Background Cystic fibrosis (CF) is a multi-system disease that causes chronic respiratory failure, malnutrition and poor growth as a result of a negative energy balance due to maldigestion and malabsorption. Achieving linear growth and height above the 50 th percentile is associated with improved lung function. In October 2022, the use of Elexacaftor/Tezacaftor/Ivacaftor (ETI) was approved for children with CF from the age of 6 years. Analyses on the effect of ETI on height velocity (HV) are not usually available from trial and real life data and our work aims to study growth pattern by HV. A secondary aim was to check for any differences according to the CFTR variants severity. Methods We conducted a single-center prospective study at the CF Unit of the Bambino Gesù Children’s Hospital, including children aged 6-11 years who were eligible for ETI. The whole population of 24 people with CF (pwCF) underwent evaluation of height, weight, body mass index (BMI), bone mineral density (BMD), body composition analysis with bioelectrical impedance analysis (BIA), and muscle weakness using the one-minute sit-to-stand test (1STST) before starting the new drug. Height, weight, height velocity (HV), BMI standard deviation scores (SDS) were calculated for both 6 months before and 6 months after the start of ETI treatment. Results The mean age of the population was 8.7 years (SD 1.87), with a balanced gender distribution (F/M 12/12) and majority naïve to previous CFTR modulators. We found a significant difference in the growth rate achieved when comparing the calculated mean HV between T (-6 months) and T0 (4.2±2.0 cm/year; -1.96±2.4 SDS) with the HV between T0 and T (+6 months) (7.1±3.0 cm/year; +1.5±3.7 SDS) (p<0.0001). The group with F508del/minimal function mutations (F/MF) – 15 pwCF – had a higher average speed than those with homozygous F508del (F/F) – 5 pts – and those with F508del/residual function mutations (F/RF) – 4 pts – ( p< 0.0001). We found no significant differences in the three different genetic groups concerning BMD and initial lean mass. Conclusion The results highlight the benefit of ETI in the pediatric CF population, particularly by increasing the HV in children aged 6-11, especially those with the F/MF genotype. This study further emphasizes the impact of CFTR restoration on a fundamental aspect of the CF child’s well-being, growth.

Background: In Europe, Omalizumab (anti-IgE) is indicated for the treatment of moderate/severe asthma, but not for IgE-mediated food allergy (FA). Objective: We prospectively assessed the impact of Omalizumab for efficacy, safety, and quality of life (FA-QoL) in patients with moderate/severe asthma and history of anaphylaxis to peanut, tree nuts, fish, egg, milk, and/or wheat. Methods: Food-allergic children (6-18yrs) with moderate/severe asthma underwent oral food challenges (OFCs) to establish the threshold of reaction to the culprit food(s) at baseline (T0) and at four-month intervals (T1, T2, T3) during their first year of treatment with Omalizumab. We recorded the number and severity of food-allergic reactions, Asthma Control Test (ACT), FA-QoL, and total IgE. Results: In 65 patients allergic to 107 foods, the No Observed Adverse Events Level (NOAEL) at T1 increased: 243- and 488-fold for raw and baked milk, respectively; 172 and 134-fold for raw and baked egg; 245-fold for hazelnut; 55-fold for peanut; 31-fold for wheat, and 10-fold for fish. Full tolerance was achieved in 66.4% of OFCs at T1, 58.3% at T2, and 75% at T3. Ninety-five foods were liberalized ad libitum in the diet of 55 patients; the remaining 12 were introduced by 10 patients at least in traces. Throughout the study, 40/65 children got a free diet. ACT increased from 17 (Q1-Q3:15-17) to 23.6 (Q1-Q3:23-25). The FA-QoL score in children ≤ 12 years decreased from 4.63±0.74 to 2.02±1.13, in adolescents from 4.68±0.92 to 1.90±1.50. Conclusions: Omalizumab allows safe reintroduction of allergenic foods. Trial registration number: ClinicalTrials.gov, NCT06316414

Monitoring is a major component of asthma management in children. Regular monitoring allows for diagnosis confirmation, treatment optimization and natural history review. Numerous factors that may affect disease activity and patient wellbeing need to be monitored: response and adherence to treatment, disease control, disease progression, comorbidities, quality of life, medication side-effects, allergen and irritant exposures, diet and more. However, the prioritization of such factors and the selection of relevant assessment tools is an unmet need. Furthermore, rapidly developing technologies promise new opportunities for closer, or even ‘real-time’, monitoring between visits. Following an approach that included needs assessment, evidence appraisal and Delphi consensus, the PeARL Think Tank, in collaboration with major international professional and patient organizations, has developed a set of 24 recommendations on pediatric asthma monitoring, to support healthcare professionals in decision-making and care pathway design.

Background: We previously proposed the whey protein beta-lactoglobulin (BLG) loaded with iron-siderophore complexes as the active principle in the farm protective effect against allergies. A lozenge as food for specific medical purposes (FSMP) was formulated to assess its therapeutical efficacy in BALB/c mice and in-vitro experiments. Methods: Binding of iron-catechin into BLG was confirmed by spectroscopy and docking calculations. Serum IgE binding of children allergic to milk, or tolerating milk, was assessed to loaded (holo-) versus empty (apo-) BLG and for human mast cell degranulation. BLG and Bet v 1 double-sensitized mice were orally treated with the lozenge or placebo, and immunologically analysed after systemic allergen challenge. Human PBMCs of pollen allergic subjects were flow cytometrically assessed after stimulation with holoBLG in conjugation with catechin-iron complexes as ligands in a dietary supplement or with the apoBLG. Results: One major IgE- and T cell epitope were masked by catechin-iron complexes, which impaired IgE binding of milk allergic children and degranulation of mast cells. In mice, only supplementation with the lozenge reduced clinical reactivity to BLG and Bet v 1, promoted Tregs, and suppressed antigen presentation. In allergic subjects, stimulation of PBMCs with holoBLG led to a significant increase of intracellular iron in circulating CD14+ cells with significantly lower expression of HLADR and CD86 compared to their stimulation with apoBLG. Conclusion: The FSMP lozenge targeted antigen presenting cells and dampened immune activation in human immune cells and allergic mice in an antigen nonspecific manner, thereby conferring immune resilience against allergic symptoms.

