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Background Long-time data of peanut allergy over time is sparse. We aimed to study the longitudinal development of sensitization to peanut extract and storage protein allergen molecules and associations with asthma status, airway and systemic inflammation markers. Methods The Swedish birth cohort BAMSE followed 4089 participants with questionnaires, clinical investigations and blood sampling between 0 and 24 years. Information on (i) background factors at 2 months, (ii) peanut allergy symptoms and IgE data (ImmunoCAP) at 4, 8, 16, and 24 years, and (iii) IgE to storage proteins, lung function data including exhaled nitric oxide (FENO) as well as systemic inflammatory markers at 24 years of age were collected. Results The prevalence of peanut extract sensitization, defined as IgE ≥ 0.35 kUA/L, was 5.4%, 8.0%, 7.5%, and 6.2% at 4, 8, 16, and 24 years of age, respectively. Between 8 and 24 years of age, (33/1565) participants developed IgE-ab to peanut extract (median 1,4, range 0.7–2.6 kUA/L), and among those 85% were also sensitized to birch. Only six individuals developed sensitization to Ara h 2 (≥0.1 kUA/L) between 8 and 24 years of age, of whom three had an IgE-ab level between 0.1–0.12 kUA/L. Storage protein sensitization was associated with elevated FENO, blood eosinophils and type 2 inflammation-related systemic proteins. Conclusion Sensitization to peanut extract after 4 years of age is mainly induced by birch cross-sensitization and IgE to Ara h 2 rarely emerges after eight years of age. Storage protein sensitization is associated with respiratory and systemic inflammation.

Background Allergic reactions to food allergens usually occur after ingestion. However, fear of reactions to airborne peanut is a common concern for people with peanut allergy. There are no scientific reports on severe reactions with airborne peanut allergen. Objective To investigate the occurrence of allergic reactions in peanut-allergic children undergoing airborne peanut challenge and to determine levels of airborne peanut protein in a separate experimental evaluation. Methods Eighty-four children with peanut allergy underwent an airborne peanut challenge, 0.5 m from a bowl of peanuts for 30 min under controlled conditions. In a separate experiment, airborne peanut proteins from roasted and dry-roasted peanuts were collected at varying distances and at varying times with an electret SensAbues filter connected to an air pump. Collected airborne peanut proteins were extracted, dissolved and detected by ELISA. Basophil activation test was used to confirm biological activity. Results No moderate/severe allergic reactions to airborne peanut allergens were observed. Two children (2%) had mild rhino-conjunctivitis which required no treatment. The IgE-antibodies to peanut or Ara h 2 did not predict a reaction. In the experimental set-up, biological active peanut proteins were detected, in a very low amount, in median 166 ng/ml for dry-roasted and 33 ng/ml for roasted peanuts and decreased dramatically when the collection occurred at a greater distance (0.5-2 m) from the peanut source. Increased exposure time did affect the amount of collected peanut protein at 0 m, and the highest median was obtained after 60 min (p = .012); for time trend p = .0006. Conclusions and clinical relevance Allergic reactions to airborne peanut proteins are rare and cannot be predicted by high levels of IgE-antibodies to peanut or Ara h 2. Only small amounts of biologically active peanut proteins were detected in the air and seem unlikely to trigger moderate/severe allergic reactions.

Background Young adults are now considered major spreaders of coronavirus disease 2019 (COVID-19) disease. Although most young individuals experience mild to moderate disease, there are concerns of long-term adverse health effects. The impact of COVID-19 disease and to which extent population-level immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exists in young adults remain unclear. Objective We conducted a population-based study on humoral and cellular immunity to SARS-CoV-2 and explored COVID-19 disease characteristics in young adults. Methods We invited participants from the Swedish BAMSE (Barn [Children], Allergy Milieu, Stockholm, Epidemiology) birth cohort (age 24-27 years) to take part in a COVID-19 follow-up. From 980 participants (October 2020 to June 2021), we here present data on SARS-CoV-2 receptor-binding domain–specific IgM, IgA, and IgG titers measured by ELISA and on symptoms and epidemiologic factors associated with seropositivity. Further, SARS-CoV-2–specific memory B- and T-cell responses were detected for a subpopulation (n = 108) by ELISpot and FluoroSpot. Results A total of 28.4% of subjects were seropositive, of whom 18.4% were IgM single positive. One in 7 seropositive subjects was asymptomatic. Seropositivity was associated with use of public transport, but not with sex, asthma, rhinitis, IgE sensitization, smoking, or body mass index. In a subset of representative samples, 20.7% and 35.0% had detectable SARS-CoV-2 specific B- and T-cell responses, respectively. B- and T-cell memory responses were clearly associated with seropositivity, but T-cell responses were also detected in 17.2% of seronegative subjects. Conclusions Assessment of IgM and T-cell responses may improve population-based estimations of SARS-CoV-2 infection. The pronounced surge of both symptomatic and asymptomatic infections among young adults indicates that the large-scale vaccination campaign should be continued.

