Asthma and other allergic diseases are among the most prevalent chronic non-communicable diseases of childhood. According to the World Health Organization, asthma affects >7.0 million children under 18 in the United States, with an economic burden that is estimated to exceed that of tuberculosis and HIV/AIDS combined. Despite much research, the natural history of asthma and its pathogenesis are still in many ways elusive. This review discusses our current understanding of the role epigenetic processes play in asthma pathogenesis, focusing on genome-wide, population-based studies.

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Basophils and mast cells play important roles in host defense against parasitic infections and allergic responses. Several progenitor populations, either shared or specific, for basophils and⁄or mast cells have been identified, thus elucidating the developmental pathways of these cells. Multiple transcription factors essential for their development and the relationships between them have been also revealed. For example, IRF8 induces GATA2 expression to promote the generation of both basophils and mast cells. The STAT5-GATA2 axis induces C⁄EBPα and MITF expression, facilitating the differentiation into basophils and mast cells, respectively. In addition, C⁄EBPα and MITF mutually suppress each other's expression. This review provides an overview of recent advances in our understanding of how transcription factors regulate the development of basophils and mast cells.

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A number of studies have suggested that a large subset of children (approximately 70%) who react to unheated milk or egg can tolerate extensively heated forms of these foods. A diet that includes baked milk or egg is well tolerated and appears to accelerate the development of regular milk or egg tolerance when compared with strict avoidance. However, the indications for an oral food challenge (OFC) using baked products are limited for patients with high specific IgE values or large skin prick test diameters. Oral immunotherapies (OITs) are becoming increasingly popular for the management of food allergies. However, the reported efficacy of OIT is not satisfactory, given the high frequency of symptoms and requirement for long-term therapy. With food allergies, removing the need to eliminate a food that could be consumed in low doses could significantly improve quality of life. This review discusses the importance of an OFC and OIT that use low doses of causative foods as the target volumes. Utilizing an OFC or OIT with a low dose as the target volume could be a novel approach for accelerating the tolerance to causative foods.

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Background: Studies have addressed the immunomodulatory effects of helminths and their protective effects upon asthma. However, anti-Ascaris IgE has been reported to be associated with an increased risk of asthma symptoms. We examined the association between serum levels of anti-Ascaris IgE and bronchial hyper-responsiveness (BHR) in children living in rural Bangladesh. Methods: Serum anti-Ascaris IgE level was measured and the BHR test done in 158 children aged 9 years selected randomly from a general population of 1705 in the Matlab Health and Demographic Surveillance Area of the International Centre for Diarrhoeal Disease Research, Bangladesh. We investigated wheezing symptoms using a questionnaire from the International Study of Asthma and Allergies in Childhood. BHR tests were successfully done on 152 children (108 ‘current wheezers’; 44 ‘never-wheezers’). We exam- ined the association between anti-Ascaris IgE level and wheezing and BHR using multiple logistic regression analyses. Results: Of 108 current-wheezers, 59 were BHR-positive; of 44 never-wheezers, 32 were BHR-negative. Mean anti-Ascaris IgE levels were significantly higher (12.51 U_A/ml; 95% confidence interval (CI), 9.21 -17.00) in children with current wheezing with BHR-positive than in those of never-wheezers with BHR- negative (3.89; 2.65-5.70; t test, p < 0.001). A BHR-positive test was independently associated with anti-Ascaris IgE levels with an odds ratio (OR) =7.30 [95% CI, 2.28-23.33], p = 0.001 when adjusted for total IgE, anti-Dermatophagoides pteronyssinus IgE, pneumonia history, parental asthma, Trichuris infection, forced expiratory volume in one second, eosinophilic leukocyte count, and sex. Conclusions: Anti-Ascaris IgE level is associated with an increased risk of BHR among 9-year-old rural Bangladeshi children.

