Effect of Corticosteroids on Treatment Failure Among Hospitalized Patients with Severe Community-Acquired Pneumonia

and High Inflammatory ResponseTorres, et al. JAMA. 2015;313(7):677-686.

Sarah Struthers, MDMarch 19, 2015

LSU Journal Club

Background- In patients with CAP, an excessive host inflammatory

response has been associated with treatment failure and mortality

- Prior studies of corticosteroid use in CAP to blunt this inflammatory response have yielded mixed results. However, these studies have not looked exclusively at the most seriously ill patients

- Two recent meta-analyses found improved mortality in the subgroup of patients with severe CAP that received corticosteroids

Hypothesis

Corticosteroids may reduce treatment failure in hospitalized patients with severe CAP and high inflammatory

response.

Study Design & Methodology- Multicenter, randomized, double-blind,

placebo-controlled trial at 3 Spanish teaching hospitals

- Enrollment period: June 2004 - February 2012

Patient Selection & EnrollmentInclusion Criteria: (1) Age >18(2) Clinical symptoms suggesting CAP (cough, fever, pleuritic

CP, dyspnea)(3) New infiltrate on CXR(4) Met severe CAP criteria (defined by modified ATS Criteria

or Class V PSI)(5) CRP level >150 mg/L at admission

Patient Selection & Enrollment Cont.Excluson Criteria:(1) Prior treatment with systemic corticosteroids(2) Nosocomial pneumonia(3) Immunosuppression(4) Pre-existing condition with life expectancy <3 months(5) Uncontrolled DM(6) Major GI bleed in last 3 months(7) Other condition requiring treatment with greater than 1

mg/kg/day of methylprednisolone (MPDN) or equivalent(8) H1N1 or influenza A

Intervention- IV bolus MDPN 0.5 mg/kg every 12

hours OR placebo started within 36 hours of hospital admission and continued for 5 days

Primary EndpointRate of treatment failure:

- Early treatment failure: Clinical deterioration within 72 hours of admission- Development of shock, need for mechanical ventilation not

present on admit, death

- Late treatment failure: Clinical deterioration from 72-120 hours- Radiographic progression (increase in pulmonary infiltrates

>50% from baseline), PaO2/FIO2 <200 or RR >30 in non-intubated patients + above

Secondary Endpoints

- Time to clinical stability- Temp <37.2, HR <100, SBP >90, PaO2 >60 or on baseline home O2, switch to po antibiotics

- Length of hospital and ICU stays- In-hospital mortality

Statistical Analysis- Categorical variables were compared using the Fisher-Exact

test and patients were analyzed according intention-to-treat and per-protocol analyses

- Logistic regression analyses were performed that adjusted for differences in baseline characteristics and potential confounders (septic shock, procalcitonin and IL-10 at day 1, year of admission and center)

Results- There was significantly less treatment failure in the MPDN

group, both in the ITT and per-protocol population- Primarily due to fewer cases of late treatment failure with radiographic progression as a primary component

- Logistic regression analyses revealed less treatment failure in MPDN group both with and without adjustment for differences in baseline characteristics and potential confounders

Results Cont…- No significant differences observed among secondary clinical

outcomes- Adverse events were evenly distributed across the 2 groups

- Post-hoc subanalyses of treatment failure removing radiographic progression variable found that the beneficial effects of corticosteroids remained for the ITT group but not for per-protocol population

Conclusions

Concomitant therapy with methylprednisolone reduces treatment failure in patients with both severe CAP and a high inflammatory response

Study Limitations- Treatment failure in placebo group lower than predicted

yielding an underpowered study- Long duration of study- Results not generalizable to all patients with CAP- No assessment of baseline adrenal function- Despite being stated in hypothesis, changes in

inflammatory markers were not treated as outcome measure

- Decrease in radiographic progression—Do we care?

Thank you