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1,Allan Becker MD, FRCPC Section of Allergy and Clinical Immunology Department of Pediatrics and Child Health University of Manitoba Winnipeg, Canada,UPDATE ON THE CLINICAL MANAGEMENT OF ASTHMA IN THE YOUNG CHILD,Shanghai, Mar 12, 2007,2,Asthma Guidelines,Based on published data Little focus on asthma in the young child Important pediatric issues need consideration,BTS-SIGN Guidelines: 2004,BTS-SIGN Guidelines: 5-12 year old,BTS-SIGN Guidelines: 5 year old,GINA Guidelines: 2005,GINA Guidelines: Adults and 5 year old,GINA Guidelines: 5 year old,9,Canadian Pediatric Asthma Guidelines: 2005,www.cma.ca,10,Asthma can be diagnosed in children Under 2 years of age Between 2 and 5 years of age Above 6 years of age Only if pulmonary function tests are available,11,I am comfortable diagnosing asthma in children Under 2 years of age Between 2 and 5 years of age Above 6 years of age Only if pulmonary function tests are available,12,Asthma in the young child,Why is it important to diagnose asthma in the young child ?,13,Annual Incidence Rates for Asthma,Yunginger et al ARRD 1992,14,Melbourne Epidemiological Study of Childhood Asthma Lung Function Over Time,Phelan et al JACI 2002,15,“Airway Remodeling”,Payne et al AJRCCM 2003,Endobronchial biopsy Children “Difficult” Asthma n=19, ages 6-16 Without Asthma n=10 Adults Healthy n=8 Mild Asthma n=10 Severe Asthma n=6,16,“Airway Remodeling”,Payne et al AJRCCM 2003,17,A Longitudinal, Population-Based Cohort Study of Childhood Asthma Followed to Adulthood “these outcomes are determined early in childhood. The challenge is to develop identification and treatment strategies applicable to early childhood that will reduce these adverse outcomes.” Sears et al N Engl J Med, 2003,18,Asthma in the young child,How can we best treat asthma in the young child ? Will early treatment change the natural history of asthma ?,19,Asthma in Childhood,Do we know who to treat?,21,Wheeze after RSV Bronchiolitis,Years post-hospitalization,Sly et al Ped Pulmonol 1989,1 2 3 4 5 (n=42) (n=40) (n=40) (n=31) (n=37) Symptoms 74% 70% 78% 58% 62%,50/247 hospitalized 3 mo old Randomly chosen,22,Diagnosis of Asthma,Wheezing in the first six years of life,Never wheezed 51.5% Transient wheezers 19.9% Persistent wheezers 13.7% Late wheezers 15.0%,Martinez et al NEJM 1995,23,A Clinical Index to Define Asthma Risk*,Castro-Rodrguez et al AJRCCM 2000,Major Criteria Minor Criteria Parental Asthma 1. Allergic Rhinitis Eczema 2. Wheezing (without colds) 3. Eosinophilia,* Wheezy child,24,Asthma in the Young Child,Do we know how to treat?,25,Inhaled corticosteroids have good data for treatment of asthma in children 6 years of age and older Yes No Unsure,26,Inhaled Corticosteroids,Education, Environmental control, Written action plan, and Follow-up,Fast-acting bronchodilator on demand,Very mild,Mild,Regularly assess: Control Triggers Compliance InhalerTechnique Co-morbidity,Modify maintenance therapy,Add-on therapy,Pred,Moderate,Moderately Severe,Severe,Low,Moderate,High,27,Inhaled corticosteroids have good data for treatment of asthma in children 5 years of age and under Yes No Unsure,BTS-SIGN Guidelines: 2004,BTS-SIGN Guidelines: 5 year old,Grade D,GINA 2005 Guidelines: 5 year old,31,GINA 2006 : Children older than 6 years,32,GINA 