Showing papers in "Pediatric Allergy and Immunology in 2016"

EAACI Molecular Allergology User's Guide.

Abstract: The availability of allergen molecules ('components') from several protein families has advanced our understanding of immunoglobulin E (IgE)-mediated responses and enabled 'component-resolved diagnosis' (CRD). The European Academy of Allergy and Clinical Immunology (EAACI) Molecular Allergology User's Guide (MAUG) provides comprehensive information on important allergens and describes the diagnostic options using CRD. Part A of the EAACI MAUG introduces allergen molecules, families, composition of extracts, databases, and diagnostic IgE, skin, and basophil tests. Singleplex and multiplex IgE assays with components improve both sensitivity for low-abundance allergens and analytical specificity; IgE to individual allergens can yield information on clinical risks and distinguish cross-reactivity from true primary sensitization. Part B discusses the clinical and molecular aspects of IgE-mediated allergies to foods (including nuts, seeds, legumes, fruits, vegetables, cereal grains, milk, egg, meat, fish, and shellfish), inhalants (pollen, mold spores, mites, and animal dander), and Hymenoptera venom. Diagnostic algorithms and short case histories provide useful information for the clinical workup of allergic individuals targeted for CRD. Part C covers protein families containing ubiquitous, highly cross-reactive panallergens from plant (lipid transfer proteins, polcalcins, PR-10, profilins) and animal sources (lipocalins, parvalbumins, serum albumins, tropomyosins) and explains their diagnostic and clinical utility. Part D lists 100 important allergen molecules. In conclusion, IgE-mediated reactions and allergic diseases, including allergic rhinoconjunctivitis, asthma, food reactions, and insect sting reactions, are discussed from a novel molecular perspective. The EAACI MAUG documents the rapid progression of molecular allergology from basic research to its integration into clinical practice, a quantum leap in the management of allergic patients.

Alterations in the gut microbiotas of children with food sensitization in early life.

Abstract: Background We hypothesized that food sensitization (FS) in children could be linked to specific gut microbiota. The aim of our study is to quantify and evaluate differences in gut microbiota composition between children with FS and healthy controls. Methods A case–control study of 23 children with FS and 22 healthy children was performed. Individual microbial diversity and composition were analyzed via parallel barcoded 454 pyrosequencing targeting the 16S rRNA gene hypervariable V3–V5 regions. Results The children with FS exhibited lower diversity of both the total microbiota (p = 0.01) and the bacterial phylum Bacteroidetes (p = 0.02). In these children, the number of Bacteroidetes bacteria was significantly decreased and that of Firmicutes were significantly increased compared with the healthy children. At the genus level, we observed significant increases in the numbers of Sphingomonas, Sutterella, Bifidobacterium, Collinsella, Clostridium sensu stricto, Clostridium IV, Enterococcus, Lactobacillus, Roseburia, Faecalibacterium, Ruminococcus, Subdoligranulum, and Akkermansia in the FS group. We also found significant decreases in the numbers of Bacteroides, Parabacteroides, Prevotella, Alistipes, Streptococcus, and Veillonella in this group. Furthermore, linear discriminant analysis (LDA) coupled with effect size measurements revealed the most differentially abundant taxa (increased abundances of Clostridium IV and Subdoligranulum and decreased abundances of Bacteroides and Veillonella), which could be used to identify FS. Conclusions Our results showed that FS is associated with compositional changes in the gut microbiota. These findings could be useful for developing strategies to control the development of FS or atopy by modifying the gut microbiota.

Chronic granulomatous disease: Clinical, molecular, and therapeutic aspects

Abstract: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by defects in the genes encoding any of the NADPH oxidase components responsible for the respiratory burst of phagocytic leukocytes. CGD is a genetically heterogeneous disease with an X-linked recessive (XR-CGD) form caused by mutations in the CYBB gene encoding the gp91(phox) protein, and an autosomal recessive (AR-CGD) form caused by mutations in the CYBA, NCF1, NCF2, or NCF4 genes encoding p22(phox) , p47(phox) , p67(phox) , and p40(phox) , respectively. Patients suffering from this disease are susceptible to severe life-threatening bacterial and fungal infections and excessive inflammation characterized by granuloma formation in any organ, for instance, the gastrointestinal and genitourinary tract. An early diagnosis of and the prompt treatment for these conditions are crucial for an optimal outcome of affected patients. To prevent infections, CGD patients should receive lifelong antibiotics and antifungal prophylaxis. These two measures, as well as newer more effective antimicrobials, have significantly modified the natural history of CGD, resulting in a remarkable change in overall survival, which is now around 90%, reaching well into adulthood. At present, hematopoietic stem cell transplantation (HSCT) is the only definitive treatment that can cure CGD and reverse organ dysfunction. Timing, donor selection, and conditioning regimens remain the key points of this therapy. In recent years, gene therapy (GT) for XR-CGD has been proposed as an alternative to HSCT for CGD patients without a matched donor. After the failure of the first trials performed with retroviral vectors, some groups have proposed the use of regulated SIN-lentiviral vectors targeting gp91(phox) expression in myeloid cells to increase the safety and efficacy of the GT protocols.

Association of pollution and climate with atopic eczema in US children

Abstract: Background We sought to determine the relationship between childhood eczema, climate, and environmental pollutants. Methods We analyzed data from the 2007–2008 National Survey of Children's Health including a representative sample of 91,642 children age 0–17 years and the 2006–2007 Environmental Protection Agency measurements of carbon monoxide (CO), nitrate (NO3), nitrogen dioxide (NO2), organic carbon (OC), sulfate (SO3), sulfur dioxide (SO2), particulate matter ≤2.5 μm (PM-2.5) and <10 μm (PM-10), and tropospheric ozone levels, and the National Climate Data Center measurements of relative humidity (%), issued UV index, outdoor air temperature, and precipitation levels. Results In multivariate survey logistic regression models controlling for age, sex, race/ethnicity, household income, US birthplace, and history of moving to a new location, eczema was associated with higher mean annual NO2 (p = 0.008), SO2 (p = 0.006), SO3 (p = 0.0002), arsenic (p = 0.0007), nickel (p = 0.0002), lead (p = 0.03), vanadium (p < 0.0001), and zinc (p = 0.003), but lower NO3 (p = 0.002), OC (p = 0.03), PM-2.5 (p = 0.006), cadmium (p < 0.0001), copper (p = 0.004), and potassium (p < 0.0001). In contrast, moderate–severe eczema was associated with higher NO3 (p = 0.03), OC (p = 0.008) and PM-2.5 (p = 0.01), copper (p = 0.04), lead (p = 0.008), and zinc (p = 0.01), but lower CO (p = 0.03). Principal component analysis was used and identified 4 combinations of pollutants and climate factors occurring in the USA, of which 1 was associated with higher prevalence and two were associated with lower prevalences of eczema (p < 0.05). Conclusions Pollutants in conjunction with climate factors may differentially impact eczema prevalence and severity, some with apparent harmful effects.

