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Community Acquired Pneumonia in previously well children An evidence based approach

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Title: Community Acquired Pneumonia in previously well children An evidence based approach


1
Community Acquired Pneumonia in previously well
children An evidence based approach
Professor Terence Stephenson Dr Maria Atkinson,
Dr Monica Lakhanpaul Division of Child Health,
Nottingham University
2
  • Right middle lobe pneumonia

3
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4
Definition of pneumonia
  • respiratory symptoms / signs
  • absence of wheeze
  • abnormal chest x-ray

5
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6
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7
Aetiology
  • Streptococcus pneumoniae
  • 4 Drummond 2000
  • 8 Clements 2000
  • 21 Korppi 1993
  • Mycoplasma pneumoniae
  • 1.5 Korppi 1993
  • 7 Juven 2000
  • 33 Eposito 2003
  • 20-60 cases a pathogen is not identified
  • 8-40 represent a mixed infection

8
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9
Distinguishing viral and bacterial pneumonia
radiologically
  • Differentiation of bacterial and viral pneumonia
  • Virkki et al 2002 Thorax
  • 254 children
  • - 72 of those with a bacterial aetiology had
    alveolar infiltrates
  • - 49 with solely viral pneumonia had alveolar
    infiltrates
  • - Interstitial changes half had viral
    infection the other half had bacterial infection

10
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11
PIVOT Trial Pneumonia Intravenous Versus Oral
Treatment Multi-Centre Randomised Controlled
Trial Of Oral Versus Intravenous Treatment For
Community Acquired Pneumonia In Children
  • M Atkinson, M Lakhanpaul, A Smyth, H Vyas, V
    Weston, J Sithole,
  • V Owen, K Halliday, H Sammons, J Crane, N
    Guntupalli, L Walton,
  • T Ninan, A Morjaria, T Stephenson
  • Department of Child Health, University of
    Nottingham


12
Hypothesis
  • The outcome for previously well children
  • (6 months-16 years) with community acquired
    pneumonia treated with oral or IV treatment will
    be no different
  • Non-inferiority trial
  • Power calculation 196 children for an 80
    powered study
  • Primary outcome measure
  • Time for temperature to remain below 38 degrees
    Celsius for 24 hours and oxygen requirement to
    cease

13
Secondary Hypotheses
  • In in-patients, oral treatment of community
    acquired pneumonia will not
  • Prolong the duration of the illness or the
    duration of the antibiotic treatment
  • Not increase the risk of morbidity or mortality
  • Reduce both the direct and indirect costs of
    healthcare

14
Exclusion Criteria
  • Children lt 6 months
  • Pleural effusion, large enough to need chest
    drain
  • Sats lt85 in air
  • Shock following 20mls/kilo fluid resuscitation or
    signs of disseminated infection
  • Chronic respiratory disease NOT asthma
  • Definite penicillin allergy
  • Immunodeficiency
  • Pre-treatment with antibiotics not an exclusion

15
Treatment
  • All ages
  • Oral amoxycillin versus IV benzyl penicillin
  • 8 mg/kg 8 hrly versus 25 mg/kg 6 hrly
  • Rescue Treatment
  • Oral erythromycin or IV clarithromycin
  • At 48 hours if no improvement or before if deemed
    appropriate by the clinician in charge

16
PIVOT Trial
  • Fulfilled exclusion criteria 71
  • chronic lung disease (4)
  • shock (3)
  • immunodeficiency (9)
  • lt 6 months (12)
  • oxygen saturations lt 85 (31)
  • penicillin allergy (7)
  • pleural effusion (5)
  • Declined to take part 43

