Intern seminar Peanut allergy

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1 Intern seminar Peanut allergy
Reporter: Intern 黃怡璇 Supervisor: 陳志安 醫師 王志堯 醫師 Date: 2015/01/13

2 Patient profile Chart no. 135401XX Name: 陳O宇 Sex: male
Birth Date: 2009/11/27   Age: 6 years old BW: 20.7 Kg (75-85 th percentile) BH:115.3 cm (85-97 th percentile)  

3 Past History Allergic history: Peanut
Birth History: G1P1,C/S,GA36+5wks, BBW:2938g, DOIC(-), PROM(-) Feeding: on full diet Vaccination: as schedule Additional vaccination: Influenza(-) HAV(-) Rota(+) Developmental milestones: WNL Allergic history: Peanut Past History: Atopic dermatitis Urticaria Asthma Allergic rhinitis Hospitalization history: 2010/05/24-05/27 UTI 2011/09/14-09/17 bronchopneumonia Social history: nothing particular Current Medications: Procaterol Levocetirizine Ketotifen Procaterol intermediate-acting β2-adrenergic receptor agonist used for the treatment of asthma Loratadine tab 10mg/tab (Finska) Antihistamines Ketotifen 1mg/tab (Zaditen) Mast cell stabilizer Levocetirizine 5mg/tab (Xyzal) Antihistamines

4 Family history asthma Atopic dermatitis Mother: atopic dermatitis

5 Clinical course Peanut allergy Birth Breast feeding: avoid
2009/11 Birth Breast feeding: avoid peanut, beef, seafood Accidentally ingestion of peanut butter Urticaria over face to inguinal area, angioedema 2010,1y/o ER s/p Epinephrine Accidentally ingestion of pesto sauce Urticaria, angioedema ER s/p Epinephrine 2012/04 Visit Dr. Wang’s OPD History, MAST test, IgE 自家提供蒸的花生 花生蛋白質萃取 *花生去殼去皮後,蒸軟後 加水用研砵磨成泥狀 *放置4℃ Stir Overnight *離心 2000rpm 30min, 取上清後測蛋白質濃度 no lip swelling nor dyspnea Risk factor Family history: peanut allergy or atopic disease Personal history: atopic disease Skin care products: containing crude peanut oil in young children with atopic dermatitis Timing of first exposure Consumption of soy products in infancy ? Maternal ingestion of food allergens: during pregnancy and lactation ? Avoidance Regular follow up Peanut allergy 2014/04 Skin patch test, ImmunoCAP start peanut SLIT 2014/04/23

6 Sublingual immunotherapy (SLIT)
SLIT peanuts protein mg (1mg/ml dilute 1000X  0.1ml *5) 2014/04/23 SLIT peanuts protein 0.1mg*1 2014/04/30 SLIT peanuts protein 0.1mg*1 2014/05/07 + 1 drop/ week, to 10 drop 2014/07/02 SLIT peanuts protein 0.1mg*10 1滴 0.1 mL 留觀20min SLIT peanuts protein 0.05mg 留觀20min (1mg/ml dilute 1000X  0.1ml *5) SLIT peanuts protein 0.1mg 1-5滴 SLIT peanuts protein 0.1mg 每週增加1滴(0.1ml) SLIT peanuts protein 0.1mg 7滴 (4Y7M) SLIT peanuts protein 0.1mg 10滴 SLIT peanuts protein 0.1mg 10滴/月 SLIT peanuts protein 1mg 1週增加1滴 2014/03/26 skin patch test: no reaction (0.3ml N/S.1000*.10000*) 04/02 patch test: (0.2ml N/S-.1000* erytema.10000*-) 04/16 skin patch test all negative(0.1ml N/S.10*.100*.1000*) 04/23 start peanut Sublingual immunotherapy (SLIT) ONE DROP(0.05mL) for 1000*peanut after 20 min: ok look for late phase reaction (e,g urticaria? ) 4/30 sublingual 100* 1mg/ml: no reaction, no discomfort after peanus sublingual 1000* ? 5/7 sublingual 10* 1mg/ml: no reaction, no discomfort after peanus sublingual 100* ? 06/18 sublingual 10* 1mg/ml: no reaction, no discomfort after peanuts sublingual 10*7drops 7/2 1mg/dl *6m no discomfort after peanuts sublingual 10*10drops 7/30 sublingual 1mg/dl* peanut no discomfort after peanuts sublingual 1*7drops 8/27 no discomfort after peanuts sublingual 1*10drops sublingual 10* 1mg/ml: no reaction skin prick test: erythema 1(5*7mm)-0.1(8*4mm)-G Anaphylactic shock due to peanuts ??? 2014/08/27 SLIT peanuts protein 1mg*1 Skin prick test + 1 drop/ week, to 10 drop

