A Changing Paradigm on Food Allergy Primary Prevention

Transcription

1 A Changing Paradigm on Food Allergy Primary Prevention Western Society of Allergy and Immunology Meeting January 30, 2017 Matthew Greenhawt, MD, MBA, MSc Assistant Professor of Pediatrics Section of Allergy/Immunology Co-director, Food Challenge and Research Unit Children s Hospital Colorado University of Colorado School of Medicine

2 Disclosures Member, Joint Task Force on Allergy Practice Parameters Member of Nutricia, Nestle, Before Brands, Kaleo, and Monsanto specialty advisory boards and have received honorarium Member of the medical advisory team for Kids With Food Allergies Foundation and the International Association for Food Protein Enterocolitis (non-financial) Have received honorarium from Nestle, Aimmune, Thermo Fisher, Medscape, ReachMD and Adamis Pharmaceuticals Consultant to Canadian Transport Agency, Aimmune, Intrommune Receiving support from 1-K08-HS (Agency for Healthcare Quality and Research) Member of AAAAI EGID, Anaphylaxis, Adverse Reaction to Food, Health Technologies and Joint Task Force on Quality Improvement Measures Committees Member ACAAI Conferences On-Line Allergy, Practice Improvement, and Adverse Reaction to Food committees Chair, ACAAI Adverse Reactions to Foods Committee AAAAI/ACAAI advisor to CDC-ACIP on Egg Allergy/Influenza Vaccine Safety ACAAI representative to consensus statement on interim consensus on early peanut introduction guidelines Member, NIAID Expert Panel on early introduction of peanut to prevent peanut allergy Associate Editor, Annals of Allergy, Asthma, and Immunology Editorial board: Allergy and Rhinology; Medscape Pediatrics; Infectious Diseases in Children Member, Scientific Advisory Council, National Peanut Board

3 Learning Objectives Review the evidence supporting a relationship between timing of peanut introduction and the risk of peanut allergy development Review and understand the recent LEAP study data Discuss the implications related to making changes to the peanut introduction policy Discuss the evidence supporting similar changes for other foods

4 A Delicate Balance Treating/curing/preventing food allergy Maximizing how we can live with food allergy

5 An Epidemic Rise of Disease 6 Food Allergy Reported Prevalence According to NHIS Data, % 5 4.3% % 3.6% 3.8% Jackson KD, et al. Trends in allergic conditions among children: United States, NCHS data brief, no 121. Hyattsville, MD: National Center for Health Statistics. 2013

6 Perspective on Growing Problem Total Annual Cost per Child: $4,184 Total Annual Cost In the U.S.: $24.8 billion Food allergy affects 8% of children --Large direct and indirect cost No cure or treatment Severity poorly predictable Associated with poor HRQL Willingness to pay of ~$3500/child for a therapy Gupta, RS et al. JAMA pediatrics (2013): Slide courtesy of Ruchi Gupta and adapted.

7 The Evolution of Food Allergy Prevention Guidance Pre-2000 s You want to know what to avoid or include in your baby s diet to prevent what? We don t have any advice for that! 2000 Delayed introduction of these highly allergenic foods in infants at high risk for allergic disease, to prevent development of future allergy: Cow s milk until age 1 year, egg until age 2 years; peanuts, tree nuts, and fish until age 3 years Other Advice to Prevent Food Allergy: - Dietary avoidance of certain allergens during pregnancy/breastfeeding - Use of hydrolyzed formula 2008 No convincing evidence for delaying the introduction of specific highly allergenic foods, but no specific guidelines on when and how to introduce the highly allergenic foods listed above Emerging data suggest the delayed introduction of complementary foods may increase the risk of food allergy, asthma, or eczema, and the early introduction of allergenic foods may prevent these outcomes. Delayed introduction beyond 4-6 months is not recommended This is a passive, not an active recommendation AAP Committee on Nutrition. Pediatrics. 2000;106(2 pt 1): Greer FR, et al. Pediatrics. 2008;121(1): Fleischer DM et al.. J Allergy Clin Immunol Pract 2013; 1: Slide courtesy Dr. David Fleischer, Children s Hospital Colorado, modified with permission

