Updated: Apr 9
The potential of glucocorticoids to reduce mortality in patients with severe community-acquired pneumonia through their anti-inflammatory and immunomodulatory effects is uncertain. Multiple previous trials did not confirm a mortality benefit of corticosteroids in severe community acquired pneumonia. A recent meta-analysis that included 16 trials and 3,842 patients suggested that corticosteroid therapy may have potential benefits in reducing disease progression in patients hospitalized with bacterial pneumonia. However, there was no mortality benefit. Larger randomized controlled trials are needed to determine any mortality benefit and effectively identify those patients who would benefit the most from adjunctive steroid therapy based surrogates of inflammation such as plasma level of C-reactive protein, degree of hypoxemia, or clinical scores such as CURB-65. In addition, the optimal type, dose, and duration of corticosteroid therapy for pneumonia management are yet to be studied .
In a phase 3, double-blind, randomized controlled trial conducted across 31 French centers, adults admitted to the ICU for severe community-acquired pneumonia were either given intravenous hydrocortisone (200 mg daily for 4 or 8 days based on clinical improvement, followed by tapering for a total of 8 or 14 days) or a placebo. All patients received standard treatment, including antibiotics and supportive care. The primary outcome was death at 28 days .
Pneumonia severity was determined by meeting at least one of the following four conditions: starting mechanical ventilation (invasive or noninvasive) with a positive end-expiratory pressure of 5 cm water or more; beginning oxygen administration via high-flow nasal cannula with a Pao2:Fio2 ratio under 300 and a Fio2 of 50% or higher; for patients using a nonrebreathing mask, an estimated Pao2:Fio2 ratio below 300 based on predefined charts; or a score exceeding 130 on the Pulmonary Severity Index. The study excluded patients with septic shock, history of aspiration, positive influenza, or if treated with antibiotics in the last 7 days among other exclusion criteria.
Out of 800 patients, data from 795 patients were analyzed before the trial was stopped after the second planned interim analysis. By day 28, 6.2% (25 out of 400) of patients in the hydrocortisone group and 11.9% (47 out of 395) in the placebo group had died, resulting in an absolute difference of -5.6 percentage points (95% CI, -9.6 to -1.7; P=0.006). Among patients not initially on mechanical ventilation, 18% (40 out of 222) in the hydrocortisone group and 29.5% (65 out of 220) in the placebo group required endotracheal intubation. Among patients not receiving vasopressors at the beginning, 15.3% (55 out of 359) in the hydrocortisone group and 25% (86 out of 344) in the placebo group required them by day 28. The incidence of hospital-acquired infections and gastrointestinal bleeding was similar in both groups, but patients in the hydrocortisone group received higher daily insulin doses during the first week of treatment.
The study concluded that ICU patients with severe community-acquired pneumonia who were treated with hydrocortisone experienced a lower risk of death by day 28 compared to those given a placebo. As per the subgroup analysis, the primary outcome of mortality benefit was favored in women, age >65 years, not mechanically ventilated patients, and in patient with no microorganism isolated.
Before implementing changes to our practice based on the results of this study, it's important to consider some limitations. Although the study was well-designed and conducted at multiple centers, it was only conducted in one country (France) which may limit its applicability to other countries and populations. Additionally, the study was terminated early and did not meet its intended sample size, but the monitoring committee felt it was unethical to continue with the control group due to the observed benefit of the intervention. It's worth noting that the mortality rate in the control group was lower than expected, but the study's severity criteria were strictly followed. Furthermore, about 45% of patients did not have a pathogen isolated, and these patients had better outcomes compared to those with isolated organisms. It's important to keep in mind that the meta-analysis mentioned in the introduction focused specifically on bacterial pneumonia. The optimal choice of corticosteroids, dosing regimen, and tapering protocol still need to be explored further. Finally, the results of subgroup analyses suggest that steroids may be effective in certain populations and further research is needed to identify and characterize these populations in larger trials.
In conclusion, while I am inclined to prescribe hydrocortisone 200 mg daily for my next patient with severe community acquired pneumonia, I will patiently await the publication of the REMAP-CAP results in non-pandemic populations as well as guidelines from relevant medical societies. The goal is to ensure the most appropriate and effective treatment approach for each individual patient, highlighting the need for personalized or precision medicine.
Saleem N, Kulkarni A, Snow TAC, Ambler G, Singer M, Arulkumaran N. 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 Mar;163(3):484-497. doi: 10.1016/j.chest.2022.08.2229. Epub 2022 Sep 7. PMID: 36087797.
Dequin PF, Meziani F, Quenot JP, Kamel T, Ricard JD, Badie J, Reignier J, Heming N, Plantefève G, Souweine B, Voiriot G, Colin G, Frat JP, Mira JP, Barbarot N, François B, Louis G, Gibot S, Guitton C, Giacardi C, Hraiech S, Vimeux S, L'Her E, Faure H, Herbrecht JE, Bouisse C, Joret A, Terzi N, Gacouin A, Quentin C, Jourdain M, Leclerc M, Coffre C, Bourgoin H, Lengellé C, Caille-Fénérol C, Giraudeau B, Le Gouge A; CRICS-TriGGERSep Network. Hydrocortisone in Severe Community-Acquired Pneumonia. N Engl J Med. 2023 Mar 21. doi: 10.1056/NEJMoa2215145. Epub ahead of print. PMID: 36942789.