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Intervention Review

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Bronchoscopy-guided antimicrobial therapy for cystic fibrosis

  1. Kamini Jain1,*,
  2. Claire Wainwright2,
  3. Alan R Smyth3

Editorial Group: Cochrane Cystic Fibrosis and Genetic Disorders Group

Published Online: 23 DEC 2013

Assessed as up-to-date: 2 DEC 2013

DOI: 10.1002/14651858.CD009530.pub2


How to Cite

Jain K, Wainwright C, Smyth AR. Bronchoscopy-guided antimicrobial therapy for cystic fibrosis. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD009530. DOI: 10.1002/14651858.CD009530.pub2.

Author Information

  1. 1

    University of Nottingham, Division of Child Health, School of Clinical Sciences, Nottingham, UK

  2. 2

    Royal Children's Hospital, Department of Respiratory Medicine, Brisbane, Queensland, Australia

  3. 3

    School of Medicine, University of Nottingham, Division of Child Health, Obstetrics & Gynaecology (COG), Nottingham, UK

*Kamini Jain, Division of Child Health, School of Clinical Sciences, University of Nottingham, E Floor, East Block, Queen's Medical Centre, Derby Road, Nottingham, NG9 2SJ, UK. mgxkj1@nottingham.ac.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 23 DEC 2013

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This is not the most recent version of the article. View current version (21 JAN 2016)

 
Characteristics of included studies [ordered by study ID]
Wainwright 2011

MethodsMulticentre (8 CF centres in Australia and New Zealand), randomized controlled study.


Participants170 Infants younger than 6 months age, with confirmed diagnosis of CF, diagnosed through newborn screening programs.

84 infants were randomized to receive BAL-directed therapy (80 completed study) and 86 randomized to receive standard therapy (77 completed study).

BAL-directed group

Mean age (SD) 3.8 (1.6) years.

Gender split: 44 male/40 female.

Mean (SD) weight at enrolment: 5.7 kg (1.40).

Number of participants with homozygous ΔF508 mutation: 57 (68%).

Number of participants with pancreatic insufficiency: 73 (87%).

Number of participants with meconium ileus: 17 (20%).

Number of participants born pre-term (under 37 week gestation): 8 (10%).

History of exposure to tobacco smoke during pregnancy present in: 22 (26%).

History of concurrent smoking in the household present in: 30 (36%).

Standard therapy group

Mean age (SD) 3.7 (1.7) years.

Gender split: 44 male/42 female.

Mean weight (SD) at enrolment: 5.6 kg (1.5).

Number of participants with homozygous ΔF508 mutation: 54 (64%).

Number of participants with pancreatic insufficiency: 71 (85%).

Number of participants with meconium ileus: 16 (19%).

Number of participants born pre-term (under 37-week gestation): 9 (11%).

History of exposure to tobacco smoke during pregnancy present in: 13 (15%).

History of concurrent smoking in the household present in: 23 (28%).


InterventionsIntervention: BAL-directed therapy for pulmonary exacerbations until age 5 years.

The patients in the BAL-directed therapy groups underwent BAL at following times:

  1. before 6 months age when well;
  2. when hospitalized for a pulmonary exacerbation (unwell with change in respiratory symptoms from baseline);
  3. if P. aeruginosa was cultured from oropharyngeal specimens;
  4. following P. aeruginosa eradication therapy.


Control: Standard therapy (directed by clinical features and oropharyngeal swab cultures) for pulmonary exacerbations until age 5 years.

The standard therapy included oropharyngeal swab at following time points:

  1. when a child was unwell with a change in respiratory symptoms from baseline (pulmonary exacerbation);
  2. at the end of the antibiotic eradication treatment for P. aeruginosa


OutcomesReported at at 5 years age.

