The Challenge of Home Allergen Re-introductions Using the Ladder Approach in Children With Non-IgE Mediated Gastrointestinal Food Allergy.

Background: Oral food challenges remain the most reliable method for allergy confirmation. Although consensus guidelines have been published to unify Immunoglobulin E (IgE)-mediated challenges, this does not exist for non-IgE mediated gastrointestinal allergies outside of Food Protein Induced Enterocolitis Syndrome. We therefore set out to establish the use of home introduction protocols (HIP) for confirmation of food allergy for milk, soya, egg and wheat using a ladder approach in children with non-IgE mediated allergy. Materials and Methods: Patients with suspected non-IgE mediated gastrointestinal allergies (0-16 years) were recruited following symptom improvement on an elimination diet. All children had skin prick or specific IgE tests to rule out IgE-mediated allergies prior to suggestion the HIP. Number of trials and outcome was documented. HIPs were developed using a published ladder approach for cow's milk as baseline and final dose was calculated based on guidelines for food protein induced enterocolitis syndrome and portions for age from the National Diet and Nutrition Survey. First foods were baked/highly processed and every 4th day patients moved to a more unprocessed/unheated food. Results: From 131 recruited patients, 117 (89.3%) followed the HIP for food allergens. No adverse events were documented. In more than 50% of cases one attempt at the HIP was sufficient to establish allergy status, but many required 2-5 attempts before the outcome was clear. About half of the children were fully tolerant to foods they initially eliminated: 36, 26 and 30% were partially tolerant to milk, soya, and egg and only 15% achieved partial tolerance to wheat. Wheat was the allergen introduced earliest, followed by soya, cow's milk and egg. Conclusions: This study indicates that home HIPs are safe in non-IgE mediated gastrointestinal food allergy and that the ladder approach may be useful in re-introducing allergens in children at home with non-IgE mediated gastrointestinal allergies. From this study we can also conclude that tolerance to processed/baked allergens was observed in many children. Further studies should be performed on the HIP and ideally reintroduction should occur pre-defined time intervals.

Renal Function in Children on Long Term Home Parenteral Nutrition.

Objectives: To assess renal function in pediatric intestinal failure (IF) patients on long term home parenteral nutrition (HPN). Methods: Children who received HPN for a minimum of 3 years between 2007 and 2017 were identified from the IF clinic of a large tertiary referral center. Estimated glomerular filtration rate (eGFR) was calculated using the Schwartz formula at discharge on HPN, after 6 months, 1, 2, and 3 years. Results: Twenty five patients (40% male) fulfilled the inclusion criteria. The indications for HPN were due to an underlying motility disorder in 56% (14/25), enteropathy in 24% (6/25), and short bowel syndrome in 20% (5/25). At the start of HPN 80% (20/25) had a normal eGFR. Four children (17%) had an abnormal eGFR. In the group of patients with normal eGFR at the start of HPN 30% (6/20) had at least one episode of decreased eGFR in the following 3 years, however there was no significant decline in eGFR at the end of the 3 year study period. Overall there was no statistically significant deterioration of eGFR in the study population (p = 0.7898). Conclusion: In our cohort of children on long term HPN no significant decline of eGFR could be demonstrated within 3 years of starting PN.

The impact on quality of life on families of children on an elimination diet for Non-immunoglobulin E mediated gastrointestinal food allergies.

BACKGROUND: The impact on health related quality of life (HRQL) has been well studied in children with Immunoglobulin E (IgE)-mediated food allergy. However limited data exists on related quality of life (QOL) of families who have a child suffering from food protein induced non-IgE mediated gastrointestinal allergies. We aimed to establish the QOL of families with children at the beginning of following an elimination diet for non-IgE mediated gastrointestinal food allergies. METHODS: A prospective, observational study was performed. Parents of children aged 4 weeks-16 years who improved after 4-8 weeks of following an elimination diet for suspected non-IgE mediated allergies were included. The Family Impact Module (FIM) of the Pediatric Quality of Life (PedsQL™) was used and we compared our data to two historical cohorts: one with sickle cell disease and another with intestinal failure. RESULTS: One hundred and twenty three children with a median age of 20 months were included (84 boys). The total FIM Score was 57.43 (SD 22.27) and particularly low for daily activities and worry. Factors that impacted significantly included age (p < 0.0001), number of foods excluded (p = 0.008), symptom severity (p = 0.041) and chronic nasal congestion (p = 0.012). Children with non-IgE mediated food allergies had worse scores in all domains (p < 0.0001) compared to sickle cell disease and worse physical (p = 0.04), emotional (p = 0.04) and worry (p = 0.01) domains compared to intestinal failure. CONCLUSIONS: This study found that parent QOL and family functioning was worse in those families who had a child on an elimination diet for non-IgE mediated allergies compared to those with sickle cell disease and intestinal failure, highlighting the impact this disease has on families.

