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Reduction in peripheral blood eosinophil counts after bronchial thermoplasty

2016; Elsevier BV; Volume: 138; Issue: 1 Linguagem: Inglês

10.1016/j.jaci.2015.11.044

1097-6825

Dorothy M. Ryan, Stephen J. Fowler, Robert Niven,

Respiratory and Cough-Related Research

Severe asthma is characterized by persistent symptoms despite maximal medical therapy and represents less than 5% of asthmatic patients.1Bousquet J. Mantzouranis E. Cruz A.A. Aït-Khaled N. Baena-Cagnani C.E. Bleecker E.R. et al.Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma.J Allergy Clin Immunol. 2010; 126: 926-938Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar Bronchial thermoplasty (BT) is a novel bronchoscopic therapy internationally approved for patients with severe asthma, delivering radiofrequency thermal energy to the airways distal to the main stem bronchi and reducing airway smooth muscle (ASM) mass long-term.2Danek C.J. Lombard C.M. Dungworth D.L. Cox P.G. Miller J.D. Biggs M.J. et al.Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs.J Appl Physiol. 2004; 97: 1946-1953Crossref PubMed Scopus (175) Google Scholar Smooth muscle hyperplasia and hypertrophy are major determinants of airway hyperresponsiveness (AHR) and airflow obstruction in patients with severe asthma.3Benayoun L. Druilhe A. Dombret M.C. Aubier M. Pretolani M. Airway structural alterations selectively associated to severe asthma.Am J Respir Crit Care Med. 2003; 167: 276-282Crossref Scopus (672) Google Scholar Canine studies demonstrated 30% to 50% reduction in ASM and reduced AHR to methacholine after BT.2Danek C.J. Lombard C.M. Dungworth D.L. Cox P.G. Miller J.D. Biggs M.J. et al.Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs.J Appl Physiol. 2004; 97: 1946-1953Crossref PubMed Scopus (175) Google Scholar This reduction in ASM contractility is considered the main mechanism of action of BT. However, ASM also produces cytokines and chemokines and might be a critical component of airway remodeling in patients with severe asthma.4Brightling C.E. Bradding P. Symon F.A. Holgate S.T. Wardlaw A.J. Pavord I.D. Mast cell infiltration of airway smooth muscle in asthma.N Engl J Med. 2002; 346: 1699-1705Crossref PubMed Scopus (1048) Google Scholar Thus BT might indirectly affect asthmatic inflammation through reduction in ASM-associated cytokine release, thereby reducing systemic asthmatic inflammation. Peripheral blood eosinophils (PBEs) are a biomarker of airway eosinophilia, with evidence for increased ASM eosinophil counts in patients with eosinophilic asthma.5Wilson S.J. Rigden H.M. Ward J.A. The relationship between eosinophilia and airway remodeling in mild asthma.Clin Exp Allergy. 2013; 43: 1342-1350Crossref PubMed Scopus (36) Google Scholar, 6Fowler S.J. Tavernier G. Niven R. High blood eosinophil counts predict sputum eosinophilia in patients with severe asthma.J Allergy Clin Immunol. 2014; 135: 822-824Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar We noticed a marked reduction in PBE counts in some patients after BT and therefore undertook a systematic retrospective investigation of PBEs before and after BT in our patients with severe asthma. We performed a retrospective review of the first 15 consecutive patients with severe asthma treated with BT in a dedicated severe asthma center with at least 1 year of follow-up. BT procedures were performed by the same physician responsible for the patients' asthma care, and all PBE counts were measured by the same laboratory according to standardized methods. Patients' demographics and clinical information were recorded in the UK Difficult Asthma Registry,7Difficult Asthma Registry. Available at: http://demo.e-dendrite.com/csp/asthma/frontpages/asthmafront.csp. Accessed April 2015.Google Scholar with BT performed during 2011-2013. Serial PBE measures within 1 year before and after BT were recorded. Eosinophil counts were measured during both routine follow-up and acute exacerbations. All blood samples available were included, regardless of indication for measurement. We excluded from analysis PBE measurements taken between the time of the first BT procedure until 1 month after the final procedure because of the likely short-term influence of the standard concomitant steroid therapy protocol. Data were analyzed with SPSS software (version 22; SPSS, Chicago, Ill). Between-group comparisons for parametric data were made by using paired t tests, and those for nonparametric data were made by using the Wilcoxon signed-rank test. Thirteen of the 15 patients had PBE data available both before and after BT; 2 patients had pre-BT PBE data only and thus were excluded from further analysis. Patients' demographics are shown in Table E1 in this article's Online Repository at www.jacionline.org. In brief, 12 were female, with a median age of 43 years (range, 