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Respiratory Physiology & Neurobiology 184 (2012) 80– 85

Contents lists available at SciVerse ScienceDirect

Respiratory Physiology & Neurobiology

j o ur nal homep age : www.elsev ier .com/ locate / resphys io l

irway distensibility with lung inflation after allogeneic haematopoietictem-cell transplantation�

iovanni Barisionea,∗, Pasquale P. Pompiliob, Andrea Bacigalupoc, Claudia Brusascod, Alex Cioèa,affaele L. Dellacàb, Teresa Lamparelli c, Alessandro Garlaschie, Riccardo Pellegrinof, Vito Brusascod

Fisiopatologia Respiratoria, IRCCS Azienda Ospedaliera Universitaria San Martino – IST, Genoa, ItalyDipartimento di Bioingegneria, Politecnico di Milano, Milan, ItalyEmatologia 2, IRCCS Azienda Ospedaliera Universitaria San Martino – IST, Genoa, ItalyDipartimento di Medicina Interna, Università di Genova, Genoa, ItalyRadiologia, IRCCS Azienda Ospedaliera Universitaria San Martino – IST, Genoa, ItalyAllergologia e Fisiopatologia Respiratoria, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy

r t i c l e i n f o

rticle history:ccepted 24 July 2012

eywords:llogeneic haematopoietic stem-cell

ransplantationorced oscillation techniqueespiratory system conductance

a b s t r a c t

The ability to reverse induced-bronchoconstriction by deep-inhalation increases after allogeneichaematopoietic stem-cell transplantation (HSCT), despite a decreased total lung capacity (TLC). Wehypothesized that this effect may be due to an increased airway distensibility with lung inflation, likelyrelated to an increment in lung stiffness. We studied 28 subjects, 2 weeks before and 2 months after HSCT.Within-breath respiratory system conductance (Grs) at 5, 11 and 19 Hz was measured by forced oscilla-tion technique (FOT) at functional residual capacity (FRC) and TLC. Changes in conductance at 5 Hz (Grs5)were related to changes in lung volume (�Grs5/�VL) to estimate airway distensibility. Grs at FRC showed

irway distensibility with lung inflationronchiolitis obliterans syndrome

a slight but significant increase at all forcing frequencies by approximately 12–16%. TLC decreased afterHSCT whereas the �Grs5/�VL ratio became higher after than before HSCT and was positively correlated(R2 = 0.87) with lung tissue density determined by quantitative CT scanning.

We conclude that airway caliber and distensibility with lung inflation are increased after HSCT. Thiseffect seems to be related to an increase in lung stiffness and must be taken into account when interpreting

er HS

lung function changes aft

. Introduction

In allogeneic haematopoietic stem-cell transplantation (HSCT)ecipients, reductions of absolute lung volume and diffusing

Abbreviations: HSCT, allogeneic haematopoietic stem-cell transplantation;SM, airway smooth muscle; BOS, bronchiolitis obliterans syndrome; FOT, forcedscillation technique; GvHD, graft-versus-host disease; Zrs, respiratory systemmpedance; Rinsp, mean inspiratory resistance; Xrs5FRC, 5 Hz respiratory system reac-ance measured at FRC; Rrs, respiratory system resistance; Grs, respiratory systemonductance; VL, lung volume; CT, computed tomography; FEV1, forced expiratoryolume in one second; VC, vital capacity; TLC, total lung capacity; FRC, functionalesidual capacity; RV, residual volume; DLCO, lung diffusing capacity for carbononoxide.

� ClinicalTrials.gov; No.: NCT01255449 (FOT-BOS); URL: http://www.linicaltrials.gov/.∗ Corresponding author. Tel.: +39 010 555 3367; fax: +39 010 555 6667.

E-mail addresses: giovanni.barisione@hsanmartino.it (G. Barisione),asquale.pompilio@gmail.com (P.P. Pompilio), andrea.bacigalupo@hsanmartino.itA. Bacigalupo), claudia.brusasco@gmail.com (C. Brusasco), alex.cioe@libero.itA. Cioè), raffaele.dellaca@polimi.it (R.L. Dellacà), teresa.lamparelli@hsanmartino.itT. Lamparelli), alessandro.garlaschi@hsanmartino.it (A. Garlaschi),ellegrino.r@ospedale.cuneo.it (R. Pellegrino), vito.brusasco@unige.it (V. Brusasco).

