Mechanisms of Allergen Immunotherapy and Potential Biomarkers for Clinical Evaluation.

Allergen-immunotherapy (AIT) is an efficacious and disease-modifying treatment option for IgE-mediated diseases. Among these allergic rhinitis, insect venom allergy, food allergy, and allergic asthma are the most common candidates for AIT. AIT gives rise to clinical immunotolerance which may last for years after the treatment cessation. Mechanisms of AIT include suppression of allergic inflammation in target tissues and stimulation of the production of blocking antibodies, especially IgG4 and IgA. These mechanisms are followed by a reduction of underlying allergen-specific Th2 cell-driven responses to the allergens. Tolerance induction takes place through the desensitization of effector cells and stimulation of regulatory T cells that show their effects by mechanisms involving cell-cell cross-talk, but also other mechanisms, e.g., by the production of immunomodulatory cytokines such as, e.g., IL-10 and TGF-beta. From a personalized medical perspective, there is a need for clinical biomarkers of value in selecting responders and optimizing patient care during AIT. Also, a deeper understanding of underlying mechanistic processes will improve AIT's future outcomes. In this paper, the current knowledge of mechanisms in AIT is reviewed with a special focus on biomarkers of this therapy.

Obesity is a risk factor for decrease in lung function after COVID-19 infection in children with asthma.

INTRODUCTION: It is not clear whether asthma, the most frequent chronic disease in childhood, is a risk for severe SARS-CoV-2 infection in the pediatric population and how SARS-CoV-2 infection affects the lung functions in these patients. PURPOSE: We aimed to investigate the course and the consequences of SARS-CoV-2 infection among children with asthma and determine the risk factors for the decline in lung function tests (LFTs). METHODS: In this retrospective study, asthmatic children with coronavirus disease 2019 (COVID-19) were compared with a random control group of asthmatic patients without COVID-19. In addition, the clinical course and the effect on LFTs of COVID-19 among children with asthma were also evaluated. RESULTS: One hundred eighty-nine patients who had COVID-19, and 792 who did not were included in the study. Fever, fatigue, and cough were the most frequent symptoms during COVID-19. Regarding the severity of COVID-19, 163 patients (87.6%) had a mild clinical condition, 13 (7%) had moderate disease, 1 (0.5%) had severe disease, and 2 had (1.1%) critically ill disease. Two patients were diagnosed with multisystem inflammatory syndrome in children (MIS-C), one patient suffered from pneumothorax. LFTs of the patients before and after COVID-19 infection were analyzed; no significant differences were found in FEV1 % (91.7% vs. 90.9%, p = 0.513), FVC% (89.8% vs. 90.8%, p = 0.502) and FEV1 /FVC (103.1% vs. 100.6%, p = 0.056), while FEF25%-75% values (107.6% vs. 98.4%, p < 0.001) were significantly lower after the COVID-19 infection. Obesity (odds ratio [OR]: 3.785, 95% confidence interval [CI]: 1.152-12.429, p = 0.028] and having a family history of atopy (OR: 3.359, 95% CI: 1.168-9.657, p = 0.025] were found to be the independent risk factors for ≥25% decrease in FEF25-75 after COVID-19 infection. CONCLUSION: COVID-19 infection leads to dysfunction of the small airways in asthmatic children and obesity is an independent risk factor for a ≥25% decrease in FEF25-75. The long-term effects of COVID-19 infection especially on small airways require close monitoring in children with asthma.

The common triggers of urticaria in children admitted to the pediatric emergency room.

