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Home , Peanut allergy

: New Advances and Ongoing Controversies Elissa M. Abrams, MD,a Edmond S. Chan, MD,b Scott Sicherer, MDc

Peanut allergy is one of the most common food in children, with abstract increasing prevalence over time. The dual- exposure hypothesis now supports transcutaneous sensitization to peanut as a likely pathophysiologic mechanism for peanut allergy development. As a result, there is emerging evidence that early peanut introduction has a role in peanut allergy prevention. Current first-line diagnostic tests for peanut allergy have limited specificity, which may be enhanced with emerging tools such as component- resolved diagnostics. Although management of peanut allergy includes avoidance and carrying an autoinjector, risk of fatal is extremely low, and there is minimal risk related to cutaneous or inhalational exposure. Quality of life in children with peanut allergy requires significant focus. Moving forward, oral and epicutaneous are emerging and exciting tools that may have a role to play in desensitization to aSection of Allergy and Clinical Immunology, Department of peanut. Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada; bDivision of Allergy and Immunology, Department of Pediatrics, University of British Columbia and British Columbia Children’s Hospital, Vancouver, British Columbia, Canada; and cDivision of Allergy and Immunology, Peanut allergy is one of the most family member who is peanut Department of Pediatrics, Jaffe Institute, Icahn School of Medicine at Mount Sinai, New York, New York common food allergies in childhood, allergic,3,4 and genetic polymorphisms with a dramatic increase over the are increasingly being linked to the Dr Abrams conceptualized and designed the article, past few decades in various parts of development of peanut allergy.5 drafted the manuscript, and revised the manuscript; 1 Drs Chan and Sicherer conceptualized and designed the Western world. Currently, Although studies vary, heritability of the article and reviewed and revised the manuscript; peanut allergy is thought to affect peanut allergy has been estimated at up and all authors approved the final manuscript as 1% to 3% of children.1 Peanut allergy to 81.6%.3 There are racial differences submitted and agree to be accountable for all is often lifelong and carries associated with the prevalence of aspects of the work. a significant daily burden that peanut allergy, although studies differ DOI: https://doi.org/10.1542/peds.2019-2102 2 adversely affects quality of life (QoL). in results, and boys appear more likely Accepted for publication Aug 21, 2019 6 As a result, prevention of peanut to develop peanut allergy than girls. Address correspondence to Elissa M. Abrams, MD, allergy, as well as accurate diagnosis Section of Allergy and Clinical Immunology, and management of peanut allergy, is Studies have supported a role for Department of Pediatrics, University of Manitoba, essential. Our goal for this narrative vitamin D deficiency and hygiene in the FE125-685 William Ave, Winnipeg, MB R2M 5L9, review is to discuss the latest development of peanut allergy. For Canada. E-mail: [email protected] evidence about peanut allergy example, an observational study of PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, prevention as well as advances and 5276 1-year-old infants in Australia 1098-4275). ongoing controversies in peanut allergy found that vitamin D insufficiency Copyright © 2020 by the American Academy of diagnosis, management, and therapy. increased the risk of peanut allergy 11- Pediatrics fold.7 Higher latitudes have been FINANCIAL DISCLOSURE: The authors have indicated associated with higher rates of both they have no financial relationships relevant to this article to disclose. MECHANISMS UNDERLYING THE food allergy and anaphylaxis.8 It is DEVELOPMENT OF PEANUT ALLERGY FUNDING: thought that with increased hygiene No external funding. There are genetic and environmental (and hence, decreased microbial contributors to the development of exposure) there are altered To cite: Abrams EM, Chan ES, Sicherer S. Peanut peanut allergy. Peanut allergy is more immunoregulatory responses that skew Allergy: New Advances and Ongoing Controversies. Pediatrics. 2020;145(5):e20192102 common in children with an immediate toward an allergic response.9

