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Original Research COPD

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Physiologic Characterization of the Chronic Bronchitis Phenotype in GOLD Grade IB COPD Amany F. Elbehairy, MD; Natya Raghavan, MD; Sicheng Cheng, BSc; Ling Yang, MD; Katherine A. Webb, MSc; J. Alberto Neder, MD; Jordan A. Guenette, PhD; Mahmoud I. Mahmoud, MD, PhD; and Denis E. O’Donnell, MD, FCCP; on behalf of the Canadian Respiratory Research Network

Smokers with persistent cough and sputum production (chronic bronchitis [CB]) represent a distinct clinical phenotype, consistently linked to negative clinical outcomes. However, the mechanistic link between physiologic impairment, dyspnea, and exercise intolerance in CB has not been studied, particularly in those with mild airway obstruction. We, therefore, compared physiologic abnormalities during rest and exercise in CB to those in patients without symptoms of mucus hypersecretion (non-CB) but with similar mild airway obstruction.

BACKGROUND:

Twenty patients with CB (ⱖ 3 months cough/sputum in 2 successive years), 20 patients without CB but with GOLD (Global Initiative for Chronic Obstructive Lung Disease) grade IB COPD, and 20 age- and sex-matched healthy control subjects underwent detailed physiologic testing, including tests of small airway function and a symptom-limited incremental cycle exercise test.

METHODS:

Patients with CB (mean ⫾ SD postbronchodilator FEV1, 93% ⫾ 12% predicted) had greater chronic activity-related dyspnea, poorer health-related quality of life, and reduced habitual physical activity compared with patients without CB and control subjects (all P , .05). The degree of peripheral airway dysfunction and pulmonary gas trapping was comparable in both patient groups. Peak oxygen uptake was similarly reduced in patients with CB and those without compared with control subjects (% predicted ⫾ SD, 70 ⫾ 26, 71 ⫾ 29 and 106 ⫾ 43, respectively), but those with CB had higher exertional dyspnea ratings and greater respiratory mechanical constraints at a standardized work rate than patients without CB (P , .05).

RESULTS:

Patients with CB reported greater chronic dyspnea and activity restriction than patients without CB and with similar mild airway obstruction. The CB group had greater dynamic respiratory mechanical impairment and dyspnea during exercise than patients without CB, which may help explain some differences in important patient-centered outcomes CHEST 2015; 147(5):1235-1245 between the groups.

CONCLUSIONS:

Manuscript received June 18, 2014; revision accepted October 17, 2014; originally published Online First November 13, 2014. ABBREVIATIONS: CAT 5 COPD Assessment Test; CB 5 chronic bronchitis; CHAMPS 5 Community Healthy Activities Model Program for Seniors; Dlco 5 diffusing capacity of the lung for carbon monoxide; EFL 5 expiratory flow limitation; EILV 5 end-inspiratory lung volume; GOLD 5 Global Initiative for Chronic Obstructive Lung Disease; HRCT 5 high-resolution CT; IC 5 inspiratory capacity; IRV 5 inspiratory reserve volume; MVC 5 maximum ventilatory capacity; Petco2 5 partial pressure of end-tidal CO2; PFT 5 pulmonary function test; RV 5 residual volume; TLC 5 total lung capacity; e 5 minute ventilation;

e/ co2 5 ventilatory equivalent for CO2; o2 5 oxygen consumption; / 5 ventilation/perfusion; Vt 5 tidal volume AFFILIATIONS: From the Department of Medicine (Drs Elbehairy, Yang, Neder, and O’Donnell and Mss Cheng and Webb), Queen’s University & Kingston General Hospital, Kingston, ON, Canada; Department of Chest Diseases (Drs Elbehairy and Mahmoud), Faculty of Medicine, Alexandria University, Alexandria, Egypt; Department of Medicine (Dr Raghavan), McMaster University, Hamilton, ON, Canada; and Department of Physical Therapy and UBC Centre for Heart Lung Innovation (Dr Guenette), University of British Columbia, Vancouver, BC, Canada.