569-9048/$ – see front matter © 2012 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.resp.2012.07.021

CT.© 2012 Elsevier B.V. All rights reserved.

capacity have been reported even in the absence of overt bron-chiolitis obliterans syndrome (BOS) or cryptogenic organizingpneumonia (Kotloff et al., 2004; Bacigalupo et al., 2012). Dataon airway physiology are however scarce and conflicting. Onestudy reported an increase in airway responsiveness after HSCT(Rodriguez-Roisin et al., 1989) but this was not confirmed in arecent investigation from our group, in which a slight decrease inthe response to methacholine was observed after HSCT (Barisioneet al., 2008). This effect was associated with an enhanced abil-ity of deep breaths to reverse the induced bronchoconstriction(Barisione et al., 2008), suggesting an increased airway distensibil-ity with lung inflation. Because airway caliber is regulated by thebalance between the force generated by the airway smooth mus-cle (ASM) and opposing forces, mainly represented by lung elasticrecoil (Brusasco and Pellegrino, 2003), it can be hypothesized thatairway caliber and distensibility may increase after HSCT becauseof an enhanced lung stiffness.

To test this hypothesis, we measured within-breath lung

mechanical impedance by forced oscillation technique (FOT) andestimated airway distensibility from the changes in respiratoryconductance during an inspiratory maneuver (Baldi et al., 2010;Brown et al., 2007; Jensen et al., 2001; Kelly et al., 2012; Pellegrino

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t al., 2010). To separate the effects of changes in distendingorce from possible changes in ASM tone, measurements wereaken before and after the acute inhalation of a bronchodila-or. Furthermore, changes in airway distensibility were comparedith changes in lung density determined by quantitative CT scan

Gattinoni et al., 2001).

. Material and methods

.1. Subjects

Twenty-eight consecutive Caucasian patients undergoing allo-eneic HSCT (sourcing from bone marrow) for acute myeloideukaemia or other haemathological malignancies were studiedetween 2010 and 2011. All patients were in stable clinical con-itions at the time of study and none had a history of bronchialsthma, chronic obstructive pulmonary disease, or other signifi-ant respiratory disease. The study protocol was approved by thenstitutional review board of San Martino University Hospital (IRBo. 120/10), and written informed consent was obtained prior to

ecruitment.All patients received a myeloablative treatment either includ-

ng or not including total body irradiation (≥9.99 Gy). Theyeceived conventional conditioning regimens with various com-ination of cyclophosphamide (n = 25), cyclosporine A (n = 25),udarabine (n = 14), mofetil mycophenolate (n = 13), methotrex-te (n = 8), thiothepa (n = 5), busulfan (n = 6), azathioprine (n = 5)nd appropriate antibiotic prophylaxis. To prevent graft-versus-ost disease (GvHD), all patients were treated with cyclosporine A6–10 mg kg−1daily) for 1 year following HSCT and 14 of them withlso antithymocyte globulin. Patients diagnosed with acute GvHDere treated with 6-�-methylprednisolone (2 mg kg−1 daily) forve consecutive days (Bacigalupo et al., 2006).

.2. Spirometry, lung volumes and diffusing capacity

Inspired and expired volumes were measured by using a massowmeter (CareFusion; VIASYS-SensorMedics Inc., Yorba Linda,A, USA), with numerical integration of the flow signal. Vital capac-

ty (VC) and forced expiratory volume in one second (FEV1) wereeasured according to the American Thoracic Society/European

espiratory Society (ATS/ERS) recommendations (Miller et al.,005). Functional residual capacity (FRC) was measured by whole-ody plethysmography (V62 J; CareFusion, VIASYS-SensorMedics

nc.) during panting against a closed shutter at a frequency rangingrom 0.5 to slightly <1.0 Hz. Residual volume (RV) was calculated byubtracting a linked expiratory reserve volume from FRC and TLCy adding the subsequent inspiratory VC (Wanger et al., 2005). Pre-icted values for spirometry and lung volumes were from Quanjert al. (1993).

