Table 1—

Summary details for included studies

First author [ref.]Patients nStudy designCommunity or hospitalCriteria for interventionInterventionsPrimary outcome variable
Duration of OCS therapy
 Hasegawa 920Randomised, open-labelHospitalHospitalised for acute asthma1 or 2 weeks of prednisone 0.5 mg·kg−1 after 3 days i.v. CSMorning PEF
 Jones 1044Double-blindHospitalHospitalised for acute asthma, PEF <65% pred5 or 10 days of prednisoloneWaking PEF and asthma exacerbations
Tapering of OCS
 O'Driscoll 1135Double-blindDischarge from hospitalHospitalised for acute asthma, PEF <65% predOCS 40 mg·day−1 during admission, randomised to abrupt cessation or taperingover 1–2 weeksMorning PEF
 Hatton 1235Double-blindDischarge from hospitalHospitalised for acute asthma; for discharge, PEF at least double cf. admission, variability <15% over 48 hPrednisolone 40 mg·day−1 during admission; post-discharge, 14-day reducing course starting at 40 mg·day−1, or placeboNot stated. PEF, FEV1, FVC and TLC reported
 Cydulka 1315Double-blindPost-EDED presentation; well enough for discharge40 mg·day−1 prednisone for 8 days, or tapered over 8 daysFEV1 and symptoms on day 12
 Karan 1426Randomised open-labelPost-EDED presentation; well enough for discharge40 mg·day−1 prednisone for 8 days, or tapered over 8 daysSymptoms of relapse <21 days; FEV1 day 12 and 21; adrenal suppression
Doubling ICS
 FitzGerald 15290Double-blindCommunityComposite criteria for 2 days (symptoms, PEF, healthcare utilisation)Double ICS dose for 14 days or maintain previous doseFailure to regain control (composite criteria)
 Harrison 7390Double-blindCommunityPEF ↓ by 15% or symptom score ↑ by 1 point from baseline (both permissible during run-in)Double ICS dose for 14 days or maintain previous doseNeed for OCS
 Rice-McDonald 1622Double-blind crossoverCommunityNight waking, symptoms reliever use or PEFPlacebo or double ICS or dexamethasone 0.1 mg·kg·day−1 for 7 daysTreatment failure (3 days) – symptoms, PEF, withdrawal due to asthma or adverse event
Higher dose ICS
 Foresi 17142#Double-blindCommunityPEF ↓ by 30% for 2 daysBudesonide 200 µg·day−1, plus 800 µg·day−1 or placebo for 7 daysExacerbations  =  PEF ↓ by 30% for 2 days
 Levy 18413Double-blindCommunity (primary care offices)Clinician judgement that OCS needed; post-BD PEF 60–90% best or predictedFluticasone 1 mg b.i.d. or prednisone 40 mg reducing (16 days)Treatment failure (symptoms, PEF)
 Nana 1981Double-blindPost-EDDischarged from EDBudesonide 1600 µg b.i.d. or prednisolone reducing course (7 days)FEV1 after 7 days
 FitzGerald 20175Double-blindPost-EDED presentation; well enough for discharge (FEV1 >50% pred)Budesonide 600 mcg q.i.d. or prednisolone 40 mg·day−1 (7–10 days)Relapse rate (return to ED)
 Lee-Wong 2140Double-blindPost-admissionAdmitted for asthma, PEF ≤50% predFlunisolide 2000 µg b.i.d. or prednisone 40 mg·day−1 for 7 daysNot stated. PEF, FEV1, symptom scores reported.
 Di Franco 2237Double-blindAsthma clinic≥5 days symptoms, FEV1 ≤70% pred and ≤80% recent bestFluticasone 1000 µg b.i.d. or prednisone reducing from 40 mg·day−1; usual ICS ceasedSputum eosinophil percentage at 2 weeks
Acute use of ICS in the ED
 Guttman 2360Double-blindEDED presentation; FEV1 <70% pred; ≥1 criterion for receiving i.v. steroidsTwo doses i.v. CS, plus inhaled beclomethasone 7000 µg or placebo, divided into five doses over 8 hFEV1 change over 12 h
 Afilalo 2454Double-blindEDED presentation; FEV1 40–69% predInhaled beclomethasone 5000 µg or placebo, over 4 hFEV1 (6-h study)
 Rodrigo 2594Double-blindEDED presentation; PEF and FEV1 <50% predFlunisolide 18000 µg or placebo (dosing every 10 min for 3 h)FEV1 (3-h study)
 Pansegrouw 2640Double-blindEDED presentation with “acute resistant asthma”  =  FEV1 and FVC <70% pred; misuse of β2-agonist in 2–4 h prior to presentation; lack of response to β2-agonistSingle-dose BDP 200 µg or placeboNot stated. Primary aim related to resensitisation of airways to β2-agonist (fenoterol)
 Rodrigo 27106Double-blindEDED presentation, PEF or FEV1 <50% predFluticasone 9000 µg (dosing every 10/60 for 3 h) or 500 mg i.v. hydrocortisoneFEV1 or PEF over 3 h; admission rate
Single high-dose ICS
 Leuppi 2819Double-blindExacerbations Induced by ICS reductionSymptoms + PEF >3 sd below baseline meanDouble last pre-exacerbation dose, plus budesonide 3200 µg or placeboNot stated
Increased dose of budesonide/formoterol – AMD
