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The impact of dysfunctional breathing on the level of asthma control in difficult asthma

Open ArchivePublished:February 08, 2020DOI:https://doi.org/10.1016/j.rmed.2020.105894

      Abstract

      Background

      Difficult asthma is defined as asthma requiring high dose treatment. However, systematic assessment is required to differentiate severe asthma from difficult-to-treat asthma. Dysfunctional breathing (DB) is a common comorbidity in difficult asthma, which may contribute to symptoms, but how it affects commonly used measures of symptom control is unclear.

      Methods

      All adult asthma patients seen in four respiratory clinics over one year were screened prospectively, and patients with possible severe asthma according to ERS/ATS criteria (‘Difficult asthma’: high–dose inhaled corticosteroids/oral corticosteroids), underwent systematic assessment. Symptoms of DB were assessed utilizing a symptom based subjective tool, Nijmegen questionnaire (NQ), and objective signs of DB with the Breathing Pattern Assessment Tool (BPAT). Asthma control and quality of life were evaluated with the Asthma Control Questionnaire (ACQ) and the mini Asthma Quality of Life Questionnaire (AQLQ).

      Results

      A total of 117 patients were included. Among these, 29.9% (35/117) had DB according to the NQ. Patients with DB had a poorer asthma control (ACQ: Mean (SD) 2.86 ± 1.05 vs. 1.46 ± 0.93) and lower quality of life (AQLQ score: Mean (SD) 4.2 ± 1.04 vs. 5.49 ± 0.85) compared to patients without DB. Similarly, patients with objective signs of DB according to the BPAT score had worse asthma control: BPAT >4 vs < 4: (ACQ: Mean (SD) 3.15 ± 0.93 vs 2.03 ± 1.15).

      Conclusion

      DB is common among patients with difficult asthma, and is associated with significantly poorer asthma control and lower quality of life. Assessment and treatment of DB is an important part of the management of difficult asthma.

      Keywords

      1. Introduction

      Dysfunctional breathing (DB)(or Breathing Pattern Disorder, BPD) is defined as divergent breathing patterns that cannot be attributed to a specific medical diagnosis such as asthma or chronic obstructive pulmonary disease [
      • Thomas M.
      • McKinley R.K.
      • Freeman E.
      • Foy C.
      Prevalence of dysfunctional breathing in patients treated for asthma in primary care: cross sectional survey.
      ,
      • Lowhagen O.
      Asthma – a disease difficult to define. Patients can receive correct treatment by means of differential diagnosis criteria.
      ]. DB is characterised by intermittent or chronic symptoms such as dyspnoea, chest pain, chest tightness, shortness of breath at rest, frequent yawning and hyperventilation [
      • Barker N.
      • Everard M.L.
      Getting to grips with dysfunctional breathing.
      ,
      • Courtney R.
      The functions of breathing and its dysfunctions and their relationship to breathing therapy.
      ]. DB is prevalent among patients with asthma and symptoms of DB can mimic asthma symptoms, which may influence the level of asthma control and potentially lead to overtreatment [
      • von Bülow A.
      • Backer V.
      • Bodtger U.
      • Søes-Petersen N.U.
      • Vest S.
      • Steffensen I.
      • Porsbjerg C.
      Differentiation of adult severe asthma from difficult-to-treat-asthma- outcomes of a systemic assessment protocol.
      ,
      • Van Der Meer A.
      • Pasma H.
      • Kempenaar-okkema W.
      • Pelinck J.-A.
      • Schutten M.
      • Storm H.
      • Ten Brinke A.
      A 1-day visit in a severe asthma centre: effect on asthma control, quality of life and healthcare use.
      ].
      The diagnosis of dysfunctional breathing can be difficult, because beyond the clinical description there is no gold standard for the diagnosis of DB. Furthermore, the symptoms of DB mimic those of other respiratory diseases [
      • Lewis R.A.
      • Howell J.B.
      Definition of the hyperventilation syndrome.
      ]. The Nijmegen Questionnaire has been used in many specialist respiratory clinics to detect DB in patients with breathing disorders [
      • Thomas M.
      • McKinley R.K.
      • Freeman E.
      • Foy C.
      Prevalence of dysfunctional breathing in patients treated for asthma in primary care: cross sectional survey.
      ]. Nonetheless, this method has some limitations because the Nijmegen Questionnaire was originally developed for assessment of chronic hyperventilation, and not specifically for DB in asthma [
      • van Dixhoorn J.
      • Duivenvoorden H.J.
      Efficacy of Nijmegen Questionnaire in recognition of the hyperventilation syndrome.
      ]. Hence, there is a need for new methods and tools for diagnosing dysfunctional breathing. In this study, we supplemented the NQ with the Breathing Pattern Assessment Tool (BPAT) for objective assessment of breathing patterns, which was recently demonstrated as a potential tool for detecting DB in patients referred to a severe asthma clinic [
      • Todd S.
      • Walsted E.S.
      • Grillo L.
      • Livingston R.
      • Menzies-Gow A.
      • Hull J.H.
      Novel assessment tool to detect breathing pattern disorder in patients with refractory asthma.
      ].
      In difficult asthma in particular, identifying DB as a co-morbidity is important, to avoid potentially harmful or expensive overtreatments such as oral steroids, or biological treatments. Difficult asthma is defined as asthma requiring high dose inhaled steroids plus a second controller, such as long-acting beta-2-agonist. These patients need to undergo systematic assessment to identify those with other causes of poor asthma control such as poor adherence, and co-morbidities (difficult-to-treat asthma), and those with severe asthma, who may require biological treatments. DB is one of the most common co-morbidities in difficult asthma: A recent study from UK, where adult patients referred with treatment-refractory asthma underwent respiratory physiotherapy assessment to diagnose DB, suggested that 22% of patients did not have asthma but only DB [
      • Todd S.
      • Walsted E.S.
      • Grillo L.
      • Livingston R.
      • Menzies-Gow A.
      • Hull J.H.
      Novel assessment tool to detect breathing pattern disorder in patients with refractory asthma.
      ]. However, the relative impact of DB on the level of asthma control has not been described.
      Previous studies have investigated the incidence of DB among highly selected populations from difficult asthma clinics [
      • Van Der Meer A.
      • Pasma H.
      • Kempenaar-okkema W.
      • Pelinck J.-A.
      • Schutten M.
      • Storm H.
      • Ten Brinke A.
      A 1-day visit in a severe asthma centre: effect on asthma control, quality of life and healthcare use.
      ,
      • Heaney L.G.
      • Conway E.
      • Kelly C.
      • Johnston B.T.
      • English C.
      • Stevenson M.
      • Gamble J.
      Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol.
      ,
      • Robinson D.S.
      • Campbell D.a.
      • Durham S.R.
      • Pfeffer J.
      • Barnes P.J.
      • Chung K.F.
      Systematic assessment of difficult-to-treat asthma.
      ,
      • Sweeney J.
      • Brightling C.E.
      • Menzies-Gow A.
      • Niven R.
      • Patterson C.C.
      • Heaney L.G.
      Clinical management and outcome of refractory asthma in the UK from the British thoracic society difficult asthma registry.
      ], but the prevalence and impact of DB in more general populations with difficult asthma has not previously been reported. Furthermore, the impact on validated measures of asthma control has not been reported, but is important to understand to which extent these measures, such as the Asthma Control score, may be affected by co-existing DB.
      The aim of this paper was therefore to describe the prevalence of DB in a highly selected population of patients managed for difficult asthma in specialist care, and to describe the impact on the level of asthma control, as well as quality of life. Furthermore, we wished to examine the prevalence of objective signs of DB, using a recently developed assessment tool, the BPAT test, and to examine how objective signs of DB associated with poor asthma control.