Direct oral provocation tests in non-immediate mild cutaneous reactions related to beta-lactam antibiotics

Abstract: Background Skin testing has a limited role in the diagnosis of non-immediate beta-lactam hypersensitivity in children. The aim of this study was to report the results of oral provocation tests performed without skin tests in children with non-immediate mild cutaneous reactions without systemic symptoms caused by beta-lactam antibiotics. Methods Oral provocation tests with suspected antibiotics were performed to patients with non-immediate mild cutaneous reactions without systemic symptoms caused by beta-lactam antibiotics. Skin tests were not performed before provocation tests. A total of five doses were administered with half-an-hour intervals in increasing doses. Provocation was continued for 5 days. Results A total of 119 patients with a median age of 4.3 (IQR: 2–7.5) years, of whom 58% were males, were included in the study. Amoxicillin–clavulanic acid was the most frequently responsible agent in 87 (73.1%) patients, and most common type of rash was maculopapular in 74 (62.2%) patients. Four patients (3.4%) had an urticarial reaction during the provocation test. Conclusion We did not experience any severe reactions during oral provocation test without previous skin tests performed to children with non-immediate mild cutaneous reactions without systemic symptoms. Omitting skin tests before oral provocation test in this group of children can help decreasing the burden of allergy clinics and alleviating the discomfort of children.

Non-immediate hypersensitivity reactions to beta-lactam antibiotics in children – our 10-year experience in allergy work-up

Abstract: Background: Non-immediate reactions to beta-lactam antibiotics (BL) occur more than one hour after drug administration, and the most common manifestations are maculopapular exanthemas and delayed-appearing urticaria and/or angioedema. Infections can lead to skin eruptions and mimic drug hypersensitivity reactions (DHR), if a drug is taken at the same time. The most of children are labeled as drug allergic' after considering only the clinical history. Objective: To diagnose/detect a hypersensitivity or an infection which mimic DHR in children with non-immediate reactions to BL Methods: A prospective survey was conducted in a group of 1026 children with histories of non-immediate reactions to BL by performing patch tests, skin tests, and in case of negative results, drug provocation tests (DPTs). In 300 children, a study was performed to detect infections by viruses or Mycoplasma pneumoniae. Results: Urticaria and maculopapular exanthemas were the most reported non-immediate reactions. Only 76 (7.4%) of 1026 children had confirmed non-immediate hypersensitivity reactions to BL. Fifty-seven children had positive delayed-reading intradermal tests (18 of these with a positive patch test). Nineteen children had positive DPT. Sixty-six of 300 children had positive tests for viruses or Mycoplasma pneumoniae and 2 of them had a positive allergy work-up. Conclusions: A diagnostic work-up should be performed in all children with non-immediate reactions to BL, to remove a false label of hypersensitivity. Even though only 57 (5.5%) of 1026 children displayed positive responses to delayed-reading intradermal tests to BL, such tests appear to be useful in order to reduce the risk for positive DPTs.

Cesarean section delivery and development of food allergy and atopic dermatitis in early childhood.

Abstract: Background Delivery by Cesarean section (CS) may predispose to allergic disorders, presumably due to alterations in the establishment of normal gut microbiota in early infancy. In this study, we sought to investigate the association between CS and physician-diagnosed food allergy and atopic dermatitis during the first 3 years of life, using data from a homogeneous, population-based, birth cohort. Methods A total of 459 children born and cared for in the same tertiary maternity unit were examined at birth and followed up at 1, 6, 12, 18, 24, 30 and 36 months of age. Participants with symptoms suggestive of food allergy or atopic dermatitis were evaluated by a pediatric allergy specialist to confirm the diagnosis based on well-defined criteria. Results The rate of CS was 50.8% (n = 233). Food allergy was diagnosed in 24 participants (5.2%) while atopic dermatitis was diagnosed in 62 children (13.5%). Cesarean section (OR 3.15; 95% CI 1.14–8.70), atopic dermatitis of the child (OR 3.01; 95% CI 1.18–7.80), parental atopy (OR 4.33; 95% CI 1.73–12.1), and gestational age (OR 1.57; 95% CI 1.07–2.37) were significant and independent predictors of food allergy. Children with at least one allergic parent delivered by CS had higher probability of developing food allergy compared with vaginally delivered children of non-allergic parents (OR 10.0; 95% CI 3.06–32.7). Conversely, the effect of CS on atopic dermatitis was not significant (OR 1.35; 95% CI 0.74–2.47). Conclusions Delivery by CS predisposes to the development of food allergy but not atopic dermatitis in early childhood. Cesarean section delivery seems to upregulate the immune response to food allergens, especially in children with allergic predisposition.

