NLRX1 knockdown attenuates pro-apoptotic signaling and cell death in pulmonary hyperoxic acute injury.

Hyperoxia is frequently used for treating acute respiratory failure, but it can cause acute lung injury. Nucleotide-binding domain and leucine-rich-repeat-containing family member X1 (NLRX1) is localized in mitochondria and involved in production of reactive oxygen species, inflammation, and apoptosis, which are the features of hyperoxic acute lung injury (HALI). The contribution of NLRX1 to HALI has not previously been addressed. Thus, to investigate the role of NLRX1 in hyperoxia, we generated a murine model of HALI in wild-type (WT) and NLRX1-/- mice by exposure to > 95% oxygen for 72 h. As a result, NLRX1 expression was elevated in mice exposed to hyperoxia. In acute lung injury, levels of inflammatory cells, protein leakage, cell cytotoxicity, and pro-inflammatory cytokines were diminished in NLRX1-/- mice compared to WT mice. In a survival test, NLRX1-/- mice showed reduced mortality under hyperoxic conditions, and apoptotic cell death and caspase expression and activity were also lower in NLRX1-/- mice. Furthermore, levels of the MAPK signaling proteins ERK 1/2, JNK, and p38 were decreased in NLRX1-deficient mice than in WT mice exposed to hyperoxia. The study shows that a genetic deficit in NLRX1 can suppress hyperoxia-induced apoptosis, suggesting that NLRX1 acts as a pivotal regulator of HALI.

Maternal Posttraumatic Stress Symptoms and Psychological Burden in Mothers of Korean Children With Anaphylaxis.

PURPOSE: Anaphylaxis is a severe allergic reaction that is potentially life-threatening, but post-traumatic stress symptoms (PTSS) in the caregivers of children with anaphylaxis have not been evaluated. This study aimed to investigate the psychological burden on mothers of children with recent anaphylaxis. METHODS: A total of 188 children with recent anaphylaxis was recruited from 13 hospitals in Korea. Validated questionnaires, including the Korean versions of the Beck Anxiety Inventory (K-BAI), the Beck Depression Inventory (K-BDI), and the Impact of Event Scale Revised-Korean version (IES-R-K), were used to evaluate maternal anxiety, depression, and PTSS. RESULTS: The median ages of children and their mothers were 4 and 36 years, respectively. PTSS (IES-R-K ≥ 25) were identified in 56.9% of mothers, and 57.9% of them showed severe PTSS. The proportions of mothers who had anxiety (K-BAI ≥ 22) and depression (K-BDI ≥ 17) were 18.6% and 33.0%, respectively. Multivariable logistic regression analysis indicated that the patient's history of asthma (adjusted odds ratio [aOR], 5.46; 95% CI, 1.17-25.59) and the presence of central nervous symptoms (aOR, 3.27; 95% CI, 1.07-9.96) were associated with PTSS. Age of 2 or older (aOR, 2.87; 95% CI, 1.10-7.52) and eggs, milk, or wheat as the cause of anaphylaxis (aOR, 2.87; 95% CI, 1.10-7.52) increased the risk of severe PTSS. CONCLUSIONS: The rate of PTSS among mothers of children with recent anaphylaxis was high at 56.9%. Clinicians who care for pediatric anaphylaxis patients should be aware of the psychological burden on their caregivers.

Clinical Characteristics of Atopic Dermatitis in Korean School-Aged Children and Adolescents According to Onset Age and Severity.

