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Respiratory Physiology & Neurobiology 185 (2013) 235– 240

Contents lists available at SciVerse ScienceDirect

Respiratory Physiology & Neurobiology

j our nal ho me p age: www.elsev ier .com/ locate / resphys io l

espiratory mechanics measured by forced oscillation technique in combinedulmonary fibrosis and emphysema

azutaka Moria,b, Toshihiro Shirai a,∗, Masashi Mikamoa, Yuichiro Shishidoa, Takefumi Akitaa,atoru Moritaa, Kazuhiro Asadaa, Masato Fujii a, Hironao Hozumib, Takafumi Sudab, Kingo Chidab

Department of Respiratory Medicine, Shizuoka General Hospital, Shizuoka, JapanDepartment of Respiratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan

r t i c l e i n f o

rticle history:ccepted 22 October 2012

eywords:OPD

mpedance

a b s t r a c t

The coexistence of emphysema and pulmonary fibrosis is known as combined pulmonary fibrosis andemphysema (CPFE). The aim of this study was to compare the lung mechanics measured by multi-frequency forced oscillation technique (FOT) among patients with CPFE, interstitial pneumonia (IP), andchronic obstructive pulmonary disease (COPD). FOT and pulmonary function tests were performed in 41patients with CPFE, 47 with IP, and 86 with COPD. Whole-breath resistance at 20 Hz was significantly

nterstitial pneumoniaulti-frequencyhole-breathithin-breath

lower in patients with CPFE than in those with IP or COPD, irrespective of the severity of airflow limitation.Within-breath analyses of resistance revealed no difference among the 3 groups; however, the differencebetween inspiratory and expiratory phases of reactance at 5 Hz, which reflects expiratory flow limitation,in patients with CPFE was significantly higher than in those with IP and lower than in those with COPD.In conclusion, both emphysema and fibrosis affect lung mechanics in CPFE, leading to different findingsfrom IP or COPD alone.

. Introduction

The forced oscillation technique (FOT) is a noninvasive methodith which to measure respiratory impedance, the spectral rela-

ionship between pressure and airflow (Oostveen et al., 2003). Theeal part of impedance is called respiratory system resistance (Rrs),hereas the imaginary part is called respiratory system reactance

Xrs), which is supposed to reflect elastic and inertial properties ofhe lung. Recently, clinical application of the FOT has progressedith the spread of commercially available multi-frequency FOTevices: the impulse oscillation system (Hellinckx et al., 2001)nd MostGraph-01 (Kurosawa et al., 2009). Increasing numbers

f reports have examined the usefulness of FOT in the evalua-ion or management of obstructive lung diseases, including chronicbstructive pulmonary disease (COPD) or asthma (Paredi et al.,

∗ Corresponding author at: Department of Respiratory Medicine, Shizuoka Gen-ral Hospital, 4-27-1 Kita-ando, Aoi, Shizuoka 420-0881, Japan.el.: +81 54 247 6111; fax: +81 54 247 6159.

E-mail addresses: mori-kazutaka@tokai.or.jp (K. Mori),mjkshi@general-hosp.pref.shizuoka.jp (T. Shirai),

asa.mikam@gmail.com (M. Mikamo), sisidiba@gmail.com (Y. Shishido),kita@general-hosp.pref.shizuoka.jp (T. Akita), cqn00563@nifty.com (S. Morita),azuhiro asada@general-hosp.pref.shizuoka.jp (K. Asada), mfujii74@gmail.comM. Fujii), jubilooreoresagi@yahoo.co.jp (H. Hozumi), suda@hama-med.ac.jpT. Suda), chidak11@hama-med.ac.jp (K. Chida).

569-9048/$ – see front matter © 2012 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.resp.2012.10.009

© 2012 Elsevier B.V. All rights reserved.

2010; Kanda et al., 2010; Mori et al., 2011); however, FOT doesnot yield distinctive data in patients with restrictive lung disease(Oostveen et al., 2003).

