Small airway lesions appear with the course of IPF and relate to the severity of pulmonary fibrosis progression

Small airway lesions appear with the course of IPF and relate to the severity of pulmonary fibrosis progression | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Small airway lesions appear with the course of IPF and relate to the severity of pulmonary fibrosis progression xiaoyan wang, Ling Zhao, Dingyun Song, Xinran Zhang, Min Liu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6653847/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Oct, 2025 Read the published version in BMC Pulmonary Medicine → Version 1 posted 11 You are reading this latest preprint version Abstract Aim Idiopathic Pulmonary Fibrosis (IPF) has been considered a disease primarily affecting the interstitium with sparing of the airways. This study was to investigate development and characteristics of small airway lesions in IPF patients. Method This study included 137 patients with IPF and 84 patients in the control group. The included IPF patients from a prospective, multicentre study. Trial registration number is NCT03666234. We grouped IPF patients by severity of disease according to fibrosis severity of CT and disease severity score. Percentage of Predicted Maximal Expiratory Flow at 25 percent(MEF25%), percentage of Predicted Maximal Expiratory Flow at 50 percent(MEF50%) and maximal Expiratory Flow between 25 and 75% of FVC(MEF25-75%) were used to evaluate the function of small airways. Airway segmentation was performed using FACT-Digital LungTM software. Differences in lung function and small airway volume, numbers and length are assessed between IPF patients with different severity and the control group. Statistical analyzes were performed using SPSS software (version 26). Results There were 114 males and 23 females in the IPF group, with an average age of 64.51 ± 10.69 years. MEF50%, MEF25% and MEF75-25% of IPF patients in different stage were lower than those in the control group. The number, length, and volume of bronchi in IPF patients were higher than those in the control group.The number of bronchi at grade 9 to 14 levels in IPF patients was higher than that in the control group. IPF patients with mild fibrosis had small airway lesions. Conclusion Small airway quantity and dysfunction exists in mild patients and persist throughout the entire disease progression. small airway idipathic pulmonary fibrosis pulmonary function high-resolution chest CT Transbronchial Cryobiopsy Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Idiopathic Pulmonary Fibrosis (IPF) is a chronic respiratory disease that predominantly affects elderly males. Most patients present with a dry cough and progressively worsening breathlessness, often accompanied by reduced exercise tolerance, decreased quality of life, and a shortened life expectancy, with an average survival period of three years [ 1 , 2 ] . The incidence of IPF is approximately 2.8 to 18 cases per 100,000 people in Europe and North America every year [ 3 , 4 ] . Traditionally, IPF has been considered a disease primarily affecting the interstitium with sparing of the airways. In recent years, a study [ 5 ] found that the number of small airways in IPF patients increased on CT scans, meanwhile, microCT examination of local lung tissues revealed a reduction in the number of terminal bronchioles. However, it remains unclear when small airway lesions appear, whether they result from parenchymal fibrosis in the late stages of IPF, or if they are accompanied by the fibrotic process. This study conducts a retrospective analysis of clinical data from IPF patients at different stages. The aim is to investigate the development and characteristics of small airway lesions in IPF patients through pulmonary function tests, CT imagings and pathological examinations. Method Study cohort and design This study was approved by the Ethics Board of the China-Japan Friendship Hospital Committee (No. 2017-25) and adhered to the Declaration of Helsinki. Informed consent to participate was obtained from all of the participants or their families if the patient unable to sign. This study includes IPF patients from a prospective, multicentre study who attented at China-Japan Friendship Hospital between June 2020 and December 2021.Trial registration number is NCT03666234. Patients diagnosed with IPF based on the guidelines of the American Thoracic Society/European Respiratory Society [ 6 ] . Exclusion Criteria: Patients lacking high-resolution chest CT (HRCT) results and pulmonary function tests. Individuals in control group were from a community health examination population who had no underlying respiratory diseases and underwent HRCT and pulmonary ventilation function testing. We recorded gender, age, disease duration, smoking history, underlying diseases, pulmonary function parameters, and high-resolution chest CT examination results. We grouped IPF patients by severity of disease.Two methods were used to assesse disease severity : fibrosis severity of CT and disease severity score. We used a visual score of fibrosis on CT to assess the severity of disease in IPF patients [ 7 ] . Each lobe was scored on a scale of 0–5 for interstitial abnormality according to the percentage of each lobe involved(Attached Table 1 ). Based on the total fibrosis scores, IPF patients are categorized into mild(0–8), moderate(9–16), and severe groups(17–25)(Fig. 1 -A,B,C). We used the GAP score proposed by LEY [ 8 ] to assess the disease severity of IPF patients. The patients were scored according to their gender, age, percentage of forced expiratory volume in one second to the predicted value, and percentage of diffusing capacity of the lung for carbon monoxide to the predicted value. The total score was calculated as the GAP score. The IPF patients were divided into 3 groups according to the GAP score. Specifically, 0–3 points corresponded to GAP stage I, 4–5 points to GAP stage II, and 6–8 points to GAP stage III. Function and quantitative assessment of small airways We use the following three indicators to evaluate the function of small airways [ 9 ] : percentage of Predicted Maximal Expiratory Flow at 25 percent(MEF25%), percentage of Predicted Maximal Expiratory Flow at 50 percent(MEF50%) and maximal Expiratory Flow between 25 and 75% of FVC(MEF25-75%). In order to be consistent with our previous research [ 10 ] , small airway dysfunction is defined as at least two of these indicators being below 65% of their predicted values. Airway segmentation was performed using FACT-Digital LungTM software(DeXin, Xi’an, China) [ 11 , 12 ] .Pulmonary airway tree was segmented(Fig. 1 -D,E), generating an airway volume, numbers and length. Differences in lung function and small airway numbers are assessed between IPF patients at different stages and the control group. pathological analysis For some mild patients without typical honeycomb shadows on chest CT, transbronchial cryobiopsy (TBCB) is used to assist in the diagnosis of IPF. We analyzed the pathological sections of these patients to observe whether there were pathological changes in the small airways of the patients with mild