Effect of oral immunotherapy in children with milk allergy: The ORIMA study.

BACKGROUND: This study was aimed at evaluating the efficacy and safety of oral immunotherapy (OIT) in children with severe cow's milk allergy. METHODS: The subjects comprised 28 children (aged 3-12 years) with allergic symptoms that were induced by ≤ 10 mL of cow's milk in an oral food challenge test (OFC). The subjects were randomly allocated to the treatment group (n = 14) and control group (n = 14); the former received rush immunotherapy for 2 weeks, followed by a gradual increase of cow's milk volume to 100 mL for 1 year, and the latter completely eliminated cow's milk for 1 year. Both groups underwent an OFC with 100 mL of cow's milk after 1 year. RESULTS: The treatment group had significantly higher rates of a negative OFC [7/14 (50%) vs. 0/14 (0%), p < 0.01] compared with the control group. The cow's milk-specific IgE level significantly decreased in the treatment group (p < 0.01) but not in the control group (p = 0.63). During the study period, adrenaline was required in 6/14 patients (43%) of the treatment group and in 0/14 patients (0%) of the control group. Long follow-up data were available at the 2-year point after the study for 8 in the treatment group and 7 (87.5%) of these continued to ingest milk (>100 mL). CONCLUSIONS: The effect of immunotherapy was 50%, but the incidence of adverse events was not low. Further studies focusing on safety is necessary to standardize OIT for cow's milk allergy.

Low-dose l-isoproterenol versus salbutamol in hospitalized pediatric patients with severe acute exacerbation of asthma: A double-blind, randomized controlled trial.

BACKGROUND: Although the guidelines in most countries do not recommend continuous inhalation of l-isoproterenol to treat pediatric patients with acute severe exacerbation of asthma, lower dose of l-isoproterenol has been widely used in Japan. To determine whether the efficacy of low-dose l-isoproterenol was superior to that of salbutamol, we conducted a double-blind, randomized controlled trial. METHODS: Hospitalized patients aged 1-17 years were eligible if they had severe asthma exacerbation defined by the modified pulmonary index score (MPIS). Patients were randomly assigned (1:1) to receive inhalation of l-isoproterenol (10 µg/kg/h) or salbutamol (500 µg/kg/h) for 12 hours via a large-volume nebulizer with oxygen. The primary outcome was the change in MPIS from baseline to 3 hours after starting inhalation. Trial registration number UMIN000001991. RESULTS: From December 2009 to October 2013, 83 patients (42 in the l-isoproterenol group and 41 in the salbutamol group) were enrolled into the study. Of these, one patient in the l-isoproterenol group did not receive the study drug and was excluded from the analysis. Compared with salbutamol, l-isoproterenol reduced MPIS more rapidly. Mean (SD) changes in MPIS at 3 hours were -2.9 (2.5) in the l-isoproterenol group and -0.9 (2.3) in the salbutamol group (difference -2.0, 95% confidence interval -3.1 to -0.9; P < 0.001). Adverse events occurred in 1 (2%) and 11 (27%) patients in the l-isoproterenol and salbutamol groups, respectively (P = 0.003). Hypokalemia and tachycardia occurred only in the salbutamol group. CONCLUSIONS: Low-dose l-isoproterenol has a more rapid effect with fewer adverse events than salbutamol.

Up-regulation of serum periostin and squamous cell carcinoma antigen levels in infants with acute bronchitis due to respiratory syncytial virus.

BACKGROUND: Periostin and squamous cell carcinoma antigen (SCCA) are involved in the pathogenesis of asthma. Acute bronchitis due to respiratory syncytial virus (RSV) infection during infancy exhibits an asthma-like pathogenesis, suggesting that it may be associated with the subsequent development of asthma. However, the mechanism by which RSV infection leads to development of asthma has not yet been fully elucidated. METHODS: Infants younger than 36 months were enrolled and classified into three groups. Group I included patients hospitalized with RSV-induced bronchitis. These patients were further stratified into two sub-groups according to whether the criteria for the modified Asthma Predictive Index (mAPI) had been met: Group I consisted of mAPI (+) and mAPI (-) patients; Group II included patients with food allergy as a positive control group; and Group III included children with no allergy as a negative control group. Serum periostin and SCCA levels were measured in the groups. This study was registered as a clinical trial (UMIN000012339). RESULTS: We enrolled 14 subjects in Group I mAPI (+), 22 in Group I mAPI (-), 18 in Group II, and 18 in Group III. In Group I, the serum periostin and SCCA levels were significantly higher during the acute phase compared with the recovery phase. However, no significant differences were found between Group I mAPI (+) and mAPI (-). CONCLUSIONS: The serum periostin and SCCA levels increased during acute RSV bronchitis. Both periostin and SCCA may play a role in the pathogenesis of acute bronchitis due to RSV.

