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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background While several single nucleotide polymorphisms are known to influence the metabolism of folate, the methylene tetrahydrofolate reductase ( MTHFR) gene has been the most extensively studied. The aim of this study was to investigate the relationship between the MTHFR polymorphisms 1298 A> C and 677 C> T and congenital heart disease. In addition, the relationship between these gene polymorphisms and homocysteine level was determined in Turkish subjects. Methods Patients with non-syndromic congenital heart defects who were admitted to the Pediatric Cardiology Unit at Hacettepe University Ihsan Dogramaci Children's Hospital, Ankara, Turkey between June 2002 and June 2003 were recruited for the study. A total of 163 children with congenital heart defects (mean age, 7.63 ± 6.03 years; M/F, 93/70) and 93 healthy controls were analyzed. Results When evaluated either separately or together, there were no differences in the frequency of MTHFR 677 C> T or 1298 A> C polymorphisms between the children with congenital heart defects and the control group. The results were the same when considering only conotruncal defects. Those with the 677 C> T polymorphism had significantly lower homocysteine level ( P = 0.004), but the 1298 A> C polymorphism was not related to homocysteine level. Conclusion No relationship was found between congenital heart defects and 1298 A> C or 677 C> T polymorphisms. The 677 C> T polymorphism was related to low homocysteine level. Because there is often much heterogeneity between populations, this study should be conducted in different populations and with larger numbers of participants. [ABSTRACT FROM AUTHOR]

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. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Test for Respiratory and Asthma Control in Kids (TRACK) questionnaire is the first to measure both the risk and impairment domains of the current guidelines in preschool children. We aimed to measure the reliability, validity and responsiveness of the Turkish version of the TRACK. Methods: A total of 268 children (69.8% boys) were included in the study. Caregivers responded to three individual TRACK questionnaires, at each clinical visit (baseline, 1st month, and 3rd month). At each visit, physicians determined the control level and the treatment strategy based on the GINA guideline recommendations. Results: The internal consistency reliability of the Turkish version of the TRACK questionnaire was found to be 0.74, 0.74, and 0.76 at each of the three visits, respectively (reliability statistics, Cronbach's alpha). There was a significant difference between the mean TRACK scores of the patients in different asthma control status categories ( p < 0.001). The test-retest reliability in stable patients was 0.90. The optimal cut-off scores according to the Youden index were 80 and 60 points for uncontrolled and very poorly controlled children, respectively. Conclusion: The Turkish version of the TRACK is an accurate and reliable tool for evaluating asthma control status among preschool Turkish children. Its widespread use may help physicians correctly assess control levels among children and may improve the quality of life for both patients and their caregivers. [ABSTRACT FROM AUTHOR]

Background Legumes, and particularly lentils, are frequently consumed in Mediterranean, Middle Eastern, and some Asian countries. The aim of this study was to document the demographic features of children with lentil allergy and to determine the role of specific Ig E (s Ig E) in predicting the risk of clinical reactivity and disease persistence. Methods Thirty children were enrolled. The diagnosis of lentil allergy was based on convincing history of symptoms or anaphylaxis after the ingestion of lentils, with positive skin tests and/or s Ig E to lentils. To determine the diagnosis and prognosis of lentil allergy, 24 children were evaluated with food challenges. Results The median age at the onset of symptoms was 1.5 yr (0.9-2.3) (inter-quartile range). The most frequent symptoms were immediate cutaneous (97%) and respiratory (30%) reactions, whereas eight patients (27%) reported anaphylactic reactions. The median level of lentil s Ig E at the time of diagnosis was 3 kU/l (1.2-9.6). Of the 24 challenges, 12 were positive. Fifteen patients (50%) outgrew the lentil allergy by the age of 3.5 (2.5-11) years. Children with an initial lentil s Ig E < 4.9 kU/l had a significantly higher likelihood (68.4% vs. 18.2%) of outgrowing the lentil allergy than children with an initial lentil s Ig E ≥ 4.9 k/l (p = 0.008). Conclusions Our results suggest that s Ig E levels may be important for predicting clinical reactivity and persistence of lentil allergy. [ABSTRACT FROM AUTHOR]