7 eyelid swelling, urticaria, no lip swelling,
no dyspnea, cough and rhinorrhea 2014/09/05 花生粉 exposure 2014/09/24-11/11 SLIT peanuts protein 1mg*10 2014/ /01 AGE and URI recently off SLIT for one+ month 2015/02/03 SLIT peanuts protein 10mg* 1 SLIT peanuts protein 1mg 最高10滴 因腸胃炎停用一個月 SLIT peanuts protein 1mg 10滴 ~ SLIT peanuts protein 10mg 每週增加1滴,最高20滴 BH:112.3cm, BW:20kg, BT:36.2℃, 5歲8月 (2015/7/28) skin test: erythema 1(5*7mm)-0.1(8*4mm)-G skin prick test: histamine ind 6*6 Ery 19*20 N/S ind 3*4 ery 5*7 peanut ind 18*9 ery 30*25 4/28 10mg*10drops asthma Allergic conjuntivitis 6/16 7/21 for peanut challenge 7/28 skin eczema, ithcy eye and sneezing 11/24 兩顆花生? 1/5 9/24 no discomfort after peanuts sublingual 1*10drops 9/5 花生粉 exposure eyelid swelling urticaria no lip swelling nor dyspnea cough and rhinorrhea no fever (sublingual 1mg/dl* 10drops peanut ) titrate dose to 2mg/dl next month 10/29 fever for 1wk(10/13-20) acute bronchitis->asthma attack 11/11 (sublingual 1mg/dl* 10drops peanut ) (arrange provocation test when 10mg/dl) (titrate dose to 2mg/dl next month) 12/09 eyelid swelling urticaria no lip swelling nor dyspnea fever for 4ds after Prevenar 12/30 eyelid swelling urticaria no lip swelling nor dyspnea acute gastritis and URI recently cough+ off SLIT for one+ month (sublingual 10mg/dl* 5drops peanut ) 2015/01/20 2/03 (sublingual 10mg/dl* 5drops peanut ) 3/03 sublingual 10mg/dl* 9drops peanut 3/31 no discomfort after peanuts sublingual 1*10drops 4/21 no discomfort after peanuts sublingual 1*10drops + 1 drop/ week, to 20 drop 2015/06 SLIT peanuts protein 10mg*20 peanut challenge: steamed peanut Fried peanut ??? 2015/07 + 1 kernel/ week, to 20 kernel

8 Discussion Peanut allergy

9 Epidemiology Prevalence of food allergy Prevalence of peanut allergy
peak: 6 – 8% at 1 y/o → fall progressively until late childhood (3 – 4%) Cow's milk(12%), egg (4.4%), fish (3%), nuts (2.1%) Prevalence of peanut allergy Western countries: % in children, 0.5 – 1% in overall population US: 5.1% in children ( y/o) PREVALENCE OF CHILDHOOD FOOD ALLERGY — Most food allergy is acquired in the first or second year of life. The peak prevalence of food allergy is approximately 6 to 8 percent at one year of age, although rates as high as 10 percent have been reported [1-4]. It then falls progressively until late childhood, after which the prevalence remains stable at about 3 to 4 percent Cow's milk was the single food item most commonly incriminated, with a cumulative incidence of 12 percent. Other problematic foods reported by parents included egg (4.4 percent), fish (3 percent), nuts (2.1 percent), and cereals (1.4 percent). Variable criteria are used to measure food allergy. In studying IgE-mediated allergy, some researchers examine rates of "sensitization," or the presence of IgE directed against a specific food, as detected by in vivo (skin testing) or in vitro testing for specific IgE (often called radioallergosorbent testing, or RAST, though nowadays the test uses fluorescence rather than radioactivity, and is termed FEIA for fluorescent-enzyme immunoassay). This is distinct from clinical reactivity, which is the development of symptoms on exposure to a food, as assessed by history or challenge. This distinction occurs because not all patients with detectable food-specific IgE antibodies will have a reaction when the food is ingested. Less commonly, patients may have clear histories of food allergic reactions with low or undetectable levels of food-specific IgE. Thus, studies measuring sensitization to food allergens may overestimate the prevalence of true food allergy. Asia Pac Allergy Jan; 3(1): 3–14.

10 Pathogenesis Arachis hypogaea (Ara h 1 to 9):
allergenic proteins in peanut IgE-mediated reactions dominant allergens: Ara h 1 to 3 Acute chronic Nine major and minor allergenic proteins in peanut (Arachis hypogaea), designated Ara h 1 to 9, have been identified that are responsible for immunoglobulin E (IgE)-mediated reactions The pathogenesis of non IgE-mediated peanut, tree nut, and seed allergy is less clear. Several reasons have been proposed to explain why peanut (and possibly tree nuts and seeds) are more allergenic than other foods: ●Seed storage proteins contain disulfide bonds that give these proteins high thermostability and resistance to extreme pH values. In addition, these proteins are often glycosylated, which further increases thermal and proteolytic stability. Ara h 1 in the glycosylated form can act as a T helper type 2 (Th2) adjuvant, activating dendritic cells to induce maturation and proliferation of Th2 cells, which promote IgE production [53]. (See "Molecular features of food allergens".) ●Certain factors involved in harvesting and processing may also make these foods more allergenic. A greater amount of Ara h 1 is found in larger, more mature peanut kernels and in peanuts dried or cured at higher temperatures [54]. High heat roasting leads to glycation reactions that increase protein stability and allergenicity. ●Metabolized vegetable oils, such as peanut oil can serve as adjuvants, increasing the immune response to antigens [55]. Whipping or emulsifying peanut butter to prevent the oil from separating from the peanut solids brings more of the water-soluble protein into direct contact with the oil, potentially increasing the immunogenicity of peanut proteins ingested in this manner. Eosinophils — Eosinophils are found mainly in peripheral organs. Their maturation is strongly induced by interleukin-5 (IL-5). Eosinophils are clearly linked to the classic manifestations of immunoglobulin E (IgE)-mediated allergy, including allergic rhinitis and asthma. Several studies have also shown that eosinophils present in large numbers in parts of the gut are linked to clinical manifestations of food allergy (eg, eosinophilic esophagitis) . Mast cells — Mast cells are present in most organs. They play a major role as effector cells in IgE-mediated food allergy. Food-specific IgE antibodies bound to Fc (fragment, crystallizable)-epsilon receptors on mast cells initiate degranulation upon activation by food antigen. Vasoactive amines are released, resulting in the common clinical reactions of food allergy. Measurement of mast cell mediators, such as tryptase, can be helpful in the diagnosis of food-related anaphylaxis. Antigens in the IgE response are identified as allergens, which in foods are glycoproteins. Eight peanut allergens have been identified that are termed as Ara h 1 to Ara h 8 (Arachis hypogaea). The two major peanut allergens, Ara h 1 and 2, are part of the vicilin and conglutin families of storage proteins, respectively The initial introduction of a food allergen generally occurs at the mucosal surface of the gastrointestinal tract.17 Food proteins are taken up by specialised epithelial cells, M cells, transferred to antigen-presenting cells such as dendritic cells, and processed into peptide fragments presented on the cell surface by class II MHC molecules (fi gure).18,19 Peptides are then presented to naive T helper (Th) cells via MHC/T cell receptor interaction, resulting in Th cell priming and activation. This event initiates humoral and cellular events associated with, in this particular case, peanut allergy. In individuals with a genetic predisposition for allergic disease, the activation of T helper cells results in secretion of cytokines that stimulate B cells to synthesise IgE antibodies specifi c for peanut in the sensitisation phase of the immune response. T helper 2 (Th2) cells cause secretion of various interleukins including interleukin-4, interleukin-5, interleukin-9, and interleukin-13. In the eff ector phase of the immune response, the IgE antibodies made specifi cally to peanut are bound primarily on mast cells and basophils by the high affi nity surface IgE receptors (FcεRI). After ingestion, the peanut protein (not carbohydrate or fat) crosslinks with the specifi c IgE antibodies on mast cells and basophils, releasing various infl ammatory mediators including histamine, prostaglandins, leukotrienes, and platelet-activating factor. Additionally, tumour necrosis factor (TNF), interleukin-5, and chemokines produced at the local site result in the activation and recruitment of eosinophils. The Lancet  , DOI: ( /S (08) ) Copyright © 2008 Elsevier Ltd Terms and Conditions