Periostin as a biomarker for the diagnosis of pediatric asthma.

BACKGROUND: There are some biomarkers for asthma diagnosis but they are often difficult in clinical use, particularly in pediatric cases. Periostin is an extracellular matrix protein, upregulated in response to IL-4 or IL-13. Serum periostin is expected to be used as a non-invasive biomarker for asthma diagnosis and management. METHODS: Twenty-eight children with asthma (BA) and 27 children without asthma (patients with pectus excavatum, etc. as control group) aged 6-16 years were included. Bronchial asthma was diagnosed according to International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Fractional exhaled nitric oxide (FeNO), lung function, blood eosinophil counts, total immunoglobulin E (IgE) levels, and serum periostin levels were assessed. Results were compared between BA and controls. Asthma diagnostic accuracies were calculated using receiver operating characteristics (ROC) curve analyses. RESULTS: Serum periostin levels in the BA group were significantly higher than those in the control group [medians (with interquartile ranges), 134.0 (116.3-166.3) vs. 112.0 (97.0-132.0) ng/ml; p = 0.012]. The area under the ROC curve (AUC) for periostin, FeNO, and eosinophil counts were 0.70, 0.72, and 0.84, respectively. After the exclusion of controls with pectus excavatum, AUC for periostin, forced expiratory volume in 1 s (FEV1 ), and maximum mid-expiratory flow rate (MMF) were 0.75, 0.74, and 0.80, respectively. CONCLUSION: Serum periostin levels were significantly higher in children with asthma. ROC AUC values for periostin were equivalent to conventional biomarkers, including FeNO levels and lung function testing, indicating the utility of serum periostin levels in diagnosing asthma in children.

Optimal step-down approach for pediatric asthma controlled by salmeterol/fluticasone: A randomized, controlled trial (OSCAR study).

BACKGROUND: Several guidelines, including the Japanese Pediatric Guideline for the Treatment and Management of Asthma (JPGL), recommend salmeterol/fluticasone combination therapy (SFC) as step 3 to 4 treatment for moderate to severe asthma. However, the optimal step-down approach to SFC remains unclear. In the current study, we examined step-down approaches in asthmatic children whose symptoms had been stabilized by SFC 100/200 µg/day. METHODS: This randomized, multicenter, open-label, parallel-group study was conducted over 12 weeks. For step-down therapy, subjects aged 5-15 years were randomly assigned to an SFC group (25/50 µg b.i.d.) or an FP group (100 µg b.i.d.), and treated for 12 weeks. Childhood Asthma Control Test (C-ACT) scores, lung function, and exhaled nitric oxide (FeNO) levels were monitored. RESULTS: Of 131 enrolled subjects, 128 completed the study and were included in the analysis. Decreases in % peak expiratory flow rate and % forced expiratory flow at 50% of vital capacity (V50) were observed in the FP group at each time point. There was a significant difference between the two groups for the change in %V50 from its previous value at each time point. There were no significant changes in FeNO levels (range 15-20 ppb) or C-ACT scores (∼26 points) within or between groups. CONCLUSIONS: A high level of asthma control was maintained with both approaches. The use of SFC step-down resulted in somewhat better respiratory function, with no worsening of airway inflammation. However, halving the dose of SFC and switching to FP alone are both optimal step-down approaches.

Treatment and managements of pediatric asthma.

In Japan, pediatric asthma is managed based on the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2012 (JPGL 2012). JPGL 2012 also recommends treat- ment and management aimed at complete control through avoiding exacerbation factors and appropriate use of anti-inflammatory drugs. In this review, we describe an overview of the newer treatment options available for treatment and management of pediatric asthma and some topics.

