Early inhalant allergen sensitization at component level: an analysis in atopic Dutch children.

Background: Allergic rhinitis is a common respiratory disease in children and sensitization to inhalant allergens plays a significant role in its development. However, limited knowledge exists regarding sensitization profiles of inhalant allergen components in atopic children, particularly in the very young individuals. Understanding these profiles could provide insights into the early development of allergic rhinitis. The objective of this cross-sectional retrospective study was to evaluate the IgE-sensitization profiles to multiple inhalant allergen components and their clinical relevance in Dutch atopic children, with specific focus on children under the age of 4 years. Methods: A total of 243 atopic children were included in the study and sensitization profiles were analyzed using multiplex microarray analysis (ISAC). Clinical information was obtained from records of a pediatric allergy outpatient clinic between 2011 and 2020. Specific IgE responses to inhalation allergen components from five allergen sources (grass pollen, tree pollen, house dust mite, cat and dog), were examined. The study encompassed children of different age groups and compared those with and without symptoms. Results: The results demonstrated that sensitization to inhalant allergen components was present in 92% of the cohort. Sensitization was already evident at a young age (87%), including infancy, with a rapid increase in prevalence after 1 year of age. House dust mite emerged as the most predominant sensitizing allergen in early childhood, followed by tree pollen in later years. Sensitization patterns were similar between symptomatic and asymptomatic children, although symptomatic children exhibited higher frequencies and values. The sensitization profiles in very young children were comparable to those of children across all age groups. Conclusion: These findings highlight the presence of sensitization to inhalant allergen components and the early onset of allergic rhinitis before the age of 4, including infancy, in Dutch atopic children. Notable allergen molecules in Dutch atopic children under the age of 4 years include Bet v 1, Fel d 1, Der f 1, Der p 1, Der p 10 and Phl p 4, with house dust mite sensitization being the most common among Dutch infants. Moreover, the prevalence of sensitization to inhalant allergens in this Dutch cohort surpassed that of general European populations, emphasizing the importance of early assessment and management of allergic rhinitis in young atopic children.

Tolerance Induction in Cow's Milk Allergic Children by Heated Cow's Milk Protein: The iAGE Follow-Up Study.

Accelerating the induction of tolerance to cow's milk (CM) reduces the burden of cow's milk allergy (CMA). In this randomised controlled intervention study, we aimed to investigate the tolerance induction of a novel heated cow milk protein, the iAGE product, in 18 children with CMA (diagnosed by a paedriatric allergist). Children who tolerated the iAGE product were included. The treatment group (TG: n = 11; mean age 12.8 months, SD = 4.7) consumed the iAGE product daily with their own diet, and the control group (CG: n = 7; mean age 17.6 months, SD = 3.2) used an eHF without any milk consumption. In each group, 2 children had multiple food allergies. The follow-up procedures consisted of a double-blind placebo-controlled food challenge (DBPCFC) with CM t = 0, t = 1 (8 months), t = 2 (16 months), and t = 3 (24 months). At t = 1, eight (73%) of 11 children in the TG had a negative DBPCFC, versus four out of seven (57%) in the CG (BayesFactor = 0.61). At t = 3, nine of the 11 (82%) children in the TG and five of seven (71%) in the CG were tolerant (BayesFactor = 0.51). SIgE for CM reduced from a mean of 3.41 kU/L (SD = 5.63) in the TG to 1.24 kU/L (SD = 2.08) at the end of intervention, respectively a mean of 2.58 (SD = 3.32) in the CG to 0.63 kU/L (SD = 1.06). Product-related AEs were not reported. CM was successfully introduced in all children with negative DBPCFC. We found a standardised, well-defined heated CM protein powder that is safe for daily OIT treatment in a selected group of children with CMA. However, the benefits of inducing tolerance were not observed.

ALEX versus ISAC multiplex array in analyzing food allergy in atopic children.

ALEX multiplex array is a relatively new multiplex allergy test which analyses more than 120 allergen extracts and 170 molecular components. ISAC is the most used and studied multiplex array to date, offering 112 molecular components. In ten atopic children with multiple food allergies good agreement was observed between ALEX and ISAC sIgE results for nearly all shared food components. Presence of larger number of allergens in ALEX could help clinicians to improve personalized dietary advice. However more positive sensitizations with unknown clinical relevance were found by ALEX, potentially increasing clinical complexity. Pediatric allergists should be aware of this, especially in young atopic children with (severe) eczema who have not introduced all sorts of food yet.

Introduction of Heated Cow's Milk Protein in Challenge-Proven Cow's Milk Allergic Children: The iAGE Study.