8 Current Early Feeding Policy 2008 AAP and 2013 AAAAI guidance already advises against delayed introduction of foods beyond 4-6 mo if standard risk Recommendation is passive, not active Reversed guidelines urging delay issued in 2000 Both AAP and AAAAI recommend allergist evaluation prior to highly allergenic food introduction in patients with hx food allergy or moderate-to-severe atopic dermatitis Guidance is based on available data from observational studies suggesting favorable benefit for early introduction of food, and the promise of several RCTs investigating these questions Fleischer DM et al.. J Allergy Clin Immunol Pract 2013; 1: Greer F. Pediatrics 2008; 121:

9 Looking Before You LEAP: The Learning Early About Peanut Study and the Evidence Supporting Early Peanut Introduction

10 What Makes Study Overview Peanut So Special Peanut allergy a growing public health problem US prevalence estimated between % --All rates based indirect assessment, however Prevalence may have doubled in a 10 yr period Only 20-25% estimated to develop tolerance Peanut allergy is an obsessive fear in the US though it is not the most prevalent allergy Du Toit G et al. N Engl J Med 2015;372: Sicherer et al J Allergy Clin Immunol 2010;125(6): Gupta R et al Pediatrics Jul;128(1):e9-17 Bunyavanich S et al J Allergy Clin Immunol Sep;134(3):753-5.

11 A Ray of Light? 2008 DuToit et al: UK babies avoiding peanut until age 3 were 10 times more likely to develop peanut allergy than Israeli babies fed Bamba before 9 mo Was not an RCT but findings were provocative --Could timing of introduction promote primary prevention? Learning Early About Peanut Allergy Study started --RCT of early vs. delayed peanut introduction in infants at high-risk for peanut allergy --Use of Bamba or peanut butter as vehicle Du Toit G et al. N Engl J Med 2015;372: Du Toit et al. J Allergy Clin Immunol 2008; 122:

12 LEAP Screening and Protocol Eligibility Infants age 4-11 months with either or both. Moderate to severe eczema (SCORAD >40 or parental self-report) OR Egg allergy Screening All participants underwent peanut skin testing prior to study entry If >5mm, excluded (felt to already be likely peanut allergic) Randomization Stratified by 0mm vs. 1-4mm skin test size, randomized within each group to consume (2g, 3x week x 60m) vs. avoid peanut All initial peanut consumption done under Allergist supervision Assessment and Challenge Food frequency and household ambient peanut dust levels assessed through 60m. Multiple interval visits All subjects underwent in office peanut challenge at age 5y Du Toit G et al. N Engl J Med 2015;372:

13 Primary Outcome. LEAP Results ARR=11.8% ARR=24.7% ARR=14% ARR=13.5% ARR=34% ARR=17% ARR=9.6% ARR=24.7% ARR=12.1% Du Toit G et al. N Engl J Med 2015;372:

14 LEAP Study: NNT Analysis Skin test negative Skin test positive Combined ITT Per protocol Imputed ITT The treatment effect is heterogeneous Study showed evidence of both primary and secondary prevention Benefit was far greater within the sensitized group Unknown effect among the not-at-risk or >4mm sensitized How can we assess the health and economic benefits of a single policy with a heterogeneous treatment effect? Du Toit G et al. N Engl J Med 2015;372:

15 Constructive Criticisms No placebo group or low risk group comparison 5mm skin test cut off chosen arbitrary No control group to test necessity of skin testing Single center, referral population Participation bias? >96% retention at 5yr Weak high risk criteria Dose/duration of exposure not tested Unknown effect of partial adherence or long-term outcomes after discontinuation

16 How Do the Findings Generalize? Standard risk infants not assessed Necessity of skin testing unproven, cut off arbitrary Single center, referral population, participation bias Weak high risk criteria Dose/duration of exposure not tested Unknown long-term outcomes after discontinuation