      2. Methods

      2.1 Design and material

      In a cross-sectional design, we prospectively recruited patients with difficult asthma based on level of treatment from four respiratory outpatient clinics in eastern Denmark. All examinations were carried out at the Respiratory Research Unit at Bispebjerg Hospital. Patients were offered to participate in this study if they fulfilled the criteria of having difficult asthma according to ERS/ATS 2014 guidelines [
      • Chung K.F.
      • Wenzel S.E.
      • Brozek J.L.
      • Bush A.
      • Castro M.
      • Sterk P.J.
      • Adcock I.M.
      • Bateman E.D.
      • Bel E.H.
      • Bleecker E.R.
      • Boulet L.-P.
      • Brightling C.
      • Chanez P.
      • Dahlen S.-E.
      • Djukanovic R.
      • Frey U.
      • Gaga M.
      • Gibson P.
      • Hamid Q.
      • Jajour N.N.
      • Mauad T.
      • Sorkness R.L.
      • Teague W.G.
      International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.
      ] treated with high-dose inhaled corticosteroids (ICS) treatment (≥1600 μg budesonide or equivalent) with a second controller (long acting beta-agonist (LABA), theophylline or leukotriene-antagonist) for the previous year or OCS for ≥ 50% of the previous year. Further details about the study population is described in previous work [
      • von Bülow A.
      • Backer V.
      • Bodtger U.
      • Søes-Petersen N.U.
      • Vest S.
      • Steffensen I.
      • Porsbjerg C.
      Differentiation of adult severe asthma from difficult-to-treat-asthma- outcomes of a systemic assessment protocol.
      ].
      All included patients with difficult asthma underwent a comprehensive systematic evaluation with focus on verification of the asthma diagnosis, exclusion of alternative diagnosis, evaluation of adherence and inhaler technique and identification of exposures and comorbidities as recommended by the ERS/ATS guidelines. They all had a physician's diagnosis of asthma after the systematic assessment.

      2.2 Dysfunctional breathing

      We used the Nijmegen questionnaire (NQ) to diagnose DB [
      • Veidal S.
      • Jeppegaard M.
      • Sverrild A.
      • Backer V.
      • Porsbjerg C.
      The impact of dysfunctional breathing on the assessment of asthma control.
      ]. The Nijmegen Questionnaire is a patient-completed 16-item questionnaire on abnormal breathing, using a 5-point Likert scale (1 = never, 5 = very often). DB was defined as a total symptom score on the Nijmegen questionnaire of ≥23.

      2.3 Breathing Pattern Assessment Tool (BPAT)

      The BPAT is completed by the physician. With the patient at rest and sitting with the back rested against the seat back, breathing pattern is observed by the physician for ≥1 min before BPAT completion. BPAT consists of seven different components including evaluation of abdominal/upper chest movement, inspiratory flow, expiratory flow, channel of inspiration and expiration (mouth or nose), air hunger, respiratory rate and rhythm. Each component is given a score from 0 (= expected normal) and 2 (=present in severe DB) and translates into a total score. Sensitivity analysis from the validation study of BPAT indicated that a BPAT score ≥4 corresponded to a sensitivity of 0.92 and a specificity of 0.75 for diagnosis of BPD [
      • Todd S.
      • Walsted E.S.
      • Grillo L.
      • Livingston R.
      • Menzies-Gow A.
      • Hull J.H.
      Novel assessment tool to detect breathing pattern disorder in patients with refractory asthma.
      ].