The introduction of baked milk products in cow's milk (CM) allergic children has previously been shown to accelerate induction tolerance in a selected group of children. However, there is no standardized baked milk product on the market. Recently, a new standardized, heated and glycated cow's milk protein (HP) product was developed. The aim of this study was to measure safety and tolerability of a new, well characterized heated CM protein (HP) product in cow's milk allergic (CMA) children between the age of 3 and 36 months. The children were recruited from seven clinics throughout The Netherlands. The HP product was introduced in six incremental doses under clinical supervision. Symptoms were registered after introduction of the HP product. Several questionnaires were filled out by parents of the children. Skin prick tests were performed with CM and HP product, sIgE to CM and α-lactalbumin (Bos d4), ß-lactoglobulin (Bos d5), serum albumin (Bos d 6), lactoferrin (Bos d7) and casein (Bos d8). Whereas 72% percent (18 out of 25) of the children tolerated the HP product, seven children experienced adverse events. Risk factors for intolerance to the HP product were higher skin prick test (SPT) histamine equivalent index (HEP) results with CM and the HP product, higher specific IgE levels against Bos d4 and Bos d8 levels and Bos d5 levels. In conclusion, the HP product was tolerated by 72% of the CM allergic children. Outcomes of SPT with CM and the HP product, as well as values of sIgE against caseins, α-lactalbumin, and ß-lactoglobulin may predict the tolerability of the HP product. Larger studies are needed to confirm these conclusions.

Food Allergy and Asthma: Is There a Link?

PURPOSE OF REVIEW: To describe and understand the links and interactions between food allergy and asthma. RECENT FINDINGS: Food allergy and asthma are characterized by an increasing prevalence. Moreover, food allergy and asthma often coexist. Both conditions are associated with each other in different ways. It has been shown that food allergy is a risk factor of developing asthma. Atopic dermatitis appears to be the common denominator in this interaction. Loss-of-function variants of the filaggrin mutation result in an impaired epidermal barrier function and have been shown to be a risk factor for the development of atopic dermatitis, allergies, and asthma. Early introduction of food allergens and optimal treatment of the skin barrier are preventive interventions for the development of food allergy and asthma. Asthma is also a risk factor for the development of severe or even fatal anaphylaxis in patients with food allergy. Isolated asthma is not a feature of a food allergic reaction; however, respiratory symptoms may be part of anaphylactic reactions. In addition, during an allergic reaction to food, non-specific bronchial hyperreactivity may increase. Cross-reactive allergens may be responsible for asthma-associated food allergy. This is particularly true for severe asthma upon ingestion of snail in patients allergic to house-dust mites. Finally, airborne allergens from occupational sources such as wheat, fish, and seafood may induce asthmatic reactions. This phenomenon is sometimes seen in non-occupational settings. SUMMARY: Food allergy and asthma are interconnected with each other beyond the presence of simple comorbidity. Food allergy precedes and predisposes to asthma, and mutual interactions range from respiratory symptoms and bronchial hyperreactivity during food-induced anaphylaxis to severe asthma due to cross-reactive food allergens and to occupational asthma upon exposure to airborne allergens. Moreover, coexisting asthma in food allergies may result in severe and sometimes fatal anaphylactic reactions.

Small percentage of anaphylactic reactions treated with epinephrine during food challenges in Dutch children.

BACKGROUND: Severe allergic reactions, including anaphylaxis, occur during oral food challenges (OFCs) and the first-line treatment of anaphylaxis is epinephrine. OBJECTIVE: To evaluate the percentage of anaphylactic reactions treated with epinephrine during OFCs and to identify associated factors for the administration of epinephrine. METHODS: Children who underwent an OFC with peanut, hazelnut, cow's milk, hen's egg, or cashew nut from 2005 through 2015 in the Netherlands were evaluated. Children with reactions meeting the criteria for anaphylaxis according to the European Academy of Allergy and Clinical Immunology guidelines for food allergy and anaphylaxis were included. Children with an anaphylactic reaction treated with vs without epinephrine were compared. Possible factors associated with the administration of epinephrine, such as age, sex, symptoms consistent with asthma, history of an allergic reaction to the tested allergen, and symptom types during the anaphylactic reaction, were evaluated using logistic regression analysis. RESULTS: Eighty-three children in clinical and research settings (43% boys; median age, 7 years; range, 1-17) who met the criteria for anaphylaxis were included in this study. Thirty-two of 83 children (39%) with anaphylaxis were treated with epinephrine. Respiratory symptoms during the OFC were treated significantly more often with epinephrine than gastrointestinal symptoms (P = .01). CONCLUSION: Only 39% of children with anaphylaxis, according to the guideline criteria, were treated with epinephrine during the OFC and most of these children had respiratory symptoms. There is need for an easy-to-use international guideline for the treatment of allergic symptoms during OFCs.

Ovarian insufficiency and pubertal development after hematopoietic stem cell transplantation in childhood.

