3/6/2014 SURVEY SAYS A BREATH OF FRESH AIR? UPDATES IN PEDIATRIC ASTHMA AND BRONCHIOLITIS DISCLOSURES PEDIATRIC ASTHMA OBJECTIVES

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1 SURVEY SAYS My main area of practice is: A BREATH OF FRESH AIR? UPDATES IN PEDIATRIC ASTHMA AND BRONCHIOLITIS Hanna Phan, PharmD, BCPS Assistant Professor, College of Pharmacy and Medicine Residency Program Director, PGY2 Pediatric Pharmacy Clinical Pharmacy Specialist, Pediatric Pulmonology A. Ambulatory care/clinic B. Community C. Hospital/inpatient D. Other DISCLOSURES No potential conflicts of interest. Off label medication use may be discussed. PEDIATRIC ASTHMA Disney Pixar, Toy Story OBJECTIVES Describe the current status of pediatric asthma, specifically including proper medication administration and disease control. Identify patient factors that may justify the use of intermittent inhaled corticosteroids in children and adolescents with asthma. Examine current evidence for the treatment of bronchiolitis in children. EXPRESSION OF ASTHMA Environment Allergens Infections Microbes Pollutants Stress Genetics Immune Lung Repair Altered Innate and Adaptive Immune Response Lower Airway Targeting Lower resp illness RSV/parainfluenza virus Adenovirus Chlamydia Mycoplasma Persistent wheezing and asthma NHLBI: section 2; 2007 Nelson Textbook of Pediatrics 1

2 PEDIATRIC ASTHMA SCARY BUT SOMETIMES TRUE Copyright image. Figure cited below. g Accessed 2/15/14. IMPACT OF ASTHMA ON KIDS RULE #1 OF DRUG THERAPY 3 rd leading cause of hospitalization Over 1/3 of children with special health care needs have asthma 10.5 million missed school days a year (1 in 2 children miss at least 1 day/year) 1 in 11 children have asthma! (7 million in total) ED visits for kids vs. adults: 9.9 vs. 6.5 per 100 persons Poor adherence to asthma medications is reported to be 60% or greater. Less than 1 in 2 children get an asthma action plan! Drugs don t work in patients who don t take them. C. Everett Koop, MD In the average pediatrician office, less than 25% of children can properly use an inhalation device. Less than 50% of controller asthma medications are refilled within 1 year of initial fill. Some patients and parents/caregivers are not aware of counters on inhalers. CDC Asthma FactSheet CDC Asthma FactSheet Bender et al. Curr Opin Allergy Clin Immunol. 2004;4: Bender et al. Immunol Allergy Clin North Am. 2005; 25(1): Bender et al. J Allergy Clin Immunol. 2003;112(3): Kuhlthau et al. Acad Pediatr Mar-Apr;11(2): Vaidya et al. Patient Prefer Adherence. 2013;7:21-6. SURVEY SAYS I review demonstrate proper inhaler technique with my patients (1 st fill and refill): A. 100% of the time, always! B. >80 % of the time C % of the time D. Less than 50% of the time THE HOW OF THERAPY IS IMPORTANT Example: asthma device technique (all steps correct) 296 children, ages 8-16 years Majority moderate/severe asthmatics Pediatric clinics Device % patients ALL steps correct Meter dose inhaler (N=270) 8.1 Diskus (N=105) 21.9 Turbuhaler (N=45) 15.6 Peak flow (N=67) 23.9 Sleath B et al. Pediatrics 2011;127:

3 ASTHMA GUIDELINES ASSESSING SEVERITY WHEN INITIATING THERAPY (12+ YR)] NHLBI Expert Panel 3 National Heart, Lung, and Blood Institute (NHLBI) 2007 and Global Initiative for Asthma (GINA) 2011 Both developed in 1993 and contain pediatric specific data NHLBI worked with the World Health Organization (WHO) to develop guidelines to manage and control asthma to prevent disability GINA developed to disseminate asthma information among professionals throughout the world 2005, developed evidence-based guidelines to ensure appropriate asthma treatment ASSESSING SEVERITY WHEN INITIATING THERAPY (0-4 YR) ASSESSING ASTHMA CONTROL Rule of two s Symptoms less than 2x/week Night time awakenings less then 2x/month Use of rescue inhaler (albuterol/salbutamol) less than 2 days/week Use of urgent care/emergency department of asthma Rx for corticosteroids Admissions? Changes in daily routine? Lung function Spirometry Peak flow ASSESSING SEVERITY WHEN INITIATING THERAPY (5-11 YR)] ASSESSING ASTHMA CONTROL. WHEN ADJUSTING THERAPY (0-4 YR) 3

4 ASSESSING ASTHMA CONTROL. WHEN ADJUSTING THERAPY (5-11 YR) CONTROLLER THERAPY OPTIONS: 0-4 YEARS OF AGE ASSESSING ASTHMA CONTROL. WHEN ADJUSTING THERAPY (12+ YR) CONTROLLER THERAPY OPTIONS: 5-11 YEARS OF AGE OUR ASTHMA ARSENAL SHORT ACTING BETA AGONISTS INHALED CORTICOSTEROIDS (ICS) LEUKOTRIENE RECEPTOR ANTAGONISTS CONTROLLER THERAPY OPTIONS: 12 YEARS & OLDER ICS + LONG ACTING BETA AGONIST OMALIZUMAB THEOPHYLLINE CDC Asthma FactSheet Bender et al. Curr Opin Allergy Clin Immunol. 2004;4: Bender et al. Immunol Allergy Clin North Am. 2005; 25(1): Bender et al. J Allergy Clin Immunol. 2003;112(3): Kuhlthau et al. Acad Pediatr Mar-Apr;11(2): Vaidya et al. Patient Prefer Adherence. 2013;7:

5 SURVEY SAYS THE ADULT DATA Intermittent corticosteroid use may be most appropriate for which of the following patients? A. A 2 year old with moderate persistent asthma who has an exacerbation approximately each year and whose triggers are smoke and pet dander. B. A 5 year old with mild persistent asthma who has not had an exacerbation in the last two years, symptoms are triggered by pollen, cold weather, and pet dander. C. An 11 year old with mild persistent asthma who has had one exacerbation every few years, mostly virally induced. D. A 15 year old with severe persistent asthma who has 2-3 viral induced exacerbations per year Design x duration (ICS choice, N) Asthma Severity Intervention Groups Secondary BASALT (2012) Randomized, parallel, 3-group, placebo controlled, multiply-blinded x 36 wk (beclomethasone, N=342) yr Mild to moderate persistent 3 groups: C=ICS+placebo, R=albuterol+placebo (physician assessment based adjusted) C=ICS+placebo, R=albuterol+placebo (biomarker based adjustment C=placebo+placebo, R=ICS+albuterol (symptom based adjustment) Time to treatment failure Asthma exacerbation rates, lung function, cumulative ICS dosage, biomarkers, missed school/work days C=control, R=rescue Calhoun et al. JAMA 2012;308(10): A NEW FRONTIER: SYMPTOM- BASED CONTROLLER THERAPY Current guidelines one size fits all 1 st step to manage individual patients Mild persistent asthma (60-70%) daily ICS recommended Food for thought Challenges with adherence Real world use sparingly or self-discontinuation For well-controlled no established maintenance treatment period or point weaning should considered What about patients who have viral-induced trigger? ICS as rescue with/without daily ICS? ICS as rescue to help reduce systemic steroid use Current debate: maintenance vs. intermittent ICS PREVIOUS PEDS DATA Design x duration (ICS choice, N) TURPEINEN ET AL (2008) Controlled, randomized, double blind, parallel x 72 wk (budesonide, N=176) PAPI ET AL (BEST