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 145, number 5, May 2020:e20192102 STATE-OF-THE-ART REVIEW ARTICLE An exciting development in to be due to inherent genetic 11 months of age) reduces the risk of understanding the causal susceptibility, has more recently been peanut allergy (P = .009).20 mechanisms of peanut allergy is the shown to be, at least partly, related to After publication of the LEAP study, proposal of the dual-allergen the environmental effect of avoidance an expert panel convened by the exposure hypothesis, which of in siblings of children with National Institute of Allergy and postulates that allergic sensitization peanut allergy.4,15,16 Infectious Diseases released to peanut (as well as other allergenic a guideline on the prevention of foods) occurs through cutaneous peanut allergy in the United States exposure, especially in children with PEANUT ALLERGY PREVENTION recommending that in infants with an impaired skin barrier such as severe eczema and/or , atopic .9,10 In contrast, In the past several years, in keeping infant-safe forms of peanut should be ingestion of allergenic foods (oral or with the dual-allergen exposure introduced as early as 4 to 6 months gastrointestinal exposure) promotes hypothesis, evidence has emerged of age after peanut allergy screening immune tolerance.9 that early ingestion of peanut has tests.21 The guideline defines severe a role in the prevention of peanut Mutations of the FLG gene (FLG is eczema as “persistent or frequently allergy. In 2008, an observational involved in skin-barrier integrity and recurring eczema with typical study revealed a 10-fold higher water retention) have been linked morphology and distribution prevalence of peanut allergy among with assessed as severe by a health care Jewish school-aged children in the development,11 with null FLG alleles provider and requiring frequent need United Kingdom compared with associated with early, persistent for prescription-strength topical Jewish school-aged children in Israel atopic dermatitis as well as increased corticosteroids, calcineurin inhibitors, (P , .001), with the major difference risk of other atopic conditions, or other anti-inflammatory agents between the populations being age at including food allergy.12 In addition, despite appropriate use of introduction of peanuts.17 Peanut was an association between atopic emollients.” This guideline introduced more commonly in the dermatitis, peanut exposure, and recommends that infants with mild first year of life and fed more peanut allergy has been documented eczema receive peanut at ∼6 months regularly as part of the diet in Israel in multiple large studies. For example, of age. Other international guidance than in the United Kingdom. In 2015, a birth cohort study of 13 971 has followed suit, suggesting that the Learning Early About Peanut children revealed that application of peanut be introduced, or not delayed, Allergy (LEAP) trial, a randomized peanut oil–containing creams onto in higher-risk infants between 4 and controlled trial of 640 infants at risk the surface of infants with atopic 6 months of age, although the for peanut allergy due to severe dermatitis was significantly definition of an infant at high risk eczema and/or egg allergy, provided – associated with the development of varies between guidelines.22 24 high-level evidence that early peanut allergy (odds ratio 6.8; 95% ingestion of peanut (between 4 and Some uncertainties about the role of confidence interval [CI]: 1.4–32.9).13 11 months of age) reduced peanut early peanut ingestion as a means of In contrast, no association was noted allergy by up to 80% compared with allergy prevention remain. The between the development of peanut peanut avoidance until 5 years of necessary amount of peanut ingested, allergy and the use of creams not age.18 A strong protective effect with as well as the required frequency of containing peanut oil (because the oil early peanut introduction was seen in peanut ingestion, is not known. The was not placed on the eczematous infants with both negative and mildly benefit of early ingestion in lower- skin of the infant) or the use of breast positive results on the peanut skin risk infants is also uncertain. It creams containing peanut oil. Of prick test (SPT), suggesting a primary remains controversial whether high- those children who became peanut and secondary preventive effect. In risk infants should have screening allergic, 84% (P , .001) had been a follow-up study to LEAP (LEAP-On), SPTs to peanut or serum peanut- exposed to peanut oil–containing 1 year of peanut avoidance after specific (IgE) creams in the first 6 months of life. 5 years of age did not increase the testing before peanut introduction, Finally, there is an intricate risk of peanut allergy between groups and screening criteria may be interaction between genetic and (P = .25), suggesting longevity of this susceptible to a variety of pitfalls, environmental factors such as protective effect.19 A recent meta- including high false-positive rates and delayed ingestion of peanut. For analysis on timing of allergenic food concern of a screening creep.25 example, the increased risk of peanut introduction and allergy prevention Although the National Institute of allergy that has been documented in revealed moderate-certainty evidence Allergy and Infectious Diseases siblings of children with peanut (2 trials; 1550 participants) that early guideline recommends that infants allergy,3,14 although initially thought peanut introduction (between 4 and with severe eczema and/or egg

