Advances in Asthma, Allergy, and Immunology Series 2009

Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2008
Scott H. Sicherer, MD,a and Donald Y. M. Leung, MD, PhDb,c This review highlights some of the research advances in anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects and in allergic skin disease that were reported in the Journal in 2008. Key epidemiologic observations include a rise in anaphylaxis in a population-based study and lower rates of peanut allergy in Israel, where infants consume peanut early compared with the United Kingdom, where dietary introduction is generally delayed. Advances in food allergy diagnosis include IgE epitope mapping that discloses the likelihood and severity of allergy; studies correlating likelihood of clinical reactivity on the basis of food-specic IgE to sesame, peanut, milk, and tree nuts; and an observation that a low baseline angiotensinconverting enzyme level may be associated with having pharyngeal edema during a reaction. Molecular, immunologic, and genetic studies are discerning pathways that are key in development of food allergy, identifying new modalities to interrupt mast cell degranulation, and elucidating risks associated with penicillin allergy. Regarding treatment, clinical studies show a majority of children with milk and egg allergy tolerate these proteins in modest amounts when they are extensively heated in baked goods, and studies show promise for oral immunotherapy to treat milk allergy and sublingual immunotherapy for honey bee venom hypersensitivity. The importance of skin barrier dysfunction has continued to be highlighted in the pathophysiology of atopic dermatitis (AD). Research has also continued to identify immunologic defects that contribute to the propensity of patients with AD to develop viral and bacterial infection. New therapeutic approaches to AD, urticaria, and angioedema have been reported including use of probiotics, biologics, vitamin D, and skin barrier creams. (J Allergy Clin Immunol 2009;123:319-27.) Key words: Dermatology, skin disease, urticaria, atopic dermatitis, anaphylaxis, allergy, hypersensitivity disorders, food, drug, insect venom
From athe Elliot and Roslyn Jaffe Food Allergy Institute, Division of Allergy and Immunology, Department of Pediatrics, Mount Sinai School of Medicine, New York; bthe Department of Pediatrics, University of Colorado Denver; and cthe Division of Pediatric Allergy/Immunology, National Jewish Health. Disclosure of potential conict of interest: S. H. Sicherer has received research support from the National Institutes of Health/National Institute of Allergy and Infectious Diseases. D. Y. M. Leung has received research support from Novartis and Genentech. Received for publication December 18, 2008; accepted for publication December 19, 2008. Reprint requests: Scott H. Sicherer, MD, Division of Allergy/Immunology, Mount Sinai Hospital, Box 1198, One Gustave L. Levy Place, New York, NY 10029-6574. E-mail: scott.sicherer@mssm.edu. 0091-6749/$36.00 2009 American Academy of Allergy, Asthma & Immunology doi:10.1016/j.jaci.2008.12.025

New York, NY, and Denver, Colo

Abbreviations used AD: Atopic dermatitis CAU: Chronic autoimmune urticaria DC: Dendritic cell HO-1: Heme oxygenase mDC: Myeloid dendritic cell OFC: Oral food challenge PPAR: Peroxisome proliferator-activated receptor SEB: Staphylococcal enterotoxin B TIM: T-cell immunoglobulin mucin Treg: Regulatory T UK: United Kingdom

This review highlights key advances in allergic skin disease, anaphylaxis, and hypersensitivity to foods, drugs, and insect venom selected primarily from among more than 85 articles on these topics published in the Journal in 2008. Some of the key advances are summarized in Table I.

FOOD ALLERGY Epidemiology and risk factors Population-based assessments of food allergy are scarce. Data from 34 emergency departments in the National Electronic Injury Surveillance System were analyzed for food-related adverse events over August and September 2003.1 Extrapolating from the available data, there were 20,281 emergency department visits, 2333 episodes of anaphylaxis, and 520 hospitalizations for food allergic reactions in the United States over this 2-month period. For adults, shellsh was the most common trigger, whereas egg, fruits, peanuts, and tree nuts were more common triggers for young children. Medical record review showed that 57% with likely anaphylaxis were not coded as such, highlighting the difculties in ascertaining event rates from coding databases. Challenges to estimating the burden of food allergy were highlighted by Zuidmeer et al,2 who undertook an exhaustive review of population-based studies of plant food allergies, excluding peanut, and found 36 population-based studies with only 6 studies that included oral food challenges (OFCs) to conrm diagnoses. Estimates varied widely from 0.1% to 4.3% for fruits and tree nuts, 0.1% to 1.4% for vegetables, and under 1% for wheat, soy, and sesame; however, even the studies with OFCs had potential selection biases that could overestimate or underestimate reaction rates. The authors also point out that studies relying on self-reported food allergy typically greatly overestimate adverse reactions compared with studies with OFCs. Like food proteins,
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TABLE I. Summary of selected key advances reported in the Journal in 2008

