A systematic review of how patients value COPD outcomes

Yuan Zhang; Rebecca L. Morgan; Pablo Alonso-Coello; Wojtek Wiercioch; Małgorzata M. Bała; Rafał R. Jaeschke; Krzysztof Styczeń; Hector Pardo-Hernandez; Anna Selva; Housne Ara Begum; Gian Paolo Morgano; Marcin Waligóra; Arnav Agarwal; Matthew Ventresca; Karolina Strzebońska; Mateusz T. Wasylewski; Lídia Blanco-Silvente; Janna-Lina Kerth; Mengxiao Wang; Yuqing Zhang; Saiprasad Narsingam; Yutong Fei; Gordon Guyatt; Holger J. Schünemann

doi:10.1183/13993003.00222-2018

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FIGURE 1
Flow diagram for systematic review on chronic obstructive pulmonary disease patients’ values and preferences.
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FIGURE 2
Forest plots for EuroQol-5D (EQ-5D) utility of chronic obstructive pulmonary disease patients with forced expiratory volume in 1 s a) ≥80%, b) <80–≥50%, c) <50–≥30% and d) <30% predicted.

TABLE 1

Summary of findings

Health state/outcome (categories of values and preferences)	Estimates of outcome importance range across studies/pooled mean (95% CI)	Participants/studies	Certainty of evidence	Interpretation of findings
Exacerbation (utility^# measured with visual analogue scale^¶)	0.259–0.580/0.462 (0.453–0.471)^####	1991/8^####	+++− Moderate certainty due to inconsistency^####	Most people find exacerbation of COPD probably has a large impact on their lives. There is probably no important variability for this assessment.
Exacerbation (EQ-5D utility⁺)	0.430–0.683/0.519 (0.502–0.537)^¶¶¶¶	927/3^¶¶¶¶	++−− Low certainty due to inconsistency and indirectness^¶¶¶¶^,^######	Most people find exacerbation of COPD probably has a large impact on their lives. There is probably no important variability for this assessment.
Exacerbation (disutility)^§	Visual analogue scale 1 nonserious exacerbation: −0.037 (0.005) 2 nonserious exacerbations: −0.068 (0.005) 1 serious exacerbation: −0.090 (0.007) 1 nonserious and 1 serious exacerbation: −0.130 (0.007) Time trade off 1 nonserious exacerbation: −0.010 (0.007) 2 nonserious exacerbations: −0.021 (0.007) 1 serious exacerbation: −0.042 (0.009) 1 nonserious and 1 serious exacerbation: −0.088 (0.009)	239/1	++++ High certainty	Most people find exacerbation of COPD has an impact on their lives, which grows larger as the severity of exacerbation progresses. There is probably no important variability for this assessment.
Level 1 dyspnoea (utility measured with visual analogue scale)^ƒ	0.751	146/1^ƒ	++++ High certainty^ƒ	Most people find level 1 dyspnoea has a small to moderate impact on lives. There is probably no important variability for this assessment.
Level 2 dyspnoea (utility measured with visual analogue scale)^ƒ	0.656	45/1^ƒ	+++− Moderate certainty due to imprecision^ƒ	Most people find level 2 dyspnoea probably has a moderate impact on lives. There is probably no important variability for this assessment.
Level 3 dyspnoea (utility measured with visual analogue scale)^ƒ	0.526	7/1^ƒ	++−− Low certainty due to very serious imprecision^ƒ	Most people find level 3 dyspnoea probably has a large impact on lives. There is probably no important variability for this assessment.
Adverse events (discrete choice)^##	Two studies suggested that patients consider adverse events as important outcomes. One study suggested adverse events were more important than onset time of medicine, ease of use, rescue medicine use. Another suggested adverse events were more important than costs of treatment, extent to which the patient sees the same doctor each time and extent to which the doctor treats the patient as an entire person. Both studies concluded symptom relief to be more important than adverse events.	564/2	+++− Moderate certainty due to risk of bias^##	People probably consider adverse events as an important outcome. There is likely no important variability for this assessment.
