Preamble

To Explore the Necessity of Bronchodilation Test in Children with Normal FEV1, FVC and FEV1/FVC but Decreased Small Airway Function

XIONG Xiaoman, LI Aijun, ZHENG Yuehong, YANG Qiuyan, ZHANG Yanli*

Department of Pediatric Respiratory Medicine, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China

*Corresponding author: ZHANG Yanli, Chief Physician; E-mail: zylandzyy@126.com

[Abstract]

Background: In clinical practice, children with asthma-related symptoms such as wheezing, cough, and chest tightness should first undergo pulmonary ventilation function examination. When forced expiratory volume in one second (FEV1) <70%, it indicates obvious airflow restriction or airway obstruction, and a bronchodilation test should be performed. However, some children have normal FEV1 but decreased small airway function, which may indicate mild airflow restriction or airway obstruction. Although bronchial provocation testing is complicated, expensive, risky, and many primary hospitals lack the equipment and personnel to perform it, bronchodilation tests in these children can still be positive, which has certain significance for asthma diagnosis.

Objective: To investigate the necessity of performing bronchodilation tests in children with normal FEV1, forced vital capacity (FVC), and FEV1/FVC but decreased small airway function.

Methods: A case-control study was conducted on 180 children with asthma aged 5-14 years who presented with wheezing, cough, chest tightness, and other related symptoms at the outpatient department of The Third Affiliated Hospital of Zhengzhou University from May 29, 2019, to September 20, 2024. All subjects underwent routine pulmonary ventilation function examination and bronchodilation test, with results showing normal FEV1, FVC, and FEV1/FVC but decreased small airway function. Using an FEV1 improvement rate ≥12% as the positive criterion for bronchodilation test, subjects were divided into a positive group (n=33) and a negative group (n=147). Basic data and pulmonary ventilation function indices were compared between the two groups. Pearson correlation analysis was used to examine the relationship between small airway function indices and bronchodilation test results. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive efficacy of small airway function indices for positive bronchodilation test results.

Results: The positive group showed significantly lower forced expiratory flow at 50% of vital capacity as percentage of predicted value (FEF50%pred), forced expiratory flow at 75% of vital capacity as percentage of predicted value (FEF75%pred), and maximum mid-expiratory flow as percentage of predicted value (MMEF%pred) compared to the negative group (P<0.05). FEF50%pred, FEF75%pred, and MMEF%pred all correlated with bronchodilation test results (P<0.001). The area under the curve (AUC) for predicting positive bronchodilation test results was 0.733 (95%CI=0.644~0.822) for FEF50%pred, 0.827 (95%CI=0.756~0.898) for FEF75%pred, and 0.849 (95%CI=0.789~0.909) for MMEF%pred, with optimal cutoff values of 66.85%, 50.00%, and 63.35%, respectively. The AUCs for combined predictions were: FEF50%pred+FEF75%pred: 0.859; FEF50%pred+MMEF%pred: 0.855; FEF75%pred+MMEF%pred: 0.865; and three-index combination: 0.865. The AUC of the three-index combination was greater than that of FEF50%pred or FEF75%pred alone (Z=-2.801, -1.994; P=0.005, 0.046).

Conclusion: For children with asthma-related symptoms such as wheezing, chest tightness, and cough, attention should be paid to small airway function indices even when FEV1, FVC, and FEV1/FVC are normal. When FEF50%pred ≤66.85%, or FEF75%pred ≤50.00%, or MMEF%pred ≤63.35%, these values can predict positive bronchodilation test results to a certain extent, and bronchodilation tests should be actively performed to assist in asthma diagnosis.

[Key words] Asthma; Bronchial asthma; Child; Bronchodilation test; Decreased small airway function; Forced expiratory volume in one second; Forced vital capacity

[Chinese Classification] R 562.25 [Document Code] A DOI: 10.12114/j.issn.1007-9572.2025.0120

Funding: Key Research and Development and Promotion Special Project (Science and Technology Tackling) of Henan Province (222102310689)

Citation: XIONG XM, LI AJ, ZHENG YH, et al. To explore the necessity of bronchodilation test in children with normal FEV1, FVC and FEV1/FVC but decreased small airway function [J]. Chinese General Practice, 2025. DOI: 10.12114/j.issn.1007-9572.2025.0120. [Epub ahead of print].

