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Respiratory infection
Impact of different corticosteroids on severe community-acquired pneumonia: a systematic review and meta-analysis
  1. Xin Ya See1,
  2. Tsu Hsien Wang2,
  3. Yu-Cheng Chang3,
  4. Juien Lo4,
  5. Weitao Liu5,
  6. Cheryn Yu Wei Choo6,
  7. Yu-Che Lee7,
  8. Kevin Sheng Kai Ma8,
  9. Cho-Hsien Chiang9,
  10. Yuan Ping Hsia10,
  11. Cho-Hung Chiang11 and
  12. Cho-Han Chiang12
  1. 1Department of Medicine, Unity Hospital, Rochester Regional Health, Rochester, New York, USA
  2. 2Department of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Foundation, New Taipei City, Taiwan
  3. 3Department of Medicine, Danbury Hospital, Danbury, Connecticut, USA
  4. 4Department of Medicine, University of California San Diego, San Diego, California, USA
  5. 5Department of Medicine, Yale New Haven Hospital, New Haven, Connecticut, USA
  6. 6Department of Internal Medicine, Singapore Health Services, Singapore
  7. 7Division of Pulmonary, Critical Care and Sleep Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA
  8. 8Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
  9. 9Department of Environmental and Occupational Medicine, National Taiwan University Hospital, Taipei, Taiwan
  10. 10Department of Family Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Foundation, New Taipei City, Taiwan
  11. 11Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
  12. 12Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, Massachusetts, USA
  1. Correspondence to Dr Yuan Ping Hsia; ustwhealth.datascience.group{at}gmail.com

Abstract

Objectives Randomised controlled trials (RCTs) have demonstrated conflicting results regarding the effects of corticosteroids on the treatment of severe community-acquired pneumonia (CAP). We aimed to investigate the efficacy and safety of different corticosteroids on patients who were hospitalised for severe CAP.

Methods We performed a systematic search through PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus from inception to May 2023. The primary outcome was all-cause mortality. Data analysis was performed using a random-effects model.

Results A total of 10 RCTs comprising 1962 patients were included. Corticosteroids were associated with a lower rate of all-cause mortality (risk ratio (RR), 0.70 (95% CI 0.54 to 0.90); I2=0.00%). When stratified into different corticosteroid types, hydrocortisone was associated with an approximately 50% lower mortality risk (RR, 0.48 (95% CI 0.32 to 0.72); I2=0.00%). However, dexamethasone, methylprednisolone or prednisolone were not associated with an improvement in mortality. Furthermore, hydrocortisone was associated with a reduction in the rate of mechanical ventilation, acute respiratory distress syndrome, shock and duration of intensive care unit stay. These trends were not observed for dexamethasone, methylprednisolone or prednisolone. Corticosteroids were not associated with an increased risk of adverse events including gastrointestinal bleeding, secondary infection or hyperglycaemia.

Conclusions The use of hydrocortisone, but not other types of corticosteroids, was associated with a reduction in mortality and improvement in pneumonia outcomes among patients hospitalised with severe CAP.

PROSPERO registration number

CRD42023431360.

  • Pneumonia
  • Respiratory Infection
  • Critical Care

Data availability statement

Data are available upon reasonable request. The authors confirm that the data supporting the findings of this study are available within the article or its supplementary materials. The template data collection forms and data used for all analyses including the analytic code can be obtained upon reasonable request from the corresponding author.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjresp-2023-002141

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Corticosteroids may provide mortality benefits in patients hospitalised for severe community-acquired pneumonia.

    WHAT THIS STUDY ADDS

    • Hydrocortisone, but not other corticosteroids, are associated with mortality benefits in patients hospitalised for severe community-acquired pneumonia.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Hydrocortisone may be used to treat patients hospitalised for severe community-acquired pneumonia.

    Introduction

    Severe community-acquired pneumonia (CAP) is a life-threatening form of pneumonia with high morbidity and mortality.1 In these patients, dysregulated lung and systemic inflammation can lead to sepsis, acute respiratory distress syndrome (ARDS) and end-organ damage.2 3 Systemic corticosteroids downregulate proinflammatory cytokine production and have been hypothesised to mitigate systemic inflammation and organ dysfunction, leading to improved outcomes of severe pneumonia.4 5

    Several randomised controlled trials (RCTs) have investigated the mortality benefits of adjunctive corticosteroids in patients with severe CAP, but the results have been inconclusive. For example, in the ESCAPe (Extended Steroid in Use in Community Acquired Pneumonia) and Santeon-CAP (dexamethasone in community-acquired pneumonia) trials, the use of methylprednisolone and dexamethasone did not improve mortality risk in patients with severe CAP.6 7 However, the CAPE COD (community-acquired pneumonia: evaluation of corticosteroids) trial showed that hydrocortisone reduces all-cause mortality in patients with CAP admitted to an intensive care unit (ICU).8

