Low-dose, short-course systemic corticosteroids probably reduce short-term mortality in severe non–COVID-19 pneumonia and acute respiratory distress syndrome, according to a systematic review and meta-analysis published in Annals of Internal Medicine.
The analysis included 20 randomized controlled trials with 3,459 participants—15 studies (2,445 participants) evaluated corticosteroids in severe pneumonia, and 5 studies (1,014 participants) evaluated treatment in acute respiratory distress syndrome (ARDS). In severe pneumonia, adjunct corticosteroids probably reduce short-term mortality, defined as all-cause mortality at the latest time point reported within 90 days (15 studies, 2,445 patients; risk ratio, 0.73; moderate certainty). In ARDS, adjunct corticosteroids probably reduce short-term mortality (5 studies, 1,014 patients; risk ratio [RR], 0.77; moderate certainty).
The primary analysis included studies using corticosteroids at 3 mg/kg of body weight per day or less (prednisone-equivalent) for 15 days or less, initiated within 7 days of pneumonia or ARDS onset. Of the 15 severe pneumonia studies, 7 used hydrocortisone, 4 used methylprednisolone, 1 used dexamethasone, and 3 used prednisolone. In severe pneumonia, 13 studies used treatment courses of 7 days or less.
Secondary Outcomes and Safety Profile
Critically, corticosteroids did not increase infection risk despite longstanding concerns about immunosuppression in patients with infectious pneumonia. Corticosteroids may reduce secondary shock in severe pneumonia (9 studies, 1,690 patients; risk ratio, 0.49; low certainty). They probably result in little to no difference in hospital-acquired infections in severe pneumonia (7 studies, 1,665 patients; RR, 0.99) and ARDS (4 studies, 677 patients; RR, 0.97).
Similarly, corticosteroids may result in little to no difference in secondary pneumonia in severe pneumonia (4 studies, 1,011 patients) and ARDS (4 studies, 677 patients).
In severe pneumonia, corticosteroids were associated with reduced need for invasive mechanical ventilation (10 studies, 1,173 patients), reduced incidence of respiratory failure (5 studies, 733 patients), and shorter ICU length of stay (10 studies, 1,756 patients).
In severe pneumonia, corticosteroids were associated with increased hyperglycemia (6 studies, 915 patients). No statistically significant differences were observed for gastrointestinal bleeding, cardiac complications, or acquired neuromyopathy.
REMAP-CAP as Source of Heterogeneity
For severe pneumonia, the Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia (REMAP-CAP) trial was identified as the main source of heterogeneity; exclusion reduced heterogeneity without altering the effect estimate (RR, 0.68). The REMAP-CAP trial, which found no mortality benefit from corticosteroids in non–COVID-19 severe pneumonia, has faced methodological criticism. These methodological concerns may help explain the trial's divergent results.
In a published correspondence, Pierre-Francois Dequin, MD, of Centre Hospitalier Régional Universitaire de Tours in France, and colleagues highlighted concerns about REMAP-CAP, including "significant protocol violations, with nearly a quarter of control patients receiving corticosteroids despite randomization, yet no per-protocol analysis was done." They also noted "important baseline imbalances emerged despite randomization, with patients receiving hydrocortisone showing higher cardiovascular Sequential Organ Failure Assessment scores, suggesting greater disease severity that may not have been adequately adjusted for."
Most critically, according to the correspondence, "REMAP-CAP's inclusion criteria failed to require documented bacterial pneumonia, unlike previous positive trials that mandated at least 1 marker of infection, such as fever, leukocytosis, or elevated C-reactive protein. This lack of systematic inflammatory assessment meant the study could not identify patients with high inflammatory burden and may have even included noninfectious pneumonia cases."
Long-Term Outcomes and Limitations
In severe pneumonia, the evidence is very uncertain about the effect on long-term mortality, with only 1 study reporting 180-day mortality (559 patients; RR, 0.76), limited to patients with septic shock at baseline. No studies reported long-term mortality in ARDS.
The researchers acknowledged heterogeneous pneumonia severity classification as a key limitation. They initially planned to include only patients with pneumonia requiring oxygen therapy; however, baseline oxygen status was inconsistently reported across studies. Consequently, they classified study populations into 3 severity groups: ARDS, severe pneumonia (American Thoracic Society severity score V or Pneumonia Severity Index class III to V or ICU admission), and nonsevere pneumonia.
Future Directions for Personalized Treatment
In an accompanying editorial, Filippo Mearelli, MD, of Clinica Medica, Dipartimento Scienze Mediche, Chirurgiche e della Salute at Università di Trieste in Italy, Chanu Rhee, MD, MPH, and Michael Klompas, MD, MPH, both of the Department of Population Medicine at Harvard Medical School and Harvard Pilgrim Health Care Institute, wrote that "patient-level meta-analyses that allow one to dissect differences within as well as between study populations helps concretize this critical point." They cited work by Smit and colleagues using data from 6 randomized trials and machine learning methods to identify predictive factors.
According to the editorial, Smit's analysis found that "among all patients, corticosteroids were associated with a 30-day mortality odds ratio of 0.71. This signal was almost entirely explained, however, by CRP levels. Among patients with high CRP levels, corticosteroids were associated with a mortality odds ratio of 0.43, whereas in those with CRP levels less than 205 mg/L corticosteroids were not beneficial (mortality odds ratio, 0.98)."
The editorialists concluded that "the future of corticosteroid therapy for pneumonia and ARDS lies not in resolving the question of 'yes or no,' but in answering 'who, when, and how.'" They wrote that "rather than asking whether steroids work in pneumonia, the right question is in which patients, with which inflammatory profiles, facing which pathogens, at which stage of disease."
Study Details
The study received no funding. The researchers searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform through September 2025. The review was prospectively registered in PROSPERO (CRD42024536301) and led by Alice Soumare, MD, of AP-HP, Hôpital La Pitié Salpêtrière, DMU DREAM, Department of Anesthesiology and Critical Care in Paris, France, and colleagues.