BACKGROUND: Atopic dermatitis (AD) is a heterogeneous disease with different age of onset, disease course, clinical symptoms, severity, and risk of comorbidity. The characteristics of children with AD also vary by age or country. However, little is known about the clinical characteristics of AD in Korean school-aged children and adolescents. Furthermore, there are few studies on phenotypic differences according to onset age. This study aimed to explore the clinical characteristics and phenotypes according to onset age and severity of AD in children and adolescents in Korea. METHODS: AD patients aged 6-18 years who presented to 18 hospitals nationwide were surveyed. The patients were examined for disease severity by pediatric allergy specialists, and data on history of other allergic diseases, familial allergy history, onset age, trigger factors, lesion sites, treatment history and quality of life were collected. The results of the patient's allergy test were also analyzed. The patients were classified into infancy-onset (< 2 years of age), preschool-onset (2-5 years of age), and childhood-onset (≥ 6 years of age) groups. Study population was analyzed for clinical features according to onset-age groups and severity groups. RESULTS: A total of 258 patients with a mean age of 10.62 ± 3.18 years were included in the study. Infancy-onset group accounted for about 60% of all patients and presented significantly more other allergic diseases, such as allergic rhinitis and asthma (P = 0.002 and P = 0.001, respectively). Food allergy symptoms and diagnoses were highly relevant to both earlier onset and more severe group. Inhalant allergen sensitization was significantly associated with both infancy-onset group and severe group (P = 0.012 and P = 0.024, respectively). A family history of food allergies was significantly associated with infancy-onset group (P = 0.036). Severe group was significantly associated with a family history of AD, especially a paternal history of AD (P = 0.048 and P = 0.004, respectively). Facial (periorbital, ear, and cheek) lesions, periauricular fissures, hand/foot eczema, and xerosis were associated with infancy-onset group. The earlier the onset of AD, the poorer the quality of life (P = 0.038). Systemic immunosuppressants were used in only 9.6% of the patients in the severe group. CONCLUSION: This study analyzed the clinical features of AD in Korean children and adolescents through a multicenter nationwide study and demonstrated the phenotypic differences according to onset age and severity. Considering the findings that the early-onset group is more severe and accompanied by more systemic allergic diseases, early management should be emphasized in young children and infants.

Chitinase 3-Like 1 Contributes to Food Allergy via M2 Macrophage Polarization.

PURPOSE: Food allergy is a hypersensitive immune response to specific food proteins. Chitinase 3-like 1 (CHI3L1, also known as YKL-40 in humans or BRP-39 in mice) is associated with various chronic diseases, such as cancer, rheumatoid arthritis, and allergic disease. CHI3L1 is involved in allergen sensitization and type 2 helper T (Th2) inflammation, but the role of CHI3L1 in food allergy remains unclear. In this study, we sought to investigate the role of CHI3L1 in the development of food allergy. METHODS: We measured serum levels of CHI3L1 in food allergic patients. Food allergy was induced in wild-type (WT) and CHI3L1 null mutant (CHI3L1-/-) BALB/c mice with ovalbumin (OVA). We investigated Th2 immune responses, M2 macrophage polarization, and mitogen-activated protein kinase (MAPK)/phosphoinositide 3-kinase (PI3K) signaling pathways, and also performed transcriptome analysis. RESULTS: Serum levels of CHI3L1 were significantly higher in children with food allergy compared with those in healthy controls. Furthermore, CHI3L1 expression levels were elevated in WT mice after OVA treatment. Food allergy symptoms, immunoglobulin E levels, Th2 cytokine production, and histological injury were attenuated in food allergy-induced CHI3L1-/- mice compared with those in food allergy-induced WT mice. CHI3L1 expression was increased in OVA-treated WT intestinal macrophages and caused M2 macrophage polarization. Furthermore, CHI3L1 was involved in the extracellular signal-regulated kinases (ERK) and AKT signaling pathways and was associated with immune response and lipid metabolism as determined through transcriptome analysis. CONCLUSIONS: CHI3L1 plays a pivotal role in Th2 inflammation and M2 macrophage polarization through MAPK/ERK and PI3K/AKT phosphorylation in food allergy.

A multicenter anaphylaxis registry in Korea: Clinical characteristics and acute treatment details from infants to older adults.

