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Effect of clarithromycin on the circulating inflammatory proteome in community-acquired pneumonia: a secondary analysis of the ACCESS trial.

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Authors: Emmanouil Stylianakis, Konstantinos Tsiakos, Georgios Niotis, Sarantia Doulou, Lamprini Skorda, Konstantina Iliopoulou, Evangelia-Maria Adami, George Chrysos, Styliani Gerakari, Haralampos Milionis, George Dalekos, Theano Kontopoulou, Vasiliki Tzavara, Karolina Akinosoglou, Styliani Sympardi, Mihai G Netea, Evangelos J Giamarellos-Bourboulis, Vinod Kumar

BACKGROUND: The ACCESS randomized double-blind controlled trial in hospitalized adults with community-acquired pneumonia (CAP) showed that adding clarithromycin to standard-of-care therapy accelerated clinical recovery within the first 72 hours after the commencement of treatment and reduced progression to organ dysfunction.

RESEARCH QUESTION: Does clarithromycin treatment modulate the circulating inflammatory protein profile in CAP, and can inflammatory endotypes identify patient subgroups with distinct clinical responses?

STUDY DESIGN AND METHODS: Serum samples obtained from ACCESS trial patients at baseline and 72 hours were profiled using the Olink Target 96 Inflammation panel. Patients were grouped by treatment arm and by achievement of the trial's composite primary endpoint. After quality control, 70 proteins from 394 paired samples across 197 patients were analyzed to assess differential expression within and between groups over time, evaluate associations with clinical outcomes, and identify immune endotypes using unsupervised clustering.

RESULTS: IL6 was selectively downregulated on day 4 in the clarithromycin arm, whereas IFN-γ, CXCL9, CXCL10, and SCF decreased over time across both treatment arms, consistent with resolution of inflammation. Among patients achieving the primary endpoint, IL6, CXCL9, CXCL10, and IFN-γ were suppressed only in clarithromycin-treated individuals. Clustering consistently identified two inflammatory endotypes with comparable SOFA, but distinct RSS scores. The endotype with lower RSS demonstrated higher IFN-γ and globally elevated inflammatory protein expression; in that endotype 90-day mortality was decreased with clarithromycin treatment.

INTERPRETATION: Clarithromycin exerts measurable immunomodulatory effects in CAP, characterized by attenuation of pro-inflammatory cytokines, particularly IL6. The identification of distinct inflammatory endotypes suggests biological heterogeneity in CAP and supports future investigation of endotype-guided approaches to identify patients most likely to benefit from immunomodulatory therapies.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT04724044, EudraCT 2020-004452-15.

Copyright © 2026. Published by Elsevier Inc.

PMID: 42892349

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