Introduction

Bronchial asthma is a common chronic respiratory disease in children, characterized by recurrent episodes of wheezing, chest tightness, cough, and other symptoms, with pathophysiological features including chronic airway inflammation, airway hyperresponsiveness, and reversible airflow limitation. The incidence of childhood asthma continues to rise in recent years [1-2]. Early diagnosis, early intervention, and standardized treatment of asthma play important roles in disease control, helping to improve quality of life and prognosis. Bronchodilation tests and bronchial provocation tests are commonly used to assist in asthma diagnosis, differential diagnosis, and treatment adjustment. The former primarily evaluates the reversibility of airflow obstruction, offering high safety and operability, and has been widely applied in clinical practice [3-4]. The latter mainly assesses airway hyperresponsiveness but is more complex, expensive, risky, and many primary hospitals lack the necessary equipment and trained personnel [5-6].

In clinical practice, children with asthma-related symptoms such as wheezing, cough, and chest tightness first undergo pulmonary ventilation function examination. When forced expiratory volume in one second (FEV1) <70%, it indicates obvious airflow limitation or airway obstruction, and a bronchodilation test should be performed. However, some children have normal FEV1 but decreased small airway function, suggesting possible mild airflow limitation or airway obstruction. Bronchodilation tests in these children can also be positive, which is meaningful for asthma diagnosis [7]. Therefore, this retrospective study investigates the necessity of performing bronchodilation tests in children with asthma-related symptoms who have normal FEV1, forced vital capacity (FVC), and FEV1/FVC but decreased small airway function, and calculates cutoff values for small airway function indices that predict positive bronchodilation test results. This study can help clinicians, especially those in primary hospitals, determine whether bronchodilation tests are needed when FEV1, FVC, and FEV1/FVC are normal, thereby avoiding missed diagnoses and improving early asthma detection rates.

Methods

1.1 Study Subjects

From May 29, 2019, to September 20, 2024, we selected 180 children with asthma aged 5-14 years who presented to the outpatient department of The Third Affiliated Hospital of Zhengzhou University with symptoms such as wheezing, cough, and chest tightness, and who underwent both pulmonary ventilation function examination and bronchodilation test.

Inclusion criteria: (1) Age 5-14 years; (2) Clinical diagnosis of asthma [8]; (3) Routine pulmonary ventilation function examination showing normal FEV1, FVC, and FEV1/FVC but decreased small airway function [FEV1 percentage of predicted value (FEV1%pred) ≥80%, FVC percentage of predicted value (FVC%pred) ≥80%, FEV1/FVC percentage of predicted value (FEV1/FVC%pred) ≥92%, but forced expiratory flow at 50% of vital capacity (FEF50) and/or forced expiratory flow at 75% of vital capacity (FEF75) and/or maximum mid-expiratory flow (MMEF) percentage of predicted value (MMEF%pred) ≤65%] [9].

Exclusion criteria: (1) Diseases other than asthma that affect pulmonary ventilation function; (2) Severe heart, liver, kidney, or other organ dysfunction; (3) Inability to cooperate with pulmonary function tests, contraindications for routine pulmonary ventilation function or bronchodilation tests, or treatment with corticosteroids within 4 weeks before the visit.

This study was approved by the Ethics Committee of The Third Affiliated Hospital of Zhengzhou University (Approval No.: 2024-205-01). As this was a retrospective study, informed consent was waived.

1.2 Data Collection

1.2.1 General Data: Age, gender, height, weight, and other information were collected through the hospital's electronic medical record system.

