By Samuel Nadler, MD, PhD
Clinical Instructor, University of Washington, Seattle
SYNOPSIS: In a multicenter, randomized, placebo-controlled trial, hydrocortisone reduced mortality in patients with severe community-acquired pneumonia.
SOURCE: Dequin PF, Meziani F, Quenot JP, et al. Hydrocortisone in severe community-acquired pneumonia. N Engl J Med 2023;March 21. doi: 10.1056/NEJMoa2215145. [Online ahead of print].
Severe community-acquired pneumonia (CAP) remains a common cause for intensive care unit (ICU) admission. The use of corticosteroids to modulate the immune response to severe CAP remains an area of active research. This most recent study, CAPE COD (Community-Acquired Pneumonia: Evaluation of Corticosteroids), was a multicenter, randomized, double-blind, placebo-controlled study of adults with severe CAP. Participants were randomized to hydrocortisone 200 mg daily for four days followed by a taper over eight to 14 days. Severe CAP was defined as clinical pneumonia with one of four additional criteria: need for mechanical ventilation, need for high-flow nasal cannula, need for non-rebreather mask, or Pneumonia Severity Index > 130 (group V). Non-inclusion criteria included the presence of a do-not-intubate order, pneumonia due to influenza, or septic shock, among others. The primary outcome was overall mortality at 28 days, with secondary outcomes including ICU length of stay (LOS), rates of intubation and mechanical ventilation, vasopressor need, and changes in Sequential Organ Failure Assessment (SOFA) and 36-item Short Form (SF-36) scores. Study enrollment paused with the onset of the COVID-19 pandemic, and a subsequent interim analysis recommended cessation after enrolling 800 patients due to the high likelihood of benefit. Notably, this study did not include patients with COVID-19 pneumonia.
The use of hydrocortisone reduced mortality in patients with severe CAP from 11.9% in the placebo arm to 6.2% in the treatment arm (95% confidence interval [CI], -9.6% to -1.7%; P = 0.006). Statistically significant secondary outcomes included a reduction in 90-day mortality (14.7% vs. 9.3%), incidence of endotracheal intubation (29.5% vs. 18%), and vasopressor use (25% vs. 15.3%). In contrast, safety outcomes were similar without differences in hospital-acquired infections, gastrointestinal bleeding, or weight gain, although a lower median daily dose of insulin was noted in patients not receiving hydrocortisone (20.5 IU vs. 35.5 IU; P < 0.001). Overall, more patients were discharged alive from the ICU who received steroids (hazard ratio [HR], 1.33; 95% CI, 1.16-1.52).
COMMENTARY
The publication of the CAPE COD study closely follows a meta-analysis by Saleem et al (reviewed previously in this edition) showing no significant effect of steroids on mortality in patients with CAP. By considering this article in the context of that recent meta-analysis as well as a previous Cochrane review, insights are gained regarding the most appropriate approach to severe CAP treatment.1,2
First, the positive effect seems most significant in severe CAP. The CAPE COD study included only severe cases, excluding septic shock, while the meta-analysis by Saleem et al included non-severe pneumonia. To this point, the 2017 Cochrane review separated severe and non-severe pneumonia, and the positive effect was observed in severe CAP (risk ratio [RR], 0.58; 95% CI, 0.4-0.84), but not in non-severe pneumonia (RR, 0.95; 95% CI, 0.45-2).2 Second, CAPE COD used hydrocortisone exclusively. Saleem et al included various steroid regimens together in the analysis. Interestingly, those studies using hydrocortisone included in the meta-analysis seemed to have the greatest positive effect compared with other steroid regimens.1 The nature of the steroids used, therefore, may modify their effectiveness. Third, there were no significant adverse effects from steroid administration. There was an overall increased need for insulin administration in CAPE COD and hyperglycemia in Saleem et al, but no change in rates of hospital-acquired infections, gastrointestinal hemorrhage, or fluid retention. Thus, the risk of adjunctive steroids seems to be challenges with glycemic control, while the benefit is reduced mortality and higher rates of successful ICU discharge.
This remains an area of controversy and continued interest. It is telling that the meta-analysis by Saleem et al included studies from 1956 through 2022. Those authors concluded with, “Larger masked randomized controlled trials are required to determine any mortality benefit, as are trials stratifying patients by illness severity.”1 The CAPE COD trial fulfills that suggestion, demonstrating a reduction in mortality and other meaningful secondary outcomes with the use of hydrocortisone in patients with severe CAP.
REFERENCES
- Saleem N, Kulkarni A, Snow TAC, et al. Effect of corticosteroids on mortality and clinical cure in community-acquired pneumonia: A systematic review, meta-analysis, and meta-regression of randomized control trials. Chest 2023;163:484-497.
- Stern A, Skalsky K, Avni T, et al. Corticosteroids for pneumonia. Cochrane Database Syst Rev 2017;12:CD007720.
In a multicenter, randomized, placebo-controlled trial, hydrocortisone reduced mortality in patients with severe community-acquired pneumonia.
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