Diagnosing new-onset asthma in a paediatric clinical trial setting in school-age children.

Asthma is a common chronic disease in children. It is a dynamic condition-symptoms change over time, and the outcome of diagnostic tests can vary. Consequently, evaluating the onset of asthma at a single point in time, perhaps when patients are asymptomatic with limited impairment of the lung function, may result in false diagnostic conclusions. The absence of consistent gold-standard diagnostic criteria in children challenges the ability of any study to ascertain an effect of treatment on asthma prevention. A comprehensive review of the diagnostic criteria used for new-onset asthma in school-age children was conducted based on existing recommendations from published clinical guidance, alongside evidence from paediatric asthma prevention trials. Findings from the review were used to propose suggestions for diagnosing new-onset asthma in future asthma prevention trials. Despite an overall lack of consensus in the published clinical guidance, there are similarities between the various recommendations for diagnosing asthma in children, which typically involve assessing the variable symptoms and supplementing the medical history with objective measures of lung function. For future paediatric asthma prevention trials, we suggest that paediatric clinical trials should use a new-onset asthma definition that incorporates the concepts of "possible", "probable" and "confirmed" asthma. "Possible" asthma would capture self-reported features of chronic symptoms and symptom relief with ß2-agonist bronchodilator (suggesting reversibility). "Probable" asthma would include symptom chronicity, self-reported symptom relief with ß2-agonist bronchodilator, and objective features of asthma (reversibility or bronchial hyper-responsiveness). A "confirmed" diagnosis would be made only if there is a positive response to controller therapy. These suggestions aim to improve the diagnosis of new-onset childhood asthma in clinical trials, which will be useful in the design and conduct of future paediatric asthma prevention trials.

Quality of life in congenital diaphragmatic hernia survivors treated at a non-ECMO centre from 1998 to 2015: a cross-sectional study.

BACKGROUND: Survival of infants with congenital diaphragmatic hernia (CDH) has increased and more insight is warranted on the long-term issues of this condition. METHODS: We conducted a cross-sectional study on consecutively born infants with CDH treated at a non-extracorporeal membrane oxygenation centre (ECMO) from 1998 to 2015. Quality of life was evaluated using the Pediatric Quality of Life Inventory Generic Core Scale 4.0 (PedsQL(4.0)) Questionnaire and an interview was conducted to assess for CDH-related morbidity. RESULTS: 71 eligible CDH survivors were identified and 51 consented to participate: aged 5-21 years, 28 (54.9%) male, 42 (82.4%) with left-sided hernias, 10 (19.6%) needed patch repair, median length of stay in hospital was 27.96 days (IQR 18.54-61.56). Forty-nine completed the questionnaire with a median PedsQL total score for participants of 82.6 vs 83.7 of the total proxy parent score (p=0.04). Total score was significantly lower for participants aged 5-12 years compared with participants aged 13-21 years (p=0.04); however, when reported by domains, only the physical score remained significantly lower (p=0.048). Two (4.1%) participants' and 8 (16.7%) proxy parents' scores were below 70 and considered at risk of impaired quality of life. We identified the presence of CDH-related morbidity in our population, and confirmed an association between respiratory morbidity and lower PedsQL scores (p=0.04). CONCLUSION: We report an overall good quality of life in our population with CDH. However, a lower physical score was noted when compared with a national Danish cohort and individuals at risk of reduced quality of life were recognised. Structured follow-up programmes to identify and ensure early management of CDH-related issues may prevent a negative impact on quality of life.

Prevention Is Better than Cure: Impact of Allergen Immunotherapy on the Progression of Airway Disease.