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COPD is a complex, heterogeneous disorder that is increasing in prevalence worldwide.1 Clinical, functional, and radiologic manifestations vary greatly among patients with COPD who have the same degree of airflow limitation as measured by spirometry.2-4 The identification of specific COPD phenotypes is crucial for a better understanding of disease pathophysiology and the future development of targeted therapy.5 In this context, chronic bronchitis (CB), defined as presence of cough and sputum production most days for ⱖ 3 months in 2 consecutive years,6 largely fulfills the proposed definition for a clinical phenotype of COPD.5 Prevalence of CB in the general population varies with the definition and ranges from 3.4% to 22% of adults.7-14 While the presence of CB per se does not reliably predict disease progression,15,16 CB in combination with expiratory flow limitation (EFL) is associated with accelerated lung function decline, increased dyspnea, poor health-related quality of life, higher risk of moderate to severe COPD exacerbations, and increased mortality.5,16-21 Further support for the notion that CB may qualify as a distinct phenotype comes from studies that showed an improved treatment response following phosphodiesterase-4 inhibitor therapy in subsets of patients with CB.22

Materials and Methods Subjects Forty patients with symptomatic COPD fitting GOLD grade IB criteria (a postbronchodilator FEV1 ⱖ 80% predicted and an FEV1/FVC , 0.7 and less than lower limit of normal25; none to one exacerbation per year; and modified Medical Research Council dyspnea scale ⱖ 2 or COPD Assessment Test [CAT] score ⱖ 10)2 were categorized into two groups (n 5 20 each) based on having CB or not (non-CB).6 Inclusion criteria included age ⱖ 50 years and a smoking history of ⱖ 20 pack-years. Exclusion criteria included the presence of asthma, other medical conditions that could contribute to dyspnea or exercise limitation, contraindications to exercise testing, use of daytime oxygen, BMI , 18.5 or ⱖ 35 kg/m2. Twenty age- and sex-matched, non-smoking, healthy control subjects were used for comparison. Study Design This cross-sectional study received ethical approval from the Queen’s University and Affiliated Teaching Hospitals Research Ethics Board (DMED-1348-10). After written informed consent, subjects completed

This study was supported by the William Spear Endowment Fund/Start Memorial Fund, Queen’s University and the Canadian Respiratory Research Network. Financial support to Dr Elbehairy was provided by an Egyptian Ministry of Higher Education and Scientific Research Scholarship. CORRESPONDENCE TO: Denis O’Donnell, MD, 102 Stuart St, Kingston, ON, K7L 2V6, Canada; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-1491 FUNDING/SUPPORT:

1236 Original Research

The mechanistic linkages between the pathophysiology of CB and patient-centered outcomes, such as increased dyspnea and reduced health status, are poorly understood. Classic studies have provided detailed physiologic assessment in patients with combined CB and severe airflow obstruction,23,24 but no studies have comprehensively examined the heterogeneous physiologic impairment in patients with CB with largely preserved FEV1. Our main objective, therefore, was to characterize the nature and extent of physiologic impairment in smokers with CB who fit GOLD (Global Initiative for Chronic Obstructive Lung Disease) grade IB criteria. Our hypothesis was that patients with dominant CB would have greater smallairway dysfunction, and greater dynamic respiratory mechanical and pulmonary gas exchange abnormalities compared with patients without CB. We further postulated that these physiologic derangements would lead to greater dyspnea and exercise intolerance than in patients without CB. To test these hypotheses, we compared detailed physiologic measurements during rest and incremental exercise in groups with and without CB who fit GOLD grade IB criteria and a third group of age- and sex-matched healthy control subjects.

two or three visits. Visit 1 included screening for eligibility; medical history, symptom, and activity assessment questionnaires26-31; Charlson Comorbidity Index32; pre- and postbronchodilator (400 mg salbutamol) pulmonary function tests (PFTs); tests of small-airway function; and an incremental cycle cardiopulmonary exercise test for familiarization. Visit 2 included spirometry followed by incremental cycle exercise testing. Visit 3 (COPD only) included sputum induction and a highresolution CT (HRCT) scan of the thorax, unless a previous scan was performed within 1 year. Subjects with COPD withdrew short- and long-acting bronchodilators for 6 and 24 h before visits, respectively, and withdrew inhaled corticosteroids ⱖ 2 weeks prior to sputum induction. Procedures Detailed PFTs were performed using automated equipment (Vmax229d, Vs62j, and MasterScreen Impulse Oscillometry; SensorMedics Corp)33-38; measurements were expressed relative to predicted normal values.39-44 Tests of small-airway function included single-breath nitrogen washout37 and impulse oscillometry.38 Impulse oscillometry measurements at multiple frequencies (5-20 Hz) were collected during tidal breathing while patients were seated with their neck slightly extended, hands firmly supporting their cheeks, lips sealed tightly around a mouthpiece, and with nose clips on. A minimum of three acceptable and reproducible trials, each lasting approximately 30 s, were performed and the mean for each parameter was calculated. Exercise tests were conducted with 2-min increments of 20 W to symptom limitation on an electronically braked cycle ergometer (Ergoline 800s; SensorMedics Corp) using a SensorMedics Vmax229d testing system as previously described.45 Exercise flow-volume loop analysis was done as previously described.46 Sputum induction using an ultrasonic nebulizer with normal (0.9%) and increasing doses of hypertonic saline (3%, 4%, and 5%) was performed as recommended.47,48 Chest HRCT scans were used for quantitative assessment of the extent of emphysema49,50 and airway wall thickness.51,52

