Ni et al.

Critical Care (2019) 23:99

https://doi.org/10.1186/s13054-019-2395-8

RESEARCH Open Access

The effect of corticosteroids on mortality of

patients with influenza pneumonia: a
systematic review and meta-analysis
Yue-Nan Ni1, Guo Chen2, Jiankui Sun3, Bin-Miao Liang1* and Zong-An Liang1

Abstract
Background: The effect of corticosteroids on clinical outcomes in patients with influenza pneumonia remains
controversial. We aimed to further evaluate the influence of corticosteroids on mortality in adult patients with
influenza pneumonia by comparing corticosteroid-treated and placebo-treated patients.
Methods: The PubMed, Embase, Medline, Cochrane Central Register of Controlled Trials (CENTRAL), and Information
Sciences Institute (ISI) Web of Science databases were searched for all controlled studies that compared the effects
of corticosteroids and placebo in adult patients with influenza pneumonia. The primary outcome was mortality, and
the secondary outcomes were mechanical ventilation (MV) days, length of stay in the intensive care unit (ICU LOS),
and the rate of secondary infection.
Results: Ten trials involving 6548 patients were pooled in our final analysis. Significant heterogeneity was found in
all outcome measures except for ICU LOS (I2 = 38%, P = 0.21). Compared with placebo, corticosteroids were associated
with higher mortality (risk ratio [RR] 1.75, 95% confidence interval [CI] 1.30 ~ 2.36, Z = 3.71, P = 0.0002), longer ICU LOS
(mean difference [MD] 2.14, 95% CI 1.17 ~ 3.10, Z = 4.35, P < 0.0001), and a higher rate of secondary infection (RR 1.98,
95% CI 1.04 ~ 3.78, Z = 2.08, P = 0.04) but not MV days (MD 0.81, 95% CI − 1.23 ~ 2.84, Z = 0.78, P = 0.44) in patients with
influenza pneumonia.
Conclusions: In patients with influenza pneumonia, corticosteroid use is associated with higher mortality.
Trial registration: PROSPERO (ID: CRD42018112384).
Keywords: Corticosteroids, Influenza pneumonia, Mortality

Introduction admitted into the intensive care unit (ICU), and 36% of
Influenza virus infections cause excessive hospitalizations those in the ICU developed ARDS [2].
and deaths among adults during seasonal peaks and pan- Influenza virus-induced pneumonia is related to an
demics. Among all patients infected with H7N9, 97% pre- uncontrolled response of the immune system [3–5]. Cor-
sented with rapidly progressive pneumonia, and 71% ticosteroids have been reported to reduce mortality in
presented with pneumonia caused by influenza virus in- patients with community-based pneumonia [6]. Patients
fection and complicated by acute respiratory distress syn- with life-threatening respiratory failure associated with
drome (ARDS); the death rate in these patients was as influenza pneumonia also commonly receive corticoste-
high as 46% [1]. In patients infected with H1N1, the rate roids. Animal model studies found that corticosteroid
of pneumonia was as high as 40%, 25% of patients were treatment decreased mortality and ameliorated the acute
lung injury induced by influenza pneumonia [7, 8]. Ste-
roids might play a role in inhibiting inflammation via
mechanisms such as reducing the overproduction of
* Correspondence: liangbinmiao@163.com
1
Department of Respiratory and Critical Care Medicine, West China School of proinflammatory cytokines/chemokines and an excess of
Medicine and West China Hospital, Sichuan University, No. 37 Guoxue Alley, activated lymphocytes, which may result in severe lung
Chengdu 610041, Sichuan, China damage and delayed recovery [9–11]. However, the
Full list of author information is available at the end of the article

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Ni et al. Critical Care (2019) 23:99 Page 2 of 9

results of clinical studies of the effect of corticosteroids determine eligibility. Disagreements were resolved by
remain controversial. In some studies, such as Diaz’s a third investigator (ZAL).
study, the use of corticosteroid therapy was not signifi-
cantly associated with mortality [12], while in others, Data extraction
such as the study of Brun-Buisson, early corticosteroid The two researchers independently extracted and re-
therapy was found to be potentially harmful in patients corded desirable information from each enrolled study
with influenza pneumonia [13]. in a standard form recommended by Cochrane; this
Therefore, based on these controversial findings re- information consisted of the authors, the publication
lated to corticosteroid use in adult patients with influ- year, the study design, the NCT No., population and
enza pneumonia, we conducted a systematic review and demographic characteristics (age, gender, etc.), disease
meta-analysis of all published trials that have compared
mortality between influenza pneumonia patients who re-
ceived corticosteroid therapy and those who did not. We
aimed to identify the roles of corticosteroids and their
influence on clinical outcomes in patients with influenza
pneumonia.

