Article

Efficacy of corticosteroid treatment for severe community-acquired pneumonia: A meta-analysis

a b s t r a c t

Background: The benefits and adverse effects of corticosteroids in the treatment of severe community-acquired pneumonia have not been well assessed. The aim of this systematic review of the literature and meta-anal- ysis was to evaluate the clinical efficacy of adjuvant Corticosteroid therapy in patients with severe CAP. Methods: The following databases were searched: PubMed, the Cochrane database, Embase, Wanfang, the China National Knowledge Infrastructure (CNKI), and the WeiPu (VIP) database in Chinese. Published randomized con- trolled clinical trial results were identified that compared corticosteroid therapy with conventional therapy for patients with severe CAP, up to November 2016. The Relative risk , Weighted mean difference , and 95% confidence interval (CI) were evaluated. Statistical analysis was performed using STATA 10.0. The quality of the published studies was evaluated using the Oxford quality scoring system (Jadad scale).

Results: Ten Randomized controlled trials were identified that included 729 patients with severe CAP. Data analysis showed that corticosteroid therapy did not have a statistically significant clinical effect in patients with severe CAP (RR: 1.19; 95% CI: 0.99-1.42), mechanical ventilation time (WMD: -2.30; 95% CI: -6.09-1.49). However, corticosteroids treatment was significantly associated with reduced in-hospital mortality (RR: 0.49; 95% CI: 0.29-0.85), reduced length of hospital stay (WMD: -4.21; 95% CI: -6.61 to -1.81).

Conclusion: Corticosteroids Adjuvant therapy in patients with severe CAP may reduce the rate of in-hospital mor- tality, reduce the length of hospital stay, and reduce CRP levels.

(C) 2017

  1. Introduction

Community-acquired pneumonia is a common and serious in- fection that has a reported annual hospitalization rate of 2.75-2.96 per 1000, and an in-hospital mortality rate of up to 14% [1-4]. However, the mortality of severe CAP is reported to rise to 20%-50% [1-4]. CAP can induce lung and systemic inflammation, severe sepsis, and acute re- spiratory distress syndrome (ARDS).

Corticosteroids are non-specific anti-inflammatory drugs that are commonly used as adjuvant treatment in patients with CAP and are rec- ommended in this role by current Chinese, European, and American clinical guidelines [5]. Corticosteroids have been shown to be beneficial in the treatment of respiratory inflammation to improve oxygenation and reduce the need for vasopressors by reducing inflammation.

? Conflict of interests: All authors declare that they have no conflict of interests. Acknowledgments: None.

* Corresponding author at: Intensive Care Unit, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China.

E-mail address: [email protected] (Q. Fang).

Corticosteroid adjuvant therapy in patients with severe CAP is contro- versial due to the concern for adverse clinical effects [6]. In multicenter Controlled clinical trials, corticosteroids have been reported to reduce the length of hospital stay, reduce the time to clinical recovery, and to improve Treatment outcome [6-8]. Also, a large clinical study that in- cluded 6925 patients concluded that corticosteroids could improve the survival rate of patients with CAP complicated by septic shock when compared with patients with severe CAP without shock [9]. Previously published controlled clinical studies have shown that adjunctive corti- costeroid therapy could improve the clinical and physiological respira- tory parameters and reduce the length of hospital stay [10-12]. Previously published systematic reviews of the literature and meta- analysis have shown that corticosteroids therapy could reduce the mor- tality in patients with severe CAP [12,13].

The previously published meta-analysis that explore the efficacy of corticosteroid in treatment of patients with severe community-acquired pneumonia has investigated only one or two indexes of the mor- tality, prognosis or the length of hospital stay. The aim of this systematic review of the literature and meta-analysis of published randomized controlled clinical trials was to evaluate the complected efficacy of cor- ticosteroid therapy in patients with severe CAP.

http://dx.doi.org/10.1016/j.ajem.2017.07.050

0735-6757/(C) 2017

  1. Methods
    1. Search strategy

The following databases were searched: PubMed, the Cochrane da- tabase, Embase, Wanfang, the China National Knowledge Infrastructure (CNKI), and the WeiPu (VIP) database in Chinese. Databases were searched using the following keywords: (“community acquired pneu- monia” OR “severe community acquired pneumonia“) AND (“cortico- steroids” OR “steroids” OR “prednisone” OR “hydrocortisone” OR “prednisolone”). Searches were conducted up to November 2016. Other related articles and reference materials were also searched. A lit- erature review was done by two independent investigators. When dis- agreement occurred, a third investigator was involved until consensus was reached.