Considered for eligibility 366
Randomised 252
Excluded 6 - withdrawn by parents (4),
clinician(2)
246
17
246
Randomised to oral treatment 126 Received study
treatment 121 Did not receive study treatment
5 Reasons - started oral treatment and
subsequently changed to IV ben pen (3) -
changed to IV ben pen prior to first dose
randomised medication (1) - would not take oral
treatment (1)
Randomised to IV treatment 120 Received study
treatment 116 Did not receive study treatment
4 Reasons - failed IV access therefore treated
with oral (4)
Eligible for ITT 120 Excluded from PP analysis
17 Reasons - Did not meet radiological criteria
(13) Protocol deviations (4) Eligible for per
protocol analysis 103
Eligible for ITT 126 Excluded from PP analysis
26 Reasons - Did not meet radiological criteria
(21) Protocol deviations (5) Eligible for per
protocol analysis 100
Unable to contact for telephone FU (2)
Unable to contact for telephone FU (3)
18
Pre-admission variables
  • IV group median age 2.5 years ( IQR1.38-4.72)
  • Oral group median age 2.4 years (IQR 1.46-5.37)
  • Antibiotics pre admission 14 and 18 in the IV
    and oral groups
  • Length of illness pre-hospital median 4.5 days
    (IQR 2-7) and median 5 days (IQR 2.5-7) in the IV
    and oral groups
  • No significant difference between the 2 groups
    for admission observations or symptoms (cough,
    recession, grunting and difficulty breathing)

19
Length of stay in hospital in the IV group (PP)
Length of stay in hospital in the oral group
(PP)
Number of children
Length of hospital stay in days
IV Group - median 2.1 days (1.8-2.9) Oral Group
- median 1.77 days (1-2.2) Plt0.001
20
Time for temperature to settle in the oral and IV
groups (PP)
IV treatment --------- oral treatment

Wellek logrank test for equivalence P0.0013 ITT
P0.0001
Probability that the child meets the primary
outcome measure after time t
Time for temperature to be less than 380C for 24
continuous hours (days)
21
Rescue Treatment (erythromycin/clarithromycin)
  • 8/103 (7.8) IV group
  • 6/100 (6) oral group
  • p0.619
  • (6/14 of these children came from 1 centre)

22
Protocol Deviations
  • Oral group
  • 3 protocol deviations which resulted in a change
    from oral to IV therapy
  • IV group
  • 7 protocol deviations which resulted in a change
    from IV benzyl penicillin to another IV
    medication (3 were also adverse events)

23
Adverse Events
  • 3 children developed empyema, all in the IV group
  • 1 child was readmitted to hospital
  • No deaths or admissions to PICU

24
Time to resolution of symptoms IV group PP
Time to resolution of symptoms oral group PP
Number of children
Number of children
Time to resolution of symptoms in days
Time to resolution of symptoms in days
Median of 9 days to full recovery in both arms of
the study
25
Further antibiotics following discharge
  • 8 children in total
  • - 2 children in the IV group
  • - 6 children in the oral group
  • 4 ongoing cough
  • (3 amoxicillin and 1 clarithromycin)
  • 4 children in the oral group received another
    course of antibiotics between 5 and 28 days for
    new coryza /- fever and cough

26
Conclusion
  • Oral and IV treatment are equivalent for CAP
  • Oral group spend significantly less time in
    hospital and require less oxygen
  • Complications are not increased in the oral group
  • Time to resolution of symptoms is the same in
    both groups
  • Yield from blood culture is low and did not
    predict complications (previous studies have not
    shown CRP and FBC are reliably predictive of
    bacterial or viral pneumonia)
  • Treatment with oral antibiotics is cheaper

27
Implications For Future Practice
  • Oral amoxicillin for children admitted with CAP
  • FBC, CRP, blood culture not indicated
  • The exclusion criteria from this trial could be
    used to suggest indications for IV antibiotics in
    the future
  • Applicability to rest of the UK

