Miles Weinberger MDProfessor of Pediatrics

www.uihealthcare.com/allerpulm

What is the best way to treat recurrent wheeze in pre-school children?

Lower airway obstructionAsthma vs bronchiolitis?

Both cause lower airway obstruction with inflammation and bronchospasm

The same viruses (RSV, paraflu, rhinoviruses, metapneumovirus, and others) that cause bronchiolitis are the major triggers for acute exacerbations of asthma in pre-school age children (and the most common cold viruses - the rhinoviruses - are the major causes of acute exacerbations in school age children and adults)

What is Bronchiolitis?

Bronchiolitis is a diagnostic term used to describe the initial episode of viral respiratory infection induced lower airway disease in an infant.

Bronchodilators for Bronchiolitis?

Patel et al, Randomized, controlled trial of neb Rx with epinephrine, albuterol, saline (placebo) in bronchiolitis. J Pediatr 2002;141:818-24

149 patients randomized (50 epi, 51 alb, 48 plac)Conclusion: No group differences in effectiveness for hospitalized infants with bronchiolitis.

Hartling et al. Meta-analysis of randomized controlled trials evaluating epinephrine for Rx of bronchiolitis. Arch Pediatr Adolesc Med 2003;157:957-64 (also in Cochrane Revue 2004).

14 studies, 7 in- 6 out-patient – epi compared with placebo or albEpi may be favorable compared with placebo and albuterol for short-term benefit in outpatients but effect is transientInsufficient evidence to support routine use of bronchodilators for bronchiolitis in hospital

Corticosteroids for Bronchiolitis

RDBPC trial in 70 children <24 months (mean age 6.5 months) with 1st episode VRIILAO (i.e. bronchiolitis)Initial dose of 1 mg/kg dexamethasone in ETC decreased hospitalization >50% by 4 hours

44% hospitalized in placebo group19% hospitalized in dexamethasone group

Shuh et al, Efficacy of dexamethasone in outpatients with bronchiolitis. J Pediatr 2002;140:27-32.

Systemic Corticosteroids for Bronchiolitis

RDBPC trial in 600 children 2-12 months (mean 5.1) with 1st episode wheezing (bronchiolitis)

Initial dose of 1 mg/kg dexamethasone in ERHospitalizations after 4 hours

40% for dexamethasone group41% for placebo

Corneli et al. A multicenter, randomized, controlled trial of dexamethasone forbronchiolitis. N Eng J Med 2007;357:331-9.

Comparison of Schuh and Multicenter Studies

Characteristics Schuh MulticenterNo. of children 70 600Mean age (months) 6.5 5.1Hospitalized after 4 hrs Dex 19% Plac 44% (p=0.03) Dex 41% Plac 40% (p=0.74)

Family history atopy Dex 83% Plac 53% Dex 56% Plac 60%

Prior duration of symptoms (days)

Dex 1.7 Plac 1.8 Dex 3.7 Plac 3.8

Differences in the two studies that could have resulted in the conflicting outcomes:

Schuh study unbalanced regarding family history of atopy

Schuh study treated earlier in the clinical course

Corticosteroids for Bronchiolitis

Lower doses than in Schuh study produced lesser but significant effect in outpatients

Goebel et al, Prednisolone plus alb vs alb alone in bronchiolitis. Clin Pediatr 2000;39:213-20.Csonka et al, Prednisolone in management of children 7-35 months with VRIILAD: A randomized, placebo-controlled trial. J Pediatr 2003;143:725-30. – Same efficacy in 1st or 2nd time wheezing

Controlled clinical trials for inpatients all negative even one at doses used by Schuh (Weinberger, Corticosteroids for first-time young wheezers: current status of the controversy. J Pediatr 2003;143:700-2.)

