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

Journal Pre-proof The impact of dysfunctional breathing on the level of asthma control in difficult asthma Farnam Barati Sedeh, Anna Von Bülow, Vibeke Backer, Uffe Bodtger, Ulrik Søes Petersen, Susanne Vest, James Hull, Celeste Porsbjerg PII:

S0954-6111(20)30034-2

DOI:

https://doi.org/10.1016/j.rmed.2020.105894

Reference:

YRMED 105894

To appear in:

Respiratory Medicine

Received Date: 25 November 2019 Revised Date:

4 February 2020

Accepted Date: 5 February 2020

Please cite this article as: Sedeh FB, Von Bülow A, Backer V, Bodtger U, Petersen UlrikSø, Vest S, Hull J, Porsbjerg C, The impact of dysfunctional breathing on the level of asthma control in difficult asthma, Respiratory Medicine (2020), doi: https://doi.org/10.1016/j.rmed.2020.105894. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Ltd. All rights reserved.

Author Contributions Dr. Sedeh, and Bülow had full access to all of data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Sedeh, Bülow and Porsbjerg. Acquisition, analysis, and interpretation of data: All authors. Drafting of the manuscript: Sedeh, Bülow and Porsbjerg. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Sedeh Obtained. Administrative, technical, or material support: All authors. Study supervision: All authors.

1

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

2 3

Farnam Barati Sedeh1, Anna Von Bülow1, Vibeke Backer1, Uffe Bodtger2, 3, 4, Ulrik Søes Petersen4,

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Susanne Vest5, James Hull6, Celeste Porsbjerg1

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Copenhagen (Denmark)

8

2

9

Health Research, University of Southern Denmark

Respiratory Research Unit, Department of Respiratory Medicine, Bispebjerg University Hospital-

Department of Respiratory and Internal Medicine, Naestved Hospital, Institute for Regional

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3

Institute for regional Health Research, University of Southern Denmark

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4

Department of Respiratory of and Internal Medicine, Roskilde Hospital (Denmark)

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5

Department of Respiratory and Infection Medicine, Hilleroed Hospital, (Denmark)

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6

Department of Respiratory Medicine, Royal Brompton Hospital, London (UK).

14 15 16

Corresponding author

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Farnam B.Sedeh. Respiratory Research Unit, Department of Respiratory Medicine, Bispebjerg

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University Hospital- Copenhagen (Denmark). [email protected]

19 20 21 22

Keywords: Severe asthma, difficult-to-treat asthma, asthma, systemic assessment, asthma

23

management.

24 25 26

1

27

Abstract:

28

Background: Difficult asthma is defined as asthma requiring high dose treatment. However,

29

systematic assessment is required to differentiate severe asthma from difficult-to-treat asthma.

30

Dysfunctional breathing (DB) is a common comorbidity in difficult asthma, which may contribute

31

to symptoms, but how it affects commonly used measures of symptom control is unclear.

32 33

Methods: All adult asthma patients seen in four respiratory clinics over one year were screened

34

prospectively, and patients with possible severe asthma according to ERS/ATS criteria (´Difficult

35

asthma´: high–dose inhaled corticosteroids/oral corticosteroids), underwent systematic

36

assessement. Symptoms of DB were assessed utilizing a symptom based subjective tool, Nijmegen

37

questionnaire (NQ), and objective signs of DB with the Breathing Pattern Assessment Tool (BPAT).

38

Asthma control and quality of life were evaluated with the Asthma Control Questionnaire (ACQ)

39

and the mini Asthma Quality of Life Questionnaire (AQLQ).

40 41

Results: A total of 117 patients were included. Among these, 29.9 % (35/117) had DB according to

42

the NQ. Patients with DB had a poorer asthma control (ACQ: Mean (SD) 2.86 ± 1.05 vs. 1.46 ±

43

0.93) and lower quality of life (AQLQ score: Mean (SD) 4.2 ± 1.04 vs. 5.49 ± 0.85) compared to

44

patients without DB. Similarly, patients with objective signs of DB according to the BPAT score had

45

worse asthma control: BPAT > 4 vs < 4: (ACQ: Mean (SD) 3.15 ± 0.93 vs 2.03 ± 1.15).

