Fractional Exhaled Nitric Oxide and Exacerbations of COPD

Fractional Exhaled Nitric Oxide (FeNO) as a Predictor of Exacerbations in COPD Patients Initiated on Triple Inhaler Therapy: A Prospective Exploratory Cohort Study

Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition with recurrent exacerbations despite guideline-based therapy. This prospective observational cohort study aims to evaluate whether baseline fractional exhaled nitric oxide (FeNO), a biomarker of type 2 airway inflammation, predicts future exacerbations and lung function decline in COPD patients initiated on triple inhaler therapy in routine clinical practice. The study will also explore the relationships between air pollution exposure, type 2 inflammatory biomarkers, and COPD outcomes.

Study Overview

• Status: Not yet recruiting
• Conditions: Chronic Obstructive Pulmonary Disease (COPD)
• Intervention / Treatment: Other: No intervention assigned

Detailed Description

This is a pragmatic, prospective, longitudinal observational cohort study conducted in patients with COPD who are initiated on triple inhaler therapy as part of routine clinical care. No investigational drugs, devices, or protocol-mandated interventions are administered. Biomarker measurements, including fractional exhaled nitric oxide (FeNO), are performed for research purposes only and do not influence clinical decision-making.

Participants will be followed for up to 12 months after enrollment with scheduled assessments of exacerbation events, lung function, symptom burden, and biomarkers. The total study duration is approximately 24 months, accounting for a 12-month enrollment period and completion of follow-up for the last enrolled participant. Environmental air pollution exposure will be estimated using a validated hybrid kriging/land-use regression model based on residential address.

• Study Type: Observational
• Enrollment (Estimated): 120

Contacts and Locations

• Study Contact: Name: Ting-Yu Lin, MD; Phone Number: 8468 +886-3-3281200; Email: h12519@cgmh.org.tw

Study Locations

• Taiwan
  • Taoyuan District, Taiwan, 333
    • Chang Gung Medical Foundation
    • Contact: Ting-Yu Lin, MD.; Phone Number: 8468 886-3-3281200; Email: h12519@cgmh.org.tw

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Participants are recruited from adult COPD patients receiving routine pulmonary care at a tertiary hospital outpatient clinic, including follow-up visits after exacerbations and referrals from primary or emergency care.

Description

Inclusion Criteria:

• Adults aged 40 years or older
• Diagnosis of chronic obstructive pulmonary disease (COPD) confirmed by post-bronchodilator spirometry (FEV₁/FVC < 0.70).
• History of cigarette smoking
• Receiving triple inhaler therapy (inhaled corticosteroid/long-acting beta-agonist/long-acting muscarinic antagonist) as part of routine clinical care, including:
• patients who have been previously escalated to triple inhaler therapy due to prior exacerbations and are already receiving triple therapy at the time of enrollment, and
• patients who are newly prescribed triple inhaler therapy at or immediately before enrollment because of a recent exacerbation.

Exclusion Criteria:

-

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

COPD Patients Initiated on Triple Inhaler Therapy; This cohort includes patients with chronic obstructive pulmonary disease (COPD) receiving triple inhaler therapy (inhaled corticosteroid/long-acting beta-agonist/long-acting muscarinic antagonist) as part of routine clinical care following one or more recent exacerbations. Eligible participants include both patients who have been escalated to triple therapy due to prior exacerbations and are already receiving triple therapy at enrollment, as well as patients who are newly prescribed triple therapy at or immediately before enrollment because of a recent exacerbation. All participants are followed prospectively for up to 12 months to assess exacerbations, lung function, symptoms, and inflammatory biomarkers. Baseline fractional exhaled nitric oxide (FeNO) is evaluated as a predictor of clinical outcomes.

