Morning symptoms in COPD: a treatable yet often overlooked factor

Figures & data

Figure 1. Occurrence of morning symptoms in all COPD patients in different clinical studies.

COPD: chronic obstructive pulmonary disease

Figure 2. Occurrence of different types of morning symptoms in COPD patients in different studies.

a) Percentage of all patients that suffer from dyspnoea in the morning. b) Percentage of all patients that suffer from cough in the morning. c) Percentage of all patients that suffer from sputum production in the morning. d) Percentage of all patients that suffer from wheezing in the morning. COPD: Chronic obstructive pulmonary disease.

Figure 3. Occurrence of different types of morning symptoms in patients COPD with morning symptoms in different clinical studies.

a) Percentage of patients with morning symptoms that suffer from dyspnoea in the morning. b) Percentage of patients with morning symptoms that suffer from cough in the morning. c) Percentage of patients with morning symptoms that suffer from sputum production in the morning. *Severe group. “Severe” was defined in this study as: regular use of COPD medication plus a third level of breathlessness or above using Medical Research Council dyspnoea scale and one or more exacerbations in the preceding 12 months. COPD: chronic obstructive pulmonary disease.

Figure 4. Occurrence of different types of morning symptoms in symptomatic COPD patients in different clinical studies.

a) Occurrence of dyspnoea in symptomatic COPD patients that mentioned the morning as most troublesome period of the day. b) Occurrence of cough in symptomatic COPD patients that mentioned the morning as most troublesome period of the day. c) Occurrence of sputum production in symptomatic COPD patients that mentioned the morning as most troublesome period of the day. COPD: chronic obstructive pulmonary disease

Table 1. Tools to measure morning symptoms.

Tool	Number of items	Range	Topics			Validated yes/no	Notable aspects of tool
			Sympt	Severity	Impact
ACQ	1	0–6	X	X		Not for COPD	Validated ACQ
‘A patient record form’	NA	1–7	X	X	X	No	Symptoms were reported in detail by the physician
‘A 30-min survey with questions about COPD symptoms’	NA	NA	X	X	X	No	Not a specific morning symptom questionnaire
Patients were asked to evaluated the severity of morning symptoms	NA	0–4	X	X	X	No	Different kind of symptoms was separately assessed and also separately reported
CSQ and MAQ	4 and 1	1–10	X	X	X	No	If the CSQ was positive for morning symptoms, the MAQ was filled out too
‘Questionnaire according to coughing/breathlessness during the morning/night’	5	0–5	X	X		No	5-Item questionnaire that contained two questions about symptoms in the morning
Morning assessment of the COPD eDiary	18	0–10	X	X	X	No	Five symptoms and two impact items were assessed
‘A 20-min questionnaire’	31	Impact: 1–3	X		X	No	The questionnaire was based on a review of previous published research on most common symptoms in COPD
COPD-MSD	19	SOB: 0–6. All other items: 0–5. Total: 0–96	X	X	X	No	Next step is reducing length of the tool and validation
Nighttime Symptoms Questionnaire	11	0–4	X	X	X	No	11-Item questionnaire that included 2 questions about morning symptoms
PRO-morning COPD Symptoms Questionnaire	2x6	0–60	X	X	X	No	6 Questions at home, at the time of waking up, pre-morning medication; 6 questions 3 h after morning medication
GCSQ and CDLM	1 and 8	GCSQ: 0–4 CDLM: 0–5	X	X	X	No	Questionnaires were filled out at home
‘20-min interview COPD symptoms’	NA	NA	X		X	No	Symptomatic patients were asked what moment of the day was most bothersome
COPD symptoms questionnaire	NA	1–5 (only for individual morning symptoms 0–4)	X	X	X	No	Questionnaire developed by the sponsor
‘20–30 min questionnaire’	NA	NA	X		X	No	A feasibility study was performed prior to patient recruitment
‘A 34-item questionnaire’	34	NA	X		X	No	There were pilot interviews before the use of this questionnaire
‘Symptom collection’	NA	Impact: 1–10	X		X	No	Symptoms were obtained in a single visit
EMSCI	14	0–4	X	X	X	No	Was completed every day between 7 AM and 11 AM
Night-time, morning and daytime symptoms of COPD questionnaire	33	1–5	X	X	X	No	33-Item questionnaire that included 10 items about morning symptoms

