Journal Club
Usha Niranjan
SPR Paediatrics/ Diabetes & Endocrine
Rationale
• Bronchiolitis season
• Several children (< 2yrs) with
bronchiolitis
• Develop fever with occasional
crackles more on one side of the
chest.
• Chest X-ray - bilateral perihilar
changes
• ? to start antibiotics
• ? large proportion get antibiotics
What are we concerned about
• In a child presenting with fever and clinical symptoms
and signs of bronchiolitis
– ? risk of serious complications such as pneumonia, septicaemia.
• Is there any added benefit?
– Macrolides thought to have anti-inflammatory activities +
immune modulatory effects.
What is known on the topic?
• Antibiotics are not recommended for bronchiolitis unless
– Concerns about secondary bacterial lobar
pneumonia.
– Respiratory failure.
• It is widely accepted in the literature that chest
radiographs cannot reliably differentiate viral from
bacterial aetiology of pneumonia.
– Harris M, Clark J, Coote N, Fletcher P, Harnden A, et al. (2011) British
Thoracic Society guidelines for the management of community acquired
pneumonia in children: update 2011. Thorax 66 Suppl 2: ii1–23
Accuracy of the interpretation of chest radiographs for the
diagnosis of paediatric pneumonia. Elemraid M.A., et al.
PLoS ONE, August 2014, 9/8, 1932-6203.
• An 18-month prospective aetiological study of pneumonia (Northern
England).
• CXR done - children aged <16 years with clinical features of
pneumonia.
• Reported independently by 2 x radiologists.
• Significant disagreement between the first and second reports
(P=0.001), notably in those aged < 5 years (26%, P=0.001).
• The most frequent sources of disagreement were the reporting of
patchy and peri-hilar changes. They did not significantly affect
– the clinical outcomes.
– management decisions of pneumonia in children .
PICO
• P: In children with bronchiolitis or viral wheeze
• I: Antibiotics
• C: placebo
• O: rapid improvement
NHS evidence database searches
• Medline
• Embase
• Cochrane database
• None focussing on the aspect of chest X-ray changes
Article
Antibiotics for bronchiolitis in children
under two years of age.
Farley R, Spurling GKP, Eriksson L, Del Mar CB.
The Cochrane Library 2014, Issue 10
Study
• Cochrane Systematic review of
– RCTs comparing antibiotics to placebo in children < 2yrs with
bronchiolitis using clinical criteria (respiratory distress preceeded
by coryzal symptoms with or without fever).
• Included 7 studies – 824 participants
• Primary outcome
– Duration of oxygen requirement and symptoms(O2 requirement,
wheeze, fever)
• Secondary outcome
– Length of hospital stay, re-admission,
CHARACTERISTICS OF STUDIES
The included studies
Characteristics of included studies [ordered by study ID]
Field 1966
Methods
Randomised controlled trial
Participants
Babies
Interventions
Ampicillin
Placebo
Outcomes
Length of hospital stay
Symptoms(not specified)
Switch to treatment arm
Death
Notes
No deathsor apparent side effectsreported from theuseof ampicillin
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
Randomised
Allocation concealment (selection bias)
Risk unclear
Unclear risk
Research Laboratoriessupplied both theampicillin and
theplacebo
Kabir 2009
Methods
Kabir
2009 (Continued)
Randomised controlled trial
Participants
Children under 2 yearsof agewith clinical suspected bronchiolitis
Interventions
IV ampicillin (parenteral ampicillin 50 mg/kg/6-hourly + supportive care), oral erythromycin (oral erythromycin 10 mg/kg6-hourly + supportivecare), control
Antibiotics
years of agerate,
(Review)
Outcomesfor bronchiolitis in children under twoRespiratory
oxygen saturation, wheeze, fever, length of hospital stay, shortnessof15
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
breath
Notes
-
Low
country – Bangladesh (blinding not described & high risk of
Risk ofincome
bias
reporting bias)
Bias
Authors’ judgement
Random sequence generation (selection Low risk
Support for judgement
Random number table
Selectivereporting (reporting bias)
High risk
Other bias
Low risk
Bangladesh Medical Research Council funded this
project (through agrant from theWorld Bank)
Kneyber 2008
Methods
Double-blinded, placebo-controlled, randomised controlled trial
Participants
Hospitalised infantsyounger than 24 monthswith clinically confirmed viral lower respiratory tract infection
Interventions
Azithromycin 10 mg/kg/day, oncedaily for 3 days
