By Jake Scott, MD
Clinical Assistant Professor, Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Antimicrobial Stewardship Program Medical Director, Stanford Health Care Tri-Valley
SYNOPSIS: A double-blind, randomized, controlled trial conducted at 31 French medical centers demonstrated that adult patients with severe community-acquired pneumonia who were given hydrocortisone had a lower risk of death by day 28, as compared with those who received placebo.
SOURCE: Dequin PF, Meziani F, Quenot JP, et al. Hydrocortisone in severe community-acquired pneumonia. N Engl J Med 2023;Mar 21. doi: 10.1056/NEJMoa2215145. [Online ahead of print].
Dequin and colleagues conducted a large, double-blind, randomized, controlled trial that assessed clinical outcomes among adult patients hospitalized with severe community-acquired pneumonia (CAP) who were given hydrocortisone compared with placebo.1 All patients had been admitted to the intensive care unit (ICU) and given standard antibiotic therapy and supportive care. Patients were excluded from the trial if they had a do-not-intubate order, if they had pneumonia caused by influenza, or if they had septic shock at baseline. Patients in the hydrocortisone group were given continuous infusions of intravenous hydrocortisone within 24 hours after the onset of clinical signs of severe CAP at a dose of 200 mg per day during the first four days, and then for a total of either eight or 14 days, depending on clinical status, at a tapering dose. Intravenous saline was given as placebo to the patients in the control group. Treatment was discontinued in all patients at the time of discharge from the ICU. The primary outcome measured was death from any cause by day 28. Several various correlates of clinical severity were evaluated as secondary outcomes, such as length of ICU stay and level of respiratory support needed.
The primary analysis included 400 patients in the hydrocortisone group and 395 patients in the placebo group. Baseline characteristics were well balanced. The median age was 67 years, and approximately 70% were male in both groups. Nearly one-quarter of patients in both groups had chronic obstructive pulmonary disease (COPD) and/or diabetes, and immunosuppression was present in 6.0% and 6.8% in the hydrocortisone and placebo groups, respectively. The vast majority of patients had high-risk pneumonia. In the study, 83.6% of patients in the hydrocortisone group and 83.2% in the placebo group were determined to have a pulmonary severity index (PSI) risk class of IV or V (37.9% and 33.9% were classified as PSI IV, and 45.7% and 49.2% were classified as PSI V, respectively). Patients in both groups were promptly admitted to the ICU after hospital admission, within a median interval of approximately five hours. Treatment was given within 24 hours of ICU admission; the median interval from ICU admission to initiation of hydrocortisone was 15.3 hours (range 7.0-20.5).
Death had occurred by day 28 in 25 of 400 patients (6.2%; 95% confidence interval [CI], 3.9 to 8.6) in the hydrocortisone group, compared with 47 of 395 patients (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, death had occurred in 9.3% in the hydrocortisone group and in 14.7% in the placebo group (absolute difference, -5.4 percentage points; 95% CI, -9.9 to -0.8). In addition to lower mortality rates, the cumulative incidence of requiring endotracheal intubation and vasopressors was significantly lower in the hydrocortisone group compared with the placebo group by day 28. There was no statistically significant difference between the groups in the incidence of hospital-acquired or ventilator-associated pneumonia, bloodstream infection, or gastrointestinal bleeding by day 28. Patients in the hydrocortisone group required higher daily doses of insulin during the first week of treatment (median of 35.5 IU vs. 20.5 IU).
COMMENTARY
The introduction of antibiotics in the 1950s led to a dramatic reduction in CAP mortality. Despite the development of a broader antimicrobial armamentarium, vaccines, and advances in diagnostics, CAP remains the single most common cause of infection-related mortality and the fourth leading cause of death among all age groups worldwide, as of 2019.2 The majority of hospital deaths among patients with CAP occur after the eradication of causative pathogens from tracheal secretions and the bloodstream, suggesting that antibiotics alone may be insufficient in certain severe cases.3 Therefore, it is critical that the role of adjunctive therapies, such as immune modulators, be explored thoroughly.
The immune response to pneumonia is heterogeneous and involves a complex orchestration of early response proinflammatory cytokines, which are needed for the recruitment of neutrophils into infected lung tissue, as well as anti-inflammatory response mediators, which are important for preventing or minimizing the destruction of noninfected tissues and other organs. Higher concentrations of inflammatory cytokines in patients with pneumonia have been associated with worse clinical outcomes.4 Corticosteroids, which are potent anti-inflammatory agents, may reduce CAP-associated morbidity and mortality in those with severe disease by downregulating proinflammatory cytokine transcription and preventing or reducing excessive inflammatory cytokine responses.5
Clinical trials of corticosteroids for CAP conducted over several decades have yielded heterogeneous results, likely because of important differences in the interventions and patient populations studied. Treatment protocols have varied in terms of agents, doses, and durations used, as well as the timing of treatment initiation. Particular benefits and harms associated with corticosteroids may depend on the type of agent used, since there are important pharmacodynamic differences, including the balance between glucocorticoid and mineralocorticoid activity. The variability in clinical settings, severity of cases, and risk factors of individuals included in the trials also likely accounts for some of the differences in results.