17 LEAP ON Does this Help? Aim to test effect of discontinuation --1 year follow-up at the end of the original 5 year LEAP study --Both consumption and avoidance group avoided peanut 3 new cases of peanut allergy in each arm Shows effect was not transient desensitization Question of applicability --Does not address partial adherence/discontinuation at younger ages --Does not address long term outcomes of shorter periods of adherence DuToit et al NEJM 2016; /NEJMoa

18 Justifying Conclusions The early introduction of peanuts significantly decreased the frequency of the development of peanut allergy among children at high risk for this allergy and modulated immune responses to peanuts. AGREE, BUT SECONDARY EFFECT MUCH GREATER THAN PRIMARY UNSURE THEY WERE AS HIGH RISK AS BILLED HOW MANY > 4MM WOULD HAVE HAD BENEFIT? Du Toit G et al. N Engl J Med 2015;372:

19 LEAP NEJM Editorial Recommended immediate implementation Screen all high-risk children 4-8mo --if skin test -, start 2g thrice weekly --if skin test 1-4mm, challenge in the office --if skin test > 5mm, do not introduce Children considered at high risk for peanut allergy not otherwise defined beyond LEAP criteria Prompted formation of the Interim Consensus Gruchalla RS and Sampson HA. N Engl J Med 2015: 372:

20 Interim Consensus There is now strong scientific supporting early introduction of peanut-containing products into the diet of high-risk infants early on in life (between 4 11 months of age) in countries where peanut allergy is prevalent, since delaying may be associated with an increased risk of developing peanut allergy. Infants with early-onset atopic disease, such as severe eczema or egg allergy in the first 4-6 months of life may benefit from evaluation by an allergist or physician trained in management of allergic diseases to assist in implementing these suggestions regarding the appropriateness of early peanut introduction. Evaluation of such patients may consist of performing peanut skin testing and/or in-office observed peanut ingestion, as they deem appropriate after discussion with the family, especially for those with evidence of a positive peanut skin test The study does not address use of alternative doses of peanut protein, minimal length of treatment necessary to induce the tolerogenic effect, or potential risks of prematurely stopping or sporadic feeding of peanut. Consensus Communication on Early Peanut Introduction and the Prevention of Peanut Allergy in High-Risk Infants. 2015, In press.

21 Measure Twice, Cut Once Danger in implementing findings from a single study Duty to replicate? Issue of generalizability to US --Referral center vs. population-level --Should still work, but with same effect sizes? --Is screening even necessary or practical? --What is skin testing cut off point? What was missed benefit? Issue of allergist supply/access and utilization Issue of compliance provider and parent

22 Implementation: Mission Impossible? ~4,000,000 US children under the age of 1 20% have eczema, and 2% have egg allergy Only 10% of the 5,500 US allergists perform >1 challenge per week Between 20, ,000 infants to be seen in 5mo window What would happen to access for other diagnoses? How many providers or parents would comply? Is this reimbursable or cost effective? What are the expectations? Martin PE, et al.. Clin Exp Allergy 2013; 43: Accessed February 24, Fleischer DM et al.. J Allergy Clin Immunol Pract 2013; 1: Accessed February 24, Pongracic JA, Bock SA, Sicherer SH. J Allergy Clin Immunol 2012;129:564-6.

23 Revising the NIAID Guidelines Balancing at home introduction vs. screening higher-risk infants : Addendum 1: infants with severe eczema, egg allergy or both have introduction of age-appropriate peanut-containing food as early as 4 to 6 months of age to reduce the risk of peanut allergy. Addendum 2: infants with mild to moderate eczema should have introduction of age-appropriate peanut-containing food around 6 months of age, in accordance with family preferences and cultural practices, to reduce the risk of peanut allergy. Addendum 3: infants without eczema or any food allergy have age-appropriate peanut-containing foods freely introduced in the diet, together with other solid foods, and in accordance with family preferences and cultural practices. NIAID 2016 Early Feeding Guideline Addendum Draft Copy