Topic Clinical or basic research concerns Advances and observations

Food allergy

Risk factors Molecular aspects/pathophysiology

Diagnostic testing

Treatment/management

Anaphylaxis

Epidemiology and management

Insect venom hypersensitivity

Treatment

Drug allergy

Diagnosis and treatment

Atopic dermatitis

Mechanisms

Treatment Chronic urticaria Mechanisms and treatment

Early ingestion of peanut may reduce the risk of peanut allergy. Soy ingestion is not a risk for peanut allergy. TIM-1/TIM-4 interactions may be key in development of food allergy. Presymptomatic differences in Treg cell function (cord blood) may inform development of food allergy. 5. IgE epitope mapping of milk and peanut proteins may better inform diagnosis and determination of severity. 6. Reduced baseline angiotensin-converting enzyme levels are associated with having pharyngeal edema during anaphylaxis. 7. Diagnostic information correlating reaction rates and specic IgE concentrations has been reported for peanut, milk, sesame, and several tree nuts. 8. Supplementation of Phadia hazelnut ImmunoCAP with Cor a 1 elevates the test result in persons with birch pollenosis. 9. Studies reveal a majority of children with egg/milk allergy tolerate modest doses in extensively heated foods (wafes/mufns), and immune outcomes of ingesting these foods mirror immunotherapy. 10. Studies show promise for milk oral immunotherapy. 11. A population-based study reveals an increase in the prevalence and rate in 2000 of 58.9 per 100,000 person-years. 12. A small molecule has been discovered that inhibits mast cell degranulation through interruption of Syk signaling in a murine model. 13. A venom immunotherapy trial in patients with mastocytosis shows promise. 14. Sublingual immunotherapy to honeybee venom reduces large local reactions in a pilot concept study. 15. Penicillin allergy is associated with a family history of penicillin allergy and with single nucleotide polymorphisms in the IL4 gene and genes involved in penicillin metabolism. 16. A successful rapid desensitization protocol is presented for chemotherapeutic agents. 17. Various lipid and protein skin barrier abnormalities contribute to AD. 18. Filaggrin null mutations are associated with severity and persistence of AD, increased allergen sensitization, and eczema-associated asthma. 19. Abnormalities in dendritic cell and T-cell function enhance TH2 responses in AD. 20. Skin barrier creams and anti-inammatory therapies including topical steroids, calcineurin inhibitors, and biological immunomodulatory agents. 21. Basophils from chronic urticaria exhibit a spectrum of histamine releasability irrespective of Syk expression. 22. Chronic autoimmune urticaria may respond to treatment with anti-IgE.

1. 2. 3. 4.

food additives are often perceived to be a likely trigger for adverse reactions, although conrmation is typically lacking. Park et al3 used double-blind, placebo-controlled OFCs to test 54 atopic persons with a mixture of 7 food additives used commonly in Korea and, after consideration of placebo reactions, found no evidence of reaction to the additives. Despite difculties in obtaining rm population-based data on the prevalence of food allergies, there has been evidence for a general increase in food allergies, documented best for peanut, sesame, and kiwi, that could be attributed to environmental and dietary factors including reduced immune stimulation from infectionthat is, the hygiene hypothesis; changes in the components of the diet, including antioxidants, fats, and nutrients such as vitamin D; and the use of medications such as antacids, among others.4-6 Peanut allergy is the focus of research on food allergy risk factors because of severity, permanence, and impairment of quality of life.7 A concern that exposure to the legume soy may increase the risk of peanut allergy was addressed in a prospective observational study of a cohort of 620 Australian infants with risk

factors for atopy followed for peanut sensitization to age 2 years.8 A relationship of soy ingestion to peanut sensitization (odds ratio, 2.0) was noted but explained by atopy factors that led parents to choose a substitute for milk formulas, resulting in no evidence for a risk after adjusting for these factors (odds ratio, 1.34; 95% CI, 0.6-2.8; P 5 .43). Another hypothesis for increased peanut allergy is that avoidance of early ingestion, possibly coupled with sensitizing noningestion exposure, especially widespread skin contact facilitated by eczematous skin lesions, may result in a reduced opportunity to develop oral tolerance.4 Circumstantial evidence supporting this hypothesis is presented by a study using a validated questionnaire that determined peanut allergy rates in a school age cohort of Israeli Jewish children (n 5 5615) to be 0.17%, compared with a cohort of Jewish children in the United Kingdom (UK), where the rate was about 10-fold higher (1.85%; P < .001).9 A separate survey was undertaken in general clinics using a validated food consumption questionnaire administered to 77 UK and 99 Israeli Jewish families. This additional survey found that

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monthly consumption of peanut at ages 8 to 14 months was 7.1 g in Israel compared with 0 g in the UK (P < .0001). Thus, these data support the notion that early oral exposure may in fact not be a risk for peanut allergy but may rather promote tolerance compared with prolonged avoidance. However, the authors indicate that randomized controlled trials are needed to conrm this hypothesis.