Extent of symptom relief (discrete choice)^##	Two studies compared extend of symptom relief with other outcomes. Extent of symptom relief was considered the most important outcome in these two studies.	564/2	+++− Moderate certainty due to risk of bias^##	Most people probably find symptom relief as important outcome. There is probably no important variability for this assessment.
Extent of symptom relief (forced choice)^¶¶	In a survey on expectation of treatment, greater symptomatic relief was chosen by 82.3% of the participants, thus the most important outcome. Extent of symptom relief was considered the second most important outcome in one cross-sectional study (less preferred “not to be kept alive on life support when there is little hope for a meaningful recovery”). Another study reported 58.0% of the participants would prefer treatment focusing on relieving pain and discomfort rather than extending life.	1640/3	+++− Moderate certainty due to risk of bias^¶¶	Most people probably find symptom relief as important outcome. There is probably no important variability for this assessment.
Very severe COPD (utility measured with visual analogue scale)⁺⁺	0.321–0.651/0.345 (0.335–0.354)⁺⁺⁺⁺	746/7	++−− Low certainty due to risk of bias⁺⁺⁺⁺⁺⁺ and inconsistency⁺⁺	Most people find very severe COPD seems to have a large impact on lives. There is probably important variability for this assessment.
Very severe COPD (EQ-5D utility)^§§	0.520–0.740/0.681 (0.667–0.694)^§§§§	898/10	+++− Moderate certainty due to inconsistency^§§§§	Most people find very severe COPD probably has a large impact on lives. There is probably important variability for this assessment.
Severe COPD (utility measured with visual analogue scale)^ƒƒ	0.446–0.689/0.508 (0.501–0.515)^ƒƒƒƒ	4683/8	++−− Low certainty due to risk of bias⁺⁺⁺⁺⁺⁺ and inconsistency ^ƒƒƒƒ	Most people find severe COPD probably has a moderate to large impact on lives. There is probably important variability for this assessment.
Severe COPD (EQ-5D utility)^###	0.620–0.810/0.741 (0.734–0.749)^#####	4352/11	+++− Moderate certainty due to inconsistency^#####	Most people find severe COPD probably has a moderate to large impact on lives. There is probably important variability for this assessment.
Moderate COPD (utility measured with visual analogue scale)^¶¶¶	0.589–0.726/0.639 (0.635–0.642)^¶¶¶¶¶	9664/10	++−− Low certainty due to risk of bias⁺⁺⁺⁺⁺⁺ and inconsistency^¶¶¶¶¶	Most people find moderate COPD probably has a moderate impact on lives. There is probably important variability for this assessment.
Moderate COPD (EQ-5D utility)⁺⁺⁺	0.680–0.890/0.821 (0.815–0.826)⁺⁺⁺⁺⁺	4620/9	+++− Moderate certainty due to inconsistency⁺⁺⁺⁺⁺	Most people find moderate COPD probably has a moderate impact on lives. There is probably important variability for this assessment.
Mild COPD (utility measured with visual analogue scale)^§§§	0.680–0.811/0.738 (0.732-0.746)^§§§§§	3623/8	++−− Low certainty due to risk of bias⁺⁺⁺⁺⁺⁺ and inconsistency^§§§§§	Most people find moderate COPD probably has a small to moderate impact on lives. There is likely important variability for this assessment.
Mild COPD (EQ-5D utility)^ƒƒƒ	0.770–0.900/0.873 (0.863–0.883)^ƒƒƒƒƒ	2067/7	+++− Moderate certainty due to inconsistency ^ƒƒƒƒƒ	Most people find moderate COPD probably has a small to moderate impact on lives. There is probably important variability for this assessment.

