Development and validation of a new asthma questionnaire to help achieve a high level of control in school-age children and adolescents.

BACKGROUND: Maintaining good asthma control minimizes the risk of exacerbations and lung function decline and is a primary goal of asthma management. The Japanese Pediatric Asthma Guidelines (JPGL) employs different classification criteria for control status from other guidelines, stressing a higher level of control. Based on JPGL, we previously developed a caregiver-completed questionnaire for assessing and achieving best asthma control in preschoolers. In this study, we aimed to develop a questionnaire for school-age children and adolescents. METHODS: A working questionnaire comprising 14 items for patients and 34 items for caregivers was administered to 362 asthma patients aged 6-15 years and their caregivers. Separately, physicians filled out a questionnaire to determine JPGL-defined control. Logistic regression analysis was performed to construct a model to predict control levels using data from a randomly selected set of completed questionnaires from two-thirds of the subjects. Validation was performed using the remaining questionnaires. RESULTS: A set of 7 questions, encompassing self-assessed control status at the time of the visit and in the past month, and nocturnal/early morning asthma symptoms for patients and frequency of asthma symptoms, dyspnea, rescue beta-agonist use, and asthma hospitalization for caregivers, were selected and the 7-item model showed a good statistical fit with AIC of 110.5. The model has been named the Best Asthma Control Test for School Children and Adolescents (Best ACT-S). Best ACT-S scores differed significantly in the hypothetical direction among the groups of different JPGL-defined control levels, step-up/down treatment decisions, and presence/non-presence of exacerbations in the previous year. CONCLUSIONS: The Best ACT-S is a valid questionnaire for children/adolescents aiming for best asthma control.

Efficacy and safety of low- and high-dose slow oral egg immunotherapy for hen's egg allergy: Single-center non-inferiority randomized trial.

BACKGROUND: Low-dose oral immunotherapy (OIT) is a safe treatment for hen's egg allergy; however, comparison of its therapeutic effects with those of high-dose OIT has not been reported. OBJECTIVE: To compare the efficacy of low- and high-dose boiled egg-white (EW) OIT for hen's egg allergy. METHODS: Patients with hen's egg allergy were randomly assigned to two groups: OIT using hard-boiled EW with a maximum maintenance dose of 2 and 20 g in the low-dose (L-D) and high-dose (H-D) groups, respectively. The intake dose was ingested twice a week, increased by approximately 20% per week until reaching the target maintenance dose (2 or 20 g hard-boiled EW), and maintained thereafter according to the schedule. The threshold was confirmed via oral food challenge (OFC) after 6 months, and the difference in the proportion of subjects passing the exit OFC between groups was evaluated. RESULTS: Fifty-two patients (L-D, n = 23; H-D, n = 29) were enrolled. Thirty-three patients (L-D, n = 17; H-D, n = 16) completed the 6-month OIT and underwent an exit OFC. In total, three (L-D, 3/17; H-D, 3/16) patients in each group tested negative for an exit OFC with a 20-g reactive dose (p = 1.000). EW-specific IgE levels in both groups decreased significantly after OIT (L-D, p < 0.001; H-D, p = 0.002). CONCLUSIONS: A threshold-elevating effect was observed in the L-D group, not inferior to that in the H-D group. Low-dose OIT may be appropriate to treat hen's egg allergy for the first 6 months.

[OBJECTIVE EVALUATION OF SUBLINGUAL IMMUNOTHERAPY FOR PEDIATRIC ALLERGIC RHINITIS RESPOND TO SQ HOUSE DUST MITE].

BACKGROUND: Sublingual immunotherapy (SLIT) has become applicable to insurance for children in Japan in 2018. However, as for the efficacy of SLIT for children, objective evaluation methods have not been sufficiently investigated. SUBJECTS AND METHODS: We investigated the efficacy of SLIT as both subjective and objective evaluation in 44 children with allergic rhinitis sensitized to house dust mite who started the treatment in the summer of 2018 in our hospital. The children and their patients wrote the allergy diary every day, and in winter/spring/summer vacations, they answered Japanese allergic rhinitis quality of life standard questionnaire and were evaluated with nasal provocation test, blood test, rhinomanometry for 3 years. RESULTS: 29 (66%) of the 44 children continued SLIT for 3 years. Symptom scores, QOL scores, symptom medication scores halved in a year and the effect lasted in the second and third year. Nasal provocation test and rhinomanometry showed significant improvement. Specific IgE increased transiently and then decreased. Specific IgG4 increased annually. CONCLUSION: The present study showed a decrease in scores not only for subjective assessments but also for objective evaluation methods, the house dust nasal provocation test and the nasal airway resistance.

