Abstract
Background: Although the impulse oscillometry system (IOS) is a noninvasive, easily accessible, well-tolerated, and alternative test, routine use of IOS in cystic fibrosis (CF) patients is not widespread. In our unit, IOS is routinely used for the evaluation and follow-up of patients with CF. We aimed to show that IOS may be utilized as a complement for measuring pulmonary function in CF patients.
Materials and Methods: Retrospective data collection and analysis of pulmonary function tests on CF patients followed at our center between January 1, 2018 and February 1, 2019. IOS and spirometry data were compared as correlated with patients' clinical exacerbation, treatment response, bronchodilator response, and trends during follow-up intervals.
Results: There was a significant correlation between spirometry and IOS parameters in 70 patients. In exacerbation, Z5, R5–R10, AX, Fres, and delta R5–R20 were significantly increased and X5–X20 was significantly decreased compared with baseline in 25 patients. After treatment, IOS parameters were observed to return to baseline values. In the evaluation of bronchodilator response in 33 patients, significant changes in IOS (decrease in Z5, R5–R10, AX, Fres, and delta R5–R20, and increase in X5–X10) and in spirometry [increase in forced expiratory volume in 1 s (FEV1) and forced expiratory flow during the middle half of forced vital capacity (FEF25–75)] were found after bronchodilator. While there was no significant difference between spirometry values in follow-up visits in 31 patients, there was a significant increase in Z5% and R5%–R20%. Unlike other studies, there was a significant correlation between clinical scores and IOS.
Conclusions: These results show that although IOS is not the gold standard method such as spirometry, it is an alternative method that can be used successfully in the evaluation and follow-up of CF patients. Clinical Trials.gov ID: 99166796-050.06.04
Keywords: cystic fibrosis, impulse oscillometry system, acute exacerbation, bronchodilator response, follow-up
Introduction
Imaging studies and bronchoscopic examinations suggest that lung damage in cystic fibrosis (CF) initiates at an early age.1–3 Until spirometry can be performed (>6 years), follow-up is performed by clinical evaluation, symptom scoring, tracing pulmonary infections, and radiological examinations in most centers. Infant pulmonary function tests (PFT) are not widely available since they are not easily accessible and present in all centers, and difficult to perform.4 Therefore, easily accessible, well-tolerated, and sensitive PFTs are needed for early detection of lung injury and patient follow-up.
The impulse oscillometry system (IOS) is one of the forced oscillatory techniques (FOT) employed for the impedance of the respiratory system. It can easily be performed on children below 6 years of age since it involves tidal breathing and has minimal co-operation requirements. The ability to measure resistance and reactance at different frequencies by IOS enables the identification of diseases affecting the proximal and distal airways.5,6 Therefore, IOS is regarded as a test that can be used in diseases affecting the peripheral airway, such as asthma and CF, and detects changes without any spirometry impairment.
In studies of asthma, IOS was found to be correlated with spirometry and sensitive to detect airway obstruction in patients with normal spirometry.7,8 Different results, on the other hand, were obtained in the studies involving CF patients.9–15 Therefore, its clinical use in CF has not gained attention. Nevertheless, recent studies have shown that IOS might be an alternative test for young patients and those patients unable to perform spirometry. Thus, given the potential benefits but conflicting results regarding the feasibility of IOS in CF, further studies are needed. In this study, we investigate whether IOS can be used effectively in different indications of CF and thus be routinely employed for the evaluation of CF patients as an alternative PFT.