Pathophysiology, allergen characterization, and diagnosis Insights on food allergy immunopathophysiology may provide inroads toward improved diagnosis, prevention, and treatment. The T-cell immunoglobulin mucin (TIM) gene family is important in TH1/TH2 differentiation, with interaction of TIM1 expressed on T cells with TIM-4 on dendritic cells (DCs) possibly leading to TH2-polarized responses.10 The potential therapeutic effect of interrupting this interaction was demonstrated in a murine model in which bone marrowderived DCs were conditioned with peanut antigen and cholera toxin, which was noted to increase DC expression of TIM-4, and adoptively transferred to mice that were subsequently orally challenged to peanut and developed signs of allergic inammation and reactions.11 Interference with the TIM-1/ TIM-4 interaction, by using RNA interference techniques or antiTIM-1 antibodies, reduced or abrogated these responses, thereby identifying a potential therapeutic target. TIM-4 may also be modulated by exposure to staphylococcal enterotoxin B (SEB).10 Ganeshan et al12 reasoned that on the basis of an association with atopic disease and ubiquity in foods, SEB may be a factor promoting food allergies. They present a murine peanut and ovalbumin allergy model using SEB and report successful sensitization of several mouse strains and allergeninduced eosinophilia (not seen in cholera toxin models). They present data indicating that the mechanism likely includes impairment of regulatory T (Treg) cell responses during lowdose sensitization protocols. The functional role of Treg cells in human food-allergic disease was evaluated by Smith et al,13 who tested cord blood mononuclear cells from children destined or not to develop egg allergy. CD41 effector T cells and antigen-presenting cells were cocultured with or without CD41CD251CD127lo/2 Treg cells, the addition of which, under stimulation with SEB, resulted in reduced IL-10, IL-13, and IFN-g; the neonates destined to be allergic showed less Treg cellassociated suppression of IFN-g compared with the group without allergy (44% vs 78%; P 5 .015). The study therefore provides preliminary evidence of presymptomatic differences in Treg cell function in neonates who develop allergic disease. Insights that are relevant to diagnosis, prediction of crossreactivity, reaction severity, persistence of allergy, and treatment are obtained through studies that evaluate allergen structure and IgE binding to food allergens and related nonfood allergens, such as pollens, in well characterized patient populations.14-16 For example, Cerecedo et al17 used microarray techniques to map IgE and IgG4 binding to sequential epitopes of 5 milk proteins and found 10 regions that were recognized by at least 75% of children with allergy and differentiated them from children who passed OFCs. Detection of IgE binding to particular proteins of a food may inform severity of an allergy because preferential binding to proteins that are more stable to digestion may result in more severe reactions compared with having IgE that primarily recognizes labile proteins. For example, Flinterman et al18 evaluated

children with reactions to hazelnut, identifying IgE reactivity toward the lipid transfer protein Cor a 8 as a risk factor predicting objective reactions, and Holzhauser et al19 found that IgE binding to soy Gly m 5 (b-conglycinin) and Gly m 6 (glycinin) was a marker of severe reactions to soy. Several studies with relevance for current and future diagnosis and prognosis focused on peanut, especially because standard allergy tests do not accurately predict severity. Flinterman et al20 performed microarray analysis of IgE epitope binding to the 3 major peanut allergens Ara h 1, 2, and 3 and found that sensitivity to peanut, determined during double-blind, placebo-controlled OFC by eliciting dose and severity scores, was related to the number of epitopes recognizedfor example, epitope diversity. Summers et al21 extended analysis of severity to clinical and laboratory parameters in evaluating 1094 patients presenting to a tertiary referral clinic with peanut or tree nut allergy over a period of 12 years. Older age and severity of atopic disease were risk factors for aspects of reaction outcomes. For example, life-threatening bronchospasm was more likely in subjects with severe asthma (relative risk, 6.8) compared with mild asthma (relative risk, 2.7), and those with severe atopic dermatitis (AD) had a 3.1-fold higher risk for experiencing altered consciousness. A subgroup of 122 patients had serum tests for angiotensin-converting enzyme, and those with levels under 37 mmol/L had a 9.6-fold higher risk of experiencing pharyngeal edema during a reaction. The authors postulated that bradykinin likely mediates this specic outcome. If the results are conrmed in additional studies, low levels of angiotensin-converting enzyme may be a marker of importance for risk assessment and treatment. Finally, Ho et al22 followed children less than 2 years of age with likely peanut allergy on the basis of their previously determined predictive skin test sizes. Children were followed up to age 8 years with repeated skin and serum tests and orally challenged when clinically indicated. Twenty-one percent were determined to have resolved peanut allergy. Predictors of resolution by age 5 years identied at age 2 years included smaller skin tests (32% remission for tests 4-6 mm vs 13% for >10 mm) and lower peanut-specic serum IgE (29% for <2 kUA/L vs 3% for >6 kUA/L). Additional studies using standard serum IgE tests provide additional diagnostic insights.23 For example, Maloney et al24 reported the diagnostic utility of the ImmunoCAP (Phadia, Inc, Uppsala, Sweden) by comparing diagnoses (primarily from history) against tests results for peanut, sesame, and 6 tree nuts among 324 subjects, primarily children. Allergen-specic IgE levels indicating an estimated 95% predictive probability were obtained for peanut (13 kUA/L) and walnut (18.5 kUA/L). The authors report probability curves for peanut, sesame (50% reaction probability ;25 kUA/L), walnut (50% reaction probability ;1 kUA/L), pistachio (50% reaction probability ;2 kUA/L) and almond (50% reaction probability ;10 kUA/L), although the calculated values for the latter 3 foods are based on few observations. Additional studies in children focused on sesame,25 for which a 95% diagnostic level could not be determined (a sesame level of 7 kUA/L or greater had a predictive value of 74%), and milk, for which double-blind, placebo-controlled OFCs were performed with 213 children and a level of 52 kUA/L was associated with a 95% predictive value (7.5 kUA/L for those under age 2.5 years).26 It is crucial to appreciate that increasing studies of these types have shown different diagnostic correlations, probably as a result of differences in patient selection, food allergy prevalence, age, underlying atopic diseases, denition and