symptoms. Small airway pathologic features include the extent of airway lumenal granulation tissue, air-space granulation tissue, airway wall inflammation,and airway wall fibrosis. Statistical analysis Statistical analyzes were performed using SPSS software (version 26). Compare the baseline data, small airway function indices, and the number and length of small airways on CT between the IPF group and the control group. To determine in which stage of IPF the abnormalities in small airway function and imaging appear, according to the imaging fibrosis score and disease severity score, compare the differences in small airway function and imaging indices between IPF patients with different severity levels and the control group. Continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as frequency (percentage). The Student’s t test was used to compare between two groups, the one-way ANOVA was used to compare the means, and the chi-square test was used to compare the frequency distribution of the two groups. Demonstrate the correlation relationship through Spearman rank correlation analysis. All statistical tests were two-sided, and P < 0.05 was considered statistically significant. Results General information in IPF and controls . This study included 137 IPF patients and 84 controls. There were 114 males and 23 females in the IPF group, with an average age of 64.51 ± 10.69 years. Average disease duration of IPF patients was 28.7 months. There was no statistical difference in gender distribution and age between the two groups, with P values of 0.72 and 0.293 respectively(Table 1 ). Table 1 General information IPF(n = 137) Control(n = 84) P value Male(%) 114(83.21%) 68(80.95%) 0.72 Age(years old) (mean ± standard deviation) 64.51 ± 10.69 65.05 ± 8.36 0.293 Smoking(%) 83(60.58%) 46(54.76%) 0.394 Comorbidities Hypertension 23 29 0.001 Coronary heart disease 32 1 <0.0001 Diabetes 19 2 0.005 Cerebrovascular disease 4 1 0.401 Small airway dysfunction exists in mild IPF patients . IPF patients with different severities have varying degrees of small airway dysfunction. Compared with the control group, IPF patients had significantly lower percentage of predicted forced expiratory volume(FVC%), percentage of predicted total lung capacity(TLC%), and percentage of predicted diffusion capacity of carbon monoxide(DLCO%). Small airway function-related indicators were all lower than the control group(Table 2 ,Fig. 2 -A). According to GAP score, compared with controls, IPF patients with different degrees of severity had reduced FVC%,TLC% and DLCO%. PEF% and MEF75% in stage I patients were higher than those in controls, while MEF50% in different GAP stage IPF patients were all lower than that in control group(GAP I 88.93% vs GAP II 78.10% vs GAP III 86.88% vs control 99.07%, p = 0.036 ); MEF25% (GAP I 64.59% vs GAP II 64.24% vs control 77.49%, p = 0.033) and MEF75-25% in stage I and II were lower than those in control group(GAP I 78.33% vs GAP II 69.40% vs control 86.98%, p = 0.029)(Fig. 2 -B). The FVC%, TLC%, and DLCO% of IPF patients with different fibrosis severity on CT were lower than those of the control group. The MEF50% of mild and moderate fibrosis patients was lower than that of the control group(mild fibrosis 78.53% vs moderate fibrosis 88.36% vs control 99.07%, p = 0.035). The MEF25% of different fibrosis patients was lower than that of control group(mild fibrosis 65.90% vs moderate fibrosis 65.52% vs severe 64.58% vs control 77.49%, p = 0.048). MEF75-25% is lower than that in control group(mild fibrosis 71.85% vs moderate fibrosis 76.08% vs severe 75.28% vs control 86.98%, p = 0.010), indicating that small airway dysfunction exists in IPF patients in the early stage(Fig. 2 -C). Table 2 Pulmonary function indexes difference between IPF and control Pulmonary function index IPF(mean ± standard deviation) Control(mean ± standard deviation) P value FVC% 83.74 ± 20.82 101.73 ± 12.12 <0.0001 PEF% 109.18 ± 20.60 101.84 ± 18.49 <0.0001 MEF75% 111.99 ± 22.45 102.22 ± 19.31 0.001 MEF50% 87.14 ± 27.20 99.07 ± 29.57 0.004 MEF25% 66.28 ± 31.95 77.49 ± 34.62 0.022 MEF75−25% 76.67 ± 22.66 86.98 ± 23.92 0.003 TLC% 72.17 ± 13.61 101.42 ± 13.19 <0.0001 DLCO% 54.66 ± 17.03 90.68 ± 12.38 <0.0001 FVC%:percentage of predicted forced expiratory volume; PEF%:percentage of Predicted Peak Expiratory Flow; MEF25%:percentage of Predicted Maximal Expiratory Flow at 25 percent; MEF50%:percentage of Predicted Maximal Expiratory Flow at 50 percent; MEF25-75%:maximal Expiratory Flow between 25 and 75% of FVC; TLC%:percentage of predicted total lung capacity; DLCO%:percentage of predicted diffusion capacity of carbon monoxide Increased number of small airways exists in mild IPF patients . Based on CT analysis, the number, length, and volume of bronchi in IPF patients were higher than those in the control group((Table 3 ,Fig. 3 -A). Both mild and severe IPF patients according to the GAP score had increased bronchial tubes, increased bronchial length and bronchial volume(Fig. 3 -B). The bronchus numbers, length and volume of IPF patients with different fibrosis severity were higher than control (Fig. 3 -C). The number of bronchi at grade 9 to 14 in IPF patients was higher than that in the control group(Table 3 ,Fig. 3 -D).Regardless of the severity of GAP stage and CT fibrosis, the number of grade 9 to grade 14 bronchi in IPF patients was higher than that in control group(Fig. 3 -E and F). It is suggested that changes in small airways exist in IPF in the early stage of fibrosis. Table 3 Bronchus number difference between IPF and control IPF(mean ± standard deviation) Control(mean ± standard deviation) P value Number of bronchus 174.83 ± 53.29 133.63 ± 44.63 <0.0001 Length of bronchus 296.73 ± 94.47 222.14 ± 78.32 <0.0001 Volume of bronchus 88.29 ± 24.97 65.90 ± 24.81 <0.0001 Number of level 9 bronchus 11.14 ± 7.53 6.88 ± 5.50 <0.0001 Number of level 10 bronchus 5.04 ± 4.59 3.24 ± 3.47 <0.0001 Number of level 11 bronchus 1.92 ± 2.54 0.95 ± 1.60 0.001 Number of level 12 bronchus 0.64 ± 1.16 0.33 ± 1.07 0.020 Number of level 13 bronchus 1.22 ± 1.44 0.10 ± 0.53 0.001 Number of level 14 bronchus 0.67 ± 0.56 0.05 ± 0.31 0.049 Small airway mucosal epithelial changes are present in TBCB specimens of IPF patients of different fibrosis severity (Fig. 4 ). The proliferation of airway epithelial mucosal cells, and cilia lodging, falling off and shortness were common in IPF. The degree of small airway lesions was consistent with the degree of peripheral alveolitis and fibrosis. Discussion IPF is characterized by fibroblasts proliferation [ 13 ] and collagen fibers deposition in the interstitium [ 14 – 17 ] . While IPF is typically considered an airway-exempt disease, our study examed IPF patients with varying degrees of disease severity and found that IPF involves small airways. In early stage of disease, there are small airway changes in the aspects of function, numbers, and mucosal epithelium. The concept of the small airways was proposed in 1968 by Hogg and colleagues [ 18 ] . Small airways refer to the airways with a diameter of less than 2 millimeters, which are mainly used in the research of chronic obstructive pulmonary