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Chronic urticaria (CU) has been shown to impact patients' quality of life negatively and may coexist with psychiatric disorders. We systematically reviewed the published evidence of comorbid psychiatric disorders in children and adolescents with CU.A systematic review of studies published until February 2022 in PubMed, Google Scholar, and Scopus was performed. An a priori set of inclusion criteria was predefined for the studies to be included: (1) clear distinction between urticaria and other allergies; (2) precise distinction between acute and CU; (3) participants younger than 18 years old, exclusively; (4) use of appropriate standardized questionnaires, psychometric tools, and standard diagnostic nomenclature for the mental health and behavioral disorders diagnosis; and (5) manuscripts written or published in the English language.Our search identified 582 potentially relevant papers. Only eight of them satisfied the inclusion criteria. Quantitative meta-analysis was not deemed appropriate, given the lack of relevant randomized control trials, the small number of relevant shortlisted, the small sample size of the patients included in each study, and the remarkable heterogeneity of the studies' protocols.The included studies suggest an increased incidence of psychopathology among children and adolescents with CU as opposed to healthy age-matched individuals, but the data are scarce. Further research is required to clarify whether psychopathology is just a comorbid entity, the cause, or the consequence of CU. Meanwhile an interdisciplinary collaboration between allergists/dermatologists and psychiatrists is expected to substantially minimize CU burden and improve patients' quality of life.

The complicated interaction between the central and the autonomic (sympathetic, parasympathetic, and enteric) nervous systems on the one hand and the immune system and its components, on the other hand, seems to substantially contribute to allergy pathophysiology, uncovering an under-recognized association that could have diagnostic and therapeutic potentials. Neurons connect directly with and regulate the function of many immune cells, including mast cells, the cells that have a leading role in allergic disorders. Proinflammatory mediators such as cytokines, neurotrophins, chemokines, and neuropeptides are released by immune cells, which stimulate sensory neurons. The release of neurotransmitters and neuropeptides caused by the activation of these neurons directly impacts the functional activity of immune cells and vice versa, playing a decisive role in this communication. Successful application of Pavlovian conditioning in allergic disorders supports the existence of a psychoneuroimmunological interplay in classical allergic hypersensitivity reactions. Activation of neuronal homeostatic reflexes, like sneezing in allergic rhinitis, coughing in allergic asthma, and vomiting in food allergy, offers additional evidence of a neuroimmunological interaction that aims to maintain homeostasis. Dysregulation of this interaction may cause overstimulation of the immune system that will produce profound symptoms and exaggerated hemodynamic responses that will lead to severe allergic pathophysiological events, including anaphylaxis. In this article, we have systematically reviewed and discussed the evidence regarding the role of the neuro-immune interactions in common allergic clinical modalities like allergic rhinitis, chronic rhinosinusitis, allergic asthma, food allergy, atopic dermatitis, and urticaria. It is essential to understand unknown - to most of the immunology and allergy experts - neurological networks that not only physiologically cooperate with the immune system to regulate homeostasis but also pathogenetically interact with more or less known immunological pathways, contribute to what is known as neuroimmunological inflammation, and shift homeostasis to instability and disease clinical expression. This understanding will provide recognition of new allergic phenotypes/endotypes and directions to focus on specialized treatments, as the era of personalized patient-centered medicine, is hastening apace.

We report a case of a 66-year-old male diagnosed with refractory to oral corticosteroids eosinophilic cystitis (EoC). Hematuria was the first and only sign of the disease that was otherwise asymptomatic, and the only abnormal lab finding he had was peripheral eosinophilia (700 cells/μl). Due to cardiovascular issues, an invasive surgical procedure was declined. As an alternative, benralizumab, an anti-IL-5Rα monoclonal antibody with anti-eosinophilic properties, was administered. The patient responded rapidly with clinical and histological complete remission of the EoC four months after benralizumab started. He continued benralizumab 30 mg Q4-weeks for 12 months without experiencing any side effects. Six months after the last dose, he is completely healthy with no peripheral eosinophilia. EoC is a rare condition with no standardized treatment. Those with corticosteroid-refractory EoC are eligible for surgery. Benralizumab has an excellent safety profile; therefore, it should be considered before deciding on invasive surgical procedures in selected, refractory to non-specific treatment cases, especially with EoC of unclear etiology. It is unclear if benralizumab may immunomodulate the unknown underlying mechanisms of EoC, considering that EoC did not relapse after benralizumab was deemed eliminated. Further studies are needed to investigate this possibility.

Cases that experienced COVID-19 postvaccination-related thrombosis have been reported after the first dose of ChAdOx1 nCov-19 (Vaxzevria, AstraZeneca) or Ad26.COV2.S (JohnsonJohnson/Janssen) vaccine. These rare thrombotic events were observed within the expected vaccine-induced seroconversion period and could be attributed to platelet-activating (auto)antibodies against platelet factor 4 (PF4). Newly, vaccine-induced, cross-reactive anti-PF4 antibodies could explain this observation. An

Delayed pressure urticaria (DPU) is a variant of physical urticaria characterised by reproducible whealing on application of sustained pressure to the skin. Clinical manifestations include delayed cutaneous erythema, edema and subcutaneous swelling, typically occurring 4-6h after application of mechanical pressure. Dyspareunia is defined as persistent or recurrent pain in the genital area or within the pelvis that occurs just before, during, or after sexual intercourse. We report an unusual case of DPU manifesting as dyspareunia.

BackgroundThe aim of the current investigation was to explore the association of food protein-induced allergic proctocolitis (FPIAP) with the maternal diet during pregnancy and breastfeeding in Greek infants.MethodsA multicenter retrospective case-control study was conducted in 6 regions in Greece, with 96 mothers of infants with and 141 mothers of infants without a history of FPIAP. Maternal dietary habits during pregnancy and breastfeeding were evaluated with the following validated questionnaires: (a) The Mediterranean Diet Score and (b) The Mediterranean Oriented Culture-Specific Semi-Quantitative Food Frequency Questionnaire.ResultsFPIAP was associated with cow's milk (83.6%), egg (7.3%), wheat (6.4%), and beef (6.4%) in the maternal diet. Adherence to Mediterranean Diet was similar among the mothers. Mothers of FPIAP infants consumed more vegetables. Elastic net prediction models showed that, in this Mediterranean population, increased consumption during pregnancy and lactation of common allergens, whole grain products, homemade food, fish and shellfish, and fruits was associated with a decreased risk of FPIAP. Conversely, a high intake of vegetables, sugar and total fat, and non-stick/grilled cooking, were associated with increased risk of FPIAP, as was a high intake of salt and white flour during lactation only.ConclusionsComponents of a maternal Mediterranean Diet may protect against FPIAP when traditional cooking methods are adopted and fish, fruit, and whole wheat products are consumed frequently during pregnancy and breastfeeding.

