Early Corticosteroids in Severe Influenza A/H1N1 Pneumonia and Acute Respiratory Distress Syndrome Christian Brun-Buisson1,2,3, Jean-Christophe M. Richard4, Alain Mercat5, Anne C. M. Thiébaut3,6, and Laurent Brochard1,2,7, for the REVA-SRLF A/H1N1v 2009 Registry Group* 1 Université Paris Est-Créteil and INSERM U955, Créteil, France; 2Assistance Publique-Hôpitaux de Paris, GH Henri Mondor, Service de réanimation médicale, Créteil, France; 3Inserm U657; Pharmacoepidemiology and Infectious Diseases, Institut Pasteur, Paris, France; 4Service de réanimation médicale, CHU de Rouen, UPRES EA 38, Rouen, France; 5Département de Réanimation Médicale et Médecine Hyperbare, CHU d’Angers, Angers, France; 6EA4499, Université de Versailles Saint-Quentin, France; and 7Department of Intensive Care Medicine University Hospital of Geneva and University of Geneva, Switzerland Rationale: Despite their controversial role, corticosteroids are often administered to patients with adult respiratory distress syndrome (ARDS) secondary to viral pneumonia. Objectives: To analyze the impact of corticosteroid therapy on outcomes of patients having ARDS associated with influenza A/H1N1 pneumonia. Methods: Patients from the French registry of critically ill patients with influenza A/H1N1v 2009 infection were selected if fulfilling criteria for ARDS, excluding patients having other indication for corticosteroids, or decompensated underlying disease as the primary cause for intensive care unit admission. Survival to hospital discharge was analyzed using Cox regression, accounting for the time to administration of steroids, and after adjustment on the propensity for receiving steroid therapy. Measurements and Main Results: Of 208 patients with ARDS, 83 (39.9%) received corticosteroids (median initial dose of 270 mg equivalent hydrocortisone per day for a median of 11 d). Steroid therapy was associated with death, both in crude analysis (33.7 vs. 16.8%; hazard ratio, 2.4; 95% CI, 1.3–4.3; P 5 0.004) and after propensity score–adjusted analysis (adjusted hazard ratio, 2.82; 95% CI, 1.5–5.4; P 5 0.002), controlling for an admission severity Simplified Acute Physiology Score, version 3, greater than 50, initial administration of vasopressors, and immunodepression. Early therapy (< 3 d of mechanical ventilation) appeared more strongly associated with mortality than late administration. Patients receiving steroids had more acquired pneumonia and a trend to a longer duration of ventilation. Conclusions: Our study provides no evidence of a beneficial effect of corticosteroids in patients with ARDS secondary to influenza pneumonia, but suggests that very early corticosteroid therapy may be harmful. Keywords: pandemic influenza; viral pneumonia; acute respiratory failure; corticosteroid therapy; host defenses. (Received in original form January 23, 2011; accepted in final form March 2, 2011) *A complete list of contributors may be found before the beginning of the REFERENCES. The REVA Registry was funded in part by the French Ministry of Health, the Inserm-Institut des Maladies Infectieuses, and the Société de Réanimation de Langue Francxaise. These funding sources had no role in the collection, analysis, or interpretation of the data. Correspondence and requests for reprints should be addressed to Christian BrunBuisson, M.D., Ph.D., Service de Réanimation Médicale, CHU Henri Mondor, 51, Ave de Lattre de Tassigny, 94000 Créteil Cedex, France. E-mail: christian.brun-buisson@ hmn.aphp.fr This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org Am J Respir Crit Care Med Vol 183. pp 1200–1206, 2011 Originally Published in Press as DOI: 10.1164/rccm.201101-0135OC on March 4, 2011 Internet address: www.atsjournals.org AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Results from clinical studies of corticosteroid therapy in acute respiratory distress syndrome (ARDS) from diverse etiologies are conflicting; however, corticosteroids are commonly used in patients with severe influenza pneumonia and ARDS. What this Study Adds to the Field In the French Réseau de Recherche en Ventilation Artificielle (REVA) influenza registry, 40% of patients with influenza A/H1N1 pneumonia and ARDS received steroids, mostly very early in its course. Steroids were independently associated with higher mortality, suggesting that this therapy may be hazardous when administered early in the context of severe influenza pneumonia, perhaps by interfering with host defenses. Data from clinical trials on corticosteroid therapy during adult respiratory distress syndrome (ARDS) do not provide