Improving the safety of oral immunotherapy for food allergy

Abstract: Food allergy is a major public health problem in children, impacting upon the affected individual, their families and others charged with their care, for example educational establishments, and the food industry. In contrast to most other paediatric diseases, there is no established cure: current management is based upon dietary avoidance and the provision of rescue medication in the event of accidental reactions, which are common. This strategy has significant limitations and impacts adversely on health-related quality of life. In the last decade, research into disease-modifying treatments for food allergy has emerged, predominantly for peanut, egg and cow's milk. Most studies have used the oral route (oral immunotherapy, OIT), in which increasing amounts of allergen are given over weeks-months. OIT has proven effective to induce immune modulation and 'desensitization' - that is, an increase in the amount of food allergen that can be consumed, so long as regular (typically daily) doses are continued. However, its ability to induce permanent tolerance once ongoing exposure has stopped seems limited. Additionally, the short- and long-term safety of OIT is often poorly reported, raising concerns about its implementation in routine practice. Most patients experience allergic reactions and, although generally mild, severe reactions have occurred. Long-term adherence is unclear, which rises concerns given the low rates of long-term tolerance induction. Current research focuses on improving current limitations, especially safety. Strategies include alternative routes (sublingual, epicutaneous), modified hypoallergenic products and adjuvants (anti-IgE, pre-/probiotics). Biomarkers of safe/successful OIT are also under investigation.

Periostin as a biomarker for the diagnosis of pediatric asthma

Abstract: Background There are some biomarkers for asthma diagnosis but they are often difficult in clinical use, particularly in pediatric cases. Periostin is an extracellular matrix protein, upregulated in response to IL-4 or IL-13. Serum periostin is expected to be used as a non-invasive biomarker for asthma diagnosis and management. Methods Twenty-eight children with asthma (BA) and 27 children without asthma (patients with pectus excavatum, etc. as control group) aged 6–16 years were included. Bronchial asthma was diagnosed according to International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Fractional exhaled nitric oxide (FeNO), lung function, blood eosinophil counts, total immunoglobulin E (IgE) levels, and serum periostin levels were assessed. Results were compared between BA and controls. Asthma diagnostic accuracies were calculated using receiver operating characteristics (ROC) curve analyses. Results Serum periostin levels in the BA group were significantly higher than those in the control group [medians (with interquartile ranges), 134.0 (116.3–166.3) vs. 112.0 (97.0–132.0) ng/ml; p = 0.012]. The area under the ROC curve (AUC) for periostin, FeNO, and eosinophil counts were 0.70, 0.72, and 0.84, respectively. After the exclusion of controls with pectus excavatum, AUC for periostin, forced expiratory volume in 1 s (FEV1), and maximum mid-expiratory flow rate (MMF) were 0.75, 0.74, and 0.80, respectively. Conclusion Serum periostin levels were significantly higher in children with asthma. ROC AUC values for periostin were equivalent to conventional biomarkers, including FeNO levels and lung function testing, indicating the utility of serum periostin levels in diagnosing asthma in children.

Anti-IgE-assisted desensitization to egg and cow's milk in patients refractory to conventional oral immunotherapy.

Abstract: To the Editor: Oral immunotherapy (OIT) is a significant focus of treatment for egg and cow’s milk food allergy, inducing desensitization in the majority of individuals with these sensitivities (1, 2). A major drawback of OIT is the frequency of adverse effects, and although most are mild and self-limited, the use of parenteral epinephrine is not infrequent. As many as 20–30% of food-allergic patients are refractory to desensitization, particularly patients with higher initial food-specific IgE levels (3). To address some of the safety issues associated with OIT, anti-IgE monoclonal antibody (omalizumab) was proposed as an adjunct to facilitate OIT by reducing OIT-induced allergic reactions. Open-label pilot studies have demonstrated efficacy of omalizumab as an adjunctive therapy with OIT in children with milk allergy, in high-risk peanut-allergic patients and in simultaneous desensitization to multiple food allergens (4–6). Additional support for the effectiveness of omalizumabfacilitated OIT comes from a randomized, double-blind, placebo-controlled trial of omalizumab combined with OIT in the treatment of cow’s milk allergy. In this trial, omalizumab significantly reduced dose-related symptoms and OIT-related side effects, including a reduction in treatments with epinephrine (7). Evolution after discontinuation of omalizumab, however, remains to be thoroughly studied. We report our experience with a protocol of omalizumabassisted OIT and the evolution during 12 months after discontinuation of omalizumab therapy in 14 eggand cow’s milk-allergic patients refractory to conventional OIT (Table 1). These patients were unable to tolerate conventional OIT because of allergic reactions, exhibiting grade 3-4 anaphylactic symptoms (Clark and Ewan grading (8)). Omalizumab as an off-label indication was dosed according to the package insert. All patients/parents provided informed consent. Nine weeks after the start of omalizumab treatment, we performed the desensitization procedure again. Cow’s milk OIT followed the protocol previously described by Martorell et al. (9) (initial dose, 0.33 mg of cow’s milk protein; final dose, 6.6 g). In themaintenance phase, children continued drinking 200 ml of cow’s milk (6.6 g of protein) once a day, every day, and consumed cow’s milk and dairy products without restrictions. Patients followed the same treatment plan for egg-OIT with pasteurized liquid raw egg white (initial dose, 0.06 mg of hen’s egg (HE) protein; final dose, 1.8 g). A dose of 1.8 g (17 ml) of liquid raw egg white is roughly equivalent to 1/2 HE (Clara Guillen, Valencia, Spain, whose allergenicity is equivalent to raw egg white (EW)). The induction phase lasted 18 weeks and started with a 2-day in-hospital rush phase in which patients received increasing doses hourly (first day: 1/100 dilution with water: 0.05 ml (0.06 mg EW protein), doubling doses up to 0.8 ml; second day: 0.8 ml 1/100, doubling doses up to 1.2 ml 1/ 10). Upon discharge, patients continued the last tolerated dose once daily for a week. Thereafter, outpatient clinic staff administered weekly increases up to the dose of 17 ml. Hospital staff supervised all dose increases, which patients subsequently maintained at home (cow’s milk twice a day and egg white once a day), with increases once a week. Patients received no premedication. One week after the end of the desensitization procedure, patients underwent an open food challenge (total dose: 33 ml pasteurized EW, around 1 HE). In the maintenance phase, children continued having 17 ml of pasteurized raw EW three times a week without interruption, along with unrestricted access to any food containing egg. Patients received omalizumab for 2 months after reaching the final dose of the induction phase and then it was discontinued. In the absence of previous experience, our great concern was the possible reduction in clinical tolerance with suspension of omalizumab. Because discontinuation of omalizumab can reduce clinical threshold reactivity, a month after suspending omalizumab we reintroduced desensitization with 25% of the maintenance dose (initial dose: 50 ml of CM and 5 ml of EW).