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Background: Asian dust (AD) has become a major health concern. The concentration of AD is typically expressed in particulate matter less than 10 μm (PM₁₀) and 2.5 μm (PM_2.5). However, PM₁₀ and PM_2.5 consist of various substances besides AD. Light detection and ranging (LIDAR) systems can selectively measure the quantity of AD particles to distinguish non-spherical airborne particles from spherical airborne particles. The objective of this study was to investigate the relationship between pulmonary function in adult asthma patients and AD using LIDAR data. Methods: Subjects were 231 adult asthma patients who had their morning peak expiratory flow (PEF) measured from March to May 2012. A linear mixed model was used to estimate the association of PEF with sand dust particles detected by LIDAR. Results: Increases in the interquartile range of AD particles (0.018 km^-1) led to changes in PEF of -0.42 L/ min (95% confidence interval [CI], -0.85 to 0.01). An increase of 11.8 μg/m³ in suspended particulate matter and 6.9 μg/m³ in PM_2.5 led to decreases of -0.17 L/min (-0.53 to 0.21) and 0.03 L/min (-0.35 to 0.42), respectively. A heavy AD day was defined as a day with a level of AD particles >0.032 km^-1, which was the average plus one standard deviation during the study period, and six heavy AD days were identified. Change in PEF after a heavy AD day was -0.97 L/min (-1.90 to -0.04). Conclusions: Heavy exposure to AD particles was significantly associated with decreased pulmonary function in adult asthma patients.

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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.

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Background: IL-33, a member of the IL-1 cytokine family, binds to heterodimeric receptors ST2 and IL-1 receptor accessory protein, and activates Th2-type immune responses. The signals from the ST2 receptor are mediated by the two major pathways, including AP-1 and NF- κB molecules. The present study examined whether IL-33 induced ICAM-1 expression in bone marrow-derived mast cells (BMMCs). Methods: BMMCs from C57BL/6J mice, cultured in media containing IL-3 (20 ng/ml), were treated with IL-33 (50 ng/ml) for up to 72 h. ICAM-1 expression with mRNA and protein, degranulation of siRNA ICAM-1 transfected BMMCs, and cell adhesion were analyzed. In the in vivo part of the experiment rIL-33 (500 ng) was injected intradermally into the ear pinnae of mice and any resulting pathological changes were assessed. Results: ICAM-1 mRNA expression was increased one hour after IL-33 stimulation while ICAM-1 protein attained maximum expression levels 24 h after IL-33 stimulation. Moreover, IL-33-treated BMMCs showed increased cell adhesion to the LFA-1-coated plate. However, siRNA ICAM-1 trans- fected BMMCs did not affect Ag/IgE-mediated degranulation level compared to the wild control siRNA. Pre-treatment with a NF-κB inhibitor dramatically reduced ICAM-1 expression in IL-33-treated BMMCs, suggesting the involvement of NF-kB in the process. In vivo study, at 6 h after IL-33 treat- ment, MCs histologically showed up-regulated ICAM-1 expression though the number of tryptase- positive cells did not change. Conclusions: These data suggest that MCs increase ICAM-1 expression and activate LFA-1 positive cells in the early phase of skin inflammation in response to IL-33.

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Background: Allergic rhinitis is one of the most common chronic diseases in children. Although it has a large impact on the patient's quality of life, little is known about the factors associated with its severity. The aim of this study was to assess the factors associated with the severity of rhinoconjunctivitis among children in the general population. Methods: A survey was conducted using an online research panel in 2012. Parents were asked to answer an International Study of Asthma and Allergies in Childhood-based questionnaire to identify children with current rhinoconjunctivitis and evaluate factors associated with the severity of its symptoms. Severity was rated according to the degree of impairment caused by the symptoms in the patient's daily life. Results: Among 26,725 children aged 6-12 years old, rhinoconjunctivitis was defined in 5175 (19.4%), and of these, 688 children (13.3% of children with current rhinoconjunctivitis) presented severe symptoms. Living in areas with a high cedar and cypress pollen count and having concurrent eczema were associated with severe rhinoconjunctivitis [adjusted OR (95% CI): 1.21 (1.00-1.46) and 1.45 (1.20-1.75), respectively]. Further, a maternal history of asthma and allergic rhinitis was a significant risk factor for severe rhinoconjunctivitis [1.34 (1.04-1.74) and 1.30 (1.10-1.53), respectively]. However, living with fur- bearing animals (pets) before 1 year of age proved to be a protective factor against severe rhino- conjunctivitis [0.70 (0.52-0.94)]. Conclusions: Environmental factors such as pets and pollen, together with comorbidities and a maternal history of allergic diseases, play an important role in determining the severity of rhinoconjunctivitis.