Background. The use of eliciting doses (EDs) for food allergens is necessary to inform individual dietary advice and food allergen risk-management. The Eliciting Dose 01 (ED01) for milk and egg, calculated from populations of allergic subjects undergoing diagnostic Oral Food Challenges (OFCs), are 0.2 mg total protein. The respective Eliciting Dose 05 (ED05) are 2.4 mg for milk and 2.3 mg for egg. As about 70% children allergic to such foods may tolerate them when baked, we sought to verify the EDs of that subpopulation of milk and egg-allergic children. Methods. We retrospectively assessed consecutive diagnostic OFC for fresh milk and egg between January 2018 and December 2020 in a population of baked food-tolerant children. Results. Among 288 children (median age 56 - IQR 36-92.5 months, 67.1% male) included, 87 (30.2%) returned positive OFC results, 38 with milk and 49 with egg. The most conservative ED01 were 0.3 mg total protein (IQR 0.03-2.9) for milk and 14.4 mg total protein (IQR 3.6-56.9) for egg. The respective ED05 were 4.2 (IQR 0.9-19.6) mg for milk and 87.7 (IQR 43-179) mg for egg. Such thresholds are respectively 1.5 (milk ED01), 1.75 (milk ED05), 72 (egg ED01), and 38.35 (egg ED05) times higher than the currently used thresholds. Conclusions The subpopulation of children allergic to milk and egg, but tolerant to baked proteins, displays higher reactivity thresholds than the general population of children allergic to milk and egg. Their risk stratification, in both individual and population terms, should consider this difference. In baked milk-tolerant children, milk causes reactions at lower doses than egg in our group of egg-tolerant children. This could be associated with the relative harmlessness of egg compared to milk in the determinism of fatal anaphylactic reactions in children

The effect of COVID-19 imposed lockdown on Italian children with Vernal Keratoconjunctivitis

Background There is substantial interest in allergen-specific immunotherapy in food allergy. We systematically reviewed its efficacy and safety. Methods We searched six bibliographic databases from 1946 to 30 April 2021 for randomised controlled trials about immunotherapy alone or with biologicals in IgE-mediated food allergy confirmed by oral food challenge. We pooled the data using random-effects meta-analysis. Results We included 36 trials with 2,126 participants, mainly children. Oral immunotherapy increased tolerance whilst on therapy for peanut (RR 9.9, 95% CI 4.5. to 21.4, high certainty); cow’s milk (RR 5.7, 1.9 to 16.7, moderate certainty) and hen’s egg allergy (RR 8.9, 4.4 to 18, moderate certainty). The number needed to treat to increase tolerance to a single dose of 300mg or 1000mg peanut protein was 2. In peanut allergy, oral immunotherapy did not increase adverse reactions (RR 1.1, 1.0 to 1.2, low certainty) or severe reactions (RR 1,6, 0.7 to 3.5, low certainty). It may increase adverse reactions in cow’s milk (RR 3.9, 2.1 to 7.5, low certainty) and hen’s egg allergy (RR 7.0, 2.4 to 19.8, moderate certainty), but reactions tended to be mild and gastrointestinal. Epicutaneous immunotherapy increased tolerance whilst on therapy for peanut (RR 2.6, 1.8 to 3.8, moderate certainty). Results were unclear for other allergies and administration routes. Conclusions Oral immunotherapy improves tolerance whilst on therapy and is probably safe in peanut, cow’s milk and hen’s egg allergy. However, our review found little about whether this improves quality of life, is sustained or cost-effective.

Background: The interplay between COVID-19 pandemic and asthma in children is still unclear. We evaluated the impact of COVID-19 on childhood asthma outcomes. Methods: The PeARL multinational cohort included 1,054 children with asthma and 505 non-asthmatic children aged between 4-18 years from 25 pediatric departments, from 15 countries globally. We compared the frequency of acute respiratory and febrile presentations during the first wave of the COVID-19 pandemic between groups and with data available from the previous year. In children with asthma, we also compared current and historical disease control. Results: During the pandemic, children with asthma experienced fewer upper respiratory tract infections, episodes of pyrexia, emergency visits, hospital admissions, asthma attacks and hospitalizations due to asthma, in comparison to the preceding year. Sixty-six percent of asthmatic children had improved asthma control while in 33% the improvement exceeded the minimal clinically important difference. Pre-bronchodilatation FEV1 and peak expiratory flow rate were improved during the pandemic. When compared to non-asthmatic controls, children with asthma were not at increased risk of LRTIs, episodes of pyrexia, emergency visits or hospitalizations during the pandemic. However, an increased risk of URTIs emerged. Conclusion: Childhood asthma outcomes, including control, were improved during the first wave of the COVID-19 pandemic, probably because of reduced exposure to asthma triggers and increased treatment adherence. The decreased frequency of acute episodes does not support the notion that childhood asthma may be a risk factor for COVID-19. Furthermore, the potential for improving childhood asthma outcomes through environmental control becomes apparent.