Effect of Oral Prednisolone on Symptom Duration and Severity in Nonasthmatic Adults With Acute Lower Respiratory Tract Infection

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Hay AD, et al. "Effect of Oral Prednisolone on Symptom Duration and Severity in Nonasthmatic Adults With Acute Lower Respiratory Tract Infection: A Randomized Clinical Trial". JAMA. 2017. 318(8):721-730.
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Clinical Question

In nonasthmatic patients with an acute lower respiratory tract infection, does oral prednisolone reduce symptom duration and severity compared to no treatment?

Bottom Line

In nonasthmatic patients with an acute lower respiratory tract infection, oral prednisolone does not reduce symptom duration and severity and therefore, should not be used.

Major Points

A 2013 systematic reviews (El-Gohary et al, 2013) reviewed literature for the use of corticosteroids in lower respiratory tract injections (LRTI), but could not identify research specifically evaluating systemic, oral corticosteroids.

Oral and inhaled corticosteroids are highly effective for acute asthma, but US, British, and European guidelines do not provide guidance on whether corticosteroids should be used for an acute LRTI.

In this RCT, oral prednisolone did not yield any benefit over placebo for symptoms management in patients with LRTI.

In a subgroup analysis, where patients were evaluated based disease severity, the researchers failed to demonstrate significant symptom resolution with systemic corticosteroids.

Duration of cough by prednisolone was reduced by half a day compared to placebo.

Guidelines

National Guideline Clearinghouse (NGC). Guideline summary: Pneumonia in adults: diagnosis and management. In: National Guideline Clearinghouse (NGC) [Web site]. Rockville (MD): Agency for Healthcare Research and Quality (AHRQ); 2014 Dec 03. [cited 2017 Sep 27]. Available: https://www.guideline.gov

Design

  • Multicenter, placebo-controlled, randomized trial
  • N=401
    • Prednisolone n=199
    • Placebo n=202 (2 did not receive placebo; 1 withdrew immediately after giving consent and before taking trial medication; 1 eligible but incorrectly withdrawn by clinician for safety reasons)
  • Setting: 54 family practices in England
  • Study conducted between July 2013 and October 2014
  • Analysis: Intent-to-treat
  • Primary outcomes:
    • Duration of moderately bad or worse cough (0 to 28 days; minimal clinically important difference, 3.79 days)
    • Mean severity of symptoms on days 2 to 4 (scored from 0 [not affected] to 6 [as bad as it could be], minimal clinically important difference, 1.66 units)

Population

Inclusion Criteria

  • Age 18 years or older
  • Presenting for an acute (≤28 days) cough as main symptom with at least 1 lower respiratory tract symptom (phlegm, chest pain, wheezing, or shortness of breath) in the previous 24 hours
  • Immunocompetent
  • Patient is willing to receive a weekly phone call from trial team

Exclusion Criteria

  • Clinically suspected to have or their medical records showed evidence of chronic pulmonary disease (i.e. lung cancer, COPD, CF)
  • Had received any asthma medication in the past 5 years
  • Met National Institute for Health and Clinical Excellence criteria for severe infection/complications
  • Required same day hospital admission
  • Required same day antibiotics
  • Are pregnant or trying to conceive or breastfeeding

Baseline Characteristics

Baseline characteristics were similar between groups with respect to deprivation, smoking status, weight, height, and clinical characteristics of acute lower respiratory tract infection. However, the prednisolone group was slightly more likely to be male, older, and have received an influenza vaccine in the last 12 months.

The following characteristics reflect the mean of both study groups (control, treatment)

  • Mean age of 47 years (44.8 y, 50 y)
  • 37% were men (33%, 41%)
  • 3.5% had diabetes
  • 17% were currently smoking (19%, 16%)
  • 5% received asthma medication more than 5 years previously (4%, 5%)
  • 77% reported phlegm (78%, 76%)
  • 46% chest pain (49%, 44%)
  • 47% wheezing (49%, 45%)
  • 70% shortness of breath (67%, 74%)
  • 42% had abnormal (defined as <80% expected) peak flow (40%, 44%)

Interventions

  • Randomized to receive prednisolone or placebo
  • Intervention group received:
    • Ten 20mg oral prednisolone tablets (Galen Pharma GmbH)
  • Placebo group received:
    • Placebo tablets matched on dimension appearance, and taste (Piramal Healthcare Ltd.)
  • Both groups were to take 2 tablets once daily for 5 days, starting on day of consultation, if possible before starting any antibiotics. (Dose and duration selected reflects the dose and duration known to be effective for acute asthma)

Outcomes

Comparisons are prednisolone vs. placebo.

Primary Outcomes

Moderately Bad or Worse Cough Duration (*days to resolution)
5 days vs. 5.45 days (HR 1.11 95% CI, 0.89-1.39; P=0.36)
Time ratio: 0.91 (95% CI, 0.76-1.10; P=0.34)
Severity of Symptoms On Days 2 to 4 (*as measured by a mean severity score- 0-6 range based on 6 main symptoms: cough, phlegm, shortness of breath, sleep disturbance, feeling generally unwell, and activity disturbance)
-0.20 point (95% CI, -.40 to 0.00 point; P= .05)
Mean symptom severity score 1.99 (SD = 0.99) vs. 2.16 (SD = 1.09)

Secondary Outcomes

The symptoms of an acute lower respiratory tract infection (i.e. cough, phlegm, shortness of breath, etc.) did not demonstrate a statistically significant reduction in duration. Additionally, there were no significant effects on any peak flow up to 28 days nor antibiotic use. (Table 4).

Subgroup Analysis

Baseline impression of severity of illness was added as a post hoc subgroup analysis because the investigators determined it was important to differentiate between participants with severe vs mild symptoms. The results showed no significant subgroup effect.

Adverse Events

There were no serious adverse events. Four participants (3 in prednisolone group and 1 in placebo group) presented to the emergency department but were not hospitalized.

Criticisms

External

  • The population is homogenous (i.e. Caucasian male)
  • Probable conflicts of interest

Internal

  • Used a patient reported outcome rather than an objective primary outcome measure
  • Possible poor adherence
  • Study eligibility criteria might have included some patients with chronic or post-infective cough rather than acute lower respiratory tract infection.

Funding

The study was sponsored by Dr. Birgit Whitman the head of Research Governance at the University of Bristol. This article presents independent research funded by the National Institute for Health Research (NIHR) School for Primary Care Research (grant reference 117a). Dr Hay is funded by an NIHR Research Professorship (NIHR-RP-02-12-012)

Further Reading

El-Gohary M, Hay AD, Coventry P, Moore M, Stuart B, Little P. Corticosteroids for acute and subacute cough following respiratory tract infection: a systematic review. Family Practice [Internet]. 2013 Aug;30(5):492–500. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23836094