Allergen immunotherapy is highly effective for seasonal pollinosis. Three years of treatment results in long-term efficacy. This disease modification is accompanied by downregulation of allergen-specific Th2 responses and the induction of persistent specific IgG- and IgA-associated IgE-blocking activity. In children with seasonal rhinitis, both subcutaneous and sublingual pollen immunotherapy have been shown to reduce the development of asthma symptoms and asthma medication requirements. House dust mite tablet allergen immunotherapy has been shown to be effective for perennial mite-driven rhinitis in adults and children and may suppress asthma exacerbations, whereas its long-term efficacy has yet to be explored. The success of primary prevention of peanut allergy in childhood by introduction of peanut into the diet during infancy provides a strong rationale to explore whether primary prevention of inhalant allergies and asthma may also be possible. House dust mite allergy is a major risk factor for developing asthma. Preliminary data in at-risk children suggest that sublingual house dust mite immunotherapy initiated during infancy could reduce the onset of multiple allergen sensitizations and prevent the development of asthma at age 6 years. This possibility should now be explored in an adequately powered, prospectively randomized controlled trial.

Real-Life Adherence to Venom Immunotherapy and Adrenaline Autoinjector.

INTRODUCTION: Venom immunotherapy (VIT) and adrenaline autoinjector (AAI) are important therapies in venom anaphylaxis. Adherence to VIT and AAI in patients with venom allergy has been evaluated in a few studies; however, solid data are lacking. This study aimed to evaluate VIT and AAI retrieval rates in patients with venom allergy with a special focus on adherence to treatment. Adherence was compared to subcutaneous immunotherapy (SCIT) with inhalant allergens. METHODS: This was a retrospective study among patients registered for allergen immunotherapy at the Allergy Center, Odense University Hospital, Denmark, from January 1, 2010, to December 31, 2014. Data on purchased immunotherapy and AAI were obtained from the Danish National Health Service Prescription Database. Multivariable logistic regression was used to analyze if allergen, age, sex, mastocytosis, and treatment site affected adherence. RESULTS: The 3-year adherence to VIT was 92.4% (244/264) compared to 87.4% (215/246) in SCIT with inhalant allergens, and the 5-year adherence to VIT was 84.1% (222/264) compared to 74.8% (184/246) in SCIT with inhalant allergens (p = 0.045). Females treated with VIT were more adherent than males (p = 0.45 [3-year], p = 0.008 [5-year]), whereas allergen, age, mastocytosis, or treatment site did not significantly affect adherence. Only 28.6% of patients (12/42) purchased an AAI after premature termination of VIT. CONCLUSION: In this register-based study, we found that the 3- and 5-year adherences to VIT and SCIT with inhalant allergens are at the upper end of the spectrum hitherto reported. Patients' 5-year adherence to VIT was higher than patients' 5-year adherence to SCIT with inhalant allergens. If VIT was prematurely terminated, less than 1/3 would have purchased an AAI.

EAACI guidelines on the diagnosis of IgE-mediated food allergy.

This European Academy of Allergy and Clinical Immunology guideline provides recommendations for diagnosing IgE-mediated food allergy and was developed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Food allergy diagnosis starts with an allergy-focused clinical history followed by tests to determine IgE sensitization, such as serum allergen-specific IgE (sIgE) and skin prick test (SPT), and the basophil activation test (BAT), if available. Evidence for IgE sensitization should be sought for any suspected foods. The diagnosis of allergy to some foods, such as peanut and cashew nut, is well supported by SPT and serum sIgE, whereas there are less data and the performance of these tests is poorer for other foods, such as wheat and soya. The measurement of sIgE to allergen components such as Ara h 2 from peanut, Cor a 14 from hazelnut and Ana o 3 from cashew can be useful to further support the diagnosis, especially in pollen-sensitized individuals. BAT to peanut and sesame can be used additionally. The reference standard for food allergy diagnosis is the oral food challenge (OFC). OFC should be performed in equivocal cases. For practical reasons, open challenges are suitable in most cases. Reassessment of food allergic children with allergy tests and/or OFCs periodically over time will enable reintroduction of food into the diet in the case of spontaneous acquisition of oral tolerance.

Early Pre- and Postoperative Enteral Nutrition and Growth in Infants with Symptomatic Congenital Diaphragmatic Hernia.