Introduction: The use of real-world data offers a possibility to perform large-scale epidemiological studies in actual clinical settings. Despite their many advantages, administrative databases were not designed to be used in research, and the validation of diagnoses and treatments in administrative databases is needed. The primary objective of this study was to validate an existing algorithm based on dispensed prescriptions and diagnoses of skin conditions to identify pediatric patients with atopic dermatitis (AD), using a diagnosis of AD in primary care as a gold standard. Methods: Retrospective observational data were collected from nation-wide secondary care and pharmacy-dispensed medication databases and two regional primary care databases in Sweden. An existing algorithm and a Modified algorithm, using skin-specific diagnoses from secondary care and/or pharmacy-dispensed prescriptions to identify patients with AD, were assessed. To verify the presence of AD, diagnoses from primary care were used in the base case and complemented with diagnoses from secondary care in a sensitivity analysis. Results: The sensitivity (30.0%) and positive predictive value (PPV) (40.7%) of the existing algorithm were low in the pediatric patient population when using primary care data only but increased when secondary care visits were also included in the Modified algorithm (sensitivity, 62.1%; PPV, 66.3%). The specificity of the two algorithms was high in both the base case and sensitivity analysis (95.1% and 94.1%). In the adult population, sensitivity and PPV were 20.4% and 8.7%, respectively, and increased to 48.3% and 16.9% when secondary care visits were also included in the Modified algorithm. Conclusion: The Modified algorithm can be used to identify pediatric AD populations using primary and secondary administrative data with acceptable sensitivity and specificity, but further modifications are needed to accurately identify adult patients with AD.

Haematohidrosis is a rare and dramatic condition in which bleeding occurs spontaneously from intact skin. We report the case of a nine-year-old boy with a typical clinical presentation. The case highlights how challenging it can be for medical professionals to recognise and evaluate rare conditions. A review of the literature was performed, showing that haematohidrosis is mainly a paediatric condition. Our case together with findings from the review indicates that treatment with Beta blockers may be effective for treatment of haematohidrosis in children. Conclusion: Paediatric haematohidrosis is a rare, but clinically distinct condition. Treatment with Beta blockers may be tested.

Objective: The economic burden of food allergy on households is poorly understood. We evaluated the household costs associated with specialist-diagnosed pediatric food allergy, with focus on age and disease severity. Study design: A cross-sectional study of 70 Swedish case-control pairs (59% boys) was conducted using Food Allergy Economic questionnaire. Household costs were analyzed between age- and gender-matched cases (children aged 0-17 years, with specialist-diagnosed food allergy) and controls (non-food allergic households). Results: Parents were predominantly university-educated and employed full-time. Most cases had parent-reported previous anaphylaxis. Mean total annual household costs were comparable between cases and controls. However, compared to controls, cases had significantly higher direct medical-, and non-medical related costs; higher indirect medical-related costs, and higher intangible costs (all p amp;lt; 0.05). In a sensitivity analyses of only cases aged 0-12 years, direct household costs, including lost earnings due to childs hospitalization, were significantly higher than controls. Results from only children with severe disease paralleled those of all cases vs. controls. Conclusions: Although pediatric food allergy is not associated with higher total annual household costs, these households have significantly higher direct medical-related, indirect and intangible costs vs. non-food allergic households. Higher household costs were identified amongst younger children, but not disease severity. Funding Agencies|Swedish Asthma and Allergy Foundation [F2015-0004, F2015-0042]

