Exhaled Nitric Oxide Predicts Glucocorticoid Response in Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Summary

This study aimed to investigate differences in responses to systemic glucocorticoid therapy among patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and varying fractional exhaled nitric oxide (FeNO) levels. The findings of this research provide a valuable reference for the clinical application of glucocorticoids.

Abstract

This retrospective study evaluated the clinical value of fractional exhaled nitric oxide in predicting glucocorticoid response in patients with acute exacerbations of chronic obstructive pulmonary disease. Based on the critical value of fractional exhaled nitric oxide (FeNO) levels ≥25 ppb at admission, patients were categorized into two groups: the high FeNO group (n = 61) and the low FeNO group (n = 61). All patients received standard basic treatment, which included inhaled corticosteroids (ICS), short-acting β2 receptor agonists (SABA), and short-acting anticholinergic drugs (SAMA). The treatment subgroup was administered additional systemic glucocorticoid therapy. The primary outcomes of this study were improvements in forced expiratory volume in 1 s (FEV₁% pred) and the COPD Assessment Test (CAT) score. Secondary outcomes included changes in the duration of hospital stay and levels of exhaled nitric oxide. Baseline exhaled nitric oxide (FeNO) levels were positively correlated with blood eosinophil counts. In the high-level FeNO group, patients in the treatment group showed significant improvements in lung function, a reduction in the COPD Assessment Test (CAT) score, and lower exhaled nitric oxide levels compared with the control group. Conversely, in the low-level FeNO group, no significant differences were observed between the treatment and control subgroups. These findings indicate that baseline fractional exhaled nitric oxide can identify eosinophilic airway inflammation and predict responsiveness to glucocorticoid therapy, supporting personalized glucocorticoid treatment selection in acute exacerbations of chronic obstructive pulmonary disease. This retrospective study shows that baseline fractional exhaled nitric oxide identifies eosinophilic airway inflammation and predicts glucocorticoid response in acute exacerbations of chronic obstructive pulmonary disease, supporting personalized treatment and reducing hospital stay.

Introduction

Chronic obstructive pulmonary disease (COPD) is a prevalent, preventable, and treatable condition characterized by persistent airflow limitation. Pathological changes can occur in the airways, pulmonary parenchyma, and pulmonary vasculature of patients, including structural and inflammatory alterations. The severity of these changes escalates with the worsening of airflow obstruction. Notably, even after a patient ceases smoking, these changes may persist. In chronic obstructive pulmonary disease (COPD), the inflammatory pathology is characterized by a significant proliferation of macrophages in the distal airways, alveolar tissue, and pulmonary vasculature, accompanied by an expansion of activated neutrophils and lymphocytes. These immune effector cells interact with bronchial epithelial cells and interstitial cells, leading to the secretion of various pro-inflammatory factors¹. These factors have a well-established pro-inflammatory effect: they not only recruit inflammatory cells from the circulation via chemotaxis but also amplify their effects through pro-inflammatory cytokine cascades.

Currently, based on the inflammatory cell spectrum, two prominent^1,2 inflammatory phenotypes of Chronic Obstructive Pulmonary Disease (COPD) have been identified: the neutrophil phenotype and the eosinophil phenotype. While the traditional perspective posits that COPD is primarily a non-eosinophilic disease, a significant subset of COPD patients exhibits characteristics of eosinophilia and type 2 inflammation^3,4,5. Specifically, approximately 20% to 40%⁶of COPD patients present with elevated eosinophil counts in their blood and/or sputum. This inflammatory subtype significantly influences disease progression, the frequency of acute exacerbations, and treatment responses. Consequently, these patients are aptly termed 'eosinophilic phenotype COPD' or 'type 2 inflammatory COPD.' Notably, the pathophysiological mechanisms in these patients resemble those of asthma⁷, characterized by airway eosinophil infiltration, elevated levels of type 2 cytokines (such as interleukin 4 and interleukin 5), and markedly increased levels of exhaled nitric oxide.