ACQ: Asthma control questionnaire; CDLM: Capacity of Daily Living during the Morning questionnaire; COPD: chronic obstructive pulmonary disease; COPD-MSD: chronic obstructive pulmonary disease morning symptom diary; CSQ: Clinical Symptom Questionnaire; EMSCI: Early-Morning Symptoms of COPD Instrument; GCSQ: Global Chest Symptoms Questionnaire; MAQ: Morning Activity Questionnaire; PRO: patient-reported outcome; SOB: shortness of breath; Sympt: Symptoms.

Table 2. Outcomes of morning symptoms questionnaires.

Tool	Studies (authors)	Occurrence of morning symptoms	Mean score in the study (at baseline)
ACQ	Tsiligianni et al. [24]	51.9%	1.1
‘A patient record form’	Roche et al. [21]	39.8%	Impact: 3.96
Night-time, Morning and Daytime Symptoms of COPD questionnaire	Miravitlles et al. [20]	81.4%	44.1% Mild (score 1); 43.8% moderate (score 2)
	Soler et al. [22] (Spanish subgroup of the ASSESS study [20])	71.3%	53.7% Mild (score 1); 40.2% moderate (score 2)
EMSCI	Singh et al. [31]	NA	NA
	D’Urzo et al. [32]	NA	ACLI/FORM 400/12 mcg: 1.19 (0.63); ACLI/FORM 400/6 mcg: 1.15 (0.64); ACLI 400 mcg: 1.13 (0.65); FORM 12 mcg: 1.13 (0.66); Placebo: 1.07 (0.58)
	Bateman et al. [16] (pooled data from AUGMENT study [32] and ACLIFORM study [31])	94.4%	1.2
‘a 30-minute survey with questions about COPD symptoms’	Stephenson et al. [23]	83.0%	NA
Patients were asked to evaluated the severity of morning symptoms	Marth et al. [19]	91.7%	Proportion of patients with at least moderate symptoms: 57.7%
CSQ and MAQ	Kim et al. [17]	57.0%	NA
‘Questionnaire according to coughing/breathlessness during the morning/night’	Lange et al. [18]	65.0%	NA
Morning assessment of the COPD eDiary	Kulich et al. [27]	NA	2.12–3.20
‘A 20-min questionnaire’	O’Hagan et al. [12]	71.0%	Most impact on stairs (only 21% symptom free)
COPD-MSD	Globe et al. [13]	Inclusion criterion	NA
Nighttime Symptoms Questionnaire	Kerwin et al. [33]	NA	NA
PRO-morning COPD Symptoms Questionnaire	Marin et al. [34]	NA	16.6
GCSQ and CDLM	Welte et al. [35]	NA	NA
	Partridge et al. [36]	NA	NA
‘20-min interview COPD symptoms’	Espinosa de los Monteros et al. [26]	NA	NA
COPD symptoms questionnaire	Beier et al. [37]	NA	ACLI: 2.36; TIO: 2.25
‘20–30 minute questionnaire’	Kessler et al. [8]	NA	NA
‘A 34-item questionnaire’	Partridge et al. [3]	NA	NA
‘Symptom collection’	Kuyucu et al. [28]	NA	Most impact ongoing up/down stairs: 6.7 (2.6)

ACLI: aclidinium; ACQ: Asthma control questionnaire; CDLM: Capacity of Daily Living during the Morning questionnaire; COPD: chronic obstructive pulmonary disease; COPD-MSD: chronic obstructive pulmonary disease morning symptom diary; CSQ: Clinical Symptom Questionnaire; EMSCI: Early-Morning Symptoms of COPD Instrument; FORM: formoterol; GCSQ: Global Chest Symptoms Questionnaire; MAQ: Morning Activity Questionnaire; PRO: patient-reported outcome.