Grading of Recommendations Assessment, Development and Evaluation Working Group grades of evidence: here we assessed the certainty of evidence on mean outcome importance. We use “certainty of evidence”, “certainty in estimates”, “quality of evidence” and “strength of evidence” interchangeably. High certainty: we are very confident that the true value of outcome importance lies close to that of the estimate. Moderate certainty: we are moderately confident in the estimate; the true value of outcome importance is likely to be close to the estimate but there is a possibility that it is substantially different. Low certainty: our confidence in the estimate is limited; the true value of outcome importance may be substantially different from the estimate. Very low certainty: we have very little confidence in the estimate; the true value of outcome importance is likely to be substantially different from the estimate EQ-5D: EuroQol-5D; COPD: chronic obstructive pulmonary disease. ^#: utilities represent the value individuals place on different outcomes; they are measured on an interval scale, with 0 reflecting states of health equivalent to death/worst imaginable health and 1 (or 100 in some cases) reflecting perfect health/best imaginable health. ^¶: eight studies [19–26] used EQ-5D visual analogue scale to elicit health state values on exacerbation of COPD. ⁺: three studies [21–23] used EQ-5D utility to elicit the importance of outcome. ^§: Rutten van Molken et al. [27] reported the disutility due to the exacerbations; the measurement tools included visual analogue scale and time trade off; the researchers estimated the disutility due to exacerbation using random effects regression analysis. ^ƒ: Kim et al. [28] reported the utility of dyspnoea, according to the levels of breathlessness (level 1, short of breath during strenuous activities; level 2, stopping to catch breath after a few minutes walking; level 3, breathless when dressing or washing); in a total sample of 200, the numbers of participants experiencing level 1, 2 and 3 breathlessness were 146, 45 and seven, respectively; due to small sample size, we downgraded the certainty of evidence by one level for the estimates of level 2 breathlessness and two levels for level 3 breathlessness. ^##: Bulcun et al. [29] compared extent of symptom relief with extent to which the doctor gives sufficient time to listen to the patient, possibility of experiencing adverse effects from treatment, costs of treatment, extent to which the patient sees the same doctor each time and extent to which the doctor treats the patient as an entire person; Kawata et al. [30] recruited 515 patients for an online voluntary survey on the comparison of importance of symptom relief, speed of symptom relief, rescue medicine use and side-effects; participants' eligibility and their answers were considered as having serious risk of bias. ^¶¶: three studies [31–33] asked directly what participants would prefer in facing a COPD treatment decision; the questions included expectation of treatment, reasons to continue or not continue with treatment and preferred treatment characteristics; the assessment was at risk of bias due to unclear reliability and validity features. ⁺⁺: [27, 28, 34–37]. ^§§: [27, 28, 35–42]. ^ƒƒ: [27, 28, 34–37, 43, 44]. ^###: [28, 35–40, 43, 44]. ^¶¶¶: [27, 28, 34–37, 43, 44–46]. ^§§§: [27, 28, 34–37, 43, 45]. ^ƒƒƒ: [28, 35–37, 42, 43, 45]. ^####: across eight included studies, the point estimates range from 0.259 to 0.580; using inverse-variance method to pool the estimates, the I² (95.5%) and statistical test (<0.001) suggest potential heterogeneity across studies; the difference in study populations cannot explain the source of heterogeneity (the participants in the studies were exacerbation patients, exacerbation patients not needing hospitalisation, ambulatory patients and hospitalised patients due to exacerbation). ^¶¶¶¶: across three included studies, the point estimates range from 0.430 to 0.683; using inverse-variance method to pool the estimates, the I² (95.5%) and statistical test (<0.001) suggest potential heterogeneity across studies; the difference in study populations cannot explain the source of heterogeneity (the participants in the three studies were exacerbation patients, exacerbation patients not needing hospitalisation and ambulatory patients). ⁺⁺⁺⁺: the point estimates range from 0.321 to 0.651; using inverse-variance method to pool the estimates, the I² (98.5%) and statistical test (<0.001) suggest potential heterogeneity across studies; the difference in study population cannot explain the source of heterogeneity. ^§§§§: the point estimates range from 0.520 to 0.740; using inverse-variance method to pool the estimates, the I² (80.2%) and statistical test (<0.001) suggest potential heterogeneity across studies; the difference in study population cannot explain the source of heterogeneity. ^ƒƒƒƒ: the point estimates range from 0.446 to 0.689; using inverse-variance method to pool the estimates, the I² (98.8%) and statistical test (<0.001) suggest potential heterogeneity across studies; the difference in study population cannot explain the source of heterogeneity. ^#####: the point estimates range from 0.620 to 0.810; using inverse-variance method to pool the estimates, the I² (94.5%) and statistical test (<0.001) suggest potential heterogeneity across studies; the difference in study population cannot explain the source of heterogeneity. ^¶¶¶¶¶: the point estimates range from 0.589 to 0.726; using inverse-variance method to pool the estimates, the I² (97.9%) and statistical test (<0.001) suggest potential heterogeneity across studies; the difference in study population cannot explain the source of heterogeneity. ⁺⁺⁺⁺⁺: the point estimates range from 0.680 to 0.890; using inverse-variance method to pool the estimates, the I² (97.8%) and statistical test (<0.001) suggest potential heterogeneity across studies; the difference in study population cannot explain the source of heterogeneity. ^§§§§§: the point estimates range from 0.680 to 0.811; using inverse-variance method to pool the estimates, the I² (88.0%) and statistical test (<0.001) suggest potential heterogeneity across studies; the difference in study population cannot explain the source of heterogeneity. ^ƒƒƒƒƒ: the point estimates range from 0.770 to 0.900; using inverse-variance method to pool the estimates, the I² (91.3%) and statistical test (<0.001) suggest potential heterogeneity across studies; the difference in study population cannot explain the source of heterogeneity. ^######: we rated down the quality of evidence for indirectness because an indirect measurement tool (EQ-5D) was used to elicit the utility of outcomes. ⁺⁺⁺⁺⁺⁺: we downgraded the certainty in evidence because of low response rate observed by Lin et al. [35] and the potentially biased sampling strategy by asking physicians to provided recruited patients by Boros and Lubinski [34].