Methods
Search strategies
A literature search was conducted in the PubMed, Embase,
Medline, Cochrane Central Register of Controlled Trails
(CENTRAL), and Information Sciences Institute (ISI) Web
of Science databases using a combination of the following
key words: “glucocorticoid” or “corticosteroid” or “steroid”
or “cortisone” or “hydrocortisone” “prednisolone” or “meth-
ylprednisolone” or “prednisone” or “dexamethasone” or “tri-
amcinolone” and “influenza pneumonia” or “viral
pneumonia” without limitations on either the publication
type or language. This search was also limited to studies
published between 1946 and January 2019. The references
listed in each identified article were also screened and
manually searched.

Inclusion and exclusion criteria

Eligible clinical trials were identified based on the fol-
lowing criteria: (1) the subjects enrolled in each study
included patients with influenza pneumonia; (2) the pa-
tients were divided into an experimental group, in which
corticosteroids were applied, and a control group, in
which patients were assigned to not receive corticoste-
roids; and (3) the outcomes included but were not lim-
ited to mortality, mechanical ventilation (MV) days,
length of stay in the ICU (ICU LOS), and the rate of sec-
ondary infection. We excluded studies if they were per-
formed in animals or patients under 18 years old or
published as non-controlled studies, reviews, or case
reports.

Study selection
Two independent investigators (YNN and BML)
reviewed all titles and abstracts to discard duplicated
and non-controlled studies. Then, the full texts of the
remaining studies were screened in accordance with
Fig. 1 Study flow diagram
previously designed study inclusion criteria to
Ni et al. Critical Care (2019) 23:99 Page 3 of 9

conditions (e.g., The Acute Physiologic and Chronic Quality assessment

Health Evaluation II (APACHE II), the type of influ- To reduce the risk of bias, all of the studies were inde-
enza, treatment details (e.g., use of antiviral drugs pendently assessed by two authors (YNN and BML), and
and the type and initial dose of corticosteroids), the Newcastle-Ottawa Scale was used [14]. Disagree-
scores on the Simplified Acute Physiologic Score II ments related to quality assessment were resolved by
(SAPS II)), the Sequential Organ Failure Assessment consensus (Additional file 1).
(SOFA), and outcome measures (such as mortality,
MV days, ICU LOS, and rate of secondary infection). Statistical analysis
If any of the abovementioned information was not in- All statistical analyses performed in the present study
cluded in a publication, we contacted the correspond- were conducted by an independent statistician using
ing authors by email to obtain the data needed to Cochrane systematic review software Review Manager
quantify the measures of association. When the opin- (RevMan; Version 5.3.5; The Nordic Cochrane Centre,
ions of the two collectors differed, a decision was The Cochrane Collaboration, Copenhagen, 2014). The
reached by consensus or consultation with a third Mann-Whitney U test was performed to test the hypoth-
investigator. esis and define statistical significance as a Z value and P