25-60 years), and all were current nonsmokers. Median (14 [range, 2-32] and 7 [range, 1-33]) serial PBE counts were measured per subject in the year before and after BT, respectively. Across all subjects, mean PBE counts in the year before BT were 0.33 × 109/L, decreasing to a mean of 0.17 × 109/L in the year after BT (P = .01). The average change in PBE counts (after minus before BT) was −0.16 (95% CI, −0.27 to −0.04; Fig 1). We systematically investigated whether a change in steroid exposure might have been associated with this reduction in PBE counts (Fig 1). Ten patients were taking daily prednisolone in the year before BT (median, 20 mg/d; range, 10-100 mg/d), and 10 were taking daily prednisolone in the year after BT (median, 20 mg/d; range, 7.5-40 mg/d; Table I). Emergency prednisolone courses were significantly reduced after BT, from a median of 3 per year before BT to 0 per year after BT (P = .01, Table I). Therefore annual steroid exposure (maintenance and emergency) was variable per patient but reduced overall (see Table E2 in this article's Online Repository at www.jacionline.org).Table IIndices of asthma control before and after BTMeasureOne year before BTOne year after BTP valuePBEs (mean)*0.33 × 109/L0.17 × 109/L.01Steroid exposure, median (range) ICS (BDP equivalent) [μg/d]2000 (1000-4000)2000 (1600-4000) Maintenance prednisolone, no.109.14 Dose of maintenance prednisolone (mg)20 (10-100)20 (7.5-40).08 Annual emergency courses of prednisolone3 (0-6)0 (0-3).01Exacerbations, median (range) Unscheduled GP visits6 (0-10)2 (0-5).03 Total no. of ITU admissions0 (0-4)0 (0-3).41 Total no. of hospitalizations1 (0-6)0 (0-3).31 Total no. of emergency department visits1 (0-6)0 (0-3).03 Days lost from work12.5 (0-20)0 (0-10).18Rescue SABA use per day, mean (SD)10.5 (3.1)12.4 (5.3).08Prebronchodilator FEV1 (% predicted)66.564.6.17BDP, Beclomethasone dipropionate; GP, general practitioner; ICS, inhaled corticosteroids; ITU, intensive therapy unit; SABA, short-acting β-agonist. Open table in a new tab BDP, Beclomethasone dipropionate; GP, general practitioner; ICS, inhaled corticosteroids; ITU, intensive therapy unit; SABA, short-acting β-agonist. There was a reduction in the median number of emergency department (P = .03) and general practitioner visits (P = .03). There was no significant difference in spirometric results (Table I). Our cohort of patients with severe asthma had a statistically and clinically significant reduction in blood eosinophil counts after BT. This is the first evidence, as far as we are aware, showing such a reduction. It is not yet known whether a distinct severe asthma phenotype might respond best to BT. Given the known effect of BT on ASM mass, AHR to methacholine was an inclusion criterion in the Asthma Intervention Research 2 (AIR2) trial.8Castro M. Rubin A. Laviolette M. Fiterman J. De Andrade Lima M. et al.Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial.Am J Respir Crit Care Med. 2010; 181: 116-124Crossref PubMed Scopus (578) Google Scholar The AHR phenotype might have a more favorable response. Two of our 13 patients had AHR testing, with positive results in 1 patient. Mirroring the AIR2 trial, our cohort had improved indices of asthma control in the year after BT, with a reduction in emergency courses of prednisolone and unscheduled general practitioner and emergency department visits (P < .05, Table I). A recent publication demonstrated reduced bronchoalveolar lavage fluid eosinophil counts and cytokine levels up to 6 weeks after BT.9Denner D.R. Doeing D.C. Hogarth D.K. Dugan K. Naureckas E.T. White S.R. et al.Airway inflammation after bronchial thermoplasty for severe asthma.Ann Am Thorac Soc. 2015; 12: 1302-1309Crossref PubMed Scopus (74) Google Scholar However, steroids administered at the time of BT could be implicated in this effect. In patients with eosinophilic asthma, ASM contains increased numbers of eosinophils,5Wilson S.J. Rigden H.M. Ward J.A. The relationship between eosinophilia and airway remodeling in mild asthma.Clin Exp Allergy. 2013; 43: 1342-1350Crossref PubMed Scopus (36) Google Scholar and ASM cells release cytokines involved in eosinophil-mediated inflammation.10Calvén J. Akbarshahi H. Menzel M. Ayata C.K. Idzko M. Bjermer L. et al.Rhinoviral stimuli, epithelial factors and ATP signalling contribute to bronchial smooth muscle production of IL-33.J Transl Med. 2015; 13: 281Crossref PubMed Scopus (15) Google Scholar Thus, our observed result could be explained by BT-induced reduction in the mass and number of ASM cells, with reduced release of eosinophil-associated cytokines. During BT, thermal energy is applied to the bronchial mucosa, although thus far only its effects on ASM mass have been well described.2Danek C.J. Lombard C.M. Dungworth D.L. Cox P.G. Miller J.D. Biggs M.J. et al.Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs.J Appl Physiol. 