OBJECTIVES: Nutritional support during the neonatal and postoperative period in congenital diaphragmatic hernia (CDH) is challenging and controversial. We aimed to report on early enteral nutritional support in symptomatic CDH patients during the pre- and postoperative period, including feasibility, associated factors with established full enteral nutrition, and weight at birth, discharge, and 18 months. METHODS: We retrospectively collected data on nutrition: type and volume of enteral nutrition and parental support. Enteral feeding was introduced preoperatively from day 1 after birth, increased step-wised (breastmilk preferred), and resumed after CDH repair on the first postoperative day. Baseline data were available from our CDH database. RESULTS: From 2011 to 2020, we identified 45 CDH infants. Twenty-two were girls (51.1%), 35 left sided (77.8%), and 40 underwent CDH repair (88.9%). Median (interquartile range) length of stay in the pediatric intensive care unit was 14.6 days (6.0-26.5), and 1-year mortality was 17.8%.Postoperatively, 120 and 160 mL/kg/d of enteral nutrition was achieved after a median of 6.5 (3.6-12.6) and 10.6 (7.6-21.7) days, respectively. In total, 31 (68.9%) needed supplemental parenteral nutrition in a median period of 8 days (5-18), and of those 11 had parenteral nutrition initiated before CDH repair. No complications to enteral feeding were reported. CONCLUSION: Early enteral nutrition in CDH infants is feasible and may have the potential to reduce the need for parental nutrition and reduce time to full enteral nutrition in the postoperative period.

Managing food allergy: GA2LEN guideline 2022.

Food allergy affects approximately 2-4% of children and adults. This guideline provides recommendations for managing food allergy from the Global Allergy and Asthma European Network (GA2LEN). A multidisciplinary international Task Force developed the guideline using the Appraisal of Guidelines for Research and Evaluation (AGREE) II framework and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We reviewed the latest available evidence as of April 2021 (161 studies) and created recommendations by balancing benefits, harms, feasibility, and patient and clinician experiences. We suggest that people diagnosed with food allergy avoid triggering allergens (low certainty evidence). We suggest that infants with cow's milk allergy who need a breastmilk alternative use either hypoallergenic extensively hydrolyzed cow's milk formula or an amino acid-based formula (moderate certainty). For selected children with peanut allergy, we recommend oral immunotherapy (high certainty), though epicutaneous immunotherapy might be considered depending on individual preferences and availability (moderate certainty). We suggest considering oral immunotherapy for children with persistent severe hen's egg or cow's milk allergy (moderate certainty). There are significant gaps in evidence about safety and effectiveness of the various strategies. Research is needed to determine the best approaches to education, how to predict the risk of severe reactions, whether immunotherapy is cost-effective and whether biological therapies are effective alone or combined with allergen immunotherapy.

IQ Was Not Improved by Post-Discharge Fortification of Breastmilk in Very Preterm Infants.

(1) Very preterm infants are at increased risk of cognitive deficits, motor impairments, and behavioural problems. Studies have tied insufficient nutrition and growth to an increased risk of neurodevelopmental impairment; (2) Methods: Follow-up study on cognitive and neuropsychological development at 6 years corrected age (CA) in 214 very preterm infants, including 141 breastfed infants randomised to mother's own milk (MOM) with (F-MOM) or without (U-MOM) fortification and 73 infants fed a preterm formula (PF-group), from shortly before discharge to 4 months CA. Infants with serious congenital anomalies or major neonatal morbidities were excluded prior to intervention. The Wechsler Intelligence Scale for Children IV was used for cognitive testing, and the children's parents completed the Five to Fifteen Questionnaire (FTF); (3) Results: Post-discharge fortification of MOM did not improve either full-scale intelligence quotient (FSIQ) with a median of 104 vs. 105.5 (p = 0.29), subdomain scores, or any domain score on the FTF questionnaire. Compared to the PF group, the MOM group had significantly better verbal comprehension score with a median of 110 vs. 106 (p = 0.03) and significantly better motor skills scores on the FTF questionnaire (p = 0.01); (4) Conclusions: The study supports breastfeeding without fortification as post-discharge nutrition in very preterm infants, and it seems superior to preterm formula.