      2.4 Asthma control and quality of life

      Patients filled in the five-item Asthma Control Questionnaire (ACQ-5) [
      • Juniper E.F.
      • Svensson K.
      • Mörk A.C.
      • Ståhl E.
      Measurement properties and interpretation of three shortened versions of the asthma control questionnaire.
      ] and mini Asthma Quality of life Questionnaire (mini AQLQ) [
      • Juniper E.F.
      • Guyatt G.H.
      • Cox F.M.
      • Ferrie P.J.
      • King D.
      Development and validation of the mini asthma quality of life questionnaire.
      ]. Asthma exacerbations, defined as a burst of OCS or an increase in the maintenance doses of OCS treatment, were retrospectively evaluated for the 12 months preceding the first study visit. Uncontrolled asthma was defined according to ERS/ATS guidelines as ACQ >1.5, ≥2 OCS requiring exacerbations in the previous year, ≥ 1 hospitalisation due to asthma, or airflow limitation (pre-bronchodilator FEV1 < 80% and FEV1/FVC < lower limit of normal) [
      • Chung K.F.
      • Wenzel S.E.
      • Brozek J.L.
      • Bush A.
      • Castro M.
      • Sterk P.J.
      • Adcock I.M.
      • Bateman E.D.
      • Bel E.H.
      • Bleecker E.R.
      • Boulet L.-P.
      • Brightling C.
      • Chanez P.
      • Dahlen S.-E.
      • Djukanovic R.
      • Frey U.
      • Gaga M.
      • Gibson P.
      • Hamid Q.
      • Jajour N.N.
      • Mauad T.
      • Sorkness R.L.
      • Teague W.G.
      International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.
      ].

      2.5 General examinations

      Spirometry and fractional exhaled nitric oxid (FeNO) were measured according to the ERS guidelines [
      • Miller M.R.
      • Hankinson J.
      • Brusasco V.
      • Burgos F.
      • Casaburi R.
      • Coates a.
      • Crapo R.
      • Enright P.
      • van der Grinten C.P.M.
      • Gustafsson P.
      • Jensen R.
      • Johnson D.C.
      • MacIntrye N.
      • McKay R.
      • Navajas D.
      • Pedersen O.F.
      • Pellegrino R.
      • Viegi G.
      • Wagner J.
      Standardisation of spirometry.
      ,
      ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide.
      ]. Induced sputum was processed as described by Bafadhel et al. [
      • Bafadhel M.
      • McCormick M.
      • Saha S.
      • McKenna S.
      • Shelley M.
      • Hargadon B.
      • Mistry V.
      • Reid C.
      • Parker D.
      • Dodson P.
      • Jenkins M.
      • Lloyd A.
      • Rugman P.
      • Newbold P.
      • Brightling C.E.
      Profiling of sputum inflammatory mediators in asthma and chronic obstructive pulmonary disease.
      ]. Blood eosinophil count and total IgE were analysed. Eosinophilic airway inflammation was defined as sputum eosinophil count ≥3% [
      • Simpson J.L.
      • Mcelduff P.
      • Gibson G.
      Assessment and reproducibility of non-eosinophilic asthma using induced sputum.
      ], blood eosinophil count ≥ 0.3*109/L or FeNO > 50 ppb [

      Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, Olin A, Plummer AL, Taylor DR, Thoracic A, Committee S. An Official ATS Clinical Practice Guideline.

      ]. Atopy was defined as a positive skin prick test (SPT) (≥3 mm) or elevated specific IgE (<0.35 kU/L) for at least one aeroallergen [
      • ARIA (Allergic Rhinitis and its Impact on Asthma)
      ]. Indirect bronchial challenge testing was investigated using mannitol (Osmohale). Patients inhaled an empty capsule (used as reference) followed by increasing inhaled doses of mannitol (from 5 to 365 mg) until maximum doses or a fall in FEV1 ≥ 15% was reached [
      • Anderson S.D.
      • Brannan J.
      • Spring J.
      • Spalding N.
      • Rodwell L.T.
      • Chan K.
      • Gonda I.
      • Walsh A.
      • Clark A.R.
      A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol.
      ]. A positive diagnostic test was defined as a decrease in FEV1 ≥ 15% from baseline with a provocation dose of mannitol ≤635 mg.

      2.6 Statistical analysis

      IBM SPSS statistics version 24.0 was used for the statistical analysis. The characteristics of patients with and without DB were compared with respect to different outcomes. We used unpaired t-test for parametric data, Mann-Whitney U test for nonparametric data and the chi2 -test and Fisher's exact test for categorical data. Differences were defined as significant at p < 0.05. In order to determine the independent contribution of DB on the level of asthma control, a linear regression analysis with ACQ as the dependent variable was performed. A univariate analysis was performed with ACQ ≤1.5 and ≥1.5 and explanatory variables with a p value < 0.3 was included in the final regression analysis including sex, smoking, BMI, blood eosinophils and subjects with or without DB.