Materials and Methods
A total of 74 patients, mostly children, diagnosed as having CF between January 1, 2018 and February 1, 2019 and who had had PFTs were included in this retrospective study. The study was approved by the local Ethics Committee (19-6T/47). Patient consent was obtained for the article. Clinical status of the patients is evaluated by Shwachman–Kulczycki Score (SKS).16
Impulse oscillometry
An IOS (Master Screen IOS, Germany) was used in accordance with the measurement criteria as described in the literature.5,17 Resistance (R) and reactance (X) were measured at frequencies of 5, 10, 15, and 20 Hz [kPa/(L/s)]. Also measured were impedance (Z), resonance frequency (Fres), and the area of reactance (AX), which represents a summation of reactance values below Fres. Delta R5–R20 (%) was expressed as a percentage of the difference in resistance at 5 and 20 Hz. The acceptable coherence level was ≥0.6 at 5 Hz and ≥0.8 at 10 Hz.5
Spirometry
Forced vital capacity (FVC) and flow rates were measured by spirometry (Flowhandy ZAN100, Germany) according to the criteria of the American Thoracic Society.18 Results were expressed as raw values, percentage of predicted values, and z-scores. z-Scores were calculated using Global Lung Initiative's reference equations.19 The standard procedure in our laboratory is to perform IOS before spirometry.
Acute exacerbation
In our clinic, the diagnosis of acute exacerbation is based on symptoms, physical examination, and PFTs [>10% decrease in forced expiratory volume in 1 s (FEV1) and FVC]. Antibiotics were chosen by the experienced physician according to last sputum culture and prior patient clinical response. The duration of antibiotherapy varied according to the causal or suspected microorganism. Spirometry and IOS were routinely performed to aid the diagnosis of acute exacerbation and evaluate treatment response after the end of 10–14 days of antibiotic treatment. To avoid conflicting results, the PFTs of patients only receiving intravenous treatment were examined.
Bronchodilator response
Bronchodilator response was evaluated by repeated PFTs 15–20 min after the inhalation of a short-acting bronchodilator (200 μg salbutamol) in stable patients considered to have newly developed airway obstruction. The bronchodilator response was defined as an increase of ≥12% for the change in FEV1.20
Statistical analysis
Statistical analysis was performed using IBM SPSS V.20.0 (SPSS, Chicago, IL). Shapiro–Wilk test was used to test the normality of data distribution. Continuous parameters are presented as mean ± SD and median (25th and 75th percentile). Categorical parameters are presented as percentages. Correlation analysis between continuous parameters was performed with Spearman's Correlation test. Comparisons of continuous paired parameters were made by Wilcoxon t-test and paired t-test. Variance analysis was performed for parameters with repeated measurements at different time points. In case of significance, paired comparisons were made with Bonferroni test. Time effect on numerical data was tested with the nonparametric Brunner–Langer model (LD-F1 design) using R 3.3.1 software (R software, version 3.3.1, package: nparLD; R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was accepted as P < 0.05.
Results
PFTs of 74 patients with 689 measurements were initially examined. Four patients with 41 measurements have tests not meeting measurement criteria and these data were excluded. A total of 648 measurements from 70 patients (60 children, 10 adults) were included in the final evaluation. The mean age was 146.1 ± 66.6 months (with 9 at <6 years). The median body weight was 34.5 kg (range: 11–103 kg), and the median height was 146 cm (range: 98–180 cm). Of the 70 patients, 28 (40%) had F508del mutation and the remaining 42 (60%) had other CF-related mutations. The median SKS was 75 (range: 40–95). Colonization was present in 41 (58.6%) patients. The most common colonizing microorganisms were Pseudomonas aeruginosa (n: 34) and Staphylococcus aureus (n: 13).
Correlation between spirometry and IOS
The results of the 70 patients who had completed PFTs were examined. The median FEV1 z-score was −1.72 (−3.17/−0.62), the FVC z-score −2.01 (−3.69/−1.17), and the forced expiratory flow during the middle half of FVC (FEF25–75) z-score −0.83 (−2.54/0.44).
There was a negative correlation between FEV1, FVC, and FEF25–75 and Z5 Hz, R5–R20 Hz, AX, and Fres (except correlation between FEF25–75 and R20 Hz) and positive correlation between FEV1, FVC, and FEF25–75 and X5–X20 Hz (P < 0.05). Additionally, there was a significant negative correlation between the clinical scores and Z5 Hz, R5 Hz, AX, Fres, and delta R5–R20, and a positive correlation of clinical scores with X5–X20 Hz (Table 1).