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Statistical Analysis A sample size of 20 was estimated to provide 80% power to detect a 1 Borg-unit difference in dyspnea intensity between-groups at a standardized work rate during exercise, based on a SD of one unit, a of 0.05, and a two-tailed test of significance. Between-group comparisons were

Results All groups had similar sex distribution, age, height, weight, and BMI (Table 1). The COPD groups had similar smoking history and medication use, except more patients with CB used a long-acting muscarinic antagonist. Both COPD groups were more symptomatic compared with the healthy group. However, the CB group had greater chronic, activity-related dyspnea, higher CAT scores, lower physical activity according to Community Healthy Activities Model Program for Seniors (CHAMPS), poorer health status according to the St. George’s Respiratory Questionnaire, and more comorbidities (Charlson Comorbidity Index) compared with the non-CB group.

TABLE 1

performed using one-way analysis of variance with Tukey post hoc test. Unpaired t tests were used to compare HRCT measurements and sputum cell counts between COPD groups. Medication history was compared using Fisher exact test. Results are reported as mean ⫾ SD unless otherwise specified. Statistical significance was set at P , .05.

Adequate sputum samples were obtained from 17 patients with CB and 11 without. Total and differential cell counts were not different between groups and showed predominant neutrophilia: 68% ⫾ 21% and 70% ⫾ 9% of total count in CB and non-CB groups, respectively. HRCT scans revealed 12% ⫾ 7% and 16% ⫾ 9% of the lungs as low attenuation areas (, 950 Hounsfield units) in the CB and non-CB groups, respectively (P 5 .080). Airway wall area expressed as a percentage of total airway area was not different between COPD groups; however, the CB group had increased airway wall thickness assessed by a higher square root of the wall area of a standardized airway with an internal perimeter

] Subject Characteristics

Characteristic Ratio of male patients to female patients, No. Age, y Height, cm

CB

Non-CB

11:9

Healthy

11:9

68.7 ⫾ 9.4 163 ⫾ 10

11:9

67.8 ⫾ 7.7 168 ⫾ 8

63.6 ⫾ 8.7 167 ⫾ 10

Weight, kg

76.9 ⫾ 17.4

77.9 ⫾ 13.8

75.0 ⫾ 13.0

BMI, kg/m2

28.8 ⫾ 5.8

27.7 ⫾ 4.9

26.8 ⫾ 2.6

Smoking history, pack-y

41.5 ⫾ 14.6a

42.8 ⫾ 21.2a

0.3 ⫾ 0.7

25

25

0

Current smokers, % Modified BDI focal score (0-12)

7.7 ⫾ 1.5

9.1 ⫾ 1.8

Modified MRC dyspnea scale (0-4)

1.4 ⫾ 0.6a,b

0.8 ⫾ 0.7a

Subjects with a modified MRC ⱖ 2, No. CAT score (0-40) Subjects with a CAT score ⱖ 10, No.

a,b

9 16.9 ⫾ 7.7a,b

a

11.6 ⫾ 0.7 0.1 ⫾ 0.2

3 11.6 ⫾ 7.6a

0 2.9 ⫾ 2.8

16

8

0

65 ⫾ 16a

72 ⫾ 16a

93 ⫾ 7

38.1 ⫾ 17.8a,b

22.5 ⫾ 15.1a

3.7 ⫾ 3.3

2,634 ⫾ 2,466a,b

5,144 ⫾ 1,033

8,004 ⫾ 4,346

5.9 ⫾ 1.6a,b

4.6 ⫾ 0.8

2.7 ⫾ 1.0

SABA

50

30

0

LAMA

50b

10

0

OCD (0-100), mm SGRQ total score CHAMPS, kcal/wk for all activities Charlson Comorbidity Index Medication usage, % of patients

ICS

10

0

0

Combined ICS/LABA

40

30

0

Data are given as mean ⫾ SD unless otherwise indicated. BDI 5 Baseline Dyspnea Index; CAT 5 COPD Assessment Test; CB 5 chronic bronchitis; CHAMPS 5 Community Healthy Activities Model Program for Seniors; ICS 5 inhaled corticosteroid; LABA 5 long-acting b2-agonist; LAMA 5 longacting muscarinic antagonist; MRC 5 Medical Research Council; OCD 5 oxygen cost diagram; SABA 5 short-acting b2-agonist; SGRQ 5 St. George’s Respiratory Questionnaire. aP , .05, patients with CB or patients without CB vs healthy control group. bP , .05, patients with CB vs patients without CB.