      3. Results

      3.1 NQ and ACQ

      In total, 1034 patients completed screening for difficult asthma, among whom 117 patients fulfilled the inclusion criteria of high dose treatment were included in the final analysis (Fig. 1).
      Fig. 1
      Fig. 1Strobe flow diagram: Selection of the study population. All patients ≥18 years with difficult asthma according to ERS/ATS 2014 guidelines seen in four respiratory outpatient clinics over a year were invited to participate in this study.
      The study population was predominately females (59%) with a median age of 46.1 years (20–80). DB defined as a Nijmegen questionnaire ≥23 was identified in 29.9% (n = 35) of patients. Table 1 and Fig. 2, Fig. 3 depict that patients with DB were more often female (74%), had higher BMI (Table 1), had significantly poorer asthma control and lower quality of life compared to patients without DB (mini AQLQ mean (SD): 4.2 ± 1.04 vs. 5.49 ± 0.85, p = 0.001). However, there were no significant differences in lung function, airway hyperresponsiveness or FENO. The NQ score correlated closely with the ACQ and AQLQ scores (Fig. 3)
      Table 1Characteristics of the study population.
      Difficult asthma patients with DB
      Nijmegen score ≥23.
      (n = 35)
      Difficult patients without DB (n = 82)P-value
      Age in years44.60 (20- 71)47.7 (20- 80)0.295
      Median (min-max)
      Sex:74% (26/35)52% (43/82)0.028
      % female
      BMI (kg/m2)30.4 ± 6.6627.20 ± 5.820.01
      Mean (SD)
      BMI (>30 kg/m2) n (%)15 (42.85%)21 (25.6%)0.08
      Smoking-status:
      Current smoker (%) n11.4% (4/35)3.7% (3/82)0.11
      Ex-smoker (%) n22.9% (8/35)40.2% (33/82)0.07
      Daily ICS dose μg
      Budesonide equivalent.
      2434 ± 9022207 ± 980.400.11
      Mean (SD)
      Use of maintenance OCS (%) n6(17.1) %)9 (11.0%)0.36
      Atopy (%) n14 (23%)47 (77%)0.09
      FEV1% (pre)71.8 ± 21.177.3 ± 21.30.15
      Mean (SD)
      FEV1/FVC (pre)0.70 ± 0.150.71 ± 0.130.51
      Mean (SD)
      FeNO (ppb)17.3 (2.9–57.5)21.10 (2.2–114.2)0.42
      Median (min-max)
      Exacerbations previous 12 months1(0- 6)1(0–10)0.62
      Median (min-max)
      Blood eosinophils
      Sputum eosinophil count ≥3%, blood eosinophil count ≥0.3 * 109/L or FeNO >50 ppb.
      0.19 (0.01–0.63)0.21 (0.04–1,47)0.26
      Median (min- max)
      Sputum Eosinophils
      Sputum eosinophil count ≥3%, blood eosinophil count ≥0.3 * 109/L or FeNO >50 ppb.
      0.50 (0.001–64.50)2.12 (0.001–92.3)0.01
      Median (min- max)
      Sputum Eosinophils >3%30% (35/117)70% (82/117)0.03
      % (n)
      RDR mannitol0.02(-0.01–11.83)0.01(-0.01–0.15)0.32
      Median (min-max)
      Nijmegen30.94 ± 7.5713.49 ± 5.810.001
      Mean (SD)
      ACQ2.86 ± 1.051.46 ± 0.930.001
      Mean (SD)
      mini AQLQ4.2 ± 1.045.49 ± 0.850.001
      Mean(SD)
      BPAT
      Median (min- max)3(0–10)2(0–10)0.04
      % (n)23% (27/117)77% (90/117)0.001
      Data are presented as mean ± SD, median (min-max) or % (n).
      ACQ: Asthma Control Questionnaire, miniAQLQ: mini Asthma Quality of Life questionnaire, BMI: Body mass index, FeNO: fractional exhaled nitric oxid, FEV1: forced expiratory volume in 1 s, FVC: forced vital capacity.
      a Nijmegen score ≥23.
      b Budesonide equivalent.
      c Sputum eosinophil count ≥3%, blood eosinophil count ≥0.3 * 109/L or FeNO >50 ppb.
      Fig. 2
      Fig. 2Boxplot of ACQ (Left) and mini AQLQ score (Right) among patients with and without DB.
      Fig. 3
      Fig. 3Relationship between ACQ score vs. Nijmegen score and mini AQLQ score vs. Nijmegen score.
      The Nijmegen questionnaire includes three question that might reflect poor asthma control (fast or deep breathing, shortness of breath and tightness across chest). When omitting these questions from the analysis, the correlations were still significant (ACQ score vs. Nijmegen score: R2 = 0.438, p < 0.0001 and mini AQLQ score vs. Nijmegen score: R2 = 0.438, p < 0.0001.)

      3.2 Regression analysis

      In order to determine the independent contribution of DB on the level of asthma control, a linear regression analysis with ACQ as the dependent variable was performed. We included explanatory variables with a p value < 0.3 from the univariate analysis with ACQ ≤1.5 and ≥1.5 In the final regression analysis. This showed that DB was founded as an independent determinant of ACQ-score (p < 0.001), which means that the effect of DB on asthma control could not be explained by other factors such as more airway hyperresponsiveness or lower lung function in patients with DB (Table 2).
      Table 2A regression analysis with different predictors of ACQ.
      Unstandardized Coefficients-BSig95.0% Confidence Interval for B lower bound95.0% Confidence Interval for B upper bound
      -Sex0.0070.941−0.1710.184
      -Smoking−0.0850.659−0.4650.295
      -BMI0.0030.670−0.0110.017
      -Blood eosinophils0.3460.056−0.0090.700
      -Nijmegen score231.286<0.0010.2140.613
      Because three of the symptoms included on the Nijmegen questionnaire are similar to some of the questions on the ACQ, the correlation between ACQ and the Nijmegen score with and without those three symptoms was performed to make sure that the reason why the subjects with DB scored higher on the ACQ was not because the questions in the questionnaires were to similar. The results showed that DB remained still an independent determinant of the ACQ score (p < 0.001).
      We performed also a linear regression analysis with ACQ-score as the dependent variable in order to determine the independent contribution of BPAT to the level of asthma control. The result showed that BPAT was also found as an independent determinant of ACQ-score (p < 0.0001).

      3.3 Objective assessment of DB

      When assessing patients with the BPAT score, 25% (29/117) had a score ≥ 4, suggesting the presence of DB. The BPAT score was significantly higher among patients with DB compared to those without DB; Median (min-max): 3.00 (0–10) vs. 2.00 (0–10), p = 0.04. Patients with objective signs of DB according to the BPAT assessment, i.e. a BPAT score ≥4 had poorer asthma control (Mean ACQ score: 2.54 ± 1.14 vs. 1.66 ± 1.09, p < 0.001) and a lower quality of life (Mean AQLQ score: 4.65 ± 1.14 vs. 5.27 ± 1.02, p < 0.001) (Fig. 4).
      Fig. 4
      Fig. 4Patients with BPAT ≥4 had also higher ACQ score and lower mini AQLQ score.
      When combining the Nijmegen score and the BPAT score, a total of 48 (41%) of patients had either symptoms or signs of DB. In order to investigate whether BPAT and Nijmegen questionnaire represent the same types of patients, we examined the relationship between Nijmegen score and BPAT. In order to do that, the patients were divided into 4 groups: 1) low BPAT/low NQ (65 patients), 2) low BPAT/high NQ (12 patients), 3) high BPAT/low NQ (15 patients) and 4) high BPAT/high NQ (21 patients).
      Patients with a low NQ, but high BPAT, i.e. objective signs of DB, had a significantly poorer asthma control, compared to patients with both low NQ and low BPAT. Whereas among patients with a high NQ, the ACQ score did not differ between those with high and low BPAT score (Fig. 5b).
      Fig. 5
      Fig. 5Relationship between BPAT-score and Nijmegen score. DB was defined as a Nijmegen score ≥23 and diagnosis of BPD was defined as BPAT score ≥4. (a-left). Comparing the 4 groups of patients based on relationship between ACQ score, Nijmegen score and BPAT score (b-right).