Table 1.
Correlation of Pulmonary Function Tests (Spirometry and Impulse Oscillometry System) Raw Values and Clinical Scores (N = 70)
| FEV1 | FVC | FEF25–75 | Shwachman–Kulczycki Scores | |
|---|---|---|---|---|
| Z5 (kPa/L/s) | r = −0.62 | r = −0.67 | r = −0.51 | r = −0.41 |
| P = 0.00 | P = 0.00 | P = 0.00 | P = 0.00 | |
| R5 (kPa/L/s) | r = −0.57 | r = −0.63 | r = −0.45 | r = −0.38 |
| P = 0.00 | P = 0.00 | P = 0.00 | P = 0.00 | |
| R10 (kPa/L/s) | r = −0.42 | r = −0.50 | r = −0.27 | r = −0.25 |
| P = 0.00 | P = 0.00 | P = 0.02 | P = 0.06 | |
| R15 (kPa/L/s) | r = −0.36 | r = −0.45 | r = −0.27 | r = −0.08 |
| P = 0.00 | P = 0.00 | P = 0.04 | P = 0.51 | |
| R20 (kPa/L/s) | r = −0.32 | r = −0.40 | r = −0.14 | r = −0.06 |
| P = 0.00 | P = 0.02 | P = 0.24 | P = 0.65 | |
| X5 (kPa/L/s) | r = 0.77 | r = 0.75 | r = 0.69 | r = 0.38 |
| P = 0.00 | P = 0.00 | P = 0.00 | P = 0.00 | |
| X10 (kPa/L/s) | r = 0.71 | r = 0.70 | r = 0.74 | r = 0.39 |
| P = 0.00 | P = 0.00 | P = 0.00 | P = 0.00 | |
| X15 (kPa/L/s) | r = 0.63 | r = 0.62 | r = 0.67 | r = 0.28 |
| P = 0.00 | P = 0.00 | P = 0.00 | P = 0.03 | |
| X20 (kPa/L/s) | r = 0.60 | r = 0.60 | r = 0.58 | r = 0.27 |
| P = 0.00 | P = 0.00 | P = 0.00 | P = 0.04 | |
| Delta R5–R20 (%) | r = −0.55 | r = −0.50 | r = −0.63 | r = −0.40 |
| P = 0.00 | P = 0.00 | P = 0.00 | P = 0.00 | |
| AX (kPa/L) | r = −0.69 | r = −0.69 | r = −0.71 | r = −0.35 |
| P = 0.00 | P = 0.00 | P = 0.00 | P = 0.00 | |
| Fres (L/s) | r = −0.58 | r = −0.55 | r = −0.57 | r = −0.35 |
| P = 0.00 | P = 0.00 | P = 0.00 | P = 0.00 |
FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; FEF25–75, forced expiratory flow during the middle half of FVC; Z5, the impedance at 5 Hz; R5, the resistance at 5 Hz; R10, the resistance at 10 Hz; R15, the resistance at 15 Hz; R20, the resistance at 20 Hz; X5, the reactance at 5 Hz; X10, the reactance at 10 Hz; X15, the reactance at 15 Hz; X20, the reactance at 20 Hz; AX, reactance area; Fres, resonance frequency.
Acute exacerbation
During the study period, 25 patients underwent PFTs for acute exacerbation. The mean age of the patients was 156.1 ± 65.1 months. Median duration of treatment was 14 (range: 10–21) days. The median values of baseline, acute exacerbation, and posttreatment FEV1 were 79% (46.5/95), 68% (32/79) and 78% (44/89), respectively, with the median values of FVC at 77% (48.5/88), 67% (41/74), and 75.5% (46/84).
When PFTs were compared with basal values in exacerbation, there was a statistically significant decrease in spirometry values, which returned to baseline after treatment. For IOS, the parameters Z5, R5–R10, AX, Fres, delta R5–R20, and X5–X20 Hz in exacerbation significantly increased compared with baseline values. These parameters were observed to return to the baseline after treatment (P < 0.05) (Fig. 1). The baseline, acute exacerbation, and posttreatment measurements of PFTs are shown for comparison in Table 2.
