Understanding low COPD exacerbation rates in Japan: a review and comparison with other countries

Figures & data

Table 1 Summary of exacerbation rates and key patient characteristics from cohort studies detailing COPD exacerbation rates in Japan^10–18

Cohort (study)	Inclusion criteria	Definition of COPD exacerbation	N	Patient baseline characteristics				Incidence of exacerbations (per person per year)a
				Age (years)a	Female (%)	GOLD stage III/IV (%)	ICS use (%)
Kyoto cohort (Takahashi et al, 2012)^Citation16	• Male patients with COPD • No exacerbation history criteria	Symptom-based (diary)	93	73	0	30/5	40.8	0.8, 1.2b
Nippon cohort (Motegi et al, 2013)^Citation12	• Patients with COPD (GOLD) • ≥40 years of age • Current or ex-smokers (≥20 pack-years) • No exacerbation history criteria	Symptom-based (diary)	183	71.4±8.7	7.1	33.9/9.8	NR	0.57
Kitano cohort (Takemura et al, 2013)^Citation18	• Patients with COPD (GOLD) • Current or ex-smokers (≥10 pack-years) • No change in medication for 3 months before study • No exacerbation history criteria	Event-based (medical records)	55	69±8	27.3	16.4/5.4	100	Baseline: 1.5±1.6; Year 4: 0.8±1.4
Hokkaido cohort (Suzuki et al, 2014)^Citation15	• Patients with COPD (GOLD) • ≥40 years of age • Current or ex-smokers (≥10 pack-years) • No exacerbation 1 month prior to study	Symptom-based and event-based	268	70±8	6	24.3/4.9	NR	0.78±1.16,c 0.24±0.47,c 0.20±0.43,c 0.13±0.28,c 0.06±0.19c
Saitama cohort (Kurashima et al, 2015)^Citation10	• Male patients with COPD • No exacerbation history criteria	Event-based	65	70.8±6.4	0	NR	50.8	0.67±0.85
CAP study (Matsunaga et al, 2015)^Citation11	• Clinical diagnosis of COPD • 40–95 years of age • No exacerbation in the 4 weeks prior to the survey	Event-based	1,168	72.1±8.3	11.4	26.0/7.7	6.8	0.53±0.87
Kurume cohort (Natori et al, 2016)^Citation13	• Patients with COPD (GOLD) • No exacerbation 4 weeks prior to study entry	Symptom-based	123	64.3, 67.8, 68.5, 70.4c	20.7, 10.5, 14.3, 0c	22.8/7.3	3.5, 15.8, 25.0, 11.1d	0.1±0.2, 0.9±0.1, 1.4±0.2, 2.1±0.4d
Keio cohort (Sato et al, 2016)^Citation14	• Patients with COPD (spirometry) • No exacerbation for ≥1 month prior to enrollment	Event-based	311	72.6±8.1	6.8	23.2/5.8	26.6, 32.8, 47.2e	0.28f
Chiba cohort (Takayanagi et al, 2017)^Citation17	• Patients with COPD (ATS/ERS) • Current or ex-smokers • No exacerbation history criteria	Event-based	58	69.7±7.3	12.1	15.5/6.9	NR	0.75 (1.5±0.9/2 years)g

Notes:

a Data are presented as mean±SD (where available) unless otherwise stated;

b data represent patients with high IgG (0.8 events/year) and normal IgG (1.2 events/year);

c data represent symptom-based due to subjective complaints (0.78±1.16), symptom-based by strict definition, confirmed by CRC (0.24±0.47), event-based due to requiring prescription change (0.20±0.43), event-based due to requiring antibiotic treatment (0.13±0.28), and event-based due to requiring hospital admission (0.06±0.19);

d data represent GOLD stages I–IV;

e data represent nonexacerbators, mild exacerbators, and moderate/severe exacerbators;

f moderate or severe exacerbations;

g one-year data calculated from 2-year data.

Abbreviations: ATS/ERS, American Thoracic Society/European Respiratory Society recommendations; CRC, Clinical Research Coordinator; GOLD, Global initiative for chronic Obstructive Lung Disease; GORD, gastro-esophageal reflux disease; ICS, inhaled corticosteroid; NR, not reported.

