Terms and Definitions Used to Describe Recurrence, Treatment Failure and Recovery of Acute Exacerbations of COPD: A Systematic Review of Observational Studies

Figures & data

Table 1 Characteristics of Studies Observing Relapse Events Following an Exacerbation

Author, Year	Relapse Definition	N^a	Country, Study	Study Setting	Time Point From Which Relapse is Measured	Proportion Relapsed [Time Frame, (Days)]^b
Aaron 2002^Citation30	Re-visit to ED or other physician for worsening symptoms	66	Canada	ED	Initial ED visit	26% (10)
Adams 2000^Citation31	Return visit to ED	362 visits	USA	ED	Initial ED visit	22% (14)
Cydulka 2003^Citation27	Patient report of same or worsening condition since last ED visit	185	USA and Canada, MARC	ED	Initial ED visit	14% (14)
Domenech 2013^Citation32	New exacerbation by pneumococci with different serotype than index exacerbation	116 exacerbations	Spain	Hospital	Not reported	69.8%^c
Durmaz 2015^Citation34	Symptoms within 5 days of index exacerbation	196	Turkey	ED	Initial ED visit	27.6% (14)
Durmaz 2015^Citation33	Re-visit to ED for worsening symptoms	92	Turkey	ED	Initial ED visit	30% (14)
Hurst 2009^Citation28	Symptoms within 5 days of index exacerbation	410 exacerbations	UK, London COPD Cohort	Outpatient	Remission of symptoms	11% (5)
Kim 2004^Citation35	Re-visit to ED or clinic	140	USA and Canada, MARC	ED	Initial ED visit	17% (14)
Minov 2018^Citation36	Worsening cough, expectoration, and shortness of breath	54	Macedonia	Outpatient	Remission of symptoms	7.4% (20)
Miravitlles 2001^Citation37	Unscheduled visit leading to change in drug prescription, an ED visit, or hospital admission	2414	Spain	Primary care	Initial primary care visit	21% (1 mo)
Miravitlles 2003^Citation38	Unscheduled office visit or hospitalization for persistent or worsening symptoms	441	Spain	Outpatient clinic	Following initial exacerbation Initiation of antibiotic therapy	34% (1 mo) Mean time to relapse: 4.6 (SD 3.3)
Stiell 2018^Citation39	Return to ED for any related problem, with or without admission to hospital	1415	Canada	Hospital and ED	Unclear if hospital discharge or admission	ED: 21.8% (14 d)^d ED with admission: 8.3% (14 d)^e
Vondracek 2006^Citation40	Hospital admission, ED visit, or clinic visit	80 admissions	USA	Hospital	Discharge	28% (30)

Notes: ^aN indicates number of patients unless otherwise specified; ^bDays unless otherwise specified; ^cNot reported in Figure 1A because no time horizon included; ^dDefined as return to ED for any related problem; ^eDefined as return to ED for any related problem followed by admission to hospital.

Abbreviations: COPD, chronic obstructive pulmonary disease; d, days; ED, emergency department; MARC, Medication Adherence Research in COPD Patients; mo, months; SD, standard deviation; UK, United Kingdom; USA, United States of America.

Table 2 Characteristics of Studies Observing Recurrence or Re-Exacerbation Events Following an Exacerbation

