Table 1.

Main observational studies evaluating steroid use in influenza infection

Ref.	Study design	Population	Steroid regimen	Outcomes
Bourdreault et al[33]	Retrospective cohort	143 hematopoietic cell transplant patients with seasonal influenza	Prednisone < 1 mg/kg per day (low dose) or prednisone > 1 mg/kg per day (high dose)	Steroid use not associated with lower respiratory disease, hypoxemia, need for MV or death
Brun-Buisson et al[36]	Retrospective cohort	208 patients with ARDS due to H1N1 pneumonia, 83 receiving steroids	Hydrocortisone 270 mg/d (median) for 11 d (median)	Steroid was associated with mortality in crude analysis (33% vs 18%, HR = 2.4; 95%CI: 1.3-4.3; P = 0.004) and after propensity score-adjusted analysis (HR = 2.82; 95%CI: 1.5-5.4; P = 0.002)
				Early therapy (≤ 3 d of MV) associated with increased mortality
				Steroid associated with bacterial pneumonia and prolonged MV
Confalonieri et al[44]	Case report	One patient with ARDS due to H1N1 infection, not responding to antiviral therapy	Methylprednisolone 1 mg/kg per day	Clinical improvement
Cornejo et al[40]	Case report	Two patients with H1N1 that developed organizing pneumonia	Methylprednisolone 500 mg/d for 3 d	Clinical improvement
Diaz et al[37]	Multicenter, prospective cohort	372 patients with primary H1H1 pandemic pneumonia, 136 receiving steroids	Not reported	Corticosteroid therapy was not significantly associated with mortality (HR = 1.06; 95%CI: 0.626-1.801; P = 0.825) after a regression analysis adjusted for severity and potential confounding factors
Han et al[45]	Multicenter, retrospective cohort	83 patients with H1N1 pneumonia with hospitalar admission, 17 with early glucocorticoid treatment	Median dose of methylprednisolone equivalent of 50 mg/d (use for fever reduction) to 61 mg/d (use for pneumonia)	Early steroid treatment (< 72 h) was associated with development of critical disease compared with who received late (> 72 h) or no steroid treatment: 71% vs 39% (HR = 1.8; 95%CI: 1.2-2.8), after adjustment for confounding variables
Kim et al[35]	Multicenter, retrospective cohort and case-control study	245 patients with H1N1 infection, 107 with steroid treatment	Median dose of prednisolone equivalent of 75 mg/d	90-d mortality rate higher in steroids group (OR = 2.2; 95%CI: 1.03-4.71), after propensity score
				Higher mortality both in cohort (58% vs 27%; P < 0.001) and case-control study (54% vs 31%; P = 0.004)
				Steroid group more likely to have secondary bacterial pneumonia, invasive fungal infection and prolonged intensive care unit stay
Luyt et al[46]	Multicenter, prospective cohort study	37 survivors of ARDS due to H1N1 infection, 20 with steroid treatment	Not reported	No relationship between steroid use and muscle weakness at 1-yr post-ICU discharge
Martin-Loeches et al[31]	Multicenter, prospective cohort study	220 patients with H1N1 infection, 126 with steroid treatment at ICU admission	Minimal equivalent dose of 24 mg/d (methylprednisolone) or 30 mg/d (prednisone)	Early use of steroids was not significantly associated with mortality by Cox regression analysis adjusted for severity and confounding factors: HR = 1.3; 95%CI: 0.7-2.4; P = 0.4
				Early steroid use associated with an increased rate of HAP (OR = 2.2; 95%CI: 1.0-4.8; P < 0.05) by Cox regression analysis
				Similar results observed when only patiens with ARDS were analyzed
				Patients who received early steroid therapy were sicker than who did not receive them according to SAPS 3 (55.9 ± 16.8 vs 49.0 ± 14.5; P = 0.001)
Quispe-Laime et al[47]	Case series	13 patients with suspected H1N1 pneumonia and ALI-ARDS diagnosis	Methylprednisolone 1 mg/kg per day (severe ARDS) or hydrocortisone 300 mg/d. Duration of 21.2 ± 6.1 d	Twelve patients improved lung function, were extubated and discharged alive from the ICU
				By day 7 of treatment patients experienced a significant improvement in lung injury and multiple organ dysfunction scores (P < 0.001)

ALI: Acute lung injury; ARDS: Acute distress respiratory syndrome; HAP: Hospital-acquired pneumonia; HR: Hazard ratio; ICU: Intensive care unit; MV: Mechanical ventilation; OR: Odds ratio; SAPS: Simplified acute physiology score.