Inclusion and exclusion criteria

The following inclusion criteria were used to identify the studies for analysis: (1) randomized controlled clinical trials; (2) inclusion of patients with severe CAP as defined by the current clinical guide- lines from the Infectious Disease Society of America and American Thoracic Society (ATS), or others criteria; (3) the inclusion of a comparative treatment group received conventional therapy, in- cluding antibiotics, oxygen therapy, expectorants, aerosol inhala- tion, nutritional supportive therapy, and Symptomatic treatment when necessary, plus placebo; (4) the inclusion of a treatment group who were treated with conventional therapy plus corticoste- roid adjuvant therapy, including the dose and length of therapy;

(5) providing the clinical outcomes, including the description of clin- ical features, incidence rate, and mortality; (6) publications only in the English literature and Chinese literature.

The following exclusion criteria were used: (1) duplicated publica- tions; (2) expert commentaries or review articles, conference reports, systematic reviews, previous meta-analysis, and case reports; (3) pub- lished theoretical or pharmaceutical reports; (4) controlled studies of therapeutic interventions in CAP that did not include corticosteroids;

(5) Inaccurate data that have obvious mistakes such as the number of deaths exceed the number of sample; (6) the main outcomes from the included studies were less than two of the analyzed indexes (clinical ef- ficacy, mechanical ventilation time, in-hospital mortality, the length of hospital stay). Literature screening was done by two independent inves- tigators. When disagreement occurred, a third investigator was in- volved until consensus was reached.

Data extraction and quality assessment

Data were extracted from the included studies in two parts. First, the basic characteristics of the studies included: the author name, date of publication, the interventions of the treatment group and the control group, the sample size, the percentage of male patients, patient age, and, the treatment period. Second, clinical outcomes included: clinical efficacy, in-hospital mortality, the length of hospital stay, mechanical ventilation time.

The quality of all the studies was evaluated by the Oxford quality scoring system (Jadad scale). The checklist for this scoring system consisted of five items: patient randomization; appropriateness of ran- domization generation; adequacy of double-blind procedure; descrip- tion of the double-blind method; details of patient’s exclusion and drop-out. If the quality score was b 3.0, the study was deemed to be of low-quality with a high risk of bias. If the quality score exceeded 3.0, the study was deemed to be of high-quality with a low risk of bias. Lit- erature quality scoring was done by two independent investigators. When disagreement occurred, a third investigator was involved until consensus was reached.

Data analysis

Chi-squared and I2 tests were used to evaluate the heterogeneity of the clinical trial results. When the Chi-squared test P-value was b 0.1 and the I2 test had a value N 50%, heterogeneity was deemed to be ac- ceptable by analysis and the random-effects model. When the Chi- squared test P-value was N 0.1 and the I2 test had a value b 50%, data ho- mogeneity was deemed to be acceptable by analysis and the random-ef- fects model. Continuous variables were expressed as the mean +- standard deviation (SD). The categorical data were presented as fre- quencies and percentages. Relative risk (RR) and the 95% confidence in- terval (CI) were used to analyze the clinical efficacy, in-hospital mortality. Weighted mean difference (WMD) and 95% CI were used to analyze the length of hospital stay, and the mechanical ventilation time. Two-tailed P-values b 0.05 were considered to be statistically sig- nificant. All statistical analysis was performed using the STATA 10.0 data analysis and statistical software (StataCorp, LLC, TX, USA).

  1. Results
    1. Characteristics of published studies

The literature search retrieved a total of 691 articles; 633 articles were excluded based on review of the article title and the abstract,

Fig. 1. Flow chart of literature search and selection of studies.

Table 1

The main characteristics of included studies.

