Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2015; published online Jan 19. http:// dx.doi.org/10.1016/s0140-6736(14)62447-8.
Web appendix Adjunct prednisone therapy for patients with community-acquired pneumonia a randomized, double-blind, placebo-controlled multicenter trial Contents Figure S1. Meta-analysis on length of hospital stay in CAP of any severity Table S1. Microbiological etiology of community-acquired pneumonia Table S2. Antibiotic treatment Table S3. Clinical Instability at baseline Table S4. Detailed results of regression analyses including sensitivity analyses Table S5. Subgroup analyses Figure S1. Meta-analysis on length of hospital stay in CAP of any severity Upper panel: before our trial Lower panel: including the data of this trial Note: We used means and SD s of the different trials. Therefore, data may slightly differ from reported data in the original publications. Appendix page 1
Table S1. Microbiological etiology of community-acquired pneumonia* Pathogen identified Prednisone (n=392) Placebo (n=393) Any 90 (23 0%) 98 (24 9%) Streptococcus pneumoniae 48 (12 2%) 50 (12 7%) Staphylococcus aureus 1 (0 3%) 6 (1 5%) Legionella pneumophila 5 (1 3%) 10 (2 5%) Mycoplasma pneumonia 3 (0 8%) 1 (0 3%) Influenza virus 10 (2 6%) 17 (4 3%) Other viral agents 30 (7 7%) 26 (6 6%) * Data are n (%).
Table S2. Antibiotic treatment* Antibiotic (antiviral) prescribed Prednisone (n=392) Placebo (n=393) Any antibiotic 386 (98 5%) 389 (99 0%) > 1 antibiotic 291 (74 2%) 303 (77 1%) Amoxicillin/clavulanate 317 (80 9%) 312 (79 4%) Amoxicillin 9 (2 3%) 17 (4 3%) Ceftriaxone 73 (18 6%) 80 (20 4%) Piperacillin/tazobactam 31 (7 9%) 42 (10 7%) Clarithromycin (overall) 242 (61 7%) 253 (64 4%) Clarithromycin only 5 (1 3%) 5 (1 3%) Penicillin 19 (4 8%) 17 (4 3%) Levofloxacin 33 (8 4%) 35 (8 9%) Ciprofloxacin 5 (1 3%) 14 (3 6%) Cefuroxime 6 (1 5%) 7 (1 8%) Moxifloxacin 3 (0 8%) 9 (2 3%) Oseltamivir 12 (3 1%) 14 (3 6%) Appendix page 3
Table S3. Clinical Instability at baseline* A. Number of patients per instability criterion Placebo (n=400) Prednisone (n=402) Temperature >37 8 C Heart rate > 100 Respiratory rate > 24/min Systolic blood pressure < 90mmHg Oxygenation Altered mental status Inability of oral intake 226 (56. 5%) 90 (22. 5%) 140 (35. 0%) 25 (6. 3%) 236 (59. 0%) 19 (4. 8%) 12 (3. 0%) 218(54. 2%) 86 (21. 4%) 135 (33. 6%) 29 (7. 2%) 229 (57. 0%) 23 (5. 7%) 14 (3. 5%) B. Number of instable criteria at baseline Placebo (n=400) Prednisone (n=402) One instability criteria 118 (29. 5%) 108 (26. 9%) Two instability criteria 146 (36. 5%) 136 (33. 8%) Three instability criteria 67 (16. 8%) 68 (16. 9%) Four instability criteria 30 (7. 5%) 26 (6. 5%) Five instability criteria 2 (0. 5%) 4 (1. 0%) Six instability criteria 0 (0. 0%) 2 (0. 5%) # The 95 (11.8%) patients who had all variables stable on study inclusion had either antipyretics or oxygen due to high fever of low oxygen saturation. Therefore, these patients were considered to be clinically instable. * Values are given as n (%). <100mmHg for patients diagnosed with hypertension) without vasopressor support Appendix page 4
Adequate oxygenation on room air was defined as PaO2 60mmHg or pulse oxymetry 90% Table S4. Detailed results of regression analyses* Endpoints Prednisone (n=392) Placebo (n=393) Unadjusted HR or OR (95%CI) Adjusted HR or OR (95%CI) Primary Endpoint Intention-to-treat: Time to clinical stability (days) 3 0 (2 5-3 4) 4 4 (4 0-5 0) HR 1 33 (1 15-1 50), p=0 0001 HR 1 41 (1 22-1 63), p=0 0001 Per-protocol: Time to clinical stability (days) 3 0 (2 5-3 2) 4 4 (4 0-5 0) HR 1 35 (1 16-1 56), p=0 0001 HR 1 44 (1 23-1 67), p=0 0001 Secondary Endpoints Time to effective hospital discharge (days) 6 0 (6 0-7 0) 7 0 (7 0-8 0) HR 1 19 (1 04-1 38), p=0 012 HR 1 28 (1 11-1 48), p=0 001 Recurrent pneumonia no. (%) 23 (5 8%) 18 (4 6%) OR 1 30 (0 69-2 44), p=0 42 OR 1 25 (0 66-2 38), p=0 52 Re-Hospitalization no. (%) 32 (8 6%) 28 (7 7%) OR 1 14 (0 67-1 93), p=0 64 OR 1 09 (0 63-1 86), p=0 76 ICU admission no. (%) 16 (4 1%) 22 (5 6%) OR 0 72 (0 37-1 39), p=0 32 OR 0 69 (0 35-1 36), p=0 29 Death from any cause no. (%) 16 (4 1%) 13 (3 3%) OR 1 24 (0 59-2 62), p=0 566 OR 1 05 (0 49-2 26), p=0 91 Total duration of antibiotic treatment (days) 9 0 (7-11) 9 0 (7-12) -0 47 days (-1 21-0 27 days), p=0 22-0 55 days (-1 27-0 17 days), p=0 13 Intravenous antibiotic treatment (days) 4 0 (3-6) 5 0 (3-7) -0 89 days (-1 57--0 20) days), p=0 011-0 98 days (-1 64--0 33) days), p=0 003 Web appendix page 5
CAP score at day 5 (points) 59 (41-78) 58 (40-74) 1 00 (-5 23-7 23), p=0 75 0 49 (-5 97-6 95), p=0 88 CAP score at day 30 (points) 83 (67-88) 84 (72-89) -1 00 (-4 38-2 38), p=0 56-2 93 (-5 43--0 43), p=0 02 Incidence of pneumonia-associated complications until day 30 CAP complications, any 11 (2 8%) 22 (5 6%) OR 0 49 (0 23-1 02), p=0 06 OR 0 46 (0 22-0 98), p=0 05 Acute respiratory distress syndrome 0 1 (0 3%) Empyema 1 (0 3%) 5 (1 3%) Respiratory failure, intubation 1 (0 3%) 6 (1 6%) Persistence of pneumonia 6 (1 5%) 5 (1 3%) CAP-associated mortality 5 (1 3%) 7 (1 8%) Incidence of adverse events compatible with corticosteroid use until day 30 Adverse events, any 96 (24 5%) 61 (15 5%) OR 1 77 (1 24-2 52), p=0 002 OR 1 71 (1 19-2 48), p=0 004 In-hospital hyperglycemia needing new insulin treatment 76 (19 4%) 43 (10 9%) OR 1 96 (1 31-2 93), p=0 001 OR 1 89 (1 25-2 86), p=0 002 New insulin dependence at day 30 5 (1 4%) 1 (0 3%) New hypertension at day 30 6 (1 7%) 2 (0 6%) Delirium 5 (1 3%) 2 (0 5%) Gastrointestinal bleeding 3 (0 8%) 4 (1 0%) Nosocomial infections 13 (3 3%) 14 (3 6%) Weight change (kg) -1 0 (-3 0-1) -1 0 (-3 0-0 4) 0 34 (-0 56-1 25), p=0 46 0 36 (-0 54-1 27), p=0 43 Other adverse events until day 30 Any 20 (5 1%) 34 (8 7%) OR 0 57 (0 32-1 00), p=0 05 OR 0 51 (0 28-0 92), p=0 02 Web appendix page 6
Falls with fracture 0 4 (1 0%) Cardiac decompensation 5 (1 3%) 10 (2 5%) Cardiac event 6 (1 6%) 3 (0 8%) Acute stroke 2 (0 5%) 2 (0 5%) Thrombembolic event 0 3 (0 8%) Other 9 (2 3%) 12 (3 1%) * Values are given as median (interquartile range), if not labeled otherwise. Abbreviations: HR, hazard ratio; OR, odds ratio; CI, confidence interval; CAP, community-acquired pneumonia Web appendix page 7
Table S5. Subgroup analyses for the primary endpoint time to clinical stability* Subgroup variables Prednisone (n=392) Placebo (n=393) Cox regression, HR (95%CI) p for heterogeneity (interaction) Median age 0 17 Age < 73 years 2 4 (2 0-2 5) 4 0 (3 0-4 0) 1 48 (1 21-1 81) Age 73 years 3 9 (3 0-4 4) 5 4 (5 0-6 0) 1 24 (1 01-1 53) Initial median CRP 0 22 CRP< 156 mg/l 3 0 (2 4-4 0) 4 0 (3 0-4 6) 1 07 (0 84-1 38) CRP 156 mg/l 3 0 (2 4-3 4) 5 0 (4 0-5 4) 1 47 (1 23-1 76) History of Chronic Obstructive Pulmonary Disease 0 18 no 2 5 (2 4-3 0) 4 3 (4 0-5 0) 1 44 (1 22-1 68) yes 4 5 (3 6-5 6) 7 0 (4 4-8 0) 1 12 (0 79-1 60) Pneumonia severity index 0 26 PSI class I-III 2 4 (2 0-2 5) 3 8 (3 0-4 0) 1 51 (95%CI 1 23-1 85) PSI class IV-V 4 0 (3 4-4 5) 5 6 (5 0-7 0) 1 29 (95%CI 1 05-1 59) Blood culture positivity 0 16 Blood culture positive 5 0 (3 3-7 0) 4 0 (2 6-7 4) 0 98 (95%CI 0 62-1 53) Blood culture negative 3 0 (2 4-3 0) 4 5 (4 0-5 0) 1 39 (95%CI 1 19-1 62) * Values are given as median days (interquartile range), if not labeled otherwise. Cox proportional hazards model including an interaction term of the respective subgroup variable with treatment group. Appendix page 8
The Pneumonia Severity Index (PSI) s a clinical prediction rule to calculate the probability of morbidity and mortality among patients with CAP. 20 PSI risk class I: age 50 or less and no risk factors, II: < 70, III: 71-90, IV: 91-130; V: > 130 points. Abbreviations: HR, hazard ratio; CRP, C-reactive protein; CI, confidence interval Web appendix page 9