consistent evidence that steroids can improve patients’ outcomes. A metaanalysis concluded that a definitive role of corticosteroids in the treatment of ARDS in adults was not established (1); in a more recent metaanalysis, the early administration of lowmoderate doses of steroids was reported to improve mortality as well as length of stay and organ dysfunction scores (2). Patients with life-threatening respiratory failure associated with viral pneumonia commonly receive corticosteroids. In reports from the 2002–2003 outbreak of severe acute respiratory syndrome associated with a new Coronavirus strain, as well as in reports of patients infected with influenza A(H5N1), about half of patients received corticosteroids (3, 4), despite the lack of evidence for a beneficial effect (5, 6). Some experimental data also suggest possible unfavorable effects of steroids on viral replication (7, 8). During the recent influenza A/H1N1v 2009 pandemic, many critically ill patients also received corticosteroid therapy as part of management of respiratory failure, ranging from 18% in the report from the Australia-New Zealand Intensive Care Society (ANZICS) (9) to 51% in the Canadian experience (10). These groups of investigators however, did not comment on the potential effects of corticosteroids in this context. A report on a small series of patients with severe influenza pneumonia suggests a beneficial effect of steroids (11), but registry data from China or Europe suggest possible harm from steroid therapy (12, 13). A randomized controlled trial did not prove feasible in the context of the recent influenza A/H1N1 pandemic. Nevertheless, the large series of patients accrued during the past winter Brun-Buisson, Richard, Mercat, et al.: Steroids in Pandemic Influenza ARDS 1201 provided a unique opportunity for analyzing the effects of steroids in homogeneous groups of patients. More than 40% of critically ill patients included in the French influenza A/H1N1 registry received low-moderate doses of steroids. The objective of the current study was therefore to examine the outcomes of a well-defined group of patients with ARDS associated with A/H1N1v 2009 influenza pneumonia and exposed or not to moderate doses of corticosteroids. METHODS This study was a retrospective analysis of data prospectively collected within the French Réseau de Recherche en Ventilation Artificielle– Société de Réanimation de Langue Franc xaise (REVA-SRLF) registry of critically ill patients hospitalized for severe A/H1N1v 2009 infection, established just after the second pandemic wave had reached France in the autumn of 2009, and recording patients over a 4-month period (1 November 2009 to 1 March 2010). Patients were notified through a Web-based registry, simultaneously to the mandatory notification to the National Institute for Public Health Surveillance (InVS, St Maurice, France) (14). Information recorded in the registry expanded over the mandatory notification form, which was generated simultaneously to the registration of each new patient. Data were checked at the coordinating center and queries sent to the participating ICUs to ensure accuracy and completeness of the data. Recording of patients’ data in the national registry was approved by the national commission for protection of patients’ rights and electronic data recording; the study was approved by the ethics committee of the French Society of Intensive Care. Selection of Patients for Inclusion in the ARDS Cohort We included patients with severe respiratory failure associated with confirmed or strongly suspected A/H1N1v 2009 infection (with or without associated bacterial infection) admitted to one of the 108 intensive care units (ICUs) participating in the registry (see list of contributors before the beginning of the REFERENCES). Influenza A/H1N1v 2009 infection was confirmed by polymerase chain reaction on nasopharyngeal swabs or bronchoalveolar lavage fluid. Patients with strongly suspected infection had a diagnosis of influenza pneumonia without further determination of the subtype. To select patients receiving corticosteroids for severe respiratory failure (with or without associated sepsis), and no underlying disease potentially interfering with the effect of steroids, we restricted this analysis to patients: (1) having a diagnosis of ARDS based on standard definitions (15); (2) requiring mechanical ventilation; (3) not admitted for a decompensated underlying disease (e.g., asthma, chronic obstructive pulmonary disease, cardiac failure) interfering with the diagnosis of ARDS or with the effect of