Chronic small airway diseases are characterized by progressive airflow limitation and irreversible pulmonary function decline, posing a significant burden on global respiratory health. Among these diseases, chronic obstructive pulmonary disease (COPD) is the most common, with a global prevalence of approximately 10% in adults over 40 years old [1]. Previous studies have confirmed that a comprehensive intervention combining nutritional support and respiratory training can effectively improve pulmonary function and exercise capacity in COPD patients [2, 3]. However, the efficacy of comprehensive intervention in obliterative bronchiolitis, another destructive but understudied small airway disease, remains largely unknown, although it shares similar clinical outcomes, such as refractory airflow limitation and poor prognosis, with COPD.

Obliterative bronchiolitis (OB) is a rare progressive inflammatory disease of small airways, characterized by subepithelial fibrosis, luminal stenosis, and bronchial obliteration. It mainly occurs as a secondary complication, with an estimated incidence of 1%–5% in patients after receiving lung transplants and up to 10% in hematopoietic stem cell transplant recipients [4, 5]. In addition, inhalation injury and connective tissue diseases (such as rheumatoid arthritis) are also common causes of OB [4, 6]. Diagnosis typically relies on examining a constellation of clinical presentations, assessing fixed airflow obstruction on the pulmonary function tests, and analyzing high-resolution computed tomography (CT) findings. Unlike COPD driven by chronic smoking-related inflammation, OB is often associated with immune-mediated injury or chronic tissue repair dysfunction, which further exacerbates nutritional imbalance and respiratory muscle weakness in affected patients [7]. Current therapeutic strategies are largely limited to immunosuppressive agents and supportive care, with limited efficacy in reversing disease progression. This gap underscores the clinical relevance of our study.

Clinically, OB patients face unique challenges that highlight the necessity of non-pharmacological interventions. Firstly, malnutrition is very common in OB patients: Up to 45% of post-transplant OB patients present with hypoalbuminemia or weight loss, attributed to immunosuppressive drug-induced gastrointestinal side effects, chronic inflammation, and increased energy expenditure from labored breathing [8, 9]. Malnutrition, in turn, impairs respiratory muscle strength and immune function, forming a vicious cycle that accelerates pulmonary function decline [10]. Secondly, OB-related bronchiolar obliteration leads to fixed airflow limitation, and pharmacologic treatments such as inhaled corticosteroids and long-acting bronchodilators can only alleviate symptoms in 30%–40% of patients and fail to reverse the underlying structural airway damage [11]. Respiratory training, capable of improving respiratory muscle endurance and alveolar ventilation, has shown promise in other obstructive lung diseases, but its efficacy in OB remains to be deciphered [12].

Notably, existing research on OB interventions is severely limited: Most studies focus on pharmacological strategies [13] or surgical options [14], while no studies have evaluated the combined effect of nutritional support and respiratory training. Moreover, observational studies on OB often suffer from selection bias (such as differences in age or comorbidities between intervention and control groups), which weakens the reliability of conclusions [15]. To address this gap and to explore non-pharmacological options in the clinical management of OB patients, this retrospective study investigated the clinical efficacy of a comprehensive intervention combining nutritional support with respiratory training in OB patients, with a particular focus on assessing their pulmonary function. The data analysis entailed the elimination of potential confounding factors using propensity score matching.

In this propensity score-matched retrospective study, we found that comprehensive intervention program integrating individualized nutritional support with structured respiratory training demonstrated significant clinical benefits in patients with OB compared with nutritional support alone. Specifically, the experimental group showed statistically significant improvements in FEV₁ and FVC compared with the control group, with multiple linear regression analysis confirming that comprehensive intervention was an independent factor contributing to the improvements in these two pulmonary function indicators. Furthermore, the experimental group also exhibited lower post-intervention MDA, CRP, and PCT levels, indicating a greater ability of comprehensive intervention to mitigate systemic inflammation and oxidative damage compared with nutritional support alone. Notably, while the comprehensive intervention resulted in a significant reduction in nutritional risk (NRS-2002), nutritional parameters such as BMI and ALB did not demonstrate significant within-group improvements in either patient’s group, suggesting that the observed clinical benefits may be mediated by mechanisms beyond mere weight gain. In addition, the significant improvements in indicators like 6WMD, mMRC and WHOQOL-BREF in the experimental group further demonstrate the important role of comprehensive intervention in improving exercise tolerance, dyspnea symptoms, and quality of life. To the best of our knowledge, this is the first study to investigate the clinical efficacy of a comprehensive intervention combining nutritional support with respiratory training in patients with OB, providing important insights into intervention strategies and research directions in the clinical management of OB patients.

