1. Summary of included studies.
| Study/year (country) | Design | Setting/inclusion criteria | CS given (n) | CS not given (n) | Demographics | Disease severity scores | Corticosteroid therapy dose/timing/duration | Outcomes reported |
| Studies included in meta‐analysis | ||||||||
| Influenza 2009 influenza A H1N1 virus (H1N1pdm09) | ||||||||
| Balaganesakumar 2013(India ‐ Tamil Nadu) | Multicentre prospective cohort study | In‐hospital/admissions with influenza | 70 | 210 | Median age (years): 26 (1 to 82) | Not reported | Not reported | Mortality |
| Brun‐Buisson 2011(France) | Multicentre retrospective analysis of prospectively collected data | ICU/severe respiratory failure (ARDS or MV) | 83 (early CS 50 and late CS 33) | 125 | Median age (years): no CS 45 (35 to 55); CS 49 (34 to 56) Immunosuppression: no CS 18.4%; CS 21.7% |
Median SAPS III cohort 52.0 (44.0 to 64.0); no CS group 53.0 (46.0 to 66.0); CS group 51.0 (44.0 to 61.0); P = 0.25 | Median daily dose: 270 mg (200 to 400 mg) of hydrocortisone equivalent Timing: within median 1 day (0 to 6) of MV Duration: median 11 days (6 to 20) |
Hospital mortality, length of ICU stay, adverse events |
| Chawla 2013(India ‐ New Delhi) | Single‐centre retrospective cohort study | ICU/admissions with influenza | 38 | 39 | Mean age (years): 40.9 (±13.4) | Not reported | Duration of therapy: mean (days) 10.6 (±7.8) | Mortality |
| Delaney 2016(Canada) | Multicentre prospective cohort study | ICU/age ≥ 18 years; critically ill with confirmed, probable, or highly suspected influenza | 280 | 327 | Mean age (years): no CS 46.2 (±15.2); CS 48.8 (±15.3) Asthma: CS 29.3%; no CS 12.8%; P < 0.001 COPD: CS 25.0%; no CS 9.2%; P < 0.001 Immunosuppressed: CS 8.9%; no CS 3.1%; P = 0.002 |
Mean APACHE II score: CS 21.2 (±10.3); no CS 20.1 (±9.7); P = 0.22 Mean SOFA score: CS 11.4 (±3.8); no CS 11.3 (±3.6); P = 0.70 |
Median daily dose: 227 mg (154 to 443 mg) of hydrocortisone equivalent Timing: median 0 days (0 to 3) of critical illness onset; median 2 days (1 to 8) from hospital admission Duration: median 7 days (4 to 13) |
Mortality, hospital‐acquired infections |
| Kim 2011(South Korea) | Multicentre retrospective cohort/case‐control | ICU/age ≥ 15 years; presence of critical illness | 107 | 138 | Mean age (years): no CS 54.1 (±19.3); CS 56.9 (±17.2) Asthma: CS 9%; no CS 7% COPD: CS 13%; no CS 4% |
Mean (SD) APACHE II: no CS group 17.5 (±8.5); CS group 21.2 (±7.7); P = 0.001 | Dose: median pred equivalent 75 mg/day (50 to 81 mg/day) Duration: median days 6 (3 to 14) |
Mortality (14‐day, 30‐day, and 90‐day), LOS, acquired infections |
| Kinikar 2012(India) | Single‐centre retrospective cohort study | ICU/admissions with influenza, age < 12 years | 21 | 71 | Cohort median age (years): 2.5 (1.3 to 6) Asthma: 4.3% Congenital heart disease: 6.5% |
Not reported | Dose: not reported Timing: not reported Duration: described as "short course" |
In‐hospital mortality |
| Li 2012(China ‐ Anhui province) | Multicentre retrospective cohort study | In‐hospital/pregnant, severe disease | 27 | 19 | Median age (years): adults who died 21 (18 to 31) and survivors 21 (18 to 27) | Not reported | Not reported | Mortality |
| Li 2017(China ‐ mainland) | Multicentre retrospective analysis of prospectively collected data | In‐hospital/viral pneumonia, age > 14 years | 1055 | 1086 | Median age (years): no CS 33.7 (24.6 to 48.7); CS 35.0 (23.8 to 52.4) Asthma: no CS 1.5%; CS 2.1% COPD: no CS 4.3%; CS 5.6% Immunosuppression: no CS 1.4%; CS 3.2% |
PaO2/FiO2 (mmHg): no CS 286.2 (191.7 to 388.2); CS 173.3 (100 to 272.4) | Dose: median methylpred equivalent 80 mg/day (53.3 to 160 mg/day); mean methylpred equivalent 141.3 (±142) Duration: median (days) 7 (4 to 8); mean (days) 7.7 (±6.8) Timing: median (days) 6 (4 to 8); mean (days) 6.7 (±4) |
Mortality, ICU admission, hospital‐acquired infection, MV |
| Linko 2011(Finland) | Multicentre prospective cohort study | ICU/admissions with influenza | 72 | 60 | Median age (years): no CS 44 (25 to 57); CS 51 (40 to 56) COPD: no CS 5%; CS 8% Other obstructive pulmonary disease: no CS 23%; CS 21% |