Single Dose of Dexamethasone for Hospitalized Children with Bronchiolitis

RDBPC of 0.6 mg/kg dexamethasone IMFirst episode of wheezing with tachypenia, increased respiratory effort, and a URI1 to 24 months of age

Median 9.2 for dexa groupMedian 10.0 for placebo 0

10

20

30

40

50

60

70

Hou

rs

Duration ofdistress

Duration ofO2

Duration inhospital

Dexamethasone(n=89)Placebo (n=85)

Teeratakulpisarn et a, Pediatric Pulmonology 2007;42:433-9l

P=0.004 P=0.003

P=0.02

So Where Are We in the Treatment of Bronchiolitis?

lBronchodilator may provide transient symptom relief but do not alter clinical courselSpeculation

lHigh dose corticosteroid may provide clinical improvement early in the coursel Perhaps more likely in infants with atopic family history

When an Infant Gets One of the Common Cold Viruses – RSV, PF, RV, etc.

URI onlyBronchiolitis

Recurrent LRI with VRI(intermittent asthma)

Chronic (persistent)asthma

Genetic and prenatal factors

No recurrent LRI with VRI

Atopy

Just What is Asthma?Asthma is a physiologic abnormality of the airways characterized by hyper-responsiveness to various stimuli resulting in airway obstruction that is reversible either spontaneously or as a result of treatment.

The airway obstruction is a result of various degrees of bronchial smooth muscle spasm and inflammation.

Clinical Patterns (phenotypes) of Asthma

Intermittent

Chronic

Seasonal allergic

Chronic with seasonal allergic exacerbations

Severity can range from trivial to life-threatening for all patterns

But What AboutReactive Airway Disease

"Reactive Airway Disease" A Lazy Term of Uncertain Meaning That Should Be

Abandoned

Am. J. Respir. Crit. Care Med., Volume 163, Number 4, March 2001, 822-823

Recurrent wheeze in pre-school age childrenis a common asthma phenotype!

When Does Asthma Begin?Asthma Incidence Rates in Rochester MN by Age

01000200030004000500060007000

<1 1-4 5-14 15-29 >29Age group (years)

Inci

denc

e ra

te p

er

100,

000

Yunginger et al. Am Rev Respir Dis 1992;146:888-894

80% of asthma has onset by age 5!

Hospital Discharge Rates for Asthma by Age Group

0

10

20

30

40

50

60

Rat

e pe

r 10

,000

pop

ulat

ion

1980-1981 1985-1986 1990-1991 1995-1996 1998-1999

Source: National Hospital Discharge Survey, National Center for Health Statistics, Centers for Disease control & Prevention

0-4 years5-10 years11-17 years

Akinbami & Schoendorf, Pediatrics 2002;110:315-322

Why the high hospitalization rate for asthma under age 5?

>80% of children with exacerbations had evidence of viral respiratory infection(Johnston et al. BMJ 1995;310:1225)

Rhinovirus predominates (Minor et al. JAMA 1974;227:292)

RSV (recurrent) common in pre-school age(McIntosh et al. J Pediatr 1973;82:578)

Metapneumovirus and others also contribute to recurrent wheeze

Infection and AsthmaBacterial infections do not exacerbate asthma

Role of Mycoplasma and Chlamydia pneumoniae are controversial

Respiratory viral infections (common cold viruses) have repeatedly been shown to be major exacerbants of asthma

Mean Annual Incidence of Colds

Figure from “The common cold” Lancet 2003;361,53

Monto & Ulman, JAMA 1974;227:164

Epidemiology of Viral Respiratory Infections (common cold viruses)

Most pre-school agechildren get 3-8 per year

10-15% get > 12 per year

Rosenstein et al, Pediatrics 101:181,1998

Autumnal Increase in Asthma

Johnston et al. JACI 2006;117:557-62

Why Do Common Cold Viruses that Usually Just Cause Upper Respiratory Symptoms Cause Lower Respiratory Inflammatory Disease in Some?

