Pediatric Asthma. Fernando D. Mar,nez, M.D. Asthma and Airways Disease Research Center The University of Arizona

Transcription

1 Pediatric Asthma Fernando D. Mar,nez, M.D. Asthma and Airways Disease Research Center The University of Arizona

2 Disclosure Grant from Johnson and Johnson to study use of Amish dust to prevent asthma Advisor to PureTech in the development of microbe-based therapies

3 Three Challenges Can we prevent asthma? Are inhaled coritcosteroids effec,ve in preschoolers? Is there any role for Azithromycin in severe, wheezy preschoolers?

4 The Emergence of a Fundamental New Concept! The last 30 years have witnessed the advent of major shifts in our understanding of the origins of human phenotypes! It is now widely accepted that most chronic diseases have their origins during the first years of life! Interactions between genes and early environment determine developmental pathways that have long term influence on health and disease for a lifetime

5 Incidence of Asthma by Age in Rochester Minnesota Yunginger et al, ARRD 1992: 146:888

6 Natural Course of Asthma in the 1958 British Birth Cohort Each symbol represents 1% of children with complete data (N=5801) Strachan et al, BMJ 1996: 312:1195

7 Natural Course of Asthma in the 1958 British Birth Cohort Each symbol represents 1% of children with complete data (N=5801) Strachan et al, BMJ 1996: 312:1195

8 Morgan et al, Ped. Pulmonol 1988;5:232

9 Trajectories of Lung Func,on in Young Children With and Without Asthma by Age 7 Yrs Bisgaard et al, AJRCCM. 2012; 185:

10 Lung Function from Birth by Wheezing at Age Yrs 0.4 Z-Scores Adjusted FEV1/FVC (+/-se) * * No Wheeze Infrequent Wheeze Frequent Wheeze Age, years * * * p<0.01 Frequent vs No Wheeze p<0.01 Frequent vs. Infrequent *

11 Trajectories of Airway Func,on in Childhood Asthma No Asthma Rela,ve Level of Lung Func,on Mild Asthma Moderate/Severe Asthma Birth Age 5-7 Years School age Adult life Mar$nez and Vercelli Lancet 2013;382:

12 Frequent Wheezing by Siblings or Daycare in the First 6 Months of Life Ball et al, NEJM 2000;343:538

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14 Exposure to Stables and/or Farm Milk in the First Year of Life. % Asthma ever Exposed Non-exposed * * Asthma attacks past 12 mo Riedler et al, Lancet Oct 6;358: * p<0.0001

15 Amish Huteritas

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17 Amish Are Exposed to Considerably Higher Microbial Products in Their Homes Stein et al, NEJM 2016; 375:411

18 Proteobacteria are Significantly More Abundant in Amish Dust Stein et al, NEJM 2016; 375:411

19 Huaerites and Amish Children Have Different Propor,on of Eosinophils and Neutrophils Stein et al, NEJM 2016; 375:411

20 Huaerite and Amish Children are Immunologically Very Different Stein et al, NEJM 2016; 375:411

21 Gene Expression Profiles in Leukocytes From Amish and Huaerite Children Blue: Increased Expression in Amish Stein et al, NEJM 2016; 375:411

22 Amish (but not Huaerite) House Dust is Protec,ve 30 PBS Resistance (cm H20.s/ml) OVA OVA/Amish OVA/Hutterite p=0.03 p= Ach (µg/g mouse) Stein et al, NEJM 2016; 375:411