Information on factors of importance for remission of eczema is scarce. This study explored factors related to the remission and course of preschool eczema (PSE) (eczema at 1, 2 and/or 4 years of age) to 16 years of age (n = 889) in a Swedish cohort. Half of the children were in complete remission by school age (at age 8, 12, and 16 years). In multivariate prognostic models, persistent PSE (eczema at 1, 2 and 4 years of age) (odds ratio 0.27 (95% confidence interval 0.18-0.41)), PSE with sleep disturbance (due to itch at least once a week at 1, 2 and/or 4 years of age) (0.59 (0.43-0.81)), parental allergy (0.73 (0.55-0.96)), parental smoking at child's birth (0.70 (0.50-0.99)) and filaggrin mutation (R501X, R2447X, 2282del4) (0.47 (0.26-0.85)) were inversely associated with complete remission by school age. Male sex (1.37 (1.03-1.82)) and exclusive breastfeeding ≥4 months (1.44 (1.01-2.05)) were positively associated with complete remission by school age. In conclusion, half of the children with PSE were in complete remission by school age. The most important prognostic factors were persistent PSE and PSE with sleep disturbance due to itch.

Background: Conflicting findings from studies evaluating associations of allergic disease with child behaviour require longitudinal studies to resolve.Objective: To estimate the magnitude of associations of atopic dermatitis (AD) in infancy, and symptoms of asthma and AD at 6.5 years, with child behaviour at 6.5 years.Methods: Secondary cohort analysis of the PROmotion of Breastfeeding Intervention Trial (PROBIT). PROBIT enrolled 17,046 infants at birth and followed them up at 6.5 years (n=13,889). Study paediatricians collected data on infantile AD at repeated follow-up examinations during the first year of life. At 6.5 years paediatricians performed skin prick tests and parents reported asthma and AD symptoms during the prior year. In addition, parents and teachers completed the Strength and Difficulties Questionnaire, which includes scales on hyperactivity/inattention, emotional problems, conduct problems, peer problems and prosocial behaviours.Results: Physician-diagnosed AD in the first year of life was not associated with increased risk for behavioural problems at 6.5 years. Emotional problems at 6.5 years were more common among children with AD symptoms (OR: 2.24, 95% CI 1.62-3.12) and asthma symptoms (OR: 1.45; 95% CI, 1.07-1.96) during the past year at 6.5 years and ORs for children with symptoms of more severe AD and asthma were also higher. AD in the past year was also associated with probable hyperactivity/inattention disorder at 6.5 years (OR: 2.05; 95% CI, 1.09-3.84). Other subscales of the SDQ were not related to asthma or AD symptoms during the past year.Conclusions and clinical relevance: Children with AD symptoms were at higher risk for concomitant hyperactivity/inattention and emotional disorder and children with asthma symptoms were at higher risk of having concomitant emotional problems. However, AD during infancy did not predict childhood behaviours.

Background Eczema, asthma, and rhinitis affect a large proportion of children, but their prevalence varies with age. IgE antibodies are also common in the pediatric population. However, the links between IgE, disease, and trajectories are unclear. Objective To better understand the links between sensitization and disease, we studied IgE sensitization ever in relation to eczema, asthma, and rhinitis, in children followed up to 16 years of age. Methods From the Swedish population-based birth cohort BAMSE, 2607 children were included. Parental reports from six time points between 1 and 16 years were used to identify children with eczema, asthma, and rhinitis. Blood was collected at 4, 8, and 16 years, and sensitization ever was defined as allergen-specific IgE ≥0.35 kUA/l to common food and/or inhalant allergens at any time point. Odds ratios for eczema, asthma, rhinitis, and multimorbidity in relation to sensitization ever were calculated using generalized estimating equations. Results Fifty-one percent were sensitized at least once up to 16 years. Almost a quarter of ever-sensitized children did not have any disease. After adjustment for potential confounders, sensitization ever was significantly associated with the following: (i) eczema throughout childhood, (ii) multimorbidity of eczema, asthma, and rhinitis from 1 to 16 years (OR for multimorbidity: 5.11, 95% CI: 3.99–6.55), (iii) asthma and rhinitis from 4 to 16 years of age. Conclusions Specific IgE is strongly associated with eczema and allergic multimorbidity throughout childhood and with asthma and rhinitis from age 4 years. However, 23% of the children with IgE sensitization do not develop any disease in childhood.