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of 10 mm compared with the non-CB group (1.7 ⫾ 0.2 mm vs 1.5 ⫾ 0.2 mm, P 5 .004). Pulmonary Function and Small-Airway Function

Both COPD groups had significant PFT abnormalities compared with healthy control subjects (Table 2). The COPD groups showed similar evidence of pulmonary gas trapping and peripheral airway dysfunction; specifically, increased residual volume (RV) and RV/total lung capacity (TLC), lower maximal midexpiratory flow rates (forced expiratory flow rate between 25% and 75% of FVC), greater resistance at low oscillation frequencies (resistance at 5 Hz and the differential change between resistance at 5 and 20 Hz), and unequal distribution of ventilation (higher phase 3 nitrogen slope). TABLE 2

Cardiopulmonary Exercise Test

Measurements at peak exercise are summarized in Table 3. Both COPD groups had a significantly reduced peak work rate, oxygen consumption ( o2) and minute ventilation ( e) compared with controls (Fig 1, Table 3). Subjects with CB had a significantly higher e at submaximal work rates compared with healthy control subjects, but the e response was similar across COPD groups (Fig 1). Although tidal volume (Vt) responses were similar at a given work rate across groups, patients with CB had significantly lower inspiratory capacity (IC) and inspiratory reserve volume (IRV) at all submaximal work rates compared with patients without CB and healthy subjects (Fig 1). All groups had a similarly reduced IRV and increased end-inspiratory lung volume (EILV)/TLC at end exercise; however, due to the smaller

] Resting Pulmonary Function

Measure of Pulmonary Function

CB

Non-CB

Healthy

2.1 ⫾ 0.5a (93 ⫾ 12a)

2.4 ⫾ 0.5a (97 ⫾ 9a)

Postbronchodilator FEV1, L FEV1/FVC, %

61 ⫾ 5a

3.1 ⫾ 0.6 (122 ⫾ 11)

61 ⫾ 6a

77 ⫾ 5

Prebronchodilator FEV1, L FEV1/FVC, %

1.9 ⫾ 0.5a (87 ⫾ 13a) 59.1 ⫾ 5.1 (86 ⫾ 8 ) a

a

2.2 ⫾ 0.5a (89 ⫾ 9a)

2.9 ⫾ 0.7 (118 ⫾ 12)

58.5 ⫾ 6.6 (84 ⫾ 8 ) a

74.6 ⫾ 5.6 (106 ⫾ 8)

a

PEFR, L/s

5.8 ⫾ 1.4a (91 ⫾ 17a)

6.4 ⫾ 1.7a (94 ⫾ 16a)

8.6 ⫾ 2.6 (124 ⫾ 24)

FEF25%-75%, L/s

0.8 ⫾ 0.3 (32 ⫾ 11 )

0.9 ⫾ 0.3 (34 ⫾ 9 )

2.4 ⫾ 0.9 (91 ⫾ 30)

SVC, L

3.4 ⫾ 0.7a,b (105 ⫾ 15a)

3.9 ⫾ 0.7 (111 ⫾ 15)

4.2 ⫾ 0.9 (117 ⫾ 12)

IC, L

2.5 ⫾ 0.6 (97 ⫾ 17 )

2.8 ⫾ 0.5 (106 ⫾ 16)

3.0 ⫾ 0.8 (112 ⫾ 18)

FRC, L

3.2 ⫾ 0.8 (106 ⫾ 21)

3.3 ⫾ 0.7 (105 ⫾ 22)

2.9 ⫾ 0.7 (93 ⫾ 23)

TLC, L

5.7 ⫾ 1.2 (102 ⫾ 12)

6.1 ⫾ 0.9 (105 ⫾ 13)

5.9 ⫾ 1.0 (102 ⫾ 13)

RV, L

2.3 ⫾ 0.7a (105 ⫾ 26a)

2.3 ⫾ 0.6a (102 ⫾ 25a)

1.7 ⫾ 0.5 (81 ⫾ 21)

RV/TLC, %

a

a

a

40 ⫾ 7

a

a

37 ⫾ 7

a

29 ⫾ 7

a

DLCO, mL/min/mm Hg

15.9 ⫾ 5.0a (82 ⫾ 20a)

sRaw, cm H2O/s

10.9 ⫾ 4.1a (258 ⫾ 94a)

MIP, cm H2O

a

74 ⫾ 21 (99 ⫾ 27)

15.7 ⫾ 4.3a (77 ⫾ 19a)

21.4 ⫾ 5.5 (104 ⫾ 16)

9.7 ⫾ 4.4a (232 ⫾ 97a)