23 Concordance Between Home Microbiome and Personal Microbiome Lax et al, Science 2014; 345:2048

24 Three Dis,nct Neonatal Gut Microbiota Paaerns Wayne County Birth Cohort Fujimura et al, Nat Med 2016; 22:1187

25 Increased Risk of Atopy and Asthma in Neonatal Carriers of NGM3 Atopy MD asthma Fujimura et al, Nat Med 2016; 22:1187

26 Bacterial Taxonomic Comparison Between NGM3 and NGM1 Fujimura et al, Nat Med 2016; 22:1187

27 Sci Transl Med 2015; 7:39

28 The INFANT Study Fitzpatrick et al, JACI 2016; 138:1608

29 The INFANT Study Fitzpatrick et al, JACI 2016; 138:1608

30 The INFANT Study Fitzpatrick et al, JACI 2016; 138:1608

31 Yr 6 Asthma By RSV- And RV Wheezing Illness In Early Life Jackson et al, AJRCCM 2008; 178:667

32 Likelihood of NP Isola,on of Bacteria and Viruses During Wheezing Episodes (Age <3 Yr) Bacteria: Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis Virus: picorna, RSV, corona, parainfluenza, influenza, human metapneumo, adeno, or boca Bisgaard et al, BMJ 2010;341:c4978

33 Risk of Persistent Wheeze at Age 5 by Pharyngeal Bacterial Coloniza,on as Newborns Hazard Ra,o: 2.40 (95% CI, 1.45 to 3.99) S. pneumoniae, H. influenzae, M. catarrhalis. Bisgaard et al, NEJM 2007;357:

34 An,bio,c Use in Preschool Children An,bio,c use in wheezing illnesses controversial Not recommended by na,onal guidelines Judicious use recommended in general in effort to prevent development of resistance However, very commonly prescribed in clinical prac,ce (1/6 visits for asthma)

35 The Effect of Azithromycin in Preven,ng Severe Lower Respiratory Tract Illnesses in Preschool Children: A Randomized Trial Leonard B. Bacharier, M.D., Theresa Guilbert, M.D., David Mauger, Ph.D., Sue Boehmer, M.A., and Fernando Mar$nez, M.D. NHLBI s AsthmaNet JAMA. 2015;314:

36 Research Ques,on Among preschool-aged children with recurrent wheezing episodes and 1 clinically significant wheezing episode in the year prior: Episode Preven$on: Is azithromycin, when administered at the ini,al and early signs of a respiratory tract illness, more effec,ve than placebo for preven,ng progression to severe lower respiratory tract symptoms?

37 Major Inclusion Criteria months of age Recurrent significant wheezing in the past year (any of the following) >3 episodes, 1 of which was clinically significant*; OR >2 clinically significant* episodes; OR > 4 months of daily controller therapy AND >1 clinically significant* episode. *Clinically significant episode: requiring any of the following: (1) systemic cor,costeroids (oral or injectable), (2) unscheduled physician office visit, (3) ED visit, (4) urgent care visit, or (5) hospitaliza,on.

38 Onset of RTI symptoms APRIL Treatment Failure (APRIL Primary Outcome): Progression of Symptoms SYMPTOMS Begin APRIL Illness Kit: Azithromycin or Placebo

39 Primary Outcome Severe LRTI: AZM 39, Placebo 57 Cumula,ve risk of severe LRTI AZM 0.24, Placebo 0.40

40 Symptom Scores During Treated RTIs All RTIs Severe LRTIs

41 Development of AZM Resistance 81 subjects provided deep oropharyngeal samples at baseline and at final visit ( 14 days auer final dose of study medica,on) Number (%) of Subjects with an AZM- Resistant Organism AZM-treated Non-AZM-treated Baseline 5/41 (12.2) 4/45 (8.9) Final visit 8/40 (20.0) 7/41 (17.0) Number (%) of Subjects with Acquisi$on of an AZM-Resistant Organism AZM-treated (N=36) Non-AZM-treated (N=37) 6 (16.7) 4 (10.8)

42 Subgroup Analyses

43 The COPSAC Azithromycin Trial 1-3 year olds with recurrent asthma-like symptoms Each episode of asthma-like symptoms las,ng at least 3 days was randomly allocated to a 3-day course of azithromycin or placebo The primary outcome was dura,on of the respiratory episode auer treatment, verified by prospec,ve daily diaries Stockholm et al, Lancet Respir Med 2016; 4: 19 26

44 Primary Outcome Stockholm et al, Lancet Respir Med 2016; 4: 19 26

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47 Conclusions Asthma begins in childhood, and environments rich in microbial exposures appear to be protec,ve In preschool children, ICS is the most effec,ve therapy in atopic children Azithromycin could be considered to prevent severe exacerba,ons in children not responsive to ICS