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methods of obtaining food allergy outcomes, and other factors. Further cautions about the interpretation of diagnostic tests include technical aspects of the tests. For example, the Phadia hazelnut ImmunoCAP was recently supplemented with Cor a 1, which makes the test value elevated for persons with birch pollen allergy (caused by Bet v 1 cross-reactivity),27 and because allergen sources and reagents differ among manufacturers, the results may not be comparable.28

Treatment Strict avoidance of the offending allergen has been the cornerstone of food allergy management. However, recent studies of egg and milk allergy have presented the possibility of a shift in this dogma because it is increasingly recognized that some children tolerate egg or milk protein when it is extensively heatedfor example, as an ingredient in baked goods.29-32 Regarding egg, it could be presumed that persons more reactive to heat-stable proteins, such as ovomucoid, may be less likely to tolerate extensively heated egg. Ando et al30 challenged 108 children with suspected egg allergy to egg that was raw or heated for 1 hour at 908C. A total of 38 reacted to heated egg, 29 tolerated heated but not raw egg, and the remainder were fully tolerant. They found that the egg white ImmunoCAP was useful for predicting reaction to raw egg with a 95% positive decision point at 7.4 kUA/L and a 95% negative decision point at 0.6 kUA/L. However, the ovomucoid ImmunoCAP was superior for predicting reactivity to heated egg, with a 95% positive decision point at 10.8 kUA/L and a 95% negative decision point at 1.2 kUA/L. The children tolerating heated egg were allowed to ingest baked goods containing egg, although no follow-up was provided. Lemon-Mule et al31 evaluated 117 subjects with possible egg allergy by challenging them to heated egg (mufn and wafe with 2.2 g egg protein baked at 3508F for 30 minutes or 5008F for 3 minutes in a wafe iron, respectively). Subjects tolerant to the baked form during an OFC were fed less cooked egg unless they had tests showing a high likelihood of current egg allergy. Of the subjects who were not proven tolerant to egg at the study outset, 64 (70%) tolerated heated egg and 27 did not. Those tolerating heated egg had lower egg white and ovalbumin and ovomucoid IgE levels and smaller skin tests than reactive subjects. The heated eggtolerant subjects incorporated baked egg products into their diet and were followed for a year. At 3 months, compared with baseline, those with baked egg in their diet had smaller skin tests and lower ovalbumin IgE levels and increased ovalbumin and ovomucoid-specic IgG4 levels that remained stable afterward. Regarding reactions during the OFCs, a similar proportion of the subjects had anaphylaxis (none severe) and were treated with epinephrine for both the heated and standard egg challenges. The study is promising in showing that a proportion of children can tolerate baked egg and that immune parameters measured on the foods appear similar to those seen during immunotherapy, but more study is needed to see whether eating baked egg promotes tolerance. Unfortunately, the study did not have a control group who could tolerate baked egg products but were followed off baked egg. The same research group took a similar approach to milk, nding that of 93 children reactive to milk, 68 (73%) tolerated the extensively heated milk products (eg, 1.3 g milk protein baked into mufn/wafe).32 Immune parameters distinguishing the 2 groups at baseline and changes from baseline for those on heated milk at 3 months generally were similar to those described for egg. However, unlike the heated egg study, heated milkreactive

