Use of Corticosteroids for patients with CAP

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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(7):677-686.
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Clinical Question

In patients with community acquired pneumonia, does the use of corticosteroids reduce mortality and/or improve clinical outcomes?

Bottom Line

In patients with severe community acquired pneumonia, combining corticosteroids with standard antibiotic treatment will reduce treatment failure.

Major Points

Patients with severe community acquired pneumonia (CAP) often have an excessive inflammatory response, and have high treatment failure rates which results in increased morbidity and mortality.1

To test the role of corticosteroids in CAP therapy, a trial of 120 patients (randomized, double-blind, placebo-control) with CAP and a high inflammatory response was performed. The control group received standard antibiotic treatment and placebo IV bolus and the experimental group received standard antibiotics plus corticosteroids IV bolus.2 The study found significant differences in treatment failure rates and late treatment failure with radiographic progression rates.7

The study showed that patients with CAP and C-Reactive Protein >150 mg/L, the addition of corticosteroids along with standard therapy will prevent 1 out of 6 patients from having treatment failure. However, more research will be needed due to limited statistical power of this current study that based its sample size calculations off of another similar study that found a 31% higher treatment failure rate in the control group.3 The article did not include the inclusion criteria of the other study, therefore that study may have had a different patient population that did not have inflammation which would support the use of corticosteroids.

Guidelines

As of April 2018, no guidelines have been published recommending the use of corticosteroids in the treatment of severe community acquired pneumonia. Patients in this trial were treated with standard antibiotic therapy for community acquired pneumonia as recommended by the Infectious Disease Society of America.2

Design

  • Multicenter, randomized, double-blind, placebo-controlled trial
  • N=120
    • Methylprednisolone and standard antibiotic therapy (n=61)
    • Placebo and standard antibiotic therapy (n=59)
  • Setting: 3 Spanish teaching hospitals
  • Enrollment: June 2004-February 2012
  • Mean follow-up: 5 days
  • Analysis: both intention to treat and per-protocol populations
  • Primary outcome: treatment failure

Population

Inclusion Criteria

  • Age: 18 and older
  • Clinical symptoms suggesting CAP (fever, cough, pleuritic chest pain, dyspnea)
  • New chest radiograph infiltrates
  • Met severe community acquired pneumonia criteria (defined by modified American Thoracic Society criteria)
  • C-reactive protein > 150 mg/L at admission

Exclusion Criteria

  • Prior treatment with systemic corticosteroids
  • Nosocomial pneumonia
  • Reported severe immunosuppression (HIV, immunosuppressive conditions or medications)
  • Pre-existing medical condition with a life expectancy of less than 3 months
  • Uncontrolled diabetes mellitus
  • Major gastrointestinal bleeding within 3 months
  • Condition requiring acute treatment with greater than 1 mg/kg/day of methylprednisolone or its equivalent
  • Patients with pandemic H1N1 influenza A pneumonia


Baseline Characteristics

  • Demographics: Age: 64.5 years (mean), male
  • Preexisting comorbid conditions:
    • Diabetes mellitus
    • Chronic pulmonary disease
    • Congestive heart failure
    • History of malignancy
    • Ischemic heart disease
  • Mean laboratory measurements: glucose 131 mg/dL, creatinine 1.3 mg/dL, platelets 214 x 109 /L, WBC 12.7 x 109 /L, c-reactive protein 273 mg/L procalcitonin 1.3 ng/dL, IL-6 256 pg/dL, IL-8 74 pg/dL, IL-10 4.7 pg/dL
  • Major severity criteria
    • Mechanical ventilation
    • Septic shock
  • Minor severity criteria
    • Systolic blood pressure < 90 mm Hg
    • Multilobar involvement
    • PaO2: fraction of inspired oxygen < 250 mm Hg
  • ICU admission
  • Time to first antibiotic dose:
    • Within 1 hr in patient with septic shock
    • Within 4 hr in patients without septic shock
  • Time from emergency department presentation to randomization, median 1 day

Interventions

Patients received standard international guideline care for CAP along with either an intravenous bolus of 0.5 mg/kg every 12 hours of methylprednisolone (n=61) or placebo (n=59) for 5 days starting within 36 hours of hospital administration.