Olfactory dysfunction in Japanese children with moderate-to-severe allergic rhinitis.

OBJECTIVE: Detailed quantitative studies on olfaction remain inadequate in patients with paediatric allergic rhinitis (AR). This study examined olfactory dysfunction in children with AR. METHODS: From July 2016 to November 2018, children aged 6-9 years were recruited and grouped as AR (n = 30) or without AR (control group, n = 10). Odour identification was evaluated by the Universal Sniff (U-Sniff) test and the Open Essence (OE). The results were compared between the AR and control groups. Intranasal mucosa findings, nasal smear eosinophil counts, blood eosinophil counts, total immunoglobulin E (IgE) levels, Japanese cedar-specific IgE and Dermatophagoides pteronyssinus-specific IgE were evaluated in all participants. Additionally, the presence of sinusitis and adenoid hypertrophy in patients with AR was also evaluated by sinus X-ray examinations. RESULTS: The median U-Sniff test scores were not significantly different between the AR and control groups (9.0 vs. 10.0, respectively; p = 0.107). The OE score was significantly lower in the AR group than in the control group (4.0 vs. 8.0; p = 0.007, respectively), especially in the moderate-to-severe AR group versus the control group (4.0 vs. 8.0; p = 0.004). Furthermore, in the OE, the correct answer rates for 'wood', 'cooking gas' and 'sweaty socks' were significantly lower in the AR group than in the control group. CONCLUSIONS: Paediatric AR patients can reduce olfactory identification ability, and the degree may be associated with the severity of AR in nasal mucosal findings. Furthermore, olfactory dysfunction may slow down the response to 'emergency situations', such as gas leak.

Effects of the tulobuterol patch on the treatment of acute asthma exacerbations in young children.

The tulobuterol patch (TP) is a beta(2)-adrenergic agonist with a favorable pharmacokinetic profile used for asthma management in Japan. Because it contains tulobuterol in a molecular, crystallized form that is gradually absorbed percutaneously, TP exerts a prolonged bronchodilator effect exceeding 24 hours. Although it is a well-established treatment for asthma and wheezing, few studies have investigated whether it can reduce or prevent the symptoms associated with upper respiratory tract infections (URTIs) in young children. This study evaluated the effect of TP on the long-term management of asthma in young children. In this 1-year, randomized, multicenter, double-blind, placebo-controlled study, children aged 0.5-3 years old with mild-to-moderate persistent asthma were treated with either TP or placebo patch. The parents/guardians applied the TP or placebo patch to their children after URTI symptoms appeared. Respiratory symptoms were recorded daily during the 1-year observation period. Overall, 86 patients were enrolled and 80 were treated and analyzed in this study. All patients had been treated with anti-inflammatory drugs before enrollment. The time to symptom resolution was significantly shorter (p = 0.001) and the total respiratory symptom score (p = 0.0457) was significantly lower in the TP group than in the placebo group. In young children with mild-to-moderate asthma who had been treated with anti-inflammatory drugs, using the TP soon after the appearance of URTI symptoms led to quicker resolution of respiratory symptoms and lower respiratory symptom scores.

Effects of the tulobuterol patch on the treatment of acute asthma exacerbations in young children.

The tulobuterol patch (TP) is a beta2-adrenergic agonist with a favorable pharmacokinetic profile used for asthma management in Japan. Because it contains tulobuterol in a molecular, crystallized form that is gradually absorbed percutaneously, TP exerts a prolonged bronchodilator effect exceeding 24 hours. Although it is a well-established treatment for asthma and wheezing, few studies have investigated whether it can reduce or prevent the symptoms associated with upper respiratory tract infections (URTIs) in young children. This study evaluated the effect of TP on the long-term management of asthma in young children. In this 1-year, randomized, multicenter, double-blind, placebo-controlled study, children aged 0.5-3 years old with mild-to-moderate persistent asthma were treated with either TP or placebo patch. The parents/guardians applied the TP or placebo patch to their children after URTI symptoms appeared. Respiratory symptoms were recorded daily during the 1-year observation period. Overall, 86 patients were enrolled and 80 were treated and analyzed in this study. All patients had been treated with anti-inflammatory drugs before enrollment. The time to symptom resolution was significantly shorter (p = 0.001) and the total respiratory symptom score (p = 0.0457) was significantly lower in the TP group than in the placebo group. In young children with mild-to-moderate asthma who had been treated with anti-inflammatory drugs, using the TP soon after the appearance of URTI symptoms led to quicker resolution of respiratory symptoms and lower respiratory symptom scores.

