Evaluation of Deficient Nutrients in Infants and Toddlers Mainly Taking Amino Acid-Based Elemental Formulas: An Exploratory Study.

INTRODUCTION: This study evaluated nutrient deficiencies in infants and toddlers with inflammatory bowel disease (IBD) and eosinophilic gastrointestinal disorders (EGIDs), whose primary nutritional source is elemental formulas (EFs). METHODS: The nutrient status of children with IBD and EGID aged 6 months to 6 years was evaluated. RESULTS: Twenty-one children fed with EFs (EF group) and 25 controls (CL group) were enrolled. The selenium level in the EF group was lower than that in the CL group (2.2 µg/dL vs. 9.3 µg/dL; p < 0.01). Although fat-soluble vitamins were deficient in some EF group participants, no significant differences were observed in their concentration and insufficiency proportion. However, ascorbic acid deficiency was more frequent in the EF group, with significantly lower levels (8.6 µg/mL vs. 12.0 µg/mL; p < 0.01). The triene:tetraene ratio was significantly higher in the EF group (0.046 vs. 0.010; p < 0.01). Asparagine and taurine levels were significantly lower in the EF group (asparagine: p < 0.01; taurine: p < 0.01) and tyrosine and phenylalanine levels were higher in the EF group, resulting in a lower Fisher's ratio (p < 0.01). CONCLUSION: Long-term feeding with EFs can cause deficiencies in essential fatty acids, selenium, and ascorbic acid and also carries a risk of amino acid imbalance in infants and toddlers.

STAT6 gain-of-function variant exacerbates multiple allergic symptoms.

BACKGROUND: Allergic diseases were long considered to be complex multifactorial disorders. However, recent findings indicate that severe allergic inflammation can be caused by monogenic immune defects. OBJECTIVES: We sought to clarify the molecular pathogenesis of a patient with early-onset multiple allergic diseases, a high serum IgE level, hypereosinophilia, treatment-resistant severe atopic dermatitis with increased dermal collagen fiber deposition, and eosinophilic gastrointestinal disorder with numerous polypoid nodules. METHODS: A missense variant in STAT6 was identified, and its function was examined using peripheral blood, transfected HEK293 cells, lymphoblastoid cell lines, and knock-in mice with the corresponding mutation. RESULTS: Whole-exome sequencing identified a de novo heterozygous missense variant in signal transducer and activator of transcription 6 (STAT6) (p.Asp419Asn). Luciferase reporter assay revealed that the transcriptional activity of this STAT6 mutant was upregulated even without IL-4 stimulation. Phosphorylation of STAT6 was not observed in either the patient's TH2 cells or lymphoblastoid cell lines without stimulation, whereas it was induced more strongly in both by IL-4 stimulation compared with healthy controls. STAT6 protein was present in the nuclear fraction of the lymphoblastoid cell lines of the patient even in the absence of IL-4 stimulation. The patient's gastric mucosa showed upregulation of STAT6-, fibrosis-, and germinal center formation-related molecules. Some of the knock-in mice with the corresponding mutation spontaneously developed dermatitis with skin thickening and eosinophil infiltration. Moreover, serum IgE levels and mRNA expression of type 2 cytokines were increased in the knock-in mice-with or without development of spontaneous dermatitis-compared with the wild-type mice. CONCLUSIONS: A novel STAT6 gain-of-function variant is a potential cause of primary atopic disorders.

A detailed intake-status profiling of seafoods in adult food-protein-induced enterocolitis syndrome patients.

BACKGROUND: Adults with food-protein-induced enterocolitis syndrome (FPIES) often develop severe abdominal symptoms after eating seafood. However, no investigation of a food elimination strategy for adult FPIES patients has been performed to date. METHODS: We conducted a retrospective cohort study of seafood-avoidant adults by telephone interview, based on the diagnostic criteria for adult FPIES reported by González et al. We compared the clinical profiles, abdominal symptoms, and causative seafoods between FPIES and immediate-type food allergy (IgE-mediated FA) patients. We also profiled the detailed intake-status of seafoods in adult FPIES patients. RESULTS: Twenty-two (18.8 %) of 117 adults with seafood-allergy were diagnosed with FPIES. Compared with the IgE-mediated FA patients, FPIES patients had an older age of onset, more pre-existing gastrointestinal and atopic diseases, more episodes, longer latency and duration of symptoms, more nausea, abdominal distention, and severe abdominal pain, and more frequent vomiting and diarrhea. In particular, abdominal distention-reflecting intestinal edema and luminal fluid retention-may be the most distinctive characteristic symptom in adult FPIES (p < 0.001). Bivalves, especially oysters, were the most common cause of FPIES. Strikingly, intake-status profiling revealed that many FPIES patients can safely ingest an average of 92.6 % of seafood species other than the causative species. CONCLUSIONS: There are many differentiators between FPIES and IgE-mediated FA, which may reflect differences in the underlying immunological mechanisms. Although seafood FPIES is unlikely to induce tolerance, many patients can ingest a wide variety of seafood species after a long period from onset.

