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Physicians’ Education Resource®, LLC, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgment of Commercial Support

This activity is supported by an educational grant from Aimmune Therapeutics.

Clinical Practice Connections™: From Diagnosis to Emerging Immunotherapeutic Options: Understanding the Burden and Risks in Peanut Allergy

Release Date: September 28, 2018
Expiration Date: September 28, 2019
Media: Internet - based

Activity Overview

Of all food allergies, peanut allergies cause the most severe cases of anaphylaxis and represent the leading cause of death from food-induced anaphylaxis. With a prevalence of approximately 2% of the US population, there is no clear-cut understanding of why peanut allergies have continued to increase. Furthermore, not only are patients and caregivers burdened with strict avoidance at all times and constant wariness of accidental exposure but with additional costs of outpatient and emergency visits or hospitalizations for severe reactions. However, a paradigm shift in peanut allergy management is evolving. In this Clinical Practice Connections™, expert faculty will address myths and misconceptions about food allergies, outline appropriate diagnosis and provide expert panel addendum guideline recommendations for early introduction of peanut protein to infants at various risk levels. Children and adults with peanut allergies may soon benefit from ongoing clinical trials of desensitization treatments as faculty describe three emerging immunotherapies and considerations for incorporation into practice.

Acknowledgment of Commercial Support

This activity is supported by an educational grant from Aimmune Therapeutics.

Target Audience

This CME activity is primarily intended for allergists, immunologists, primary care physicians, pediatricians, and clinicians who treat patients with peanut allergy.

Educational Objectives

At the conclusion of this activity, you should be better prepared to:

  • Elaborate on the prevalence and psychosocial burden of peanut allergies for patients and caregivers
  • Identify key studies and guideline recommendations for early introduction of peanuts
  • Describe considerations for implementation of upcoming immunotherapies into clinical practice

Faculty, Staff, and Planners' Disclosures

Faculty

David R. Stukus
David R. Stukus, MD
Associate Professor of Pediatrics
Division of Allergy and Immunology
Nationwide Children’s Hospital and The Ohio State University College of Medicine
Columbus, OH

Disclosure: No relevant financial information to disclose

The staff of Physicians' Education Resource®, LLC, (PER®) have no relevant financial relationships with commercial interests to disclose.

Disclosure Policy and Resolution of Conflicts of Interest (COI)

As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.

Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.

Off-Label Disclosure and Disclaimer

This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical and nursing education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER®.

PER Pulse Recap™

PER Pulse Recap (1 of 3)

Peanut allergy is among the most common food allergies in children, affecting roughly 1 to 2 children in every classroom in every school in the United States at any given time.1 The prevalence has continued to increase over the past decades, with an estimated 3.5-fold increase over an 11-year period.2 There is no straightforward cause for the increasing prevalence, and the most likely explanation may be a combination of factors such as increased genetic susceptibility, alterations in the microbiome, changes in food preparation, intentional avoidance of peanut products, and improvements in hygiene. Severity of reactions ranges from mild, with hives and itching or mild swelling, to life-threatening anaphylaxis; severity is unpredictable based on prior reactions. Food-related allergic reactions lead to an emergency department visit approximately once every 3 minutes in the United States.3 Furthermore, peanut allergy is the leading cause of death due to food-induced anaphylaxis.4

Peanut allergies impose significant psychosocial and physical burdens on both patients and their families, such as:

  • Constant vigilance for accidental exposure in every setting in which food is served
    • Labeling on packaged foods must be read and interpreted
    • Caregivers must question preparers of food served at social occasions, extended family meals, and school
    • Immediate recognition and treatment of reaction
      • An epinephrine autoinjector must be available at all times
  • Limitations and negative social interactions
    • Children with peanut allergies may be bullied, teased, harassed, or not included in activities due to additional responsibility for caregivers
    • Children with peanut allergies feel more restricted regarding physical activities and are more worried about being away from home5
    • Teenagers may take risks with ingestion of peanuts, postpone treatment, or not carry an epinephrine autoinjector6

Key Points:

  • Peanut allergies impose significant psychosocial and physical burdens on patients and their caregivers
  • Prevalence is increasing without a clear-cut etiology
  • Severity of reactions is unpredictable

“Symptoms can vary over time, and prior reactions do not necessarily predict future reactions. There are many instances where people have mild hives with the first ingestion, but then have severe anaphylaxis or life-threatening symptoms with subsequent ingestions.” 
 —David R. Stukus, MD