5.2 ⫾ 2.1 (126 ⫾ 53)

69 ⫾ 25 (90 ⫾ 33 ) a

88 ⫾ 29 (111 ⫾ 26)

a

Closing volume, L

0.5 ⫾ 0.3

0.5 ⫾ 0.3

0.4 ⫾ 0.2

N2 slope, %/L

6.4 ⫾ 3.0a

5.7 ⫾ 2.4a

2.8 ⫾ 1.1

R5, cm H2O/L/s

5.7 ⫾ 2.1a

4.9 ⫾ 1.4

4.2 ⫾ 1.3

R5-20, cm H2O/L/s

25.2 ⫾ 10.5

25.6 ⫾ 10.7

12.7 ⫾ 7.5

X5, cm H2O/L/s

22.1 ⫾ 1.3a

21.6 ⫾ 0.8a

21.1 ⫾ 0.5

Fres, Hz

17.5 ⫾ 5.3a

16.8 ⫾ 4.6a

11.7 ⫾ 3.7

a

a

Data are given as mean ⫾ SD with % predicted normal values given in parentheses. CV 5 closing volume; DLCO 5 diffusing capacity of the lung for carbon monoxide; FEF25%-75%5 forced expiratory flow between 25% and 75% of FVC; FEV1/FVC 5 ratio between FEV1 and FVC; FRC 5 functional residual capacity; Fres 5 resonant frequency; IC 5 inspiratory capacity; MIP 5 maximum inspiratory mouth pressure; PEFR 5 peak expiratory flow rate; R5 5 resistance at 5 Hz during impulse oscillometry; R5-20 5 differential change in resistance between 5 and 20 Hz; RV 5 residual volume; sRaw 5 specific airway resistance; SVC 5 slow vital capacity; TLC 5 total lung capacity; X5 5 distal capacitive reactance at 5 Hz. See Table 1 legend for expansion of other abbreviations. aP , .05, patients with CB or patients without CB vs healthy control group. bP , .05, patients with CB vs patients without CB.

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TABLE 3

] Measurements at the Peak of Symptom-Limited Incremental Cycle Exercise

Measure Work rate, W (% predicted)

CB 82 ⫾ 23

a,b

Non-CB

(66 ⫾ 25 ) a

Healthy

99 ⫾ 29 (72 ⫾ 16 ) a

a

165 ⫾ 55 (110 ⫾ 22)

O2, mL/kg/min (% predicted)

19.8 ⫾ 3.9a (70 ⫾ 26a)

20.9 ⫾ 6.1a (71 ⫾ 29a)

33.2 ⫾ 8.2 (106 ⫾ 43)

E, L/min (% MVC)

52.9 ⫾ 13.6a (81 ⫾ 21)

61.1 ⫾ 20.0a (78 ⫾ 19a)

97.5 ⫾ 27.7 (93 ⫾ 19)

VT, L VT/IC, %

1.5 ⫾ 0.3a,b

1.8 ⫾ 0.5a 70 ⫾ 9a

71 ⫾ 15a

2.3 ⫾ 0.6 79 ⫾ 10

Fb, breaths/min, No.

36.3 ⫾ 7.0

34.1 ⫾ 7.1

41.7 ⫾ 7.6

TI/TTOT

0.44 ⫾ 0.04a

0.46 ⫾ 0.04a

0.49 ⫾ 0.02

IC, L (% predicted) D IC from rest, L IRV, L

a

a

2.2 ⫾ 0.6a,b (85 ⫾ 18a,b) 20.33 ⫾ 0.44 0.7 ⫾ 0.4

2.6 ⫾ 0.6 (96 ⫾ 17a) 20.26 ⫾ 0.49 0.8 ⫾ 0.3

2.9 ⫾ 0.8 (108 ⫾ 18) 20.02 ⫾ 0.55 0.6 ⫾ 0.3

88 ⫾ 7

87 ⫾ 4

89 ⫾ 5

34.6 ⫾ 4.8

32.4 ⫾ 3.1

32.1 ⫾ 4.7

E/ CO2

33.3 ⫾ 5.0

35.2 ⫾ 3.8

34.8 ⫾ 5.7

SpO2, %

95.5 ⫾ 2.1

95.2 ⫾ 1.7

95.4 ⫾ 1.9

RER

1.07 ⫾ 0.1a

1.08 ⫾ 0.1

1.14 ⫾ 0.1

EILV, % TLC PETCO2, mm Hg

HR, beats/min (% predicted)

129 ⫾ 21a (78 ⫾ 12a)

138 ⫾ 18a (83 ⫾ 10a)

158 ⫾ 15 (94 ⫾ 8)