Downloaded from www.aappublications.org/news by guest on September 25, 2021 2 ABRAMS et al allergy be considered for preemptive or specific IgE for diagnosis.33,34 younger sibling of child who is screening, recent international Although 95% positive predictive a peanut allergic largely appears to be guidelines do not.22,23,26 In addition, values for allergic reactions to peanut a consequence of delayed ingestion or significant cost, feasibility, and have been determined for both SPT introduction, a balanced and practical logistic challenges have been raised (wheal . 8 mm) and specific IgE approach for most is, first, counseling with preemptive screening on (.34 kU/L in the absence of about the safety of home introduction a population level.27,28 In addition, no a history),35 these numbers vary for young siblings if done early guideline recommends screening to between studies and vary on the basis enough (eg, ∼6 months of age). If, foods other than peanut, and panel of the age of the population studied. despite counseling, the family testing to foods is not advisable. In addition, it has been noted that remains hesitant to introduce at sensitization to foods in children who home, then preemptive testing, are not food allergic is a relatively followed by observed ingestion if PEANUT ALLERGY DIAGNOSIS normal phenomenon.34 As stated in results are positive, would be “ 15 The most important test in the a recent review, the greatest source indicated. of misdiagnosis in food allergy might diagnosis of peanut allergy is the A medically supervised peanut oral 1 well be the lack of appreciation that clinical history. Symptoms, such as food challenge (OFC) is the current a positive test result (sensitization) urticaria, may be due to either allergy diagnostic gold standard and involves does not equate with allergy.”1 This or other causes such as a viral ingestion of incremental amounts of again speaks to the value of a medical infection or facial contact irritation. In peanut under supervision.29 However, history to provide context (pretest addition, allergic reactions or chronic the OFC is time intensive, can cause probability) for test selection and symptoms, such as eczema or anaphylaxis that could be dangerous, interpretation. , may be attributed and is resource intensive,37 with long erroneously to peanut. These The limitations of first-line allergy wait lists for patients.28 As a result, concerns can be addressed by testing are well illustrated in the case there is a need for better diagnostic 1 a thorough medical history. First-line of a younger sibling of a child who is tests for peanut allergy. peanut allergy testing includes either peanut allergic. Previous An improved specific IgE test is SPT or serum peanut-specific IgE observational studies, some that component-resolved diagnostic measurement. SPT involves the relied on allergy testing (either SPT testing (CRD), which measures the introduction of a peanut allergen into or peanut-specific IgE), noted an IgE toward specific the epidermis by using standardized approximate sevenfold increased risk allergenic protein components within extracts and a device to scratch or of peanut allergy in siblings of 29 peanut rather than the usual mixture puncture the skin. A wheal or flare children who were peanut allergic.3,14 of peanut . The 6 indicates sensitization to peanut. However, recent nested data of 2834 commercially available proteins that Serum peanut-specific IgE children from a food allergy cohort can be measured are Ara h 1, Ara h 2, measurement identifies IgE that correlated sensitization with 29 Ara h 3, Ara h 6, Ara h 8, and Ara h 9 to peanut. clinical history revealed a fourfold (Table 1). The significant components higher rate of clinically irrelevant Both tests are highly sensitive, with associated with peanut allergy (Ara h sensitization (ie, positive allergy test a sensitivity of .90% for SPT and 1, Ara h 2, Ara h 3, and Ara h 6) are results in the absence of a history of 70% to 90% for peanut-specific seed-storage proteins and are stable reaction) than true food allergy IgE.30,31 As a result, both tests are to heating.37 In some studies, Ara h among siblings of children who were useful for ruling out peanut allergy. 