2006: Children 5 years and Younger,33,GINA 2006 : Children 5 years and younger,The available literature on treatment of asthma for children 5 years and younger precludes detailed treatment recommendations.,34,How should we manage intermittent wheezing in the young child ?,35,Intermittent Asthma in Early Childhood,Male, 2 years old RSV bronchiolitis at 3 months Cough and Wheezing with “colds” 5-6 times since Atopic dermatitis Slightly better with salbutamol How would you manage ?,36,Intermittent inhaled corticosteroid treatment is effective for recurrent wheezing in children Yes No Unsure,Inhaled Corticosteroids for Children Intermittent ICS for URI,3 episodes wheeze with URI (3 days) age 1-3 yrs n = 55 Budesonide 400 g qid 3 days 400 g bid 7 days,Svedmyr et al Acta Pediatr 1999,Inhaled Corticosteroids for Children Intermittent ICS for URI,Svedmyr et al Acta Pediatr 1999,Inhaled Corticosteroids for Children Intermittent ICS for URI,Budesonide Placebo n=26 n=26 Courses with oral steroids 14 (9) 17 (10) Emergency visits due to asthma 16 (10) 23 (12) Hospital admissions due to asthma 6 (5) 2 (2),Svedmyr et al Acta Pediatr 1999,40,Bisgaard et al NEJM 2006,Intermittent ICS in Infants with Episodic Wheezing,411 infants of mothers with asthma 294 randomized to ICS or placebo with 1st wheezing episode (budesonide 400 g per day for 2 weeks) Rx started on 3rd day of “wheezing”,“Prevention of Asthma in Childhood”,41,Bisgaard et al NEJM 2006,Intermittent ICS in Infants: 3 yrs treatment,Budesonide Placebo n=149 n=145,Symptom free days % 83 (24) 82 (27) Days without Sx meds % 91 (16) 94 (14) Withdrawal (persistent wheeze)% 24 21 Pulmonary function (Raw) 1.32 (0.25) 1.31 (0.21),Recurrent Wheeze in the Young Child,If intermittent ICS do not work, what about short courses of oral corticosteroids ?,Intermittent Oral Steroids,Previous hospital for viral wheeze Age 1-5 years Rx five days (prednisolone or placebo) at start of next episode,Oommen et al Lancet 2003,Intermittent Oral Steroids,Prednisolone Placebo N (completed) 109 (52) 108 (69) Age (months) 25(17-37) 27(19-38) MD Dx Asthma 32% 32% FHx Asthma 77% 74% Inhaled CS 28% 29%,Oommen et al Lancet 2003,Intermittent Oral Steroids,Prednisolone Placebo (52) (69) Daytime Score 0.95 0.96 Nighttime Score 0.92 0.82 eta 2 / day 1.59 1.66 Oral Predisolone 9 (17%) 8 (12%) Hospitalisation 6 (12%) 2 (3%)*,Oommen et al Lancet 2003,* P=0.058,Recurrent Wheeze in the Young Child,If intermittent corticosteroids do not work, what about short courses of montelukast ?,Short course montelukast for intermittent asthma in children : Pre-Empt,Montelukast Placebo Age 2-5 yrs 79 83 6-14 yrs 18 22 Total 97 105 Male 61% 63% Exercise Sx 52% 39%* * p=0.058,Robertson et al AJRCCM 2007,48,Short course montelukast for intermittent asthma in children,Robertson et al AJRCCM 2007,Pre-Empt Health Resource Use,Montelukast Placebo GP visits 114 140 Specialist visit 14 23 Emergency Room 25 48 Hospital Admissions 10 17 % episodes HRU 30.1%* 39.9%,Robertson et al AJRCCM 2007,* P=0.0081 OR 0.57 (0.41-0.81),Pre-empt :Time Off School,Montelukast Placebo Number of Episodes 329 325 Time off School (median) 0 1 p=0.003 Days Absent 349 552 p=0.0001,Robertson et al AJRCCM 2007,Pre-empt :Time Off School/Work,Montelukast Placebo Number of Episodes 329 325 Time off School (median) 0 1 