Outcomes

Primary Outcomes

Intention-to-treat Population

  • Treatment Failure
    • 13% vs 31% (95% CI 3-32; P=0.02) NNT=6
  • Late Treatment Failure (72-120 hrs)
    • 3% vs 25% (95% CI 10-34; P=0.001) NNT=5
  • Radiographic Progression
    • 2% vs 15% (95% CI 4-23; P=0.007) NNT=8
  • Insignificant: early treatment failure (0-72 hrs), early mechanical ventilation, early septic shock, death, respiratory failure, late mechanical ventilation, late septic shock
  • Per Protocol Population
    • Results were similar to the Intention-to-treat population.

Secondary Outcomes

Insignificant: time to clinical stability, hospital and ICU stay, and inpatient mortality.

Subgroup Analysis

Post hoc analysis showed that there was a statistical significant difference in late treatment failure that did not include the radiographic progression in favor of the methylprednisolone group compared to the placebo group. There was no significant difference in the per-protocol population in favor of the methylprednisolone group compared to the placebo group.

Adverse Events

Methylprednisolone vs placebo: insignificant statistical difference with hyperglycemia, acute kidney injury, superinfection, acute hepatic failure, and GI bleeding.

Criticisms

  • Study did not have rules in place to reduce the dosage or the use of antibiotics.
  • Methylprednisolone was only used for 5 days, but recent studies suggested for it to be used as adjunct therapy should be more than 5 days to have a beneficial effect.4
  • Study results cannot be generalized to all patients with CAP (excluded patients with CRP < 150 mg/L and other criteria).
  • The antibiotic treatments were not guided by the algorithms on the levels of procalcitonin.

Funding

This study was supported by:

  • The Sociedad Española de Neumología
  • The Societat Catalana de Pneumologia
  • The Fundació Catalana de Pneumologia
  • The Grup de Recerca de Qualitat de Generalitat de Catalunya
  • The Fondo de Investigación Sanitaria
  • The Institut d ́Investigacions Biomèdiques August Pi i Sunyer
  • The Centro de Investigación Biomédica En Red-Enfermedades Respiratorias

The funders had no role in the design, collection, management, analysis and interpretation of the data, in the approval of the manuscript or the decision to submit the manuscript for publication.

Further Reading

1. Fine MJ, Smith MA, Carson CA, etal. Prognosis and outcomes of patients with community acquired pneumonia: a meta-analysis.JAMA.1996; 275(2):134-141.

2. Mandell LA, Wunderink RG, Anzueto A, et al; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. ClinInfect Dis. 2007;44 (suppl 2):S27-S72.

3. Menéndez R,Torres A,Zalacaín R, et. al; Neumofail Group.Risk factors of treatment failure in community acquired pneumonia:implications for disease outcome.Thorax.2004;59(11):960-965.

4. Nie W, Zhang Y, Cheng J, Xiu Q. Corticosteroids in the treatment of community-acquired pneumonia in adults: a meta-analysis. PLos One. 2012;7(10):e47926.

5. Siemieniuk RAC, Meade MO, Alonso-Coello P, et al. Corticosteroid therapy for patients hospitalized with community-acquired pneumonia. Ann Intern Med 2015;163(7):519-528

6. Stern A, Skalsky K, Avni T, Carrara E, Leibovici L, Paul M. Corticosteroids for pneumonia. Cochrane Database of Systematic Reviews 2017, Issue 12. Art. No.: CD007720. DOI: 10.1002/14651858.CD007720.pub3

7. 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. JAMA 2015;313(7):677-686.