Listeria monocytogenes bacteremia mimicking the systemic metastasis of adrenal cancer: a case report.

BACKGROUND: Listeria monocytogenes is a causative agent of food poisoning and is also known to cause invasive diseases, such as bacteremia, meningitis, and encephalitis, in neonates, elderly and immunocompromised patients. However, the clinical course of a multi-organ disseminated disease secondary to bacteremia has been rarely reported. CASE PRESENTATION: A 76-year-old woman undergoing immunosuppressive therapy for rheumatoid arthritis presented to our outpatient clinic with a chief complaint of weight loss. Computed tomography showed a left adrenal mass, enlarged lymph nodes, and multiple intrahepatic nodules. Positron emission tomography demonstrated accumulation of fluorodeoxyglucose F18 in the adrenal mass, lymph nodes, hepatic nodules, and bones, leading to the suspicion of systemic metastasis of adrenal cancer. She subsequently developed a fever. Blood culture results led to the diagnosis of Listeria monocytogenes bacteremia. Percutaneous needle biopsy of the adrenal lesion revealed no malignant findings. After extended treatment with antimicrobial agents, the fever resolved, along with the disappearance of the systemic lesions. CONCLUSIONS: This case shows that listeriosis can lead to lesions in the adrenal gland, which can exhibit clinical presentation that is difficult to differentiate from malignancy on imaging studies.

[LUNG FUNCTION IN EARLY-PERIOD SCHOOL-AGED ASTHMATIC CHILDREN MAY BE A PREDICTOR OF TREATMENT LEVEL AT ADOLESCENCE].

BACKGROUND: Lung function in early-period school-aged children with asthma influences remission in adolescence. However, there are no reports of this in Japan. OBJECTIVE: This study investigated the influence of lung function in early-period school-aged asthmatic children on medication during adolescence. SUBJECTS AND METHODS: Forty-nine subjects who had visited our hospital at age 6 years or younger were evaluated on March 31, 2018, at the ages of 16 to 18, to determine their asthma treatment step (step 1 to 4). The patients were divided into four groups, and lung function at six years old. RESULTS: The groups for steps 1, 2, 3 and 4 had 11, 13, 6, and 8 participants, respectively. FEV1.0% at six years old for step 1, 2, 3 and 4 had 88.4%, 89.1%, 86.9%, 80.9%, and %V50 had 111.5%, 107.9%, 108.2% and 69.9%, respectively. There were significant differences between the groups of step 4 and 1, 2 regarding FEV1.0% and %V50. CONCLUSION: As for the patient of treatment step 4 of adolescence, lung function decreased at 6 years old in comparison with step 1, 2 patients. Lung function in early-period school-aged asthmatic children may predict the treatment level at adolescence.

Single-Center Noninferiority Randomized Trial on the Efficacy and Safety of Low- and High-Dose Rush Oral Milk Immunotherapy for Severe Milk Allergy.

INTRODUCTION: Oral immunotherapy (OIT) has been reported to be effective but associated with a risk of severe symptoms. Thus, an OIT method with decreased risk is required. OBJECTIVES: We aimed to evaluate the efficacy and safety of low- and high-dose OIT regimens in children with severe milk allergy. METHODS: Overall, 33 participants (median age, 9 years; median final dose of the milk oral food challenge [OFC], 2 mL) were included. The participants were randomly assigned to groups that received either a low (20 mL; n = 19) or high (100 mL; n = 14) maintenance target dose of OIT. The dose was gradually increased to the target dose in the rush escalation phase and was then maintained daily at home. The primary endpoint was the final OFC dose at 6 months of OIT. Adverse events during OIT were evaluated. RESULTS: The final OFC dose after OIT was significantly higher than that before OIT in both groups (low-dose, p = 0.000; high-dose, p = 0.006), but there was no significant difference in the final OFC dose between the 2 groups (p = 0.767). In the maintenance phase, the high-dose group had significantly more severe symptoms than did the low-dose group (0.5%, 11/2,355 total intake events vs. 0.1%, 4/3,230 total intake events; p = 0.018). CONCLUSIONS: An equally increased dose effect was observed for maintenance OIT doses of 20 and 100 mL in children with severe milk allergy. The risk of severe symptoms in the maintenance phase was lower in the low-dose group. A low-dose OIT regimen is recommended for severe milk allergy.

Effectiveness and Safety of Double-Blind, Placebo-Controlled, Low-Dose Oral Immunotherapy with Low Allergen Egg-Containing Cookies for Severe Hen's Egg Allergy: A Single-Center Analysis.