24 Redefined Risk Criteria Severe eczema is defined as persistent or frequently recurring eczema with typical morphology and distribution, assessed as severe by a health care provider and requiring frequent need for prescription-strength topical corticosteroids, calcineurin inhibitors or other anti-inflammatory agents despite appropriate use of emollients. Egg allergy is defined as a history of an allergic reaction to egg and a skin prick test wheal diameter of 3 mm with egg white extract; or a positive oral egg food challenge. A specialist is defined as a health care provider with the training and experience to: 1) perform and interpret skin prick testing and oral food challenges; and 2) know and manage their risks. Such individuals must have appropriate medications and equipment on site.. NIAID 2016 Early Feeding Guideline Addendum Draft Copy

25 NIAID Guideline Algorithm * * To minimize a delay in peanut introduction for children who may test negative, testing for peanut-specific IgE may be the preferred initial approach in certain health care settings. Food allergen panel testing or the addition of sige testing for foods other than peanut is not recommended due to poor positive predictive value. NIAID 2016 Early Feeding Guideline Addendum Draft Copy

26 Medicalizing Peanut Introduction? Are data strong enough to suggest a policy? Have all stakeholders bought in & who benefits? How will the knowledge translate? Should expectations for success be tempered? --TIPS Study: 7% introduce solids by 4mo, 13% by 6 mo --Wheat (8.7m), egg (11.2m), fish (13.4m), peanut/tree nut (20-22m) --Asian race, maternal hx food allergy associated w/delay What are the possible health and economic benefits? McKean et al. Clin Pediatrics 2015; 54:

27 Are We Missing Something? Secondary analysis of LEAP dataset Aim to investigate sub-group trends not noted in initial publication Goal to exploring relationship between peanut tolerance, baseline peanut skin test size, and age of peanut introduction Greenhawt et al. Allergy 2016; In press. DOI: /all.13100

28 Greenhawt et al. Allergy 2016; In press. DOI: /all Looking Inside the Response

29 A Deeper Look at the Data Wheal size matters most if you DELAY introduction! There is a larger age window than realized to introduce peanut Early peanut introduction and exclusive breastfeeding for can co-exist! Greenhawt et al. Allergy 2016; In press. DOI: /all.13100

30 A C B D Greenhawt et al Allergy 2016 Submitted, under revision

31 What About Other Foods Is there Similar Evidence to Support a Change in Recommendation

32 EAT: Multiple Food Introduction Enquiring About Tolerance study --Early introduction of allergens in breastfed infants at 3mo vs. 6 mo --Infants were not considered high-risk as in LEAP study --Milk 1 st, then egg, fish, sesame, wheat, peanut in random order --Assessed rates of allergy development between 1-3 years in 1303 children 68% unable to follow protocol in the early intro group --Influenced by perceived sx, nonwhite race, poor caregiver QoL, eczema --Adherence: milk 85%, peanut 62%, fish 60%, sesame 51%, egg 43% No significant differences between groups --Concern for limited power, drop out, possible reverse causality --Best case scenario, shows these ages of introduction likely non-inferior --Was this more a trial of effect of timing of enhanced dietary diversity? Perkin et al NEJM 2016; OI: /NEJMoa

33 ARR=2.5 ARR=2.5 NNT=40 ARR=4.1 ARR=3.8 NNT~25 What are the health and economic effects of changing policy given such small effect sizes? What are the concerns given this was only demonstrated in the per protocol population? Perkin et al NEJM 2016; OI: /NEJMoa

