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Oral steroids for long-term use in cystic fibrosis

  1. Katharine Cheng1,*,
  2. Deborah Ashby2,
  3. Rosalind L Smyth3

Editorial Group: Cochrane Cystic Fibrosis and Genetic Disorders Group

Published Online: 24 JUN 2013

Assessed as up-to-date: 12 AUG 2013

DOI: 10.1002/14651858.CD000407.pub3

How to Cite

Cheng K, Ashby D, Smyth RL. Oral steroids for long-term use in cystic fibrosis. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD000407. DOI: 10.1002/14651858.CD000407.pub3.

Author Information

  1. 1

    Institute of Child Health, University of Liverpool, c/o Cochrane Cystic Fibrosis & Genetic Disorders Review Group, Liverpool, UK

  2. 2

    Imperial College London, School of Public Health, London, UK

  3. 3

    UCL, Institute of Child Health, London, UK

*Katharine Cheng, c/o Cochrane Cystic Fibrosis & Genetic Disorders Review Group, Institute of Child Health, University of Liverpool, Alder Hey Children's NHS Foundation Trust, Eaton Road, Liverpool, L12 2AP, UK. nikkij@liv.ac.uk.

Publication History

  1. Publication Status: Stable (no update expected for reasons given in 'What's new')
  2. Published Online: 24 JUN 2013

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Characteristics of included studies [ordered by study ID]
Auerbach 1985

MethodsRandomised.
Double-blinded.


Participants45 participants recruited aged 1 - 12 years.
CF diagnosed on clinical features and raised sweat electrolytes. Mild to moderate pulmonary disease.
24 assigned to placebo group and 21 to prednisone group.
11 participants did not complete study (7 placebo, 4 prednisone) - 2 moved cities, 5 excluded for non-compliance and steroids prescribed to 4 for clinical indications.


InterventionsPrednisone 2 mg/kg (maximum 60 mg) on alternate days or placebo.


OutcomesThe following were measured at baseline and 6 monthly: FEV1; FVC; PEFR.
Liver function tests (aspartate aminotransferase, alkaline phosphatase, bilirubin and lactate dehydrogenase), glycosylated haemoglobin, circulating immune complexes, IgG, IgM, IgA, albumin, total protein, C3, C4, total white cell count, erythrocyte sedimentation rate and haematocrit.
Height and weight measurements (not stated how frequently measured) expressed as percentage of mean height or weight for age from reference standards.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised, but method not stated.

Allocation concealment (selection bias)Unclear riskUnclear.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind, but this might not have been possible since at the doses used, it would have been obvious which participants were in the treatment group.

Incomplete outcome data (attrition bias)
All outcomes
Low risk11 participants did not complete study (7 placebo, 4 prednisone) - 2 moved cities, 5 excluded for non-compliance and steroids prescribed to 4 for clinical indications.

Eigen 1995

MethodsRandomised within each centre by computer-generated random number sequence in blocks of 6.
Double-blinded. Parallel study.
Multicentre (15 centres).


Participants285 participants recruited.
CF diagnosed on clinical features and 2 raised sweat chloride (or sweat sodium) values.
Inclusion criteria: aged 6 - 14 years; clinical stability without hospitalisation for CF-related problems within 2 months of entry; serum IgG within 2 standard deviations of normal for centre or hypogammaglobulinaemia; reliable performance of lung function tests for at least 6 months prior to enrolling in trial; FEV1 > 60% predicted and FEV1/FVC ratio > 60% predicted.
Exclusion criteria included previous treatment with oral, inhaled or nasal corticosteroids for more than 2 weeks within 6 months of entry or any form of corticosteroids in previous month, evidence of liver disease, treatment with non-steroidal anti-inflammatory treatment.


InterventionsPrednisone 2 mg/kg or prednisone 1 mg/kg or placebo on alternate days (maximum dose 60 mg). Participants who missed 30% or more of total prescribed study medication were labelled as non-compliant but still included in analysis.