BACKGROUND: Urticaria frequently causes pediatric emergency department (PED) admissions. Children with urticaria may unnecessarily avoid suspected allergens. We aimed to investigate the possible and exact triggers of urticaria in children admitted to the PED. METHODS: Medical records of children admitted to the PED within a 1-year period were evaluated for the International Classification of Diseases 10 (ICD-10) L50 urticaria code, noting symptoms, and possible triggers of urticaria. We performed telephone interviews to complete the missing data and further diagnostic tests for IgE-mediated allergies to identify the exact triggers of urticaria. RESULTS: Among 60,142 children, 462 (0.8%) with the L50 code were evaluated. Possible triggers based on the history and physical examination could be identified in 46%: infections (18%), drugs (11%), foods (8%), infections and drugs (3%), insects (3%), pollen (1%), blood products (0.4%), and vaccines (0.4%). The most frequent infections related to urticaria were upper respiratory tract infections (74.5%), urinary tract infections (13.2%), gastroenteritis (8.2%), and otitis media (4.1%). After a diagnostic workup, IgE-mediated allergic diseases were diagnosed in 6% of patients. Twenty-two percent of the patients had multiple PED admission for the same urticaria flare. Urticaria severity was found to be the most important risk factor for readmissions to the PED (odds ratio: 3.86; 95% confidence interval: 2.39-6.23; p < .001). No relationship between urticaria severity, duration, and the triggers was present. CONCLUSIONS: Despite detailed diagnostic tests, IgE-mediated allergic triggers were rarely the cause of urticaria in children admitted to the PED. Infections are the most frequent trigger. Severe urticaria causes more frequent readmissions to the PED.

Subcutaneous Allergen Immunotherapy in Children: Real Life Compliance and Effect of COVID-19 Pandemic on Compliance.

BACKGROUND: Subcutaneous allergen immunotherapy (SCIT) is an effective treatment for allergic rhinitis, asthma, and venom allergy. Compliance is essential for SCIT to obtain maximal benefit as it is a long-term treatment. OBJECTIVES: This study aimed to determine the level of real-life SCIT compliance in pediatric patients and the associated factors. Additional aims were to determine how SCIT compliance was affected by the COVID-19 pandemic and why some patients dropped out SCIT. METHOD: Pediatric patients diagnosed with allergic rhinitis, allergic asthma, or venom allergy that received SCIT between September 2012 and July 2020 were analyzed. RESULTS: The study included 201 children (66.7% male) with a median (interquartile range) age of 12.8 years (9.4-15.2) at the time of the first SCIT injection. The overall compliance rate before COVID-19 pandemic was 86.1%. Short SCIT follow-up time and venom anaphylaxis were found to be risk factors for drop out. The leading causes of drop outs were moving to another city/country (32.1%), symptom improvement (17.8%), treatment ineffectiveness (14.2%), and adverse reactions (14.2%). Among the 108 patients that were still receiving SCIT during the COVID-19 pandemic, 31 (28.7%) dropped out the therapy. The most frequent reasons for drop-out were fear of being infected with COVID-19 (35.4%) and thinking that the AIT practise stopped due to COVID-19 pandemic (29%). Male gender and older age were found to be the independent risk factors for drop-out of SCIT. CONCLUSIONS: Real life compliance in children was found 13.9% and it was higher than adults. Nearly one-third of children dropped out during the CO-VID-19 pandemic. Male gender and older age are associated with SCIT drop-out during the COVID-19 pandemic.

Over restrictive elimination of foods in children with food allergy.

BACKGROUND: Previous studies demonstrated critical deficits in diagnosis and management of childhood food allergy (FA), and recent developments in FA research support adopting a proactive approach in FA management. Our objective was to describe FA knowledge and management patterns of pediatricians. METHOD: We applied a 24-item survey to 170 general pediatricians, pediatric allergists and pediatric gastroenterologists practicing in Turkey. RESULTS: Some IgE-mediated symptoms of FA such as cough, urticaria, wheezing and anaphylaxis were falsely recognized as symptoms of non-IgE-mediated FA by 30%, 29%, 25% and 19% of the participants, respectively. By contrast, 50% of the participants falsely recognized bloody stool, a finding of IgE-mediated FA. Most frequently and least frequently used diagnostic tools were specific IgE (30.5%) and oral food challenge test (1.7%), respectively. Maternal diet restrictions and infant diet restrictions were advised by 82% and 82%, respectively. Percentages of physicians eliminating only 1 food were 21%, 19%; 2 foods were 15%, 11%; 3 foods were 7%, 8%; 4-5 foods were 8%, 11%; 5 to 10 foods were 21%, 26%; and > 10 foods were 28%, 25% from the maternal and infant diet, respectively. Cow`s milk, cheese, butter, yoghurt, baked milk products and hen`s egg were the most commonly restricted items. CONCLUSION: Overall, FA knowledge of pediatricians was fair. Pediatricians utilize an overly restrictive approach when advising diet eliminations in FA. Recent developments favor a more proactive approach to induce immune tolerance and need to be encouraged in pediatric clinical practice. Future educational efforts should focus on emphasizing the deleterious effects of injudicious and extensive eliminations.