Background: Although well described in adults, there are scarce and heterogeneous data on the diagnosis and management of chronic urticaria (CU) in children (0-18 years) throughout Europe. Our aim was to explore country differences and identify the extent to which the EAACI/GA²LEN/EDF/WAO guideline recommendations for paediatric urticaria are implemented. Methods: The EAACI Taskforce for paediatric CU disseminated an online clinical survey among EAACI paediatric section members. Members were asked to answer 35 multiple choice questions on current practices in their respective centres. Results: The survey was sent to 2,773 physicians of whom 358 (13.8%) responded, mainly paediatric allergists (80%) and paediatricians (49.7%), working in 69 countries. For diagnosis, Southern European countries used significantly more routine tests (e.g., autoimmune testing, allergological tests, and parasitic investigation) than Northern European countries. Most respondents (60.3%) used a 2nd generation antihistamine as first- line treatment of whom 64.8% up dosed as a second- line. Omalizumab, was used as a second line treatment by 1.7% and third-line by 20.7% of respondents. Most clinicians (65%) follow EAACI/WAO/GA2LEN/EDF guidelines when diagnosing CU, and only 7.3% follow no specific guidelines. Some clinicians prefer to follow national guidelines (18.4%, mainly Northern European) or the AAAAI practice parameter (1.7%). Conclusions: Even though most members of the Paediatric Section of EAACI are familiar with the EAACI/WAO/GA2LEN/EDF guidelines, a significant number do not follow them. Also, the large variation in diagnosis and treatment strengthens the need to re-evaluate, update and standardize guidelines on the diagnosis and management of CU in children.

Purpose It has been observed that certain patients with chronic spontaneous or idiopathic urticaria (CSU/CIU) have a personal history of a significant stressor before urticaria onset, while the prevalence of any psychopathology among these patients is significantly higher than in healthy individuals. Research has confirmed that skin is both an immediate stress perceiver and a target of stress responses. These complex interactions between stress, skin, and the nervous system may contribute to the onset of chronic urticaria. This systematic review investigated the association between CSU/CIU and neuroimmune inflammation with or without evidence of co-existing psychological stress from in vivo and ex vivo studies in human beings. Methods PubMed and Scopus were searched to September 2019 for reports in human beings describing neuroimmune inflammation, stress, and CSU/CIU. A comprehensive search strategy was used that included all the relevant synonyms for the central concept. Findings A total of 674 potentially relevant articles were identified. Only 13 satisfied the predefined inclusion criteria and were included in the systematic review. Five of these 13 studies evaluated the correlation between CSU/CIU, stress, and neuro-immune-cutaneous factors, while the remaining 8 focused on the association between CSU/CIU and these factors without examining any evidence of stress. Implications The complex neuro-immune-cutaneous model that involves numerous neuropeptides and neurokinins, inflammatory mediators and cells, hypothalamic-pituitary-adrenal axis hormones, and the skin may better explain the underlying pathophysiological mechanisms involved in the onset of urticaria. In addition, the elevated psychological stress level that has been closely related to CSU/CIU could be attributed to the imbalance or irregularity of this neuro-immune-cutaneous circuit. It is still unclear and must be further investigated whether any psychological stress results in or triggers CSU/CIU onset on top of a preexisting neuroimmune dysregulation. Nevertheless, new psycho-phenotypic or neuro-endotypic CSU/CIU subsets should be considered as the era of personalized treatment strategies emerges. A better understanding of CSU/CIU pathophysiology and consideration of the patient as a whole is vital for identifying targets for new potential treatment options

Purpose of review There is a subgroup of individuals with egg or cow’s milk (CM) allergy that can tolerate heated egg or CM. Thermal processing has been shown to affect antigen allergenicity either directly by denaturation of significant epitopes, or indirectly by synergistically altering their susceptibility to the digestion process under specific pH conditions. CM and egg proteins have heat labile molecules that become hypoallergenic after thermal treatment. The allergenicity may be further reduced when the CM and egg allergens are interacting with wheat proteins, and in particular gluten, in an interplay that teleologically affects solubility and therefore bioavailability. This phenomenon is known as the food matrix effect. By exploiting these observations, it has been suggested that diets containing extensively heated CM and egg might comprise an oral immunotherapeutic approach that could alter the expected natural allergy resolution or immunomodulate to tolerance the cases with persistent allergy. Recent findings There is evidence suggesting that most of the baked-tolerant patients can be benefited from baked CM or egg oral immunotherapy (OIT). Following this approach, these patients can be desensitized, can be promoted to a transition from baked CM/egg OIT-induced tolerance to unheated CM and egg OIT-induced tolerance, or may acquire sustained tolerance. Summary Baked CM or egg OIT may accelerate CM or egg allergy resolution and therefore may be a new therapeutic option to etiologically and not just symptomatically treating CM and egg allergy. It remains to be appropriately studied which are the phenotypic characteristics of these patients and which will be the appropriate immunotherapeutic protocol so that OIT can be easily and safely be offered to them.

Background There is a substantial body of evidence on the epidemiology of allergic conditions, which has advanced the understanding of these conditions. We aimed to systematically identify systematic reviews and meta-analyses on the epidemiology of allergic diseases to assess what has been studied comprehensively and what areas might benefit from further research. Methods We searched PubMed and EMBASE up to 12/2014 for systematic reviews on epidemiological research on allergic diseases. We indexed diseases and topics covered and extracted data on the search characteristics of each systematic review. Results The search resulted in 3991 entries after removing duplicates, plus 20 other items found via references and conference abstracts; 421 systematic reviews were relevant and included in this overview. The majority contained some evidence on asthma (72.9%). Allergic rhinitis, atopic eczema and food hypersensitivity were covered in 15.7%, 24.5% and 9.0%, respectively. Commonly studied risk factors for atopic eczema included dietary and microbial factors, while for asthma, pollution and genetic factors were often investigated in systematic reviews. There was some indication of differing search characteristics across topics. Conclusion We present a comprehensive overview with an indexed database of published systematic reviews in allergy epidemiology. We believe that this clarifies where most research interest has focussed and which areas could benefit from further research. We propose that this effort is updated every few years to include the most recently published evidence and to extend the search to an even broader list of hypersensitivity/allergic disorders.

