Conventional oxygen therapy versus CPAP as a ceiling of care in ward-based patients with COVID-19: a multi-centre cohort evaluation.

BACKGROUND: Continuous positive airway pressure (CPAP) therapy is commonly used for respiratory failure due to severe COVID-19 pneumonitis, including in patients deemed not likely to benefit from invasive mechanical ventilation (nIMV). Little evidence exists demonstrating superiority over conventional oxygen therapy, whilst ward-level delivery of CPAP presents practical challenges. We sought to compare clinical outcomes of oxygen therapy versus CPAP therapy in patients with COVID-19 who were nIMV. METHODS: This retrospective multi-centre cohort evaluation included patients diagnosed with COVID-19 who were nIMV, had a treatment escalation plan of ward-level care and clinical frailty scale ≤ 6. Recruitment occurred during the first two waves of the UK COVID-19 pandemic in 2020; from 1st March to May 31st, and from 1st September to 31st December. Patients given CPAP were compared to patients receiving oxygen therapy that required FiO2 ≥0.4 for more than 12 hours at hospitals not providing ward-level CPAP. Logistic regression modelling was performed to compare 30-day mortality between treatment groups, accounting for important confounders and within-hospital clustering. FINDINGS: Seven hospitals provided data for 479 patients during the UK COVID-19 pandemic in 2020. Overall 30-day mortality was 75.6% in the oxygen group (186/246 patients) and 77.7% in the CPAP group (181/233 patients). A lack of evidence for a treatment effect persisted in the adjusted model (adjusted odds ratio 0.84 95% CI 0.57-1.23, p=0.37). 49.8% of patients receiving CPAP-therapy (118/237) chose to discontinue it. INTERPRETATION: No survival difference was found between using oxygen alone or CPAP to treat patients with severe COVID-19 who were nIMV. A high patient-initiated discontinuation rate for CPAP suggests a significant treatment burden. Further reflection is warranted on the current treatment guidance and widespread application of CPAP in this setting. FUNDING: L Pearmain is supported by the MRC (MR/R00191X/1). TW Felton is supported by the NIHR Manchester Biomedical Research Centre.

Therapeutic targeting of NOD1 receptors.

The nucleotide-binding oligomerization domain 1 (NOD1) protein is an intracellular receptor for breakdown products of peptidoglycan (PGN), an essential bacterial cell wall component. NOD1 responds to γ-D-glutamyl-meso-diaminopimelic acid, which is an epitope unique to PGN structures from all Gram-negative bacteria and certain Gram-positive bacteria. Upon ligand recognition, NOD1 undergoes conformational changes and self-oligomerization mediated by the nucleotide-binding NACHT domains, followed by the recruitment and activation of the serine threonine kinase receptor-interacting protein 2 leading to the activation of NF-κB and MAPK pathways and induction of inflammatory genes. Much of our knowledge is derived from seminal studies using mice deficient in NOD1 and confirming an essential role for NOD1 in the host immune response against gastrointestinal and respiratory pathogens. In addition, recent studies have revealed a role for intracellular NOD1 receptors in the regulation of vascular inflammation and metabolism. This review will discuss our current understanding of intracellular NOD1 receptors in host immunity and chronic inflammatory disorders with a focus on cardiovascular diseases. Although therapeutic advances may have to wait until the complex interplay with pathogens, danger signals, other pattern recognition receptors and overlapping metabolic pathways is further unravelled, the steadily growing body of knowledge suggest that NOD1 antagonism might represent attractive candidate to reduce excessive inflammation associated to intestinal, cardiovascular and metabolic diseases.

Pharmacology and therapeutic potential of pattern recognition receptors.

Pharmacologists have used pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) for decades as a stimulus for studying mediators involved in inflammation and for the screening of anti-inflammatory compounds. However, in the view of immunologists, LPS was too non-specific for studying the mechanisms of immune signalling in infection and inflammation, as no receptors had been identified. This changed in the late 1990s with the discovery of the Toll-like receptors. These 'pattern recognition receptors' (PRRs) were able to recognise highly conserved sequences, the so called pathogen associated molecular patterns (PAMPs) present in or on pathogens. This specificity of particular PAMPs and their newly defined receptors provided a common ground between pharmacologists and immunologists for the study of inflammation. PRRs also recognise endogenous agonists, the so called danger-associated molecular patterns (DAMPs), which can result in sterile inflammation. The signalling pathways and ligands of many PRRs have now been characterised and there is no doubt that this rich vein of research will aid the discovery of new therapeutics for infectious conditions and chronic inflammatory disease.

Nucleotide oligomerization domain 1 is a dominant pathway for NOS2 induction in vascular smooth muscle cells: comparison with Toll-like receptor 4 responses in macrophages.

BACKGROUND AND PURPOSE: Gram-negative bacteria contain ligands for Toll-like receptor (TLR) 4 and nucleotide oligomerization domain (NOD) 1 receptors. Lipopolysaccharide (LPS) activates TLR4, while peptidoglycan products activate NOD1. Activation of NOD1 by the specific agonist FK565 results in a profound vascular dysfunction and experimental shock in vivo. EXPERIMENTAL APPROACH: Here, we have analysed a number of pharmacological inhibitors to characterize the role of key signalling pathways in the induction of NOS2 following TLR4 or NOD1 activation. KEY RESULTS: Vascular smooth muscle (VSM) cells expressed NOD1 mRNA and protein, and, after challenge with Escherichia coli or FK565, NOS2 protein and activity were induced. Macrophages had negligible levels of NOD1 and were unaffected by FK565, but responded to E. coli and LPS by releasing increased NO and expression of NOS2 protein. Classic pharmacological inhibitors for NF-kappaB (SC-514) and mitogen-activated protein kinase (SB203580, PD98059) signalling pathways inhibited responses in both cell types regardless of agonist. While TLR4-mediated responses in macrophages were specifically inhibited by the pan-caspase inhibitor z-VAD-fmk and the PKC inhibitor Gö6976, NOD1-mediated responses in VSM cells were inhibited by the Rip2 inhibitor PP2. CONCLUSIONS AND IMPLICATIONS: Our findings suggest a selective role for NOD1 in VSM cells, and highlight NOD1 as a potential novel therapeutic target for the treatment of vascular inflammation.