Tolerance development in cow's milk-allergic children receiving amino acid-based formula with synbiotics: 36-Months follow-up of a randomized controlled trial (PRESTO Study).

The objective of the present study is to assess the rates of acquired tolerance to cow's milk (CM) after 36 months in subjects who consumed amino acid-based formula with synbiotics (AAF-S) or amino acid-based formula without synbiotics (AAF) during a 1-year intervention period in early life as part of the PRESTO study (Netherlands Trial Register number NTR3725). Differences in CM tolerance development between groups were analysed using a logistic regression model. Results show that the proportion of subjects (mean [±SD] age, 3.8 ± 0.27 years) who developed CM tolerance after 36 months was similar in the group receiving AAF-S (47/60 [78%]) and in the group receiving AAF (49/66 [74%]) (p = 0.253), that is, figures comparable to natural outgrowth of CM allergy. Our data suggest that the consumption of AAF and absence of exposure to CM peptides do not slow down CM tolerance acquisition.

A real-world retrospective observational study exploring NHS resource use in England for the management of moderate-to-severe atopic dermatitis in secondary care for children and adolescents.

PURPOSE: To describe secondary care health care resource utilization (HCRU) for children and adolescents with atopic dermatitis (AD). PATIENTS AND METHODS: This UK chart review of patients with moderate-to-severe AD was conducted in four National Health Service hospitals. Cohorts were defined by age (children 6-11 years, adolescents 12-17) at first consultation. Eligible patients were selected consecutively, starting with the most recently consulting patient. At least 12 months' data were abstracted from medical records. Data were collected on HCRU, demographics/clinical characteristics, treatment, and patient-reported outcomes. RESULTS: Data were abstracted for 55 patients. Most patients (80%) had severe AD at first referral, a mean (SD) of 3.2 (10.7) patient-reported flare episodes/patient/year-of-observation, and 18.5 (16.7) tests/scans/procedures/patient/year. Mean (SD) observation duration was 3.6 (1.8) years. Patients had tried mean (SD) 7.9 (5.3) treatments/patient/year of observation. Topical corticosteroids (TCS; 24.5% of prescriptions) were most frequently prescribed. Mean (SD) use of emollients/moisturizers, TCS, systemic corticosteroids, and systemic immunosuppressants was 30.9 (21.3), 21.1 (23.4), 1.7 (8.3), and 7.8 (8.2) months. There was a mean (SD) of 5.3 (2.9) consultations/patient/year-of-observation; 116 (10.7%) for flare. Most hospitalizations (87.5%) were for children; the 8/55 (15%) hospitalized patients (mean 2.0 hospitalizations/patient during observation period) spent 6.2 (SD: 5.1) nights in hospital/hospitalization. Earliest mean (SD) Children's Dermatology Life Quality Index score was 15.3 (7.2); latest was 12.9 (7.5). CONCLUSION: Children and adolescents with moderate-to-severe AD had a high HCRU burden and small changes in quality of life, indicating that current treatments may provide suboptimal AD control in most cases.

Mixed Milk Feeding: A New Approach to Describe Feeding Patterns in the First Year of Life Based on Individual Participant Data from Two Randomised Controlled Trials.

'Mixed Milk Feeding' (MMF), whereby infants are fed with both breastmilk and infant formula during the same period, is a common feeding practice. Despite its high prevalence, knowledge regarding MMF practices and their association with (health) outcomes is limited, potentially because MMF behaviours are highly variable and difficult to standardise longitudinally. In this paper, we applied a statistical clustering algorithm on individual infant feeding data collected over the first year of life from two clinical trials: 'TEMPO' (n = 855) and 'Venus' (n = 539); these studies were conducted in different years and world regions. In TEMPO, more than half of infants were MMF. Four distinct MMF clusters were identified: early exclusive formula feeding (32%), later exclusive formula feeding (25%), long-term MMF (21%), and mostly breastfeeding (22%). The same method applied to 'Venus' resulted in comparable clusters, building trust in the robustness of the cluster approach. These results demonstrate that distinct MMF patterns can be identified, which may be applicable to diverse populations. These insights could support the design of future research studying the impact of infant feeding patterns on health outcomes. To standardise this in future research, it is important to establish a unified definition of MMF.

Clinical spectrum of paediatric and adult eosinophilic oesophagitis in the North East of England from 2016 to 2019.

