Acute Bronchodilator Responsiveness in Bronchiolitis Obliterans Syndrome Following Hematopoietic Stem Cell Transplantation

doi:10.1378/chest.10-1442

Chest

Volume 139, Issue 3, March 2011, Pages 633-639

https://doi.org/10.1378/chest.10-1442 Get rights and content

Background

The obstructive abnormality of bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) is deemed to be virtually insensitive to treatment with inhaled bronchodilators. We studied whether nonconventional assessment of bronchodilation may help to detect physiologically meaningful airway responses missed by traditional criteria.

Methods

Standard spirometry, partial and maximal expiratory flow-volume curves, and lung volumes were measured before and 90 min after inhalation of albuterol plus tiotropium in 17 patients who developed mild to very severe BOS following HSCT.

Results

After treatment with bronchodilators, the standard criteria of reversibility based on FEV₁ and FVC were met in seven out of 17 patients. In eight patients, residual volume (RV) decreased beyond its within-session spontaneous variability, and functional residual capacity (FRC) was reduced in four of them. Partial forced expiratory flow (

part) increased beyond its within-session spontaneous variability in nine patients. Out of 10 patients in whom neither FEV₁ nor FVC met the standard criteria of reversibility, six had a positive increase in

part or a decrease of lung hyperinflation (ie, FRC) or RV. In six patients with limited expiratory flow during tidal breathing, the postbronchodilator increase in

part was correlated with a decrease in FRC (R² = 0.83; P = .011).

Conclusions

This study suggests that airway smooth muscle tone plays a significant role in BOS after HSCT and that the common knowledge of BOS as an irreversible obstructive disease may stem from the limitation of simple spirometry to detect changes in small airways.

Trial registry

ClinicalTrials.gov; No.: NCT01112241 (BOS-01); URL: www.clinicaltrials.gov

Section snippets

Study Subjects

Seventeen consecutive, clinically stable, white outpatients presenting with mild to very severe BOS after HSCT for hematologic malignancies were studied (Table 1, Table 2). They were selected from 460 patients (253 men and 207 women) undergoing HSCT (sourcing from bone marrow) between April 2003 and July 2009. According to our follow-up protocol, all patients underwent pulmonary function testing before HSCT and every 3 to 6 months afterward. In 17 patients, airflow obstruction was found at

Prebronchodilators

After the development of BOS, all patients presented with an obstructive abnormality of variable severity (FEV₁ range, 29%–87% predicted) that was associated with a significant absolute decrease in IVC by 0.75 ± 0.85 L (P = .002) and increments of FRC by 0.69 ± 0.92 L (P = .007) and RV by 0.82 ± 1.14 L (P = .009) compared with their respective pretransplantation values. Three patients had a reduction in TLC below the lower limit of normality (66%, 75%, and 79% predicted), indicating a mixed

Discussion

The novel findings of this study are as follows: (1) one-half of the patients with BOS following HSCT showed changes in lung function, suggesting positive bronchodilator responses to a β₂-agonist plus an anticholinergic; (2)

part increased even in the absence of changes in FEV₁; and (3) this was associated with a decrease of FRC in patients with limited expiratory flow during tidal breathing. These data may shed new light on the role of ASM tone in BOS.

It appears from the collective literature

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Cited by (16)

