“Frequent exacerbator” is a phenotype of poor prognosis in Japanese patients with chronic obstructive pulmonary disease

Figures & data

Figure 1 Study design.

Notes: *Diagnosis of asthma–COPD overlap syndrome (ACOS) was made in accordance with history of dyspnea and wheezing attacks at rest, and large variations of daily symptoms and FEV₁ after bronchodilator administration (reversibility >15% and >400 mL). A total of 110 patients provided informed consent. Eight patients with asthma or ACOS, six with cor pulmonale or congestive heart failure, four with depression, and two with persistent arrhythmia were excluded. As a result, 90 patients with COPD were finally analyzed.
Abbreviation: FEV₁, forced expiratory volume in 1 second.

Table 1 Characteristics of nonexacerbators and infrequent and frequent exacerbators

Characteristics	Non exacerbators (n=58)	Infrequent exacerbators (n=12)	Frequent exacerbators (n=20)
Age, years	66.2±6.5	69.6±4.6	68.0±6.4
Male sex, n (%)	53 (91.4)	11 (91.7)	14 (70.0)*
Body mass index, kg/m^2	22.7±3.1	21.4±3.0	18.8±3.2***,#
Current smokers, n (%)	26 (44.8)	3 (25.0)	3 (15.0)*
Smoking index, pack-years	59.2±27.2	62.1±23.6	60.9±26.8
Frequency of previous hospitalizations within the last	0	1.67±0.39* (0–1)	1.50±0.37* (0–1)
year, times/patient (range)
mMRC dyspnea scale, grades	0.60±0.98	1.50±1.00*	1.65±1.35**
Total CAT score, points	8.29±6.12	15.8±5.61**	21.2±10.8***,#
Spirometric stage I/II/III/IV, n (% of stage III and IV)	18/26/12/2 (24.1)	1/7/2/2 (33.3)	0/11/4/5a (45.0)
Hypertension, n (%)	19 (32.8)	2 (16.7)	6 (30.0)
Diabetes, n (%)	23 (39.7)	2 (16.7)	6 (30.0)
Dyslipidemia, n (%)	31 (53.5)	6 (50.0)	10 (50.0)
Gastroesophageal reflux disease, n (%)	3 (5.2)	3 (25.0)	4 (20.0)a
Duration of COPD, years	4.79±4.01	7.00±3.64	5.90±3.89
Pneumococcal vaccination within 5 years, n (%)	9 (15.5)	1 (8.3)	7 (35.0)
Required long-term oxygen therapy, n (%)	2 (3.5)	0	3 (15.0)
Required home ventilation support, n (%)	1 (1.7)	0	1 (5.0)
No respiratory medication, n (%)	18 (31.0)	2 (16.7)	2 (10.0)
ICS–LABA–LAMA triple combo, n (%)	7 (12.1)	1 (8.3)	4 (20.0)
ICS–LAMA or ICS–LABA double combo, n (%)	1 (1.7)	0	3 (15.0)a
LABA–LAMA double combo, n (%)	4 (6.9)	3 (8.3)	1 (10.0)
LAMA or LABA alone, n (%)	28 (48.3)	8 (66.7)	9 (45.0)
Regimen included ICS, n (%)	8 (13.8)	1 (8.33)	7 (35.0)
Regimen included SRT, n (%)	1 (1.7)	1 (8.3)	2 (10.0)
Regimen included mucolytic agents, n (%)	0	1 (8.3)*	0
Prebronchodilator
FVC, L	3.70±0.79	3.28±0.71	2.82±0.81**
FVC predicted, %	105±18.0	93.4±15.6	88.6±18.2**
FEV1, L	1.86±0.64	1.44±0.66	1.20±0.59**
FEV1 predicted, %	65.4±21.9	50.8±19.9	47.5±21.4**
FEV1/FVC ratio, %	50.0±13.5	42.6±13.1	42.0±14.5
Postbronchodilator
FVC, L	3.74±0.77	3.38±0.74	2.88±0.84**
FVC predicted, %	106±18.0	95.4±15.6	88.6±18.2**
FEV1, L	1.92±0.65	1.51±0.68	1.28±0.63**
FEV1 predicted, %	67.3±21.8	53.5±20.2	50.4±22.6**
FEV1/FVC ratio, %	51.2±13.9	43.9±13.7	43.3±14.2
Reversibility of FEV1 postbronchodilation, %	3.65±7.96	5.64±4.24	6.85±12.8

Notes:

a P<0.05 vs nonexacerbators by χ²-test for trend.

* P<0.05,

** P<0.01, and

*** P<0.0001 vs nonexacerbators;

# P<0.05 vs infrequent exacerbators. Data expressed as mean ± standard deviation and number (percentage) of patients.

Abbreviations: CAT, COPD Assessment Test; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; ICS, inhaled corticosteroids; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council; SRT, slow-release theophylline.

Figure 2 Stability of the phenotypes of frequent and infrequent exacerbators, nonexacerbators, and severe exacerbators.

Notes: ^#Three patients who had subsequent severe exacerbations in 78 completed patients, and two of 17, zero of eleven, and one of 50 patients were frequent, infrequent, and nonexacerbators, respectively (dotted lines). Two frequent exacerbators required hospitalization due to COPD exacerbations, and one died due to respiratory failure. In analysis of subphenotypes with severe exacerbators, two of five patients had subsequent severe exacerbations (dotted line). The bars at the previous (left) and future (right) risk show the proportions of patients who suffered severe, frequent, and infrequent exacerbations, and nonexacerbators retrospectively and prospectively, respectively, based on the number of previous moderate and severe exacerbations for 1 year.