Outcomes
Respiratory rate, accessory muscle use, malaise severity, disease complications, use of
alternative therapies, length of hospital stay, length of intensive care stay, deaths, need
for NG feeding
Notes
-
RiskHigh
of bias income
country (Netherlands)
Antibiotics for bronchiolitis in children under two years of age (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
16
All outcomes
Selectivereporting (reporting bias)
Low risk
Other bias
Unclear risk
Funding sourcesdo not appear to be identified
Mazumder 2009
Methods
Randomised controlled trial
Participants
Children aged 1 month to 2 yearspresenting to an outpatientsdepartment in ateaching
hospital
Interventions
Supportive management, supportive management plusIV ampicillin, supportive management plusoral erythromycin
Outcomes
Breathing difficulty, feeding difficulty, social smile, tachypnoea (rapid breathing), hypoxia, wheeze, rhonchi, crepitation, WBC, Hb, ESR, CRP, X-ray, rateof recovery
Notes
-
Low income country (Bangladesh) - high risk of selection
bias
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection High risk
bias)
Oddsand evens
Allocation concealment (selection bias)
Not discussed
Unclear risk
Selectivereporting (reporting bias)
Unclear risk
Unsure
Other bias
Unclear risk
Funding sourcesdo not appear to be identified
McCallum 2013
Methods
Randomised controlled trial
Participants
Children aged≤ 18months, admittedwith aclinical diagnosisof bronchiolitis(according
to standardised hospital protocols; ≤ 18 months, with cough and coryza, wheezing
+/- crackles, respiratory distress with both tachypnoea (respiratory rate > 50 breaths/
minute) and retractions). Themajor reason why 450 children did not meet theinclusion
criteriawasbecausethey did not requiresupplemental oxygen or wereadmitted over the
weekend. During recruitment, 21 children admitted into intensive carewereexcluded
Interventions
A single largedose (30 mg/kg) of azithromycin within 24 hoursof hospitalisation
Outcomes
Primary outcomes: length of stay for respiratory illness - time from admission to time
for ’ready for discharge’ (SpO2 consistently > 94% in air for > 16 hours and feeding
adequately), duration of O2 requirement
Other outcomes: any respiratory-related readmissionswithin 6 monthsof dischargeand
identification of respiratory virusesand bacterial pathogens
Notes
-
Risk of bias
Bias
Authors’ judgement
Random sequence generation (selection Low risk
bias)
Support for judgement
Randomisation wasstratified by age(≤ 6 or >6 months),
ethnicity (Indigenousor non-Indigenous) and site(Darwin or Townsville). Randomisation was by computer-
rolein studydesign, datacollection and analysis, decision
to publish, or preparation of themanuscript
Pinto 2012
Methods
Randomised controlled trial
Participants
Children < 12 monthsof agehospitalised with acuteviral bronchiolitis
Interventions
Azithromycin administered orally for 7 days
Outcomes
Length of hospitalisation and duration of oxygen requirement
Notes
-
Risk of bias
Bias
Authors’ judgement
Random sequence generation (selection Unclear risk
bias)
Support for judgement
Infantswererandomised (simple/unrestricted randomisation) to receiveeither adaily oral doseof azithromycin
or an equivalent volumeof placebo
Selectivereporting (reporting bias)
Low risk
Other bias
Low risk
Funded by Fundacao de Amparo a Pesquisa do Estado
do Rio Grande do Sul, which did not participate in the
collection, analysis or interpretation of data, nor in the
writing or thedecision to submit themanuscript
Tahan 2007
Methods
Double-blind, randomised controlled trial
Participants
Infants lessthan or equal to 7 monthswith immunologically confirmed RSV infection
admitted to 1 hospital
Interventions
Clarithromycin 15 mg/kg/day, once daily for 3 weeks
Outcomes
Respiratory rate, wheeze, use of supplemental oxygen, cyanosis, hospital admission,
length of stay
Notes
-
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Unclear risk
bias)
“... infants were randomised by a single
study nurse...”
“Simplerandomisation wasused”
Allocation concealment (selection bias)
Allocation after enrolment by study nurse
Unclear risk
Primary outcome- Days of supplemental oxygen
Analysis 1.1. Comparison 1 Use of alternative therapy (including duration of supplementary oxygen
requirement), Outcome 1 Days of supplementary oxygen.
