Two Japanese Pediatric Patients With Primary Ciliary Dyskinesia Caused by Loss-of-Function Variants in the CCNO gene.

Primary ciliary dyskinesia (PCD) is a rare congenital disorder caused by pathogenic variants of genes related to cilia. Here, we report two Japanese pediatric patients with PCD caused by pathogenic compound heterozygous variants in the cyclin O (CCNO) gene (Case 1, NM_021147.4:c.[262C>T];[781delC], p.[Gln88Ter];[Leu261fs]; Case 2, c.[262C>T];[c.248_252dupTGCCC], p.[Gln88Ter];[Gly85fs]). The clinical symptoms of the patients were varied. Neither of the patients had situs inversus. Transmission electron microscopy of the respiratory cilia from the nasal mucosa in Case 1 showed a remarkable reduction of cilia and the few residual cilia had central pair defects and microtubular disorganization.

Practical guide for the diagnosis and management of primary ciliary dyskinesia.

OBJECTIVE: Primary ciliary dyskinesia (PCD) is a relatively rare genetic disorder that affects approximately 1 in 20,000 people. Approximately 50 genes are currently known to cause PCD. In light of differences in causative genes and the medical system in Japan compared with other countries, a practical guide was needed for the diagnosis and management of Japanese PCD patients. METHODS: An ad hoc academic committee was organized under the Japanese Rhinologic Society to produce a practical guide, with participation by committee members from several academic societies in Japan. The practical guide including diagnostic criteria for PCD was approved by the Japanese Rhinologic Society, Japanese Society of Otolaryngology-Head and Neck Surgery, Japanese Respiratory Society, and Japanese Society of Pediatric Pulmonology. RESULTS: The diagnostic criteria for PCD consist of six clinical features, six laboratory findings, differential diagnosis, and genetic testing. The diagnosis of PCD is categorized as definite, probable, or possible PCD based on a combination of the four items above. Diagnosis of definite PCD requires exclusion of cystic fibrosis and primary immunodeficiency, at least one of the six clinical features, and a positive result for at least one of the following: (1) Class 1 defect on electron microscopy of cilia, (2) pathogenic or likely pathogenic variants in a PCD-related gene, or (3) impairment of ciliary motility that can be repaired by correcting the causative gene variants in iPS cells established from the patient's peripheral blood cells. CONCLUSION: This practical guide provides clinicians with useful information for the diagnosis and management of PCD in Japan.

Is oral food challenge test useful for avoiding complete elimination of cow's milk in Japanese patients with or suspected of having IgE-dependent cow's milk allergy?

BACKGROUND: Cow's milk, along with hen's egg, are common causes of food allergies in children worldwide. Accidental ingestion of milk is common and often induces severe allergic reactions. Oral food challenge test (OFC) is usually performed in patients with or suspected of having a food allergy. However, the evidence of whether cow's milk OFC is useful in IgE-dependent cow's milk allergy patients to avoid total elimination is not known. METHODS: After setting the clinical question and outcomes, we performed a systematic review for relevant articles published from January 1, 2000 to August 31, 2019 using PubMed® and Ichushi-Web databases. Each article was then evaluated for the level of evidence. All positive results of the OFC were defined as adverse events. RESULTS: Forty articles were selected in this study. Our review revealed that cow's milk OFC was able to avoid the complete elimination of cow's milk in 66% of the patients with cow's milk allergy. We also found that adverse events occurred frequently (50.5%). CONCLUSIONS: This analysis supports the recommendation of conducting cow's milk OFC to avoid complete elimination of cow's milk, however the test should be conducted with careful consideration of the patient's safety. As the methods of OFC and subjects varied among the articles selected in this study, further studies are needed to obtain higher quality evidence.

Wheezing Characteristics and Predicting Reactivity to Inhaled ß2-Agonist in Children for Home Medical Care.

Background: Given that wheezing is treated with inhaled ß2-agonists, their effect should be reviewed before the condition becomes severe; however, few methods can currently predict reactivity to inhaled ß2-agonists. We investigated whether preinhalation wheezing characteristics identified by lung sound analysis can predict reactivity to inhaled ß2-agonists. Methods: In 202 children aged 10-153 months, wheezing was identified by auscultation. Lung sounds were recorded for 30 s in the chest region on the chest wall during tidal breathing. We analyzed the wheezing before and after ß2-agonist inhalation. Wheezing was displayed as horizontal bars of intensity defined as a wheeze power band, and the wheezing characteristics (number, frequency, and maximum intensity frequency) were evaluated by lung sound analysis. The participants were divided into two groups: non-disappears (wheezing did not disappear after inhalation) and disappears (wheezing disappeared after inhalation). Wheezing characteristics before ß2-agonist inhalation were compared between the two groups. The characteristics of wheezing were not affected by body size. The number of wheeze power bands of the non-responder group was significantly higher than those of the responder group (P < 0.001). The number of wheeze power bands was a predictor of reactivity to inhaled ß2-agonists, with a cutoff of 11.1. The 95% confidence intervals of sensitivity, specificity, and positive and negative predictive values were 88.8, 42, 44, and 81.1% (P < 0.001), respectively. Conclusions: The number of preinhalation wheeze power bands shown by lung sound analysis was a useful indicator before treatment. This indicator could be a beneficial index for managing wheezing in young children.

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.

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.

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.