Steroids for Severe Community-Acquired Pneumonia: More Evidence or More Uncertainty?
Community-acquired pneumonia (CAP) is the leading cause of mortality from infection in industrialized countries, and treatment failure occurs in 10-20% of cases despite appropriate antibiotic therapy. Thus, effective treatment strategies that reduce the burden of CAP would have a major impact on public health. Several previous studies that investigated the role of corticosteroids in CAP produced mixed results. Torres and colleagues hypothesized that corticosteroids modulate the immune response in severe CAP, thereby decreasing treatment failure.
The study was conduced at three teaching hospitals in Spain. Patients were prospectively enrolled between June 2004 and February 2012. The inclusion criteria included age > 18 years, had symptoms of CAP, a new infiltrate on chest radiograph, met severe CAP criteria, and had a C-reactive protein (CRP) greater than 150 mg/L on admission. Patients were excluded if they had previously been on corticosteroids, had HIV, had uncontrolled diabetes mellitus, had gastrointestinal bleeding in the preceding 3 months, or had influenza or a condition that required treatment with methylprednisolone. All enrollees were randomized to receive either intravenous methylprednisolone or placebo for five days started within 36 hours of hospital admission. The primary endpoint was the rate of treatment failure, which the authors divided into early (clinical deterioration within 72 hours of treatment) and late (defined as radiographic progression, persistence of respiratory failure including mechanical ventilation, development of shock, and death between 72 hours and 120 hours after treatment initiation). Secondary endpoints were time to clinical stability, length of stay, and in-hospital mortality. CRP levels were obtained on days 1, 3, and 7 of treatment.
A total of 120 patients were randomized, 61 to the methylprednisolone group and 59 to the placebo group. Ninety patients (75%) were admitted to the intensive care unit. The antibiotic regimens chosen, mostly ceftriaxone with levofloxacin or azithromycin, did not differ between the groups. There was significantly less treatment failure in the steroid group (8 patients [13%]) compared to the placebo group (18 patients [31%) (P = 0.02). There were no statistically significant differences in the secondary endpoints between the steroid and placebo groups. At hospital day 3, decreases in CRP levels were greater in the steroid group, while those patients with persistent high CRP at day 7 had a higher percentage of treatment failure and mortality.
This study showed that patients with severe CAP who received methylprednisolone had reduced inflammation and less treatment failure compared to those who received placebo. However, these results need to be interpreted with caution. First of all, baseline cortisol levels were not measured. It is possible that undiagnosed adrenal insufficiency may have led to more treatment failures, especially in critically ill patients admitted to the ICU. Second, the placebo group had a higher proportion of patients with septic shock and acute respiratory failure requiring mechanical ventilation. This could be interpreted that steroids were given to patients who were less ill and therefore expected to have better outcomes. Third, the main treatment difference between the two groups was mainly due to less radiologic progression 72 hours or more from time of randomization. As noted in an accompanying editorial, the two likely explanations for this phenomenon are worsening pneumonia and the development of acute respiratory distress syndrome (ARDS).1 It seems illogical that steroids would help with the former condition but plausible they might modulate the latter. One theory is that ARDS is caused by cytokine release from a Jarisch-Herxheimer-like reaction in tissue with a high bacterial genomic load after the initiation of antibiotics. Thus, steroids may block this inflammatory reaction from occurring. But additional larger and more definitive studies are necessary to confirm that less radiologic progression leads to improved mortality.
In the current (albeit outdated) IDSA/ATS clinical practice guidelines for CAP,2 CRP is not a recommended diagnostic test, although it is used in European countries.3 Torres and colleagues used a CRP level of 150 mg/L or greater as an inclusion criterion for quantifying inflammation, yet only 57% of eligible patients (162/284) had this level. Therefore, the patients in their study represented only a fraction of those with severe CAP. The possible benefits of steroids for patients with severe CAP and lower CRP levels remain to be elucidated.
Because the immunosuppressive effects of steroids could theoretically worsen an already severe infection, it is important to recall the old adage “primum non nocere” (first, do no harm). The results of the study by Torres and colleagues need further confirmation before the widespread use of steroids in severe CAP can be endorsed.
- Wunderink, RG. Corticosteroids for severe community-acquired pneumonia: Not for everybody. JAMA 2015;313:673-674.
- Mandell LA, et al. Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults. Clin Infect Dis 2007;44:S27-72.
- Lim WS, et al. BTS guidelines for the management of community acquired pneumonia in adults: Update 2009. Thorax 2009;64 Suppl3:1-35.
A multicenter, randomized, double-blind, placebo-controlled trial involving patients with severe community-acquired pneumonia and evidence of high inflammation found less treatment failure in those who received steroids. However, in-hospital mortality did not differ between the groups.
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