      4. Discussion

      The prevalence of DB in the current study was 29.9% and we found that DB is a prevalent condition among patients with difficult asthma in general, which has a very significant impact on the level of asthma control. Considering that the assessments herein were not performed by a respiratory physiotherapist meaning that the examination was not carried out by those with the requisite skills, the prevalence of DB could have been either under or overestimated in our study. At the same time, respiratory specialist doing the examination, was not hugely sensitive to concomitant psychiatric disease, which been proposed as a modulator of difficult asthma [
      • Heaney L.G.
      • Conway E.
      • Kelly C.
      • Gamble J.
      Prevalence of psychiatric morbidity in a difficult asthma population: relationship to asthma outcome.
      ]. The prevalence of DB in our study aligns closely with the previous studies from the UK (22%) and Romania (29.7%) [
      • Thomas M.
      • McKinley R.K.
      • Freeman E.
      • Foy C.
      Prevalence of dysfunctional breathing in patients treated for asthma in primary care: cross sectional survey.
      ,
      • Agache I.
      • Ciobanu C.
      • Paul G.
      • et al.
      Dysfunctional breathing phenotype in adults with asthma – incidence and riskfactors.
      ], when DB was defined based on the Nijmegen questionnaire. Our results are in accordance with the findings from other studies suggesting that having breathing disorders can decrease health-related quality of life [
      • Hagman C.
      • Janson C.
      • Emtner M.
      A comparison between patients with dysfunctional breathing and patients with asthma.
      ,
      • Ringsberg K.C.
      • Löwhagen O.
      • Sivik T.
      Psychological differences between asthmatics and patients suffering from an asthma-like condition, functional breathing disorder: a comparison between the two groups concerning personality, psychosocial and somatic parameters.
      ,
      • Ringsberg K.C.
      • Wetterqvist H.
      • Lowhagen O.
      • Sivik T.
      Physical capacity and dyspnea in patients with asthma-like symptoms but negative asthma tests.
      ,
      • Tay T.R.
      • Radhakrishna N.
      • Hore-Lacy F.
      • Smith C.
      • Hoy R.
      • Dabscheck E.
      • Hew M.
      Comorbidities in difficult asthma are independent risk factors for frequent exacerbations, poor control and diminished quality of life.
      ]. The relative impact on the level of asthma control was high: patients with DB had an ACQ score that was 2 times higher than those without (2.86 vs.1.46). Furthermore, we demonstrated that a novel scoring system for objective signs of DB could also identify patients with poor asthma control, possibly relating to DB. In our study, the BMI of patients with DB was noticeably high compared to those without DB, indicating a possible overlap between obese-asthma phenotype and DB. Obese asthma-phenotype is associated with increased asthma severity, poor asthma control, and varying response to corticosteroids [
      • Taylor B.
      • Mannino D.
      • Brown C.
      • et al.
      Body mass index and asthma severity in the National Asthma Survey.
      ,
      • Boulet L.P.
      • Franssen E.
      Influence of obesity on response to fluticasone with or without salmeterol in moderate asthma.
      ,
      • Sutherland E.R.
      • Goleva E.
      • Strand M.
      • et al.
      Body mass and glucocorticoid response in asthma.
      ,
      • Mosen D.M.
      • Schatz M.
      • Magid D.J.
      • et al.
      The relationship between obesity and asthma severity and control in adults.
      ,
      • Farah C.S.
      • Kermode J.A.
      • Downie S.R.
      • et al.
      Obesity is a determinant of asthma control independent of inflammation and lung mechanics.
      ]. Obesity is usually associated with deconditioning which is the factor leads to increased breathlessness, and this should be considered as a contributory factor to DB. This is important, as even as moderate weight loss has been shown to improve asthma control [
      • Novosad S.
      • Khan S.
      • Wolfe B.
      • Khan A.
      Role of obesity in asthma control, the obesity-asthma phenotype.
      ], which demonstrates that our current tools for asthma control do not factor in non-asthma factors. Although patients with DB had a higher BMI in our study population, adjusting for BMI did not impact the association between DB and poor asthma control, suggesting that in these patients, symptoms were not driven by obesity. As part of detecting DB, it is also important to explore this condition as part of spectrum of associated maladaptive behaviours such as anxiety, depression, slepp apnea, gastroesophageal reflux and elevated sino-nasal outcome test score [
      • Denton E.
      • Bondarenko J.
      • Tay T.
      • Lee J.
      • Radhakrishna N.
      • Hore-Lacy F.
      • Martin C.
      • Hoy R.
      • O'Hehir R.
      • Dabscheck E.
      • Hew M.
      Factors associated with dysfunctional breathing in patients with difficult to treat asthma.
      ], highlighting an important interaction between comorbid treatable traits in difficult asthma.
      Our study is the first to investigate the prevalence and impact of DB on measures of asthma control in a selected population: those referred for further assessment for poorly controlled asthma. All patients were screened and all patients with difficult asthma were included confirming that DB is very common in this patient group suggesting that DB should be part of the part of the assessment of those referred to a difficult/severe asthma clinic; it is likely that our results could be extrapolated to other respiratory outpatient clinics but this requires further evaluation.