Pulmonary graft-versus-host disease and chronic lung allograft dysfunction: two sides of the same coin?
2022, The Lancet Respiratory Medicine
Allogeneic haematopoietic stem-cell transplantation (HSCT) and lung transplantation are both established life-saving treatment options for carefully selected patients with various haematological disorders or end-stage lung diseases, respectively. However, long-term survival after allogeneic HSCT is severely limited by chronic graft-versus-host disease (cGVHD)—of which pulmonary cGVHD in particular has a very poor prognosis—and long-term survival after lung transplantation is hampered by chronic lung allograft dysfunction (CLAD). Both pulmonary cGVHD and CLAD are characterised by similar underlying immunopathology, which results in transplant-related pulmonary fibrosis and structural lung remodelling, leading to respiratory dysfunction. Accurate clinical identification and appropriate management is of utmost importance to allow for timely diagnosis, to further optimise current preventive and treatment strategies of pulmonary cGVHD and CLAD, and to ameliorate quality of life and long-term outcomes after allogeneic HSCT and lung transplantation. In this Review, we provide a unique state-of-the-art perspective of both entities for respiratory care practitioners.
The ISHLT chronic lung allograft dysfunction consensus criteria are applicable to pulmonary chronic graft-versus-host disease
2022, Blood Advances
Citation Excerpt :
We intended to systematically evaluate post-HCT PFTs and thoracic CTs to novel PcGVHD phenotypes with clinical features that are distinct from patients with obstruction, some of which were not captured by the NIH cGVHD consensus criteria. Different from the NIH criteria that used post-bronchodilator FEV1 and FVC, the adapted criteria used pre-bronchodilator values, as airway smooth muscle tone could play a significant role in the pathophysiology in BOS, and bronchodilator reversibility could not exclude BOS.17 The TLC cutoff of 90% was used, as a previous study has shown that the combination of TLC < 90% and interstitial changes on the thoracic CT was sensitive and specific for diagnosing interstitial disease after HCT, with positive and negative predictive values 1.00 and 0.75, respectively.18
Pulmonary chronic graft-versus-host disease (PcGVHD) is a devastating complication of allogeneic hematopoietic stem cell transplant (HCT). The 2014 National Institutes of Health cGVHD consensus criteria (NIH criteria) only captures bronchiolitis obliterans syndrome (BOS). In this study, we adapted the 2019 International Society for Heart and Lung Transplantation (ISHLT) criteria of chronic lung allograft dysfunction (CLAD) to define novel phenotypes of PcGVHD and compared the performance of this criteria with the NIH criteria to identify patients with high-risk PcGVHD. We reviewed consecutive patients in a cGVHD natural history protocol (#NCT00092235) and adapted the 2019 CLAD criteria (the adapted criteria) to define PcGVHD as post-HCT forced expiratory volume at 1 second < 80% predicted value, with 4 phenotypes: obstructive, restrictive, mixed obstructive/restrictive, and undefined. An independent adjudication committee evaluated subjects for diagnosis and phenotyping. We identified 166 (47.4%) patients who met the adapted criteria, including obstruction (n = 12, 3.4%), restriction (n = 67, 19.1%), mixed obstruction/restriction (n = 47, 13.4%), and undefined (n = 40, 11.4%). In these patients, less than half (n = 78) met the NIH criteria for BOS (NIH+); the rest (n = 88) did not (NIH−). The NIH− subjects showed increased risk of death compared with those without PcGVHD (hazard ratio = 1.88, 95% confidence interval = 1.20-2.95; P = .006) that was similar to NIH+ subjects (P = .678). Our study demonstrated the potential of the adapted criteria in identifying patients with high-risk PcGVHD that have been missed by the NIH criteria. The adapted criteria could become a valuable tool to better phenotype and study lung disease in cGVHD.
Bronchiolitis Obliterans Syndrome and Other Late Pulmonary Complications After Allogeneic Hematopoietic Stem Cell Transplantation
2017, Clinics in Chest Medicine
Citation Excerpt :
The only randomized clinical trial completed for BOS to date involved the use of inhaled budesonide/formoterol without an addition or increase in corticosteroid dose.56 Evidence that there may be a smooth muscle component of larger bronchioles in BOS prompted the use of a long-acting beta-agonist.57 In a crossover design involving 36 subjects, patients who received budesonide/formoterol experienced an improvement in FEV1 by at least 200 mL and 12% at 1 month.
Airway inflammation in children and adolescents with bronchiolitis obliterans
2015, Cytokine
Airway inflammation plays a major role in the progression of chronic lung diseases. The features of airway inflammation are not well defined among patients with cases of bronchiolitis obliterans (BO) that began in childhood.
To investigate the sputum cell and cytokine profiles of stable cases of BO regarding lung function and the involvement of small airway disease (SAD).