subjects had more severe reactions during their heated milk OFC than did heated milktolerant subjects during the positive challenge to unheated milk (35% vs 0% given epinephrine). This distinction from the study of egg may indicate that the matrix effect of heating egg with wheat may additionally alter allergenicity. Like the egg study, more research is needed to determine who may tolerate baked forms and the specic implications of including these foods in the diet. Increasing studies are approaching treatment of food allergy by oral immunotherapy.33 Longo et al34 specically targeted 60 children with severe cows milk allergy who reacted to under 0.8 mL milk and had serum IgE >85 kUA/L. Thirty underwent a 10-day in-hospital rush protocol aiming for a nal dose of 20 mL, and then home dosing proceeded gradually, aiming for 150 mL. After 1 year, 11 (36%) achieved 150 mL or more, 3 could not achieve 5 mL, and the remainder (54%) tolerated 5 to 150 mL. These nal tolerated doses were conrmed by observation under challenge. In contrast, the untreated controls had no improvement in their threshold to milk as conrmed by challenge after a year. Almost all treated children had reactions during the protocol, mostly oral or cutaneous, although more severe reactions did occur during for both in-hospital and at-home treatments (intramuscular epinephrine was given 4 times in the hospital and once at home). Milk IgE levels declined in the treated group. In the rst randomized, double-blind, placebo-controlled study of cows milk oral immunotherapy, Skripak et al35 included 20 children (12 completed active treatment, 7 placebo) in a regimen of an escalation day (aiming for 50 mg), 8 weekly updosings to a nal dose of 500 mg, and maintenance for 3 to 4 months. The median dose eliciting a reaction at baseline was 40 mg, which increased to 5140 mg (range, 2540-8140 mg) in the treated group but was unchanged in the placebo group. Of active doses, 45% resulted in reactions, mostly mild, 4 treated with epinephrine, versus an 11% reaction rate among those on placebo doses. Milk IgG4 levels increased in the treated group, although IgE levels did not change. These 2 studies show promise for treatment of milk allergy with oral immunotherapy, but additional studies are needed to determine more about side-effect proles and safety, long-term efcacy, and especially whether these protocols induce transient desensitization or more permanent tolerance. In a different approach to milk allergy treatment, a study using probiotics did not show efcacy in speeding resolution of milk allergy.36 Current therapy still relies on allergen avoidance and emergency treatment of severe reactions with epinephrine. Jarvinen et al37 documented a 19% rate of use of more than 1 dose of epinephrine for a food-allergic reaction among children using any epinephrine. The study group was 413 children with food allergy in a referral population in which epinephrine was used for 95 reactions. The second (or for 6 children, even a third) dose were provided by health care professionals for 94% of the reactions. Although the need to carry 2 rather than just 1 dose is debated, it is clear that schools with multiple children having epinephrine prescriptions often store 2 doses for multiple children; this costly practice was surveyed against an alternative, namely that each child has 1 injector specied for that child and the school maintains 2 total spares for anyone to use.38 Parents were generally in favor of this potential cost-savings approach. Regarding anaphylaxis management, a prospective study of 785 children with food allergy given an allergist-directed management plan showed high efcacy for avoiding reactions and treating them appropriately with a reduced need for epinephrine after the plan.39