Deficient Innate Immunity to Rhinovirus in Asthma

Asthmatic and normal epithelial cells infected with rhinovirusAsthmatic epithelial cells produce less interferon-β than normalGreater replication of virus occurs in asthmatic epithelial cells

Wark et al. Journal Experimental Medicine 2005; 201: 937-947

Deficient Innate Immunity to Rhinovirus

Adapted from Papadopoulos et al, Thorax 2002;57:328-32*Peripheral Blood Mononuclear Cells

Stimulation of PBMC* by Rhinovirus

Contoli et al. Role of deficient type III interferon-λproduction in asthma exacerbations.Nature Medicine 2006;12(9):1023-6.

Infection with rhinovirus associated with increased respiratory epithelial cells interferon-λComparing asthmatics and normals infected with rhinovirus

Greater interferon-λ from BAL cells from asthmaticsGreater viral production in BAL cells from asthmaticsGreater cold symptoms in asthmaticsGreater decrease in FEV1 in asthmatics

What happens to the pre-school asthmatic? Do they outgrow it?

Prevalence of Symptoms by Age in Atopic and Non-Atopic Asthma

Illi et al. Lancet 2006;368:763-770

atopic (n=94)

non-atopic (n=59)

Allergy in Asthma

Bioassay for specific IgE

No age limitation

10% of asthmatic infants with positive skin tests

Prognostic value even if not correlating with symptoms at initial evaluation

11 month old with CA pollen season rhinoconjunctivitis and asthma

Implications from Epidemiology and Natural History Data

Asthma is commonAsthma typically begins in early childhoodThe highest hospitalization rate for asthma is those under 5 years of ageAn intermittent pattern (not necessarily mild) is the most prevalent clinical pattern for asthmaThe long term outlook for remission of intermittent (but not chronic) asthma is most commonly good despite early morbidity

How should children with viral respiratory infection induced asthma be treated?

Medication Use for Asthma

Maintenance - daily scheduled medication to prevent asthma

Intervention - as needed medication to stop acute symptoms of asthma

Limitation of Maintenance TherapyEffect of inhaled corticosteroids on episodes of viral induced

exacerbations of asthma

104 Children (7-9 yrs)Only wheezed with URIsRDBPC - BDP 400 mcg/dFollowed 6 monthsOutcome

No significant differences in frequency, severity , or duration of symptomsSmall but significant difference in airway reactivity during intercurrent periods

Doull et al, BMJ 1997

0123456789

BDPPlac.

Freq. (#/Yr)Severity Score(Days)

Limitation of Maintenance TherapyEffect of inhaled corticosteroids on episodes of viral induced

exacerbations of asthma

4 month DBPC 400 mcg/day in 41 children (0.7-6 years) with acute asthma with colds (Wilson et al, Arch Dis Child 1995)

No difference in number of episodes

No difference in mean symptoms score

Cochrane review: “There is no current evidence to favour maintenance low dose inhaled corticosteroids in the prevention and management of episodic viral induced wheeze.”(The Cochrane Library, Issue 3, 2002. Oxford: Update Software)

Medication Use for Asthma

Maintenance - daily scheduled medication to prevent asthma

Intervention - as needed medication to stop acute symptoms of asthma

β2 Bronchodilator Aerosol

Hand Position for VHC with Mask for Infant or Toddler

Limitation of Inhaled Bronchodilators in Asthma

Episodic use of an inhaled corticosteroid or leukotrienereceptor antagonist in preschool children

238 children aged 12 to 59 months with intermittent asthmaRDBPC to budesonide, montelukast, placeboMonitored for 12 monthsSeverity reduced in those that were atopicNo difference in episode-free daysNo difference in use oral corticosteroids

Bacharier et al. J Allergy Clin Immunol 2008;122:1127-35

What About Higher Doses of Inhaled Corticosteroids During an Exacerbation?

Four studies in children not receiving maintenance meds compared effect of high dose inhaled corticosteroid (1600-3200 µg/day) with placebo for VRI induced asthma

Conclusion: some clinical effect but no overall significant decrease in need for intervention with oral corticosteroids or hospitalization

Wilson et al. Arch Dis Chid 1990;65:407Connett et al. Arch Dis Child 1993;68:85 Svedmyr et al. Acta Paediatr 1995;84:884Nuhoglu et al. Ann Allergy Asthma Immunol 2001;86:318

What can be done for the pre-school wheezer?