disease (COPD). Verleden and others [ 19 ] also believed that bronchi with a diameter of less than 2 millimeters were small airways, and small airways are generally located at the 9th to 14th levels of the bronchial branches. Our study found an increase in the number of visible bronchioles on CT in patients with IPF. Since the diameter of small airways is less than 2 millimeters, pathology is the most direct way to understand small airway lesions. However, most IPF patients cannot obtain pathological data. CT is not the best method for observing small airways, but IPF patients undergo regular CT examinations. Estimating the condition of small airway lesions through CT is both cost - effective and convenient. Consistent with our observations, Verleden [ 19 ] found that the number of small airways on CT scans of IPF patients was increased. Through the study of pathological sections and MicroCT of end-stage IPF patients, it has been found that the increase in the number of small airways is related to the thickening of the small airway walls and lumenal deformation. Kohei Ikezoe [ 5 ] et al. also found that the total number of airways on CT was greater in IPF patients than in control lungs(P = 0.01). They recognized an augmentation in bronchial wall and lumen area, making small airways more easily visible on CT scans. A previous study [ 20 ] in our group found that there was small airway dysfunction in IPF patients. There were 40% patients with IPF having spirometry-defned small airway disease. IPF patients with small airway disease showed poorer prognosis. Similarly, Fulmer and associates [ 21 ] found that there were pathological and physiological abnormalities in the small airways in patients with IPF, on the basis of qualitative assessment of small airways in the open lung biopsies. They also found dynamic compliance and the maximum expiratory flow-volume curve could predict small airways diameter in IPF. Additionally, our study has found that patients with IPF have abnormal small airway function in the early stage. We speculate that bronchial changes may predate extensive fibrosis rather than being the result of structural destruction of the lung fibrosis. This study also has certain limitations. Being a retrospective study, it is challenging to avoid inherent biases associated with retrospective research. However, the clinical data included in this study were sourced from an electronic medical record system, with real-time data entry and verification by different physicians, ensuring a relatively high level of accuracy. Secondly, the classification of cases as early-stage patients in this study was based on GAP scores and degree of fibrosis in CT imaging. From the perspective of disease progression, it is reasonable to assume that patients with milder conditions are more likely in the early stages, although the unevenness in the development of IPF cannot be entirely ruled out. Therefore, it is essential to objectively and cautiously interpret the characteristics of IPF small airway lesions as presented in the results of this study. Future research would benefit from more prospective studies to further elucidate the timing and evolving features of small airway lesions in IPF patients over time. Conclusion Small airway quantity and dysfunction exists in mild patients and persist throughout the entire disease progression. Abbreviations IPF Idiopathic Pulmonary Fibrosis HRCT high-resolution chest CT TBCB transbronchial cryobiopsy FVC% percentage of predicted forced expiratory volume PEF% percentage of Predicted Peak Expiratory Flow MEF25% percentage of Predicted Maximal Expiratory Flow at 25 percent MEF50% percentage of Predicted Maximal Expiratory Flow at 50 percent MEF25-75% maximal Expiratory Flow between 25 and 75% of FVC TLC% percentage of predicted total lung capacity DLCO% percentage of predicted diffusion capacity of carbon monoxide COPD chronic obstructive pulmonary disease Declarations Ethics approval and consent to participate . This study was approved by the Ethics Board of the China-Japan Friendship Hospital Committee (No. 2017-25). Informed consent to participate was obtained from all of the participants or their families if the patient unable to sign. This study adhered to the Declaration of Helsinki. Consent for publication . Not applicable. Availability of data and materials . The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests . The authors declare that they have no competing interests. Funding . This study was supported by the CAMS Innovational Fund for Medical Sciences (No. 2021-I2M-1-011) and National Nature Science Foundation of China (82370072). Authors' contributions . X.W. designed the research and was a major contributor in writing the manuscript. L.Z. provided pathological guidance and ensured the quality of the research. D.S. conducted the experiments and collected the data. X.Z. analyzed and interpreted the patient data. M.L. was responsible for HRCT reading and imaging scoring. H.D. revised the manuscript and provided the necessary research materials and equipment. All authors read and approved the final manuscript. Acknowledgements . Not applicable. References David J, Lederer, Fernando J, Martinez.Idiopathic Pulmonary Fibrosis. N Engl J Med. 2018;378(19):1811–23. 10.1056/NEJMra1705751 . Raghu G, Remy-Jardin M, Myers JL et al. Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. American journal of respiratory and critical care medicine 2018 09 01;198(5):e44-e68 10.1164/rccm.201807-1255ST Hutchinson J, Fogarty A, Hubbard R, et al. Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir J. 2015;46(3):795–806. 10.1183/09031936.00185114 . Robert B, Hopkins N, Burke C, Fell, et al. 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Am J Pathol. 1993;143(6):1754–65. Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med. 1968;278(25):1355–60. 10.1056/NEJM196806202782501 . Stijn E, Verleden N, Tanabe JE, McDonough, et al. Small airways pathology in idiopathic pulmonary fibrosis: a retrospective cohort study. Lancet Respiratory Med. 2020;06(6):573–84. 10.1016/S2213-2600(19)30356-X . Zhang X, Xie B, Ban C, et al. Small airway dysfunction in Chinese patients with idiopathic pulmonary fibrosis. BMC Pulm Med. 2022;22(1):297. 