The role of pulmonary function testing in predicting risk of pneumothorax by CT-guided percutaneous core needle biopsy of the lung

Background To determine risk factors for pneumothorax associated with computed tomography (CT)-guided percutaneous core needle biopsy (PCNB) of the lung. Whether the lung function characteristics are related to pneumothorax is unclear. This study was designed to provide a risk assessment of pneumothorax based on pulmonary function analysis, which can predict the risk especially for patients with severe pulmonary dysfunction. We retrospectively evaluated 343 patients who received CT-guided pulmonary PCNBs and underwent preoperative pulmonary function testing. Demographical, lesion-related, procedure-related features and histopathological diagnosis, as well as results of pulmonary function test were analyzed for risk factors of pneumothorax Results


Abstract Background
To determine risk factors for pneumothorax associated with computed tomography (CT)-guided percutaneous core needle biopsy (PCNB) of the lung. Whether the lung function characteristics are related to pneumothorax is unclear.
This study was designed to provide a risk assessment of pneumothorax based on pulmonary function analysis, which can predict the risk especially for patients with severe pulmonary dysfunction.

Methods
We retrospectively evaluated 343 patients who received CT-guided pulmonary PCNBs and underwent preoperative pulmonary function testing. Demographical, lesion-related, procedure-related features and histopathological diagnosis, as well as results of pulmonary function test were analyzed for risk factors of pneumothorax

Results
Variables associated with higher rate of pneumothorax were location of lesion, presence of emphysema and dwell time. Furthermore, there was signi cant difference of pulmonary function parameters between groups with or without pneumothorax as expressed by FEV 1 /FVC ratio, FEV 1 /FVC ratio (%, pred), FEF 50% (% pred), FEF 75% (% pred), and FEF 25 − 75% (% pred). Obstructive pulmonary function abnormalities were associated with a higher incidence of pneumothorax. However, no correlation was found between the pneumothorax rate and the severity of pulmonary function abnormalities. Multivariate logistic regression analysis showed lower location of lesion sampled and presence of emphysema were independent predictors of pneumothorax.

Conclusions
Patients with obstructive pulmonary dysfunction have a higher risk of pneumothorax. FEV 1 /FVC ratio, FEF 50% , FEF 75% and FEF 25 − 75% has the potential to identify the high-risk population of pneumothorax.

Background
Computed tomography (CT)-guided percutaneous core needle biopsy (PCNB) of the lung has been widely considered as a common and effective procedure, with accurate histology diagnosis. Pooled overall complication rates for PCNB and ne needle aspiration biopsy (FNAB) from 32 articles (8,133 procedures) were 38.8% (95% CI: 34.3-43.5%) and 24.0% (95% CI: 18.2 − 30.8%), respectively [1]. Although overall complication rate was higher for PCNB than FNAB, the trend has been to replace FNAB with PCNB to provide the diagnosis of lung abnormalities with lower false-negative rate (< 10%) [2]. As is well known, the false-negative rate of FNAB in lung lesions is as high as 20% in the diagnosis of malignant tumors. When nonspeci c or inadequate tissue is biopsied, it is usually unreliable to exclude malignant diagnosis [3]. PCNB has become an important procedure to obtain enough specimens for further biological identi cation and molecular spectrum analysis in the individualized target therapy [4].
Pneumothorax is one of the most common complications of PCNB of the lung. Pooled pneumothorax rate for core biopsy was 25.3% (95% CI: 22.2-28.6%) [1]. Previous studies predicted the risk factors for pneumothorax mainly based on the demographical, lesion-related, procedure-related features, such as patient age, emphysema, lesion size, dwell time, number of needle punctures, and distance of lesion from the pleura [1,5,6], whereas the in uence of pulmonary function-related factors were seldom reported. The performance of periprocedural pulmonary function analysis is to recognize patients with an increased risk of complications and to best evaluate the risk of the patients. However, there is no clear clinical quantitative index of pulmonary function to estimate the risk of pneumothorax during needle biopsy.
This study focused on the role of lung function in predicting the risk of pneumothorax caused by PCNB, as well as the common risk factors.

