Respiratory Impedance and Obliterative Bronchiolitis
Condition: Hematopoietic Stem Cell Transplantation; Obliterative Bronchiolitis
MeSH terms: Bronchiolitis; Bronchiolitis Obliterans; Bronchiolitis Obliterans Syndrome
Study type: Interventional

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.
    

Detailed 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.
    

Intervention name(s): albuterol
Intervention type(s): Drug
Intervention description(s): 400 mcg by inhalation
Other intervention name(s): Broncovaleas pressurized solution
Intervention MeSH terms: Albuterol
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Forced oscillation technique; Respiratory input impedance; Allogeneic hematopoietic stem cell transplantation; Obliterative bronchiolitis