steroid therapy; (4) not treated with steroids either chronically or during the ICU stay for reasons other than acute respiratory failure, with or without associated sepsis. Patients receiving corticosteroid therapy as rescue therapy (i.e., later than 2 wk after initiation of mechanical ventilation) were also excluded (Figure 1). Obese patients (as defined by a body mass index of at least 30 kg/m2), patients with diabetes, and pregnant women were included in the absence of the above exclusion criteria. Preliminary data from the REVA registry were presented at the 23rd Annual European Society of Intensive Care Medicine congress (16). Data Recorded Data recorded included: (1) demographics and presence of risk factors for complicated influenza infection (see Table E1 in the online supplement); (2) the course of influenza infection: date of onset, antiviral therapy administered and time to therapy from onset of acute respiratory illness, associated bacterial infection documented on hospital admission; (3) severity at presentation to the ICU, assessed by the Simplified Acute Physiology Score, version 3 (SAPS 3) (17), presence of shock on admission; (4) steroid use: primary indication (respiratory failure or sepsis), drug administered, date of initiation relative to ICU admission and mechanical ventilation (MV), initial dosage (expressed in equivalent hydrocortisone dose), and duration of administration; and (5) use of rescue therapies for respiratory failure, including inhaled Figure 1. Selection process for patients admitted to the intensive care unit (ICU) with A/H1N1v2009 pneumonia and acute respiratory distress syndrome (ARDS) included in the cohort, with reasons for exclusions. COPD 5 chronic obstructive pulmonary disease; MV 5 mechanical ventilation; Rx 5 therapy. nitric oxide, prone positioning, and extracorporeal membrane oxygenation (ECMO). Statistical Analysis The primary outcome was hospital mortality; secondary outcomes included ICU-acquired infections, duration of mechanical ventilation, and length of stay in the ICU. Data are reported as percentage for categorical variables and as mean 6 SD or median with interquartile range (IQR, 25–75%) for continuous variables. The characteristics of patients receiving corticosteroids (treated group) and of those not treated were compared by using the Kruskall-Wallis test for continuous variables or proportions and chi-square test for dichotomous variables. Survival of the two groups of patients from the time of initiation of MV (invasive or noninvasive) was analyzed using Cox regression with hospital death as the dependent variable and including variables differing between the two groups or associated with death in bivariate analyses (with a P value , 0.10), allowing a maximum of eight variables for entry in the final model (18); because corticosteroid therapy was prescribed at varying times after initiation of MV (Figure E1), it was entered in the model as a time-dependent covariate. The follow-up was extended to Day 60 after initiation of MV, and patients discharged alive before day 60 were considered alive at the end of follow-up. In sensitivity analyses, we repeated this analysis after adjustment on the propensity for receiving corticosteroid therapy, based on logistic regression analysis of variables recorded on ICU admission, including markers of severity and interventions performed during the first 72 hours of mechanical ventilation. Propensity score–adjusted Cox survival analysis was repeated after stratification of steroid therapy by timing of administration, within the first 72 hours of MV or later (early versus late therapy). Two-sided P values less than 0.05 were considered statistically significant. All analyses were performed using Stata version 10.1 (Stata Corporation, College Station, TX). RESULTS Description of the Cohort Of the 567 patients with confirmed or strongly suspected infection with influenza A/H1N1 admitted to the 108 units participating in the REVA registry, 342 (60.3%) had a final 1202 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE diagnosis of ARDS. After applying our selection criteria and excluding patients receiving steroids for other reasons or treated more than 14 days after initiation of MV, 208 patients were included in the study cohort (Figure 1). The 208 patients were admitted to 78 ICUs (151 and 57 patients in university and nonuniversity hospitals, respectively). Seven patients (two and five in the treated and nontreated group, respectively) were transferred from one unit to another for potential ECMO, and data from the two