Successful sublingual immunotherapy for severe egg allergy in children: a case report.

BACKGROUND: Egg allergy is one of the most common food allergies in children. To date, oral immunotherapy (OIT) has been considered as a promising treatment option for egg allergy. However, safety issues remain concerning severe adverse events requiring epinephrine injection. Hence, establishing a safer method to treat egg allergy would be beneficial. We report here two children with egg allergy who were safely treated with sublingual immunotherapy (SLIT) before transitioning to OIT. CASE PRESENTATION: Patient 1 was a 7-year-old girl and Patient 2 was a 5-year-old girl. Although OIT for egg had been attempted in both patients, severe anaphylactic symptoms were induced by ingesting only 0.1 g of heated whole egg. Therefore, SLIT was conducted with aqueous suspensions consisting of water and heated whole egg powder. Suspensions were administered sublingually, kept in the mouth for 2 min, and spat out immediately thereafter. SLIT was continued for 7 months for Patient 1 and 8 months for Patient 2 due to the exploratory character of the study. Afterwards, the patients successfully transferred to low-dose OIT with 1 g of heated whole egg (≒170 mg of egg protein) daily, and are continuing the therapy as of June 2020. As for adverse reactions, Patient 1 expressed oral cavity itchiness once at the beginning of SLIT. Patient 2 had no adverse reaction. The levels of antigen-specific IgE decreased in both patients after SLIT, and further decreased after switching to OIT. CONCLUSIONS: Few clinical studies have evaluated the efficacy and safety of SLIT for egg allergy. Although the treatment was conducted in only two patients, our results have shown that SLIT is a promising treatment procedure for egg allergy. Further clinical trials will be needed to additionally assess the efficacy and safety of SLIT in children with food allergy.

Hypoxia-inducible factor 1alpha induces corticosteroid-insensitive inflammation via reduction of histone deacetylase-2 transcription.

Corticosteroids are potent anti-inflammatory agents, but corticosteroid insensitivity is a major barrier for the treatment of some chronic inflammatory diseases. Here, we show that hypoxia induces corticosteroid-insensitive inflammation via reduced transcription of histone deacetylase-2 (HDAC2) in lung epithelial and macrophage cells. HDAC2 mRNA and protein expression was reduced under hypoxic conditions (1% O(2)). Hypoxia enhanced interleukin-1beta-induced interleukin-8 (CXCL8) production in A549 cells and decreased the ability of dexamethasone to suppress the CXCL8 production. Deletion or point mutation studies revealed that binding of the transcription factor hypoxia-inducible factor (HIF) 1alpha to a HIF response element at position -320, but not HIF-1beta or HIF-2alpha, results in reduced polymerase II binding at the site, leading to reduced promoter activity of HDAC2. Our results suggest that activation of HIF-1alpha by hypoxia decreases HDAC2 levels, resulting in amplified inflammation and corticosteroid resistance.

Increased leukotriene E4 in the exhaled breath condensate of children with mild asthma.