Differential response in allergen-specific IgE, IgGs, and IgA levels for predicting outcome of oral immunotherapy

Abstract: Background Oral immunotherapy (OIT) induces desensitization and/or tolerance in patients with persistent food allergy, but the biomarkers of clinical outcomes remain obscure. Although OIT-induced changes in serum allergen-specific IgE and IgG4 levels have been investigated, the response of other allergen-specific IgG subclasses and IgA during OIT remains obscure. Methods A pilot study was conducted to investigate egg OIT-induced changes in allergen-specific IgE, IgG subclasses, and IgA levels and search for possible prediction biomarkers of desensitization. We measured serum levels of egg white-, ovomucoid-, and ovalbumin-specific IgE, IgA, and IgG subclasses by high-sensitivity allergen microarray in 26 children with egg allergy who received rush OIT. Results Allergen-specific IgE gradually decreased while IgG4 increased during 12-month OIT. Serum levels of IgG1, IgG3, and IgA increased significantly after the rush phase, then decreased during the maintenance phase. IgG2 levels changed in a manner similar to that of IgG4. In particular, significantly high fold increases in egg white-specific IgG1, relative to baseline, after the rush phase and high IgA levels before OIT were observed in responders, compared with low-responders to OIT. Patients who could not keep desensitization showed relatively small changes in all immunoglobulin levels during OIT. Conclusion The response to OIT was associated with significant increases in serum allergen-specific IgG1 levels after rush phase and high baseline IgA levels, compared with small changes in immunoglobulin response in low-responders. The characteristic IgG1 changes and IgA levels in the responders could be potentially useful biomarkers for the prediction of positive clinical response to OIT.

Prospective neonatal screening for severe T- and B-lymphocyte deficiencies in Seville.

Abstract: Background Early diagnosis of primary immunodeficiency such as severe combined immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) improves outcome of affected children. T-cell-receptor-excision circles (TRECs) and kappa-deleting-recombination-excision circles (KRECs) determination from dried blood spots (DBS) identify neonates with severe T- and/or B-lymphopenia. No prospective data exist of the impact of gestational age (GA) and birth weight (BW) on TRECs and KRECs values. Methods TRECs and KRECs determination using triplex RT-PCR (TRECS-KRECS-β-actin-Assay) from prospectively collected DBS between 02/2014 and 02/2015 in three hospitals in Seville, Spain. Cut-off levels were TRECs 700/punch. Internal (SCID, XLA, ataxia telangiectasia) and external controls (NBS quality assurance program, CDC) were included. Results A total of 5160 DBS were tested. Re-punch was needed in 77 samples (1.5%) due to insufficient β-actin (<700 copies/punch). Pre-term neonates (GA<37 weeks) and neonates with a BW<2500 g showed significantly lower TRECs and KRECs levels (p < 0.001). Due to repeat positive results five neonates were re-called (<0.1%): Fatal chromosomopathy (n = 1; TRECs 1/KRECs 4); extreme pre-maturity (n = 2; TRECs 0/KRECs 0 and TRECs 1/KRECs 20 copies/punch); neonates born to mothers receiving azathioprine during pregnancy (n = 2; TRECs 92/KRECs 1 and TRECs 154/KRECs 3 copies/punch). All internal and external controls were correctly identified. Conclusions TRECS-KRECS–β-actin-Assay correctly identifies T- and B-cell lymphopenias. Pre-maturity and low BW is associated with lower TREC and KREC levels. Extreme pre-maturity and maternal immune suppressive therapy may be a cause for false positive results of TRECs and KRECs values, respectively. To reduce the rate of insufficient samples, DBS extraction and storage need to be improved.

Clinical and immunological characteristics of a pediatric population with food protein-induced enterocolitis syndrome (FPIES) to fish

Abstract: Background Food protein-induced enterocolitis (FPIES) is an uncommon, non-IgE-mediated food allergy that usually debuts in infancy with profuse vomiting, lethargy, and pallor 2–4 h following ingestion of the offending food. Its immune mechanism is not known. We aimed to describe the clinical features and outcome of children with fish-FPIES as well as to investigate on cellular immune response implicated. Methods Prospective and follow-up clinical study of children with FPIES by fish over a period between 2004 and 2013 was conducted. Measurement in vitro of both cytokine production in peripheral blood mononuclear cells (PBMCs) and expression of HLA-DR in monocyte-derived dendritic cells stimulated with fish extracts. Results Sixteen children (seven male and nine female) were included, with a mean age of onset at 10 months. Diagnosis was established after a median of 4 reactions. Twelve patients were treated in emergency room, and two were admitted in intensive care. Patch tests were positive in six patients. Skin prick tests (SPTs) and specific IgE to all fish tested were negative. Only three children reached tolerance at a mean age of 4.5 years. Eight children avoided fish because of positive oral food challenge (OFC) after 6 years of age. Other patients have not been challenged because of parent refusal to OFC or a recent diagnosis. TNF-α was increased in patients, and a significant elevation of the HLA-DR marker was also observed in these patients vs. control donors. Conclusions FPIES caused by fish in many cases presents with severe clinical manifestations. Patch test has poor diagnostic value, and OFC is the gold standard to test tolerance. The cytokine TNF-α may be implicated in the clinical symptoms. Higher expression of HLA-DR in dendritic cells has also been detected in our patients.

