Conclusion: Patients admitted to the ICU for COVID-19-related ARDS display a proximal tubular dysfunction, prior to the onset of AKI, which predicts AKI. Proximal tubular damage seems an important mechanism of COVID-19-induced nephropathy. Analysis of urinary proteins is a reliable and non-invasive tool to assess proximal tubular dysfunction in the ICU. Trial Registration: Registered retrospectively with www.clinicaltrials.gov (NCT05699889) 26 January 2023.

Impact of Early Corticosteroids on 60-day Mortality in Critically Ill Patients with COVID-19: A Multicenter Cohort Study of the OUTCOMEREA Network (preprint)

ObjectivesIn severe COVID-19 pneumonia, the appropriate timing and dosing of corticosteroids(CS) is not known. Patient subgroups for which CS could be more beneficial also need appraisal. The aim of this study was to assess the effect of early CS in COVID-19 pneumonia patients admitted to the ICU on the occurrence of 60-day mortality, ICU-acquired-bloodstream infections(ICU-BSI), and hospital-acquired pneumonia and ventilator-associated pneumonia(HAP-VAP).MethodsWe included patients with COVID-19 pneumonia admitted to 11 ICUs belonging to the French OutcomeReaTM network from January to May 2020. We used survival models with ponderation with inverse probability of treatment weighting (IPTW). Inflammation was defined as Ferritin >1000 µg/l or D-Dimers >1000 µg/l or C-Reactive Protein >100 mg/dL.ResultsThe study population comprised 302 patients having a median age of 61.6(53-70) years of whom 78.8% were male and 58.6% had at least one comorbidity. The median SAPS II was 33(25-44). Invasive mechanical ventilation was required in 34.8% of the patients. Sixty-six (21.8%) patients were in the Early-CS-subgroup. Most of them (n=55, 83.3%) received high doses of steroids. Overall, 60-day mortality was 29.4%. The risks of 60-day mortality (IPTWHR =0.88;95% CI 0.55 to 1.39, p=0.58), ICU-BSI and HAP-VAP were similar in the two groups. Importantly, early CS treatment was associated with a lower mortality rate in patients aged 60 years or more (IPTWHR, 0.51;95% CI, 0.29 – 0.91; p=0.02). But, CS was associated with an increased risk of death for the patients younger than 60 years without inflammation on admission (IPTWHR =8.17;95% CI, 1.76, 37.85; p=0.01).ConclusionFor patients with COVID-19 pneumonia, early CS treatment was not associated with patient survival. Interestingly, inflammation and age can significantly influence the effect of CS.

Identification of immune checkpoints in COVID-19 (preprint)

Coronavirus disease 2019 (COVID-19) is a new pandemic acute respiratory disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)11-3. We provide here a longitudinal analysis of immune responses, including immune cell phenotyping and assessments of the soluble factors present in the blood and broncho-alveolar lavage fluid (BALF) of patients at various stages of COVID-19 severity: paucisymptomatic, pneumonia and acute respiratory distress syndrome (ARDS). While we confirm a lymphopenia associated with COVID-19 severity4-7, we report an increase in expression of the NKG2A and PD-1 inhibitory receptors on T and natural killer (NK) cells, as well as an increase in CD39 expression on NK cells, suggesting that therapeutic blocking antibodies targeting these molecules already used for cancer immunotherapy8 could be repurposed as first line of defense to promote SARS-CoV-2 clearance. In addition, the C5a anaphylatoxin and its receptor C5aR1 (CD88) play a key role in the initiation and maintenance of inflammatory responses, by recruiting neutrophils and monocytes to the lungs9,10. We report an increase in soluble C5a levels proportional to COVID-19 severity and high levels of C5aR1 expression in blood and BALF myeloid cells, indicating a potential role of the C5a-C5aR1 axis in the pathophysiology of ARDS. Avdoralimab is a clinical-stage anti-C5aR1 therapeutic monoclonal antibody (mAb) that prevents C5a-mediated myeloid cell recruitment and activation. We propose the use of this antibody to limit myeloid cell infiltration in the lung and to prevent the excessive lung inflammation associated with ARDS in COVID-19 patients.