INTRODUCTION: The usefulness of low-dose oral immunotherapy (OIT) for the treatment of egg allergy has been unclear. OBJECTIVE: To evaluate the efficacy and safety of OIT with low allergen cookies (LACs) containing a low dose of hen's egg. METHOD: Thirty-three patients with severe hen's egg allergy were randomly administered either OIT with LACs (n = 21) or placebo (n = 12). Two patients in the LACs group withdrew before completing OIT. The primary endpoint was the number of good responders (G-R), patients with negative results in the oral food challenge (OFC) with a final dose of 2 g hard-boiled egg whites after 4 months of OIT, in each group. Total OFC Aichi score for anaphylaxis/cumulative protein dose (TS/Pro) as the marker of severity of food allergy was also compared. Adverse events during OIT were evaluated using patients' diaries. RESULTS: The proportion of G-R in the LACs group was higher than in the placebo group (7/19 [37%] vs. 1/12 [8%], χ2 test; p = 0.077). The TS/Pro after OIT in the LACs group was lower than in the placebo group (median score, 44.2 vs. 104.1, p = 0.059; Mann-Whitney U test). The threshold and TS/Pro before and after OIT significantly improved in the LACs group (p = 0.015, p = 0.027, respectively; Wilcoxon signed-rank test). There were 99 recorded incidences of symptoms of 1,938 intake events in the LACs group during OIT. Of these, 90 were mild; no severe symptoms occurred. CONCLUSIONS: OIT with LACs potentially increases the OFC threshold and decreases allergy severity and is a relatively safe treatment modality.

THE COMPARISON OF EFFECTIVENESS OF SLOW SPECIFIC ORAL IMMUNOTHERAPY FOR WHEAT ALLERGY USING TWO DIFFERENT INTAKE FREQUENCY.

OBJECTIVE: We performed a constructive study on the effectiveness of oral immunotherapy for wheat allergy using two different intake frequency, and evaluated the impact of intake frequency. SUBJECTS: Of all the subjects who had a positive result in an oral food challenge test for udon (wheat noodles), informed consent was obtained from 49 subjects. Forty-one of the subjects successfully completed testing; data was tabulated for only the 16 in each group who complied with their assigned intake frequency. METHOD: Oral immunotherapy was administered after randomly dividing the subjects into the following two groups according to intake frequency: the frequent group, whose intake was six times/week or more; and the intermittent group, whose intake was two times/week. The ability of these patients to ingest the noodles at the target dose was evaluated after 6 months. RESULTS: After six months, the proportion of subjects who had a negative result on testing with the target dose (20g dried noodle weight for subjects ≤3 years of age, and 50g dried noodle weight for those ≥4 years of age) or who were capable of the target intake within six months was 75%, and there was no difference among the both groups. CONCLUSION: The findings suggest that even when intake frequency is reduced to twice/week, no clear difference is seen with the target dose after six months of immunotherapy.

[The Safety and efficacy of airway-hyperresponsiveness test for asthma using by SK-1211 (Methacholine Chloride)].

BACKGROUND: In abroad, Methacholine Chloride (Provocholine®) is used to meet the indications of the diagnosis of bronchial airway hyperreactivity in subjects who do not have clinically apparent asthma. We examined efficacy, safety and pharmacokinetics of Methacholine Chloride (name of study drug: SK-1211) in order to get approved for the airway hyperresponsiveness test in Japan. METHODS: Fifteen adult healthy volunteers, fifteen adult patients with asthma and ten pediatric patients with asthma were enrolled in this study. The airway hyperresponsiveness test with SK-1211 was conducted in accordance with Japanese Society of Allergology Standard Method. RESULTS: When the threshold value of PC20 was 8 mg/mL, the sensitivity of adult patients with asthma was 66.7% (10/15 subjects) and the specificity of adult healthy volunteers was 86.7% (13/15 subjects). The sensitivity of pediatric patients with asthma was 70.0% (7/10 subjects). Not all subjects experienced some adverse reactions during inhalation of SK-1211, all of which were mild in severity and resolved soon with inhalation of a bronchodilator. There were no serious adverse reactions reported. CONCLUSION: The airway hyperresponsiveness test with SK-1211 was no specific concern with safety and useful in the diagnosis of bronchial airway hyperresponsiveness.

Case Report: A Rare Case of Esophagogastric Junctional Squamous Cell Carcinoma After the Successful Treatment of Neuroendocrine Carcinoma: Clonal Tumor Evolution Revealed by Genetic Analysis.