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ANAPHYLAXIS The incidence of anaphylaxis determined by a comprehensive index of medical records in Rochester, Minn, from 1990 to 2000 showed an overall incidence rate of 49.8 cases per 100,000 person-years, more than double that of estimates from this region from 1983 to 1987.40 Although subtle differences in acquisition of cases may have partly accounted for the increase compared with a decade before in this primarily white community, there was also an increase in annual incidence rate from 46.9 to 58.9/100,000 from 1990 to 2000 (P 5 .03). Foods accounted for 33.2%, insect stings 18.5%, and medications 13.5% of episodes. Current prevention and therapy of anaphylaxis require education about avoidance of triggers and treatment of reactions. Nurmatov et al41 reviewed the literature on studies of available anaphylaxis management plans and noted that aside from encouraging early use of epinephrine, they vary widely and have not been well studied. The authors encourage more studies of these plans to determine efcacy. Specic therapies for anaphylaxis are lacking. Mazuc et al42 reported the discovery of a small molecule that inhibits mast cell degranulation through interruption of Syk signaling. The compound was given orally to mice who then demonstrated reduced anaphylaxis to antigen challenge as measured by rectal temperature and capillary leak measured by extravasation of Evans blue dye, indicating promise for this compound. HYPERSENSITIVITY TO STINGING INSECTS Immunotherapy for stinging insect allergy is a major therapeutic accomplishment. Several studies have further elucidated clinical therapy for this disease. Gonzalez de Olano et al43 extended venom immunotherapy to 21 patients with mastocytosis, 18 of whom had experienced anaphylaxis to a previous sting. Six experienced adverse reactions to the treatment, including 5 with reduced blood pressure, and 2 of them discontinued it. Subsequent stings occurred in 12 treated subjects. Nine had only local reactions, and 3 had systemic reactions (1 severe requiring intubation, but this patient was just initiating therapy). IgE to Hymenoptera decreased signicantly over a period of 4 years of treatment. The authors presented cautions about increased risks of venom immunotherapy in this group but suggested the treatment is recommended given the observed efcacy. Severino et al44 reported the use of sublingual immunotherapy to honeybee venom in a controlled trial of individuals who had large local reactions only and were sensitized. They compared sting responses 6 months after therapy and noted in the active group of 14 subjects that the reaction size decreased from 20.5 to 8.5 cm (P 5.014) and specic IgG increased signicantly with no change in these parameters for 12 controls. There were no side effects. Immunotherapy is not indicated for large local reactions, but this proof of concept study shows promise of sublingual immunotherapy for treatment of insect venom hypersensitivity. Another advance in honeybee venom immunotherapy was reported by Mller et al,45 who noted that previous studies u showed antihistamine treatments may reduce side effects but also, through immunomodulatory effects, may improve efcacy of immunotherapy. In a double-blind, placebo-controlled prospective study that included a sting challenge at 4 months, ultrarush honeybee venom immunotherapy was administered with 5 mg levocetirizine or placebo from 2 days before to day 21 of therapy. Although side effects during treatment on levocetirizine were fewer, sting challenge outcomes were similar, so improved

outcomes on antihistamine noted in a previous retrospective study (using terfenadine at twice the usual dose) were not conrmed. However, the authors made several interesting observations about immune responses distinguishing the treated subjects. In particular, in vitro studies showed those on levocetirizine had a stronger increase in IL-10 response that was associated with a slightly stronger increase in IgG, indicating a potentially benecial effect. They also observed a higher histamine receptor 1/histamine receptor 2 ratio in the levocetirizine-treated group, the implications of which require additional study.

DRUG ALLERGY Drug hypersensitivity remains a major focus of care and research for allergists. To promote better care for individual patients and for all persons with drug hypersensitivity, the reader is encouraged to review a Current Perspectives article by Davis and Shearer46 that presents diagnosis and management of HIV drug hypersensitivity and a Rostrum by Cresswell and Sheikh47 describing how information technologies can improve safety for persons with drug allergies. Regarding advances in risk assessment, Apter et al48 sought to identify clinical and genetic risk factors for penicillin allergy by evaluating atopy genes (IL4, IL4 receptor, IL10) and genes involved in penicillin metabolism (b-lactamase [LACTB]) as candidates in a case (n 5 23)/control (n 5 39) study. Penicillin allergy was associated with a history of penicillin allergy in rst-degree relatives (P 5 .002), a history of other adverse drug reactions (P 5 .008), and atopy (P 5 .039). However, in the multivariable analysis, only family history of penicillin allergy remained signicant. They found 3 IL4 (P 5 .012-.035) and 1 LACTB (P 5 .058) single-nucleotide polymorphisms that were associated with penicillin allergy. These results indicate an important step toward obtaining genetic risk factors that may better inform the diagnosis or risk of penicillin allergy. Castells et al49 developed a standardized approach for rapid desensitization to chemotherapy agents including carboplatin, cisplatin, oxaliplatin, paclitaxel, liposomal doxorubicin, doxorubicin, and rituximab. They report the safety and efcacy of a 12-step protocol tested through 413 desensitizations in 98 patients over a period of 22 months, nding that 94% induced mild or no reactions. Although there were 24 severe reactions, there were no life-threatening reactions, and all patients received their full target dose. They further note that the approach was successful both for IgE and non-IgEassociated reactions. This protocol is now a standard of care in their institution. Another emerging concern for patients with cancer is allergic hypersensitivity to vital dyes used for lymphatic mapping and sentinel node biopsy. Mertes et al50 reported the clinical features of 14 cases of anaphylaxis to Patent Blue. The reactions were delayed, starting about 30 minutes after injection, typically severe, and in 9 of 14 subjects the reactions continued for hours, requiring prolonged continuous epinephrine infusion. Skin test results were positive in 8 by prick and 5 by intradermal and not prick. The study underscores another potential allergen resulting in hospital-based anaphylaxis. ATOPIC DERMATITIS Skin barrier During the past year, it has been increasingly well recognized that skin barrier function plays a critical role in the development of AD. These defects in skin barrier likely result from a

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combination of factors including a deciency of skin barrier proteins, increased peptidase activity, the lack of certain protease inhibitors, and lipid abnormalities.51-53 However, loss-of-function mutations in the skin structural protein, laggrin, are now considered a major risk factor for AD. It has been repeatedly reported that laggrin gene mutations are associated with persistent and more severe eczema, early onset of AD, and an increased risk of asthma in patients with a previous history of eczema, likely accounting for the atopic march.54-59 Importantly, laggrin protein is not found in the lung60 and therefore is not an asthma gene.61 However, laggrin mutations markedly enhance systemic allergen sensitization via the skin and can thereby contribute to the atopic march.