The coexistence of emphysema and pulmonary fibrosis is knownas combined pulmonary fibrosis and emphysema (CPFE), character-ized by dyspnea, upper-lobe emphysema, and lower-lobe fibrosis(Cottin et al., 2005; Jankowich and Rounds, 2012). This conditioncommonly occurs in male smokers and is complicated by pul-monary hypertension and lung cancer. Pulmonary function testsdemonstrate normal or near-normal spirometry and lung volumesbut severely diminished diffusing capacity of the lung. The former isattributed to the counterbalancing effect of the restrictive defect ofpulmonary fibrosis and hyperinflation due to emphysema. Thus,emphysema and pulmonary fibrosis have different physiologiceffects; however, forced oscillatory mechanics in this disorder isunknown.

Expiratory flow limitation (EFL) during tidal breathing is com-mon in patients with COPD and is caused by the loss of lungelastic recoil due to emphysema. Recent studies have indicated thatwithin-breath changes (the difference between inspiratory andexpiratory phases) of Xrs measured with FOT reflect EFL (Dellacàet al., 2004; Paredi et al., 2010; Kanda et al., 2010). In contrast to

COPD or emphysema, interstitial pneumonia or pulmonary fibrosisresults in increased lung elastic recoil; therefore, we hypothesizedthat there would be a counterbalancing effect of emphysema andfibrosis on lung mechanics, in particular within-breath changes of

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rs, in patients with CPFE. In this cross-sectional study we assessedhe differences in lung mechanics measured with multi-frequencyOT between patients with CPFE and those with COPD or interstitialneumonia (IP).

. Methods

.1. Subjects

One hundred and eighty-nine patients with COPD or IP whottended outpatient clinics at Shizuoka General Hospital for routineheck-ups between October 2009 and August 2012 were enrolledn this study.

The COPD patients satisfied the definition of the Global Initia-ive for Chronic Obstructive Lung Disease (GOLD, 2011). They werelinically stable and had had no exacerbations, defined as increasedyspnea associated with a change in the quality and quantity of spu-um, for at least one month before the study. We classified COPDatients into mild to moderate with GOLD 1 and 2, and severe withOLD 3 and 4 according to the severity of airflow limitation of theOLD guideline (GOLD, 2011).

The IP patients were diagnosed by chest radiologists usingigh-resolution computed tomography (HRCT). Patients who hadhe following HRCT findings, including honeycombing or reticularpacity, were enrolled. Patients diagnosed with collagen vascularisease, chronic hypersensitivity pneumonitis, drug-induced lung

njury, sarcoidosis, pneumoconiosis, lung cancer and other infec-ious pulmonary disease were excluded.

The protocols were approved by the local ethics committee andnformed consent was obtained from all subjects prior to the study.

.2. Evaluation of HRCT findings and patient classification

CT scans were performed with a helical CT system with a4-row detector (Aquilion; Toshiba, Tokyo, Japan). HRCT imagesonsisted of 1-mm collimation sections, at 10-mm intervals, at endnspiration, taken in a supine position and reconstructed by a high-patial-frequency algorithm. The images were obtained at windowettings appropriate for viewing the lung parenchyma (windowevel from −600 to −800 Hounsfield units (HU) and window widthrom 1200 to 2000 HU). Intravenous constant medium was notsed.

HRCT images of the study patients were reviewed indepen-ently by 2 well-trained pulmonary physicians who were unawaref the clinical information and determined by consensus reading.n each patient, CT findings were evaluated at 3 anatomic levelsn both lungs: near the superior margin of the aortic arch (level ofhe upper lung field), at the level of the carina (level of the middleung field), and at the level of the orifice of the inferior pulmonaryeins (level of the lower lung field). Each HRCT finding was inter-reted according to current Fleischner criteria (Hansell et al., 2008;ozumi et al., 2011).

Emphysema was defined as a focal region of low attenuationithout visible walls. Cysts were defined as round air spaces with

well-defined wall. Emphysema with cysts, if any, was scoredisually in the 6 fields according to the methods of Goddard et al.Goddard et al., 1982; Kitaguchi et al., 2010) and summed. The scoren each lung field was calculated according to the percentage of low-ttenuation areas (%LAA): score 0, %LAA <5%; score 1, %LAA ≥5% to25%; score 2, %LAA ≥25% to <50%; score 3, %LAA ≥50% to <75%;nd score 4, %LAA ≥75%. Thus, the total emphysema scores ranged

rom 0 to 24.