28
Thank you
  • Dr Maria Atkinson
  • British Lung Foundation
  • Steering Group
  • Monica Lakhanpaul, Harish Vyas, Alan Smyth,
    Jabulani Sithole, Vivienne Weston, Victoria Owen
  • Collaborating hospitals
  • Dr Clements, Dr Groggins, Professor Choonara, Dr
    Anderson, Dr Lenney, Dr Alexander and Dr Ninan
  • Radiologists Dr Halliday, Dr Broderick and Dr
    Minford
  • SpRs
  • Helen Sammons, Lynda Walton, Dougie Thomas,
    Stuart Hartshorn, Narin Guntupalli, Ian Lewins,
    Anu Morjaria, Sophie Cater, Jo Crane, Ayesha
    Qureshi, Osama Hamood

29
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30
A double blind placebo controlled randomised
trial comparing oral amoxicillin versus oral
amoxicillin plus azithromycin for community
acquired pneumonia in children 
  • What next?

31
Oxygen requirement
  • 18/103 (17.5) IV group required oxygen
  • 28/100 (28) oral group required oxygen, at any
    point during the admission (p0.073)
  • Median length of time oxygen required was
  • 20.5 hrs (IQR 33.25) IV group
  • 11 hrs (IQR 21.5) oral group
  • (p0.039)

32
Adverse Events (n3)
33
Direct Costs



34
Indirect Costs
  • Travel to and from hospital
  • Extra expenditure whilst in hospital
  • Loss of earnings
  • Other costs

35
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36
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37
RESERVES
38
Oral protocol deviations (n3)
39
IV protocol deviations (n7)
40
Investigations
  • Blood culture
  • All positive cultures were Streptococcus
    pneumoniae sensitive to pencillin
  • 3/89 (3) IV group
  • 1/90 (1) oral group
  • NPA or viral throat swab
  • IV group 7/52 13.5 (5 RSV, 1 flu A,
  • 1 paraflu virus)
  • Oral group 8/54 16.7 (4 RSV, 2 flu A,
  • 1 adenovirus, 1 rhinovirus)

41
CRP
42
WCC
43
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44
Number of doses of IV antibiotic given in
hospital PP
Number of doses of oral antibiotic given in
hospital PP
Number of children
Number of children
Median number of doses 6 IQR (4.7-7.5)  
Median number of doses 3.4 IQR (2-5)
45
Implications For Future Practice
  • Less painful invasive treatment for children
  • Oral antibiotics for children admitted with CAP
    using BTS guideline indications for admission
  • Indications for IV antibiotics should be the
    exclusion criteria from this trial
  • Applicability to rest of the UK and Europe

46
Future Work
  • Different combinations of oral antibiotics
  • Long term follow-up of children with pneumonia
  • Predictive signs for diagnosing pneumonia

47
Indications for admission to hospital
  • BTS guidelines indications for admission
  • In infants
  • Oxygen saturations lt 92 air
  • Respiratory rate gt 70 breaths/min
  • Difficulty breathing
  • Intermittent apnoea/grunting
  • Not feeding
  • Family not able to support the infant at home
  • lt 1 yr 19/21 in the per protocol group

48
Indications for admission to hospital
  • Older children
  • Oxygen saturation lt92
  • Respiratory rate gt 50
  • Difficulty breathing
  • Grunting
  • Signs of dehydration (data not collected)
  • Family not able to support at home
  • gt 1 year 120/182 (66) met 1 or more criteria

49
  • Graham Watson computer randomisation
  • Radiologists Dr Halliday, Dr Broderick and Dr
    Minford
  • Sue Waring, Gillian Wilson, Julia Payne
  • Parents and children

50
Clinical Trials Network
51
Aims
  • To facilitate recruitment to paediatric trials
  • Ensure input from all potential participating
    centres in the early stages of designing a trial
  • Ensure research is carried out in a range of
    paediatric units big and small

52
Atypical Pneumonia
  • Most commonly caused by Mycoplasma pneumoniae and
    Chlamydia pneumoniae
  • Incidence varies from 1.5 to 33
  • Clinical presentation -
  • 203 children, 33 had evidence of
  • M pneumoniae infection
  • 40 acute onset symptoms, 60 gradual
  • 19 had lobar changes
  • Esposito S, European Respiratory Journal 2001