Lung diffusing capacity for carbon monoxide (DLCO) waseasured (MacIntyre et al., 2005) using commercial available

quipment (Vmax22D; CareFusion, VIASYS-SensorMedics Inc.).redicted values for DLCO were from Cotes et al. (1993). MeasuredLCO was compared with predicted values adjusted for the clos-st measurement of effective blood haemoglobin concentrationMacIntyre et al., 2005).

.3. FOT

Within-breath respiratory system input impedance (Zrs) waseasured using an experimental set-up described elsewhere

Dellacà et al., 2010), which met ERS Task Force recommenda-ions (Oostveen et al., 2003). Shortly, mouth flow was measuredy a mesh-type pneumotachometer connected to a piezoresis-ive differential pressure transducer (DCXL10DS, Sensortechnics

& Neurobiology 184 (2012) 80– 85 81

GmbH, Puchheim, Germany). A second differential pressure sen-sor (DCXL01DS, Sensortechnics GmbH) was used to simultaneouslymeasure mouth pressure. A microcontroller-based electronicboard, connected to a personal computer, was used to drive a loud-speaker for the generation of the pressure stimulus and to samplepressure and flow signals. A low-resistance, high-inertance tubewas used in parallel with the loudspeaker to allow the subjects tobreathe room air without significant loss of forcing pressure. A biasflow of ∼15 L/min reduced the equipment deadspace to the vol-ume of the pneumotachograph and the mouthpiece. The frequencyresponse of the whole measuring system was assessed up to 30 Hz(Brusasco et al., 1994) and it was flat. A pseudo-random noise withthree components at 5, 11 and 19 Hz chosen to meet a “nonsumnondifference criterion of order 3” (Suki and Lutchen, 1992) andwith amplitude of ∼2 cm H2O was selected as forcing waveform. Zrs

was measured by FOT, with the subject sitting and breathing quietlywhile firmly supporting his/her cheeks with hands. Measurementswere taken during 3 min of tidal breathing at FRC before and duringa 5-s inspiratory capacity maneuver to TLC. Special care was takento maintain the position of the trunk fairly constant during the test.

Starting from pressure and flow signals, Zrs was determined byusing a least squares algorithm taking advantage of the a prioriknowledge of the frequency spectrum components of the forcingsignals (Dellacà et al., 2004, 2009; Horowitz et al., 1983; Kaczkaet al., 1995) and partitioned into resistance (Rrs) and reactance(Xrs). Breaths where impedance tracings did not show spikes oroscillations due to swallowing or glottis closure were manuallyselected and used to calculate impedance and breathing patternparameters. To exclude possible artifacts due to the presence ofexpiratory flow-limitation, the analysis of impedance parameterswas restricted only to the inspiratory phase (Dellacà et al., 2004,2009; Horowitz et al., 1983). Therefore, Zrs was characterized bythe mean values of its resistive and reactive components assumedduring the inspiratory phase (Rinsp and Xinsp, respectively) and bytheir instantaneous values measured at FRC (RrsFRC and XrsFRC) andat the end of a slow inspiratory capacity maneuver to TLC (RrsTLC).Subsequently, respiratory system conductance (Grs = 1/Rrs) at 5, 11and 19 Hz was calculated and GrsFRC, measured at 5 Hz, was dividedby the respective plethysmographically-measured FRC to obtainits specific value (sGrs5FRC). The difference in Grs5 measured at FRC(Grs5FRC) and TLC (Grs5TLC) was divided by the simultaneous changein lung volume (�Grs5/�VL) and taken as an estimate of airwaydistensibility (Baldi et al., 2010). Predicted values for Rinsp5 werefrom Pasker et al. (1994).

2.4. CT scanning

A chest computed tomography (CT) scan was routinely obtainedby multidetector row spiral scanner (SOMATOM Emotion 6,Siemens AG Medical, Forchheim, Germany) before conditioningtreatment and 2 months after HSCT. The scans were obtainedat 130 kV (70 effective mA s) with 2.0 and 5.0 mm slice colli-mation and width, respectively. Scanning was performed fromapex to base with 0.8-s rotation time (pitch factor 0.5–1.8) and16 mm feed/rotation. CT scans, in a format suitable for softwareanalysis, were available in 8 patients only. The digital data wereretrospectively elaborated to obtain 8-mm thickness slices. Recon-structed images were then analysed using dedicated software(Maluna, Mannheim Lung Analyzing Tool, version 2.02, Mannheim,Germany). Lung gas and tissue volumes were calculated using stan-dard equations for the whole lung (Gattinoni et al., 2001).

