Corticosteroids as Adjuvant Therapy for Community-Acquired Pneumonia
Sydney Hyder
May 1, 2024 11 minutes read
By Sydney Hyder, MD, MS
Division of Pulmonary and Critical Care Medicine, Stroger Hospital of Cook County, Chicago
Community-acquired pneumonia (CAP) remains a significant public health concern in the United States, contributing substantially to morbidity, mortality, and healthcare costs. Pneumonia ranks among the top 10 leading causes of hospitalization in the United States, with an estimated 1 million individuals hospitalized annually for pneumonia-related complications, and it accounts for approximately 50,000 deaths per year.1 The mortality risk is particularly high among older adults, individuals with immunocompromising conditions, and those with delayed or inadequate access to healthcare services.2 Furthermore, the burden of CAP extends beyond hospital admissions, with a substantial impact on outpatient care and societal well-being.
Given its high rate of mortality and global health impact, exploring therapeutic interventions to optimize patient outcomes is necessary. Among the various treatment modalities under investigation, the use of adjunctive corticosteroids has gained attention for their potential immunomodulatory and anti-inflammatory effects. Many trials studying corticosteroid use have been released over the years with variable outcomes, making it difficult to reach consensus on their application. This article aims to provide a summative analysis of the existing medical literature surrounding the effect of steroid treatment on CAP, including recent updates.
Mechanisms of Action
The immunomodulatory mechanisms underlying the potential benefits of steroids in CAP are not fully elucidated. In the context of pneumonia, steroids are believed to mitigate excessive inflammation and its associated detrimental effects on lung tissue. By suppressing the production of pro-inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), steroids may help attenuate the inflammatory cascade, thereby preventing tissue damage and reducing the severity of lung injury.3 Additionally, steroids may enhance the resolution of inflammation, promote surfactant production, and modulate immune cell activity, which collectively can contribute to improving clinical outcomes.4 However, the precise balance between anti-inflammatory benefits and the risk of immunosuppression remains a subject of ongoing research and necessitates careful consideration in clinical practice.
Early Research
The idea of using steroids for pneumonia can be traced back to the 1950s, but more evidence has come to light in the past few years. A study conducted by Snijders and colleagues randomized 213 hospitalized patients diagnosed with CAP to prednisolone 40 mg vs. placebo daily for a week in conjunction with antibiotics.5 Results showed there was no difference in the primary outcome of clinical improvement at one week, length of stay, or time to clinical stability. Additionally, analysis showed that patients treated with steroids were more likely to decompensate more than 72 hours after admission than those receiving placebo. The authors’ final takeaway was that prednisolone is not recommended as a routine adjunctive treatment for CAP.
In 2011, Meijvis and colleagues randomized 304 patients admitted to the general medicine floor with a diagnosis of CAP to dexamethasone 5 mg vs. placebo daily for four days.6 The study population excluded patients admitted to the intensive care unit (ICU). The authors found a reduction in hospital length of stay in the dexamethasone group vs. placebo (6.5 days vs. 7.5 days, respectively; P = 0.048). The greatest risk associated with steroid use was an increase in hyperglycemia for patients treated with dexamethasone. The authors concluded that dexamethasone can reduce hospital length of stay when added to antibiotic therapy in non-immunocompromised patients with CAP.
In light of the Meijvis paper, Snijders et al re-examined their data two years after their original trials. The re-analysis separated ICU patients from non-ICU admissions.7 Of the 213 patients studied, 90% were not admitted to the ICU. On re-examination of the 2010 data, after excluding ICU patients, the non-ICU group had faster clinical stabilization and reduced length of stay, although there was no comment on mortality. These updated results, which focused on non-ICU patients, aligned with the Meijvis trial and suggested the possibility that steroids may be beneficial for non-critically ill CAP patients. Snijders continues to acknowledge that despite these results, steroids should be examined further in the critically ill.
In 2015, Blum and colleagues conducted one of the largest, double-blind, multicenter randomized controlled trials examining steroid use in the treatment of CAP.8 The study enrolled 785 patients who were diagnosed with either severe or non-severe CAP, started on antibiotics, and then randomized to either prednisone 50 mg or placebo daily for seven days. The primary outcome was time to clinical stability, which was shorter in the patients receiving steroids vs. placebo (3.0 vs. 4.4 days, respectively; P < 0.0001). Secondary outcomes, which included hospital length of stay and need for intravenous antibiotics, also showed improvement. The major side effect of steroids was the risk of hyperglycemia requiring insulin treatment compared to placebo (19% vs. 11%, respectively; P = 0.001). Unlike previous major trials, Blum hoped to show a mortality benefit, but ultimately the study was not powered to show a mortality difference between groups.
