Adjunct Prednisone Therapy for Patients with Community-Acquired Pneumonia

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Blum CA, et al. "Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial". The Lancet. 2015. 385(9977):1511-1518.
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Clinical Question

In adults with community-acquired pneumonia, will the addition of prednisone, to conventional therapy with antibiotics, decrease time to clinical stability and risk of morbidity and mortality?

Bottom Line

In patients with community-acquired pneumonia, the addition of prednisone therapy along with standard antibiotic therapy was associated with decreased time to clinical stability, hospital discharge time, and duration of antibiotic treatment, but there was no significant change in death from any cause.

Major Points

The clinical question asked is whether or not Adjunct Prednisone Therapy for Patients with Community-Acquired Pneumonia prednisone therapy should be used as an adjunct for patients with community-acquired pneumonia. Multiple clinical trials have been representing opposing data as to whether there is a benefit to adding systemic corticosteroids for treatment of community-acquired pneumonia. This applies to practice since community-acquired pneumonia is a prevalent illness in the patient population.

The study design used by the trial was a multicentre, double-blind, randomized placebo-controlled trial. 785 patients were randomized with 392 assigned to prednisone and 393 assigned to placebo. The treated patients received 50 mg of prednisone daily for 7 days in addition to amoxicillin and clavulanic acid or ceftriaxone, and the placebo patients received placebo daily for 7 days with the same standard therapy as previously mentioned. The endpoint was time to clinical stability, which was time in days until patient had stable vital signs. Median time to clinical stability was 3 days in the prednisone and 4.4 days in the placebo. Pneumonia associated complications until the 30th day did not differ between the groups and the prednisone group had a higher incidence of in-hospital hyperglycemia needing insulin treatment.

Overall, the study presented internal validity by exhibiting randomisation and allocation concealment, similar equally treated groups, accountability and objective measures. Externally, this is a study that focuses solely on community-acquired pneumonia patients who are hospitalized. Although this cannot be applied to those in home care, this topic can affect a broad spectrum of patients, as this is a common health problem.

Guidelines

Throughout the trial, the providers referenced various guidelines. They are, as followed, ERS/ESCMID guidelines for empiric antibiotic regimen, Surviving Sepsis Campaign for treatment of patients with sepsis conditions, Guidelines for the Management of Adults with Community-Acquired Pneumonia, Guidelines for the Management of Adult Lower Respiratory Tract Infections, the Declaration of Helsinki and Good Clinical Practice Guidelines for ethics, and the Effect of Procalcitonin-based Guidelines vs. Standard Guidelines on Antibiotic Use in Lower Respiratory Tract Infections.

Design

  • Investigator-initiated multicentre, double-blind, randomised, placebo-controlled trial
  • N= 802 randomised, with 17 people excluded after randomization
    • Experimental arm= 392 included in intention-to-treat analysis
    • Standard arm= 393 included in intention-to-treat analysis
  • Setting: emergency departments or medical wards in seven tertiary care hospitals in Switzerland
  • Enrollment: Dec 1, 2009 to May 21, 2014
  • Mean follow-up: Structured follow-up telephone interviews for secondary outcomes after discharge were done on day 30 and included assessment of adverse events such as infections, recurrent pneumonia, re-admission to hospital, new onset diabetes or insulin dependence, and new onset hypertension. Patients who died prior to the 30-day follow-up date were censored at time of death.
  • Primary Analysis: Intention-to-treat. As a sensitivity analysis, the primary analysis was repeated on the per-protocol population.
  • Primary outcome: The primary endpoint was time to clinical stability defined as time (days) until stable vital signs for 24 hours or longer.