10.1186/s12890-022-02089-6 . Fulmer JD, Roberts WC, von Gal ER et al. Small airways in idiopathic pulmonary fibrosis. Comparison of morphologic and physiologic observations. J Clin Invest 1977 09;60(3):595–610 10.1172/JCI108811 Additional Declarations No competing interests reported. Supplementary Files Attachedtables.docx Cite Share Download PDF Status: Published Journal Publication published 10 Oct, 2025 Read the published version in BMC Pulmonary Medicine → Version 1 posted Editorial decision: Revision requested 15 Jul, 2025 Reviews received at journal 06 Jul, 2025 Reviews received at journal 02 Jul, 2025 Reviewers agreed at journal 17 Jun, 2025 Reviewers agreed at journal 14 Jun, 2025 Reviewers agreed at journal 11 Jun, 2025 Reviewers invited by journal 11 Jun, 2025 Editor assigned by journal 11 Jun, 2025 Editor invited by journal 10 Jun, 2025 Submission checks completed at journal 07 Jun, 2025 First submitted to journal 07 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6653847","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":470580480,"identity":"6dbf59d2-8ecf-4b69-8295-48a4086ee826","order_by":0,"name":"xiaoyan wang","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"xiaoyan","middleName":"","lastName":"wang","suffix":""},{"id":470580481,"identity":"44e84355-b740-4fce-9a1a-8c467c064561","order_by":1,"name":"Ling Zhao","email":"","orcid":"","institution":"China-Japan Friendship Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ling","middleName":"","lastName":"Zhao","suffix":""},{"id":470580482,"identity":"536c6788-185e-4a33-a92f-eb33ee46e919","order_by":2,"name":"Dingyun Song","email":"","orcid":"","institution":"China-Japan Friendship Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dingyun","middleName":"","lastName":"Song","suffix":""},{"id":470580483,"identity":"f58677c3-500c-4882-86a7-2af2d61ee2f1","order_by":3,"name":"Xinran Zhang","email":"","orcid":"","institution":"China-Japan Friendship Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xinran","middleName":"","lastName":"Zhang","suffix":""},{"id":470580484,"identity":"4ffd2338-23bc-4e44-800e-a31ceae7d287","order_by":4,"name":"Min Liu","email":"","orcid":"","institution":"China-Japan Friendship Hospital","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"","lastName":"Liu","suffix":""},{"id":470580485,"identity":"cf167228-9bff-44f0-a7a7-82b897a19c95","order_by":5,"name":"Huaping Dai","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7klEQVRIiWNgGAWjYDCCA4xtIIqHgYH5AFQogWgtbDClBLUwsEFZPAbEaeE7frjtMU/NHRlz/jUfP/zMOczAz55jwPBzB24tkmcS2415jj3jsZzxdrNk77bDDJI9bwwYe8/g1mJwILFNmoftMI/BjbPbmBmBWgxu5BgwQzyIQ8v5h0At/0BazjwDa7EnqOUG0BbeNqCW8z1sEFskCGiRvPGwTXJu3zOgLWzGQL+k80iceVZwsBePFr7z6c8k3ny7Y29w/vDDDz+3WcvxtydvfPATjxYoOMDAIJEAZvFAucRo4SdG3SgYBaNgFIxIAAD6m1chcaPa+wAAAABJRU5ErkJggg==","orcid":"","institution":"Capital Medical University","correspondingAuthor":true,"prefix":"","firstName":"Huaping","middleName":"","lastName":"Dai","suffix":""}],"badges":[],"createdAt":"2025-05-13 09:23:54","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6653847/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6653847/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12890-025-03939-9","type":"published","date":"2025-10-10T15:56:59+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84819889,"identity":"598d21b5-21ed-441e-9864-f9e2330e5244","added_by":"auto","created_at":"2025-06-17 16:03:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":477978,"visible":true,"origin":"","legend":"\u003cp\u003eA, B and C respectively represent mild, moderate and severe fibrosis. Figures D and E are the reconstructed diagrams of the bronchial trees of the patients in the control group and the IPF group.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-6653847/v1/0938f55b5ff417dc52d50a23.png"},{"id":84818896,"identity":"4d4ac9f9-2c53-4590-8aa2-b162a27e7a60","added_by":"auto","created_at":"2025-06-17 15:55:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":155618,"visible":true,"origin":"","legend":"\u003cp\u003eA,B and C Pulmonary function parameters of IPF patients and controls. Figure A showed the comparison of pulmonary function indexes between the IPF group and the control group; Figure B indicated that according to the GAP classification, the small airway function indexes of IPF patients with different degrees of severity were lower than those of the control group; Figure C demonstrated that according to the degree of pulmonary fibrosis shown in CT scans, the small airway function of IPF patients with different degrees of severity was lower than that of the control group.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-6653847/v1/7c0076710da74c2bd4765128.png"},{"id":84818900,"identity":"ee64c870-988a-480c-9d1a-f1c96d0e7ab9","added_by":"auto","created_at":"2025-06-17 15:55:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":141885,"visible":true,"origin":"","legend":"\u003cp\u003eFigure A showed that the number, length and volume of bronchus in the IPF group were lower than those in the control group. B and C indicated that bronchus number, length and volume in IPF patients with different GAP stage and fibrosis severity were higher than those in control. D demonstrated bronchus numbers of level 9 to 14 in IPF patients were higher than those in the control group. E and F showded bronchus numbers of level 9 to 14 in different severity IPF patients were higher compared with control. *means statistical significance.\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-6653847/v1/e95414a548f28d74ad249a61.png"},{"id":84818898,"identity":"d20e74ca-5b7b-42d4-8571-43cc9e7ead59","added_by":"auto","created_at":"2025-06-17 15:55:48","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1043808,"visible":true,"origin":"","legend":"\u003cp\u003eA was the chest CT scan of the control group; B and C were the HE and Masson staining of the lung tissues of the control group. The alveolar structure was intact, the ciliated cells were neatly arranged, and no fibrous deposition was observed. Figure D was the chest CT scan of a 66-year-old male patient with IPF, in which a small amount of reticular under the pleura could be seen. Figures E and F were the HE and Masson sections of the lung tissues of this patient respectively. Focal bronchiolar epithelial metaplasia could be seen, with lymphocytes aggregated around, the lung tissue structure distorted, and interstitial fibrous tissue hyperplasia. Figure G was the chest CT scan of a 54-year-old male patient with IPF, with ground-glass shadows under the pleura accompanied by mild traction bronchiectasis. Figures H and I were the HE and Masson staining of this patient. The alveolar septa were widened, fibrous tissue hyperplasia occured, part of the bronchial epithelial cells were shed, the cilia were toppled over, shed, and shortened, and there was obvious collagen deposition around the bronchi. Original magnification, ×200\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-6653847/v1/99da2a60a61118851de7a0a0.png"},{"id":93419686,"identity":"d3699a50-0b93-4225-8b79-71c51acf8dd8","added_by":"auto","created_at":"2025-10-13 16:05:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2493370,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6653847/v1/7b069f26-91ee-495e-83cc-063a9111d38b.pdf"},{"id":84818895,"identity":"28d80dc5-19f1-4c7c-a49a-b1a8a47d0c21","added_by":"auto","created_at":"2025-06-17 15:55:48","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":11145,"visible":true,"origin":"","legend":"","description":"","filename":"Attachedtables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6653847/v1/52c956f1ab70ef9e96f6e5ba.