Methods
Patients and data collection Three hundred and forty-three patients with pulmonary function testing have been retrospectively evaluated from 1,110 consecutive patients who received CT-guided PCNBs of the lung between January 2018 and December 2019. Pulmonary function testing was performed within 7 days before PCNB. All the patients had received PCNBs for histopathological diagnosis of lung lesions at Qilu Hospital, Cheeloo College of Medicine, Shandong University, under consistent procedure. This single institutional retrospective study was approved by our hospital institutional review board (registration number: KYLL-202008-145) and complied with the Declaration of Helsinki and the ethical standards of the institutional research committee of Qilu Hospital, Cheeloo College of Medicine, Shandong University. Inclusion criteria also consisted of patients with normal electrocardiogram and with adequate hepatic, renal and hematological function. If patients were given aspirin, warfarin or low-molecular-weight heparin, they were required to suspend their medication one week before the procedure and monitor the prothrombin time. Platelet count should be ≥ 50 × 10 9 / L for biopsy.
Patient records were anonymized and de-identi ed prior to analysis. Collected data included patient demographics (age, gender, smoking, prior surgery, radiotherapy or chemotherapy), characteristics of target lesions (location, the size of the sampled lesions, abut pleura and emphysema), and procedure-related information (patient positon, needle puncture site, length of biopsy pathway, dwell time, needle-pleural angle, number of needle redirections and pleural planes traversed, and number of tissue samplings), results of pulmonary function test, procedure-related complications (pneumothorax, chest drainage catheter insertion, and pulmonary hemorrhage), and the histopathological diagnosis in all the cases.
Middle lobe, lingular, and lower lobe lesions were categorized as "lower locations"; upper lobe lesions, as "upper locations" [7]. Lesion size was measured as the largest diameter of the sampled lesion in the previous CT images. The depth of the lesion was gauged as the length of the needle track from the punctured pleura to the edge of the lesion sampled. The needle-pleural angle was calculated on the transverse 3-mm section in the craniocaudal dimension, according to the method suggested by Ko et al. [6]. It was de ned as the minimum angle formed by a line tangent to the pleura at the puncture point and a line drawn along the needle (Figure 1) [6]. Pneumothorax was evaluated by CT scan after biopsy, as the largest separation between the visceral and parietal pleura. Less than or equal to 1 cm was categorized as "minor pneumothorax"; greater than 1 cm but less than or equal to 2 cm, as "intermediate pneumothorax"; greater than 2 cm, symptomatic or chest drainage catheter insertion needed, as "severe pneumothorax" [8].
CT-guided core needle biopsy PCNBs were performed by one intervention team led by Prof. C. L. (7 years of experience in CT-guided needle biopsy), using only one type of needle, 17-gauge coaxial introducer and 18-gauge automated cutting needle (Biopince, Argon Medical Devices, Frisco, Texas). All the biopsies were carried out according to the standard protocol. All patients underwent enhanced CT before the biopsy. Averting obvious emphysema or bulla, the safest and shortest route from the chest wall to solid part of the lesion was chosen to determine the supine, prone or lateral position of the patient on the CT table. All patients were given intravenous indwelling needles, allowing for the infusion of rescue drugs if necessary. The patients were instructed to breathe shallowly and avoid moving, coughing, speaking or deep breathing during and 3 hours after the procedure. If the biopsy route needed to be changed, the patient's position could also be changed. After aseptic technique and local anesthesia with 1% lidocaine, the introducer needle was inserted. The needle is inserted rapidly during pleural puncture, and the needle is withdrawn slowly after the biopsy. Rapid insertion at breath-hold can form a precise puncture point, while slow extraction of the guide needle can make the elastic lung tissue seal the pleural hole. Then the position of the coaxial introducer was determined by CT scans. If the introducer was correctly located within the periphery of the lesion, the biopsy was performed to obtain su cient tissue samples.
The representative images of the CT-guided PCNB are shown in Figure 1. After slowly removing the needle, CT scans were performed to evaluate the complications. The patient was then asked to rest for 24 hours. Patients with pneumothorax or bleeding were monitored in the impatient ward. Patients with intermediate or severe pneumothorax had follow-up CT to determine its stability. If patients had pneumothorax with symptoms of respiratory distress or shortness of breath, a thoracic drainage catheter was placed.

