Respiratory Impedance and Obliterative Bronchiolitis (FOT-BOS)

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

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

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.

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: 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; 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.

Forced oscillation technique, Respiratory input impedance, Allogeneic hematopoietic stem cell transplantation, Obliterative bronchiolitis

Twenty-six consecutive patients undergoing allogeneic HSCT for hematological malignancies were studied. All patients were in stable clinical conditions at the time of study. All patients received a myeloablative conditioning regimen either including or not including total body irradiation. Spirometry, lung volumes, FOT and lung CT scan were obtained before the start of conditioning treatment and, approximately, two months after HSCT. On each study day, all the above measurements were taken before and 30 min after inhaling four consecutive albuterol doses, of 100 mcg each, through a valved-holding chamber. DLco was measured only after bronchodilator inhalation.

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)

Changes in lung tissue density were measured by quantitative computed tomography(CT) scan 2 weeks before and 2 months after HSCT

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

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

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