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Small airway lesions appear with the course of IPF and relate to the severity of pulmonary fibrosis progression","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIdiopathic Pulmonary Fibrosis (IPF) is a chronic respiratory disease that predominantly affects elderly males. Most patients present with a dry cough and progressively worsening breathlessness, often accompanied by reduced exercise tolerance, decreased quality of life, and a shortened life expectancy, with an average survival period of three years \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. The incidence of IPF is approximately 2.8 to 18 cases per 100,000 people in Europe and North America every year\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Traditionally, IPF has been considered a disease primarily affecting the interstitium with sparing of the airways. In recent years, a study\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e found that the number of small airways in IPF patients increased on CT scans, meanwhile, microCT examination of local lung tissues revealed a reduction in the number of terminal bronchioles. However, it remains unclear when small airway lesions appear, whether they result from parenchymal fibrosis in the late stages of IPF, or if they are accompanied by the fibrotic process.\u003c/p\u003e \u003cp\u003eThis study conducts a retrospective analysis of clinical data from IPF patients at different stages. The aim is to investigate the development and characteristics of small airway lesions in IPF patients through pulmonary function tests, CT imagings and pathological examinations.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003eStudy cohort and design\u003c/p\u003e \u003cp\u003eThis study was approved by the Ethics Board of the China-Japan Friendship Hospital Committee (No. 2017-25) and adhered to the Declaration of Helsinki. Informed consent to participate was obtained from all of the participants or their families if the patient unable to sign. This study includes IPF patients from a prospective, multicentre study who attented at China-Japan Friendship Hospital between June 2020 and December 2021.Trial registration number is NCT03666234. Patients diagnosed with IPF based on the guidelines of the American Thoracic Society/European Respiratory Society\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Exclusion Criteria: Patients lacking high-resolution chest CT (HRCT) results and pulmonary function tests. Individuals in control group were from a community health examination population who had no underlying respiratory diseases and underwent HRCT and pulmonary ventilation function testing. We recorded gender, age, disease duration, smoking history, underlying diseases, pulmonary function parameters, and high-resolution chest CT examination results. We grouped IPF patients by severity of disease.Two methods were used to assesse disease severity : fibrosis severity of CT and disease severity score. We used a visual score of fibrosis on CT to assess the severity of disease in IPF patients\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Each lobe was scored on a scale of 0\u0026ndash;5 for interstitial abnormality according to the percentage of each lobe involved(Attached Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Based on the total fibrosis scores, IPF patients are categorized into mild(0\u0026ndash;8), moderate(9\u0026ndash;16), and severe groups(17\u0026ndash;25)(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e-A,B,C). We used the GAP score proposed by LEY\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e to assess the disease severity of IPF patients. The patients were scored according to their gender, age, percentage of forced expiratory volume in one second to the predicted value, and percentage of diffusing capacity of the lung for carbon monoxide to the predicted value. The total score was calculated as the GAP score. The IPF patients were divided into 3 groups according to the GAP score. Specifically, 0\u0026ndash;3 points corresponded to GAP stage I, 4\u0026ndash;5 points to GAP stage II, and 6\u0026ndash;8 points to GAP stage III.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eFunction and quantitative assessment of small airways\u003c/h2\u003e \u003cp\u003eWe use the following three indicators to evaluate the function of small airways\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e: percentage of Predicted Maximal Expiratory Flow at 25 percent(MEF25%), percentage of Predicted Maximal Expiratory Flow at 50 percent(MEF50%) and maximal Expiratory Flow between 25 and 75% of FVC(MEF25-75%). In order to be consistent with our previous research\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e, small airway dysfunction is defined as at least two of these indicators being below 65% of their predicted values. Airway segmentation was performed using FACT-Digital LungTM software(DeXin, Xi\u0026rsquo;an, China)\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e.Pulmonary airway tree was segmented(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e-D,E), generating an airway volume, numbers and length. Differences in lung function and small airway numbers are assessed between IPF patients at different stages and the control group.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003epathological analysis\u003c/h3\u003e\n\u003cp\u003eFor some mild patients without typical honeycomb shadows on chest CT, transbronchial cryobiopsy (TBCB) is used to assist in the diagnosis of IPF. We analyzed the pathological sections of these patients to observe whether there were pathological changes in the small airways of the patients with mild symptoms. Small airway pathologic features include the extent of airway lumenal granulation tissue, air-space granulation tissue, airway wall inflammation,and airway wall fibrosis.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyzes were performed using SPSS software (version 26). Compare the baseline data, small airway function indices, and the number and length of small airways on CT between the IPF group and the control group. To determine in which stage of IPF the abnormalities in small airway function and imaging appear, according to the imaging fibrosis score and disease severity score, compare the differences in small airway function and imaging indices between IPF patients with different severity levels and the control group.\u003c/p\u003e \u003cp\u003eContinuous variables are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, and categorical variables are expressed as frequency (percentage). The Student\u0026rsquo;s t test was used to compare between two groups, the one-way ANOVA was used to compare the means, and the chi-square test was used to compare the frequency distribution of the two groups. Demonstrate the correlation relationship through Spearman rank correlation analysis. All statistical tests were two-sided, and P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cb\u003eGeneral information in IPF and controls\u003c/b\u003e. This study included 137 IPF patients and 84 controls. There were 114 males and 23 females in the IPF group, with an average age of 64.51\u0026thinsp;\u0026plusmn;\u0026thinsp;10.69 years. Average disease duration of IPF patients was 28.7 months. There was no statistical difference in gender distribution and age between the two groups, with P values of 0.72 and 0.293 respectively(Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGeneral information\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIPF(n\u0026thinsp;=\u0026thinsp;137)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl(n\u0026thinsp;=\u0026thinsp;84)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e114(83.21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68(80.95%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge(years old)\u003c/p\u003e \u003cp\u003e(mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.51\u0026thinsp;\u0026plusmn;\u0026thinsp;10.