Twenty patients with BO (median age = 14.5, range = 7–23 years) and 22 healthy controls (median age = 16.5 years, range = 7–24 years) were investigated. Lung function parameters and bronchial reversibility testing as well as sputum cell and cytokine profiles (IL-1β, IL-6, IL-8, TNF-α, IL-5, IFN-γ, and NFκB regulation) were analysed using quantitative RT-PCR and cytometric bead assay (CBA) in induced sputum.
Patients with BO had significantly lower lung function values, including FVC, forced expiratory volume (FEV1), the Tiffeneau index (FEV1/VC)_, and MEF25, but increased functional residual capacity (RV/TLC) values. Bronchial reversibility was found in five patients (25%). Moreover, airway inflammation (as indicated by total cells, neutrophils, IL-1β, IL-6, IL-8, TNF-α, and NFκB) was significantly increased among patients with BO compared with controls.
BO is predominantly a neutrophilic disease of the small bronchioles featuring elevated levels of pro-inflammatory cytokines leading to tissue remodelling and fibrosis of the small airways. Future therapies for patients with BO should more efficiently target the small airways.
A new classification system for chronic lung allograft dysfunction
2014, Journal of Heart and Lung Transplantation
Although survival after lung transplantation has improved significantly during the last decade, chronic rejection is thought to be the major cause of late mortality. The physiologic hallmark of chronic rejection has been a persistent fall in forced expiratory volume in 1 second associated with an obstructive ventilatory defect, for which the term bronchiolitis obliterans syndrome (BOS) was defined to allow a uniformity of description and grading of severity throughout the world. Although BOS was generally thought to be irreversible, recent evidence suggests that some patients with BOS may respond to azithromycin with > 10% improvement in their forced expiratory volume in 1 second. In addition, a restrictive form of chronic rejection has recently been described that does not fit the strict definition of BOS as an obstructive defect. Hence, the term chronic lung allograft dysfunction (CLAD) has been introduced to cover all forms of graft dysfunction, but CLAD has yet to be defined. We propose a definition of CLAD and a flow chart that may facilitate recognition of the different phenotypes of CLAD that can complicate the clinical course of lung transplant recipients.
Acute bronchodilator responsiveness to tiotropium in postinfectious bronchiolitis obliterans in children
2013, Chest
Citation Excerpt :
FEV1 measurement is a comparatively insensitive parameter when analyzing changes in the caliber of small airways, which are the anatomic sites where the histopathological lesions of BO are located. Plethysmography permits a more sensitive evaluation of the severity and reversibility of the obstruction and hyperinflation in patients, as was also shown in a study of adults suffering from BO after a bone marrow transplantation.40 Second, there are no studies on the treatment of PIBO with tiotropium; PIBO studies are mainly based on the use of β-adrenergic bronchodilators, disregarding the possibility that PIBO may present with increased cholinergic tone, as in COPD.
Patients with postinfectious bronchiolitis obliterans (PIBO) usually have severe airflow obstruction and respond poorly to β-adrenergic drugs. However, the bronchodilator response to an anticholinergic agent such as tiotropium bromide is not known. We studied the acute bronchodilator response to tiotropium for up to 24 h in children with PIBO using spirometric and plethysmographic criteria.
A randomized, double-blind, placebo-controlled, crossover, prospective study was performed in patients with stable PIBO, 6 to 16 years of age. Standard spirometry and plethysmography were performed before and at 30, 60, 120, and 180 min and 24 h after inhalation of 18 μg of tiotropium or a placebo. After 7 to 14 days, the drugs were inverted, and the procedures were repeated. The changes in lung function parameters at each time point were compared with the baseline by analysis of variance and Tukey posttest, and the differences in all time points assessments vs baseline in tiotropium vs placebo groups were compared using the Friedman test.
A total of 30 patients were enrolled in the study (23 boys, seven girls; aged 10.9 ± 2.8 years) with baseline lung function values (% predicted) of FVC, FEV₁, FEV₁/FVC, forced expiratory flow between 25% and 75% of FVC (FEF_25%-75%), total lung capacity (TLC), residual volume (RV), RV/TLC, airway resistance (Raw), and specific airway conductance (sGaw) of 75 ± 15, 48 ± 14, 59 ± 11, 22 ± 11, 120 ± 19, 281 ± 101, 49 ± 13, 250 ± 65, and 23 ± 9, respectively. Statistically significant differences were observed after tiotropium inhalation in the following parameters compared with baseline: FVC at 60, 120, and 180 min and 24 h; FEV₁ at 30, 60, 120, and 180 min; FEV₁/FVC at 60, 120, and 180 min; FEF_25%-75% at 60, 120, and 180 min; RV at 30, 60, 120, and 180 min; TLC at 30, 120, and 180 min; RV/TLC at 30, 60, 120, and 180 min; Raw at 30, 60, 120, and 180 min and 24 h; and sGaw at 30, 60, 120, and 180 min and 24 h. For the placebo group, no significant differences were observed in any lung function parameters at any time. The differences in the main functional measurements between the tiotropium and placebo groups were statistically significant.
Tiotropium acutely decreased airway obstruction and air trapping for up to 24 h in children with PIBO.