Other: No intervention assigned; No investigational intervention is assigned in this observational study. All treatments, including triple inhaler therapy, are prescribed at the discretion of the treating physicians as part of routine clinical care. The research team does not assign, modify, or mandate any therapeutic intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized rate of moderate-to-severe COPD exacerbations	Moderate exacerbations are defined as those requiring systemic corticosteroids, antibiotics, or both. Severe exacerbations are defined as those requiring hospitalization or emergency department visits lasting more than 24 hours.	Up to 12 months after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in lung function (FEV₁)	Rate of decline in pre-bronchodilator FEV₁	Up to 12 months after enrollment
Change in COPD Assessment Test (CAT) score	Change in symptom burden assessed by CAT	Up to 12 months after enrollment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Multimarker and Environmental Interaction	Multivariable negative binomial models will include FeNO (spline + categories), eosinophils (<100, 100-<300, ≥300 cells/µL), IgE (log-transformed), and air pollutants (PM10, PM2.5, NO2, SO2, CO, and O3; levels of baseline, 1-month, 6-month, and 1-year follow-up). FeNO-specific adjusted IRRs and predicted rates at 15, 20, 25, 35, and 50 ppb will be presented. Significant interactions (FeNO×smoking, FeNO×ICS dose, FeNO×PM₂.₅ quartiles) will be visualized with stratum-specific curves. This analysis will determine whether FeNO remains a consistent predictor across different inflammatory or environmental contexts, or whether its predictive value varies depending on eosinophil counts, smoking status, or air pollution exposure.	up to 12 months

Collaborators and Investigators

• Sponsor: Chang Gung Memorial Hospital
• Investigators: Principal Investigator: Ting-Yu Lin, MD., Chang Gung Memorial Hospital

Publications and helpful links

General Publications

• Papi A, Romagnoli M, Baraldo S, Braccioni F, Guzzinati I, Saetta M, Ciaccia A, Fabbri LM. Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000 Nov;162(5):1773-7. doi: 10.1164/ajrccm.162.5.9910112.
• Alcazar-Navarrete B, Ruiz Rodriguez O, Conde Baena P, Romero Palacios PJ, Agusti A. Persistently elevated exhaled nitric oxide fraction is associated with increased risk of exacerbation in COPD. Eur Respir J. 2018 Jan 18;51(1):1701457. doi: 10.1183/13993003.01457-2017. Print 2018 Jan.
• Zhou A, Zhou Z, Deng D, Zhao Y, Duan J, Cheng W, Liu C, Chen P. The Value of FENO Measurement for Predicting Treatment Response in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease. Int J Chron Obstruct Pulmon Dis. 2020 Sep 24;15:2257-2266. doi: 10.2147/COPD.S263673. eCollection 2020.
• Romero-Linares A, Alvarez-Muro L, Hammadi A, Hoyas-Sanchez C, Jimenez-Anton A, Almansa-Lopez A, Casares-Martin-Moreno L, Sanchez-Alvarez E, Murillo-Rodriguez A, Gomez-Mora M, Gomez-Pontes Cabrera T, Romero-Palacios PJ, Alcazar-Navarrete B. Short term exacerbation risk and exhaled nitric oxide in COPD. Respir Med. 2025 Jul;243:108134. doi: 10.1016/j.rmed.2025.108134. Epub 2025 Apr 30.

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): February 29, 2028
• Study Completion (Estimated): February 29, 2028

Study Registration Dates

• First Submitted: February 1, 2026
• First Submitted That Met QC Criteria: February 1, 2026
• First Posted (Actual): February 9, 2026

Study Record Updates

• Last Update Posted (Actual): February 9, 2026
• Last Update Submitted That Met QC Criteria: February 1, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: COPD; Air Pollution; Exacerbation; FeNO; Type 2 Inflammation; Triple Inhaler Therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pathological Conditions, Signs and Symptoms; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: 2512090251

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data (IPD) will not be shared. The study involves clinical and environmental data that may pose a risk of re-identification despite de-identification, and no data-sharing infrastructure is currently established.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No