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Background: The increasing incidence and prevalence of atopic dermatitis (AD) demands new thera- peutic approaches for treating the disease. We investigated the therapeutic efficacy of immunomodulator FTY720 ointment (fingolimod) for mite-induced intractable AD using an NC/Nga mouse model. Methods: Female NC/Nga mice that developed severe AD were divided into four groups: (1) FTY720 (0.001% FTY720 ointment), (2) tacrolimus (tacrolimus hydrate ointment) (3) betamethasone (betame- thasone ointment), and (4) ointment base (hydrophilic petrolatum), all of which received treatment six times per week. Therapeutic efficacy after two weeks was evaluated in terms of AD severity, histo- chemical observations (epidermal hypertrophy, mast cell accumulation, and CD3⁺ T cell infiltration), transepidermal water loss (TEWL), and epidermal barrier function (filaggrin expression). Results: Betamethasone treatment showed little effect, confirming that the AD was intractable. In the FTY720 group, AD improved significantly compared with the ointment base group, as did epidermal hypertrophy, mast cell accumulation, and CD3⁺ T cell infiltration. In contrast, AD in the tacrolimus and betamethasone groups did not improve significantly, nor did epidermal hypertrophy or mast cell accumulation. Furthermore, in the FTY720 group, TEWL decreased significantly compared with the ointment base group, and filaggrin expression significantly increased compared with the betamethasone and ointment base groups. Conclusions: FTY720 ointment is a promising candidate for treatment of intractable AD. These findings also provide the first evidence that FTY720 ointment ameliorates epidermal barrier function.

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Background: Many patients with vocal cord dysfunction (VCD), with or without asthma, receive inap- propriate treatment because they are misdiagnosed as having difficult-to-control asthma alone. We developed a clinical screening check list designed to aid the diagnosis of VCD. Methods: A prospective observational study involving 80 patients aged ≥18 years, diagnosed with severe asthma. After anamnesis and physical examination, physicians completed a check list with 6 questions to identify VCD, for which the answer “yes” counted one point. Then patients underwent spirometry and laryngoscopy. On the basis of the laryngoscopic findings, we created three patient groups: VCD (vocal cord adduction during inspiration, n =14); unconfirmed VCD (inconclusive findings, n = 29); and control (normal findings, n = 37). We attempted to determine whether any of those groups were associated with the responses to individual questions or sets of questions on the check list. Results: The proportion of affirmative answers to the question “Does pulmonary auscultation reveal wheezing, predominantly in the cervical region, and/or stridor?” was significantly higher for the VCD group than for the other two groups (P = 0.006), notably in elderly patients. The variable “4 or more affirmative answers” was more common in VCD and unconfirmed VCD groups in comparison to controls (P = 0.022). Conclusions: A finding of wheezing or stridor on auscultation of the cervical region is suggestive of vocal cord dysfunction, especially in elderly patients, and such dysfunction can be confirmed through laryn- goscopy. Our VCD screening check list proved to be useful in the screening of VCD among patients with severe asthma.

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Background: Some western countries recently have shown a slowdown in the incidence of allergic diseases after worldwide increasing trends, but there are few data from Asian populations concerning changing trend of allergic diseases. We evaluated the recent trends in the prevalence of asthma and other allergic diseases in Korea. Methods: From the database of Korean National Health Insurance, a nationwide diagnostic data from 2009 to 2014 were extracted and the national prevalence was analyzed. Results: The prevalence per 1000 people of atopic dermatitis, allergic rhinitis, and asthma in 2014 was 19.0, 133.1, and 36.3, respectively. The prevalence of three diseases was highest in the age group under 10 as, 95.0, 384.1, and 132.1 per 1000 people, while the prevalence in the over-10-year-group was only 11.6, 109.5, and 27.3, respectively. The prevalence of atopic dermatitis and allergic rhinitis gradually decreased with older age, but the prevalence of asthma showed a re-increasing pattern from the age group 30-39 and reached another peak for the age group 70-79. During the study period, the prevalence of asthma and atopic dermatitis showed decreasing tendency. In contrast, the prevalence of allergic rhinitis steadily increased until 2013, especially in the age group under 10. Conclusions: The national prevalence of atopic dermatitis, and asthma did not show noticeable increase any more in Korea. However, the prevalence of allergic rhinitis still on the rise until recently, especially in the age group under 10. This is the first report in Asia suggesting a slowdown of the incidence of allergic diseases.