References

  1. Gupta R, Warren C, Blumenstock J, Kotowska J, Mittal K, Smith B. The prevalence of childhood food allergy in the United States: an update. Ann Allergy Asthma Immunol. 2017;199(5 suppl):S11. Abstract OR078. doi: 10.1016/j.anai.2017.08.060.
  2. Sicherer SH, Muñoz-Furlong A, Godbold JH, Sampson HA. US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year follow-up. J Allergy Clin Immunol. 2010;125(6):1322-1326. doi: 10.1016/j.jaci.2010.03.029.
  3. Clark S, Espinola J, Rudders SA, Banerji A, Camargo CA Jr. Frequency of US emergency department visits for food-related acute allergic reactions. J Allergy Clin Immunol. 2011;127(3):682-683. doi: 10.1016/j.jaci.2010.10.040.
  4. Togias A, Cooper SF, Acebal ML, et al. Addendum guidelines for the prevention of peanut allergy in the United States: report of the National Institute of Allergy and Infectious Diseases–sponsored expert panel. J Allergy Clin Immunol. 2017;139(1):29-44. doi: 10.1016/j.jaci.2016.10.010.
  5. Avery NJ, King RM, Knight S, Hourihane JO. Assessment of quality of life in children with peanut allergy. Pediatr Allergy and Immunol. 2003;14(5):378-382. doi: 10.1034/j.1399-3038.2003.00072.x.
  6. Sicherer SH, Allen K, Lack G, Taylor SL, Donovan SM, Oria M. Critical Issues in Food Allergy: A National Academies Consensus Report. Pediatrics. 2017;140(2):e20170194. doi: 10.1542/peds.2017-0194.

PER Pulse Recap (2 of 3)

As a follow-up to the online CME activity, Clinical Practice Connections™: From Diagnosis to Emerging Immunotherapeutic Options: Understanding the Burden and Risks in Peanut Allergy, this second of 3 PER Pulse™ Recaps for the activity will focus on the early introduction of peanut for prevention of peanut allergy.

The American Academy of Pediatrics and other organizations previously recommended avoidance of peanut for infants, until a child was aged 2 to 3 years, in order to prevent peanut allergies. However, the concept of early introduction to peanuts came from an epidemiology study that found Jewish children growing up in Israel had a tenfold lower risk of developing peanut allergies than Jewish children from the United Kingdom.1 Upon investigating factors associated with this finding, researchers found that almost all infants in Israel were given a peanut product to snack on when teething and postulated that the earlier introduction would prevent peanut allergy or promote tolerance. The results of the Learning Early About Peanut Allergy (LEAP) trial, published in 2015, provided the first solid evidence that early introduction of peanuts to infants at high risk for developing peanut allergy could prevent development of peanut allergy.2 In 2017 the National Institute of Allergy and Infectious Diseases (NIAID) convened an expert panel to publish addendum guidelines to guide the introduction of peanut for infants.3 Following is a recap of those guidelines:

  • All infants should be introduced to peanut before age 1 year, but introduction should be stratified according to risk.
  • Infants without moderate-to-severe eczema or egg allergy should be introduced to age-appropriate peanut products at 4 to 6 months of age with other solid foods and continue to be fed peanut products on a consistent basis.
  • Infants with demonstrated moderate-to-severe eczema should receive a peanut allergy test prior to introduction, either a blood IgE level or peanut skin prick test or both.
    • If the IgE level is undetectable or <0.35 kUA/L, the infant can be introduced to peanuts at around 6 months.
  • Infants with demonstrated moderate to severe eczema with an IgE level >0.35 kUA/L should have the skin prick test to determine the manner of peanut introduction.

“The addendum guidelines take the latest evidence and break it down in a way for pediatricians, primary care physicians, and parents to understand: that we want infants to eat peanut and keep it in their diet, that a risk stratification should occur, that the majority of infants are not at risk of having a reaction with introduction, and we should just put it in the diet when they're ready. But those at highest risk, including those with moderate-to-severe eczema and/or egg allergy, should have a peanut allergy test first, prior to introduction.” 
 —David R. Stukus, MD

Key Points:

  • The LEAP trial provided solid evidence that early introduction of peanut could prevent peanut allergy
  • The NIAID published addendum guidelines in 2017 for implementation of early introduction of peanuts

References

  1. Du Toit G, Katz Y, Sasieni P, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol. 2008;122(5):984-991. doi: 10.1016/j.jaci.2008.08.039.
  2. Du Toit G, Roberts G, Sayre PH, et al; LEAP Study Team. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372(9):803-813. doi: 10.1056/NEJMoa1414850.
  3. Togias A, Cooper SF, Acebal ML, et al. Addendum guidelines for the prevention of peanut allergy in the United States: report of the National Institute of Allergy and Infectious Diseases–sponsored expert panel. J Allergy Clin Immunol. 2017;139(1):29-44. doi: 10.1016/j.jaci.2016.10.010.