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.05\u0026thinsp;\u0026plusmn;\u0026thinsp;8.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.293\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83(60.58%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46(54.76%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.394\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComorbidities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCoronary heart disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCerebrovascular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.401\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eSmall airway dysfunction exists in mild IPF patients\u003c/b\u003e. IPF patients with different severities have varying degrees of small airway dysfunction. Compared with the control group, IPF patients had significantly lower percentage of predicted forced expiratory volume(FVC%), percentage of predicted total lung capacity(TLC%), and percentage of predicted diffusion capacity of carbon monoxide(DLCO%). Small airway function-related indicators were all lower than the control group(Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e,Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e-A).\u003c/p\u003e \u003cp\u003eAccording to GAP score, compared with controls, IPF patients with different degrees of severity had reduced FVC%,TLC% and DLCO%. PEF% and MEF75% in stage I patients were higher than those in controls, while MEF50% in different GAP stage IPF patients were all lower than that in control group(GAP I 88.93% vs GAP II 78.10% vs GAP III 86.88% vs control 99.07%, p\u0026thinsp;=\u0026thinsp;0.036 ); MEF25% (GAP I 64.59% vs GAP II 64.24% vs control 77.49%, p\u0026thinsp;=\u0026thinsp;0.033) and MEF75-25% in stage I and II were lower than those in control group(GAP I 78.33% vs GAP II 69.40% vs control 86.98%, p\u0026thinsp;=\u0026thinsp;0.029)(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e-B).\u003c/p\u003e \u003cp\u003eThe FVC%, TLC%, and DLCO% of IPF patients with different fibrosis severity on CT were lower than those of the control group. The MEF50% of mild and moderate fibrosis patients was lower than that of the control group(mild fibrosis 78.53% vs moderate fibrosis 88.36% vs control 99.07%, p\u0026thinsp;=\u0026thinsp;0.035). The MEF25% of different fibrosis patients was lower than that of control group(mild fibrosis 65.90% vs moderate fibrosis 65.52% vs severe 64.58% vs control 77.49%, p\u0026thinsp;=\u0026thinsp;0.048). MEF75-25% is lower than that in control group(mild fibrosis 71.85% vs moderate fibrosis 76.08% vs severe 75.28% vs control 86.98%, p\u0026thinsp;=\u0026thinsp;0.010), indicating that small airway dysfunction exists in IPF patients in the early stage(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e-C).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePulmonary function indexes difference between IPF and control\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePulmonary function index\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIPF(mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl(mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFVC%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e83.74\u0026thinsp;\u0026plusmn;\u0026thinsp;20.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e101.73\u0026thinsp;\u0026plusmn;\u0026thinsp;12.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePEF%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e109.18\u0026thinsp;\u0026plusmn;\u0026thinsp;20.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e101.84\u0026thinsp;\u0026plusmn;\u0026thinsp;18.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMEF75%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e111.99\u0026thinsp;\u0026plusmn;\u0026thinsp;22.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e102.22\u0026thinsp;\u0026plusmn;\u0026thinsp;19.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMEF50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e87.14\u0026thinsp;\u0026plusmn;\u0026thinsp;27.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e99.07\u0026thinsp;\u0026plusmn;\u0026thinsp;29.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMEF25%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e66.28\u0026thinsp;\u0026plusmn;\u0026thinsp;31.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e77.49\u0026thinsp;\u0026plusmn;\u0026thinsp;34.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMEF75\u0026minus;25%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e76.67\u0026thinsp;\u0026plusmn;\u0026thinsp;22.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e86.98\u0026thinsp;\u0026plusmn;\u0026thinsp;23.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTLC%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e72.17\u0026thinsp;\u0026plusmn;\u0026thinsp;13.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e101.42\u0026thinsp;\u0026plusmn;\u0026thinsp;13.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDLCO%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e54.66\u0026thinsp;\u0026plusmn;\u0026thinsp;17.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e90.68\u0026thinsp;\u0026plusmn;\u0026thinsp;12.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eFVC%:percentage of predicted forced expiratory volume; PEF%:percentage of Predicted Peak Expiratory Flow; MEF25%:percentage of Predicted Maximal Expiratory Flow at 25 percent; MEF50%:percentage of Predicted Maximal Expiratory Flow at 50 percent; MEF25-75%:maximal Expiratory Flow between 25 and 75% of FVC; TLC%:percentage of predicted total lung capacity; DLCO%:percentage of predicted diffusion capacity of carbon monoxide\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eIncreased number of small airways exists in mild IPF patients\u003c/b\u003e.\u003c/p\u003e\u003cp\u003eBased on CT analysis, the number, length, and volume of bronchi in IPF patients were higher than those in the control group((Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e,Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e-A). Both mild and severe IPF patients according to the GAP score had increased bronchial tubes, increased bronchial length and bronchial volume(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e-B). The bronchus numbers, length and volume of IPF patients with different fibrosis severity were higher than control (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e-C).