Table 1 Characteristics of studies included in the present meta-analysis

Study ID Study design RCT Population Type of Type of Initial dose of corticosteroids Antiviral drug
no. (corticosteroids/control) influenza corticosteroids (mean ± SD)
Brun- Retrospective NR 83/125 H1N1 57.8% 328 ± 160 (equivalent NR
Buisson [13] analysis hydrocortisone hydrocortisone)
37.3%
methylprednisolone
4.8% prednisone
Cao [15] Retrospective NR 204/84 H7N9 91.7% 81.1 ± 83.2 (equivalent Corticosteroids
study methylprednisolone methylprednisolone) group: 201/204
3.9% Control group: 84/
dexamethasone 84
2.5% hydrocortisone
2.0% others
Diaz [12] Prospective NR 136/236 H1N1 NR NR Corticosteroids
observational group: 136/136
multicenter study Control group: 236/
236
Jung [16] Multicenter NR 99/120 H1N1 NR NR Survivor: 130/141
retrospective Death: 68/78
study
Perez- Retrospective NR 7/11 H1N1 NR NR NR
Padilla [17] study
Lee [18] Cohort study NR 264/817 H1N1 NR NR 151 in all the
patients
Li [19] Case control NR 1055/1086 H1N1 89.0% 141.3 ± 142 (equivalent Corticosteroids:
methylprednisolone methylprednisolone) 1025/1055
8.1% Control group:
dexamethasone 1022/1086
2.0% hydrocortisone
0.9% prednisolone
Moreno Secondary NR 604/1242 Viral A/ 95.7% A median (interquartile range) NR
[20] analysis of a B/C methylprednisolone; daily dose equivalent to 80
prospective 3.8% prednisolone; (60–120) mg of
cohort study 0.5% methylprednisolone
dexamethasone
Rois [21] Multicenter NR 75/103 H1N1 NR NR Survivors: 91/93
prospective Death: 82/85
study
Viasus [22] Observational, NR 37/160 H1N1 NR NR Corticosteroids
prospective group: 8/37
cohort study Control group: 41/
160
NR not reported, SD standard deviation
Ni et al. Critical Care (2019) 23:99 Page 4 of 9

Table 2 Characteristics of patients included in the present analysis

Study ID Corticosteroids (n = 2564) Control (n = 3984)
Age Male BMI APACHE II SAPS III Age (year) Male BMI APACHE II SAPS III
(year) (n,%) (n,%)
Brun-Buisson [13] 49 (34–56) 47 (56.6) 29 (24–33) NR 51 (44–61) 45 (35–55) 56 (44.8) 27 (23–33) NR 53 (46–66)
Cao [15] NR NR NR NR NR NR NR NR NR NR
Diaz [12] 43.1 (12.9) 50.7 (69) NR 13.25 (6.26) NR 43.6 (13.6) 57.6 (69) NR 12.54 (6.7) NR
Jung [16] NR NR NR NR NR NR NR NR NR NR
Perez-Padilla [17] NR NR NR NR NR NR NR NR NR NR
Lee [18] NR NR NR NR NR NR NR NR NR NR
Li [19] 35.0 (23.8–52.4) 530 (50.2) NR NR NR 33.7 (24.6–48.7) 565 (52) NR NR NR
Moreno [20] 53 (41–62) 357 (59.1) NR 14 (10–19) NR 51 (39–61) 739 (59.5) NR 15 (10–20) NR
Rois [21] NR NR NR NR NR NR NR NR NR NR
Viasus [22] 44 (36–53) 15 (40.5) NR NR NR 34 (26–44.5) 13 (41.9) NR NR NR
APACHEII Acute Physiologic and Chronic Health Evaluation II, BMI body mass index, NR not reported, SAPS III Simplified Acute Physiologic Score III

value < 0.05. The results are displayed in Forest plots. remaining 5 were extracted from a review of reference lists
Continuous variables are reported as the mean and (Fig. 1). After screening titles and abstracts, we discarded
standard deviation (SD), while dichotomous variables are 617 studies because they were duplicates (n = 119), animal
shown as frequencies and proportions. Statistical hetero- experiments (n = 248), non-adult patients (n = 177), or
geneity was tested by the χ2 test and qualified as P < 0.1 non-randomized controlled studies (NRCTs, n = 73). We
and I2 > 50%. We also performed a sensitivity analysis to searched the full-text articles of the remaining 17 studies,
substitute alternative decisions or ranges of values for and after we excluded those with inadequate reporting of
decisions that were arbitrary or unclear. A outcomes (n = 7), 10 reports were included in our final
random-effects model was applied in the presence of analysis.
statistical heterogeneity. For continuous data, we calcu-
lated the mean difference (MD) and 95% confidence Study description
interval (CI), while for dichotomous data, we calculated All 10 studies compared outcomes between cortico-
the risk ratio (RR) and 95% CI. We also performed sub- steroid and non-corticosteroid groups. Mortality was
group analyses according to viral types. recorded in all 10 studies [12, 13, 15–22], MV days
were described in three studies [12, 13, 20], the rate
Results of secondary infection was presented in five studies
A total of 634 records were initially identified. Of these, 629 [12, 13, 15, 19, 20], and the ICU LOS was reported
were extracted from electronic databases, and the in two studies [13, 20]. Eight studies included patients
Table 3 Risk of bias summary
A. Selection B. Comparability C. Outcome
of cohorts
Represent-activeness of Selection of Ascertainment Outcome not Assessment of F/U long Adequacy of
exposed cohort non-exposure of exposure present at start exposure enough? F/U
Brun-Buisson ☆ ☆ ☆ ☆ ☆ ☆
[13]
Cao [15] ☆ ☆ ☆ ☆ ☆ ☆
Diaz [12] ☆ ☆ ☆ ☆ ☆ ☆ ☆
Jung [16] ☆ ☆ ☆ ☆ ☆ ☆ ☆
Perez-Padilla [17] ☆ ☆ ☆ ☆ ☆ ☆
Lee [18] ☆ ☆ ☆ ☆ ☆ ☆ ☆
Li [19] ☆ ☆ ☆ ☆ ☆ ☆ ☆
Moreno [20] ☆ ☆ ☆ ☆ ☆ ☆
Rois [21] ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆
Viasus [22] ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆
Stars indicate the scores assigned to each study
Ni et al. Critical Care (2019) 23:99 Page 5 of 9