Innate lymphoid cells: The missing part of a puzzle in food allergy.

Food allergy is an increasingly prevalent disease driven by uncontrolled type 2 immune response. Currently, knowledge about the underlying mechanisms that initiate and promote the immune response to dietary allergens is limited. Patients with food allergy are commonly sensitized through the skin in their early life, later on developing allergy symptoms within the gastrointestinal tract. Food allergy results from a dysregulated type 2 response to food allergens, characterized by enhanced levels of IgE, IL-4, IL-5, and IL-13 with infiltration of mast cells, eosinophils, and basophils. Recent studies raised a possible role for the involvement of innate lymphoid cells (ILCs) in driving food allergy. Unlike lymphocytes, ILCs lack They represent a group of lymphocytes that lack specific antigen receptors. ILCs contribute to immune responses not only by releasing cytokines and other mediators but also by responding to cytokines produced by activated cells in their local microenvironment. Due to their localization at barrier surfaces of the airways, gut, and skin, ILCs form a link between the innate and adaptive immunity. This review summarizes recent evidence on how skin and gastrointestinal mucosal immune system contribute to both homeostasis and the development of food allergy, as well as the involvement of ILCs toward inflammatory processes and regulatory mechanisms.

Allergic reactions during childhood vaccination and management.

BACKGROUND: Vaccination is one of the most effective public health tools to prevent a variety of infectious diseases. However, concerns about vaccine related adverse effects cause difficulties in clinical practice. METHODS: This review was prepared based on the latest literature available in the PUBMED database in English language (as of March 2021), and all articles with the keywords pediatric vaccine, allergy, hypersensitivity, adverse reaction were evaluated to prepare the article. RESULTS: Vaccine related confirmed allergic reactions are rare in children, ranging between 0,65-1.45 cases per million vaccine doses. Most of the allergic reactions are self-limited local reactions although in some cases severe anaphylaxis with multisystem involvement can be observed. Allergic reactions may occur because of either the active component (the antigen) of the vaccine, or additional components, such as preservatives, adjuvants, antimicrobials, stabilizers and other substances. Finding the culprit allergen is necessary to prevent future exposure to the allergen and to use alternative vaccines if possible. Diagnosis is largely based on a detailed history and clinical manifestation; also in vivo and in vitro tests may be helpful. CONCLUSIONS: In this review we provide information about hypersensitivity reactions to allergen components of childhood vaccines along with the diagnosis and management of vaccine allergy. Besides the tremendous benefits of vaccination for the health of children, we emphasized that the risk of adverse effects is rare and poses a negligible threat.

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.

IgE and IgG4 binding to lentil epitopes in children with red and green lentil allergy.