PER Pulse Recap (3 of 3)

As a follow-up to the online CME activity, Clinical Practice Connections™: From Diagnosis to Emerging Immunotherapeutic Options: Understanding the Burden and Risks in Peanut Allergy, this third of 3 PER Pulse™ Recaps for the activity will focus on new and emerging immunotherapies for desensitization of peanut allergen.

“It's important for families to understand the various forms of immunotherapy and how some of them achieve higher levels of tolerance or desensitization compared with others, and it's also really important to understand what the protocols are like at home. And they also need to understand what they're really trying to achieve by undergoing immunotherapy.”
 — David R. Stukus, MD

Immunotherapy offers the opportunity for desensitization or reduced symptom severity by introducing small amounts of allergen to the immune system and maintaining ongoing exposure to that allergen. To overcome earlier challenges when evaluating oral immunotherapies (OITs), the PRACTALL guidelines provide standardized recommendations for the performance of double-blind, placebo-controlled food challenges (DBPCFCs), which are considered the gold standard.1 In the PRACTALL guidelines, recommendations for the DBPCFC involve escalating food protein doses in set amounts, starting at 1 mg and increasing up to 3000 mg, or until a reaction occurs.1 Understanding these guidelines and the definitions of reported outcomes in clinical trials is important for comparing efficacy data and evaluating the new and emerging immunotherapies. For reference, a single peanut kernel contains approximately 250 to 300 mg of peanut protein.2 Baumert et al determined that increasing the reactivity threshold from a baseline of 100 mg to <300 mg reduced the risk of accidental reaction by 95%.3

Three immunotherapies with different mechanisms of action have ongoing clinical trials and two have completed phase 3 trials (Table):

  • AR101, an oral immunotherapy (OIT)– characterized peanut protein powder
  • DBV712 IHRP, an epicutaneous immunotherapy (EPIT) – allergen uptake by Langerhans cells in epidermis using a skin patch
  • Sublingual immune therapy (SLIT) – allergen extract uptake by oral Langerhans cells

Table. Status of Immunotherapies for Peanut Allergy4-10

  ARC101 EPIT SLIT
Clinical trial and FDA status PALISADE: phase 3 completed;
n = 550, aged 4-17 years. Duration: 12 months.
BLA submitted December 2018.
 
POSEIDON, phase 3, recruiting.
PEPITES: phase 3 completed;
n = 356; aged 4-11 years. Duration: 12 months.
BLA to be resubmitted.
 
EPITOPE, phase 3, recruiting.
Phase 2:
n = 49; ages 1-11 years. Duration: 48-52 months.
 
 
Primary endpoint Proportion of subjects tolerating a single highest dose of ≥600 mg (CTD, 1043 mg) at exit DBPCFC Percentage of treatment responders in overall population with ED ≥300 mg or ≥1000 mg peanut protein with baseline ED of ≤10 mg or ≥10 mg, respectively Percentage of subjects who pass final DBPCFC 1-17 weeks post treatment
Inclusion criteria DBPCFC Peanut-specific IgE ≥0.35 kUA/L and/or (+) SPT ≥3 mm vs control.
Experience dose limiting symptoms at or before the 100 mg challenge dose.
Peanut-specific IgE ≥0.7 kUA/L; (+) SPT; entry challenge to ≤300 mg peanut protein Peanut-specific IgE ≥0.35 kUA/L or medical history; entry challenge to 1 gm peanut protein
Efficacy 67.2% tolerated ≥600 mg SCD in exit DBPCFC vs 4.0% in placebo. Significantly more patients in active group responded vs placebo (33.3% vs 13.6%), but confidence interval in the difference between active and placebo groups not met Ongoing investigation
AEs leading to study withdrawal in active group All AEs, 12.4%:
- GI (6.7%)
- Systemic hypersensitivity (2.7%)
- Respiratory (1.1%)
- Cutaneous (0.8%)
1.1% dropout due to treatment-emergent AEs in both active and placebo groups Ongoing investigation
[Key for Table] AE indicates adverse event; BLA, Biologics License Agreement; CTD, Cumulative Tolerated Dose; DBPCFC, double-blind, placebo-controlled food challenge; ED, Eliciting Dose; GI, gastrointestinal; SCD, Successfully Consumed Dose; SPT, Skin Prick Test.

