Section 2.2: Re-evaluating Glucocorticoids in Severe Community-Acquired Pneumonia

Severe community-acquired pneumonia (CAP) is one of the most common and highest-mortality infectious diseases in the ICU. Glucocorticoids (GC) are widely used in clinical practice due to their low cost and ready availability across all levels of healthcare institutions. The 2025 SONIA trial, published in the New England Journal of Medicine, further validates the potential benefits of GC in CAP across multiple dimensions, including drug type, mineralocorticoid activity, and timing of administration. This article re-examines the clinical value of GC in severe CAP based on the latest evidence and historical research.

I. Pathophysiological Mechanisms and Clinical Evidence
(I) Pathophysiological Mechanisms of GC in Severe CAP
GC exert anti-inflammatory effects by binding to glucocorticoid receptors, inhibiting key signaling pathways such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), thereby reducing pro-inflammatory cytokines like tumor necrosis factor (TNF)-α and interleukin (IL)-6. This mitigates alveolar-capillary barrier injury and pulmonary edema, improving lung compliance and oxygenation. Additionally, GC with mineralocorticoid activity can enhance vascular smooth muscle responsiveness to catecholamines via mineralocorticoid receptors, facilitating shock reversal.

The primary causes of mortality in severe CAP are systemic inflammatory response syndrome, septic shock, and acute respiratory distress syndrome (ARDS), rather than the localized pulmonary infection itself. Some CAP patients experience critical illness-related corticosteroid insufficiency, where endogenous cortisol secretion is inadequate to suppress uncontrolled inflammation, maintain vascular tone, or preserve catecholamine responsiveness. In these cases, exogenous GC serves a physiological replacement role.

(II) Clinical Evidence for GC in Severe CAP
Despite theoretical support, clinical trial results have been inconsistent, leaving GC application in CAP in a state of uncertainty. Early trials like STEP, which enrolled moderately severe inpatients, found that short-course oral prednisone (50 mg/d for 7 days) shortened time to clinical stability and hospital stay but did not significantly affect mortality. The CAPE COD trial, focusing on ICU-admitted severe CAP patients, administered intravenous hydrocortisone (200 mg/d for 8–14 days with tapering) and demonstrated a significant reduction in 28-day mortality, alongside decreased mechanical ventilation and vasopressor days. Based on this high-quality trial and supporting meta-analyses, hydrocortisone in severe CAP has been viewed as a strategy with potential prognostic benefit.

Conversely, the ESCAPE trial, also targeting ICU patients with severe CAP, found no significant difference in 60-day mortality between methylprednisolone and control groups. Systematic reviews note significant heterogeneity across trials, closely tied to disease severity, timing of administration, and GC type. Some small studies even suggest that late initiation of GC may correlate with adverse outcomes. Secondary analyses of STEP indicated increased risks of pneumonia relapse, secondary infections, and new-onset insulin dependence in the GC group. Thus, clinicians must carefully weigh risks and benefits, and whether GC should be routinely used in severe CAP remains debated.

II. The SONIA Trial
The SONIA trial is one of the most anticipated studies in the CAP field in 2025. Unlike previous trials focused on ICU environments, intravenous administration, and limited sample sizes, the SONIA trial enrolled a broad population with a concise intervention protocol, offering practical reference value for healthcare institutions in China.

(I) Trial Design
Conducted across multiple hospitals in Kenya, the trial enrolled adult inpatients with CAP, spanning various disease severities from general wards to ICUs. All patients received standard antimicrobial and supportive care, then were randomized to standard care or GC therapy. The GC group received oral low-to-moderate dose GC for approximately 10 days on top of standard care. Specific drug types were selected based on local availability, with dosages adjusted per protocol.

(II) Core Findings
The primary endpoint was 30-day all-cause mortality. Results showed that early addition of short-course oral GC to standard care significantly reduced 30-day mortality risk. The need for mechanical ventilation or hemodynamic support also trended downward, suggesting that early GC intervention may inhibit excessive inflammatory responses and block progression of CAP to severe stages. Regarding safety, hyperglycemia was the most common adverse reaction in the GC group, but the rate of serious adverse events was low (~8.9%). Researchers emphasized that early, short-course, low-to-moderate dose GC can effectively reduce CAP mortality, but its promotion must account for institutional capacity to monitor and manage hyperglycemia.

(III) GC Type and Survival Benefit
SONIA trial subgroup analyses of 30-day hazard ratios (HR) for different GC types revealed: dexamethasone group (minimal mineralocorticoid activity) HR=1.00 (95% CI 0.76–1.30), showing no survival benefit; prednisone/prednisolone or methylprednisolone groups (mineralocorticoid activity ≤80% of hydrocortisone) HR=0.78 (95% CI 0.67–0.90), demonstrating clear survival advantage; hydrocortisone group (mineralocorticoid activity closest to physiological cortisol) HR=0.29 (95% CI 0.03–2.78), showing significant survival benefit despite a smaller sample size due to local resource constraints. These results indicate that GC efficacy is closely related to mineralocorticoid activity. Hydrocortisone, prednisone/prednisolone, and methylprednisolone, which possess such activity, are more likely to yield survival benefits, whereas dexamethasone lacking this activity showed no clear advantage in CAP. Therefore, whether hydrocortisone should become the standard GC for severe CAP requires further validation.