Background: Autoimmune chronic spontaneous urticaria (aiCSU) is an important subtype of chronic spontaneous urticaria (CSU) in which functional IgG autoantibodies to IgE or its high-affinity receptor (FcεRI) induces mast cell degranulation and subsequent symptom development. However, it has not been tightly characterized. This study aimed to better define the clinical and immunological features and to explore potential biomarkers of aiCSU. Methods: This was a multinational, multicenter study of 182 CSU patients. The clinical features studied included: urticaria activity and impact (UAS7 and quality of life); autologous serum skin test (ASST); IgG anti-FcεRI and IgG anti-IgE; IgG-anti-thyroperoxidase (IgG anti-TPO); total serum IgE; and basophil reactivity (BASO) using the basophil activation test (BAT) and basophil histamine release assay (BHRA). Results: Of the 182 patients, 107 (59%) were ASST+, 46 (25%) were BASO+, and 105 (58%) were IgG anti-FcεRI+/IgE+. Fifteen patients (8%) fulfilled all three criteria of aiCSU. aiCSU patients appeared more severe (UAS7 21 vs 9 P

Background: Global chronic urticaria (CU) disease experience and management is not well documented. This study descriptively compares these aspects among CU patients residing in Europe (EU) and Central and South America (C/SA). Methods: AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) is a global prospective, non-interventional study of CU in the real-world setting. Patients were ≥ 18 years with a diagnosis of H1-antihistamine-refractory CU for > 2 months. Differences between the EU and C/SA regions in demographic and clinical characteristics, quality of life (QoL), work and activity impairment, pharmacological treatment, and healthcare resource use were examined. Results: In total, 4224 patients were included in the analysis (C/SA 492; EU 3732). Rates of untreated patients were greater in the C/SA region (45.1% vs. 31.9%; P < 0.005) and escalation to third-line therapy was rare in both regions. Differences in disease experience emerged, with C/SA patients more commonly experiencing angioedema (C/SA 50.8% vs. EU 46.1%; P = 0.03) or comorbid chronic inducible urticaria (C/SA 30% vs. EU 22%; P < 0.001). Correspondingly, rates of uncontrolled urticaria were higher among C/SA patients (82.8% vs. 77.5%; P = 0.017) and patients in the C/SA region showed significantly greater work and activity impairment (absenteeism: 10.4 ± 19.7 vs. 6.7 ± 19.0, P = 0.004; presenteeism: 30.3 ± 31.9 vs. 24.4 ± 25.8, P = 0.001; work productivity loss: 33.9 ± 33.9 vs. 26.5 ± 27.5, P < 0.001; activity impairment: 37.7 ± 34.7 vs. 32.7 ± 30.1, P = 0.001). However, QoL impairment was greater in the EU region (Dermatology Life Quality Index: C/SA 6.5 ± 5.9 vs. EU 8.3 ± 7.0; P < 0.001). There was a significant difference in use of healthcare resources, including emergency services (39.6% vs. 29.3%; P < 0.001), hospitalization (7.7% vs 21.9%; P < 0.001) general practitioners (31.7% vs 57.3%; P < 0.001), and additional allergists or dermatologists (50.6% vs. 47.3%, P < 0.001), among patients in the C/SA and EU region, respectively. In both regions, patients with a primary diagnosis of CU with angioedema had significantly greater impairment in work and non-work activities and healthcare resource utilization compared to those without angioedema. Conclusions: This study revealed that CU is a heterogeneous condition with differences in healthcare utilization and outcomes between EU and C/SA. However, overall there is a high unmet need of H1-antihistamine-refractory CU patients, which is associated with high use of healthcare resources, and has a large negative effect on QoL and work productivity.

BACKGROUND The PreDicta cohort was designed to prospectively evaluate wheeze/asthma persistence in preschoolers in association with viral/microbial exposures and immunological responses. We present the cohort design and demographic/disease characteristics and evaluate unsupervised and predefined phenotypic subgroups at inclusion. METHODS PreDicta is a 2-year prospective study conducted in five European regions, including children 4-6 years with a diagnosis of asthma as cases and healthy age-matched controls. At baseline, detailed information on demographics, asthma and allergy-related disease activity, exposures, and lifestyle were recorded. Lung function, airway inflammation, and immune responses were also assessed. Power analysis confirmed that the cohort is adequate to answer the initial hypothesis. RESULTS A total of 167 asthmatic children (102 males) and 66 healthy controls (30 males) were included. Groups were homogeneous in respect to most baseline characteristics, with the exception of male gender in cases (61%) and exposure to tobacco smoke. Comorbidities and number and duration of infections were significantly higher in asthmatics than controls. 55.7% of asthmatic children had at least one positive skin prick test to aeroallergens (controls: 33.3%, P = .002). Spirometric and exhaled nitric oxide values were within normal limits; only baseline FEV0.5 and FEV1 reversibility values were significantly different between groups. Viral infections were the most common triggers (89.2%) independent of severity, control, or atopy; however, overlapping phenotypes were also common. Severity and control clustered together in an unsupervised analysis, separating moderate from mild disease. CONCLUSIONS The PreDicta cohort presented no differences in non-asthma related measures; however, it is well balanced regarding key phenotypic characteristics representative of "preschool asthma".

An epitope is a part of an immunogenic protein that can be recognized by the immune system. The peptides that can be recognized by the T-cell receptors after a particular antigen has been intracellularly processed, bound to at least one MHC molecule and expressed on the surface of the antigen presenting cell as a MHC-peptide complex, are called a T-cell epitope. Individuals who have at least one MHC molecule able to most avidly bind to allergenic amino acid sequences from an allergen, and at the same time have the appropriate T-cell clone that can recognize this MHC-peptide complex, are expected to be genetically prone to allergic reactions against that allergen. This possibility can be examined in silico by utilizing modern computational techniques that are based on sophisticated mathematics and statistics. The design principles of these techniques are different and therefore variations in their predictions are expected. The available software programs that have been developed on this basis are able to combine the increasing amount and complexity of the available experimental data that have been organized in immunoinformatics databases to predict potential allergen T-cell epitopes. All relevant T-cell epitope prediction methods can be accessed online as a freeware.

