Management of Preschool Recurrent Wheezing and Asthma: A Phenotype-Based Approach

Transcription

1 Maagemet of Preschool Recurret Wheezig ad Asthma: A Pheotype-Based Approach Leoard B. Bacharier, MD Robert C. Struk Edowed Chair for Lug ad Respiratory Research Professor of Pediatrics & Medicie Cliical Director, Divisio of Allergy, Immuology, & Pulmoary Medicie Uit Leader Patiet Orieted Research Uit

2 Disclosures Employmet Washigto Uiversity Fiacial Iterests Cosultat: DBV, Merck, Novartis, Teva, Regeero/Saofi, Vectura, Circassia Hooraria/Speakers Bureau: GSK, Teva AstraZeeca, Novartis, Boehriger Igelheim Research Support: Vectura, Saofi/Regeero Research Iterests NIH NHLBI, NIAID Orgaizatioal Iterests Gifts AAAAI Aual Meetig Plaig Committee ABAI Director JACI Associate Editor GINA Sciece Committee Nothig to Disclose Other Iterests Nothig to Disclose

3 Learig Objectives Describe the heterogeeity i the developmet & presetatio of asthma i preschool childre Outlie optimal itervetio strategies for preschool childre with Mild persistet asthma Severe episodic wheezig Develop strategies for pheotype directed therapy i preschool childre

4 Patters of Early Childhood Wheezig Patter of Wheeze Durig 1 st 6 Years 0-3 Years 4-6 Years % of Cohort Relative Risk of Wheeze at 16 years Never Wheeze 51% 1.0 Trasiet Early Wheeze 20% 1.3 Late-Oset Wheeze 15% 3.1* Persistet Wheeze 14% 3.8* * p<0.001 compared with ever wheezers Tucso Childre s Respiratory Study Martiez FD et al NEJM 1995;332:133 Morga WJ et al AJRCCM 2005;172:1253

5 Estimated Prevalece of Wheezig Idetified by Latet Class Aalysis ALSPAC logitudial birth cohort of 6265 childre Idetified six wheezig pheotypes Four pheotypes very similar to Tucso study Two additioal subpheotypes idetified: itermediate ad prologed early All wheezig pheotypes were associated with physicia-diagosed asthma, lower lug fuctio, ad greater AHR by 8-9 years compared to ever/ifrequet wheeze pheotype Hederso, J et al. Thorax 2008;63:974-80

6 Modified Asthma Predictive Idex (mapi) Idetifies High Risk Childre Ages 2-3 Years 4 wheezig episodes i the past year (at least oe must be MD diagosed) PLUS Oe major criterio ØParet with MD asthma ØMD atopic dermatitis ØAeroallerge sesitivity OR Two mior criteria ØFood sesitivity ØPeripheral eosiophilia (³4%) ØWheezig ot related to ifectio Modified from Castro-Rodriguez JA et al. Am J Respir Crit Care Med 2000;162:1403-6

7 Asthma Predictive Idex (API) Active Asthma OR (95% CI) Positive Predictive Value (%) Negative Predictive Value (%) At Yr ( ) 47.5% 91.6% At Yr ( ) 51.5% 84.2% Castro-Rodriguez JA et al Am J Respir Crit Care Med 2000;162:1403-6

8 Maagig Asthma amog Preschool Childre is Challegig A heterogeeous disorder with may pheotypic ad variable expressios durig early childhood Cross-over betwee pheotypes Compared to older school-age childre: potetial differeces i disease pathophysiology ad i the type of backgroud airway iflammatio Selectio of asthma therapy is complicated by Lack of objective measuremets ad biomarkers May of guidelie recommedatios are based o extrapolatio of fidigs from school-age childre

9 Patiet #1 3 y/o male with history of asthma for the past year Albuterol used for rescue 3 days/wk Over the past yr 2 ED visits for exacerbatios Meds: albuterol PRN, predisoloe durig exacerbatios (4x i past yr) Past Medical History: eczema sice 4m/o Family History: mother has asthma PE: ormal exam; Ski testig + for cat Questio: Is daily treatmet with a asthma cotroller idicated? If so, which oe?

