A randomized, double-blind placebo-controlled study on the efficacy of Omalizumab on food allergy threshold in children with severe food allergy.

BACKGROUND: Food allergy is common in childhood with some children having a low threshold and being difficult to protect from accidental ingestion of the offending food. Therapies for this potentially life-threatening condition are highly needed. The aim of this study was to evaluate the efficacy of Omalizumab in food-allergic children. METHODS: This is a single-center, double-blind, placebo-controlled study. Food allergic children with a cumulative threshold ≤443 mg food protein at DBPCFC were randomized to Omalizumab (asthma dose) or placebo (3:1). After 3 months, a second DBPCFC was performed (steps 3, 10, 30, 100, 300, 1000, and 3000 mg food protein), followed by a separate open challenge up to 10,000 and 30,000 mg food protein if negative. Responders were defined as ≥2-step increases in threshold. Non-responders received high-dose Omalizumab. A third DBPCFC was performed after 6 months. Skin testing, blood samples, and the severity of atopic co-morbidity were registered during the study and 3 months after treatment. RESULTS: In total, 20 children were evaluated at 3 months (14 Omalizumab, 6 placebo). All treated with Omalizumab increased their threshold at least two steps and with a significant difference between the Omalizumab and the placebo group (p = .003), although the intended number of included children was not reached. The threshold before Omalizumab treatment was 13-443 mg food protein while the threshold after 3 months of treatment increased up to 44,000 mg (1143-44,000). In the placebo group, two children improved threshold during the study. CONCLUSION: An increase in the threshold level during Omalizumab treatment significantly improve patient safety and protected all children against small amount of allergen.

Challenge-verified thresholds for allergens mandatory for labeling: How little is too much for the most sensitive patient?

BACKGROUND: It is mandatory to label food products with the 14 main allergens in the EU. Reasonable allergen labeling requires knowledge of population-based thresholds derived from food challenges. The aim of this study was to evaluate the threshold-distribution in clinically verified food allergic patients for allergens mandatory for labeling. METHODS: All positive open oral food challenges and double-blind placebo-controlled food challenges (DBPCFC) performed at the Allergy Center, Odense University Hospital, Denmark (2000-2022) were included. For each included challenge, the cumulative threshold (LOAEL) was obtained and NOAEL estimated. Data were modelled as an interval censored log-normal distribution. RESULTS: Overall, 38 of all 2612 challenges (1.5%) in 1229 patients (717 male, 986 children) reacted to <5 mg protein. The majority of the most sensitive patients reacted with a Sampson severity score of 2-3. Using interval censored log-normal models only five groups (hens´ egg, fish, peanut, milk, tree-nuts) elicited reactions after ingestion of 0.5 mg protein and in low frequencies of the population. Hen's egg was the most potent allergen, with reactivity to <0.5 mg protein in 0.24% [0.13-0.44%] of egg allergic patients while the estimated fraction of allergic patients reacting to a eliciting dose on 0.5 mg protein for most other allergens were below 0.04%. CONCLUSION: Our data demonstrates that the majority of food allergic patients as expected tolerating traces of allergenic foods without developing severe allergic symptoms and signs. Hen's egg appears to be the food most likely to elicit reactions in the most sensitive individuals at very low doses.

Does early onset asthma increase childhood obesity risk? A pooled analysis of 16 European cohorts.

The parallel epidemics of childhood asthma and obesity over the past few decades have spurred research into obesity as a risk factor for asthma. However, little is known regarding the role of asthma in obesity incidence. We examined whether early-onset asthma and related phenotypes are associated with the risk of developing obesity in childhood.This study includes 21 130 children born from 1990 to 2008 in Denmark, France, Germany, Greece, Italy, The Netherlands, Spain, Sweden and the UK. We followed non-obese children at 3-4 years of age for incident obesity up to 8 years of age. Physician-diagnosed asthma, wheezing and allergic rhinitis were assessed up to 3-4 years of age.Children with physician-diagnosed asthma had a higher risk for incident obesity than those without asthma (adjusted hazard ratio (aHR) 1.66, 95% CI 1.18-2.33). Children with active asthma (wheeze in the last 12 months and physician-diagnosed asthma) exhibited a higher risk for obesity (aHR 1.98, 95% CI 1.31-3.00) than those without wheeze and asthma. Persistent wheezing was associated with increased risk for incident obesity compared to never wheezers (aHR 1.51, 95% CI 1.08-2.09).Early-onset asthma and wheezing may contribute to an increased risk of developing obesity in later childhood.