Early polysensitization is associated with allergic multimorbidity in PARIS birth cohort infants

Abstract: Background Profiles of allergic sensitisation are poorly documented in infancy. Relations between early sensitisation and allergic morbidity need to be clarified. Methods This study dealt with children involved in the Pollution and Asthma Risk: an Infant Study (PARIS), a population-based prospective birth cohort. Allergic sensitisation to 12 food and 4 inhalant allergens was assessed at 18 months and defined by a specific IgE level ≥ 0.35 kUA/L. Health data were collected by standardised questionnaires at 2 and 6 years. Early allergic profiles were identified by an unsupervised cluster analysis based on health data at 2 years and IgE measurements. Profiles were compared with regard to allergic morbidity and multimorbidity at 6 years. Results Sensitisation to any allergen concerned 13.6% of infants. By cluster analysis, 1525 infants were grouped in 3 profiles: 89.2% not or rarely sensitised (only 3.7% of sensitised), 9.2% mainly sensitised to one or few allergens (45.2% of monosensitised and 45.9% of paucisensitised), and 1.6% all polysensitised. The prevalence of doctor-diagnosed asthma, rhinitis, eczema, food allergy, and multimorbidity at 2 years increased from profile 1 to profile 3 (p-trend < 0.001). At 6 years, symptoms of current asthma, rhinitis, eczema, and multimorbidity were significantly more frequent in the last two profiles. Conclusions This study highlights, as early as 18 months of age, 3 profiles of increasing severity with regard to allergic sensitisation and diseases. These profiles also differ in terms of allergic morbidity at 6 years. Early sensitisation can predict allergic multimorbidity in childhood, and in the case of early polysensitisation, multimorbidity is more frequent as soon as infancy. This article is protected by copyright. All rights reserved.

Maternal vitamin D status and childhood asthma, wheeze, and eczema: A systematic review and meta-analysis.

Abstract: Background Maternal vitamin D status has been reported to be associated with childhood allergic diseases. However, this association remains to be fully elucidated. Methods A systematic review and meta-analysis was conducted using prospective cohort studies that examined the association between maternal vitamin D status and childhood allergic diseases including wheeze, eczema and asthma. We searched electronic databases of PubMed, EMBASE, the Cochrane library, the Wanfang (Chinese) database, the VIP (Chinese) database, and Chinese National Knowledge Infrastructure (CNKI) up to August 2014. Odds ratios and 95% confidence intervals (CIs) from individual studies were synthesized using a fixed effects model. Results Four studies on the association between maternal vitamin D status and childhood asthma (3666 mother-child pairs), four studies on the association between maternal vitamin D status and childhood wheeze (2225 mother-child pairs) and three papers on the association between maternal vitamin D status and childhood eczema (2172 mother-child pairs) met our inclusion criteria. Maternal vitamin D status during pregnancy was associated with childhood eczema (pooled OR=0.904, 95% CI=0.831-0.983). However, the meta-analysis showed no statistical association between maternal vitamin D status and childhood asthma (pooled OR=0.981, 95% CI=0.944-1.019) or childhood wheeze (pooled OR=0.995, 95% CI=0.982-1.009). Conclusions Our meta-analysis found that lower maternal vitamin D during pregnancy was associated with an increased risk of childhood eczema but was not associated with childhood asthma or wheeze. The role of maternal vitamin D as an important protective factor for the development of childhood eczema remains to be elucidated.

Asthma and allergic rhinitis in childhood: what's new

Abstract: Novel approaches are currently offered for the diagnostic workup and therapeutic management of allergic rhinitis and asthma. New predictive biomarkers of allergy and asthma are available. Primary and secondary prevention, earlier intervention, and modification of the natural history of allergic rhinitis and asthma are being intensively investigated. This review highlights advances in the understanding of the etiology, diagnosis, and management of atopic airway diseases in childhood, as well as prenatal and early-life risk factors and strategies for prevention.

Vitamin D levels in allergic rhinitis: a systematic review and meta-analysis.

Abstract: Background We aimed to systematically review observational studies investigating the relationship between vitamin D levels and allergic rhinitis (AR). Methods Studies were selected if they evaluated the relationship between vitamin D levels and AR, and included studies that evaluated other allergic conditions if those studies also contained data on AR. We assessed the incidence and prevalence of AR according to vitamin D levels and compared vitamin D levels in patients with AR to levels in controls. Results Nineteen studies were selected. Of these, only seven focused solely on AR; 10 studies evaluated the other allergic diseases as well as AR; and two studies evaluated asthma primarily, but also included data on patients with AR. The pooled odds ratios (ORs) for the incidence of AR according to vitamin D levels were not statistically significant for either children or adults. Lower vitamin D levels were associated with a higher AR prevalence only in children (pooled OR [95% confidence interval (CI)], 0.75 [0.58, 0.98]). The pooled mean vitamin D level in patients with AR was lower than that of controls only in children (pooled means difference [95% CI], −7.63 [−13.08, −2.18]). Conclusions Prior vitamin D levels were not related to developing AR, but lower vitamin D levels were associated with a higher AR prevalence only in children. There is insufficient evidence to support vitamin D supplementation for AR prevention. However, physicians should consider evaluating patients for vitamin D deficiency during AR management, especially in children.

Vitamin D3 for uncontrolled childhood asthma: A pilot study

Abstract: Background Observational and mechanistic data suggest a role for vitamin D in childhood asthma. However, subsequent interventional trials have been inconsistent. We aimed to assess the effect of 15 weeks of vitamin D3 supplementation compared with placebo (PL) in Irish children with asthma. Methods We conducted a double-blind, randomized, PL-controlled trial of vitamin D supplementation (2000 IU/day) in 44 urban, Caucasian children at high latitude. Assessments were completed at baseline and after 15 weeks of supplementation. Outcome measures were lung function, subjective asthma control and biochemical parameters of total vitamin D, allergy, immunity, airway inflammation, and systemic inflammation. Finally, parents/guardians completed a weekly diary during the trial. Results There was no significant difference in baseline 25(OH)D levels, but there was a significant increase in median 25(OH)D in the vitamin D3 group (57.5–105 nmol/l) compared with the PL group (52.5–57.5 nmol/l) (p < 0.0001). There was no significant difference between groups regarding subjective asthma control. Compared with PL, there was a significant decrease in school days missed due to asthma (1 vs. 5 days, p = 0.04) and alkaline phosphatase (−3.4 vs. +16; p = 0.037) in the vitamin D3 group, but there were no beneficial effects regarding several other secondary end-points. However, there were non-significant, advantageous changes in the PL group compared with the vitamin D3 group in subjective asthma control and lung function, particularly percentage of predicted forced expiratory volume in 1 s (+2.5 vs. −4; p = 0.06). Conclusion Vitamin D3 supplementation led to a significant increase in serum 25(OH)D and decreased school days missed (p = 0.04), but no other advantageous changes in asthma parameters compared with PL. The potential adverse effect of vitamin D deficiency on growth and the potential negative effect of high serum 25(OH)D on pulmonary function warrant further investigation.