2–specific IgE has been the most food allergic.36 As a result, the However, neither test correlates well predictive of clinical allergy,38 and authors concluded that preemptive with reaction severity.29 In addition, a correlation has been noted (the testing for food allergy is unjustified the specificity of either test is higher the level of Ara h 2, the more for siblings. between 50% and 60%,32 and the likely there is clinical peanut positive predictive value varies on the However, preemptive testing may allergy39). Testing for Ara h 2 may be basis of the pretest probability of have a role when the risk of peanut particularly valuable in some allergy (such as atopic history of the allergy is high in an unexposed infant circumstances (such as an unclear child and the likelihood of allergy or child. For example, in the LEAP history or an intermediate SPT or based on clinical history). In various trial, 17% in the avoidance group peanut-specific IgE in a child studies, up to 80% to 100% of atopic enrolled with severe eczema and/or sensitized to pollen) Ara h 2 provides children could tolerate foods to which egg allergy had peanut allergy at extra diagnostic information and is they were sensitized, illustrating how study end. Because any potential useful in stratifying which children misleading it is to overly rely on SPT increased risk of peanut allergy in the are eligible for an OFC.40 For example,

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 145, number 5, May 2020 3 TABLE 1 Common Components of the Peanut there is concurrent pollen Component Protein Type Clinical Significance sensitization, which may indicate Ara h 1 Seed-storage Major peanut allergen a milder phenotype of peanut 37 protein allergy. CRD may help stratify Ara h 2 Seed-storage Major peanut allergen; component most predictive of clinical peanut peanut allergy severity as well. It may protein allergy play less of a role in preschool-aged Ara h 3 Seed-storage Major peanut allergen children who are not sensitized to protein Ara h 4 Isoform of Ara h Potential major peanut allergen pollen or in children with 3 a convincing history of a systemic Ara h 6 Seed-storage Major peanut allergen reaction to peanut and very high protein positive SPT and/or specific IgE Ara h 8 Birch pollen Labile protein; not usually associated with severe reactions; associated results. homolog with pollen sensitization Ara h 9 Lipid-transfer Stable protein; associated with more-severe symptoms in There are several other emerging protein Mediterranean region; associated with peach allergy tests that may play an increasing role Adapted from Sicherer SH, Sampson HA. Food allergy: a review and update on epidemiology, pathogenesis, diagnosis, over the next several years in the prevention, and management. J Allergy Clin Immunol. 2018;141(1):46. diagnosis of peanut allergy. The activation test measures basophil activation to peanut protein consider a hypothetical case of a 13- because studies have revealed (offering the potential to greatly year-old who had a cutaneous symptoms to be almost exclusively reduce the need to offer OFCs) and reaction to peanut as a toddler and mild in this case.41 Considering the has been shown in some studies to then developed a pollen allergy as he previous hypothetical example, if predict clinical peanut allergy, as well became older. If there was component testing had instead as peanut allergy severity, although, a combination of highly positive SPT revealed monosensitization to Ara h at present, it is largely a research tool and Ara h 2 results, this would likely 8, this would likely indicate mild (or because of the requirement for lead to a diagnosis of persisting no) reaction to peanut and would freshly collected blood, the lack of peanut allergy. help determine if the patient was standardization, and cost.43 Other eligible for an OFC (and, if no or mild tests with similar possible utility In contrast, Ara h 8 is a labile protein reactivity, carrying an epinephrine include the activation test that is not stable to heating and is autoinjector would not be necessary). 37 and the release assays, a birch homolog. In general, However, if cost is a consideration, which are also predominantly sensitization to Ara h 8 (especially if a low Ara h 2 result alone is likely research tools at this time. An there is no sensitization to Ara h 2) sufficient information to determine emerging test that has the potential to suggests either a more mild OFC eligibility. phenotype of peanut allergy or a lack diagnose peanut allergy with greater of clinical peanut allergy, especially if There are remaining uncertainties accuracy and predict prognosis, the patient is pollen allergic. Often, with CRD, such as the 95% positive severity, and response to peanut these patients demonstrate predictive values for Ara h 2 (a immunotherapy is peptide assays sensitization to peanut due to birch variety of cutoffs have been described such as the Luminex-based peptide in the literature), the role of other assay, which measures IgE binding to cross-reactivity, and the risk of 40 a systemic reaction to peanut in these peanut components, and whether linear epitopes of peanut protein. At children is low.41 A representative sensitization to certain components, present, this remains a research tool study revealed that Ara h 8 such as Ara h 2 and Ara h 6, can as well. predict