Early-life sensitization to hen's egg predicts asthma and rhinoconjunctivitis at 14 years of age.

BACKGROUND: Sensitization to both inhalant and food allergens has been shown to be risk factors for development of asthma and rhinoconjunctivitis (RC). However, few studies have addressed the role of transient or persistent IgE sensitization to specific allergens in early life for later development of allergic diseases. The aim of this study was to explore the association between transient and persistent sensitization in early life and the development of asthma and RC at 6 and 14 years. METHODS: The Danish Allergy Research Center (DARC) cohort is a prospective non-interventional birth cohort study comprising 562 children. For the purpose of this study, we examined a subgroup of the original cohort with specific IgE measured at, at least 3 of 4 follow-ups between 3 and 18 months of age (n = 366). Multiple logistic regression models were used to investigate the association between transient and persistent early-life sensitization to groups of and to individual allergens and asthma and RC at 6 and 14 years compared to a reference group with no sensitization. RESULTS: Both transient early-life sensitization and persistent early-life sensitization to cow's milk or hen's egg proteins were associated with asthma (aOR 3.99[1.41-11.32] and 5.95[1.78-19.92]) and RC (aOR 2.94[1.19-7.28] and 6.18[1.86-20.53]) at 14 years, this association being driven mainly by sensitization to hen's egg. Transient early-life sensitization to house dust mite (HDM) had increased risk of asthma (aOR 3.80[1.17-12.41]) at 14 years. CONCLUSIONS: Early transient IgE sensitization and persistent IgE sensitization to hen's egg were associated with asthma and RC at 14 years. Furthermore, sensitization to HDM was associated with asthma at 14 years.

Neonatal BCG has no effect on allergic sensitization and suspected food allergy until 13 months.

BACKGROUND: Vaccination with Bacillus Calmette-Guérin (BCG) is used in many countries as protection against tuberculosis. Studies have suggested that BCG may also have non-specific effects, reducing non-tuberculosis mortality, morbidity, and atopic manifestations. In this study, we evaluated the effect of neonatal BCG vaccination on allergic sensitization and suspected food allergy at 13 months of age. METHODS: The Danish Calmette Study was conducted from 2012 to 2015 at three Danish hospitals. Within 7 days of birth, the 4262 newborns of 4184 included mothers were randomized 1:1 to BCG or to a no-intervention control group. Exclusion criteria were gestational age <32 weeks, birth weight <1000 g, known immunodeficiency, or no Danish-speaking parent. Follow-up information was collected through telephone interviews at 3 and 13 months of age. Subgroups of participants were offered blood sampling at 13 months of age. RESULTS: By 13 months of age, the parents and/or general practitioners of 5.6% (117/2089) of the children in the BCG group and 6.1% (126/2061) of the control group suspected food allergy, resulting in a risk ratio comparing BCG-vaccinated children with control children of 0.91 (95% CI 0.71-1.16). Among 1370 blood samples, sensitization (Phadiatop Infant >0.35 kUA/L) was found in 55 of 743 (7.4%) children in the BCG group and 50 of 627 (8.0%) of the control group (risk ratio 0.94 [0.65-1.36]). CONCLUSION: In this randomized clinical trial, neonatal BCG had no significant effect on suspected food allergy or on sensitization at 13 months of age.

The prevalence of atopic diseases and the patterns of sensitization in adolescence.