TABLE 2

Utility of exacerbation or hospitalisation due to exacerbation

Study	Instrument	Report format	Results
*Alcazar et al.* [19]**	EQ-5D VAS	Mean±sd	Hospitalised patients: 0.551±0.197
*Antoniu et al.* [20]**	EQ-5D VAS	Mean±sd	Hospitalised patients: 0.279±0.252
*Bourbeau et al.* [47]**	EQ-5D VAS	Mean±sd	Change from baseline: −0.126±0.190
*Cross et al.* [21]**	EQ-5D VAS	Mean±sd	Exacerbation of COPD: manual chest physiotherapy arm 0.450±0.210; no manual chest physiotherapy arm 0.466±0.214
*Cross et al.* [21]**	EQ-5D utility	Mean±sd	Exacerbation of COPD: manual chest physiotherapy arm 0.450±0.320; no manual chest physiotherapy arm 0.430±0.360
*Goossens et al.* [22]**	EQ-5D VAS	Mean±sd	Exacerbation (at enrolment): 0.367±0.252
*Goossens et al.* [22]**	EQ-5D utility	Mean±sd	Exacerbation (at enrolment): 0.683±0.209
*Menn et al.* [39]**	EQ-5D utility	Mean±sd	EQ-5D Admission Stage III: 0.620±0.260
	EQ-5D utility	Mean±sd	EQ-5D Admission Stage IV: 0.600±0.260
	SF-6D utility	Mean±sd	SF-12-SF-6D Admission Stage III: 0.610±0.130
	SF-6D utility	Mean±sd	SF-12-SF-6D Admission Stage IV: 0.540±0.080
*Miravitlles et al.* [23]**	EQ-5D utility	Mean±sd	EQ-5D index baseline (exacerbation): 0.540±0.230
*Miravitlles et al.* [23]**	EQ-5D VAS	Mean±sd	EQ VAS baseline (exacerbation): 0.344±0.274
*O'Reilly et al.* [24]**	EQ-5D utility	Mean±sd	Hospital admission: −0.077±0.397
*O'Reilly et al.* [24]**	EQ-5D VAS	Mean±sd	Hospital admission: 0.259±0.170
*Punekar et al.* [43]**	EQ-5D utility	Mean (95% CI)	1–2 exacerbations in primary care physician setting: 0.740 (0.720–0.770)
			>3 exacerbations in primary care physician setting: 0.610 (0.590–0.640)
			1–2 exacerbations in respiratory specialist setting: 0.730 (0.710–0.760)
			>3 exacerbations in respiratory specialist setting: 0.570 (0.540–0.600)
*Rutten van Molken et al.* [27]**	VAS	Regression coefficient±sem	1 nonserious exacerbation: −0.037±0.005 2 nonserious exacerbations: −0.068±0.005 1 serious exacerbation: −0.090±0.007 1 nonserious and 1 serious exacerbation: −0.130±0.007
*Rutten van Molken et al.* [27]**	TTO	Regression coefficient±sem	1 nonserious exacerbation: −0.010±0.007 2 nonserious exacerbations: −0.021±0.007 1 serious exacerbation: −0.042±0.009 1 nonserious and 1 serious exacerbation: −0.088±0.009
*Seymour et al.* [25]**	EQ-5D VAS	Mean±sd	COPD baseline in usual care group: 0.540±0.170 COPD baseline in post-exacerbation pulmonary rehabilitation group: 0.580±0.180
*Solem et al.* [40]**	EQ-5D utility	Mean±sd	Patients recently experiencing a severe exacerbation: 0.627±0.210 Patients recently experiencing a moderate exacerbation. 0.698±0.197 Patients who had experienced ≥3 exacerbations in the previous year: 0.638±0.212 Patients who had experienced 2 exacerbations in the previous year: 0.684±0.204 Patients who had experienced 1 exacerbation in the previous year: 0.727±0.175 Current health (last exacerbation): 0.552±0.283 Thought back, patients experiencing a severe exacerbation (last exacerbation): 0.471±0.313 Thought back, patients experiencing a moderate exacerbation (last exacerbation): 0.595±0.257 Very severe COPD (last exacerbation): 0.494±0.312 Severe COPD (last exacerbation): 0.590±0.256 Patients who had experienced ≥3 exacerbations in the previous year (last exacerbation): 0.520±0.282 Patients who had experienced 2 exacerbations in the previous year (last exacerbation): 0.552±0.306 Patients who had experienced one exacerbation in the previous year (last exacerbation): 0.610±0.254
*Torrance et al.* [48]**	HUI	Mean±sd	For the first acute exacerbation of chronic bronchitis: ciprofloxacin group: 0.720±0.200); usual care group 0.680±0.190 For the remaining acute exacerbation of chronic bronchitis: ciprofloxacin group: 0.740±0.180; usual care group 0.690±0.220
*Wildman et al.* [26]**	EQ-5D VAS	Mean±sd	0.549±0.195
*Wildman et al.* [26]**	EQ-5D VAS	Median (IQR)	0.500 (0.400–0.700)

