Predictors of Persistent Milk Allergy in Children: A Retrospective Cohort Study.

BACKGROUND: Cow's milk (CM) allergy is the second most common food allergy developed during infancy in Japan. To identify predictors of persistent CM allergy, we investigated the tolerance acquisition rate based on an oral food challenge in children under 6 years of age, diagnosed with immediate-type CM allergy. METHODS: This retrospective cohort study included 131 children born in 2005 with a history of immediate allergic reaction to CM, of whom 39 were excluded because of ongoing oral immunotherapy (n = 18) or a lack of follow-up data (n = 21). The 92 remaining participants were followed for 6 years. Tolerance was defined as no adverse reaction to 200 mL of CM and regular intake of milk at home. Subjects were divided into 3 groups based on age at tolerance acquisition: group I (<3 years; n = 31), group II (3-6 years; n = 42), and group III (persistent allergic group; n = 19). RESULTS: Tolerance acquisition rates by 3, 5, and 6 years of age were 32.6% (30/92), 64.1% (59/92), and 84.8% (70/92), respectively. Age at first hospital visit was significantly higher in groups II and III than in group I (p < 0.001). The incidence of anaphylaxis to other foods was also higher in group III than in group I (p = 0.04), as was CM-induced anaphylaxis (p = 0.03). Furthermore, milk and casein-specific immunoglobulin E (IgE) levels were significantly higher in group III than in group II after birth and remained high thereafter (p < 0.05). CONCLUSIONS: The history of anaphylaxis and high milk-specific IgE levels were associated with persistent CM allergy.

Predictors of Persistent Wheat Allergy in Children: A Retrospective Cohort Study.

BACKGROUND: Wheat allergy is the third most common food allergy that develops during infancy in Japan. To identify factors associated with persistent wheat allergy, we assessed the rate of tolerance acquisition among Japanese children aged less than 6 years with an immediate-type wheat allergy using the oral food challenge (OFC) method. METHODS: This retrospective cohort study included 83 children (born in 2005-2006) who had a history of immediate-type allergic reaction to wheat and were followed until 6 years of age. The subjects were divided to form "tolerant" (n = 55; tolerance acquired by 6 years of age) and "allergic" (n = 28; tolerance not acquired by 6 years of age) groups based on their OFC results. RESULTS: The rates of tolerance acquisition to 200 g of udon noodles at 3, 5, and 6 years of age were 20.5% (17/83), 54.2% (45/83), and 66.3% (55/83), respectively. The total number of anaphylactic reactions experienced prior to 3 years of age in response to all foods (p < 0.01) and to wheat (p = 0.043) was significantly higher in the allergic than in the tolerant group. Wheat- and ω-5 gliadin-specific immunoglobulin E (IgE) levels were significantly higher in the allergic group than in the tolerant group (p < 0.01), and wheat-specific IgE levels were more likely to increase after infancy in the allergic group. CONCLUSIONS: A history of anaphylaxis to all foods including wheat and/or a high level of wheat- or ω-5 gliadin-specific IgE antibodies were identified as risk factors for persistent wheat allergy.

Natural history of immediate-type hen's egg allergy in Japanese children.

BACKGROUND: Hen's egg (HE) allergy develops during infancy. We investigated tolerance acquisition in Japanese children allergic to HE aging <6 years. METHODS: In this retrospective study, 226 children born in 2005 with a history of immediate-type HE allergy underwent an oral food challenge (OFC). Tolerance was defined as no reaction to an OFC with half of whole heated HE or accidental HE consumption at home. Participants were divided into three groups based on age at tolerance acquisition: group I (<3 years) (n = 66), group II (3-6 years) (n = 98), and group III (prolonged allergic groups) (n = 62). RESULTS: Tolerance acquisition occurred in 30% (66/226) by 3 years of age, 59% (133/226) by 5 years of age, and 73% (164/226) at 6 years of age. At 3 years, incidences of allergy-related complications (bronchial asthma, p = 0.02; atopic dermatitis, p = 0.04) were higher in the group III than in the group I. Anaphylaxis to any food occurred more frequently in the group III than in the group I (p = 0.03); anaphylaxis to HE was more common in the group III (p = 0.04). Egg white (EW)- and ovomucoid (OM)-specific immunoglobulin E (IgE) levels were higher in the group III than in the group I (p < 0.05). CONCLUSIONS: The group III experienced HE-related anaphylaxis and complications more frequently and exhibited sustained, high EW- and OM-specific IgE levels.

Analysis of inflammatory signals in Japanese children with Crohn's disease.