11 Risk factors Family history Personal history of atopic disease
peanut allergy atopic disease Personal history of atopic disease Timing of first exposure Skin care products Maternal ingestion pregnancy ? lactation ? Timing of first exposure — The timing of introduction of a food may influence the development of allergy versus tolerance, although this phenomenon has been difficult to study in humans and is a source of ongoing debate. Peanut allergy has more than doubled in young children in countries where delayed introduction of peanut until at least three years of age was recommended [1,4]. In addition, the rate of peanut allergy is lower in countries where peanuts are introduced at a younger age [6,14,62]. However, dietary advice was generally poorly followed in countries that recommended delayed introduction, so the impact of these recommendations is unclear [4]. One study noted that the age at first exposure in children who developed peanut allergy and age at initial reaction (19 and 21 months) was lower during the period in which delayed introduction was recommended, compared with the age of exposure and allergy onset (22 and 24 months) in the period prior to those recommendations Skin care products: containing crude peanut oil in young children with atopic dermatitis Maternal ingestion of food allergens: during pregnancy and lactation ?

12 Clinical features Co-allergy Associated atopic diseases
Egg (53 %), cow's milk (26%) Tree nuts (25-50%) Associated atopic diseases asthma (60 – 75%) atopic dermatitis (60 – 75%) allergic rhinitis (55 – 60%) most common causes of food-induced anaphylaxis Threshold dose  1-3 peanut kernels Patients with severe reactions: lower Threshold dose — The typical threshold dose for triggering objective symptoms is equivalent to one to three peanut kernels [70]. A peanut kernel contains roughly 162 mg of peanut protein Patients with severe reactions typically have lower threshold doses of peanut protein than patients with mild symptoms [71]. The lowest reported level of peanut triggering an immunoglobulin E (IgE)-mediated reaction in both children and adults is 0.05 mg of peanut protein [71-75]. Allergies to other foods — One-quarter to one-half of patients with peanut allergy have co-allergy to tree nuts, and about one-half of the patients with allergy to tree nuts are allergic to more than one nut [1,70,77]. Some of this co-allergy is due to cross-reactive homologous IgE-binding epitopes Concurrent sensitization and allergy to other foods is common in patients with peanut allergy. In one study, sensitization or co-allergy to other food was seen in two-thirds of patients with peanut allergy [63]. Egg was the most common (53 percent), followed by cow's milk (26 percent), fish (11 percent), shellfish (9 percent), soy (7 percent), wheat (6 percent) and sesame seed (6 percent). Associated atopic diseases -- Patients with peanut allergy often have asthma (60 to 75 percent), atopic dermatitis (60 to 75 percent), and/or allergic rhinitis (55 to 60 percent) [87]. Coexisting asthma is a risk factor for anaphylactic reactions to peanut Natural history and prognosis — The age at first exposure and age at first reaction are commonly between one to two years of age, although allergy to peanut, tree nuts, and seeds can develop later in life [8,32,45,63,88]. Symptoms occur with first known direct ingestion in up to three-quarters of children [31,89]. Subsequent reactions when the child is older are often more severe than the initial episode

13 Natural history of peanut allergy
Resolution Most food allergies: usually outgrown Peanut allergy: Mostly lifelong disorder 20 -25% lose sensitivity 80% of resolutions <8 y/o Recurrence infrequent exposure may be a risk factor for re-sensitization. Although it was initially believed to be a lifelong sensitivity in nearly all cases, subsequent studies have shown that tolerance can develop in approximately 20 to 25 percent of patients Resolution Peanut — Early studies suggested that peanut allergy was persistent [66]. However, subsequent data have revealed that up to one-quarter of patients become tolerant over time. Resolution was associated with smaller-sized skin prick test reaction and fewer allergies to other foods in one study [67]. In a longitudinal study of children diagnosed with peanut allergy at ≤18 months of age, 80 percent of resolutions occurred before eight years of age, with decreasing annual rates of resolution over time Later onset peanut allergy is often associated with oral allergy syndrome due to birch pollen allergy, and may not be lifelong. Recurrence In this and several other small series of patients with resolved peanut allergy, it appears that recurrence may be more common among those who continue to avoid peanut or eat it infrequently [57,59,72,73]. In the study previously discussed, each of the three patients with recurrent allergy consumed concentrated peanut products less than once a month [72]. In contrast, none of a group of 23 patients who ate peanut more frequently had recurrent allergy. Thus, infrequent exposure may be a risk factor for resensitization.