Summary Background There is a well-known association between atopic dermatitis (AD) and hand eczema but less is known about how age at onset, persistence and severity of AD influence the risk of developing hand eczema. Objectives To examine the role of AD in the occurrence of hand eczema in adolescence. In addition, associations between asthma and rhinoconjunctivitis, sensitization to common airborne and food allergens, and hand eczema were studied. Methods From the population-based birth cohort BAMSE, 2927 adolescents who had been followed up repeatedly concerning allergy-related disease were included. Questionnaires identified adolescents with hand eczema at 16 years, and their blood was analysed for specific IgE. Results A total of 152 (5·2%) adolescents had hand eczema at the age of 16 years. Many of these adolescents had a history of AD (n = 111; 73·0%) and asthma and/or rhinitis (n = 83; 54·6%), respectively. Children with AD (aged 0–16 years) had more than threefold increased odds ratios (OR) for having hand eczema; those with persistent or severe AD had a crude OR of 6·1 [95% confidence interval (CI) 4·0–9·1] and 5·3 (95% CI 2·9–9·6), respectively. Conclusions We confirm a strong association between AD during childhood and hand eczema in adolescence. Children with persistent or more severe AD are at greater risk of developing hand eczema. Asthma and/or rhinoconjunctivitis, positive specific IgE or age at onset of AD are not associated with hand eczema in adolescence.

BACKGROUND Both allergic and non-allergic rhinitis are associated with worse asthma control. However, it is unclear how IgE sensitization and/or rhinitis are associated with lung function. We therefore evaluated the effect of rhinitis and sensitization on lung function, including the periphery of the airway system, and inflammatory biomarkers in individuals with and without asthma. METHODS Participants in the BAMSE longitudinal birth cohort study underwent measures of spirometry, impulse oscillometry, and FeNO at age 16 years. Questionnaires were used to obtain data on asthma and rhinitis. Blood samples were analyzed for eosinophils and allergen-specific IgE. RESULTS Groups based on the combination of asthma, rhinitis, and sensitization were compared to a healthy reference group. Lower FEV1 /FVC levels were seen for groups with asthma only (adjusted mean difference -2.8% units (95% CI -4.7; -1.0), P

International audience; BACKGROUND:Children with multimorbid asthma and rhinitis show IgE polysensitization to several allergen sources. This association remains poorly studied in adolescents and adults using defined allergen molecules. We investigated IgE sensitization patterns towards a broad panel of aeroallergen components in adults and adolescents with a focus on individuals with asthma and rhinitis multimorbidity.METHODS:IgE reactivity to 64 micro-arrayed aeroallergen molecules was determined with the MeDALL-chip in samples from the French EGEA study (n = 840, age = 40.7 ± 17.1) and the Swedish population-based birth cohort BAMSE (n = 786, age = 16 ± 0.26). The age- and sex-adjusted associations between the number of IgE-reactive allergen molecules (≥0.3 ISU) and the asthma-rhinitis phenotypes were assessed using a negative binomial model.RESULTS:Groups representing 4 phenotypes were identified: no asthma-no rhinitis (A-R-; 30% in EGEA and 54% in BAMSE), asthma alone (A+R-; 11% and 8%), rhinitis alone (A-R+; 15% and 24%) and asthma-rhinitis (A+R+; 44% and 14%). The numbers of IgE-reactive aeroallergen molecules significantly differed between phenotypes (median in A-R-, A+R-, A-R+ and A+R+: 0, 1, 2 and 7 in EGEA and 0, 0, 3 and 5 in BAMSE). As compared to A-R- subjects, the adjusted ratio of the mean number of IgE-reactive molecules was higher in A+R+ than in A+R- or A-R+ (10.0, 5.4 and 5.0 in EGEA and 7.2, 0.7 and 4.8 in BAMSE).CONCLUSION:The A+R+ phenotype combined the sensitization pattern of both the A-R+ and A+R- phenotypes. This multimorbid polysensitized phenotype seems to be generalizable to various ages and allergenic environments and may be associated with specific mechanisms.

Allergy and immune dysregulation may have a role in the pathophysiology of recurrent abdominal pain of functional origin, but previous studies of allergy-related diseases and abdominal pain have contradictory results.To examine the association between allergy-related diseases or sensitisation during childhood and abdominal pain at age 12 years.In this birth cohort study of 4089 children, parents answered questionnaires regarding asthma, allergic rhinitis, eczema and food hypersensitivity ('allergy-related diseases') at ages 0,1,2,4,8 and 12 years. Blood for analyses of allergen-specific IgE was sampled at 4 and 8 years. At 12 years, the children answered questions regarding abdominal pain. Children with coeliac disease or inflammatory bowel disease were excluded. Associations were examined using multivariable logistic regression.Among 2610 children with complete follow-up, 9% (n = 237) reported abdominal pain at 12 years. All allergy-related diseases were associated with concurrent abdominal pain at 12 years and the risk increased with increasing number of allergy-related diseases (P for trend0.001). Asthma at 1 and 2 years and food hypersensitivity at 8 years were significantly associated with abdominal pain at 12 years. There was an increased risk of abdominal pain at 12 years in children sensitised to food allergens at 4 or 8 years, but in stratified analyses, this was confined to children whose parents had not reported food hypersensitivity at time of sensitisation.Allergy-related diseases as well as sensitisation to food allergens were associated with an elevated risk of abdominal pain, and the risk increased with the number of allergy-related diseases.