Biomarkers in asthma in the context of atopic dermatitis in young children.

BACKGROUND: Diverse pathways stemming from a history of atopic dermatitis (AD) might modulate different biomarkers associated with the development of asthma. Biomarkers associated with AD and asthma separately have been investigated, but none have characterized a combined AD+asthma phenotype. We investigated the clinical and molecular characteristics associated with an AD+asthma phenotype compared with AD, asthma and controls. METHODS: From a prospective birth cohort and the outpatient allergy clinic, we included four groups of 6-12-year-old children: (1) healthy controls (2) previous, current, or present AD without asthma, (3) previous, current, or present AD and current asthma and (4) current asthma without AD. We performed clinical examinations and interviews and measured serum IgE, natural moisturizing factors (NMF), and plasma cytokine levels. RESULTS: We found an increased number of IgE sensitizations in AD+asthma, prominent after stratifying for food allergens (p < .05). Pro-Th2 cytokines CCL18, TSLP, and Eotaxin-3 were elevated in AD+asthma, though not significantly higher than asthma, and elevated in asthma compared with controls. NMF levels were decreased in AD compared with asthma and control groups (p = .019, p < .001, respectively). NMF levels correlated negatively to sensitization (p = .026), though nonsignificant with only the patient groups. CONCLUSION: Our results indicate that Th2 cytokines and increased number of sensitizations are associated with AD + asthma phenotypes compared with AD alone and that skin barrier impairment as well as decreased airway epithelial integrity may play a role in sensitization and immune modulation. Our findings suggest candidate biomarkers that should be further explored for their functional roles and prognostic potential.

Early priming of asthma and respiratory allergies: Future aspects of prevention: A statement by the European Forum for Education and Research in Allergy and Airway Disease (EUFOREA) and the EAACI-Clemens von Pirquet Foundation.

In order to summarize recent research on the prevention of allergies-particularly asthma-and stimulate new activities for future initiatives, a virtual workshop sponsored by the EAACI Clemens von Pirquet foundation and EUFOREA was held in October 2021. The determinants of the "allergic march" as well as the key messages from intervention studies were reviewed by an international faculty of experts. Several unmet needs were identified, and a number of priorities for future studies were proposed.

Risk factors for severe reactions in food allergy: Rapid evidence review with meta-analysis.

This rapid review summarizes the most up to date evidence about the risk factors for severe food-induced allergic reactions. We searched three bibliographic databases for studies published between January 2010 and August 2021. We included 88 studies and synthesized the evidence narratively, undertaking meta-analysis where appropriate. Significant uncertainties remain with respect to the prediction of severe reactions, both anaphylaxis and/or severe anaphylaxis refractory to treatment. Prior anaphylaxis, an asthma diagnosis, IgE sensitization or basophil activation tests are not good predictors. Some molecular allergology markers may be helpful. Hospital presentations for anaphylaxis are highest in young children, yet this age group appears at lower risk of severe outcomes. Risk of severe outcomes is greatest in adolescence and young adulthood, but the contribution of risk taking behaviour in contributing to severe outcomes is unclear. Evidence for an impact of cofactors on severity is lacking, although food-dependent exercise-induced anaphylaxis may be an exception. Some medications such as beta-blockers or ACE inhibitors may increase severity, but appear less important than age as a factor in life-threatening reactions. The relationship between dose of exposure and severity is unclear. Delays in symptom recognition and anaphylaxis treatment have been associated with more severe outcomes. An absence of prior anaphylaxis does not exclude its future risk.

Association of serum surfactant protein D and SFTPD gene variants with asthma in Danish children, adolescents, and young adults.