    Previous meta-analyses have attempted to address these inconsistencies by summarising evidence from RCTs,9–11 but the data have been conflicting. In aggregate-data meta-analyses conducted by Siemieniuk and colleagues and Wu and colleagues,10 11 corticosteroids were associated with a reduction in mortality in severe CAP. However, an individual patient data meta-analysis performed by Briel and colleagues showed no mortality benefits associated with corticosteroids in severe CAP.9 In a recent meta-analysis conducted by Pitre and colleagues, only hydrocortisone provided mortality benefits.12 However, this analysis included both severe and non-severe CAP. Based on prior data, corticosteroids were associated with subgroup effects based on disease severity.10 Therefore, an updated and focused meta-analysis is warranted to evaluate the effects of different corticosteroids on severe CAP. In this systematic review and meta-analysis, we aimed to evaluate the efficacy and safety of different types of corticosteroids in patients who were hospitalised for severe CAP.

    Methods

    Data sources and searches

    We conducted a systematic review through PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science and Scopus, searching for studies published from inception to May 2023, without language restrictions, using an approach that incorporated keywords including pneumonia and corticosteroids (online supplemental table 1). Referenced citations of included studies as well as articles citing the included studies were manually searched to identify any other potentially relevant studies. Articles published in languages other than English were interpreted using Google Translate. This study was performed in accordance with the PRISMA guidelines.13 The review protocol is registered with PROSPERO (CRD42023431360).

    Study selection

    Eligible studies were RCTs that investigated the effectiveness of intravenous or oral corticosteroid therapy in adults hospitalised for severe CAP. Corticosteroids included hydrocortisone, prednisolone, methylprednisolone and dexamethasone. Studies were required to report on at least one of the following outcomes: all-cause mortality, need for mechanical ventilation or development of serious complications of CAP or adverse events commonly associated with corticosteroids. Studies that focused on specific pneumonia populations, such as ventilator-associated pneumonia, aspiration pneumonia or Pneumocystis jirovecii pneumonia as well as those limited to specific patient populations such as chronic obstructive pulmonary disease or diabetes mellitus, were excluded from the analysis. Severe CAP was defined according to commonly used criteria: a Pneumonia Severity Index score of IV or V,14 a CURB-65 (Confusion, blood Urea nitrogen, Respiratory rate, Blood pressure, and age 65 or older) score greater than 2,15 fulfilment of one major or three minor criteria from the 2007 consensus guideline of the Infectious Diseases Society of America and the American Thoracic Society,16 a score of 3 or greater using British Thoracic Society criteria,17 development of respiratory failure defined by a PaO2:FiO2 <300 or admission to the ICU (online supplemental table 2). Studies that enrolled patients with different severity of CAP were included if they reported subgroup data on severe CAP. The primary authors were contacted when subgroup data were not available in the published article.

    The eligibility of each study was determined through a rigorous screening process conducted by two reviewers (CHa Chiang and CHu Chiang), who independently screened titles and abstracts, and obtained full texts of articles that were considered potentially eligible. The final inclusion of studies was determined through discussion with a third reviewer (JL). The inclusion and exclusion of included studies are summarised in online supplemental table 3.

    Data abstraction and quality assessment

    Two reviewers (CHa Chiang and Y-CC) independently extracted data on study demographics and outcomes of interest. The outcomes were all-cause mortality, requirement for mechanical ventilation, duration of stay in the ICU and development of complications or adverse events including shock, ARDS, hyperglycaemia requiring treatment, secondary infection and gastrointestinal bleeding. Two reviewers (XYS and THW) evaluated the risk of bias in individual studies using the Cochrane risk-of-bias tool for randomised trials.18 In cases of disagreements, a consensus was reached by discussing with a third reviewer (YPH).

    Data synthesis and analysis

    We used a random-effects model based on the DerSimonian and Laird approach by using risk ratios (RRs) for dichotomous outcomes and mean differences for continuous outcomes. For outcomes with fewer than five studies, we used the Hartung-Knapp-Sidik-Jonkman model.19 20 In studies reporting only the median, range and size of the trial, we approximated the means and SD using previously established techniques.21 We used the inconsistency index (I2) statistic to evaluate the extent of interstudy heterogeneity.22 The I2 value ranges from 0% to 100%, where I2<25% signifies minimal heterogeneity, 25%≤I2<50% signifies moderate heterogeneity, 50%≤I2<75% signifies substantial heterogeneity and I2>75% indicates large heterogeneity. Publication bias was evaluated through inspection of the Funnel’s plot and statistical testing using the Egger’s test.