Establishing the prevalence of low vitamin D in non-immunoglobulin-E mediated gastrointestinal food allergic children in a tertiary centre.

BACKGROUND: There is no data on the prevalence of vitamin D deficiency in children with non-immunoglobulin-E (IgE) mediated gastrointestinal food allergy. The aims of our study were to understand the prevalence of vitamin D insufficiency and deficiency in children with non-IgE mediated gastrointestinal food allergy and identify predisposing factors. METHODS: This was a retrospective study which looked at data from Great Ormond Street Hospital from January 2002 to September 2015. Children 0-18 years old with a confirmed diagnosis of non-IgE mediated gastrointestinal food allergy who had a vitamin D level measured during the course of their disease were included. Low vitamin D levels were defined as <50 nmol/L; insufficient levels were defined as 25-50 nmol/L and deficient levels as <25 nmol/L. Patient characteristics and clinical factors were also recorded. RESULTS: Ninety-two patients met the study criteria; 49% were female and median age was 10 years 2 months [IQR: 4 years 8 months to 13 years 7 months]. Of the cohort, 26% (24/92) had low vitamin D levels; 16% had insufficient vitamin D levels and 10% had vitamin D deficiency. Gender (p = 0.043) and age (p = 0.035) were significantly associated with low vitamin D levels. Twelve percent of children who were on an amino acid formula (AAF) had low vitamin D compared to 31% of children who were not (p = 0.06). No other clinical factors were found to be significantly associated with low vitamin D levels. CONCLUSIONS: Children with non-IgE mediated gastrointestinal food allergy are at risk of vitamin D insufficiency and deficiency. Further prospective studies need to be performed in all children with non-IgE mediated gastrointestinal food allergies. TRIAL REGISTRATION: The study was registered with the GOSH Research & Development department as a retrospective case note review. The Health Research Authority confirmed that NHS Research and Ethics Committee approval was not required; thus there is no trial registration number.

Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years.

OBJECTIVES: Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of 2 years and establish phenotypic features associated with underlying monogenicity. METHODS: Phenotype data of 62 children with disease onset before the age of 2 years presenting over the past 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing. RESULTS: In all, 62 patients [55% male] were identified. The median disease onset was 3 months of age (interquartile range [IQR]: 1 to 11). Conventional IBD classification only applied to 15 patients with Crohn's disease [CD]-like [24%] and three with ulcerative colitis [UC]-like [5%] phenotype; 44 patients [71%] were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition [40%], extensive immunosuppression [31%], haematopoietic stem-cell transplantation [29%], and abdominal surgery [19%]. In 31% of patients, underlying monogenic diseases were established [EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A]. Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease onset before the 6th month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities. CONCLUSIONS: IBD in children with disease onset before the age of 2 years is frequently unclassifiable into Crohn's disease and ulcerative colitis, particularly treatment resistant, and can be indistinguishable from monogenic diseases with IBD-like phenotype.

The impact of the elimination diet on growth and nutrient intake in children with food protein induced gastrointestinal allergies.