p=0.003 Days Absent 349 552 p=0.0001 Parents time away from work Days Absent 419 622 p0.0001,Robertson et al AJRCCM 2007,Canadian Pediatric Asthma Consensus,Intermittent vs Continuous inhaled corticosteroids Efficacy and safety of intermittent ICS has not been defined ? What about regular ICS,53,Guilbert et al NEJM 2006,Long-Term ICS in Preschool Children at High Risk for Asthma: the PEAK study,Can we alter the natural history of asthma by very early treatment ?,CARE network,54,Guilbert et al NEJM 2006,Long-Term ICS in Preschool Children at High Risk for Asthma: the PEAK study,285 high risk (“API”) 2-3 yr olds,CARE network,55,A Clinical Index to Define Asthma Risk*,Castro-Rodrguez et al AJRCCM 2000,Major Criteria Minor Criteria Parental Asthma 1. Allergic Rhinitis Eczema 2. Wheezing (without colds) 3. Eosinophilia,* Wheezy child,ST+ inhalant ST+ food,56,Guilbert et al NEJM 2006,Long-Term ICS in Preschool Children at High Risk for Asthma: the PEAK study,285 high risk (“API”) 2-3 yr olds Treatment period 2 years Fluticasone 88g bid vs placebo Observation period 1 year No study medication,CARE network,57,Guilbert et al NEJM 2006,Long-Term ICS in Preschool Children at High Risk for Asthma: the PEAK study,58,Guilbert et al NEJM 2006,Long-Term ICS in Preschool Children: the PEAK study,59,Murray et al Lancet 2006,Prevention of asthma by use of Inhaled Fluticasone in Wheezy Infants: the IFWIN study,200 children with one atopic parent followed from birth (MAAS) Randomized after one prolonged or two confirmed wheezy episodes Median age 1-2 years Fluticasone 100g bid vs placebo Followed to 5 years,60,Murray et al Lancet 2006,The IFWIN study: OUTCOMES,Placebo Treatment (n=88) (n=85) Current wheeze 47% 52% MD Dx asthma 64% 61% Asthma Rx current 66% 66%,61,First-line maintenance therapy,Recommend ICS as the best option for anti-inflammatory monotherapy for childhood asthma There is insufficient evidence to recommend LTRAs as first-line mono-therapy for childhood asthma. For children who cannot or will not use ICS, LTRAs represent an alternative.,Canadian Asthma Consensus Guideline 2003,Pediatric Recommendations,Prevention of Viral-Induced Asthma Montelukast in the Prevention of Exacerbations in Children Aged 25 Years with Asthma,Bisgaard et al AJRCCM 2004,Study Design PREVIA,Week,48,Visits,7,8,Placebo run-in,Placebo,Montelukast 4 mg (or 5 mg depending on age)*,Period I,Period II,36,1,2,3,4,5,6,24,16,8,0,-2,-3,*5 mg chewable tablet administered instead if patient turned 6 years of age during the study,Montelukast Significantly Reduced the Rate of Exacerbations,2.34,1.60,0,1,2,3,Montelukast 4 mg (n=265),Placebo (n=257),Exacerbation episode rate / year,32%,p0.001,Montelukast Reduced Exacerbations from Autumn Through to Spring,Patients with exacerbation episode (%),Winter,Spring,Summer,Autumn,Montelukast 4 mg,Placebo,66,What about safety of medications used for asthma in young children ?,67,Inhaled corticosteroids are safe for use in children 5 years of age and younger Yes No Unsure,68,I am concerned about use of ICS in children 5 years of age and younger because of Linear (height) growth Bone density Lung growth No concerns,69,Guilbert et al NEJM 2006,ICS and Linear Growth in Preschool Children The PEAK study,Linear growth Fluticasone Placebo P value 1-8 months Rx 6.6 cm 7.3 cm 0.005 4-12 