With an aim to focus on severe CAP, Torres et al recruited only patients with severe CAP and a high inflammatory response.9 High inflammatory responses were defined as a level of C-reactive protein (CRP) greater than 150 mg/L at admission. The hope was that steroids would modulate cytokine release in these patients. In all, 120 patients with severe CAP and an elevated CRP were randomized to methylprednisolone 0.5 mg/kg vs. placebo twice daily for five days. The primary outcome of treatment failure was found to be lower in patients treated with methylprednisolone vs. placebo (13% vs. 31%, respectively; P = 0.02), although in-hospital mortality did not differ between the two groups. Torres’ trial raised the possibility of subgroups within patients with CAP and their differing responses to steroids.
Lastly, Siemieniuk and colleagues performed a large meta-analysis of steroids in CAP.10 The authors found that there was an abundance of measured outcomes, although no same combination was analyzed consistently among the reviewed papers. Many trials avoided enrolling patients at high risk for adverse events, which is a large subset of ICU patients. The analysis found that systemic corticosteroid treatment may minimally reduce mortality, mechanical ventilation, and hospital length of stay. Overall, trials consistently showed that there was no evidence of significant harm other than hyperglycemia.
The trials mentioned earlier highlight the difficulty of studying a steroid intervention in CAP because variability in patient populations, steroid regimens, and outcome measures across studies complicates the interpretation of findings, emphasizing the need for further well-designed randomized controlled trials.
Recent Updates
Many of the previous trials and meta-analyses performed suggest that steroids reduced time to clinical stabilization and hospital length of stay in patients with high inflammatory responses but were not able to comment on mortality benefit. The researchers for the ESCAPe and CAPE COD trials hoped to evaluate the relationship of mortality in patients with severe CAP.11,12
The ESCAPe trial (2022) was a randomized, multicenter, double-blind, placebo-controlled trial that was based out of Veterans Affairs hospitals. Enrolled patients had severe CAP, as defined by the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) criteria, and were admitted to the ICU. The intervention included a tapering dose of methylprednisolone continuous infusion for 20 days, which was switched to twice a day (intravenous or enteral) at the time of ICU discharge. The primary outcome was mortality at 60 days. The study enrolled 584 patients, which was much lower than the desired sample of 1,406 patients. Overall, 33% of patients were mechanically ventilated at the time of enrollment, and 96% of enrolled patients were male. The final analysis showed that the primary outcome of mortality at 60 days showed no difference between the methylprednisolone vs. placebo groups (16% vs. 18%, respectively; P = 0.61), and there was no difference in mortality at 180 days between groups.
CAPE COD was a double-blind, randomized trial that enrolled 800 patients with severe pneumonia.12 Exclusion criteria included pneumonia caused by influenza, septic shock, aspiration pneumonia, baseline steroid use equivalent to 15 mg of prednisone or more daily, active tuberculosis, or fungal infection. The primary outcome was death from any cause by day 28. Participants enrolled were randomized to hydrocortisone 200 mg intravenously per day for four to seven days, with a taper depending on clinical improvement at day 4, vs. placebo. The results showed that hydrocortisone was associated with a significant reduction in all-cause mortality at 28 days vs. placebo (6.2% vs. 11.9%, respectively; P = 0.006). Intubation and use of vasopressors was less common in the hydrocortisone arm. There were no obvious differences in safety outcomes between groups other than hyperglycemia in the steroid group.
When comparing the two studies, it should be highlighted that the ESCAPe trial was underpowered because it was unable to meet its goal enrollment. Additionally, ESCAPe allowed for a longer duration of time from admission to administration of the intervention: a median of about two days in ESCAPe vs. about 20 hours in CAPE COD. Lastly, ESCAPe allowed for enrollment of patients on vasopressors, approximately 13% of its study population, while those were excluded in CAPE COD. CAPE COD’s broad exclusion criteria helped ensure that the enrolled patients truly had pneumonia, but in exchange makes it difficult to generalize steroid use to the common ICU population. The possibility is that the CAPE COD results likely will be applied broadly without attention to the exclusion criteria, and it is unknown if the harms outweigh the benefits when corticosteroids are distributed injudiciously.
Guidelines: Then and Now
The ATS released guidelines in 2019 providing recommendations on the topic of steroids in CAP.13 While the 2007 ATS guideline did not address steroid use, the 2019 guideline is “recommended not to use” but to consider its use in patients with refractory septic shock. ATS cited the lack of data suggesting mortality benefit in corticosteroid use in non-severe CAP and only limited data in those with severe CAP. The guidelines also note the complications of hyperglycemia resulting in higher re-hospitalization rates.