1.2.2 Pulmonary Ventilation Function Examination: According to the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines [10], trained professionals performed routine pulmonary ventilation function tests using a pulmonary function analyzer (MasterScreen IOS, Germany). Each child had at least three tests meeting quality control standards, and the best result was selected for data analysis. Pulmonary ventilation function indices included: FVC%pred, FEV1 percentage of predicted value (FEV1%pred), FEV1/FVC%pred, MMEF%pred, forced expiratory flow at 25% of vital capacity (FEF25) percentage of predicted value (FEF25%pred), FEF50 percentage of predicted value (FEF50%pred), and FEF75 percentage of predicted value (FEF75%pred). Predicted values for pulmonary ventilation parameters were calculated using the Zapletal prediction equation.

1.2.3 Bronchodilation Test and Grouping: Children were required to discontinue medications that could affect test results before undergoing the bronchodilation test. According to each child's weight, those ≤20 kg received 2.5 mg and those >20 kg received 5 mg of terbutaline sulfate solution for nebulization (Hebei Renhe Yikang Pharmaceutical Co., Ltd., Batch No.: 0282407315). After 15 minutes of nebulization, a second pulmonary ventilation function test was performed. The improvement rate for pulmonary ventilation parameters was calculated as: (post-medication value - pre-medication value) / pre-medication value × 100%. An FEV1 improvement rate ≥12% was considered positive for the bronchodilation test [7]. Based on the bronchodilation test results, children were divided into two groups: positive group (n=33) and negative group (n=147).

1.3 Statistical Analysis

Data analysis was performed using SPSS 26.0 software. Categorical data were expressed as counts and percentages, and inter-group comparisons were made using the χ² test. Normally distributed continuous data were expressed as mean ± standard deviation (x̄±s) and compared between groups using independent samples t-test. Non-normally distributed continuous data were expressed as median (P25, P75) and compared using the Mann-Whitney U test. Pearson correlation analysis was used to examine the relationship between small airway function indices and bronchodilation test results. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value of small airway function indices for positive bronchodilation test results. Area under the curve (AUC) <0.7 indicated low predictive efficacy, 0.7-0.9 indicated moderate efficacy, and >0.9 indicated high efficacy [11]. Comparisons between AUCs were performed using Delong's test. P<0.05 was considered statistically significant.

Results

2.1 Comparison of Basic Data and Pulmonary Function Indices Between Groups

This study included 180 children, comprising 114 males (63.33%) and 66 females (36.67%), with a median age of 7.0 (6.0, 9.0) years. There were no significant differences between the two groups in gender, BMI, FEV1%pred, FVC%pred, or FEF25%pred (P>0.05). However, the positive bronchodilation test group had significantly lower age, FEV1/FVC%pred, FEF50%pred, FEF75%pred, and MMEF%pred compared to the negative group (P<0.05). Details are shown in Table 1 [TABLE:1].

2.2 Correlation Between Small Airway Function Indices and Bronchodilation Test Results

Pearson correlation analysis of small airway function indices (FEF50%pred, FEF75%pred, MMEF%pred) and bronchodilation test results showed that FEF50%pred (r=0.308), FEF75%pred (r=0.459), and MMEF%pred (r=0.453) all correlated with bronchodilation test results (P<0.001). See Figure 1 [FIGURE:1].

2.3 Predictive Efficacy of Small Airway Function Indices for Positive Bronchodilation Test Results

ROC curve analysis showed that the AUCs for FEF50%pred, FEF75%pred, and MMEF%pred in predicting positive bronchodilation test results were 0.733 (95%CI=0.644~0.822), 0.827 (95%CI=0.756~0.898), and 0.849 (95%CI=0.789~0.909), respectively, with optimal cutoff values of 66.85%, 50.00%, and 63.35%. Using binary logistic regression models, we fitted pairwise combinations and all three indices together, returned the predicted probability as an independent test variable, and plotted ROC curves. The AUCs for FEF50%pred+FEF75%pred, FEF50%pred+MMEF%pred, FEF75%pred+MMEF%pred, and the three-index combination were 0.859, 0.855, 0.865, and 0.865, respectively. The three-index combination had high sensitivity and specificity of 90.9% and 70.1%, respectively. The AUC of the three-index combination for predicting positive bronchodilation test results was greater than that of FEF50%pred or FEF75%pred alone (Z=-2.801, -1.994; P=0.005, 0.046). However, there were no significant differences between the three-index combination and MMEF%pred alone or the two-index combinations (Z=-0.934, -0.768, -1.038, -0.199; P=0.350, 0.442, 0.299, 0.842). See Table 2 [TABLE:2] and Figure 2 [FIGURE:2].