BACKGROUND: Although the prevalence of anaphylaxis is increasing worldwide, the large-scale studies in Asia evaluating anaphylaxis in all age groups are limited. We aimed to collect more precise and standardized data on anaphylaxis in Korea using the first multicenter web-based registry. METHODS: Twenty-two departments from 16 hospitals participated from November 2016 to December 2018. A web-based case report form, designed by allergy specialists, was used to collect anaphylaxis data. RESULTS: Within the 2-year period, 558 anaphylaxis cases were registered. The age of registered patients ranged from 2 months to 84 years, and 60% were aged <18 years. In children and adolescents, foods (84.8%) were the most common cause of anaphylaxis, followed by drugs (7.2%); in adults, drugs (58.3%) were the most common cause, followed by foods (28.3%) and insect venom (8.1%). The onset time was ≤10 min in 37.6% of patients. Among the 351 cases registered via the emergency department (ED) of participating hospitals, epinephrine was administered to 63.8% of patients. Among those receiving epinephrine in the ED, 13.8% required 2 or more epinephrine shots. Severe anaphylaxis accounted for 23.5% cases (38.1% in adults; 13.7% in children); patients with drug and insect venom-induced anaphylaxis had higher rates of severe anaphylaxis. CONCLUSION: This multicenter registry provides data on anaphylaxis for all age groups for the first time in Asia. The major causes and severity of anaphylaxis were remarkably different according to age group, and the acute treatment features of anaphylaxis in the EDs were examined in detail.

Infantile Anaphylaxis in Korea: a Multicenter Retrospective Case Study.

BACKGROUND: Anaphylaxis is increasing in young children. The aim of the present study was to analyze the clinical characteristics of anaphylaxis in Korean infants, with a focus on food triggers. METHODS: The study analyzed the medical records of infants aged 0 to 2 years old who had been diagnosed with anaphylaxis in 23 secondary or tertiary hospitals in Korea. RESULTS: We identified 363 cases of infantile anaphylaxis (66.9% male). Cutaneous symptoms were most prevalent (98.6%), followed by respiratory (83.2%), gastrointestinal (29.8%), and neurologic (11.6%) symptoms. Cardiovascular symptoms were noted in 7.7% of the cases. Most of the cases of anaphylaxis (338; 93.1%) were induced by foods. The most common trigger food was cow's milk and cow's milk products (43.8%), followed by hen's eggs (21.9%), walnuts (8.3%), wheat (7.7%), peanuts (4.8%), other nuts (3.0%), and fish (2.1%). In cow's milk-induced anaphylaxis cases, more than half the cases had cow's milk specific immunoglobulin E (sIgE) levels that were lower than the diagnostic decision points (DDPs), which is 5 kUA/L for those under the age of 1 and 15 kUA/L for those over the age of 1. In anaphylaxis induced by hen's egg, most of the cases (91.8%) had hen's egg sIgE levels that were higher than the DDP, which is 2 kUA/L for those under the age of 2 and 7 kUA/L for those over the age of 2. Of the infantile anaphylaxis cases, 46.8% had been treated with epinephrine, and 25.1% had been prescribed an epinephrine auto-injector. CONCLUSION: Cow's milk is the most frequent trigger food of anaphylaxis in Korean infants. However, we found no significant correlation between the sIgE level and clinical severity. Education is required regarding the importance of epinephrine as the first line therapy for anaphylaxis and on properly prescribing epinephrine for infants with a history of anaphylaxis.

Age-Based Causes and Clinical Characteristics of Immediate-Type Food Allergy in Korean Children.