Background and study aims: Eosinophilic oesophagitis (EoE) is a common disease with a significant impact on physical health and quality of life (QoL). Outcomes and management vary widely, with no agreed UK national guideline. This paper aims to describe an up-to-date description of demographics, clinical spectrum and outcomes for paediatric and adult patients with EoE from the North East of England between 2016 and 2019. Patients and methods: Patients from two large University Hospitals and the specialist paediatric hospital for the North East of England with histologically or clinically confirmed EoE were included in this analysis. Data were collected retrospectively via electronic patient records. Remission was defined as either the resolution of symptoms or improvement on histology. Results: Data were collected on 74 paediatric and 59 adult patients. Dysphagia was the most common presenting symptom in both groups, accounting for 51%-84% of all presentations. Proton pump inhibitors and dietary manipulation were the most common therapies associated with remission in children (95% of those achieving remission), whereas the use of swallowed topical steroids was more prevalent in the treatment of adults (55% achieving remission). Conclusions: EoE is a complex disease and poses significant challenges. Outcomes vary widely and need to be tailored to individual patient groups. Dietary manipulation plays a major role in treatment for EoE, but this is likely to be challenging for patients, especially children. Future work should continue to assess the outcomes in EoE, including on QoL and potential novel targeted therapies.

Tolerance development in cow's milk-allergic infants receiving amino acid-based formula: A randomized controlled trial.

BACKGROUND: Tolerance development is an important clinical outcome for infants with cow's milk allergy. OBJECTIVE: This multicenter, prospective, randomized, double-blind, controlled clinical study (NTR3725) evaluated tolerance development to cow's milk (CM) and safety of an amino acid-based formula (AAF) including synbiotics (AAF-S) comprising prebiotic oligosaccharides (oligofructose, inulin) and probiotic Bifidobacterium breve M-16V in infants with confirmed IgE-mediated CM allergy. METHODS: Subjects aged ≤13 months with IgE-mediated CM allergy were randomized to receive AAF-S (n = 80) or AAF (n = 89) for 12 months. Stratification was based on CM skin prick test wheal size and study site. After 12 and 24 months, CM tolerance was evaluated by double-blind, placebo-controlled food challenge. A logistic regression model used the all-subjects randomized data set. RESULTS: At baseline, mean ± SD age was 9.36 ± 2.53 months. At 12 and 24 months, respectively, 49% and 62% of subjects were CM tolerant (AAF-S 45% and 64%; AAF 52% and 59%), and not differ significantly between groups. During the 12-month intervention, the number of subjects reporting at least 1 adverse event did not significantly differ between groups; however, fewer subjects required hospitalization due to serious adverse events categorized as infections in the AAF-S versus AAF group (9% vs 20%; P = .036). CONCLUSIONS: After 12 and 24 months, CM tolerance was not different between groups and was in line with natural outgrowth. Results suggest that during the intervention, fewer subjects receiving AAF-S required hospitalization due to infections.

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.

Characterising the allergic profile of children with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a genetic condition that affects multiple organ systems. Allergic bronchopulmonary aspergillosis (ABPA) is a well-recognised problem but other allergic conditions are less well documented in CF. OBJECTIVE: To characterise the allergic profile of a cohort of children with CF, with a focus on those with ABPA. METHODS: A cohort of children with CF were interviewed and retrospective data were collected regarding their allergic histories and other relevant clinical features. RESULTS: The cohort included 37 children with median age of 9 years (interquartile range: 6-12). There was a history of ≥1 allergic condition(s) in 28/37 children (76%). The most common allergic condition was allergic rhinitis (AR) in 21/37 (57%) and 16 of these 21 children (76%) had another allergic condition. All children with ABPA (8) had another allergic condition. In some children ABPA exacerbations appeared to be seasonal, suggesting possible cross-sensitisation between Aspergillus fumigatus and aeroallergens associated with seasonal AR. Allergic conditions were also common in children with Pseudomonas aeruginosa infection.

Diagnosing, managing and preventing anaphylaxis: Systematic review.

