Evaluation of Small Airway Function During COPD Exacerbation and Recovery Using Impulse Oscillometry (IOS) Device
Conditions: COPD Exacerbation, COPD
Sponsor: Deniz Bilici

September 30, 2024 
TITLE PAGE 
 
Word count 
Abstract: two hundred and fifty-nine 
Main text: three thousand seventeen 
 
TITLE OF THE MANUSCRIPT: Evaluation of Small Airway Function 
During COPD Exacerbation and Recovery Using Impulse 
Oscillometry (IOS) Device 
SHORT TITLE: Impulse Oscillometry in COPD Exacerbation 
 
AUTHORS AND AFFILIATIONS 
 
1Esra Ertan Yazar, -Professor:1Istanbul Medeniyet University, Medical Faculty, Department 
of Chest Diseases, Istanbul, Turkey 
Email: esraertan76@yahoo.com 
Orcid id: 0000-0002-6081-3463 
Tel: 05057781059 
 
 2Esma Seda Akalın Karaca - MD: 1Istanbul Medeniyet University Faculty of 
Medicine, Department of Pulmonary Medicine, Istanbul, Turkey 
Email: esmasedaakalin@gmail.com 
Orcid id: 0000-0002-9512-9223 
Tel: 05333510087 
 
3Deniz Koçak-Research Assistant:: 1Istanbul Medeniyet University Faculty of Medicine, 
Department of Pulmonary Medicine, Istanbul, Turkey 
Email: kocakdenizz@gmail.com 
Orcid id: 0009-0002-0290-7063 
Tel: 05433641775 
 
4Elif Hazal Karadağ-Research Assistant:: 1Istanbul Medeniyet University Faculty of 
Medicine, Department of Pulmonary Medicine, Istanbul, Turkey 
Email: dr.elifhazal@gmail.com 
Orcid id: 0009-0008-7768-1795 
Tel: 05326651349 
 
5Burcu Arpinar Yigitbas- Associate professor: 1Istanbul Medeniyet University Faculty of 
Medicine, Department of Pulmonary Medicine, Istanbul, Turkey 
Email: drburcuayigitbas@yahoo.com 
Orcid id: 0000-0003-1367-5253 

Tel: 05336653549 
 
6Deniz Bilici- MD: Istanbul Medeniyet University Faculty of 
Medicine, Department of Pulmonary Medicine, Istanbul, Turkey 
Email: dr.deniz.bilici@gmail.com 
Orcid id: 0000-0003-3707-2502 
Tel: 05057590406 
 
7Handan Ankaralı Professor2: Istanbul Medeniyet University Faculty of 
Medicine, Department of Biostatistics, Istanbul, Turkey 
Email: handanankarali@gmail.com 
Orcid id: 0000-0002-3613-0523 
Tel: 05337212242 
 
 
CORRESPONDING AUTHOR: Esra Ertan Yazar, Prof.Dr., Istanbul Medeniyet University, 
Medical Faculty, Department of Chest Diseases, Istanbul, Turkey 
ORCID ID: 0000-0002-6081-3463 
E mail: esraertan76@yahoo.com 
Tel:  +905057781059 
 
Conflict of interest 
The authors acknowledge Chiesi Pharmaceuticals for the unconditional provision of iOS 
device. The company had no role in the design of the study, collection, analysis, or 
interpretation of data, or in writing the manuscript. The authors declare no conflicts of interest 
related to this manuscript. All authors have significantly contributed to the research and 
preparation of this manuscript and have no financial or personal relationships that could 
improperly influence or bias the presented work. 
 
All authors contributed to data collection and/or analysis and critically reviewed the 
manuscript before submission. 
 
 
 
 

 
 
 
Keywords: COPD, exacerbation, IOS, small airway 
 
Abbreviations 
• (ATS) The American Thoracic Society 
• (AX) Reactance area  
• (BORG) The Modified Borg Dyspnea Scale  
• (CAT) The COPD Assessment Test  
• (COPD) Chronic obstructive pulmonary disease  
• (CRP) C-reactive protein  
• (ECOPD) COPD exacerbations  
• (ERS) The European Respiratory Society  
• (FeNO) Fractional exhaled nitric oxide  
• (FEV1) Forced expiratory volume in 1 second  
• (Fres) Frequency response  
• (FVC) Forced vital capacity  
• (GOLD) Global Initiative for Obstructive Lung Disease  
• (IOS) Impulse Oscillometry  
• (MEF) Mean expiratory flow  
• (mMRC) The modified Medical Research Council  
• (PEF) Peak expiratory flow  
• (PFTs) Pulmonary function tests  
• (R5) Resistance at 5 Hz 
• (R5−R20) Difference between resistance at 5 Hz and 20 Hz 
• (R20) Resistance at 20 Hz 
• (SAD) Small airway disease  
• (SII) Systemic immune inflammation index  
• (SIRI) Systemic inflammation response index  
• (X5) Reactance at 5 Hz 
 