for Children 2009) Double bling, double dummy, randomized, parallel x 12 wk (beclomethasone, N=267) 5-10 yr 1-4 yr Asthma Severity No formal asthma definition. Symptoms (i.e., wheezing, prolonged cough or shortness of breath), suggesting asthma for at least 1 month before entry into the study, and significant bronchial reversibility. No formal asthma definition. Documented history of at least three episodes of wheezing requiring medical attention in the previous 6 months. Intervention Groups Primary Outcome Secondary C=control, R=rescue 3 groups: C=ICS (taper down dose), R=albuterol C=ICS for 6 months, then ICS for R C=Disodium cromoglycate, R=ICS Morning peak expiratory flow FEV1, asthma exacerbations, asthma free days, rescue medication use 3 groups: C=ICS, R=salbutamol C=placebo, R=ICS+salbutamol C=placebo, R=salbutamol % symptom free days Asthma symptoms, relief med use, frequency/# exacerbations Turpienen et al. Ach Dis Child 2008;93: Papi et al. Allergy 2009;64: THE ADULT DATA TREXA TRIAL (2011) Design x duration (ICS choice, N) IMPACT (2005) BEST (2007) Double blind randomized x 54 wk (budesonide, N=199) Double blind, double dummy, randomized x 24 wk (beclomethasone, N=393) y 18-65y Asthma Severity Mild persistent Mild persistent Intervention Groups Secondary 3 groups: C=placebo+ICS, R=ICS C=zarfirlukast+placebo (inhaled), R=ICS C=placebo (PO/inhaled), R=ICS Change in AM peak expiratory flow (pre-post trial) # symptom-free days, discomfort/impairment 4 groups: C=ICS+albuterol, R=albuterol C=ICS, R=albuterol C=placebo, R=ICS+albuterol C=placebo, R=albuterol Mean rate of AM peak expiratory flow in last 2 weeks trial Symptom score, #/severity exacerbations Design x duration (ICS choice, N) Asthma Severity Intervention Groups Secondary Randomized, double blind, placebo-controlled x 44wk (beclomethasone, N=288) 5-18 yr Mild persistent 4 groups Combined - C=ICS, R=ICS+albuterol Daily - C=ICS+placebo, R=albuterol Rescue - C=placebo, R=ICS+albuterol Placebo - C=placeo, R=albuterol Time to 1 st exacerbation requiring prednisone Linear growth, frequency treatment failure, frequency of exacerbations C=control, R=rescue Boushey et al. N Engl J Med 2007; 118: Papi et al. N Engl J Med 2007; 356: C=control, R=rescue Martinez FD et al. Lancet 2011; 19:377(9776):

6 TREXA TRIAL: RESULTS MIST TRIAL: RESULTS Copyright image. Figure 2, cited article below. Copyright image. Figure 2, cited article below. Martinez FD et al. Lancet 2011; 19:377(9776): Zieger et al. N Engl J Med 2011; 365: TREXA TRIAL: RESULTS Primary Secondary Time to 1 st exacerbation Difference between Combo vs. placebo (p=0.033) and Daily vs. placebo (p=0.011), but not Rescue vs. placebo (p=0.073) Linear growth less growth in Daily and Combo (1.1 cm); no difference between Rescue and Placebo Frequency treatment failure 23% Placebo, 5.6% Combo, 2.8% Daily, 8.5% Rescue Frequency of exacerbations 49% Placebo, 31% Combo, 28% Daily, 35% Rescue Conclusions: Should not use albuterol alone, ICS is most effective. ICS rescue may be effective step-down for well-controlled, mild asthma, more effective than rescue albuterol alone. Rescue ICS may help reduce risk of adverse effects of growth impairment from daily ICS MIST TRIAL: RESULTS Copyright image. Figure 3, cited article below. Martinez FD et al. Lancet 2011; 19:377(9776): Zieger et al. N Engl J Med 2011; 365: MIST TRIAL (2011) MIST TRIAL: RESULTS