BACKGROUND: This systematic review used the GRADE approach to compile evidence to inform the European Academy of Allergy and Clinical Immunology's (EAACI) anaphylaxis guideline. METHODS: We searched five bibliographic databases from 1946 to 20 April 2020 for studies about the diagnosis, management and prevention of anaphylaxis. We included 50 studies with 18 449 participants: 29 randomized controlled trials, seven controlled clinical trials, seven consecutive case series and seven case-control studies. Findings were summarized narratively because studies were too heterogeneous to conduct meta-analysis. RESULTS: It is unclear whether the NIAID/FAAN criteria or Brighton case definition are valid for immediately diagnosing anaphylaxis due to the very low certainty of evidence. There was also insufficient evidence about the impact of most anaphylaxis management and prevention strategies. Adrenaline is regularly used for first-line emergency management of anaphylaxis but little robust research has assessed its effectiveness. Newer models of adrenaline autoinjectors may slightly increase the proportion of people correctly using the devices and reduce time to administration. Face-to-face training for laypeople may slightly improve anaphylaxis knowledge and competence in using autoinjectors. We searched for but found little or no comparative effectiveness evidence about strategies such as fluid replacement, oxygen, glucocorticosteroids, methylxanthines, bronchodilators, management plans, food labels, drug labels and similar. CONCLUSIONS: Anaphylaxis is a potentially life-threatening condition but, due to practical and ethical challenges, there is a paucity of robust evidence about how to diagnose and manage it.

A survey of school's preparedness for managing anaphylaxis in pupils with food allergy.

Allergic diseases are on the increase and can affect the child's well-being. The aim of this survey was to assess regional schools' preparedness in dealing with anaphylaxis following the publication of national and international guidelines for schools in 2014. The survey was developed in 2015 and distributed to schools in Cumbria, North West England, UK between 2015 and 2016. Only 47% of the respondents (95% CI, 39-57%) felt confident to manage anaphylaxis. Schools without allergic pupils were significantly less likely to have a standard management protocol in place for emergencies compared to those with allergic pupils (p < 0.001). The majority of the schools indicated that further training was needed (81% (95% CI, 74-88%).Conclusion: At the time of the survey, schools' preparedness in the region, did not meet safety standards recommended by national and international organisations. Although schools have shown eagerness in accessing training in the management of anaphylaxis, tailored training for schools is not yet widely available. There is now an urgent need to design feasible training strategies that create a safe environment for allergic pupils across all UK schools. What is Known: • One quarter of the severe allergic reactions take place for the first time while at school with some of them being fatal. • School staff is ill-prepared in the management of anaphylaxis. Access to formal training is not widely available. What is New: • School staff remains unconfident in managing the severe allergic child. Training in the management of anaphylaxis is scarce, and when available, it does not offer the required depth to cover the holistic needs of allergic pupils. • Schools would welcome generic adrenaline autoinjectors and a national policy with central funding which would describe step by step the necessary measures for the management of anaphylaxis.

Classification of Human White Blood Cells Using Machine Learning for Stain-Free Imaging Flow Cytometry.

Imaging flow cytometry (IFC) produces up to 12 spectrally distinct, information-rich images of single cells at a throughput of 5,000 cells per second. Yet often, cell populations are still studied using manual gating, a technique that has several drawbacks, hence it would be advantageous to replace manual gating with an automated process. Ideally, this automated process would be based on stain-free measurements, as the currently used staining techniques are expensive and potentially confounding. These stain-free measurements originate from the brightfield and darkfield image channels, which capture transmitted and scattered light, respectively. To realize this automated, stain-free approach, advanced machine learning (ML) methods are required. Previous works have successfully tested this approach on cell cycle phase classification with both a classical ML approach based on manually engineered features, and a deep learning (DL) approach. In this work, we compare both approaches extensively on the problem of white blood cell classification. Four human whole blood samples were assayed on an ImageStream-X MK II imaging flow cytometer. Two samples were stained for the identification of eight white blood cell types, while two other sample sets were stained for the identification of resting and active eosinophils. For both data sets, four ML classifiers were evaluated on stain-free imagery with stratified 5-fold cross-validation. On the white blood cell data set, the best obtained results were 0.778 and 0.703 balanced accuracy for classical ML and DL, respectively. On the eosinophil data set, this was 0.871 and 0.856 balanced accuracy. We conclude that classifying cell types based on only stain-free images is possible with all four classifiers. Noteworthy, we also find that the DL approaches tested in this work do not outperform the approaches based on manually engineered features. © 2019 International Society for Advancement of Cytometry.

Upskilling healthcare professionals to manage clinical allergy.