months Rx 4.5 cm 4.9 cm 0.001 1-24 months Rx 12.6 cm 13.7 cm 0.001 1-36 months * 19.2 cm 19.9 cm 0.008 * No fluticasone 24-36 months,70,Murray et al Lancet 2006,The IFWIN study: OUTCOMES,Placebo FP only Pb+open FP FP+open FP (n=47) (n=51) (n=41) (n=34) Asthma + Rx 34% 45% 59%* 59%* FEV1 (L/s) 1.04 1.05 1.03 1.00 sRaw (post 2) 0.96 1.05 1.08 1.04* Height (Z score) 0.08 0.02 -0.10 -0.20*,*P0.05,71,The Linear Growth Study: LTRA vs ICS in Children,Montelukast Beclomethasone Placebo (n=120) (n=119) (n=121) Age (yrs) 7.5 0.7 7.5 0.8 7.7 0.8 Male (%) 60.8% 67.2% 65.3% Asthma Duration (yrs) 4.1 2.0 4.1 1.9 4.1 1.9,Linear Growth Study Becker et al Ann Allergy Asthma Immunol 2006,72,Growth in Children with Asthma,Linear Growth Study Becker et al Ann Allergy Asthma Immunol 2006,Osteocalcin BDP,73,LTRA vs ICS in Children,Montelukast Beclomethasone Placebo (n=120) (n=119) (n=121) Sx relief (%days) 10.5%* 6.7%* 14.6% Oral CS (%patients) 25.0% 23.5% 34.7% 2 or more courses 5.8%* 5.9%* 15.7% FEV1 change from baseline (L) 0.07 0.10 0.09,Linear Growth Study Becker et al Ann Allergy Asthma Immunol 2006,*p0.05,74,Asthma in the Young Child,Do we know how to treat? ICS or LTRA ?,75,Fluticasone vs Montelukast in Childhood Asthma: the CARE network study,Szefler et al JACI 2005,n=144, age 6-17 years,76,Fluticasone vs Montelukast in Childhood Asthma: the CARE network study,Szefler et al JACI 2005,6-17 yrs,55%,77,LTRA vs ICS in Children,CARE study (montelukast vs fluticasone) Age range 6-17 years Response to: Both FP only MTK only Neither Age (years) 10 (7, 13) 12 (10, 14) 9 (7, 9)* 12 (8, 14) Duration asthma 7 (5, 9) 9 (3, 11) 4 (1, 4)* 7 (5,10),Pre-empt :Predictors of Efficacy,Robertson et al AJRCCM 2007,79,LTRA vs ICS in Children,CARE study Age range 6-17 years Linear Growth Boys 6-8 years Girls 6-7 years Pre-Empt Age range 2-5 years,80,Education, Environmental control, Written action plan, and Follow-up,Fast-acting bronchodilator on demand,Very mild,Mild,Regularly assess: Control Triggers Compliance InhalerTechnique Co-morbidity,Modify maintenance therapy,Add-on therapy,Pred,Moderate,Moderately Severe,Severe,Low,Moderate,High,Asthma Guidelines for the Young Child,Montelukast in place of ICS?,81,Rx.Does it work ?,Initiate Rx as “n of one” trial Introduction of new treatment should be considered a therapeutic trial written action plan follow-up assessment 4-6 weeks,82,Inhaled Corticosteroids,Education, Environmental control, Written action plan, and Follow-up,Fast-acting bronchodilator on demand,Very mild,Mild,Regularly assess: Control Triggers Compliance InhalerTechnique Co-morbidity,Modify maintenance therapy,Add-on therapy,Pred,Moderate,Moderately Severe,Severe,Low,Moderate,High,83,FACET - Rate of Mild Exacerbations,Pauwels et al., NEJM, 1997,40,0,10,20,30,Exacerbations / patient / year,Pulmicort 100g bid,Pulmicort 100g bid + Oxeze 12g bid,Pulmicort 400g bid,Pulmicort 400g bid + Oxeze 12g bid,p0.001,p 0.001,p = 0.76,84,Add-on Therapy,LABAs are not recommended as maintenance mono-therapy in asthma After reassessment of compliance, control of environment and diagnosis, for patients not controlled on low dose ICS, modify Rx by addition of a LABA. Alternatively, addition of LTRAs or increasing ICS to moderate dose may be considered. Theophylline may be an option,Adult Recommendations,Adult Ast