Phenotypes of persistent hen`s egg allergy in children and adolescents.

BACKGROUND: Optimum management of food allergy (FA) includes consideration of co-allergies and multimorbidities and tolerance assessment. Documentation of FA practices may pave the way for better practice. METHODS: Patients aged 3-18 years, with persistent IgE-mediated hen`s egg allergy were reviewed. RESULTS: A total of 102 children with a median age of 59 months (IQR= 40-84) (72.2% males) were included. All were diagnosed during infancy and the initial symptoms were atopic dermatitis (65.6%), urticaria (18.6%), and anaphylaxis (5.9%). Of the total population, 21 (20.6%) experienced anaphylaxis with hen`s eggs, and 79.4%, 89.2%, and 30.4% had multiple FAs (≥2 food categories), ever atopic dermatitis, and asthma, respectively. The most common co-allergies were tree nuts, cow`s milk, and seeds, respectively. From 52 heated egg yolk and 47 baked egg oral food challenges, 48 (92.3%) and 41 (87.2%) were found as tolerant, respectively. The baked egg nontolerant group had a greater egg white skin prick test diameter [9 mm (IQR: 6-11.5) vs. 6 mm (IQR: 4.5-9); (p=0.009)] and specific IgE [12.6 kU/L (IQR: 4.11-45.4) vs. 6.2 kU/L (IQR: 1.9-12.4) (p=0.009)], respectively. In the multivariate analysis, baked egg tolerance was more likely in those with egg yolk-tolerant subgroup (OR: 6.480, 95% CI: 2.524-16.638; p < 0.001) and heated egg tolerance in those with baked egg tolerance (OR: 6.943, 95% CI: 1.554-31.017; p=0.011). CONCLUSIONS: Persistent hen`s egg allergy is characterized by multiple food allergies and age-related multimorbidities. Baked egg and heated egg yolk tolerance were more likely to be considered in a subgroup with a high expectation for finding a way to eliminate their allergy.

Exploring the Heterogeneity of IgE-Mediated Food Allergy through Latent Class Analysis.

INTRODUCTION: Food allergy (FA) is a heterogeneous disease with multiple morbidities and a huge burden for patients and healthcare systems. Variable manifestations, comorbidities (atopic dermatitis [AD], asthma, and/or allergic rhinitis [AR]), severity (anaphylaxis), and outcomes suggest the existence of different endotypes that cluster analyses may reveal. In this study, we aimed to investigate distinct subgroups among patients with FAs using data from 524 children/adolescents. METHODS: 524 patients with IgE-mediated FA (353 male [67%]; median age 4.4 years [IQR:3.0-6.8]), 354 (68%) had multiple FA. The history of AD, asthma, AR, and anaphylaxis was recorded in 59.4%, 35.5%, 24.2%, and 51.2% of the patients, respectively. Latent class analysis was carried out to distinguish clinical FA phenotypes using five potential markers of allergy severity (single/multiple FA, never/inactive/current asthma and AD, AR, and anaphylaxis). RESULTS: Three distinct phenotypes were identified: (1) multiple FA with eczema and respiratory multimorbidity (42%), (2) multiple FA with persistent eczema (34%), and (3) single FA with respiratory multimorbidity without eczema (24%). Compared with the single FA cluster, the prevalence of AD was significantly higher in multiple FA groups. Cluster 1 had the highest frequency of AR and allergic asthma, and the lowest rate of total tolerance of FA. DISCUSSION: We put forward the hypothesis of underlying pathogenesis according to the clinical phenotypes. While skin barrier defect may play a dominant role in the pathogenesis in Cluster 2, immune dysregulation may be dominant in Cluster 3. In Cluster 1, the most severe group, a combination of both skin barrier defects and immune dysregulation may be responsible for the clinical features.

Oral Immunotherapy in Food Allergy: A Critical Pediatric Perspective.

There is evidence that in children with persistent IgE-mediated food allergy (FA) to cow's milk, hen's egg, and peanut, oral allergen-specific immunotherapy (OIT) may increase the reaction threshold to the culprit food allergen(s). OIT may protect patients from the occurrence of severe reactions in case of accidental ingestion of the culprit food during treatment. Notwithstanding, many gaps are still unsolved, including safety issues, identification of predictive biomarkers, and post-desensitization efficacy. In this perspective, the use of omalizumab (Anti-IgE monoclonal antibody) has been proposed as an adjunctive treatment to OIT in order to reduce the risk of allergic reactions related to OIT. This review aims to summarize the current evidence and unmet needs on OIT in children with FA to enhance the development of longitudinal, prospective, and well-designed studies able to fill the current gaps soon.