Population

Inclusion Criteria

  • 18 years or older and hospital admission with community-acquired pneumonia defined by a new infiltrate on chest radiograph and the presence of at least one of the following acute respiratory signs and symptoms
    • Cough
    • Sputum production
    • Dyspnea
    • Core body temperature of 38.0 degrees Celsius or higher
    • Auscultatory findings of abnormal breathing sounds or rales
    • Leukocyte counts > 10,000 cells/microL or < 4000 cells/microL

Exclusion Criteria

    • Permanent inability to consent
    • Active intravenous drug use
    • Acute burn injury
    • Gastrointestinal bleeding within past 3 months
    • Known adrenal insufficiency
    • A condition requiring more than 0.5mg/kg per day prednisone equivalent
    • Pregnancy or breastfeeding
    • Severe immunosuppression

Baseline Characteristics

  • Median age of patients was 74 years
  • 487 of 785 were men (298 women)
  • Pneumonia severity index core I-V
  • Half of the patients were in high-risk PSI classes IV and V
  • Comorbidities included: diabetes, chronic obstructive pulmonary disorder, chronic heart failure, cerebrovascular disease, chronic renal insufficiency, neoplastic disease, liver disease, co-infections, antibiotic pretreatment
  • Clinical variables: days with symptoms, temperature, systolic blood pressure, heart rate, respiratory rate, SaO2, bacteremia, confusion, and CAP score
  • Lab values: procalcitonin, C-reactive protein, WBC count, glucose

Interventions

Study participants were given daily oral medications of either 50 mg of prednisone or a placebo for a length of 7 days along with the normal treatment according to ERS/ESCMID guidelines. The standard treatment for most patients involved either amoxicillin/clavulanic acid or ceftriaxone. Treatment was streamlined according to culture and sensitivity test once it is completed with results. Prednisone belongs to a class of drugs known as corticosteroids, which when given systemically have anti-inflammatory effects. Community-acquired pneumonia can cause inflammation by releasing excessive amounts of pro-inflammatory cytokines which can cause harm and pulmonary dysfunction, therefore it is believed that the use of systemic corticosteroids can reduce inflammatory response from CAP.

Outcomes

Primary Outcome

Time to clinical Stability
Intention to Treat Analysis: HR 1.33; 95% CI (1.15-1.50); P value- <0.0001; NNT= 72
Per-Protocol Analysis: HR 1.35; 95% CI (1.16-1.56); P value- <0.0001; NNT=72

Secondary Outcomes

Time to effective hospital discharge, days
HR 1.19; 95% CI (1.04-1.38); P value-0.012
IV antibiotic treatment, days
Difference of -0.89 days; 95% CI (-1.57 to -0.20 days); P value- 0.011

All other secondary outcomes were not statistically significant.

Subgroup Analysis

There was no evidence of effect modification on the pre-specified subgroups, which included median age, initial median CRP concentration, previous chronic obstructive pulmonary disorder severity of symptoms based on PSI score, and blood score positivity. There was a larger treatment effect noted in patients with sepsis.

Adverse Events

  • Incidence of complications and adverse events associated with corticosteroids was higher in the prednisone group than the placebo group. The main adverse event that was seen was a higher rate of hyperglycemia that required insulin treatment in-hospital, in patients on prednisone. However, the rates of new need for insulin treatment at day 30 were low in both groups. Other adverse events associated with corticosteroid use were small and similar in both groups.

Criticisms

  • The assignments of patients to treatment were randomized, and allocation was concealed with a pre-specified computer-generated randomization list.
  • Table 1 shows baseline characteristics of the enrolled patients and verified that patients of both groups were similar.
  • Both groups were treated equally including routine laboratory tests and follow-up telephone interviews for secondary outcomes.
  • Figure 1 shows that no patient was lost to follow up before reaching the primary endpoint. One patient in the prednisone group and three patients in the placebo group were lost to follow-up at 30 days. It also shows those who were assessed for eligibility and how they did not qualify.
  • This study lost patients to follow-up which diminishes the quality of the results of the study.
  • Patients, treating physicians, investigators and data assessors were masked to treatment allocation. The manufacturer of the prednisone and placebo was prepared before the initiation of the study and packed into identical containers by the Pharmacology Department, University Hospital, Basel, according to the randomization list.
  • The study only includes those hospitalized with CAP, this does not account for treatment of CAP in an outpatient setting.
  • Due to the fact that this study was conducted in Switzerland, certain protocols may vary from country to country.

Funding

The following organizations and individuals funded the study, Swiss National Science Foundation, Viollier AG, Nora van Meeuwen Haefliger Stiftung, Julia and Gottfried Bangerter- Rhyner Stiftung. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report