severity of peanut allergy.42 sensitization, in the absence of A test that is uniformly recommended There is regional variability regarding sensitization to Ara h 1, Ara h 2, and against by multiple international immune responses against these Ara h 3, in 144 children indicated societies, including the American components as well. For example, Ara tolerance to peanut in almost all Academy of Allergy, , and 41 h 9 plays an important role in peanut cases. As a result, Ara h 8 Immunology and the Canadian allergy in patients from the component testing would be Society of Allergy and Clinical Mediterranean region.37 potentially useful in children who do Immunology is not have a history of a severe reaction In general, CRD will have the highest testing to peanut, which is a normal to peanut, especially if they have utility in specific situations: when finding in children without food concurrent pollen allergies; if they are there has been a mild reaction or lack allergy and is, in fact, a measure of monosensitized to Ara h 8, the of recent reaction in the context of tolerance and exposure to peanut (eg, likelihood of future anaphylaxis is low peanut sensitization and especially if in peanut immunotherapy clinical

Downloaded from www.aappublications.org/news by guest on September 25, 2021 4 ABRAMS et al trials) and not a measure of an reactions, with disparities noted in Although are often adverse food reaction.44,45 staff training and policies around used as first-line therapy in peanut epinephrine administration.52,53 A reactions, they are only effective in lack of preparedness has also been controlling cutaneous symptoms such MANAGEMENT noted in restaurants, where the as urticaria.57 The only life-saving Many people are involved in the day- majority of staff have no food allergy measure in an acute food allergic to-day management of peanut allergy training.54 Families could be reaction is epinephrine because it has in children, including family, close counseled to discuss the child’s a vasoconstrictive effect that contacts, schools, restaurants, and the peanut allergy with staff at schools alleviates laryngeal edema, supports food industry, among others.1 Some of and restaurants as well as be circulation with chronotropic and these management issues are counseled to carry a written inotropic effects and breathing with highlighted in Table 2. emergency plan and an epinephrine bronchodilation effects, and autoinjector at all times. In addition, additionally may reduce the release of Peanut bans and other policies to preparation for mealtimes outside of inflammatory mediators from mast reduce exposure in schools remain the home, where there may be cross- cells.58 Intramuscular epinephrine controversial.47 It has been shown contact, could be recommended. should always be used as first-line that peanut residue in school therapy in a systemic reaction to environments is low and typically There are misconceptions around peanut. Epinephrine autoinjectors are unlikely to result in a reaction48 and precautionary labeling among food often underused, and studies have that peanut-free policies have not allergic families. In both Canada and revealed a delay in, or lack of, significantly reduced the rate of the United States, although it is epinephrine administration to be accidental peanut exposures at mandatory to label products associated with increased risk of schools because there is likely some containing peanuts, families of mortality.29 peanut exposure despite the policy.49 children who are food allergic are However, accidental exposures at often unaware that precautionary Despite the need for ongoing school do occur,50 and this policy may “ ” labeling (ie, may contain )is vigilance, there is also paradoxically have value especially in younger unregulated and that there is no increasing recognition that the children, when accidental ingestion is correlation between the amount of likelihood of mortality due to more likely.47 Of interest, a recent peanut present in a manufactured anaphylaxis is exceedingly rare. In retrospective study of peanut-free product and the type of precautionary fact, the risk of fatality in the general policies and the rate of epinephrine “ label used (such as may contain population due to food-induced administration in Massachusetts peanut” versus “manufactured in anaphylaxis is approximately public schools revealed that although a facility that also processes equivalent to death by being struck policies restricting peanuts from peanut.”)55 Improved guidance is by lightning (∼1:10 million ratio).59 home being served in schools or required to help peanut allergic For children living with peanut policies for peanut-free classrooms families purchase foods safely while allergy, the major impact of allergy on did not affect epinephrine minimizing unnecessary food their lives is the day-to-day impact on administration