Safety and efficacy of rapid drug desensitization in children.

BACKGROUND: Any drug taken at the recommended dosage may cause hypersensitivity reactions (DHR). Rapid drug desensitization (RDD) protocols have been developed in the case of a confirmed or highly suspected HSR to allow safe administration of the medicine when there is no alternative drug or in the presence of a less effective or more toxic alternative. The aim of this study was to evaluate the characteristics of children who underwent desensitization, the safety and efficacy of RDD in children, as well as, the characteristics and management of breakthrough reactions. METHOD: This retrospective study concerned children who underwent RDD due to physician-diagnosed HSRs during or up to 48 hours after the infusion of various drugs between February 2010-February 2021. Patients with a chronic disease needing chronic drug usage and acute infections seen in patients with chronic diseases were included. The results of RDD were documented. RESULTS: The study included 48 patients [8.1(IQR = 3.32-13.4) years, 60.4% male] with 58 HSRs of which 62.1% were classified as moderate and 5.2% as severe. Most of the patients were being treated for leukemia (41.7%), solid tumors (29.2%), and infections (6.3%). Skin tests were done for 41 out of 58 HSRs in 35 patients, and twenty of them were positive. A total of 269 RDDs were performed for 18 different drugs. Ninety percent of desensitizations were achieved with no reaction, and 3.7% and 5.6% with mild and moderate reactions, respectively. In multivariate analysis, skin test positivity was the only risk factor for breakthrough reactions (OR = 8.5, CI = 1.72-42.15, p = .009). CONCLUSION: We demonstrated the safety and efficacy of RDD in childhood, thereby offered the first line treatment options to children with chronic diseases with hypersensitivity reactions (HSRs).

Multiplex component-based allergen macroarray test is useful to predict clinical reactivity to tree nuts in children.

BACKGROUND: In tree nut (TN) allergy, singleplex tests showed the diagnostic utility of rAna o 3, rCor a 14/nCor a 9, and nJug r 1/nJug r 4 for cashew/pistachio, hazelnut, and walnut allergies, respectively. However, disadvantages of the tests include high costs and excessive blood sampling in multi-sensitized patients, and a limited number of components. We investigated the utility of a multiplex macroarray (i.e., the ALEX2 test) in TN allergy. METHODS: In 169 children, skin prick test, the component- and extract-specific IgEs of TNs were investigated for clinical reactivity and tolerance. RESULTS: The predictors (AUC = 0.962-0.749) of clinical reactivity to cashew, pistachio, hazelnut, and walnut were rPis v 1/rAna o 3, rPis v 1/rAna o 3/nPis v 2/nPis v 3, rCor a 14/nCor a 11/nCor a 9, and nJug r 1/nJug r 2/nJug r 6/nJug r 4, respectively. More than 93% of the patients with clinical reactivity to pistachio/cashew, hazelnut and walnut had positivity of (≥0.3 kUA/L) rPis v 1/rAna o 3, rCor a 14 and nJug r 1/nJug r 2, respectively. The highest accuracies of clinical reactivity to culprit nut were obtained with combination of rPis v 1, sIgE and SPT positivities for cashew/pistachio, rPis v 1 ≥ 1.0 kUA/L for pistachio, rCor a 14 ≥ 1.0 kUA/L for hazelnut and combination of nJug r 1 and nJug r 2 positivities for walnut, respectively. Also, higher concentrations of rPis v 1 (≥15.0 kUA/L), rCor a 14 (≥5.0 kUA/L) and nJug r 1/nJug r 2 (≥15.0 kUA/L) had %100 specificity and PPV in predicting clinical reactivity to cashew, hazelnut and walnut, respectively. CONCLUSIONS: Multiplex macroarray test is useful and reliable in the diagnosis of TN allergy in children, confirms and expands existing knowledge, and can be used as a stand-alone tool in the bottom-up diagnostic approach.