A nationwide survey of non-IgE-mediated gastrointestinal food allergies in neonates and infants.

BACKGROUND: Non-IgE-mediated gastrointestinal food allergies (non-IgE-GIFAs) seem to be increasing rapidly worldwide. However, nationwide studies have been limited to food-protein-induced enterocolitis (FPIES) and food-protein-induced allergic proctocolitis (FPIAP), with little attention to other non-IgE-GIFA subgroups. The aim of this study was to elucidate the clinical features of all patients with non-IgE-GIFAs, not just certain subgroups. METHODS: We conducted a nationwide cross-sectional survey of non-IgE-GIFAs in Japan from April 2015 through March 2016. A questionnaire was sent to hospitals and clinics throughout Japan. The questionnaire asked about the number of physician-diagnosed non-IgE-GIFA patients, the status of fulfillment of the diagnostic criteria, tentative classification into 4 clusters based on the initial symptoms, the day of onset after birth, complications, and the suspected offending food(s). RESULTS: The response rate to that questionnaire was 67.6% from hospitals and 47.4% from clinics. Analyses were conducted about "diagnosis-probable" patient cohort (n = 402) and the "diagnosis-confirmed" patients (n = 80). In half of the reported non-IgE-GIFA patients, onset occurred in the neonatal period. The patients were evenly distributed among 4 non-IgE-GIFA clusters. In Cluster 1, with symptoms of vomiting and bloody stool, the onset showed a median of 7 days after birth, which was the earliest among the clusters. Cow's milk was the most common causative food. CONCLUSIONS: In half of the patients, the onset of non-IgE-GIFAs was in the neonatal period. This highlights the importance of studying the pathogenesis in the fetal and neonatal periods.

Comparison of adult food protein-induced enterocolitis syndrome to crustaceans and immediate-type food allergy.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is increasingly found in adults. FPIES requires different treatment from immediate-type food allergy (FA) in emergency medicine. However, no comparison of the clinical presentations of these diseases has been reported. OBJECTIVE: To compare the clinical presentations and causative crustaceans of adult FPIES and FA using a standardized questionnaire and to thereby lay the groundwork for establishing an algorithm that distinguishes those diseases. METHODS: We conducted a retrospective cohort study of crustacean-avoidant adults by telephone interview based on the previously reported diagnostic criteria for adult FPIES to compare the clinical features and crustacean intake status between FPIES and FA. RESULTS: Of 73 adult patients with crustacean allergy, 8 (11%) were diagnosed with having FPIES and 53 (73%) FA. Compared with the patients with FA, those with FPIES had a longer latency period (P < .01), more episodes (P = .02), longer duration of symptoms (P = .04), more frequent abdominal distention (P = .02), and severe colic pain (P = .02). Half of the patients with FPIES experienced fear of death during an episode. Panulirus japonicus (Japanese spiny lobster) and Homarus weber (lobster) were significantly common FPIES-causing foods. A statistically significant 62.5% of patients with FPIES were able to ingest some type of crustacean. CONCLUSION: FPIES and FA can be clearly differentiated by the abdominal symptoms, latency period, and duration of episodes. Furthermore, some patients with FPIES do not necessarily need to avoid all crustaceans. Our findings lay the groundwork for establishing an algorithm that distinguishes FPIES from FA in adults.

Tolerability and safety of a new elimination diet for pediatric eosinophilic gastritis and duodenitis.