Fibrosis consisted of honeycombing and reticular opacity in theresent study. Honeycombing was defined as the appearance oflustered cystic air spaces, typically of comparable diameters in

eurobiology 185 (2013) 235– 240

the order of 3–10 mm, but occasionally as large as 2.5 cm, in thesubpleural regions, with well-defined walls. Reticular opacity wasconsidered present when interlacing line shadows separated by afew millimeters were seen. Fibrosis was scored according to thesame procedure as emphysema and summed; thus, the total fibro-sis scores ranged from 0 to 24.

The study patients were classified into 3 groups according to thetotal scores of emphysema and fibrosis: CPFE group, emphysema≥4 and fibrosis ≥4; COPD group, emphysema ≥4 and fibrosis <4;and IP group, emphysema <4 and fibrosis ≥4. Patients with bothemphysema and fibrosis scores of <4 were excluded from the study.

2.3. Measurement of respiratory impedance and pulmonaryfunction tests

On the same examination day, when their clinical symptomswere stable, measurements of respiratory impedance using FOTand pulmonary function tests were performed in that order. Short-acting beta-2 agonists were not used for more than 12 h beforethese tests in every case. Long-acting beta-2 agonists or inhaledcorticosteroid/long-acting beta-2 agonist combinations were takenafter the test.

Respiratory impedance was measured with multi-frequencyFOT using a commercially available device (MostGraph-01; ChestM.I. Co. Ltd., Tokyo, Japan) (Kurosawa et al., 2009; Mori et al.,2011) and met standard recommendations (Oostveen et al., 2003).Impulse oscillatory signals generated by a loud speaker at inter-vals of 0.25 s were applied to the respiratory system through themouthpiece during tidal breathing at rest. Mouth pressure andflow signals were measured and calculated to obtain Rrs and Xrsproperties against oscillatory frequency ranging from 4 to 36 Hz.During measurements, the subjects supported their cheeks firmlyto reduce upper airway shunting while sitting with their neck in acomfortable neutral posture. We used Rrs at 5 and 20 Hz (R5 andR20, respectively), Xrs at 5 Hz (X5), which reflects elastic or inertialproperties of the lung, resonant frequency (Fres) where Xrs crosseszero and the elastic and inertial forces are equal in magnitude andopposite, and a low-frequency reactance area (ALX), which is theintegral of Xrs at 5 Hz to the Fres. Each oscillatory index is expressedas the mean of 5 respiratory cycles (whole-breath), inspiratory andexpiratory phases, and the differences between inspiratory andexpiratory phases (�).

Spirometry, lung volumes, diffusing capacity of the lung for car-bon monoxide (DLco), and DLco/alveolar volume (DLco/VA) weredetermined using computerized equipment (model CHESTAC-8800; Chest M.I. Co. Ltd., Tokyo, Japan) according to the recommen-dations of the American Thoracic Society 1994 (American ThoracicSociety, 1995; Wanger et al., 2005).

2.4. Statistical analysis

Comparisons among 3 groups were made using theKruskal–Wallis test, followed by multiple comparisons amonggroups using the Mann–Whitney U test. p values in multiplecomparisons were adjusted using Holm’s method. The chi-squareor Fisher’s exact test was used to test significance in group dif-ferences with respect to the percentage of patients in variouscategories. Correlations between variables were performed usingthe Spearman rank correlation coefficient. The Wilcoxon singedrank test was used to analyze inspiratory–expiratory changes in

the same subjects. All statistical analyses were performed using Rversion 2.11.1 (The R Foundation for Statistical Computing, Vienna,Austria, 2010). A value of p < 0.05 was considered significant forthe results of all statistical analyses, and all tests were 2 sided.