BACKGROUND: Non immunoglobulin E (IgE) mediated allergies affecting the gastrointestinal tract require an elimination diet to aid diagnosis. The elimination diet may entail multiple food eliminations that contribute significantly to macro- and micro-nutrient intake which are essential for normal growth and development. Previous studies have indicated growth faltering in children with IgE-mediated allergy, but limited data is available on those with delayed type allergies. We therefore performed a study to establish the impact on growth before and after commencing an elimination diets in children with food protein induced non-IgE mediated gastrointestinal allergies. METHODS: A prospective, observational study was performed at the tertiary gastroenterology department. Children aged 4 weeks-16 years without non-allergic co-morbidities who were required to follow an elimination diet for suspected food protein induced gastrointestinal allergies were included. Growth parameters pre-elimination were taken from clinical notes and post-elimination measurements (weight and height) were taken a minimum of 4 weeks after the elimination diet. A 3-day estimated food diary was recorded a minimum of 4 weeks after initiating the elimination diet, including also any hypoallergenic formulas or over the counter milk alternatives that were consumed. RESULTS: We recruited 130 children: 89 (68.5 %) boys and a median age of 23.3 months [IQR 9.4-69.2]. Almost all children (94.8 %) in this study eliminated CM from their diet and average contribution of energy in the form of protein was 13.8 % (SD 3.9), 51.2 % (SD 7.5) from carbohydrates and 35 % (SD 7.5) from fat. In our cohort 9 and 2.8 % were stunted and wasted respectively. There was a statistically significant improvement in weight-for-age (Wtage) after the 4 week elimination diet. The elimination diet itself did not improve any of the growth parameters, but achieving energy and protein intake improved Wtage and WtHt respectively, vitamin and/or mineral supplements and hypoallergenic formulas were positively associated with WtHt and Wtage. CONCLUSION: With appropriate dietary advice, including optimal energy and protein intake, hypoallergenic formulas and vitamins and mineral supplementation, growth parameters increased from before to after dietary elimination. These factors were positively associated with growth, irrespective of the type of elimination diet and the numbers of foods eliminated.

Cow's Milk Allergy Prescribing Is Influenced by Regional and National Guidance.

OBJECTIVES: Cow's milk allergy (CMA) is the most common food allergy in children with many clinical manifestations, leading to misdiagnoses such as gastro-oesophageal reflux, infantile colic, and lactose intolerance with inappropriate prescribing. We aimed to determine the impact of infant feeding guidelines on CMA prescribing in UK primary care using a simple and inexpensive training package. METHODS: Prospectively collected data of infant feeding prescriptions in Northern Ireland from June 2012 to March 2014 were analysed with the intervention period between November 2012 and March 2013. A comparison was made between hypoallergenic formulae, appropriate for CMA, versus alternative prescriptions including antiregurgitation and colic products, lactose-free and partially hydrolysed milks, or infant Gaviscon. RESULTS: Comparing pre- and postintervention period, the total quantity of hypoallergenic formulae increased by 63.2% and alternative prescriptions decreased by 44.6% (P < 0.001). The total amount of all prescribed products decreased by 41.0% (P < 0.001). During the study period, the proportion of recommended CMA treatment increased from 3.4% before training to 9.8% in the short- and long-term follow-up (P < 0.001). The overall increase was £33,508 per year or £95.5 per general practitioner's surgery. CONCLUSIONS: We present the first study evaluating the impact of infant feeding guidelines on CMA prescribing in UK primary care. Practical advice and teaching of health professionals allowed for effective implementation of regional and national guidelines, with a significant impact on prescription patterns. This study shows promising results for prospective research on a national scale, including socioeconomical impact and cost-effectiveness.

Histological findings in infants with Gastrointestinal food allergy are associated with specific gastrointestinal symptoms; retrospective review from a tertiary centre.

BACKGROUND: Gastrointestinal food allergy (GIFA) occurs in 2 to 4 % of children, the majority of whom are infants (<1 year of age). Although endoscopy is considered the gold standard for diagnosing GIFA, it is invasive and requires general anaesthesia. Therefore, we aimed to investigate whether in infants with GIFA, gastrointestinal symptoms predict histological findings in order to help optimise the care pathway for such patients. METHODS: All infants <1 year of age over a 20 year period who underwent an endoscopic procedure gastroscopy or colonoscopy for GIFA were evaluated for the study. Symptoms at presentation were reviewed and compared with mucosal biopsy histological findings, which were initially broadly classified for study purposes as "Normal" or "Abnormal" (defined as the presence of any mucosal inflammation by the reporting pathologist at the time of biopsy). RESULTS: Of a total of 1319 cases, 544 fitted the inclusion criteria. 62 % of mucosal biopsy series in this group were reported as abnormal. Infants presenting with diarrhoea, rectal (PR) bleeding, irritability and urticaria in any combination had a probability >85 % (OR > 5.67) of having abnormal histological findings compared to those without. Those with isolated PR bleeding or diarrhoea were associated with 74 % and 68 % probability (OR: 2.85 and 2.13) of an abnormal biopsy, respectively. Conversely, children presenting with faltering growth or reflux/vomiting showed any abnormal mucosal histology in only 50.8 % and 45.3 % (OR: 1.04 and 0.82) respectively. CONCLUSIONS: Food allergy may occur in very young children and is difficult to diagnose. Since endoscopy in infants has significant risks, stratification of decision-making may be aided by symptoms. At least one mucosal biopsy demonstrated an abnormal finding in around half of cases in this selected population. Infants presenting with diarrhoea, PR bleeding, urticaria and irritability are most likely to demonstrate abnormal histological findings.