14 Predictors of resolution
Peanut-specific IgE levels: best predictor SPT wheal size Non-predictive factor: severity of the initial reaction age at diagnosis presence of other atopic diseases history of outgrowing other food allergies The size of the skin test reaction or specific IgE level for peanut and tree nuts, and specific IgE levels to component proteins for peanut, are the most reliable predictors of resolution versus persistence of the allergy, although up to 25 percent of children may have mean wheal diameters to peanut >10 mm, peanut-specific IgE >15 kU/L, or IgE to the peanut protein Ara h 2 and be nonreactive to oral challenge [94-96]. In contrast, clinical features do not reliably predict persistence. Prognostic factors  ●Low or undetectable specific IgE levels were the best predictors of a negative challenge. ●Clinical features do not reliably predict persistence; neither the presence of other atopic diseases, age at diagnosis, nor the severity of initial peanut or tree nut reactions predicted subsequent loss of the allergy. ●Challenge was essential to determine the loss of allergy with certainty, as some patients still reacted even when their skin prick tests and/or in vitro tests became completely negative. It has been our estimation that this may occur in as many as 10 percent of patients in such studies. ●Tolerance of peanut does not imply tolerance of tree nuts or seeds. In patients who outgrow peanut allergy, tree nut allergy or seed allergy can persist or subsequently develop for the first time [71]. Potential allergy to these foods must be independently evaluated. skin prick tests or in vitro tests negative ≠ resolution Factors that did not predict the development of tolerance included the severity of the initial reaction and the history of having outgrown other food allergies other than peanut. In contrast, patients who had outgrown peanut allergy were more likely to outgrow tree nut allergy. No child that had reactions to more than two different tree nuts achieved tolerance. Summary — Peanut and tree nut allergy affects at least 0.5 to 1.4 percent of children and 0.5 to 1 percent of the general population, and may be increasing over time. This type of allergy is likely to be a lifelong disorder for most, but not all patients. Because a substantial minority (ie, 20 to 25 percent for peanut and 9 percent for tree nut) of patients lose their sensitivity over time, it is appropriate to reevaluate children on a regular basis. ●Patients who have not had reactions in the past one to two years and who have low TN- or PN-IgE levels (≤2 kUA/L) should be considered for an oral peanut challenge in a supervised setting. In our clinic, we measure in vitro specific IgE levels (eg, ImmunoCAP) values yearly, and because of safety concerns, only challenge children older than four years of age. A negative in vitro test is not a guarantee that the allergy is resolved, and challenge is necessary to make this determination. ●Peanut allergy can recur following resolution, although this is unusual. Tree nut allergy has not been studied as well. Infrequent ingestion of peanut may be a risk factor for recurrence, but these data are derived from small numbers of cases. The severity of symptoms in a given individual with peanut, tree nut, or seed allergy may vary considerably between reactions. In addition, the severity of an initial reaction does not predict the severity of subsequent reactions. Furthermore, skin test and specific IgE results are not predictive of the severity of reactivity to a food.

15 Diagnosis or Clinical history Skin prick tests
In vitro immunoassays for specific IgE Double-blind, placebo-controlled oral food challenge (DBPCFC) gold standard or History and test not consistent IgE-MEDIATED REACTIONS — An unequivocal history of an immediate reaction consisting of typical allergic symptoms following the isolated ingestion of a peanut, tree nut, or seed product, supported by positive tests for specific immunoglobulin E (IgE) antibodies, is usually sufficient to establish the diagnosis for suspected IgE-mediated reactions. Either skin prick tests or in vitro tests for IgE are usually performed initially. skin prick testing: Sensitivities and negative predictive values at these decision points or cutoff levels are generally poor. do not reflect the severity of the allergy SPTs are quite sensitive and have a negative predictive accuracy of greater than 90% [5]. Moreover, a positive test (defined in most studies as a mean wheal diameter 3 mm >the saline control) simply confirms sensitization but does not alone confirm the diagnosis. With increasing SPT wheal size, however, there is an increasing likelihood of a reaction to the tested food The skin prick test wheal size and level of specific IgE correlate with the likelihood of an allergic reaction, but by themselves are not diagnostic of food allergy. Serum Food-Specific IgE positive values simply reveal sensitization and do not assure clinical reactivity. This provides further evidence that the test should not be used in isolation to diagnose food allergy. IgE level of 13 to 15 kUA/L to peanut has a 95 to 99 percent PPV for clinical reactivity to peanut in patients with suggestive histories of allergic reactivity Similar to SPTs, many published studies have attempted to correlate serum-specific IgE levels with results of food challenges and therefore to provide the clinician with IgE levels that can predict the likelihood that a patient will react on ingestion of the food and thus abrogate the need for an OFC [12, 20–28]. Data from these studies are not always consistent and have not been able to assign one specific cutoff value that provides optimum specificity and sensitivity for any single food across all populations. Rather, what is clear is that in all studies, a direct correlation exists between increasing concentrations of food-specific serum IgE and the probability that an individual will react to an ingested food. Double-blind, placebo-controlled oral food challenges (DBPCFC) are the gold standard for the diagnosis of food allergy. A clinician-supervised oral food challenge is required if the history and IgE test results do not clearly indicate an allergy. False-negative food challenges have been documented to occur in up to 3% of cases Diagnostic approach — The clinical history is important for guiding the diagnostic evaluation in a patient with suspected peanut, tree nut, or seed allergy. Foods suspected of provoking an IgE-mediated reaction may be evaluated with skin prick tests, which indicate whether or not the patient has IgE antibodies to the suspected food. The larger the mean wheal diameter of the skin prick test, the greater the likelihood that the food being tested is the cause of the allergic reaction. Obtaining food-specific IgE levels (eg, ImmunoCAP) to foods suspected by history or by the presence of positive skin tests provide further evidence regarding whether or not a specific food is the cause of a suspected allergic reaction, as described previously. However, an oral food challenge should be performed if these tests are positive in the absence of a suggestive history or in the presence of an equivocal history. Similarly, an oral food challenge should be performed to establish the diagnosis if these tests are negative in the face of a convincing history clinical history : history of an immediate reaction following the isolated ingestion of a peanut oral food challenge should be performed if these tests are positive in the absence of a suggestive history or in the presence of an equivocal history. Similarly, an oral food challenge should be performed to establish the diagnosis if these tests are negative in the face of a convincing history. Non-IgE-mediated reaction IgE tests are expected to be negative Atopy patch testing DIAGNOSTIC PITFALLS  The higher rate of sensitization than clinical allergy may be due in part to cross-reactions to homologous plant allergens, such as birch and grass pollen [24,25]. Thus, the positive predictive value (PPV) of skin testing to peanut is poor if the test is performed in individuals who have a low probability of peanut allergy based upon clinical history. The presence of undetectable IgE levels (<0.35 kUA/L) does not exclude clinical reactivity SKIN TESTING Prick/puncture skin tests --IgE-mediated reaction. Because of the low specificity of skin testing, it should not be used to screen patients for allergy by testing with broad panels of food allergens without regard for clinical history, since this is likely to yield false-positive results. intradermal skin testing should not be performed in the evaluation of food allergy, because of the risk of triggering a systemic reaction. Immunoassays — Radioallergosorbent tests (RASTs) and fluorescent enzyme immunoassay (FEIA) tests are in vitro assays used to identify food-specific immunoglobulin E (IgE) antibodies in the serum. The test results are reported as food-specific IgE levels (in kUA/L). Thus, the patient’s clinical history is critical to both determining the tests to perform and confirming the diagnosis. By comparison, lower food-specific IgE levels are less helpful because food challenge is still frequently required to make a definitive diagnosis Component testing — Foods are comprised of numerous proteins, and an individual with a food allergy may have immune responses of varying degrees to any of them. Proteins that are destroyed easily by heating or digestion are less likely to cause significant allergic reactions compared with heat or digestion-stable proteins. Ara h 2, for example, is a peanut seed storage protein that is stable. IgE responses to this protein are associated with severe reactions compared with IgE responses to the peanut protein Ara h 8, which is a labile protein homologous to a protein in birch tree pollen Basophil histamine release TRIAL ELIMINATION DIETS FOOD DIARIES FOOD CHALLENGES Studies have shown that the peanut-specifi c IgE measured in the ImmunoCAP-FEIA system are generally predictive of having peanut allergy when the peanut-specifi c IgE level is greater than 14 kU/L.