The Society of Critical Care Medicine (SCCM) has released their new 2024 guidelines on the use of corticosteroids in CAP.14 SCCM provided a strong recommendation to administer corticosteroids to adult patients with severe bacterial CAP and had no recommendation for the administration of corticosteroids to those with less severe CAP. This differs from the 2017 SCCM guidelines that previously did not differentiate between severe and non-severe CAP and supported the broad use of hydrocortisone as treatment.15 Additionally, the conditional recommendation about steroid use in severe CAP was promoted from conditional in the 2017 guidelines to strongly recommended in 2024. The most updated guideline goes further to recommend the use of corticosteroids for five to seven days at a daily dose of hydrocortisone < 400 mg intravenously or the equivalent in those with severe CAP. The authors believed that sufficient evidence was present to show that steroids reduced hospital mortality in those with severe CAP, with moderate and less certain evidence showing reduced need for invasive mechanical ventilation and decreased duration of ICU and hospital stay for both severe and non-severe CAP. Recommendations for severe CAP were based heavily on the recent publication of CAPE COD, but the guidelines also note that further research must be conducted on the use of corticosteroids in the less severe CAP population.
Commentary and Summary
There now are a plethora of trials surrounding corticosteroids as adjunct therapy in CAP treatment. While current evidence is convincing that the benefit of using corticosteroids in severe CAP outweighs the risk, there continues to be a need for standardized definitions and treatments. As it stands currently, the definition of pneumonia, especially severe pneumonia, remains broad and vague, allowing for trials to define and analyze it differently. Many patients diagnosed with “pneumonia” may end up having another process as the culprit, such as aspiration pneumonitis or heart failure. Such entities result in similar symptoms and radiographic findings to pneumonia but are not the same physiologic process. The misdiagnosis of pneumonia may contribute to some of the variability in corticosteroid response. Similarly, there is no consensus on the dose and duration of steroids for CAP treatment among trials.
A highlight of the CAPE COD trial was that the benefit of corticosteroids was stratified based on admission CRP level. Steroid use was found to be most beneficial in patients with a CRP level > 150 mg/L. This makes logical sense, as those with greater systemic inflammation would be expected to respond better to steroids. It raises the question of whether biomarkers should be incorporated into the definition of pneumonia to help streamline a more comparable and meaningful clinical construct.
The role of corticosteroids in the management of CAP remains a topic of ongoing research and discussion within the medical community. Most recent literature suggests that adjunct corticosteroid treatment is beneficial for those with severe CAP who do not have contraindications to steroid administration, although a mortality benefit continues to be debated. While these trials have suggested potential advantages, it is essential to recognize the heterogeneity of patient populations, varying severity of pneumonia, and methodological differences across studies. As medical knowledge continues to evolve, further well-designed, randomized controlled trials and comprehensive meta-analyses will be crucial for establishing more definitive guidelines on the appropriate use of corticosteroids in the context of CAP. Clinical decisions should be made based on the most current evidence and tailored to individual patient characteristics, ensuring a balanced approach that maximizes benefits while minimizing potential risks.
REFERENCES
- American Thoracic Society. Top 20 Pneumonia Facts — 2019. https://www.thoracic.org/patients/patient-resources/resources/top-pneumonia-facts.pdf
- Jain S, Self WH, Wunderink RG, et al. Community-acquired pneumonia requiring hospitalization among U.S. adults. N Engl J Med 2015;373:415-427.
- Barnes PJ. Glucocorticosteroids: Current and future directions. Br J Pharmacol 2011;163:29-43.
- Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol 2011;335:2-13.
- 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;181:975-982.
- Meijvis SC, Hardeman H, 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;377:2023-2030.
- Snijders D, de Graaff C, van der Werf T, Boersma W. Effect of excluding ICU-admission on clinical outcomes in a randomized control trial studying the effect of corticosteroids in patients hospitalized with CAP. Eur Respir J 2012;40 (Suppl 56):P1734.
- 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;385:1511-1518.
- 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;313:677-686.
- Siemieniuk RA, Meade MO, Alonso-Coello P, et al. Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: A systematic review and meta-analysis. Ann Intern Med 2015;163:519-528.
- Meduri GU, Shih MC, Bridges M, et al. Low-dose methylprednisolone treatment in critically ill patients with severe community-acquired pneumonia. Intensive Care Med 2022;48:1009-1023.
- Dequin PF, Meziani F, Quenot JP, et al. Hydrocortisone in severe community-acquired pneumonia. N Engl J Med 2023;388:1931-1941.
- 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:e45-e67.
- Chaudhuri D, Nei AM, Rochwerg B, et al. 2024 Focused Update: Guidelines on use of corticosteroids in sepsis, acute respiratory distress syndrome, and community-acquired pneumonia. Crit Care Med 2024; Jan 19. doi: 10.1097/CCM.0000000000006172. [Online ahead of print].
- Pastores SM, Annane D, Rochwerg B; Corticosteroid Guideline Task Force of SCCM and ESICM. 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;44:474-477.
This article aims to provide a summative analysis of the existing medical literature surrounding the effect of steroid treatment on community acquired pneumonia, including recent updates.
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