Author: Allison Lee, PGY-2
Background:
- Respiratory tract infections and pneumonia account for a leading cause of death worldwide.
- Although outcome of CAP improved with antibiotics, it is still associated with a high risk for long-term morbidity and mortality.
- In CAP, an excessive release of circulating inflammatory cytokines can be harmful and cause pulmonary dysfunction.
- Corticosteroids have anti-inflammatory effects, and adjunct treatment for pneumonia with corticosteroids has been discussed. Previous small studies, reviews, and meta- analyses have suggested a reduction in all-mortality and in-hospital mortality, but a large, randomisedtrial has not yet been done.
Article Reviewed:
Population:
- Adult patients aged 18 years or older admitted to the hospital for CAP from 7 tertiary hospitals in Switzerland
Outcomes:
- Primary:
- Time to clinical stability (AKA # of days until stable vital signs for 24 hours or longer (T<37.8C, HR<100, RR<24, SBP>90, no vasopressors, mental status at baseline, tolerating PO, PaO2>60 or SpO2>90% RA)
- Secondary:
- Time to effective discharge from hospital,
- Recurrence of pneumonia,
- Readmission to hospital,
- ICU admission,
- All-cause mortality,
- Duration of total and IV antibiotic treatment,
- Disease activity scores specific to CAP,
- Incidence of complications due to CAP (ARDS, empyema,
persistence of PNA), - Side effects of corticosteroids (ie, rate of hyperglycemia, HTN, delirium, nosocomial infections, weight gain), and
- Time to earliest possible hospital discharge
- Intervention:
- Prednisone 50 mg daily for 7 days
- Control:
- Placebo
- Design:
- Multicenter, double-blind, randomised, placebo-controlled trial
- Inclusion Criteria:
- 18 years or older, with hospital admission with CAP defined by a new infiltrate on CXR and the presence of at least one of the following acute respiratory distress signs and symptoms:
- Cough
- Sputum production
- Dyspnea
- Core body temperature > 38.0 C
- Auscultatory findings of abnormal breathing signs or rales
- Leukocyte counts >10,000 cells/uL or <4000 cells/uL
- 18 years or older, with hospital admission with CAP defined by a new infiltrate on CXR and the presence of at least one of the following acute respiratory distress signs and symptoms:
- Excluded:
- Patients unable to give informed consent,
- Active IVDU,
- Acute burn injury,
- GI bleeding within last 3 months,
- Known adrenal insufficiency,
- A pre-existing condition requiring more than 0.5 mg/kg/day prednisone equivalent,
- Pregnant or breast-feeding,
- Severe immunosuppression (HIV w/ CD4<350, on immunosuppression after solid organ transplant, neutropenia <500 cells or 500-1000 cells, undergoing chemo),
- cystic fibrosis, or
- active TB
Primary Results:
- 2911 patients assess for eligibility
- 1504 did not meet inclusion criteria
- 605 were eligible but declined to participate
- 802 patients were randomized
- Prednisone: n = 402 → 10 blinded post-randomization, 30 protocol violations → n = 362
- Placebo: n = 400 → 7 blinded post-randomization, 27 protocol violations → n = 366
Critical Findings:
Strengths:
- Largest and most conclusive randomized placebo-controlled trial of corticosteroids in CAP, including >800 patients
- Included all-severity classes of CAP inpatients (PSI score, ICU, septic patients)
- Prednisone oral was used (vs. prior studies which used intravenous), which allows easier application
- Baseline characteristics were similar between groups
- No patient lost to follow up before reaching primary endpoint (discharge)
- The patients, treating physicians, investigators, and data assessors were masked to treatment allocation.
Limitations:
- Only included patients who were admitted to the hospital; did not acknowledge patients who were treated for CAP outpatient.
- Study was not powered to mortality
- “Time to clinical stability” endpoint limited as it was a combination of several parameters (based on vital signs). Repeat CXRs not included
- Corticosteroid-induced hyperglycemia lead to unblinding in certain patients.
- ICU patients and septic patients were underrepresented in the study
- Total of 4 patients lost to follow up at 30 day mark (1 in prednisone group, and 3 in placebo group).
- Included hospitals from only one country (Switzerland).
Discussion:
- A 7-day treatment with prednisone in patients admitted with CAP led to a reduction in time to clinical stability of 1.4 days, to an overall reduction of length of hospital stay of 1 day, and reduction in duration of IV abx by 1 day.
- Pneumonia-associated complications until day 30 (empyema, ARDS, respiratory failure) was also lower in the prednisone group compared to placebo.
- CAP is seen to trigger an increase in pulmonary and circulating cytokines. A prolonged unrestrained inflammatory condition may be detrimental. Corticosteroid affects this pathway by modulating the immune response.
- This is not only relevant from a patient’s stand point, but is also an important determinant of hospital costs and efficiency.
- In this study, results were similar in non-ICU and ICU patients. Effect modification was not noted in different subgroups including median age, initial median CRP, previous hx of COPD, severity of CAP defined by PSI score, or blood culture positivity. A positive treatment response to prednisone was found irregardless of the identified microorganism implicated in CAP.
- A larger treatment effect was noted in patients with sepsis.
- Recurrence rate was also similar in prednisone vs. placebo groups.
- The main prednisone-associated adverse event found was hyperglycemia. CAP patients treated with prednisone had a higher incidence of hyperglycemia requiring insulin treatment than the placebo group. This, however, did not affect clinical outcome and did not prolong hospital stay. Rate of new need for insulin at day 30 were low in both groups.
- There was no significant effect on mortality (from any cause, at day 30).
- Author’s Conclusion:
- “Prednisone treatment for 7 days in patients with CAP admitted to hospital shortens time to clinical stability (CAP of any severity) without an increase in complications.”
- “Time to hospital discharge and duration of IV antibiotic treatment are reduced by 1 day.”
- “However, hyperglycemia has to be anticipated, and the usual contraindications for corticosteroids must be taken into consideration.”
- Clinical Bottom Line:
- Adjunct prednisone treatment should be considered in patients with CAP who don’t have a contraindication to steroids, as it may decrease time to clinical stability and time to discharge, which affects hospital costs.
- This study did not, however, show any mortality benefit.
- Hyperglycemia should be anticipated in patients receiving prednisone.