Study

Country

Number

Treatment

Gender

Age

The patient included

Control

Treat

Control

Treat

Control

Treat

Control

Treat

criteria

Antoni Torres [7]

Spain

59

61

Conventional therapy + placebo

Conventional therapy + 0.5 mg/kg per 12 h of methylprednisolone for 5 days

39 m

35 m

66.1

64.5

American Thoracic Society criteria

Silivia

Fernandez-Serrano [15]

Dominic Snijders

Spain

The

23

109

22

104

Conventional therapy + placebo

Conventional

Conventional therapy + MPDN

(METHYL-PREDNISOLONE) 20 mg/6 h for three days, 20 mg/12 h for three days, 20 mg/day for three days

Conventional therapy + 40 mg prednisolone for

14 m

69 m

16 m

55 m

61

64

66

63

The Respiratory Branch of the Chinese Medicine Academy

American Journal of

[16]

Netherlands

therapy +

placebo

7 days

Respiratory and

Critical Care

Katsunaka Mikami

Japan

16

15

Conventional

Conventional therapy + 40 mg prednisolone for

12 m

11 m

68.4

75.9

Medicine

American Thoracic

[17]

Marco Confalonieri

Italy

23

23

therapy + placebo

Conventional

3 days

Conventional therapy + hydrocortisone 200

15 m

17 m

66.6

60.4

Society criteria

PORT criteria

[19]

Paul Marik [20]

South Africa

16

14

therapy + placebo

Conventional

mg/day for 7 days

Conventional therapy + hydrocortisone 10

40.6

31.7

The Respiratory

Nirmeen A. Sabry

Egypt

40

40

therapy + placebo

Conventional

mg/kg

Conventional therapy + hydrocortisone 300

28 m

30 m

62.5

61.95

Branch of the Chinese Medicine Academy

American Thoracic

[21]

Sui, DongJiang [14]

China

30

30

therapy + placebo

Conventional

mg/day for 7 days

Conventional therapy + methylprednisolone 8

27 m 33f

62.71

Society criterion

British Thoracic

therapy +

mg/per 12 h for 7 days

Society criteria of

Zhou, Ming [18]

China

23

23

placebo

Conventional

Conventional therapy + methylprednisolone

30 m 16f

50.2

severe pneumonia

American Thoracic

Li, Gang [22]

China

29

29

therapy + placebo

Conventional

120 mg/per day for 7 days

Conventional therapy + methylprednisolone 80

16 m

15 m

59.32

62.31

Society criterion

The Respiratory

therapy +

placebo

mg/per day for 7 days

Branch of the

Chinese Medicine

Academy

and full text was obtained for the remaining 58 articles. Of these, 12 were repeat publications, 24 were not randomized controlled clinical trials (RCTs), eight did not contain clinical outcome data, and four pub- lications included patients with other non-pulmonary diseases. There were ten published RCT studies that satisfied the inclusion criteria, with 368 patients in the control group and 361 patients in the treatment group (Fig. 1). The main characteristics of the ten included studies are shown in Table 1 [7,14-22]. Five studies adopted the American Thoracic Society criterion, three studies adopted the Respiratory Branch of the Chinese Medicine Academy, one study adopted PORT criteria, and one study adopted British Thoracic Society criteria of severe pneumonia. Of the final ten studies, three studies were considered to be of good quality (Jadad/Oxford quality score 4-6), seven studies were of fair quality (Jadad/Oxford quality score 3) and one of poor quality (Jadad/Oxford quality score 1-2), with a mean quality score of 3.0 (Table 2).

In-hospital mortality

Seven published RCTs that included 592 patients reported the in- hospital mortality, which was 12.04% (36/299) for patients treated with placebo therapy versus 5.80% (17/293) for patients treated with corticosteroid therapy. Based on the Chi-squared test P = 0.307 N 0.1 and I2 = 7.15% b 50%, the fixed-effects model was selected to analyze the in-hospital mortality. Fig. 2 shows the results of the in-hospital mor- tality (RR: 0.49; 95% CI: 0.29-0.85) of the corticosteroid group, which was lower than the placebo group.

Clinical efficacy

Six published RCTs that included 577 patients reported the clinical efficacy of steroid therapy, which was 70.34% (204/290) in the placebo-treated group compared with 78.75% (226/287) in

Table 2

Jadad scores for Jadad scale.

Study

Jadad score

Generation of random sequences

Randomize hidden

Blind

Withdraw and exit

Antoni Torres [7]

5

2

0

2

1

Silivia Fernandez-Serrano [15]

2

2

0

0

0

Dominic Snijders [16]

5

2

0

2

1

Katsunaka Mikami [17]

3

1

0

2

0

Marco Confalonieri [19]

3

2

0

0

1

Paul Marik [20]

2

2

0

0

0

Nirmeen A. Sabry [21]

4

2

0

1

1

Sui, DongJiang [14]

2

2

0

0

0

Zhou, Ming [18]

2

2

0

0

0

Li, Gang [22]

2

2

0

0

0

Fig. 2. Effect of corticosteroids vs placebo on in-hospital mortality for severe community-acquired pneumonia .

the corticosteroid-treated group. Based on the Chi-squared test P = 0.006 b 0.1 and I2 = 16.41% b 50%, the random-effects model was chosen. Fig. 3 shows that there was no significant difference in clinical efficacy (RR: 1.19; 95% CI: 0.99-1.42) in the two groups.

