Professor Terence Stephenson

President Royal College of Paediatrics &

Child Health

Nuffield Professor, Institute of Child Health,

University College London

& Great Ormond Street Hospital, London

Respiratory infection – what works

Community Acquired in

Previously Well Children:

• Pneumonia

• Bronchiolitis (RSV)

• Swine Flu (H1N1 Influenza)

Local microbiology

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

Definition of

pneumonia

• respiratory symptoms / signs

• absence of wheeze

• abnormal chest x-ray

89 children recruited

51 positive aetiological diagnoses in 48 children

S.pneumoniae 7

M.pneumoniae 14

B.pertussis 6

C.pneumoniae 1

Viruses 23

iv antibiotic use before and after introduction of

a written guideline

1994-95 (%) 1996-97 (%)

Benzyl-

penicillin

24 69

Erythromycin 2 7

Cefotaxime 38 15

Ampicillin 21 3

Flucloxacillin 7 2

Metronidazole 0 2

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, 1101-1106, 2007

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

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

Admission

observations: -

(mean and 95% CI)

Temperature

Pulse

Respiratory rate

< 1 year

> 1 year

SaO2 (in air)

Neutrophil count x109/l

C-reactive protein mg/l

38.6 deg (38.4-38.8)

151 (146-156)

50 (45-61)

40 (37-43)

95% (94-96)

14 (12.3-15.9)

159 (128-190)

38.4 deg (38.2-38.6)

149 (144-153)

50 (45-61)

43 (40-46)

95% (95-96)

13.4 (11.9-14.9)

172 (144-199)

HOW ILL WERE THE CASES?

Time for temperature to settle in the oral and IV groups (PP)

14121086420

1.0

.8

.6

.4

.2

0.0

=IV treatment

--------- = oral treatment

Pro

ba

bil

ity t

ha

t th

e c

hil

d m

ee

ts t

he

pri

ma

ry

ou

tco

me

me

as

ure

aft

er

tim

e t

Time for temperature to be less than 380C for 24 continuous hours (days)

Wellek log rank

test for equivalence

P=0.0013

0 10 20 30 40 50

0

5

10

15

20

25

0 10 20 30 40 50

0

5

10

15

20

25

30

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

Nu

mb

er

of

ch

ild

ren

Nu

mb

er

of

ch

ild

ren

Median of 9 days to full recovery in both arms of the study

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

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 40 000 units in 40 ml 0.9% saline for children

weighing 10 kg or above, and 10 000 units in 10 ml 0.9% saline

for children weighing under 10 kg.

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

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)

J Yong. Pediatric Pulmonology Volume 44, Issue 2,

pages 122–127, February 2009

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%.

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 -0.18 days; 95% CI -0.39 to 0.04).

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) -0.96

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 -0.27 to

0.39, n = 349).

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 -0.52

favouring epinephrine (95% CI -1.00,-0.03).

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.

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 = -0.15 days, 95% CI -0.92 to 0.61, P

= 0.69, n = 58).

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 co-

morbidity.

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) -0.94 days, 95% CI -1.48

to -0.40, P = 0.0006)

• Length of Stay reduced from 3.5 to 2.5 days

• 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).

“Catch it, bin it, kill it”

Treatment Fluids Paracetamol Ibuprofen No Aspirin

Antivirals and Vaccines

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

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

Antibiotics?

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

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

PRIORITY GROUPS FOR H1N1 VACCINE

Straus W et al

Co-trimoxazole versus amoxycillin for pneumonia in

children in Pakistan – an RCT

Lancet 1998; 352: 270-274

• 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

MASCOT pneumonia study group

3 days versus 5 days amoxycillin for pneumonia in

children in Pakistan – an RCT

Lancet 2002; 360: 835-841

• 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

ISCAP pneumonia study group

3 days versus 5 days amoxycillin for pneumonia in

children in India – an RCT

BMJ 2004; 360: 791-794

• Oral amoxil 31-54 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

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: 270-274

• 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

3% nebulised saline + salbutamol

• Luo Z. Liu E. Luo J. Li S. Zeng F. Yang X. Fu Z. Pediatrics International.

52(2):199-202, 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 3.8 + or - 1.1 days in the control group

and 2.7 + or - 0.9 days in the treatment group (P < 0.01). Cough

remission time was 6.3 + or - 0.9 days in the control group and 5.3 + or -

0.8 days in the treatment group (P < 0.01). Length of hospital stay

decreased from 7.4 + or - 1.5 days in the control group to 6.0 + or - 1.2

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.

GSK H1N1 Vaccine

(Pandremix)

• 18-60 yrs one dose

• Including pregnant women

• 6 months -18 years two doses

• 2010-2011 Winter: UK government did NOT recommend seasonal flu vaccine (H1N1 and Flu B) for healthy children

Neonates

• Vaccination in pregnancy protects

• Breast feeding OK with Anti-Virals for mother

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

Unable to contact for

telephone FU (2) Unable to contact

for telephone FU (3)

Did not meet radiological criteria (21)

Eligible for per protocol analysis 100

Did not meet radiological criteria (13)

Eligible for per protocol analysis 103

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

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