Primary outcome measures

  • Prevalence of P. aeruginosa on BAL cultures (defined as ≥ 103 CFU/ml)
  • Total CF-CT score (as percentage of the maximum score) on high resolution chest CT scan


Secondary outcome measures

  • Weight z score
  • Height z score
  • BMI z score
  • Lung function parameters: standard spirometry measures (FEV1, FVC)
  • CF-CT components: bronchiectasis score, parenchymal disease score, mucus plugging score, airway wall thickening score and air trapping score
  • Respiratory exacerbation rate
  • Number and duration of hospitalizations for respiratory exacerbations not associated with P. aeruginosa infection
  • Number of episodes of P. aeruginosa infection per child per year
  • Final BAL microbiology and inflammatory indices


NotesThe BAL-directed therapy group had BAL before age 6 months when well, when hospitalized for pulmonary exacerbations, when P. aeruginosa was cultured from their oropharyngeal specimens and following P. aeruginosa therapy.

The standard therapy included taking oropharyngeal swabs when having pulmonary exacerbation and at the end of antibiotic therapy. Children in both groups had BAL and HRCT scan of chest at 5 years age.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAfter consent, the participants were randomly assigned in 1:1 ratio to 2 groups by a centralized computer-generated schedule with stratification by site and sex.

Allocation concealment (selection bias)Low riskThe allocation was done by a centralized computer-generated schedule; the randomization key was concealed and held remotely. Allocation was revealed by telephone after confirmed recruitment.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAlthough the study was set up to be analysed on intention-to-treat basis, the patients with missing outcomes were not included in the primary analysis. The risk of bias is considered moderate to low as less than 10% of the data were missing and the reasons of exclusions were balanced across both groups.

Selective reporting (reporting bias)Low riskThe economic analysis was planned but was not reported; however, this outcome is unlikely to have influenced the results of the study. This is expected to be reported in future.

Other biasLow riskNo other potential source of bias was identified.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe participants and the personnel were not blinded to the randomization (which might not have been possible in this study setting). However, the risk of bias is low as the primary outcome measures were unlikely to be influenced by the lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskRisk of bias is low as the outcome assessors were blinded for both the primary outcome measures.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Chmiel 2007Study of induced sputum and not bronchoscopy.

Henig 20013-way cross-over study of single sample from sputum induction, bronchoalveolar lavage and expectorated sputum to identify pathogens; did not lead to comparison of treatment.

Jyothish 2005A different intervention (cough plates) was studied.

Maiya 2004A different intervention (cough plates) was studied.

McGarvey 20022-way cross-over study of induced sputum and BAL to compare inflammatory markers; no comparison of treatment.

Paul 2004Study of the effect of dornase alfa on lungs using bronchoalveolar lavage; all participants underwent bronchoalveolar lavage.

Rosenfeld 2006Study to establish levels of tobramycin, not comparison of therapy depending on sampling technique.

Taylor 2006Comparison of throat swabs and nasopharyngeal suction specimens not bronchoscopy.

 
Comparison 1. BAL-directed therapy versus standard therapy

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

 1 Z score FEV11Mean Difference (IV, Fixed, 95% CI)Totals not selected

    1.1 At 5 years
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Z score FVC1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    2.1 At 5 years
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Total CF-CT score (Brody-II)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    3.1 At 5 years
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Individual CF-CT scores (at 5 years)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

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

    4.2 Parencymal disease
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.3 Mucus plugging
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.4 Airway wall thickening
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.5 Air trapping
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Z score for weight1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    5.1 At 5 years
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Z score BMI1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    6.1 At 5 years
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 7 Positive P.aeruginosa isolates per patient per year1Rate Ratio (Fixed, 95% CI)Totals not selected

    7.1 At 5 years
1Rate Ratio (Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Prevalence of P. aeruginosa in BAL at 5 years age1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 9 Sensitivity analysis - Prevalence of P. aeruginosa in BAL at 5 years age (40% vs 5%)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 10 Sensitivity analysis - Prevalence of P. aeruginosa in BAL at 5 years age (5% vs 40%)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 11 Clearance of P.aeruginosa after 1 or 2 eradication treatments1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    11.1 At 5 years
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 12 Age at first acquisition of P. aeruginosa infection1Rate Ratio (Fixed, 95% CI)Totals not selected