Patients with high FeNO levels and asthma are more likely to benefit from ICS treatment, and FeNO monitoring can optimize ICS dose adjustments. However, FeNO levels vary significantly in patients with COPD. In COPD patients, elevated FeNO levels are significantly associated with increased eosinophil counts in either blood or sputum. For instance, studies⁸ have demonstrated that for every 50 cells/µL increase in blood eosinophil count, FeNO levels rise by 3.2%. Another study⁹ found that the fractional exhaled nitric oxide (FeNO) levels in patients with asthma-COPD overlap (ACO) were significantly higher than those in patients with COPD alone. Additionally, FeNO exhibited a moderate positive correlation with the percentage of eosinophils in induced sputum (r = 0.521). This suggests that elevated FeNO may indicate a phenotype of COPD characterized by acute exacerbations driven by eosinophilic inflammation.

Eosinophil count has been recognized as a significant therapeutic trait biomarker in the management of Chronic Obstructive Pulmonary Disease (COPD). A higher baseline eosinophil count (EOS)¹⁰ can reliably predict a better response to ICS treatment. Therefore, the rational and appropriate use of EOS in routine clinical practice benefits clinicians by enabling them to apply ICS to specific patient groups that are more likely to benefit from this treatment.

The most prominent application value of fractional exhaled nitric oxide (FeNO) in clinical practice lies in its role as a biomarker for inflammation and type 2 immune responses. In particular, in type 2 inflammatory conditions such as allergic asthma and chronic sinusitis with nasal polyps¹¹, airway epithelial cells are activated by cytokines including interleukin-4 (IL-4) and interleukin-13 (IL-13). This stimulation leads to the upregulation of inducible nitric oxide synthase (iNOS), resulting in a marked increase in nitric oxide (NO) production within the airways.

In recent years, significant advancements have been made in the study of fractional exhaled nitric oxide (FeNO) detection technology. In 2005, the American Thoracic Society and the European Respiratory Society (ATS/ERS)¹² collaboratively developed a standardized guide for measuring exhaled nitric oxide. In 2011, ATS/ERS¹³ further clarified that this biomarker not only reflects the degree of eosinophil-mediated airway inflammation but also serves as a reliable predictive tool for the sensitivity to glucocorticoid therapy. Furthermore, the detection standards established clear and differentiated thresholds for adults and children: if the FeNO value in adults exceeds 50 ppb (children >35 ppb), it indicates eosinophilic airway inflammation. Values ranging from 25 to 50 ppb (children 20–35 ppb) necessitate a comprehensive judgment and dynamic monitoring in conjunction with clinical efficacy. Results below 25 ppb (children <20 ppb) can generally exclude the possibility of eosinophilic airway inflammation.

There is substantial evidence¹⁴ indicating that FeNO levels are highly correlated with eosinophil counts, making FeNO a highly practical and non-invasive biomarker for type 2 airway inflammation.

A systematic review and meta-analysis¹⁵ summarized that ICS treatment can significantly reduce fractional exhaled nitric oxide (FeNO) levels in patients with COPD. Notably, the reduction in FeNO is more pronounced in patients with higher baseline FeNO levels, which corresponds to a more significant improvement in lung function, as measured by forced expiratory volume in 1 s (FEV₁), during the same treatment period. However, there remains an absence of a unified conclusion regarding the variability and repeatability of FeNO measurements in patients with COPD. Furthermore, the existing literature predominantly emphasizes the response of patients with stable COPD to ICS treatment. Consequently, there is still no definitive answer regarding the utility of FeNO in guiding the administration of systemic glucocorticoids for patients experiencing AECOPD.

The relative advantage of fractional exhaled nitric oxide over traditional biomarkers, such as peripheral blood eosinophils, in identifying glucocorticoid-responsive patients remains unclear. Therefore, this study aimed to evaluate the predictive value of fractional exhaled nitric oxide for glucocorticoid treatment response in patients with acute exacerbations of chronic obstructive pulmonary disease and to explore its relationship with peripheral blood eosinophils. By comparing clinical outcomes between high- and low-fractional exhaled nitric oxide groups and analyzing their association with treatment response, this study seeks to provide evidence for more precise, individualized selection of glucocorticoid therapy.

This study focuses on patients experiencing acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The primary objective is to systematically investigate the correlation between FeNO levels and the degree of respiratory inflammation, as well as the severity of the disease. Additionally, this research aims to compare FeNO with eosinophil counts as potential biomarkers. Ultimately, the goal is to elucidate the predictive value of FeNO in relation to the response to glucocorticoid therapy, thereby providing a scientific basis for optimizing the diagnostic and therapeutic strategies for AECOPD. This approach aims to minimize excessive glucocorticoid use and facilitate personalized treatment in clinical practice.