EQ-5D: EuroQol-5D; VAS: visual analogue scale; TTO: time trade-off; HUI: Health Utility Index; IQR: interquartile range; COPD: chronic obstructive pulmonary disease.

TABLE 3

Importance on breathlessness, shortness of breath, or dyspnoea

Study	Instrument	Report format	Results
*Gruenberger et al.* [49]**	SF-6D utility	Mean	SF-6D health utilities were 0.060 points lower in higher dyspnoea patients (modified Medical Research Council score ≥2) than in lower dyspnoea patients
*Kim et al.* [28]**	EQ-5D VAS	Mean±sem	EQ-5D utility Level 1 breathlessness (short of breath during strenuous activities): 0.870±0.020 Level 2 breathlessness (stopping to catch breath after a few minutes walking): 0.740±0.030 Level 3 breathlessness (breathless when dressing or washing): 0.540±0.060
*Kim et al.* [28]**	EQ-5D utility	Mean±sem	EQ-VAS Level 1 breathlessness (short of breath during strenuous activities): 0.751±0.026 Level 2 breathlessness (stopping to catch breath after a few minutes walking): 0.656±0.035 Level 3 breathlessness (breathless when dressing or washing): 0.526±0.071
*Punekar et al.* [43]**	EQ-5D utility	Mean (95% CI)	All in primary care physician setting: 0.700 (0.680–0.710) Breathlessness after exercising heavily in primary care physician setting: 0.880 (0.860–0.900) Breathlessness when hurrying on level ground in primary care physician: 0.790 (0.770–0.810) Too breathless to leave house in primary care physician: 0.170 (0.110–0.240) All in respiratory specialist setting: 0.680 (0.660–0.690) Breathlessness after exercising heavily in respiratory specialist setting: 0.880 (0.850–0.900) Breathlessness when hurrying on level ground in respiratory specialist setting: 0.790 (0.770–0.810) Too breathless to leave house in respiratory specialist setting: 0.290 (0.220–0.350)
*Braido et al.* [50]**	Uncategorised survey	Choice or proportion of choice	Breathlessness as most troublesome symptom: 64.6% (ranking first; chronic cough: 13.9%; sputum production: 11.0%; exacerbation: 8.3%)
*Downey et al.* [51]**	Uncategorised survey: End of life Priority Score (the highest priority aspect of the end-of-life period)	Mean±sd	In a survey on end-of-life priority score measured by rank order (out of 5), breathing comfort was considered as priority: 1.27±1.83 (ranking third, only after time with family and friends, and pain under control)
*Haughney et al.* [52]**	Conjoint analysis/discrete choice analysis	Mean	Breathlessness was considered important for patients. Of all the attributes, it was after “impact on everyday life”, “need for medical care” and “number of future attacks”. It is more important than speed of recovery, productive cough, social impact, sleep disturbance and impact on mood.
*Hernández et al.* [53]**	Impact of shortness of breath	Choice or proportion of choice	Shortness of breath is an important outcome, because 6.0% of participants stated the impact on activities of daily living was extreme, 29.0% “very much”, 24.0% “a little” and 13.0% “not at all”
*Miravitlles et al.* [54]**	Ideal characteristics of a COPD therapy	Choice or proportion of choice	37.0% of the participants chose “increased shortness of breath” as the symptom that has a high impact on wellbeing (ranking second; increased coughing 42.0%, increased fatigue 37.0%, increased production of sputum 35.0%, increased frequency of chest pains 20.0% and fever 13.0%)
*Pisa et al.* [55]**	Direct choice: relative importance of COPD attributes (%, higher proportion indicating more importance)	Choice or proportion of choice	Dyspnoea was considered the most important COPD attribute Relative importance of COPD attributes Dyspnoea: 36.0% Performance capability (bodily resilience) due to COPD: 19.0% Sleep quality due to COPD: 19.0% Onset of action of the medication: 3.0% Frequency of administration of the medication: 6.0% Health state after awakening (day start) due to COPD: 13.0% Emotional state due to COPD base medication: 4.0% Effect of attribute levels on health state preference: part-worth utilities (higher value indicating more importance): Dyspnoea Never dyspnoea, except on strong exertion: 115.80 Dyspnoea on exertion: 38.20 Dyspnoea at normal walking pace: −6.60 Dyspnoea on slight effort: −10.10 Dyspnoea even at rest: −137.40
*Polati et al.* [56]**	Uncategorised survey: expectation of treatment	Choice or proportion of choice	120 (24.1%) patients would like to have more ease with “breathing” due to treatment; if they were doctors, 215 (43.3%) patients would like to first heal shortness of breath. For both questions, breathing problems were considered most important compared with other symptoms.
*Reinke et al.* [57]**	Forced choice: treatment	Choice or proportion of choice	Preferences about death and dying questionnaire. 52.6% of 357 patients chose “being able to breath comfortably in the last 7 days of life” as preferred characteristics of treatment.
*Rocker et al.* [31]**	Uncategorised survey: reasons to continue (or not) with opioids	Choice or proportion of choice	I would strongly prefer when followed up at 2 months, 8 (23.5%) and 1 (2.9%) patient claimed would “strongly prefer” and “prefer” to continue on opioids because they provide significant relief from dyspnoea; while at 4–6 months, 12 (29.3%) and 7 (17.1%) patients claimed would “strongly prefer” and “prefer” to continue on opioids because they provide significant relief from dyspnoea.
*Wilson et al.* [58]**	Importance of mechanical ventilation: scales for the specific questions about mechanical ventilation	Median (IQR)	On a scale of 1–4 (0: not at all important; 1: a little; 2: quite a bit; 3: very much; 4: extremely important), the score for easing breathlessness was 2.5 (1.8–3.0) for those forego mechanical ventilation, and 3.0 (2.8–4.0) for those uncertain/accept mechanical ventilation.

EQ-5D: EuroQol-5D; VAS: visual analogue scale; COPD: chronic obstructive pulmonary disease; IQR: interquartile range.