BACKGROUND: The consumption of lentil is common in the Mediterranean area and is one of the causes of IgE-mediated food allergy in many countries. Len c 1 is a well-defined allergen of lentil and approximately 80% of the patients with lentil allergy recognize the purified Len c 1 protein. We sought to identify IgE and IgG4 sequential epitopes of Len c 1 in patients with red and/or green lentil allergy. We also aimed to determine IgE and IgG4 binding differences between those patients who had outgrown or remained reactive to lentil. METHODS: Children with IgE-mediated lentil allergy were included in the study. We applied a microarray immunoassay to determine the characterization of positive IgE and IgG4 binding to Len c 1 epitopes in the patients' sera. RESULTS: The peptides specifically recognized by IgE and IgG4 antibodies were mainly detected between peptides 107 and 135 of Len c 1. The signal intensities of positive epitopes were significantly greater in reactive patients than tolerant ones (P = .008 for IgE and P = .002 for IgG4). Moreover, IgE and IgG4 antibodies bound largely the same sequential epitopes in patients who remained reactive or outgrew their allergy. CONCLUSION: IgG4-binding epitopes in lentil allergy were identified and IgE and IgG4 binding to epitopes in both red and green lentils was compared. Our data regarding signal intensity differences between reactive and outgrown patients and overlap binding of IgE and IgG4 antibodies may be important for the development of more accurate diagnostic tests and understanding of natural tolerance development.

Spirometry in children with asthma and/or allergic rhinitis: comparison of FEF25-75% with the standard measures.

BACKGROUND: Forced expiratory flow between 25% and 75% of vital capacity (FEF25-75%), a spirometric measure of small airways, may predict the presence of airway responsiveness both in asthmatics and in allergic rhinitis (AR). We aimed to search the correlation between FEF25-75% and standard measures of spirometry (forced expiratory volume in the first second [FEV1%] and FEV1/FVC [forced vital capacity]) in different clinical conditions, that is in children with asthma, in children with asthma and AR, in children with AR and in healthy children. METHODS: Children with asthma (N.=116), asthma plus AR (N.=25), AR (N.=75) and healthy controls (N.=52) were evaluated. Clinical examinations, spirometry and bronchodilation tests were performed. RESULTS: In asthmatics there was a strong correlation between FEF25-75% and FEV1% (r=0.596, P<0.001); and between FEF25-75% and FEV1/FVC (r=0.740, P<0.001). In AR patients correlation between FEF25-75% and FEV1% (r=0.367, P=0.001); and between FEF25-75% and FEV1/FVC (r=0.534, P<0.001) were less prominent compared to asthmatics but they were still significant and strong. In children with both AR and asthma correlation between FEF25-75% and FEV1% (r=0.633, P=0.001) and between FEF25-75% and FEV1/FVC (r=0.539, P=0.005) were again significant. Pre-test FEV1% and FEF25-75% in AR patients were lower than that of the control subjects. After the bronchodilation, percentage change in the FEV1 in AR patients were significantly higher than the control subjects (P=0.010). AR patients showed significant increases in FEV1%, (P<0.001), FEF25-75%, (P<0.001) and (P=0.001) after the bronchodilation test. Within the AR patients, only 12/75 (16.0%) showed bronchodilation with salbutamol. Among the ones with a FEF25-75% <65%, FEV1% was normal in 6/43 (14%) patients in asthmatics, and FEV1% was normal in 3/9 (33%) patients in asthma +AR patients. CONCLUSIONS: Besides the FEV1% and FEV1/FVC, the FEF25-75% may be a useful and early spirometric parameter to evaluate the children with asthma and or AR.

Oxidative stress in asthma: Part of the puzzle.

An imbalance between the production of reactive oxygen species and the capacity of antioxidant defense mechanisms favoring oxidants is called oxidative stress and is implicated in asthmatic inflammation and severity. Major reactive oxygen species that are formed endogenously include hydrogen peroxide, superoxide anion, hydroxyl radical, and hypohalite radical; and the major antioxidants that fight against the endogenous and environmental oxidants are superoxide dismutase, catalase, and glutathione. Despite the well-known presence of oxidative stress in asthma, studies that target oxidative burden using a variety of nutritional, pharmacological, and environmental approaches have generally been disappointing. In this review, we summarize the current knowledge on oxidative stress and antioxidant imbalance in asthma. In addition, we focus on possible biomarkers of oxidative stress in asthma and on current and future treatment strategies using the modulation of oxidative stress to treat asthma patients.

Factors Affecting Food Allergy-Related Quality of Life From Parents' Perception in Turkish Children.

