Circulating dipeptidyl peptidase 3 and bio-adrenomedullin levels are associated with impaired outcomes in critically ill COVID-19 patients: a prospective international multicentre study.

Introduction: Dipeptidyl peptidase-3 (DPP3) is a protease involved in the degradation of several cardiovascular mediators. Adrenomedullin (bio-ADM) is a peptide essential for regulation of endothelial barrier function. In different shock-pathologies, both biomarkers are associated with disease severity, organ dysfunction and mortality. Associations with outcome in critically ill COVID-19 patients are unknown. The objectives of the present study were to investigate associations of bio-ADM and "circulating DPP3" (cDPP3) with short-term outcome in critically ill COVID-19 patients (n=80). Methods: A multicentre prospective cohort study was performed. The primary end-point was 28-day mortality. Secondary end-points included different severities of acute kidney injury (AKI). Results: cDPP3 levels were mainly associated with 28-day mortality; Area under the receiver operating characteristics (AUROCs) of 0.69 (0.56-0.82, p=0.023), 0.77 (0.64-0.90, p<0.001) and 0.81 (0.65-0.96, p<0.001) at admission, day 3 and day 7, respectively. In contrast, bio-ADM levels were mainly associated with AKI, with AUROCs of 0.64 (0.51-0.77, p=0.048), 0.75 (0.64-0.86, p<0.001) and 0.83 (0.74-0.93, p<0.001) for day 1, 3 and 7, respectively. Interestingly, patients with high levels of both cDPP3 and bio-ADM at day 7 had an additionally increased risk of 28-day mortality (hazard ratio 11.8; 95% CI 2.5-55.3, p<0.001). Conclusions: cDPP3 and bio-ADM responses were associated with short-term mortality and AKI in critically ill COVID-19 patients, respectively. These findings suggest that treatment with specific antibodies modulating cDPP3 or bio-ADM-related pathways may improve outcome of COVID-19.

Circulating dipeptidyl peptidase 3 and bio-adrenomedullin levels are associated with impaired outcomes in critically ill COVID-19 patients: a prospective international multicentre study

Introduction Dipeptidyl-peptidase-3 (DPP3) is a protease involved in the degradation of several cardiovascular mediators. Adrenomedullin (bio-ADM) is a peptide essential for regulation of endothelial barrier function. In different shock-pathologies, both biomarkers are associated with disease-severity, organ dysfunction and mortality. Associations with outcome in critically ill COVID-19 patients are unknown. Objectives To investigate associations of bio-ADM and cDPP3 with short-term outcome in critically ill COVID-19 patients (n=80). Methods Multicenter prospective cohort study. Primary endpoint was 28-day mortality. Secondary endpoints included different severities of acute kidney injury (AKI). Results cDPP3 levels were mainly associated with 28-day mortality;AUROC's of 0.69 (0.56–0.82, p=0.023), 0.77 (0.64–0.90, p<0.001) and 0.81 (0.65–0.96, p<0.001) at admission, day 3 and day 7, respectively. In contrast, bio-ADM levels were mainly associated with AKI: AUROC's of 0.64 (0.51–0.77, p=0.048), 0.75 (0.64–0.86, p<0.001) and 0.83 (0.74–0.93, p<0.001) for day 1, 3 and 7, respectively. Interestingly, patients with high levels of both cDPP3 and bio-ADM at day 7 had an additionally increased risk of 28-day-mortality;HR 11.8 (2.5–55.3, p<0.001). Conclusions cDPP3 and bio-ADM responses were associated with short-term mortality and AKI in critically ill COVID-19 patients, respectively. These findings suggest that treatment with specific antibodies modulating cDPP3 or bio-ADM related pathways may improve outcome of COVID-19.

Effect of intravenous almitrine on intubation or mortality in patients with COVID-19 acute hypoxemic respiratory failure: A multicentre, randomised, double-blind, placebo-controlled trial.

Background: Severe hypoxemia in patients with COVID-19 pneumonia might result from hypoxic pulmonary vasoconstriction, contributing to ventilation/perfusion (V/Q) mismatch. Because almitrine improves V/Q, it might reduce the risk for mechanical ventilation (MV) in such patients. Our primary objective was to determine the effect of almitrine on the need for MV at day 7. Methods: In a randomised double-blind placebo-controlled trial involving 15 ICUs, patients hospitalized for COVID-19 pneumonia and experiencing acute hypoxemic respiratory failure were randomly assigned to receive 5 days of intravenous low-dose (2 µg.kg-1.min-1) almitrine or placebo. The primary outcome was endotracheal intubation for MV or death within 7 days after randomisation. Secondary outcomes included in-hospital mortality, 28-day mortality, number of ventilator-free days, number of days in the ICU and the hospital, and treatment discontinuation for pre-specified adverse effects. This trial was registered with ClinicalTrials.gov, NCT04357457. Findings: Between September 3, 2020 and September 25, 2021 181 patients were enrolled and randomly assigned to almitrine (n=89) or placebo (n=92). 179 patients (excluding two who withdrew from the study) were included in the intention-to-treat analysis (mean age: 60·1 years; 34% women) and analyzed. On day 7, the primary endpoint occurred in 32 patients assigned to almitrine (36%) and in 37 patients assigned to placebo (41%), for a difference of -4·3% (95% confidence interval: -18·7% to 10·2%). Secondary outcomes (28-day mortality, in-hospital mortality, ventilator-free days at day 28, days in the ICU and the hospital, and treatment discontinuation for pre-specified adverse effects) did not differ between the two groups. Interpretation: In patients with COVID-19 acute hypoxemic respiratory failure, low-dose almitrine failed in reducing the need for MV or death at day 7. Funding: Programme Hospitalier de Recherche Clinique (PHRC COVID 2020) funded by the French Ministry of Health, Les Laboratoires Servier (Suresnes, France) providing the study drug free of charge.