Design x duration (ICS choice, N) Asthma Severity Intervention Groups Secondary Double blind, placebo controlled, parallel x 52 wk (budesonide, N=213) months Recurrent wheezing and positive modified asthma predictive index (API) score 2 groups: C=ICS (low dose PM); R=albuterol+placebo (AM), ICS (low dose) x 7 days for RTI C=placebo; R=albuterol+ICS (high dose) BID x7 days for RTI Frequency of exacerbations Types of symptoms, episode-free days, frequency/distribution of respiratory viruses in nasal secretions, exposure to ICS Primary Secondary Frequency of exacerbations -- no difference between groups (p=0.6) Types of symptoms no difference Episode-free days no difference Frequency/distribution of respiratory viruses in nasal secretions no difference Exposure to ICS less in intermittent ICS group (45.7mg vs 149.9mg) Conclusions: Daily low dose ICS not superior to intermittent high dose ICS in reducing exacerbations Daily administration resulted in greater ICS exposure C=control, R=rescue, RTI=respiratory tract infection Zieger et al. N Engl J Med 2011; 365: Zieger et al. N Engl J Med 2011; 365: REFS 6

7 CURRENT LIMITATIONS IN PEDS DATA Lack of defined asthma for some studies High % not randomized Sub-additive interaction between treatments Changed analysis decreased power Rescue vs. anticipated exacerbation therapy Expectation of caregiver health literacy Recognition of when to start regimen for respiratory tract illness SURVEY SAYS Which of the following is a likely advantage of dexamethasone to prednisolone for treatment of pediatric asthma exacerbations? A. Palatability B. Duration of therapy C. Cost D. Available routes of administration 2013 COCHRANE REVIEW Six trials included 4 pediatric, 2 adult Randomized control trials comparing intermittent ICS vs. daily ICS No other interventions other than rescue inhaler and oral corticosteroids permitted Conclusions Low quality evidence Similar effective in use of rescue oral steroids and rate of adverse events Cannot assume equivalence Daily ICS superior for: lung function, airway inflammation, asthma control, and reliever use but modest growth suppression Should weight risk vs. benefit in determining patient regimen PRED VS. DEX? Asthma exacerbations in children are most commonly treated with either: Prednisone (PO) Prednisolone (PO) Dexamethasone (PO, IM) Duration 1-5 days Prednisone/prednisolone usually 3-5 days Dexamethasone is usually 1-2 doses Dexamethasone possible advantages? Adherence (less doses) Less nausea/vomiting Chauhan et al. Cochrane Database Syst Rev Feb 28;2:CD RECOMMENDATION BY CLINICIANS? Not evidence based Stabilize asthma Oral prednisone x 3-5 days and SABA (up to q4h) Maintenance ICS bid x 6-8 weeks + SABA bid x 2 weeks May stop early if no asthma sign/symptoms x2 weeks Restart regimen if symptoms recur HOT OFF THE PRESS! Meta-analysis of 6 randomized controlled studies Children 18 yr, emergency room setting Purpose: determine whether dexamethasone is equivalent or superior to a 5-day course of prednisone or prednisolone Dexamethasone dosing: mg/kg/dose x1-2 Prednisone/prednisolone dosing: 1-2 mg/kg/day x 3-5 days Findings No difference in risk for relapse Dex patients less likely to experience vomiting in ED or at home Conclusion: Consider dex (1-2 dose) as alternative to prednisone/prednisolone SABA=short acting beta agonist Naspitz and Cropp. Pediatr Pulmonol 2009;44: Keeney at al. Pediatrics 2014; 133:

8 TAKE HOME MESSAGES Intermittent ICS use in the management of pediatric asthma is not a common practice yet Patients who may be considered for this approach Mild persistent asthma, well-controlled Viral-illness induced trigger Good health literacy, regular follow up with clinicians Dexamethasone may be a good option for treatment exacerbation Less doses, less nausea/vomiting WHEEZY BUT NOT EASY Bronchodilators: Not routine use, trial OK Ribavirin: No routine use Systemic steroids: No routine use Hydration: Should be maintained and provided, oral preferred. Inhaled corticosteroids: No routine use, no acute benefit long term? Antimicrobials: Only in coexistence of co infection Hypertonic saline (HTS): No mention in 2006 rec s Pediatrics 2006; 118: COCHRANE REVIEWS BRONCHIOLITIS THERAPY (YR) BRONCHODILATOR (2010) DORNASE ALFA (2012) SURFACTANT THEARPY (2012) INHALED OR SYSTEMIC STEROID (2013) HYPERTONIC SALINE (2013) EVIDENCE REVIEWED FINDINGS & RECOMMENDATION 28 RCTs; infants Does not improve oxygen saturation, LOS, time to resolution of illness; small improvements in clinical score. Recommend cost/ades vs. benefits. 3 RCTs; <24 mo No benefit seen in LOS, clinical score, supplemental O 2, ICU admission. Does not support use for acute bronchiolitis. 3 RCTs; infants/children requiring MV 17 RCTs; <24 mo No difference in MV duration; ICU LOS less with surfactant; favorable effect on oxygenation, CO 2 elimination with surfactant. Insufficient evidence to establish effectiveness. Current evidence does not support a clinically relevant effect of systemic or inhaled glucocorticoids on admissions or LOS. Possible reduction in outpatient admission with dex/epi combination, but limited data. 11 RCTs, quasi- Nebulized 3% sodium chloride may help reduce LOS, RCTs; up to 24 improve clinical severity score mo; inpatient/outpatie nt Disney Pixar, Toy Story RCT=randomized controlled trial, MV=mechanical ventilation, LOS=length of stay Cochrane Database Syst Rev Dec 8;(12):CD Cochrane Database Syst Rev Nov 14;11:CD Cochrane Database Syst Rev Sep 12;9:CD Cochrane Database Syst Rev Jul 31;7:CD Cochrane Database Syst Rev Jun 4;6:CD LIL WHEEZERS SURVEY SAYS Most common cause: respiratory syncytial virus (RSV) 125,000+ hospitalizations per year in age <1 yr Greatest risk for complications Premature, immunospressed AAP guidelines Released in 2006 Newer data since Which of the following patient factors is least likely associated with improved time to discharge when using dexamethasone for treatment of bronchiolitis? A. Current use of a bronchodilator B. Concurrent eczema C. Family history of asthma in a 1 st degree relative D. Accessed 2/16/14. 8

9 SYSTEMIC STEROIDS? Design (drug, N) Criteria Intervention Groups Double blind, placebo controlled (Dexamethasone 1mg/kg x1, then 0.6mg/kg x 5 days PO+ epinephrine 3mL of 1:1000 nebulized, N=800) 6-12 months; in emergency department Bronchiolitis; score of 4 to 15 on the respiratory distress assessment index (RDAI) 4 groups: Neb epi + PO dex Neb epi + PO placebo Neb placebo + PO dex Neb placebo + PO placebo Hospital admission up to 7d after enrollment Secondary Change in heart and respiratory rate, RDAI score, and oxygen saturation from baseline to 30, 60, 120, and 240 minutes, length and severity of symptoms, time to discharge ALANSARI ET AL - RESULTS OUTCOME DEXAMETHASONE PLACEBO MEAN TIME TO READINESS 