Fig. 2 Effect of corticosteroids on mortality. CI, confidence interval; RR, risk ratio

infected with H1N1, one included patients infected Heterogeneity

with H7N9 [15], and another included patients with Significant statistical heterogeneity was found in the ana-
viral A/B/C [20]. The details of each enrolled study lysis of the effect of corticosteroids on mortality (I2 = 84%,
are presented in Table 1. P < 0.00001), MV days (I2 = 53%, P = 0.12), and the rate of
A total of 6548 patients were pooled from all the in- secondary infection (I2 = 94%, P < 0.00001) in the patients
cluded trials into our final systematic review and with influenza pneumonia, but not in ICU LOS (I2 = 38%,
meta-analysis. Among these, 2564 patients were treated P = 0.21).
with corticosteroids, and 3984 were treated with
non-corticosteroids. The detailed baseline characteristics Mortality
of the patients in each enrolled study are shown in Mortality was higher in patients who received corticoste-
Table 2. roids (RR 1.75, 95% CI 1.30 ~ 2.36, Z = 3.71, P = 0.0002).
Similar results were also observed in the subgroup ana-
Quality assessment lysis of patients with H1N1 (RR 1.69, 95% CI 1.15 ~ 2.47,
To ascertain quality, a maximum of nine points was Z = 2.68, P = 0.007) (Figs. 2, and 3) and patients with
assigned to each study: four for selection, two for other viral types (Additional file 2).
comparability, and three for outcomes. A composite
score > 6 was regarded as indicative of high quality. MV days
Two studies were rated a total score of 9, four studies Corticosteroids had no effect on MV days (MD 0.81,
had a score of 7, and four studies had a score of 6 95% CI − 1.23 ~ 2.84, Z = 0.78, P = 0.44) (Fig. 4). The
(Table 3). The funnel plots showed no evidence of same result was found in the subgroup analysis
publication bias. (Additional file 2).

Fig. 3 Subgroup analysis of the effect of corticosteroids on mortality in patients with H1N1. Diamonds indicate overall estimates from the meta-
analysis; squares indicate point estimates of the result of each study; horizontal lines represent 95% CI. CI, confidence interval; RR, risk ratio
Ni et al. Critical Care (2019) 23:99 Page 6 of 9

Fig. 4 Effect of corticosteroids on MV days. Diamonds indicate overall estimates from the meta-analysis; squares indicate point estimates of the
result of each study; horizontal lines represent 95% CI. CI, confidence interval; MV, mechanical ventilation; MD, mean difference