(IV) Comparison with REMAP-CAP Trial
The REMAP-CAP trial, also published in 2025, evaluated hydrocortisone use in ICU patients with severe CAP but observed no significant overall survival benefit, further questioning the strategy of “adding GC to all severe CAP patients.” Comparing the two studies reveals that SONIA emphasizes early low-to-moderate dose oral GC use in general wards to improve prognosis, whereas REMAP-CAP shows that adding GC to patients already critically ill in the ICU yields markedly diminished survival benefits. This discrepancy suggests a clear “therapeutic window” for GC: early (ward-stage) intervention is superior to late (ICU-stage) rescue.

III. Heterogeneous Effects of Glucocorticoids
As research deepens, GC efficacy in severe CAP has been proven to be highly heterogeneous. Clinical application must comprehensively consider drug class, administration timing, dose/duration, and pathogen background to achieve precise intervention.

(I) Drug Type
Common GCs differ significantly in receptor affinity, half-life, and tissue distribution. Hydrocortisone possesses both GC and mineralocorticoid activity, has a short half-life, and pharmacologically most closely resembles endogenous cortisol, showing clinical benefits in both CAPE COD and SONIA trials. Prednisone/prednisolone and methylprednisolone retain moderate mineralocorticoid activity and high oral bioavailability, also showing survival benefits in SONIA. Dexamethasone has strong GC activity but almost no mineralocorticoid effect and a long half-life. Although proven to reduce mortality in COVID-19-related ARDS, it showed no survival advantage in CAP in the SONIA trial. Therefore, in severe CAP, preparations with certain mineralocorticoid activity should be prioritized, rather than blindly adopting the dexamethasone regimen used for COVID-19.

Notably, fludrocortisone is one of the strongest synthetic mineralocorticoids. Although no prospective CAP studies exist, a subgroup analysis of the APROCCHSS trial showed that in CAP-related septic shock, a “hydrocortisone + fludrocortisone” combination significantly reduced 90-day mortality. This finding echoes SONIA trial results and provides a theoretical basis for exploring combination GC therapy in severe CAP patients (especially those with shock).

(II) Administration Timing
Existing evidence consistently indicates that initiating GC therapy within 24–48 h of admission or ICU transfer yields optimal clinical benefits; late addition shows no clear benefit. Therefore, GC should be viewed as an early “anti-infective + physiological replacement” intervention, not a terminal rescue measure. Additionally, in immunosuppressed patients, GC use may increase infection risk and requires strict risk-benefit assessment.

(III) Dose and Duration
Recent GC application strategies have shifted from “high-dose pulse” to “physiological replacement.” Multiple studies support hydrocortisone-equivalent doses of 100–240 mg/d for 7–10 days, achieving an optimal balance between efficacy and safety. Supratherapeutic doses or prolonged duration do not yield additional benefits but increase GC-related adverse event risks.

(IV) Special Populations
Unlike its established role in COVID-19, GC use in severe influenza-associated CAP remains controversial. Existing studies associate GC use in severe influenza CAP with increased mortality, higher secondary infection risk, prolonged ICU stay, and extended mechanical ventilation. Given the low evidence level (primarily observational studies and meta-analyses), current guidelines do not recommend routine GC use for severe influenza-associated CAP. However, some studies suggest GC may reduce mortality in specific subgroups with influenza-associated ARDS, though high-quality RCTs are still needed.

IV. Summary
GC application in severe CAP should not follow a “one-size-fits-all” strategy but should be individualized based on pathogen type, disease stage, and drug characteristics. Existing evidence supports early (within 48 h of admission), short-course (7–10 days), low-to-moderate dose preparations with certain mineralocorticoid activity (e.g., hydrocortisone 100–240 mg/d), which may improve prognosis through dual “anti-infective + physiological replacement” mechanisms.

However, strict adherence to GC indications is mandatory in clinical practice to avoid blind promotion. Particularly for CAP caused by viral pathogens like influenza A, routine GC use lacks benefit and may increase mortality and secondary infection risks. In such patients, comprehensive assessment combining oxygenation indices, inflammatory markers, and clinical progression is essential for prudent decision-making.

Future high-quality, pathogen-stratified RCTs are urgently needed to advance GC application in severe CAP from “experience-driven” to “precision evidence-based.”
(Liu Jiao; Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine; Xing Qian; Fudan University Shanghai Cancer Center)

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