Figure 3 Comparison of annual exacerbation and hospitalization among nonexacerbators and infrequent and frequent exacerbators.

Notes: **P<0.01 vs nonexacerbators. (A) All data expressed as the frequency (exacerbations/year) of moderate or severe (deaths and hospitalizations) exacerbation (error bars = standard deviation). (B) Kaplan–Meier curves of periods until first moderate and severe exacerbations.

Table 2 Baseline characteristics of patients with future exacerbation (once or more) and frequent exacerbation (twice or more) by univariate analysis

Parameters	Once or more		Twice or more
	n/total	OR (95% CI)	n/total	OR (95% CI)
Age ≥68 years	20/40	2.80 (1.08–7.25)*	14/40	6.28 (1.63–24.1)**
Male sex	27/69	1.29 (0.30–5.58)	15/69	0.97 (0.18–5.18)
Body mass index ≤21.4 kg/m^2	21/39	3.89 (1.47–10.3)**	11/39	2.16 (0.71–6.59)
Current smokers	7/26	0.46 (0.17–1.29)	3/26	0.35 (0.09–1.37)
Smoking index ≥53.5 pack-years	17/39	1.55 (0.62–3.87)	10/39	1.57 (0.53–4.68)
Previous exacerbations once or more in the last year	17/28	4.40 (1.64–11.8)**	10/28	3.41 (1.12–10.4)*
Previous exacerbations twice or more in the last year	13/17	8.41 (2.40–29.3)**	7/17	3.57 (1.10–9.24)*
Previous hospitalizations in the last year	2/5	1.07 (0.17–6.82)	2/5	2.58 (0.40–16.8)
mMRC scale ≥2 grades	13/21	3.82 (1.34–10.9)*	9/24	4.59 (1.47–14.4)*
Total CAT score ≥10 points	22/42	3.85 (1.43–10.4)**	13/42	3.59 (1.05–12.2)
Hypertension, yes	9/23	1.04 (0.38–2.83)	6/23	1.41 (0.45–4.42)
Diabetes, yes	12/27	1.46 (0.57–3.80)	9/30	2.14 (0.72–6.37)
Dyslipidemia, yes	14/38	0.88 (0.35–2.18)	7/38	0.68 (0.23–2.01)
Gastroesophageal reflux disease, yes	7/9	7.00 (1.35–36.4)*	6/10	10.5 (2.29–48.6)**
Duration of COPD ≥4 years	19/41	2.04 (0.80–5.20)	13/41	3.83 (1.12–13.1)*
Pneumococcal vaccination, yes	11/15	6.34 (1.80–22.6)**	8/15	6.86 (2.00–23.6)*
Regular users of ICS, yes	12/15	10.0 (2.52–39.7)**	9/15	10.3 (2.89–37.8)**
FEV1 predicted <50%	18/24	10.5 (3.41–32.3)***	12/24	9.80 (2.89–33.2)**

Notes:

* P<0.05;

** P<0.01;

*** P<0.0001.

Abbreviations: CAT, COPD Assessment Test; CI, confidence interval; FEV₁, forced expiratory volume in 1 second; ICSs, inhaled corticosteroids; mMRC, modified Medical Research Council; OR, odds ratio.

Table 3 Baseline characteristics of patients with future exacerbation (once or more) and frequent exacerbation (twice or more) by multivariate analysis

Parameters	Once or more		Twice or more
	OR (95% CI)	P-value	OR (95% CI)	P-value
Age ≥68 years	2.38 (0.51–11.9)	0.3	2.29 (0.35–16.5)	0.4
BMI ≤21.4 kg/m^2	5.66 (1.24–32.4)	0.0245	–	–
Previous exacerbations twice or more in last year*	3.73 (0.74–20.8)	0.1	1.52 (0.24–8.94)	0.6
mMRC scale ≥2 grades	0.31 (0.04–1.95)	0.2	0.83 (0.10–5.96)	0.8
Total CAT score ≥10 points	1.35 (0.31–5.90)	0.7	1.00 (0.17–5.76)	1.0
GERD, yes	10.2 (1.06–130)	0.0440	14.5 (1.68–197)	0.0139
Duration of COPD ≥4 years	–	–	2.19 (0.43–12.8)	0.3
Regular users of ICS, yes**	8.12 (1.31–68.4)	0.0236	6.92 (1.14–48.9)	0.0356
FEV1 predicted <50%	16.6 (3.37–115)	0.0003	8.69 (1.68–57.1)	0.0095

Notes:

* OR (95% CI) of previous exacerbations once or more in the last year to future exacerbation once or more and twice or more 3.37 (0.64–18.5, P<0.05) and 1.40 (0.42–28.0, P<0.05), respectively, by multivariate analysis adjusted for age, BMI, mMRC scale, total CAT score, presence of GERD, duration of COPD, and regular use of ICS.

** OR (95% CI) of inoculation of pneumococcal vaccination to future exacerbation once or more and twice or more 1.56 (0.22–10.1, P<0.05) and 2.23 (0.41–11.8, P<0.05), respectively, by multivariate analysis adjusted for age, BMI, previous exacerbations twice or more, mMRC scale, total CAT score, presence of GERD, and duration of COPD.

Abbreviations: BMI, body mass index; CAT, COPD Assessment Test; CI, confidence interval; FEV₁, forced expiratory volume in 1 second; GERD, gastroesophageal reflux disease; ICS, inhaled corticosteroids; mMRC, modified Medical Research Council; OR, odds ratio.