ICU LOS 27]. One of our included studies showed that patients
ICU LOS was longer in the corticosteroid group (MD 2.14, who received corticosteroids had lower procalcitonin
95% CI 1.17 ~ 3.10, Z = 4.35, P < 0.0001) (Fig. 5), and the levels (0.5 vs 0.7 ng/mL, P = 0.02) [20], while another
same result was found in the subgroup analysis showed that the patients who died had a higher rate
(Additional file 2). of immunosuppression (34.7% vs. 15.1%, P = 0.02)
[13]. Second, our analysis found that patients who re-
Secondary infection ceived corticosteroids were more likely to develop
The rate of secondary infection was higher in patients secondary bacterial pneumonia due to immunosup-
who received corticosteroids (RR1.98, 95% CI 1.04 ~ pression. In addition, longer ICU LOS has also been
3.78, Z = 2.08, P = 0.04) than in the control group (Fig. 6), shown to contribute to secondary infection [28].
and the same result was found in the subgroup analysis Third, due to immune-suppressing effects of cortico-
(Additional file 2). steroids, the risk of developing critical illness is in-
creased in corticosteroid-treated patients [29]. One
Discussion study found that the rate of shock was 8% in the cor-
In the present systematic review and meta-analysis, the ticosteroid group and 4.4% in the control group [19].
use of corticosteroids increased mortality, ICU LOS, and In addition, the invasive MV rate was also increased
the rate of secondary infection in patients with influenza by corticosteroids, at 38.4% in the corticosteroid
pneumonia but did not influence MV days. group and 4.5% in the control group [19]. Fourth,
Our analysis demonstrates that corticosteroids not other corticosteroid-related adverse outcomes, such as
only increase mortality but also prolong ICU LOS. There cardiovascular events, including fluid retention, pre-
are several potential mechanisms that could underlie the mature atherosclerotic disease, and arrhythmias, also
higher mortality and ICU LOS observed in patients who increased mortality in patients with influenza pneu-
received corticosteroids. First, corticosteroids reduce monia [30–32]. In the included studies, patients who
systemic inflammation [23]. Once attacked by the virus, used more vasopressors had higher mortality [13].
the immune system is activated [24]. Corticosteroids in- Thus, the above mechanisms may contribute to why
hibit immune reactions by suppressing inflammatory reac- patients with influenza pneumonia had higher
tions, preventing the migration of inflammatory cells from mortality.
the circulation to issues by suppressing the synthesis of We also performed a subgroup analysis according to
chemokines and cytokines, and inhibiting immune re- viral types. In all types of influenza virus, mortality was
sponses mediated by T cells and B cells [25, 26]. Thus, the higher in those treated with corticosteroids than in con-
alterations in immune reactions caused by corticosteroids trols, although symptoms were more rapidly progressive
might lead to prolonged virus viremia and delay viral patients and the risk of ARDS higher in patients infected
clearance, ultimately increasing the risk of mortality [6, with H7N9 [1, 2]. Moreover, we included more large

Fig. 5 Effect of corticosteroids on ICU LOS. Diamonds indicate overall estimates from the meta-analysis; squares indicate point estimates of the
result of each study; horizontal lines represent 95% CI. CI, confidence interval; ICU, intensive care unit; LOS, length of stay; MD, mean difference
Ni et al. Critical Care (2019) 23:99 Page 7 of 9

Fig. 6 Effect of corticosteroids on the rate of secondary infection. Diamonds indicate overall estimates from the meta-analysis; squares indicate
point estimates of the result of each study; horizontal lines represent 95% CI. CI, confidence interval; RR, risk ratio