    For all outcomes, we compared the effects of different types of corticosteroids: dexamethasone, hydrocortisone, methylprednisolone and prednisolone on CAP outcomes. For the outcome of all-cause mortality, we performed additional subgroup analyses on potential sources of heterogeneity: risk of bias, cumulative dose of corticosteroids administered and geographic location of study. To calculate the cumulative dosages of corticosteroids, we converted all types of corticosteroids to the equivalent dosages of dexamethasone. We used the recommended dose of dexamethasone for the treatment of COVID-19 (ie, 6 mg/day for up to 10 days with a cumulative dose of 60 mg) as a cut-off to distinguish between low-dose and high-dose corticosteroids. To address differences between studies that could contribute to biased results, we performed sensitivity analyses by excluding studies that only included patients admitted to the ICU and studies that did not exclude patients with sepsis or septic shock. All analyses were performed using STATA V.16.0 (StataCorp, College Station, Texas). All p values were two-tailed and were considered statistically significant if less than 0.05.

    Results

    The initial search identified 7830 articles. After the removal of duplicates, 4878 articles remained. Of these articles, 151 studies underwent full-text review. Three trials were excluded because they included a mixed population of severe and non-severe CAP but did not report data on severe CAP.23–25 One trial was excluded because it did not report on prespecified study outcomes.26 We attempted to contact the authors of these trials through emails but did not obtain any responses. Two trials were excluded because they defined CAP severity based on clinical impression without the use of objective criteria.27 28 One study used corticosteroids as part of a bundled intervention and was excluded.29 Subsequently, a total of 10 studies were included in the final analysis (figure 1).

    Figure 1
    Figure 1

    Flowchart showing the process of systematic review. CAP, community-acquired pneumonia.

    Study characteristics

    Among the 10 trials, 6 studies were conducted in Europe,7 8 30–33 2 in the USA6 34 and 2 in the Middle East35 36 (table 1). A total of 1962 patients were enrolled, with sample sizes ranging from approximately 30 to 800 hospitalised patients. Only one study received pharmaceutical funding.7 The corticosteroid regimen varied across studies, including dexamethasone in one trial,7 prednisolone in one trial,31 methylprednisolone in three trials6 32 33 and hydrocortisone in five trials.8 30 34–36 All studies used a placebo in the control group. Most of the studies excluded patients who had conditions requiring corticosteroids prior to enrolment.6–8 30–33 35 Two trials excluded patients with sepsis or septic shock8 32 (online supplemental table 4).

    View this table:
    Table 1

    Summary of study characteristics

    Risk-of-bias assessment

    Among the 10 studies included, 9 trials were double blinded6–8 30–33 35 36 and 1 trial was open labelled34 (table 1). Six studies were evaluated as having a low risk of bias,6–8 30 31 33 while four studies were determined to have some concerns over the risk of bias due to the randomisation process.32 34–36 Two studies also had some risk of bias in the measurement of the outcome34 35 (online supplemental table 5).

    Outcomes

    All-cause mortality

    All studies (1962 patients) reported on outcomes in all-cause mortality. Corticosteroids were associated with a 30% lower rate of all-cause mortality compared with placebo (RR, 0.70 (95% CI 0.54 to 0.90); I2=0.00%) (figure 2). The mortality benefits varied according to the type of corticosteroid used. Patients receiving hydrocortisone had an approximately 50% lower mortality risk as compared with placebo (RR, 0.48 (95% CI 0.32 to 0.72); I2=0.00%). On the other hand, patients receiving dexamethasone, methylprednisolone or prednisolone did not experience a reduction in mortality. There is no publication detected on the funnel plot (online supplemental figure 1).

    Figure 2
    Figure 2

    Forest plot summarising the effects of corticosteroids on all-cause mortality. Note: The inconsistency index (I2) statistic indicates the extent of inter-study heterogeneity.

    Mechanical ventilation

    Six studies (763 patients) reported on outcomes in mechanical ventilation. Corticosteroids were associated with about 50% lower rate of mechanical ventilation compared with placebo (RR, 0.54 (95% CI 0.43 to 0.67); I2=0.00%) (online supplemental figure 2). Patients who received hydrocortisone experienced an approximately 50% reduction in the need for mechanical ventilation (RR, 0.54 (95% CI 0.43 to 0.69); I2=0.00%), whereas patients who received methylprednisolone did not experience this reduction (RR, 0.44 (95% CI 0.17 to 1.10); I2=0.00%).

    Acute respiratory distress syndrome

    Four studies (666 patients) reported on the outcome of ARDS. Corticosteroids were associated with a 55% lower rate of ARDS compared with placebo, but this risk reduction was not statistically significant (RR, 0.45 (95% CI 0.14 to 1.43); I2=40.49%) (online supplemental figure 3). Patients who received hydrocortisone experienced a 77% reduction in ARDS (RR, 0.23 (95% CI 0.07 to 0.82); I2=3.46%), whereas patients who received methylprednisolone did not experience this reduction (RR, 1.14 (95% CI 0.46 to 2.83)).

    Shock

    Seven studies (1573 patients) reported on the outcome of shock. Corticosteroids were associated with a 60% lower rate of shock compared with placebo (RR, 0.40 (95% CI 0.21 to 0.77); I2=53.03%) (online supplemental figure 4). Patients who received hydrocortisone experienced a 78% reduction in shock (RR, 0.22 (95% CI 0.06 to 0.74); I2=67.29%), whereas patients who received methylprednisolone did not experience this reduction (RR, 0.69 (95% CI 0.29 to 1.63); I2=22.93%).