Discussion

This study explored the necessity of bronchodilation testing in children with normal FEV1, FVC, and FEV1/FVC but decreased small airway function, and determined optimal cutoff values for small airway function indices to predict positive bronchodilation test results through ROC curve analysis. The results demonstrated that small airway function indices FEF50%pred, FEF75%pred, and MMEF%pred have predictive value for positive bronchodilation test results, with optimal efficacy achieved when all three indices are combined.

Our findings showed no significant differences in FEV1, FVC, and FEV1/FVC between the positive and negative bronchodilation test groups (P>0.05), but FEF50%pred, FEF75%pred, and MMEF%pred were significantly lower in the positive group (P<0.001) and correlated with bronchodilation test results, suggesting that decreased small airway function may be an early marker of airflow limitation in children with asthma. Chronic inflammation in asthmatic children often involves the entire airway, particularly small airways [12]. Small airways refer to airways below the terminal bronchioles, with internal diameter <2 mm, large numbers, large total cross-sectional area, relatively increased smooth muscle, no cartilage support, easy occlusion, and are susceptible to early involvement in disease, while large airway function indices such as FEV1 and FVC cannot sensitively reflect these changes [13-14].

Previous studies have shown that small airway dysfunction exists in early-stage asthma before large airway function indices such as FEV1 become abnormal [15]. A study of 1,631 asthmatic children with normal large airway function indices in China found that 217 had small airway dysfunction, with a positive bronchodilation test rate of 28.57% [16]. Shi et al. [17] reported that the degree of decline in small airway function indices positively correlates with positive bronchodilation test results. Our study further supports these previous findings, suggesting that in children with normal FEV1, FVC, and FEV1/FVC, decreased small airway indices may indicate occult airflow limitation, providing a physiological basis for positive bronchodilation test results. Therefore, clinical practice should strengthen attention to small airway function indices, and bronchodilation tests should be actively performed in children with decreased small airway function indices even when large airway function indices are normal, to assist in asthma diagnosis and reduce missed diagnoses.

This study determined optimal cutoff values for FEF50%pred, FEF75%pred, and MMEF%pred to predict positive bronchodilation test results as 66.85%, 50.00%, and 63.35%, respectively. The AUC for MMEF%pred was 0.849, likely related to its characteristic of reflecting mid-expiratory flow, a phase that primarily depends on small airway function [9]. Studies have found that MMEF changes early in asthmatic children [18], indicating its sensitivity to airway obstruction. Another study found that MMEF has stronger diagnostic efficacy for asthma than other conventional single pulmonary function indices and can more effectively differentiate asthmatic from non-asthmatic children [19]. Further research has shown that MMEF independently correlates with asthma severity [20], consistent with our findings. Additionally, Zhan et al. [21] demonstrated that cutoff values of 70.690% for FEF50%pred and 66.665% for MMEF%pred could effectively differentiate asthmatic from non-asthmatic children. A study of adult asthma showed that cutoff values of 67.95% for FEF50%pred, 59.75% for FEF75%pred, and 69.25% for MMEF%pred could effectively distinguish between positive and negative bronchodilation test groups [22]. Our cutoff values are similar to those in these studies. However, cutoff values for small airway function indices to determine positive bronchodilation test results in children have not been previously studied. Moreover, the AUC of the three-index combination (0.865) was greater than that of single indices FEF50%pred and FEF75%pred (P<0.05), with high sensitivity and specificity of 90.9% and 70.1%, respectively, indicating that combined use of the three indices improves predictive comprehensiveness and avoids limitations of single indices, providing more reliable evidence for clinical decision-making. Therefore, this study provides a theoretical basis for determining when to perform bronchodilation tests in children with asthma-related symptoms and normal FEV1, FVC, and FEV1/FVC but decreased small airway function indices.