10 Stepwise Approach Pharmacotherapy (childre 5 years) STEP 4 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Daily low dose ICS STEP 3 Double low dose ICS Cotiue cotroller & refer for specialist assessmet Other cotroller optios Leukotriee receptor atagoist (LTRA) Itermittet ICS Low dose ICS + LTRA Add LTRA Ic. ICS frequecy Add itermitt ICS RELIEVER As-eeded short-actig beta 2 -agoist (all childre) CONSIDER THIS STEP FOR CHILDREN WITH: Ifrequet viral wheezig ad o or few iterval symptoms Symptom patter cosistet with asthma ad asthma symptoms ot well-cotrolled, or 3 exacerbatios per year Symptom patter ot cosistet with asthma but wheezig episodes occur frequetly, e.g. every 6 8 weeks. Give diagostic trial for 3 moths. Asthma diagosis, ad ot well-cotrolled o low dose ICS First check diagosis, ihaler skills, adherece, exposures Not wellcotrolled o double ICS

11 Stepwise Approach Pharmacotherapy (childre 5 years) PREFERRED CONTROLLER CHOICE Other cotroller optios RELIEVER CONSIDER THIS STEP FOR CHILDREN WITH: Ope questios regardig optimal Step 2 therapy amog preschool childre: Evidece A for daily ihaled corticosteroids STEP 3 STEP 1 STEP 2 Ifrequet viral wheezig ad o or few iterval symptoms (ICS), but: Leukotriee receptor atagoist (LTRA) Itermittet ICS As-eeded short-actig beta 2 -agoist (all childre) Symptom patter ot cosistet with asthma but wheezig episodes occur frequetly, e.g. every 6 8 weeks. Give diagostic trial for 3 moths. Double low dose ICS Is daily Daily low-dose ICS better tha daily motelukast? Low dose ICS + LTRA No radomized, double-blid trials i preschool childre What Symptom is patter the cosistet role with of asthma as-eeded ad asthma symptoms ot well-cotrolled, or ICS+albuterol? 3 exacerbatios per year Asthma diagosis, ad ot well-cotrolled o low dose ICS Is there a BEST choice for Step 2 asthma care? If so, for which patiets? STEP 4 Cotiue cotroller & refer for specialist assessmet Add LTRA Ic. ICS frequecy Add itermitt ICS Not wellcotrolled o double ICS First check diagosis, ihaler skills, adherece, exposures

12 Idividualized Therapy For Asthma i Toddlers (INFANT) 300 childre mo ecessitatig treatmet with Step 2 cotroller Ru-I (2-8 weeks) Placebo or Active Therapy Daily ICS Placebo LTRA As eeded placebo ICS Placebo ICS Daily LTRA As eeded placebo ICS Placebo ICS Placebo LTRA As eeded active ICS 16 weeks 16 weeks 16 weeks Blood ad urie sample collectio for predictor aalyses Ihaled fluticasoe (44 mcg/actuatio) 2 ihalatios twice daily Oral motelukast (4 mg) oce daily HS As-eeded albuterol plus ihaled fluticasoe (44 mcg/actuatio) 2 ihalatios for every 2 ihalatios albuterol Fitzpatrick AM et al. J Allergy Cli Immuol 2016:138;

13 Primary Outcome: Differetial Respose Differetial respose was a hierarchical composite variable of asthma cotrol based o (i order of importace): Risk domai Time from the start of the treatmet period to a asthma exacerbatio that requires systemic corticosteroids Impairmet domai Aualized umber of Asthma Cotrol Days withi that treatmet period Fitzpatrick AM et al. J Allergy Cli Immuol 2016:138;

14 Primary Outcome Aalysis Pla: 3 Stages Each child was idetified as a differetial respoder if: Time to a exacerbatio was at least 4 weeks loger Number of aualized asthma cotrol days was at least 31 days more Rak order of the treatmets from best to worst was determied for each differetial treatmet respoder Amog differetial treatmet respoders, assessed 3 pre-specified primary predictors of differetial respose: Allergic sesitizatio, sex, previous exacerbatio Fitzpatrick AM et al. J Allergy Cli Immuol 2016:138;