53
Atypical Pneumonia
  • Age
  • lt 5 years of age
  • S pneumoniae incidence 8.6/1000 per year
  • M pneumoniae 1.7/1000/year
  • 5-15 years
  • S Pneumonia fell to 5.4/1000
  • M pneumoniae rose to 6.6/1000
  • Jokien C, American Journal Epidemiology 1993

54
Atypical Pneumonia
  • Clark J, Archives Disease Childhood 2003
  • Mean age of children with M pneumoniae 3.5 yrs
  • Block S, Paediatric Infectious Disease Journal
    1995
  • Compared erythromycin with clarithromycin, 23
    of 3-4 year old children had M pneumoniae

55
Previous studies comparing macrolides with other
groups of antibiotics
  • Only 1 study in children comparing beta-lactams
    with macrolides
  • Divided children clinically into atypical
    (randomised to azithromycin or erythromycin) or
    classic pneumonia (randomised to amoxicillin or
    azithromycin)
  • Results no difference between the 2 groups
  • Kogan et al Pediatric Pulmonology 2003

56
Previous studies comparing macrolides with other
groups of antibiotics
  • Azithromycin compared with conventional treatment
    (augmentin lt 5 year age group and erythromycin in
    gt 5 year age group)
  • Results no difference between the 2 groups
  • Harris et al Pediatric Infectious Disease
    Journal 1998

57
Adult Studies
  • Observational study in adults - 1100 adult
    patients (from 26 hospitals in 11 countries)
    Community Acquired Pneumonia Organisation (CAPO)
    International Cohort Study) 2001-2003 23-25 ATS
    2004
  • Results patients treated with antibiotics
    covering typical and atypical organisms have
    better outcomes
  • RCTs needed

58
BTS CAP Guidelines
  • because M pneumoniae is more prevalent in older
    children, macrolide antibiotics may be used as
    first line empirical treatment in children gt 5
    years
  • (Grade D consensus statement)  

59
  • Null Hypothesis
  • The outcome for previously well children with
    community acquired pneumonia treated with
    azithromycin plus amoxicillin or amoxicillin
    alone will be no different

60
Experimental design and method
  • Multi-centre double blind placebo controlled
    randomised trial (superiority trial)
  • Intervention
  • Azithromycin (po) plus amoxicillin (po)
  • OR
  • Azithromycin placebo (po) plus amoxicillin

61
Primary Outcome Measure
  • Time for the temperature to be less than 38
    degrees for 24 hours and for oxygen requirement
    to cease
  • Other options
  • Some measure of time to resolution of symptoms

62
Secondary Outcome Measures
  • Treatment with azithromycin and amoxicillin
    will
  • 1. Reduce the time to resolution of symptoms,
    defined as energy levels back to normal and not
    coughing more than prior to the pneumonic
    illness.
  • 2. Reduce morbidity and mortality (length of stay
    in hospital, representation to the GP or AE
    department, further courses of antibiotics,
    empyema and admission to PICU or ventilation).

63
Operational definition of pneumonia
  • All 3 have to be present
  • Respiratory symptoms or signs (wheeze NOT
    excluded)
  • Temperature of 37.5 degrees or a history of fever
    at home
  • Radiological diagnosis of pneumonia (defined as
    consolidation as per the World Health
    Organization Guidelines).

64
Inclusion Criteria
  • Children 1 year -16 years
  • Meets the operational definition of pneumonia
    above
  • Eligible for treatment with oral antibiotics
  • NB Inclusion in the trial is not dependant on
    whether the child is admitted to hospital

65
Exclusion Criteria
  • Oxygen saturations lt 85 in air
  • Shock requiring gt 20mls/kg fluid resuscitation
  • Chronic lung disease
  • Treatment with a macrolide antibiotic in the week
    prior to presentation at hospital
  • Pleural effusion large enough to need draining
  • Immunodeficiency