PURPOSE: Food allergy (FA) affects the daily lives of children and parents in varying degrees. The Food Allergy Quality of Life Questionnaire-Parent Form (FAQLQ-PF) is a valid and reliable instrument to assess the quality of life (QoL) of children from parents' perception. The aim of this study was to validate and determine the reliability of the Turkish FAQLQ-PF and to assess QoL in food-allergic children. METHODS: Children aged between 0 and 12 years and diagnosed with immunoglobulin E (IgE)-mediated FA for at least 1 month were enrolled. The English FAQLQ-PF was translated into Turkish according to the World Health Organization guidelines. The Food Allergy Independent Measure and the Turkish Child Health Questionnaire-Parent Form 50 were used for construct validity. RESULTS: One hundred and fifty-seven patients participated. The median age of patients and FA duration were 2.4 years (1.2-5.2 years, interquartile-ranges) and 2 years (0.8-5.1), respectively. Ninety-six (61.1%) patients had anaphylaxis. The Cronbach's alpha coefficient and intra-class correlation coefficient for test-retest reliability was good for all age groups of children (<4, 4-6, and 7-12 years). Patients with either asthma or anaphylaxis had worse scores than others. Total scores of FAQLQ-PF tended to increase with age. Patients aged 7-12 had the highest total scores among all patients (2.2±0.1, 3.0±0.2, and 3.3±0.3 for <4, 4-6, and 7-12 years, respectively, P<0.001, P for trend <0.001). Other factors causing the poor QoL were cow's milk allergy, sibling allergy, mother's age over 30 years, mother's high education level and lower number of persons in household. CONCLUSIONS: The Turkish FAQLQ-PF is a valid and reliable scale. FA-related QoL was significantly worse with age. Coexistent asthma, anaphylaxis regardless of its severity, cow's milk allergy, sibling allergy and the older and educated mothers seem to poorly affect QoL.

Characteristics of drug-induced anaphylaxis in children and adolescents.

BACKGROUND: Although data on anaphylaxis in the general population exist for different allergens, there is still lack of detailed etiologic data on drug-induced anaphylaxis (DIA), particularly in children. OBJECTIVE: To define the etiology of DIA, to determine the accuracy of drug-related anaphylaxis histories, along with the severity and culprit drug associations among individuals <18 years old. METHODS: Patients with a history of drug hypersensitivity reaction (DHR) referred to our center between January 2012 and February 2016 were included. After the collection of European Network for Drug Allergy questionnaire results, initial skin tests and/or provocation tests were performed for the offending drug. RESULTS: Among 561 children and adolescents referred due to a suspected DHR, 113 (19%) (median age [interquartile range], 9.6 years [5.4-13.8 years]; 55% boys) had anaphylaxis in their history. At the end of diagnostic evaluation of the patients, 84 (74% of the patients with a history of DIA) were actually hypersensitive to the offending drug. Major drugs that resulted in DIA were antibiotics (33%), nonsteroidal anti-inflammatory drugs (25%), and chemotherapeutics (19%). The majority of patients reported grade 2 (moderate) (45%) and grade 3 (severe) (33%) anaphylactic reactions. A history of systemic illness (41.7 versus 7.1%; p = 0.001), concomitant intake of other drugs regularly (36.9 versus 10.3%; p = 0.007), and the use of chemotherapeutics as the culprit drug (19 versus 0%; p = 0.011) were more frequent, whereas the use of antibiotics was less frequent (34.5 versus 75.9%; p < 0.001) among patients with actual DIA compared to drug tolerant patients. CONCLUSION: Three-fourths of the children and adolescents referred due to a suspected history of DIA were found to actually be drug hypersensitive. Prediagnosed systemic illness and different types of drugs would have an impact on the risk of DIA; however, atopic disease or a family history of drug hypersensitivity did not have an impact on actual DIA.

Characteristics of children with food protein-induced enterocolitis and allergic proctocolitis.