TABLE 4

Importance of adverse events

Study	Instrument	Reported format	Results
*Bulcun et al.* [29]**	Conjoint analysis/discrete choice analysis	Influence or contribution or weight of certain aspects/attributes	Possibility of experiencing adverse effects from treatment 20%: −0.90 10%: −0.06 4%: 1.00 Difference between highest and lowest utility levels: 8.20 The sequence of attributes from most important to least important: extent to which the doctor gives sufficient time to listen to the patient, possibility of experiencing adverse effects from treatment, costs of treatment, extent to which the patient sees the same doctor each time, and extent to which the doctor treats the patient as an entire person.
*Kawata et al.* [30]**	Willingness to pay, conjoint analysis/discrete choice analysis	Mean (95% CI)	Utility score Mild side-effects (no side-effects as reference): −0.29 (−0.33– −0.24) Moderate to severe side-effects (no side-effects as reference): −1.13 (−1.18– −1.09) Willingness to pay Mild side-effects (no side-effects as reference): $14.81 ($12.40–17.22) Moderate to severe side-effects (no side-effects as reference): $58.69 ($56.28–61.11) Adverse event was considered important for COPD treatment. It was the second most important, only after “complete symptom relief”, and more important than “rarely use rescue medication”, “quick and easy to use inhaler” and “feeling medication work quickly”.
*Miravitlles et al.* [54]**	Ideal characteristics of a COPD therapy	Choice or proportion of choice	Ideal characteristics of a COPD therapy as listed by survey respondents Fewer side-effects 36.0% The sequence of ideal characteristics from most important to least important: quick symptom relief, longer intervals between flare-ups, fewer side-effects, better ability to cope with daily chores again, lower costs of treatment, better doses.
*Patridge et al.* [59]**	Uncategorised survey: perception of disease severity	Choice or proportion of choice	30.6% of participants expressed concern regarding potential medication side-effects, and on average, patients considered that explaining clearly what are the possible side-effects and risks of the products was very important (9.0 out of 10 on a scale with 1 indicating not at all important and 10 indicating extremely important).
*Sharafkhaneh et al.* [60]**	Primary disadvantages of nebulisation therapy	Choice or proportion of choice	Question: what do you see as the main negatives or disadvantages of nebulisation? No negatives: 86 (21.5%) Side-effects: 46 (11.5%) The sequence of disadvantages from most important to least important: device immobile/bulky/cumbersome, time-consuming, side-effects, inconvenient, don't like doing it, having to use it several times a day, care and clean-up after use, too expensive.

COPD: chronic obstructive pulmonary disease.

