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
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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.
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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.
References
1. Peter JV, John P, Graham PL, Moran JL, George IA, Bersten A.
Corticosteroids in the prevention and treatment of acute respiratory
distress syndrome (ARDS) in adults: meta-analysis. BMJ 2008;336:
1006–1009.
1205
2. Tang BM, Craig JC, Eslick GD, Seppelt I, McLean AS. Use of
corticosteroids in acute lung injury and acute respiratory distress
syndrome: a systematic review and meta-analysis. Crit Care Med 2009;
37:1594–1603.
3. Chen RC, Tang XP, Tan SY, Liang BL, Wan ZY, Fang JQ, Zhong N.
Treatment of severe acute respiratory syndrome with glucosteroids:
the Guangzhou experience. Chest 2006;129:1441–1452.
4. Sung JJ, Wu A, Joynt GM, Yuen KY, Lee N, Chan PK, Cockram CS,
Ahuja AT, Yu LM, Wong VW, et al. Severe acute respiratory
syndrome: report of treatment and outcome after a major outbreak.
Thorax 2004;59:414–420.
5. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of
treatment effects. PLoS Med 2006;3:e343.
6. Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD,
Lochindarat S, Nguyen TK, Nguyen TH, Tran TH, et al. Avian influenza
A (H5N1) infection in humans. N Engl J Med 2005;353:1374–1385.
7. Jung K, Alekseev KP, Zhang X, Cheon DS, Vlasova AN, Saif LJ.
Altered pathogenesis of porcine respiratory coronavirus in pigs due to
immunosuppressive effects of dexamethasone: implications for corticosteroid use in treatment of severe acute respiratory syndrome
coronavirus. J Virol 2007;81:13681–13693.
8. Salomon R, Hoffmann E, Webster RG. Inhibition of the cytokine
response does not protect against lethal H5N1 influenza infection.
Proc Natl Acad Sci USA 2007;104:12479–12481.
9. Webb SA, Pettila V, Seppelt I, Bellomo R, Bailey M, Cooper DJ,
Cretikos M, Davies AR, Finfer S, Harrigan PW, et al., The ANZIC
Influenza investigators. Critical care services and 2009 H1N1 influenza in Australia and New Zealand. N Engl J Med 2009;361:
1925–1934.
10. Kumar A, Zarychanski R, Pinto R, Cook DJ, Marshall J, Lacroix J,
Stelfox T, Bagshaw S, Choong K, Lamontagne F, et al. Critically ill
patients with 2009 influenza A(H1N1) infection in Canada. JAMA
2009;302:1872–1879.
11. Quispe-Laime AM, Bracco JD, Barberio PA, Campagne CG, Rolfo VE,
Umberger R, Meduri GU. H1N1 influenza A virus-associated acute
lung injury: response to combination oseltamivir and prolonged
corticosteroid treatment. Intensive Care Med 2010;36:33–41.
12. Martin-Loeches I, Lisboa T, Rhodes A, Moreno RP, Silva E, Sprung C,
Chiche JD, Barahona D, Villabon M, Balasini C, et al. Use of early
corticosteroid therapy on ICU admission in patients affected by
severe pandemic (H1N1)v influenza A infection. Intensive Care
Med 2011;37:272–283.
13. Xi X, Xu Y, Jiang L, Li A, Duan J, Du B. Hospitalized adult patients
with 2009 influenza A(H1N1) in Beijing, China: risk factors for
hospital mortality. BMC Infect Dis 2010;10:256.
14. Fuhrman C, Bonmarin I, Bitar D, Cardoso T, Duport N, Herida M,
Isnard H, Guidet B, Mimoz O, Richard JC, et al. Adult intensive-care
patients with 2009 pandemic influenza A(H1N1) infection. Epidemiol
Infect 2010;26:1–8.
15. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson LD,
Lamy M, Le Gall JR, Morris AH, Spragg R. The American-European
consensus conference on ARDS: definitions, mechanisms, relevant
outcomes and clinical trials coordination. Am J Respir Crit Care Med
1994;149:818–824.
16. Brun-Buisson C, Richard J-CM, Mercat A, Brochard L, for the REVAGRIPPE-SRLF Registry. Corticosteroid therapy in early ARDS
secondary to Influenza A/H1N1 (2009) pneumonia: data from the
REVA-SRLF Registry [abstract]. Intensive Care Med 2010;36:S237.
17. Moreno RP, Metnitz PG, Almeida E, Jordan B, Bauer P, Campos RA,
Iapichino G, Edbrooke D, Capuzzo M, Le Gall JR. SAPS 3–From
evaluation of the patient to evaluation of the intensive care unit. Part
2: Development of a prognostic model for hospital mortality at ICU
admission. Intensive Care Med 2005;31:1345–1355.
18. Vittinghoff E, McCulloch CE. Relaxing the rule of ten events per variable
in logistic and Cox regression. Am J Epidemiol 2007;165:710–718.
19. Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy
R, Thompson BT, Ancukiewicz M. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med
2006;354:1671–1684.
20. Giannella M, Alonso M, Garcia de Viedma D, Roa PL, Catalan P, Padilla
B, Muñoz P, Bouza E. Prolonged viral shedding in pandemic influenza
A(H1N1): clinical significance and viral load analysis in hospitalized
patients. Clin Microbiol Infect (In press)
21. Lat A, Bhadelia N, Miko B, Furuya EY, Thompson GR III. Invasive
aspergillosis after pandemic (H1N1) 2009. Emerg Infect Dis 2010;16:
971–973.
1206
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
22. Roberts C, Nirmalan M, O’Shea S. Steroid-sensitive post-viral inflammatory pneumonitis (PVIP). Am J Respir Crit Care Med 2010;182:
1089–1090.
23. Meduri GU, Chinn AJ, Leeper KV, Wunderink RG, Tolley E, WinerMuram HT, Khare V, Eltorky M. Corticosteroid rescue treatment of
progressive fibroproliferation in late ARDS. Patterns of response and
predictors of outcome. Chest 1994;105:1516–1527.
24. Meduri GU, Headley AS, Golden H, Carson SJ, Umberger RA, Kelso
T, Tolley EA. Effect of prolonged methylprednisolone therapy in
unresolving acute respiratory distress syndrome. A randomized
controlled trial. JAMA 1998;280:159–165.
VOL 183
2011
25. Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, Gibson
M, Umberger R. Methylprednisolone infusion in early severe ARDS:
results of a randomized controlled trial. Chest 2007;131:954–963.
26. Annane D, Sebille V, Bellissant E. Effect of low doses of corticosteroids
in septic shock patients with or without early acute respiratory
distress syndrome. Crit Care Med 2006;34:22–30.
27. Meduri GU, Annane D, Chrousos GP, Marik PE, Sinclair SE. Activation and regulation of systemic inflammation in ARDS: rationale for
prolonged glucocorticoid therapy. Chest 2009;136:1631–1643.
28. Diaz JV, Brower R, Calfee CS, Matthay MA. Therapeutic strategies for
severe acute lung injury. Crit Care Med 2010;38:1644–1650.