Table 4 Description of the derived phenotypes and association with outcomes analyzed in the included studies of clinical phenotypes for COPD

Burgel et al. (2010)

Phenotype

• Young individual Very severe respiratory disease Frequent exacerbator Poor nutritional status Low prevalence of cardiovascular comorbidities High prevalence of depression and very poor HRQoL

• Older individual Mild respiratory disease High prevalence of overweight Low prevalence of cardiovascular comorbidities and depression Mildly impaired HRQoL

• Young individual Moderate respiratory disease Normal nutritional status Low prevalence of cardiovascular comorbidities and depression Moderately impaired HRQoL

• Older individual Moderate respiratory disease Frequent exacerbator High prevalence of overweight High prevalence of cardiovascular comorbidities and depression Poor HRQoL

N (%)

44 (13.7)

89 (27.6)

93 (28.9)

96 (29.8)

Outcome analyzed- BOD score*

5 (4-6)

1 (1-2)

3 (2-3)

4 (3-6)

Burgel et al.^§ (2012)

Outcome analyzed- crude mortality rate

15 (35%)

7 (8%)

17 (20%)

21 (25%)

Outcome analyzed- age at death, median, IQR

62 (58-68)

77 (66-83)

67 (58-69)

76 (74-79)

Age-adjusted mortality risk (Cox model)

8.35 (3.13,22.22) v Phenotype 2 1.91 (0.94,3.06) v Phenotype 3 3.18 (1.37,7.4) v Phenotype 4

Reference group with lowest mortality risk

4.33 (1.73,11.06) v Phenotype 2 1.67 (0.78, 3.57) v Phenotype 4

2.63 (1, 6.25) v Phenotype 2

Burgel et al. (2012)

Phenotype

• Young individual Mild to moderate airflow limitation Absent or mild emphysema Absent or mild dyspnea Normal nutritional status Limited comorbidities

• Young individual Over-representation of women in the group Severe airflow limitation Marked emphysema and hyperinflation Low BMI Severe dyspnea Impaired HRQoL Osteoporosis, muscle weakness highly prevalent Diabetes and cardiovascular comorbidities less prevalent.

• Older individual Mostly male Moderate to severe airflow limitation Less severe emphysema than subjects in Phenotype 2 Higher prevalence of bronchial thickening Higher prevalence of obesity, diabetes and cardiovascular comorbidities

N (%)

219 (41.5)

99 (18.8)

209 (39.7)

Outcome analyzed- crude mortality rate

1 (0.5%)

20 (20.6%)

29 (14.3%)

Age-adjusted mortality risk (Cox model)

Reference group with lowest mortality risk

47.5 (6.3,358.6) v Phenotype 1 3.3 (1.5,7.2) v Phenotype 3

14.3 (1.9,110.3) v Phenotype 1

Cho et al. (2010)

Phenotype

• Emphysema predominant Lower BMI Fewer pack-years of smoking Higher TLC, lower DLCO Lower 6MWD and maximum work

• Milder severity, fewer symptoms of dyspnea Fewer exacerbations, despite being of slightly older age Bronchodilator responsive Higher BMI Greater FVC and DLCO Lower PaCO₂ Higher 6MWD and maximum work,

• Less emphysema and lower wall thickness (similar to Phenotype 2) Lower FEV₁, less bronchodilator responsiveness, more dyspnea compared to Phenotype 2 despite a relatively younger age

• Airway predominant, highest airway thickness Higher BMI Lower TLC Less severe emphysema Lower PaO₂ and lower 6MWD

N (%)

66 (21.4)

102 (33.1)

88 (28.6)

52 (16.9)

Outcome analyzed- exacerbations (retrospectively over 3.3 years)

0.19

0

0.19

0.15

DiSantostefano et al. (2013)

Phenotype

• Treated with diuretics Higher BMI Fewer current smokers Frequent moderate exacerbations Higher use of cardiac medications and psycholeptics

• Not treated with diuretics Lower FEV₁ Highest FEV₁ reversibility post-bronchodilator Fewer proportion of subjects on cardiac medications and psycholeptics

• Not treated with diuretics Higher proportion of current smokers Higher FEV₁ Lowest FEV₁ reversibility post-bronchodilator

N (%)

454 (29)

756 (49)

333 (22)

Outcome analyzed- response in the rate of exacerbations to SFC as compared to SAL

Reduction in the annual rate of moderate/severe exacerbations among patients randomized to SFC as compared with SAL alone (RR = 0.56, p < 0.001);

Reduction in the annual rate of moderate/severe exacerbations among patients randomized to SFC as compared with SAL alone (RR = 0.67, p < 0.001)

No change in the annual rate of moderate/severe exacerbations among patients randomized to SFC as compared with SAL alone (RR = 1, p not significant)

Garcia-Aymerich et al. (2011)

Phenotype

• Severe respiratory disease Poor functional capacity Emphysematous Few comorbidities

• Milder respiratory disease Preserved BMI Few comorbidities

• Mild respiratory disease High BMI Higher prevalence of comorbidities and inflammatory markers

N (%)

126 (36.9)

125 (36.5)

91 (26.6)

Outcome analyzed- ATS/ERS severity stage adjusted - COPD admission risk

2.89 (1.59 - 5.25)

Reference group with lowest mortality risk

1.54 (0.91 - 2.63)

Outcome analyzed- ATS/ERS severity stage adjusted -Mortality

2.01 (0.72 - 5.62)

Reference group with lowest mortality risk

1.55 (0.67 - 3.58)

Spinaci et al. (1985)

Phenotype

• Severe respiratory disease Heavy smokers Emphysematous Frequent hospitalizations

• Milder respiratory disease Preserved body weight Lower prevalence of emphysema Fewer hospitalizations

N (%)

189 (36)

343 (64)

Outcome analyzed- Analysis of contingency tables

Worse prognosis of life (details not provided)

Vanfleteren et al. (2013)

Phenotype

• Younger individuals Fewer comorbidities Higher HRQoL

• Older individuals Higher prevalence of cardiovascular comorbidities Poor HRQoL

• Younger individuals Women over-represented in the group Higher prevalence of emphysema Higher prevalence of underweight, muscle wasting, osteoporosis

• Predominantly male High prevalence of obesity, hyperglycemia, dyslipidemia and atherosclerosis

• Younger individuals

• Severe dyspnea

• High prevalence of anxiety and depression,

• Poor HRQoL

N (%)

67 (31.4)

49 (23)

44 (21)

33 (15.5)

20 (9.4)

Outcome analyzed- Updated BODE score**

2.4 (2.6)

3.4 (3.3)

3 (1.8)

2.6 (2.3)

3.1 (1.9)

Outcome analyzed- Framingham 10-year risk, %

8.6 (6.6)

11.5 (6.6)

7.6 (6)

11.9 (7.3)

6.6 (4.5)