\u003c/p\u003e\u003cp\u003eThe number of bronchi at grade 9 to 14 in IPF patients was higher than that in the control group(Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e,Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e-D).Regardless of the severity of GAP stage and CT fibrosis, the number of grade 9 to grade 14 bronchi in IPF patients was higher than that in control group(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e-E and F). It is suggested that changes in small airways exist in IPF in the early stage of fibrosis.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBronchus number difference between IPF and control\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eIPF(mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControl(mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of bronchus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e174.83\u0026thinsp;\u0026plusmn;\u0026thinsp;53.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e133.63\u0026thinsp;\u0026plusmn;\u0026thinsp;44.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of bronchus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e296.73\u0026thinsp;\u0026plusmn;\u0026thinsp;94.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e222.14\u0026thinsp;\u0026plusmn;\u0026thinsp;78.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVolume of bronchus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e88.29\u0026thinsp;\u0026plusmn;\u0026thinsp;24.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65.90\u0026thinsp;\u0026plusmn;\u0026thinsp;24.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of level 9 bronchus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e11.14\u0026thinsp;\u0026plusmn;\u0026thinsp;7.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.88\u0026thinsp;\u0026plusmn;\u0026thinsp;5.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of level 10 bronchus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e5.04\u0026thinsp;\u0026plusmn;\u0026thinsp;4.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.24\u0026thinsp;\u0026plusmn;\u0026thinsp;3.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of level 11 bronchus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1.92\u0026thinsp;\u0026plusmn;\u0026thinsp;2.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.95\u0026thinsp;\u0026plusmn;\u0026thinsp;1.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of level 12 bronchus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0.64\u0026thinsp;\u0026plusmn;\u0026thinsp;1.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.33\u0026thinsp;\u0026plusmn;\u0026thinsp;1.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of level 13 bronchus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1.22\u0026thinsp;\u0026plusmn;\u0026thinsp;1.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of level 14 bronchus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\u003cp\u003e \u003cb\u003eSmall airway mucosal epithelial changes are present in TBCB specimens of IPF patients of different fibrosis severity\u003c/b\u003e(Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The proliferation of airway epithelial mucosal cells, and cilia lodging, falling off and shortness were common in IPF. The degree of small airway lesions was consistent with the degree of peripheral alveolitis and fibrosis.\u003c/p\u003e "},{"header":"Discussion","content":" \u003cp\u003eIPF is characterized by fibroblasts proliferation\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e and collagen fibers deposition in the interstitium\u003csup\u003e[\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. While IPF is typically considered an airway-exempt disease, our study examed IPF patients with varying degrees of disease severity and found that IPF involves small airways. In early stage of disease, there are small airway changes in the aspects of function, numbers, and mucosal epithelium.\u003c/p\u003e\u003cp\u003eThe concept of the small airways was proposed in 1968 by Hogg and colleagues\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Small airways refer to the airways with a diameter of less than 2 millimeters, which are mainly used in the research of chronic obstructive pulmonary disease (COPD). Verleden and others\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e also believed that bronchi with a diameter of less than 2 millimeters were small airways, and small airways are generally located at the 9th to 14th levels of the bronchial branches. Our study found an increase in the number of visible bronchioles on CT in patients with IPF. Since the diameter of small airways is less than 2 millimeters, pathology is the most direct way to understand small airway lesions. However, most IPF patients cannot obtain pathological data. CT is not the best method for observing small airways, but IPF patients undergo regular CT examinations. Estimating the condition of small airway lesions through CT is both cost - effective and convenient.\u003c/p\u003e\u003cp\u003eConsistent with our observations, Verleden\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e found that the number of small airways on CT scans of IPF patients was increased. Through the study of pathological sections and MicroCT of end-stage IPF patients, it has been found that the increase in the number of small airways is related to the thickening of the small airway walls and lumenal deformation. Kohei Ikezoe\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e et al. also found that the total number of airways on CT was greater in IPF patients than in control lungs(P\u0026thinsp;=\u0026thinsp;0.01). They recognized an augmentation in bronchial wall and lumen area, making small airways more easily visible on CT scans.\u003c/p\u003e\u003cp\u003eA previous study\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e in our group found that there was small airway dysfunction in IPF patients. There were 40% patients with IPF having spirometry-defned small airway disease. IPF patients with small airway disease showed poorer prognosis. Similarly, Fulmer and associates\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e found that there were pathological and physiological abnormalities in the small airways in patients with IPF, on the basis of qualitative assessment of small airways in the open lung biopsies. They also found dynamic compliance and the maximum expiratory flow-volume curve could predict small airways diameter in IPF. Additionally, our study has found that patients with IPF have abnormal small airway function in the early stage. We speculate that bronchial changes may predate extensive fibrosis rather than being the result of structural destruction of the lung fibrosis.\u003c/p\u003e\u003cp\u003eThis study also has certain limitations. Being a retrospective study, it is challenging to avoid inherent biases associated with retrospective research. However, the clinical data included in this study were sourced from an electronic medical record system, with real-time data entry and verification by different physicians, ensuring a relatively high level of accuracy. Secondly, the classification of cases as early-stage patients in this study was based on GAP scores and degree of fibrosis in CT imaging. From the perspective of disease progression, it is reasonable to assume that patients with milder conditions are more likely in the early stages, although the unevenness in the development of IPF cannot be entirely ruled out. Therefore, it is essential to objectively and cautiously interpret the characteristics of IPF small airway lesions as presented in the results of this study. Future research would benefit from more prospective studies to further elucidate the timing and evolving features of small airway lesions in IPF patients over time.