PURPOSE: Age-based causes and clinical characteristics of immediate-type food allergy (FA) have not been sufficiently studied. Therefore, we investigated age-dependent clinical profiles of FA in Korean children through an extensive multicenter investigation. METHODS: Using a case report form developed by the authors, a retrospective medical record review was performed of patients (0-18 years old) diagnosed with immediate-type FA between September 2014 and August 2015 in 14 tertiary hospitals in Korea. RESULTS: A total of 1,353 children and adolescents, 93% younger than 7 years, were enrolled in the present study, and 1,661 cases of immediate-type FA were recorded in these patients. The 7 major causative foods were cow's milk (28.1%), hen's eggs (27.6%), wheat (7.9%), walnuts (7.3%), peanuts (5.3%), buckwheat (1.9%), and shrimps (1.9%). Categorizing the patients into 4 age groups revealed that the most common causative food was different for each age group: cow's milk (<2 years), walnuts (2-6 years), walnuts (7-12 years), and buckwheat (13-18 years). The onset time of symptoms was less than 10 minutes in 49%, between 10 and 30 minutes in 17%, and between 30 minutes and 2 hours in 34% of cases. Food-induced anaphylaxis was reported in 506 (30.5%) out of 1,661 cases, and the 7 major causes of food-induced anaphylaxis was cow's milk (27.5%), hen's eggs (21.9%), wheat (11.3%), walnuts (10.5%), peanuts (5.9%), buckwheat (4.2%), and pine nuts (3.0%). The proportion of anaphylaxis was highest in the patients allergic to buckwheat (67.7%), followed by those allergic to pine nuts (57.7%), walnuts (43.8%), wheat (43.5%), and peanuts (34.1%). CONCLUSIONS: The 5 major causative foods of immediate-type FA in Korean children were cow's milk, hen's eggs, wheat, walnuts, and peanuts. The distribution of causative foods was considerably distinctive according to different age groups. Anaphylaxis was reported in 30.5% of immediate-type FA cases.

A Multicenter Retrospective Case Study of Anaphylaxis Triggers by Age in Korean Children.

PURPOSE: Although anaphylaxis is recognized as an important, life-threatening condition, data are limited regarding its triggers in different age groups. We aimed to identify anaphylaxis triggers by age in Korean children. METHODS: We performed a retrospective review of medical records for children diagnosed with anaphylaxis between 2009 and 2013 in 23 secondary or tertiary hospitals in South Korea. RESULTS: A total of 991 cases (mean age=5.89±5.24) were reported, with 63.9% involving patients younger than 6 years of age and 66% involving male children. Food was the most common anaphylaxis trigger (74.7%), followed by drugs and radiocontrast media (10.7%), idiopathic factors (9.2%), and exercise (3.6%). The most common food allergen was milk (28.4%), followed by egg white (13.6%), walnut (8.0%), wheat (7.2%), buckwheat (6.5%), and peanut (6.2%). Milk and seafood were the most common anaphylaxis triggers in young and older children, respectively. Drug-triggered anaphylaxis was observed more frequently with increasing age, with antibiotics (34.9%) and nonsteroidal anti-inflammatory drugs (17.9%) being the most common causes. CONCLUSIONS: The most common anaphylaxis trigger in Korean children was food. Data on these triggers show that their relative frequency may vary by age.

A practical view of immunotherapy for food allergy.

Food allergy is common and sometimes life threatening for Korean children. The current standard treatment of allergen avoidance and self-injectable epinephrine does not change the natural course of food allergy. Recently, oral, sublingual, and epicutaneous immunotherapies have been studied for their effectiveness against food allergy. While various rates of desensitization (36% to 100%) and tolerance (28% to 75%) have been induced by immunotherapies for food allergy, no single established protocol has been shown to be both effective and safe. In some studies, immunologic changes after immunotherapy for food allergy have been revealed. Adverse reactions to these immunotherapies have usually been localized, but severe systemic reactions have been observed in some cases. Although immunotherapy cannot be recommended for routine practice yet, results from recent studies demonstrate that immunotherapies are promising for the treatment of food allergy.

IgE reactivity to carbohydrate moieties of glycoproteins in wheat allergy.