FIG. 1.
(A) Changes in FEV1 (%) at exacerbation and after exacerbation according to baseline values. (B) Changes in FVC (%) at exacerbation and after exacerbation according to baseline values. (C) Changes in IOS resistance values at exacerbation and after exacerbation according to baseline values. (D) Changes in IOS reactance values at exacerbation and after exacerbation according to baseline values. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; IOS, impulse oscillometry system.
Table 2.
Comparison of Baseline, Acute Exacerbation and After Exacerbation of Spirometry and Impulse Oscillometry System Raw Values [Median (IQR: 25–75)] (N = 25)
| Parameters | Baseline | At exacerbation | After exacerbation | Pa | Pb |
|---|---|---|---|---|---|
| Spirometry | |||||
| FEV1 | 1.49 (1.13/2.41) | 1.24 (0.78/2.05) | 1.49 (0.99/2.39) | 0.001 | 0.002 |
| FVC | 1.57 (1.29/2.88) | 1.53 (0.85/2.31) | 1.60 (1.24/2.69) | 0.004 | 0.01 |
| FEF25–75 | 1.85 (0.97/2.64) | 1.14 (0.72/2.38) | 1.72 (1.36/2.69) | 0.007 | 0.001 |
| IOS | |||||
| Z5 (kPa/L/s) | 0.87 (0.67/1.11) | 0.95 (0.77/1.24) | 0.76 (0.70/1.08) | 0.02 | 0.003 |
| R5 (kPa/L/s) | 0.81 (0.62/1.05) | 0.93 (0.75/1.15) | 0.74 (0.64/0.93) | 0.03 | 0.002 |
| R10 (kPa/L/s) | 0.68 (0.50/0.84) | 0.76 (0.56/0.88) | 0.65 (0.56/0.74) | 0.23 | 0.01 |
| R15 (kPa/L/s) | 0.60 (0.45/0.80) | 0.68 (0.55/0.76) | 0.59 (0.48/0.69) | 0.47 | 0.28 |
| R20 (kPa/L/s) | 0.60 (0.42/0.76) | 0.58 (0.50/0.70) | 0.55 (0.48/0.69) | 0.82 | 0.35 |
| X5 (kPa/L/s) | −0.26 (−0.37/−0.12) | −0.30 (−0.42/−0.20) | −0.26 (−0.34/−0.15) | 0.03 | 0.003 |
| X10 (kPa/L/s) | −0.16 (−0.24/−0.02) | −0.23 (−0.35/−0.13) | −0.14 (−0.21/−0.06) | 0.001 | 0.002 |
| X15 (kPa/L/s) | −0.10 (−0.18/0.00) | −0.17 (−0.27/−0.08) | −0.09 (−0.14/0.00) | 0.001 | 0.001 |
| X20 (kPa/L/s) | −0.02 (−0.07/0.04) | −0.06 (−0.14/−0.02) | −0.03 (−0.07/0.04) | 0.002 | 0.001 |
| Delta R5–R20 (%) | 25.15 (10.6/36.7) | 35.78 (21.3/46.3) | 25.72 (13.7/34.4) | 0.01 | 0.009 |
| AX (kPa/L) | 2.22 (0.38/3.51) | 3 (1.57/6.07) | 1.85 (0.7/2.6) | 0.001 | 0.001 |
| Fres (L/s) | 20.97 (15.49/23.5) | 22.2 (21.1/29.3) | 21.4 (15.3/23.5) | 0.001 | 0.002 |
Comparison between baseline and at exacerbation.
Comparison between at exacerbation and after exacerbation.
FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; FEF25–75, forced expiratory flow during the middle half of FVC; Z5, the impedance at 5 Hz; R5, the resistance at 5 Hz; R10, the resistance at 10 Hz; R15, the resistance at 15 Hz; R20, the resistance at 20 Hz; X5, the reactance at 5 Hz; X10, the reactance at 10 Hz; X15, the reactance at 15 Hz; X20, the reactance at 20 Hz; AX, reactance area; Fres, resonance frequency; IOS, impulse oscillometry system.