Pulmonary function test
All patients were selected who received pulmonary function tests within 7 days before CT-guided PCNBs, in one single center of Qilu Hospital. Patients were mainly classi ed into normal, small airway dysfunction, obstructive, restrictive and mixed pulmonary function abnormalities, according to pulmonary function test, as well as their illnesses and severity [9]. The judgment processes of pulmonary function abnormalities were referred to [9][10][11]. Forced expiratory volume in one second (FEV 1 ) / forced vital capacity (FVC) ratio, FVC and TLC should be considered rst [9,10].
Obstructive abnormality is defined as a xed ratio of FEV 1 /FVC < 70% [10]. Even if FEV 1 percent predicted (FEV 1 % pred) is more than 80%, it can be judged as obstructive abnormalities. This slowing of expiratory ow is most obviously re ected in a concave shape on the ow-volume curve. FEF 25-75% and MVV can descend at the same time, but FVC and TLC is limited in normal range [9,11]. Restrictive abnormality is characterized by a normal FEV 1 /FVC and a reduction in FVC and TLC. The ow-volume curve may show a convex pattern [10,11]. A mixed pulmonary function abnormality is characterized by the coexistence of obstruction and restriction. According to ATS/ERS criteria [8], all the obstructive, restrictive and mixed ventilation abnormalities were strati cated into ve severity groups based on the FEV 1 % pred.
Conventional ventilation function parameters such as FEV 1 , FEV 1 /FVC, FVC and TLC are still in the normal range, but two of these three parameters FEF 50% , FEF 75% and FEF 25-75% are lower than 65% of the predicted value, which can be diagnosed as small airway dysfunction [11].

Statistical analysis
Patients were classi ed into two groups with or without pneumothorax after CT-guided lung biopsy. Clinical variables included demographic, lesion, technique, diagnostic and pulmonary function characteristics. All the quantitative data showed non-normal distribution by the Shapiro-Wilk test. Signi cant differences between these groups were identi ed using the chi-square test for categorical variables, the Mann-Whitney U test for quantitative variables with non-normal distribution. Multivariate logistic regression analysis was used to calculate odds ratios with 95% con dence intervals for potential of the hazard of pneumothorax. Logistic regression model only included signi cant covariates from univariate analysis. P value < 0.05 was defined to be significant different. All statistical tests were performed by SPSS software package, standard Version 17.0 (SPSS Inc., Chicago, IL, USA).

Comparison of groups with and without pneumothorax evaluated by univariate analysis
There were 206 (60.06%) male and 137 (39.94%) female patients in this study. Only two patients received prior chemotherapy, one received prior thoracic surgery, and no one received prior thoracic radiotherapy. The baseline characteristics of these 343 patients were summarized in Table 1. All the quantitative data showed non-normal distribution, so the median and the lower quartile to the upper quartile were presented here. The median age was 62 years (range, 18 to 82 years) and the median depth from the pleura to the lesion was 11.6 mm (range, 0 to 70.3 mm).
The diameter of the lesions punctured varied from 6.8 to 212.1 mm, with a median of 26.7 mm in previous CT images.
The main complications of PCNBs were pneumothorax, chest drainage catheter insertion and pulmonary hemorrhage. Fifty patients (14.58%) had pneumothorax after PCNBs. Among those, only three patients (6.00%) revealed severe pneumothorax on post-biopsy CT scans, which required placement of chest drainage catheter. In the most serious case of pneumothorax, the lung was compressed by 1/3. All patients with mild or moderate pneumothorax were stable without deterioration and any interventional treatment. Of all the 343 patients, 88 (25.66%) had pulmonary hemorrhage, most of which were slight hemorrhage.
The differences in clinical characteristics between groups with and without pneumothorax were evaluated by univariate analysis (Table 1). Variables associated with higher rate of pneumothorax were location of lesion (P = 0.004), presence of emphysema (P = 4.929 × 10 -8 ), and dwell time (P = 0.046), whereas all the other parameters including demographic and diagnostic parameters showed nonsigni cant ndings. As shown, the proportion of middle lobe, lingular, or lower lobe lesions in pneumothorax group (30/50, 60.00%) is higher than non-pneumothorax group (113/293, 38.57%). The dwell time varied from 70 to 1200 s, with a median of 240 s in patients with pneumothorax and 200 s in patients without pneumothorax. The incidence of emphysema in pneumothorax group was signi cantly higher than that in nonpneumothorax group (34.00% vs 7.51%). However, other possible risk factors about lesion and technique, previously reported, such as lesion size, abut pleura, length of intrapulmonary needle tract, needle-pleural angle, and number of pleural punctures, showed no statistically signi cance of pneumothorax in this study.