Introduction: Children with coexisting asthma and rhinitis have more polysensitization than those with asthma or rhinitis alone. These associations remain poorly studied in older populations. Aims: We investigated the association between IgE sensitization patterns towards a large variety of respiratory allergen components and asthma and rhinitis multimorbidity in adults of the French EGEA cohort and adolescents of the Swedish BAMSE birth cohort. Methods: IgE reactivity to microarrayed allergens was determined for 64 respiratory allergen molecules with the MeDALL-chip in samples from EGEA (n=840, age=40.7±17.1yrs) and BAMSE (n=786, age=16yrs). Asthma and rhinitis were defined by questionnaire and four groups were identified, with their respective prevalences in EGEA and BAMSE: no asthman 30% and 54%), asthma alone (A+R-; 11% and 8%), rhinitis alone (A-R+; 15% and 24%), and asthma+rhinitis (A+R+; 44% and 14%). The age- and sex-adjusted associations between the number of IgE-reactivities (≥0.3 ISU) and the asthma-rhinitis phenotypes were assessed using a negative binomial model. Results: The numbers of IgE-reactivities significantly differed between the phenotypes (median values in A-R-, A+R-, A-R+ and A+R+ were 0, 1, 2 and 7 in EGEA and 0, 0, 3, and 5 in BAMSE). As compared to A-R- subjects, the adjusted ratio of the mean number of IgE-reactivities was higher in A+R+ than in A+R- or A-R+ (10.0, 5.4 and 5.0 in EGEA and 7.2, 0.7 and 4.8 in BAMSE). Conclusion: In two different populations, we showed that the asthma-plus-rhinitis multimorbidity is associated with multiple sensitizations to respiratory allergens, and that the phenotype can be generalized to any age.

Availability of “exotic” foods is steadily increasing. In this report, we describe the first case of anaphylaxis to crocodile meat. The patient was a 13-year-old boy with severe immunoglobulin E–mediated allergy to chicken meat. When tasting crocodile meat for the first time, he developed an anaphylactic reaction. Cross-reactivity between chicken and crocodile meat was suspected to have triggered this reaction. Basophil activation and immunoglobulin E testing confirmed the boy’s allergic reaction to crocodile meat proteins. Molecular analysis identified a crocodile α-parvalbumin, with extensive sequence homology to chicken α-parvalbumin, as the main cross-reactive allergen. We conclude that crocodile meat can be a potent food allergen and patients with allergy to chicken meat should be advised to avoid intake of meat from crocodile species. Both foods and people travel around the world and accessibility to exotic foods is steadily growing. As a result, novel allergic cross-reactivities are likely to become a challenge in the management of food allergy and, as our report illustrates, cross-reactivity has to be considered even between foods that might not intuitively be perceived as related.

The aim was to assess the impact of eczema on health-related quality of life in the population-based birth cohort BAMSE with 2,756 pre-adolescent children. All answered the following questions on self-perceived health; "How are you feeling?", "How healthy do you consider yourself to be?" and "How happy are you with your life right now?". Children with ongoing eczema answered the "Children's Dermatology Life Quality Index (CDLQI)" questionnaire. In total, 350 (12.7%) of the children had eczema. Girls with eczema reported impaired self-perceived health as evaluated in the 3 questions; adjusted OR 1.72 (95% CI 1.16-2.55), 1.89 (95% CI 1.29-2.76) and 1.69 (95% CI 1.18-2.42). Eczema among boys was not associated with impairment of self-perceived health. The mean CDLQI score was 3.98 (95% CI 3.37-4.58). Since eczema affects up to 20% of pre-adolescent girls, the findings have implications both for health care providers and for society as a whole.