2.5. Study protocol

Spirometry, lung volumes, FOT and CT were obtained 2 weeksbefore the start of conditioning treatment and, approximately, 2

82 G. Barisione et al. / Respiratory Physiology & Neurobiology 184 (2012) 80– 85

Table 1Characteristics and pre-HSCT lung function data of the included subjects (n = 26).

Male/female 17/9Age, years 37 ± 14BMI (kg m−2) 26 ± 3Current/former/never smoker 8/7/11Acute myeloid leukaemia/other haematological malignancies 7/19VC (% of predicted) 110 ± 17FEV1 (% of predicted) 107 ± 11FEV1/VC 0.81 ± 0.06TLC (% of predicted) 101 ± 14FRC (% of predicted) 89 ± 19RV (% of predicted) 84 ± 25DLCO (% of predicted corrected for Hb) 72 ± 13DLCO/VA (% of predicted) 82 ± 15Rinsp5(% of predicted) 117 ± 37

HSCT, allogeneic haematopoietic stem-cell transplantation; BMI, body mass index;VC, vital capacity; FEV1, forced expiratory volume in one second; TLC, total lungcapacity; FRC, functional residual capacity; RV, residual volume; DLCO, single-breathdid

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Fig. 1. Multifrequency (5, 11 and 19 Hz) impedance spectra for respiratory systemresistance (Rrs) measured at FRC (circles) and TLC (triangles) in 26 clinically-stablepatients before (open symbols) and 2 months after (closed symbols) allogeneichaematopoietic stem-cell transplantation (HSCT) (mean values ± standard error).

interactions were found between responses to salbutamol beforeand after HSCT.

iffusing capacity of the lung for carbon monoxide; VA, alveolar volume; Rinsp5, meannspiratory resistance at 5 Hz. Values are absolute numbers or means ± standardeviation.

onths after HSCT. On each study day, all the above measure-ents were taken before and 30 min after inhaling four consecutive

albutamol doses of 100 �g each, through a valved-holding cham-er. DLCO was measured only after bronchodilator inhalationPellegrino et al., 2005).

.6. Statistical analysis

A two-factor repeated-measure analysis of variance was usedo test for statistical significant differences related to HSCTnd inhaled salbutamol. Post hoc comparisons were made byolm–Sidak or paired t-test, whenever appropriate. Values of

< 0.05 were considered statistically significant. Values are pre-ented as mean ± standard deviation, unless otherwise stated.

. Results

Two patients were excluded from the final analysis becausef clinical-radiological signs suggestive of cryptogenic organiz-ng pneumonia and BOS, respectively. Baseline spirometry, lungolumes, and Rinsp 5 of the 26 subjects included in the analysisere within the predicted normal range whereas DLCO was slightly

educed (Table 1). Eighteen patients developed clinical signs ofvHD, with dry eyes, mouth, and skin (i.e. sicca syndrome).

.1. Effects of HSCT

There was a mild, but statistically significant, decrease of TLC by ± 7% (p = 0.009), which was associated with a tendency for VC toecrease (4 ± 11%; p = 0.07) and significant reductions of both DLCOnd DLCO/VA by 9 ± 13% (p < 0.001) and 8 ± 11% (p < 0.001), respec-ively. There were no significant changes in FEV1, FEV1/VC, FRC, andV (Table 2). As compared with pre-HSCT values, RrsFRC was slightlyecreased at 5 Hz (p = 0.051), 11 Hz (p = 0.046) and 19 Hz (p = 0.039),ithout significant frequency-dependence (Fig. 1). After HSCT,

rs5FRC became less negative (p = 0.010) whereas sGrs5FRC increasedignificantly (p = 0.022) and so did Grs both at FRC (p = 0.008 at 5 Hz;

= 0.001 at 11 and 19 Hz) and TLC (p < 0.001 at 5 Hz; p = 0.008 at1 Hz and p = 0.013 at 19 Hz). Together with the significant incre-ent in mean slope of �Grs5/�VL, this would suggest an increase in

irway caliber and distensibility with lung inflation (Fig. 2). In the 8

atients in whom quantitative CT scan analysis could be conducted,

significant increase in lung tissue density was observed (18 ± 11%; < 0.001). This was positively correlated (R2 = 0.87; p < 0.001) withhe increment in �Grs5/�VL slope (Fig. 3).