Author, Year	Re-Exacerbation or Recurrence Definition	N^a	Country, Study	Setting	Time Point From Which Re-Exacerbation or Recurrence is Measured	Proportion with Re-Exacerbation or Recurrence [Time Frame, (Days)]^b
Bartziokas 2014^Citation41	The need for antibiotics and/or OCS, visits to ED, and/or hospitalizations	314	Greece	Hospital	Discharge^c	High uric acid 50% (3 mo), 80% (6 mo) Low uric acid 15% (3 mo), 60% (6 mo)
Bathoorn 2017^Citation42	Prescription of subsequent course of corticosteroids within 60 days of first course	1558 exacerbations	The Netherlands	Primary care	First course of prescribed corticosteroids^d	28% (60)
Chang 2014^Citation43	Re-exacerbation after symptoms from initial exacerbation returned to pre-exacerbation level	135	China	Hospital	Discharge	18.5% (56)
Cushen 2016^Citation44	Requiring antibiotics and/or steroid therapy	62	Ireland	Hospital	Discharge	14.5% (14)
Hu 2019^Citation45	Worsening respiratory symptoms for ≥2 consecutive days requiring intervention or medication changes after sustained relief from last exacerbation of ≥14 days	686	China	Hospital	Discharge	15% (30)
Hurst 2009^Citation28	New exacerbation after symptom free for 5 days within 8 weeks of previous exacerbation	410 exacerbations	UK, London COPD Cohort	Outpatient	Remission of symptoms^e	27.4% (56) Median days to re-exacerbation or recurrence: 5 [Q1, Q3: 3, 8]
Johannesdottir 2013^Citation46	Inpatient readmission or re-visit, mechanical ventilation, or simultaneous antibiotics and steroid prescription	6240 exacerbations	Denmark	Hospital	Discharge	19.7% (30) 31.6% (60) 40.1% (90) 57.4% (180)
Liu 2015^Citation47	Sustained worsening of symptoms for ≥2 days requiring visit to doctor, ED, and/or antibiotics, corticosteroids, or both	176	China	Hospital	Discharge	48.9% (90)
Perera 2007^Citation48	New exacerbation after symptom recovery from index exacerbation	73	UK, London COPD Cohort	Outpatient	Onset of index exacerbation^f	22% (50) Median days to re-exacerbation or recurrence: 9 [Q1, Q3: 4, 18]
Wang 2012^Citation49	Worsening cough, expectoration, and shortness of breath	136	China	Hospital	Discharge	7.4% (30) 25% (90) 55.6% (180) 88.2% (365)
Yount 2019^Citation50	Sustained worsening of COPD symptoms beyond normal day-to-day variations with acute onset requiring change in regular medication, admission for COPD, and/or treatment with antibiotics or corticosteroids	85	USA	Hospital inpatients and outpatients	Enrollment into the study^g	17.6% (84)

Notes: ^aN represents patients unless otherwise noted; ^bDays unless otherwise specified; ^cPatients were evaluated on admission and at discharge by the study investigators and were followed up for 1 year; ^dUnclear whether follow-up began at prescription start or end; ^eAfter 5 consecutive symptom-free days; ^fNot explicitly mentioned in article, but for other outcomes such as non-recovery the starting point is onset of index exacerbation; ^gMaximum of 3 days from start of treatment for patients recruited in outpatient setting and maximum of 6 days from treatment start for patients recruited in the inpatient setting.

Abbreviations: COPD, chronic obstructive pulmonary disease; ED, emergency department; mo, months; OCS, oral corticosteroids; Q1, quartile 1; Q3, quartile 3; UK, United Kingdom; USA, United States of America.

Table 3 Characteristics of Studies Observing Treatment Failure Following an Exacerbation

Author, Year	Treatment Failure Definition	N^a	Country, Dataset	Setting	Time Point From Which Treatment Failure is Measured	Proportion with Treatment Failure [Time Frame, (Days)]^b
Beauchesne 2008^Citation51	Prolonged use of antibiotics, ED visit, or hospitalization	1180 exacerbations	Canada	Home care program	Initiation of antibiotic treatment	29.5% (30)
Crisafulli 2016^Citation52	Need for NIMV, ICU admission, new course of antibiotics, or death	110	Spain	Hospital	Day 2 of admission	14.5% (7)
Dewan 2000^Citation53	Readmission or re-visit requiring a change of antibiotic	107	USA	Outpatient	Commencement of initial treatment	26% (28)
Garcia-Sidro2015^Citation54	Exacerbation with or without readmission, or death	106	Spain	Hospital	Discharge	36.8% (90)
Gaude 2015^Citation55	Return visit requiring change of antibiotic or hospitalization	115	India	Hospital	Discharge	34.8% (28)
Lindenauer 2010^Citation56	Mechanical ventilation after second hospital day, death during hospitalization, or readmission	79,985	USA, Premier Perspective	Hospital	Discharge	10.8% (30)
Miravitlles 2005^Citation57	Failure to return to baseline or need for new treatment or medication	1147	Spain	Primary care	Initial visit	15.1% (10)
Miravitlles 2011^Citation58	Absence of sign/symptom resolution, worsening of signs/symptoms or death	346	Spain	Outpatients	Initial visit	28.2% (30)
Miravitlles 2013^Citation59	Incomplete resolution, persistence, or worsening of symptoms requiring new course of antibiotics and/or OCS or hospitalization	260	Spain	Outpatients	Initial visit	13.5% (28) Mean days to treatment failure: 7 [SD 4.6]
Planquette 2015^Citation60	Increased mechanical ventilator support, initiation of OCS, or death	111	France	Hospital (ICU)	Admission	21.6% (2)
Rothberg 2010^Citation61	Initiation of hospital mechanical ventilation, in-hospital death, or readmission	19,608	USA, Premier Perspective	Hospital	Day 2 of admission^c, or discharge	7.7% (30)
Rothberg 2010^Citation62	Initiation of hospital mechanical ventilation, in-hospital death, or readmission	84,621	USA, Premier Perspective	Hospital	Day 2 of admission^c, or discharge	10.2% (30)