15 Which Step 2 Asthma Therapy is BEST for the Greatest Number of Childre? A. p < Hierarchical composite variable of time to exacerbatios ad umber of asthma cotrol days Differetial respose betwee at least two treatmets was observed i 74% (170 of 230) of childre who provided usable data for aalysis B. Probability of best respose Asthma Cotrol Days (%) No-differetial respoders N = 60 Differetial respoders N = % of childre (60 of 230) did ot have a differetial respose C. Cumulative exacerbatio probability No-differetial respoders N = 60 Differetial respoders N = 170 Fitzpatrick AM et al. J Allergy Cli Immuol 2016:138;

16 A. Probability of best respose C. Probability of best respose E. Probability of best respose Not aeroallerge sesitized (N = 130) Female (N = 87) Not sesitized ad eosiophils <300/μL (N = 87) Aeroallerge sesitized (N = 100) Male (N = 143) p = p = Not sesitized ad eosiophils 300/μL (N = 28) B. Probability of best respose D. Probability of best respose Sesitized ad eosiophils <300/μL (N = 26) No exacerbatio i 12 moths (N = 57) Blood eosiophils <300/μL (N = 113) Sesitized ad eosiophils 300/μL (N = 64) p = exacerbatio i 12 moths (N = 173) p = Blood eosiophils 300/μL (N = 92) p = Are there baselie characteristics that predict which treatmet will produce the best respose (for the greatest umber of childre)? Aeroallerge sesitizatio & blood eosiophils 300/µL (but ot exacerbatio history or sex) associated with differetial respose favorig daily ICS Fitzpatrick AM et al. J Allergy Cli Immuol 2016:138;

17 A. No-differetial respoders (N = 60) Not aeroallerge sesitized (N = 91) Aeroallerge sesitized (N = 79) Cumulative exacerbatio probability I childre with aeroallerge No-differetial Blood Blood eosiophils B. respoders (N = 60) eosiophils 300/μL (N = 71) <300/μL (N = 82) sesitizatio or eosiophilia: start with Cumulative exacerbatio probability ICS first. I childre who are ot sesitized to aeroallerges No-differetial Not or sesitized without Not sesitized Sesitized ad eosiophilia: Sesitized ad C. respoders ad eosiophils ad eosiophils eosiophils eosiophils (N = 60) <300/μL (N = 61) 300/μL (N = 19) <300/μL (N = 21) 300/μL (N = 52) ca choose ay of these treatmets. Cumulative exacerbatio probability Fitzpatrick AM et al. J Allergy Cli Immuol 2016:138;

18 Severe Itermittet (Episodic) Wheezig Pheotype Itermittet disease is commo Acute exacerbatios of lower respiratory tract illesses (LRTI) usually triggered by viral URIs May childre have miimal (or o) symptoms betwee these acute episodes Disease severity is NOT mild Severe morbidity durig acute episodes 50% more ambulatory visits, ~2x ED visits, ad ~3x hospitalizatio relative to school age childre 1 1 Akibami L. Adv Data 2006: 12;1-24.

19 Patiet #2 3 y/o boy with 3 episodes of wheezig i the cotext of URIs i the past year. He has had miimal/o respiratory symptoms betwee these illesses. Oe ED visit over the past year Meds: albuterol PRN, predisoloe durig sigificat exacerbatios (3 courses over the past year) PMH: eczema sice 4 m/o FH: mother has asthma PE: ormal exam; ski tests are egative Questio: Should we recommed daily treatmet with ICS?

20 Pheotype: Positive Asthma Predictive Idex

21 Modified Asthma Predictive Idex (mapi) Idetifies High Risk Childre Ages 2-3 Years 4 wheezig episodes i the past year (at least oe must be MD diagosed) PLUS Oe major criterio ØParet with MD asthma ØMD atopic dermatitis ØAeroallerge sesitivity OR Two mior criteria Ø Food sesitivity Ø Peripheral eosiophilia (³4%) Ø Wheezig ot related to ifectio Modified from Castro-Rodriguez JA et al. Am J Respir Crit Care Med 2000;162:1403-6

22 Asthma Predictive Idex (API) Active Asthma OR (95% CI) Positive Predictive Value (%) Negative Predictive Value (%) At Yr ( ) 47.5% 91.6% At Yr ( ) 51.5% 84.2% Castro-Rodriguez JA et al Am J Respir Crit Care Med 2000;162:1403-6

