Respiratory infection what works Professor Terence Stephenson President Royal College of Paediatrics & Child Health

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1 Respiratory infection what works Professor Terence Stephenson President Royal College of Paediatrics & Child Health Nuffield Professor, Institute of Child Health, University College London & Great Ormond Street Hospital, London

2 Community Acquired in Previously Well Children: Pneumonia Bronchiolitis (RSV) Swine Flu (H1N1 Influenza)

3 Local microbiology

4 Right middle lobe pneumonia 36/1000/year < 5 years 16/1000/year children 5-14 years

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

6 89 children recruited 51 positive aetiological diagnoses in 48 children S.pneumoniae 7 M.pneumoniae 14 B.pertussis 6 C.pneumoniae 1 Viruses 23

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9 iv antibiotic use before and after introduction of a written guideline Benzylpenicillin (%) (%) Erythromycin 2 7 Cefotaxime Ampicillin 21 3 Flucloxacillin 7 2 Metronidazole 0 2

10 ATKINSON M, LAKHANPAUL M, SMYTH A, VYAS H, WESTON V, STIHOLE J, OWEN V, HALLIDAY K, SAMMONS H, CRANE J, GUNTUPALLI N, WALTON L, NINAN T, MORJARIA A, STEPHENSON T. A multicentre randomised controlled equivalence trial comparing oral amoxicillin and intravenous benzyl penicillin for community acquired pneumonia in children: PIVOT Trial. Thorax 62, , 2007

11 DEFINITION OF PNEUMONIA - ENTRY CRITERIA All 3 must be present: Respiratory symptoms or signs but no wheeze Documented fever of 37.5 deg C or a history of fever at home CXR reviewed by 2 masked radiologists independently confirms radiological pneumonia Excluded: children younger than 6 months; SaO2 < 85%; shocked despite 20 ml/kg fluid; chronic lung disease; immunodeficiency; penicillin allergy NOT excluded: asthma; already receiving antibiotics

12 Treatment - all ages randomised to either: 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

13 HOW ILL WERE THE CASES? Admission observations: - (mean and 95% CI) Temperature Pulse Respiratory rate < 1 year > 1 year SaO2 (in air) Neutrophil count x10 9 /l C-reactive protein mg/l 38.6 deg ( ) 151 ( ) 50 (45-61) 40 (37-43) 95% (94-96) 14 ( ) 159 ( ) 38.4 deg ( ) 149 ( ) 50 (45-61) 43 (40-46) 95% (95-96) 13.4 ( ) 172 ( )

14 Probability that the child meets the primary outcome measure after time t Time for temperature to settle in the oral and IV groups (PP) =IV treatment = oral treatment.6.4 Wellek log rank test for equivalence P= Time for temperature to be less than 38 0 C for 24 continuous hours (days)

15 Number of children Number of children Time to resolution of symptoms IV group PP Time to resolution of symptoms oral group PP 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

16 REPEAT CHEST X-RAY? Gibson NA. Hollman AS. Paton JY. Value of radiological follow up of childhood pneumonia. BMJ. 307(6912):1117, 1993 Oct 30

17 Pleural effusion If a child remains pyrexial or unwell 48 hours after admission for pneumonia, effusion/empyema must be excluded. If a child has significant pleural infection, a drain should be inserted at the outset and repeated taps are not recommended. Ultrasound should be used to guide thoracocentesis or drain placement. Since there is no evidence that large bore chest drains confer any advantage, small drains (including pigtail catheters) should be used Intrapleural fibrinolytics for thick fluid with loculations or empyema (overt pus). Urokinase has been studied in an RCT in children: recommended twice daily for 3 days (6 doses in total) using units in 40 ml 0.9% saline for children weighing 10 kg or above, and units in 10 ml 0.9% saline for children weighing under 10 kg.