708 admitted with acute lower respiratory tract symptoms345 excluded following review130 refused consent217 randomized to 20 mg qd or placebo

Outcome – of 217 children, mean age 25 months~30% with no further symptoms~15% with no symptom diary121 remaining – mean symptom scores <1 on scale of 0-3 (1= no sleep disturbance & treatment not given) for prednisolone and placebo group

Oonmen , Lambert, Grigg. Lancet 2003;362:1111433-38

These investigators say oral corticosteroids are of no value!

What can be done for the pre-school wheezer?

Oonmen , Lambert, Grigg. Lancet 2003;362:1111433-38

My interpretation of their data: Children with symptoms as mild and self limited as those don’t need oral corticosteroids

No Benefit from Oral Corticosteroid?

700 children, mean age 26 months, placebo or prednisoloneDosage used

10 mg once daily for 10 to 24 months20 mg once daily for 2-6 years of age

OutcomeRapid improvement in placebo and treated Symptom scores ~1.5 on scale of 12 by 24 hrs

Panickar J, Lakhanpaul M, Lambert PC, Kenia P, Stephenson T, Smyth A, Grigg J. N Eng J Med 2009;360:329-38

Consequence of Patient Selection

Primary outcome: Decision to dischargeMedian 12 hours for placeboMedian 10.1 hours for prednisolone

Logical conclusion: for children with acute wheezing (presumably asthma) who will rapidly improve spontaneously within 12 hours, a low dose of prednisolone doesn’t significantly shorten the course.

Panickar J, Lakhanpaul M, Lambert PC, Kenia P, Stephenson T, Smyth A, Grigg J. N Eng J Med 2009;360:329-38

Practice Imperfect — Treatment for Wheezing in PreschoolersAndrew Bush, M.D. N Engl J Med 2009;360;409-10.

“Prednisolone should be administered to preschoolers only when they are severely ill in the hospital.”Question: If they are effective in preschoolers when they are severely ill in the hospital, why wouldn’t they be effective if an adequate dose was given prior to entering the hospital?Answer: Logic and data indicate they are!

Issues: Dosage

0

50

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150

200

250

0 24 hrs 48 hrs 72 hrs

Time from Starting Methylprednisolone

Perc

ent C

hang

e of

FE

V1

15 mg40 mg125 mg

Haskell et al. Arch Intern Med 1983;143:1324-7

n=8 for each

Percent Change of FEV1 after Starting Different Doses of 6 hourly MPR

Value of Early Corticosteroid Use in the Emergency Room

Randomized DBPC trial (age 0.5 - 5 yrs)Methylprednisolone, 4 mg/kg, or normal salineDecision to admit made 3 hours after IM blinded study medicationSignificantly more admissions among placebo treated

0

10

20

30

40

50

% of pts hospitalized at 3 hour evaluation

Methylprednisolone (n=39)

Placebo (n-35)

from Tal et al, Pediatrics 1990.

Value of Early Corticosteroid Use in the Hospitalized Child

Randomized DBPC trial (mean age = 5 yrs)Prednisolone, 30 mg PO for < 5 yr old; 60 mg for > 5 or matched placeboSignificantly more rapid improvement for patients receiving prednisoloneSignificantly earlier discharge for patients receiving prednisolone 0

5

10

15

20

Number of patients discharged at 5 hr exam

prednisolone(n=67)placebo (n=73)

from Storr et al, Lancet 1987.