    Duration of ICU stay

    Five studies (1808 patients) reported on the duration of ICU stay. Corticosteroids were associated with a shorter duration of ICU stay compared with placebo (mean difference, −0.92 (95% CI −1.68 to −0.17) days; I2=43.36%) (online supplemental figure 5). Hydrocortisone, but not methylprednisolone, was associated with a shorter duration of ICU stay (mean difference, −1.27 (95% CI −1.91 to −0.64) days; I2=0.00%).

    Adverse events

    The use of corticosteroids was not associated with an increased risk of gastrointestinal bleeding or secondary infection regardless of the type of corticosteroids. There appeared to be a trend towards a higher risk of hyperglycaemia in patients treated with methylprednisolone compared with placebo, though this was not statistically significant (RR, 1.40 (0.93 to 2.11); I2=4.98%). The results are summarised in online supplemental figures 6–8.

    Sensitivity analyses

    In studies that did not use ICU admission as an inclusion criterion, corticosteroids appeared to be associated with a lower risk of all-cause mortality, though this effect was not statistically significant (RR, 0.64 (0.35 to 1.16); I2=0.00%). Similarly, hydrocortisone appeared to be associated with a lower risk of all-cause mortality, though this effect was not statistically significant (RR, 0.43 (0.17 to 1.11); I2=0.00%). In studies that excluded patients with sepsis or septic shock, hydrocortisone was associated with a lower risk of all-cause mortality (RR, 0.53 (0.33 to 0.84); I2=0.00%). These results are summarised in online supplemental figures 9 and 10.

    Subgroup analyses

    There was no statistical difference in the risk of mortality between studies that had low versus high risk of bias, used cumulative high-dose versus low-dose corticosteroids, performed in Europe versus outside of Europe and duration of corticosteroids less than versus more than 7 days (online supplemental figures 11–14).

    Discussion

    In this updated meta-analysis of 10 studies comprising 1962 patients, the use of corticosteroids results in a reduction in overall mortality in patients with severe CAP. In particular, hydrocortisone reduces the risk of all-cause mortality. These clinical benefits were not observed for other types of corticosteroids.

    Prior to this study, three meta-analyses have examined the use of corticosteroids in patients with severe CAP, but the results have been inconclusive.9–11 In 2015, in an aggregated-data meta-analysis of six trials, Siemieniuk and colleagues found that adjunctive corticosteroids reduced mortality in severe CAP by about 60% (RR 0.39 (95% CI 0.20 to 0.77)). The authors also reported that corticosteroids were associated with a reduction in mechanical ventilation and ARDS.10 In 2018, in an individual patient data meta-analysis of five trials, Briel and colleagues found that adjunctive corticosteroids did not provide significant mortality benefits for patients with severe CAP (RR 0.70 (95% CI 0.44 to 1.13)).9 Nevertheless, subsequently in 2023, in an aggregated-data meta-analysis of seven trials,11 Wu and colleagues reported that corticosteroids were associated with an approximately 40% reduction in 30-day mortality among patients hospitalised with severe CAP (RR 0.61 (95% CI 0.44 to 0.85)). One recent meta-analysis performed by Pitre and colleagues did report hydrocortisone to be associated with mortality benefits.12 However, these results were likely confounded by disease severity as the analysis included both severe and non-severe CAP. Prior data have demonstrated that corticosteroids can have subgroup effects depending on disease severity.10 In this updated meta-analysis of 10 trials, we found that corticosteroids were associated with a reduction in mortality among patients with severe CAP. The novel finding of this study was that hydrocortisone, but not other types of corticosteroids, was associated with an approximately 50% reduction in mortality among patients with severe CAP. Furthermore, hydrocortisone, but not other corticosteroids, was associated with concomitant benefits in secondary outcomes such as reductions in mechanical ventilation, ARDS, shock and duration of stay in the ICU. This result was critical because it suggests that there are differential effects of corticosteroids on severe CAP and only hydrocortisone was associated with improved outcomes among patients hospitalised for severe CAP.

    Overall, the clinical benefits associated with corticosteroids in patients with severe CAP appeared to be driven by the positive effects of hydrocortisone. Whether this finding represents a class effect in that only hydrocortisone provides outcome benefits in severe CAP or a difference between studies was not entirely clear. In most of the included studies, hydrocortisone was dosed at 200 mg/day, which was similar in terms of equivalent dosing in other corticosteroid groups. In our subgroup analyses, mortality outcomes did not differ based on the doses of corticosteroids given to patients. Therefore, the differences in mortality benefits between different corticosteroids were unlikely to be related to dose differences. We explored the effects of geography and risk of bias on all-cause mortality and did not find a difference in outcomes between studies performed in different geographical regions and studies with a low versus high risk of bias. We also performed a sensitivity analysis by excluding studies that focused on ICU patients as the clinical effects of corticosteroids were thought to have greater benefits in patients admitted immediately to the ICU than those admitted to the regular wards. In this sensitivity analysis, corticosteroids, and primarily hydrocortisone, showed a trend towards a reduction in all-cause mortality among patients admitted to the regular wards, similar to the primary analysis. Therefore, the mortality benefits of hydrocortisone on severe CAP may be generalised to the non-ICU population. Given these findings, patients who were not admitted to the ICU but fulfilling severe CAP criteria may be considered for hydrocortisone treatment.