Bronchodilator response
A total of 33 patients were evaluated for bronchodilator response. The mean age of these patients was 146.7 ± 52.5 months.
The mean FEV1s before and after the bronchodilator were 67.3% ± 19.3% and 71.1% ± 21.4%, respectively, with a statistically significant difference. The median increase in FEV1 was 4.5% (−9/20) after bronchodilators. Five patients had a ≥ 12% increase in FEV1. The highest change in IOS was observed in AX [−42.4% (−5.3/−81.4) decrease]. In the bronchodilator response, significant changes in spirometry (increase in FEV1 and FEF25–75) and changes in IOS (decrease in Z5, R5–R10, AX, Fres, delta R5–R20 and increase in X5–X10) were found (P < 0.05) (Table 3). Significant correlations between the change in FEV1 and the change in Z5, R5, X10, AX, Fres, and delta R5–R20 were found. The change in FEF25–75 was correlated with the Z5, X10, AX, Fres, and delta R5–R20 changes.
Table 3.
Spirometry and Impulse Oscillometry System Raw Values Before and After Bronchodilator Administration (N = 33)
| Before | After | P | |
|---|---|---|---|
| Spirometry | |||
| FEV1 | 1.73 ± 0.76 | 1.83 ± 0.83 | 0.001 |
| FVC | 2.08 ± 0.96 | 2.10 ± 0.97 | 0.65 |
| FEF25–75 | 1.89 ± 0.97 | 2.18 ± 1.06 | 0.00 |
| IOS | |||
| Z5 (kPa/L/s) | 0.87 ± 0.27 | 0.74 ± 0.19 | 0.003 |
| R5 (kPa/L/s) | 0.86 ± 0.23 | 0.70 ± 0.17 | 0.00 |
| R10 (kPa/L/s) | 0.71 ± 0.15 | 0.59 ± 0.13 | 0.00 |
| R15 (kPa/L/s) | 0.64 ± 0.12 | 0.56 ± 0.11 | 0.00 |
| R20 (kPa/L/s) | 0.60 ± 0.10 | 0.53 ± 0.10 | 0.00 |
| X5 (kPa/L/s) | −0.26 ± 0.14 | −0.20 ± 0.11 | 0.00 |
| X10 (kPa/L/s) | −0.18 ± 0.12 | −0.10 ± 0.08 | 0.00 |
| X15 (kPa/L/s) | −0.12 ± 0.10 | −0.05 ± 0.07 | 0.00 |
| X20 (kPa/L/s) | −0.05 ± 0.07 | 0.00 ± 0.05 | 0.00 |
| AX (kPa/L) | 2.62 ± 1.84 | 1.15 ± 1.14 | 0.00 |
| Fres (L/s) | 21.27 ± 6.31 | 18.69 ± 4.97 | 0.01 |
| Delta R5–R20 (%) | 27.23 ± 9.77 | 21.67 ± 8.13 | 0.001 |
FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; FEF25–75, forced expiratory flow during the middle half of FVC; Z5, the impedance at 5 Hz; R5, the resistance at 5 Hz; R10, the resistance at 10 Hz; R15, the resistance at 15 Hz; R20, the resistance at 20 Hz; X5, the reactance at 5 Hz; X10, the reactance at 10 Hz; X15, the reactance at 15 Hz; X20, the reactance at 20 Hz; AX, reactance area; Fres, resonance frequency; IOS, impulse oscillometry system.
Follow-up
Of the 70 patients included in the study, 31 were evaluated by PFT at 3-monthly intervals. Their mean annual z-score for FEV1 was observed to decrease from −2.96 to −3.24, FVC from −3.4 to −3.56, and FEF25–75 from −1.75 to −2.10. There was no significant difference between the spirometry z-scores (P > 0.05). While a statistically significant increase was observed in Z5% and R5%–R20%, no significant change was found for AX, Fres, or delta R5–R20. There was a gradual increase in X5–X20, but this was not significant (Fig. 2). When the clinical scores were evaluated, a significant decrease was observed (P < 0.05) (Table 4).