Background: Severe systemic reactions (SRs) to insect ven-om are rare in childhood and there are few data on this study population. The aim of our study is to analyze the clinical fea-tures and to document the risk factors for severe SRs in chil-dren with insect venom allergy. Methods: Children with SRs after Hymenoptera sting were analyzed. The diagnosis was based on medical history, skin tests and/or specific IgE test-ing. Results: Seventy-six children were included [57 boys (75%), mean age 9.8 ± 3.4 years]. The mean age of children atthe time of SR was 8.3 ± 3.4 years. Reactions were account-ed for Vespula (wasp) venom in 58 (76%) and Apis mellifera (bee) venom in 18 (24%) patients. Twenty-six percent of pa-tients had aeroallergen sensitization and 33% had atopic dis-ease, whereas 66% had experienced previous stings. The up-per limb was the most frequent area of sting (43%), and the cutaneous system (99%) was the most frequent involved sys-tem. SRs occurred in 59% of patients. Multivariate logistic re-gression analysis revealed eosinophilia (>5%) [odds ratio (OR) 12.6; confidence interval (CI) 1.5-109.7; p = 0.022], female sex (OR 6.4; CI 1.5-26.9; p = 0.011) and accompanying atopic dis-ease (OR 3.4; CI 1.2-12.3; p = 0.016) as significant risk factors for severe SRs. Ninety-seven percent of patients were admit-ted to the emergency department; however, epinephrine was used in only 46% of patients. Conclusions: There was a high frequency of hypersensitivity to wasp venom among the study population, and severe reactions were related to mild eosinophilia, female sex and concomitant atopic diseas-es. A better understanding of the risk factors may lead to ef-fective utilization of health care sources in the future. [ABSTRACT FROM AUTHOR]

Background: Chronic spontaneous urticaria (CSU) in childhood is infrequent, and information about the disease in children is limited. We attempted to investigate its etiologic factors, natural course, and predictors of prognosis. Methods: All children aged ≤18 years followed for CSU during an 8-year period were analyzed retrospectively, and the final outcomes were queried via a telephone interview. Results: One hundred patients (male/female ratio 1.27) with a median age of 9.2 years (range 0.7-17.2) at symptoms onset were evaluated. The median follow-up was 2.5 years (range 0.2-18.1). An autologous serum skin test was positive in 46.7% of the subjects (n = 45), with a female predominance (71.4%) (p = 0.023). In 13.8% of the children, ANA titers were over 1/100. Food allergy (n = 1), thyroid autoantibodies (n = 3), possible collagen disease (n = 1), and drug usage (deferoxamine) (n = 1) were found to be associated factors. Infections could not be confirmed as the cause of CSU. Recovery was seen in 16.5, 38.8, and 50.0% of the children after 12, 36, and 60 months, respectively. Though in multivariate analysis none of the factors, including age, gender, autologous serum skin test positivity, the presence of angioedema, or other allergic diseases, appeared to predict the prognosis, in univariate analysis being female and being older than 10 years of age predicted an unfavorable prognosis. Conclusion: The etiology of CSU in children is mainly related to an autoreactive background, as in adults. CSU has a favorable prognosis, and resolution is seen in half of the children within 5 years. Girls older than 10 years may have an unfavorable prognosis. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In hypersensitive reactions to native L-asparaginase, either premedication and desensitization or substitution with polyethylene glycol conjugated asparaginase ( PEG-ASP) is preferred. Anaphylaxis with PEG-ASP is rare. An 8-year-old girl and a 2.5-year-old boy, both diagnosed as having acute lymphoblastic leukemia, presented with native L-asparaginase hypersensitivity and substitution with PEG-ASP was preferred. They received a premedication (methylprednisolone, hydroxyzine and ranitidine) followed by desensitization with PEG-ASP infusion. Both patients developed anaphylaxis with peg-asparaginase. These are the first reported cases of anaphylactic reaction to PEG-ASP, despite the application of both premedication and desensitization. Anaphylaxis with PEG-ASP is very rare and premedication and desensitization protocols may not prevent these hypersensitive reactions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Pollen plays an important role in the development and exacerbation of allergic diseases. We aimed to investigate the days with highest counts of the most allergenic pollens and to identify the meteorological factors affecting pollen counts in the atmosphere of Ankara, Turkey. Airborne pollen measurements were carried out from 2005 to 2008 with a Burkard volumetric 7-day spore trap. Microscope counts were converted into atmospheric concentrations and expressed as pollen grains/m. Meteorological parameters were obtained from the State Meteorological Service. All statistical analyses were done with pollen counts obtained from March to October for each year. The percentages of tree, grass and weed pollens were 72.1% ( n = 24,923), 12.8% ( n = 4,433) and 15.1% ( n = 5,219), respectively. The Pinaceae family from tree taxa (39% to 57%) and the Chenopodiaceae/Amaranthaceae family from weed taxa, contributed the highest percentage of pollen (25% to 43%), while from the grass taxa, only the Poaceae family was detected from 2005 to 2008. Poaceae and Chenopodiaceae/Amaranthaceae families, which are the most allergenic pollens, were found in high numbers from May to August in Ankara. In multiple logistic regression analysis, wind speed (OR = 1.18, CI95% = 1.02-1.36, P = 0.023) for tree pollen, daily mean temperature (OR = 1.10, CI95% = 1.04-1.17, P = 0.001) and sunshine hours (OR = 1.15, CI95% = 1.01-1.30, P = 0.033) for grass pollen, and sunshine hours (OR = 3.79, CI95% = 1.03-13.92, P = 0.044) for weed pollen were found as significant risk factors for high pollen count. The pollen calendar and its association with meteorological factors depend mainly on daily temperature, sunshine hours and wind speed, which may help draw the attention of physicians and allergic patients to days with high pollen counts. [ABSTRACT FROM AUTHOR]