    Hydrocortisone is a short-acting glucocorticoid with low potency. By contrast, prednisolone, methylprednisolone and dexamethasone are longer acting glucocorticoids with higher potency than hydrocortisone.37 Mechanistically, hydrocortisone may modulate the immune response and reduce inflammation without excessive immune activation, whereas other corticosteroids may lead to prolonged immunosuppression, potentially hindering the host response against infection. Thus, hydrocortisone’s shorter duration of action and lower potency may allow for anti-inflammatory effects without significant immunosuppression, contributing to its observed mortality benefits in severe CAP. Furthermore, hydrocortisone acts as a glucocorticoid with both glucocorticoid and mineralocorticoid effects, whereas dexamethasone and methylprednisone, being synthetic glucocorticoids, predominantly exert glucocorticoid effects with minimal mineralocorticoid activity.38 Mineralcorticoid plays a pivotal role in regulating sodium and potassium balance.39 This dual effect of hydrocortisone, encompassing both glucocorticoid and mineralocorticoid actions, may confer unique therapeutic advantages, particularly in the context of severe CAP, where maintaining fluid balance and blood pressure is crucial during heightened stress conditions.

    Previous meta-analyses focusing on sepsis showed that hydrocortisone, but not other corticosteroids, was associated with sepsis reversal and mortality benefits.40 41 Of the 10 studies included in this meta-analysis, 2 studies excluded patients with sepsis or septic shock. In the pooled analysis of studies that excluded sepsis or septic shock, hydrocortisone remained to be associated with a reduction in CAP mortality. Thus, hydrocortisone likely potentiates mortality benefits in severe CAP via mechanisms other than shock reversal. For example, hydrocortisone has been shown to improve the PaO2/FiO2 and lung injury score in patients with sepsis-associated ARDS.42 Similarly, Sabry and Omar reported that hydrocortisone improved PaO2/FiO2 in patients with CAP.36 Consistent with these observations, we found that hydrocortisone was associated with reductions in the need for mechanical ventilation and the occurrence of ARDS. There were three studies comprising approximately 750 patients that investigated the effects of methylprednisolone in severe CAP.6 32 33 In our pooled analyses, methylprednisolone was not associated with mortality benefits or improvements in pneumonia-related outcomes, suggesting that methylprednisolone likely does not improve overall outcomes in patients with severe CAP. Nevertheless, there was only one study each that investigated the effects of dexamethasone or prednisolone in severe CAP, and, therefore, it remained unclear if these two types of corticosteroids might provide clinical benefits for patients with severe CAP. Interestingly, dexamethasone has been demonstrated to reduce mortality in patients with ARDS and COVID-19, though the mortality benefits were not superior to methylprednisolone.43–45 It is unclear why there was a discrepancy between our study and prior COVID studies. Potential explanations include differences in response to corticosteroids between COVID pneumonia and CAP, and only a single study (and inadequate statistical power) investigating the effects of dexamethasone in CAP.

    The current study is subjected to several limitations. First, there were differences in inclusion and exclusion criteria, the definition of severe CAP as well as administration routes and dosages of corticosteroids among the included studies, which might contribute to some degree of interstudy heterogeneity. For example, in the study conducted by Marik and colleagues, a single dose of hydrocortisone was used; in other studies, a prolonged duration of corticosteroids was used. The initiation time of corticosteroids also varied among studies. In the study performed by Dequin and colleagues, hydrocortisone was administered within 24 hours of enrolment; however, in the trial performed by Meduri and colleagues, methylprednisolone was administered up to 96 hours of enrolment.46 Furthermore, the initiation time of corticosteroids was unreported in many studies. Because we did not have access to individual patient data, we were unable to assess how these differences might influence the reported outcomes. Nevertheless, we were able to minimise potential interstudy heterogeneity by stratifying corticosteroids into their subtypes; accordingly, the measure of interstudy heterogeneity, I2, was non-substantial across most reported outcomes. We also performed multiple subgroup analyses to identify potential sources of heterogeneity, such as different corticosteroid dosages, geographical regions and risk of bias. Second, the generalisability of our findings may be limited due to the exclusion of certain patient populations in most primary studies. For example, most studies excluded patients who were immunosuppressed, pregnant, with recent gastrointestinal bleeding or at high risk for neuropsychiatric adverse effects. It is unclear how the results of this study apply to these populations. Third, the number of studies and sample size in some of the reported outcomes were small and likely underpowered for some types of corticosteroids after stratification. Fourth, the data presented in this study were limited to hospitalised patients with severe CAP and do not apply to patients with less severe CAP. Therefore, the effects of corticosteroids on less severe CAP remain unclear. Fifth, we used mean differences for continuous outcomes, even though reductions in the duration of ICU or hospital stay were probably not normally distributed. Finally, we were not able to evaluate for publication bias through the funnel plot for most of the outcomes due to the small number of studies available.

