Cynthia S. Kelly, M.D. Professor of Pediatrics Eastern Virginia Medical School Division Director Allergy Children s Hospital of The King s Daughters Disclosures Speakers bureau of Novartis and Genentech 1
Pediatric Asthma Update Review recent literature regarding management of preschool aged children with recurrent wheeze and asthma Discuss the potential for reduced lung growth and COPD in children with mild to moderate persistent asthma Outline new therapies on the horizon for severe asthma in children Recurrent Wheeze in Preschool Aged Children 50% of children experience wheezing illness during first 6 years of life Increased health care utilization for these toddlers compared to older children with asthma 50% greater rate of ambulatory visits Twice the number of ED visits 3x the number of hospitalizations 2
PEAK trial: Prevention of Early Asthma in Kids Question: Does the use of daily low dose ICS therapy in toddlers at high risk for asthma reduce the symptom burden after stopping ICS? Result: During the 2 years of ICS treatment toddlers had 1. Significantly more episode free days 2. Significantly fewer exacerbations requiring OCS But 3. The number of episode free days during the 3 rd year did not differ No disease modifying effects for early initiation of ICS! Guilbert, Morgan, Krawiec et al, 2004 AIMS: Acute Intervention Management Strategies Question: Does early use of either high dose ICS (1mg budesonide 2 x/day for 7 days) or montelukast (4 mg/d for 7 days) prevent significant exacerbations requiring OCS in preschool aged children with intermittent wheeze? Result: 1. No difference between the active groups and placebo for episode free days or exacerbations requiring OCS 2. Children in the treatment group with a positive mapi did have decreased symptom burden during URI. So it may be helpful in children who are more likely to develop persistent asthma Bacharier, Phillips, Zeiger, et al, 2011 3
MIST: Maintenance vs Intermittent Inhaled Steroids in Wheezing Toddlers Question: Is it better to treat high risk children with daily low dose ICS (budesonide 0.5 mg/d) or episodic high dose (budesonide 1 mg 2x/day for 7 days with onset of URI) to prevent need for OCS? Result: 1. No difference between the two groups in the frequency of exacerbation requiring OCS, symptom burden or other clinical outcome. 2. Daily ICS groups had significantly more ICS exposure than the intermittent group (150 mg vs 46 mg), but no difference in linear growth. So for motivated families intermittent use may be better! Zeiger, Manger, Bacharier et al 2011 Which Preschool Aged Child Is Most Likely to Respond to ICS? (Post hoc analysis) White males Prior ED visits or hospitalizations Higher frequency of symptoms during study run in period Allergic kids (positive skin tests or elevated IgE) Guilbert, et al, 2006 4
Which Preschool Aged Child is Most Likely to see an Impact on Linear Growth? Children <2 years of age and <15 kg had significantly less linear growth during the 2 years fluticasone treatment and 2 years after treatment was discontinued. Suggested 10 micrograms/kg/day of fluticasone as an upper limit for children 2 to 3 years of age to avoid growth suppression. Use lowest dose possible that provides clinical benefit; discontinue ICS in preschoolers who don t respond. Guilbert, et al 2007 INFANT: Individual Therapy for Persistent Asthma in Young Children Question: is there a difference between 3 different treatment approaches (daily ICS, LTRA, prn albuterol) on asthma symptom control and exacerbations in toddlers meeting Step 2 criteria (daily asthma controller therapy) AND If there is a differential response, can it be related to phenotypic features or clinical biomarkers? Fitzpatrick et al, 2016 5
Individualized Therapy for Asthma in Toddlers (INFANT) Probability of Best Response (INFANT) 6
Probability of Exacerbation Predictors of Differential Response (INFANT) 7
INFANT Trial Conclusions Daily low dose ICS is the most effective therapy for the majority of young children with asthma symptoms and recurrent wheezing episodes for whom step 2 therapy is warranted. Aeroallergen sensitization and eosinophil counts help identify children for whom ICS would be most beneficial Many participants did best with daily LTRA or asneeded ICS Declining Lung Function in Persistent Childhood Asthma Studied 684 children from CAMP (5 to 12 years with mild to moderate persistent asthma) into 3 rd decade of life to evaluate growth and decline in lung function 170 (25%) had normal patterns of lung growth without early decline 514 (75%) had abnormal growth pattern McGeachie, Yates, et al 2016 8
Lung function in persistent childhood asthma Factors Associated with Reduced Lung Growth Lower baseline FEV-1 Smaller bronchodilator response Airway hyperresponsiveness at baseline (methacholine challenge) Male sex 9
Conclusions about Reduced Lung Growth 52% of children (5 to 12 years of age) with mild to moderate persistent asthma have early lung function decline Early and serial FEV-1 measurements may help identify children at risk for abnormal lung function and COPD in the future. Whether there are interventions to modify the outcome is unknown Definition of Severe Asthma in Children Treatment with high dose ICS and either LABA or LTRA for the previous year OR Systemic corticosteriods for at least 50% of the previous year to prevent asthma from becoming uncontrolled OR Asthma that remains uncontrolled despite this therapy 10
Difficult to Treat vs Severe Asthma in Children Difficult to treat asthma includes Poor adherence to medications Improper inhaler technique Adverse environmental or psychological factors Comorbid conditions rhinosinusitis, VCD, obesity, OSA and GER Tiotropium Long acting anticholinergic approved for children >6 y/o given once daily Add on therapy for children and adults with moderate to severe asthma not controlled with high dose ICS and LABAs May work better in patients with higher cholinergic tone (lower resting heart rate), lower lung function and higher degree of bronchodilator reversibility 11
Approved and Pipeline Biologic Therapies Biologic therapy Omalizumab (6-12) Xolair Mepolizumab (>12) Nucala Reslizumab (>18) Cinqair Benralizumab Dupilumab Target Anti IgE Anti IL5 Anti IL5 Anti IL5 Anti IL4 Biologic Therapies for Asthma The best treatment option for an individual patients will need to include consideration of the patient s biomarkers, the target and mechanism of action for each of these agents Optimal treatment duration, approach to discontinuation, and ability or lack thereof to modify disease progression needs to be better characterized. 12
Conclusions Preschool children with episodic wheeze who are at high risk for asthma, but without daily symptoms, have improved clinical courses with ICS therapy, either daily low dose or intermittent high dose when given early during URI. ICS response in preschool children with episodic wheeze is heterogeneous. Children with atopy and greater disease burden may have greater benefit with ICS. Conclusions Although young children requiring daily asthma therapy are phenotypically diverse, those with aeroallergen sensitization and high eos counts respond best to ICS as opposed to LTRA or prn ICS 2 year old children < 15 kg may have greater growth effects from ICS. 10 micrograms/kg/d fluticasone recommended 13
Conclusions Biologic therapies call for a new paradigm of tailored therapy for asthma based on phenotype (age, gender, ethnicity), endotype (blood and sputum biomarkers) and genotype Thank You 14