BACKGROUND: Chronic airway inflammation is a feature of asthma. Increased levels of cysteinyl leukotrienes (cys-LTs; leukotriene [LT]C(4), LTD(4), LTE(4)) have been shown in the exhaled breath condensate (EBC) of children with moderate-to-severe asthma. The aim of this study was to examine the relationship between EBC cys-LTs (LTE(4)) levels and bronchial hyperreactivity in children with mild asthma in order to evaluate the clinical utility of measuring EBC cys-LTs levels. METHODS: We measured LTE(4) levels in the EBC of children aged 8 to 18 years, including healthy nonasthmatic children (n = 6) and children with mild asthma (n = 37). Patients with mild asthma were classified into the following three groups: group 1, participants who had been asymptomatic (no wheezing/symptoms of asthma) for > 6 months prior to examination (n = 12); group 2, participants who were asymptomatic but had had wheezing/symptoms of asthma within 6 months before examination (n = 18); and group 3, patients with current wheeze and/or mild symptoms of asthma exacerbation at the time of examination. RESULTS: Exhaled LTE(4) levels were increased in all children with mild asthma compared with nonasthmatic control subjects (5.69 +/- 9.62 pg/20 min vs 0.74 +/- 0.79 pg/20 min, p < 0.05) [mean +/- SD]. In particular, the EBC LTE(4) levels in group 2 (4.99 +/- 6.70 pg/20 min) and group 3 (14.66 +/- 17.11 pg/20 min) were increased compared with control subjects and group 1 (1.50 +/- 1.69 pg/20 min). The EBC LTE(4) levels negatively correlated with the provocative concentration of methacholine causing a 15% fall in FEV(1) (r = - 0.454, p = 0.012). CONCLUSION: EBC cys-LTs may be useful as a noninvasive marker assessing airway inflammation and hyperreactivity in children with asthma.

Late volar plate repair for chronic, post-traumatic hyperextension deformity of the proximal interphalangeal joint of the little finger.

A chronic traumatic hyperextension of the proximal interphalangeal (PIP) joint can result from traumatic volar plate (VP) disruption. For the treatment of this disorder, reconstruction procedures have been traditionally recommended, because the condition of the VP was not considered susceptible to repair due to retraction or attenuation. The purpose of this paper is to present the operative technique and report the clinical results of late VP repair. Late VP repair was performed for chronic, post-traumatic hyperextension deformity of the PIP joint of the little finger resulting from VP disruption in seven consecutive patients. The range of motion and the lateral stability of the PIP joint were evaluated. The radiographic images were also used to evaluate the alignment and degenerative changes of the PIP joint. Clinical results were classified according to Catalano's criteria. Intraoperative findings showed that the VP could be mobilised and repaired in all cases. The hyperextension was well corrected, and none showed recurrence of the initial deformity. Average flexion of the PIP joint was 92° (range = 75-98°), and flexion contracture was 9° (range = 0-20°). On clinical evaluation, there were two excellent, three good, and two fair results. The postoperative radiographs revealed no degenerative change in the PIP joint in six patients. Late VP repair is a successful and reliable alternative and more physiologic than other reconstruction methods. One should first consider late VP repair, despite a long interval between injury and repair.

Passive smoking impairs histone deacetylase-2 in children with severe asthma.

BACKGROUND: Parental smoking is known to worsen asthma symptoms in children and to make them refractory to asthma treatment, but the molecular mechanism is unclear. Oxidative stress from tobacco smoke has been reported to impair histone deacetylase-2 (HDAC2) via phosphoinositide-3-kinase (PI3K)/Akt activation and, thus, to reduce corticosteroid sensitivity. The aim of this study was to investigate passive smoking-dependent molecular abnormalities in alveolar macrophages (AMs) by comparing passive smoke-exposed children and non-passive smoke-exposed children with uncontrolled severe asthma. METHODS: BAL fluid (BALF) was obtained from 19 children with uncontrolled severe asthma (10 non-passive smoking-exposed subjects and nine passive smoking-exposed subjects), and HDAC2 expression/activity, Akt/HDAC2 phosphorylation levels, and corticosteroid responsiveness in AMs were evaluated. RESULTS: Parental smoking reduced HDAC2 protein expression by 54% and activity by 47%, with concomitant enhancement of phosphorylation of Akt1 and HDAC2. In addition, phosphorylation levels of Akt1 correlated positively with HDAC2 phosphorylation levels and negatively with HDAC2 activity. Furthermore, passive smoke exposure reduced the inhibitory effects of dexamethasone on tumor necrosis factor-α-induced CXCL8 release in AMs. There were relatively higher neutrophil counts and CXCL8 concentrations in BALF and lower Asthma Control Test scores compared with non-passive smoke-exposed children with uncontrolled severe asthma. CONCLUSIONS: Passive smoking impairs HDAC2 function via PI3K signaling activation, which could contribute to corticosteroid-insensitive inflammation in children with severe asthma. This novel mechanism will be a treatment target in children with severe asthma and stresses the need for a smoke-free environment for asthmatic children.