In summary, for children with asthma-related symptoms such as wheezing, chest tightness, and cough, small airway function indices should be closely monitored even when FEV1, FVC, and FEV1/FVC are normal. When FEF50%pred ≤66.85%, or FEF75%pred ≤50.00%, or MMEF%pred ≤63.35%, these values can predict positive bronchodilation test results to a certain extent, and bronchodilation tests should be actively performed to assist in asthma diagnosis.

This study focused on early changes in small airway function and innovatively proposed multiple small airway function indices as predictors of positive bronchodilation test results, calculating cutoff values to help clinicians determine the need for bronchodilation tests when FEV1 and FVC are normal, thereby avoiding missed diagnoses and improving early asthma detection rates. This is particularly valuable in primary hospitals where the high cost and complexity of bronchial provocation tests limit their clinical application, as our study provides an alternative approach based on small airway function indices with practical clinical significance.

This study has several limitations. First, it is a single-center study with a relatively small sample size, and the results may have certain limitations. Future multi-center collaborative studies with larger sample sizes will be conducted. Additionally, this was a retrospective study; prospective studies will be conducted in the future to further verify the accuracy of the proposed small airway function indices in predicting positive bronchodilation test results and to explore their applicability across different age groups and disease stages.

Author Contributions: XIONG Xiaoman was responsible for data collection, analysis, interpretation, and drafting the manuscript. LI Aijun and ZHENG Yuehong were responsible for data collection. ZHANG Yanli and YANG Qiuyan provided critical review and guidance on the intellectual content of the article.

Conflict of Interest: The authors declare no conflict of interest.

ORCID IDs:
- XIONG Xiaoman: https://orcid.org/0009-0004-0867-9203
- ZHANG Yanli: https://orcid.org/0009-0009-2766-2729

References

[1] PORSBJERG C, MELÉN E, LEHTIMÄKI L, et al. Asthma[J]. Lancet, 2023, 401(10379): 858-873. DOI: 10.1016/S0140-6736(22)02125-0.

[2] GARCÍA-MARCOS L, CHIANG C Y, ASHER M I, et al. Asthma management and control in children, adolescents, and adults in 25 countries: a Global Asthma Network Phase I cross-sectional study[J]. Lancet Glob Health, 2023, 11(2): e218-228. DOI: 10.1016/S2214-109X(22)00506-X.

[3] KAMINSKY D A, SIMPSON S J, BERGER K I, et al. Clinical significance and applications of oscillometry[J]. Eur Respir Rev, 2022, 31(163): 210208. DOI: 10.1183/16000617.0208-2021.

[4] STANOJEVIC S, KAMINSKY D A, MILLER M R, et al. ERS/ATS technical standard on interpretive strategies for routine lung function tests[J]. Eur Respir J, 2022, 60(1): 2101499. DOI: 10.1183/13993003.01499-2021.

[5] MOHNING M P, MENESES-TAMAYO E, RODRÍGUEZ FLORES C. Diagnostic testing in exercise-induced bronchoconstriction[J]. Immunol Allergy Clin North Am, 2025, 45(1): 89-99. DOI: 10.1016/j.iac.2024.08.010.

[6] LOUIS R, SATIA I, OJANGUREN I, et al. European Respiratory Society guidelines for the diagnosis of asthma in adults[J]. Eur Respir J, 2022, 60(3): 2101585. DOI: 10.1183/13993003.01585-2021.

[7] Chinese Pediatric Pulmonary Function Guidelines (Part V): Bronchodilation Test[J]. Chinese Journal of Applied Clinical Pediatrics, 2017, 32(1): 17-21. DOI: 10.3760/cma.j.issn.2095-428X.2017.01.006.

[8] Chinese Pediatric Respiratory Group of Chinese Medical Association Pediatrics Branch, Editorial Board of Chinese Journal of Pediatrics, Chinese Medical Education Association Pediatrics Professional Committee, et al. Guidelines for diagnosis and prevention of bronchial asthma in children (2025)[J]. Chinese Journal of Pediatrics, 2025, 63(4): 324-337. DOI: 10.3760/cma.j.cn112140-20250124-00074.