Length of hospital stay

Seven published RCTs that included 499 patients reported the re- sults of the length of hospital stay. Based on the Chi-squared test P =

0.008 b 0.1 and I2 = 17.42% b 50%, the random-effects model was

Fig. 3. Effect of corticosteroids vs placebo on clinical efficiency for severe Community-acquired pneumonia .

Fig. 4. Effect of corticosteroids vs placebo on length of hospital stay for severe Community-acquired pneumonia .

chosen. Fig. 4 shows that the length of hospital stay (WMD: -4.21; 95% CI: -6.61 to -1.81) in corticosteroid-treated group was significantly lower than in the placebo-treated group.

Mechanical ventilation time

Four published RCTs that included 230 patients reported the me- chanical ventilation time. Based on the Chi-squared test P = 0.000 b

0.1 and I2 = 178.51% N 50%, the random-effects model was chosen to

analyze the mechanical ventilation time. Fig. 5 shows that there was no significant difference in the mechanical ventilation time (WMD:

-2.30; 95% CI: -6.09-1.49) between the two treatment groups.

  1. Discussion

This systematic review of the literature and meta-analysis of the clinical efficacy of corticosteroid therapy and clinical outcomes for pa- tients with severe community-acquired pneumonia resulted in

Fig. 5. Effect of corticosteroids vs placebo on mechanical ventilation time for severe Community-acquired pneumonia .

four main findings. Corticosteroid therapy in severe CAP reduced pa- tient mortality, reduced the length of hospital stay, reduced in-hospital patient mortality. However, corticosteroid therapy in severe CAP had no significant clinical efficacy, no significant influence on mechanical ven- tilation time. The findings regarding patient mortality and length of hos- pital stay are consistent with the previously published studies.

Only three of previously published meta-analysis has reported the corticosteroid therapy for patients with severe community-acquired pneumonia (SCAP) [12,13,23] that analysis the mortality, prognosis and the length of hospital stay. The others three meta-analysis explored the efficacy of corticosteroid in CAP [10,11,24]. Marti and colleagues [10] reported that adjunctive corticotherapy was associated with a reduction of length of stay, time to clinical stability, and severe complications among patients with CAP, but the effect on mortality remained uncer- tain. Horita and colleagues [11] found that corticosteroid therapy re- duced the length of hospital stay in patients with CAP, and the length of time to clinical recovery for patients with CAP, and reduced patient mortality in severe CAP. Cheng and colleagues [13] suggested that corti- costeroid therapy may reduce mortality and improve the prognosis of adult patients with severe CAP, the results should be interpreted with caution due to the instability of pooled estimates. Wan and colleagues

[24] found that short-term treatment with corticosteroids is safe and may reduce the risk of ARDS, shortening the length of the disease in pa- tients with CAP. Wang and colleagues [12] reported that corticosteroid therapy showed beneficial effects in the treatment of severe CAP in the elderly, and reduced patient mortality and length of hospital stay. This clinical efficacy of corticosteroid therapy in the treatment of pa- tients with severe CAP has recently been proposed [23].

This meta-analysis had limitations. First, the published studies ana- lyzed included different doses of corticosteroids and varying duration of treatment, which could result in analysis bias. Also, there were differ- ences in the patient inclusion criteria and exclusion criteria in the pub- lished studies. Published studies gave few details about previous diseases and treatments. Several low-quality RCTs were included in the study, and pooled data were used for analysis. Because of these lim- itations and the lack of available data on individual patients, the findings of this study should be interpreted with caution until further large, con- trolled, multicenter clinical studies become available.

  1. Conclusion

This systematic review of the literature identified ten controlled clin- ical trials that compared corticosteroid therapy with Standard care in patients with severe CAP, with an average Oxford quality score (Jadad scale) of 3.08. Meta-analysis supported that adjunctive corticosteroid therapy may be considered for patients with severe CAP to reduce hos- pital mortality, length of hospital stay. However, the findings of this meta-analysis should be supported by large-scale, multicenter, con- trolled clinical studies to confirm the clinical efficacy of corticosteroids in the treatment of patients with severe CAP.

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