Our findings are consistent with—and extend—the results of previous studies on nutritional support and pulmonary rehabilitation in chronic lung diseases. A systematic review of nutritional interventions in COPD patients showed that nutritional support can improve anthropometric measures and muscle strength, though its effects on pulmonary function are limited when used alone [25], consistent with our observation that patients receiving nutritional support alone did not show significant improvements in nutritional indicators and pulmonary function. In contrast, our research demonstrates that combining nutritional support with respiratory training yields superior outcomes, especially in terms of pulmonary function parameters such as FEV₁ and FVC. Notably, previous studies on pulmonary rehabilitation in COPD patients have reported inconsistent effects on systemic inflammation, with some studies showing no significant changes in inflammatory markers after high-intensity pulmonary rehabilitation [26]. However, our study found significant reductions in CRP and PCT in the experimental group, which might be attributed to the synergistic effect of nutritional support and respiratory training in addressing the specific pathological features of OB. In this study, baseline PCT levels of the patients were generally above the normal range ($>$0.05 ng/mL), while the WBC count did not show a significant increase. This phenomenon may be related to the characteristics of OB as a chronic inflammatory disease. In chronic inflammatory states, especially in the presence of structural lung damage, PCT levels may show a mild to moderate increase. This does not necessarily represent active bacterial infection but rather reflects persistent, low-grade immune activation and epithelial damage. In addition, our positive results in reducing oxidative stress (MDA) are robust and novel in the context of OB. Recent studies have found that organized exercise training can enhance the antioxidant defense mechanism in patients with chronic respiratory diseases, thereby reducing oxidative damage [27]. In the context of OB management, current treatment options remain limited, and there is a lack of direct evidence demonstrating the beneficial impacts of nutritional support combined with respiratory training. Previous research efforts have mainly centered on pharmacological or surgical strategies (such as azithromycin for bronchiolitis obliterans syndrome or retransplantation) [28], while non-pharmacological reports have evaluated pulmonary rehabilitation programs without prespecified nutritional components [18]. Our study fills this gap by providing evidence that comprehensive intervention can improve the key clinical outcomes of OB patients—a direction that has not been adequately addressed in previous literature. Furthermore, previous studies on transplantation-related bronchiolitis obliterans syndrome have shown significant improvements in 6MWD, physical fitness, subjective dyspnea, and some dimensions of quality of life following the implementation of pulmonary rehabilitation [29], consistent with the results of 6MWD, mMRC, and WHOQOL-BREF in the present study. It is worth noting that although there was no significant difference in pulmonary function indicators between the two groups before the intervention, the 6MWD and WHOQOL-BREF scores of the experimental group were significantly lower than those of the control group. This difference may reflect individual variations in patients’ subjective symptom perception, comorbidities, muscle function or psychological state, and these factors were not captured during the PSM procedure.

The superior efficacy of comprehensive intervention observed in this research can be explained by several complementary mechanisms. Nutritional support may provide the necessary foundation for respiratory muscle function and immune regulation. Adequate protein intake is essential for maintaining the quality and strength of respiratory muscles, while micronutrients such as zinc, vitamin D, and selenium can enhance immune function and reduce the risk of respiratory infections [30]. This is also supported by the improvement of NRS-2002 in our experimental group, indicating a reduction in nutritional risk for the patients. It is noteworthy that within the patient group receiving comprehensive intervention, significant improvement was only observed in the NRS-2002 score, but not in objective measures such as BMI and ALB. This can be explained by the composite nature of the NRS-2002, which incorporates not only nutritional status but also disease severity. The significant improvements in respiratory function, exercise capacity (6MWD), and dyspnea (mMRC) achieved through respiratory training would directly lower the ‘disease severity’ component of the NRS-2002, thereby reducing the total score. In contrast, BMI and ALB—being less sensitive to short-term functional changes—tend to respond more slowly. Furthermore, in patients without severe baseline malnutrition, the primary role of nutritional support may shift from driving significant anabolic gains to preventing catabolism and supporting the increased metabolic demands of exercise, an effect that may not be fully captured by static measures like BMI and ALB over 12 weeks. On the other hand, respiratory training can enhance the endurance and efficiency of respiratory muscles. Diaphragmatic breathing and inspiratory muscle training can enhance ventilation capacity and oxygen utilization [31], which may explain the significant improvements in FEV₁ and FVC observed in our study. Meanwhile, the improvement of respiratory muscle strength and endurance can better overcome the increased airway resistance in OB patients, thereby reducing dynamic hyperinflation and subjective dyspnea (as shown in the improvement of mMRC score results) [3]. In addition, respiratory training can regulate the inflammatory response by increasing lymphatic drainage and improving systemic circulation, which helps to suppress inflammation [32]. The synergistic effect of nutritional support and respiratory training is particularly noteworthy. Nutritional support provides the essential substrates for muscle repair and function, while respiratory training enhances nutrient utilization and promotes physiological adaptation, thereby improving pulmonary function. This might explain why comprehensive intervention yields superior outcomes compared with nutritional support alone. Furthermore, the observed pattern of pulmonary function response is consistent with the pathophysiology of OB. Significant improvements in FVC and FEV₁ occurred without a corresponding change in the FEV₁/FVC ratio, reflecting the characteristic fixed airflow limitation of OB. This suggests that while comprehensive intervention can enhance respiratory muscle function and lung volumes, it cannot reverse the underlying structural narrowing of the small airways. Similarly, the PEF and MVV remained largely unaltered following the intervention, indicating their dependence on both respiratory muscle strength and the fixed airway obstruction characteristic of OB.