Available evidence suggests that OIT is more effective at inducing desensitization but with more adverse events.11-14 As immunotherapies become available, clinicians must weigh the benefits and risks for individualization of treatment.

Key Points:

  • PRACTALL guidelines provide standardized recommendations for the performance of DBPCFCs
  • Understanding study design methodology and outcome definitions is important when comparing published data on immunotherapies
  • Three immunotherapies for desensitization (oral, epicutaneous, and sublingual  are being evaluated in phase 2 and 3 trials

References

  1. Sampson HA, Gerth van Wijk R, Bindslev-Jensen C, et al. Standardizing double-blind, placebo-controlled oral food challenges: American Academy of Allergy, Asthma & Immunology–European Academy of Allergy and Clinical Immunology PRACTALL consensus report. J Allergy Clin Immunol. 2012;130(6):1260-1274. doi: 10.1016/j.jaci.2012.10.017.
  2. Baumert JL, Taylor SL, Koppelman SJ. Quantitative assessment of the safety benefits associated with increasing clinical peanut thresholds through immunotherapy. J Allergy Clin Immunol Pract. 2018;6(2):457-465.e4. doi: 10.1016/j.jaip.2017.05.006.
  3. Parrish CP, Har D, Bird JA. Current status of potential therapies for IgE-mediated food allergy. Curr Allergy Asthma Rep. 2018;18(3):18. doi: 10.1007/s11882-018-0772-z.
  4. PALISADE Group of Clinical Investigators, Vickery BP, Vereda A, et al. AR101 oral immunotherapy for peanut allergy. N Engl J Med. 2018;379(21):1991-2001. doi: 10.1056/NEJMoa1812856.
  5. Peanut oral immunotherapy study of early intervention for desensitization (POSEIDON). clinicaltrials.gov/ct2/show/NCT03736447. Updated January 8, 2019. Accessed January 10, 2019.
  6. Efficacy and safety of Viaskin Peanut in children with immunoglobulin E (IgE)-mediated peanut allergy (PEPITES). clinicaltrials.gov/ct2/show/record/NCT02636699. Updated September 8, 2017. Accessed January 10, 2019.
  7. Safety and efficacy study of Viaskin Peanut in peanut-allergic young children 1-3 years of age (EPITOPE). clinicaltrials.gov/ct2/show/NCT03211247. Updated November 14, 2018. Accessed January 10, 2019.
  8. FARE peanut SLIT and early tolerance induction (FARE/SLIT). clinicaltrials.gov/ct2/show/record/NCT02304991. Updated October 12, 2018. Accessed January 10, 2019.
  9. Aimmune Therapeutics submits BLA to FDA for AR101 for the treatment of peanut allergy in children and adolescents ages 4-17 [news release]. Brisbane, CA: Aimmune Therapeutics, Inc; December 21, 2018. ir.aimmune.com/news-releases/news-release-details/aimmune-therapeutics-submits-bla-fda-ar101-treatment-peanut. Accessed January 10, 2019.
  10. DBV Technologies provides update on Viaskin Peanut for children four to 11 years of age [news release]. Montrouge, France: DBV Technologies S.A.; December 19, 2018. globenewswire.com/news-release/2018/12/19/1669940/0/en/DBV-Technologies-DBV-Technologies-Provides-Update-on-Viaskin-Peanut-for-Children-Four-to-11-Years-of-Age.html. Accessed January 10, 2019.
  11. Dulmi G, Harricharan A, Jeyasegaran V, Buhas F, Halari M. Comparing the effectiveness of oral immunotherapy and epicutaneous immunotherapy on the desensitization of peanut allergies. J Allergy Ther. 2018;9(1):272. doi: 10.4172/2155-6121.1000272.
  12. Virkud YV, Burks AW, Steele PH, et al. Novel baseline predictors of adverse events during oral immunotherapy in children with peanut allergy. J Allergy Clin Immunol. 2017;139(3):882-888.e5. doi: 10.1016/j.jaci.2016.07.030.
  13. Lucendo AJ, Arias A, Tenias JM. Relation between eosinophilic esophagitis and oral immunotherapy for food allergy: a systematic review with meta-analysis. Ann Allergy Asthma Immunol. 2014;113(6):624-629. doi: 10.1016/j.anai.2014.08.004.
  14. Petroni D, Spergel JM. Eosinophilic esophagitis and symptoms possibly related to eosinophilic esophagitis in oral immunotherapy. Ann Allergy Asthma Immunol. 2018;120(3):237-240.e4. doi: 10.1016/j.anai.2017.11.016.

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