Time to symptom improvement using elimination diets in non-IgE-mediated gastrointestinal food allergies.

BACKGROUND: The prevalence of food allergy has increased in recent decades, and there is paucity of data on time to symptom improvement using elimination diets in non-Immunoglobulin E (IgE)-mediated food allergies. We therefore aimed to assess the time required to improvement of symptoms using a symptom questionnaire for children with non-IgE-mediated food allergies on an elimination diet. METHODS: A prospective observational study was performed on patients with non-IgE-mediated gastrointestinal food allergies on an elimination diet, who completed a questionnaire that includes nine evidence-based food allergic symptoms before and after the exclusion diet. The questionnaire measured symptoms individually from 0 (no symptom) to 5 (most severe) and collectively from 0 to 45. Children were only enrolled in the study if collectively symptoms improved with the dietary elimination within 4 or 8 weeks. RESULTS: Data from 131 patients were analysed including 90 boys with a median age of 21 months [IQR: 7 to 66]. Based on the symptom questionnaire, 129 patients (98.4%) improved after 4-week elimination diet and only two patients improved after 8 weeks. A statistically significant difference before and after commencing the elimination diet was seen in all nine recorded symptoms (all p < 0.001), and in the median of overall score (p < 0.001). CONCLUSION: This is the first study attempting to establish time to improve after commencing the diet elimination. Almost all children in this study improved within 4 weeks of following the elimination diet, under dietary supervision.

A practical approach to vitamin and mineral supplementation in food allergic children.

BACKGROUND: The management of food allergy in children requires elimination of the offending allergens, which significantly contribute to micronutrient intake. Vitamin and mineral supplementation are commonly suggested as part of dietary management. However a targeted supplementation regime requires a complete nutritional assessment, which includes food diaries. Ideally these should be analysed using a computerised program, but are very time consuming. We therefore set out to evaluate current practice of vitamin and mineral supplementation in a cohort of children with non-Immunoglobulin E (IgE) mediated food allergies. METHODS: This prospective, observational study recruited children aged 4 weeks - 16 years, who required to follow an elimination diet for non-IgE mediated allergies. Only children that improved according to a symptom score and were on a vitamin and/or mineral supplement were included. A 3-day food diary including vitamin and mineral supplementation was recorded and analysed using Dietplan computer program. We assessed dietary adequacy with/without the supplement using the Dietary Reference Values. RESULTS: One hundred-and-ten children had completed food diaries and of these 29% (32/110) were taking vitamin and/or mineral supplements. Children on hypoallergenic formulas were significantly (p = 0.007) less likely to be on supplements than those on alternative over-the-counter milks. Seventy-one percent had prescribable supplements, suggested by a dietitian/physician. Sixty percent of those without a vitamin supplement had a low vitamin D intake, but low zinc, calcium and selenium was also common. Of the supplemented cohort many continued to be either under or over-supplemented. CONCLUSION: This study has raised the question for the first time, whether clinicians dealing with paediatric food allergies should consider routine vitamin and/or mineral supplements in the light of deficient intake being so common in addition to being so difficult to predict.

Cow's Milk Protein Allergy from Diagnosis to Management: A Very Different Journey for General Practitioners and Parents.

Cow's milk protein allergy (CMPA) is the most common food allergy in infants and can affect a family's quality of life. The purpose of this paper is to evaluate the knowledge and experience of general practitioners (GPs) in terms of CMPA diagnosis and management and to explore the views of parents on the current diagnostic process. Two surveys were conducted in June 2014, which collected data from GPs and parents of infants diagnosed with CMPA in the United Kingdom. The questionnaires included quantitative and qualitative questions, which measured self-reported knowledge, management and perceived treatment progression, and the educational needs of GPs. We also explored parents' experiences of local healthcare support in relation to CMPA. A total of 403 GPs and 300 parents completed the surveys. The main symptoms of CMPA and diagnosis period differed between GPs and parents. Other key points include different perceptions on symptom presentation and improvement, lack of awareness from GPs about current guidelines, and the significant burden on both families and GPs. This is the first study attempting to establish GP and parental experience in diagnosing CMPA. It is notable that the difference can be improved through training, appropriate diagnostic tools and improved communication between physicians and parents.