BACKGROUND: Non-esophageal eosinophilic gastrointestinal disorders (non-EoE EGIDs) are chronic inflammatory disorders with massive infiltration of eosinophils into the gastrointestinal tract. Food elimination diets are potentially effective treatments. But the existing dietary therapies have various weak points. We developed a new regimen to compensate for the shortcomings of the elemental diet and 6-food elimination diet. The new regimen consists of an amino-acid-based formula, potatoes, vegetables, fruits and restricted seasonings. We named it the "Rainbow Elimination Diet (ED)." The aims of this study were to evaluate the tolerability and safety of this diet. METHODS: A retrospective medical record examination was conducted at the National Center for Child Health and Development covering the period from January 2010 through December 2018. The medical records of patients (age 2-17 y) with histologically diagnosed non-EoE EGIDs were reviewed. The tolerability, nutritional intake, symptoms, and blood test findings were evaluated. RESULTS: Nineteen patients were offered several kinds of food-elimination diets. Seven patients (eosinophilic gastritis: 5; gastroenteritis: 1; duodenitis: 1) were treated with Rainbow ED. Six patients were compliant with this diet. The median duration of the diet induction phase was 15 days (range 14-30). All 5 patients who had had symptoms just before the induction phase became symptom-free. The body weight decreased in 5 patients (median -0.6 kg), probably because the serum protein increased, resulting in reduced edema. All 5 patients with hypoproteinemia had elevated serum albumin (median 2.9-3.5 g/dL). The ingested nutritional elements were calculated, and most of them were sufficient, except for fat and selenium. CONCLUSIONS: The Rainbow ED was well-tolerated and safe for pediatric non-EoE EGIDs.

[A CASE OF INDUCIBLE LARYNGEAL OBSTRUCTION UNSUCCESSFULLY TREATED AS SEVERE ASTHMA WAS WELL CONTROLLED AFTER APPROPRIATE DIAGNOSIS AND INSTRUCTION OF THERAPEUTIC BREATHING MANEUVERS].

BACKGROUND: Inducible laryngeal obstruction (ILO) refers to respiratory disorders caused by airflow limitation in the larynx, including vocal cord dysfunction, and may sometimes be misdiagnosed as bronchial asthma (BA). Here, we report the case of an 11-year-old boy diagnosed with BA in infancy. He was referred to our Allergy Center and was taking a high dose of inhaled corticosteroids (ICS) due to frequent coughing from the age of 10 years and persistent coughing following COVID-19 infection at the age of 11. However, the patient continued to experience frequent coughing attacks and repeated visits to the emergency department after inhalation of ß2-stimulants failed to improve his cough. We admitted him to the allergy center for examinations to assess the BA severity. In the airway hypersensitiveness test, saline inhalation performed prior to methacholine inhalation caused expiratory stridor and respiratory distress in the larynx, which worsened with ß2-stimulant inhalation. Based on these results, we ruled out BA and diagnosed ILO. We instructed him on breathing maneuvers, and he was able to respond appropriately when symptoms appeared. We then started reducing his ICS dose.

[ACUTE TREATMENT AND LONG-TERM PROGNOSIS OF SEVERE PROTEIN-LOSS IN ATOPIC DERMATITIS (SPLAD)].

BACKGROUND: Atopic dermatitis (AD) in early infancy can lead to severe protein-loss in atopic dermatitis (SPLAD). The aim of this study was to elucidate the prognosis of SPLAD. METHODS: This was a single-center, retrospective, observational study based on medical records. Participants comprised 61 children with SPLAD hospitalized at the Allergy Center, National Center for Child Health and Development, from 2002 to 2017. We examined patient characteristics, blood test results, and prognoses up to 3 years, including frequency of topical corticosteroid-(TCS) use and food intake status. RESULTS: All participants improved hypoproteinemia and electrolyte abnormalities with AD treatment alone, without intravenous fluids. We performed proactive therapy to maintain remission by gradually decreasing the frequency of TCS-use. After 1, 2, and 3 years, 77%, 92%, and 95%, respectively, remission was maintained by using TCS 2 days a week or less, whereas 39% did not require TCS after 3 years. No participants received systemic therapy, including systemic steroids, immunosuppressants, or biologics. We observed that 29% of infants younger than 1 year at admission had eliminated one or more egg, milk, or wheat component after 3 years. CONCLUSIONS: Even in patients with SPLAD, the most severe AD, TCS-use may be reduced to 2 days per week or less after 3 years with appropriate skin treatment.

[A CASE OF EOSINOPHILIC GASTROENTERITIS FOUND BY PICA DURING ORAL IMMUNOTHERAPY].