BACKGROUND: The aim of this study was to determine and compare the clinical and laboratory features of food protein-induced enterocolitis syndrome (FPIES) and food protein-induced allergic proctocolitis (FPIAP), and to provide information about the short-term prognoses. METHOD: Children diagnosed with FPIES or FPIAP between 2010 and 2015 were enrolled in this study. RESULTS: Overall, 64 infants (37 FPIAP, 27 FPIES) were evaluated, with the average age at the onset of symptoms being significantly lower in the patients with FPIAP than in the patients with FPIES (2 months [1-3 months] versus 4 months [1.5-6 months]; p = 0.043). Fifteen of the patients with FPIAP (40.5%) and six of the patients with FPIES (22.2%) were exclusively breast-fed at the time of the onset of symptoms. Cow's milk was the most frequent trigger (100% FPIAP, 74% FPIES); solid foods caused FPIES more frequently. Forty-eight of the 64 patients were followed up until at least 2 years of age, with the resolution rates being 91.3% for FPIAP and 60% for FPIES. The solid food-induced cases of FPIES (27.3%) had a significantly lower rate of resolution than the liquid food-induced FPIES (83.3%) (p = 0.003). CONCLUSION: Cow's milk is the most common trigger of both FPIAP and FPIES. The symptom onset age seemed to be earlier in FPIAP. The resolution age was similar, however, the recovery in FPIES may be later if the trigger food is solid. To our knowledge, this was the first clinical study to compare the clinical and laboratory characteristics of patients with FPIAP and FPIES.

Allergy-specific Phenome-Wide Association Study for Immunogenes in Turkish Children.

To dissect the role of immunogenetics in allergy and asthma, we performed a phenome-wide association study in 974 Turkish children selected from a cross-sectional study conducted using ISAAC (International Study of Asthma and Allergies in Children) Phase II tools. We investigated 9 loci involved in different immune functions (ADAM33, ADRB2, CD14, IL13, IL4, IL4R, MS4A2, SERPINE1, and TNF) with respect to 116 traits assessed through blood tests, hypertonic saline challenge tests, questionnaires, and skin prick tests. Multiple associations were observed for ADAM33: rs2280090 was associated with reduced MEF240% (i.e., the ratio of Mean Expiratory Flow after 240s of hypertonic saline inhalation with respect to the age- and ancestry-matched reference value) and with an increased risk of allergic bronchitis (p = 1.77*10(-4) and p = 7.94*10(-4), respectively); rs3918396 was associated with wheezing and eczema comorbidity (p = 3.41*10(-4)). IL4 rs2243250 was associated with increased FEV240 (Forced Expiratory Flow Volume after 240s of hypertonic saline inhalation; p = 4.81*10(-4)) and CD14 rs2569190 was associated with asthma diagnosis (p = 1.36*10(-3)). ADAM33 and IL4 appeared to play a role in the processes linked to allergic airway inflammation and lung function. Due to its association with wheezing and eczema comorbidity, ADAM33 may also be involved in the atopic march.

Basal serum tryptase is not a risk factor for immediate-type drug hypersensitivity during childhood.

BACKGROUND: High serum basal tryptase (sBT) levels have been identified as a risk factor for both venom- and food-induced severe allergic reactions. The aim of this study was to compare sBT levels in children with different severity of actual drug hypersensitivity reactions (DHRs) with those of age- and sex-matched controls without any history of DHRs. METHOD: Patients between 0 and 18 years of age with a history of immediate-type DHRs manifested in 0-6 h after the culprit drug intake were included. Following ENDA (European Network for Drug Allergy) inquiries, patients were evaluated with skin and/or provocation tests to define the actual drug-hypersensitive patients. Serum BT levels were determined for both patients and controls. RESULTS: Of 345 children, 106 patients (30.7%) [(58.5% male), median age (interquartile range) 8.0 years (4.2-12.2)] were diagnosed as drug hypersensitive. Ninety-eight controls were also included. The sBT levels of drug-hypersensitive patients with and without anaphylaxis and the control group were similar [2.6 (2.0-3.6) µg/l vs. 2.8 (1.6-4.3) µg/l vs. 2.6 (1.8-3.6) µg/l, respectively, (p > 0.05)]. The sBT levels of the patients with sole cutaneous symptoms 2.8 (1.6-4.3) µg/l, mild anaphylaxis 3.0 (1.9-4.9) µg/l, and moderate-to-severe anaphylaxis 2.6 (2.0-3.6) µg/l were also comparable (p > 0.05). The onset of DHRs [those occurring in 1 h (n = 87) or in 1-6 h (n = 19) after the drug intake], positive results with skin tests with the culprit drug, or the classification of the patients according to different age groups [(0-2 years), (2-6 years), (6-12 years), (12-18 years)] did not correlate with sBT levels. CONCLUSION: The sBT levels in children with actual drug hypersensitivity would not be a risk factor for severe systemic reactions on the contrary to children with allergic reactions to food or insect venom.

Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages.

BACKGROUND: Asthma is a disease affecting more boys than girls in childhood and more women than men in adulthood. The mechanisms behind these sex-specific differences are not yet understood. OBJECTIVE: We analyzed whether and how genetic factors contribute to sex-specific predisposition to childhood-onset asthma. METHODS: Interactions between sex and polymorphisms on childhood asthma risk were evaluated in the Multicentre Asthma Genetics in Childhood Study (MAGICS)/Phase II International Study of Asthma and Allergies in Childhood (ISAAC II) population on a genome-wide level, and findings were validated in independent populations. Genetic fine mapping of sex-specific asthma association signals was performed, and putatively causal polymorphisms were characterized in vitro by using electrophoretic mobility shift and luciferase activity assays. Gene and protein expression of the identified gene doublesex and mab-3 related transcription factor 1 (DMRT1) were measured in different human tissues by using quantitative real-time PCR and immunohistochemistry. RESULTS: Polymorphisms in the testis-associated gene DMRT1 displayed interactions with sex on asthma status in a population of primarily clinically defined asthmatic children and nonasthmatic control subjects (lowest P = 5.21 × 10(-6)). Replication of this interaction was successful in 2 childhood populations clinically assessed for asthma but showed heterogeneous results in other population-based samples. Polymorphism rs3812523 located in the putative DMRT1 promoter was associated with allele-specific changes in transcription factor binding and promoter activity in vitro. DMRT1 expression was observed not only in the testis but also in lung macrophages. CONCLUSION: DMRT1 might influence sex-specific patterns of childhood asthma, and its expression in testis tissue and lung macrophages suggests a potential involvement in hormone or immune cell regulation.

Cor a 14, Hazelnut-Specific IgE, and SPT as a Reliable Tool in Hazelnut Allergy Diagnosis in Eastern Mediterranean Children.

BACKGROUND: Improving the diagnostic efficacy of laboratory tests might reduce the need for oral food challenges and facilitate our daily practice. OBJECTIVE: We aimed to determine cutoff values and probability curves, as well as to investigate the role of component-resolved diagnosis in predicting clinical reactivity in children with hazelnut allergy and to evaluate the association with pollen sensitivity. METHODS: A total of 56 children with hazelnut allergy who underwent double-blind placebo-controlled food challenge and 8 children who experienced anaphylaxis after accidental hazelnut intake were included. Serum IgE levels to hazelnut extract, Cor a 1, Cor a 8, Cor a 9, Cor a 14, and Bet v 1 were measured with the ImmunoCAP system. Skin prick tests (SPT) with hazelnut, other implicated foods, and aeroallergens were performed. RESULTS: The optimal cutoff levels for hazelnut sIgE and SPT wheal diameter that predicted clinical reactivity with the highest sensitivity and specificity were 3.15 kU/L and 7.5 mm, respectively. Among the components, only Cor a 14 discriminated between reactive and nonreactive children. The area under curve (AUC) at the optimal cutoff point of 0.63 kU/L for Cor a 14 (0.936) was higher than the AUC of hazelnut sIgE (0.818) and SPT wheal diameter (0.803). For the first time, a 95% probability for clinical reactivity was estimated for SPT wheal diameter, IgE to hazelnut extract, and to Cor a 14 at 12 mm, 10.2 kU/L, and 1.0 kU/L, respectively. CONCLUSION: Cor a 14 was found to be a useful and reliable tool for predicting clinical reactivity in children with hazelnut allergy in the Eastern Mediterranean area.