Sputum plasminogen activator inhibitor-1 elevation by oxidative stress-dependent nuclear factor-κB activation in COPD.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is an important regulator of fibrinolysis at sites of vascular injury and thrombus formation. Recently, sputum PAI-1 was reported to be elevated in COPD. However, the mechanism of PAI-1 elevation in COPD has yet to be clarified. Here, we show that PAI-1 elevation in COPD is closely associated with oxidative stress-induced nuclear factor κB (NF-κB) activation. METHODS: Patients and control subjects were recruited from the outpatient department of Royal Brompton Hospital, local general practice, and the National Heart and Lung Institute. Sputum samples were obtained, and sputum sample processing was performed to obtain sputum supernatants and sputum macrophages. RESULTS: The mean PAI-1 level in COPD sputum (1.92 ± 3.11 ng/mL, n = 32) was higher than that of both age-matched smokers without COPD (0.48 ± 0.63 ng/mL, n = 11) and healthy nonsmokers (0.55 ± 1.11 ng/mL, n = 9). Sputum PAI-1 significantly correlated with sputum malondialdehyde (MDA) in COPD (r = 0.59, P < .001). In addition, NF-κB activity in sputum macrophages (three control and seven COPD subjects) significantly correlated with both sputum PAI-1 (r = 0.72, P < .05) and sputum MDA (r = 0.78, P < .01). An in vitro study showed that both hydrogen peroxide and cigarette smoke-conditioned medium induced PAI-1 production in A549 cells, and the production was inhibited by an inhibitor of I κB kinase-ß in a concentration-dependent manner. Furthermore, histone deacetylase 2 (HDAC2) knockdown by RNA interference, a mimic of oxidative-stress-dependent HDAC2 reduction, enhanced tumor necrosis factor-α-induced PAI-1 induction (half maximal effective concentration [EC50], 0.64 ± 0.19 ng/mL in HDAC2-KD, 7.64 ± 3.70 ng/mL in control) concomitant with enhancement of NF-κB p65 acetylation and NF-κB DNA-binding activity. CONCLUSIONS: Oxidative stress, directly or indirectly via HDAC reduction, plays a role in PAI-1 expression in COPD via activation of NF- κ B.

Defect of adaptation to hypoxia in patients with COPD due to reduction of histone deacetylase 7.

BACKGROUND: Hypoxia inducible factor (HIF)-1 plays an important role in cellular adaptation to hypoxia by activating oxygen-regulated genes such as vascular endothelial growth factor (VEGF) and erythropoietin. Sputum VEGF levels are reported to be decreased in COPD, despite hypoxia. Here we show that patients with COPD fail to induce HIF-1α and VEGF under hypoxic condition because of a reduction in histone deacetylase (HDAC) 7. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from patients with moderate to severe COPD (n = 21), smokers without COPD (n = 12), and nonsmokers (n = 15). PBMCs were exposed to hypoxia (1% oxygen, 5% CO(2), and 94% N(2)) for 24 h, and HIF-1α and HDAC7 protein expression in nuclear extracts were determined by sodium dodecyl sulfate poly acrylamide gel electrophoresis (SDS-PAGE)/Western blotting. RESULTS: HIF-1α was significantly induced by hypoxia in each group when compared with the normoxic condition (12-fold induction in nonsmokers, 24-fold induction in smokers without COPD, fourfold induction in COPD), but induction of HIF-1α under hypoxia was significantly lower in patients with COPD than in nonsmokers and smokers without COPD (P < .05 and P < .01, respectively). VEGF messenger RNA detected by quantitative real-time polymerase chain reaction was correlated with HIF-1α protein in nuclei (r = 0.79, P < .05), and HDAC7 protein expression was correlated with HIF-1α protein in nuclei (r = 0.46, P < .05). HDAC7 knockdown inhibited hypoxia-induced HIF-1α activity in U937 cells, and HIF-1α nuclear translocation and HIF-1α binding to the VEGF promoter in A549 cells. CONCLUSIONS: HDAC7 reduction in COPD causes a defect of HIF-1α induction response to hypoxia with impaired VEGF gene expression. This poor cellular adaptation might play a role in the pathogenesis of COPD.