66
Investigations
  • CXR
  • Throat swab for mycoplasma PCR

67
Follow up
  • Telephone call 24 hours following discharge and
    weekly until the child is back to normal

68
Power Calculation
  • In the previous study the mean time for the
    temperature to be less than 38 degrees for 24
    hours was 1.8 days (SD 1.2)
  • To show an improvement in time for temperature to
    settle of 8 hours in the group treated with
    amoxicillin and azithromycin, 205 children will
    be needed in each arm of the study (5
    significance, 80 power)

69
RESERVES
70
Definition Pneumonia Entry Criteria
  • All 3 must be present
  • Respiratory symptoms or signs but no wheeze
  • Documented fever in AE 37.5 or a history of
    fever at home
  • CXR consistent with the clinical diagnosis of
    pneumonia

71
Outcome Measures
  • Short Term
  • Temperature
  • Oxygen requirement
  • Time in hospital
  • Lansky play scale
  • Complications
  • Long Term
  • Phone call to parents to assess time till back to
    school or deemed to be back to normal by the main
    carer
  • Complications such as re-admission and further
    antibiotics

72
  • Pragmatic trial
  • Analysis of the primary outcome measure
  • Survival analysis

73
Time for temperature to settle in the oral and IV
groups using censored data (PP)
Wellek logrank test for equivalence P0.049
74
Cost of treating CAP in the UK
  • In 1992/93 prices 440.7 million was spent
    treating 261,000 annual episodes of CAP (adult
    and children)
  • 96 of the cost was to treat the 32 who were
    treated in hospital
  • Average costs-
  • Community 100
  • Hospital 1,700-5,100
  • Guest J, European Respiratory Journal 1997

75
Paediatric Studies
  • Control group
  • Mean total healthcare costs 2463 (1995/6
    prices)
  • New protocol
  • Mean total healthcare costs 1167
  • The estimated saving for the 45 patients who were
    treated under the new protocol was 58,000
  • Al-Eidan F, Journal Antimicrobial Chemotherapy
    1999

76
Economic Analyses
  • An economic evaluation is defined as
  • The comparative analysis of alternative
    courses of action in terms of both their costs
    and consequences
  • Cost minimization analyses (CMA) are a special
    form of cost-effectiveness analysis where the
    consequences of the alternative treatments being
    compared turn out to be equivalent

77
Economic Hypothesis
  • The cost of treating children with CAP with oral
    antibiotics will be less than treatment with IV
    antibiotics

78
Sources of cost data
  • Direct costs
  • Netten and Curtis (2002)
  • Investigations and antibiotics
  • Local hospital costs
  • Indirect Costs
  • New Earnings Survey 2002

79
Parenteral and oral route of antibiotic
administration for CAP
  • Developing world
  • Campbell H, The Lancet 1988
  • Keeley D, Bulletin WHO 1990
  • Developed world
  • Tsarouhas N, Pediatric Emergency Care 1988

80
SWT Therapy
  • No RCTs in children
  • 2 prospective observational studies
  • Both demonstrate that IV therapy for CAP can be
    successfully be decreased to 2-4 days Al-Eidan
    F, Journal Antimicrobial Chemotherapy 1999
  • Ciommo V, Journal of evaluation in clinical
    practice 2002

81
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82
Gibson NA. Hollman AS. Paton JY. Value of
radiological follow up of childhood pneumonia.
BMJ. 307(6912)1117, 1993 Oct 30.
83
Pneumonia
  • Common paediatric diagnosis
  • High mortality in the developing world
  • Developed world incidence 21-36/1000/year lt 5
    year age group with 40 children requiring
    hospitalisation
  • Korrpi M et al, European Journal of
  • Paediatrics 1993
  • Macintyre C, Epidemiology of Infections 2003

84
Rational
  • Evidence Based Guideline For Assessment of Acute
    Breathing Difficulty In Children
  • Dr Monica Lakhanpaul and the Paediatric AE
    Research Group
  • Treatment of Community Acquired Pneumonia in
    Children 2002
  • British Thoracic Society Guidelines
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