TABLE 5

Utility of different chronic obstructive pulmonary disease (COPD) severities

Study	Instrument	Reported format	GOLD classifications
Study	Instrument	Reported format	Mild COPD^#	Moderate COPD^¶	Severe COPD⁺	Very severe COPD^§
Boros and Lubinski [34]	VAS	Mean (95% CI, sd)	0.730 (0.722–0.739, 0.164)	0.626 (0.621–0.630, 0.164)	0.446 (0.439–0.452, 0.161)	0.321 (0.302–0.339, 0.171)
*Chen et al.* [38]**	EQ-5D utility	Mean			0.686	0.565
*Chen et al.* [38]**	SF-6D utility^ƒ	Mean			0.646	0.597
*Hong et al.* [45]**	EQ-5D utility	Mean±sd	0.900±0.140	0.890±0.140	0.840±0.150
*Hong et al.* [45]**	EQ-5D VAS	Mean±sd	0.730±0.186	0.708±0.191	0.609±0.234
*Kim et al.* [28]**	EQ-5D utility	Mean±sd (adjusted mean±sem)	0.830±0.170 (0.830±0.040)	0.880±0.120 (0.880±0.020)	0.820±0.160 (0.810±0.030)	0.610±0.260 (0.600±0.040)
*Kim et al.* [28]**	EQ-5D VAS	Mean±sd (adjusted mean±sem)	0.719±0.189 (0.739±0.054)	0.719±0.178 (0.751±0.029)	0.650±0.206 (0.689±0.033)	0.609±0.139 (0.651±0.056)
*Lin et al.* [35]**	EQ-5D utility	Mean±sd	0.810±0.140	0.810±0.140	0.760±0.170	0.740±0.150
*Lin et al.* [35]**	EQ-5D VAS	Mean±sd	0.766±0.175	0.726±0.191	0.657±201	0.611±0.197
*Menn et al.* [39]**	EQ-5D utility	Mean±sd			0.620±0.260	0.600±0.260
*Menn et al.* [39]**	SF-6D utility	Mean±sd			0.610±0.130	0.540±0.080
*Pickard et al.* [36]**	EQ-5D utility^##	Mean±sd	0.800±0.130	0.700±0.210	0.720±0.190	0.720±0.160
	EQ-5D utility^¶¶	Mean±sd	0.730±0.190	0.590±0.320	0.630±0.250	0.630±0.240
	EQ-5D VAS	Mean±sd	0.743±0.163	0.662±0.200	0.601±0.184	0.587±0.158
*Punekar et al.* [43]**	EQ-5D utility	Mean (95% CI)	0.770 (0.730–0.810) in primary care setting	0.680 (0.620–0.740)	0.620 (0.560–0.680)
*Punekar et al.* [43]**	EQ-5D utility	Mean (95% CI)	0.680 (0.640–0.720) in respiratory specialist care setting	0.720 (0.690–0.750)	0.640 (0.610–0.720)
*Rodriguez Gonzalez-Moro et al.[46]*	EQ-5D VAS	Mean (95% CI)		0.589 (0.581–0.599)	0.459 (0.449–0.467)
*Rutten van Molken et al.* [44]**	EQ-5D VAS	Mean (95% CI)		0.677 (0.665–0.690)	0.625 (0.610–0.639)	0.578 (0.545–0.612)
	EQ-5D utility^¶¶	Mean (95% CI)		0.787 (0.771–0.802)	0.750 (0.731–0.768)	0.647 (0.598–0.695)