It has long been recognised that given the high prevalence and considerable impact of allergic disease globally, there needs to be a focus on appropriate training for clinical professionals. The health-economic consequences of allergic disease are significant, with both direct healthcare costs (doctor, nurse and dietitian consultations, hospital admissions and prescribed medications) and indirect costs (lost school and work time, reduced productivity and over-the-counter medications). There is also a well-recognised impairment of quality of life, with less tangible costs including anxiety, distress, discomfort, disability and, occasionally, death. To help to mitigate these effects, there is a need to upskill the professional workforce at all levels, and also to equip those trained with the skills to become future healthare professional trainers. Upskilling the workforce from the grass-roots of undergraduate study in Medical, Nursing and Allied Health Professionals (AHP) through the entirety of training to senior consultant levels could have a major beneficial impact on the patient and their families, lead to a reduction in emergency use of clinical service, and help increase economic productivity.

A specific synbiotic-containing amino acid-based formula restores gut microbiota in non-IgE mediated cow's milk allergic infants: a randomized controlled trial.

BACKGROUND: Altered gut microbiota is implicated in cow's milk allergy (CMA) and differs markedly from healthy, breastfed infants. Infants who suffer from severe CMA often rely on cow's milk protein avoidance and, when breastfeeding is not possible, on specialised infant formulas such as amino-acid based formulas (AAF). Herein, we report the effects of an AAF including specific synbiotics on oral and gastrointestinal microbiota of infants with non-IgE mediated CMA with reference to healthy, breastfed infants. METHODS: In this prospective, randomized, double-blind controlled study, infants with suspected non-IgE mediated CMA received test or control formula. Test formula was AAF with synbiotics (prebiotic fructo-oligosaccharides and probiotic Bifidobacterium breve M-16V). Control formula was AAF without synbiotics. Healthy, breastfed infants were used as a separate reference group (HBR). Bacterial compositions of faecal and salivary samples were analysed by 16S rRNA-gene sequencing. Faecal analysis was complemented with the analysis of pH, short-chain fatty acids (SCFAs) and lactic acids. RESULTS: The trial included 35 test subjects, 36 controls, and 51 HBR. The 16S rRNA-gene sequencing revealed moderate effects of test formula on oral microbiota. In contrast, the gut microbiota was substantially affected across time comparing test with control. In both groups bacterial diversity increased over time but was characterised by a more gradual increment in test compared to control. Compositionally this reflected an enhancement of Bifidobacterium spp. and Veillonella sp. in the test group. In contrast, the control-fed infants showed increased abundance of adult-like species, mainly within the Lachnospiraceae family, as well as within the Ruminococcus and Alistipes genus. The effects on Bifidobacterium spp. and Lachnospiraceae spp. were previously confirmed through enumeration by fluorescent in situ hybridization and were shown for test to approximate the proportions observed in the HBR. Additionally, microbial activity was affected as evidenced by an increase of l-lactate, a decrease of valerate, and reduced concentrations of branched-chain SCFAs in test versus control. CONCLUSIONS: The AAF including specific synbiotics effectively modulates the gut microbiota and its metabolic activity in non-IgE mediated CMA infants bringing it close to a healthy breastfed profile.Trial registration Registered on 1 May 2013 with Netherlands Trial Register Number NTR3979.

A specific synbiotic-containing amino acid-based formula in dietary management of cow's milk allergy: a randomized controlled trial.

BACKGROUND: Here we report follow-up data from a double-blind, randomized, controlled multicenter trial, which investigated fecal microbiota changes with a new amino acid-based formula (AAF) including synbiotics in infants with non-immunoglobulin E (IgE)-mediated cow's milk allergy (CMA). METHODS: Subjects were randomized to receive test product (AAF including fructo-oligosaccharides and Bifidobacterium breve M-16V) or control product (AAF) for 8 weeks, after which infants could continue study product until 26 weeks. Fecal percentages of bifidobacteria and Eubacterium rectale/Clostridium coccoides group (ER/CC) were assessed at 0, 8, 12, and 26 weeks. Additional endpoints included stool markers of gut immune status, clinical symptoms, and safety assessments including adverse events and medication use. RESULTS: The trial included 35 test subjects, 36 controls, and 51 in the healthy reference group. Study product was continued by 86% and 92% of test and control subjects between week 8-12, and by 71% and 80%, respectively until week 26. At week 26 median percentages of bifidobacteria were significantly higher in test than control [47.0% vs. 11.8% (p < 0.001)], whereas percentages of ER/CC were significantly lower [(13.7% vs. 23.6% (p = 0.003)]. Safety parameters were similar between groups. Interestingly use of dermatological medication and reported ear infections were lower in test versus control, p = 0.019 and 0.011, respectively. Baseline clinical symptoms and stool markers were mild (but persistent) and low, respectively. Symptoms reduced towards lowest score in both groups. CONCLUSION: Beneficial effects of this AAF including specific synbiotics on microbiota composition were observed over 26 weeks, and shown suitable for dietary management of infants with non-IgE-mediated CMA.Trial Registration NTR3979.