 

 
 
 
Abstract 
Background: Although recent guidelines emphasize objective criteria for assessing 
exacerbation severity, pulmonary function tests are still not included. This study aimed to 
evaluate small airway function during ECOPD and recovery periods using IOS. 
Research questions: Can small airway function be assessed with IOS in ECOPD? Is there a 
relationship between IOS measurements and exacerbation severity? Is there an improvement 
in IOS measurements during the recovery period? 
Study Design and Methods: In this prospective single-center study, patients with ECOPD 
underwent evaluation of their pulmonary functions using IOS and spirometry during 
exacerbation and recovery (6–12 weeks after exacerbation). The patients were divided into 
two groups: mild exacerbations and (moderate and severe) exacerbations based on ROME 
criteria. 
Results: A total of 41 patients were initially enrolled, with 38 completing the study. At the 
onset of exacerbation, R5, R5-R20, X5, AX, and Fres were significantly correlated with 
FEV1%, and R5, R5-R20, AX, and Fres were also significantly correlated with the BORG 
score. Spirometry results were higher, while inflammation markers were lower in the mild 
exacerbation group. No differences in IOS parameters were observed based on exacerbation 
severity. Additionally, significant improvements were seen in CAT and BORG scores, 
FEV1%, FVC%, R5, R5-R20, AX, and Fres, along with a decrease in inflammation markers 
during the recovery period.  
Interpretation: This study reveals several important and novel findings. IOS can be easily 
used in ECOPD, and IOS parameters that reflect small airways (R5–R20, AX, and Fres) are 
correlated with FEV1% and the severity of dyspnea. Additionally, IOS parameters 
significantly improve during recovery, except for R20. Further research is necessary on its 
application in the functional assessment of patients with COPD exacerbations. 
 
 
 
 
 

 
 
Take-Home Points  
Study Question 
Can IOS measurements be used to evaluate pulmonary functions during COPD 
exacerbations? 
Results  
IOS measurements were easily applied to COPD patients during exacerbations.  They showed 
a correlation with FEV1 and dyspnea at the onset of exacerbations, and there was a significant 
improvement in IOS measurements during recovery. 
Interpretation 
The IOS parameters, which reflect small airways, correlated better with FEV1 and dyspnea at 
the onset of an exacerbation and improved throughout recovery more than those of the large 
airway. This suggests that small airways are more affected during exacerbations, just as they 
are during stable periods. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
Introduction 
Exacerbations are the most common cause of morbidity and mortality in COPD. In the 
treatment of COPD, managing current exacerbations and preventing future ones are crucial.1,2 
Exacerbation of COPD (ECOPD) was defined as an acute worsening of respiratory symptoms 
that requires additional treatment. Its severity was evaluated based on the treatments 
administered or hospital admission.3 This depended on patients' perception of symptoms, their 
self-management skills, or physicians' preferences for treatment of exacerbations, making it 
far from an objective measure. The definition of exacerbation in the Global Initiative for 
Obstructive Lung Disease (GOLD) 2023 report has been updated to reflect the Rome 
proposal, published in 2021.1,4 A more detailed and objective definition was developed, 
incorporating respiratory findings and their duration, as well as etiology factors and related to 
pathogenesis, such as inflammation. Similarly, it was suggested that exacerbation severity 
should be determined according to more objective criteria, including clinical and laboratory 
findings.1 However, pulmonary function tests (PFTs) have not been recommended by any 
guideline to define exacerbation or assess its severity in COPD to date. 
On the other hand, the severity of asthma exacerbations has been assessed for many years 
based on objective criteria such as clinical and physical examination findings, peak expiratory 
flow (PEF) values, and oxygen saturation.5 The complex maneuvers involved in spirometry 
often present challenges for elderly patients or those with impaired cognitive or 
neuromuscular functions, even during stable periods. Therefore, alternative PFTs to 
spirometry have been explored for many years in COPD patients. Impulse Oscillometry (IOS) 
is a simple, non-invasive, effort-independent method that uses sound waves to detect airway 
changes quickly. It only requires the patient to breathe normally to assess lung function by 
measuring both resistance and reactance of the airways.6,7 These features of IOS suggest it 
may be a useful test for assessing patient respiratory function during exacerbation periods 
when airway resistance, airflow limitation, and respiratory muscle weakness further impair 
breathing. 

