2023 Top Story in Respiratory Medicine: Steroid Use in Community-Acquired Pneumonia
The debate surrounding steroid use in community-acquired pneumonia (CAP) has been stirring for decades. And while there might be a difference of opinion on the role of steroids, there is a strong consensus that the answer matters. Pneumonia is a common disease that has a high impact on morbidity and mortality. It was estimated that there were 489 million lower respiratory infections worldwide in 2019.1 In the United States, over 1.5 million adults are hospitalized annually with CAP.2 For patients admitted to the hospital with CAP, approximately 10% have severe disease requiring admission to the intensive care unit (ICU),3 and the mortality rate in these patients is as high as 24%.4 In 2021, CAP was the ninth leading cause of death in the United States and the most common infectious cause of death, accounting for more than 50,000 deaths in 2020.5 Given the burden on our healthcare system and our patients, there has been an ongoing search for any way to improve outcomes in the treatment of CAP, and steroids have been a focal point in the search for an answer.
In addition to supportive care and antibiotics for the treatment of CAP, the immunomodulatory and anti-inflammatory effects of steroids have been an area of interest for adjuvant therapy. From 2005–2021, six randomized controlled trials found that steroids were helpful but there was no clear mortality benefit.6–11 During this timeframe, one study did find a mortality benefit when using a hydrocortisone infusion for severe CAP; however, it should be noted that the mortality in the intervention arm was 0% owing to the small nature (46 patients in total) of the study.12 A Cochrane review in 2011 showed improvement in time to symptom resolution with steroids13 and another meta-analysis in 2018 demonstrated reduced time to stability and improved length of stay by approximately 1 day, but there was no survival benefit when using steroids in CAP.14 Contrary to these studies, a larger Cochrane review in 2017 did demonstrate a mortality benefit with a number needed to treat of 18 to prevent 1 death.15 Based on concerns with the quality of the data, variations in how severe CAP was defined and inconsistency in study results, there are different recommendations about the use of steroids in CAP from various medical bodies. The ATS/IDSA guidelines from 2019 recommend against the use of steroids,16 while the 2017 SCCM/ESICM guidelines made a conditional recommendation to use corticosteroids in patients hospitalized with CAP.17 This has set the stage for variations in practice and a spectrum of belief on the utility of steroids in CAP.
The Community-Acquired Pneumonia: Evaluation of Corticosteroids (CAPE COD) trial was published in the NEJM in May 2023.18 This double-blind randomized controlled trial was conducted at 31 French hospitals from October 2015 until March 2020. In total, 800 patients were randomized in a 1:1 ratio stratified by center to receive either hydrocortisone 200 mg/day or a placebo. Inclusion criteria included adults >18 years old admitted to the ICU or intermediate care unit with severe CAP. The diagnosis of pneumonia was defined as having an infiltrate on imaging plus at least two of the following symptoms: cough, purulent sputum, chest pain, or dyspnea. CAP had to be diagnosed within 48 hours of admission. To meet a diagnosis of severe CAP, the patient had to require invasive or noninvasive mechanical ventilation, high-flow nasal cannula with FiO2>50% with PaO2/FiO2 (P/F) <300, Oxymizer or non-rebreathing with P/F<300, or a Pneumonia Severity Index score (PSI) of >130. Exclusion criteria included a diagnosis of influenza, vasopressors for treatment of septic shock, history of aspiration of gastric content, do-not-intubate order, mechanical ventilation within the last 14 days, active viral hepatitis or herpes virus, myelosuppression, hypersensitivity to steroids, antibiotic use for >7 days, cystic fibrosis, post-obstructive pneumonia, TB or fungal pneumonia, active steroid use (including nebulized steroids) or a current need for steroids, guardianship, and pregnancy or breastfeeding. There were 400 patients randomized to the intervention arm who received hydrocortisone 200 mg/day for 4–7 days followed by a taper while 395 patients in the control arm received placebo infusion. The trial was interrupted due to the COVID-19 pandemic; but, when the planned second interim analysis was performed, there was a significant difference in 28-day mortality (the primary outcome), demonstrating a 6.2% mortality rate in the intervention arm compared with an 11.9% rate in the control arm (P = .006), at which time the trial was stopped. Similar to the 2017 Cochrane review mentioned above,15 the number needed to treat to prevent 1 death was 18. There was also a trend toward improvements in the intervention arm when examining secondary outcomes such as 90-day mortality and the initiation of vasopressors or mechanical ventilation among patients who were not receiving either intervention at baseline. In terms of safety issues with hydrocortisone use, the incidence of hospital-acquired infections and gastrointestinal bleeding were similar between the two arms; however, patients in the intervention arm received higher daily doses of insulin.