Immune response Studies of the immune response in AD were an active area of investigation in 2008. Evidence continues to accumulate that a defective innate immune response contributes to increased bacterial and viral infections in AD (see review62). Recent articles suggest that IgE-mediated reactions are only part of a much more complex immunologic picture in AD. Using recombinant allergen derivatives lacking IgE epitopes but containing allergen-derived T-cell epitopes, Campana et al63 demonstrated an important role for nonIgE-mediated reactions in chronic allergen-induced skin inammation in patients with AD. These observations are supported by epidemiologic studies showing only a weak association of atopic sensitization in exural eczema.64 Furthermore, Raap et al65 found that serum levels of IL-31, a pruritogenic TH2 cytokine, correlates with severity of AD, suggesting a role for T cells in the pathogenesis of pruritus that is independent of mast cell degranulation and accounting for the observation that the pruritus of AD is often resistant to H1-antihistamine treatment. A variety of cell types and inammatory mechanisms contribute to AD. DCs act both as innate cells in host defense and as antigen-presenting cells for T-cell activation in adaptive immunity. To assess whether AD is associated with aberrant DCs, Lebre et al66 examined puried myeloid DCs (mDCs) from patients with AD and reported a dramatic reduction of IL-12p70 and TNF-a release. Mature mDCs from patients with AD induced considerably less IFN-gproducing and more IL-4producing TH cells compared with mDCs from healthy controls. These abnormalities in mDC function may contribute to increased susceptibility to infection and maintenance of the TH2 cellmediated response in AD. During the past year, Reefer et al67 analyzed the properties of CD25hi T-cell subtypes in AD associated with increased serum IgE. CD25hi T cells expressing Treg cell markers (forkhead box protein 3 [Foxp3], CCR4, cutaneous lymphocyte-associated antigen) were increased in AD compared with controls with low serum IgE. This phenomenon was linked to disease severity. Two subtypes of CD25hi T cells were identied on the basis of differential expression of the chemokine receptor CCR6. Activated CCR6neg cells secreted TH2 cytokines, and coculture with effector T cells selectively enhanced IL-5 production. Moreover, induction of a TH2-dominated cytokine prole on activation with bacterial superantigen was restricted to the CCR6neg subtype. These studies indicate that despite a regulatory phenotype, activated CD25hi T cells that lack expression of CCR6 promote TH2 responses and may therefore contribute to the atopic immune response. Siebenhaar et al68 investigated the role of skin nerves and neuropeptides in the regulation of mast cellmediated skin

inammation. They found that passive cutaneous anaphylaxis was signicantly impaired in the absence of sensory nerves. This effect was not the result of an alteration of mast cell numbers in denervated skin. Moreover, IgE-mediated activation of mast cells was markedly decreased in denervated compared with normal skin. Pretreatment of mice with selective antagonists of the neuropeptides substance P and/or calcitonin generelated peptide also resulted in decreased inammatory responses after mast cell activation. These data suggest that sensory skin nerves augment mast celldriven inammatory responses by releasing neuropeptides to increase mast cell degranulation. Staumont-Salle et al69 studied the role of peroxisome proliferator-activated receptor (PPAR)a, a ligand-activated transcription factor belonging to the nuclear receptor superfamily, in the regulation of skin inammation in a mouse model of AD. Previous studies had demonstrated that PPAR-a regulates keratinocyte proliferation/differentiation and contributes to wound healing. On antigen sensitization, PPAR-adecient mice displayed increased epidermal thickening, dermal recruitment of inammatory cells, and IgE production compared with their wild-type counterparts. PPAR-a expression was decreased in eczematous skin from patients with AD compared with skin from nonatopic donors, suggesting that defective PPAR-a expression might contribute to the pathology. Topical application of WY14643, a specic PPAR-a agonist, signicantly decreased antigen-induced skin inammation in the AD model. Thus PPAR-a may act as a negative regulator of skin inammation in AD. Kirino et al70 reported on the potential role of heme oxygenase (HO-1), one of the stress-response proteins, in the development of AD. Serum HO-1 levels were signicantly increased in patients with AD compared with those seen in healthy control subjects and were associated with AD disease severity. Serum HO-1 levels correlated with serum IgE, lactate dehydrogenase, IL-18, and thymus and activation-regulated chemokine levels. HO-1expressing cells were accumulated in skin lesions of patients with AD and DS-Nh mice. Enhancement of HO-1 attenuated the development of skin lesions in mice, suggesting that HO-1 induction may be a potential therapeutic strategy for AD.