46 47

Conclusion: DB is common among patients with difficult asthma, and is associated with

48

significantly poorer asthma control and lower quality of life. Assessment and treatment of DB is an

49

important part of the management of difficult asthma.

50 51 52

Word count: 262

53 54 55 56

2

57 58

Introduction:

59

Dysfunctional breathing (DB)(or Breathing Pattern Disorder, BPD) is defined as divergent breathing

60

patterns that cannot be attributed to a specific medical diagnosis such as asthma or chronic

61

obstructive pulmonary disease [1,2]. DB is characterised by intermittent or chronic symptoms such

62

as dyspnoea, chest pain, chest tightness, shortness of breath at rest, frequent yawning and

63

hyperventilation [3,4]. DB is prevalent among patients with asthma and symptoms of DB can

64

mimic asthma symptoms, which may influence the level of asthma control and potentially lead to

65

overtreatment [5,6].

66 67

The diagnosis of dysfunctional breathing can be difficult, because beyond the clinical description

68

there is no gold standard for the diagnosis of DB. Furthermore, the symptoms of DB mimic those

69

of other respiratory diseases [7]. The Nijmegen Questionnaire has been used in many specialist

70

respiratory clinics to detect DB in patients with breathing disorders[1]. Nonetheless, this method

71

has some limitations because the Nijmegen Questionnaire was originally developed for

72

assessment of chronic hyperventilation, and not specifically for DB in asthma [8]. Hence, there is a

73

need for new methods and tools for diagnosing dysfunctional breathing. In this study, we

74

supplemented the NQ with the Breathing Pattern Assessment Tool (BPAT) for objective

75

assessment of breathing patterns, which was recently demonstrated as a potential tool for

76

detecting DB in patients referred to a severe asthma clinic [9].

77 78

In difficult asthma in particular, identifying DB as a co-morbidity is important, to avoid potentially

79

harmful or expensive overtreatments such as oral steroids, or biological treatments. Difficult

80

asthma is defined as asthma requiring high dose inhaled steroids plus a second controller, such as

81

long-acting beta-2-agonist. These patients need to undergo systematic assessment to identify

82

those with other causes of poor asthma control such as poor adherence, and co-morbidities

83

(difficult-to-treat asthma), and those with severe asthma, who may require biological treatments.

84

DB is one of the most common co-morbidities in difficult asthma: A recent study from UK, where

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adult patients referred with treatment-refractory asthma underwent respiratory physiotherapy

3

86

assessment to diagnose DB, suggested that 22 % of patients did not have asthma but only DB [9].

87

However, the relative impact of DB on the level of asthma control has not been described.

88

Previous studies have investigated the incidence of DB among highly selected populations from

89

difficult asthma clinics [6,10,11,12] , but the prevalence and impact of DB in more general

90

populations with difficult asthma has not previously been reported. Furthermore, the impact on

91

validated measures of asthma control has not been reported, but is important to understand to

92

which extent these measures, such as the Asthma Control score, may be affected by co-existing

93

DB.

94 95

The aim of this paper was therefore to describe the prevalence of DB in a highly selected

96

population of patients managed for difficult asthma in specialist care, and to describe the impact

97

on the level of asthma control, as well as quality of life. Furthermore, we wished to examine the

98

prevalence of objective signs of DB, using a recently developed assessment tool, the BPAT test,

99

and to examine how objective signs of DB associated with poor asthma control.

100 101

Methods:

102

Design and material

103

In a cross-sectional design, we prospectively recruited patients with difficult asthma based on level

104

of treatment from four respiratory outpatient clinics in eastern Denmark. All examinations were

105

carried out at the Respiratory Research Unit at Bispebjerg Hospital. Patients were offered to

106

participate in this study if they fulfilled the criteria of having difficult asthma according to ERS/ATS

107

2014 guidelines [13] treated with high-dose inhaled corticosteroids (ICS) treatment (≥ 1600 µg

108

budesonide or equivalent) with a second controller (long acting beta-agonist (LABA)), theophylline

109

or leukotriene-antagonist) for the previous year or OCS for ≥ 50 % of the previous year. Further

110

details about the study population is described in previous work [5].