Notes: ^aN represents patients unless otherwise noted; ^bDays unless otherwise specified; ^cStarting point for treatment failure defined as initiation of mechanical ventilation at day 2 of hospital admission.

Abbreviations: ICU, intensive care unit; NIMV, non-invasive mechanical ventilation; OCS, oral corticosteroids; SD, standard deviation; USA, United States of America.

Table 4 Characteristics of Studies Observing Non-Recovery or Time to Recovery Events Following an Exacerbation

Author, Year	Non-Recovery or Recovery Definition	N^a	Country/Study	Setting	Time Point From Which Non-Recovery is Measured	Proportion Not Recovered [Time Frame, (Days)]^b
Anzueto 2012^Citation63	Non-Recovery: Acute increase in 1 or more symptoms (dyspnea, sputum volume, sputum purulence) Recovery: Clinician assessment that patient is free of symptoms	40,435	GIANT^c	Not reported	Unclear	15% not recovered (8) Mean time to recovery among those with late and early recovery: 10.2 [SD 2.5]; 3.1 [SD 0.9]^d
Cydulka 2003^Citation27	Non-Recovery: Symptoms at telephone interview for ≥24 hours or condition same or worsened since last ED visit	186	MARC^e	ED	Presenting to ED	40% not recovered (14)
Donaldson 2003^Citation10	Non-Recovery: PEF or symptom score below baseline with symptoms recorded on diary card	1111 exacerbations	UK, London COPD Cohort	Outpatient	Onset of index exacerbation	Symptom recovery: 9.6% not recovered (35) PEF recovery: 11.6% not recovered (35)
Donaldson 2015^Citation72	Non-Recovery: Worsening symptoms or change in medication required or PEF below baseline Time to recovery: First of 2 consecutive symptom-free days or PEF returned to baseline	3087 exacerbations	UK, London COPD Cohort	Outpatient	Onset of index exacerbation	Symptom recovery: 3.1% not recovered (99 d) Days to recovery: Mean: 14.7 [SD: 14.2] Median: 10 [Q1, Q3: 6, 18] PEF recovery: 7.3% not recovered (99) Days to recovery: Mean: 10.3 [SD 15] Median: 5 [Q1, Q3: 0, 14] (0, 14 d)
Perera 2007^Citation48	Non-Recovery: Total symptom score not returned to baseline Time to recovery: time from onset of exacerbation to day on which a 3-day moving average of symptom score returned to baseline	73	UK, London COPD Cohort	Outpatient	Onset of index exacerbation	23% not recovered (35) Median days to recovery: 9 [Q1, Q3: 4, 18]
Seemungal 2000^Citation71	Non-Recovery: PEF or symptoms not returning to baseline Time to recovery: symptoms or PEF returned to baseline	504 exacerbations	UK, London COPD Cohort	Outpatient	Onset of index exacerbation	Symptom recovery: 13.9% (35) 9.1% (91) Median days to recovery: 7 (Q1, Q3: 4, 14) PEF recovery: 24.8% (35) 19.8% (91) Median days to recovery: 6 (Q1, Q3; 1, 14)
Tsai 2009^Citation70	Non-Recovery: Patient report of COPD status as much worse, a little worse, or about the same during telephone interview	330	MARC^e	ED	Presenting to ED	18% (14)
Aaron 2012^Citation73	Time to Recovery: first date of 5 consecutive days where self-reported symptoms return to usual baseline	1995 exacerbations	UK, London COPD Cohort	Outpatient	Onset of index exacerbation	Sudden onset of index exacerbation: Median days to recovery: 11 [Q1, Q3: 6, 22]^f Gradual onset of index exacerbation: Median days to recovery: 13 [Q1, Q3: 7, 29]^g