      We believe that the presence of DB should not only be identified by the Nijmegen Questionnaire but also by a clinical observation of the breathing pattern. We used BPAT to make an objective assessment of DB among patients in our study, and found that by adding this assessment to the NQ, we could identify a group of patients without immediate symptoms of DB, but who had objective signs of DB, and a poorer asthma control. The NQ was developed to assess symptoms of hyperventilation and resulting hypocapnia, and may hence not capture other types of dysfunctional breathing, such as patient with apical breathing (Boulding). These patients predominantly use their apical respiratory muscles, and may have disproportionate dyspnea, but not symptoms of hyperventilation, and may hence not be identified if the NQ is used alone. Hence, objective assessment of the breathing pattern may complement the NQ as a screening tool for DB. They are both fast and easy to use in a busy everyday clinic by the physicians.
      The limitations of this study are firstly, that patients were not reviewed by a respiratory specialist physiotherapist, with experience in DB, which may have impacted the BPAT assessment. All assessments applied in the present study were performed by a medical doctor, which probably is an argument for assessment by a multidisciplinary team (MDT), especially given very high doses of ICS these patients were using. Furthermore, we did not include objective measures of hyperventilation, such as capnography with an expected low end-tidal carbon dioxide in hyperventilation. Not having a validated diagnostic tool for DB is a limitation in this field and there is no universally accepted gold standard diagnostic tool. Many of the proposed ‘objective’ tools also actually influence the measurement of interest, i.e. by virtue of direct tactile stimulation or by making the subject acutely aware of their breathing pattern and thus potentially indirectly influencing or altering breathing pattern. We acknowledge that NQ is not validated in severe asthma. However, it was used in our study, because it remains one of the most commonly used questionnaires and it thus does make it possible to compare our results with other studies. The BPAT is new tool and thus evaluated in only a few studies, but it does extend our capability to provide a semi-objective assessment. Another limitation of this study was that the assessment of patients did not include a psycho-social-assessment, which has been shown to impact significantly on asthma control of quality of life.
      A significant strength of the study is that patients all underwent a very thorough assessment including objective markers of poor asthma control, such bronchial provocation testing for airway hyperresponsiveness, and airway inflammation. By adjusting for these factors, we could ensure that the poorer asthma symptom control among patients with signs of DB was not simply a reflection of more severe asthma.
      Our findings demonstrate the importance of DB in patients with difficult asthma, and physicians should be aware that some patients may have an alternative explanation for their symptoms as there are many other diseases which may give a similar picture. The symptoms could be improved by appropriate intervention, suggesting that DB is amenable to treatment. Intervention such as explanation, specific breathing retraining exercises have been used as parts of treatment for dysfunctional breathing reducing the severity and frequency of symptoms [
      • Boulding R.
      • Stacey R.
      • Niven R.
      • Fowler S.J.
      Dysfunctional breathing: a review of the literature and proposal for classification.
      ]. A recent study from UK where patients with DB were recruited to a controlled physiotherapy breathing retraining, suggested that over half of patients with a diagnosis of asthma and DB obtained a clinically relevant improvement in their asthma related quality of life at 1 month which persisted for at least 6 months, concluding that these patients may potentially benefit from a simple safe and relatively non-pharmacological intervention [
      • Thomas M.
      • McKinley R.K.
      • Freeman E.
      • Foy C.
      • Prodger P.
      • Price D.
      Breathing retraining for dysfunctional breathing in asthma: a randomised controlled trial.
      ] Breathing modification therapies including the Butekyo breathing method and yogic breathing has also been used before and many physiotherapy-based breathing studies have reported beneficial outcomes in ACQ, mini AQLQ and reductions in bronchodilator use in patients with mild and moderate asthma [
      • Thomas M.
      • McKinley R.K.
      • Freeman E.
      • Foy C.
      • Prodger P.
      • Price D.
      Breathing retraining for dysfunctional breathing in asthma: a randomised controlled trial.
      ,
      • Slader C.A.
      • Reddel H.K.
      • Spencer L.M.
      • et al.
      Double blind randomised controlled trial of two different breathing techniques in the management of asthma.
      ,
      • Bruton A.
      • Lee A.
      • Yardley L.
      • Raftery J.
      • Arden-Close E.
      • Kirby S.
      • Zhu S.
      • Thiruvothiyur M.
      • Webley F.
      • Taylor L.
      • Gibson D.
      • Yao G.
      • Stafford-Watson M.
      • Versnel J.
      • Moore M.
      • George S.
      • Little P.
      • Djukanovic R.
      • Price D.
      • Pavord I.D.
      • Holgate S.T.
      • Thomas M.
      Physiotherapy breathing retraining for asthma: a randomised controlled trial.
      ].
      In conclusion, DB is an important confounder to lack of asthma control and poorer quality of life ain patients with difficult asthma. Hence, asthma patients with poor symptom control despite high dose treatment should be routinely screened for dysfunctional breathing. We furthermore found that patients with DB tended to receive higher doses of asthma treatment (inhaled corticosteroids (ICS)) compared to patients without DB, suggest that having a comorbidity such as dysfunctional breathing may lead to overtreatment. This indicates a high risk of overtreatment of patients with DB, if signs of DB are not recognised, and supports the proposition that patients with difficult asthma should be routinely assessed for DB. Furthermore, we found that objective signs of DB, assessed with the BPAT score were also associated with poor asthma control. Combining assessment of subjective and objective signs of DB appears to be important for identifying all cases of DB.

