Severe community-acquired pneumonia (sCAP) is the term used to describe ICU-admitted patients with CAP requiring organ support. The most widely accepted criteria for defining sCAP are taken from the 2007 Infectious Disease Society of America (IDSA)/American Thoracic Society (ATS) consensus guidelines on the management of CAP in adults (1).
Even when early and adequate antibiotic treatment is administered, mortality observed in patients with sCAP remains high. Since elevated and persistent lung and systemic inflammatory responses constitute one of the demonstrated causes of this increased mortality, corticosteroids have been studied as adjunctive therapy in sCAP.
Results from randomized controlled trials (RCTs) suggest that there may be benefit in terms of frequency of treatment failure (including radiographic progression, mechanical ventilation duration and septic shock). However, they did not show a clear benefit in terms of mortality (2).
For this reason, recent European Respiratory Society (ERS) guidelines for the management of sCAP suggest the use of corticosteroids only if shock is present (conditional recommendation, low quality of evidence). They suggest methylprednisolone as the steroid of choice (3).
In this scenario, Dequin and collegues [4] conducted a RCT with 800 patients to evaluate the efficacy of adjunctive therapy with hydrocortisone in sCAP.

Methods

This phase-3, multicenter, double-blind, randomized, controlled superiority trial included adults who had been admittee to the intensive care unit (ICU) for severe community-acquired pneumonia.
The severity of pneumonia was defined by the presence of at least one of four criteria:

• the requirement of mechanical ventilation (invasive or non-invasive) with a positive end-expiratory pressure (PEEP) level ≥ 5 cmH2O;
• the need of administration of oxygen through a high-flow nasal cannula (HFNC) with a ratio of the partial pressure of arterial oxygen to the inspired fraction of oxygen (PaO₂:FiO₂) < 300, with a FiO₂ ≥ 50%;
• an estimated PaO2:FiO2 ratio < 300 for patients wearing nonrebreathing mask;
• A score ≥ 130 on the Pulmonary Severity Index (PSI).

Non-inclusion criteria were a do-not-intubate order, pneumonia caused by influenza and septic shock.
A total of 401 patients were assigned to the hydrocortisone group and 399 to the placebo one.
Patients received state-of-art standard therapy for severe community-acquired pneumonia. Moreover, within 24 hours after the onset of any severity criterion listed above, patients in the hydrocortisone group received intravenous hydrocortisone administered continuously at a dose of 200 mg per day during the first 4 days. On the fourth day, the medical team decided the length of the hydrocortisone administration, for a total of 8 or 14 days.
The primary outcome was death at 28 days. 

Results

By day 28, 25 of 400 patients died (6.2%; 95% confidence interval [CI], 3.9 to 8.6) in the hydrocortisone group and 47 of 395 patients died (11.9%; 95% CI, 8.7 to 15.1) in the placebo group (absolute difference, −5.6 percentage points; 95% CI, −9.6 to −1.7; P=0.006).
By day 90, mortality absolute difference was −5.4 percentage points (95% CI, −9.9 to −0.8) in the hydrocortisone group if compared to the placebo group. Among the patients who were not undergoing mechanical ventilation at baseline, endotracheal intubation was performed in 18.0% in the hydrocortisone group and in 29.5% in the placebo group (hazard ratio, 0.59; 95% CI, 0.40 to 0.86). Among 618 patients who had received no invasive ventilation at baseline, the cumulative incidence of invasive mechanical ventilation before day 28 was 19.5% in the hydro-cortisone group and 27.7% in the placebo group (hazard ratio, 0.69; 95% CI, 0.50 to 0.94).
The frequencies of hospital-acquired infections and gastrointestinal bleeding were similar in the two groups. Higher daily doses of insulin were given to the patients in the hydrocortisone group during the first week of treatment.

Future directions

This multicentred trial indicates a consistent difference in reducing mortality by day 28 if early hydrocortisone therapy is administered in patients admitted to the ICU for sCAP.
Even though results are consistent and encouraging, several limitations of the trial had been outlined by the authors themselves. The exclusion of the patients with septic shock, the inclusion of immunocompromised ones and the various types of oxygen-delivery interface and ventilation support could have been the main disadvantages and critical points of the study.
Overall, discrepancies regarding the benefit of corticosteroids on mortality in patients with sCAP are perhaps due to heterogeneity found within the populations studied. It is possible that corticosteroids only work in select patient groups, such as those with a high systemic inflammatory response.
For these reasons, as suggested by recent ERS sCAP guidelines, determining those phenotypes of patients and biomarkers that would help identify who would most benefit from corticosteroid use remains a research priority.

References

1. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med 2019;200:e45–e67.
2. Niederman MS, Torres A. Severe community-acquired pneumonia. Eur Respir Rev 2022;31:220123.
3. Martin-Loeches I, Torres A, Nagavci B, et al. ERS/ESICM/ESCMID/ALAT guidelines for the management of severe community-acquired pneumonia. Intensive Care Med 2023;49:615-32.
4. Dequin PF, Meziani F, Quenot JP, et al. Hydrocortisone in Severe Community-Acquired Pneumonia. N Engl J Med 2023;388:1931-41.