Eosinophilic esophagitis has been reported as a complication of oral immunotherapy (OIT), but there are only a few reports of eosinophilic gastroenteritis (EGE) occurring after OIT. EGE causes eosinophil infiltration into the gastrointestinal (GI) tract and is characterized by various digestive symptoms. We report the case of a 6-year-old boy with EGE. He was diagnosed as having immediate-type food allergies (egg, milk and wheat) by oral food challenges at 1 year of age. OIT for each food was carried out, and the amounts of the offending foods were able to be gradually increased without causing any immediate-type allergy symptoms. However, the total IgE and specific IgE values were remarkably increased at the age of 4 years and 4 months. He first developed oral mucosa symptoms and vomiting at 4 years and 10 months of age, and they gradually worsened. Stopping eggs and milk alleviated the symptoms. Nevertheless, he still occasionally vomited. He started Pica eating disorder (sand and sponge) due to anemia from 5 years and 10 months of age and developed eosinophilia without diarrhea or bloody stool. Upper and lower GI tract endoscopic examinations found no bleeding. The GI mucosa showed eosinophil infiltration of more than 40/high-power field in the stomach and duodenum, so he was diagnosed with EGE. No eosinophils were found in the esophageal mucosa. His GI symptoms and anemia improved on a multiple-food-elimination diet. Patients undergoing OIT should be closely followed up for a long time, and those with GI symptoms should be evaluated by GI endoscopy.

International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: Executive summary-Workgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy, Asthma & Immunology.

Food protein-induced enterocolitis (FPIES) is a non-IgE cell- mediated food allergy that can be severe and lead to shock. Despite the potential seriousness of reactions, awareness of FPIES is low; high-quality studies providing insight into the pathophysiology, diagnosis, and management are lacking; and clinical outcomes are poorly established. This consensus document is the result of work done by an international workgroup convened through the Adverse Reactions to Foods Committee of the American Academy of Allergy, Asthma & Immunology and the International FPIES Association advocacy group. These are the first international evidence-based guidelines to improve the diagnosis and management of patients with FPIES. Research on prevalence, pathophysiology, diagnostic markers, and future treatments is necessary to improve the care of patients with FPIES. These guidelines will be updated periodically as more evidence becomes available.

Randomized controlled trial of oral immunotherapy for egg allergy in Japanese patients.

BACKGROUND: Egg allergy is one of the most common food allergies in young children. While oral immunotherapy (OIT) is not routinely recommended in current guidelines, it has been considered as a potential alternative treatment strategy. Studies on OIT for food allergy have been explored, but no controlled trials have been reported in Japan. METHODS: The first oral food challenge (OFC) was performed before treatment to ensure diagnosis and evaluate the threshold dose for egg using the double-blind, placebo-controlled food challenge. Participants were randomly assigned by computerized algorithm to receive OIT using egg (OIT group) or no egg (egg elimination [EE] group). A second OFC was performed in both groups approximately 6 months after therapy. Blood samples were collected and egg white-specific immunoglobulin (Ig)E and IgG4 were measured before and after the treatment period. RESULTS: Eight of the 14 patients (57%) in the OIT group had no allergic reaction to 4 g dry egg powder whereas none of the 16 patients in the EE group did. All 14 patients in the OIT group had increased threshold for egg powder in the second OFC compared with baseline. There was no significant change in egg white-specific IgE level during therapy. After therapy, egg white-specific IgG4 increased significantly in the OIT group, but not in the EE group. CONCLUSION: OIT is effective in increasing the threshold for allergens and inducing desensitization in Japanese egg allergy patients, similarly to North American and European patients.

Racial differences in eosinophilic gastrointestinal disorders among Caucasian and Asian.

BACKGROUND: Although there is an increasing number of eosinophilic gastrointestinal disorders (EGID) cases including eosinophilic esophagitis (EoE) and eosinophilic gastroenteritis (EGE), being reported globally, no systematic reviews have been conducted to elucidate the racial differences in these disorders. We aimed to show the racial differences, especially among Caucasians and Asians, in the risk of EoE and EGE. METHODS: We conducted a systematic review using PubMed in September 2012. All case reports and case series on EGID that involved human subjects and described race or ethnicity, as well as pathological findings, were included. For the comparison of reported cases between Caucasians and Asians, a chi-squared test was used. RESULTS: Among the 687 studies found in PubMed, 121 studies fulfilled the eligibility criteria. In total, 2621 patients were reviewed. Among Caucasian EGID patients, 94% had EoE; while among Asian EGID patients, 72% had EGE (p < 0.001). Among EoE, Asians were significantly less likely to have dysphagia and heartburn, but more likely to have vomit and abdominal pain, compared to Caucasians (p < 0.001). Further, among EGE, Asians were significantly more likely to have eosinophil-infiltrated colon than Caucasians (OR: 3.22, 95% confidence interval [CI]: 1.60-7.04), but were less likely to have eosinophil-infiltrated stomach (OR: 0.29, 95% CI: 0.17-0.49). CONCLUSIONS: We found that EoE occurs more frequently in Caucasian EGID patients than Asian EGID patients, while the reverse is true for EGE. Also, racial disparities in symptoms and eosinophil-infiltrated tissues were observed. Our findings suggest further genetic and environmental studies to elucidate the etiology of EGID.