Table 2 Summary of exacerbation rates and key patient characteristics from RCTs detailing COPD exacerbation rates in Japan^7,9,19–21

Study	Inclusion criteria relating to disease severity and exacerbation history	Definition of COPD exacerbation	Interventions	N	Patient baseline characteristics				Incidence of exacerbations (per person per year)a
					Age (years)a	Female (%)	GOLD stage III/IV (%)	ICS use (%)
Furumoto et al (2008)^Citation20	• Patients with chronic lung disease including COPD, with sequelae of pulmonary tuberculosis • Previous exacerbations	Symptom-based	PV+IV IV alone	87 80	69.0±9.0	36.5	NR	NR	0.53 (COPD population; n=55)
Sasaki et al (2009)^Citation21	• Patients with COPD • No exacerbation criteria for inclusion or exclusion	Symptom-based	Lansoprazole 15 mg/day	50	74.9±8.9	6	34/6	26.0	0.34±0.72
			Placebo	50	74.8±7.5	4	40/2	24.0	1.18±1.4
Fukuchi et al (2011)^Citation7	• Patients with COPD • Post-FEV1% pred: ≤70% • Post-FEV1/FVC: ≤70% • No exacerbation 4 weeks before screening	Symptom-based	TIO	50	66.9±6.0	8	48/6	26.0	0.37 (95% CI: 0.26–0.51)
			Placebo	50	68.0±5.5	4	56/0	24.0	0.61 (95% CI: 0.46–0.81)
Fukuchi et al (2016)^Citation19	• Patients with COPD • Post-FEV1% pred: <80% • Post-FEV1/FVC: <70% • ≥1 exacerbations in the previous year • No exacerbation 7 days prior to drug administration	Symptom-based	Lysozyme 270 mg/day	202	68.8±9.3	9.4	36.1/5.0	8.4	1.4±1.5
			Placebo	204	70.3±7.2	8.8	29.4/5.4	7.4	1.2±1.4
Jones et al (2016)^Citation9	• Patients with COPD	Event-based, symptom-based	FP/SAL TIO	405	68.3±7.0	5	NR	NR	1.79 (95% CI: 1.56–2.05) (EXACT criteria) 0.33 (0.24–0.44) (physician reported)

Notes:

a Data are presented as mean±SD unless otherwise stated. TIO, tiotropium 18 µg once daily.

Abbreviations: EXACT, Exacerbations of Chronic Pulmonary Disease Tool; FP/SAL, fluticasone propionate/salmeterol 250/50 µg twice daily; GOLD, Global initiative for chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; IV, influenza vaccine; pred, predicted; PV, pneumococcal vaccine; RCT, randomized controlled trial.

Figure 1 Exacerbations in the (A) UPLIFT study⁷ and (B) ACCESS study.³⁰

Abbreviation: CVD, cardiovascular disease.

Table S1 Summary of key study design information from cohort studies detailing COPD exacerbation rates in Japan^1–9