Protocol

The study protocol was reviewed and approved by the Ethics Committee of Tianshui First People's Hospital (approval number: 2025-054; approval date: October 28, 2025). Given that this is a retrospective study, only anonymized clinical data were used, and no interventions were applied to patients. The informed consent of patients was waived with the approval of the ethics committee.

1. Research object

This study is a single-center, retrospective clinical investigation of 122 patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) who were admitted to the Department of Respiratory and Critical Care Medicine at Tianshui First People's Hospital from July 2024 to September 2025. As a significant regional medical center in southeastern Gansu Province, the hospital serves a population of approximately 3 million.

1. Inclusion criteria
   In accordance with the diagnostic criteria proposed by the 'Global Initiative for Chronic Obstructive Pulmonary Disease 2023', the following criteria are established: (1) The primary manifestations include chronic respiratory symptoms such as chronic cough, expectoration, wheezing, and chest tightness, which often occur during seasonal transitions (primarily in autumn and winter); (2) Physical examination reveals an increase in the anteroposterior diameter of the thorax (barrel chest), and the presence of emphysema, evidenced by the auscultation of diminished breath sounds; (3) A history of potential risk factors, including long-term smoking, prolonged exposure to irritant gases such as lampblack, and α1-antitrypsin deficiency; (4) Pulmonary function test results indicate FEV1/FVC <0.7 following bronchodilator administration, suggesting persistent airflow limitation. The patient was hospitalized due to an acute exacerbation characterized by dyspnea, cough, or increased sputum production. A comprehensive assessment was conducted considering the patient's exposure history to harmful gases or dust, genetic predisposition, and other risk factors, alongside clinical manifestations, physical examination findings, and laboratory test results. Additionally, it is crucial to differentiate other diseases that may present with similar symptoms and abnormal lung function.
2. Exclusion criteria
   (1) The presence of comorbidities that may impair respiratory function, including pneumonia, pneumothorax, interstitial lung disease, cardiogenic pulmonary edema, and pulmonary embolism; (2) Patients with compromised immune function, such as those with severe cardiac insufficiency, autoimmune diseases (including rheumatic diseases), hematological disorders, AIDS, and individuals post-organ transplantation; (3) Patients experiencing respiratory failure requiring mechanical ventilation who are unable to cooperate with pulmonary function and FeNO tests; (4) Conditions that may lead to an abnormal increase in eosinophils include parasitic infections, allergic diseases (such as allergic rhinitis, asthma, and drug allergies), hematological disorders, and drug-related effects; (5) Patients who cannot participate in the Chronic Obstructive Pulmonary Disease Assessment Test (CAT); (6) Patients with incomplete case data;(7) Patients with unexplained elevated eosinophil levels.

2. Grouping and treatment allocation

Based on the critical value of fractional exhaled nitric oxide (FeNO) levels ≥25 ppb at admission, patients were categorized into two groups: the high FeNO group (n = 61) and the low FeNO group (n = 61). Each group was further subdivided into a treatment subgroup, which received systemic glucocorticoid therapy, and a control subgroup, which did not receive systemic hormone therapy, with 36 and 25 cases in each subgroup, respectively. All patients received standard basic treatment, which included inhaled corticosteroids (ICS), short-acting β2 receptor agonists (SABA), and short-acting anticholinergic drugs (SAMA). The treatment subgroup was administered additional systemic glucocorticoid therapy. Whether to receive systemic glucocorticoid therapy depends on the severity of the patient 's clinical symptoms. At both admission and discharge, eosinophil counts (EOS), FeNO levels, lung function indices (FEV1, FVC, FEV1/FVC, FEV1% predicted), CAT scores, and duration of hospitalization were recorded and analyzed for comparison.

For glucocorticoid administration, the budesonide-formoterol compound inhalant was utilized in two formulations: (1) Each spray contains 160 µg of budesonide and 4.5 µg of formoterol fumarate, with a recommended dosage of 1–2 sprays twice daily; (2) Each spray contains 320 µg of budesonide and 9 µg of formoterol fumarate, with one spray administered twice daily. For intravenous administration, methylprednisolone was given at a dosage of 40–80 mg/day. The treatment regimen was tailored to the clinical symptoms of the patients. The study conducted a baseline equilibrium analysis between the groups to exclude the effects of dosage and treatment duration on the primary indicators. In terms of antibiotic use, empirical treatment was initiated in the early stages, followed by individualized adjustments based on sputum culture results and drug sensitivity. Cases requiring hormone therapy during the study were excluded, specifically those patients who did not receive hormone therapy and whose clinical symptoms did not improve (Figure 1).

