By Kathryn Radigan, MD, MSc
Assistant Professor, Pulmonary Medicine, Northwestern University, Feinberg School of Medicine
Dr. Radigan reports no financial relationships relevant to this field of study.
SYNOPSIS: Treating patients with severe community-acquired pneumonia and high inflammatory mediators with methylprednisolone may decrease the number of treatment failures.
SOURCE: Torres A, 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.
Treatment failure in hospitalized patients with severe community-acquired pneumonia (CAP) is associated with an excessive inflammatory response and worse outcomes. Torres and colleagues sought to determine the effect of corticosteroids in patients with severe CAP and a significant inflammatory response. In this multicenter, randomized, double-blind, placebo-controlled trial, 120 severe CAP patients with C-reactive protein (CRP) levels >150 mg/L were randomized to receive either an IV methylprednisolone bolus of 0.5 mg/kg every 12 hours or placebo. Treatment began within 36 hours of hospital admission and lasted for 5 days. Severe CAP was defined as two out of the three minor criteria independently associated with severity including PaO2 /FiO2 < 250, multilobar involvement, and systolic blood pressure < 90 mmHg, or one out of two major criteria, including a requirement for mechanical ventilation or septic shock.1 Risk class V for the Pneumonia Severity Index was also considered severe CAP.2 The primary outcome was early or late treatment failure. Early treatment failure was defined as the development of shock, need for mechanical ventilation not present at baseline, or death within 72 hours of treatment. Late treatment failure was defined as radiographic progression, persistence of severe respiratory failure, development of shock, need for invasive mechanical ventilation not present at baseline, or death between 72 hours and 120 hours after treatment.
Treatment failure was less common in patients treated with methylprednisolone (8 patients, 13%) compared with the placebo group (18 patients, 31%) (P = 0.02). Although treatment with corticosteroids in patients with severe CAP reduced the risk of treatment failure (OR, 0.34; 95% CI, 0.14-0.87; P = 0.02), there was no difference in in-hospital mortality in the methylprednisolone group (six patients [10%] vs nine patients [15%] in the placebo group; P = 0.37). Eleven patients (18%) in the methylprednisolone group and seven patients (12%) in the placebo group experienced hyperglycemia (P = 0.34). There were no additional adverse reactions in the methylprednisolone group.
In developed countries, community-acquired pneumonia is the leading cause of death from infection and the sixth most common cause of mortality.3 Severe CAP is often associated with a profound increase of inflammatory cytokines that often correlates with outcome. Although the upregulation of cytokines helps to eliminate infection, an excessive inflammatory response may be detrimental to other organ systems. Attenuating this response may be beneficial for improved patient outcomes.
Corticosteroids are one of the most potent inflammatory inhibitors. The idea for attenuating the inflammatory response in CAP is an old one, with the first randomized control trial (RCT) being published in 1972.4 These investigators concluded there may be some benefit to steroid use in CAP (e.g., relieve fever) but cautioned that more robust trials were needed. Almost 50 years and a number of RCTs later, we have failed to make substantial progress. Torres and colleagues concluded that the use of methylprednisolone compared with placebo decreased treatment failure with less radiographic progression. This suggests that the benefit of corticosteroids may result from a controlled inflammatory response preventing ARDS or an attenuated reaction to endotoxin-like products released by the death of bacteria during antibiotic treatment. The decreased numbers of treatment failures were observed without a significant benefit on length of stay or mortality. Unfortunately, this study had significant limitations including an eight-year recruitment period, less statistical power than predicted, and no assessment of adrenal function was performed. Again, the investigators recommended their study be replicated prior to general use.
Unfortunately, it is not clear how far we have come since 1972 when the first trial of steroids for use in pneumonia was published. Ut is fair to say that the use of corticosteroids for regular use in severe CAP is not favored until further trials are completed. Torres and his colleagues suggest there is a trial already underway. Hopefully, this trial will be able to recruit adequate patients within a shorter time frame. One may question how many trials must be done before we decide that at best, steroids have a marginal, if any, benefit. For the time being, the controversy continues.
- Ewig S, et al. Severe community-acquired pneumonia. Assessment of severity criteria. Am J Respir Crit Care Med 1998;158:1102-1108.
- Fine MJ, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med1997;336:243-250.
- File TM, Jr. Streptococcus pneumoniae and community-acquired pneumonia: A cause for concern. Am J Med 2004;117(Suppl 3A):39S-50S.
- McHardy VU, Schonell ME. Ampicillin dosage and use of prednisolone in treatment of pneumonia: Co-operative controlled trial. BMJ 1972;4:569-73.