We aimed to examine the parameters reflecting small airways during exacerbation using IOS, 
their relationship with clinical findings, exacerbation severity, and PFTs. We also compared 
the exacerbation measurements with those taken during recovery in the same patients.  
 
 
 
Materials and Methods 
Study design and setting 
This single-center, prospective study was conducted at Medeniyet University Prof. Dr. 
Süleyman Yalçın Hospital in accordance with the Declaration of Helsinki. The study protocol 
received approval from the local institutional ethics committee (Date; No: 20.12.2023; 
2023/0971), and written informed consent was obtained from all participants. 
Study Population 
Between March 2024 and September 2024, patients who were consecutively admitted to the 
emergency department or pulmonology outpatient clinic of our hospital with a diagnosis of 
ECOPD, as defined by the GOLD 2023 Report1, were enrolled in the study. Patients 
diagnosed with pneumonia, pulmonary embolism, heart failure, pleural effusion, or 
pneumothorax were excluded. Additionally, patients who were unable to perform spirometry 
during exacerbation or had a forced expiratory volume in one second (FEV1) to forced vital 
capacity (FVC) ratio of ≥ 0.70 were also excluded. The most common reasons for patient 
exclusion were the presence of pneumonia, inability to perform PFT, or an FEV1/FVC ratio ≥ 
0.70. Patients were divided into two groups: mild exacerbations (group 1) and moderate and 
severe exacerbations (group 2) based on ROME criteria.4 
Data Collection 
The patients underwent IOS and PFT, along with completing questionnaires that included the 
case report form, the modified Medical Research Council (mMRC), the COPD Assessment 
Test (CAT), and the Modified Borg Dyspnea Scale (BORG). 8-10 PFT and IOS measurements 
were performed in all patients during both the acute exacerbation and the recovery period, 
which was defined as 6 to 12 weeks after the exacerbation. Relevant laboratory data, 
including complete blood counts and routine biochemical parameters, were retrospectively 

documented from hospital records for further analysis. The systemic immune inflammation 
index (SII) and the systemic inflammation response index (SIRI) were calculated for each 
patient.11,12  
 
 
IOS and Spirometry Measurements 
Respiratory impedance was measured using a commercially available impulse oscillometry 
system (Jager, Germany; MS-IOS, V.5.72) following established protocols. Patients sat 
upright with their heads in a neutral position and were instructed to breathe normally through 
a mouthpiece connected to a pneumotachograph. A nose clip was used to prevent nasal 
airflow. To minimize upper airway shunting, patients supported their cheeks with their hands 
and kept their tongue and chin in a steady position throughout the procedure. Once stable tidal 
breathing was achieved, IOS measurements were recorded for at least 30 seconds. The test 
was repeated at least three times for each patient, and the measurement identified as a 'good 
test' by the oscillometry device was recorded as the patient's result. IOS measures three 
standard parameters for assessing airway resistance, including resistance at 5 Hz (R5), which 
indicates total airway resistance; resistance at 20 Hz (R20), representing the resistance of 
large airways; and the difference between resistance at 5 Hz and 20 Hz ( R5-R20 ), which 
reflects resistance in small airways. The parameters that assess reactance are X5, which 
measures peripheral elastic resistance at 5 Hz; AX, the area under the reactance curve 
between 5 Hz and the resonant frequency, reflecting the elastic properties of the lung; and 
Fres, the oscillation frequency at which reactance is zero, helping to distinguish low-
frequency from high-frequency reactance. Small airways dysfunction can be evaluated using 
R5-R20 along with X5, Fres, and AX. The data were analyzed following the European 
Respiratory Society (ERS) Task Force on forced oscillation technique testing.13 After the IOS 
measurements, spirometry was performed according to the guidelines of the American 
Thoracic Society (ATS) and the ERS.14 The FEV1%, FVC%, and FEV1/FVC ratio were 
recorded. 
Statistical Analysis 
Descriptive statistics for the numerical and categorical variables were calculated as median, 
25th and 75th percentiles, number, and percentage frequencies. The Shapiro-Wilk test was 
used to check the normality assumption of the numerical characteristics, and it was 

determined that they do not have a normal distribution. Differences between the mild 
exacerbation and moderate/severe exacerbation groups concerning numerical or categorical 
variables were examined using the Mann-Whitney U test or the Pearson chi-square test, 
respectively. The differences between exacerbation and recovery periods were evaluated by 
using the Wilcoxon Signed-Rank test. Correlations between numerical measurements were 
investigated using Spearman's Rank Correlation Analysis. Statistical significance was 
accepted as P<=0.05. SPSS (Version 29) was used for calculations. 
 