Neuroendocrine carcinoma (NEC) of the esophagogastric junction (EGJ) is a rare disease with no established treatments. Herein, we describe a case of recurrent squamous cell carcinoma (SCC) after achieving complete response to chemotherapy against NEC of the EGJ. A 67-year-old man was referred to our hospital because of epigastric discomfort. Computed tomography imaging and esophagogastroduodenoscopy revealed ulcerated tumors at the EGJ. Endoscopic biopsy revealed small tumor cells with a high nuclear/cytoplasmic ratio, suggesting small-cell NEC. Immunohistochemistry (IHC) analysis showed tumor cells with an MIB-1 index of 80%. The patient achieved complete response after 10 cycles of chemotherapy. Follow-up endoscopic examination revealed small red-colored mucosal lesions in the center of the cicatrized primary lesion. Re-biopsy detected cancer cells harboring large eosinophilic cytoplasm with keratinization and no evidence of NEC components. IHC of the cells were cytokeratin 5/6-positive and p53-negative. The tumor persisted without evidence of metastases after chemoradiotherapy, and total gastrectomy with lymph node dissection was performed. Pathological assessment of the resected specimens revealed SCC, without evidence of NEC. The patient survived without a recurrence for >3 years after the initial presentation. Somatic mutation profiles of the primary NEC and recurrent SCC were analyzed by targeted amplicon sequencing covering common cancer-related mutations. Both tumors possessed TP53 Q192X mutation, whereas SMAD4 S517T was found only in SCC, suggesting that both tumor components originated from a founder clone with a stop-gain mutation in TP53. The somatic mutation profile of the tumors indicated that that loss of heterozygosity (LOH) at the TP53 gene might have occurred during the differentiation of the founder clone into NEC, while a SMAD4 mutation might have contributed to SCC development, indicating branching and subclonal evolution from common founder clone to both NEC and SCC. The mutation assessments provided valuable information to better understand the clonal evolution of metachronous cancers.

[A case of pancreatic carcinoma presenting as pancreaticopleural fistula with pancreatic pleural effusion].

A 63-year-old man was admitted with left pleural effusion, and an amylase level of 30994IU/l. A diagnosis of pancreaticopleural fistula was made, based on the findings of magnetic resonance cholangiopancreatography and endoscopic retrograde pancreatography (ERP). After the placement of an endoscopic naso-pancreatic drainage tube, the pleural effusion markedly reduced. When ERP was performed for internal drainage, the main pancreatic duct and stricture were biopsied and showed pancreatic ductal adenocarcinoma histologically. CT revealed a mass in the head of the pancreas. He underwent pylorus-preserving pancreaticoduodenectomy. To the best of our knowledge this is the first case of pancreatic carcinoma presenting as pancreaticopleural fistula with pancreatic pleural effusion. Clinicians should pay attention to the possible presence of cancer and pancreaticopleural fistula in patients with pancreatic pleural effusion.

Very short gastroesophageal acid reflux during the upright position could be associated with asthma in children.

BACKGROUND: Gastroesophageal reflux disease (GERD) is diagnosed by the reflux index of 24-hour pH monitoring (pH monitoring). In our previous study, GER episodes during the upright position were more frequent than those during the supine position in asthmatic children. In this study, we investigated the clinical usefulness of the mean hourly number of acid refluxes, designated as the mean number of acid refluxes/hour (h) during the upright position in addition to the pH index for the diagnosis of GERD. METHODS: The subjects were 22 preschool asthmatic children. When the reflux index was over 4% or the mean number of acid refluxes/h during the upright position were three times more frequent than those during the supine position even if the reflux index was below 4%, we prescribed famotidine. Children whose asthmatic symptoms improved with famotidine were included in a GERD group. Children who did not meet the criteria by pH monitoring were included in a non-GERD group in asthmatic children. RESULTS: The GERD group was comprised of 9 children. In 2 out of 9 GERD group children, the reflux index was below 4%. The median of the mean number of acid refluxes/h during the upright position was 12.9 in the GERD group, and 3.15 in the non-GERD group. The mean number of acid refluxes/h during the upright position were associated with asthmatic symptoms (p < 0.05). CONCLUSIONS: Reflux during the upright position was associated with asthmatic symptoms. The mean number of acid refluxes/h during the upright position in addition to the reflux index could be useful in the diagnosis of GERD when associated with asthma.

[Gastroesophageal reflux disease in preschool children with asthma].