 Canonica 292358Open-labelCommunityStep up if 2 consecutive days of reliever ≥3 times·day−1 or night wakingBudesonide/formoterol 200/6 or 100/6 AMD or FMD; AMD included step-up to four puffs b.i.d. until symptoms resolved or 14 daysExacerbations (asthma-related SAE, hospitalisation/ED, OCS ≥5 days; asthma-related withdrawal)
 Ind 301539Open-labelCommunityStep up if 2 consecutive days of reliever ≥3 times·day−1 or night wakingBudesonide/formoterol 200/6 or 100/6 AMD or FMD; AMD included step-up to four puffs b.i.d. until symptoms resolved or for 14 daysTreatment successes (NHLBI criteria for asthma severity) and treatment failures (serious asthma exacerbation, OCS ≥5 days, hospitalisation, emergency treatment, asthma-related withdrawal)
 Leuppi 31127Open-labelCommunityStep up if 2 consecutive days of reliever ≥3 times·day−1 or night waking or PEF <80% baseline meanBudesonide/formoterol 200/6 AMD or FMD; AMD included step-up to 2–4 puffs b.i.d. for 7–14 daysTreatment successes (NHLBI criteria for asthma severity) and treatment failures (serious asthma exacerbation, OCS ≥5 days, hospitalisation, emergency treatment, asthma-related withdrawal)
 Buhl 324025Open-labelCommunityStep up if reliever ≥3 times·day−1 or night waking or PEF <80% baseline meanBudesonide/formoterol 200/6 AMD or FMD; AMD included step-up to two puffs b.i.d. for 7 days, +/- step up to four puffs b.i.d. for further 7 daysAsthma-related quality of life over 12 weeks
 Stallberg 331034Open-labelCommunity2 consecutive days of: reliever ≥3 times·day−1, or night waking or PEF <85% baseline meanBudesonide/formoterol 200/6 or 100/6 AMD or FMD; AMD included step-up to four puffs b.i.d. for 7–14 daysExacerbations (OCS, medical care unit, asthma-related SAE, asthma-related withdrawal)
 FitzGerald 34995Open-labelCommunity2 consecutive days of: reliever ≥3 times·day−1, or night waking or PEF <85% baseline meanBudesonide/formoterol 200/6 or 100/6 AMD or FMD; AMD included step-up to four puffs b.i.d. for 7–14 daysExacerbations (OCS or extra ICS, ED visit, asthma-related SAE, asthma-related withdrawal)
Acute use of budesonide/formoterol
 Balanag 35103Double-blindEDED presentation, FEV1 30–60% predBudesonide/formoterol 1600/48 µg in two doses or salbutamol 1600 µg MDI+spacer in two dosesMean FEV1 up to 3 h
Use of LABA for exacerbations
 Turner 3634Double-blindCommunityMild exacerbations of at least 2 weeks duration, post-BD FEV1 ≥75% pred or personal best, sputum eosinophils >4%Salmeterol 50 µg b.i.d. or beclomethasone 500 µg b.i.d. or placebo (3 weeks)Sputum eosinophils
 Boonsawat 3788Double-blindEDED presentation, FEV1 30–60% predFormoterol 54 µg by Turbuhaler® cf. with 2400 µg salbutamol MDI+spacer, as three doses over 1 hFEV1 at 75 min
Studies not specifically of exacerbations, but relevant to self-management
Treatment of sputum eosinophilia
 Gibson 3826Double-blind crossoverInduced by ICS cessation for 4 daysNo exacerbations required – sputum eosinophilia onlySingle dose budesonide 2400 µg or placeboSputum eosinophils at 6 h
SMART Symbicort® studies
 Scicchitano 391890Double-blindCommunityAs-needed for symptoms including during early stages of exacerbations(Budesonide 400 µg b.i.d. + terbutaline prn or Budesonide/formoterol 200/6 2 od + Symbicort® 200/6 1 puff prn)Time to first severe exacerbation (hospitalisation or ED, OCS or PEF ↓30% for 2 consecutive days)
 O'Byrne 402760Double-blindCommunityAs-needed for symptoms including during early stages of exacerbations(Budesonide 400 µg b.i.d. + terbutaline prn or Budesonide/formoterol 100/6 2 puffs b.i.d. + terbutaline prn or Budesonide/formoterol 100/6 b.i.d. + Budesonide/formoterol 100/6 prn)Time to first severe exacerbation (hospitalisation or ED, OCS or PEF ↓ 30% for 2 consecutive days)
  • OCS: oral corticosteroids; ICS: inhaled corticosteroid; ED: Emergency Department; AMD: adjustable maintenance dosing (see text for explanation); LABA: long-acting β2-agonist; SMART: (Symbicort® Maintenance And Reliever Therapy) Symbicort® studies; i.v.: intravenous; CS: corticosteroids; PEF: peak expiratory flow; % pred: % predicted; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; TLC: total lung capacity; BD: bronchodilator; BDP: beclomethasone dipropionate; FMD: fixed maintenance dosing (see text for explanation); SAE: serious adverse event; NHLBI: National Heart, Lung and Blood Institute; MDI: metered dose inhaler; od: one daily; prn: as needed. #: Groups 2 and 3 of the study by Foresi et al. 17. : These studies did not specifically examine the management of exacerbations, but as-needed use of the study medication would have included periods of mild-to-moderate exacerbations.