2004; 97: 1946-1953Crossref PubMed Scopus (175) Google Scholar Could the effects of BT on bronchial, submucosal, and ASM eosinophils and not solely ASM mass reduction be a mechanism by which BT improves asthma control? The median dose of maintenance prednisolone remained unchanged before and after BT at 20 mg, although the dose range was reduced, with a maximum dose of 40 mg compared with 100 mg before BT. Thus in our opinion suppression of PBEs after BT in this cohort cannot be explained by systemic steroid exposure given that the maintenance steroid dose was unchanged, the maintenance prednisolone dose range was reduced, and prednisolone emergency courses were significantly reduced (P < .05). We acknowledge that the lack of a control group is a limiting factor in data interpretation given the notable placebo effect of sham treatment demonstrated in the AIR2 trial.8Castro M. Rubin A. Laviolette M. Fiterman J. De Andrade Lima M. et al.Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial.Am J Respir Crit Care Med. 2010; 181: 116-124Crossref PubMed Scopus (578) Google Scholar This is a small retrospective study with interesting, hypothesis-generating findings. We conclude that PBE suppression, a surrogate of improved asthma control, occurs after treatment with BT in patients with severe asthma. A controlled prospective mechanistic study is warranted to assess changes in asthma biomarkers over time in the airway (eg, fraction of exhaled nitric oxide and sputum eosinophil counts), blood (eg, eosinophils, cytokines, and chemokines), and tissue (eg, eosinophils and cytokines) before and after BT. We thank Gill McCumesky, who provided assistance with data input and retrieval for the UK Difficult Asthma Registry. Table E1Characteristics of patients with severe asthmaFemale sex, no. (%)12 (92.3)White race, no. (%)12 (92.3)Age∗At the time of the first BT procedure. (y), median (range)43 (25-60)Duration of asthma (y), median (range)28 (15-52)BMI (kg/m2), mean (SD)29.7 (5.4)Smoking status, no. (%) Nonsmoker10 (76.9) Former smoker3 (23.1)Pack years, mean (SD)11.7 (2.9)Lung function, mean (SD) Prebronchodilator FEV1 (L)1.9 (0.5) Prebronchodilator FEV1 (% predicted)66.5 (17.5) Postbronchodilator FEV1 (L)2.2 (0.4) Postbronchodilator FEV1 (% predicted)84.2 (20.9)Steroid exposure Maintenance prednisolone, no. (%)10 (76.9) Daily prednisolone dose (mg), median (range)20 (10-100)Chest HRCT,†No computed tomography was performed in 3 patients (all had normal chest x-ray results). no. (%) Abnormal9 (90)Air trapping6 (60)Ground glass1 (10)Bronchial wall thickening8 (80)Bronchiectasis‡Mild and confined to a single lobe.2 (20)HRCT, High resolution computed tomography.∗ At the time of the first BT procedure.† No computed tomography was performed in 3 patients (all had normal chest x-ray results).‡ Mild and confined to a single lobe. Open table in a new tab Table E2Comparison of pre-BT and post-BT PBE counts, maintenance steroid dose, and asthma exacerbation severity per patientPatient no.:12345678910111213PBEs (109/L)Group mean Pre-BT mean0.470.520.160.180.070.310.050.040.820.770.330.300.300.33 Pre-BT SD0.050.040.100.170.050.190.030.050.720.490.170.100.22 Mean during BT∗Because of standard concomitant steroid therapy, blood eosinophil counts measured during or between BT procedures were excluded from the final analysis, with data shown here for comparative information.0.400.120.080.030.050.040.210.010.370.120.13 SD during BT∗Because of standard concomitant steroid therapy, blood eosinophil counts measured during or between BT procedures were excluded from the final analysis, with data shown here for comparative information.0.000.110.100.010.040.020.140.010.150.10 Post-BT mean0.070.350.310.170.070.180.050.000.400.270.130.190.110.17 Post-BT SD0.000.000.090.100.050.130.040.000.270.210.110.13 Suppressed PBEs after BT (P < .05)YesYesNoNoNoYesNoNoYesYesYesYesYesMaintenance steroid dose (mg)Group median Pre-BT00201010025102010204002020 Post-BT004020207.51007.54040204020Asthma exacerbations (no.) Pre-BT ITU admission00401020010000 Post-BT ITU admission00003000000000 Pre-BT hospitalization in previous year01205161130031 Post-BT hospitalization in previous year33013000004000 Pre-BT emergency department visits previous year01205161130031 Post BT emergency room visits in previous year03000000000000 Pre-BT unscheduled GP visits6610082646521086 Post-BT unscheduled GP visits54350011202402 Reduced asthma exacerbation frequency after BTYesNoYesNoNoYesYesYesYesYesNoYesYesGP, General practitioner; ITU, intensive therapy unit.∗ Because of standard concomitant steroid therapy, blood eosinophil counts measured during or between BT procedures were excluded from the final analysis, with data shown here for comparative information. Open table in a new tab HRCT, High resolution computed tomography. GP, General practitioner; ITU, intensive therapy unit.