BACKGROUND: In pediatric intractable asthma, there is occasionally an association with GERD (gastroesophageal reflux disease). It is not clear in which cases GERD should be suspected or how effective the GERD therapy is in treating the asthma. METHODS: Twenty-seven preschool children (<6 years of age) suffering from recurrent asthma attack in spite of asthma therapy underwent 24-hour esophageal pH monitoring. We examined retrospectively the incidence of GERD and the effectiveness of famotidine in GERD positive patients. RESULTS: 18 of the 27 patients (66.7%) had positive results (GERD positive group). In 12 of the 15 patients (80%) who underwent GERD therapy (famotidine), respiratory symptoms were decreased. In the GERD positive group, the incidence of acid reflux during waking hours was more frequent than during sleeping hours. In 8 of 12 patients (66.7%) in whom famotidine was effective, cough and wheeze often occurred during the daytime and corresponded with the time when acid reflux must commonly occurred. CONCLUSION: We conclude that children suffering from recurrent asthma attack in spite of asthma therapy must be examined for the presence of GERD.

[Influence of changing from chlorofluorocarbon (CFC)-beclomethasone dipropionate (BDP) to hydrofluoroalkane (HFA)-BDP on pulmonary function in asthmatic children].

UNLABELLED: The discontinuation of chlorofluorocarbon- beclomethasone dipropionate (CFC-BDP) products has made it necessary to switch to hydrofluoroalkane (HFA)-BDP. We studied the influence of the changing from CFC-BDP to HFA-BDP on pulmonary function in asthmatic children. METHODS: In twenty asthmatic children (mean: 10.5 years of age) who were clinically well-controlled with CFC-BDP for longer than 6 months, CFC-BDP was switched to HFA-BDP, at half the dose of CFC-BDP. We examined the changes in spirometric parameters at 3-6 months after the switch. RESULTS: FEV1.0% ([FEV1.0/FVC]x100) and %V50 ([V50 measured/V50 predicted]x100) were significantly improved (FEV1.0%: pre 81.7+/-4.7-->post 84.1+/-4.1 [p<0.05], % V50: pre 66.9+/-6.9-->post74.4+/-11.3 [p<0.05]). Comparison between patients with greater than 10% improvement in %V50 and those with less than 10% improvement revealed differences in the duration of using CFC-BDP (former 2.8+/-0.9 years, latter 5.2+/-2.4 years [p<0.05]) despite lack of difference in age at initiation of treatment with CFC-BDP. CONCLUSION: The changing from CFC-BDP to HFA-BDP showed the improvement of lung function in a part of asthmatic children. We should keep in mind that there are some differences of efficacy among the inhaled corticosteroid products. The long-term anti-inflammatory medication should be adjusted to normalize the pulmonary function on the basis of the degree of airway inflammation.

The enigmatic role of the hemochromatosis protein (HFE) in iron absorption.

The HFE gene, a member of the class-I transplantation antigen gene family, is responsible for hereditary hemochromatosis, one of the most common inherited diseases in individuals of European descent. Patients exhibit predictable changes in iron homeostasis, including elevations in both transferrin saturation and serum ferritin levels. A subset of patients progress to overt clinical sequelae, resulting from iron overload. A hallmark of the disease is increased absorption of iron by the intestine. Although the HFE protein appears to modulate the function of the transferrin receptor in vitro, its precise role in vivo remains obscure. With multiple cell types involved in iron metabolism, the function of HFE is likely to be complex.

Hemochromatosis protein (HFE) and tumor necrosis factor receptor 2 (TNFR2) influence tissue iron levels: elements of a common gut pathway?

Quantitative genetic analysis of hepatic and splenic iron levels in recombinant inbred mice yielded a quantitative trait locus that was found to coincide with the genomic locale encompassing the tumor necrosis factor receptor 2 gene (Tnfr2). When fed an iron-enriched diet, mice nullizygous with respect to Tnfr2, but not the Tnfr1 gene, showed a significant increase in splenic non-heme iron levels. This result contrasted with mice deficient in the hemochromatosis protein, HFE, which demonstrated a significant increase in normally high hepatic iron levels, but no change in splenic iron, when fed an iron-enriched chow. Both Tnfr2 knockout and HFE knockout mice fed an iron-enriched diet failed to demonstrate intestinal epithelial cell iron following the application of the Perls' stain, as compared to both Tnfr1 knockout and normal control mice. Moreover, intestinal intraepithelial lymphocytes (IELs) isolated from HFE knockout mice did not show an increase in TNF expression following challenge with the iron-enriched diet, in contrast to normal controls. These results suggest that HFE and TNFR2 are both involved in regulating iron deposition in tissues and that the regulation occurs at the level of the intestine through IEL-orchestrated production of TNF following the binding to TNFR2. These data suggest that HFE and TNFR2 may contribute to a common pathway of the iron stores regulator insuring the controlled efflux of gut iron.