Median SAPS II: no CS 22 (15 to 30); CS 31 (24 to 36); P = 0.001 | Methylpred and/or hydrocortisone Dose: mean (SD) of highest methylpred dose 94 mg (±43) and hydrocortisone 214 mg (± 66) Timing: median (IQR) days after symptom onset 5.0 (2.8 to 8.3) |
In‐hospital mortality, MV, LOS |
| Mady 2012(Saudi Arabia) | Single‐centre retrospective cohort study | ICU/influenza with respiratory failure | 43 | 43 | Cohort mean age (years): 40.8 Asthma or COPD: 38.3% |
Mean APACHE IV: 110.5 versus 100.6 (P = 0.05), not specified for which treatment group | Methylpred Dose: 1 mg/kg per day for 7 days |
Mortality |
| Patel 2013(India ‐ Gujarat) | Single‐centre retrospective cohort study | In‐hospital/admissions with influenza | 39 | 24 | Cohort median age (years): 34 (3 to 69) | Not reported | Dose: methylpred 40 mg 3 times a day, twice a day, and once a day, for weeks 1, 2, and 3, respectively | Mortality |
| Sertogullarindan 2011(Turkey) | Single‐centre prospective cohort study | ICU/severe community‐acquired pneumonia and influenza | 7 | 13 | Cohort median age (years): 36 (15 to 72) COPD: 10% |
Not reported | Not reported | Mortality |
| Viasus 2011(Spain) | Multicentre prospective cohort study | In‐hospital/ non‐immunosuppressed, admitted > 24 hours | 37 | 129 | Median age (years): no CS 35 (28 to 47); CS 44 (36 to 53) Chronic pulmonary disease: no CS 17.1%; CS 45.9% |
Number in high‐risk PSI classes: CS 8 (21.6); no CS 8 (6.4); P = 0.05 |
Duration: median days 9 (5 to 13.5) | Severe disease (composite outcome of ICU admission/death), acquired infection |
| Xi 2010(China ‐ Beijing) | Multicentre retrospective cohort study | In‐hospital/age ≥ 18 years | 52 | 103 | Cohort mean age (years): 43 (±18.6) COPD: 6.5% |
Not reported | Dose: daily median dose equivalent to methylpred 80 mg (IQR 80 to 160 mg) | In‐hospital mortality Subgroup analysis of mortality by CS dose |
| Yu 2011a(China ‐ Zhengzhou) | Multicentre retrospective cohort study | Not defined | 54 | 74 | Cohort mean age (years): females 28.5 (±16.4); males 28.5 (±20.4) Range 8 months to 79 years |
Not reported | Dose: not reported Duration: mean (days): died 8.3 (±8.0); survived 2.6 (±4.2) Timing: "Early" |
Mortality |
| Avian influenza A(H5N1) | ||||||||
| Liem 2009(Vietnam) | Multicentre retrospective cohort | In‐hospital/hospitalised patients with influenza | 29 | 38 | Cohort median age (years): 25 (16 to 42) | Not reported | Dose: methylpred 1 to 3 mg/kg/day for 7 days | In‐hospital mortality |
| Avian influenza A(H7N9) | ||||||||
| Cao 2016(China) | Multicentre retrospective cohort study | In‐hospital/age ≥ 14 years with pneumonia | 204 | 84 | Median age (years): 58 (IQR 45 to 68) | Moderate to severe ARDS 207 (71.9) | Low‐moderate dose: 168 (82.4), high dose 36 (17.6). Median dose (mg/day of methylpred equivalent) 80 (IQR 40 to 120) | Mortality, adverse events, viral shedding |
| Mixed influenza A/B | ||||||||
| Huang 2017(Taiwan) | Single‐centre retrospective cohort study | In‐hospital/age > 18 years | 29 | 19 | Cohort mean age (years): 65.9 (±19.2) Chronic pulmonary disease: respiratory distress cohort 27.1% |
Respiratory distress | Dose and type: not reported ("Medium to high dose" defined as ≥ 0.5 to 2 mg/kg/day) Timing: early (before/within 72 hours of NAIs) 58.6% Duration: short (≤ 3 days) 13.8%; 4 to 13 days 48.3%; ≥ 14 days 34.5% |
Mortality |
| Lee 2015(China) | Multicentre retrospective analysis of prospectively collected data | In‐hospital/age > 17 years | 610 | 2039 | Cohort median age (years): 63 (42 to 79) | Ventilatory support and/or ICU 305 (11.5) | Not reported | Mortality, bacterial superinfection, LOS |
| Moreno 2018(Spain) | Multicentre prospective cohort study | ICU/viral pneumonia | 604 | 1242 | Median age (years): CS 53 (41 to 62); no CS 51 (39 to 61) | Median APACHE II score: CS group 15 (10 to 20); no CS group 14 (10 to 19); P < 0.0001 | Median daily dose methylpred equivalent 80 mg (60 to 120 mg) Median duration (days) 7 (5 to 10) Administered within 24 hours of ICU admission |
ICU mortality |
| Sheu 2017(Taiwan) | Multicentre retrospective cohort study | ICU admissions with confirmed influenza | 101 | 91 | Cohort mean age (years): 58.3 | ARDS: Mild 8.3%; moderate 29.2%; severe 62.5% |