The prevalence, natural history and time trends of peanut allergy over the first 10 years of life in two cohorts born in the same geographical location 12 years apart

Abstract: Background The aim of this study was to explore the natural history of peanut allergy in childhood in two birth cohorts from the same geographical region in the South of England. Methods The FAIR birth cohort was established on the Isle of Wight (UK) between 2001 and 2002 (n = 969). Children were followed up prospectively, skin prick tested (SPT) to peanut allergens at 1, 2, 3 and 10 years and food challenges performed. The Isle of Wight (IOW) birth cohort was established in 1989 (n = 1456). SPTs were performed at 1, 2, 4 and 10 years. Peanut allergy was based on positive SPT and a good clinical history. Results In the FAIR cohort, the prevalence of sensitization to peanut was 0.4%, 2.0%, 2.0% and 2.4% at 1, 2, 3 and 10 years, respectively. At 10 years of age, 12 of 828 (1.5%) children were diagnosed with peanut allergy. One child (8%) outgrew her peanut allergy between 3 and 10 years and two children (15%) presented with new onset peanut allergy. Over the first 10 years of life, 13 of 934 (1.4%) children were diagnosed with peanut allergy. In the IOW cohort, 6 of 1034 (0.58%) were diagnosed with peanut allergy at 10 years. We found no significant differences between the FAIR and the IOW birth cohort for any of the time points studied. Conclusion Peanut allergy appears to be stable over the first 10 years of life in our cohorts. There was no significant difference in peanut sensitization or clinical peanut allergy between 1989 and 2001.

Formula with long-chain polyunsaturated fatty acids reduces incidence of allergy in early childhood.

Abstract: Background Allergy has sharply increased in affluent Western countries in the last 30 years. N-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) may protect the immune system against development of allergy. Methods We prospectively categorized illnesses by body system in a subset of 91 children from the Kansas City cohort of the DIAMOND (DHA Intake and Measurement of Neural Development) study who had yearly medical records through 4 years of age. As infants, they were fed either a control formula without LCPUFA (n = 19) or one of three formulas with LCPUFA from docosahexaenoic acid (DHA) and arachidonic acid (ARA) (n = 72). Results Allergic illnesses in the first year were lower in the combined LCPUFA group compared to the control. LCPUFAs significantly delayed time to first allergic illness (p = 0.04) and skin allergic illness (p = 0.03) and resulted in a trend to reduced wheeze/asthma (p = 0.1). If the mother had no allergies, LCPUFAs reduced the risk of any allergic diseases (HR = 0.24, 95% CI = 0.1, 0.56, p = 0.0.001) and skin allergic diseases (HR = 0.35, 95% CI = 0.13, 0.93, p = 0.04). In contrast, if the mother had allergies, LCPUFAs reduced wheezing/asthma (HR = 0.26, 95% CI = 0.07, 0.9, p = 0.02). Conclusions LCPUFA supplementation during infancy reduced the risk of skin and respiratory allergic diseases in childhood with effects influenced by maternal allergies.

Cows' milk exclusion diet during infancy: Is there a long-term effect on children's eating behaviour and food preferences?

Abstract: Background: Dietary restriction during infancy may influence later eating behaviour. The aim of this study was to determine if consuming a cows’ milk exclusion (CME) diet during infancy affects eating habits in later childhood, once cows’ milk has been reintroduced into the diet. Methods: Children were recruited from two large birth cohort studies in the UK. A small number of participants were recruited from allergy clinic. Two groups were recruited: an experimental group of children who had consumed a CME diet during infancy and a control group, who had consumed an unrestricted diet during infancy. Parents and children completed questionnaires regarding eating behaviour and food preferences. Results: 101 children of mean age 11.5 years were recruited (28 CME and 73 control). The CME group scored significantly higher on “slowness of eating” and on the combined “avoidant eating behaviour” construct (p < 0.01). The number of foods avoided and symptoms were associated with higher levels of avoidant eating behaviour (p < 0.05). The CME group rated liking for several dairy foods (butter, cream, chocolate, full fat milk and ice cream) significantly lower than the control group (p < 0.05), although there were no significant differences seen for any other category of food. Conclusion: This study demonstrated that consuming a CME diet during infancy has persistent and long-term effects on eating habits and food preferences. To reduce future negative eating behaviours, children’s exclusion diets need to be as varied as possible and reintroduction of cows’ milk products closely monitored.

How relevant is panallergen sensitization in the development of allergies

Abstract: Panallergens comprise various protein families of plant as well as animal origin and are responsible for wide IgE cross-reactivity between related and unrelated allergenic sources. Such cross-reactivities include reactions between various pollen sources, pollen and plant-derived foods as well as invertebrate-derived inhalants and foodstuff. Here, we provide an overview on the most clinically relevant panallergens from plants (profilins, polcalcins, non-specific lipid transfer proteins, pathogenesis-related protein family 10 members) and on the prominent animal-derived panallergen family, tropomyosins. In addition, we explore the role of panallergens in the sensitization process and progress of the allergic disease. Emphasis is given on epidemiological aspects of panallergen sensitization and clinical manifestations. Finally, the issues related to diagnosis and therapy of patients sensitized to panallergens are outlined, and the use of panallergens as predictors for cross-reactive allergy and as biomarkers for disease severity is discussed.

Provocation tests for the diagnosis of food‐dependent exercise‐induced anaphylaxis

Abstract: Background Little has been reported regarding provocation tests for the diagnosis of food-dependent exercise-induced anaphylaxis (FDEIA), especially in children and adolescents. Hence, we here aimed to examine the usefulness and safety of such tests for FDEIA. Methods We retrospectively analyzed 41 patients with 184 provocation tests. The patients underwent ergometer stress tests after ingesting the suspected foods along with aspirin. When one or more allergic symptoms appeared, we judged the provocation test as positive. Results Based on 30 positive test results (16%), we diagnosed 20 patients (49%) as FDEIA. The major causative foods were as follows: wheat alone (five patients), combination of wheat and shrimp (three patients), combination of wheat and apple (two patients), and peach alone (two patients). The symptoms appeared within 45 min after initiating exercise in 29 tests (97%). The most frequent symptoms were cutaneous symptoms, which appeared in 25 tests (83%). Of the 30 positive tests, 6 (20%) required administration of adrenaline. After discharge, the patients with negative test results had no episodes of FDEIA due to the suspected foods that they had been tested for. Conclusion Provocation tests enabled us to confirm the diagnosis of FDEIA when positive and to exclude the diagnosis when negative. However, as severe symptoms may appear, these tests should be performed in a hospital under constant supervision of a physician.

