Summary of the studies which looked at exacerbations as end-points, demonstrating that each study used a different exacerbation definition with potential implications for the study results
| Trial, first author [ref.] | Exacerbation definition | Method of assessment/measurement |
| Nebulised gentamicin, Murray [11] | A clinical deterioration with all of the following: increasing cough, increasing sputum volume and worsening sputum purulence All patients subsequently received antibiotics for 14 days | TTF: median Number: count |
| 7% hypertonic saline, Kellett [14] | Unscheduled primary or secondary events leading to provision of rescue medications, either steroid or antibiotic, Accident and Emergency attendance or hospitalisation | Number: count |
| 6% hypertonic saline, Nicolson [16] | ≥3 symptoms in 1 day for two or more consecutive days | Number: median (IQR) |
| Budesonide, Hernando [17] | Worsening of at least 3 out of 4 symptoms for at least 48 h | Number: mean Duration: mean |
| EMBRACE, Wong [18] | Two definitions Event-based exacerbation: an increase in or new onset of more than one pulmonary symptom (sputum volume, sputum purulence, or dyspnoea) requiring treatment with antibiotics Symptom-based exacerbation: an increase in or new onset of more than one pulmonary symptom reported on the daily diary card and the mean of the three symptom scores from the daily diary card on two consecutive days had to increase by at least one point (on a five-point scale) compared with the same calculation 1 week earlier | Median TTF: Cox proportional hazard presented as Kaplan–Meier plots Number: rate ratio (Poisson regression model frequency) |
| Mannitol, Bilton [20] | Treated with parenteral antibiotics for any four of the following 12 signs or symptoms: change in sputum; new or increased haemoptysis; increased cough; increased dyspnoea; malaise, fatigue or lethargy; temperature above 38°C; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10% or more from a previously recorded value; or radiographic changes indicative of pulmonary infection | TTF: presented as Kaplan–Meier plots |
| Ciprofloxacin DPI, Wilson [21] | Not clear | TTF: method not reported |
| BAT, Altenburg [12] | Two definitions Protocol defined exacerbation: at least four of the following nine symptoms, signs or findings were present: 1) change in sputum production (consistency, colour, volume or haemoptysis); 2) increased dyspnoea (chest congestion or shortness of breath); 3) increased cough; 4) fever (>38°C); 5) increased wheezing; 6) decreased exercise tolerance, malaise, fatigue or lethargy; 7) FEV1 or FVC decreased by at least 10% from previous recorded value; 8) radiographic changes indicative of a new pulmonary infectious process; or 9) changes in chest sounds Non-protocol defined exacerbation: fewer than four of the above abnormalities | Number: median (IQR) TTF: Cox proportional hazard presented as Kaplan–Meier plots |
| BLESS, Serisier [22] | Antibiotic treatment for a sustained (more than 24 h) increase in sputum volume or purulence accompanied by new deteriorations in at least two additional symptoms: sputum volume, sputum purulence, cough, dyspnoea, chest pain or haemoptysis | Number: rate ratio (Poisson regression model frequency) Frequency: rate ratio (Poisson regression model frequency) |
| ORBIT-2, Serisier [23] | Deterioration in ≥4 of the following nine signs or symptoms: sputum production (volume, colour, consistency or haemoptysis), dyspnoea, cough, fever, wheezing, exercise tolerance (or fatigue/lethargy/malaise), FEV1 or FVC fall of at least 10%, new changes on chest radiograph and changes in chest sounds on auscultation | Median TTF: Kaplan–Meier plot |
| Azithromycin, De Diego [24] | No definition stated | Number: mean |
| Inhaled colistin, Haworth [25] | Presence of ≥3 of the following signs or symptoms for at least 24 h: increased cough, increased sputum volume, increased sputum purulence, haemoptysis, increased dyspnoea, increased wheezing, fever (>38°C) or malaise, and the treating physician agreed that antibiotic therapy was required | TTF: median (IQR) presented as Kaplan–Meier plots |
| Atorvastatin, Mandal [26] | As per British Thoracic Society guidelines and treated them according to baseline sputum bacteriological findings and administered 14 days of oral antibiotic treatment | Frequency: median (IQR) |
| AIR-BX1 and AIR-BX2, Barker [27] | Acute worsening of respiratory disease meeting ≥3 major (or two major and at least two minor) criteria Major criteria were increased sputum production, change in sputum colour, dyspnoea and cough Minor criteria were fever (>38°C) at clinic visit, increased malaise or fatigue, FEV1 (L) or FVC decreased by more than 10% from baseline, and new or increased haemoptysis | TTF: median presented as Kaplan–Meier plots Rate: negative binomial model |
| Inhaled mannitol, Bilton [29] | Worsening of signs and symptoms requiring changes in treatment | Number: count Rate: negative binomial model TTF: Cox proportional hazard |
| Roxithromycin, Liu [15] | At least four of the following nine symptoms, signs or findings: 1) change in sputum production (consistency, colour, volume or haemoptysis); 2) increased dyspnoea (chest congestion or shortness of breath); 3) increased cough; 4) fever (>38°C); 5) increased wheezing; 6) decreased exercise tolerance, malaise, fatigue or lethargy; 7) FEV1 or FVC decreased by at least 10% from previous recorded value; 8) radiographic changes indicative of a new pulmonary infectious process; or 9) changes in chest sounds | TTF: Kaplan–Meier plot |
| Tobramycin, Orriols [13] | More frequent coughing, greater dyspnoea and increased sputum volume and purulence | TTF: Kaplan–Meier plot Number: count |
| STRATUS, De Soyza [30] | Increased dyspnoea, sputum production and sputum purulence | Not clear |
| RESPIRE I and II, De Soyza [8] and Aksamit [9] | Two definitions For primary end-point: exacerbations had to meet three criteria: 1) worsening of at least three signs or symptoms (dyspnoea, wheezing, cough, 24-h sputum volume or sputum purulence) beyond normal day-to-day variations for at least 2 consecutive days; 2) fever (body temperature >38.0°C) or malaise/fatigue; and 3) systemic antibiotic treatment For secondary end-point: respiratory event with worsening of at least one of the aforementioned signs or symptoms and systemic antibiotic use | TTF: (HR) Frequency: ratio (IRR) Number: mean |
TTF: time to first; DPI: dry powder inhaler; IQR: interquartile range; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; HR: hazard ratio; IRR: incidence rate ratio.