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Background: Second hand tobacco smoke (SHS) and overweight/obesity are risk factors for asthma and lower airway respiratory symptoms. We investigated whether SHS or overweight/obesity were also associated with allergic or non-allergic rhinitis. Methods: Cross-sectional data were obtained during the second SAPALDIA Study. Interviewer adminis- tered questionnaires were completed by 8047 participants from 8 communities in Switzerland. Blood was collected from 5841 participants and tested for allergen specific IgE. Allergic rhinitis was defined as nasal symptoms with detectable IgE. Data were analysed by multinomial logistic regression with four outcome categories defined according to the presence or absence of rhinitis and/or atopy. Results: The prevalence of allergic rhinitis was 885 (15.2%) and non-allergic rhinitis 323 (5.5%). The risk of allergic rhinitis was increased in subjects with physician diagnosed asthma (Relative Risk Ratio 6.81; 95%CI 5.39, 8.6), maternal atopy (1.56; 1.27, 1.92) and paternal atopy (1.41; 1.11, 1.79). Older subjects were at lower risk (0.96; 0.95,0.97 per year), as were those raised on a farm (0.64; 0.49,0.84), with older siblings (0.92; 0.86,0.97 per sib) or from rural areas. The risk of non-allergic rhinitis was also increased in subjects with physician diagnosed asthma (4.02; 2.86, 5.67), reduced in males (0.59; 0.46, 0.77), but not associated with upbringing on a farm or older siblings. There were no significant associations of SHS or overweight/obesity with either form of rhinitis. Conclusions: Allergic and non-allergic rhinitis have different risk factors apart from asthma. There are significant regional variations within Switzerland, which are not explained by the factors examined.

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Background: Total nasal symptom score is widely used to evaluate the severity of allergic rhinitis, but the clinical significance of extranasal symptoms is largely unknown. We wished to analyze the presenting symptoms in allergic rhinitis, as well as their relationship with quality of life (QoL) and therapeutic outcomes. Methods: Presenting symptoms and QoL were assessed using the OptumTM SF-12v2^® Health Survey in 260 patients with allergic rhinitis. Clinical response at 3 months after treatment was measured. Results: Ten most common symptoms presenting with at least moderate severity in allergic rhinitis were: blocked nose (82.7%), rhinorrhea (75.0%), sneeze (70.9%), itchy nose (68.5%), fatigue (63.6%), mouth breathing (61.1%), daytime somnolence (52.7%), postnasal drip (49.1%), itchy eyes (47.3%), and dry mouth (46.3%). Severity of sneeze was correlated with physical component summary (PCS) whereas postnasal drip and daytime somnolence were correlated with mental component summary (MCS). Severity of dry mouth was correlated with PCS and MCS. The symptoms with the highest severity scores after treatment were blocked nose, postnasal drip, fatigue, and dry mouth, respectively. Conclusions: Extranasal symptom scores correlated well with physical health and mental health in allergic rhinitis patients. Assessment of extranasal symptoms should be included to evaluate disease severity and assess therapeutic outcomes. Clinical trial NCT02000648, http://www.clinicaltrials.gov.

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Background: The characteristics of phenotypes of elderly patients with asthma are unknown. The aim of this study was to classify these phenotypes using lung function tests and images from high-resolution computed tomography (HRCT), and to identify associations between clinical characteristics and phenotypes. Methods: A cross-sectional study was conducted in 165 elderly patients ( >65 years of age) who un- derwent a multidimensional assessment of clinical and functional status and comorbidity. The patients were divided into three phenotypes: (1) asthma-predominant, (2) asthma-obstructive airway disease (OAD) overlap without emphysema, and (3) asthma-OAD overlap with emphysema (asthma-emphysema overlap) based on chest HRCT. A receiver operating characteristic (ROC) curve was constructed to eval- uate the cutoff for differentiating between the two OAD phenotypes. Multivariate analysis was also used to distinguish between these two phenotypes. Results: The phenotypes were asthma-predominant in 48 patients (29%), asthma-OAD without emphysema in 36 (22%), and asthma-emphysema in 81 (49%). Patients with asthma-emphysema were more frequent smokers. In multivariate analysis, smoking status (odds ratio 2.92: 95% CI 1.21-7.00, P = 0.03) and % predicted FEV₁ ≤70% (odds ratio 3.18: 95% CI 1.13-8.92, P = 0.03) differed significantly between the asthma-emphysema and asthma-OAD without emphysema phenotypes. Conclusions: Half of elderly patients with asthma are characterized by asthma-emphysema overlap. Our results showed that elderly patients with asthma who are smokers and have moderate or severe OAD are also likely to have emphysema.

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