111 112

All included patients with difficult asthma underwent a comprehensive systematic evaluation with

113

focus on verification of the asthma diagnosis, exclusion of alternative diagnosis, evaluation of

114

adherence and inhaler technique and identification of exposures and comorbidities as

4

115

recommended by the ERS/ATS guidelines. They all had a physician’s diagnosis of asthma after the

116

systematic assessment.

117 118

Dysfunctional breathing

119

We used the Nijmegen questionnaire (NQ) to diagnose DB[14]. The Nijmegen Questionnaire is a

120

patient-completed 16-item questionnaire on abnormal breathing, using a 5-point Likert scale

121

(1=never, 5= very often). DB was defined as a total symptom score on the Nijmegen questionnaire

122

of ≥ 23.

123 124

Breathing Pattern Assessment Tool (BPAT)

125

The BPAT is completed by the physician. With the patient at rest and sitting with the back rested

126

against the seat back, breathing pattern is observed by the physician for ≥ 1 minute before BPAT

127

completion. BPAT consists of seven different components including evaluation of

128

abdominal/upper chest movement, inspiratory flow, expiratory flow, channel of inspiration and

129

expiration (mouth or nose), air hunger, respiratory rate and rhythm. Each component is given a

130

score from 0 (= expected normal) and 2 (=present in severe DB) and translates into a total score.

131

Sensitivity analysis from the validation study of BPAT indicated that a BPAT score ≥ 4

132

corresponded to a sensitivity of 0.92 and a specificity of 0.75 for diagnosis of BPD[9].

133 134

Asthma control and quality of life

135

Patients filled in the five-item Asthma Control Questionnaire (ACQ-5) [15] and mini Asthma

136

Quality of life Questionnaire (mini AQLQ) [16]. Asthma exacerbations, defined as a burst of OCS or

137

an increase in the maintenance doses of OCS treatment, were retrospectively evaluated for the 12

138

months preceding the first study visit. Uncontrolled asthma was defined according to ERS/ATS

139

guidelines as ACQ >1.5, ≥ 2 OCS requiring exacerbations in the previous year, ≥ 1 hospitalisation

140

due to asthma, or airflow limitation (pre-bronchodilator FEV1 < 80 % and FEV1/FVC < lower limit

141

of normal) [13].

142 143

General examinations

5

144

Spirometry and fractional exhaled nitric oxid (FeNO) were measured according to the ERS

145

guidelines [17,18]. Induced sputum was processed as described by Bafadhel et al [19]. Blood

146

eosinophil count and total IgE were analysed. Eosinophilic airway inflammation was defined as

147

sputum eosinophil count ≥ 3 %[20], blood eosinophil count ≥ 0.3*109/ L or FeNO > 50 ppb[21].

148

Atopy was defined as a positive skin prick test (SPT) (≥ 3 mm) or elevated specific IgE (< 0.35 kU/L)

149

for at least one aeroallergen [22]. Indirect bronchial challenge testing was investigated using

150

mannitol (Osmohale). Patients inhaled an empty capsule (used as reference) followed by

151

increasing inhaled doses of mannitol (from 5 to 365 mg) until maximum doses or a fall in FEV1 ≥

152

15 % was reached[23]. A positive diagnostic test was defined as a decrease in FEV1 ≥ 15 % from

153

baseline with a provocation dose of mannitol ≤ 635 mg.

154 155 156

Statistical analysis

157

IBM SPSS statistics version 24.0 was used for the statistical analysis. The characteristics of patients

158

with and without DB were compared with respect to different outcomes. We used unpaired t-test

159

for parametric data, Mann-Whitney U-test for nonparametric data and the chi2 -test and Fisher´s

160

exact test for categorical data. Differences were defined as significant at p < 0.05. In order to

161

determine the independent contribution of DB on the level of asthma control, a linear regression

162

analysis with ACQ as the dependent variable was performed. A univariate analysis was performed

163

with ACQ ≤ 1.5 and ≥ 1.5 and explanatory variables with a p value < 0.3 was included in the final

164

regression analysis including sex, smoking, BMI, blood eosinophils and subjects with or without

165

DB.