Summary Background Filaggrin (FLG) mutations are major genetic determinants for eczema, but their role in eczema severity needs further investigation. Children with eczema are at higher risk of having asthma and rhinitis but it is not known if this risk is associated with the severity of eczema. Objectives To investigate eczema severity in relation to sex, FLG mutations, asthma, rhinitis and topical treatment among preadolescent children in a population-based cohort. Methods Parental questionnaires were used to obtain data on symptoms of eczema, asthma, and rhinitis among 3301 preadolescent children. Eczema severity was evaluated based on sleep disturbance, extent of disease and total time with eczema the previous year. Genotyping was performed in 1854 individuals for three common FLG mutations (R501X, R2447X and 2282del4). Results Eczema was more prevalent among girls (14·5%) than boys (9·4%). FLG mutations were detected in 13·1% of children with mild eczema and 12·5% with moderate-to-severe eczema. Of children with moderate-to-severe eczema, 45·1% had rhinitis and 22·0% had asthma compared with 32·7% and 13·8% of children with mild eczema, respectively. Children with moderate-to-severe eczema used moisturizers and topical glucocorticoids more frequently than children with mild eczema. Boys used moisturizers less frequently than girls. Conclusions More preadolescent girls than boys had eczema. FLG mutations did not influence eczema severity in our population-based cohort. Prevalence of rhinitis and asthma was associated with eczema severity, with the highest prevalence among boys with moderate-to-severe eczema.

BACKGROUND: Fish is one of the most allergenic foods. While clinical cross-reactivity among different fishes is a widely accepted feature of fish allergy, associations with other food allergies are not well understood. This study aims at analyzing the relevance of clinical cross-reactivity between fish and chicken meat in patients with allergy to chicken meat without sensitization to hen's eggs.METHODS: Patients with food allergy to fish and chicken meat (n = 29) or chicken meat only (n = 7) were recruited. IgE-reactive chicken proteins were identified (Edman, MS analysis) and quantified (ELISA). Allergens were used in IgE ELISA and skin testing.RESULTS: Chicken parvalbumin and two new allergens, aldolase and enolase, were identified at 12, 40, and 50 kDa, respectively. They were recognized by sIgE of 61%, 75%, and 83% of all patient sera which were in the majority of the cases positive for the fish homologues as well. Fish and chicken meat allergens were highly cross-reactive while high inhibition rates with fish or chicken allergens correlated with the patients' primary sensitization to fish or chicken. In cooked or roasted foods, enolase and aldolase were detectable in chicken breast while parvalbumin was detectable in chicken legs and wings.CONCLUSIONS: Fish and chicken meat are cross-reactive foods; both fish-allergic and chicken meat-allergic patients might be at risk of developing a food allergy to chicken meat or to fish, respectively. This clinical phenomenon is proposed to be termed 'fish-chicken syndrome' with cross-reactive allergens involved being parvalbumins, enolases, and aldolases.

Background Eczema (atopic dermatitis) is associated with an increased risk of having IgE antibodies. IgE sensitization can occur through an impaired skin barrier. Filaggrin gene (FLG) mutation is associated with eczema and possibly also with IgE sensitization. Objective We sought to explore the longitudinal relation between preschool eczema (PSE), FLG mutation, or both and IgE sensitization in childhood. Methods A total of 3201 children from the BAMSE (Children Allergy Milieu Stockholm Epidemiology) birth cohort recruited from the general population were included. Regular parental questionnaires identified children with eczema. Blood samples were collected at 4, 8, and 16 years of age for analysis of specific IgE. FLG mutation analysis was performed on 1890 of the children. Results PSE was associated with IgE sensitization to both food allergens and aeroallergens up to age 16 years (overall adjusted odds ratio, 2.30; 95% CI, 2.00-2.66). This association was even stronger among children with persistent PSE. FLG mutation was associated with IgE sensitization to peanut at age 4 years (adjusted odds ratio, 1.88; 95% CI, 1.03-3.44) but not to other allergens up to age 16 years. FLG mutation and PSE were not effect modifiers for the association between IgE sensitization and PSE or FLG mutation, respectively. Sensitized children with PSE were characterized by means of polysensitization, but no other specific IgE sensitization patterns were found. Conclusions PSE is associated with IgE sensitization to both food allergens and aeroallergens up to 16 years of age. FLG mutation is associated with IgE sensitization to peanut but not to other allergens. Sensitized children with preceding PSE are more often polysensitized.

