Shifting Tides: Is It Time to Embrace Adjunctive Corticosteroids for Community-Acquired Pneumonia?

Résumé fourni par la source

(See the Major Article by Bergmann et al. on pages 1704–13.) Community-acquired pneumonia (CAP) continues to be a major contributor to morbidity and mortality in the United States despite advances in supportive care and antimicrobial therapy. A recent report estimated annual hospitalizations due to CAP to be over 1.5 million admissions, with a 30-day mortality rate of 13% [1]. As the population at risk for poor outcomes from CAP (older individuals, those with comorbidities and/or immune suppression) continues to grow [2, 3], outcomes are often poor despite treatment. This compels us to search for adjuncts to traditional antibiotic therapy to optimize management. Perhaps the most tried and tested of these is corticosteroids. Corticosteroids have a proven record in improving outcomes in patients affected by several types of infections, such as bacterial meningitis, Pneumocystis jirovecii pneumonia, severe coronavirus disease 2019 (COVID-19), and septic shock [4, 5]. However, conflicting results from several studies investigating the effect of corticosteroids in community-acquired bacterial pneumonia have led to the 2019 American Thoracic Society/Infectious Diseases Society of America Community Acquired Pneumonia Guidelines recommendation against their use in both severe and nonsevere CAP, except when indicated for associated refractory septic shock [6]. Previous meta-analyses on the topic have also led to disparate conclusions. One by Briel et al [7] from 2018 included 6 randomized clinical trials (RCTs; 1506 patients) and showed no significant association between corticosteroids and mortality risk in patients hospitalized for CAP (5.0% vs 5.9%; odds ratio [OR]: .75; 95% confidence interval [CI]: .46–1.21). While there was a reduction of approximately 1 day in both hospital length of stay and time to clinical stability among patients with CAP receiving corticosteroids, there was also an increased risk of rehospitalization. Of note, only 10% of included patients were immediately admitted to the intensive care unit and overall mortality rate was low (5.4%), indicating an overall low severity of CAP in included studies. Another meta-analysis by Stern et al [8] published in 2017 included 13 RCTs (1954 patients) and showed lower mortality rates among adult patients receiving corticosteroids compared with placebo (OR: .66; 95% CI: .47–.92), as well as shorter hospital stay and shorter time to cure. On subgroup analysis, the mortality benefit was only significant in patients with severe pneumonia; however, the signal was driven predominantly by studies with unclear risk of bias. In pursuit of this important, yet unanswered question, 2 large RCTs focusing on hospitalized patients with severe CAP were recently published. The first was a large RCT conducted by Meduri and colleagues [9] at 42 Veterans Affairs (VA) medical centers that randomized 586 patients to receive intravenous methylprednisolone or placebo for 20 days, which found no significant difference in mortality (adjusted OR: .90; 95% CI: .57–1.40). However, the trial was terminated early due to slow recruitment, leaving the study underpowered and inferences weak. Moreover, time to receipt of corticosteroids was delayed at a median of 1.7 (1–2.2) days, which may have attenuated any potential benefit. The second study, which was published this year by Dequin et al [10], was also a large multicenter RCT conducted in France randomizing 800 patients with severe CAP to hydrocortisone or placebo for 8–14 days. The results showed a significant reduction in mortality in the hydrocortisone group (6.2% vs 11.9%; absolute difference: −5.6 percentage points; 95% CI: −9.6 to −1.7 percentage points; P = .006), as well as lower rates of mechanical ventilation and vasopressor use. The time to receipt of study drug in this trial was much shorter than in Meduri et al, with a median of less than 15 hours. The state of the evidence was now ripe for another meta-analysis. The timely and well-done meta-analysis by Bergmann et al published in this issue of Clinical Infectious Diseases included the recent RCTs among studies investigating the effect of corticosteroids on mortality among hospitalized patients with CAP. Fifteen RCTs and 3367 patients were included in the analysis, including 9 trials (1537 patients) with severe CAP. What is unique about this meta-analysis is the inclusion of high-quality studies, with an 87% cumulative weight of low-risk-of-bias studies. The study showed a significant reduction in mortality among patients randomized to corticosteroids (6.2% vs 9.1%; risk ratio [RR]: .67; 95% CI: .53–.85; P = .001; I2 = 0%), with the number needed to treat to prevent 1 death being 34. The analysis showed a reduced risk of developing acute respiratory distress syndrome (ARDS) in the corticosteroids group (RR: .24; 95% CI: .08–.77) and reduced time-to-clinical stability (mean difference: −1.46 d; 95% CI: −1.51 to −1.41 d), without an increase in risk of adverse events (other than hyperglycemia) or hospital readmission. The benefit of corticosteroids was consistent, seen in both large and small studies, as well as studies with low versus unclear risk of bias. While the optimal type, dose, and duration of corticosteroids are yet to be determined, a recent RCT by Dequin et al [10] used a continuous infusion of hydrocortisone at a dose of 200 mg/24 hours, which was associated with a significant reduction in mortality. This regimen can be challenging in some hospital settings that do not use continuous corticosteroid infusion and can lead to increased errors in medication administration. Also, in many critically ill patients, venous access can be limited and having an additional continuous infusion can take up a line needed for other essential, but incompatible drips. It is reassuring that the current meta-analysis did not show any significant differences in outcome among different corticosteroid types and doses. This offers grounds to use simpler regimens of intermittent corticosteroids that are easier to implement and require less resources. Is the observed benefit of corticosteroids in CAP generalizable across patients? While the study showed a survival benefit in all hospitalized patients with CAP, it is important to note that the effect was more pronounced in patients with severe CAP and generalizing the benefit to all patients needs additional studies. In fact, a previous meta-analysis by Stern et al [8] showed a survival benefit only in the subgroup with severe pneumonia. Also, a recent meta-analysis that focused on RCTs including only patients with severe CAP showed a significant mortality reduction in the corticosteroid group [11]. From all of the above, it appears that we have corroborating evidence that supports the use of corticosteroids in patients with severe pneumonia. Another important unanswered question is about the generalizability of the benefit of corticosteroids in severe pneumonia across different pathogens. It is unclear whether the benefit is limited to bacterial pneumonia or extends to viral etiologies as many of the included studies had a minority of patients with viral pneumonia. Even among bacterial pathogens is the effect more general or is it limited to certain pathogens such as Streptococcus pneumoniae, which constituted the most frequently isolated pathogen (21%) of cases. Meningitis studies suggested that the survival benefit occurs mostly in patients with S. pneumoniae and it is plausible that the observed benefit of corticosteroids in severe CAP could be driven by the same pathogen [12]. Studies on COVID-19 and influenza have taught us that the benefit of corticosteroids in viral pneumonia does not appear to be uniform across viruses [5, 13]. Does the meta-analysis by Bergman and colleagues call for a practice change? Several questions are left to be answered. What is the optimal time for corticosteroid administration? Is there a time period beyond which corticosteroids lose their be

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