sample studies than were included in previous In terms of MV days, corticosteroids did not seem to
meta-analyses related to influenza [33]. In addition, make a difference. However, only three studies in our
we focused only on patients with influenza pneumo- analysis reported data on MV days, and the insignificant
nia and not on those infected with influenza alone or results might therefore be due to the fact that we had
those with influenza who were admitted to the ICU. such a small sample size. In other words, a type II error
Influenza pneumonia has been shown to be related to might have occurred because of the limited number of
life-threatening respiratory failure and mortality [34]; patients.
however, not all patients infected with influenza de- Other than the aforementioned reasons, the effects of
velop influenza pneumonia. In the present study, we corticosteroids could also be influenced by the following
tried to determine whether patients who develop in- three factors. First, the condition of the respiratory system
fluenza pneumonia benefit from corticosteroids. could be responsible. Corticosteroids can provide benefits
Nevertheless, we may have omitted patients with in- to patients with an oxygenation index (OI; partial arterial
fluenza pneumonia who were included in trials that pressure of oxygen/fraction of inspired oxygen) < 300, but
studied all influenza patients, and this may have influ- it may also increase the 60-day mortality rate in those with
enced the final results of our analysis. OI > 300 [19]. Second, the time of corticosteroid initiation
Studies exploring the effects of corticosteroids on could be a contributing factor. Compared with no treat-
patients with community-based pneumonia have pro- ment, administration within the first 3 days was more
duced positive results [6]. The main reason for these strongly associated with an increased risk of death [13,
findings is that those infected by bacteria benefit from 36]. Moreover, corticosteroids are beneficial if used early
corticosteroids when given appropriate antibiotic ther- after ARDS onset but otherwise increase mortality. In
apy. The early use of antiviral therapy could also re- reality, however, some patients received corticosteroids
duce mortality. Seven studies reported the use of after ARDS onset, which offset the negative effect of corti-
antiviral therapy. On the one hand, we did not ex- costeroids on mortality [37]. Third, the dose of corticoste-
plore the exact role of antiviral therapy in the effects roids may affect results. High doses of corticosteroids
of corticosteroids due to a lack of raw data. On the have been associated with greater mortality and a longer
other hand, we also only included patients who devel- duration of viral shedding [15]. In Li’s study, mortality was
oped influenza pneumonia, which resulted in the in- twice as high in patients who received a high dose of corti-
cluded cases being more severe than those included costeroids than in those who received a low-moderate
in studies in which patients using antiviral therapy dose [19]. The initial dose of corticosteroids varied among
were included. our included studies, and some of them did not report re-
Moreover, patients who received corticosteroids were lated information. Additionally, due to the study design,
more likely to have a superinfection, such as secondary not all patients in one study received a unified dose of cor-
bacterial pneumonia or invasive fungal infection, and ex- ticosteroids. Moreover, studies have shown that corticoste-
acerbation of underlying conditions, and they also had roids are usually initiated when shock is non-responsive to
more prolonged ICU LOS than was found in the fluids and vasopressors. Thus, patients who receive corti-
no-corticosteroid group [35]. In addition, one study costeroids tend to have more severe disease, as evidenced
showed that the use of corticosteroids delayed the initi- by their higher APACHE II scores [36]. It is therefore un-
ation of neuraminidase inhibitors, with ICU LOS longer clear whether their increased risk of mortality is directly
in patients who did not receive neuraminidase inhibitors associated with corticosteroid use or due to the severity of
within 5 days of illness [18]. disease. None of the studies included in our analysis was a
Ni et al. Critical Care (2019) 23:99 Page 8 of 9

randomized controlled study (RCT). Because the influen- Ethics approval and consent to participate
cing factors could not be controlled, our analysis was Each enrolled trial was approved by the corresponding institutional ethical
committee, and all participants provided written informed consent.
highly heterogeneous. This might explain why corticoste-
roids did not make a difference in some studies. Consent for publication
Despite these findings, the limitations of our study Not applicable.
should be addressed. First, the applicability of our study
Competing interests
results is limited because none of the studies included in The authors declare that they have no competing interests.
our analysis was an RCT. Second, only two studies re-
ported the dose of corticosteroids and the duration of it
Publisher’s Note
use. Third, the baseline characteristics of the patients Springer Nature remains neutral with regard to jurisdictional claims in
can influence outcomes and varied among the studies published maps and institutional affiliations.
included in our analysis. For example, younger age and
Author details
fewer underlying diseases might be associated with fewer 1
Department of Respiratory and Critical Care Medicine, West China School of
secondary infections [38]. Finally, the effect of cortico- Medicine and West China Hospital, Sichuan University, No. 37 Guoxue Alley,
steroids on patients with influenza pneumonia remains Chengdu 610041, Sichuan, China. 2Department of Geriatrics, Sichuan
Academy of Medical Sciences & Sichuan Provincial People’s Hospital,
controversial. Previous studies that showed a negative ef- Chengdu, Sichuan, China. 3State Key Laboratory of Oral Diseases, West China
fect for corticosteroids may have influenced how the cli- School of Stomatology, Sichuan University, No. 14, Section 3 Renmin Nanlu,
nicians used corticosteroids in our included studies. Chengdu 610041, Sichuan, China.
Finally, there may have been selection bias because none Received: 15 January 2019 Accepted: 15 March 2019
of the studies included was an RCT.

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