Study	Study design	Study center(s), recruitment period	Inclusion criteria	Definitions of COPD exacerbation
Kyoto cohort (Takahashi et al, 2012)^Citation1	Prospective cohort study	• Kyoto University Hospital • September 2006–August 2008	• Male patients with COPD • No exacerbation history criteria	Prospectively identified using diary cards, based on an increase in any two major symptoms (dyspnea, sputum purulence, and sputum quantity) or an increase in one major and one minor symptom (wheeze, sore throat, cough, and nasal congestion/discharge) for at least 2 consecutive days
Nippon cohort (Motegi et al, 2013)^Citation2	Prospective cohort study	• Nippon Medical School Respiratory Care Clinic • April–October 2007	• Patients with COPD (GOLD) • ≥40 years of age • Current or ex-smokers (≥20 pack-years) • No exacerbation history criteria	Onset or worsening of more than two symptoms (dyspnea, sputum purulence or volume, cough, or wheeze) for more than 2 consecutive days
Kitano cohort (Takemura et al, 2013)^Citation3	Prospective, pre–post, nonequivalent group study	• Kitano Hospital Medical Research Institute • November 2006–December 2010	• Patients with COPD (GOLD) • Current or ex-smokers (≥10 pack-years) • No change in medication for 3 months before study • No exacerbation history criteria	Symptomatic deterioration (dyspnea, cough, sputum purulence/volume, or wheeze) that required treatment with oral corticosteroids and/or antibiotics or hospitalization
Hokkaido cohort (Suzuki et al, 2014)^Citation4	Prospective, 5-year follow-up, observational study	• Hokkaido University Hospital • May 2003–May 2005	• Patients with COPD (GOLD) • ≥40 years of age • Current or ex-smokers (≥10 pack-years) • No exacerbation 1 month prior to study	Symptom definition: worsening or new onset of either two major symptoms or one major and one minor symptom
Saitama cohort (Kurashima et al, 2015)^Citation5	Observational study conducted to evaluate airway structure and exacerbation	• Saitama Cardiovascular and Respiratory Center • March–October 2013	• Male patients with COPD • No exacerbation history criteria	Respiratory exacerbations requiring treatment with antibiotics and/or steroid
CAP study (Matsunaga et al, 2015)^Citation6	Cross-sectional study	• Multicenter study in 15 primary or secondary care facilities in Japan	• Clinical diagnosis of COPD • 40–95 years of age • No exacerbation in the 4 weeks prior to the survey	An acute event characterized by a worsening of respiratory symptoms that was beyond normal day-to-day variations and led to a change in medication (identified using medical records)
Kurume cohort (Natori et al, 2016)^Citation7	A 52-week prospective observational study	• Kurume University and Chikugo City Hospital	• Patients with COPD (GOLD) • No exacerbation 4 weeks prior to study entry	Increased cough and sputum production, a change in sputum color, and worsening of dyspnea from a stable state and beyond normal day-to-day variations
Keio cohort (Sato et al, 2016)^Citation8	Prospective observational cohort study	• Keio University and affiliated Hospitals • April 2010–December 2012	• Patients with COPD (spirometry) • No exacerbation for ≥1 month prior to enrollment	Moderate COPD: requirement for treatment with systemic corticosteroids/antibiotics/both. Severe COPD: requiring hospitalization and emergency admission for >24 hours
Chiba cohort (Takayanagi et al, 2017)^Citation9	Prospective, 2-year, observational study	• Chiba University Hospital • May 2012–July 2014	• Patients with COPD (ATS/ERS) • Current or ex-smokers • No exacerbation history criteria	Deterioration of COPD that requires antibiotics and/or systemic steroid use

Note: All data reported as mean±SD unless otherwise stated.

Abbreviations: ATS/ERS, American Thoracic Society/European Respiratory Society recommendations; GOLD, Global initiative for chronic Obstructive Lung Disease.

Table S2 Summary of key study design information from RCTs detailing COPD exacerbation rates in Japan^10–14