Management Recent approaches to the management of AD has focused on the development of improved skin barrier creams, early dietary interventions, and novel immunomodulators that can reduce skin inammatory responses (see reviews51,71). There remains interest in treating infants with hydrolyzed infant formulas72 or probiotics to control eczema early in life by directing allergic responses.73-76 Perhaps the most interesting development is the observation that oral supplementation with vitamin D augments the innate immune response in patients with AD77 and downregulates expression of the skin homing receptor, cutaneous lymphoid antigen.78 There remains interest in the use of topical calcineurin inhibitors as an anti-inammatory therapy. Long-term studies have demonstrated that topical tacrolimus does not inhibit the response to recall antigens.79 Indeed, it can shift the balance of dendritic cells to Langerhans cells, thereby enhancing immunotolerance of the skin.80 Promising novel anti-inammatory therapies are also gaining attention. Although these require further controlled trials, they include lymphocyte function-associated molecule 3/IgG fusion protein,81 TNF-antagonists,82 antiCD20,83 and signal transducer and activator of transcription 1 decoy molecules.84

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CHRONIC URTICARIA Vonakis and Saini85 assessed signaling pathways that lead to histamine secretion in the basophils of patients with chronic idiopathic urticaria after stimulation of their basophils with anti-IgE. After FceRI aggregation, the tyrosine kinase, Syk, is recruited to the phosphorylated FceRI-g subunit, thereby propagating the signaling pathway that results in histamine secretion. A poorly secreting subpopulation of human basophils, termed nonresponder basophils (NOR-NR basophils), from healthy donors release less than 10% of their total histamine content on stimulation with anti-IgE. Protein levels of Syk have been reported to be 10-fold lower in NOR-NR basophils than Syk levels in basophils averaging 65% histamine release. These previous data suggested that downregulation of Syk kinase might have a protective effect. In the current study, investigators examined the hypothesis that a deciency of Syk kinase might be responsible for reduced secretion in basophils from patients with chronic idiopathic urticaria. They found that Syk-decient basophils from donors with chronic idiopathic urticaria exhibited a wide range of histamine releasability. Therefore, Syk deciency does not always prevent histamine release, and additional mechanisms must exist to bypass the requirement for active Syk kinase in these Syk-decient but normally secreting basophils. Kaplan et al86 investigated the efcacy of omalizumab, a humanized anti-IgE, in patients with chronic autoimmune urticaria (CAU) who were symptomatic despite antihistamine therapy. Patients with CAU have an IgG autoantibody directed to the a-subunit of the high-afnity IgE receptor leading to cutaneous mast cell and basophil activation. Treatment of allergic asthma with omalizumab produces rapid reduction in free IgE levels and a subsequent decrease in FceRI expression on mast cells and basophils. These investigators postulated that if this occurs in CAU, crosslinking of IgE receptors by autoantibody would be less likely, and thus would reduce cell activation and urticaria. Twelve patients with CAU, identied by basophil histamine release assay and autologous skin test, with persistent symptoms for at least 6 weeks despite antihistamines, were treated with placebo for 4 weeks followed by omalizumab every 2 or 4 weeks for 16 weeks. The primary efcacy variable was change from baseline to the nal 4 weeks of omalizumab treatment in mean Urticaria Activity Score. Mean Urticaria Activity Score declined signicantly from baseline to the nal 4 weeks of omalizumab treatment. Seven patients achieved complete symptom resolution. Rescue medication use also was reduced signicantly, and quality of life improved. This exploratory proof-of-concept study suggests omalizumab may be an effective therapy for CAU resistant to antihistamines. CONCLUSIONS In the year since our last review,87 numerous exciting advances have been reported in the Journal. In particular, basic and clinicaltranslational studies are bringing us closer to improving the diagnosis and treatment of food allergies. The studies of oral ingestion of food allergens as a means of therapy are encouraging, but more needs to be done to characterize risks and efcacy. A key unanswered question is whether the treatments promote persistent tolerance or only transient desensitization. In atopic dermatitis, there has been further progress in our understanding of the skin barrier and the role of the innate and adaptive immune response as well as different inammatory pathways involved in the pathogenesis of this common skin disease. The potential role of anti-IgE therapy

in chronic urticaria is intriguing but requires conrmation in larger randomized controlled clinical trials. These advances present information that can improve patient care today and provide insights on how we will be improving diagnosis and treatment in the future.
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