Farias 2019^Citation69	Treated recovery time: time elapsed between medication start date and exacerbation end date Exacerbation recovery time: time elapsed between exacerbation start and end date	68 exacerbations	Canada	Outpatient	Initial study visit	Mean days of treated recovery time: 10.4 [SD 10.5] Mean days of exacerbation recovery time: 13.3 [SD 13.3]
Hurst 2009^Citation28	Time to Recovery: number of days from exacerbation onset to first of 2 consecutive symptom-free days	410 exacerbations	UK, London COPD Cohort	Outpatient	Onset of index exacerbation	Median time to recovery: 5 [Q1, Q3: 3, 8]
Liang 2017^Citation66	Time to Recovery: self-reported recovery period	890	China	Cohort study	Following last COPD exacerbation	Mean days to recovery among patients with bronchitis: 19 [SD: 16.2] Mean days to recovery among patients without bronchitis: 15.2 [SD 14.7]
Mackay 2014^Citation67	Time to Recovery: number of days that major lower airway symptoms (dyspnea, sputum volume, sputum purulence) were still being recorded	128 exacerbations	UK, London COPD Cohort	Outpatient	Onset of exacerbation	Median days to recovery: 7 [Q1, Q3: 0, 12]
Minov 2018^Citation36	Time to Recovery: Resolution of cardinal symptoms or return to baseline severity	54	Macedonia	Outpatient	Onset of index exacerbation	Mean days to recovery: 5.2 [SD 1.1]
Miravitlles 2003^Citation38	Time to Recovery: number of days required for symptoms to return to baseline	441	Spain	Outpatient clinic	Following initial exacerbation Initiation of antibiotic therapy	Mean days to recovery: 4.6 [SD 3.3]
Miravitlles 2005^Citation57	Time to Recovery: number of days for symptoms to return to baseline	1147	Spain	Primary care	Onset of index exacerbation	Median: 5 days^g
Miravitlles 2009^Citation68	Time to Recovery: physician assessment of antibiotic therapy; patient reports number of days to feeling better	9225	GIANT^h	Outpatient	Initial clinic visit	Physician assessed: 6.3 [SD: 3.1] Patient report: 7.3 [SD 3.1]
Wilkinson 2004^Citation65	Time to Recovery: time for 3-day moving average of total daily symptom count to return to baseline	1099 exacerbations	UK, London COPD Cohort	Outpatient	Onset of exacerbation	Median days to recovery: 10.7 [Q1, Q3: 7, 14]

Notes: ^aN represents patients unless otherwise noted; ^bDays unless otherwise specified; ^cGIANT study, worldwide; ^dLate recovery defined as ≥8 days, early recovery defined as ≤4 days; ^eMARC study, USA and Canada; ^fSudden exacerbations had an onset of 0 days and “gradual” exacerbations had an onset of 4 days with starting point after 5 consecutive days free of symptoms; ^gNo measure of spread reported; ^hGIANT study, European.

Abbreviations: COPD, chronic obstructive pulmonary disease; ED, emergency department; MARC, Medication Adherence Research in COPD Patients; PEF, peak expiratory flow; Q1, quartile 1; Q3, quartile 3; SD, standard deviation; UK, United Kingdom.

Figure 1 PRISMA* flow diagram of included and excluded articles. *Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71.²⁶

Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; PRISMA, The Preferred Reporting Items for Systematic reviews and Meta-Analyses.