A 2015 meta-analysis that included 13 randomized controlled trials (RCTs) concluded that corticosteroid treatment in patients hospitalized with CAP was associated with a reduction in the need for mechanical ventilation, time to clinical stability, and duration of hospitalization.6 A subgroup analysis of RCTs that specifically investigated severe CAP suggested a substantial mortality benefit. An individual patient data meta-analysis of six trials likewise showed that CAP patients treated with adjunctive corticosteroids had shorter time to clinical stability and reduced hospital length of stay, but no significant mortality benefit was found.7
In addition to the recent study by Dequin and colleagues, the use of adjunctive hydrocortisone in CAP has been studied in a multiple other trials, some of which also yielded impressive results.8-10 The earliest clinical study of corticosteroids in patients with pneumonia, conducted by Wagner and colleagues and published in 1955, demonstrated that the use of adjunctive hydrocortisone in combination with penicillin was associated with a more rapid improvement in symptoms as compared with penicillin alone.8 Sixty years later, a double-blinded RCT of 46 patients admitted to the ICU with severe CAP, conducted by Confalonieri and colleagues, showed that a seven-day course of low-dose hydrocortisone infusion resulted in a significant reduction in duration of mechanical ventilation, length of stay, and hospital mortality, and was well tolerated.9
In a recent double-blind RCT conducted by Meduri and colleagues, which included 586 patients with severe CAP requiring ICU admission, treatment with a 20-day low-dose course of methylprednisolone did not significantly reduce 60-day mortality, as compared with placebo (16% vs. 18%, respectively; adjusted odds ratio, 0.90; 95% CI, 0.57 to 1.40), nor did it improve secondary outcomes.11 It is possible that the failure of this study to demonstrate a clinical benefit was related to the low dosage and the timing of administration; the study allowed for randomization up to 72-96 hours within hospital presentation, and the median interval from hospital presentation to treatment initiation was 40 hours. In an earlier study by Torres and colleagues, a higher dose of methylprednisolone given sooner after hospital presentation decreased treatment failure compared to placebo.12
In conclusion, this study by Dequin and colleagues makes an informative and important contribution to our knowledge of adjunctive corticosteroids in patients with severe CAP. In this well-conducted, large, multicenter trial, the early administration of hydrocortisone to patients admitted to the ICU with severe CAP led to a reduction in mortality rates without causing significant harm. The absolute difference in mortality was similar at day 28 and day 90, and improvements in multiple other clinical outcomes were consistently seen among hydrocortisone recipients in different subgroups. Although hydrocortisone use was not associated with higher rates of ICU-acquired infections, other potential adverse effects commonly seen with glucocorticoids, such as neuropsychological and neuromuscular side effects, were not evaluated. Future studies are needed to more thoroughly investigate the various effects of corticosteroids in patients with severe CAP and to identify who may benefit the most. Improving our understanding of individual immune responses to CAP and how and when to modulate them to optimize clinical outcomes remains vitally important.
REFERENCES
- Dequin PF, Meziani F, Quenot JP, et al. Hydrocortisone in severe community-acquired pneumonia. N Engl J Med 2023; Mar 21: doi:10.1056/NEJMoa2215145. [Online ahead of print].
- World Health Organization. The top 10 causes of death. Dec. 9, 2020. https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
- Musher DM, Montoya R, Wanahita A. Diagnostic value of microscopic examination of Gram-stained sputum and sputum cultures in patients with bacteremic pneumococcal pneumonia. Clin Infect Dis 2004;39:165-169.
- Kellum JA, Kong L, Fink MP, et al. Understanding the inflammatory cytokine response in pneumonia and sepsis: Results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med 2007;167:1655-1663.
- Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med 2005;353:1711-1723.
- Siemieniuk RAC, Meade MO, Alonso-Coello P, et al. Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: A systematic review and meta-analysis. Ann Intern Med 2015;163:519-528.
- Briel M, Spoorenberg SMC, Snijders D, et al. Corticosteroids in patients hospitalized with community-acquired pneumonia: Systematic review and individual patient data metaanalysis. Clin Infect Dis 2018;66:346-354.
- Wagner HN Jr, Bennett IL Jr, Lasagna L, et al. The effect of hydrocortisone upon the course of pneumococcal pneumonia treated with penicillin. Bull Johns Hopkins Hosp 1956;98:197-215.
- Confalonieri M, Urbino R, Potena A, et al. Hydrocortisone infusion for severe community-acquired pneumonia: A preliminary randomized study. Am J Respir Crit Care Med 2005;171:242-248.
- Nafae RM, Ragab MI, Amany FM, Rashed SB. Adjuvant role of corticosteroids in the treatment of community-acquired pneumonia. Egypt J Chest Dis Tuberc 2013;62:439-445.
- Meduri GU, Shih MC, Bridges L, et al. Low-dose methylprednisolone treatment in critically ill patients with severe community-acquired pneumonia. Intensive Care Med 2022;48:1009-1023.
- Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: A randomized clinical trial. JAMA 2015;313:677-686.
A double-blind, randomized, controlled trial conducted at 31 French medical centers demonstrated adult patients with severe community-acquired pneumonia who were given hydrocortisone had a lower risk of death by day 28 compared with those who received placebo.
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