23 PEAK Screeig/ Eligibility Treatmet Phase: Exacerbatios (57.4/100 child-yrs vs 89.4/100 child-yrs) Supplemetal medicatios (ICS ad LTRA) = brochodilator use ad uscheduled visits Ru-i 1 moth Treatmet FP 88mcg BID or Placebo Observatio Years 1 & 2 Year 3 Observatio Phase: = Exacerbatios = Supplemetal medicatios (ICS ad LTRA) = Brochodilator use ad uscheduled visits EFD: No cough or wheeze, uscheduled cliic, urget care, ED or hospital visits; o use of asthma medicatios Guilbert TW et al. NEJM 2006;354:

24 PEAK - Heterogeeity of ICS Respose Withi the mapi+ Populatio Stratifyig Variable ICS Mea (95% CI) Percetage of Episode-Free Days Placebo Mea (95% CI) Differece (95% CI) P-value (ICS vs Placebo) Male 93 (92, 95) 86 (83, 89) 7.3 (3.9, 11.1) Female 92 (89, 94) 92 (89, 94) 0.1 (-3.4, 3.5) 0.9 Caucasia 93 (91, 95) 84 (80, 88) 9.1 (4.8, 13.9) No-Caucasia 92 (89, 94) 93 (91, 94) -1.0 (-3.9, 1.7) 0.6 Ru-I EFD <80% 92 (90, 94) 84 (79, 87) 8.6 (4.2, 13.2) Ru-I EFD 80% 93 (91, 95) 93 (91, 95) 0.0 (-2.5, 2.5) 0.9 ED/Hospitalizatio History 95 (93, 96) 87 (83, 90) 7.7 (3.9, No ED/Hospitalizatio History 90 (87, 92) 91 (89, 93) -1.1 (-4.4, 2.1) Positive Aeroallerge Ski Test Negative Aeroallerge Ski Test 93 (91, 94) 86 (83, 89) 6.5 (3.2, 10.0) (90, 95) 92 (89, 94) 0.9 (-2.5, 4.4) 0.6 Bacharier LB et al. J Allergy Cli Immuol 2009:123:

25 PEAK - Heterogeeity of ICS Respose Withi the mapi+ Populatio Stratifyig Variable ICS Mea (95% CI) Number of Predisoloe Bursts Placebo Mea (95% CI) Relative Rate (95% CI) P-value (ICS vs Placebo) Male 1.1 (0.9, 1.4) 1.8 (1.5, 2.2) 0.6 (0.5, 0.8) Female 1.6 (1.2, 1.9) 1.4 (1.1, 1.7) 1.2 (0.8, 1.6) 0.4 Caucasia 1.4 (1.1, 1.7) 2.2 (1.9, 2.7) 0.6 (0.5, 0.8) No-Caucasia 1.3 (1.0, 1.6) 1.1 (0.9, 1.4) 1.2 (0.8, 1.7) 0.3 ED/Hospitalizatio History 1.2 (0.98, 1.6) 2.3 (1.9, 2.8) 0.5 (0.4, 0.7) < No ED/Hospitalizatio History 1.4 (1.1, 1.8) 1.1 (0.8, 1.3) 1.3 (0.97, 1.8) Positive Aeroallerge Ski Test 1.3 (1.0, 1.5) 2.1 (1.7, 2.4) 0.6 (0.5, 0.8) Negative Aeroallerge Ski Test 1.4 (1.1, 1.8) 1.2 (0.9, 1.5) 1.2 (0.8, 1.7) 0.4 Bacharier LB et al. J Allergy Cli Immuol 2009:123:

26 Challeges Associated with Daily ICS Daily ICS therapy reduces the rate of severe exacerbatios by approximately 40%, but does ot completely prevet exacerbatios 1 Suboptimal real world adherece: 40-45% adherece i a cliical trial that measured adherece 2 Small but sigificat effect of ICS o reducig liear growth i preschool-aged childre May be oly partially reversed after discotiuatio 3 Additioal strategies that effectively prevet or atteuate these exacerbatios are eeded 1. Guilbert TW. N Egl J Med 2006; 354: Jóasso G. Arch Dis Child. 2000;83(4): Guilbert TW. J Allergy Cli Immuol. 2011;128(5):