An epitope is a part of an immunogenic protein that can be recognized by the immune system. The peptides that can be recognized by the T-cell receptors after a particular antigen has been intracellularly processed, bound to at least one MHC molecule and expressed on the surface of the antigen presenting cell as a MHC-peptide complex, are called a T-cell epitope. Individuals who have at least one MHC molecule able to most avidly bind to allergenic amino acid sequences from an allergen, and at the same time have the appropriate T-cell clone that can recognize this MHC-peptide complex, are expected to be genetically prone to allergic reactions against that allergen. This possibility can be examined in silico by utilizing modern computational techniques that are based on sophisticated mathematics and statistics. The design principles of these techniques are different and therefore variations in their predictions are expected. The available software programs that have been developed on this basis are able to combine the increasing amount and complexity of the available experimental data that have been organized in immunoinformatics databases to predict potential allergen T-cell epitopes. All relevant T-cell epitope prediction methods can be accessed online as a freeware.

Food allergy is a public health concern especially after recognizing its constantly increased prevalence and severity. Despite careful reading of food ingredient statements, food allergic individuals may experience reactions caused by "hidden", "masked", or "contaminated" proteins that are known major allergens. Many techniques have been developed to detect even small traces of food allergens, for clinical or laboratory purposes. Enzyme-linked immunosorbent assay (ELISA) is one of the best validated and most routinely used immunoassay in allergy research, in allergy diagnosis in allergy-related quality control in various industries. Although as a technique it has been implemented for the last 45 years, the evolution in biochemistry allowed the development of ultrasensitive ELISA variations that are capable of measuring quantities in the scale of picograms, rendering ELISA attractive, robust, and very famous.

Children with food allergy have been shown to have increased small intestinal permeability (IP) following ingestion of the offending food as well as during elimination diets. We investigated IP in asymptomatic food allergic children during an elimination diet to identify clinical characteristics associated with altered IP.Urinary recovery ratios of lactulose and mannitol (L/M) were determined 5 h following ingestion of 7.5 g of lactulose and 2 g of mannitol in 131 cow's milk and egg allergic children. An L/M ratio of ≥0.025 was considered abnormal based upon previously established laboratory internal references. A chart review was conducted to assess the clinical characteristics of these patients.A total of 50 (38%) of the 131 children (median 6.7, range 4.8-8.9 yr; 66.2% male) with food allergy had elevated IP while asymptomatic on strict elimination diets. Age and height negatively correlated with IP. However, in the regression model analysis, abnormal IP was associated with shorter stature independently of age. Otherwise, food allergic patients with increased IP were comparable in gender, nutritional status, age of onset of food allergy, history of reactions, atopic diseases, and family history of food allergies to those with normal IP.Elevated IP was found in about one-third of asymptomatic food allergic children on elimination diets and was associated with shorter stature. Our results suggest that increased IP may be an intrinsic trait in a subset of food allergic children. However, large, prospective studies are necessary to determine the role of impaired intestinal barrier in food allergy.

BACKGROUND Despite the frequency and severity of peanut allergy, the only approved treatment is strict avoidance. Different types of immunotherapy with crude peanut extract are not universally effective and have been associated with relatively high adverse reaction rates. OBJECTIVE We sought to determine whether in silico predictive algorithms were useful in identifying candidate peptides for an Ara h 2 peptide-based vaccine using peanut-allergic patients' peripheral blood mononuclear cells (PBMCs) in vitro. A human leucocyte antigen (HLA) distribution analysis was also performed. METHODS Major histocompatibility complex (MHC)-class II-binding peptides were predicted using NetMHCIIpan-2.0 and NetMHCII-2.2 algorithms. PBMCs from 80 peanut-allergic patients were stimulated with overlapping 20-mer Ara h 2 peptides. Cell supernatant cytokine profiles were evaluated by multiplex assays. HLA-DRB1* and HLA-DQB1* typing were performed. RESULTS Four regions of overlapping sequences induced PBMC proliferation and predominant Th2 cytokine production. HLA genotyping showed 30 different DRB1* allele specificities and eight DQ serological specificities. The in silico analysis revealed similar relevant regions and predicted identical or similar core 9-mer epitopes to those identified in vitro. If relevant peptides, as determined by either in vitro or in silico analysis (15 peptides and 9 core epitopes respectively), were used in a peptide-based vaccine, they would cover virtually all subjects in the cohort studied. CONCLUSIONS AND CLINICAL RELEVANCE Four dominant regions in Ara h 2 have been identified, containing sequences that could serve as potential candidates for peptide-based immunotherapy. MHC-class II-based T cell epitope prediction algorithms for HLA-DR and -DQ loci accurately predicted Ara h 2 T cell epitopes in peanut-allergic subjects, suggesting their potential utility in a peptide-based vaccine design for food allergy.

An autoimmune subset of chronic spontaneous urticaria is increasingly being recognized internationally, based on laboratory and clinical evidence that has accrued over the last 20 years. This evidence has been reviewed by a taskforce of the Dermatology section of the European Academy of Allergy and Clinical Immunology. Functional autoantibodies in chronic urticaria (CU) patient sera have been demonstrated against IgE and FcεRIα by basophil and mast cell histamine release assays and by basophil activation assays. Antibody specificity has been confirmed by immunoassay, but there is a poor correlation between functionality and immunoreactivity. Approximately 25% of CU patients have a positive basophil histamine release assay and show autoreactivity (a positive autologous serum skin test), whereas 50% are negative regarding both. Functionality of CU sera appears to be complement dependent on mast cells but not exclusively on basophils. Basophil activation by CU sera is predominantly restricted to IgG1 and IgG3 subclasses. Circumstantial evidence for CU being an autoimmune disease comes from an observed association with other autoimmune diseases, a strong association between serum functionality and HLA-DR4 haplotype and the good response of CU patients to immunotherapies. It was proposed that a study should be undertaken to prospectively validate potentially relevant clinical criteria (from the history, examination and routinely available clinical investigations) against a new 'gold standard' for the diagnosis of ACU (positive autoreactivity, functional bioassay and immunoassay) to define preliminary criteria sets for the diagnosis of ACU based on clinical and laboratory features with highest individual sensitivity and specificity.