Combination of Mycological Criteria: a Better Surrogate to Identify COVID-19-Associated Pulmonary Aspergillosis Patients and Evaluate Prognosis?

Diagnosis of coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) remains unclear especially in nonimmunocompromised patients. The aim of this study was to evaluate seven mycological criteria and their combination in a large homogenous cohort of patients. All successive patients (n = 176) hospitalized for COVID-19 requiring mechanical ventilation and who clinically worsened despite appropriate standard of care were included over a 1-year period. Direct examination, culture, Aspergillus quantitative PCR (Af-qPCR), and galactomannan testing were performed on all respiratory samples (n = 350). Serum galactomannan, ß-d-glucan, and plasma Af-qPCR were also assessed. The criteria were analyzed alone or in combination in relation to mortality rate. Mortality was significantly different in patients with 0, ≤2, and ≥3 positive criteria (log rank test, P = 0.04) with death rate of 43.1, 58.1, and 76.4%, respectively. Direct examination, plasma qPCR, and serum galactomannan were associated with a 100% mortality rate. Bronchoalveolar lavage (BAL) galactomannan and positive respiratory sample culture were often found as isolated markers (28.1 and 34.1%) and poorly repeatable when a second sample was obtained. Aspergillus DNA was detected in 13.1% of samples (46 of 350) with significantly lower quantitative cycle (Cq) when associated with at least one other criterion (30.2 versus 35.8) (P < 0.001). A combination of markers and/or blood biomarkers and/or direct respiratory sample examination seems more likely to identify patients with CAPA. Af-qPCR may help identifying false-positive results of BAL galactomannan testing and culture on respiratory samples while quantifying fungal burden accurately.

Continuous Lower Abdominal Compression as a Therapeutic Intervention in COVID-19 ARDS.

We report the case of a patient with severe COVID-19 ARDS, suggesting a possible therapeutic intervention by applying a continuous lower abdominal compression. In order to assess ventilation distribution, a lung CT scan was performed with and without lower abdominal compression.

Rapid identification of bacteria from respiratory samples of patients hospitalized in intensive care units, with FilmArray Pneumonia Panel Plus.

OBJECTIVES: This study aimed to evaluate the performance of FilmArray Pneumonia Panel Plus (FA-PP) for the detection of typical bacterial pathogens in respiratory samples from patients hospitalized in intensive care units (ICUs). METHODS: FA-PP was implemented for clinical use in the microbiology laboratory in March 2020. A retrospective analysis on a consecutive cohort of adult patients hospitalized in ICUs between March 2020 and May 2020 was undertaken. The respiratory samples included sputum, blind bronchoalveolar lavage (BBAL) and protected specimen brush (PSB). Conventional culture and FA-PP were performed in parallel. RESULTS: In total, 147 samples from 92 patients were analysed; 88% had coronavirus disease 2019 (COVID-19). At least one pathogen was detected in 46% (68/147) of samples by FA-PP and 39% (57/147) of samples by culture. The overall percentage agreement between FA-PP and culture results was 98% (93-100%). Bacteria with semi-quantitative FA-PP results ≥105 copies/mL for PSB samples, ≥106 copies/mL for BBAL samples and ≥107 copies/mL for sputum samples reached clinically significant thresholds for growth in 90%, 100% and 91% of cultures, respectively. FA-PP detected resistance markers, including mecA/C, blaCTX-M and blaVIM. The median turnaround time was significantly shorter for FA-PP than for culture. CONCLUSIONS: FA-PP may constitute a faster approach to the diagnosis of bacterial pneumonia in patients hospitalized in ICUs.

Performance of a multiplex polymerase chain reaction panel for identifying bacterial pathogens causing pneumonia in critically ill patients with COVID-19.

The FilmArray® Pneumonia Plus (FA-PP) panel can provide rapid identifications and semiquantitative results for many pathogens. We performed a prospective single-center study in 43 critically ill patients with coronavirus disease 2019 (COVID-19) in which we performed 96 FA-PP tests and cultures of blind bronchoalveolar lavage (BBAL). FA-PP detected 1 or more pathogens in 32% (31/96 of samples), whereas culture methods detected at least 1 pathogen in 35% (34/96 of samples). The most prevalent bacteria detected were Pseudomonas aeruginosa (n = 14) and Staphylococcus aureus (n = 11) on both FA-PP and culture. The FA-PP results from BBAL in critically ill patients with COVID-19 were consistent with bacterial culture findings for bacteria present in the FA-PP panel, showing sensitivity, specificity, and positive and negative predictive value of 95%, 99%, 82%, and 100%, respectively. Median turnaround time for FA-PP was 5.5 h, which was significantly shorter than for standard culture (26 h) and antimicrobial susceptibility testing results (57 h).

Activation of the renin-angiotensin-aldosterone system is associated with Acute Kidney Injury in COVID-19.

The pathophysiology of acute kidney injury (AKI) in COVID-19 patients is still poorly understood. SARS-CoV-2 has been suggested to modulate the renin-angiotensin-aldosterone system (RAAS). In this series of COVID-19 critically ill patients, we report evidence of activation of the RAAS in COVID-19 patients with AKI.