A single-center study points to diverse features and outcome in patients with Hyperimmunoglobulin M Syndrome and Class- Switch Recombination defects.

Isotype class-switch recombination (CSR), somatic hypermutation (SHM), B cell signalling and DNA repair mechanisms defects are responsible for high IgM. The hyperimmunoglobulin M (HIGM) phenotype and CSR-related defects are now classified under primary antibody defects, combined immunodeficiencies or syndromic immunodeficiencies groups. The aim of the study is to evaluate the diverse phenotypic/genotypic/laboratory characteristics and outcome of patients with CSR defects and HIGM-related defects. We enrolled 50 patients. The most common gene defect was Activation-induced cytidine deaminase (AID) deficiency (n = 18), followed by CD40 Ligand (CD40L) (n = 14) and CD40 (n = 3) deficiency. Median ages at first symptom and diagnosis were significantly lower in CD40L deficiency (8.5 and 30 months, respectively) than AID deficiency (30 and 114 months, respectively) (p = .001 and p = .008, respectively). Frequent clinical symptoms were recurrent (66%) and severe (14.9%) infections, and/or autoimmune/non-infectious inflammatory features (48.4%). Eosinophilia and neutropenia were at a higher rate in CD40L deficiency patients (77.8%, p = .002 and 77.8%, p = .002, respectively) when compared to AID deficiency. Median serum IgM level was low in 28.6% of CD40L deficiency patients. It was significantly lower when compared to AID deficiency (p < 0.001). Six patients (CD40L deficiency n = 4, CD40 deficiency n = 2) underwent hematopoietic stem cell transplantation. Five were alive at the last visit. Four patients two patients with CD40L deficiency, one with CD40 deficiency and one with AID deficiency had novel mutations. In conclusion; patients with CSR defects and HIGM phenotype may present with a wide range of clinical manifestations and laboratory findings. Low IgM, neutropenia and eosinophilia were prominent in patients with CD40L deficiency. Characterization of genetic defect-specific clinical and laboratory features may ease the diagnosis, prevent the underdiagnoses of patients and ameliorate the outcome.

From Allergen Molecules to Molecular Immunotherapy of Nut Allergy: A Hard Nut to Crack.

Peanuts and tree nuts are two of the most common elicitors of immunoglobulin E (IgE)-mediated food allergy. Nut allergy is frequently associated with systemic reactions and can lead to potentially life-threatening respiratory and circulatory symptoms. Furthermore, nut allergy usually persists throughout life. Whether sensitized patients exhibit severe and life-threatening reactions (e.g., anaphylaxis), mild and/or local reactions (e.g., pollen-food allergy syndrome) or no relevant symptoms depends much on IgE recognition of digestion-resistant class I food allergens, IgE cross-reactivity of class II food allergens with respiratory allergens and clinically not relevant plant-derived carbohydrate epitopes, respectively. Accordingly, molecular allergy diagnosis based on the measurement of allergen-specific IgE levels to allergen molecules provides important information in addition to provocation testing in the diagnosis of food allergy. Molecular allergy diagnosis helps identifying the genuinely sensitizing nuts, it determines IgE sensitization to class I and II food allergen molecules and hence provides a basis for personalized forms of treatment such as precise prescription of diet and allergen-specific immunotherapy (AIT). Currently available forms of nut-specific AIT are based only on allergen extracts, have been mainly developed for peanut but not for other nuts and, unlike AIT for respiratory allergies which utilize often subcutaneous administration, are given preferentially by the oral route. Here we review prevalence of allergy to peanut and tree nuts in different populations of the world, summarize knowledge regarding the involved nut allergen molecules and current AIT approaches for nut allergy. We argue that nut-specific AIT may benefit from molecular subcutaneous AIT (SCIT) approaches but identify also possible hurdles for such an approach and explain why molecular SCIT may be a hard nut to crack.

IgE mediated food allergy in Turkey: different spectrum, similar outcome.