16 Management Avoidance Immunotherapy Humanized monoclonal anti-IgE
Oral (OIT) Sublingual (SLIT) Subcutaneous Humanized monoclonal anti-IgE These studies offer the possibility of at least raising the threshold of the amount of peanut that it would take to cause a life-threatening allergic reaction; whether these types of treatments are likely to cause eventual clinical tolerance to develop remains to be seen. In view of the severity of the clinical reactions from peanut allergy and because the allergy can be life-long, effective treatments need to be developed FOOD ALLERGEN-SPECIFIC THERAPY — The aim of allergen-specific therapies is to alter the allergic response to the food allergen so that the patient becomes desensitized or, preferably, tolerant to the specific food. Possible future food allergen-specific therapies include oral, sublingual, and subcutaneous immunotherapy. ORAL-IMMUNOTHERAPY PROTOCOL The protocol for oral immunotherapy consisted of three phases: an initial-day dose escalation, a build-up phase, and a maintenance phase dur- ing which participants ingested up to 2 g of egg- white powder per day, which is the approximate equivalent of one third of an egg the degree of protection following successful immunotherapy was likely to prevent accidental peanut anaphylaxis initial escalation phase, home dosing, build up visits and maintenance phase??? It is clear from the above studies that peanut oral immunotherapy presents an interesting novel form of intervention for peanut-allergic children, resulting in good efficacy for desensitisation. The safety profile is also good with most subjects experiencing mild or moderate reactions. NONSPECIFIC THERAPY — The aim of nonspecific therapies for food allergy is primarily to downregulate the allergic immune response. Some therapies in development have only a transient effect, but others may be curative. Humanized monoclonal anti-IgE — Allergen-specific immunoglobulin E (IgE) antibodies play an important role in the pathophysiology of food allergy. IgE antibodies bind to high-affinity receptors (Fc-epsilon-RI) on the surface of mast cells and basophils. Crosslinking of IgE molecules on the surface of mast cells by allergen leads to the release of preformed mast cell mediators (the early phase of an allergic reaction) as well as synthesis of proinflammatory cytokines and chemokines that result in late-phase reaction [115]. (See "The biology of IgE".) Humanized monoclonal anti-IgE antibodies bind to the constant region (third domain of the Fc region) of IgE molecules and prevent the IgE molecules from binding to receptors (Fc-epsilon-RI and Fc-epsilon-RII). Anti-IgE cannot interact with IgE molecules once they are already bound to the IgE receptor, and, thus, anti-IgE is not capable of crosslinking IgE. Furthermore, anti-IgE downregulates the expression of Fc-epsilon-RI receptor on mast cells and decreases basophil histamine release [116]. (See "Anti-IgE therapy".) A multicenter, randomized trial evaluated humanized monoclonal anti-IgE mouse immunoglobulin G1 (IgG1) antibody (talizumab) in 84 patients with a history of immediate hypersensitivity to peanut [117]. Peanut hypersensitivity was confirmed and the threshold dose of peanut protein established by a double-blind, placebo-controlled, food challenge (DBPCFC) at screening. Patients were randomly assigned to receive either TNX-901 (150, 300, or 450 mg) or placebo subcutaneously every four weeks for four doses. Patients underwent a second oral peanut challenge within two to four weeks after the fourth dose. The mean baseline threshold of sensitivity increased in all groups, with an apparent dose response, but was only significant in the 450 mg group. In this group, the sensitivity threshold increased from a level equal to approximately half a peanut (178 mg) to one equal to almost nine peanuts (2805 mg); an effect that should provide protection against most accidental ingestion. However, even at the highest dose of TNX-901, approximately 25 percent were not protected. It remains to be determined whether further dose increases might confer protective effect in these patients. Anti-IgE therapy is not a cure, and protection would require administration at regular intervals indefinitely. However, its appeal is that it should be useful for patients with food anaphylaxis regardless of the offending food. Prior to clinical application, further studies are necessary to confirm and optimize the protective effect of anti-IgE against food anaphylaxis, establish a safety profile in young children, and identify markers for selecting patients who are most likely to benefit from anti-IgE therapy.