166 167

6

168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191

Fig. 1. Strobe 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.

192 193

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194 195

Table 1. Characteristics of the study population Difficult asthma patients

Difficult patients without

with DB1

DB

(n=35)

(n=82)

44.60 (20- 71)

47.7 (20- 80)

0.295

74 % (26/35)

52 % (43/82)

0.028

30.4 ± 6.66

27.20 ± 5.82

0.01

15 (42.85 %)

21 (25.6 %)

0.08

Current smoker (%) n

11.4 % (4/35)

3.7 % (3/82)

0.11

Ex-smoker (%) n

22.9 % (8/35)

40.2 % (33/82)

0.07

Mean (SD)

2434 ± 902

2207 ± 980.40

0.11

Use of maintenance OCS

6(17.1) %)

9 (11.0 %)

0.36

14 (23 %)

47 (77 %)

0.09

71.8 ± 21.1

77.3 ± 21.3

0.15

0.70 ± 0.15

0.71 ± 0.13

0.51

17.3 (2.9- 57.5)

21.10 (2.2- 114.2)

0.42

1(0- 6)

1(0-10)

0.62

0.19 (0.01- 0.63)

0.21 (0.04- 1,47)

0.26

0.50 (0.001-64.50)

2.12 (0.001- 92.3)

0.01

30 % (35/117)

70 % (82/117)

0.03

0.02( -0.01-11.83)

0.01(-0.01- 0.15)

0.32

30.94 ± 7.57

13.49 ± 5.81

0.001

P-value

Age in years Median (min-max) Sex: % female BMI ( kg/m2) Mean (SD)

BMI (>30 kg/m2) n (%) Smoking-status:

Daily ICS dose µg2

(%) n Atopy (%) n FEV1 % (pre) Mean (SD) FEV1/FVC (pre) Mean (SD) FeNO (ppb) Median (min-max) Exacerbations previous 12 months Median (min-max)

Blood eosinophils3 Median (min- max) Sputum Eosinophils

3

Median (min- max) Sputum Eosinophils >3 percent % (n) RDR mannitol Median (min-max)

Nijmegen Mean (SD)

8

ACQ

2.86 ± 1.05

1.46 ± 0.93

0.001

4.2 ± 1.04

5.49 ± 0.85

0.001

3(0-10)

2(0-10)

0.04

23 % (27/117)

77 % (90/117)

0.001

Mean (SD) mini AQLQ Mean(SD) BPAT Median (min- max) % (n)

196 197 198

Data are presented as mean ± SD, median (min-max) or % (n).

199 200

1

201

3

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. Nijmegen score ≥ 23.

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Budesonide equivalent. Sputum eosinophil count ≥ 3 %, blood eosinophil count ≥ 0.3 * 10 /L or FeNO > 50 ppb. 9

202 203 204

Results:

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1.1. NQ and ACQ

206

In total, 1034 patients completed screening for difficult asthma, among whom 117 patients

207

fulfilled the inclusion criteria of high dose treatment were included in the final analysis (figure 1).

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The study population was predominately females (59 %) with a median age of 46.1 years (20-80).

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DB defined as a Nijmegen questionnaire ≥ 23 was identified in 29.9 % (n=35) of patients. Table 1

210

and Figures 2 and 3 depict that patients with DB were more often female (74 %), had higher BMI

211

(table 1), had significantly poorer asthma control and lower quality of life compared to patients

212

without DB (mini AQLQ mean (SD): 4.2 ± 1.04 vs. 5.49 ± 0.85, p= 0.001). However, there were no

213

significant differences in lung function, airway hyperresponsiveness or FENO. The NQ score

214

correlated closely with the ACQ and AQLQ scores (Figure 3)

215 216 217 218 219 220 221

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222 223

Fig.2. Boxplot of ACQ (Left) and mini AQLQ score (Right) among patients with and without DB.