Differences in pulmonary function between groups with and without pneumothorax evaluated by univariate analysis
On the other hand, the pulmonary function of these 343 patients was also evaluated ( Furthermore, there was statistically signi cant difference of pulmonary function parameters between the two groups with or without pneumothorax as expressed by FEV 1 /FVC ratio (P = 0.004), FEV 1 /FVC ratio (%, pred) (P = 0.005), FEF 50% (% pred) (P = 0.014), FEF 75% (% pred) (P = 0.037), and FEF 25-75% (% pred) (P = 0.033). No difference was found in VC, FVC or PEF between the two groups. And more importantly, as seen in Table 3, although FEV 1 was not signi cantly different between the two groups of patients, the FEV 1 /FVC ratio (% pred) was signi cantly lower in patients with pneumothonax (median, lower-upper quartile: 94.43, 86.64 -98.86) than without pneumothorax (97.45, 90.73 -103.54). Interestingly, as no other research has been studied so far, the small airway function parameters, such as FEF 50% , FEF 75% and FEF 25-75% , showed signi cant negative correlations with pneumothorax rate. However, PEF and FEF 25% which re ect the large airway function were not associated with the risk of pneumothorax.

Relationship between incidence of pneumothorax and pulmonary function abnormalities
Patients with pneumothorax had signi cantly reduced FEV 1 /FVC ratio compared with those without pneumothorax, as shown above, indicating that patients with obstructive diseases were more likely to have pneumothorax. Table 4 shows the relationship between pulmonary function abnormalities and pneumothorax. The chi-square test revealed that obstructive pulmonary function abnormalities, as assessed by a decrease in FEV 1 /FVC ratio, were associated with a higher incidence of pneumothorax (P = 0.005). The incidence of pneumothorax in the obstructive ventilation abnormalities was 24.66%, whereas in the normal group the rate dropped to 10.71%. The restrictive and mixed ventilation function abnormalities were not found to correlate with the pneumothorax rate (P = 1.000 and P = 0.961, respectively).
All the obstructive, restrictive and mixed ventilation abnormalities were strati cated into ve severity groups based on FEV 1 % pred (Table 4). However, no correlation was found between the pneumothorax rate and the severity of all pulmonary function abnormalities (P = 0.066). Similarly, in patients with obstructive ventilation abnormalities, the severity of spirometric abnormality was not associated with the incidence of pneumothorax (P = 0.604).
In addition, the incidence of pneumothorax was not signi cantly different between patients with small airway dysfunction and patients with normal ventilation function (P = 0.413).

Multivariable logistic regression model for predictors of pneumothorax in all patients studied
Multivariate logistic regression analysis was carried out to nd the relationship between multiple dependent variables, and to adjust the differences in confounding factors (Table 6). Here, the analysis only considered covariables signi cant by univariate analysis mentioned in Table 1 and 3. Since FEF 50% , FEF 75% and FEF 25-75% are clinically related to FEV 1 /FVC, only FEV 1 /FVC ratio (%) is retained. Lower location of lesion sampled and presence of emphysema were identi ed to be independent predictors of pneumothorax after CT-guided PCNB (P = 0.022 and P = 1.150 × 10 -4 , respectively). In all patients, risk of pneumothorax was significantly higher in lower location of lesion sampled (odds ratio [OR], 2.128; 95% confidence interval [CI], 1.117 -4.051) and presence of emphysema (OR, 4.937; 95% CI, 2.193 -11.115). Although dwell time, FEV 1 /FVC ratio were signi cantly correlated with pneumothorax on univariate analysis, these were not con rmed to be independent risk factors here.