Table 5 Summary of the Four Terms Identified to Describe Subsequent AECOPD Events

Relapse	Typically defined as a re-visit to the emergency department or other physician visit for worsening symptoms within 5–30 days of presentation to clinician
Re-exacerbation/recurrence	Subsequent exacerbation typically within 1–6 months from hospital discharge or following X consecutive days free of recorded symptoms
Treatment failure	Definition typically included death and/or was related to in-hospital failure. Often overlapping with relapse and non-recovery terms/definitions. Predominantly measured in hospital settings within 1 month of either initial AECOPD visit or discharge
Non-recovery/time to recovery	(Includes late recovery, non-recovery and ongoing AECOPD.) Non-recovery typically defined using daily diaries as not returning to baseline within 30–90 days from onset of initial AECOPD. Time to recovery often defined based on self-reported symptom recording, and often specified a return to baseline

Abbreviation: AECOPD, acute exacerbation of chronic obstructive pulmonary disease.

Figure 2 Reported proportions of patients with (A) relapse event, (B) recurrence/re-exacerbation event, (C) treatment/clinical failure, and (D) non-recovery, by starting point of observation time frame. (A) Includes estimates from 12 observational studies reporting outcomes using a relapse term and definition. Defined as a re-visit to the emergency department or physician for a worsening of symptoms but typically not differentiated from “recurrence” or “re-exacerbation”. One study used two definitions for relapse at 14 days and thus has two data points. Domenach (2013) is not plotted because the study did not report a timeframe. (B) Includes estimates from 10 observational studies reporting outcomes using a recurrence/re-exacerbation term and definition. Mostly defined as a “re-exacerbation” (n = 3), a prescription course of corticosteroids or antibiotics (n = 3), or as a composite outcome (n = 3) including death or AECOPD treatment and/or remission. Some studies (n = 4) required recovery of initial AECOPD prior to subsequent AECOPD. Two studies have data points at several time horizons (30, 90, 180, and 365 days from Wang et al [2012] and 30, 60, 90, and 180 days from Johannesdottir et al [2013]). Bartziokas et al (2014) reported proportion at 3 months and 6 months in “low uric acid” and “high uric acid” groups, but not overall, and therefore these data points are not presented in the figure. (C) Includes estimates from 12 observational studies reporting outcomes using a treatment failure term and definition with some definitions similar to relapse and non-recovery. Often included death (n = 7) and/or was related to in-hospital treatment failure (n = 6). (D) Includes estimates from seven observational studies reporting outcomes using a non-recovery term and definition. Some studies (n = 2) reported estimates at multiple time points and using different methods of measurement (eg, non-recovery ascertained daily symptom score reports or spirometry). Most were from the London COPD cohort. Two studies have multiple data points due to different measurement methods (symptom report and peak expiratory flow, Donaldson [2015] and Seemungal [2000]) over several time horizons (Seemungal [2000] at 35 days and 91 days).Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; ED, emergency department.

Aaron SD, Vandemheen KL, Clinch JJ, et al. Measurement of short-term changes in dyspnea and disease-specific quality of life following an acute COPD exacerbation. Chest. 2002;121(3):688–696. doi:10.1378/chest.121.3.688

 PubMed Web of Science ®Google Scholar

Adams SG, Melo J, Luther M, Anzueto A. Antibiotics are associated with lower relapse rates in outpatients with acute exacerbations of COPD. Chest. 2000;117(5):1345–1352. doi:10.1378/chest.117.5.1345

 PubMed Web of Science ®Google Scholar

Cydulka RK, Rowe BH, Clark S, Emerman CL, Camargo CA Jr. Emergency department management of acute exacerbations of chronic obstructive pulmonary disease in the elderly: the Multicenter Airway Research Collaboration. J Am Geriatr Soc. 2003;51(7):908–916. doi:10.1046/j.1365-2389.2003.51302.x

 PubMed Web of Science ®Google Scholar

Domenech A, Ardanuy C, Pallares R, et al. Some pneumococcal serotypes are more frequently associated with relapses of acute exacerbations in COPD patients. PLoS One. 2013;8(3):e59027. doi:10.1371/journal.pone.0059027

 PubMed Web of Science ®Google Scholar

Durmaz D, Goksu E, Yildiz G, et al. The factors influencing relapse in patients presenting to the emergency department with COPD exacerbation. Turk J Emerg Med. 2015;15(2):59–63. doi:10.5505/1304.7361.2014.37791