BACKGROUND: Surfactant Protein D (SP-D) is a pattern recognition molecule belonging to the family of collectins expressed in multiple human organ systems, including the lungs. Previous studies have shown that SP-D levels in bronchoalveolar lavage samples decrease and serum levels increase in patients suffering from asthma, possibly due to a combination of induced SP-D synthesis and decreased air-blood barrier integrity. The aims of this study were to investigate whether serum levels of SP-D and common variants in the SP-D gene were associated with asthma in adolescents and young adults. METHODS: Prospective observational study including 449 adolescents and young adults (age 11-27 years) previously diagnosed with asthma during a 2-year period from 2003 to 2005 (0-16 years). At follow-up from 2016 to 2017, 314 healthy controls with no history of asthma were recruited. Serum SP-D was analyzed on samples obtained at baseline as well as samples obtained at follow-up. SP-D genotyping was performed for rs721917, rs2243639, and rs3088308. RESULTS: No differences were found in mean levels of sSP-D and SFTPD genotype among subjects with current asthma, no current asthma, and controls. Serum SP-D and SFTPD genotype were not associated with any clinical parameters of asthma. Furthermore, baseline sSP-D was not associated with asthma at follow-up. CONCLUSION: Serum surfactant protein D and common SP-D gene variants were not associated with asthma in Danish adolescents and young adults with mild to moderate asthma. Serum surfactant protein D did not demonstrate any value as a clinical biomarker of asthma.

EAACI guidelines: Anaphylaxis (2021 update).

Anaphylaxis is a clinical emergency which all healthcare professionals need to be able to recognize and manage. The European Academy of Allergy and Clinical Immunology Anaphylaxis multidisciplinary Task Force has updated the 2014 guideline. The guideline was developed using the AGREE II framework and the GRADE approach. The evidence was systematically reviewed and recommendations were created by weighing up benefits and harms. The guideline was peer-reviewed by external experts and reviewed in a public consultation. The use of clinical criteria to identify anaphylaxis is suggested with blood sampling for the later measurement of tryptase. The prompt use of intramuscular adrenaline as first-line management is recommended with the availability of adrenaline autoinjectors to patients in the community. Pharmacokinetic data should be provided for adrenaline autoinjector devices. Structured, comprehensive training for people at risk of anaphylaxis is recommended. Simulation training and visual prompts for healthcare professionals are suggested to improve the management of anaphylaxis. It is suggested that school policies reflect anaphylaxis guidelines. The evidence for the management of anaphylaxis remains mostly at a very low level. There is an urgent need to prioritize clinical trials with the potential to improve the management of patients at risk of anaphylaxis.

Partially Hydrolysed Whey Has Superior Allergy Preventive Capacity Compared to Intact Whey Regardless of Amoxicillin Administration in Brown Norway Rats.

Background: It remains largely unknown how physicochemical properties of hydrolysed infant formulas influence their allergy preventive capacity, and results from clinical and animal studies comparing the preventive capacity of hydrolysed infant formula with conventional infant formula are inconclusive. Thus, the use of hydrolysed infant formula for allergy prevention in atopy-prone infants is highly debated. Furthermore, knowledge on how gut microbiota influences allergy prevention remains scarce. Objective: To gain knowledge on (1) how physicochemical properties of hydrolysed whey products influence the allergy preventive capacity, (2) whether host microbiota disturbance influences allergy prevention, and (3) to what extent hydrolysed whey products influence gut microbiota composition. Methods: The preventive capacity of four different ad libitum administered whey products was investigated in Brown Norway rats with either a conventional or an amoxicillin-disturbed gut microbiota. The preventive capacity of products was evaluated as the capacity to reduce whey-specific sensitisation and allergic reactions to intact whey after intraperitoneal post-immunisations with intact whey. Additionally, the direct effect of the whey products on the growth of gut bacteria derived from healthy human infant donors was evaluated by in vitro incubation. Results: Two partially hydrolysed whey products with different physicochemical characteristics were found to be superior in preventing whey-specific sensitisation compared to intact and extensively hydrolysed whey products. Daily oral amoxicillin administration, initiated one week prior to intervention with whey products, disturbed the gut microbiota but did not impair the prevention of whey-specific sensitisation. The in vitro incubation of infant faecal samples with whey products indicated that partially hydrolysed whey products might confer a selective advantage to enterococci. Conclusions: Our results support the use of partially hydrolysed whey products for prevention of cow's milk allergy in atopy-predisposed infants regardless of their microbiota status. However, possible direct effects of partially hydrolysed whey products on gut microbiota composition warrants further investigation.

