Community Acquired Pneumonia in previously well children An evidence based approach

1. Community Acquired Pneumonia in previously well childrenAn evidence based approach

2. Right middle lobe pneumonia

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

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

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

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 < 6 months Pleural effusion, large enough to need chest drain Sats <85% 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

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)

21. Rescue Treatment(erythromycin/clarithromycin) 8/103 (7.8%) IV group 6/100 (6%) oral group p=0.619 (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

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 SpR’s Helen Sammons, Lynda Walton, Dougie Thomas, Stuart Hartshorn, Narin Guntupalli, Ian Lewins, Anu Morjaria, Sophie Cater, Jo Crane, Ayesha Qureshi, Osama Hamood

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 (p=0.073) Median length of time oxygen required was 20.5 hrs (IQR 33.25) IV group 11 hrs (IQR 21.5) oral group (p=0.039)

32. Adverse Events (n=3)

33. Direct Costs

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

37. RESERVES

38. Oral protocol deviations (n=3)

39. IV protocol deviations (n=7)

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)

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 < 92% air Respiratory rate > 70 breaths/min Difficulty breathing Intermittent apnoea/grunting Not feeding Family not able to support the infant at home < 1 yr 19/21 in the per protocol group

48. Indications for admission to hospital Older children Oxygen saturation <92% Respiratory rate > 50 Difficulty breathing Grunting Signs of dehydration (data not collected) Family not able to support at home > 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 < 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 < 5 year age group and erythromycin in > 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 RCT’s 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 > 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 A&E 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 < 85% in air Shock requiring > 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 A&E 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

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 RCT’s 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

83. Pneumonia Common paediatric diagnosis High mortality in the developing world Developed world incidence 21-36/1000/year < 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 A&E Research Group Treatment of Community Acquired Pneumonia in Children 2002 British Thoracic Society Guidelines