Discussion
The CT-guided pulmonary PCNB can biopsy smaller pulmonary nodules with the progress of technology, but pneumothorax is still one of the most frequent complications. The rate of pneumothorax induced by PCNB was 14.58% in this study, and that of chest tube placement was 0.87%, which were similar to the rates reported in other studies [12][13][14]. In order to explore the risk factors of pneumothorax, clinical data such as patient demographics, characteristics of target lesions, procedure-related information, the histopathological diagnosis and results of pulmonary function test were all collected here. However, patient-related and diagnosis-related predictors had no in uence on the occurrence of pneumothorax. Interestingly, Ko et al. [6] reported that pneumothorax was unlikely to occur in patients who had previous thoracic surgery, focal or diffuse pleural disease, or chest wall involvement. However, it may be that few patients in this study had prior thoracic surgery, so this phenomenon was not found.
Concerning lesion characteristics in this study, several predictors in uenced the incidence of pneumothorax, such as the location of lesion and the presence of emphysema. No association was found between the incidence of pneumothorax and the depth, the size of the lesion and the invasion of adjacent pleura or chest wall, which were former risk factors for pneumothorax [5,7,[14][15][16][17][18][19][20]. This re ects the progress of biopsy technology. For instance, the lesion size and the depth of the lesion from the pleural surface were known to be an important predictor of the incidence of pneumothorax associated with FNAB [14,19]. The incidence of pneumothorax increased 2 times (66% vs 32%) when the depth of lesion was larger than 2.0 cm, partly due to the prolongation of dwell time and the increased amount of lung tissues that the needle penetrates [14]. However, other studies on the depth of lesions and pneumothorax were quite opposite. Some studies thought that the lesion abutting the pleura was more prone to pneumothorax. K M Yeow et al. [20] reported that when the subpleural lesions were within 2 cm below the pleural surface, the risk of pneumothorax was 7-fold higher than the lesion depth more than 2 cm. They explained that subpleural lesions tend to shift the needle into the pleural cavity, causing air to enter [20]. We did not observe the similar phenomenon, probably because we used oblique needle approach to deal with the lesions abut pleura. Similarly, for smaller lesions, technical success rate of FNAB was signi cantly lower (74% for ≤ 1.5 cm vs 97% for > 1.5 cm) [19]. Taleb et al. [17] believed that achieving su cient tissue from smaller lesions is technically more demanding, which may lead to increased number of punctures and increased risk of pneumothorax. At present, CT-guided PCNB has been improved to biopsy pulmonary nodules less than 1 cm, and rarely more than twice.
In terms of procedure-related factors, dwell time was signi cantly correlated with pneumothorax on univariate analysis, but it was not con rmed as an independent predictor in logistic regression model here. The longer time the needle dwelled in the lung, the more likely the respiratory movement would cause the lung to be punctured. Several studies [5,6] reported that patients with needle-pleural angles less than 80° and, in particular, less than 50°, had a higher risk of pneumothorax. However, we did not observe any impact of needle-pleural angle on complication rate of CT-guided PCNB. The negative correlation between needle-pleural angle and pneumothorax was not only due to the prolongation of intrapulmonary needle tract, but also due to the enlargement of pleural foramen torn by the needle passage [6]. The shape of the pleural aperture increased the amount of air leaking from the lung [6]. Therefore, in clinical practice, we have been willing to sacri ce the risk of changing the needle puncture site or prolonging the intrapulmonary needle tract in order to make the needle as perpendicular to the pleura as possible (median, lower-upper quartile: 65º, 48º -80º).
Patients with obstructive pulmonary function abnormalities were at greater risk for PCNB-induced pneumothorax, which was consistent with other studies [7]. For patients with severe impairment of pulmonary function, clinicians are usually reluctant to use core needle biopsy for fear of continuous air leakage. In order to derive a quantitative index of risk for pneumothorax, pulmonary function characteristics were evaluated here. FEV 1 /FVC ratio was found to be most strongly associated with pneumothorax, which was in accordance to previous reports [6,13,14]. FEV 1 /FVC ratio has the potential to identify the high risk population of pneumothorax. However, there were some controversies in the literature about the correlation between the abnormal pulmonary function analysis and the incidence of pneumothorax [12,13,15]. Vitulo et al. [12] reported in a retrospective analysis of 243 patients that no predictive value for pneumothorax was found in pulmonary function test. Several authors [6,[13][14][15] revealed a signi cant relationship between pneumothorax and FEV 1 . But our results were contrary to the observations of these studies. No difference was found in FEV 1 % pred between the two groups here. Obstructive pulmonary function abnormalities were related to higher risk for pneumothorax, but the severity demonstrated no association with the incidence of pneumothorax, which was probably due to FEV 1 % pred. Although FEV 1 /FVC ratio is the most important parameter for determining obstructive impairments, the severity of obstruction should be strati ed by reduced FEV 1 % [9][10][11]. Pulmonary function examination before biopsy can risk stratify patients with different types of pulmonary dysfunction, but the severity of pulmonary dysfunction does not affect the risk of pneumothorax. Patients with obstructive functional abnormalities had signi cantly higher incidence of pneumothorax than those with normal or other types of pulmonary abnormalities.
