Molecular pathways driving clarithromycin benefit in community-acquired pneumonia: analysis of the ACCESS randomised trial

Background The double-blind randomised controlled ACCESS trial (ClinicalTrials.govNCT04724044), conducted in hospitalised patients with community-acquired pneumonia (CAP), showed that the addition of clarithromycin to the standard-of-care (SoC) provided earlier resolution of symptoms during the first 72 h and prevented progression to respiratory failure and secondary sepsis.The molecular pathways underpinning these favourable effects of action of clarithromycin were investigated in this research. Methods Gene expression was compared between treatment arms and within each arm between baseline and 72 h using DESeq2. Reactome pathway and Gene Ontology analyses were followed.Cytokine stimulation data of peripheral blood mononuclear cells (PBMCs) from the same time points were also analysed.Findings Trajectory analysis showed that the unique upregulated genes in the clarithromycin group were mainly involved in pathways of T-cell activation and positive regulation of cytokine production.The expression of genes encoding for the major histocompatibility complex II was upregulated; genes encoding for the receptors of interleukin (IL)-1 and for neutrophil degranulation were downregulated.The production of cytokines of the IL-1 cluster was positively associated with progression to respiratory failure; fewer patients treated with clarithromycin experienced increases in production of IL-1 cytokines (odds ratio 0.47; 95% confidence intervals 0.23-0.96;p = 0.038).The production of monocyte-derived pro-inflammatory cytokines and chemokines (other than the ILcytokines) was positively associated with attainment of the primary endpoint; more patients treated with