Non-IgE-mediated gastrointestinal allergies-Do they have a place in a new model of the Allergic March.

The rise in food allergy has been described as the "second wave" of the allergy epidemic, with some developed countries reporting a prevalence of 10% of challenge-proven food allergies. Recognition of the Allergic March has played a crucial role in identifying causality in allergic conditions, linking atopic dermatitis to food allergy and food allergy to other atopic disorders, thereby highlighting opportunities in prevention and the importance of early intervention. This publication will establish the value of weaving the less well-understood, non-IgE-mediated food allergy into the Allergic March and mapping its progression through childhood and its associated co-morbidities. The proposed non-IgE-mediated Allergic March highlights the concomitant presentation of gastrointestinal symptoms and atopic dermatitis as early presenting symptoms in confirmed non-IgE-mediated allergies and the later development of atopic co-morbidities, including asthma and allergic rhinitis, similar to the IgE-mediated Allergic March. This publication highlights recent observations of a link between non-IgE-mediated food allergy in early childhood and functional gastrointestinal disorders in later life and also the reported occurrence of extra-intestinal manifestations at later ages. Although significant limitations exist in regard to the proposed evolution of the Allergic March model, the authors hope that this publication will influence the management of non-IgE-mediated gastrointestinal allergies and inform future research and interventions.

A synbiotic-containing amino-acid-based formula improves gut microbiota in non-IgE-mediated allergic infants.

BackgroundPrebiotics and probiotics (synbiotics) can modify gut microbiota and have potential in allergy management when combined with amino-acid-based formula (AAF) for infants with cow's milk allergy (CMA).MethodsThis multicenter, double-blind, randomized controlled trial investigated the effects of an AAF-including synbiotic blend on percentages of bifidobacteria and Eubacterium rectale/Clostridium coccoides group (ER/CC) in feces from infants with suspected non-IgE-mediated CMA. Feces from age-matched healthy breastfed infants were used as reference (healthy breastfed reference (HBR)) for primary outcomes. The CMA subjects were randomized and received test or control formula for 8 weeks. Test formula was a hypoallergenic, nutritionally complete AAF including a prebiotic blend of fructo-oligosaccharides and the probiotic strain Bifidobacterium breve M-16V. Control formula was AAF without synbiotics.ResultsA total of 35 (test) and 36 (control) subjects were randomized; HBR included 51 infants. At week 8, the median percentage of bifidobacteria was higher in the test group than in the control group (35.4% vs. 9.7%, respectively; P<0.001), whereas ER/CC was lower (9.5% vs. 24.2%, respectively; P<0.001). HBR levels of bifidobacteria and ER/CC were 55% and 6.5%, respectively.ConclusionAAF including specific synbiotics, which results in levels of bifidobacteria and ER/CC approximating levels in the HBR group, improves the fecal microbiota of infants with suspected non-IgE-mediated CMA.

An interpretation of the new international MAP guideline for the management of Milk Allergy in Primary Care.

General Practitioners suffer from guideline fatigue. They come fast and furious in many complicated forms. Cow's milk allergy (CMA) is one of the most common presentations of food allergy seen in early childhood presenting to primary and secondary care. The early and accurate diagnosis continues to be highlighted in many countries worldwide. International surveys have found that primary care clinicians would like clearer explanations for the options for the diagnosis of CMA and in so doing a means to increase their understanding of management options for both IgE and Non IgE mediated CMA. In 2013 in response to General Practitioner demands, the UK guideline, 'Diagnosis and management of non-IgE-mediated CMA in infancy-a UK primary care practical guide' was published in this journal. This Milk Allergy in Primary Care (MAP) guideline outlines in simple algorithmic form how to diagnose, manage and refer children with CMA in a primary care setting. Based on the international uptake of the MAP guideline, a global practical guideline International MAP is presented by the Venter and Brown et al to help practitioners in primary care settings. It incorporates further published UK guidance, feedback from UK healthcare professionals and affected families and, importantly, also international guidance and expertise.