    12.1 At 5 years
1Rate Ratio (Fixed, 95% CI)0.0 [0.0, 0.0]

 13 Number of hospital admissions per patient per year1Rate Ratio (Fixed, 95% CI)Totals not selected

    13.1 At 5 years
1Rate Ratio (Fixed, 95% CI)0.0 [0.0, 0.0]

 14 Number of hospitalizations per person per year due to non-P. aeruginosa exacerbations1Rate Ratio (Fixed, 95% CI)Totals not selected

    14.1 At 5 years
1Rate Ratio (Fixed, 95% CI)0.0 [0.0, 0.0]

 15 Duration of hospital admissions due to non-P.aeruginosa exacerbations1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    15.1 New Subgroup
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 16 Days as hospital inpatient per patient per year1Risk Difference (Fixed, 95% CI)Totals not selected

    16.1 New Subgroup
1Risk Difference (Fixed, 95% CI)0.0 [0.0, 0.0]

 17 Number of pulmonary exacerbations (requiring oral or intravenous antibiotics) per patient per year1Rate Ratio (Fixed, 95% CI)Totals not selected

    17.1 At 5 years
1Rate Ratio (Fixed, 95% CI)0.0 [0.0, 0.0]

 
Summary of findings for the main comparison. BAL directed therapy versus standard therapy for cystic fibrosis

BAL directed therapy versus standard therapy for cystic fibrosis

Patient or population: patients with pulmonary exacerbations in cystic fibrosis
Settings:
Intervention: BAL-directed therapy
Comparison: standard therapy

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Standard therapyBAL-directed therapy

z score FEV1
spirometry
Follow up: 5 years
The mean z score FEV1 in the intervention groups was
0.15 lower
(0.54 lower to 0.24 higher)
157
(1 study)
⊕⊕⊕⊝
moderate1
2,3

z score FVC
spirometry
Follow up: 5 years
The mean z score FVC in the intervention groups was
0.05 lower
(0.44 lower to 0.34 higher)
157
(1 study)
⊕⊕⊕⊝
moderate1
2,3

HRCT score (Brody-II)
HRCT scan
Follow up: 5 years
The mean HRCT score (Brody-II) in the intervention groups was 0.19 higher
(0.93 lower to 1.31 higher)
152
(1 study)
⊕⊕⊕⊕
high
The study had adequate power to detect difference in HRCT Score. It had low statistical power for other primary outcome (prevalence of P.aeruginosa at 5yr age).4

z score for weight
weight
Follow up: 5 years
The mean z score for weight in the intervention groups was 0.06 higher
(0.21 lower to 0.33 higher)
157
(1 study)
⊕⊕⊕⊝
moderate1
5

Number of hospitalizations per patient per year
Follow-up: 5 years
See commentSee comment157
(1 study)
⊕⊕⊕⊝
moderate1
The number of hospitalizations per patient per year in the intervention group was 1.4 times higher (1.08 lower to 1.82 higher).

z score BMI
weight in kg/height in meters squared
Follow up: 5 years
The mean z score BMI in the intervention groups was 0.02 higher
(0.26 lower to 0.30 higher)
157
(1 study)
⊕⊕⊕⊝
moderate1
5

Days as hospital inpatient per patient per year
Follow up: 5 years
See commentSee comment157
(1 study)
⊕⊕⊕⊝
moderate1
The duration of hospital admission per patient per year in the intervention group was 0.08 days per person per year higher (-3.31 lower and 3.47 higher).

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 The study had low statistical power and research is needed to provide definitive answers.
2 FEV1 and FVC were measured using standard Spirometer after bronchodilatation.
3 Z scores for FEV1, FVC were calculated from British reference values (www.lungfunction.org/growinglungs).
4 HRCT scans were assesses by an independent assessor who was blinded to subject allocation using an updated version of Brody-II score.
5 The z scores for weight and BMI were calculated from the 2000 CDC Growth Reference Charts (http://cdc.gov/growthcharts).