Table 3. Effects of inhaled medication on morning symptoms.

Author	Tool	Medication	Score on baseline	Effect size (p-value if available)
Kerwin et al. [33]	Nighttime Symptoms Questionnaire	ACLI 200 mcg^a vs. ACLI 400 mcg^a vs. placebo	NA	Severity of breathlessness ACLI 200 mcg −0.31 (0.77)^b vs. placebo p < 0.01 ACLI 400 mcg −0.32 (0.79)^b vs. placebo p < 0.001 Placebo −0.09 (0.61)^b Impact of breathlessness: ACLI 200 mcg −0.22 (0.69)^b vs. placebo p < 0.01 ACLI 400 mcg −0.28 (0.76)^b vs. placebo p < 0.001 Placebo −0.03 (0.56)^b
Marin et al. [34]	PRO-morning COPD Symptoms Questionnaire	GLY 50 mcg once-daily vs. TIO 18 mcg once-daily	GLY: 16.7 (11.1) TIO: 16.6 (10.0)	GLY: 1.9 (7.8) p = 0.002^b TIO: 1.2 (7.9) p = 0.063^b
Singh et al. [31]	EMSCI	ACLI/FORM 400/12 mcg^a vs. ACLI/FORM 400/6 mcg^a vs. ACLI 400 mcg^a vs. FORM 12 mcg^a vs. placebo	NA	ACLI/FORM 400/12 mcg −0.21 units (−17.7%)^b ACLI/FORM 400/6 mcg −0.24 units (−20.2%)^b ACLI 400 mcg −0.13 units (−10.2%)^b FORM 12 mcg −0.17 units (−14.0%)^b Placebo −0.12 units (−9.6%)^b ACLI/FORM (both doses) vs. placebo p < 0.05 ACLI/FORM (both doses) vs. ACLI 400 mcg p < 0.01 ACLI/FORM 400/6 mcg vs. FOR 12 mcg p < 0.05
D’Urzo et al. [32]	EMSCI	ACLI/FORM 400/12 mcg^a vs. ACLI/FORM 400/6 mcg^a vs. ACLI 400 mcg^a vs. FORM 12 mcg^a vs. placebo	ACLI/FORM 400/12 mcg: 1.19 (0.63) ACLI/FORM 400/6 mcg: 1.15 (0.64) ACLI 400 mcg: 1.13 (0.65) FORM 12 mcg: 1.13 (0.66) Placebo: 1.07 (0.58)	ACLI/FORM 400/12 mcg −0.24 units (−20.3%)^b ACLI/FORM 400/6 mcg −0.26 units (−22.3%)^b ACLI 400 mcg −0.15 units (−12.9%)^b FORM 12 mcg −0.18 units (−15.7%)^b Placebo −0.11 units (−10.5%)^b ACLI/FORM (both doses) vs. placebo p < 0.01 ACLI/FORM (both doses) vs. ACLI 400 mcg p < 0.05
Bateman et al. [16] (pooled data from AUGMENT study [32] and ACLIFORM study [31])	EMSCI	ACLI/FORM 400/12 mcg^a vs. ACLI 400 mcg^a vs. FORM 12 mcg^a vs. placebo	ACLI/FOR 400/12 mcg 1.3 (0.7) ACLI 400 mcg 1.3 (0.7) FOR 12 mcg 1.2 (0.7) Placebo 1.2 (0.6)	ACLI/FORM 400/12 mcg −0.23 units (−17.0%)^b ACLI 400 mcg −0.14 units (−10.7%)^b FORM 12 mcg −0.17 units (−13.6%)^b ACLI/FORM 400/12 mcg vs. ACLI 400 mcg p < 0.001 ACLI/FORM 400/12 mcg vs. FOR 12 mcg p < 0.01
Welte et al. [35]	GSCQ and CDLM	TIO 18 mcg once-daily plus placebo vs. TIO 18 mcg once-daily plus BUD/FORM 320/9 mcg^a	NA	GSCQ predose breathlessness: TIO + placebo: −0.036^b; TIO + BUD/FORM: −0.184^b; TIO + BUD/FORM vs. TIO + placebo: −0.148 p = 0.001 GSCQ predose chest tightness: TIO + placebo: −0.029^b; TIO + BUD/FORM: −0.119^b; TIO + BUD/FORM vs. TIO + placebo: −0.090 p = 0.051 GSCQ 15 min postdose breathlessness: TIO + placebo: −0.310^b; TIO + BUD/FORM: −0.495^b; TIO + BUD/FORM vs. TIO + placebo: −0.185 p < 0.001 GSCQ 15 min postdose chest tightness: TIO + placebo: −0.231^b; TIO + BUD/FORM: −0.352^b; TIO + BUD/FORM vs. TIO + placebo: −0.121 p = 0.014 CDLM: TIO + placebo: 0.083^b; TIO + BUD/FORM: 0.264^b; TIO + BUD/FORM vs. TIO + placebo: 0.180 p < 0.014