224 Fig.3. Relationship between ACQ score vs. Nijmegen score and mini AQLQ score vs. Nijmegen score.

225 226

The Nijmegen questionnaire includes three question that might reflect poor asthma control (fast

227

or deep breathing, shortness of breath and tightness across chest). When omitting these questions

228

from the analysis, the correlations were still significant (ACQ score vs. Nijmegen score: R2 = 0.438,

229

p<0.0001 and mini AQLQ score vs. Nijmegen score: R2= 0.438, p<0.0001.)

230 231 232

1.2. Regression analysis:

10

233

In order to determine the independent contribution of DB on the level of asthma control, a linear

234

regression analysis with ACQ as the dependent variable was performed. We included explanatory

235

variables with a p value<0.3 from the univariate analysis with ACQ ≤1.5 and ≥ 1.5 In the final

236

regression analysis. This showed that DB was founded as an independent determinant of ACQ-

237

score (p<0.001), which means that the effect of DB on asthma control could not be explained by

238

other factors such as more airway hyperresponsiveness or lower lung function in patients with DB

239

(Table 2).

240 241

Table 3: A regression analysis with different predictors of ACQ. Unstandardized

Sig

Coefficients-

95.0 % Confidence Interval for B

95.0 % Confidence Interval for B

lower bound

upper bound

B -Sex

0.007

0.941

-0.171

0.184

-Smoking

-0.085

0.659

-0.465

0.295

-BMI

0.003

0.670

-0.011

0.017

-Blood

0.346

0.056

-0.009

0.700

1.286

<0.001

0.214

0.613

eosinophils

-Nijmegen score ≥23

242 243

Because three of the symptoms included on the Nijmegen questionnaire are similar to some of the

244

questions on the ACQ, the correlation between ACQ and the Nijmegen score with and without

245

those three symptoms was performed to make sure that the reason why the subjects with DB

246

scored higher on the ACQ was not because the questions in the questionnaires were to similar.

247

The results showed that DB remained still an independent determinant of the ACQ score (p <

248

0.001).

11

249

We performed also a linear regression analysis with ACQ- score as the dependent variable in order

250

to determine the independent contribution of BPAT to the level of asthma control. The result

251

showed that BPAT was also found as an independent determinant of ACQ-score (p < 0.0001).

252 253 254 255

1.3. Objective assessment of DB

256

When assessing patients with the BPAT score, 25% (29/117) had a score ≥ 4, suggesting the

257

presence of DB. The BPAT score was significantly higher among patients with DB compared to

258

those without DB; Median (min-max): 3.00 (0-10) vs. 2.00 (0-10), p=0.04). Patients with objective

259

signs of DB according to the BPAT assessment, i.e. a BPAT score ≥ 4 had poorer asthma control

260

(Mean ACQ score: 2.54 ± 1.14 vs. 1.66 ± 1.09, p < 0.001 ) and a lower quality of life (Mean AQLQ

261

score: 4.65 ± 1.14 vs. 5.27 ± 1.02, p < 0.001 ) (Fig.4).

262

263 264

Fig.4. Patients with BPAT ≥ 4 had also higher ACQ score and lower mini AQLQ score.

265 266

When combining the Nijmegen score and the BPAT score, a total of 48 (41 %) of patients had

267

either symptoms or signs of DB. In order to investigate whether BPAT and Nijmegen questionnaire

268

represent the same types of patients, we examined the relationship between Nijmegen score and

269

BPAT. In order to do that, the patients were divided into 4 groups: 1) low BPAT/low NQ (65

12

270

patients), 2) low BPAT/ high NQ (12 patients), 3) high BPAT/ low NQ (15 patients) and 4) high

271

BPAT/ high NQ (21 patients).

272 273

Patients with a low NQ, but high BPAT, i.e. objective signs of DB, had a significantly poorer asthma

274

control, compared to patients with both low NQ and low BPAT. Whereas among patients with a

275

high NQ, the ACQ score did not differ between those with high and low BPAT score. (Fig.5b)

276 277 278 279 280

Fig. 5. Relationship 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).