27 Itermittet ICS i Preschool Childre Reduce Risk of Severe Exacerbatio Subgroup aalysis of childre with itermittet asthma or viral-triggered wheezig showed reduced risk of exacerbatio with preemptive high-dose itermittet ICS compared to placebo (5 studies, N=422, RR 0.65, 95% CI , NNT=6) Kaiser SV et al. Pediatr 2016;137

28 N=278; moths Number of wheezig episodes i the prior year: 4 or 3 with at least 3 moths of asthma cotroller therapy Positive modified Asthma Predictive Idex 1 severe exacerbatio requirig systemic corticosteroids, urget uscheduled, emerget visit or hospitalizatio i prior year No evidece of persistet symptomatic asthma durig 2 week ru-i o placebo Radomized Treatmet Group Daily low-dose budesoide Itermittet high-dose budesoide Treatmet Phase: 52 Weeks Nightly EXCEPT Durig Respiratory Tract Illesses 0.5 mg PM Placebo PM Durig Respiratory Tract Illesses ONLY for 7 days Placebo AM 0.5 mg PM 1.0 mg AM 1.0 mg PM Zeiger RS et al. NEJM 2011;365:

29 No Sigificat Differeces Betwee % of Patiets A. Itermittet ad Daily ICS Itermittet Daily p-value = Number of Predisoloe Courses (Rate 0.95/perso yr) (Rate 0.97/perso yr) Episode Free Days Itermittet Daily % overall 78 (75-80) 78 (76-81) % excludig days durig treatmet for RTI 85 (82-87) 84 (82-86) No differece i Albuterol use Time to 1 st exacerbatio # of RTIs % of RTIs requirig oral steroids (25%) Severity of symptoms durig RTI Health care utilizatio Growth Itermittet group used less budesoide durig trial (150mg vs 46mg) Zeiger RS et al. NEJM 2011;365:

30 Potetial Role of Macrolides for the Prevetio of Acute Wheezig Illesses i Preschool Childre Atibiotic use i wheezig illesses is ot recommeded by atioal guidelies However, atibiotics are commoly prescribed i cliical practice (1/6 US ambulatory visits for asthma)* Viral ifectios are the most commo trigger for acute wheeze, but bacteria have a emergig role i illess pathogeesis ad exacerbatio risk Macrolides atibiotics have bee show to provide beefits i other iflammatory airway diseases (e.g., CF) Ati-bacterial ad ati-iflammatory properties *Paul IM et al. Pediatrics 2011:127:

31 Would early admiistratio of azithromyci, started prior to the oset of severe lower respiratory tract symptoms, i preschool childre with history of recurret severe lower respiratory tract illesses, prevet the progressio of these episodes?

32 Radomized, double-blid, parallel group trial Azithromyci (AZM) 12mg/kg (maximum 500mg/d) or Placebo oce daily for 5 days Begi at oset of each RTI whe patiet developed sigs or symptoms that parets defied as the patiet s usual startig poit before developmet of LRT symptoms Albuterol 4 times daily for 48 hours ad as eeded Duratio - 52 weeks (3 treated RTIs), exteded to 78 weeks (4 treated RTIs) Bacharier LB et al. JAMA. 2015;314(19):

33 Study Populatio moths of age Recurret cliically sigificat wheezig* i the past year (ay of the followig) >3 episodes, 1 of which was cliically sigificat*; OR >2 cliically sigificat* episodes; OR > 4 moths of daily cotroller therapy AND >1 cliically sigificat* episode. *Cliically sigificat episode: requirig ay of the followig: (1) systemic corticosteroids (oral or ijectable), (2) uscheduled physicia office, urget care or ED visit, or (3) hospitalizatio. Bacharier LB et al. JAMA. 2015;314(19):