Value of Early Corticosteroid Use in the Emergency Room

Randomized DBPC trial (mean age = 5 yrs)Prednisone, 2 mg/kg PO, or placeboRepeated albuterol nebulizationsNo difference at 2 hrsSignificant decrease in decision to hospitalize at 4 hrs 0

10

20

30

40

50

60

70

80

All Most Sick

% of pts hospitalized

Prednisone (n=36)

Placebo (n=39)

from Scarfone et al, Pediatrics 1993

High Inhaled vs Oral Steroids for Acute Asthma in the ER

100 children RDBPC trial in ER

2 gm fluticasone (8 puffs of Flovent MDI via AeroChamber2 mg/kg oral prednisone

Albuterol and ipratropium nebs for allSubstantially better lung function in prednisone treated

Schuh et al. N Eng J Med 2000;343:689-94

0

5

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30

35

Perc

enta

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f pat

ient

s

Discharged at 4 hours Hospitalized

FloventPrednisone

Value of Early Corticosteroid Use to Prevent Progression of Acute Asthma

RDBPC trial of 1 week PO prednisone, 30-40 mg bid, or placebo in 41 pts with chronic asthma (median age 12 yrs)Prednisone or placebo started for bronchodilator subresponsive symptomsAll prednisone pts improved; 8/19 placebo pts worsened while 11 improved at a slower rate 0

102030405060708090

100

% of pts improved

Prednisone(n=22)Placebo(n=19)

From Harris et al, J Pediatr 1987

Prevention of Acute Asthma With Oral Corticosteroids in High Risk Patients

32 children < 6 yrs old requiring repeated hospitalization from asthma triggered by URIAfter 1 year, 16 received 1 mg/kg/day prednisone at beginning of URIPrednisone treated group had 90% reduction in hospitalization 0

12345678

prior year Rx year

# of hospitalizations

prednisoneno prednisone

From Brunette et al, Pediatrics 1988.

Signs and Symptoms that Precede Wheezing Children with Intermittent Asthma

Which most important? Which resulted in treatment?

Most importantInitiation of therapy

Rivera-Spoljaric K, et alJ Pediatr 2009;154:877-81

When Should Oral Corticosteroids Be Started?

238 children 12 to 59 months History of recurrent wheezing but well betweenMonitored for 12 monthsSurvey captured signs and symptoms at start of a respiratory illness that led to wheezing and onset of treatment

Rivera-Spoljaric K, et alJ Pediatr 2009;154:877-81

Signs and Symptoms that Precede Wheezing Children with Intermittent Asthma

Signs and Symptoms that Precede Wheezing Children with Intermittent Asthma

Symptoms preceding wheezing requiring intervention

NasalCough, minor Cough, troublesome

Sleep disturbanceActivity interference“Asthma cough”

Troublesome cough most important predictor

Rivera-Spoljaric K, et alJ Pediatr 2009;154:877-81

Contrary DataDosage used

10 mg once daily for 10 to 24 months20 mg once daily for 2-6 years of age

OutcomeRapid improvement in placebo and treated Primary outcome – duration of hospitalization

12 hours for placebo group10.1 hours for prednisolone group

Symptom scores ~1.5 on scale of 12 by 24 hrs

Panickar et al. N Eng J Med 2009;360:329-38

Contrary Data

Dosage used – 20 mg once dailyOutcome

High dropout rateMean symptom scores low for prednisolone and placebo group

Oonmen et al. Lancet 2003;362:1111433-38

Our Experience with Intermittent Viral Induced Asthma in Young Children

Prednisolone started at onset of requiring repeated albuterol

20 mg bid for ages 1-330 mg bid for ages >3

Outcome93% reduction in acute care90% reduction in hospitalizations

Najada et al. Ann Allergy Asthma Immunol 2001;87:335-43

High dose systemic corticosteroids may be of clinical value early in the course of bronchiolitisSystemic corticosteroids are indicated early in the course of acute exacerbations of asthma at any age, most of which are induced by viral respiratory infectionsBronchodilators provide transient symptomatic relief but do not alter the course of VRI induced asthma or bronchiolitis

Parents can generally identify in advance when a viral respiratory infections will be followed by wheezing and respiratory distress warranting interventionInhaled corticosteroids don’t significantly alter the course Prednisone in adequate dose favorably alters the clinical courseLimit maintenance Rx to persistent Sx