 PubMedGoogle Scholar

Durmaz D, Goksu E, Kilic T, Ozbudak O, Eray O. The role of nitric oxide in predicting revisit of patients with exacerbated chronic obstructive pulmonary disease. J Emerg Med. 2015;48(2):247–253. doi:10.1016/j.jemermed.2014.06.026

 PubMed Web of Science ®Google Scholar

Hurst JR, Donaldson GC, Quint JK, Goldring JJ, Baghai-Ravary R, Wedzicha JA. Temporal clustering of exacerbations in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;179(5):369–374. doi:10.1164/rccm.200807-1067OC

 PubMed Web of Science ®Google Scholar

Kim S, Emerman CL, Cydulka RK, Rowe BH, Clark S, Camargo CA. Prospective multicenter study of relapse following emergency department treatment of COPD exacerbation. Chest. 2004;125(2):473–481. doi:10.1378/chest.125.2.473

 PubMed Web of Science ®Google Scholar

Minov J, Stoleski S, Petrova T, Vasilevska K, Mijakoski D, Bislimovska-Karadzhinska J. Moxifloxacin in the outpatient treatment of moderate exacerbations of chronic obstructive pulmonary disease. Open Access Macedon J Med Sci. 2018;6(11):2017–2022. doi:10.3889/oamjms.2018.445

 PubMedGoogle Scholar

Miravitlles M, Murio C, Guerrero T. Factors associated with relapse after ambulatory treatment of acute exacerbations of chronic bronchitis. DAFNE Study Group. Eur Respir J. 2001;17(5):928–933. doi:10.1183/09031936.01.17509280

 PubMed Web of Science ®Google Scholar

Miravitlles M, Zalacain R, Murio C, et al. Speed of recovery from acute exacerbations of chronic obstructive pulmonary disease after treatment with antimicrobials: results of a two-year study. Clin Drug Investig. 2003;23(7):439–450. doi:10.2165/00044011-200323070-00003

 PubMed Web of Science ®Google Scholar

Stiell IG, Perry JJ, Clement CM, et al. Clinical validation of a risk scale for serious outcomes among patients with chronic obstructive pulmonary disease managed in the emergency department. CMAJ. 2018;190(48):E1406–E1413. doi:10.1503/cmaj.180232

 PubMed Web of Science ®Google Scholar

Vondracek SF, Hemstreet BA. Retrospective evaluation of systemic corticosteroids for the management of acute exacerbations of chronic obstructive pulmonary disease. Am J Health Sys Pharm. 2006;63(7):645–652. doi:10.2146/ajhp050316

 PubMed Web of Science ®Google Scholar

Bartziokas K, Papaioannou AI, Loukides S, et al. Serum uric acid as a predictor of mortality and future exacerbations of COPD. Eur Respir J. 2014;43(1):43–53. doi:10.1183/09031936.00209212

 PubMed Web of Science ®Google Scholar

Bathoorn E, Groenhof F, Hendrix R, et al. Real-life data on antibiotic prescription and sputum culture diagnostics in acute exacerbations of COPD in primary care. Int J Chron Obstruct Pulmon Dis. 2017;12:285–290. doi:10.2147/COPD.S120510

 PubMed Web of Science ®Google Scholar

Chang C, Yao W. Time course of inflammation resolution in patients with frequent exacerbations of chronic obstructive pulmonary disease. Med Sci Monit. 2014;20:311–320. doi:10.12659/MSM.889828

 PubMed Web of Science ®Google Scholar

Cushen B, McCormack N, Hennigan K, Sulaiman I, Costello RW, Deering B. A pilot study to monitor changes in spirometry and lung volume, following an exacerbation of Chronic Obstructive Pulmonary Disease (COPD), as part of a supported discharge program. Respir Med. 2016;119:55–62. doi:10.1016/j.rmed.2016.08.019

 PubMed Web of Science ®Google Scholar

Hu WP, Lhamo T, Liu D, et al. Development of a nomogram to predict the risk of 30-day re-exacerbation for patients hospitalized for acute exacerbation of chronic obstructive pulmonary disease. COPD. 2019;16(2):160–167. doi:10.1080/15412555.2019.1606187