BACKGROUND: Atopic diseases are among the most common chronic diseases in adolescents, and it is uncertain whether the prevalence of atopic diseases has reached a plateau or is still increasing. The use of the ISAAC (International Study of Asthma and Allergy in Childhood) questionnaire has provided comparable prevalence rates from many countries, whereas studies including clinical examinations and strict diagnostic criteria are scarce. We aimed to investigate the prevalence of atopic diseases, the pattern of sensitization, and comorbidities at 14 years in a prospective birth cohort. METHODS: The children were examined eight times from birth to 14 years. Visits included questionnaire-based interviews, clinical examination, skin prick test, and specific IgE. RESULTS: Follow-up rate at 14 years was 66.2%. The 12-month prevalence of any atopic disease was high (40.3%) mostly due to a high prevalence of rhinoconjunctivitis (32.8%), whereas the prevalence of asthma was 12.9% and of atopic dermatitis 8.1%. In children with at least one atopic disease, 60% were sensitized, while only 16% of those without atopic diseases were sensitized. The frequency of sensitization depended on the phenotype. Among children with rhinoconjunctivitis only, rhinoconjunctivitis with concomitant asthma or atopic dermatitis or both 62.5%, 81.5%, 70%, and 100%, respectively, were sensitized, whereas it was 7.7% and 33.3% of children with only asthma or atopic dermatitis. CONCLUSION: The prevalence of rhinoconjunctivitis was high in adolescence. Children with rhinoconjunctivitis with and without comorbidities were frequently sensitized. Children with asthma without concomitant allergic rhinoconjunctivitis were rarely sensitized.

Maternal smoking in pregnancy and asthma in preschool children: a pooled analysis of eight birth cohorts.

RATIONALE: Although epidemiological studies suggest that exposure to maternal smoking during fetal and early life increases the risk of childhood wheezing and asthma, previous studies were not able to differentiate the effects of prenatal from postnatal exposure. OBJECTIVES: To assess the effect of exposure to maternal smoking only during pregnancy on wheeze and asthma among preschool-age children. METHODS: A pooled analysis was performed based on individual participant data from eight European birth cohorts. Cohort-specific effects of maternal smoking during pregnancy, but not during the first year, on wheeze and asthma at 4 to 6 years of age were estimated using logistic regression and then combined using a random effects model. Adjustments were made for sex, parental education, parental asthma, birth weight, and siblings. MEASUREMENTS AND MAIN RESULTS: Among the 21,600 children included in the analysis, 735 children (3.4%) were exposed to maternal smoking exclusively during pregnancy but not in the first year after birth. In the pooled analysis, maternal smoking only during pregnancy was associated with wheeze and asthma at 4 to 6 years of age, with adjusted odds ratios of 1.39 (95% confidence interval, 1.08-1.77) and 1.65 (95% confidence interval, 1.18-2.31), respectively. The likelihood to develop wheeze and asthma increased statistically significantly in a linear dose-dependent manner in relation to maternal daily cigarette consumption during the first trimester of pregnancy. CONCLUSIONS: Maternal smoking during pregnancy appears to increase the risk of wheeze and asthma among children who are not exposed to maternal smoking after birth.

Prevalence of allergic sensitization with vernal keratoconjunctivitis: A systematic review with meta-analyses.

To determine the prevalence of allergic sensitization in patients with vernal keratoconjunctivitis (VKC) and to provide an overview of published studies on this topic. We systematically searched 11 literature databases on 24 May 2021, for studies with cross-sectional data on the prevalence of positive allergy tests in patients with VKC. Our main outcome of interest was the prevalence of allergic sensitization and the allergens involved. Prevalence meta-analyses were made to provide summary estimates. We identified 33 eligible studies for qualitative review with 2122 patients with VKC. Studies were predominantly based on patients seen in ophthalmology clinics. Overall, studies reported that the most prevalent positive allergen tests were the inhaled allergens house dust mites and pollen. Twenty-nine studies were eligible for the quantitative analysis. Here, we calculated the prevalence of allergen-positive patients to 57.7% (95% confidence interval: 52.5%-62.8%). Subgroup analyses of pooled estimates on sensitization based on specific testing methods found prevalence estimates of 51.4% for conjunctival provocation test, 68.7% for total tear IgE, 58.9% for specific tear IgE, and 58.2% for skin prick test. The prevalence of allergic sensitization in patients with VKC is 57.7%, and mostly towards inhaled allergens. The most frequent positive allergens are house dust mites and pollen. Identifying possible clinically relevant allergens provide information that may aid in managing VKC, such as environmental allergy-avoidance or allergy-specific treatment.