records were merged. The 208 patients had a mean age of 45.5 6 14.5 (median, 47) years; 105 (50.5%) were men. One or more risk factors for complicated influenza were recorded in 145 (69.7%) patients, mostly obesity (86, 41.4%), immunodepression (41, 19.7%), or diabetes (27, 13.0%); there were 14 (6.7%) pregnant women. Patients were admitted to the hospital a median of four (IQR, 2–6) days after onset of the influenza syndrome, and bacterial coinfection was documented on admission in 66 (31.7%). The median (IQR) severity score SAPS 3 on ICU admission was 52 (44–64). All patients received MV, with 95.0% receiving endotracheal intubation within a few hours of ICU admission. Within the first 3 days of MV, vasopressors, inhaled nitric oxide, and prone positioning were administered to 128 (61.5%), 56 (26.9%), and 43 (20.7%) patients, respectively. ECMO was eventually required in 53 (25.5%) patients, including 32 (15.4%) within the first 3 days of MV. Forty-nine patients (23.6%) died in the ICU, including two (both in the nontreated group) on the first day of mechanical ventilation. Corticosteroid Therapy Corticosteroid therapy was administered to 83 (39.9%) patients, mostly for isolated respiratory failure (n 5 50; 60.2%), whereas the primary indication recorded by the treating physician in 33 (39.8%) of these 83 patients was associated sepsis. Baseline characteristics of treated and untreated patients were comparable, except for a trend to a lower proportion of men (P 5 0.095) and to a lower proportion of patients with diabetes (P 5 0.11) among those treated (Table 1). Steroid therapy was initiated within a median of 1 (IQR, 0–6) day of initiation of MV (Table 2); 50 of the 83 (60.2%) patients received therapy within the first 3 days, and the remaining 33 within 7 (6–9) days (Figure E1). Steroid therapy was initiated at a median daily dose equivalent to 270 (IQR, 200–400) mg hydrocortisone, and patients were treated for a median duration of 11 (IQR, 6–20) days. Outcomes of Patients There were 28 (33.7%) and 21 (16.8%) deaths in the treated group and the nontreated group, respectively (hazard ratio [HR], 2.39; 95% CI, 1.32–4.31; P 5 0.004). Patients in the treated group developed more ICU-acquired infection (P 5 0.05) and pneumonia (P 5 0.01). The duration of MV or length of ICU stay did not differ significantly between the two groups (Table 3). In addition to steroid therapy, death was associated (at P , 0.10) in bivariate analyses with age, male sex, severity of underlying disease, immunodepression, cancer or hematologic malignancy, SAPS 3, and shock on admission or administration of vasopressors (Table 4). Obesity, diabetes, and pregnancy were not associated with death. After Cox regression analysis including administration of steroids as a time-dependent variable (Table 5), death remained significantly associated with SAPS 3 (P 5 0.004), together with immunodepression (P 5 0.02) and corticosteroid therapy (adjusted hazard ratio [aHR], 2.6; 95% CI, 1.4–4.7; P 5 0.002). Propensity Score–Adjusted Analysis and Sensitivity Analyses Seventeen variables potentially associated with the administration of corticosteroids, including other interventions recorded VOL 183 2011 within the first 3 days of MV, were included in a logistic regression model with steroid therapy as the dependent variable to determine a propensity score for treatment. The probability for receiving steroid therapy varied linearly across quintiles of propensity score from a median of 9.5% and 14.4% to 66.0% and 74.4%, respectively, in the untreated and treated group (Figure 2). After adjustment for the propensity score and other variables listed Table 5, the association between corticosteroid therapy (as a time-dependent covariate) and death remained significant (aHR, 2.82; 95% CI, 1.48–5.40; P 5 0.002). Because the timing of administration of steroids after initiation of mechanical ventilation appeared to follow a bimodal distribution (Figure E1), we repeated the survival analysis after stratification of steroid recipients in two subgroups (Tables E2 and E3) of early (within first 3 d of MV, n 5 50) or late (beyond 3 d, n 5 33) therapy. In this analysis, only early administration of corticosteroids remained significantly associated with death (aHR, 3.42; 95% CI, 1.73–6.75; P 5 0.001), whereas later administration was not (aHR, 1.93; 05% CI, 0.84–4.43; P 5 0.12). DISCUSSION The main result of this cohort study of well-defined patients having ARDS secondary to A/H1N1v 2009 infection is that corticosteroid therapy administered within the first 2 weeks of the