Comparison of gene expression profiles in eosinophilic esophagitis (EoE) between Japan and Western countries.

BACKGROUND: The prevalence rate of eosinophilic esophagitis (EoE) between Japan and Western countries is quite different. Although multiple factors, including the genetic background, lifestyle and dietary habits, may account for the difference, the pathogenic mechanism of EoE has not been fully clarified in Japanese. To elucidate whether EoE's pathogenic mechanisms differ between those populations, we performed transcriptome analysis of esophageal biopsy specimens from Japanese EoE patients and compared the identified gene signatures with published microarray data for EoE patients in the US. METHODS: We prospectively enrolled adult Japanese EoE patients (n = 4) according to the 2011 consensus guidelines for diagnosis of EoE. Age-matched healthy volunteer subjects (n = 4) were also enrolled as controls. We assessed the gene expression profiles of esophageal biopsies using microarray technology and then compared the identified gene signatures with earlier data generated in the US. RESULTS: Of 42,545 transcripts represented on the microarray, 385 were differentially expressed between the EoE and control samples (≥2 fold change and adjusted p-value of <0.05). Our microarray data showed strong overlapping with the data from US patients with EoE. An EoE-specific-transcript signature is typically composed of IL-13-inducible and eosinophil-related genes, including eotaxin-3/C-C chemokine ligand 26 (CCL26). CONCLUSIONS: This transcriptome study suggests that the pathogenetic mechanisms of EoE in Japan and Western countries are similar. Our findings may contribute to a better understanding of the pathogenesis of EoE and to more accurate diagnosis of this disease in Japanese individuals.

Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations.

Asthma is a complex phenotype influenced by genetic and environmental factors. We conducted a genome-wide association study (GWAS) with 938 Japanese pediatric asthma patients and 2,376 controls. Single-nucleotide polymorphisms (SNPs) showing strong associations (P<1×10(-8)) in GWAS were further genotyped in an independent Japanese samples (818 cases and 1,032 controls) and in Korean samples (835 cases and 421 controls). SNP rs987870, located between HLA-DPA1 and HLA-DPB1, was consistently associated with pediatric asthma in 3 independent populations (P(combined) = 2.3×10(-10), odds ratio [OR] = 1.40). HLA-DP allele analysis showed that DPA1*0201 and DPB1*0901, which were in strong linkage disequilibrium, were strongly associated with pediatric asthma (DPA1*0201: P = 5.5×10(-10), OR = 1.52, and DPB1*0901: P = 2.0×10(-7), OR = 1.49). Our findings show that genetic variants in the HLA-DP locus are associated with the risk of pediatric asthma in Asian populations.

Salivary cortisol response to stress in young children with atopic dermatitis.

Poor responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis under stress may be one explanation for stress-induced exacerbation of atopic dermatitis (AD) symptoms. In previous studies, children and adults with AD showed attenuated salivary cortisol responses to psychosocial stress, suggesting hyporesponsiveness of the HPA axis, but few studies have been conducted in young children, who are vulnerable to systemic side effects of topical corticosteroid (TCS) therapy. We evaluated whether salivary cortisol responses to the stress of venipuncture in young children with AD were related to the severity of AD or performance of TCS therapy. We studied 38 young children with AD (median age 16.5 mos, range 3-66 mos) being treated at our outpatient unit. Patients were divided into three groups according to the scoring of atopic dermatitis index: mild (n = 12), moderate (n = 14), and severe (n = 12). To evaluate the responsiveness of the HPA axis to stress, salivary cortisol was determined before and after venipuncture. Salivary cortisol responsiveness to stress correlated negatively with severity of AD (p = 0.048) but not with previous use of TCS (p = 0.43) in young children with AD. Our findings suggest that the disease activity of AD, rather than TCS use, is responsible for HPA axis dysfunction in children with AD.