BACKGROUND: Although it is recognized that the Th1 and Th17 cytokines are directly involved in the pathogenesis of Crohn's disease (CD), the precise cause of pediatric CD in the Japanese population has not been well established. In the present study, we examined the expression of pro-inflammatory cytokines and their signaling molecules in the intestinal mucosa of Japanese children with acute- and remission-phase CD. METHODS: A total of 11 children with acute-phase CD (mean age 10.32 ± 6.02 years) and 20 children with remission-phase CD (mean age 11.87 ± 4.29 years) provided samples for a serum cytokine assay. Among these children, seven with acute-phase CD (mean age 13.63 ± 1.94 years), six with remission-phase CD (mean age 9.93 ± 4.33 years), and six healthy controls (mean age 9.90 ± 4.88 years) provided samples for a signaling assay. Among this group, the expression of Th1, Th2, Th17, and regulatory T-cell signaling molecules were examined by real-time polymerase chain reaction. RESULTS: A significant elevation in the serum level of interleukin-6 and tumor necrosis factor-α was confirmed in pediatric patients with acute-phase CD compared to patients with remission-phase CD (P < 0.01 and 0.05, respectively). The mucosal expression of interferon-γ, signal transducer and activator of transcription 4, and transforming growth factor-ß1 were significantly enhanced in pediatric patients with acute-phase CD compared to patients with remission-phase CD or those with normal mucosa. CONCLUSIONS: These results suggest the possible involvement of Th1 and Th17 signaling in the pathogenesis of CD in Japanese children.

Pulse steroids as induction therapy for children with ulcerative colitis.

BACKGROUND: Corticosteroids therapy, classically the first-line treatment for ulcerative colitis (UC), often causes serious side-effects. Theoretically, pulse steroid therapy where high doses are given for a shorter period may have maximal beneficial effects and minimal side-effects as induction therapy for UC. We have therefore retrospectively compared induction therapy using pulse steroids with conventional steroid treatment for children and adolescents with moderate-to-severe UC. METHODS: We utilized conventional steroid treatment (prednisolone 1-1.5 mg/kg/day) as an induction treatment in 17 UC patients between 1985 and 2006. Alternatively we used a 3-day megadose pulse steroid therapy (methylprednisolone intravenously 20-30 mg/kg/day, max. 1000 mg/day) in 20 UC patients from 1993 to 2006. RESULTS: Pulse steroid therapy successfully induced rapid remission in UC patients with moderate-to-severe disease compared with conventional treatment (13.2 days vs 25.1 days; P < 0.05). The amelioration of Pediatric Ulcerative Colitis Activity Index score between before and 1 week after pulse steroid therapy was significantly more than that of conventional treatment (P < 0.01). No serious adverse effects were observed in the patients treated with pulse steroid therapy. However, the rate of the relapse episodes during the next 12 months after pulse steroid therapy was not significantly different from that after conventional treatment. CONCLUSION: These findings suggest that pulse steroid therapy is an option to be considered in children with moderate-to-severe UC.

Wheeze Recognition Algorithm for Remote Medical Care Device in Children: Validation Study.

BACKGROUND: Since 2020, peoples' lifestyles have been largely changed due to the COVID-19 pandemic worldwide. In the medical field, although many patients prefer remote medical care, this prevents the physician from examining the patient directly; thus, it is important for patients to accurately convey their condition to the physician. Accordingly, remote medical care should be implemented and adaptable home medical devices are required. However, only a few highly accurate home medical devices are available for automatic wheeze detection as an exacerbation sign. OBJECTIVE: We developed a new handy home medical device with an automatic wheeze recognition algorithm, which is available for clinical use in noisy environments such as a pediatric consultation room or at home. Moreover, the examination time is only 30 seconds, since young children cannot endure a long examination time without crying or moving. The aim of this study was to validate the developed automatic wheeze recognition algorithm as a clinical medical device in children at different institutions. METHODS: A total of 374 children aged 4-107 months in pediatric consultation rooms of 10 institutions were enrolled in this study. All participants aged ≥6 years were diagnosed with bronchial asthma and patients ≤5 years had reported at least three episodes of wheezes. Wheezes were detected by auscultation with a stethoscope and recorded for 30 seconds using the wheeze recognition algorithm device (HWZ-1000T) developed based on wheeze characteristics following the Computerized Respiratory Sound Analysis guideline, where the dominant frequency and duration of a wheeze were >100 Hz and >100 ms, respectively. Files containing recorded lung sounds were assessed by each specialist physician and divided into two groups: 177 designated as "wheeze" files and 197 as "no-wheeze" files. Wheeze recognitions were compared between specialist physicians who recorded lung sounds and those recorded using the wheeze recognition algorithm. We calculated the sensitivity, specificity, positive predictive value, and negative predictive value for all recorded sound files, and evaluated the influence of age and sex on the wheeze detection sensitivity. RESULTS: Detection of wheezes was not influenced by age and sex. In all files, wheezes were differentiated from noise using the wheeze recognition algorithm. The sensitivity, specificity, positive predictive value, and negative predictive value of the wheeze recognition algorithm were 96.6%, 98.5%, 98.3%, and 97.0%, respectively. Wheezes were automatically detected, and heartbeat sounds, voices, and crying were automatically identified as no-wheeze sounds by the wheeze recognition algorithm. CONCLUSIONS: The wheeze recognition algorithm was verified to identify wheezing with high accuracy; therefore, it might be useful in the practical implementation of asthma management at home. Only a few home medical devices are available for automatic wheeze detection. The wheeze recognition algorithm was verified to identify wheezing with high accuracy and will be useful for wheezing management at home and in remote medical care.