      CRediT authorship contribution statement

      Farnam Barati Sedeh: Data curation, Funding acquisition, Writing - original draft, Formal analysis, Supervision. Anna Von Bülow: Data curation, Formal analysis, Writing - original draft, Supervision. Vibeke Backer: Funding acquisition, Formal analysis, Data curation, Supervision. Uffe Bodtger: Funding acquisition, Formal analysis, Data curation, Supervision. Ulrik Søes Petersen: Formal analysis, Data curation, Supervision. Susanne Vest: Funding acquisition, Formal analysis, Data curation, Supervision. James H. Hull: Funding acquisition, Formal analysis, Data curation, Supervision. Celeste Porsbjerg: Funding acquisition, Formal analysis, Data curation, Writing - original draft, Supervision.

      Declaration of competing interest

      This study was supported by unrestricted grants from The Danish Lung Association and Novartis Healthcare, Denmark .

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

      References

        • Thomas M.
        • McKinley R.K.
        • Freeman E.
        • Foy C.
        Prevalence of dysfunctional breathing in patients treated for asthma in primary care: cross sectional survey.
        Br. Med. J. 2001; 322: 1098-1100
        • Lowhagen O.
        Asthma – a disease difficult to define. Patients can receive correct treatment by means of differential diagnosis criteria.
        Lakartidningen. 2005; 102: 3872-3878
        • Barker N.
        • Everard M.L.
        Getting to grips with dysfunctional breathing.
        Paediatr. Respir. Rev. 2015; 16: 53-61
        • Courtney R.
        The functions of breathing and its dysfunctions and their relationship to breathing therapy.
        Int. J. Osteopath. Med. 2009; 12: 78-85
        • von Bülow A.
        • Backer V.
        • Bodtger U.
        • Søes-Petersen N.U.
        • Vest S.
        • Steffensen I.
        • Porsbjerg C.
        Differentiation of adult severe asthma from difficult-to-treat-asthma- outcomes of a systemic assessment protocol.
        Respir. Med. 2018; 145: 41-47
        • Van Der Meer A.
        • Pasma H.
        • Kempenaar-okkema W.
        • Pelinck J.-A.
        • Schutten M.
        • Storm H.
        • Ten Brinke A.
        A 1-day visit in a severe asthma centre: effect on asthma control, quality of life and healthcare use.
        Eur. Respir. J. 2016; 48: 726-733
        • Lewis R.A.
        • Howell J.B.
        Definition of the hyperventilation syndrome.
        Bull. Eur. Physiopathol. Respir. 1986; 22: 201-205
        • van Dixhoorn J.
        • Duivenvoorden H.J.
        Efficacy of Nijmegen Questionnaire in recognition of the hyperventilation syndrome.
        J. Psychosom. Res. 1985; 29: 199-206
        • Todd S.
        • Walsted E.S.
        • Grillo L.
        • Livingston R.
        • Menzies-Gow A.
        • Hull J.H.
        Novel assessment tool to detect breathing pattern disorder in patients with refractory asthma.
        Respirology. 2017 Sep 14; https://doi.org/10.1111/resp.13173
        • Heaney L.G.
        • Conway E.
        • Kelly C.
        • Johnston B.T.
        • English C.
        • Stevenson M.
        • Gamble J.
        Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol.
        Thorax. 2003; 58: 561-566
        • Robinson D.S.
        • Campbell D.a.
        • Durham S.R.
        • Pfeffer J.
        • Barnes P.J.
        • Chung K.F.
        Systematic assessment of difficult-to-treat asthma.
        Eur. Respir. J. 2003; 22: 478-483
        • Sweeney J.
        • Brightling C.E.
        • Menzies-Gow A.
        • Niven R.
        • Patterson C.C.
        • Heaney L.G.
        Clinical management and outcome of refractory asthma in the UK from the British thoracic society difficult asthma registry.
        Thorax. 2012; 67: 754-756
        • Chung K.F.
        • Wenzel S.E.
        • Brozek J.L.
        • Bush A.
        • Castro M.
        • Sterk P.J.
        • Adcock I.M.
        • Bateman E.D.
        • Bel E.H.
        • Bleecker E.R.
        • Boulet L.-P.
        • Brightling C.
        • Chanez P.
        • Dahlen S.-E.
        • Djukanovic R.
        • Frey U.
        • Gaga M.
        • Gibson P.
        • Hamid Q.
        • Jajour N.N.
        • Mauad T.
        • Sorkness R.L.
        • Teague W.G.
        International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.
        Eur. Respir. J. 2014; 43: 343-373
        • Veidal S.
        • Jeppegaard M.
        • Sverrild A.
        • Backer V.
        • Porsbjerg C.
        The impact of dysfunctional breathing on the assessment of asthma control.
        Respir. Med. 2017 Feb; 123: 42-47
        • Juniper E.F.
        • Svensson K.
        • Mörk A.C.
        • Ståhl E.
        Measurement properties and interpretation of three shortened versions of the asthma control questionnaire.
        Respir. Med. 2005; 99: 553-558
        • Juniper E.F.
        • Guyatt G.H.
        • Cox F.M.
        • Ferrie P.J.
        • King D.
        Development and validation of the mini asthma quality of life questionnaire.
        Eur. Respir. J. 1999; 14: 32-38
        • Miller M.R.
        • Hankinson J.
        • Brusasco V.
        • Burgos F.
        • Casaburi R.
        • Coates a.
        • Crapo R.
        • Enright P.
        • van der Grinten C.P.M.
        • Gustafsson P.
        • Jensen R.
        • Johnson D.C.
        • MacIntrye N.
        • McKay R.
        • Navajas D.
        • Pedersen O.F.
        • Pellegrino R.
        • Viegi G.
        • Wagner J.
        Standardisation of spirometry.
        Eur. Respir. J. 2005; 26: 319-338
      1. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide.
        Am. J. Respir. Crit. Care Med. 2005; 171 (2005): 912-930
        • Bafadhel M.
        • McCormick M.
        • Saha S.
        • McKenna S.
        • Shelley M.
        • Hargadon B.
        • Mistry V.
        • Reid C.
        • Parker D.
        • Dodson P.
        • Jenkins M.
        • Lloyd A.
        • Rugman P.
        • Newbold P.
        • Brightling C.E.
        Profiling of sputum inflammatory mediators in asthma and chronic obstructive pulmonary disease.
        Respiration. 2012; 83: 36-44
        • Simpson J.L.
        • Mcelduff P.
        • Gibson G.
        Assessment and reproducibility of non-eosinophilic asthma using induced sputum.
        Respiration. 2010; 79: 147-151
      2. Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, Olin A, Plummer AL, Taylor DR, Thoracic A, Committee S. An Official ATS Clinical Practice Guideline.