FIG. 2.
Changes in spirometry parameters (%) (A), IOS resistance values (%) (B) and IOS reactance values (C) in follow-up visits.
Table 4.
Comparison of Pulmonary Function Tests (Spirometry and Impulse Oscillometry System) in Follow-Up Visits (N = 31)
| First visit | Second visit (3 months) | Third visit (6 months) | Fourth visit (12 months) | P | |
|---|---|---|---|---|---|
| Spirometry, % | |||||
| FEV1 | 67.47 ± 26.40 | 64.05 ± 25.31 | 65.15 ± 24.74 | 64.10 ± 25.58 | 0.26 |
| FVC | 62.73 ± 23.41 | 60.21 ± 22.14 | 63.42 ± 22.29 | 61.52 ± 21.66 | 0.31 |
| FEV1/FVC | 105.84 ± 8.17 | 104.42 ± 10.13 | 100.15 ± 11.41 | 102.21 ± 12.51 | 0.05 |
| FEF25–75 | 70.10 ± 40.12 | 67.36 ± 41.87 | 61.26 ± 34.09 | 63.68 ± 37.74 | 0.07 |
| IOS | |||||
| Z5a, % | 150 (118.8/199.8) | 152.2 (114.7/257.9) | 150.2 (128.3/266.9) | 171.3 (132.1/273.9) | <0.001b |
| R5a, % | 151.6 (120/193.5) | 157.2 (119/235) | 157.7 (132.5/263.2) | 177.7 (133.9/240.7) | <0.001c |
| R10, % | 147.7 ± 47.23 | 162.23 ± 65.59 | 179.88 ± 68 | 191.74 ± 73 | 0.000d |
| R15, % | 131.13 ± 53.34 | 149 ± 55.31 | 165.73 ± 56.77 | 163.5 ± 63.42 | 0.02e |
| R20a, % | 136.9 (117.9/148.2) | 144.2 (108.2/170.2) | 160 (120.9/209.5) | 170.3 (133.8/207.5) | <0.001f |
| X5a, (kPa/L/s) | −0.23 (−0.40/−0.11) | −0.22 (−0.39/−0.11) | −0.17 (−0.32/−0.12) | −0.23 (−0.42/−0.14) | 0.13 |
| X10a, (kPa/L/s) | −0.18 (−0.23/−0.05) | −0.15 (−0.27/−0.05) | −0.12 (−0.28/−0.06) | −0.12 (−0.33/−0.03) | 0.83 |
| X15a, (kPa/L/s) | −0.11 (−0.16/−0.02) | −0.10 (−0.20/−0.03) | −0.07 (−0.20/−0.02) | −0.06 (−0.24/0.00) | 0.85 |
| X20, (kPa/L/s) | −0.02 ± 0.08 | −0.03 ± 0.08 | −0.03 ± 0.09 | −0.04 ± 0.09 | 0.77 |
| AXa, (kPa/L) | 2.39 (0.69/3.3) | 1.85 (0.70/4.26) | 1.45 (0.59/3.83) | 1.7 (0.52/4.73) | 0.77 |
| Fres, (L/s) | 21 ± 6.59 | 21.43 ± 5.97 | 21.21 ± 7 | 20.71 ± 6.83 | 0.73 |
| Delta R5–R20, % | 26.88 ± 13.27 | 28.98 ± 12.39 | 25.17 ± 12.85 | 23.73 ± 13.36 | 0.07 |
| Shwachman–Kulczycki Score | 55 (40/75) | 55 (40/75) | 55 (45/75) | 55 (40/75) | 0.04g |
Paired comparisons with Bonferroni test.
Nonparametric Brunner–Langer model.
Statistically significant difference between the first visit and the third and fourth visits, the second visit and the fourth visit (P < 0.05).