 PubMedGoogle Scholar

Johannesdottir SA, Christiansen CF, Johansen MB, et al. Hospitalization with acute exacerbation of chronic obstructive pulmonary disease and associated health resource utilization: a population-based Danish cohort study. J Med Econ. 2013;16(7):897–906. doi:10.3111/13696998.2013.800525

 PubMedGoogle Scholar

Liu D, Peng SH, Zhang J, Bai SH, Liu HX, Qu JM. Prediction of short term re-exacerbation in patients with acute exacerbation of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2015;10:1265–1273. doi:10.2147/COPD.S83378

 PubMed Web of Science ®Google Scholar

Perera WR, Hurst JR, Wilkinson TM, et al. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J. 2007;29(3):527–534. doi:10.1183/09031936.00092506

 PubMed Web of Science ®Google Scholar

Wang L, Zang XY, Zhang Q, Liu SY, Shen YH, Zhao Y. Study on factors influencing recrudescent time of postdischarge patients with chronic obstructive pulmonary disease. J Clin Nurs. 2012;21(11–12):1507–1514. doi:10.1111/j.1365-2702.2011.03899.x

 PubMed Web of Science ®Google Scholar

Yount SE, Atwood C, Donohue J, et al. Responsiveness of PROMIS(R) to change in chronic obstructive pulmonary disease. J Patient Rep Outcomes. 2019;3(1):65. doi:10.1186/s41687-019-0155-9

 PubMedGoogle Scholar

Beauchesne MF, Julien M, Julien LA, et al. Antibiotics used in the ambulatory management of acute COPD exacerbations. Int J Chron Obstruct Pulmon Dis. 2008;3(2):319–322. doi:10.2147/COPD.S2624

 PubMedGoogle Scholar

Crisafulli E, Torres A, Huerta A, et al. Predicting in-hospital treatment failure (</= 7 days) in patients with COPD exacerbation using antibiotics and systemic steroids. COPD. 2016;13(1):82–92. doi:10.3109/15412555.2015.1057276

 PubMedGoogle Scholar

Dewan NA, Rafique S, Kanwar B, et al. Acute exacerbation of COPD: factors associated with poor treatment outcome. Chest. 2000;117(3):662–671. doi:10.1378/chest.117.3.662

 PubMed Web of Science ®Google Scholar

Garcia-Sidro P, Naval E, Martinez Rivera C, et al. The CAT (COPD Assessment Test) questionnaire as a predictor of the evolution of severe COPD exacerbations. Respir Med. 2015;109(12):1546–1552. doi:10.1016/j.rmed.2015.10.011

 PubMed Web of Science ®Google Scholar

Gaude GS, Rajesh BP, Chaudhury A, Hattiholi J. Outcomes associated with acute exacerbations of chronic obstructive pulmonary disorder requiring hospitalization. Lung India. 2015;32(5):465–472. doi:10.4103/0970-2113.164150

 PubMedGoogle Scholar

Lindenauer PK, Pekow PS, Lahti MC, Lee Y, Benjamin EM, Rothberg MB. Association of corticosteroid dose and route of administration with risk of treatment failure in acute exacerbation of chronic obstructive pulmonary disease. JAMA. 2010;303(23):2359–2367. doi:10.1001/jama.2010.796

 PubMed Web of Science ®Google Scholar

Miravitlles M, Llor C, Naberan K, Cots JM, Molina J; EFEMAP study group. Group Es. Variables associated with recovery from acute exacerbations of chronic bronchitis and chronic obstructive pulmonary disease. Respir Med. 2005;99(8):955–965. doi:10.1016/j.rmed.2005.01.013

 PubMed Web of Science ®Google Scholar

Miravitlles M, Izquierdo I, Herrejon A, et al. COPD severity score as a predictor of failure in exacerbations of COPD. The ESFERA study. Respir Med. 2011;105(5):740–747. doi:10.1016/j.rmed.2010.12.020

 PubMed Web of Science ®Google Scholar

Miravitlles M, Garcia-Polo C, Domenech A, Villegas G, Conget F, de la Roza C. Clinical outcomes and cost analysis of exacerbations in chronic obstructive pulmonary disease. Lung. 2013;191(5):523–530. doi:10.1007/s00408-013-9487-z