K. Mori et al. / Respiratory Physiology & N

Fig. 1. Patient classification on the basis of high-resolution computed tomographyfindings. Study patients were classified into 3 groups according to the total scoresof emphysema and fibrosis: CPFE group, emphysema ≥4 and fibrosis ≥4; COPDg≥s

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roup, emphysema ≥4 and fibrosis <4; and IP group, emphysema <4 and fibrosis4. Patients with both emphysema and fibrosis scores of <4 were excluded from the

tudy. Abbreviations: E, emphysema; F, fibrosis.

. Results

.1. Characteristics of the subjects

The patient grouping is presented in Fig. 1. On the basis of theRCT findings, 189 subjects were grouped into 41 patients withPFE, 47 with IP, and 86 with COPD. Fifteen patients were excludedrom the study. All the patients in the COPD group satisfied theefinition of GOLD.

The clinical characteristics of the patients are shown in Table 1.atients with CPFE and those with COPD had significant male pre-ominance and more pack-years than those with IP. Patients withOPD had the lowest body mass index. Patients with CPFE showed

ormal or near-normal spirometry and lung volumes but severelyiminished diffusing capacity. FEV1, FEV1/FVC, and FEF25–75%ere significantly higher and RV and TLC were lower in patientsith CPFE than in those with COPD. There was no difference in

able 1haracteristics of the study patients.

CPFE (n = 41) IP (n = 47) CO

Age (years) 71 (57–85) 70 (32–85) 72

Gender (male/female) 39/2* 20/27† 79/Body mass index (kg/m2) 23.4 (15.4–29.6)† 23.1 (15.6–38.1)† 21.Smoking history

Current/ex/never smoker 5/34/2* 1/20/26† 14/Pack years 44 (0–180)* 0 (0–125)† 54

CT scoresEmphysema 9 (4–21)*,† 0 (0–2)† 12

Fibrosis 8 (4–12)† 10 (4–21)† 0 (0Pulmonary functions

FVC (% predicted) 77.4 (37.6–113.1) 73.7 (31.0–120.7)† 83.FEV1 (% predicted) 77.1 (30.3–114.5)† 78.7 (27.5–141.2)† 53.FEV1/FVC (%) 77.5 (30.4–121)*,† 83.0 (63.0–100)† 49.FEF25–75% (% predicted) 59.4 (9.5–146.5)*,† 70.8 (17.5–216.7)† 17.RV (% predicted) 85.0 (35.3–206.1)† 80.8 (37.3–226.6)† 150TLC (% predicted) 85.3 (42.9–130.8)† 79.9 (47.7–151.9)† 112DLco (% predicted) 49.9 (11.6–78.6)*,† 69.1 (27.8–145.1) 65.DLco/VA (% predicted) 59.2 (18.8–101.8)*,† 93.3 (52.7–125.3)† 51.

alues are shown in median (range) or numbers. Abbreviations: DLco, diffusing capacity

nd 75% of FVC; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; RV, resi* p < 0.05 versus IP.† p < 0.05 versus COPD.‡ p < 0.05 versus CPFE.

eurobiology 185 (2013) 235– 240 237

FEV1 between patients with CPFE and those with mild to moder-ate COPD or IP. The DLco was lowest in patients with CPFE and theDLco/VA was lower in patients with CPFE and COPD than in thosewith IP.

3.2. HRCT scores

Table 2 shows the HRCT scores of each lung field in the studypatients. Patients with CPFE showed a trend of upper-lobe emphy-sema and lower-lobe fibrosis. Emphysema scores of all lung zoneswere significantly higher in patients with CPFE and COPD thanin those with IP. There were some differences in the distributionof emphysema between patients with CPFE and COPD; however,there was no difference in the distribution of emphysema betweenpatients with CPFE and those with mild to moderate COPD. Fibrosisscores were significantly higher in patients with CPFE and IP than inthose with COPD. There were some differences in the distributionof fibrosis between patients with CPFE and IP; however, there wasno difference in fibrosis scores between the 2 groups.

