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

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.

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.

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.

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.

Hellenic Institute for the Study of Sepsis; Abbott Products Operations.