Monitoring 6-thioguanine nucleotide concentrations in Japanese children and adolescents with inflammatory bowel disease.

BACKGROUND AND AIM: 6-Mercaptopurine (6-MP) and azathioprine (AZA) are widely used as maintenance therapy in children with inflammatory bowel disease (IBD). However, proper 6-thioguanine nucleotide (6-TGN) concentrations in Japanese children with IBD have not been reported. METHODS: This retrospective review examines 32 ulcerative colitis (UC) patients and 19 Crohn's disease (CD) patients (12.87 ± 3.56 years) who required 6-MP or AZA to maintain disease remission. All patients were treated with 6-MP or AZA for at least 3 weeks prior to this study in addition to previous treatment. 6-MP dose, 6-TGN levels, assayed by high-performance liquid chromatography, as well as laboratory data were evaluated. RESULTS: Thirty-five children were successfully kept in remission with 6-MP and AZA therapy after weaning off corticosteroids. Overall, 123 measurements (59 active disease, 64 in remission) were analyzed. The mean 6-TGN concentration of the entire study population was 499.61 ± 249.35 pmol/8 × 10(8) red blood cell. The mean 6-MP dose in patients with active disease (0.910 ± 0.326 mg/kg per day) was significantly higher than for patients in remission (0.749 ± 0.225) (P = 0.0016). A significant inverse correlation was found between white blood cell counts and 6-TGN concentrations (r = 0.275, P < 0.002). Two patients experienced leukopenia with alopecia, and four transiently experienced increased serum levels of pancreatic enzymes, although no thiopurine S-methyl transferase mutations were confirmed. CONCLUSION: The doses of 6-MP or AZA needed to maintain remission in Japanese children with IBD are lower than those reported in Western countries. However, 6-TGN concentrations in this population are higher than previously reported.

Increased mucosal expression of GATA-3 and STAT-4 in pediatric ulcerative colitis.

BACKGROUND: Serum pro-inflammatory cytokine levels are frequently elevated in the acute phase of pediatric inflammatory bowel disease (IBD). Because the role of pro-inflammatory cytokine in the acute phase of pediatric IBD has not been well investigated, the serum levels of pro-inflammatory cytokines and the expression of Th1 and Th2 signaling molecules in mucosa from the acute phase of pediatric IBD were examined. METHODS: Twenty children with ulcerative colitis (UC; mean age, 9.95 ± 4.10 years) and 12 with Crohn's disease (CD; mean age, 10.0 ± 4.90 years) were enrolled for the serum cytokine (interleukin [IL]-4, IL-5, IL-6, tumor necrosis factor-α, tumor growth factor-ß1, and interferon-γ) assay. Expression of T-helper cell 1 (Th1) (T-box expressed in T cells: T-bet and signal transducer and activator of transcription-4: STAT-4) and Th2 (GATA-3 and STAT-6) signaling molecules was examined on real-time polymerase chain reaction using mucosal samples from eight children in the acute phase of UC, eight with CD and eight controls. RESULTS: Significant elevation of serum IL-4 and IL-6 levels was detected at the acute phase of pediatric UC and CD compared with levels at remission (P < 0.05 in each). The mucosal expression of GATA-3 and STAT-4 was significantly enhanced in the acute phase of pediatric UC compared with normal mucosa. No significant difference was observed in the expression of all examined molecules in the acute phase of pediatric CD. CONCLUSIONS: IL-4 and its signaling molecule GATA-3, as well as the Th1 signaling molecule STAT-4, are involved in the pathogenesis of acute phase of pediatric UC.

Estimation of postoperative fat absorption using the 13C mixed-triglyceride breath test in children with choledochal cyst.