FVC negatively correlated with fibrosis scores in patients withCPFE and those with IP (rho = −0.50, p < 0.001 for CPFE; andrho = −0.61, p < 0.001 for IP, respectively). TLC correlated withemphysema and fibrosis scores in patients with CPFE (rho = 0.53,p < 0.001; and rho = −0.69, p < 0.001, respectively), and fibrosisscores in patients with IP (rho = −0.69, p < 0.001) (data not shown).

3.3. Whole-breath and within-breath analyses of Rrs and Xrs

As shown in Table 3 and Fig. 2, whole-breath R20 values weresignificantly lower in patients with CPFE than in those with IP orCOPD, irrespective of the severity of airflow limitation in patientswith COPD. X5 was less negative and R5, Fres, and ALX were lowerin patients with CPFE than in those with COPD, in particular severeCOPD.

Within-breath analyses of Rrs revealed that the expiratory val-ues were significantly higher than the inspiratory values; however,there was no difference among the 3 groups. In contrast, there was

no significant difference between inspiratory and expiratory valuesof Xrs in patients with CPFE compared to those with COPD or IP.Also, expiratory X5 was less negative and Fres and ALX were lowerthan inspiratory values in patients with IP, which was a reverse

PD (n = 86) Mild to moderate COPD (n = 46) Severe COPD (n = 40)

(54–86) 73 (54–84) 70 (57–86)7 42/4 37/30 (15.2–27.7) 22.0 (15.6–27.7) 20.0 (15.2–24.6)‡

72/0 9/37/0 5/35/0(5–300) 46 (7–150) 65 (5–300)‡

(4–23) 10 (5–21) 14 (4–23)‡

–3) 0 (0–3)‡ 0 (0–3)‡

7 (33.0–144.0) 95.0 (66.7–144.0)‡ 68.4 (33.0–103.4)‡

2 (17.0–111.7) 73.1 (50.5–111.7) 32.3 (17.0–46.4)‡

5 (25.3–70.0) 59.7 (42.0–70.0)‡ 38.8 (25.3–68.0)‡

4 (0.3–73.8) 30.0(12.0–73.8)‡ 9.6 (0.3–22.0)‡

.3 (69.6–332.0) 124.4(69.6–240.6)‡ 185.7 (105.3–332.0)‡

.8 (76.5–152.2) 108.0 (79.0–137.3)‡ 114.7 (76.5–152.2)‡

3 (30.9–122.7) 68.5 (32.9–120.8)‡ 53.2 (30.9–122.7)1 (22.1–135.2) 57.1 (25.4–85.2) 45.1 (22.1–135.2)‡

of the lung for carbon monoxide; FEF25–75%, forced expiratory flow between 25%dual volume; TLC, total lung capacity; VA, alveolar volume; VC, vital capacity.

238 K. Mori et al. / Respiratory Physiology & Neurobiology 185 (2013) 235– 240

Table 2High-resolution CT scores of the study patients.

CPFE IP COPD Mild to moderate COPD Severe COPD

Right Left Right Left Right Left Left Left Right Left

EmphysemaUpper zone 2.17*,† 1.83* 0.15† 0.06† 2.62 2.20 2.39 2.00 2.88‡ 2.43Middle zone 1.68*,† 1.54*,† 0.04† 0.02† 2.09 1.87 1.91 1.72 2.30‡ 2.05‡

Lower zone 1.49* 1.39* 0.02† 0.02† 1.79 1.72 1.59 1.44 2.03 2.05‡

FibrosisUpper zone 0.76*,† 0.61*,† 1.11† 1.11† 0.16 0.09 0.09‡ 0.07‡ 0.25‡ 0.13‡

Middle zone 1.00*,† 1.00*,† 1.45† 1.38† 0.11 0.02 0.16‡ 0.02‡ 0.05‡ 0.03‡

Lower zone 2.05† 2.22† 2.13† 2.19† 0.26 0.16 0.38‡ 0.16‡ 0.13‡ 0.18‡

Values are shown in means.* p < 0.05 versus IP.† p < 0.05 versus COPD.‡ p < 0.05 versus CPFE.

Table 3Whole-breath and within-breath analyses of respiratory system resistance and reactance.