The CAPE COD trial seems to support the early use of hydrocortisone in the treatment of severe CAP in patients not on vasopressors. This study is in stark contrast to the ESCAPe trial, which was published in 2022 and showed no mortality difference in 584 patients admitted to 42 Veteran Health Administration ICUs with CAP.19 The CAPE COD trial may have had a positive result because of the use of hydrocortisone compared with methylprednisone used in negative studies such as ESCAPe. Additionally, the CAPE COD trial had a very short duration between ICU admission and time to hydrocortisone (mean time, <20 hours) and had a higher percentage of women (30.6%) compared with the ESCAPe trial. Another caveat of the CAPE COD trial is that no pathogen was identified in almost half (44.9%) of study participants and, in the 55.1% of patients with an identified bacterial pathogen, 37.7% had Streptococcus pneumoniae. Additionally, almost 70% of participants had an elevated C-reactive protein (CRP), which is a potential marker of bacterial infection, and the subgroup analysis in the CAPE COD trial showed that steroid use was most beneficial among patients with an elevated CRP level of >15 mg/dL. In a prior trial, patients with severe CAP and an elevated CRP, showed a lower risk of treatment failure when treated with steroids.10 It’s possible that the benefit of steroid use is most evident in true bacterial CAP, which can be diagnosed from identifying a bacterial pathogen or presumed from an elevated CRP. There are several limitations to the CAPE COD trial that are worth mentioning. The mortality rate of 11.9% in the control group was lower than anticipated based on prior studies and may have been due to the exclusion of patients with septic shock. Another limitation of CAPE COD is that race and ethnicity were not reported in this French trial. Both of these limitations raise issues around the generalizability of the results. Furthermore, the CAPE COD trial did not examine the effect of steroid use on psychiatric or neuromuscular problems.
The most recent 2023 non-Cochrane meta-analyses included the CAPE COD and ESCAPe trials plus many of randomized controlled trials mentioned above from 2005–2021. This meta-analysis concluded that adjunctive systemic steroid therapy in patients hospitalized with CAP was associated with reduced 30-day mortality, lower risk of developing ARDS, and a shorter time to clinical stability. The benefits were more pronounced in patients with severe CAP admitted to the ICU or on at least high-flow oxygen without septic shock.20 Based on the CAPE COD trial and this recent meta-analysis, there is now more robust evidence to support the early use (within 24 hours) of hydrocortisone in severe CAP for patients admitted to the ICU. After the past year, it seems there’s more clarity on the utility of steroids in severe CAP; however, further trials are needed to clarify recommendations and provide consistency in published guidelines.
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Additional Info
- Kyu HH, Vongpradith A, Sirota SB, et al. Age–sex differences in the global burden of lower respiratory infections and risk factors, 1990–2019: results from the Global Burden of Disease Study 2019. Lancet Infect Dis. 2022;22(11):1626-1647.
- Ramirez JA, Wiemken TL, Peyrani P, et al. Adults Hospitalized With Pneumonia in the United States: Incidence, Epidemiology, and Mortality. Clin Infect Dis. 2017;65(11):1806-1812.
- Liapikou A, Ferrer M, Polverino E, et al. Severe Community‐Acquired Pneumonia: Validation of the Infectious Diseases Society of America/American Thoracic Society Guidelines to Predict an Intensive Care Unit Admission. Clin Infect Dis. 2009;48(4):377-385.
- Cavallazzi R, Wiemken T, Arnold FW, et al. Outcomes in patients with community-acquired pneumonia admitted to the intensive care unit. Respir Med. 2015;109(6):743-750.
- Kochanek KD, Murphy SL, Xu J, Arias E. Natl Vital Stat Rep. Deaths: Final Data for 2020. 2023 Sep;72(10):1-92.
- Snijders D, Daniels JMA, 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(9):975-982.
- Meijvis SC, Hardeman H, Remmelts HH, et al. Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet. 2011;377(9782):2023-2030.
- Fernández-Serrano S, Dorca J, Garcia-Vidal C, et al. Effect of corticosteroids on the clinical course of community-acquired pneumonia: a randomized controlled trial. Crit Care. 2011;15(2):R96.
- Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2015;385(9977):1511-1518.
- Torres A, Sibila O, 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(7):677-686.
- Wittermans E, Vestjens SMT, 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(2):2002535.
- Confalonieri M, Urbino R, Potena A, et al. Hydrocortisone Infusion for Severe Community-acquired Pneumonia: A Preliminary Randomized Study. Am J Respir Crit Care Med. 2005;171(3):242-248.
- Chen Y, Li K, Pu H, Wu T. Corticosteroids for pneumonia. Cochrane Database Syst Rev. 2011;(3): CD007720.
- Briel M, Spoorenberg SMC, Snijders D, et al. Corticosteroids in Patients Hospitalized With Community-Acquired Pneumonia: Systematic Review and Individual Patient Data Metaanalysis. Clin Infect Dis. 2018;66(3):346-354.
- Stern A, Skalsky K, Avni T, et al. Corticosteroids for pneumonia. Cochrane Acute Respiratory Infections Group, ed. Cochrane Database Syst Rev. 2017;2017(12):CD007720.
- Metlay JP, Waterer GW, 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(7):e45-e67.
- The Corticosteroid Guideline Task Force of SCCM and ESICM, Pastores SM, Annane D, Rochwerg B. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part II): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive Care Med. 2018;44(4):474-477.
- Dequin PF, Meziani F, Quenot JP, et al. Hydrocortisone in Severe Community-Acquired Pneumonia. N Engl J Med. 2023;388(21):1931-1941.
- Meduri GU, Shih MC, Bridges L, et al. Low-dose methylprednisolone treatment in critically ill patients with severe community-acquired pneumonia. Intensive Care Med. 2022;48(8):1009-1023.
- Bergmann F, Pracher L, Sawodny R, et al. Efficacy and Safety of Corticosteroid Therapy for Community-Acquired Pneumonia: A Meta-Analysis and Meta-Regression of Randomized, Controlled Trials. Clin Infect Dis. 2023 Oct 25: doi: 10.1093/cid/ciad496. Online ahead of print.
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