Does treatment with antidepressants, antipsychotics, or benzodiazepines hamper allergy skin testing?

BACKGROUND: Treatment with commonly used drugs such as antidepressants (ADs), antipsychotics (APs), and benzodiazepines (BDs) may hamper the use of allergy skin testing due to possible antihistaminic effects. OBJECTIVE: To examine the antihistaminic effect of AD, AP, and BD as measured by the ability of these drugs to suppress the normal wheal reaction caused by skin prick test (SPT). METHODS: Skin prick test was performed in patients receiving treatment with AD, AP, and/or BD. Double SPT was performed with histamine solutions of 10, 30, and 100 mg/ml and mean wheal diameter calculated. RESULTS: A total of 313 patients were included. 236 (75%) patients were treated with one of the examined drugs and 77 (25%) patients with more than one of these drugs. Drugs most frequently used was sertraline (n = 65), citalopram (n = 63), mirtazapine (n = 36), venlafaxine (n = 33), and quetiapine (n = 32). Treatment with mirtazapine and/or quetiapine was associated with negative SPTs in 30/36 (83%) and 22/32 (69%), and the antihistaminic effect of these drugs was dose-dependent. For patients treated with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin norepinephrine reuptake inhibitors (SNRIs), or BD alone, almost all SPTs were positive (94%, 95%, 100%, and 100%, respectively). Negative SPTs in patients treated with SSRI, TCA, SNRI, or BD and ≥1 other of the examined drugs were associated with simultaneous treatment with mirtazapine or quetiapine in 39/44 (89%) patients. CONCLUSION: Skin testing has little meaning in patients treated with mirtazapine or quetiapine. Treatment with SSRI, SNRI, and BD does not seem to affect the results of SPTs, whereas skin tests in patients treated with TCA should be interpreted with caution.

Patients with suspected allergic reactions to COVID-19 vaccines can be safely revaccinated after diagnostic work-up.

BACKGROUND: When initiating the Danish vaccination program against COVID-19, the incidence of anaphylaxis was estimated to be 10 times higher compared to other virus-based vaccines. In this study, we present data on patients referred with suspected allergic reactions to COVID-19 vaccines. The main purpose of the study is to investigate the incidence and severity of the allergic reactions, and to evaluate the safety of revaccination. METHODS: All patients in the region of Southern Denmark with case histories of allergic reactions to COVID-19 vaccines in a defined period are included in this study. Diagnostic work up consisted of a detailed case history, evaluation of Brighton level of diagnostic certainty and World Allergy Organization grade of anaphylaxis and skin prick testing- and basophil histamine release testing with COVID-19 vaccines and relevant drug excipients. Patients were revaccinated at the Allergy Center when possible. RESULTS: Sixty-one patients are included in this study. In 199,377 doses administered, nine patients fulfilled the criteria of anaphylaxis when using the Brighton Criteria (incidence being 45 per million). Of 55 patients with reactions to the first dose, 52 patients were revaccinated without adverse reactions. We found no proven cases of immediate anaphylaxis due to COVID-19 vaccines. By skin prick test, we diagnosed three patients with drug excipient allergy and further a patient with mastocytosis was found. CONCLUSIONS: Anaphylactic reactions to COVID-19 vaccines are rare and the incidence is similar to what is seen with other virus-based vaccines. Revaccination is safe in the majority of patients; however, allergological evaluation is important since some prove to have drug excipient allergy.

Development of atopic dermatitis in the DARC birth cohort.