We examined the use of surgical eye spears for saliva collection and recovery of secretory immunoglobulin A (s-IgA). We established a protocol for recovering s-IgA at concentrations equivalent to those present in the control samples (untreated by surgical eye spears). Four different types of eye spears were submerged in the salivary fluid. Saliva was recovered from each spear by centrifugation. Novel ultra-sensitive enzyme-linked immunosorbent assay was used to determine s-IgA concentration in each sample. The results revealed that Weck-Cel eye spears recovered s-IgA at concentrations not significantly different from s-IgA concentrations in control samples as long as the appropriate protocol was followed. We demonstrated that the use of surgical eye spears for saliva collection is a viable method for recovering s-IgA. (J Oral Sci 58, 205-210, 2016).

To cite this article: Koutsoubari I, Papaevangelou V, Konstantinou GN, Makrinioti H, Xepapadaki P, Kafetzis D, Papadopoulos NG. Effect of clarithromycin οn acute asthma exacerbations in children: an open pilot randomized study. Pediatric Allergy Immunology 2012: 23: 385–390. Abstract Background: Asthma exacerbations are major contributors to asthma morbidity and rather difficult to treat. There is inconclusive evidence that macrolide antibiotics may have an effect on asthma exacerbations through their antibacterial and/or anti-inflammatory properties. The aim of the study was to evaluate the efficacy of clarithromycin on medium-term asthma activity when given as an add-on therapy in children with acute asthma. Methods: This pilot, open-labeled, randomized, prospective study included 40 school-aged children, with intermittent or mild persistent asthma, presenting with an acute exacerbation. Children were randomized to receive 15 mg/kg of clarithromycin for 3 wk, in addition to their regular (GINA-guided) exacerbation treatment. The microbial trigger of exacerbations was assessed by serology and PCR. Children were followed up with diary cards for 12 wk; lung function was assessed at entry, 3, and 12 wk after the exacerbation. Results: Children in the clarithromycin group had significantly more symptom-free days (78 ± 2 vs. 69 ± 6 days, p

Acute urticaria (AU) is a common condition that often presents in childhood. Although there is a general perception of cyclic annual trends in AU, no one has tried to identify any seasonal variation on its prevalence and incidence, associate environmental influences and impute geographic, ethnic, or even genetic features that may contribute to its onset. We aimed to analyze the influence of climate and geographic parameters on annual fluctuation of AU cases referred to the Emergency Departments (EDs) of Norwich (UK) and Heraklion (Crete, Greece), compare all identifiable potential triggers and severity, and calculate the prevalence and incidence of AU. Record-based data of all children up to 14 yr of age referred to both EDs between June 2005 and May 2007 were examined retrospectively. Demographic characteristics and any potential identifiable triggers of AU were recorded and compared. Poisson's regression was utilized to examine any influence of meteorological parameters on AU incidence. Edwards' test for seasonality was applied to identify any significant seasonal trend of the AU incidence within each city. Seven hundred and twenty-nine AU cases were identified (324 in Norwich and 405 in Heraklion), among 56,624 total referrals (28,931 and 27,693 cases, respectively). Respiratory infections were found to be the most commonly associated potential triggers of AU and food allergens the least. AU cases and incidence rates in both cities were equally distributed during the study period. A non-significant seasonal trend in AU incidence (October, April-May) was observed in Norwich, in contrast to a significant seasonal pattern (December, February-May) of AU in Heraklion. Temperature was inversely associated with AU incidence, while the statistically significant effect of relative humidity varied. Acute childhood urticaria shows a similar epidemiological pattern in northern and southern Europe regardless of the expected differences in genetic, geographic, and environmental background. Temperature and humidity are correlated with AU incidence. Seasonality of several acute respiratory viral infections, the most prominent associated trigger of AU, coincides with the observed AU seasonality, suggesting a potential linkage. However, this needs to be elucidated from larger epidemiological studies.

A major part of the burden of asthma is caused by acute exacerbations. Exacerbations have been strongly and consistently associated with respiratory infections. Respiratory viruses and bacteria are therefore possible treatment targets. To have a reasonable estimate of the burden of disease induced by such infectious agents on asthmatic patients, it is necessary to understand their nature and be able to identify them in clinical samples by employing accurate and sensitive methodologies. This systematic review summarizes current knowledge and developments in infection epidemiology of acute asthma in children and adults, describing the known impact for each individual agent and highlighting knowledge gaps. Among infectious agents, human rhinoviruses are the most prevalent in regard to asthma exacerbations. The newly identified type-C rhinoviruses may prove to be particularly relevant. Respiratory syncytial virus and metapneumovirus are important in infants, while influenza viruses seem to induce severe exacerbations mostly in adults. Other agents are relatively less or not clearly associated. Mycoplasma and Chlamydophila pneumoniae seem to be involved more with asthma persistence rather than with disease exacerbations. Recent data suggest that common bacteria may also be involved, but this should be confirmed. Although current information is considerable, improvements in detection methodologies, as well as the wide variation in respect to location, time and populations, underline the need for additional studies that should also take into account interacting factors.

Background: Until now, it is unknown whether and to what extent arteriosclerotic disease affects the bronchial arteries. Objectives: We conducted this pilot study to estimate the prevalence of arteriosclerosis of the bronchial arteries, to correlate it with certain clinicolaboratory arteriosclerotic parameters or any coexistent coronary artery disease (CAD) and to validate the clinical significance. Methods: Bronchial arteries 10–15 mm long were obtained from 40 patients with a mean age of 62.3 years who underwent major thoracic procedures. Their medical history and detailed clinical and laboratory arteriosclerotic risk factors were documented. Results: The mean diameter of bronchial artery specimens was 0.97 mm. Histology revealed medial calcific sclerosis only in 1 patient (2.5%) without simultaneous, established atherosclerotic lesions or narrowing of the lumen. Furthermore, the vessel diameter was significantly correlated not only with the advanced stage of the disease (p = 0.031), but also with the proximal occlusion of the bronchial tree (p = 0.042). We noted a marginally not significant correlation between arteriosclerosis and metabolic syndrome (p = 0.075), independent from a history of CAD (p = 0.84). Conclusions: Bronchial arteries exhibit only medial calcific sclerosis. CAD and chronic obstructive pulmonary disease do not seem to affect them in terms of atherosclerotic alteration findings or vessel diameter changes. The bronchial resistance to arteriosclerosis might support the mediastinal status quo through their anastomoses, contributing to all its structures, and might be indirect evidence of a different physiological function of the bronchial endothelium, which needs to be further investigated.