Study	Study characteristics	Study center(s), recruitment period	Inclusion criteria	Definitions of COPD exacerbation
Furumoto et al (2008)^Citation10	Open-label, randomized, controlled study in patients with chronic lung disease	• Thirteen hospitals in Kyushu and Okinawa district • November 2001–April 2002	• Patients with chronic lung disease including COPD, sequelae of pulmonary tuberculosis • Previous exacerbations	Two of the three defined respiratory symptoms existed or when one of these and one additional symptom, such as a fever without any other causes or increased cough, was present
Sasaki et al (2009)^Citation11	Randomized, 12-month, observer-blind, controlled trial	• One University Hospital and three city hospitals in Miyagi prefecture • October 2005–March 2007	• Patients with COPD • No exacerbation criteria for inclusion or exclusion	Acute and sustained worsening of COPD symptoms requiring changes to regular treatment
Fukuchi et al (2011)^Citation12	Randomized, double blinded, placebo controlled study (UPLIFT)	• Multicenter study	• Patients with COPD • Age ≥40 years • Post-FEV1% pred: ≤70% • Post-FEV1/FVC: ≤70% • Smoking history ≥10 pack-years • No exacerbation 4 weeks before screening	An increase in or the new onset of more than one respiratory symptom (cough, sputum, sputum purulence, wheezing, or dyspnea) lasting 3 days or more and requiring treatment with an antibiotic or a systemic corticosteroid
Fukuchi et al (2016)^Citation13	Randomized, double-blind, placebo-controlled parallel trial	• Multicenter study across 47 medical institutions in Japan • August 2012–January 2015	• Patients with COPD • Age: ≥20 to <85 years • Post-FEV1% pred: <80% • Post-FEV1/FVC: <70% • ≥1 exacerbations in the previous year • No exacerbation 7 days prior to drug administration	Worsening of more than one symptom of COPD (cough, sputum volume, purulent sputum, or breathlessness) leading to a change in medication
Jones et al (2016)^Citation14	Randomized, controlled, 24-week study assessing exacerbations using EXACT and physician diagnosis (COSMOS-J study)	• Multicenter study • February 2013–September 2015	• Patients with COPD (GOLD) • Age 40–80 years • Post-FEV1/FVC: <70% • Current or ex-smokers (>10 pack-years)	Physician diagnosis of exacerbation and evaluation of EXACT diary

Note: All data reported as mean±SD unless otherwise stated.

Abbreviations: EXACT, Exacerbations of Chronic Pulmonary Disease Tool; GOLD, Global initiative for chronic Obstructive Lung Disease; pred, predicted.

KurashimaKTakakuYHoshiTLobe-based computed tomography assessment of airway diameter, airway or vessel number, and emphysema extent in relation to the clinical outcomes of COPDInt J Chron Obstruct Pulmon Dis2015101027103326082626

 PubMed Web of Science ®Google Scholar

TakemuraMMitsuiKIdoMEffect of a network system for providing proper inhalation technique by community pharmacists on clinical outcomes in COPD patientsInt J Chron Obstruct Pulmon Dis2013823924423696699

 PubMed Web of Science ®Google Scholar

TakahashiTMuroSTanabeNRelationship between periodontitis-related antibody and frequent exacerbations in chronic obstructive pulmonary diseasePLoS One201277e4057022792372

 PubMed Web of Science ®Google Scholar

MotegiTJonesRCIshiiTA comparison of three multidimensional indices of COPD severity as predictors of future exacerbationsInt J Chron Obstruct Pulmon Dis2013825927123754870

 PubMed Web of Science ®Google Scholar

SuzukiMMakitaHItoYMClinical features and determinants of COPD exacerbation in the Hokkaido COPD cohort studyEur Respir J20144351289129724232696

 PubMed Web of Science ®Google Scholar

MatsunagaKHayataAAkamatsuKStratifying the risk of COPD exacerbation using the modified Medical Research Council scale: a multi-center cross-sectional CAP studyRespir Investig20155328285

 Google Scholar

NatoriHKawayamaTSuetomoMEvaluation of the Modified Medical Research Council Dyspnea Scale for predicting hospitalization and exacerbation in Japanese patients with chronic obstructive pulmonary diseaseIntern Med2016551152426726080

 PubMed Web of Science ®Google Scholar

SatoMChubachiSSasakiMImpact of mild exacerbation on COPD symptoms in a Japanese cohortInt J Chron Obstruct Pulmon Dis2016111269127827354785

 PubMed Web of Science ®Google Scholar

TakayanagiSKawataNTadaYLongitudinal changes in structural abnormalities using MDCT in COPD: do the CT measurements of airway wall thickness and small pulmonary vessels change in parallel with emphysematous progression?Int J Chron Obstruct Pulmon Dis20171255156028243075

 PubMed Web of Science ®Google Scholar

FukuchiYFernandezLKuoHPEfficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trialRespirology201116582583521539680

 PubMed Web of Science ®Google Scholar

JonesPKatoMFujimotoKLATE-BREAKING ABSTRACT: large differences in rate of reported and unreported COPD exacerbations in Japanese patientsEur Respir J201648A635