course of ARDS was not associated with improved outcome. Treatment was actually associated with significantly poorer outcomes, and a two- to threefold higher risk of mortality in crude and adjusted analyses, including after propensity score–adjusted analysis. This negative effect was apparent when corticosteroids were administered very early (first 3 d) in the course of ARDS. Given the common use of corticosteroids in severe respiratory failure associated with influenza pneumonia (10, 13), our results are of potential importance for clinical practice. To analyze the potential role of corticosteroid therapy in patients with severe acute respiratory failure associated with A/H1N1v 2009 influenza pneumonia, we restricted our analysis to a well-defined cohort of patients with ARDS having a limited number of associated conditions potentially interfering with their short-term outcome or corticosteroid therapy. Although about two-thirds of patients in each group had at least one risk factor for complicated influenza infection, a majority of these were accounted for by obesity (Table 1). We also selected patients treated with steroids within 2 weeks of ICU admission, to avoid the inclusion of patients receiving late rescue therapy after several weeks on the ventilator. Most patients in our cohort actually received corticosteroid therapy very early in the course of ARDS (median time to administration of corticosteroids, 1 d), and therapy was initiated before 7 days of mechanical ventilation in more than 80% of patients treated (Figure E1). Accounting for our selection criteria, we found no indication that steroids had a positive impact on outcomes of patients, after careful adjustments, including a propensity score–adjusted analysis. The controversy on the use of corticosteroid therapy in ARDS has been persisting over the past two decades. Results of controlled studies are difficult to interpret because of differences in timing, doses, and duration of steroids administration (2). In the largest trial published so far and conducted by the ARDS Network to test the potential benefit of a late administration of corticosteroids to patients with acute lung injury/ ARDS, there was no indication of benefit on outcomes of patients in the overall population and a suggestion of harm in the subgroup of patients treated beyond the second week of mechanical ventilation, possibly associated with increased incidence of secondary infections (19). Conversely, this study did Brun-Buisson, Richard, Mercat, et al.: Steroids in Pandemic Influenza ARDS 1203 TABLE 1. CHARACTERISTICS OF 208 PATIENTS WITH ADULT RESPIRATORY DISTRESS SYNDROME ASSOCIATED WITH INFLUENZA A/H1N1V 2009 INFECTION, STRATIFIED BY TREATMENT WITH CORTICOSTEROIDS All Patients (N 5 208) Hospital category University hospital Nonuniversity hospital Age, yr Female sex Severity of underlying disease Absent or nonfatal Ultimately fatal At least one risk factor Immunodepression Cancer, hematologic malignancy HIV infection Chronic renal failure Neuromuscular disease Chronic liver disease, alcohol abuse Pregnancy or postpartum Diabetes BMI Obesity (BMI > 30 kg/m2) Bacterial coinfection on ICU admission Time from ARI to hospital admission, d Time from ARI to antiviral therapy, d† SAPS 3 PaO2/FIO2 on Day 1 of MV Shock on ICU admission No Steroids (n 5 125) Steroids (n 5 83) 151 57 47 103 (72.6) (27.4) (35–55) (49.5) 87 38 45 56 (69.6) (30.4) (35–55) (44.8) 64 19 49 47 (77.1) (22.9) (34–56) (56.6) 179 29 145 41 26 7 3 6 14 14 27 28 86 66 4 5 52 106 99 (86.1) (13.9) (69.7) (19.7) (12.5) (3.3) (1.4) (2.9) (6.7) (6.7) (13.0) (24–33) (41.3) (31.7) (2–6) (3–7) (44–64) (74–158) (47.6) 106 19 89 23 16 4 2 4 8 9 20 27 52 43 4 5 53 107 55 (84.8) (15.2) (71.2) (18.4) (12.8) (3.2) (1.6) (3.2) (6.4) (7.2) (16.0) (23–33) (41.6) (34.4) (2–6) (3–7) (46–66) (78–144) (44.0) 73 10 56 18 10 3 1 2 6 5 7 29 34 23 5 5 51 101 44 (87.9) (12.1) (67.5) (21.7) (12.1) (3.6) (1.2) (2.4) (7.2) (6.0) (8.4) (24–33S) (41.0) (27.7) (3–6) (3–8) (44–61) (73–174) (53.0) P Value* 0.23 0.58 0.095 0.52 0.57 0.56 0.87 0.94 0.81 0.74 0.81 0.74 0.11 0.71 0.93 0.41 0.14 0.33 0.25 0.94 0.20 Definition of abbreviations: ARI 5 acute respiratory illness; BMI 5 body mass index; ICU 5 intensive care unit; IQR 5 interquartile range; MV 5 mechanical ventilation; SAPS 3 5 Simplified Acute Physiology Score, version 3. Data are reported as n (%) or median (IQR). * P value for comparison of patients treated or not with steroids, estimated from chi-square test or Wilcoxon rank-sum test. † Four patients did not receive antiviral therapy (three not treated