Review:
Antibiotics for bronchiolitis in children under two years of age
Comparison:
Outcome:
1 Use of alternative therapy (including duration of supplementary oxygen requirement)
1 Days of supplementary oxygen
Study or subgroup
Antibiotics
Mean
Difference
Placebo/control
Mean
Difference
Weight
N
Mean(SD)[days]
N
Mean(SD)[days]
McCallum 2013
50
1.9 (1.22)
46
2.7 (3.74)
21.6 %
-0.80 [ -1.93, 0.33 ]
Pinto 2012
88
4.4 (2.54)
95
4.9 (3.38)
37.3 %
-0.50 [ -1.36, 0.36 ]
Kneyber 2008
32
3.8 (1.74)
39
3.4 (1.78)
41.1 %
0.40 [ -0.42, 1.22 ]
Total (95% CI )
170
IV,Fixed,95% CI
IV,Fixed,95% CI
180
100.0 % -0.20 [ -0.72, 0.33 ]
Heterogeneity: Chi2 = 3.59, df = 2 (P = 0.17); I2 =44%
Test for overall effect: Z = 0.73 (P = 0.47)
Test for subgroup differences: Not applicable
-10
-5
Antibiotics
0
5
10
Placebo/control
The three studies  adequate data  showed no difference between antibiotics
and placebo (pooled MD -0.20; 95% CI -0.72 to 0.33)
Primary outcome – O2 Saturation
• One study – Majumder 2009 (children <24 months)
• I.V ampicillin (n=29), oral erythromycin(n=32)
• No antibiotics - Control (n=43)
• No significant difference in O2 saturation for the
antibiotics group combined or individually with the
control.
Primary outcome - Wheeze
• One study – Majumder 2009
• On day 3 – fewer children with wheeze in the combined
antibiotics arm vs control ( Chi2 test = 24.82)
• P value <0. 001
• On day 5 - more children had wheeze in the antibiotic
arm (Chi2 test = 5.69 (P value = 0.058))
Primary outcome - Fever
• Kabir 2009 (Children <2yrs)
– Symptom resolution rapid (< 4 days) vs gradual ( >4 days)
– None of symptoms including fever on day 2 were significantly
different among the i.v ampicillin, oral erythromycin or control
group (Chi2 = 0.38 (P value = 0.83))
• Kneyber 2008
– Azithromycin vs placebo
– No significant difference in duration of fever.
– MD 0.47 (95% CI -0.12 to 1.06); (P = 0.12)
Secondary outcome
• Duration of admission/ time to discharge
–
–
–
–
3 x studies pooled (Kneyber 2008; McCallum 2013; Pinto 2012)
No difference between antibiotics (azithromycin) and placebo
MD – 0.58; 95% CI (-1.18 to 0.02)
Chi2 test = 0.40, df = 2 (P value = 0.82)
• Re-admissions
– Two studies (McCallum 2013; Tahan 2007)sufficient data
– found no significant difference.
– Data not pooled  due to substantial risk of heterogeneity.
• Complications/ adverse events – none
• Radiological findings- not reported.
Critical appraisal
• Validity
1) Did the review address a clearly focused question?
• Yes
2) Did the authors look for the appropriate sort of papers?
• Yes
Validity
• Do you think the important, relevant studies were
included?
– YES
• personal contact with experts
• search for unpublished as well as published studies
• search for non-English language studies
• Did the review’s authors do enough to assess the quality
of the included studies?
– Yes
• If the results of the review have been combined, was it
reasonable to do so?
– Yes
What are the results?
• What are the overall result of the reviews?
• Primary outcomes:
– Duration of oxygen requirement – no significant difference.
– Wheeze –mixed results for effects of antibiotics( study - high risk
of bias).
– Fever – no difference in duration of fever or the presence of
fever on day 2.
• Secondary outcomes:
– 6 x studies –no difference in length of illness or hospital stay
– Length of hospital stay – No significant difference between
azithromycin and placebo.
– Hospital readmission – No significant difference.
– Radiological findings were not reported as an outcome
in any of the included studies.
Results
• Were the results precise?
• Yes
– Pooled data – sufficient to assess effect
– Confidence intervals reported.
Applicability
• Can the results be applied to the local population?
– Yes
Applicability
• Were all the clinically important outcomes considered?
• Yes
• Are the benefits worth the harm and costs?
•
Yes
Conclusion:
• The review highlights:
– No evidence to support the use of antibiotics for bronchiolitis.
– No RCTs  assessing the usefulness of antibiotics for
bronchiolitis in an intensive care setting.
• Further research  focused on determining
• the reasons that clinicians use antibiotics in bronchiolitis.
• how to reduce clinician anxiety about not using antibiotics
• Further research to identify the subgroup
– At risk of secondary bacterial infection following bronchiolitis
especially in the context of respiratory failure.
THANK
YOU