Carbohydrate moieties of different glycoproteins, such as cross-reactive carbohydrate determinants (CCDs) and galactose α-1,3-galactose, can induce IgE reactivity with varied clinical significance. In this study, the possible participation of glycan from wheat gliadin, with respect to its IgE-binding capacity, was investigated in children with food allergies to wheat. Total IgE and wheat-specific IgE quantification, documentation of history, and/or oral food challenge (OFC) were performed for 52 children. Subjects with positive wheat-specific IgE were characterized as the symptomatic group, never-exposed group, or asymptomatic group. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and glycan detection in gliadin were performed. IgE binding to gliadin and deglycosylated gliadin was measured by immunoblotting and ELISA. Gliadin-specific IgE was detected and correlated with wheat-specific IgE in the symptomatic, never-exposed, and asymptomatic groups. The glycan range overlapped significantly with the gliadin range. Deglycosylation of gliadin reduced the allergenicity of gliadin. In gliadin, the allergenicity of the glycan portion was greater in the symptomatic group than in the never-exposed and asymptomatic groups. We conclude that N-glycan in gliadin might exhibit allergenicity as a possible carbohydrate epitope in wheat allergy in children.

Massive pulmonary hemorrhage in enterovirus 71-infected hand, foot, and mouth disease.

Hand, foot, and mouth disease (HFMD) is an acute, mostly self-limiting infection. Patients usually recover without any sequelae. However, a few cases are life threatening, especially those caused by enterovirus 71 (EV71). A 12-month-old boy was admitted to a primary hospital with high fever and vesicular lesions of the mouth, hands, and feet. After 3 days, he experienced 3 seizure episodes and was referred to our hospital. On admission, he was conscious and his chest radiograph was normal. However, 6 hours later, he suddenly lost consciousness and had developed a massive pulmonary hemorrhage that continued until his death. He experienced several more intermittent seizures, and diffuse infiltration of both lung fields was observed on chest radiography. Intravenous immunoglobulin, dexamethasone, cefotaxime, leukocyte-depleted red blood cells, fresh frozen plasma, inotropics, vitamin K, and endotracheal epinephrine were administered. The patient died 9 hours after intubation, within 3 days from fever onset. EV71 subgenotype C4a was isolated retrospectively from serum and nasopharyngeal swab by real-time reverse transcription-polymerase chain reaction. Here, we report a fatal case of EV71-associated HFMD with sudden-onset massive pulmonary hemorrhage and suspected encephalitis.

Oral food challenges in children.

Many patients assume that allergic reactions against foods are responsible for triggering or worsening their allergic symptoms. Therefore, it is important to identify patients who would benefit from an elimination diet, while avoiding unnecessary dietary restrictions. The diagnosis of food allergy depends on the thorough review of the patients's medical history, results of supplemented trials of dietary elimination, and in vivo and in vitro tests for measuring specific IgE levels. However, in some cases the reliability of such procedures is suboptimal. Oral food challenges are procedures employed for making an accurate diagnosis of immediate and occasionally delayed adverse reactions to foods. The timing and type of the challenge, preparation of patients, foods to be tested, and dosing schedule should be determined on the basis of the patient's history, age, and experience. Although double-blind, placebo-controlled food challenges(DBPCFC) are used to establish definitively if a food is the cause of adverse reactions, they are time-consuming, expensive and troublesome for physician and patients. In practice, An open challenge controlled by trained personnel is sufficient especially in infants and young children. The interpretation of the results and follow-up after a challenge are also important. Since theses challenges are relatively safe and informative, controlled oral food challenges could become the measure of choice in children.

Utility of impulse oscillometry in young children with asthma.