and one treated with steroids). not allow excluding that patients treated before the second week of mechanical ventilation might benefit from steroid therapy. We examined whether outcomes differed between patients treated within the first 3 days of mechanical ventilation or later in the course of the ICU stay. In adjusted analyses stratified on the timing of initiation of steroid therapy, we found that administration within the first 3 days was more strongly associated with an increased risk of death compared with untreated patients. This finding suggests that very early administration of corticosteroid therapy may be detrimental in severe influenza pneumonia, possibly by favoring persistent viral replication and further limiting host defenses (20). This is consistent with some experimental studies of animals infected with respiratory viruses receiving steroids and no antiviral therapy (7, 8). Recent clinical reports also suggest that corticosteroid therapy may be associated with persistent viral shedding TABLE 2. ADMINISTRATION OF CORTICOSTEROIDS IN 83 PATIENTS WITH ACUTE RESPIRATORY DISTRESS SYNDROME ASSOCIATED WITH INFLUENZA A/H1N1V 2009 INFECTION Drug administered, n (%) Hydrocortisone Methylprednisolone Prednisone Initial dosage (equivalent hydrocortisone), mg/d Mean 6 SD Median (IQR) Time to initiation from mechanical ventilation, d Mean 6 SD Median (IQR) Duration of therapy, d Mean 6 SD Median (IQR) 48 (57.8) 31 (37.3) 4 (4.8) 328 6 160 270 (200–400) 3.2 6 3.8 1.0 (0–6) 15.7 6 17 11 (6–20) and poorer outcome in patients with severe A/H1N1 pneumonia (12, 13, 20) and possibly favor fungal superinfection (21). Because almost all patients in our cohort received antiviral therapy, it can be speculated that a later treatment could have less detrimental effect, once viral replication is controlled, or even be beneficial at a later stage in selected patients (22). Follow-up of viral load was not routinely obtained in our patients, and we are unable to specify the potential reasons for adverse outcomes associated with steroid therapy, except for TABLE 3. OUTCOMES OF 208 PATIENTS WITH ADULT RESPIRATORY DISTRESS SYNDROME SECONDARY TO INFLUENZA A/H1N1V 2009 INFECTION, ACCORDING TO TREATMENT WITH CORTICOSTEROIDS Variable Death in hospital ICU-acquired infection ICU-acquired pneumonia Duration of MV, d All patients (n 5 208) Survivors only (n 5 158) Length of ICU stay, d* All patients Survivors only Ventilator-free days† At 28 d At 60 d No Steroids (n 5 125) Steroids (n 5 83) P Value 21 (16.8) 44 (35.2) 33 (26.4) 28 (33.7) 38 (45.8) 34 (41.0) 0.005 0.052 0.01 13 (8–24) 16 (9–24) 17 (10–29) 17 (12–26) 0.07 0.26 17 (11–30) 20 (14–33) 22 (13–39) 25 (14–40) 0.11 0.15 8 (0–17) 40 (25–49) 0 (0–12) 31 (0–44) 0.01 0.005 Definition of abbreviations: ICU 5 intensive care unit; IQR 5 interquartile range; MV 5 mechanical ventilation. Data are reported as n (%) or median (IQR). * Includes ICU and step-downS unit stay, when appropriate. † Calculated as days alive and free from mechanical ventilation, from the date of its initiation. 1204 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 183 2011 TABLE 4. BIVARIATE ANALYSIS OF VARIABLES ASSOCIATED WITH DEATH OF PATIENTS WITH INFLUENZA A/H1N1V 2009 INFECTION AND ADULT RESPIRATORY DISTRESS SYNDROME Survivors (n 5 159) Male sex Age Age > 45 yr Ultimately fatal underlying disease Immunodepression Cancer, hematologic malignancy Chronic liver disease Diabetes BMI > 30 Pregnancy/postpartum Bacterial coinfection SAPS 3, median SAPS 3 score . 50 Shock on admission Time from ARI to antiviral therapy, days Corticosteroid therapy† Vasopressors‡ ECMO‡ 76 45 77 16 24 14 10 20 68 12 55 50 79 68 5 55 89 24 (47.8) (34–55) (48.3) (10.0) (15.1) (8.8) (6.3) (12.6) (42.8) (7.6) (34.6) (43–61) (49.7) (42.8) (3–7) (34.6) (56.0) (15.1) Deceased (n 5 49) 29 49 33 13 17 12 4 7 18 2 11 61 39 31 5 28 39 8 (59.2) (42–56) (67.4) (26.5) (34.7) (24.5) (8.2) (14.3) (36.7) (4.1) (22.5) (53–82) (79.6) (63.3) (3–8) (57.1) (79.6) (16.3) HR (95% CI) 1.66 1.11 2.14 2.50 2.08 2.92 1.60 1.33 0.74 0.42 0.70 1.04 3.31 2.01 1.01 2.39 2.44 0.86 (0.92–2.98) (1.01–1.23)* (1.16–3.95) (1.29–4.84) (1.13–3.82) (1.51–5.63) (0.57–4.46) (0.59–2.97) (0.41–1.34) (0.10–1.75) (0.36–1.38) (1.03–1.06)* (1.68–6.51) (1.10–3.68) (0.93–1.10)* (1.32–4.31) (1.18–5.05) (0.40–1.85) P Value 0.09 0.04 0.01 0.006 0.02 0.001 0.37 0.49 0.32 0.23 0.30 ,0.0001 0.001 0.02 0.77 0.004 0.016 0.70 Definition of abbreviations: ARI 5 acute respiratory illness; BMI 5 body mass index; CI 5 confidence interval; ECMO 5 extracorporeal membrane oxygenation; IQR 5 interquartile