Oral allergy syndrome (OAS) or pollen-fruit allergy syndrome represents a mucosal allergic contact urticaria in people sensitized to common pollens, due to IgE cross-reactivity between homologous pollen allergens and various plant foods. It is the most prevalent food allergy, affecting millions of people with respiratory allergies. Usually, symptoms are mild, self-limiting and localized to the oropharyngeal mucosa, although they may sometimes become generalized and life-threatening. Although patients usually recognize the offending foods, diagnosis may sometimes be complicated. Several clinical syndromes and association between pollens and plant-derived foods have been described. Crossreactivity on the basis of stringent immunological and allergological criteria can also occur in people without pollen sensitization or concomitant respiratory allergies, as in latex-fruit syndrome. The term 'food contact hypersensitivity syndrome' (FCHS) is proposed in this paper for the first time, to include all mucosal hypersensitivity reactions presenting with contact to food (both immunological and nonimmunological), whether due to crossreactivity with homologous plant-derived allergens or not. At this time, prophylaxis and treatment can only be attained by avoidance, even when symptoms are mild, with consequent impairment in quality of life. A better understanding of the pathophysiological mechanisms of FCHS and food allergy in general is essential for deeper insights and future emergence of effective therapies.

Background Immune responses to rhinovirus (RV) as well as direct effects of RV on respiratory epithelium may contribute to the induction of asthma exacerbations. Objective To evaluate the effect of the environment resulting from an atopic immune response on RV-induced epithelial inflammation, replication and cytotoxicity. Methods Peripheral blood mononuclear cells (PBMC) from atopic asthmatic subjects and matched controls (12 pairs) were isolated and stimulated by RVs. Human bronchial epithelial (BEAS-2B) cells were infected with RV in the presence of conditioned media from RV-stimulated PBMC cultures. IL-6, IL-8, RANTES and TGF-beta1 levels were measured by ELISA, RV-induced cytotoxicity by a colorimetric method and RV titres on Ohio-HeLa cells. Results RV-induced epithelial production of IL-6, IL-8 and RANTES was significantly lower, while TGF-beta1 was higher when cells were exposed to conditioned media from atopic asthmatic subjects compared with those from normal controls. Exposure to the 'atopic' environment also resulted in elevated RV titres and increased RV-induced cytotoxicity. Conclusions Under the influence of an atopic environment, the epithelial inflammatory response to RV is down-regulated, associated with increased viral proliferation and augmented cell damage, while TGF is up-regulated. These changes may help explain the propensity of atopic asthmatic individuals to develop lower airway symptoms after respiratory infections and indicate a mechanism through which viral infections may promote airway remodelling.

Our aim was to compare the perfusion [blood flow (BF)] values obtained by first-pass dynamic contrast-enhanced (DCE) T2-weighted magnetic resonance (MR) and computed tomography (CT) imaging of squamous cell carcinoma (SCC) in the upper aerodigestive tract in the same patient population. Seventeen patients with histologically proven primary SCC of the upper aerodigestive tract were prospectively evaluated. The perfusion CT studies were obtained using a 16-row multi-slice CT scanner running a commercial software package with a deconvolution-based technique; while the perfusion MR studies (1.5 T) were analysed with in-house-written MR perfusion software based also on a deconvolution technique. The mean perfusion values of SCC assessed by perfusion CT and MR imaging were 68.93 +/- 31.61 and 81.56 +/- 49.25 ml/min/100 g, respectively. The Bland-Altman graph showed a proportional error in the perfusion values measured by DCE-CT and -MR imaging; however, the degree of agreement was acceptable (95% limits of agreement: -66.1 to 40.8). Regression analysis of the perfusion values demonstrated significant correlation between the modalities: BF(MR) = 1.34 x BF(CT) - 10.93 (P < 0.0005, r (2) = 0.74). The parametric maps generated by both modalities provided insights into the tumour perfusion, while analysis of the obtained perfusion values demonstrated that both modalities may be used interchangeably in SCC in the upper aerodigestive tract.

Background: Although development of clinical tolerance is the rule in allergy to cow’s milk (CM), food challenges are required in order to reintroduce CM into the patient’s diet. Less ‘invasive’ procedures able to predict tolerance would be useful as clinical tools. The purpose of this study was to identify potential risk factors for clinical reactivity in CM-allergic children assessed for CM reintroduction. Methods: One hundred and sixteen open challenges performed in children 10–47 months old with IgE-mediated allergy to CM, in order to reintroduce CM into the diet, were retrospectively evaluated. Specific IgE (sIgE) levels assessed by the CAP System FEIA and skin prick tests (SPT) were obtained at diagnosis and prechallenge. Demographic parameters and measures of sIgE were evaluated as potential predictors of a positive challenge in univariate and multivariate logistic regression models. Results: Twenty-four out of 116 challenges were positive, 9 of which required the use of adrenaline. In order of performance, prechallenge sIgE 7.5 mm or sIgE >25.4 kU/l, or their combination, had a high positive predictive value. The presence of atopic dermatitis did not affect the predictive accuracy of these values. Conclusions: Milk sIgE level prechallenge is a useful predictor of challenge outcome in patients with milk allergy. SPT do not offer an additional predictive value, but can be used when sIgE is not available.

Food protein-induced enterocolitis syndrome (FPIES) is a gastrointestinal hypersensitivity disorder with a poorly understood pathophysiology and no biomarkers to aid in diagnosis.To investigate humoral and cellular responses to casein in children with milk-FPIES, including the role of casein-specific (cs) IgA and T-cell mediated TGF-β responses.Thirty-one children previously diagnosed with milk-FPIES were challenged with milk. Twelve age-matched children with FPIES to other foods and 6 milk-tolerant children without a history of FPIES were used as controls. Casein-specific IgE, IgG, IgG4, and IgA were measured in serum and TGF-β levels in supernatants of casein-stimulated PBMCs.Twenty-six children with milk-FPIES reacted (active milk-FPIES) and five tolerated milk (milk-FPIES resolved) during food challenge. All of them had significantly lower levels of csIgG, csIgG4, and csIgA than control children (p-value0.001). There were no TGF-β responses in supernatants of active milk-FPIES children.Children with milk-FPIES have low levels of csIgG, csIgG4, and csIgA. In particular, children with active FPIES to cow's milk have deficient T-cell mediated TGF-β responses to casein, rendering TGF-β a promising biomarker in identifying children who are likely to experience FPIES reactions to this allergen. Prospective studies are needed to validate these findings, elucidate their role in FPIES pathophysiology, and establish the diagnostic utility of TGF-β in milk-induced FPIES.