*p = 0.010, #p = 0.046 and §p = 0.039 versus pre-HSCT values by Holm–Sidak post hoccomparison.

3.2. Effects of salbutamol

After inhalation of salbutamol, there were increments of FEV1,FEV1/VC, sGrs5FRC, GrsFRC at all forcing frequencies (p < 0.001) andGrsTLC at 5 Hz (p = 0.003) (Table 2), indicating a positive bron-chodilator response. However, the �Grs5/�VL slope did not changesignificantly, suggesting that the presence of ASM tone did not con-tribute to limit airway distensibility before HSCT. No significant

Fig. 2. Individual relationships between baseline respiratory system conductanceat 5 Hz (Grs5) and lung volume (VL) before (upper panel) and 2 months after (lowerpanel) HSCT. Lung volume is expressed as percent (%) of total lung capacity (TLC).Interrupted lines marked with numbers identify the patients with quantitative CTscan analysis available. See Table 2 for statistical significance.

G. Barisione et al. / Respiratory Physiology & Neurobiology 184 (2012) 80– 85 83

Table 2Standard lung function and multifrequency FOT data before and after allogeneic haematopoietic stem-cell transplantation (HSCT).

Parameters Before HSCT (−2 weeks) After HSCT (2 months) ANOVA(p-values)

Baseline Salbutamol Baseline Salbutamol HSCT Salbutamol Interaction

VC (L) 4.58 ± 0.99 4.59 ± 0.96 4.37 ± 0.97 4.40 ± 0.96 0.07 0.53 0.80FEV1 (L) 3.67 ± 0.74 3.76 ± 0.76 3.54 ± 0.75 3.69 ± 0.79 0.17 <0.001 0.45FEV1/VC 0.81 ± 0.06 0.82 ± 0.07 0.81 ± 0.15 0.84 ± 0.06 0.10 <0.001 0.23TLC (L) 6.08 ± 1.17 6.00 ± 1.18 5.75 ± 1.11 5.75 ± 1.08 0.004 0.29 0.15FRC (L) 2.71 ± 0.63 2.60 ± 0.61 2.70 ± 0.58 2.70 ± 0.63 0.39 0.16 0.023RV (L) 1.50 ± 0.59 1.42 ± 0.51 1.38 ± 0.40 1.36 ± 0.39 0.20 0.20 0.23DLCO (mL min−1 mm Hg−1) 18.5 ± 4.20 16.6 ± 4.50 0.014DLCO/VA (mL min−1 mm Hg−1 L−1) 3.99 ± 0.54 3.62 ± 0.50 <0.001Xrs5FRC (cm H2O s L−1) −0.50 ± 0.29 −0.43 ± 0.21 −0.43 ± 0.28 −0.38 ± 0.28 0.010 0.18 0.31sGrs5FRC (cm H2O−1 s−1) 0.13 ± 0.04 0.16 ± 0.05 0.15 ± 0.04 0.16 ± 0.04 0.022 <0.001 0.93Grs5FRC (L cm H2O−1 s−1) 0.34 ± 0.09 0.39 ± 0.10 0.38 ± 0.10 0.45 ± 0.12 0.008 <0.001 0.41Grs5TLC (L cm H2O−1 s−1) 0.58 ± 0.20 0.79 ± 0.42 0.77 ± 0.23 0.82 ± 0.25 <0.001 0.003 0.25�Grs5/�VL (cm H2O−1 s−1) 0.11 ± 0.10 0.14 ± 0.11 0.19 ± 0.09 0.19 ± 0.10 <0.001 0.51 0.70Grs11FRC (L cm H2O−1 s−1) 0.31 ± 0.07 0.35 ± 0.08 0.36 ± 0.10 0.41 ± 0.10 0.001 <0.001 0.42Grs11TLC (L cmH2O−1 s−1) 0.64 ± 0.27 0.72 ± 0.27 0.81 ± 0.23 0.86 ± 0.30 0.008 0.36 0.57Grs19FRC (L cm H2O−1 s−1) 0.29 ± 0.07 0.33 ± 0.07 0.33 ± 0.09 0.37 ± 0.09 0.001 <0.001 0.55Grs19TLC (L cm H2O−1 s−1) 0.57 ± 0.20 0.65 ± 0.22 0.68 ± 0.19 0.69 ± 0.21 0.013 0.18 0.24