\u003c/p\u003e "},{"header":"Conclusion","content":"\u003cp\u003eSmall airway quantity and dysfunction exists in mild patients and persist throughout the entire disease progression.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eIPF Idiopathic Pulmonary Fibrosis\u003c/p\u003e\u003cp\u003eHRCT high-resolution chest CT\u003c/p\u003e\u003cp\u003eTBCB transbronchial cryobiopsy\u003c/p\u003e\u003cp\u003eFVC% percentage of predicted forced expiratory volume\u003c/p\u003e\u003cp\u003ePEF% percentage of Predicted Peak Expiratory Flow\u003c/p\u003e\u003cp\u003eMEF25% percentage of Predicted Maximal Expiratory Flow at 25 percent\u003c/p\u003e\u003cp\u003eMEF50% percentage of Predicted Maximal Expiratory Flow at 50 percent\u003c/p\u003e\u003cp\u003eMEF25-75% maximal Expiratory Flow between 25 and 75% of FVC\u003c/p\u003e\u003cp\u003eTLC% percentage of predicted total lung capacity\u003c/p\u003e\u003cp\u003eDLCO% percentage of predicted diffusion capacity of carbon monoxide\u003c/p\u003e\u003cp\u003eCOPD chronic obstructive pulmonary disease\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e. This study was approved by the Ethics Board of the China-Japan Friendship Hospital Committee (No. 2017-25). Informed consent to participate was obtained from all of the participants or their families if the patient unable to sign. This study adhered to the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e. Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e. The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e. This study was supported by the CAMS Innovational Fund for Medical Sciences (No. 2021-I2M-1-011) and National Nature Science Foundation of China (82370072).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026apos; contributions\u003c/em\u003e. X.W. designed the research and was a major contributor in writing the manuscript. L.Z. provided pathological guidance and ensured the quality of the research. D.S. conducted the experiments and collected the data. X.Z. analyzed and interpreted the patient data. M.L. was responsible for HRCT reading and imaging scoring. H.D. revised the manuscript and provided the necessary research materials and equipment. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e. Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDavid J, Lederer, Fernando J, Martinez.Idiopathic Pulmonary Fibrosis. 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J Clin Invest 1977 09;60(3):595\u0026ndash;610 \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1172/JCI108811\u003c/span\u003e\u003cspan address=\"10.1172/JCI108811\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"small airway, idipathic pulmonary fibrosis, pulmonary function, high-resolution chest CT, Transbronchial Cryobiopsy","lastPublishedDoi":"10.21203/rs.3.rs-6653847/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6653847/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eAim\u003c/h2\u003e \u003cp\u003eIdiopathic Pulmonary Fibrosis (IPF) has been considered a disease primarily affecting the interstitium with sparing of the airways. This study was to investigate development and characteristics of small airway lesions in IPF patients.\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e \u003cp\u003eThis study included 137 patients with IPF and 84 patients in the control group. The included IPF patients from a prospective, multicentre study. Trial registration number is NCT03666234. We grouped IPF patients by severity of disease according to fibrosis severity of CT and disease severity score. Percentage of Predicted Maximal Expiratory Flow at 25 percent(MEF25%), percentage of Predicted Maximal Expiratory Flow at 50 percent(MEF50%) and maximal Expiratory Flow between 25 and 75% of FVC(MEF25-75%) were used to evaluate the function of small airways. Airway segmentation was performed using FACT-Digital LungTM software. Differences in lung function and small airway volume, numbers and length are assessed between IPF patients with different severity and the control group. Statistical analyzes were performed using SPSS software (version 26).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThere were 114 males and 23 females in the IPF group, with an average age of 64.51\u0026thinsp;\u0026plusmn;\u0026thinsp;10.69 years. MEF50%, MEF25% and MEF75-25% of IPF patients in different stage were lower than those in the control group. The number, length, and volume of bronchi in IPF patients were higher than those in the control group.The number of bronchi at grade 9 to 14 levels in IPF patients was higher than that in the control group. IPF patients with mild fibrosis had small airway lesions.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eSmall airway quantity and dysfunction exists in mild patients and persist throughout the entire disease progression.\u003c/p\u003e","manuscriptTitle":"Small airway lesions appear with the course of IPF and relate to the severity of pulmonary fibrosis progression","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-17 15:47:43","doi":"10.21203/rs.3.rs-6653847/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-07-15T07:54:04+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-06T11:55:45+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-03T00:37:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"102780231427121852012154749008823114328","date":"2025-06-17T15:46:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"129121105962276978580157661434782201027","date":"2025-06-14T07:40:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"134899721573369998426745468888582846764","date":"2025-06-11T16:22:40+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-11T07:24:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-11T06:33:55+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-10T05:36:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-07T15:05:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2025-06-07T15:02:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"45ad8054-eff0-419f-adeb-867e21d2f199","owner":[],"postedDate":"June 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-13T16:00:22+00:00","versionOfRecord":{"articleIdentity":"rs-6653847","link":"https://doi.org/10.1186/s12890-025-03939-9","journal":{"identity":"bmc-pulmonary-medicine","isVorOnly":false,"title":"BMC Pulmonary Medicine"},"publishedOn":"2025-10-10 15:56:59","publishedOnDateReadable":"October 10th, 2025"},"versionCreatedAt":"2025-06-17 15:47:43","video":"","vorDoi":"10.1186/s12890-025-03939-9","vorDoiUrl":"https://doi.org/10.1186/s12890-025-03939-9","workflowStages":[]},"version":"v1","identity":"rs-6653847","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6653847","identity":"rs-6653847","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}