Background: Mean diameter or longest diameter are the 2 most frequently used parameters for wheal response assessment after skin prick testing (SPT). We aimed to compare these 2 parameters taking as gold standard the surface of the wheal skin response. Patients and Methods: Patients suspected of having an allergic reaction against inhalant allergens have been skin prick tested using the Pan-European GA2LEN SPT panel. Fifteen minutes later, macroscopically evident wheal and flare reactions were marked with a pen and transferred to paper with a transparent scotch tape. Each paper-transferred wheal was scanned with an ordinary scanner, and its surface-corresponding maximum perpendicular diameters and longest diameters were measured using a computer software application for image recognition, developed for this purpose. Correlation coefficients (Spearman’s ρ) between surfaces and respective mean (ρmean) or longest (ρlongest) diameters were calculated and subsequently compared. Results: 1,554 SPTs were performed in 74 patients. In 264, a macroscopically evident wheal and flare response was observed. Both mean and longest diameters correlated significantly with the wheal surfaces. However, ρlongest was statistically significantly larger than ρmean when the surface of the wheal was >17 mm2 (ρlongest > 0.860 vs. ρmean < 0.660; p < 0.05).Such a surface corresponds to a maximum diameter of approximately 7 mm and a mean diameter of approximately 6 mm. Thus, the larger the surface of the wheal, the more appropriate the usage of the longest diameter. Conclusions: The longest wheal diameter alone seems to be a better surrogate marker of the wheal surface in comparison with the mean diameter. In addition, it is easier and faster to measure. Therefore, we propose this as the optimal methodology to evaluate SPTs.

Background Decreased serum food-specific IgA antibodies have been associated with allergic disease in cross-sectional, case–control studies. The purpose of this study was to prospectively compare egg-white-(EW)-specific IgA and IgA2 levels between egg-allergic children and children tolerating egg. Methods Seventeen egg-allergic children were followed prospectively. Total IgA, EW-specific IgA, and EW-specific IgA2 levels were measured in their sera with a sensitive ELISA. As negative controls were used children with no previous history of egg allergy. Egg-allergic children with or without concomitant milk allergy were evaluated as additional controls with measurement of casein-specific IgA. Results After 2.5 ± 0.9 yrs, nine out of the 17 allergic children became tolerant and eight remained allergic to baked egg. Baseline EW-specific IgA2 levels were significantly lower in the egg-allergic subjects (median 23.9 ng/ml) compared with the negative control subjects (99.4 ng/ml) and increased significantly by 28% over the study time period in eight out of the nine allergic children that became tolerant to baked egg. There was no significant change over time in EW-specific IgA in any of the study groups. Non-milk-allergic subjects with concomitant egg allergy had almost threefold higher casein-specific IgA levels than the milk- and egg-allergic subjects (p = 0.025). Conclusions These results suggest a potential role for allergen-specific IgA2 antibodies in the induction of food tolerance. Furthermore, they support the hypothesis that immature or impaired production of allergen-specific IgA2 may be associated with the pathophysiology of food allergy, a defect that seems to be selective for the culprit allergen.

Background Fibrosis of the esophageal lamina propria is a known complication of eosinophilic esophagitis (EoE). To date, therapy with topical corticosteroids has been shown to reverse esophageal fibrosis in some patients; however, there is little evidence to suggest that dietary therapy can also reverse it. Our aim was to examine whether dietary therapy alone can reverse esophageal fibrosis in children with EoE. Methods We performed a historical cohort study based on children with EoE who had esophageal fibrosis on pretreatment biopsies using trichrome staining. Post-treatment biopsies were analyzed for fibrosis reversal, and results were compared between patients treated with dietary restriction and those that received topical steroids. Clinical characteristics (age, symptoms, duration of symptoms prior to therapy, treatment type, and duration of therapy) were recorded. Histological markers (eosinophil numbers and eosinophilic degranulation in both epithelium and lamina propria, basal zone hyperplasia, and the presence of eosinophilic microabscesses in the epithelium) were examined by reviewing hematoxylin and eosin-stained biopsies and by immunohistochemical staining. These were examined as potential predictors for fibrosis reversal. Results Fibrosis resolved following both dietary restriction and topical steroids (3/17 and 5/9 patients respectively, P = 0.078). Post-treatment symptom resolution and decreased intraepithelial eosinophil numbers were found to be the only significant predictors of fibrosis resolution. Conclusions Dietary restriction alone, similar to topical steroids, can reverse fibrosis in children with EoE.

Asthma exacerbations are major contributors to asthma morbidity and rather difficult to treat. There is inconclusive evidence that macrolide antibiotics may have an effect on asthma exacerbations through their antibacterial and/or anti-inflammatory properties. The aim of the study was to evaluate the efficacy of clarithromycin on medium-term asthma activity when given as an add-on therapy in children with acute asthma.This pilot, open-labeled, randomized, prospective study included 40 school-aged children, with intermittent or mild persistent asthma, presenting with an acute exacerbation. Children were randomized to receive 15 mg/kg of clarithromycin for 3 wk, in addition to their regular (GINA-guided) exacerbation treatment. The microbial trigger of exacerbations was assessed by serology and PCR. Children were followed up with diary cards for 12 wk; lung function was assessed at entry, 3, and 12 wk after the exacerbation.Children in the clarithromycin group had significantly more symptom-free days (78 ± 2 vs. 69 ± 6 days, p0.00001) and less total number of periods with loss of control (9 vs. 19, respectively, p = 0.013) during the follow-up period, compared to controls. Moreover, treated children presented reduced duration of the index episode (5.0 ± 1 vs. 7.5 ± 1 days, p0.00001). Lung function did not differ between groups.When added to regular treatment, a 3-wk course of clarithromycin was associated with an increase in the number of symptom-free days, reductions in the number and severity of days with loss of control following index episode, and a decrease in the duration of the initial asthma exacerbation.