Results 
A total of 41 patients were initially enrolled. Among them, 38 completed the study because 
two experienced frequent exacerbations during the study, and one did not return for follow-
up. Table 1 shows the clinical and laboratory characteristics of 41 patients at the onset of their 
exacerbation. FEV1% was correlated with all IOS parameters except R20, and BORG was 
correlated with IOS parameters except R20 and X5. Furthermore, IOS parameters reflecting 
the small airways (R5-R20, X5, AX, Fres) also showed strong intercorrelations. The p and r 
values for the correlations at the onset of exacerbation are shown in Table 2. The correlation 
between IOS measurements (absolute R5, R20, R5-R20, X5, AX, Fres) and FEV1% is 
illustrated in Figure 1, and their correlation with BORG is displayed in Figure 2. When 
patients were compared based on exacerbation severity, C-reactive protein (CRP) and SII, 
which are indicators of inflammation, were lower, while spirometry results (FEV1%, FVC%, 
and FEV1/FVC) were higher in Group 1. No difference was found between the groups 
regarding IOS parameters at the onset of exacerbation (Table 3). 
Thirty-eight patients were re-evaluated during the recovery period. Significant improvements 
were observed in FEV1%, FVC%, R5, R5-R20, AX, and Fres, along with a decrease in CRP 
and inflammation indices (SII and SIRI) during recovery. Clinically, participants showed 
significant improvement in symptoms, as measured by the CAT and BORG scales. 
Comparison of clinical and functional characteristics of patients during exacerbation and 
recovery periods is provided in Table 4. The median and 25th and 75th quartiles of IOS 
measurements during the exacerbation and recovery periods are shown in Figure 3 using a 
box plot.  
 
Disscussion 
To our knowledge, this is the first study in the literature investigating changes in IOS 
parameters during exacerbation and recovery periods in COPD patients. We showed that at 

the onset of exacerbation, R5, R5-R20, X5, AX, and Fres were significantly correlated with 
FEV1%, and R5, R5-R20, AX, and Fres were also significantly correlated with the BORG 
score. The resistance and reactance parameters of the IOS also showed a strong correlation 
with each other, besides the low correlation of R20 with X5 and Fres.  At the onset of 
exacerbation, CRP and SII levels were lower in mild exacerbations, while FEV1%, FVC%, 
and FEV1/FVC ratios were higher. No differences were observed in IOS parameters based on 
the severity of exacerbation. Additionally, significant improvements were observed in 
FEV1%, FVC%, R5, R5-R20, AX, and Fres, along with a decrease in CRP, SII, and SIRI 
during recovery. Clinically, participants demonstrated notable improvement in symptoms, as 
measured by the CAT and BORG scales. 
IOS Reproducibility 
A key requirement for widespread use of PFTs in clinical practice is that they are consistent 
and reliable across different centers. One of the most significant findings of the ECLIPSE 
Study was the reliability of IOS parameters across continents.15 In a prospective study of 94 
COPD patients, changes in IOS measurements and FEV1% were monitored over one year in 
58 patients. After this period, there were no statistically significant differences in the mean or 
median values of FEV1%, R5, X5, or Fres.16 Another retrospective study showed that IOS 
resistance parameters demonstrate long-term reproducibility in both asthma and COPD. 
Additionally, the repeatability of spirometry parameters is lower than that of IOS resistance 
parameters across different GOLD stages.17 Another important issue is the determination of 
cut-off values for these tests. A comprehensive review established practical IOS cutoff values 
for peripheral airway resistance in COPD as R5 > 0.5 kPa/L/s, R5-R20 > 0.10 kPa/L/s, and 
AX > 1.0 kPa/L.18 In our study, the median values of R5 (0.51 kPa/L/s), R5-R20 (0.21 
kPa/L/s), and AX (1.85 kPa/L/s) at the onset of exacerbation significantly exceeded these 
recommended thresholds. During recovery, although lower than during exacerbation, R5-R20 
(0.17 kPa/L/s) and AX (1.51 kPa/L/s) still remained above these thresholds, with R5 at 0.42, 
just below the cutoff. Our results generally support the threshold values suggested in the 
review.  
Small airway disease and its role in exacerbations 
Small airway disease (SAD) is a key pathological feature that occurs early in COPD 
progression. In healthy individuals, the peripheral airways contribute minimally to overall 
airway resistance, whereas in patients with COPD, resistance in the peripheral airways 
increases significantly. 19, 20 Additionally, studies demonstrate that patients with COPD have 