CPFE (n = 41) IP (n = 47) COPD (n = 86) Mild to moderate COPD (n = 46) Severe COPD (n = 40)

R5 (cmH2O/L/s)Whole-breath 3.37 ± 1.18† 4.23 ± 1.89 4.48 ± 1.46 4.01 ± 1.44 5.02 ± 1.30§

Inspiratory 3.09 ± 1.19† 3.76 ± 1.83 4.00 ± 1.32 3.23 ± 1.20 4.66 ± 1.14§

Expiratory 3.65 ± 1.23*,† ,‡ 4.83 ± 2.14‡ 5.00 ± 1.83‡ 4.50 ± 1.96‡ ,§ 5.46 ± 1.58‡ ,§

�R5 −0.55 ± 0.53 −1.06 ± 1.17 −1.00 ± 1.35 −1.18 ± 1.48 −0.80 ± 1.16�R5/Ave. R5 −0.16 ± 0.16 −0.25 ± 0.28 −0.22 ± 0.30 −0.29 ± 0.37 −0.16 ± 0.23

R20 (cmH2O/L/s)Whole-breath 2.60 ± 0.78*,† 3.40 ± 1.37 3.26 ± 0.95 3.09 ± 1.02§ 3.46 ± 0.83§

Inspiratory 2.47 ± 0.80† 3.14 ± 1.29 3.05 ± 0.88 2.82 ± 0.92 3.32 ± 0.76§

Expiratory 2.72 ± 0.83*,† ,‡ 3.66 ± 1.51‡ 3.47 ± 1.15‡ 3.35 ± 1.28‡ ,§ 3.60 ± 0.97‡ ,§

�R20 −0.25 ± 0.37 −0.51 ± 0.60 −0.42 ± 0.74 −0.53 ± 0.86 −0.28 ± 0.55�R20/Ave. R20 −0.10 ± 0.14 −0.15 ± 0.18 −0.13 ± 0.23 −0.17 ± 0.28 −0.08 ± 0.16

X5 (cmH2O/L/s)Whole-breath −0.86 ± 0.65† −1.01 ± 0.71 −1.75 ± 1.48 −1.00 ± 1.11 −2.62 ± 1.39§

Inspiratory −0.81 ± 0.58 −1.09 ± 0.80 −1.13 ± 0.94 −0.64 ± 0.57§ −1.69 ± 0.98§

Expiratory −0.88 ± 0.87† −0.92 ± 0.71† ,‡ −2.36 ± 2.22‡ −1.34 ± 1.83‡ −3.54 ± 2.04‡ ,§

�X5 0.07 ± 0.63*,† −0.18 ± 0.56† 1.23 ± 1.68 0.69 ± 1.58§ 1.85 ± 1.59§

�X5/Ave. X5 −0.08 ± 0.73*,† 0.18 ± 0.56† −0.70 ± 0.96 −0.70 ± 1.59§ −0.71 ± 0.61§

Fres (Hz)Whole-breath 10.30 ± 3.61† 10.37 ± 3.54† 14.05 ± 6.26 10.21 ± 4.10 18.47 ± 5.39§

Inspiratory 10.24 ± 3.02 10.64 ± 3.61 12.33 ± 5.75 8.80 ± 2.90§ 16.40 ± 5.53§

Expiratory 10.25 ± 4.67† 10.08 ± 3.79† ,‡ 15.67 ± 7.47‡ 11.42 ± 5.96‡ 20.55 ± 5.91‡ ,§

�Fres −0.01 ± 2.70† 0.56 ± 2.11† −3.34 ± 4.54 −6.36 ± 5.02§ −4.15 ± 3.82§

�Fres/Ave. Fres −0.001 ± 0.26† 0.05 ± 0.20† −0.24 ± 0.32 −0.26 ± 0.49§ −0.22 ± 0.21§

ALX (cmH2O/L/s Hz)Whole-breath 4.61 ± 4.51† 5.11 ± 4.85† 13.56 ± 14.06 6.27 ± 9.45 21.95 ± 13.90§