Evidence of hypothalamic-pituitary-adrenal axis suppression during moderate-to-high-dose inhaled corticosteroid use.

The possible risk of adverse effects due to regular use of inhaled corticosteroids (ICS) is a real concern. Our aim was to describe the factors that have an impact on hypothalamic-pituitary-adrenal axis suppression (HPA-AS) in children and adolescents taking ICS regularly. The HPA axis status of patients who were on moderate-to-high-dose ICS [>176 and >264 µg/day fluticasone propionate-hydrofluoroalkane (FP-HFA) for patients 0-11 and ≥12 years, respectively] was investigated. Various types of ICS were converted to FP-HFA equivalent according to National Asthma Education and Prevention Program (NAEPP) guidelines. Participants with a baseline (8 a.m.) serum cortisol <15 µg/dL underwent a low-dose ACTH stimulation test (LDAT) to diagnose HPA-AS. Among 91 patients, 60 (75.9 %) participants underwent LDAT, and seven (7.7, 95 % CI 3.5-15.3 %) were diagnosed with HPA-AS. Ciclesonide was more frequently used by the participants with HPA-AS compared to patients with a normal HPA axis (42.9 vs. 4.8 %, p = 0.009). Use of ICS at moderate-to-high doses for at least 7 months distinguished participants with HPA-AS from those with a normal HPA axis. Among the duration, type, and dose of ICS, solely the use of ICS with a body mass index (BMI)-adjusted daily dose of ≥22 µg FP was found to increase the risk for HPA-AS (odds ratio (OR) 7.22, 95 % confidence interval (CI) 1.23-42.26, p = 0.028). The receiver operating characteristics (ROC) curve analysis revealed a cutoff value of 291 µg/day FP (area under the curve (AUC) = 0.840, p = 0.003) for predicting HPA-AS Conclusion: The prevalence of HPA-AS was found to be 7.7 % in children taking not only high-dose ICS but also moderate-dose ICS. Dose alone was found to be an actual risk factor for HPA-AS.

The genetic variants of thymic stromal lymphopoietin protein in children with asthma and allergic rhinitis.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is expressed by airway epithelial cells and plays a key role in immunological events in asthma. Data on the genetic variants of TSLP and its association with asthma and allergic rhinitis are scarce. We aimed to investigate the effects of the genetic variants of TSLP in children with asthma and allergic rhinitis. METHODS: The genetic variants of the TSLP gene were determined by sequencing 25 asthmatic and 25 healthy children. In an association study, a population of 506 asthmatics and 157 healthy controls was screened for the following single-nucleotide polymorphisms (SNPs): rs3806933 and rs2289276 in the promoter region; rs11466741, rs11466742, and rs2289278 in intron 2; rs10073816, rs11466749, and rs11466750 in exon 4, and rs11466754 in 3'-UTR. RESULTS: In Multifactor Dimensionality Reduction analysis, presence of the rs11466749 AA genotype with atopy was significantly associated with a diagnosis of asthma (testing set accuracy: 0.720 and cross validation: 9/10). Two functional SNPs showed a gender-specific association with allergy, i.e. the rs3806933 CC genotype with asthma in boys (p = 0.032, nonsignificant after multiple testing) and the rs2289276 CC genotype with higher eosinophil numbers in asthmatic girls (p = 0.003). The presence of allergic rhinitis in asthmatic children strengthened the association of the rs11466749 GG genotype with asthma (p = 0.001), and rs2289276 was significantly associated with lower FEV1 levels in asthmatics without allergic rhinitis (p = 0.003). CONCLUSION: Variants in the gene encoding the TSLP protein may have differential effects on asthma phenotypes depending on gender, atopy, and the presence of allergic rhinitis.