The aim was to describe the relapsing pattern, sensitization and prognosis of atopic dermatitis (AD) in the first 6 yr in a population-based, prospective birth cohort. The DARC cohort includes 562 children with clinical examinations, specific-IgE and skin prick test at all follow-ups. All children were examined for the development of AD using Hanifin-Rajka criteria and for food hypersensitivity by oral challenges. Severity of AD was measured by objective SCORing Atopic Dermatitis (SCORAD). Point-prevalence of AD peaked at 18 months of age (10%) and decreased at 36 and 72 months to slightly below 7%. The 6-yr cumulative incidence was 22.8% and sensitization was found in 43% of children with AD. It was predominately sensitization to foods, however shifting toward inhalant allergens with age. Sensitization at >or=2 follow-ups affected severity, whereas short-term sensitization at one follow-up does not. Children with early, non-IgE mediated (intrinsic) AD outgrew more often their eczema; however if they develop persistent AD, they remain intrinsic. Early long-term sensitization worsens the prognosis, but 38% of all children have a debut later than 18 months of age. Boys had earlier onset of AD than girls. The large number of follow-ups gives a detailed picture of the relapsing pattern and shows that the relapses occur independently of time of onset. We could not establish any clear correlation between elimination diets and AD duration nor severity.

The association between early sensitization patterns and subsequent allergic disease. The DARC birth cohort study.

Prevention of allergic diseases depends on early identification of clinical markers preceding such disorders. This study describes the natural course of sensitization as measured by skin prick test (SPT) and specific immunoglobulin E (S-IgE) and analyses the association between early sensitization patterns and subsequent allergic disease at 6 yr of age. In an ongoing population-based birth cohort study of 562 children, follow-up visits were performed at 0, 3, 6, 9, 12, 18, 36, and 72 months. Visits included an interview, physical examination, SPTs, and S-IgE measurements for 12 food and inhalant allergens. The frequency of S-IgE sensitization to > or = 1 inhalant allergen was constant from 0 to 6 months (9-10%), decreased at 12-18 months before increasing from 36 months onwards. S-IgE sensitization to at least one food allergen remained constant from 0 to 6 yr. SPT sensitization to food and inhalant allergens appeared from 3 and 12 months, respectively. Early food sensitization (S-IgE) between 3 and 18 months was found to be significantly (p < 0.05) associated with atopic dermatitis (OR: 4.0 [1.6-9.9]) and asthma (OR 4.0 [1.1-12.5]) at the age of 6 yr. Children with atopic dermatitis, asthma, or rhinoconjunctivitis, and sensitization at 6 yr, were sensitized to food allergens to a large extent (53%, 42%, and 47%, respectively) already at 6 months. Early inhalant sensitization (S-IgE) did not increase the risk of later allergic disease. Early atopic dermatitis (0-18 months) was also highly associated with subsequent allergic disease. Children with early food sensitization and/or atopic dermatitis would be a proper target group for future interventional studies.

Adherence to adrenaline autoinjector prescriptions in patients with anaphylaxis.

This study evaluates adherence to adrenaline autoinjector prescriptions in a cohort of well-characterized anaphylaxis patients. The overall retrieval rate was 76% with the highest rate in patients with severe anaphylaxis. Special attention is needed in patients with unknown elicitors and in young adults, comprising the largest proportion of non-adherent patients. Trial registration No intervention performed. Retrospective data used with permission from the Danish Data Protection Agency and Regional Committees on Health Research Ethics.

The prevalence of allergic diseases in an unselected group of 6-year-old children. The DARC birth cohort study.