Dietary elimination of children with food protein induced gastrointestinal allergy - micronutrient adequacy with and without a hypoallergenic formula?

BACKGROUND: The cornerstone for management of Food protein-induced gastrointestinal allergy (FPGIA) is dietary exclusion; however the micronutrient intake of this population has been poorly studied. We set out to determine the dietary intake of children on an elimination diet for this food allergy and hypothesised that the type of elimination diet and the presence of a hypoallergenic formula (HF) significantly impacts on micronutrient intake. METHOD: A prospective observational study was conducted on children diagnosed with FPIGA on an exclusion diet who completed a 3 day semi-quantitative food diary 4 weeks after commencing the diet. Nutritional intake where HF was used was compared to those without HF, with or without a vitamin and mineral supplement (VMS). RESULTS: One-hundred-and-five food diaries were included in the data analysis: 70 boys (66.7%) with median age of 21.8 months [IQR: 10 - 67.7]. Fifty-three children (50.5%) consumed a HF and the volume of consumption was correlated to micronutrient intake. Significantly (p <0.05) more children reached their micronutrient requirements if a HF was consumed. In those without a HF, some continued not to achieve requirements in particular for vitamin D and zinc, in spite of VMS. CONCLUSION: This study points towards the important micronutrient contribution of a HF in children with FPIGA. Children, who are not on a HF and without a VMS, are at increased risk of low intakes in particular vitamin D and zinc. Further studies need to be performed, to assess whether dietary intake translates into actual biological deficiencies.

Targeted gene panel sequencing in children with very early onset inflammatory bowel disease--evaluation and prospective analysis.

BACKGROUND: Multiple monogenetic conditions with partially overlapping phenotypes can present with inflammatory bowel disease (IBD)-like intestinal inflammation. With novel genotype-specific therapies emerging, establishing a molecular diagnosis is becoming increasingly important. DESIGN: We have introduced targeted next-generation sequencing (NGS) technology as a prospective screening tool in children with very early onset IBD (VEOIBD). We evaluated the coverage of 40 VEOIBD genes in two separate cohorts undergoing targeted gene panel sequencing (TGPS) (n=25) and whole exome sequencing (WES) (n=20). RESULTS: TGPS revealed causative mutations in four genes (IL10RA, EPCAM, TTC37 and SKIV2L) discovered unexpected phenotypes and directly influenced clinical decision making by supporting as well as avoiding haematopoietic stem cell transplantation. TGPS resulted in significantly higher median coverage when compared with WES, fewer coverage deficiencies and improved variant detection across established VEOIBD genes. CONCLUSIONS: Excluding or confirming known VEOIBD genotypes should be considered early in the disease course in all cases of therapy-refractory VEOIBD, as it can have a direct impact on patient management. To combine both described NGS technologies would compensate for the limitations of WES for disease-specific application while offering the opportunity for novel gene discovery in the research setting.

Feeding difficulties in children with food protein-induced gastrointestinal allergies.

BACKGROUND AND AIM: There is paucity of data on the prevalence of feeding difficulties in Food Protein-Induced Gastrointestinal Allergies (FPIGA) and their clinical characteristics. However, it is a commonly reported problem by clinicians. We set out to establish the occurrence of feeding difficulties in children with FPIGA, the association with gastrointestinal and extra-intestinal symptoms and number of foods eliminated from the diet. METHODS: This retrospective observational analysis was performed in patients seen between 2002 and 2009 at Great Ormond Street Children's Hospital, Gastroenterology Department, London. Medical records where FPIGA was documented using the terms from the National Institute of Allergy and Infectious Disease and National Institute of Clinical Excellence and confirmed using an elimination diet, followed by a challenge were included. Feeding difficulties were assessed using a criteria previously used in healthy toddlers in the UK. RESULTS: Data from 437 children (203 female) were collected. Significantly more children with feeding difficulties presented with abdominal distention and bloating (P = 0.002), vomiting (P < 0.0001), weight loss (P < 0.0001), rectal bleeding (P = 0.025), and constipation (P < 0.0001). We also found that having extra-intestinal manifestations were significantly (P < 0.0001) associated with the presence of feeding difficulties. Additionally, a significantly higher number of foods eliminated from the diet in the children with/without feeding difficulties (P = 0.028). CONCLUSIONS: Clinical manifestations like vomiting, constipation, rectal bleeding, weight loss, and the presence of extra-intestinal manifestations in addition to the number of foods avoided are in our FPIGA population linked to feeding difficulties.