    In conclusion, the use of hydrocortisone was associated with a reduction in overall mortality and improvement in pneumonia-related outcomes among patients with severe CAP. Other types of corticosteroids did not appear to provide these benefits though these analyses were limited by the number of studies available. Further RCTs are needed to evaluate the effects of dexamethasone and prednisolone on severe CAP.

    Data availability statement

    Data are available upon reasonable request. The authors confirm that the data supporting the findings of this study are available within the article or its supplementary materials. The template data collection forms and data used for all analyses including the analytic code can be obtained upon reasonable request from the corresponding author.

    Ethics statements

    Patient consent for publication

    Ethics approval

    Not applicable.

    References

    1. ↵
      1. Roth GA,
      2. Abate D,
      3. Abate KH
      . Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the global burden of disease study 2017. Lancet 2018;392:1736–88. doi:10.1016/S0140-6736(18)32203-7
      OpenUrlCrossRefPubMed
    2. ↵
      1. Rittirsch D,
      2. Flierl MA,
      3. Ward PA
      . Harmful molecular mechanisms in sepsis. Nat Rev Immunol 2008;8:776–87. doi:10.1038/nri2402
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      1. Meyer NJ,
      2. Gattinoni L,
      3. Calfee CS
      . Acute respiratory distress syndrome. Lancet 2021;398:622–37. doi:10.1016/S0140-6736(21)00439-6
      OpenUrlCrossRefPubMed
    4. ↵
      1. Montón C,
      2. Ewig S,
      3. Torres A, et al
      . Role of glucocorticoids on inflammatory response in nonimmunosuppressed patients with pneumonia: a pilot study. Eur Respir J 1999;14:218–20. doi:10.1034/j.1399-3003.1999.14a37.x
      OpenUrlAbstract/FREE Full Text
    5. ↵
      1. Tomazini BM,
      2. Maia IS,
      3. Cavalcanti AB, et al
      . Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the codex randomized clinical trial. JAMA 2020;324:1307–16. doi:10.1001/jama.2020.17021
      OpenUrlCrossRefPubMed
    6. ↵
      1. Meduri GU,
      2. Shih M-C,
      3. Bridges L, et al
      . Low-dose methylprednisolone treatment in critically ill patients with severe community-acquired pneumonia. Intensive Care Med 2022;48:1009–23. doi:10.1007/s00134-022-06684-3
      OpenUrl
    7. ↵
      1. Wittermans E,
      2. Vestjens SMT,
      3. Spoorenberg SMC, et al
      . Adjunctive treatment with oral dexamethasone in non-ICU patients hospitalised with community-acquired pneumonia: a randomised clinical trial. Eur Respir J 2021;58:2002535. doi:10.1183/13993003.02535-2020
    8. ↵
      1. Dequin P-F,
      2. Meziani F,
      3. Quenot J-P, et al
      . Hydrocortisone in severe community-acquired pneumonia. N Engl J Med 2023;388:1931–41. doi:10.1056/NEJMoa2215145
      OpenUrl
    9. ↵
      1. Briel M,
      2. Spoorenberg SMC,
      3. Snijders D, et al
      . Corticosteroids in patients hospitalized with community-acquired pneumonia: systematic review and individual patient data metaanalysis. Clin Infect Dis 2018;66:346–54. doi:10.1093/cid/cix801
      OpenUrlCrossRefPubMed
    10. ↵
      1. Siemieniuk RAC,
      2. Meade MO,
      3. Alonso-Coello P, et al
      . Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis. Ann Intern Med 2015;163:519–28. doi:10.7326/M15-0715
      OpenUrlCrossRefPubMed
    11. ↵
      1. Wu J-Y,
      2. Tsai Y-W,
      3. Hsu W-H, et al
      . Efficacy and safety of adjunctive corticosteroids in the treatment of severe community-acquired pneumonia: a systematic review and meta-analysis of randomized controlled trials. Crit Care 2023;27:274. doi:10.1186/s13054-023-04561-z
    12. ↵
      1. Pitre T,
      2. Abdali D,
      3. Chaudhuri D, et al
      . Corticosteroids in community-acquired bacterial pneumonia: a systematic review, pairwise and dose-response meta-analysis. J Gen Intern Med 2023;38:2593–606. doi:10.1007/s11606-023-08203-6
      OpenUrl
    13. ↵
      1. Page MJ,
      2. McKenzie JE,
      3. Bossuyt PM, et al
      . The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi:10.1136/bmj.n71
    14. ↵
      1. Fine MJ,
      2. Auble TE,
      3. Yealy DM, et al