Inspiratory 4.15 ± 4.05 5.51 ± 5.43 7.97 ± 9.66 3.13 ± 4.03§ 13.55 ± 11.19§

Expiratory 4.72 ± 6.04† 4.69 ± 4.87† ,‡ 19.52 ± 21.30‡ 9.49 ± 16.35‡ 31.05 ± 20.63‡ ,§

�ALX −0.82 ± 4.77† 0.81 ± 3.47† −11.54 ± 9.66 −6.36 ± 14.37§ −17.50 ± 16.79§

�ALX/Ave. ALX −0.18 ± 1.04† 0.16 ± 0.68† −0.85 ± 1.21 −1.01 ± 2.29§ −0.80 ± 0.76§

Values are the means ± SD or (range). Abbreviations: Ave., average whole-breath; �, difference between inspiratory and expiratory phases; X5, respiratory system reactanceat 5 Hz; R5 and R20, respiratory system resistance at 5 Hz and 20 Hz; Fres, resonant frequency; ALX, low-frequency reactance area.

* p < 0.05 versus IP.† p < 0.05 versus COPD.‡

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p < 0.05 versus inspiratory phase.§ p < 0.05 versus CPFE.

hange compared to those observed in patients with COPD. �X5as significantly higher in patients with CPFE than in those with IP

nd lower than in those with COPD, irrespective of the severity ofirflow limitation in patients with COPD. There was also a similarrend for �Fres and �ALX. These relationships among the 3 groupsere confirmed by the corrected values for average whole-breathrs.

. Discussion

We assessed the differences in respiratory impedance measuredith multi-frequency FOT between patients with CPFE and those

with COPD or IP. We demonstrated that whole-breath R20 wassignificantly lower in patients with CPFE than in those with IP orCOPD. Within-breath analyses of Rrs revealed no difference amongthe 3 groups; however, �X5 was significantly higher in patientswith CPFE than in those with IP and lower than in those with COPD.There was no difference in the degree of fibrosis between patientswith CPFE and IP. Moreover, the degree of obstructive impairmentin patients with CPFE was similar to that with mild to moderateCOPD. These results suggest that both emphysema and fibrosis

affect lung mechanics in CPFE, leading to different findings fromIP or COPD alone.

Whole-breath, inspiratory, or expiratory R5 and R20 were sig-nificantly lower in patients with CPFE than in COPD, whereas

K. Mori et al. / Respiratory Physiology & Neurobiology 185 (2013) 235– 240 239

Fig. 2. Comparison of respiratory resistance at 20 Hz (R20) and reactance at 5 Hz (X5) among patients with CPFE, COPD, and IP. Whole-breath R20 values were significantlylower in patients with CPFE than in those with IP or COPD, while whole-breath X5 values were lower in patients with CPFE than in those with COPD. There was no significantdifference in the �R20 among the 3 groups; however, �X5 was significantly higher in the CPFE group than in the IP group and lower than in the COPD group. Abbreviations:�, difference between inspiratory and expiratory phases. Closed and open circles and triangles represent patients with CPFE, COPD, and IP, respectively. Horizontal barss

tRCsf(rpe

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how median values in each group.

he differences were statistically significant only for whole-breath20 and expiratory R5 and R20 compared to mild to moderateOPD. Similarly, whole-breath R5 and expiratory R5 and R20 wereignificantly lower in patients with CPFE than in those with IP. Inact, the R20 values for CPFE seem close to the average Rrs values2.97 cmH2O/L/s) of the normal control subjects in our previouseport (Mori et al., 2011). One explanation for this finding includesseudonormalization of lung mechanics in CPFE, as seen on spirom-try in CPFE.