18.6 h ( )* 21.7 h ( )* FOR DISCHARGE % READY FOR DISCHARGE 12 h 18 h 24 h 36 h 48 h # PATIENTS NEEDED NEBULIZED EPINEPHRINE # PATIENTS NEEDING HOSPTIAL ADMISSION WITHIN 1 WEEK # PATIENTS NEEDED URGENT CARE WITHIN 1 WEEK # PATIENTS NEEDED CLINIC VISIT WITHIN 1 WEEK 48.0 ( )* 54.0 ( )* 65.0 ( )* 77.0 ( )* 82.0 ( )* 36.6 ( )* 36.6 ( )* 50.0 ( )* 57.7 ( )* 68.8 ( )* Plint et al. N Engl J Med 2009;360: *95% CI **N Alansari et al. Pediatrics 2013; 132:e PLINT ET AL PRIMARY OUTCOME Copyright image. Figure 3, cited article below. EVIDENCE WORTH ITS WEIGHT IN SALT? Updated meta-analysis (2014) 11 RCTs or quasi RCTs s 24 months in outpatient/inpatient/ed settings 3% and 5% sodium chloride nebulized, various intervals OUTCOME RATE OF HOSPITALIZATION (5 studies) RATE OF READMISSION (3 studies) CLINICAL SEVERITY SCORE (8 studies) FINDINGS & RECOMMENDATIONS HTS beneficial effect on reducing rate of hospitalization vs. control (RR 0.59; 95%CI= ; p=0.02) No significant difference in rate of readmission (RR 1.08; 95%CI= ; p=0.74) 1 st, 2 nd, 3 rd day of treatment significantly lower CS score post-inhalation (p<0.001) Plint et al. N Engl J Med 2009;360: RR=risk ratio Chen et al. Pediatr Neonatol Jan 21. pii: S (13) doi: /j.pedneo [Epub ahead of print] SYSTEMIC STEROIDS? HOT OFF THE PRESS! Design (drug, N) Criteria Intervention Groups Secondary Double blind, placebo controlled (Dexamethasone 1mg/kgx1, then 0.6mg/kg x4 day, N=190) 18 months Moderate-severe bronchiolitis w/ positive history of eczema or known parent or full sibling with asthma 2 groups: Dexamethasone + salbutamol Placebo + salbutamol Time to physician determined discharge Proportion of patients ready for discharge at 12, 18, 24, 36, 48 hours; need for nebulized epinephrine; hospital admission within 1 week after discharge; need for follow up care within 1 week after discharge Design (drug, N) Criteria Intervention Groups Secondary Double bling, randomized, comparative controlled (7% sodium chloride 3mL nebulized/2.25% racemic epinephrine 0.5mL nebulized, N=101) 6 weeks to 18 months Bronchiolitis (viral respiratory illness, 1 st episode) 2 groups: 7% sodium chloride 3mL nebulized/2.25% racemic epinephrine 0.5mL nebulized 0.9% sodium chloride 3mL nebulized/2.25% racemic epinephrine 0.5mL nebulized Bronchiolitis severity score (BSS), pre-, post-, discharge Hospitalization rate, proportion of admitted patients discharged at 23 h, ED and inpatient length of stay Alansari et al. Pediatrics 2013; 132:e Jacobs et al. Pediatrics 2014; 133:e

10 JACOBS ET AL - RESULTS OUTCOME 7% NaCl 0.9% NaCl P-VALUE CHANGE IN BSS AT ED 2.6± ± DISPOSITION CHANGE IN BSS AFTER 1 ST NEBULIZER TREATMENT CHANGE IN BSS FOR ADMITTED PATIENTS AT 24 HR LENGTH OF STAY: ED (HOURS) PROPORTION PATIENTS ADMITTED PROPORTION PATIENT DISCHARGED AT 24 HR 2.06± ± ± ± ± ± /52 (42%) 24/49 (49%) OR = 0.76 ( ) 3/21 (14%) 3/23 (13%) OR = 1.1 ( ) *MEAN ± SD Jacobs et al. Pediatrics 2014; 133:e8-13. TAKE HOME MESSAGES Evidence for various treatment options for bronchiolitis is lacking. Systemic steroids, like dexamethasone, should not be used routinely, but may considered in a sub-population of patients (data limited). Hypertonic saline has not demonstrated much benefit compared to normal saline. Additional studies with regards to impact on hospitalization and utility of clinical severity score are needed. QUESTIONS? hphan@pharmacy.arizona.edu 10