Partridge et al. [36]	GSCQ and CDLM	BUD/FORM 320/9 mcg^a vs. SAL/FLU 50/500 mcg^a	NA	CDLM BUD/FORM: −0.22^b SAL/FLU: −0.12^b BUD/FORM vs SAL/FLU: mean difference 0.10 (p < 0.05)
Marth et al. [19]	Patients were asked to evaluated the severity of morning symptoms	Newly initiated on treatment with ACLI 400 mcg twice-daily as first-line or add-on	Proportion of patients with at least moderate symptoms: 57.7%	p < 0.0001^b
Kim et al. [17]	CSQ and MAQ	‘Treated according to routine clinical practices based on the GOLD guidelines’	Getting out of bed: 5.2 (2.6) Using the toilet: 4.3 (2.6) Washing yourself: 5.7 (2.4) Drying yourself: 4.3 (2.6) Dressing yourself: 3.7 (2.4) Preparing breakfast: 2.7 (2.3) Eating breakfast: 2.8 (2.2)	Getting out of bed: −1.2 (1.4) p < 0.0001^b Using the toilet: −0.8 (1.7) p = 0.0001^b Washing yourself: −1.9 (2.0) p < 0.0001^b Drying yourself: −1.2 (1.6) p < 0.0001^b Dressing yourself: −1.1 (1.6) p < 0.0001^b Preparing breakfast: −0.7 (1.2) p = 0.0021^b Eating breakfast: −1 (1.5) p < 0.0001^b
Lange et al. [18]	Questionnaire according to: coughing/breathlessness during the morning/night and sleep quality	ACLI 322 mcg^a (initial therapy, change of treatment, or add-on therapy)	Proportion of patients with morning symptoms: 65% Moderate to very severe: 40%	Severity of morning symptoms: −0.60 (2.51)^b p < 0.001
O’Hagan et al. [12]	‘A 20-min questionnaire’	‘Their medication’	NA	79% of patients believed that their medication provided sufficient relief in morning symptoms
Globe et al. [13]	NA	Rescue inhaler or nebulizer	NA	14% of patients described reduction of the severity of shortness of breath
Beier et al. [37]	COPD symptoms questionnaire (developed by the sponsor)	ACLI 322 mcg^a vs. TIO 18 mcg once-daily vs. placebo	ACLI 2.36 TIO 2.25	ACLI −0.22 vs. placebo p < 0.001 TIO −0.12 vs. placebo p < 0.05

ACLI: Aclidinium; BUD: budesonide; CDLM: Capacity of Daily Living during the Morning questionnaire; COPD: chronic obstructive pulmonary disease; CSQ: Clinical Symptom Questionnaire; EMSCI: Early-Morning Symptoms of COPD Instrument; FLU: Fluticasone; FORM: formoterol; GCSQ: Global Chest Symptoms Questionnaire; GLY: glycopyrronium; GOLD: Global Initiative for Chronic Obstructive Lung Disease; MAQ: Morning Activity Questionnaire; PRO: patient-reported outcome; SAL: salmeterol; TIO: tiotropium.

^atwice-daily.

^bvs. baseline.

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