comparatively higher levels of small airway dysfunction than those with asthma and 
idiopathic pulmonary fibrosis. 21, 22 
Spirometry, commonly used for diagnosing and monitoring patients with COPD, falls short in 
assessing SAD. IOS, which has gained more widespread use in asthma and COPD in recent 
years, provides a more specific and comprehensive assessment of small airways, including 
resistance and reactance parameters. 23, 24 However, the ECLIPSE study showed no significant 
relationship between the presence of SAD and the R5-R20 and mean expiratory flow (MEF) 
values.15  
Studies conducted so far have focused on the role of IOS measurements in early COPD 
diagnosis, their relationship with disease severity, and their role in predicting exacerbation 
risk. 15,18,23,24 We designed this study based on the assumption that small airway function 
would decline further during exacerbations. In the literature, studies on exacerbations and IOS 
are mainly found in the field of asthma, which suggests that damage to the peripheral airways 
could be a key factor in such asthma attacks. Additionally, while IOS alone was capable of 
predicting future exacerbations, fractional exhaled nitric oxide (FeNO), FEV1%, FEV1/FVC 
ratio, and bronchial hyperresponsiveness alone were not sufficient to predict exacerbations. 
25,26,27 There are few studies in the literature examining the relationship between IOS 
parameters and exacerbation risk in COPD patients, which suggest that IOS parameters can be 
used to predict ECOPD. 24,28, 29 We performed IOS along with spirometry during both 
exacerbation and recovery periods in 38 patients. A key finding was that patients struggled or 
could not perform spirometry during exacerbations but could perform IOS with ease and in 
less time. We observed significant improvements in IOS parameters (R5, R5-R20, AX, and 
Fres), except for X5 and R20, as well as in FEV1%, FVC%, and the FEV1/FVC ratio during 
recovery compared to the onset of the exacerbation. Although there was no difference in 
median R20 values between exacerbation and recovery (0,29 vs 0,28), there was a significant 
decrease in median R5-R20 levels (0,21 vs 0,17). Our findings suggest that small airway 
resistance plays a more important role than large airway resistance during exacerbation, 
similar to the stable period in COPD patients. We can conclude that new medications and 
devices targeting the small airways are essential for treating COPD exacerbations.  
Relationship of IOS measurements with exacerbation severity 
To our knowledge, no studies in the literature have evaluated small airways using IOS during 
ECOPD. Several studies compare disease severity and IOS measurements in stable COPD. 
15,29,30 The ECLIPSE cohort shows that R20 values are similar across GOLD stages 2-4, while 
R5-R20 values increase proportionally in these stages, suggesting that small airways mainly 

contribute to the rise in lung resistance. 15 A study involving 215 stable COPD patients 
showed that IOS parameters, except R20, varied significantly with COPD severity, a finding 
similar to those in the ECLIPSE cohort. 29 Conversely, a retrospective observational study 
indicated that IOS parameters did not effectively differentiate stage 1 COPD patients from the 
general population or identify GOLD stage 3 and 4 patients among all COPD patients. 30 We 
compared individuals with mild exacerbations to those with moderate and severe 
exacerbations based on the ROME criteria. Significant differences were observed in 
spirometry results and inflammation markers according to exacerbation severity; FEV1%, 
FVC%, and FEV1/FVC ratios were higher, while CRP and SII were lower in the mild 
exacerbation group. We found no difference in IOS measurements between the two groups. 
The lack of differences in IOS parameters may be due to the small number of patients in our 
study. 
Correlation between IOS and spirometry parameters at the onset of exacerbation  
Many studies showed a significant correlation between IOS and spirometry parameters in 
patients with stable COPD.16,29,31 In a prospective study of 94 COPD patients, R5, X5, and 
Fres were found to be significantly correlated with FEV1%. By measuring changes in FEV1% 
and IOS parameters in 58 patients after one year, it was observed that X5 was the only IOS 
measurement significantly correlated with FEV1% changes [14]. Similarly, in our study, at 
the onset of the ECOPD, the IOS measurement that had the strongest correlation with FEV1 
was X5. A retrospective study found a stronger correlation between IOS and spirometry in 
COPD than in ACO across all severity levels.31 A study comparing IOS measurements with 
spirometry parameters in patients with COPD observed a good correlation; reactance 
parameters showed a stronger correlation than resistance parameters.29 We found that the IOS 
parameters measured at the onset of the ECOPD showed a significant correlation with the 
FEV1% value, except for R20. Additionally, aside from the weak correlation of R20 with X5 
and Fres, the resistance and reactance parameters of IOS demonstrated a strong correlation 
with each other.  
Correlation between IOS and respiratory symptoms at the onset of exacerbation  
It is essential that PFTs used in COPD patients also relate to clinical features such as patients' 
complaints, quality of life, or mortality. In a study examining the relationships between IOS 
parameters and patient-reported outcomes in stable COPD, multiple regression analyses 
showed that R5-R20 or X5 most significantly explained the quality of life and dyspnea 
scores.32 A study involving 768 COPD patients was conducted; small airway dysfunction, 
assessed by R5, R5–R20, X5, AX, and Fres, was linked to more severe respiratory symptoms 