[9] Chinese Pediatric Pulmonary Function Guidelines (Part II): Lung Volume and Ventilation Function[J]. Chinese Journal of Applied Clinical Pediatrics, 2016, 31(10): 744-750. DOI: 10.3760/cma.j.issn.2095-428X.2016.10.006.

[10] BEYDON N, DAVIS S D, LOMBARDI E, et al. An official American thoracic society/European respiratory society statement: pulmonary function testing in preschool children[J]. Am J Respir Crit Care Med, 2007, 175(12): 1304-1345. DOI: 10.1164/rccm.200605-642ST.

[11] HE X, FREY E. ROC, LROC, FROC, AFROC: an alphabet soup[J]. J Am Coll Radiol, 2009, 6(9): 652-655. DOI: 10.1016/j.jacr.2009.06.001.

[12] HOPP R J, WILSON M C, PASHA M A. Small airway disease in pediatric asthma: the who, what, when, where, why, and how to remediate. a review and commentary[J]. Clin Rev Allergy Immunol, 2022, 62(1): 145-159. DOI: 10.1007/s12016-021-08899-8.

[13] KRAFT M, RICHARDSON M, HALLMARK B, et al. The role of small airway dysfunction in asthma control and exacerbations: a longitudinal, observational analysis using data from the ATLANTIS study[J]. Lancet Respir Med, 2022, 10(7): 661-668. DOI: 10.1016/S2213-2600(21)00536-1.

[14] YI L Q, ZHAO Y, GUO Z Y, et al. The role of small airway function parameters in preschool asthmatic children[J]. BMC Pulm Med, 2023, 23(1): 219. DOI: 10.1186/s12890-023-02531-6.

[15] ARSHAD S H, HODGEKISS C, HOLLOWAY J W, et al. Association of asthma and smoking with lung function impairment in adolescence and early adulthood: the Isle of Wight Birth Cohort Study[J]. Eur Respir J, 2020, 55(3): 1900477. DOI: 10.1183/13993003.00477-2019.

[16] MA J G, CHEN X, WANG K, et al. Analysis of bronchodilation test results in children with bronchial asthma and normal FEV1, FVC, and FEV1/FVC[J]. Chinese Journal of Applied Clinical Pediatrics, 2021, 36(4): 275-278. DOI: 10.3760/cma.j.cn101070-20191104-01084.

[17] SHI D Y, ZHANG R F, LI Y L, et al. Diagnostic value of bronchodilation test in children with bronchial asthma[J]. Maternal and Child Health Care of China, 2022, 37(14): 2574-2578. DOI: 10.19829/j.zgfybj.issn.1001-4411.2022.14.015.

[18] ZHANG H, CHI Y X. Bronchodilation test and its clinical application in children[J]. Journal of Clinical Pediatrics, 2023, 41(5): 321-327. DOI: 10.12372/jcp.2023.23e0206.

[19] EOM S Y, LEE J K, LEE Y J, et al. Combining spirometry and fractional exhaled nitric oxide improves diagnostic accuracy for childhood asthma[J]. Clin Respir J, 2020, 14(1): 21-28. DOI: 10.1111/crj.13095.

[20] Shanghai Medical Association Pediatrics Branch Respiratory Group, Shanghai Children's Medical Center Pediatric Medical Consortium Pudong, Shanghai Smart Pediatric Clinical Diagnosis and Treatment Technology Engineering Research Center, et al. Expert consensus on evaluation and treatment of small airway dysfunction in childhood asthma[J]. Chinese Journal of Applied Clinical Pediatrics, 2021, 36(23): 1761-1768. DOI: 10.3760/cma.j.cn101070-20210927-01165.

[21] ZHAN L. Application of exhaled nitric oxide combined with small airway pulmonary function in asthmatic children[D]. Taiyuan: Shanxi Medical University, 2023. DOI: 10.27288/d.cnki.gsxyu.2023.001035.

[22] LI W Q. Investigation on the necessity of performing bronchodilation test when FEV1 is normal but small airway function is decreased[D]. Shenyang: China Medical University, 2023.

Received date: 2025-05-14; Revised date: 2025-07-14

Edited by: KANG Yanhui