Hashimoto et al 1 have conducted an interesting study to offer a practical and pragmatic insight into steroid-dependent asthma therapeutics in real-world practice. They proposed a strategy based on internet monitoring of objective (spirometry and fraction of exhaled nitric oxide) and subjective (asthma control and asthma-related quality of life questionnaires) measurements to adjust the dose of oral corticosteroids in patients with severe, uncontrolled asthma. However, how ‘pragmatic’ is …

Acute urticaria (AU) is a common condition that often presents in childhood. Although there is a general perception of cyclic annual trends in AU, no one has tried to identify any seasonal variation on its prevalence and incidence, associate environmental influences and impute geographic, ethnic, or even genetic features that may contribute to its onset. We aimed to analyze the influence of climate and geographic parameters on annual fluctuation of AU cases referred to the Emergency Departments (EDs) of Norwich (UK) and Heraklion (Crete, Greece), compare all identifiable potential triggers and severity, and calculate the prevalence and incidence of AU. Record-based data of all children up to 14 yr of age referred to both EDs between June 2005 and May 2007 were examined retrospectively. Demographic characteristics and any potential identifiable triggers of AU were recorded and compared. Poisson's regression was utilized to examine any influence of meteorological parameters on AU incidence. Edwards' test for seasonality was applied to identify any significant seasonal trend of the AU incidence within each city. Seven hundred and twenty-nine AU cases were identified (324 in Norwich and 405 in Heraklion), among 56,624 total referrals (28,931 and 27,693 cases, respectively). Respiratory infections were found to be the most commonly associated potential triggers of AU and food allergens the least. AU cases and incidence rates in both cities were equally distributed during the study period. A non-significant seasonal trend in AU incidence (October, April-May) was observed in Norwich, in contrast to a significant seasonal pattern (December, February-May) of AU in Heraklion. Temperature was inversely associated with AU incidence, while the statistically significant effect of relative humidity varied. Acute childhood urticaria shows a similar epidemiological pattern in northern and southern Europe regardless of the expected differences in genetic, geographic, and environmental background. Temperature and humidity are correlated with AU incidence. Seasonality of several acute respiratory viral infections, the most prominent associated trigger of AU, coincides with the observed AU seasonality, suggesting a potential linkage. However, this needs to be elucidated from larger epidemiological studies.

Venom immunotherapy (VIT) has been shown to be an effective and safe treatment for preventing sting-induced anaphylaxis in patients with systemic reactions to hymenoptera stings. A remaining problem is the relative effectiveness and safety of different immunotherapy protocols used with respect to maintenance dose, injection interval, and duration.We aimed to describe a modified cluster VIT protocol with a maintenance dose of 50 μg lasting 5 yr and to evaluate retrospectively its safety and efficacy in children.Fifty four children 9.5±3.2 yr old with a history of at least one anaphylactic reaction to hymenoptera stings underwent VIT between 1995 and 2006. The identification of the offending insect(s) was based on patient's report and documented with in-vivo (SPTs and IDs) and in-vitro (RAST/CAP) test results. A modified cluster outpatient protocol lasting 5 wks, reaching a maintenance dose of 50 μg was followed according to clinical history and test results. After the maintenance dose was achieved, the followed injection-intervals were 4 wks for the first year, 5 wks for the 2nd year and 3rd year, and 6 wks for the last 2 yr.Of the 54 children, 52 tolerated the 50 μg VIT protocol without side effects. Twenty one of them reported at least one field sting from at least one of the culprit, for their allergy, insects, 6±3.5 yr after they have started VIT treatment. In 11 of them, sting occurred 3.5±2.9 yr after the VIT was completed, whereas the other 10 of them during immunotherapy, 3.2±1.4 yr after they have started VIT. In the remaining two children, the maintenance dose was increased to 100 μg due to systemic reactions from the VIT. The data reflect outcomes 6-16 yr after the patients' initial allergic reaction.VIT with 50 μg maintenance dose lasting 5 yr appears to be safe and effective enough to induce tolerance in children with hymenoptera venom hypersensitivity.

Injection of autologous serum collected during disease activity from some patients with chronic spontaneous urticaria (CU) into clinically normal skin elicits an immediate weal and flare response. This observation provides a convincing demonstration of a circulating factor or factors that may be relevant to the understanding of the pathogenesis and management of the disease. This test has become known as the autologous serum skin test (ASST) and is now widely practised despite incomplete agreement about its value and meaning, the methodology and the definition of a positive response. It should be regarded as a test for autoreactivity rather than a specific test for autoimmune urticaria. It has only moderate specificity as a marker for functional autoantibodies against IgE or the high affinity IgE receptor (FcepsilonRI), detected by the basophil histamine release assay, but high negative predictive value for CU patients without them. It is usually negative in other patterns of CU, including those that are physically induced. Positive ASSTs have been reported in some subjects without CU, including those with multiple drug intolerance, patients with respiratory allergy and healthy controls, although the clinical implications of this are uncertain. It is essential that failsafe precautions are taken to ensure that the patient's own serum is used for skin testing and aseptic procedures are followed for sample preparation and handling. CU patients with a positive ASST (ASST(+)) are more likely to be associated with HLADR4, to have autoimmune thyroid disease, a more prolonged disease course and may be less responsive to H1-antihistamine treatment than those with a negative ASST (ASST(-)) although more evidence is needed to confirm these observations conclusively.

Although a wide variety of infectious agents have been implicated in the aetiology of acute pancreatitis, their true incidence is unknown because they coexist quite often with other noninfectious causes. Acute herpes simplex viral pancreatitis is a rarely encountered entity in the literature. We report a patient who developed acute pancreatitis and hepatitis in association with herpes simplex virus infection as well as cholestatic syndrome because of compression of the intrapancreatic part of the common bile duct by the oedematous pancreatic head. Herpes simplex virus infection, although a rare entity, should be included in the conditions causing acute pancreatitis, when common noninfectious factors have been excluded and hepatic inflammation coexists. Diagnostically, a combination of serum amylase or lipase elevation, more than three times over the upper normal limits, as well as serologic evidence of the infectious agent should exist. Dilatation of the biliary tree is not invariably compatible with a biliary cause of acute pancreatitis.