 Web of Science ®Google Scholar

FukuchiYTatsumiKInoueHPrevention of COPD exacerbation by lysozyme: a double-blind, randomized, placebo-controlled studyInt J Chron Obstruct Pulmon Dis20161183183827143873

 PubMed Web of Science ®Google Scholar

SasakiTNakayamaKYasudaHA randomized, single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patientsJ Am Geriatr Soc20095781453145719515110

 PubMed Web of Science ®Google Scholar

FurumotoAOhkusaYChenMAdditive effect of pneumococcal vaccine and influenza vaccine on acute exacerbation in patients with chronic lung diseaseVaccine200826334284428918585831

 PubMed Web of Science ®Google Scholar

JonesPWMullerovaHAgustiACardiovascular disease does not predict exacerbation rate or mortality in COPDAm J Respir Crit Care Med2017

 Google Scholar

TakahashiTMuroSTanabeNRelationship between periodontitis-related antibody and frequent exacerbations in chronic obstructive pulmonary diseasePLoS One201277e4057022792372

 PubMed Web of Science ®Google Scholar

TakayanagiSKawataNTadaYLongitudinal changes in structural abnormalities using MDCT in COPD: do the CT measurements of airway wall thickness and small pulmonary vessels change in parallel with emphysematous progression?Int J Chron Obstruct Pulmon Dis20171255156028243075

 PubMed Web of Science ®Google Scholar

MotegiTJonesRCIshiiTA comparison of three multidimensional indices of COPD severity as predictors of future exacerbationsInt J Chron Obstruct Pulmon Dis2013825927123754870

 PubMed Web of Science ®Google Scholar

TakemuraMMitsuiKIdoMEffect of a network system for providing proper inhalation technique by community pharmacists on clinical outcomes in COPD patientsInt J Chron Obstruct Pulmon Dis2013823924423696699

 PubMed Web of Science ®Google Scholar

SuzukiMMakitaHItoYMClinical features and determinants of COPD exacerbation in the Hokkaido COPD cohort studyEur Respir J20144351289129724232696

 PubMed Web of Science ®Google Scholar

KurashimaKTakakuYHoshiTLobe-based computed tomography assessment of airway diameter, airway or vessel number, and emphysema extent in relation to the clinical outcomes of COPDInt J Chron Obstruct Pulmon Dis2015101027103326082626

 PubMed Web of Science ®Google Scholar

MatsunagaKHayataAAkamatsuKStratifying the risk of COPD exacerbation using the modified Medical Research Council scale: a multicenter cross-sectional CAP studyRespir Investig20155328285

 Google Scholar

NatoriHKawayamaTSuetomoMEvaluation of the Modified Medical Research Council Dyspnea Scale for predicting hospitalization and exacerbation in Japanese patients with chronic obstructive pulmonary diseaseIntern Med2016551152426726080

 PubMed Web of Science ®Google Scholar

SatoMChubachiSSasakiMImpact of mild exacerbation on COPD symptoms in a Japanese cohortInt J Chron Obstruct Pulmon Dis2016111269127827354785

 PubMed Web of Science ®Google Scholar

FurumotoAOhkusaYChenMAdditive effect of pneumococcal vaccine and influenza vaccine on acute exacerbation in patients with chronic lung diseaseVaccine200826334284428918585831

 PubMed Web of Science ®Google Scholar

JonesPKatoMFujimotoKLATE-BREAKING ABSTRACT: large differences in rate of reported and unreported COPD exacerbations in Japanese patientsEur Respir J201648A635

 Web of Science ®Google Scholar

SasakiTNakayamaKYasudaHA randomized, single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patientsJ Am Geriatr Soc20095781453145719515110

 PubMed Web of Science ®Google Scholar

FukuchiYFernandezLKuoHPEfficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trialRespirology201116582583521539680

 PubMed Web of Science ®Google Scholar

FukuchiYTatsumiKInoueHPrevention of COPD exacerbation by lysozyme: a double-blind, randomized, placebo-controlled studyInt J Chron Obstruct Pulmon Dis20161183183827143873

 PubMed Web of Science ®Google Scholar