      . A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997;336:243–50. doi:10.1056/NEJM199701233360402
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      1. Buising KL,
      2. Thursky KA,
      3. Black JF, et al
      . Identifying severe community-acquired pneumonia in the emergency Department: a simple clinical prediction tool. Emerg Med Australas 2007;19:418–26. doi:10.1111/j.1742-6723.2007.01003.x
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      1. Metlay JP,
      2. Waterer GW,
      3. Long AC, et al
      . Diagnosis and treatment of adults with community-acquired pneumonia. an official clinical practice guideline of the American Thoracic society and infectious diseases society of America. Am J Respir Crit Care Med 2019;200:e45–67. doi:10.1164/rccm.201908-1581ST
      OpenUrlCrossRefPubMed
    17. ↵
      1. Lim WS,
      2. Baudouin SV,
      3. George RC, et al
      . BTS guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax 2009;64 Suppl 3:iii1–55. doi:10.1136/thx.2009.121434
      OpenUrlCrossRefPubMed
    18. ↵
      1. Sterne JAC,
      2. Savović J,
      3. Page MJ, et al
      . Rob 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898. doi:10.1136/bmj.l4898
    19. ↵
      1. Bender R,
      2. Friede T,
      3. Koch A, et al
      . Methods for evidence synthesis in the case of very few studies. Res Synth Methods 2018;9:382–92. doi:10.1002/jrsm.1297
      OpenUrl
    20. ↵
      1. Saueressig T,
      2. Pedder H,
      3. Bowe SJ, et al
      . Six meta-analyses on treatments for femoroacetabular Impingement syndrome in a year and readers are none the wiser: methods advice for researchers planning meta-analysis of data from fewer than 5 trials. J Orthop Sports Phys Ther 2021;51:201–3. doi:10.2519/jospt.2021.0107
      OpenUrl
    21. ↵
      1. Hozo SP,
      2. Djulbegovic B,
      3. Hozo I
      . Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 2005;5:13. doi:10.1186/1471-2288-5-13
    22. ↵
      1. Higgins JPT,
      2. Thompson SG,
      3. Deeks JJ, et al
      . Measuring inconsistency in meta-analyses. BMJ 2003;327:557–60. doi:10.1136/bmj.327.7414.557
      OpenUrlFREE Full Text
    23. ↵
      1. Blum CA,
      2. Nigro N,
      3. Briel M, et al
      . Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2015;385:1511–8. doi:10.1016/S0140-6736(14)62447-8
      OpenUrlCrossRefPubMed
    24. ↵
      1. Meijvis SCA,
      2. Hardeman H,
      3. Remmelts HHF, et al
      . Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet 2011;377:2023–30. doi:10.1016/S0140-6736(11)60607-7
      OpenUrlCrossRefPubMedWeb of Science
    25. ↵
      1. Nafae RM,
      2. Ragab MI,
      3. Amany FM, et al
      . Adjuvant role of corticosteroids in the treatment of community-acquired pneumonia. Egypt J Chest Dis Tuberc 2013;62:439–45. doi:10.1016/j.ejcdt.2013.03.009
      OpenUrl
    26. ↵
      1. Mikami K,
      2. Suzuki M,
      3. Kitagawa H, et al
      . Efficacy of corticosteroids in the treatment of community-acquired pneumonia requiring hospitalization. Lung 2007;185:249–55. doi:10.1007/s00408-007-9020-3
      OpenUrlCrossRefPubMedWeb of Science
    27. ↵
      1. WAGNER HN,
      2. BENNETT IL,
      3. LASAGNA L, et al
      . The effect of hydrocortisone upon the course of pneumococcal pneumonia treated with penicillin. Bull Johns Hopkins Hosp 1956;98:197–215.
      OpenUrlPubMedWeb of Science
    28. ↵
      1. McHardy VU,
      2. Schonell ME
      . Ampicillin dosage and use of prednisolone in treatment of pneumonia: co-operative controlled trial. Br Med J 1972;4:569–73. doi:10.1136/bmj.4.5840.569
      OpenUrlAbstract/FREE Full Text
    29. ↵
      1. Lloyd M,
      2. Karahalios A,
      3. Janus E, et al
      . Effectiveness of a bundled intervention including adjunctive corticosteroids on outcomes of hospitalized patients with community-acquired pneumonia: a stepped-wedge randomized clinical trial. JAMA Intern Med 2019;179:1052–60. doi:10.1001/jamainternmed.2019.1438
      OpenUrl
    30. ↵
      1. Confalonieri M,
      2. Urbino R,
      3. Potena A, et al
      . Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med 2005;171:242–8. doi:10.1164/rccm.200406-808OC
      OpenUrlCrossRefPubMedWeb of Science
    31. ↵
      1. Snijders D,
      2. Daniels JMA,
      3. de Graaff CS, et al