3. Data collection

1. Baseline data collection
   General patient information was obtained from the hospital’s electronic medical record system, including age, gender, body mass index (BMI), smoking history (pack-years and pack-days), GOLD classification, and comorbidities such as hypertension, diabetes, coronary heart disease, and pulmonary disease. CAT scores were recorded on admission to assess the severity of patient symptoms.
2. Laboratory examinations
   Peripheral venous blood was collected from all patients within 24 h of admission. Routine blood parameters, including eosinophil (EOS) count, white blood cell (WBC) count, and neutrophil (Neut) count, were evaluated using an automatic blood cell analyzer. The blood routine was assessed using the automatic blood and body fluid analyzer via the electrical impedance method. C-reactive protein (CRP) and serum amyloid A (SAA) levels were measured using a biochemical analyzer with transmission turbidimetry. Procalcitonin (PCT) was detected through immunoturbidimetry. Exhaled nitric oxide (FeNO) was measured using an exhaled nitric oxide detector.
3. Clinical outcome indicators
   The lung function, fractional exhaled nitric oxide (FeNO) levels, COPD Assessment Test (CAT) scores, and hospitalization durations of all patients were recorded both before and after treatment. Differences between the groups were subsequently compared. The therapeutic effects and hormone responsiveness were assessed through changes in various clinical indicators.

4. Statistical analysis

The statistics were performed by an analysis software. Variables with a missing rate >35% were excluded. For continuous variables with a missing rate <5%, multiple imputation was applied; for categorical variables with a missing rate <5%, mode imputation was used. The measurement data were assessed for normality, with normally distributed data expressed as mean ± standard deviation (x̄ ± s). Data that did not conform to a normal distribution are presented as median ( interquartile range ) ( M, IQR ).

1. For comparisons between groups
   For normally distributed data, an independent sample t-test was employed, with Cohen's d effect size and its 95% confidence interval reported. For non-normally distributed data, the Mann-Whitney U test was applied, and the effect size r ( r = z / sqrt{N} ) was documented.
2. For comparisons within groups
   The Wilcoxon signed-rank test was utilized to analyze differences before and after the intervention, reporting the effect size r along with its 95% confidence interval.
3. For classified data
   Data were expressed as frequency (percentage) ( n, % ), and the chi-square test was used for inter-group comparisons, with Cramér's V effect size reported.
4. For correlation analysis
   The Spearman correlation test was conducted to evaluate the relationship between variables, with the correlation coefficient and its 95% confidence interval reported. All statistical tests were two-sided, and a p-value of <0.05 was deemed statistically significant.

Results

In this study, regression analysis and other multi-factor methods were not used to correct the above factors. The core reason is that the study group has achieved the balance of baseline confounding factors. Such factors have no statistical interference with the study outcome and do not need further correction. The specific basis is as follows:

In this study, 122 patients with AECOPD were divided into high and low FeNO groups (61 cases each) according to FeNO ≥25 ppb. After the statistical tes...

Discussion

In this study, patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) were treated with a combination of inhaled corticosteroids ICS, SABA, and SAMA. Within this triple therapy, patients were categorized into high and low groups based on baseline FeNO levels, and systemic corticosteroids were added to each subgroup. The aim was to investigate and assess the clinical significance of FeNO in stratifying AECOPD patients, identify potential beneficiaries of corticosteroid therapy, and monitor the...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Automated Hematology Analyzer	Mindray	CAL-8000	Complete blood count including EOS
Automatic biochemical analyzer	Mindray	BS-2800M	Quantification of serum CRP´SAA
Automatic biochemical analyzer	Mindray	CL-8000i	Detection of PCT
Electronic Medical Record System	Zhejiang Heren Technology Co., Ltd.	Hi Assistant	Extraction of patient clinical data
FeNO Analyzer	Weigu Medical	HFWG-F013	Measurement of fractional exhaled nitric oxide
Pulmonary Function Test System	Jaeger	Ganshorn	Assessment of FEV1, FVC, FEV1/FVC