The increase in pneumothorax was due to poor lung elasticity, reduced alveolar air retraction, rupture of the expanded alveoli, emphysema along the needle tract and di culty in holding breath [7,14]. Similarly, in patients with obstructive ventilation abnormalities, the severity of spirometric abnormality was not associated with the incidence of pneumothorax.
Furthermore, in this study, FEF 50% , FEF 75% and FEF 25 − 75% are signi cantly negatively correlated with the incidence of pneumothorax. Other lung function parameters such as VC, FVC, FEF 25% and PEF showed no statistical difference. This study is unique because so far, no other research paper has dealt with such detailed lung function predictors for pneumothorax. FEF 50% , FEF 75% and FEF 25 − 75% are the middle and end expiratory indexes of exertion dependence, which re ect small airway ventilation function. Small airway dysfunction refers to the dysfunction caused by infection, smoking and external environment in the airway with a diameter of less than 2 mm, including both small bronchi and proximal bronchioles. Small airways are known as the major sites of air ow obstruction in chronic obstructive pulmonary diseases (COPDs). Even before the destruction of emphysema, the narrowing and disappearance of small airways can be observed in patients with obstructive functional abnormalities, leading to the increase of peripheral airway resistance [21]. Small airway dysfunction is a common but easily ignored lung dysfunction, long known as the silent zone of the lung. Small airway lesions are characterized by smooth muscle hyperplasia and hypertrophy, in ammatory cells including neutrophils and macrophages increased, goblet cell hyperplasia, mucus hypersecretion and obstruction, airway wall thickening and brosis [22]. As a result, the air ow is restricted, the alveoli are overin ated, the alveolar attachment of the small airways is destroyed, the elastic retraction of lung is reduced, and the internal pressure of the alveoli increases, thereby increasing the occurrence of pneumothorax [10,21]. Interestingly, in this study, small airway function parameters FEF 50% , FEF 75% and FEF 25 − 75% , showed signi cant negative correlations with pneumothorax rate (Table 3). However, no signi cant correlation was found between small airway dysfunction and pneumothorax (Table 4). This was mainly because small airway function indicators were signi cantly reduced not only in small airway dysfunction group, but also in obstructive functional abnormalities group (Supplementary Table 1). Therefore, logistic regression analysis was further employed to evaluate the roles of pulmonary function parameters in the risk of pneumothorax, respectively (Table 5). Since FEF 50% , FEF 75% and FEF 25 − 75% are clinically related to FEV 1 /FVC, only FEV 1 /FVC ratio (%) is retained in multivariable logistic regression model for predictors of pneumothorax. Although FEV 1 /FVC ratio signi cantly correlated with pneumothorax on univariate analysis, multivariate logistic regression analysis shows it was not an independent risk factor. This study had several limitations. CT-guided PCNB studied here were all performed by one intervention team with only one type of needle according to the standard protocol. Some factors demonstrated no statistical signi cance here, which does not mean that they have nothing to do with pneumothorax. This may be due to the standardization of the procedures. Ko et al. [6] indicated that pneumothorax more commonly occurred in patients with lesions adjacent pleura or invading the chest wall. However, our puncture approach was deliberately avoided the ssure. Hence, no statistical signi cance of this factor was found. We used only one size of biopsy needle in this study, making it impossible to compare different sizes of the biopsy specimens. Furthermore, the limited reliability of this study on the risk for pneumothorax in restrictive and mixed ventilation abnormalities may be due to the limited number of such patients.

Conclusions
Pneumothorax is still the most common complication following CT-guided PCNB. With the improvement of the technique, some of the previous risk factors have become less important. This is the real purpose of this study. Several factors have been con rmed to be associated with a higher rate of pneumothorax, including location of lesion, presence of emphysema and dwell time, as well as pulmonary function parameters FEV 1 /FVC ratio, FEV 1 /FVC ratio (%, pred), FEF 50% (% pred), FEF 75% (% pred) and FEF 25 − 75% (% pred). Multivariate logistic regression model showed that CHL and WZ wrote the paper. All authors read and approved the nal manuscript

Competing interests
The authors declare that they have no competing interests.

Availability of data and materials
All data generated and analyzed during the current study are included in this published article.

Consent for publication
Not applicable.
Each group compared with normal ventilation function group.
Overall comparison among different severity levels in obstructive, restrictive and mixed function abnormalities. ‡ Overall comparison among different severity levels in obstructive function abnormalities. † Chi-square test.