Sensitization to milk, egg and peanut from birth to 18 years: A longitudinal study of a cohort at risk of allergic disease.

Abstract: Background Longitudinal data on the natural history of food sensitization beyond early childhood are scarce. We aimed to investigate the natural history of milk, egg and peanut sensitization from infancy to 18 years and assess whether early food sensitization predicted adolescent food allergy. Methods Sensitization to cow's milk, hen's egg and peanut was measured by skin prick testing at ages 6 months, 1, 2, 12 and 18 years in a high-risk allergy birth cohort (n = 620). Generalized additive models investigated interactions with sex, eczema and aeroallergen sensitization in infancy. Logistic regression assessed the relationships between early food sensitization and adolescent sensitization and probable food allergy up to 18 years. Results The prevalence of egg and peanut sensitization peaked at 12 months, while milk sensitization peaked at both 1 and 12 years. Boys with early eczema had the highest prevalences of milk and egg sensitization throughout follow-ups. However, neither sex nor eczema influenced the prevalence of peanut sensitization over time. New onset food sensitization beyond the age of 2 was observed in 7% of participants. Food sensitization at 12 months was associated with increased risk of adolescent food sensitization and adolescent probable food allergy, with sensitization to more than one food allergen had the strongest predictor. Conclusions Food sensitization prevalence is highest in infancy and declines after 12 months of age. Boys with early-life eczema have the highest prevalence of milk and egg sensitization. Food sensitization at 12 months can predict children at greater risk of adolescent sensitization and probable food allergy at 12 and 18 years.

Early gut colonization by Bifidobacterium breve and B. catenulatum differentially modulates eczema risk in children at high risk of developing allergic disease.

Abstract: BACKGROUND: An altered compositional signature and reduced diversity of early gut microbiota are linked to development of allergic disease. We investigated the relationship between dominant Bifidobacterium species during early postnatal period and subsequent development of allergic disease in the first year of life. METHODS: Faecal samples were collected at age 1 week, 1 month and 3 months from 117 infants at high risk of allergic disease. Bifidobacterium species were analysed by quantitative PCR and terminal restriction fragment length polymorphism. Infants were examined at 3, 6 and 12 months, and skin prick test performed at 12 months. Eczema was diagnosed according to the UK-Working Party criteria. RESULTS: The presence of B. catenulatum at 3 months was associated with a higher risk of developing eczema (ORadj =4.5; 95% CI 1.56 to 13.05, padj =0.005). Infants colonised with B. breve at 1 week (ORadj =0.29; 95% CI 0.09 to 0.95, padj =0.04) and 3 months (ORadj =0.15; 95% CI 0.05 to 0.44, padj =0.00001) had a reduced risk of developing eczema. Furthermore, the presence of B. breve at 3 months was associated with a lower risk of atopic sensitisation at 12 months (ORadj =0.38; 95% CI 0.15 to 0.98, padj =0.05). B. breve colonisation patterns were influenced by maternal allergic status, household pets and number of siblings. CONCLUSIONS: Temporal variations in Bifidobacterium colonisation patterns early in life are associated with later development of eczema and/or atopic sensitisation in infants at high risk of allergic disease. Modulation of the early microbiota may provide a means to prevent eczema in high risk infants. This article is protected by copyright. All rights reserved.

Safety and tolerability of bilastine 10 mg administered for 12 weeks in children with allergic diseases

Abstract: Background Regulations on medicinal products for paediatric use require that pharmacokinetics and safety be characterized specifically in the paediatric population. A previous study established that a 10-mg dose of bilastine in children aged 2 to <12 years provided an equivalent systemic exposure as 20 mg in adults. The current study assessed the safety and tolerability of bilastine 10 mg in children with allergic rhinoconjunctivitis and chronic urticaria. Methods In this phase III, multicentre, double-blind study, children were randomized to once-daily treatment with bilastine 10-mg oral dispersible table (n = 260) or placebo (n = 249) for 12 weeks. Safety evaluations included treatment-emergent adverse events (TEAEs), laboratory tests, cardiac safety (ECG recordings) and somnolence/sedation using the Pediatric Sleep Questionnaire (PSQ). Results The primary hypothesis of non-inferiority between bilastine 10 mg and placebo was demonstrated on the basis of a near-equivalent proportion of children in each treatment arm without TEAEs during 12 weeks' treatment (31.5 vs. 32.5%). No clinically relevant differences between bilastine 10 mg and placebo were observed from baseline to study end for TEAEs or related TEAEs, ECG parameters and PSQ scores. The majority of TEAEs were mild or moderate in intensity. TEAEs led to discontinuation of two patients treated with bilastine 10 mg and one patient treated with placebo. Conclusions Bilastine 10 mg had a safety and tolerability profile similar to that of placebo in children aged 2 to <12 years with allergic rhinoconjunctivitis or chronic urticaria.

Genetic associations of the response to inhaled corticosteroids in children during an asthma exacerbation.