range; SAPS 3 5 Simplified Acute Physiology Score, version 3. Data are reported as n (%) or median (IQR). * Per increase of 5 yr (age), 1 point of severity score (SAPS 3), or 1 d (time from ARI or time to antiviral therapy). † Time-dependent variable. ‡ Within first 3 d of mechanical ventilation. a potential role of excess ICU-acquired infections and pneumonia (Table 3). Other outcomes, such as critical illness neuromyopathy, were not assessed in our study. Our patients received corticosteroids at various initial doses, ranging from 200 to 1,600 mg of equivalent hydrocortisone. Differing dosages have been tested in previous clinical studies of steroids in ARDS from various etiologies (18, 23–26). In the ARDSNet trial testing steroids in persistent ARDS (19), patients received high initial dosages of 2 mg/kg/d methylprednisolone for 2 weeks, tapered over 3 weeks. The lower, moderate doses administered to patients in our cohort (Table 2) are consistent with those currently suggested for use in patients with ARDS (27). Finally, our patients received steroids for a median duration of 11 days, which may be viewed by some as shorter than required to achieve adequate control of lung inflammation, although the optimal duration of steroid therapy is unknown (27, 28). These results were obtained in a rather homogeneous population with severe influenza pneumonia treated in a single country; they should be interpreted with caution. The observational design of this study is an obvious limitation, as well as its organization through a national registry of ICU physicians voluntary to participate, limiting the amount of information coll- ected. Patients included in the REVA-SRLF registry, however, account for more than half of all patients admitted to ICUs throughout the country during the pandemic period, as notified to the French National Institute for Public Health Surveillance (14). A strength of this study, shared with other studies conducted in patients with severe influenza pneumonia (9, 10), is that it includes a homogeneous population of patients with a lung insult from a well-defined cause. In addition, we have validated the information collected through repeated direct contacts with the corresponding physician in each ICU. Our data should alert physicians to be very cautious when considering early corticosteroid therapy in patients with ARDS resulting from influenza pneumonia. Although our results do not exclude the possibility that some selected patients might benefit from corticosteroids, they strongly argue against their TABLE 5. COX REGRESSION ANALYSIS OF SURVIVAL IN 208 PATIENTS WITH ADULT RESPIRATORY DISTRESS SYNDROMEASSOCIATED WITH INFLUENZA A/H1N1V 2009 INFECTION Variable aHR 95% CI P Value Immunodepression SAPS 3 score . 50 Vasopressors* Corticosteroid therapy† 2.17 2.80 1.98 2.59 1.15–4.09 1.38–5.66 0.90–4.32 1.42–4.73 0.02 0.004 0.09 0.002 Definition of abbreviations: aHR 5 adjusted hazard ratio; CI 5 confidence interval; SAPS 3 5 simplified acute Physiology Score, version 3. Variables included but not retained in the model (at P , 0.10) were: sex, ultimately fatal disease, and shock on ICU admission. * Within first 3 d of mechanical ventilation. † Included as a time-dependent covariate. Figure 2. Estimated probability of receiving corticosteroid therapy in patients treated (T) or not treated (NT), stratified by quintiles (Q) of propensity score for steroid therapy. The propensity score was derived form multivariable analysis of patients’ characteristics and other initial interventions potentially associated with the administration of steroids. Brun-Buisson, Richard, Mercat, et al.: Steroids in Pandemic Influenza ARDS routine use early in the course of influenza-associated ARDS. Corticosteroid therapy should be considered as experimental therapy in severe viral pneumonia and tested only within the context of a placebo-controlled randomized trial, preferably testing delayed administration. Author Disclosure: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Acknowledgment: The authors thank Dr. Isabelle Bonmarin and Elise Chiron (French National Institute for Public Health Surveillance, St Maurice, France) for cross-checking notifications forms, as well as Mr. Wenceslas Yaba and Dr Tài Pham for data monitoring. They also thank the numerous physicians contributing to the REVA H1N1 registry. *Contributors to the REVA Influenza H1N1 2009 Registry (CHU 5 University hospital; CH 5 nonuniversity hospital): Arnaud W. Thille, Elise Cuquemelle, CHU Henri Mondor, Créteil; Francxois Blot, Institut Gustave