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

BACKGROUND: The double-blind randomised controlled ACCESS trial (ClinicalTrials.gov NCT04724044), 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 IL-cytokines) was positively associated with attainment of the primary endpoint; more patients treated with clarithromycin exhibited increases in production of monocyte-derived cytokines and chemokines (odds ratio 1.87; 95% confidence intervals 1.05-3.35; p = 0.035). Production of anti-inflammatory cytokines by PBMCs was also attenuated in clarithromycin-treated patients. INTERPRETATION: Treatment with clarithromycin attenuates the IL-1 pathway, increases production of other monocyte-derived pro-inflammatory cytokines and chemokines, improves antigen presentation and decreases neutrophil degranulation. These effects may explain the clinical benefit of clarithromycin in hospitalised patients with CAP. FUNDING: Hellenic Institute for the Study of Sepsis; Abbott Products Operations.