11.9 ⫾ 3.2a

11.7 ⫾ 3.4a

Dyspnea, Borg units

5.2 ⫾ 2.3

5.6 ⫾ 2.2

6.1 ⫾ 3.1

Leg discomfort, Borg units

6.3 ⫾ 2.2

5.8 ⫾ 1.9

6.7 ⫾ 3.3

O2 pulse, mL/beat

15.9 ⫾ 5.1

Reason for stopping, % Breathing discomfort

5

5

0

Leg discomfort

20

0

10

Both breathing and legs

70

90

90

5

5

0

Other

Data given as mean ⫾ SD unless otherwise indicated. EILV 5 end-inspiratory lung volume; Fb 5 breathing frequency; HR 5 heart rate; IRV 5 inspiratory reserve volume; MVC 5 maximal ventilatory capacity estimated as 35 3 FEV1; O2 5 oxygen; PETCO2 5 end-tidal CO2; RER 5 respiratory exchange ratio; SpO2 5 arterial oxygen saturation; TI/TTOT 5 inspiratory duty cycle; E 5 minute ventilation; E/ CO2 5 ventilatory equivalent for CO2; O2 5 oxygen uptake; VT 5 tidal volume. See Table 1 and 2 legends for expansion of other abbreviations. aP , .05, patients with CB or patients without CB vs healthy group. bP , .05, patients with CB vs patients without non-CB.

IC in CB, there were greater constraints on Vt expansion and a significantly smaller peak Vt in the patients with CB compared with the non-CB and healthy groups. Moreover, the CB group had a significantly higher breathing frequency compared with control subjects at a given work rate, as well as compared with the non-CB group at 40 W (Fig 1). The decrease in IC from rest to peak exercise (dynamic hyperinflation) was 0.33 ⫾ 0.4 L and 0.02 ⫾ 0.6 L in the CB and healthy groups, respectively (P 5 .05), and was similar across COPD groups. Although IC responses were essentially parallel in the CB and non-CB groups throughout exercise, the non-CB group behaved like control subjects and “deflated” from rest to 20 W (P 5 .06), whereas the CB group did not change IC (Fig 1).

The CB group had significantly greater EFL (P , .05) at a standardized work rate (60 W) compared with the non-CB and control groups: The percentage of Vt that overlapped the maximal expiratory flow-volume loop was 71% ⫾ 25%, 55% ⫾ 22%, and 32% ⫾ 26%, respectively.46 o2 at the anaerobic/ventilatory threshold was significantly lower (P , .05) in the CB and non-CB groups compared with control subjects: 1.0 ⫾ 0.2 L/min, 1.0 ⫾ 0.2 L/min, and 1.6 ⫾ 0.5 L/min, respectively. All groups had a statistically similar ventilatory equivalent for CO2 ( e/ co2) at work rates up to 60 W and at peak exercise, but the e/ co2 nadir was higher (P , .05) in the CB and non-CB groups compared with the control group (31.3 ⫾ 4.2, 32.1 ⫾ 3.4, and 27.8 ⫾ 3.4, respectively) (Fig 2). Within the group of patients with COPD, a

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Figure 1 – Ventilatory, breathing pattern, and respiratory mechanical responses to incremental cycle exercise in patients with chronic bronchitis (CB), patients without CB, and in age- and sex-matched healthy control subjects. A, Oxygen consumption. B, Ventilation. C, Tidal volume. D, Breathing frequency. E, Inspiratory capacity. F, Inspiratory reserve volume. Values plotted are mean ⫾ SEM at rest, at standardized work rates, and at peak exercise. *P , .05 CB group vs healthy group; †P , .05 CB group vs non-CB group at a given work rate or at peak exercise. Fb 5 breathing frequency; TLC 5 total lung capacity; VO2 5 oxygen consumption.

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Figure 2 – Ventilatory, cardiovascular, and gas exchange responses to incremental cycle exercise in patients with CB, patients without CB, and in age- and sex-matched healthy control subjects. A, Ventilatory equivalent for carbon dioxide. B, Partial pressure of end-tidal CO2. C, Arterial oxygen saturation. D, Heart rate. E, Oxygen pulse. F, Respiratory exchange ratio. Values plotted are mean ⫾ SEM at rest, at standardized work rates, and at peak exercise. *P , .5 CB group vs healthy group; †P , .05 CB group vs non-CB group at a given work rate or at peak exercise. O2 5 oxygen; PETCO2 5 partial pressure of end-tidal CO2; SpO2 5 oxygen saturation; VE/VCO2 5 ventilatory equivalent for CO2. See Figure 1 legend for expansion of other abbreviations.

