Respiratory Impedance and Obliterative Bronchiolitis

Hematopoietic Stem Cell Transplantation Clinical Trial

— FOT-BOS  

Official title:

Predictive Value of Within-breath Respiratory Input Impedance in the Early Diagnosis of Obliterative Bronchiolitis After Allogeneic Hematopoietic Stem Cell Transplantation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01255449
• Other study ID #: FOT-BOS-01
• Status: Completed
• Phase: N/A
• First received: December 6, 2010
• Last updated: December 22, 2012
• Start date: December 2010
• Est. completion date: June 2012

Study information

• Verified date: December 2012
• Source: IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The aim of the present study will be to test the hypothesis that changes in within-breath total respiratory input impedance (Zrs) may provide an early evidence of obliterative bronchiolitis after allogeneic hematopoietic stem cell transplantation (HSCT). Before and after HSCT, Zrs will be measured by a modified forced oscillation technique (FOT) during spontaneous breathing both at baseline and 30 min after albuterol inhalation . Such technique may be particularly sensitive to small changes in lung mechanics observed in the early stages of peripheral airflow obstruction.

Description:

1.0 INTRODUCTION

• Shortly after the introduction of allogeneic HSCT in clinical practice, it was recognized that standard pulmonary function tests (PFTs) are sensitive enough to detect HSCT-related respiratory complications [PMID: 2661259; PIMD: 8823260]. Accordingly, the finding of a progressive obstructive abnormality of new onset was considered as the functional hallmark of obliterative bronchiolitis (OB) [PMID: 16338616; PMID: 19896545]. As a result, routinely performed spirometry has been proposed as a non-invasive tool to monitor the risk of OB in HSCT population [PMID: 17470622]. Yet, due to a peripheral airway involvement in OB, the sensitivity of conventional PFTs for early detection of OB is low [PMID: 2298060]. For instance, it does not exceed 75% in lung-transplanted population as the decrease of forced expiratory volume in 1 s (FEV1) may occur at a stage when the process is already irreversible and potentially life-threatening [PMID: 9246138].

2.0 EXPERIMENTAL HYPOTHESIS

• Because the branching pattern of the bronchial tree results in an increasingly large number of small airways with a luminal diameter of less than 2 mm in peripheral generations, these airways contribute little to total pulmonary resistance [PMID: 5442364; PMID: 651978]. Intuitively, a large proportion of small airways may be damaged or obliterated without impairing any of the conventional PFTs. In this regard, a previous study [PMID: 12186817] pointed out that indexes of ventilation distribution may provide an early evidence of OB after lung transplantation. In particular, some authors [PMID: 12186817] have found that tests of ventilation distribution invariably deteriorated about 1 yr before a 20% decrease in FEV1 was apparent. Previous studies [PMID: 970731; PMID: 507525] showed that total respiratory input impedance (Zrs), measured by a forced oscillation technique (FOT) during spontaneous breathing, may be particularly sensitive to small changes in lung mechanics observed in the early stages of smoking-related airflow obstruction. Subsequently, it was developed a modified FOT to identify within-breath differences in Zrs, with values of Zrs representing the sum of respiratory system resistance (Rrs) and reactance (Xrs), the latter being the imaginary part of the former [PMID: 14979497; PMID: 19164347]. This method allows the assessment of more breaths and adds a potential quantitative evaluation of instantaneous inspiratory and expiratory Rrs and Xrs before and after external interventions such as a deep inspiration, bronchodilator drugs, etc. Although these effects can be identified when within-breath analysis is performed [PMID: 14979497], most published reports of oscillatory mechanics on chronic obstructive pulmonary disease (COPD) only report total respiratory cycle data [PMID: 1519830; PMID: 10489847].

3.0 STUDY RATIONALE

• The aim of the present study will be to test the hypotheses that:

1. post-HSCT changes in within-breath Rrs and Xrs may provide an earlier evidence of OB than standard PFTs. Indeed, the obliteration of terminal bronchioles, observed in up to 48% of OB patients following HSCT [PMID: 17470622], could make the real part of Zrs abnormally high [PMID: 5653219] and ventilation more heterogeneous;

2. post-HSCT changes of airway responsiveness to acute bronchoactive interventions such as a deep inspiration to total lung capacity and/or a bronchodilator drug (i.e., albuterol) may be detected by our modified FOT. We speculate that these changes may represent an early sign of OB. Although a previous study from our group failed to find an increase in airway responsiveness after HSCT without pulmonary complications [PMID: 18684842], we have recently shown that airway smooth muscle tone may play an active role in the airflow obstruction of OB [PMID: 20724742].

4.0 STUDY DESIGN

• Before and at regular intervals (2-4 wk onward) after HSCT, patients will attend our laboratory and perform all PFTs measurements in the same order. Firstly, the patient will breathe spontaneously through the modified FOT system for 5 min and then, without disconnecting from the apparatus, perform an inspiratory capacity maneuver and soon after resume spontaneous breathing for the next 2 min. Subsequently, spirometry, transmural total body plethysmography and CO diffusing capacity of the lung (standard PFTs) will be taken in triplicate. Thirty minutes after inhaling four separate doses of 100 μg of albuterol, the modified FOT measurements and standard PFTs will be repeated anew.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 26
• Est. completion date: June 2012
• Est. primary completion date: March 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• consecutive, clinically-stable, outpatients undergoing allogeneic HSCT (sourcing from bone marrow) for hematological malignancies

• values of standard PFTs within normal range before HSCT

• good collaboration during the maneuvers

Exclusion Criteria:

• patients showing any spirometric and/or volumetric abnormality before HSCT

• poor collaboration and/or coordination during the maneuvers

• any clinically-significant respiratory disease (bronchial asthma, COPD, cystic fibrosis, etc.) before HSCT