34 Early Egg Introduction: HEAP Trial Similar aim to LEAP, but with egg --Egg allergy nearly twice as prevalent as peanut, but transient DBRCT of egg consumption at 4-6mo through 12 mo --All had screening egg IgE, 23/406 +; 16/17 challenged, 11 had anaphylaxis* --If -IgE, randomized to 2.5g egg white (n=184) vs. placebo (n=199) thrice weekly Outcomes --5.6% (8/142) egg vs. 2.6% (4/156) placebo +IgE at 1yr (NS) --2.1% (3/142) egg vs. 0.6% (1/156) placebo allergic at 1yr (NS) --Only 1 egg vs. 0 placebo subjects were allergic in per protocol group Differs from LEAP, overall rates NS between groups --Sensitized subjects censored, so no possible secondary prevention effect --High rate of severe initial reactions, but using raw egg (most allergenic form) Bellach J et al J Allergy Clin Immunol 2016; In press

35 Early Egg Introduction: STEP Trial Exclusively non-eczema population, no exclusion based on testing Egg vs. placebo at 4-6 vs. 10mo (0.4g/TIW), challenge at 12m Effect NS, no anaphylaxis, no harm shown for intro at 4-6mo Per protocol analysis was significant (3% vs. 9.9%, p=0.002) Significantly higher IgG4 levels with early introduction Used raw egg vehicle, but >90% baked/cooked egg tolerant at 12mo Underpowered, but trend towards benefit in non-eczematous sample Palmer et al J Allergy Clin Immunol 2016; In press

36 Meta-analysis of Prevention Trials UK Food Standards sponsored systematic review --16,289 titles screened, 51 studies identified --Included published abstracts of studies in progress/preparation Moderate certainty evidence from 5 trials for protective benefit of early egg introduction (4 raw, 1 cooked) --RR 0.56, I2=36%; P=0.009; ARR 24 cases per 1000 Moderate certainty evidence from 2 trials for protective benefit for early peanut introduction --RR 0.29, I2=66%; P=0.009; ARR 18 cases per 1000 Ierodiakonou D et al JAMA 2016; 311:

37 Pooled Data Supports Early Introduction Ierodiakonou D et al JAMA 2016; 311:

38 Preventative Effects of Hydrolyzed Formulas Hydrolyzed formula vs. cow s milk recommended for primary prevention of allergic diseases as a breast feeding alternative for first 4-6mo of life (US,CAN,EU) --Australasian society retracted this guidance due to conflicting data --Review commissioned by UK food standards agency Search of 16,289 titles yielding 52 studies of 19,000pts --28 RCT, 6 quasi RT, 3 controlled trials (observational studies excluded) --Outcomes of asthma, eczema, AR/ARC, food allergy, sensitization --Autoimmne outcomes of IDDM, celiac disease, IBD, thyrodidits, JRA, vitiligo, psoriasis --23 studies of phf (15 from Nestle), 18 ehf --Most were high risk due to FHx, studies at high risk of bias Boyle RJ et al. BMJ 2016; 352:i974

39 Evidence for phf (vs. CM) No effect on eczema in first 4 yrs No effect for wheeze No effect for food allergy No effect for sensitization No data for autoimmunity Protection noted for only allergic rhinitis in first 4yrs Boyle RJ et al. BMJ 2016; 352:i974

40 Recommendations: How Much Should Change? Introduce peanut early, especially in high-risk infants! NIAID has already changed peanut introduction policy --Aimed correctly based on data, but needs real-time data calibration and assessment of risks/benefits of screening for high-risk --Additional peanut RCT s would help, but need time to embrace this Egg data more difficult to interpret --Trials differed by egg form and population, but pooled effect strong --No present NIAID plan to change egg introduction policy yet --STEP trial showed >90% tolerated cooked egg at 1yr, so timing is correct Still awaiting a milk RCT This story will evolve towards more active guidance

41 Final Take Home Messages There is no benefit to delaying introduction of any food past 4-6 months follow the 2008 guidelines! Introduce peanut as early as 4-6mo in all children --But this may benefit the high-risk child the most No firm conclusion as to the benefits of early egg introduction, or its optimal timing With more trials, the guidance will become more allergen specific and specify optimal age and target population

42 Sampson and Sicherer J Allergy Clin Immunol 2007; 120: Food Allergy: Is there an Answer?

43 Thanks! The view from the Food Challenge Unit, Children s Hospital Colorado