OutcomesPrimary outcomes were lung function (FEV1, FVC), serum IgG concentrations, growth and hospitalisation rates.
Lung function was assessed at baseline and at 6, 12, 18, 24, 30, 36, 42 and 48 months.
Serum IgG was measured at baseline and at 3, 6, 12, 24, 36, 42 and 48 months.
Height and weight were measured by techniques standardised across all participating centres. Height scores were calculated on the basis of age-stratified normal populations.
Adverse events were monitored every 3 months with emphasis on raised blood glucose concentration, cataracts, raised liver enzymes and respiratory infection with unusual organisms (opportunistic infection).
Growth was assessed in a 10-year follow-up study.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised within each centre by computer-generated random number sequence in blocks of 6.

Allocation concealment (selection bias)Unclear riskUnclear.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind and same number of tablets given for each regimen, but true blinding might not have been possible since at the doses used, it would have been obvious from treatment effects which participants were in the treatment group.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskParticipants who missed 30% or more of total prescribed study medication were labelled as non-compliant but still included in analysis.

Greally 1994

MethodsRandomised.
Double-blinded.


Participants24 participants aged 5.5 years to 19.5 years recruited.
CF diagnosed by raised sweat sodium (>70 mmol/l) and established respiratory disease (FEV1 < 85% predicted).


InterventionsSoluble prednisolone 2 mg/kg/ daily for 14 days and then 1 mg/kg/ day on alternate days for 10 weeks (maximum dose 40 mg) or identical inert placebo tablets.


OutcomesThe following were measured at baseline, 14 days and 12 weeks: FEV1, FVC, Serum interleukin- 1- alpha, interleukin- 2R, IgG.
Specific side effects (raised blood pressure, high blood sodium, low blood potassium, fluid retention and glucose intolerance) were looked for at each visit.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised, but method not stated.

Allocation concealment (selection bias)Unclear riskUnclear.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind and placebo and prednisolone tablets were identical, but true blinding might not have been possible since at the doses used, it would have been obvious which participants were in the treatment group.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo withdrawals.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Cohen-Cymberknoh 2008Trial of treatment of ABPA (a specific condition) rather than part of the general anti-inflammatory management of CF.

Dovey 2007Steroids given for less than 30 days.

Linnane 2001Crossover study, each arm lasting 5 days only (9 day washout).

Pantin 1986Not randomised.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Kapustina 2008

MethodsComparison of inhaled and oral steroids; not clear if randomised.

Participants40 children with cystic fibrosis (23 female, 17 male), aged 5 - 17.4 years. All patients had "severe" phenotype.

Interventions14 children inhaled corticosteroids for mean (SD) 34.29 (37.62) months (range 6 -120 months).
26 children received oral steroids (0,5 mg/kg every other day) for mean (SD) 33.04 (37.98) months (range 1 - 185 months).

All patients received adequate basic therapy including calcium (500-1000 mg/day) and vitamin D (100-400 IU/day) supplementation.

OutcomesBMD (g/cm2) in the lumbar spine (L2 - L4)

NotesPublished as abstract only.

Nyamugunduru 1998

MethodsDescribed as randomised (method not stated), double-blind (not specified who) parallel trial.

Participants51 children with cystic fibrosis.

3 children excluded - 1 had allergic bronchopulmonary aspergillosis, 2 on nasogastric feeds.

Interventions14 days of high-dose prednisolone (2 mg/kg once daily, maximum 30 mg daily) compared to placebo in addition to intravenous antibiotics in acute respiratory exacerbations.

OutcomesSpirometry (FEV1, FVC), serum IL-8 levels.

NotesPublished as three separate abstracts only, numbers of participants don't agree across the publications (50, 48, 48)

Pukhalsky 2007

MethodsComparison of azithromycin, prednisolone and no treatment; not clear if randomised.

Participants136 CF patients (mean (SD) age 12.0 (0.6) years) and 100 healthy children (mean (SD) age 11.5 (0.9) years). Of the 136 CF patients, 83 received no anti-inflammatory treatment, 16 received an alternated course of prednisolone and 37 were treated with azithromycin.

InterventionsNo treatment versus alternated prednisolone (0.3 to 0.5 mg/kg body weight every other day) versus azithromycin (500 mg orally 2 times a week).