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Bronchiolitis
• Bronchiolitis Obliterans
• Hematopoietic Stem Cell Transplantation
• Obliterative Bronchiolitis

Intervention

Drug:
• albuterol
400 mcg by inhalation

Locations

Country	Name	City	State
Italy	U.O. Medicina Preventiva e del Lavoro, Laboratorio di Fisiopatologia Respiratoria, IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro	Genova

Sponsors (1)

Lead Sponsor	Collaborator
IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

Country where clinical trial is conducted

Italy, 

References & Publications (20)

Barisione G, Bacigalupo A, Crimi E, Brusasco V. Acute bronchodilator responsiveness in bronchiolitis obliterans syndrome following hematopoietic stem cell transplantation. Chest. 2011 Mar;139(3):633-9. doi: 10.1378/chest.10-1442. Epub 2010 Aug 19. — View Citation

Barisione G, Bacigalupo A, Crimi E, Van Lint MT, Lamparelli T, Brusasco V. Changes in lung volumes and airway responsiveness following haematopoietic stem cell transplantation. Eur Respir J. 2008 Dec;32(6):1576-82. doi: 10.1183/09031936.0139807. Epub 2008 Aug 6. — View Citation

Barisione G, Pompilio PP, Bacigalupo A, Brusasco C, Cioè A, Dellacà RL, Lamparelli T, Garlaschi A, Pellegrino R, Brusasco V. Airway distensibility with lung inflation after allogeneic haematopoietic stem-cell transplantation. Respir Physiol Neurobiol. 201 — View Citation

Chalker RB, Celli BR, Habib RH, Jackson AC. Respiratory input impedance from 4 to 256 Hz in normals and chronic airflow obstruction: comparisons and correlations with spirometry. Am Rev Respir Dis. 1992 Sep;146(3):570-6. — View Citation

Chien JW, Duncan S, Williams KM, Pavletic SZ. Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2010 Jan;16(1 Suppl):S106-14. doi: 10.1016/j.bbmt.2009.11.002. Epub 2009 Nov 5. Review. — View Citation

Cosio M, Ghezzo H, Hogg JC, Corbin R, Loveland M, Dosman J, Macklem PT. The relations between structural changes in small airways and pulmonary-function tests. N Engl J Med. 1978 Jun 8;298(23):1277-81. — View Citation

Dellacà RL, Pompilio PP, Walker PP, Duffy N, Pedotti A, Calverley PM. Effect of bronchodilation on expiratory flow limitation and resting lung mechanics in COPD. Eur Respir J. 2009 Jun;33(6):1329-37. doi: 10.1183/09031936.00139608. Epub 2009 Jan 22. — View Citation

Dellacà RL, Santus P, Aliverti A, Stevenson N, Centanni S, Macklem PT, Pedotti A, Calverley PM. Detection of expiratory flow limitation in COPD using the forced oscillation technique. Eur Respir J. 2004 Feb;23(2):232-40. — View Citation

Estenne M, Hertz MI. Bronchiolitis obliterans after human lung transplantation. Am J Respir Crit Care Med. 2002 Aug 15;166(4):440-4. Review. — View Citation

Farré R, Peslin R, Rotger M, Barberá JA, Navajas D. Forced oscillation total respiratory resistance and spontaneous breathing lung resistance in COPD patients. Eur Respir J. 1999 Jul;14(1):172-8. — View Citation

Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56. — View Citation

Gore EM, Lawton CA, Ash RC, Lipchik RJ. Pulmonary function changes in long-term survivors of bone marrow transplantation. Int J Radiat Oncol Biol Phys. 1996 Aug 1;36(1):67-75. — View Citation

Grimby G, Takishima T, Graham W, Macklem P, Mead J. Frequency dependence of flow resistance in patients with obstructive lung disease. J Clin Invest. 1968 Jun;47(6):1455-65. — View Citation

Hayes DA, Pimmel RL, Fullton JM, Bromberg PA. Detection of respiratory mechanical dysfunction by forced random noise impedance parameters. Am Rev Respir Dis. 1979 Nov;120(5):1095-100. — View Citation

Kjeldgaard JM, Hyde RW, Speers DM, Reichert WW. Frequency dependence of total respiratory resistance in early airway disease. Am Rev Respir Dis. 1976 Sep;114(3):501-8. — View Citation

Mead J. The lung's "quiet zone". N Engl J Med. 1970 Jun 4;282(23):1318-9. — View Citation

Otulana BA, Higenbottam T, Ferrari L, Scott J, Igboaka G, Wallwork J. The use of home spirometry in detecting acute lung rejection and infection following heart-lung transplantation. Chest. 1990 Feb;97(2):353-7. — View Citation

Rodríguez-Roisin R, Roca J, Grañena A, Agustí AG, Marín P, Rozman C. Lung function in allogeneic bone marrow transplantation recipients. Eur Respir J. 1989 Apr;2(4):359-65. — View Citation

Soubani AO, Uberti JP. Bronchiolitis obliterans following haematopoietic stem cell transplantation. Eur Respir J. 2007 May;29(5):1007-19. Review. — View Citation

Van Muylem A, Mélot C, Antoine M, Knoop C, Estenne M. Role of pulmonary function in the detection of allograft dysfunction after heart-lung transplantation. Thorax. 1997 Jul;52(7):643-7. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Airway Distensibility With Lung Inflation After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)	We studied 26 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 oscillation technique (FOT) at functional residual capacity (FRC) and total lung capacity (TLC)	2 weeks before and 2 months after HSCT	No
Secondary	Post-HSCT Changes in Lung Tissue Density	Changes in lung tissue density were measured by quantitative computed tomography(CT) scan 2 weeks before and 2 months after HSCT	Before and 2 months after HSCT	No