17 Mechanism of immunotherapy
increasing, tolerable doses build up peripheral cell tolerance promotion of Treg cell formation Allergen-specific immunotherapy (allergen-SIT) involves administration of allergen proteins to patients in increasing, tolerable doses to build up peripheral tolerance and modulate the immune response. It is currently regarded as the single curative approach to allergic disease[29]. The induction of peripheral T cell tolerance and promotion of Treg cell formation are key mechanisms in SIT high doses of SIT are associated with a higher risk of these adverse events, low doses are found to be ineffective[30]. It is therefore critical to calculate an optimal dosing plan to strike the correct balance between the two. An effective dosing plan must ensure several factors: the induction of therapeutic tolerance, achievement of long-term change in T cell populations and absence of serious adverse effects. When explored within the autoimmune encephalomyelitis model of multiple sclerosis in mice, treatment with subcutaneous self-peptide immunotherapy demonstrated the strong dose-dependent nature of tolerance induction using several markers (e.g. IL-10 levels and severity of disease[34]). The study also indicated that high initial antigen doses induced adverse effects across almost all of the mice. Dose escalation was therefore found to be vital, with the ability to diminish adverse effects and lower or delay the level of inflammatory cytokines. Oral tolerance is mediated through different mechanisms, depending upon the antigen dose. (A) Low doses of ingested antigen induce tolerance via activation of regulatory T cells that produce suppressive cytokines, such as IL-10 and TGF-beta. (B) High doses of oral antigen lead to induction of tolerance via anergy (TCR cross-linking occurs without costimulation) or deletion (TCR is cross-linked in the presence of inhibitory molecules, CD95 and CD95L, leading to FAS-mediated apoptosis). Th3: T helper cell type 3; CD: cluster of differentiation; Tr1: regulatory T cell type 1; TGF-beta: transforming growth factor-beta; R: receptor; IL-10: interleukin-10; MHC: major histocompatibility complex; TCR: T cell receptor; L: ligand. Oral tolerance is thought to be mediated by induction of regulatory T cells with low-dose antigen exposure, or lymphocyte anergy or deletion with high antigen doses. The humoral immunologic changes include a gradual increase in serum levels of specific immunoglobulin G4 (IgG4) antibodies and in saliva levels of specific immunoglobulin A (IgA) antibodies. In addition, an initial increase in serum levels of specific immunoglobulin E (IgE) antibodies is seen in the first 12 months, followed by a subsequent decrease. Specific T regulatory cells increase and peak at approximately 12 months, with a subsequent decrease. Increased antigen-induced regulatory T-cell function is associated with hypomethylation of forkhead box protein 3 (FOXP3) [13]. Basophil reactivity, skin prick test responses, and serum levels of T helper type 2 (Th2) cytokines decrease gradually, whereas interferon (IFN)-gamma, macrophage inflammatory protein (MIP)-1 alpha and monocyte chemotactic protein (MCP)-1 increase over the course of OIT Oral immunotherapy involves the administration of initially very small doses (usually micro or milligrams) of food allergen to food allergic patients in a controlled clinical setting. The dose of the administered food allergen is then systematically increased until a maximum tolerated dose of food allergen is quantified (Jones 2009). Regular dosing with this maximal dose is then maintained at home by the patient. Successful desensitisation is thought to induce immunological tolerance by generating allergen specific IL-10 secreting Tr1 and/or TGF-secreting Th3 regulatory T-cell Immunologic changes during the course of AIT. Starting with the first injection, decreases in mast cell and basophil activity, degranulation and tendency for systemic anaphylaxis degranulation takes place within the first hours. This is followed by generation of allergen-specific Treg and Breg cells and suppression of allergen-specific Th1 and Th2 cells. Specific IgE shows an early increase and decreases relatively late. These events are in parallel to increases of IgG4 that continuously increases as long as the treatment continues. After several months, the allergen-specific IgE/IgG4 ratio decreases. After a few months, decreases in tissue mast cells and eosinophils and release of their mediators and skin late phase response occurs. A significant decrease in type I skin test reactivity is also observed relatively late in the course. It has to be noted that there is significant variation between donors and protocols. World Allergy Organ J. 2015; 8(1): 17.

18 Early exposure v.s Avoidance ???
The Learning Early about Peanut Allergy (LEAP) trial was conceived to determine whether the early introduction of dietary peanut could serve as an effective primary and secondary strategy for the prevention of peanut allergy. Here we report the primary findings of the LEAP trial. Terms peanut (PN) primary prevention: non-sensitized persons secondary prevention: persons sensitized on test results for allergen-specific IgE or skin-prick testing. ITT: intention-to-treat SPT: skin-prick test Background guidelines: elimination Failed to prevent IgE-mediated food allergy early consumption of peanuts: protection from development of peanut allergy in similar ancestry. Clinical practice guidelines from the United Kingdom in and from the United States in recommended the exclusion of allergenic foods from the diets of infants at high risk for allergy and from the diets of their mothers during pregnancy and lactation. failed to show that elimination from the diet prevented the development of IgE-mediated food allergy Several years ago, we found that the risk of the development of peanut allergy was 10 times as high among Jewish children in the United Kingdom as it was in Israeli children of similar ancestry. 14 This observation correlated with a striking difference in the time at which peanuts are introduced in the diet in these countries: in the United Kingdom infants typically do not consume peanut-based foods in the first year of life, whereas in Israel, peanut-based foods are usually introduced in the diet when infants are approximate- ly 7 months of age, and their median monthly consumption of peanut protein is 7.1 g. 14 This finding led us to hypothesize that the early introduction of peanuts to the diet may offer protection from the development of peanut allergy.