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significant correlation was found between the e/ co2 nadir and diffusing capacity of the lung for carbon monoxide (Dlco) % predicted (Pearson r 5 0.346, P 5 .029). Partial pressure of end-tidal CO2 (Petco2) was lower in the non-CB group compared with control subjects, but did not reach statistical significance at all work rates for the CB group compared with the control group (Fig 2). The respiratory exchange ratio was greater in patients with CB than in those without CB and the healthy control subjects at 60 W (P , .05) and possibly at higher work rates (Fig 2). Patients with CB had modestly lower oxygen saturation than control subjects early in exercise, but all groups reached the same end-exercise value (Fig 2). Patients with CB had higher dyspnea ratings at all submaximal work rates compared with healthy control subjects, and greater dyspnea at 60 W compared with patients without CB (Fig 3). Intensity of leg discomfort was greater (P , .05) at all submaximal work rates in the CB group compared with the non-CB and control groups (data not shown). Dyspnea ratings relative to Ve expressed as a proportion of maximum ventilatory capacity (MVC estimated as 35 3 FEV1) and Vt/IC were superimposed (Fig 3).

Discussion The main findings of this study are the following: (1) patients with CB had greater chronic activity-related dyspnea and poorer perceived health status than patients without CB who had similar spirometric abnormalities; (2) both

CB and non-CB groups had extensive but comparable peripheral airway dysfunction at rest; and (3) exercise tolerance was similarly reduced in both COPD groups, but those with CB experienced greater exertional dyspnea and dynamic respiratory mechanical constraints than patients without CB. The CB and non-CB groups in this study were well matched for age, sex, BMI, and smoking history. The CB group reported significantly greater chronic activityrelated dyspnea, poorer perceived health status, and reduced physical activity compared with patients without CB and with healthy control subjects. Both COPD groups had active neutrophilic airway inflammation. The CB group had increased wall thickness of the smaller airways compared with the non-CB group. Despite a largely preserved FEV1, both COPD groups had extensive small-airway dysfunction at rest: increased respiratory impedance, reduced mid-volume maximal expiratory flow rates, increased pulmonary gas trapping, and maldistribution of ventilation. Although average Dlco was within normal limits in both COPD groups, it was significantly lower than in control subjects, in keeping with HRCT scan evidence of structural emphysema. All subjects expended maximal volitional effort during exercise testing, with severe dyspnea (and leg discomfort)

Figure 3 – Relative exertional dyspnea intensity during incremental cycle exercise testing in patients with CB, patients without CB, and in age- and sex-matched healthy control subjects. A, Exertional dyspnea intensity relative to work rate. B, Exertional dyspnea intensity relative to VE/MVC. C, Exertional dyspnea intensity relative to VT/IC. Circles represent the points at the highest equivalent work rate (60 W): The mean difference in dyspnea intensity at 60 W between CB and non-CB groups is 1.2 Borg units. Values are mean ⫾ SEM. *P , .05 CB group vs healthy group; †P , .05 CB group vs non-CB group. ⌬ 5 difference; VE/MVC 5 ventilation as a fraction of maximum ventilatory capacity; VT/IC 5 tidal volume as fraction of inspiratory capacity. See Figure 1 legend for expansion of other abbreviation.

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and respiratory exchange ratio . 1 at end exercise. Our results confirmed that in both COPD groups, peak o2 was diminished as a result of a combination of increased ventilatory requirements, limiting respiratory mechanical constraints and increased exertional symptoms.45,53-55 As previously suggested, the increased ventilatory demand in COPD is likely the result of abnormal ventilation-perfusion ( / ) relations56-58: The e/ co2 nadir was elevated and Petco2 tended to be lower in both COPD groups compared with control subjects. Increased ventilatory stimulation suggests increased physiologic dead space with or without adaptive alterations of the respiratory controller.56,57 In this study, an earlier decrease in arterial oxygen saturation during exercise in both COPD groups points to the possibility of low regional / ratios. Wagner et al23 showed high, low, and mixed / ratios in equal proportions in patients with CB with more severe airway obstruction. In the current study, indirect assessments also suggest similar mixed-pattern / abnormalities in both COPD groups. The relative contribution of cardiocirculatory impairment, metabolic acidosis, and mechano- and metabo-receptor activation in active peripheral muscles to the increased ventilatory stimulation during exercise in the COPD groups could not be determined.59,60 In this context, it is noteworthy that the anaerobic threshold and heart rate responses to exercise were similar in both COPD groups despite greater self-reported activity restriction in CB, which might predispose to greater deconditioning. Despite apparently preserved breathing reserve (MVC-peak e), significant ventilatory constraints were evident. In both COPD groups, Vt expanded to reach a critically reduced IRV (increased EILV/TLC) at a lower peak work rate than in healthy subjects. This is in keeping with recent reports that the respiratory system approaches or reaches its physiologic limits at end exercise in symptomatic mild COPD.53,54 A smaller resting IC and IRV in the CB group meant that, despite similar dynamic hyperinflation during exercise, EILV expanded closer to TLC at any given work rate compared with the non-CB and control groups. This meant that in CB, Vt was positioned closer to the upper, less compliant part of the respiratory system’s pressure-volume relation, where greater contractile inspiratory muscle effort is required for a given volume displacement.61 The finding that perceived dyspnea intensity was greater at a given work rate in patients with CB (vs those without CB) is consistent with increased self-reported chronic dyspnea in this group. This disparity in dyspnea between the CB and non-CB groups may be the result of subtle