Statistically significant difference between the first visit and the third and fourth visits, the second visit and the fourth visit (P < 0.05).
Statistically significant difference between all visits (P < 0.05).
Statistically significant difference between the first visit and the fourth visit, the second visit and the fourth visit (P < 0.05).
Statistically significant difference between first and third and fourth visits, second and third and fourth visits (P < 0.05).
Statistically significant between the first visit and the third and fourth visit (P < 0.05).
FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; FEF25–75, forced expiratory flow during the middle half of FVC; Z5, the impedance at 5 Hz; R5, the resistance at 5 Hz; R10, the resistance at 10 Hz; R15, the resistance at 15 Hz; R20, the resistance at 20 Hz; X5, the reactance at 5 Hz; X10, the reactance at 10 Hz; X15, the reactance at 15 Hz; X20, the reactance at 20 Hz; AX, reactance area; Fres, resonance frequency; IOS, impulse oscillometry system.
Discussion
In this study, a significant correlation was observed between spirometry and IOS. Additionally, in exacerbation, we demonstrated impairment in both spirometry and IOS (an increase in Z5 Hz, R5–R10 Hz, AX, Fres, and delta R5–R20, and decrease in X5–X20 Hz). After treatment, the IOS and spirometry parameters were found to return to the baseline. In the bronchodilator response, significant changes in spirometry (increase in FEV1 and FEF25–75) and changes in IOS (decrease in Z5, R5–R10, AX, Fres, delta R5–R20 and increase in X5–X10) were found. While there was no difference between the spirometry values in follow-up visits, a significant increase in IOS (Z5% and R5%–R20%) was found. Although not statistically significant, there was a gradual increase in X5–X20. Unlike other studies, there was a significant negative correlation between the clinical scores and Z5, R5, AX, Fres, and delta R5–R20, and a positive correlation of these with X5–X20 Hz. These results show that IOS may be an alternative method that can be used for follow-up pulmonary function testing for CF patients.
In the early studies comparing spirometry and low-frequency FOT, the resistance of all airways was evaluated by FOT so there was no strong relationship between spirometry and FOT for CF patients with early peripheral airway involvement.21,22 This study has the highest number of patients yet recorded when comparing spirometry and IOS. The IOS values were significantly correlated with spirometry values for all aspects. Additionally, unlike other studies, there was a significant correlation between clinical scores and IOS. It is considered that patients who cannot perform spirometry can be evaluated and followed up with IOS if clinical status deteriorates.
Brennan et al.1 showed a significant correlation between pulmonary inflammation markers and low-frequency FOT in CF. After this study, it was aimed to determine whether IOS can detect changes in lung function by treatment of exacerbation.14,15 In a study by Sakarya et al.,15 IOS was used in the evaluation of the acute exacerbation and treatment response of 16 patients. When the IOS measurements were compared with the baseline values in exacerbation, a significant increase was detected in Z5 Hz, R5–R20 Hz, AX, and Fres, whereas a decrease was detected in X5–X20 Hz. All IOS parameters were shown to return to baseline after treatment, and it was concluded that IOS could be used to diagnose acute exacerbation and identify improvements after treatment. However, a comparison of IOS with spirometry was not made. Unlike other studies, we were able to measure IOS and spirometry and thus demonstrate that IOS can be used to evaluate both acute exacerbation and treatment response.
During acute exacerbation, compliance of lung tissue decreases due to increased inflammation and mucus secretion. Reactance decreases with the reduction in lung compliance and increases after treatment. Also, resistance increases due to airway obstruction during acute exacerbation and decreases after treatment.4–6 Consistent with this, we observed an increase in R5, AX, Fres, delta R5–R20, and in all reactance values compared with baseline in exacerbation. IOS parameters were shown to return to baseline after treatment.