Abstract: BACKGROUND Genetic associations of the response to inhaled corticosteroids (ICSs) during an asthma exacerbation are unknown. OBJECTIVE To evaluate the role of genetic variants in the therapeutic response to high-dose ICS in children with moderate-to-severe asthma exacerbations. METHODS Eighty-two children (56 boys/26 girls, mean age 9.6 ± 3.2 years) with moderate-severe asthma exacerbation were genotyped for eight single-nucleotide polymorphisms that were a priori associated with ICS response in chronic asthma treatment: glucocorticosteroid receptor (NR3C1) rs41423247; corticotrophin-releasing hormone receptor1 (CRHR1) rs242939, rs242941, and rs1876828; T-box 21 (TBX21) rs2240017; glucocorticoid-induced transcript 1 (GLCCl1); and T gene rs3099266 and rs2305089. Children were treated with a single high-dose (4000 μg) fluticasone propionate given by a nebulizer followed by 1000 μg/day of inhaled fluticasone propionate for 6 days. Primary outcome measure was the improvement in FEV1 at 4 h. RESULTS Mean FEV1 was 71.7 ± 14.2% at presentation. Overall, fluticasone treatment resulted in a significant improvement in asthma score and FEV1 (p < 0.0001 for both). Children with the GG genotype at NR3C1 rs41423247 (n = 26) had a higher improvement in FEV1 [24.2% (interquartile range 11.5-36.3)] compared to those with CG+CC (n = 19), [7.9% (interquartile range 6.1-24.6) (p = 0.006)]. CONCLUSION Homozygosity for the G allele at rs41423247 of the glucocorticosteroid receptor (NR3C1) gene is associated with a higher improvement in FEV1 at 4 h in children with moderate-to-severe asthma exacerbation treated with high-dose ICS. This observation may have important clinical implications especially for children who use systemic steroids frequently for recurrent asthma exacerbations.

Prospective investigation on the transfer of Ara h 2, the most potent peanut allergen, in human breast milk.

Abstract: BACKGROUND Peanut allergy is one of the most severe food allergies. Whether breastfeeding induces tolerance to peanuts or on the contrary, pre-disposes at risk-babies to occult allergic sensitization to peanuts is still a matter of discussion. We sought to investigate the transfer of the most potent peanut allergen Ara h 2 into human breast milk in a German breast milk study and to shed light on the time kinetics of Ara h 2 appearance. METHODS We recruited 32 lactating, non-peanut-allergic women and collected breast milk samples at different time points after consumption of 100 g dry roasted peanuts. Breast milk samples were investigated for Ara h 2 with different immunological methods: by 2D immunoblotting with a patient's serum, by affinity enrichment using a monoclonal antibody against Ara h 2 followed by LC-MS/MS-based detection and by a competitive inhibition ELISA for the detection of Ara h 2 and its digestion-resistant peptides (DRP-Ara h 2). RESULTS In a qualitative analysis, Ara h 2 could be identified in a breast milk sample by 2D immunoblot by means of a patient's serum and furthermore by immunoaffinity enrichment followed by LC-MS/MS analysis. In a semi-quantitative analysis, Ara h 2 and its digestion-resistant peptides were detected in the breast milk of 9 of 32 subjects. Evidence suggests that Ara h 2 is excreted individually either rapidly (after 1, 2, 3 or 4 h) or delayed (after 8 or 12 h) and in different concentrations. CONCLUSIONS Time and concentration of secreted Ara h 2 in breast milk appears to be individually regulated. The identification of Ara h 2 in breast milk is the prerequisite for the investigation of its sensitizing or tolerogenic properties.

Key findings to expedite the diagnosis of hyper-IgE syndromes in infants and young children.

Abstract: BackgroundHyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by elevated serum IgE, eczema, and recurrent infections. Despite the availability of confirmatory molecular diagnosis of several distinct HIES entities, the differentiation of HIES particularly from severe forms of atopic dermatitis remains a challenge. The two most common forms of HIES are caused by mutations in the genes STAT3 and DOCK8. MethodsHere, we assess the clinical and immunologic phenotype of DOCK8- and STAT3-HIES patients including the cell activation, proliferation, and cytokine release after stimulation. ResultsExisting HIES scoring systems are helpful to identify HIES patients. However, those scores may fail in infants and young children due to the age-related lack of clinical symptoms. Furthermore, our long-term observations showed a striking variation of laboratory results over time in the individual patient. Reduced memory B-cell counts in concert with low specific antibody production are the most consistent findings likely contributing to the high susceptibility to bacterial and fungal infection. In DOCK8-HIES, T-cell lymphopenia and low IFN-gamma secretion after stimulation were common, likely promoting viral infections. In contrast to STAT3-HIES, DOCK8-HIES patients showed more severe inflammation with regard to allergic manifestations, elevated activation markers (HLA-DR, CD69, CD86, and CD154), and significantly increased inflammatory cytokines (IL1-beta, IL4, IL6, and IFN-gamma). ConclusionDifferentiating HIES from other diseases such as atopic dermatitis early in life is essential for patients because treatment modalities differ. To expedite the diagnosis process, we propose here a diagnostic workflow.

School personnel's self-efficacy in managing food allergy and anaphylaxis.

Abstract: BACKGROUND Food allergy affects up to 4-7% European schoolchildren. Studies identified important shortcomings on food allergy and anaphylaxis management in schools. In social cognitive theory, personal beliefs in own capabilities influence choices, effort levels, perseverance and performance accomplishments. This study aimed to investigate school personnel's self-efficacy in managing food allergy and anaphylaxis, providing a valid instrument to deeply understand how to support schools to effectively manage students at risk of food reactions. METHODS A total of 440 schoolteachers and caretakers from north-east Italy completed a questionnaire assessing self-efficacy in managing food allergy and anaphylaxis at school. Exploratory factor analysis was performed. Factors' internal consistency was evaluated using Cronbach's alpha. Factors' scores were estimated using Bartlett approach, and kernel density estimate of distributions was provided. Descriptive statistics explored school personnel's self-efficacy. A regression model assessed the influence of gender, school, job and previous experience. RESULTS Two factors emerged from exploratory factor analysis related to anaphylaxis management (AM) and food allergy management (FAM). The two subscales both showed good internal consistency. School personnel showed lower self-efficacy in recognizing symptoms, administering drugs and guaranteeing full participation to extra-curricular activities to food-allergic students. Participants who previously had food-allergic students showed a significantly increased self-efficacy in AM and a significantly decreased self-efficacy in FAM. CONCLUSIONS The study supports the use of self-efficacy scale to identify specific areas where teachers' confidence in their ability to care for food-allergic students is especially weak. This would empower the development of training programs specifically tailored to the needs of teachers and caregivers.