18 CONCLUSION Oral and IV treatment are equivalent for Community Acquired Pneumonia Oral group spent significantly less time in hospital and required 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

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20 Omitting radiography in diagnosis of acute bronchiolitis 265 infants, 2 23 months old, presenting to Toronto Sick Childrens Hospital Emergency Department with typical clinical bronchiolitis (wheeze + crepitations) Post-CXR: ED doctor diagnosed 40 pneumonias which were not confirmed. This interpretation resulted in a fivefold increase in the rate of antibiotic therapy after radiography, from 2.6% to 14.7%. J Yong. Pediatric Pulmonology Volume 44, Issue 2, pages , February 2009

21 Steroids for bronchiolitis systemic & inhaled 17 trials (2596 participants): only two had low overall risk of bias. Highest dose = 6 doses of oral dexamethasone (1 mg/kg followed by 0.6 mg/kg for five days) Outpatients: No significant reduction in outpatient admissions by days 1 and 7 when compared to placebo (pooled risk ratios (RRs) 0.92; 95% CI 0.78 to 1.08; and 0.86; 95% CI 0.7 to 1.06, respectively). Inpatients: There was no benefit in Length of Stay for inpatients (mean difference days; 95% CI to 0.04).

22 Bronchodilators 28 trials (1912 infants) with bronchiolitis. In 10 inpatient and 10 outpatient studies, oxygen saturation did not improve with bronchodilators (mean difference (MD) -0.45, 95% confidence interval (CI) to 0.05, n = 1182). Outpatient bronchodilator treatment did not reduce the rate of hospitalization (12% in bronchodilator group versus 16% in placebo, odds ratio (OR) 0.78, 95% CI 0.47 to 1.29, n = 650). Inpatient bronchodilator treatment did not reduce the duration of hospitalization (MD 0.06, 95% CI to 0.39, n = 349).

23 Epinephrine Epinephrine versus Placebo Five inpatient studies: Only one out of ten inpatient outcomes demonstrated a significant difference between treatment groups: change in clinical score at 60 minutes showed a SMD of favouring epinephrine (95% CI -1.00,-0.03).

24 Epinephrine Epinephrine versus Salbutamol Four inpatient studies: Only one of the seven outcomes evaluated was statistically significant: respiratory rate at 30 minutes favoured epinephrine over salbutamol (WMD -5.12; 95% CI -6.83,- 3.41). Changes in clinical score, oxygen saturation, heart rate, and length of stay were not significantly different between the treatment groups.

25 Heliox four trials involving 84 infants under two years of age with respiratory distress secondary to bronchiolitis caused by respiratory syncytial virus (RSV) and requiring PICU when compared to those treated with air or oxygen, there was no clinically significant reduction in the rate of intubation (risk ratio (RR) 1.38, 95% CI 0.41 to 4.56, P = 0.60, n = 58), in the need for mechanical ventilation (RR 1.11, 95% CI 0.36 to 3.38, P = 0.86, n = 58), or in the length of stay in a PICU (MD = days, 95% CI to 0.61, P = 0.69, n = 58).

26 Physiotherapy Based on the results of three RCTs in infants with acute bronchiolitis, chest physiotherapy using vibration and percussion techniques does not: reduce length of hospital stay oxygen requirements or improve the severity clinical score. These were infants who were not on mechanical ventilation and who did not have any other comorbidity.

27 3% nebulised saline Four trials involving 254 infants with acute viral bronchiolitis (189 inpatients and 65 outpatients) Patients treated with nebulized 3% saline had a significantly shorter mean length of hospital stay compared to those treated with nebulized 0.9% saline (mean difference (MD) days, 95% CI to -0.40, P = ) Length of Stay reduced from 3.5 to 2.5 days

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31 70 paediatric deaths related to H1N1 were reported. Childhood mortality rate was 6 per million population. The rate was highest for children aged less than 1 year. 15 (21%) children who died were previously healthy. 45 (64%) had severe pre-existing disorders especially chronic neurological disease (1536 per million population). Overall, 45 (64%) children had received oseltamivir (seven within 48 h of symptom onset).