rates, schools with avoidances because peanut allergy QoL. Studies of children with peanut peanut-free tables, compared with can cause nutritional issues in allergy reveal significant impact on those without, had lower rates of chidren.56 QoL, including overall QoL, health- epinephrine administration (P = Standard management in children related QoL, QoL in school, and .009).51 who are peanut allergic includes emotional QoL, as well as increased A more pressing issue is the counseling on avoidance of peanut separation anxiety.60 The impact of documented systemic lack of school ingestion and carrying an peanut allergy on QoL has been noted preparedness to treat allergic epinephrine autoinjector at all times. to be significantly higher than the impact of other chronic childhood TABLE 2 Management Priorities in Children With Peanut Allergy for the Pediatrician diseases such as rheumatologic disease and insulin-dependent Management Priorities diabetes mellitus.61,62 Regular social Strict avoidance of peanut, including discussion of precautionary labeling activities in childhood are Availability of epinephrine autoinjector at all times, including review of of fi anaphylaxis signi cantly disrupted because of Train family about hidden ingredients and cross-contact peanut allergy, including field trips, Discuss food ingestion outside of the home, including at restaurants, at school, and while traveling play dates, parties, sleepovers, and Screen for QoL, bullying, and anxiety related to peanut allergy other social events.63 In addition to Resources on management of peanut allergy in children include refs 1 and 46. the social isolation that children with

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 145, number 5, May 2020 5 peanut allergy feel, up to 50% of with peanut allergy.69 In this study, epicutaneous immunotherapy (EPIT) children also report bullying due to Ara h 2–specific IgE levels appeared (peanut patch on the surface of the their food allergy.64 to differ between groups, but the skin).70 Thus far, immunotherapy has sample size was too small for primarily been offered in a research Anxiety and impact on QoL in analysis. This increased phenotypic setting, although OIT is increasingly children with food allergy is largely variability of peanut allergy should be offered within community allergy related to concern of an accidental considered in the context of practices as well.71 exposure that could result in a life- avoidance of precautionary labeling, threatening reaction.60 There can be Studies on peanut OIT in children activity restriction, and, often, social concern that exposures in the have revealed it to be effective in isolation in children with peanut absence of ingestion, such as desensitization (ie, eating peanut allergy. Further research is required cutaneous or inhalational exposures, safely while on peanut OIT), with to determine if component testing – could result in a life-threatening rates between 67% and 92%.72 76 will help identify those who are low- reaction to peanut. However, this is For example, a study of 40 toddlers dose tolerant and high-dose mild. extremely unlikely. Multiple studies aged 9 to 36 months with suspected Further studies are required before have revealed minimal or no reaction peanut allergy who were randomly ED can be considered in counseling to peanut through either inhalational assigned to receive low-dose (300 mg individuals with peanut allergy on or cutaneous routes.48,65,66 A recent of peanut protein) or high-dose management. narrative review revealed minimal (3000 mg of peanut protein) peanut risk of a systemic reaction to peanut Further research is required into low- OIT over a median of 29 months from casual contact with peanut, dose–tolerant, high-dose–mild revealed an 85% desensitization rate proximity to peanut, or inhalational reactors as well as strategies to in the low-dose group and a 76% 65 exposure. Simply discussing with identify which children are more desensitization rate in the high-dose 73 a family and patient that smelling or likely to have a phenotypically mild group. The impact of peanut OIT on touching peanut is unlikely to trigger peanut allergy (eg, broadly offering sustained unresponsiveness (SU) (the a severe reaction can significantly low single-dose OFCs may improve ability to ingest peanut once stopping 67 reduce their worries. QoL in many children who are peanut OIT) is less clear, although studies with this outcome in children are Recent studies have revealed that allergic). In the interim, it is promising, with rates of SU between even with ingestion, small amounts of imperative that physicians are aware 58% and 78%.73,74 The outcome of peanut are often tolerated, of the dramatic impact peanut allergy SU is more variable because it is not highlighting the phenotypic can have on QoL and that they screen based on a standardized time after