Roussy, Villejuif; Achille Kouatchet, CHU d’Angers; Yves le Tulzo, CHU Pontchaillou, Rennes, Hadrien Rozé, CHU Haut-Léveque, Jérôme Pillot, CHU Pellegrin, Bordeaux; Jihad Youssef, CHU St-André, Bordeaux; Alexandre Duguet, CHU Pitié-Salpétrière, Paris; Francxois Fourrier, CHU Roger Salengro, Lille; Bertrand Guidet, CHU St Antoine, Paris; Christophe Faisy, CHU Georges Pompidou, Paris; Michel Rivoal, CH d’Arpajon; Claude Galland, CH de St Omer, Helfaut; Alain Combes, CharlesEdouard Luyt, Matthieu Schmidt, Alexis Soummer, CHU Pitié-Salpétrière, Paris; Philippe Quiniot, CH de Bretagne Sud, Lorient; Muriel Fartoukh, Michel Djibré, CHU Tenon, Paris; Jean Reignier, Centre hospitalier Les Oudaries, La Roche-surYon; Christian Bengler, CHU Carémeau, Nimes; Frank Thomas, Hôpital La Croix St Simon, Paris; René Robert, Hôpital Jean Bernard, CHU de Poitiers; Philippe Lutun, CHU Hautepierre, Strasbourg; David Osman, CHU Bicêtre, Le KremlinBicêtre; Daniel Villers, CHU Hotel-Dieu, Nantes; Daniel Tonduangu, CH Gaston Ramon, Sens; Boris Jung, CHU St Eloi, Montpellier; Pascal Beuret, CH de Roanne; Jack Richecoeur, CH René Dubos, Pontoise; Laurence Donetti, CH de Montfermeil; Matthieu Henry-Lagarrigue, CH de Versailles, Le Chesnay; Gaetan Beduneau, Fabien Soulis, CHU Charles Nicolle, Rouen; Jean-Damien Ricard, Rusel Leon, CHU Louis Mourier, Colombes; Claude Guérin, CHU Croix-Rousse, Lyon; Gilles Capellier, CHU Jean Minjoz, Besanc xon; Antoine Rabbat, CHU Hotel Dieu, Paris; Bruno Megarbane, CHU Lariboisière, Paris; Claire Boulle-Geronimi, CH Douai; Dominique Prat, CHU Antoine Béclère, Clamart; Jonathan Théodore, CH Salon-de-Provence; Philippe Berger, CH de Châlons-en-Champagne; Jean-Marie Tonnelier, CHU La Cavale Blanche, Brest; Yannick Monseau, CH de Périgueux; Cyril Charron, CHU Ambroise Paré, Boulogne-Billancourt; Anne-Gaelle Si-Larbi, CH Foch, Suresnes; Benoit Manoury, CH de St-Quentin; Matthias Castagnier, CHU Ste-Marguerite, Marseille; Alain Combes, CH de Meaux; Laurent Argaud, CHU Edouard Herriot, Lyon; Philippe Badia, Walter Picard, CH Franc xois Mitterand, Pau; Bernard Just, CH Manchester, Charleville-Mézières; Aymeric Luzi, Béatrice Riu-Poulenc, CHU Purpan, Toulouse; Bernard Georges, CHU Rangueil, Toulouse; Virginie Lemiale, CHU St Louis, Paris; Hervé Gastinne, CHU Dupuytren, Limoges; Pierre-Edouard Bollaert, Alexis Tatopoulos, CHU Central, Nancy; Jean Dellamonica, hopital Archet1, CHU de Nice; Nicolas Robin, CH de Nemours; Didier Thévenin, Clinique Dr Schaffner, Lens; Dany Goldgran-Toledano, CH de Gonesse; Bruno Mourvillier, CHU Bichat-Claude Bernard, Paris; Karim Merouani, CH Alenc xon; Christian Lemaire, Hôpital Victor Provo, Roubaix; Magali Ciroldi, CH André Grégoire, Montreuil; Vincent Cadiergue, CH D’Annonay; Robert Chausset, CH de Montlucxon; Santhy Sami-Modelia, CHU d’Amiens; Sylvène Rosselli, Emmanuel Vivier, CH St-Joseph et St-Luc, Lyon; Bernard Lecomte, CH d’Ajaccio; Marion Antona, CHU Raymond Poincaré, Garches; Jerome Hoff, CH de StNazaire; Jean-Louis Le Bivic, CH de Saintonge, Saintes; Thomas Lanz, CH Fleyriat, Bourg-en-Bresse; Jean-Claude Lachérade, Jean-Louis Ricôme, CH de Poissy-StGermain; Elie Zogheib, CHU Amiens Sud; Sylvie Calvat, CH d’Angoulême; Emmanuelle Mercier, Elodie Masseret, CHU Bretonneau, Tours; Sylvain Cantagrel, CHU Clocheville, Tours; Ali Ait Hssain, CHU Gabriel Montpied, ClermontFerrand; Mathieu Mattei, CH de Brive-la-Gaillarde; Jean-Franc xois Cesari-Giordani, CH Bonnet, Fréjus; Gilbert Guivarch, CH de St-Brieuc; Benoit Grandclerc, CH de Trappes; Sophie Malhiere, CH les Chaneaux, Macon; Matthieu Capron, CH de Moulins-Yzeure; Anne-Marie Guérin, CH de Beauvais; Jean Campistron, CH du Val d’Ariège, Foix; Pascal Hazera, CH Mémorial de St-Lô; Thierry Boulain, CH d’Orleans; Fabrice Tiger, CH d’Antibes Juan-les Pins; Marie-Hélène Hausermann, CH Henri Mondor, Aurillac; Khaldoun Kuteifan, CH Emile Muller, Mulhouse; Vincent Ribordy, Hôpital Cantonal de Fribourg, Switzerland; Michel Sirodot, CH d’Annecy; Claire Ara Somohano, Jean-Franc xois Timsit, Géraldine Dessertaine, CHU Albert Michallon, Grenoble; Fabien Grelon, CH du Mans; Jean-Michel Arnal, CH Fontpré, Toulon; Mehdi Bousta, CH Jean Monod, Le Havre; Tong Hang Chau, CH Léon Binet, Provins; Damien du Cheyron, CHU Cote de Nacre, Caen; René-Gilles Patrigeon, CH d’Auxerre; Patrick Ragot, Polyclinique Jean Villar, Bruges; Farhat Riyad, CH Dracenie, Draguignan; Jérôme Larché, CH de Narbonne; Julien Charpentier, Jean-Daniel Chiche, CHU Cochin, Paris; Ferran Roche Campo, Jordi Mancebo, Hôpital San Pau, Barcelona, Spain. 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