Preventive Effect of Allergen Immunotherapy on Asthma and New Sensitizations.

Allergen immunotherapy (AIT) is a disease-modifying treatment for some IgE-mediated allergic diseases with the potential to have important preventive effects. Children with allergic rhinitis have a high risk of developing asthma, and treating allergic rhinitis with AIT may interfere with disease progression and prevent onset of asthma. Although the evidence is limited due to relatively few and heterogeneous studies, data nevertheless suggest that AIT has a preventive effect on development of asthma especially in children with rhinitis due to grass pollen allergy. AIT may also affect the development of new sensitizations. Both the degree of sensitization and the specific sensitization pattern may influence future disease severity and development of comorbidities. Hitherto, the indication for AIT for prevention of development of asthma in grass/birch pollen allergic children has been the same as for treatment of allergic rhinitis. Probably, AIT should be applied in the early stage of the allergic disease to have the greatest preventive effect on disease progression. Consequently, in the future, the potential preventive effects should influence the timing of initiating AIT. The window of opportunity to prevent asthma may primarily exist in young children with mild symptoms and a low degree of sensitization.

EAACI guideline: Preventing the development of food allergy in infants and young children (2020 update).

BACKGROUND: This guideline from the European Academy of Allergy and Clinical Immunology (EAACI) recommends approaches to prevent the development of immediate-onset / IgE-mediated food allergy in infants and young children. It is an update of a 2014 EAACI guideline. METHODS: The guideline was developed using the AGREE II framework and the GRADE approach. An international Task Force with representatives from 11 countries and different disciplinary and clinical backgrounds systematically reviewed research and considered expert opinion. Recommendations were created by weighing up benefits and harms, considering the certainty of evidence and examining values, preferences and resource implications. The guideline was peer-reviewed by external experts, and feedback was incorporated from public consultation. RESULTS: All of the recommendations about preventing food allergy relate to infants (up to 1 year) and young children (up to 5 years), regardless of risk of allergy. There was insufficient evidence about preventing food allergy in other age groups. The EAACI Task Force suggests avoiding the use of regular cow's milk formula as supplementary feed for breastfed infants in the first week of life. The EAACI Task Force suggests introducing well-cooked, but not raw egg or uncooked pasteurized, egg into the infant diet as part of complementary feeding. In populations where there is a high prevalence of peanut allergy, the EAACI Task Force suggests introducing peanuts in an age-appropriate form as part of complementary feeding. According to the studies, it appears that the most effective age to introduce egg and peanut is from four to 6 months of life. The EAACI Task Force suggests against the following for preventing food allergy: (i) avoiding dietary food allergens during pregnancy or breastfeeding; and (ii) using soy protein formula in the first 6 months of life as a means of preventing food allergy. There is no recommendation for or against the following: use of vitamin supplements, fish oil, prebiotics, probiotics or synbiotics in pregnancy, when breastfeeding or in infancy; altering the duration of exclusive breastfeeding; and hydrolysed infant formulas, regular cow's milk-based infant formula after a week of age or use of emollients. CONCLUSIONS: Key changes from the 2014 guideline include suggesting (i) the introduction of peanut and well-cooked egg as part of complementary feeding (moderate certainty of evidence) and (ii) avoiding supplementation with regular cow's milk formula in the first week of life (low certainty of evidence). There remains uncertainty in how to prevent food allergy, and further well-powered, multinational research using robust diagnostic criteria is needed.