BACKGROUND: Ovarian insufficiency (OI) and infertility are common and devastating late effects of cancer treatment and hematopoietic stem cell transplantation (HSCT). In children, gonadal insufficiency may subsequently lead to abnormal pubertal development. The aim of this study was to assess the cumulative incidence of OI and the need for hormonal induction of pubertal development after HSCT in childhood. We additionally assessed HSCT-related risk factors for OI. PROCEDURES: A single center cohort study was undertaken of female patients transplanted during childhood, surviving at least 2 years post-HSCT and who were at least 10 years old at initiation of the study. Of 141 eligible patients, 109 were included and hormone levels and clinical data of these patients during follow-up were collected. Risk factors for OI were analyzed by multivariate Cox regression analysis. RESULTS: Cumulative incidence of OI was 56% at a median follow-up of 7.2 years. Eight patients, initially diagnosed with OI, showed recovery of ovarian function over time. Hormonal induction of puberty was necessary in 44% of females who were pre-pubertal or pubertal at HSCT. In multivariate analysis, more advanced pubertal stage at HSCT was associated with OI. We found a trend for an association of busulfan with OI in patients conditioned with chemotherapy only. CONCLUSIONS: The incidence of OI after HSCT was high and associated with more advanced pubertal stage at HSCT. Almost half of the females who were pre-pubertal or pubertal at HSCT required hormonal induction of pubertal development.

Fetal mesenchymal stromal cells differentiating towards chondrocytes acquire a gene expression profile resembling human growth plate cartilage.

We used human fetal bone marrow-derived mesenchymal stromal cells (hfMSCs) differentiating towards chondrocytes as an alternative model for the human growth plate (GP). Our aims were to study gene expression patterns associated with chondrogenic differentiation to assess whether chondrocytes derived from hfMSCs are a suitable model for studying the development and maturation of the GP. hfMSCs efficiently formed hyaline cartilage in a pellet culture in the presence of TGFß3 and BMP6. Microarray and principal component analysis were applied to study gene expression profiles during chondrogenic differentiation. A set of 232 genes was found to correlate with in vitro cartilage formation. Several identified genes are known to be involved in cartilage formation and validate the robustness of the differentiating hfMSC model. KEGG pathway analysis using the 232 genes revealed 9 significant signaling pathways correlated with cartilage formation. To determine the progression of growth plate cartilage formation, we compared the gene expression profile of differentiating hfMSCs with previously established expression profiles of epiphyseal GP cartilage. As differentiation towards chondrocytes proceeds, hfMSCs gradually obtain a gene expression profile resembling epiphyseal GP cartilage. We visualized the differences in gene expression profiles as protein interaction clusters and identified many protein clusters that are activated during the early chondrogenic differentiation of hfMSCs showing the potential of this system to study GP development.

The role of p27Kip1 in the regulation of growth plate chondrocyte proliferation in mice.

p27/Kip1, a cyclin-dependent kinase inhibitor, negatively regulates proliferation of multiple cell types. The goal of this study was to assess the role of p27 in the spatial, temporal, and conditional regulation of growth plate chondrocyte proliferation. p27 mRNA expression was detected by real-time RT-PCR in all zones of the mouse growth plate at levels approximately 2-fold lower than in the surrounding bone. To determine whether this expression is physiologically important, we studied skeletal growth in 7-wk-old mice lacking a functional p27 gene. In these mice, body length was modestly increased and proliferation of proximal tibial growth plate chondrocytes was increased, but tibia length was not significantly greater than in controls. p27 ablation had no measurable effect on growth plate morphology. Treatment with dexamethasone inhibited longitudinal bone growth similarly in p27-deficient mice and controls, indicating that p27 is not required for the inhibitory effects of glucocorticoids on longitudinal growth. p27-deficient mice had increased width of the femoral diaphysis, suggesting that p27 acts normally to inhibit periosteal bone growth. In conclusion, our findings suggest that p27 has modest inhibitory effects on growth plate chondrocyte proliferation but is not required for the spatial or temporal regulation of proliferation or the conditional regulation by glucocorticoid.

Depletion of resting zone chondrocytes during growth plate senescence.

With age, the growth plate undergoes senescent changes that cause linear bone growth to slow and finally cease. Based on previous indirect evidence, we hypothesized that this senescent decline occurs because growth plate stem-like cells, located in the resting zone, have a finite proliferative capacity that is gradually depleted. Consistent with this hypothesis, we found that the proliferation rate in rabbit resting zone chondrocytes (assessed by continuous 5-bromo-2'-deoxy-uridine labeling) decreases with age, as does the number of resting zone chondrocytes per area of growth plate. Glucocorticoid excess slows growth plate senescence. To explain this effect, we hypothesized that glucocorticoid inhibits resting zone chondrocyte proliferation, thus conserving their proliferative capacity. Consistent with this hypothesis, we found that dexamethasone treatment decreased the proliferation rate of rabbit resting zone chondrocytes and slowed the numerical depletion of these cells. Estrogen is known to accelerate growth plate senescence. However, we found that estradiol cypionate treatment slowed resting zone chondrocyte proliferation. Our findings support the hypotheses that growth plate senescence is caused by qualitative and quantitative depletion of stem-like cells in the resting zone and that growth-inhibiting conditions, such as glucocorticoid excess, slow senescence by slowing resting zone chondrocyte proliferation and slowing the numerical depletion of these cells, thereby conserving the proliferative capacity of the growth plate. We speculate that estrogen might accelerate senescence by a proliferation-independent mechanism, or by increasing the loss of proliferative capacity per cell cycle.