BACKGROUND: Food allergies (FAs) potentially differ across cultures. METHODS: All medical records of 534 children and adolescents with IgE-mediated FA over a 5-year period were reviewed to document the regional characteristics with regard to spectrum and outcome. RESULTS: According to their last visit, the most common FAs were tree nuts (TNs) (52.4%), cow`s milk (27.3%), seeds (24.7%), egg white (23.2%) and peanuts (14.9%). Hazelnut and Anacardia nuts were the most common etiologies for TN allergies, whereas lentils and chickpeas for legumes and sesame and pumpkin seed for seeds were most common, respectively. TN allergy was in first place in school-age children (55.3%) and adolescents (57.1%) while in the second place in preschoolers (57.7%) after egg white (60%). Of these 534 children, 59.2% had at least one resolved FA (mainly egg white, cow`s milk) and 21% had no residual FA during the study period. Emerging FAs (fish, shellfish, fruit, TN and seed) after the age of 3 years was reported in 94 children. The prevalence of current asthma (22.3%, 38.2%, 40%) and allergic rhinitis (11.6%, 45.2%, 60%) increased, while current atopic dermatitis (17.5%, 8.6%, 8,6%) decreased in preschoolers, school age children and adolescents, respectively. CONCLUSIONS: The FA spectrum of Turkish children and adolescents differs from many regions of the world with high rates of TN (hazelnut, Anacardia nuts), seed (sesame, pumpkin seed) and lentils, and low rates of soy, peanut and seafood allergies. However, resolution, emergence and persistence of allergies and comorbidities are similar, which points to the limited role of the environment in the outcome.

Health-related quality of life in children with hereditary angioedema compared with patients with histaminergic angioedema.

Background: Hereditary angioedema (HAE) is a potentially life-threatening disease that remarkably impacts patients' health-related quality of life (HRQoL). This study evaluated the HRQoL in children with HAE and compared it with healthy controls and patients with histaminergic angioedema (HA). Methods: Fifty-nine children with HAE (median [interquartile range {IQR}], ages, 8.9 years [5.4-12.6 years]), 60 children with HA (median [IQR] ages, 10.3 years [8-15.4 years]), and 72 healthy controls (median [IQR] ages, 10.3 years [6.6-13.9 years]) were recruited. All the children and their families completed the age-adapted KINDL generic instrument for assessing health-related quality of life in children and adolescents. Results: The total HRQoL score and other subscales scores of both the patients with HAE and patients with HA, and the parent-proxy reports were significantly lower than those of the healthy children (p < 0.05). In the patients with HAE, the age at symptom onset was positively correlated with physical well-being (r = 0.335; p = 0.043) and negatively correlated with self-esteem (r = -0.324; p = 0.049). In addition, the physical well-being scores were affected by the site of attacks, which was significantly lower in the patients with abdominal pain attacks (p = 0.045). The family scores and total scores were statistically significantly higher in the HA group than the HAE group (p < 0.001 and p = 0.009, respectively). A significant correlation was found between self-report and parent-proxy HRQoLs in total and all subscales scores in the patients with HAE. For HA, there were no significant correlations for family scores. Conclusion: HAE caused significant impairment of the HRQoL of children and their families, and affected their lifestyle and quality of life. In pediatric patients with HAE, the HRQoL is mainly related to age at symptom onset and the site of attacks. Although patients with HAE are affected more negatively than the patients with HA, HA affected the quality of life as well.

Food protein-induced enterocolitis syndrome: Current practices in oral food challenge.

Background: Oral food challenges (OFC) in food protein-induced enterocolitis syndrome (FPIES) are performed to confirm a diagnosis, test for development of tolerance, and find safe alternatives. Objective: We aimed to define OFC outcomes and identify safer test strategies. Methods: OFCs performed in children with FPIES over a 5-year period were reviewed. Results: A total of 160 OFCs were performed in 59 children (median age, 2.3 years). The most commonly tested foods were hen's egg, fish, and cow's milk. Sixty-six OFC results (41.3%) were positive. Twelve (18.2%) reactions were mild, 18 (27.3%) were moderate, and 36 (54.5%) were severe. Intravenous fluid, ondansetron, and corticosteroids were administered in 83.3, 72.7, and 66.7% of the patients, respectively; one patient required hospitalization. A reaction was most likely with fish (odds ratio [OR] 2.878 [95% confidence interval {CI}, 1.279-6.473]; p = 0.011), and least likely with cow's milk (OR 0.268 [95% CI, 0.082-0.872]; p = 0.029). Of the 36 OFCs with egg yolk, 23 patients had a failed OFC, and of the 17 OFCs with egg white (all tolerant to egg yolk), only 2 patients had a failed result. Interestingly, two patients tolerated baked whole egg but not egg yolk. In cow's milk FPIES, two patients could consume fermented milk but not fresh milk. Of the 11 patients with anchovy-triggered FPIES, 6 tolerated sea bass, and 5 tolerated trout, whereas 4 patients with sea bass FPIES tolerated trout. Conclusion: The search for alternative food species, processing, or subdivision of a trigger food is common practice in FPIES, which reflects the expectations of children and their families. The experience gained can be put into practice and will contribute to the understanding of the disease mechanism.