and a higher risk of ECOPD in previous years. Patients with IOS parameter abnormalities had 
higher mMRC and CAT scores.28 However, a study analyzing data from 57 COPD patients 
found that mMRC did not correlate with IOS or spirometry.33 While no correlation was found 
between IOS measurements and CAT and mMRC, a good correlation was observed between 
IOS parameters (R5, R5-R20, AX, Fres) and BORG in our study. Since BORG allows for the 
instantaneous assessment of dyspnea during exacerbations, it may better evaluate dyspnea and 
thus show a good correlation with IOS parameters. BORG can also be considered an 
alternative to the visual analog scale (VAS) in determining the severity of exacerbations. 
 
Limitations 
The primary limitation of our study is the small sample size. However, this is the first pilot 
study in the literature. Our strict adherence to the definition of exacerbation resulted to the 
exclusion of many patients from the study. Another limitation is that it is single-centered. 
Nonetheless, the strengths include its prospective design, performing IOS measurements 
during both exacerbation and recovery periods, and the consistency of our results throughout. 
 
Interpretation  
This study reveals several important and novel findings. IOS can be easily used in ECOPD. 
IOS parameters that reflect small airways (R5–R20, AX, and Fres) are correlated with 
FEV1% and the severity of dyspnea at the onset of an exacerbation. This correlation was not 
observed with R20, which represents large airways. No differences were observed in IOS 
measurements related to the severity of exacerbation. Additionally, IOS measurements 
significantly improve during recovery, except for R20. In conclusion, our results suggest that 
small airways are more affected than large airways during exacerbations, consistent with the 
findings during the stable period. 
 
Acknowledgments 
Author contributions: E.E.Y. acts as guarantor for the content of this manuscript. E.E.Y., 
E.S.A.K., and B.A.Y. contributed to the conception and design of the study. D.K., E.H.K., 
D.B., and H.A. collected data. A.H. conducted data analysis and interpretation. E.E.Y. and 
E.S.A.K. drafted the manuscript. All authors contributed to data acquisition and/or 
interpretation and critically reviewed the manuscript before submission. 
  
 

 
 
 
 
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Table 1: Clinical and laboratory characteristics of the patients at the onset of  
the exacerbation (n=41) 
Variables  
Median (25th-75th) or n (%) 
Age (years) 
66,0 (58,0-71.5) 
Gender, male  
31 (75.6) 
BMI (kg/m2) 
26,0 (23,4-29,8) 
Smoking (package-year) 
40,0 (30,0-50,0) 
Duration of COPD diagnosis (years) 
6,00 (1,00-17,50) 
Percentage of patients with frequent exacerbations  
%75,6 
CAT score  
22,0 (11,0-29,5) 
BORG score 
5,00 (3,00-6,00) 
Percentage of patients with VAS score<5 
%61,0 
SatO2 (%) 
94,0 (91,0-96,0) 
FEV1%   
43,0 (34,5-58,5) 
FVC %  
62,0 (47,5-76,0) 
FEV1/FVC  
60,0 (50,6-66,7) 
R5 (kPa/L/s)  
0,54 (0,40-0,68) 
R20 (kPa/L/s) 
0,29 (0,24-0,34) 
 
 
R5-R20 (kPa/L/s)  
0,21 (0,13-0,32) 
X5 (kPa/L/s)  
-0,19 (-0,35- -0,12) 
AX (kPa/L)  
1,98 (0,92-3,24) 
FRes (Hz) 
23,8 (18,2-27,8) 
CRP  
3,9 (1,3-20,5) 
NLR 
3,15 (2,15-10,99) 
Number of eosinophils 
240,0 (95,0- 445,0) 
Percentage of eosinophils 
2,70 (0,95-4,55) 
SII 
818497,0 (550943,5- 1361526,0) 
SIRI 
7,1 (1,9- 206,4) 
Abbreviations: BMI: Body mass index, CAT: COPD Assessment Test, BORG: the Modified Borg Dyspnea Scale, VAS: Visual analog 
scale, SatO₂:peripheral oxygen saturation measured by pulse oximetry, FEV1: Forced expiratory volume in one second, FVC: Forced vital 
capacity, FEV1/FVC: ratio of FEV1 to FVC, R5: Resistance at 5 Hz, R20: Resistance at 20 Hz, R5−R20: Difference between resistance at 5 
Hz and 20 Hz, X5: Reactance at 5 Hz, AX: Area of low-frequency reactance, Fres: Frequency response, CRP: C-reactive Protein, NLR: 
Neutrophil-to-lymphocyte ratio, SII: Systemic immune-inflammation index, SIRI: Systemic inflammation response index 
 