34 Primary Outcome The umber of respiratory tract illesses (RTIs) ot progressig to severe lower respiratory tract illess (LRTI) >6 albuterol treatmets over a 24 hour period, OR If symptoms are more tha mild ad ot improved after 3 albuterol treatmets i 1 hour, OR Require albuterol more ofte tha every 4 hours o 2 cosecutive occasios, OR Moderate-severe cough or wheeze for 5 days durig which study therapy was used, OR Need for acute/urget/emergecy care for respiratory symptoms, OR Physicia discretio Bacharier LB et al. JAMA. 2015;314(19):

35 Reductio i Risk of Progressio to Severe LRTI PLACEBO AZM 1 st RTI Severe LRTI Severe LRTI 2 d RTI Severe LRTI Severe LRTI 3 rd RTI 74 9 Severe LRTI 78 5 Severe LRTI 4th RTI 23 7 Severe LRTI 26 1 Severe LRTI 57 Severe LRTI 35 Severe LRTI *Adjusted for study site, age, modified API status, seaso durig which the RTI occurred, ad whether the child erolled before or after the study was exteded to 78 weeks Bacharier LB et al. JAMA. 2015;314(19):

36 Subgroup Aalyses Bacharier LB et al. JAMA. 2015;314(19):

37 Developmet of Azithromyci Resistace 81 subjects provided deep oropharygeal samples at baselie ad at fial visit ( 14 days after fial dose of study medicatio) Number (%) of Subjects with a AZM-Resistat Orgaism AZM-treated No-AZM-treated Baselie 5/41 (12.2) 4/45 (8.9) Fial visit 8/40 (20.0) 7/41 (17.0) Number (%) of Subjects with Acquisitio of a AZM-Resistat Orgaism AZM-treated (N=36) No-AZM-treated (N=37) 6 (16.7) 4 (10.8) Bacharier LB et al. JAMA. 2015;314(19):

38 Summary Azithromyci, started at the earliest sigs of RTIs, was effective i reducig the risk of experiecig episodes of severe lower respiratory tract illesses No differece i respose by API status Well-tolerated with low rates of adverse effects Bacharier LB et al. JAMA. 2015;314(19):

39 Preschool Asthma Pheotypes ad Treatmet Optios mapi NEGATIVE Early Azithromyci Itermittet Disease mapi POSITIVE Boys, Caucasia, More Symptoms, ED/Hosp, Sesitized Itermittet Hi Dose ICS Daily ICS Persistet Asthma Eosiophilia &/or Sesitized No Eosiophilia or Sesitizatio Daily ICS Daily ICS or Daily LTRA or Itermittet ICS

40 Take-home Messages: Step 2 therapy i preschool childre with persistet asthma A differetial respose i ~ ¾ of childre Aeroallerge sesitizatio &/or peripheral eosiophilia strogly predict differetial Step 2 treatmet respose i favor of daily ICS Preschool childre with persistet asthma should be tested for aeroallerge sesitizatio ad/or eosiophilia If preset: Daily ICS is the preferred iitial cotroller A child with o sesitizatios: Ucertai The choice of cotroller should be determied based o paret ad cliicia prefereces If the child does ot respod to a give cotroller, explore other Step 2 therapies before movig to Step 3 therapies

41 Take-home Messages: Preschool childre with severe episodic wheeze A trial of itermittet high dose ICS should be cosidered (particularly amog mapi positive childre) A therapeutic trial of azithromyci, early i the course of respiratory tract illesses (RTI), should be cosidered to prevet progressio to severe lower-rti ad eed for OCS Childre who demostrate a azithromyci respose (less severe episodes of RTI) may beefit from repeatig azithromyci with subsequet illesses Cocer of atimicrobial resistace moitor frequecy of RTIs promptig azithromyci use ad respose to the itervetio More iformatio is eeded regardig the developmet of atibiotic resistat pathoges with this strategy Ukow: efficacy of this (AZM) prevetio approach compared to the efficacy of daily (or itermittet) ICS therapy or role i patiets already receivig cotroller therapy

42 Summary Heterogeeity of early life wheezig adds complexity to asthma diagosis ad treatmet Cotroller therapy for mild persistet asthma ICS as the preferred cotroller Atopy as a strog predictor of ICS respose Emergig approaches for severe recurret wheezig Episodic vs itermittet approaches effective, especially amog atopic childre Azithromyci early i developmet of RTI Not just for atopic childre