Oral food challenge in IgE mediated food allergy in eastern Mediterranean children.

BACKGROUND: The oral food challenge (OFC) in IgE mediated food allergy causes anxiety both in parents and in patients due to its inherent risks. OBJECTIVE: Documentation of the rate, spectrum, and predictors of positive reactions is instructive. METHODS: Children, who underwent OFC between January 1, 2017 and December 31, 2019 were analyzed. RESULTS: A total of 1361 OFCs in 613 cases were reviewed. Most of them were performed in preschool children (≤2 years 50%) and 55% of them had more than one OFC. Mainly considered food groups were cow's milk (31.8%), hen's egg (28.5%), tree nuts (20%), legumes (7%), seeds (4.9%), and wheat (2.7%). The overall OFC positivity was 9.6%, whereas 6.7% with cow's milk, 4.9% with hen's egg, 16.1% with tree nuts, 21.6% with wheat, and 32.8% with seeds. The severity scoring revealed grade I (24.4%), II (45.8%), and III (29.7%) reactions. Fifty (38%) cases required epinephrine and four cases required hospitalization. OFCs with sesame seeds (odds ratio [OR]: 7.747, [confidence interval (CI) 95%: 4.03-14.90]), wheat (OR: 3.80, [CI: 1.64-8.84]), and tree nuts (OR: 2.78, [CI: 1.83-4.23]) predicted a positive OFC while a concomitant asthma (OR: 3.61 [CI: 1.27-10.28]) was more likely to elicit anaphylaxis. CONCLUSION: In OFC practice, priority is given to basic nutritional sources and the most frequent food allergens, where preschool children with multiple sensitizations are the primary subjects. Increased risks of positive reactions with sesame, tree nut, and wheat and increased risk of anaphylaxis with concomitant asthma should be considered while performing OFC.

IgE-mediated food allergy throughout life

Food allergy (FA) has become an increasing problem throughout the world. Over the last 2 decades, the frequency of FA has increased in both children and adults. The prevalence differs according to the research methodology, age, and geographic regions, ranging between 2.0% and 10.0%. The most common form of FA is immunoglobulin E (IgE)-mediated FA. In this form, patients may present with life-threatening conditions, such as anaphylaxis, or milder conditions, such as urticaria, angioedema, sneezing, and nausea alone. The gold standard in the diagnosis of FA is oral provocation tests. Epidermal skin prick tests and specific IgE measurements, as well as component-resolved diagnostic techniques are helpful in the diagnosis and follow-up of patients. In this review, the epidemiology, diagnosis, follow-up, and prognosis of IgE-mediated FA in children and adults were discussed and some specific forms of FA, such as pollen FA syndrome, alpha-gal allergy, and food-dependent exercise-induced anaphylaxis were explained.

Phenotypes and natural history of food protein-induced enterocolitis syndrome in the east Mediterranean region.