variability in severity among children for it as part of peanut allergy finishing OIT; for example, SU who are peanut allergic. Some studies management because food – fi outcomes in pediatric peanut OIT have been focused on clinical- allergy speci c instruments for studies have been at 2,74 4,73 and 874 threshold doses above which assessing QoL have recently become 63 weeks after completion of OIT. A a certain percentage of children with available. Management of peanut recent meta-analysis and systematic peanut allergy would react, termed allergy should be focused on review of the use of food allergen eliciting dose (ED). For example, ED prevention of ingestion and school 05 immunotherapy revealed efficacy would be a dose of peanut at which preparedness to treat reactions, with with desensitization but did not 5% of children with peanut allergy reassurance provided that confirm a benefit for SU, although the would react. A recent multicenter inhalational or cutaneous exposure is meta-analysis included pediatric and study of 518 children given a single- unlikely to cause a reaction. adult patients, and the authors did dose OFC of 1.5 mg peanut protein not look specifically at peanut.70 (6 mg whole peanut; ∼1% of a peanut EMERGING THERAPIES kernel) revealed a low rate of A limitation of peanut OIT is the high reactivity (2.1%; 95% CI: Immunotherapy to peanut is rate of adverse events associated with 0.6%–3.4%), with all reactions being emerging as an exciting treatment of this treatment, although, in general, mild.68 Ara h 2–specific IgE levels peanut allergy and involves the adverse events are mild (such as were not associated with objective administration of increasing doses of mild cutaneous or gastrointestinal reactions to peanut. In another study, peanut to children who are peanut symptoms).70 There can be it was noted that up to 50% of allergic, with the goal of allowing safe anaphylaxis with peanut OIT, children with peanut allergy did not and ongoing exposure to peanut. The although, in studies thus far, this rate react until the fourth or fifth dose of majority of research thus far is tends to be much lower in preschool- peanut on OFCs, termed “low-dose- focused on oral immunotherapy (OIT) aged children than in school-aged tolerant, high-dose-mild” children (ingestion of peanut) and children and older.73,77,78 Reactions

Downloaded from www.aappublications.org/news by guest on September 25, 2021 6 ABRAMS et al TABLE 3 Advances and Ongoing Controversies in the Prevention, Diagnosis, Management, and Emerging Therapies of Peanut Allergy Description Prevention Advances Early peanut ingestion prevents PA up to 80% of the time in high-risk infants Controversies and Whether high-risk infants require screening before peanut ingestion and the definition of high risk limitations Whether this benefit applies to lower-risk infants Once ingested, how much peanut and how often is required to promote ongoing tolerance Whether tolerance would remain if peanut is no longer ingested regularly Diagnosis Advances CRD may allow for better prediction of clinical PA as well as phenotypic severity, especially in pollen-sensitized patients Other emerging research tests, in particular, basophil activation testing and peptide assays, may have the benefit of greater diagnostic accuracy and improved ability to predict prognosis, severity, and response to peanut immunotherapy Controversies and First-line testing (SPT and specific IgE), although sensitive, lacks specificity and should not be overly relied on limitations Sensitization (positive testing results) in the absence of clinical allergy is common among atopic children OFC is the gold standard but carries risk of anaphylaxis and is resource intensive Management Advances Increasing recognition of phenotypic variability of PA severity ED studies on threshold tolerance may help improve QoL in the future Recognition that fatality due to anaphylaxis is extremely low Controversies and The role of peanut-free policies in schools limitations Disparities in education and training among schools and restaurants Variance in precautionary labeling Emerging therapies Advances Studies have revealed peanut OIT to be robust in peanut desensitization, but it carries notable side effects, especially in older children and adolescents EPIT reveals modest desensitization and excellent safety Additional therapeutics are under clinical study Controversies and Attaining SU limitations The use of peanut OIT outside of a research setting Whether efficacy and safety of OIT could be enhanced with probiotics or omalizumab The best application of emerging therapies PA, peanut allergy. are more common with cofactors, the meta-analysis, making it difficult weighed against the ability to such as viral infection or exercise, and for the reader to arrive at any increase threshold tolerance to can occur even once at maintenance