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. Discussion

The main findings of the present study are that: (1) airway cal-ber and distensibility with lung inflation were increased followingSCT, (2) these effects were not altered by salbutamol, and (3) the

ncrement in airway distensibility correlated with the increase ofung tissue density.

Several studies have consistently shown that reductions in lungolumes and diffusing capacity occur early after HSCT, even inhe absence of symptoms or clinical signs of pulmonary diseaseBarisione et al., 2008; Gore et al., 1996; Rodriguez-Roisin et al.,989). These changes suggest the development of a restrictiveisorder, which has been attributed to infections (Kotloff et al.,004), acute GvHD (Ferrara et al., 2009), myeloablative condition-

ng regimens (Gore et al., 1996), or any combination of these.ess consistent changes have been reported in airway mechanics

fter uncomplicated HSCT. One study suggested the developmentf airway hyperresponsiveness (Rodriguez-Roisin et al., 1989)ut this was not confirmed in a subsequent investigation of ourroup (Barisione et al., 2008), where the dose of methacholine

ig. 3. Relationship between increase in airway distensibility (�Grs5/�VL slope)nd percent increase of CT-determined lung density following HSCT. Noteworthy,fter deleting the outlier (no. 1), the correlation maintains statistical significanceR2 = 0.68, p = 0.023).

ry system conductance at 5 Hz measured at FRC; Grs5, Grs11 and Grs19, respiratoryrs5 versus change in lung volume. Other abbreviations are as given in Table 1. Data

causing a 20% decrease of FEV1 tended to increase after HSCT andthis was associated with a significantly lower decrease of FVC,suggesting attenuations of both airway responsiveness and air-trapping. Moreover, the ability of deep breaths to reverse inducedbronchoconstriction was enhanced after HSCT and was inverselycorrelated with the decrease in TLC (Barisione et al., 2008). Theability to dilate airways by lung inflation depends on the magnitudeof the distending force which, in turn, is proportional to lung vol-ume change and lung elastic recoil (Brusasco and Pellegrino, 2003).Thus, in the presence of a reduction of absolute lung volume, theincreased distensibility of airways after HSCT can be ascribed to anincreased elastic force acting on airway walls or a reduction of ASMtone.

The results of the present study show that airway distensibilitywith lung inflation was increased after HSCT but it was independentof ASM tone, as suggested by the similarity of the bronchodila-tor effect of salbutamol before and after HSCT. Were the ASMtone substantially reduced, then the effect of salbutamol shouldhave been also reduced after HSCT. Thus, the results of the currentstudy suggest that airway distensibility with lung inflation doesincrease after HSCT presumably because of an enhanced elasticload on airway walls. The effects due to a reduction in lung vol-ume and an increased pulmonary elastance cannot be separatedwithout measurement of quasi-static pressure–volume curve ofthe lung. However, the strong positive correlation between theindex of distensibility (�Grs5/�VL slope) and lung density, mea-sured by CT, suggest that an increased stiffness of lung parenchymamay have played a major role. Previous studies have suggestedthat an HSCT-related restrictive defect may occur as a consequenceof pulmonary fibrosis due to radiation injury (Kotloff et al., 2004;Gore et al., 1996) or intensive myeloablative conditioning regimen(Panoskaltsis-Mortari et al., 2011).