Not reported | Mortality |
| Studies not included in meta‐analysis | ||||||||
| Influenza 2009 influenza A H1N1 virus (H1N1pdm09) | ||||||||
| Delgado‐Rodriguez 2012(Spain) | Multicentre prospective cohort | In‐hospital/ILI, RTI, septic shock, multi‐organ failure | 31 | 782 | Cohort median age (years): 41 (19 to 55) | Not reported | Corticosteroid use 90 days prior to admission | Poor outcome (ICU admission and in‐hospital death), LOS |
| Han 2011(China ‐ Shenyang City) | Multicentre retrospective cohort | In‐hospital/age > 3 years | 46 (early CS 17 and late CS 29) | 37 | Median age (years): no CS 38 (5 to 75); CS 43 (3 to 70) | Median PMEWS: no CS group 2 (0 to 5); CS group 2 (0 to 5) | Methylpred and dexamethasone | Critical illness |
| Jain 2009(USA) | Multicentre retrospective cohort | In‐hospital/ILI with hospital admission ≥ 24 hours | 86 | 153 | Cohort median age: 21 years (21 days to 86 years) Asthma: 28% COPD: 8% Immunosuppression: 15% |
Not reported | Not reported | Death/ICU admission versus survival/no ICU admission |
| Kudo 2012(Japan) | Single‐centre retrospective cohort | In‐hospital/hospitalised patients with respiratory disorders | 46 | 12 | Cohort median age (years): 8 (0 to 71) Asthma: 29.2% |
Not reported | Dose: methylpred 1 to 1.5 mg/kg, 2 to 4 times/day Duration: median 5.1 days Timing: median 2.1 days following symptom onset |
LOS |
| Interpandemic (seasonal) influenza | ||||||||
| Boudreault 2011(USA) | Single‐centre retrospective cohort | Non‐ICU/HSCT recipients with RTI | 80 (low dose 43 and high dose 37) |
63 | Median age (years): no CS 42 (32 to 51); low‐dose CS 42 (28 to 53); high‐dose CS 40 (32 to 54) | Not reported | Highest dose in 2/52 preceding influenza Low dose (pred/methylpred < 1 mg/kg/day); high dose (pred/methylpred >= 1 mg/kg/day) | MV, time to death, PVS |
| Ono 2016(Japan) | Multicentre retrospective cohort study | Medical insurance database, < 65 years, first episode of hospitalisation with confirmed influenza | 804 | 87,250 | All < 65 years Asthma: hospitalised 39.5%; non‐hospitalised 23.5% COPD: hospitalised 2.9%; non‐hospitalised 0.5% Immunosuppression: hospitalised 0.36%; non‐hospitalised 0.13% |
Not reported | Dose not reported. Timing: > 30 days steroid use in 6‐month baseline prior to influenza diagnosis |
Rate of hospitalisation |
| Wirz 2016(Switzerland) | Multicentre randomised controlled trial of adjunctive prednisone therapy versus placebo in community‐acquired pneumonia | Non‐ICU with community‐acquired pneumonia (influenza subgroup n = 24) | 11 | 13 | All trial participants: mean age (years): CS arm 70.3 (±17.5); placebo arm 69.0 (±17) COPD: CS arm 19.3%; placebo 15.4% |
PSI mean score: CS 92.5 (±38.2); placebo 89.2 (±35.5) | Dose: oral prednisone 50 mg/day Duration: 7 days Timing: early |
Any‐cause mortality at 30 days, hospital readmission at 30 days postdischarge, time to effective hospital discharge, time to clinical stability |
| Wu 2012(Taiwan) | Single‐centre prospective cohort | Mixed cohort of outpatients and inpatients | 17 | 189 | Age >= 65 years in cohort: 12.6% Chronic lung disease: 9.7% Malignancy: 8.7% |
Not reported | Dose/duration: not reported Unclear if CS commenced prior to or following diagnosis |
Complicated influenza (requiring hospitalisation) |
APACHE: Acute Physiology and Chronic Health Evaluation ARDS: adult respiratory distress syndrome COPD: chronic obstructive pulmonary disease CS: corticosteroid therapy HSCT: haematopoietic stem cell transplant ICU: intensive care unit ILI: influenza‐like illness IQR: interquartile range LDH: lactate dehydrogenase LOS: length of stay methylpred: methylprednisolone MV: mechanical ventilation NAI: neuraminidase inhibitor PaO2/FiO2: ratio of partial pressure of oxygen in arterial blood to inspired fraction of oxygen PMEWS: Pandemic Modified Early Warning Score pred: prednisolone PSI: Pneumonia Severity Index PVS: persistent viral shedding RTI: respiratory tract infection SAPS: Simplified Acute Physiology Score SD: standard deviation SOFA: Sequential Organ Failure Assessment