Previous studies have indicated that within-breath changes ofrs measured with FOT allowed detection of the EFL (Dellacà et al.,004; Paredi et al., 2010). EFL during tidal breathing is a majoreterminant of dynamic hyperinflation and exercise limitation inOPD. EFL is common in patients with COPD and is caused byhe loss of lung elastic recoil. It is supposed that reactance nor-

ally reflects the elastic and inertial properties of the respiratoryystem but, with flow limitation, oscillatory signals cannot passhrough the choke points and reach the alveoli, producing a marked

eduction in the apparent compliance and a fall in reactance. In arevious study, we found that within-breath changes in Xrs (�X5nd �Fres) discriminated between patients with COPD and asthmaMori et al., 2011). Other investigators obtained similar results with

the impulse oscillation system, a slight different method of FOTfrom the method in the present study. Paredi et al. (2010) foundthat inspiratory–expiratory X5 analysis differentiated patients withasthma from those with COPD. Kanda et al. (2010) also demon-strated that within-breath changes in X5 were significantly greater,but not R5, in patients with COPD than in those with asthma or con-trols. Thus, these results indicate that within-breath Xrs analysesare a useful technique to diagnose COPD or pulmonary emphysemaand possibly to detect EFL as a surrogate marker.

Very few investigators have examined respiratory impedancein restrictive lung diseases. Van Noord et al. (1989) measured Rrsand Xrs between 4 and 26 Hz by means of FOT in patients withdiffuse interstitial lung diseases. They observed higher values ofRrs and decreases in Xrs, which were similar to those in moderateobstructive lung diseases, but they did not analyze within-breathchanges. In the present study, we also confirmed no difference inwhole-breath Rrs and Xrs between patients with IP and those withmild to moderate COPD. Within-breath analyses of Xrs showed that

expiratory X5 values were less negative and Fres and ALX valueswere lower than inspiratory values in patients with IP, which was areverse change compared to patients with COPD. We speculate thatthese changes may be derived from increased lung elastic recoil

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Standardisation of the measurement of lung volumes. European Respiratory

40 K. Mori et al. / Respiratory Physiolo

esulting from pulmonary fibrosis. Also, the severity of airflowimitation is another speculation because there was no differencen whole-breath X5 or �X5 between patients with IP and those

ith mild to moderate COPD. Further studies are needed to confirmhese changes, investigate their cause and establish the usefulnessf FOT in restrictive lung diseases.

CPFE consists of different physiologic disorders: emphysemand pulmonary fibrosis. Emphysema causes reduced lung elas-ic recoil, increased lung compliance, and increased lung volumesith reduced maximal expiratory flow rates, whereas pulmonarybrosis results in increased lung elastic recoil, decreased lungompliance, and reduced lung volumes with preserved or evenncreased maximal expiratory flow rates at a given lung volumeJankowich and Rounds, 2012; West, 2012). We speculate thato within-breath changes of Xrs found in patients with CPFE isttributed to the counterbalancing effect of emphysema and pul-onary fibrosis; that is, increased traction caused by pulmonary

brosis prevents the typical expiratory airway collapse seen inmphysema. Thus, �X5 values in patients with CPFE showed inter-ediate values between patients with COPD and those with IP. To

he best of our knowledge, this is the first study to demonstrate theignificance of FOT in patients with CPFE compared to those withOPD or IP.

There is currently no consensus definition of CPFE; in particu-ar, it is unclear what extent of emphysema and fibrosis is requiredo discriminate patients with CPFE from those with COPD or IP.n the basis of HRCT findings in the present study, we definedatients with CPFE as those with emphysema score ≥4 and fibrosiscore ≥4. We considered significant emphysema or fibrosis as theresence of each finding in over half of the total lung fields. As aesult, patients with CPFE had the same clinical and physiologicaleatures as reported previously (Cottin et al., 2005; Jankowich andounds, 2012). Also, there were significant correlations betweenmphysema or fibrosis scores and pulmonary functions, indicatinghe validity of disease criteria in the present study. Most patientsith CPFE were derived from those with the initial diagnosis of IP,

uggesting the possibility that CPFE may be underestimated in IPatients. Patients with COPD had emphysema and patients with

ess or no emphysema were excluded from the study, whereasatients with IP were clinically diagnosed without pathologicalonfirmation.

In conclusion, both emphysema and fibrosis affect lung mechan-cs in CPFE, leading to different findings from IP or COPD alone.

ithin-breath analyses of respiratory reactance using a multi-requency FOT device are a useful tool to investigate lung mechanicsn not only COPD, but also in CPFE and IP.

unding

None.

eurobiology 185 (2013) 235– 240

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