 
 
Table 2: The correlation between IOS measurements with each other, spirometric 
parameters, and BORG dyspnea scale in patients at the onset of the exacerbation  
 
FEV1 
% 
FVC % 
FEV1/FVC 
BORG 
R5 
R20 
R5-R20 
X5 
AX 
Fres 
R5 
-.366* 
-.405** 
-,104 
-,316* 
-- 
,811*** 
,924*** 
-,645*** 
,896*** 
,647*** 
R20 
-,290 
-,405** 
-,016 
,061 
,811*** 
-- 
,559*** 
-,390* 
,583*** 
,437* 
R5-R20 
-,325* 
-,295 
-,117 
,411** 
,924*** 
,559*** 
-- 
-,695*** 
,948*** 
,662*** 
X5 
,461* 
,385* 
,261 
-,255 
-,645*** 
-,390* 
-,695*** 
-- 
-,840*** 
-,580*** 
AX 
-,366* 
-,335* 
-,169 
,369* 
,896*** 
,583*** 
,948*** 
-,840*** 
-- 
,762*** 
Fres 
-,368* 
-,311* 
-,240 
,378* 
,647*** 
,437* 
,662*** 
-,580*** 
,762*** 
-- 
P value˂ 0.05*, P value˂ 0.01 **, P value˂ 0.001***  
Abbreviations: R5: Resistance at 5 Hz, R20: Resistance at 20 Hz, R5−R20: Difference between resistance at 5 Hz and 20 Hz, X5: Reactance 
at 5 Hz, AX: Reactance area, Fres: Frequency response, FEV1: Forced expiratory volume in one second 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Table 3: Comparison of clinical and functional characteristics of patients based on 
ROME classification at the onset of the exacerbation (n=41) 
Variables 
Mild exacerbation 
(n=26) 
Moderate and severe 
exacerbation (n=15) 
P 
median (25th-75th) or n (%) 
Age (years) 
66(55-70) 
66(59-73) 
0,515 
Gender, male  
%61,3 
%38,7 
0,619 
BMI (kg/m2) 
25,6 (23,3-29,1) 
26,6(23,4-34,5) 
0,465 
Smoking (package-year) 
40(30-48) 
45(30-55) 
0,222 
Duration of COPD 
diagnosis (years) 
6 (2-18) 
4 (1-15) 
0,505 
Number of exacerbations in 
the previous year  
2,5 (1-4) 
3 (0-5) 
0,701 
CAT score  
20 (11-28) 
27 (11-34) 
0,357 
BORG score 
5 (3-6) 
5(3-7) 
0,538 
VAS score<5 
%88 
%12 
0,01 
SatO2 (%) 
95 (93-96) 
90 (84-95) 
0,005 
FEV1%  
49,5 (38-66) 
35(24-46) 
0,002 
FVC %   
70 (54-78) 
51 (34-65) 
0,006 
FEV1/FVC  
62,7(55,7-67) 
52,6 (46,6-61,2) 
0,050 
R5 (kPa/L/s)  
0,51 (0,39-0,72) 
0,55 (0,41-0,65) 
0,807 
R20 (kPa/L/s) 
0,27 (0,24-0,32) 
0,31 (0,28-0,36) 
0,184 
R5-R20(kPa/L/s)  
0,22 (0,15-0,36) 
0,21 (0,11-0,29) 
0,379 
X5 (kPa/L/s)  
-0,19 (-0,35- -0,13) 
-0,19 (-0,35- -0,11) 
0,860 
AX (kPa/L)  
1,94 (0,93-3,37) 
1,98 (0,88-3,10) 
0,808 
FRes (Hz) 
23,75(18,36-27,48) 
24,22 (16,88-28,20) 
1,000 
CRP 
3 (1-9) 
20 (2-61) 
0,041 
Number of eosinophils 
265(160-460) 
160(10-430) 
0,113 
percentage of eosinophils 
2,85 (1,5-4,8) 
1,70(0,1-3,5) 
0,044 
SII 
742876,5 (449261-1044047) 
1256520 (744230- 1496205) 
0,015 
SIRI 
9,10 (1,53-170,4) 
7,14 (2,04-242,3) 
0,823 
Abbreviations: BMI: Body mass index, CAT: COPD assessment test, BORG: Modified Borg dyspnea scale, VAS: Visual analog scale, 
SpO₂:peripheral oxygen saturation measured by pulse oximetry, FEV1: Forced expiratory volume in one second, FVC: Forced vital capacity, 
FEV1/FVC: Ratio of FEV1 to FVC, R5: Resistance at 5 Hz, R20: Resistance at 20 Hz, R5−R20: Difference between resistance at 5 Hz and 
20 Hz, X5: Reactance at 5 Hz, AX: Area of low-frequency reactance, Fres: Frequency response, CRP: C-reactive protein. 
. 