This study determines the prevalence of atopic dermatitis, asthma, rhinoconjunctivitis, food hypersensitivity and urticaria and the frequency of sensitization in children with and without clinical allergic disease. In an ongoing prospective non-interventional birth cohort study of 562 unselected children, 404 children were subjected to interview, clinical examination, lung function measurements and allergy testing at 6 yr of age. Sensitization measured by skin prick test (SPT) and specific immunoglobulin E (S-IgE) was determined for 24 different allergens. The 1-yr period prevalence of atopic dermatitis, asthma and rhinoconjunctivitis was 14.4%, 6.2% and 13.6%. 25.7% of the children suffered from at least one of the three diseases. The frequency of sensitization in children with no disease (controls), any allergic disease, atopic dermatitis, asthma and rhinoconjunctivitis was 17%, 45%, 47%, 56% and 55% (defined as SPT >or=3 mm and/or S-IgE >or=0.35 kU/l for at least one allergen). Symptoms were linked to sensitization for 44% in the asthma group and 42% in the rhinoconjunctivitis group, whereas sensitization could not be linked to worsening of the eczema in any cases of atopic dermatitis. Overlap between the three diseases was significantly more frequent in sensitized children than in non-sensitized (19/46 = 41% vs. 9/58 = 16%, p = 0.004). The prevalence of food hypersensitivity and urticaria was 1.2% and 5.4% respectively. In unselected 6 yr old children, approximately half of the children with atopic dermatitis, asthma or rhinoconjunctivitis are IgE-sensitized. Sensitization tends to link these diseases to each other.

Pediatric Expression of Mast Cell Activation Disorders.

Mast cell activation disorders is a term proposed to cover diseases and conditions related to activation of mast cells and effects of mast cell mediators. In its broadest sense, the term encompasses a wide range of diseases from allergic asthma to rhinoconjunctivitis, urticaria, food allergy, anaphylaxis, mastocytosis, and other conditions where MC activation is contributing to the pathogenesis. This article focuses on clinical presentations, challenges, and controversies in pediatric mastocytosis and gives an overview of current knowledge and areas in need of further research.

Three cases of anaphylaxis following injection of a depot corticosteroid with evidence of IgE sensitization to macrogols rather than the active steroid.

We present three cases with anaphylaxis after injection of a depot corticosteroid. First, the steroid was suspected as the elicitor, but after evaluation the excipient macrogol was found to be the elicitor. One of the patients had reactions to several unrelated drugs. Increased awareness of anaphylaxis to excipients such as macrogols is needed, especially when allergy tests for the active drug is negative and in patients with a history of repeated anaphylaxis to seemingly unrelated drugs. To establish the correct diagnosis it is important to test with the exact formulation of the culprit drug, as well as all the ingredients including excipients.

Early childhood risk factors for rhinoconjunctivitis in adolescence: a prospective birth cohort study.

BACKGROUND: Rhinoconjunctivitis is a global health problem and one of the most common chronic conditions in children. Development of rhinoconjunctivitis depends on both genetic and environmental factors. Many studies have investigated rhinoconjunctivitis, but only few studies have evaluated the risk factors for non-allergic rhinoconjunctivitis in children finding family history of atopic diseases and gender to be of importance. The aim of this study was to investigate possible risk factors in early life for rhinoconjunctivitis, allergic as well as non-allergic, in adolescence. METHODS: The children in the Danish Allergy Research Center cohort were examined eight times from birth to 14 years of age. Visits included questionnaire-based interview, clinical examination, skin prick test and specific IgE. We used univariate and multivariate logistic regression to investigate the relationship between early-life risk factors and the development of rhinoconjunctivitis, allergic as well as non-allergic, in adolescence. RESULTS: Follow-up rate at 14-years was 66.2%. The prevalence of rhinoconjunctivitis was 32.8%. Family history of atopic diseases (aOR 2.25), atopic dermatitis (aOR 3.24), food allergy (aOR 3.89), early sensitization to inhalant and food allergens (aOR 2.92 and aOR 3.13) and male gender (aOR 1.90) were associated with allergic rhinoconjunctivitis but not with non-allergic rhinoconjunctivitis. Early environmental tobacco exposure was inversely associated with rhinoconjunctivitis (aOR 0.42), allergic (aOR 0.47) as well as non-allergic (aOR 0.43). CONCLUSION: Different patterns of associations were revealed when stratifying rhinoconjunctivitis in allergic and non-allergic suggesting that allergic rhinoconjunctivitis and non-allergic-rhinoconjunctivitis are different phenotypes.