      . Efficacy of corticosteroids in community-acquired pneumonia: a randomized double-blinded clinical trial. Am J Respir Crit Care Med 2010;181:975–82. doi:10.1164/rccm.200905-0808OC
      OpenUrlCrossRefPubMedWeb of Science
    32. ↵
      1. Fernández-Serrano S,
      2. Dorca J,
      3. Garcia-Vidal C, et al
      . Effect of corticosteroids on the clinical course of community-acquired pneumonia: a randomized controlled trial. Crit Care 2011;15:R96. doi:10.1186/cc10103
    33. ↵
      1. Torres A,
      2. Sibila O,
      3. Ferrer M, et al
      . Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA 2015;313:677–86. doi:10.1001/jama.2015.88
      OpenUrlCrossRefPubMed
    34. ↵
      1. Marik P,
      2. Kraus P,
      3. Sribante J, et al
      . Hydrocortisone and tumor necrosis factor in severe community-acquired pneumonia. A randomized controlled study. Chest 1993;104:389–92. doi:10.1378/chest.104.2.389
      OpenUrlCrossRefPubMedWeb of Science
    35. ↵
      1. El-Ghamrawy A,
      2. Shokeir M,
      3. Esmat A
      . Effects of low-dose hydrocortisone in ICU patients with severe community-acquired pneumonia. Egypt J Chest Dis Tuberc 2006;55:91–9.
      OpenUrl
    36. ↵
      1. Sabry NA,
      2. Omar EE-D
      . Corticosteroids and ICU course of community acquired pneumonia in Egyptian settings. PP 2011;02:73–81. doi:10.4236/pp.2011.22009
      OpenUrl
    37. ↵
      1. Meduri GU,
      2. Annane D,
      3. Confalonieri M, et al
      . Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS. Intensive Care Med 2020;46:2284–96. doi:10.1007/s00134-020-06289-8
      OpenUrl
    38. ↵
      1. Hicks CW,
      2. Sweeney DA,
      3. Danner RL, et al
      . Efficacy of selective mineralocorticoid and glucocorticoid agonists in canine septic shock. Crit Care Med 2012;40:199–207. doi:10.1097/CCM.0b013e31822efa14
      OpenUrlCrossRefPubMedWeb of Science
    39. ↵
      1. Shibata S
      . 30 Years of the mineralocorticoid receptor: mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron. J Endocrinol 2017;234:T35–47. doi:10.1530/JOE-16-0669
      OpenUrlAbstract/FREE Full Text
    40. ↵
      1. Fang F,
      2. Zhang Y,
      3. Tang J, et al
      . Association of corticosteroid treatment with outcomes in adult patients with sepsis: a systematic review and meta-analysis. JAMA Intern Med 2019;179:213–23. doi:10.1001/jamainternmed.2018.5849
      OpenUrl
    41. ↵
      1. Gibbison B,
      2. López-López JA,
      3. Higgins JPT, et al
      . Corticosteroids in septic shock: a systematic review and network meta-analysis. Crit Care 2017;21:78. doi:10.1186/s13054-017-1659-4
    42. ↵
      1. Tongyoo S,
      2. Permpikul C,
      3. Mongkolpun W, et al
      . Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial. Crit Care 2016;20:329. doi:10.1186/s13054-016-1511-2
    43. ↵
      1. Villar J,
      2. Ferrando C,
      3. Martínez D, et al
      . Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med 2020;8:267–76. doi:10.1016/S2213-2600(19)30417-5
      OpenUrl
    44. ↵
      1. The RECOVERY Collaborative Group
      . Dexamethasone in hospitalized patients with COVID-19. N Engl J Med 2021;384:693–704. doi:10.1056/NEJMoa2021436
      OpenUrlCrossRefPubMed
    45. ↵
      1. Salton F,
      2. Confalonieri P,
      3. Centanni S, et al
      . Prolonged higher dose methylprednisolone versus conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS). Eur Respir J 2023;61:2201514. doi:10.1183/13993003.01514-2022
    46. ↵
      1. Dequin PF,
      2. Ramirez JA,
      3. Waterer G
      . What’s new with glucocorticoids in severe community-acquired pneumonia Intensive Care Med 2023;49:1397–9. doi:10.1007/s00134-023-07179-5
      OpenUrl

    Supplementary materials

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    Footnotes

    • XYS, THW and Y-CC are joint first authors.

    • XYS, THW and Y-CC contributed equally.

    • Contributors Study design: YPH, C-HuC, C-HaC. Data collection: XYS, THW, Y-CC, JL, WL, CYWC. Data analysis: Y-CL, KSKM, C-HsC. Drafting of manuscript: XYS, THW, Y-CC, YPH, C-HuC, C-HaC. Review of manuscript: Y-CL, KSKM, C-HsC, YPH, C-HuC, C-HaC. C-HaC accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer-reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.