INCREASED CYTOKINE LEVELS DEFINE THE AIRWAY OF STABLE CYSTIC FIBROSIS PATIENTS COMPARED TO HEALTHY CONTROLS

Abstract

TOPIC: Genetic and Developmental Disorders TYPE: Original Investigations PURPOSE: Cystic Fibrosis (CF) is a multisystem autosomal recessive disease caused by mutations in the CFTR (CF transmembrane conductance regulator) gene. Airway inflammation and infection in CF leads to tissue injury, worsening lung function, and disease progression. Increased cytokine levels reflect the exaggerated inflammation characteristic of the CF airway environment and contribute to pathogenesis even in the absence of respiratory symptoms. We sought to define individual CF-specific cytokine variations as a means to characterize the difference between healthy and CF airways, and to identify patients at risk of clinical deterioration. METHODS: Sputum samples were obtained from Forty-four adult patients with confirmed CF diagnosis from the Yale Adult CF Program. Patients were classified as CF stable at each visit if they did not meet predefined criteria for an acute exacerbation. Ten healthy controls (HC) were recruited to undergo sputum induction. Sputum samples were assayed for twelve cytokines using a multiplexed indirect ELISA. Differences in cytokine levels between CF stable and healthy controls were analyzed using the Mann-Whitney Test with Bonferroni correction. RESULTS: Twelve inflammatory cytokine levels were measured. Six cytokines were significantly increased in the sputum of stable CF patients compared to healthy controls (median values, pg/mL). These cytokines included: IL-1beta (CF 1720; HC 39.7), IL-8 (CF 28173; HC 3468), TNF-alpha (CF 98.65; HC 10.70), and IFN-alpha (CF 38.90; HC 5.60) [p < 0.0001] as well as IFN-gamma (CF 68.45; HC 17.10) and IL-13 (20.10; 0.00) [p < 0.01]. Cytokines tested without significant difference between groups included: CXCL10, G-CSF, IFNI, IL-6, MCP1, and MIP-alpha. CONCLUSIONS: Inflammatory cytokine levels of IL-1beta, IL-8, TNF-alpha, IFN-a, IFN-gamma and IL-13 are significantly increased in the sputum of stable CF patients compared to the sputum of healthy controls. CLINICAL IMPLICATIONS: Monitoring basal sputum cytokine levels may help identify patients with worsening inflammation before symptoms develop and thus prevent irreversible lung damage and disease progression. Additionally, further understanding of inflammatory cytokine dysregulation in stable CF airways may serve as the basis for a sputum inflammation marker panel that guides future therapeutic interventions. DISCLOSURES: No relevant relationships by Clemente Britto, source=Web Response Consultant relationship with AstraZeneca Please note: >$100000 by Geoffrey Chupp, source=Web Response, value=Consulting fee Consultant relationship with Genentech Please note: $20001 - $100000 by Geoffrey Chupp, source=Web Response, value=Consulting fee Consultant relationship with Genzyme Corporation Please note: $5001 - $20000 by Geoffrey Chupp, source=Web Response, value=Consulting fee Consultant relationship with Novartis Please note: $5001 - $20000 by Geoffrey Chupp, source=Web Response, value=Consulting fee Consultant relationship with Circassia Please note: $1001 - $5000 by Geoffrey Chupp, source=Web Response, value=Consulting fee Consultant relationship with Boehringer Ingelheim Please note: $1001 - $5000 by Geoffrey Chupp, source=Web Response, value=Consulting fee Consultant relationship with GlaxoSmithKline Please note: $1-$1000 by Geoffrey Chupp, source=Web Response, value=Consulting fee Consultant relationship with Regeneron Please note: 5/2019-present Added 04/26/2021 by Lauren Cohn, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Genentech Please note: 5/2019-11/2019 Added 04/26/2021 by Lauren Cohn, source=Web Response, value=Honoraria Advisory Committee Member relationship with novartis Please note: 10/2019 Added 04/26/2021 by Lauren Cohn, source=Web Response, value=Consulting fee Advisory Committee Member relationship with glaxosmithkline Please note: 12/2019 Added 04/26/2021 by Lauren Cohn, source=Web Response, value=Consulting fee Advisory Committee Member relationship with sanofi Please note: 5/2020 Added 04/26/2021 by Lauren Cohn, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Pieris Please note: 5/2019 Added 04/26/2021 by Lauren Cohn, source=Web Response, value=Consulting fee Advisory Committee Member relationship with AstraZeneca Please note: 5/2019-7/2020 Added 04/26/2021 by Lauren Cohn, source=Web Response, value=Consulting fee Consultant relationship with Biohaven Please note: 6/23/2020 Added 04/26/2021 by Lauren Cohn, source=Web Response, value=Consulting fee No relevant relationships by Sara Khanal, source=Web Response No relevant relationships by qing liu, source=Web Response No relevant relationships by Jana Zielonka, source=Web Response