Trial Information

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

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.