19 4-11m/o ±severe eczema±egg allergy
No wheal Wheal=1~4mm Randomize Randomize baseline challenge baseline challenge Some families agreed to have peanut protein levels measured in dust collected from the participant’s bed 2 to 4 weeks before the final visit. Clinical assessments were Adequate adherence to treatment was defined in the peanut-avoidance group as consumption of less than 0.2 g of peanut protein (the equivalent of one peanut) on any occasion and less than 0.5 g over a single week in the first 2 years of life. In the peanut-consumption group, adequate adherence was defined as consumption of at least 2 g of peanut protein on at least one occasion in both the first and second years of life and of at least 3 g of peanut protein (25 g of Bamba [a snack food made from peanut butter and puffed maize] or 12 g of peanut butter) per week for at least 50% of the weeks during which data were recorded. undertaken at baseline (when participants were between 4 months and 11 months of age) and at the ages of 12, 30, and 60 months until 60 m/o

20 Methods Randomized, open-label, controlled trial Primary outcome
peanut allergy at 60 m/o oral food challenge History, SPT, peanut-specific IgE Immune markers skin-prick tests: 1-2mm peanut-specific IgE, IgG, IgG4, IgG4:IgE ratio primary outcome was the proportion of participants with peanut allergy at 60 months of age and was determined in 617 participants by means of an oral food challenge Participants in whom peanut allergy was unlikely (no wheal after a skin-prick test at months 30 and 60, no history of allergic symptoms after ingestion of peanut, no diagnosis or suspicion of allergies to sesame or tree nut, and no history of anaphylaxis in response to any food) received 5 g of peanut protein in a single dose. A double-blind, placebo-controlled food challenge was conducted for other participants (with a total of 9.4 g of peanut protein administered in increments) in accordance with standard dose-escalation pr Immune Markers positive values of 1 mm and 2 mm (which are associated with peanut-specific IgE production 21 ) were considered to be indicative of early sensitization, even though these values are lower than the traditional cut-off of 3 mm Serum levels of peanut-specific IgE, IgG, and IgG4 antibodies were measured at each visit, since these are known biomarkers of allergic responses, antigen exposure, and potential immune modulation, respectively. The peanut-specific IgG4:IgE ratio was calculat-ed, since it has been reported that this ratio may additionally reflect immune modulation. Statistical Analysis The analyses compared the proportion of participants with peanut allergy in the peanut-avoidance group with the proportion with peanut allergy in the peanut-consumption group at month 60 with the use of a two-tailed chi-square test.

21 Results Peanut consumption and allergy in high-risk children
86.1% relative reduction 70.0% relative reduction The results of a worst-case imputation analysis in the intention-to-treat population were also consistent with the results of the main intention-to-treat analysis The worst-case imputation analysis (Panel C) assumes that participants with missing data in the peanut-consump- tion group would have been allergic to peanuts and that participants with missing data in the peanut-avoidance group would have been nonallergic.

22 Primary and secondary prevention
In this study, the intervention was effective in reducing the prevalence of peanut allergy in terms of both primary prevention (prevalence of 6.0% in the avoidance group vs. 1.0% in the consumption group, P=0.008) and secondary prevention (33.1% vs. 6.8%, P<0.001) The primary prevention group comprised those participants who were both peanut SPT-negative AND specific IgE negative (<0.1 kU A /L) at baseline, as shown in Table 1. The overall secondary prevention group comprised participants who were either SPT-positive, peanut-specific IgE positive (IgE ≥0.1 kU A /L), or both at baseline. Table S3 shows the results for the sensitization permutations within the secondary prevention group; these three groups include participants with baseline sensitization results that are SPT Negative AND IgE Positive, SPT Positive AND IgE Positive, and SPT Positive AND IgE Negative. The results demonstrate that the intervention was highly effective in all groups; however, the SPT-Positive AND IgE Negative group included only 22 participants and was not sufficiently powered to detect a statistically significant difference in the prevalence of peanut allergy (21.4% versus 0%, p=0.1589). The sample size for this analysis is 625 (not 628) because of 3 missing peanut specific-IgE values at baseline Safety no significant differences in rates of hospitalization or serious adverse events Higher frequencies of adverse events in consumption group: URI, viral skin infection, gastroenteritis, urticaria, conjunctivitis Adherence For both measures of adherence, there were no significant differences between the cohort with negative results on the skin-prick test and the cohort with positive results Response to Oral Food Challenge Among the 57 participants (9 randomly assigned to consumption and 48 to avoidance) who had a positive response to the oral food challenge at 60 months, 14 had respiratory or cardiovascular signs and 9 received intramuscular epinephrine owing to concerns about the severity of the allergic reaction

23 Immunologic Assessments
Figure 3. Immunologic Outcomes for the Peanut-Avoidance and Peanut-Consumption Groups at Baseline (4 to <11 Months of Age) and at 12, 30, and 60 Months of Age. A significant increase from baseline in wheal size was seen only in the peanut-avoidance group. Participants who were allergic to peanuts at month 60 showed a more pronounced increase in wheal size over time. These participants also had higher peanut-specific IgE levels. Although peanut-specific IgE levels increased over time in both the peanut-avoidance and peanut-consumption groups, there were fewer participants in the consumption group with very high IgE levels at 12, 30, and 60 months Panel A shows wheal sizes after the peanut-specific skin-prick test and the levels of peanut-specific IgE in participants in the avoidance and consumption groups who met the per-protocol criteria. The solid black lines show the group mean over the course of the study period; the mean wheal size after the peanut-specific skin-prick test differed significantly between the randomized groups at all time points after baseline (P = at 12 months and P<0.001 at 30 months and 60 months). The thin red lines represent the trajectory of the development of allergic responses among participants who were allergic at 60 months of age.