Background: Asthma in combination with rhinitis and eczema has been suggested to be associated with worse lung function than isolated asthma. Aim: To examine associations between asthma with and without rhinitis, eczema, allergic sensitization and; (1) spirometry, and (2) small airway involvement measured by impulse oscillometry (IOS). Methods: In the Swedish population-basedbirth cohort BAMSE (n= 4089), we used questionnaire data to identify children with rhinitis, eczema and asthma at 16 yrs. Sensitization was defined asspecific IgE ≥0.35 kU A /L. Subjects with asthma, with and without comorbidities, where compared to subjects without disease. Results: Asthma with and without rhinitis or eczema resulted in similar negative associations with FEV1/FVC (only asthma -2.6 %-units, 95% CI -3.9;-1.6, asthma + rhinitis -2.3, -3.4;-1.3). No significant associations were seen between isolated rhinitis/eczema and spirometric indices. Associations with increased peripheral resistance in the small airway resistance index R 5-20 was observed only for asthma in combination with rhinitis, but not for isolated asthma, rhinitis or eczema. Further analyses to assess the relationship between small airway involvement, asthma, rhinitis and sensitization status showed significant associations with R 5-20 only for asthma with sensitization, independent of rhinitis status (p= 0.438 for asthma + rhinitis without sensitization and p= 0.001 for asthma + rhinitis with sensitization). Conclusions: Asthma with allergic sensitization is associated with small airway involvement measured by IOS. Rhinitis and eczema did not alter the negative associations between asthma and lung function once sensitization was taken into account.

Allergic diseases (asthma, rhinitis and atopic dermatitis) are complex. They are associated with allergen-specific IgE and non-allergic mechanisms that may coexist in the same patient. In addition, these diseases tend to cluster and patients present concomitant or consecutive diseases (multimorbidity). IgE sensitization should be considered as a quantitative trait. Important clinical and immunological differences exist between mono or polysensitized subjects. Multimorbidities of allergic diseases share common causal mechanisms that are only partly IgE-mediated. Persistence of allergic diseases over time is associated with multimorbidity and/or IgE polysensitization. The importance of the family history of allergy may decrease with age. This review puts forward the hypothesis that allergic multimorbidities and IgE polysensitization are associated and related to the persistence or re-occurrence of foetal Type 2 signalling. Asthma, rhinitis and atopic dermatitis are manifestations of a common systemic immune imbalance (mesodermal origin) with specific patterns of remodelling (ectodermal or endodermal origin). This paper proposes a new classification of IgE-mediated allergic diseases that allows the definition of novel phenotypes in order to (i) better understand genetic and epigenetic mechanisms, (ii) better stratify allergic preschool children for prognosis, and (iii) propose novel strategies of treatment and prevention.

SummaryBackground There is limited information on clinical manifestations of atopic eczema (AE) and non-AE in teenagers. Objectives To describe the characteristics of adolescent eczema in the general population and to identify potential differences between AE and non-AE in teenagers. Methods Overall, 3108 teenagers were included from the population-based BAMSE cohort and 2529 of these teenagers provided blood samples for analysis of specific IgE. At age 16 years, the teenagers answered questionnaires regarding the symptoms of eczema, asthma and rhinitis for the previous year. Results The prevalence of eczema in adolescence was 9·6% (n = 297). More girls than boys had eczema (12·5% vs. 6·5%; P

Asthma, rhinitis, and eczema are complex diseases with multiple genetic and environmental factors interlinked through IgE-associated and non–IgE-associated mechanisms. Mechanisms of the Development of ALLergy (MeDALL; EU FP7-CP-IP; project no: 261357; 2010-2015) studied the complex links of allergic diseases at the clinical and mechanistic levels by linking epidemiologic, clinical, and mechanistic research, including invivo and invitro models. MeDALL integrated 14 European birth cohorts, including 44,010 participants and 160 cohort follow-ups between pregnancy and age 20years. Thirteen thousand children were prospectively followed after puberty by using a newly standardized MeDALL Core Questionnaire. Amicroarray developed for allergen molecules with increased IgE sensitivity was obtained for 3,292 children. Estimates of air pollution exposure from previous studies were available for 10,000 children. Omics data included those from historical genome-wide association studies (23,000 children) and DNA methylation (2,173), targeted multiplex biomarker (1,427), andtranscriptomic (723) studies. Using classical epidemiology and machine-learning methods in 16,147 children aged 4years and 11,080 children aged 8years, MeDALL showed the multimorbidity of eczema, rhinitis, and asthma and estimated that only 38% of multimorbidity was attributable to IgE sensitization. MeDALL has proposed a new vision of multimorbidity independent of IgE sensitization, and has shown that monosensitization and polysensitization represent 2 distinct phenotypes. The translational component of MeDALL is shown by the identification of a novel allergic phenotype characterized by polysensitization and multimorbidity, which is associated with the frequency, persistence, and severity of allergic symptoms. The results of MeDALL will help integrate personalized, predictive, preventative, and participatory approaches in allergic diseases.