differences in resting and dynamic respiratory mechanics. The tendency for a smaller IC (by 0.3 L) in CB cannot be explained by differences in static inspiratory muscle strength, but could reflect unmeasured differences in EFL.62,63 The findings of slightly increased small-airway thickness, differences in end-expiratory lung volume behavior at the onset of exercise, and greater overlap of tidal and maximal expiratory flow-volume plots in patients with CB vs patients without CB support this latter contention. More precise assessment of EFL and mucus plugging of smaller airways in CB may have helped to better explain differences in resting IC between the groups. Regardless of the mechanism, dynamic IRV was lower (by 0.39 L) and dyspnea was greater (by 1.2 Borg units) at a standardized work rate (60 W) in patients with CB vs those without CB. In accordance with a recent study, the increase in dyspnea intensity during exercise is more closely associated with the rate of dynamic reduction in IRV (increase in Vt/IC) than increase in end-expiratory lung volume (decrease in IC), which was similar in both COPD groups.61 Dyspnea ratings in the CB and non-CB groups increased with the increased ratios of e/MVC and Vt/IC. At a standardized work rate, both ratios of demand-capacity imbalance (and corresponding dyspnea intensity) were higher in patients with CB compared with the non-CB group. Perceived leg discomfort was also increased in both COPD groups (more with patients with CB than those who did not have CB) compared with healthy control subjects, in keeping with similar observations in populations with mild COPD.45,53-55 Despite having a higher Charlson Comorbidity Index in patients with CB compared with the non-CB group, cardiovascular comorbidities were comparable between the groups, as were cardiocirculatory responses to exercise. However, patients with CB were less active (lower CHAMPS), so they could be more deconditioned, and this might be one explanation for the greater leg discomfort during exercise in this group. Limitations

We relied on self-reported, historical information to make the diagnosis of CB. However, careful, individual, clinical assessment by experienced pulmonologists confirmed the diagnosis of CB in all patients so designated. Presence of mucus hypersecretion in CB was also corroborated by concomitant selection of relevant items (cough and phlegm) in the CAT test and by relatively easy recovery of adequate sputum samples in patients with CB. We have no prospective information about the stability of the CB phenotype beyond a minimum

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of 2 years. The degree to which increased usage of longacting antimuscarinics in the CB group (compared with the non-CB group) led to underestimation of baseline mechanical abnormalities and respiratory symptoms was not determined.

Conclusions This study provides the first comprehensive, physiologic characterization of CB in smokers with only minor spirometric abnormalities. Patients with CB experienced greater chronic activity-related dyspnea and poorer health-related quality of life than patients without CB. Both mild COPD groups had extensive peripheral airway dysfunction, dynamic respiratory mechanical abnormalities, and reduced exercise tolerance. Those

Acknowledgments Author contributions: D. E. O. was the principal investigator and takes responsibility for the integrity of the data and the accuracy of the data analysis. D. E. O. contributed to the study concept; A. F. E., N. R., K. A. W., and D. E. O. contributed to the study design; A. F. E., N. R., K. A. W., J. A. N., M. I. M., and D. E. O. contributed to the conduct of the study; A. F. E., N. R., S. C., L. Y., K. A. W., and J. A. G. contributed to data collection; A. F. E. and K. A. W. contributed to the data analysis; and A. F. E., N. R., S. C., L. Y., K. A. W., J. A. N., J. A. G., M. I. M., and D. E. O. contributed to writing the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr O’Donnell has received research funding via Queen’s University from AstraZeneca plc, Boehringer Ingelheim GmbH, GlaxoSmithKline plc, Novartis AG, Nycomed International Management GmbH, and Pfizer Inc and has served on speakers bureaus, consultation panels, and advisory boards for AstraZeneca plc, Boehringer Ingelheim GmbH, GlaxoSmithKline plc, and Pfizer Inc. The remaining authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.

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