281 282 283

Discussion:

284

The prevalence of DB in the current study was 29.9 % and we found that DB is a prevalent

285

condition among patients with difficult asthma in general, which has a very significant impact on

286

the level of asthma control. Considering that the assessments herein were not performed by a

287

respiratory physiotherapist meaning that the examination was not carried out by those with the

288

requisite skills, the prevalence of DB could have been either under or overestimated in our study.

289

At the same time, respiratory specialist doing the examination, was not hugely sensitive to

290

concomitant psychiatric disease, which been proposed as a modulator of difficult asthma [24]. The

13

291

prevalence of DB in our study aligns closely with the previous studies from the UK (22 %) and

292

Romania (29.7 %) [1,25], when DB was defined based on the Nijmegen questionnaire. Our results

293

are in accordance with the findings from other studies suggesting that having breathing disorders

294

can decrease health-related quality of life [26,27,28,29]. The relative impact on the level of

295

asthma control was high: patients with DB had an ACQ score that was 2 times higher than those

296

without (2.86 vs.1.46). Furthermore, we demonstrated that a novel scoring system for objective

297

signs of DB could also identify patients with poor asthma control, possibly relating to DB. In our

298

study, the BMI of patients with DB was noticeably high compared to those without DB, indicating a

299

possible overlap between obese-asthma phenotype and DB. Obese asthma-phenotype is

300

associated with increased asthma severity, poor asthma control, and varying response to

301

corticosteroids [30, 31, 32, 33, 34]. Obesity is usually associated with deconditioning which is the

302

factor leads to increased breathlessness, and this should be considered as a contributory factor to

303

DB. This is important, as even as moderate weight loss has been shown to improve asthma control

304

[35], which demonstrates that our current tools for asthma control do not factor in non-asthma

305

factors. Although patients with DB had a higher BMI in our study population, adjusting for BMI did

306

not impact the association between DB and poor asthma control, suggesting that in these

307

patients, symptoms were not driven by obesity. As part of detecting DB, it is also important to

308

explore this condition as part of spectrum of associated maladaptive behaviours such as anxiety,

309

depression, slepp apnea, gastroesophageal reflux and elevated sino-nasal outcome test score [36],

310

highlighting an important interaction between comorbid treatable traits in difficult asthma.

311 312

Our study is the first to investigate the prevalence and impact of DB on measures of asthma

313

control in a selected population: those referred for further assessment for poorly controlled

314

asthma. All patients were screened and all patients with difficult asthma were included confirming

315

that DB is very common in this patient group suggesting that DB should be part of the part of the

316

assessment of those referred to a difficult/severe asthma clinic; it is likely that our results could be

317

extrapolated to other respiratory outpatient clinics but this requires further evaluation.

318

We believe that the presence of DB should not only be identified by the Nijmegen Questionnaire

319

but also by a clinical observation of the breathing pattern. We used BPAT to make an objective

320

assessment of DB among patients in our study, and found that by adding this assessment to the

14

321

NQ, we could identify a group of patients without immediate symptoms of DB, but who had

322

objective signs of DB, and a poorer asthma control. The NQ was developed to assess symptoms of

323

hyperventilation and resulting hypocapnia, and may hence not capture other types of

324

dysfunctional breathing, such as patient with apical breathing (Boulding). These patients

325

predominantly use their apical respiratory muscles, and may have disproportionate dyspnea, but

326

not symptoms of hyperventilation, and may hence not be identified if the NQ is used alone.

327

Hence, objective assessment of the breathing pattern may complement the NQ as a screening tool

328

for DB. They are both fast and easy to use in a busy everyday clinic by the physicians.