Background Allergy-related diseases are a public health issue, but knowledge on development and comorbidity among children is scarce. The aim was to study the development of eczema, asthma and rhinitis in relation to sex and parental allergy, in a population-based cohort, during childhood. Methods At 1, 2, 4, 8 and 12 years, parental questionnaires were used to obtain data on allergy-related diseases. Complete data for all five follow-up occasions were available from 2916 children. Odds ratios for the risk of any allergy-related disease in relation to heredity and sex were calculated using generalized estimating equations. Results At 12 years, 58% of the children had had eczema, asthma and/or rhinitis at some time. Disease turnover was high for all three diseases throughout the study. Comorbidity increased with age, and at 12 years, 7.5% of all the children were affected by at least two allergy-related diseases. Parental allergy was associated with increased comorbidity and more persistent disease and increased the risk of having any allergy-related disease (adjusted OR 1.76; 95% CI 1.57–1.97) up to 12 years. Male sex was associated with an increased risk throughout childhood. Boys and girls did not differ in disease persistence, and for comorbidity, the differences were minor. Conclusions Allergy-related diseases may affect a majority of children. Eczema, asthma and rhinitis develop dynamically throughout childhood, and allergic comorbidity is common. These findings indicate that allergy-related diseases should be neither seen nor studied as isolated entities.

Background Tree nut allergy may cause anaphylaxis. There are limited population-based studies on prevalence and early-life risk factors. Methods We evaluated the prevalence of reported symptoms and allergic sensitization to tree nuts at age 24 years in the BAMSE population-based cohort study and assessed early-life factors associated with the development of tree nut allergy. We estimated tree nut allergy prevalence, by analysing questionnaire data on tree nut ingestion and symptoms at age 12, 16 and 24 years, and IgE sensitization at age 24 years to hazelnut, walnut, pecan, cashew, pistachio, Brazil nut, almond extracts and allergen molecules Cor a 1, 9, 14 (hazelnut), Jug r 1 (walnut) and Ana o 3 (cashew). We evaluated eczema, asthma, food allergies, inherited risk of allergy and gender as potential early-life risk factors. Results Data were available for 2215/4089 (54%) BAMSE study participants, for estimation of the prevalence of tree nut sensitization (21.2%), tree nut allergy symptoms (9.8%) and combined sensitization and symptoms (7.9%, 2.1% for storage protein sensitization and symptoms, 4.3% for any sensitization and non-mild symptoms). Sixty-three per cent of sensitized individuals (295/470) were asymptomatic, but only 76/470 (16%) storage protein sensitized individuals. Egg allergy (ORadj 8.50 95% CI 2.15-33.6), eczema (ORadj 2.53 95% CI 1.21-5.32) and asthma (ORadj 5.59 95% CI 2.35-13.3)) at pre-school age were associated with future development of tree nut symptoms and storage protein sensitization. At age 24 years, tree nut allergy was associated with current eczema and with markers of current asthma severity. Sensitization to storage proteins was more strongly associated with symptoms than sensitization to whole extract for all tree nuts evaluated. Conclusions In this Swedish cohort, we found tree nut whole extract sensitization is common but usually asymptomatic. Storage protein sensitization is a more reliable indicator of tree nut symptoms. Tree nut allergy is associated with early onset, persistent and severe atopic disease.

Atopic dermatitis (AD) is a prevalent inflammatory skin disease. Loss-of-function mutations in filaggrin gene (FLG) represent the strongest genetic risk factors for AD, being strongly associated with early disease onset and persistence into adulthood.1 The epidermis of individuals with mutations in FLG is fundamentally different from normal skin being characterized by increased penetration of allergens.2 Recent birth cohort studies showed a significant interaction between cat ownership at birth and mutations in FLG (R501X, 2282del4) on the development of early-onset AD.3 This finding was replicated for the 2282del4 FLG mutation in a Dutch cohort study, and extended to further associate with risk of allergic sensitization.4 We performed analyses in multiple birth cohorts to examine the consistency and overall strength of the previously observed interaction.