In keeping with a previous study of our group (Barisione et al.,2008), the present series of patients did not show a significantdecrease in FRC, which may appear inconsistent with an increasedparenchymal stiffness. However, it is possible that changes in lungelastic recoil at low lung volume were too small to cause measur-able reductions in FRC but large enough to increase sGrs5FRC. Studiesdone both in situ (Tisi et al., 1975) and in isolated (Martin and

Proctor, 1958; Hyatt and Flath, 1966; Hyatt et al., 1975) bronchihave suggested that the compliance of small airways is large atlow transpulmonary pressures and may even exceed lung com-pliance (Brown and Mitzner, 1996). Therefore, if chest wall and

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irway compliance were not altered by HSCT, even a small increasen transpulmonary pressure due to an increase in lung elastic recoilould have resulted in an appreciable increase of airway caliber.

In our patients, we did not observe any change in frequency-ependence of RrsFRC while Xrs5FRC became slightly less negative,hich is inconsistent with an increased lung elastance. As FRC

emained unmodified after HSCT, the reduction of Xrs5FRC could bexplained by an increased mechanical homogeneity, which seemsonsistent with a reduction of Rrs5FRC. So, our results may appear inontrast with those by Lahzami et al. (2011) who found an increasedeterogeneity of peripheral ventilation after HSCT. But they found aild tendency of Rrs at 6 Hz to decrease after HSCT, which is in keep-

ng with the increased airway caliber and distensibility observed inur patients.

. Limitations and strengths of the study

This study has some limitations. First, the increase in GrsFRC afterSCT was small at all forcing frequencies (ranging from 12 to 16%),lbeit statistically significant. This change, by itself, is unlikely toave clinical significance but it should be considered when serialeasurements of lung function are made for follow-up purposes.

econd, we did not measure lung elastic recoil, which might haveeen difficult in the presence of sicca syndrome, and we usedT density as a surrogate. Moreover, this was possible only in ainority of subjects. However, the strong correlation between dis-

ensibility index and lung density and the fact that these subjectshowed reductions of TLC and DLCO and increments of �Grs5/�VLlope that were similar to those of the group as the whole, seems toustify the conclusion that the increased airway distensibility afterSCT was likely due to an increment in lung stiffness. Third, we

nferred changes in airway caliber from respiratory impedance byOT, which also includes measurement of parenchymal and chestall properties (Nagels et al., 1980; Peslin and Fredberg, 1986).owever, the similarity of changes in Grs5, Grs11, and Grs19 with

ung volume does suggest that Grs was an acceptable surrogate ofirway conductance in our subjects.

. Conclusions

One of the main purposes to measure lung function in HSCTecipients is to detect BOS at an early stage (Barisione et al., 2011).n the present study, measurements of within-breath respiratorympedance by FOT allowed us to show that airway caliber mayncrease after uncomplicated HSCT, likely because of an enhancedistending force of lung parenchyma independent of changes inSM tone. This effect must be taken into account when interpret-

ng lung function changes after HSCT. A practical implication is thathanges in airway caliber at follow-up should be compared withhose obtained early after rather than before HSCT, in order to avoidnderestimation of occurring airway narrowing.

uthor contributions

Dr Barisione – pulmonary function testing, data collection andnalysis, and the writing of the manuscript; Drs Pompilio and Del-acà – technical support and advice, data collection and analysis,eading and checking of the manuscript; Drs Bacigalupo and Lam-arelli – organization of the study and patients’ selection; Drs

rusasco C and Garlaschi – digital reconstruction and elaborationf CT scan; Dr Cioè – pulmonary function testing; Dr Pellegrino –ata analysis, reading and checking of the manuscript; Dr Brusasco

– data analysis and writing of the manuscript.

& Neurobiology 184 (2012) 80– 85

Laboratory of origin: The data were collected at FisiopatologiaRespiratoria, IRCCS Azienda Ospedaliera Universitaria San Martino– IST, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.

Conflict of interest statement

The authors do not have any conflict of interest.

Acknowledgments

The current authors would like to thank Maria GiuseppinaMarras (Fisiopatologia Respiratoria, IRCCS Azienda OspedalieraUniversitaria San Martino – IST, Genova, Italy) for technical help andsupport. This study was supported in part by Fondazione RicercaTrapianto di Midollo Osseo (FA-RI.T.M.O.), Genoa; AssociazioneItaliana contro le Leucemie-linfomi e Mieloma (AIL), Rome; andAssociazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy.

References

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