	EQ-5D utility^##	Mean (95% CI)		0.832 (0.821–0.843)	0.803 (0.790–0.816)	0.731 (0.699–0.762)
*Rutten van Molken et al.* [27]**	VAS	Mean±sem	Mild COPD: 0.811±0.011	Disutility of moderate COPD in relation to mild COPD: −0.133±0.006	Disutility of severe COPD in relation to mild COPD: −0.354±0.006	Disutility of very severe COPD in relation to mild COPD: −0.508±0.006
*Rutten van Molken et al.* [27]**	TTO	Mean±sem	Mild COPD: 0.974±0.017	Disutility of moderate COPD in relation to mild COPD: −0.045±0.008	Disutility of severe COPD in relation to mild COPD: −0.257±0.008	Disutility of very severe COPD in relation to mild COPD: −0.452±0.008
*Scharf et al.* [62]**	HUI utility	Mean±sd	0.400±0.330	0.580±0.360	0.530±0.350	0.390±0.510
*Solem et al.* [40]**	EQ-5D utility	Mean±sd			0.707±0.174	0.623±0.234
*Stahl et al.* [37]**	EQ-5D VAS	Mean±sd	0.730±0.210	0.650±0.240	0.620±0.210	0.370±0.280
*Stahl et al.* [37]**	EQ-5D utility	Mean±sd	0.840±0.150	0.730±0.230	0.740±0.250	0.520±0.260
*Starkie et al.* [41]**	EQ-5D utility	Mean±sd		Observed utility for moderate COPD: 0.752±0.220	Observed utility for severe COPD: 0.708±0.230	Observed utility for very severe COPD: 0.672±0.220
*Szende et al.* [42]**	EQ-5D utility	Mean±sd	0.850±0.160	0.730±0.210	0.740±0.240	0.530±0.280
*Szende et al.* [42]**	SF-6D utility	Mean±sd	0.800±0.130	0.730±0.130	0.730±0.140	0.620±0.150

GOLD: Global Initiative for Chronic Obstructive Lung Disease; VAS: visual analogue scale; EQ-5D: EuroQol-5D; TTO: time trade-off; HUI: Health Utility Index. ^#: forced expiratory volume in 1 s (FEV₁) ≥80% predicted; ^¶: FEV₁ <80–≥50% predicted; ⁺: FEV₁ <50–≥30% predicted; ^§: FEV₁ <30% predicted; ^ƒ: Hong Kong value set; ^##: US value set; ^¶¶: UK value set.

Supplementary Materials

Figures
Tables

Supplementary Material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Search strategy ERJ-00222-2018_Search_Strategy
References of all included studies ERJ-00222-2018_References_of_Included_Studies
TABLE S1 Study characteristics ERJ-00222-2018_tableS1
TABLE S2 Summary of risk of bias ERJ-00222-2018_tableS2
TABLE S3 Quantitative results ERJ-00222-2018_tableS3