No previous studies have focused on postoperative fat malabsorption in children with choledochal cyst (CC) who undergo cyst excision and Roux-en-Y (RY) hepatico-jejunostomy (HJ), a combination of procedures that can lead to the non-physiological mixture of food and bile juice. To examine the effect of RYHJ with cholecystectomy on the fat absorption ability of children with CC, we estimated postoperative fat-absorption ability using the carbon 13-labeled mixed triglyceride (13C-MTG) breath test. Twelve postoperative children with CC and 12 normal control children were administered 13C-MTG orally and asked to give breath samples at six time points: once before the 13C-MTG ingestion and at five 60-min intervals postingestion. Fecal chymotrypsin activity and fecal fat excretion were also measured. The delta value of breath 13CO2 at 3, 4, and 5 h after administration and the 5-h cumulative breath 13CO2 were significantly lower in the CC children than in the controls. There were no significant differences in the fecal chymotrypsin activity or fecal fat excretion of the two groups. Conclusion. Occult fat malabsorption occurs in patients with CC after RYHJ, even in the absence of clinical symptoms or abnormal laboratory data.

A review of biomarkers for predicting clinical reactivity to foods with a focus on specific immunoglobulin E antibodies.

PURPOSE OF REVIEW: The purpose of this study is to assess the latest studies that focus on specific immunoglobulin (Ig)E antibodies for predicting clinical reactivity to foods. RECENT FINDINGS: Persistent hen's egg and cow's milk allergy patients have higher antigen-specific IgE levels at all ages than those who have outgrown these allergies. Recent studies on the natural histories of hen's egg and cow's milk allergies suggested that baseline antigen-specific IgEs are the most important predictors of tolerance. Oral immunotherapy (OIT), which is a novel therapeutic approach for food allergy, requires biomarkers for predicting outcomes after therapy. Several studies indicate that the initial antigen-specific IgE level may be a useful biomarker for the prognosis of OIT. Recently, component-resolved diagnostics (CRD) has been used for food allergy diagnosis. Current studies have suggested that Ara h 2, omega-5 gliadin and ovomucoid are good diagnostic markers for peanut, wheat and egg allergies, respectively. SUMMARY: Antigen-specific IgE can be a useful biomarker for predicting clinical reactivity to food allergies. Monitoring hen's egg and cow's milk-specific IgE is useful for predicting prognosis, and baseline specific IgE levels may be associated with the outcome of OIT. The use of CRD provides us with a better tool for diagnosing food allergy.

Effects of leukotriene receptor antagonists on peripheral eosinophil counts and serum IgE levels in children with food allergy.

BACKGROUND: Although the efficacy of leukotriene receptor antagonists (LTRAs) for bronchial asthma is already established, their effect on food allergy remains unclear. OBJECTIVE: To investigate the efficacy of LTRAs in children with food allergy. METHODS: This retrospective study examined 65 children with food allergy who were aged between 3 and 36 months (mean 14 ± 9.6 months) from 2005 to 2008. Thirty-two children were treated as a dietary control group by avoiding any antigenic foods to which they had previously experienced adverse reactions. The remaining 33 children, designated the LTRA group, were treated with pranlukast (7 mg/kg bodyweight/day) in addition to maintaining dietary control. Clinical symptoms and laboratory data before and after 1 year of treatment were compared between the groups. RESULTS: Allergic symptoms improved in both the dietary controlled and LTRA groups, and there was no significant difference observed in the clinical parameters examined between the groups after the 1-year trial. Peripheral eosinophil count, serum IgE, interleukin (IL)-4, IL-5, IL-6, and eosinophil cationic protein (ECP) levels in children with food allergy were above standardized values in both groups. Although both the dietary controlled and LTRA groups showed a decreased eosinophil count (-273 ± 232 vs -595 ± 295/µL; p < 0.05 and p < 0.001, respectively), only children treated with LTRA showed a significant decrease in serum IgE (-73.5 ± 115 IU/mL; p < 0.01); conversely, the control group exhibited a significant increase in serum IgE (+159 ± 138 IU/mL; p < 0.01). Furthermore, the LTRA group also showed a significant decrease in serum IL-4 (54.5 ± 31.0 to 27.3 ± 10.1 pg/mL), IL-5 (6.7 ± 5.2 to 5.0 ± 0.4 pg/mL), and ECP (45.4 ± 15.0 to 15.0 ± 9.8 µg/L) levels (p < 0.05 for each). CONCLUSION: Early intervention with LTRAs may be effective in regulating eosinophil count and serum IgE, IL-4, IL-5, and ECP levels. These data support the potential effectiveness of LTRAs in young children with food allergy to prevent further allergic development.