 PubMed Web of Science ®Google Scholar

Planquette B, Peron J, Dubuisson E, et al. Antibiotics against Pseudomonas aeruginosa for COPD exacerbation in ICU: a 10-year retrospective study. Int J Chron Obstruct Pulmon Dis. 2015;10:379–388. doi:10.2147/COPD.S71413

 PubMed Web of Science ®Google Scholar

Rothberg MB, Pekow PS, Lahti M, Brody O, Skiest DJ, Lindenauer PK. Comparative effectiveness of macrolides and quinolones for patients hospitalized with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). J Hosp Med. 2010;5(5):261–267. doi:10.1002/jhm.628

 PubMed Web of Science ®Google Scholar

Rothberg MB, Pekow PS, Lahti M, Brody O, Skiest DJ, Lindenauer PK. Antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease. JAMA. 2010;303(20):2035–2042. doi:10.1001/jama.2010.672

 PubMed Web of Science ®Google Scholar

Anzueto A, Miravitlles M, Ewig S, Legnani D, Heldner S, Stauch K. Identifying patients at risk of late recovery (>/= 8 days) from acute exacerbation of chronic bronchitis and COPD. Respir Med. 2012;106(9):1258–1267. doi:10.1016/j.rmed.2012.06.002

 PubMed Web of Science ®Google Scholar

Donaldson GC, Seemungal TA, Patel IS, Lloyd-Owen SJ, Wilkinson TM, Wedzicha JA. Longitudinal changes in the nature, severity and frequency of COPD exacerbations. Eur Respir J. 2003;22(6):931–936. doi:10.1183/09031936.03.00038303

 PubMed Web of Science ®Google Scholar

Donaldson GC, Law M, Kowlessar B, et al. Impact of prolonged exacerbation recovery in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;192(8):943–950. doi:10.1164/rccm.201412-2269OC

 PubMed Web of Science ®Google Scholar

Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161(5):1608–1613. doi:10.1164/ajrccm.161.5.9908022

 PubMed Web of Science ®Google Scholar

Tsai CL, Rowe BH, Camargo CA Jr. Factors associated with short-term recovery of health status among emergency department patients with acute exacerbations of chronic obstructive pulmonary disease. Qual Life Res. 2009;18(2):191–199. doi:10.1007/s11136-008-9437-z

 PubMed Web of Science ®Google Scholar

Aaron SD, Donaldson GC, Whitmore GA, Hurst JR, Ramsay T, Wedzicha JA. Time course and pattern of COPD exacerbation onset. Thorax. 2012;67(3):238–243. doi:10.1136/thoraxjnl-2011-200768

 PubMed Web of Science ®Google Scholar

Farias R, Sedeno M, Beaucage D, et al. Innovating the treatment of COPD exacerbations: a phone interactive telesystem to increase COPD Action Plan adherence. BMJ Open Respir Res. 2019;6(1):e000379. doi:10.1136/bmjresp-2018-000379

 PubMed Web of Science ®Google Scholar

Liang Y, Chen Y, Wu R, et al. Chronic bronchitis is associated with severe exacerbation and prolonged recovery period in Chinese patients with COPD: a multicenter cross-sectional study. J Thorac Dis. 2017;9(12):5120–5130. doi:10.21037/jtd.2017.11.54

 PubMed Web of Science ®Google Scholar

Mackay AJ, Donaldson GC, Patel AR, Singh R, Kowlessar B, Wedzicha JA. Detection and severity grading of COPD exacerbations using the exacerbations of chronic pulmonary disease tool (EXACT). Eur Respir J. 2014;43(3):735–744. doi:10.1183/09031936.00110913

 PubMed Web of Science ®Google Scholar

Miravitlles M, Anzueto A, Ewig S, Legnani D, Stauch K. Characterisation of exacerbations of chronic bronchitis and COPD in Europe: the GIANT study. Ther Adv Respir Dis. 2009;3(6):267–277. doi:10.1177/1753465809352791

 PubMedGoogle Scholar

Wilkinson TM, Donaldson GC, Hurst JR, Seemungal TA, Wedzicha JA. Early therapy improves outcomes of exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;169(12):1298–1303. doi:10.1164/rccm.200310-1443OC

 PubMed Web of Science ®Google Scholar

Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71

 Web of Science ®Google Scholar