Table 4: Comparison of clinical and functional characteristics of patients                                  
exacerbation and recovery periods 
 
Exacerbation 
Recovery 
P 
Variables 
median (25th-75th) 
FEV1%  
43,0 (35,0- 59,0) 
47,0 (39,0-75,0) 
0,001 
FVC %  
62,0 (48,0-76,0) 
66,0 (49,0-81,0) 
0,045 
FEV1/FVC  
60,3 (51,6- 66,8) 
63,0 (50,7-73,7) 
0,017 
R5 (kPa/L/s)  
0,51(0,39-0,66) 
0,42 (0,35-0,56) 
0,040 
R20 
0,29 (0,24-0,34) 
0,28 (0,24-0,31) 
0.793 
R5-R20 (kPa/L/s) 
0,21 (0,13-0,32) 
0,17 (0,10-0,23) 
0,024 
X5 (kPa/L/s)  
-0,18 (-0,33- -0,12) 
-0,17 (-0,25- -0,10) 
0,593 
AX (kPa/L/s)  
1,85 (0,90-3,17) 
1,51 (0,57- 2,57) 
0,050 
FRes (Hz) 
23,8 (18,0-27,7) 
19,9 (16,3-23,9) 
0,013 
CAT score  
22,0 (11,0-29,0) 
13,0 (6,0-20,0) 
0,001 
BORG score 
5,00 (3,00-6,00) 
1,00 (0-3,00) 
0,001 
CRP 
3,92 (1,23-20,90) 
2,26 (1,21-4,55) 
0,014 
NLR 
3,15 (2,15-12,21) 
2,00 (2,00-3,00) 
0,001 
Number of eosinophils 
250,0 (147,5-465,0) 
220,0 (160,0-320,0) 
0,187 
Eosinophils % 
2,70 (1,10-4,63) 
3,00 (2,05- 3,95) 
0,919 
SII 
813880 (550943,5-1361526) 637813(434617- 832727,5) 0,004 
SIRI 
5,92 (1,90-137,69) 
699,3 (509,8- 1172,4) 
0,001 
Abbreviations; FEV1: Forced expiratory volume in one second, FVC: Forced vital capacity, FEV1/FVC: ratio of FEV1 to FVC, R5: 
Resistance at 5 Hz, R20: Resistance at 20 Hz, R5−R20: Difference between resistance at 5 Hz and 20 Hz, X5: Reactance at 5 Hz, AX: Area 
of low-frequency reactance, Fres: Frequency response, CAT: COPD assessment test, BORG: Modified Borg dyspnea scale, CRP: C-reactive 
protein, NLR: Neutrophil-to-lymphocyte ratio, SII: Systemic immune-inflammation index, SIRI: Systemic inflammation response index. 
 
 
 
 
 
 
 
 
 
 

 
 
 
Figure 1. Correlation between IOS parameters and FEV1% at the onset of exacerbation.  
FEV1: Forced expiratory volume in one second, R5: Resistance at 5 Hz, R20: Resistance at 
20, R5−R20: Difference between resistance at 5 Hz and 20 Hz, X5: Reactance at 5 Hz, AX: 
Reactance area, Fres: Frequency response (n=41). 

 
 
 
Figure 2. Correlation between IOS parameters and BORG score at the onset of exacerbation 
BORG: Modified Borg dyspnea scale, R5: Resistance at 5 Hz, R20: Resistance at 20 Hz, 
R5−R20: Difference between resistance at 5 Hz and 20 Hz, X5: Reactance at 5 Hz, AX: 
Reactance area, Fres: Frequency response (n=41). 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Figure 3. Median and interquartile range of IOS parameters during exacerbation and recovery 
are displayed using a box plot.  R5: Resistance at 5 Hz, R20: Resistance at 20 Hz, R5−R20: 
Difference between resistance at 5 Hz and 20 Hz, X5: Reactance at 5 Hz, AX: Reactance area, 
Fres: Frequency response (n=38).