There are few studies comparing spirometry and IOS use in the evaluation of bronchodilator response in CF. In a study by Hellinckx et al.,22 spirometry and IOS (Rrs6 and Xrs6) before and after bronchodilator were compared. The change in FEV1 (mean 3% ± 11%) in 20 patients was not significant, but a significant decrease in R6 (−16% ± 9%) and increase in X6 (21% ± 20%) were found. Six patients had a paradoxical decrease in FEV1, whereas none had an increase in R6. There was no correlation between the change in spirometry and IOS. In this study, a significant increase in FEV1 and FEF25–75 and a significant change in all IOS parameters were found after bronchodilator. Decreased airway tone after bronchodilator and a paradoxical decrease in FEV1 with forced expiratory maneuvers can occur during spirometry, resulting in difficulties in CF patients. IOS eliminates this difficulty of forced maneuver as it is only measured with patients doing tidal breathing.
After bronchodilator, beta-adrenergic receptors in the peripheral airways are affected. Spirometry may not provide detailed information at the early stage of obstruction as it reflects changes in larger airways. Since IOS can distinguish pressure waves from peripheral airways, it can provide more detailed information for bronchodilator response than spirometry. We demonstrated that IOS can be used to evaluate bronchodilator response. Reversible airway obstruction is frequently observed, especially in younger CF patients.23,24 IOS is a method that can be used to evaluate the bronchodilator response in young patients unable to perform spirometry.
In one of the studies on the use of IOS in CF, 30 CF patients, 2 to 7 years of age, were followed up for 48 months. Body plethysmography, Rint, IOS (Rrs5 and Xrs5), and spirometry (>6 years) were performed at 1-year intervals. A decrease in FEV1 was shown from the initial spirometry measurements, which was followed by a further, progressive decrease during the study period. IOS was found to be insufficient for the detection and follow-up of PFT impairment.9 In a study by Moreau et al.12 the results of 15 CF patients who underwent 5 different measurements at varying time intervals were examined. Whereas a significant decrease in FEV1 (74.3% to 60.1%) was found between the initial and final visits (range 1–5.9 years), only Fres among the IOS measurements showed a significant decrease. In this study, there was a progressive decline in spirometry, although not statistically significant. A significant increase was observed in Z5% and R5%–R20% and a gradual but nonsignificant increase in X5–X20. Nonsignificant spirometry results may have stemmed from the evaluation of repeated measurements in a short period of time. There was a significant decrease in the clinical scores and an increase in resistance values in IOS without a significant decrease in spirometry. The changes in IOS during the follow-up period may be a warning signal for pulmonary function impairment and indication to provide closer patient follow-up.
In our study, different usage areas of IOS in CF patients were evaluated. The retrospective study design is the most important limitation of our study. ROC analysis, to determine the power of IOS parameters identifying the degree of pulmonary function impairment found in spirometry (FEV1 40%, 60%, and 80%), was not evaluated. No specific IOS parameter and threshold value that could determine pulmonary exacerbation was determined. In addition, the specific IOS parameter showing improvement after bronchodilator and the amount of change were not determined. We believe that the results of our study provide preliminary work for different areas of use of IOS in CF. There are reference equations available for use in preschool and school-aged children. Not all studies reporting reference equations have reported all of the IOS parameters. Prospective studies can be conducted with larger number of patients for the steps that constitute the restrictive aspects of our study and clinical usage of IOS.
In conclusion, although IOS is less well recognized than spirometry, it may provide additional information in case of CF and be useful for patients who are unable to perform spirometry. IOS can provide a patient assessment by comparing the patient's own measurements and may be a warning method in case of impaired pulmonary function in patient follow-up. IOS can provide valuable information about lung mechanics in children with CF before the impairment in spirometry. Further studies with a larger sample size and patients with different degrees of pulmonary impairments will provide valuable further information on the use of IOS in CF.
Acknowledgments
The authors would like to thank biostatistician Gülden Hakverdi for helping with the statistical evaluation, and laboratory staff member Gökay Çelik for pulmonary function tests.
Author Disclosure Statement
The authors have reported to Pediatric Allergy, Immunology, and Pulmonology that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Funding Information
No funding was received for this article.
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