Background: Food protein-induced enterocolitis syndrome (FPIES) is a rare non-IgE mediated food allergy. Objective: To delineate the differences in the spectrum of culprit foods, remission patterns, and predictors among varying cultures. Methods: We reviewed demographics, culprit foods, outcomes, and predictors in 81 children with a diagnosis of FPIES who were followed up between 2015 and 2020. Results: Eighty-one patients (55.6% boys) were enrolled, including 72 with acute FPIES and 9 with chronic FPIES. Hen's egg was the most common culprit food (36.6%), followed by fish (26.9%), and cow's milk (21.5%). Interestingly, cow's milk was significantly prevalent in chronic FPIES cases (p = 0.006). The most common clinical symptoms were vomiting (100%), pallor (63.4%), and lethargy (55.9%). Emergency department visits were noted in 39 patients (41.9%), of whom 37 (39.8%) were treated with intravenous (IV) fluid. The subjects were followed up for a median (interquartile range) of 19.4 months (12.3-41.2 months), and 26 subjects (32.1%) achieved tolerance. The median (interquartile range) age at tolerance was 2.5 years (2.1-3.2 years). With regard to the culprit foods, hen's egg was observed more frequently in the subjects with resolved FPIES cases (p = 0.008), whereas fish FPIES cases were high in the persistent group (p = 0.001). IgE sensitization of the culprit food was found to be an independent risk factor for the persistence of FPIES (odds ratio 4.855 [95% confidence interval, 1.131-20.844]; p = 0.034). Conclusion: In our cohort, unlike other published series, hen's egg and fish were the two most common culprit foods. Fish differed from other culprit foods, with significantly delayed onset and persistence, and may create a model that allows for the understanding of the disease.

Food-induced anaphylaxis in infants, as compared to toddlers and preschool children in Turkey.

BACKGROUND: The literature includes scarce data on infants with food-induced anaphylaxis (FIA). MATERIALS AND METHODS: Medical records of the patients diagnosed with FIA aged 0-6 years between 2015 and 2020 were retrospectively analyzed. RESULTS: During the study period, there were 451 instances of FIA in 314 patients, of which 175 (38.8%) occurred in 160 infants (50.9%). The median (IQR) age of infants was 7 months (6-9 months) with a male predominance (67.5%), of which 7.5% had multiple instances (≥2) and 60% atopic dermatitis. The most common triggers were cow's milk (51.4%), tree nuts (16.6%), and hen's egg (15.4%), whereas tree nut was the most common trigger in toddlers (35.8%) and preschool children (35.2%). Skin and neurologic symptoms, and nausea-vomiting occurred more frequently (P = .003, P ≤ .001, and P = .003, respectively), whereas respiratory symptoms occurred less commonly in infants compared to toddlers and preschool children (P ≤ .001). In infants, 65 (37.1%) mild, 92 (52.6 %) moderate, and 18 (10.3%) severe episodes of anaphylaxis were detected. History of recurrent wheezing (OR: 6.837 [95% CI: 1.940-24.097], P = .003) and tree nut allergy (OR: 2.849 [95% CI: 1.056-7.688], P = .039) were found to be independent risk factors for moderate-to-severe anaphylactic reactions. 40.6% of the infants received adrenaline, which was lower than the toddlers (49.7%) and preschool children (57.6%) (P = .005). CONCLUSION: There is no doubt that food-induced anaphylaxis is a medical emergency, specifically in young children. Pediatricians should be aware of the distinct features of infant anaphylaxis, particularly gastrointestinal and neurologic symptoms to provide effective treatment as soon as possible.

Hypersensitivity Reactions to Biologicals: from Bench to Bedside.

PURPOSE OF REVIEW: Biologic agents are new treatment options for chronic inflammatory diseases and cancers. As a result of their unique mechanism of action, they are more effective and less toxic treatment option and their clinical usage is increasing. While they are more commonly used, various adverse effects have been observed including life-threatening ones, including anaphylaxis. The aim of this review is to distinguish the anaphylaxis from other hypersensitivity reactions (HSR) and provide a management algorithm for the anaphylactic reactions induced by biological agents. RECENT FINDINGS: Many case reports and series have been published regarding anaphylaxis and other hypersensitivity reactions (concerning cytokine release syndrome, acute infusion-related reactions) due to biologic agents. Although acute treatment of HSR varies according to the clinical presentation, desensitization with the drug is the major management option for subsequent administrations in the case of anaphylactic reactions. SUMMARY: Anaphylaxis and other immediate onset hypersensitivity reactions are occasionally difficult to differentiate from each other, and mixed-type reactions may be observed. Immediate management of anaphylaxis includes discontinuation of infusion, immediate administration of adrenaline, antihistamines, corticosteroids, and other treatment options depending on the symptoms. After 30-120 min of the reaction, a blood sample for serum tryptase levels should be obtained and after 4-6 weeks skin testing with the culprit drug should be performed for decision of long-term management via either graded challenge or desensitization.