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Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

Funding/Support: This study was supported by the Associazione Italiana Ricerca contro il Cancro (AIRC), Milano, Italy.

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Chest

Original ResearchObstructive Lung DiseasesAcute Bronchodilator Responsiveness in Bronchiolitis Obliterans Syndrome Following Hematopoietic Stem Cell Transplantation

Background

Methods

Results

Conclusions

Trial registry

Section snippets

Study Subjects

Prebronchodilators

Discussion

Biol Blood Marrow Transplant

Chest

Chest

Blood

Biol Blood Marrow Transplant

Chest

Int J Radiat Oncol Biol Phys

Pulmonary complications of solid organ and hematopoietic stem cell transplantation

Am J Respir Crit Care Med

Bronchiolitis obliterans following haematopoietic stem cell transplantation

Eur Respir J

Airways obstruction associated with graft versus host disease after bone marrow transplantation

Thorax

Obstructive lung disease after allogeneic marrow transplantation. Clinical presentation and course

Ann Intern Med

The lung's quiet zone

N Engl J Med

The relations between structural changes in small airways and pulmonary function tests

N Engl J Med

Bronchial hyper-responsiveness after human cardiopulmonary transplantation

Clin Sci (Lond)

Airway hyperreactivity in patients undergoing lung and heart/lung transplantation

Am Rev Respir Dis

Effect of a deep inspiration on expiratory flow in normals and patients with chronic obstructive pulmonary disease

Bull Eur Physiopathol Respir

Partial flow-volume curves to measure bronchodilator dose-response curves in normal humans

J Appl Physiol

Interpretative strategies for lung function tests

Eur Respir J

Lung hyperinflation and flow limitation in chronic airway obstruction

Eur Respir J

Measurement of symptoms, lung hyperinflation, and endurance during exercise in chronic obstructive pulmonary disease

Am J Respir Crit Care Med

Significant involvement of CCL2 (MCP-1) in inflammatory disorders of the lung

Microcirculation

Anti-inflammatory agents and allergen-induced beta2-receptor dysfunction in isolated human bronchi

Am J Respir Crit Care Med

Cysteinyl-leukotrienes in the regulation of beta2-adrenoceptor function: an in vitro model of asthma

Respir Res

Original Research
Obstructive Lung Diseases
Acute Bronchodilator Responsiveness in Bronchiolitis Obliterans Syndrome Following Hematopoietic Stem Cell Transplantation

Anti-inflammatory agents and allergen-induced beta₂-receptor dysfunction in isolated human bronchi

Cysteinyl-leukotrienes in the regulation of beta₂-adrenoceptor function: an in vitro model of asthma