32 Catch it, bin it, kill it

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34 Treatment Fluids Paracetamol Ibuprofen No Aspirin

35 Antivirals and Vaccines

36 Evidence that Neuraminidase blockers treat children? 2 randomised trials of Tamiflu and 2 of Relenza 1766 children aged less than 12 years Illness shortened by 36 hours on average Otitis media reduced from 30% to 15% in children 1-5 years old No reduction in asthma episodes in children with asthma

37 Side-effects of Tamiflu in large Randomised Controlled Trials In untreated Winter flu, 1 in 20 children vomit In Winter flu treated with Tamiflu, 1 in 10 children vomit

38 Antibiotics?

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41 Evidence that winter flu vaccine protects children? 51 trials of winter flu vaccine in children 294,159 children Inactivated vaccines 59% efficacy in children over 2 years but no better than placebo under 2 years Live vaccines 82% efficacy in children over 2 years

42 PRIORITY GROUPS FOR H1N1 VACCINE 1. Individuals aged six months to 65 years with underlying health problems and the immuno-supressed including chemotherapy patients 2. Pregnant women 3. Household contacts of people with compromised immune systems 4. Individuals aged over 65 with health problems

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44 Straus W et al Co-trimoxazole versus amoxycillin for pneumonia in children in Pakistan an RCT Lancet 1998; 352: Oral amoxil 45 mg/kg/day successful in 82% of children with severe pneumonia severe pneumonia defined as lower chest indrawing with or without tachypnoea Wheeze was not an exclusion All 600 children had CXR but only 150/600 had radiological confirmation of pneumonia

45 MASCOT pneumonia study group 3 days versus 5 days amoxycillin for pneumonia in children in Pakistan an RCT Lancet 2002; 360: Oral amoxil 45 mg/kg/day successful in 80% of children with pneumonia, irrespective of 3 or 5 days Rx Only non-severe pneumonia by WHO criteria Wheeze was not an exclusion only 14% had radiological confirmation of pneumonia

46 ISCAP pneumonia study group 3 days versus 5 days amoxycillin for pneumonia in children in India an RCT BMJ 2004; 360: Oral amoxil mg/kg/day successful in 90% of children with pneumonia, irrespective of 3 or 5 days Rx Only non-severe pneumonia by WHO criteria Wheeze was not an exclusion (24% had RSV) No CXR performed

47 Addo-Yobo E et al Oral amoxycillin versus injectable penicillin for severe pneumonia in children in Africa, Asia and S. America an RCT Lancet 1998; 352: Oral amoxil 45 mg/kg/day versus parenteral penicillin 200,000 iu/kg/day [120 mg/kg/day] successful in 82% of children with severe pneumonia severe pneumonia defined as lower chest indrawing with or without tachypnoea Wheeze at presentation was an exclusion but 46% heard to wheeze subsequently CXR not required

48 3% nebulised saline + salbutamol Luo Z. Liu E. Luo J. Li S. Zeng F. Yang X. Fu Z. Pediatrics International. 52(2): , 2010 Apr randomized controlled trial, 93 infants with mild to moderate bronchiolitis the infants received inhalation of 2.5 mg (0.5 ml) salbutamol dissolved in either 4.0 ml normal (0.9%) saline (control group, n= 43) or 4.0 ml hypertonic (3%) saline (treatment group, n= 50). The therapy was repeated three times daily until discharge. Wheezing remission time was or days in the control group and or days in the treatment group (P < 0.01). Cough remission time was or days in the control group and or days in the treatment group (P < 0.01). Length of hospital stay decreased from or days in the control group to or days in the treatment group (P < 0.01). CONCLUSIONS: Inhalation of nebulized 3% hypertonic saline solution and salbutamol is a safe and effective therapy for patients with mild to moderate bronchiolitis.

49 GSK H1N1 Vaccine (Pandremix) yrs one dose Including pregnant women 6 months -18 years two doses Winter: UK government did NOT recommend seasonal flu vaccine (H1N1 and Flu B) for healthy children

50 Neonates Vaccination in pregnancy protects Breast feeding OK with Anti-Virals for mother

51 246 Randomised to oral treatment 126 Received study treatment 121 Did not receive study treatment 5 Randomised to IV treatment 120 Received study treatment 116 Did not receive study treatment 4 Did not meet radiological criteria (21) Eligible for per protocol analysis 100 Did not meet radiological criteria (13) Eligible for per protocol analysis 103 Unable to contact for telephone FU (3) Unable to contact for telephone FU (2)

52 Cumulative weekly number of reports of Invasive Pneumococcal Disease due to any of the serotypes in Prevenar7 : Persons aged over 5 Years in England and Wales

53 Cumulative weekly number of reports of Invasive Pneumococcal Disease due to any of the serotypes not in Prevenar7 : Persons aged over 5 Years in England and Wales

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