conclusions about QoL.71,75,76 peanut. Drop-out rates may be lower dosing.71 There is also the risk of in preschool-aged children because (estimated at There remain ongoing controversies OIT is well before long-standing 2.7%, although lower in toddlers), with peanut OIT. There are aversion and anxiety become which, in general, tends to resolve arguments for and against its use entrenched.78 with discontinuation of peanut outside of a research setting.69 It is OIT.78,79 A recent meta-analysis and unclear whether the efficacy or safety EPIT is also emerging as a therapy in of peanut OIT of OIT in older children could be children who are peanut allergic and revealed that OIT (versus no OIT) enhanced with concurrent use of has been described to have increased anaphylaxis risk and either probiotics or omalizumab and potentially better adherence and epinephrine use and did not improve what role and cost US Food and Drug safety profiles than OIT.81 However, QoL.80 However, this meta-analysis Administration–approved OIT the treatment response thus far has did not include preschool-aged products will have when they come to been more modest than that of children, and emerging real-world market.71 It is unclear what peanut OIT.81 A recent phase III study data have revealed different safety contributes to drop-out rates over of 356 children with peanut allergy outcomes according to age, with rates time and whether OIT long-term will revealed that daily peanut-patch of epinephrine use between 14.5% alter anaphylaxis fatality rates. therapy for 12 months resulted in and 23% in school-aged children and Further long-term data on the safety a 21.7% (95% CI: 12.4%–29.8%) older, compared with 4% in of OIT, its role in SU, and its role in better response (response was preschool-aged children. Also, QoL modulating immune pathways are defined as tolerating a much higher outcomes were only available for required. Common adverse events, dose of peanut at the OFC after EPIT) a minority of the subjects included in although usually mild, must be compared with a placebo, which was

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 145, number 5, May 2020 7 statistically significant (P , .001) but Table 3, we summarize advances and allergy, although its role in SU is did not meet the prespecified lower limitations and/or ongoing less clear. bound of the CI threshold.82 EPIT in controversies in the field. Current general only caused local skin first-line diagnostic tools for peanut reactions, although the rate of these allergy have good sensitivity but ABBREVIATIONS patch-site reactions was high in both fi limited speci city, which may be CI: confidence interval active and placebo groups.81,82 enhanced with component-resolved CRD: component-resolved diag- Other emerging therapies that are diagnostic tools, especially under nostic testing being studied include sublingual certain clinical circumstances. ED: eliciting dose immunotherapy, the use of Chinese Management of peanut allergy EPIT: epicutaneous herbal formula, DNA vaccines, and requires avoidance and carrying of an immunotherapy adjuvant-enhanced immunotherapy.83 epinephrine autoinjector. However, IgE: immunoglobulin E the risk of fatality due to anaphylaxis LEAP: Learning Early About - is extremely low, and there is minimal CONCLUSIONS Allergy risk associated with cutaneous or OFC: oral food challenge There have been exciting inhalational exposure. The focus of OIT: oral immunotherapy developments in the field of peanut ongoing management should be on QoL: quality of life allergy prevention, with early peanut improving QoL. Immunotherapy is SPT: skin prick test or testing ingestion demonstrating a strong emerging as an exciting tool to SU: sustained unresponsiveness preventive role in infants at risk. In desensitize children with peanut

POTENTIAL CONFLICT OF INTEREST: Dr Abrams is a member of the scientific advisory board for Food Allergy Canada. Dr Chan has received research support from DBV Technologies; has been a member of advisory boards for Pfizer, Pediapharm, Leo Pharma, and Kaleo; is a member of the scientific advisory board for Food Allergy Canada; and was an expert panel and coordinating committee member of the National Institute of Allergy and Infectious Diseases–sponsored guidelines for peanut allergy prevention. Dr Sicherer reports royalty payments from UpToDate and from Johns Hopkins University Press; grants to his institution from the National Institute of Allergy and Infectious Diseases, from Food Allergy Research and Education, and from HAL Allergy; and personal fees from the American Academy of Allergy, Asthma, and Immunology outside of the submitted work. He was an expert panel and coordinating committee member of the National Institute of Allergy and Infectious Diseases–sponsored guidelines for peanut allergy prevention.

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