OutcomesLevels of plasma cytokines (IL-10, IFNγ, TGF-β1, TNF-α)

NotesPossibly same trial as Pukhalsky 2008 - trying to contact authors to clarify.

Pukhalsky 2008

MethodsComparison of azithromycin, prednisolone and no treatment; not clear if randomised.

Participants160 children with CF and 100 healthy controls. Of the 160 children with CF, 90 received no anti-inflammatory treatment and 70 received anti-inflammatory treatment (either azithromycin or prednisolone).

InterventionsAzithromycin Group (n = 48): 500 mg orally 3 times a week.

Prednisolone Group (n = 22): 0.3 mg/kg body weight every other day.

OutcomesPlasma cytokines including IL-l0, lFNy and TGF-ß1, hepatobiliary abnormalities.

NotesPossibly same trial as Pukhalsky 2007 - trying to contact authors to clarify.

 
Comparison 1. Oral corticosteroids (any dose) versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Absolute change in per cent predicted FEV11Mean Difference (IV, Fixed, 95% CI)Subtotals only

    1.1 Up to 2 weeks
124Mean Difference (IV, Fixed, 95% CI)8.7 [2.32, 15.08]

    1.2 Up to 12 weeks
124Mean Difference (IV, Fixed, 95% CI)8.1 [0.45, 15.75]

 2 Absolute change in per cent predicted FVC1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    2.1 Up to 2 weeks
124Mean Difference (IV, Fixed, 95% CI)12.81 [4.73, 20.89]

    2.2 Up to 12 weeks
124Mean Difference (IV, Fixed, 95% CI)6.70 [-2.12, 15.52]

 3 Growth retardation (at 4 years)1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    3.1 1 mg prednisone
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 2 mg prednisone
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Height at age over 18 years (boys)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    4.1 1 mg prednisone
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.2 2 mg prednisone
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Height at over 18 years (girls)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    5.1 1 mg prednisone
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.2 2 mg prednisone
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Absolute change in weight (kg)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    6.1 Up to 12 weeks
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 7 Weight at over 18 years (boys)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    7.1 1 mg prednisone
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    7.2 2 mg prednisone
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Weight at over 18 years (girls)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    8.1 1 mg prednisone
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    8.2 2 mg prednisone
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 9 Adverse events1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

    9.1 Cataracts (1 mg prednisone) (up to 4 years)
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    9.2 Cateracts (2 mg prednisone) (up to 3 years)
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    9.3 Diabetes mellitus (1 mg prednisone) (up to 4 years)
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    9.4 Diabetes mellitus (2 mg prednisone) (up to 3 years)
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    9.5 Glucosoria (1 mg prednisone) (up to 4 years)
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    9.6 Glucosoria (2 mg prednisone) (up to 3 years)
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    9.7 Hyperglycemia (1 mg prednisone) (up to 4 years)
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    9.8 Hyperglycemia (2 mg prednisone) (up to 3 years)
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 10 Mortality1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

    10.1 At 4 years
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Table 1. Long-term growth - follow up data at 4 years (Auerbach 1985)

TimeGroup I

n = 9
Group II

n = 5
Group III

n = 10
Group IV

n = 6





 MeanSDMeanSDMeanSDMeanSD

Baseline-0.440.73-0.300.85-0.750.78-1.640.45

End of study (4 years)-0.890.42-0.620.84-0.790.86-1.580.58

Follow up (10 yrs)-1.860.89-1.341.42-0.700.69-2.020.74

 Group I: originally randomised to steroids for 4 years, continued on steroids for mean (SD) 9.5 (1.2) years
Group II: originally randomised to steroids for 4 years, ceased taking steroids after mean (SD) 4.5 (0.46) years
Group III: originally randomised to placebo for 4 years, 5 in this group never received steroids and 5 received variable doses of steroids for mean (SD) 0.6 (0.3) years
Group IV: originally randomised to placebo for 4 years, subsequently received steroids for mean (SD) 3.6 (1.2) years
SD: standard deviation