329 330

The limitations of this study are firstly, that patients were not reviewed by a respiratory specialist

331

physiotherapist, with experience in DB, which may have impacted the BPAT assessment. All

332

assessments applied in the present study were performed by a medical doctor, which probably is

333

an argument for assessment by a multidisciplinary team (MDT), especially given very high doses of

334

ICS these patients were using. Furthermore, we did not include objective measures of

335

hyperventilation, such as capnography with an expected low end-tidal carbon dioxide in

336

hyperventilation. Not having a validated diagnostic tool for DB is a limitation in this field and there

337

is no universally accepted gold standard diagnostic tool. Many of the proposed ´objective´ tools

338

also actually influence the measurement of interest, i.e. by virtue of direct tactile stimulation or by

339

making the subject acutely aware of their breathing pattern and thus potentially indirectly

340

influencing or altering breathing pattern. We acknowledge that NQ is not validated in severe

341

asthma. However, it was used in our study, because it remains one of the most commonly used

342

questionnaires and it thus does make it possible to compare our results with other studies. The

343

BPAT is new tool and thus evaluated in only a few studies, but it does extend our capability to

344

provide a semi-objective assessment. Another limitation of this study was that the assessment of

345

patients did not include a psycho-social-assessment, which has been shown to impact significantly

346

on asthma control of quality of life.

347 348

A significant strength of the study is that patients all underwent a very thorough assessment

349

including objective markers of poor asthma control, such bronchial provocation testing for airway

350

hyperresponsiveness, and airway inflammation. By adjusting for these factors, we could ensure

15

351

that the poorer asthma symptom control among patients with signs of DB was not simply a

352

reflection of more severe asthma.

353 354

Our findings demonstrate the importance of DB in patients with difficult asthma, and physicians

355

should be aware that some patients may have an alternative explanation for their symptoms as

356

there are many other diseases which may give a similar picture. The symptoms could be improved

357

by appropriate intervention, suggesting that DB is amenable to treatment. Intervention such as

358

explanation, specific breathing retraining exercises have been used as parts of treatment for

359

dysfunctional breathing reducing the severity and frequency of symptoms [37]. A recent study

360

from UK where patients with DB were recruited to a controlled physiotherapy breathing

361

retraining, suggested that over half of patients with a diagnosis of asthma and DB obtained a

362

clinically relevant improvement in their asthma related quality of life at 1 month which persisted

363

for at least 6 months, concluding that these patients may potentially benefit from a simple safe

364

and relatively non-pharmacological intervention [38] Breathing modification therapies including

365

the Butekyo breathing method and yogic breathing has also been used before and many

366

physiotherapy- based breathing studies have reported beneficial outcomes in ACQ, mini AQLQ and

367

reductions in bronchodilator use in patients with mild and moderate asthma [38,39,40].

368 369

In conclusion, DB is an important confounder to lack of asthma control and poorer quality of life

370

ain patients with difficult asthma. Hence, asthma patients with poor symptom control despite high

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dose treatment should be routinely screened for dysfunctional breathing. We furthermore found

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that patients with DB tended to receive higher doses of asthma treatment (inhaled corticosteroids

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(ICS)) compared to patients without DB, suggest that having a comorbidity such as dysfunctional

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breathing may lead to overtreatment. This indicates a high risk of overtreatment of patients with

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DB, if signs of DB are not recognised, and supports the proposition that patients with difficult

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asthma should be routinely assessed for DB. Furthermore, we found that objective signs of DB,

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assessed with the BPAT score were also associated with poor asthma control. Combining

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assessment of subjective and objective signs of DB appears to be important for identifying all

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cases of DB.

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16

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This study was supported by unrestricted grants from The Danish Lung Association and Novartis

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Healthcare, Denmark.

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

Comment Reviewer #2: I suspect that the authors are sufferinga little from review fatigue: A couple of things need to be re written line 313: Our study is the first to investigate the prevalence and impact of DB on measures of asthma control as in representative of a highly selected populationi.e. all patients were screened, and for this study only patient with difficult asthma were included, confirming that DB is very common in this patient group, and supporting that our results can be extrapolated to other respiratory outpatient clinics. DB assessment should be part of the diagnostic assessment of patients referred to a difficult asthma clinic. I would suggest: 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

Response Thank you for your comments. It is a pleasure to get help from you in order to improve the paper. We agree with your comment and have added it to the paper.

Response and change This has been added to line 313: “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.”

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. Line 337: I think I would suggest very high doses of ICS rather than industial doses given that this is a scientific document. My comment was made tongue in cheek!!

Thank you for this comment. We agree with you.

This has been corrected on line 337 “especially given very high doses of ICS…”