24 Consumption > avoidance
Significantly larger change in consumption group The levels of peanut-specific IgG and IgG4 were higher in the consumption group than in the avoidance group. Peanut-specific IgG4 levels increased over time in both groups, but these changes were significantly larger in the consumption group (P<0.001). The ratio of peanut-specific IgG4 to IgE increased up to 30 months of age in the consumption group but was relatively constant in the avoidance group. At month 60, the IgG4:IgE ratio in nearly all the participants with peanut allergy in the avoidance group fell below the mean ratio for the group. Panel B shows the levels of peanut-specific IgG and IgG4 and the peanut-specific IgG4:IgE ratio over the course of the study period. The means of each of these measures differed significantly between the two study groups at all postbaseline time points (P<0.001). The log10 of the ratio of peanut-specific IgG4:IgE was calculated after peanut-specific IgG4 levels were converted from milligrams per liter to nanograms per milliliter and the peanut-specific IgE levels were converted from kilo unit per liter to nanograms per milliliter with the use of the formula (IgG4 × 1000) ÷ (IgE × 2.4). At month 60, all the participants in the peanut-avoidance group who had peanut-specific IgE levels of more than 10.0 kU per liter were allergic to peanuts, regardless of their level of peanut-specific IgG4. All other allergic participants had levels of peanut-specific IgE between 0.1 and 10 kU per liter and levels of IgG4 that were less than µg per liter. - Consumption group: increased up to 30 m/o - avoidance group: constant

25 Discussion Among infants with high-risk atopic disease, early peanut consumption, as compared with avoidance, resulted in significantly less peanut allergy at 60 m/o. Safety and effectiveness of early peanut consumption is unknown. excluded SPT >4 mm adherence rate = 92.0% Among infants with high-risk atopic disease, sustained peanut consumption beginning in the first 11 months of life, as compared with peanut avoidance, resulted in a significantly smaller proportion of children with peanut allergy at the age of 60 months. Safety and effectiveness of early peanut consumption in that population remain unknown ←the LEAP study excluded SPT >4 Peanut consumption may not be possible in some children who meet the LEAP eligibility criteria ←adherence rate = 92.0% The overall rate of adherence to the two as- signed interventions was 92.0%. Among the 319 participants randomly assigned to consumption, 7 were instructed not to consume peanuts be- cause they had a positive result at baseline to the oral food challenge, and 9 terminated consump- tion largely because they began to have allergic symptoms to peanuts. This indicates that peanut consumption may not be possible in some chil- dren who meet the LEAP eligibility criteria. the LEAP study design excluded 9.1% of the infants who were screened (76 of 834) because large wheals (greater than 4 mm in di- ameter) developed after the skin-prick test 21 that were probably associated with peanut allergy; the safety and effectiveness of early peanut consump- tion in that population remain unknown.

26 Mirrors the immunologic changes in successful immunotherapy
Peanut-avoidance group ↑ diameter of wheals ↑ peanut-specific IgE Peanut-consumption group greater and earlier increase in peanut-specific IgG and IgG4

27 Take home message Peanut allergy mostly do not outgrow.
Peanut immunotherapy safely induced a modest level of desensitization and established tolerance. Early oral introduction of peanuts could prevent allergy in high-risk, sensitized and nonsensitized infants. Our findings showed that early, sustained consumption of peanut products was associated with a substantial and significant decrease in the development of peanut allergy in high-risk infants. The question of whether the participants who consumed peanut would continue to remain protected against the development of peanut allergy even after prolonged cessation of peanut consumption requires further study and is under investigation in the LEAP-On study

28 Reference Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy. N Engl J Med. 2015, 372;9, A Wesley Burks. Peanut allergy. The Lancet. 2008, 371, No.9623, 1538–1546. J. A. Lieberman et al. Diagnosis of food allergy: epicutaneous skin tests, in vitro tests, and oral food challenge. Curr Allergy Asthma Rep, 2011, 11: 58–64. Fleischer et al. Sublingual immunotherapy for peanut allergy:Arandomized, double-blind, placebo-controlled multicenter trial. J Allergy Clin Immunol, 2013, 131: A J Lee et al. Food allergy in Asia: how does it compare? Asia Pac Allergy Jan; 3(1): 3–14. Cezmi A Akdis et al. Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens. World Allergy Organ J. 2015; 8(1): 17. UpToDate Peanut allergy A Wesley Burks

29 Thanks for your attention!

30 Multiple Allergen Simultaneous Test
2012/04/03 2013/03/05 Multiple Allergen Simultaneous Test 4 檢測到非常高濃度的抗體

31 2014/03/04 ImmunoCAP fluorescent enzyme immunoassay system
Phadia ImmunoCAP fluorescent enzyme immunoassay (CAP-FEIA) system

32 2014. 04. 16 skin patch test 1mg/ml peanuts protein (0. 1ml N/S
skin patch test 1mg/ml peanuts protein (0.1ml N/S.10X, 100X, 1000X) ​ skin patch test 1mg/ml peanuts protein (0.3ml N/S.1000*.10000*) 無明顯反應? skin patch test 1mg/ml peanuts protein (0.2ml N/S.1000*.10000*) 無明顯反應? 1mg/ml peanuts protein (0.1ml N/S.10X, 100X, 1000X) 無明顯反應

33 skin prick test skin prick test: erythema 1(5*7mm)-0.1(8*4mm)-G ?

34 2015/04/21


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