        • ARIA (Allergic Rhinitis and its Impact on Asthma)
        (Update. available on)
        www.whiar.org
        Date: 2008
        (Date last updated 2016, accessed June 1 2017)
        • Anderson S.D.
        • Brannan J.
        • Spring J.
        • Spalding N.
        • Rodwell L.T.
        • Chan K.
        • Gonda I.
        • Walsh A.
        • Clark A.R.
        A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol.
        Am. J. Respir. Crit. Care Med. 1997 Sep; 156: 758-765
        • Heaney L.G.
        • Conway E.
        • Kelly C.
        • Gamble J.
        Prevalence of psychiatric morbidity in a difficult asthma population: relationship to asthma outcome.
        Respir. Med. 2005 Sep; 99: 1152-1159
        • Agache I.
        • Ciobanu C.
        • Paul G.
        • et al.
        Dysfunctional breathing phenotype in adults with asthma – incidence and riskfactors.
        Clin. Transl. Allergy. 2012; 2: 18
        • Hagman C.
        • Janson C.
        • Emtner M.
        A comparison between patients with dysfunctional breathing and patients with asthma.
        Clin. Res. J. 2008; 2: 86-91
        • Ringsberg K.C.
        • Löwhagen O.
        • Sivik T.
        Psychological differences between asthmatics and patients suffering from an asthma-like condition, functional breathing disorder: a comparison between the two groups concerning personality, psychosocial and somatic parameters.
        Integr. Physiol. Behav. Sci. 1993; 28: 358-367
        • Ringsberg K.C.
        • Wetterqvist H.
        • Lowhagen O.
        • Sivik T.
        Physical capacity and dyspnea in patients with asthma-like symptoms but negative asthma tests.
        Allergy. 1997; 52: 532-540
        • Tay T.R.
        • Radhakrishna N.
        • Hore-Lacy F.
        • Smith C.
        • Hoy R.
        • Dabscheck E.
        • Hew M.
        Comorbidities in difficult asthma are independent risk factors for frequent exacerbations, poor control and diminished quality of life.
        Respirology. 2016; 21: 1384-1390
        • Taylor B.
        • Mannino D.
        • Brown C.
        • et al.
        Body mass index and asthma severity in the National Asthma Survey.
        Thorax. 2008; 63: 14-20
        • Boulet L.P.
        • Franssen E.
        Influence of obesity on response to fluticasone with or without salmeterol in moderate asthma.
        Respir. Med. 2007; 101: 2240-2247
        • Sutherland E.R.
        • Goleva E.
        • Strand M.
        • et al.
        Body mass and glucocorticoid response in asthma.
        Am. J. Respir. Crit. Care Med. 2008; 178: 682-687
        • Mosen D.M.
        • Schatz M.
        • Magid D.J.
        • et al.
        The relationship between obesity and asthma severity and control in adults.
        J. Allergy Clin. Immunol. 2008; 122: 507-511
        • Farah C.S.
        • Kermode J.A.
        • Downie S.R.
        • et al.
        Obesity is a determinant of asthma control independent of inflammation and lung mechanics.
        Chest. 2011; 140: 659-666
        • Novosad S.
        • Khan S.
        • Wolfe B.
        • Khan A.
        Role of obesity in asthma control, the obesity-asthma phenotype.
        J. Allergy. 2013; 2013538642
        • Denton E.
        • Bondarenko J.
        • Tay T.
        • Lee J.
        • Radhakrishna N.
        • Hore-Lacy F.
        • Martin C.
        • Hoy R.
        • O'Hehir R.
        • Dabscheck E.
        • Hew M.
        Factors associated with dysfunctional breathing in patients with difficult to treat asthma.
        J. Allergy Clin. Immunol. Pract. 2019 May - Jun; 7: 1471-1476
        • Boulding R.
        • Stacey R.
        • Niven R.
        • Fowler S.J.
        Dysfunctional breathing: a review of the literature and proposal for classification.
        Eur. Respir. Rev. 2016 Sep; 25: 287-294https://doi.org/10.1183/16000617.0088-2015
        • Thomas M.
        • McKinley R.K.
        • Freeman E.
        • Foy C.
        • Prodger P.
        • Price D.
        Breathing retraining for dysfunctional breathing in asthma: a randomised controlled trial.
        Thorax. 2003 Feb; 58: 110-115
        • Slader C.A.
        • Reddel H.K.
        • Spencer L.M.
        • et al.
        Double blind randomised controlled trial of two different breathing techniques in the management of asthma.
        Thorax. 2006; 61: 643-645
        • Bruton A.
        • Lee A.
        • Yardley L.
        • Raftery J.
        • Arden-Close E.
        • Kirby S.
        • Zhu S.
        • Thiruvothiyur M.
        • Webley F.
        • Taylor L.
        • Gibson D.
        • Yao G.
        • Stafford-Watson M.
        • Versnel J.
        • Moore M.
        • George S.
        • Little P.
        • Djukanovic R.
        • Price D.
        • Pavord I.D.
        • Holgate S.T.
        • Thomas M.
        Physiotherapy breathing retraining for asthma: a randomised controlled trial.
        Lancet Respir. Med. 2018 Jan; 6: 19-28