This study provides important clinical insights into the management of OB patients. Based on the research results, we recommend incorporating nutritional support combined with respiratory training into the standardized treatment plan for OB patients. Specifically, for patients with high nutritional risk reflected by NRS-2002 score $\ge$3, individualized nutritional support should be prioritized, followed by respiratory training to achieve optimal efficacy. This “stepwise intervention” strategy is in line with the NHS-recommended nutrition and exercise management framework for chronic respiratory diseases, which is further optimized for OB patients. From the perspective of functional improvement, comprehensive intervention has substantial practical utility in improving dyspnea, cardiopulmonary function, and the overall functional status, indicating that this strategy can effectively improve patients’ ability to perform daily activities, as well as their life autonomy. Considering the progressive development characteristics of OB, early initiation of comprehensive intervention may delay the progression of the disease and reduce the risk of acute exacerbation. For clinicians, FEV₁ and FVC can be utilized as the primary indicators for evaluating the intervention efficacy, while the dynamic changes of biomarkers such as CRP, PCT and MDA should be continuously monitored for the purposes of treatment optimization.

This study has several limitations that should be considered when interpreting the results. First, the retrospective design and single-center data of this study may introduce selection bias. To address this, we employed PSM to balance key baseline characteristics. While PSM significantly improved the comparability of the groups, as evidenced by the substantial reduction in SMDs for all covariates and the absence of statistically significant differences in the matched cohort, a degree of residual imbalance persisted for some variables (such as BMI, history of smoking, and history of pulmonary infection). Although an SMD below 0.2 is generally considered acceptable and the observed residual imbalances are unlikely to fully account for the magnitude of the intervention effects we observed, they nonetheless represent a potential source of confounding that should be acknowledged. Second, this study has a limited sample size. Although post-hoc analysis indicated that the matched cohort (44 pairs) provided adequate power (89.5% and 98.5%) to detect the significant differences observed in FEV₁ and FVC, the sample size may still be insufficient to detect smaller effect sizes for other outcomes. This is a plausible explanation for the lack of statistically significant differences in certain parameters, such as the FEV₁/FVC ratio and MVV. These non-significant findings should therefore be interpreted with caution. Third, due to the retrospective design, we were unable to obtain and account for the precise dosage and duration of glucocorticoid use prior to the intervention, which could represent a potential unmeasured confounder. However, we employed PSM on key clinical variables to minimize baseline differences, and all patients received guideline-based standard care, which can, to some extent, mitigate major disparities in background treatment. Furthermore, without monitoring the intervention compliance among the patients, the study was unable to analyze the impact of compliance differences on outcomes, which is crucial in nutrition and exercise intervention research. Finally, due to the lack of long-term follow-up data, we were also unable to assess the sustained effect of comprehensive intervention, especially for OB as a chronic progressive disease, whose advantages in long-term prognosis still need to be verified. Therefore, future research should include multicenter prospective randomized controlled trials to assess the efficacy of this comprehensive intervention framework across diverse clinical settings and populations, incorporating wearable devices to monitor exercise adherence. Additionally, extended follow-up periods are needed to clarify the impact of comprehensive intervention on the long-term prognosis of OB patients.

Compared with nutritional support alone, comprehensive intervention combining nutritional support with respiratory training provides greater improvements in pulmonary function, oxidative stress, inflammatory status, quality of life, and respiratory symptoms in patients with OB. Our findings provide new evidence for non-pharmacological interventions in the clinical management of OB patients, but larger-scale prospective randomized controlled trials are warranted for validation.

• Both comprehensive intervention and nutritional support alone can significantly improve the pulmonary function, oxidative stress, inflammatory status, quality of life, and respiratory symptoms of obliterative bronchiolitis (OB) patients.

• Compared with nutritional support alone, comprehensive intervention has greater advantages in improving FEV₁, FVC, MDA, CRP, PCT, 6MWD, mMRC and WHOQOL-BREF in OB patients.

• Among the nutritional indicators analyzed, significant improvement was only observed in the NRS-2002 scores of OB patients receiving comprehensive intervention.

• Compared with nutritional support alone, comprehensive intervention was an independent factor associated with greater improvements in FEV₁ and FVC.

All data included in this study are available from the corresponding author upon reasonable request.

YXC and XYY designed this research program. XTH, YC, and DQ collected and analyzed the data. YXC drafted the initial manuscript. All authors contributed to the critical revision of the manuscript for important intellectual content. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study protocol was reviewed and approved by the Ethics Committee of The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital) (Approval No.2025-251266). Written informed consent was obtained from all participants and their legal guardians. All procedures were conducted in accordance with the ethical principles outlined in the Declaration of Helsinki.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.