Impulse Oscillometry (IOS) was developed as a tool to measure lung function, and as it only requires passive cooperation, it has been successfully used in younger children. The aim of this study was to assess the utility of IOS compared to conventional spirometry for lung function measures in asthmatic Korean children aged 3 to 6 yrs. Total serum IgE levels, total eosinophil counts, and specific IgE levels were measured in 77 children with asthma and 55 control subjects. IOS and spirometry were performed in the children before and after bronchodilator administration. Asthmatic children significantly differed from control subjects in baseline resistance at 10 Hz and in their IOS-assessed bronchodilator responses through a Delta resistance at 5 Hz (mean, -27.4% vs. -13.1%; p = 0.002), 10 Hz (mean, -20.4% vs. -11.5%; p = 0.012), 20 Hz (mean, -16.4% vs. -9.4%; p = 0.016), and 35 Hz (mean, -17.2% vs. -10.2%; p = 0.020). Conventional spirometry did not show statistically significant findings. Asthmatic children significantly differed from control subjects in IOS-assessed bronchodilator response through a Delta resistance at 5 Hz, both in atopic children and in non-atopic children. For atopic children, atopic asthmatic children (n = 58) also significantly differed from atopic controls (n = 30) in baseline resistance at 10 Hz, 20 Hz, 35 Hz and impedance and in IOS-assessed bronchodilator responses through a Delta resistance at 10 Hz and 35 Hz. There were some significant correlations between bronchodilator responses of spirometric parameters and IOS parameters. IOS is useful diagnostic tool in early asthma development and might be a helpful objective outcome measure of early interventions.

Correlation between spirometry and impulse oscillometry in children with asthma.

AIM: In certain patients, such as young children or individuals with cerebral palsy or severe mental retardation, it is difficult to perform forced expiratory manoeuvres to measure expiratory flow volume. In such cases, we could evaluate obstructive lung disease through the measurement of airway resistance instead of expiratory flow volume. METHODS: In this study, we evaluated the correlation of Impulse Oscillometry (IOS) parameters with spirometry values and peak expiratory flow rate (PEFR) measurements to give coherence to IOS recordings in lung function exploration. Total serum IgE levels, total eosinophil counts and specific IgE levels were measured in 48 children with asthma and 66 control subjects, aged 7-15 years of age. IOS, spirometry and PEFR measurements were performed, as well as methacholine challenge. We further analyzed the correlations in atopic asthma, atopic control, nonatopic asthma and nonatopic control groups. RESULTS: FEV(1) and PEFR showed a significant correlation with impedance and resistance (R) at 5, 10, 20 and 35 Hz, both in atopic asthmatic and in atopic control children. FVC also showed a correlation with impedance and R at 10, 20 and 35 Hz, both in atopic asthmatic and atopic control children. FEF(25-75%) did not show a correlation with resistances. CONCLUSION: FEV(1), FVC and PEFR were significantly correlated with IOS parameters, in both asthmatic and control subjects, especially for atopic children. IOS could be used as a suitable measure of lung function when spirometry and PEF cannot be performed.

Cytotoxic T lymphocyte-associated antigen-4 gene polymorphisms confer susceptibility to atopic asthma in Korean children.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a negative regulator of T lymphocyte activation. The gene encoding CTLA-4 is a candidate gene for conferring susceptibility to allergic disease. The purpose of this study was to evaluate the potential effects of CTLA-4 gene polymorphisms in Korean children on asthma. We genotyped 272 children with atopic asthma, 54 children with nonatopic asthma (NAA), and 254 control children for allelic determinants at two polymorphic sites in the region at positions promoter - 318 C > T and exon 1 + 49 G > A using restriction fragment length polymorphism methods. As a result, allele and genotype frequencies of the CTLA-4 exon 1 + 49 G > A polymorphism were different to some extent between the atopic asthma children and the controls with P<0.05, which did not reach statistical significance after the correction of multiple comparisons. In addition, CTLA-4 + 49 G > A polymorphism was significantly associated with elevated serum IgE levels (P=0.01). Of the four haplotype, haplotype 1 (C-G) was only associated with atopic asthma susceptibility after the correction of multiple comparisons (P=0.01, OR=0.702, 95% CI= 0.541-0.911). Polymorphisms in the CTLA-4 gene likely confer susceptibility to atopic asthma in Korean children.

Serum eosinophil-derived neurotoxin (EDN) in diagnosis and evaluation of severity and bronchial hyperresponsiveness in childhood asthma.

This study sought to evaluate the use of serum eosinophil-derived neurotoxin (EDN), which has been proposed as a marker of airway inflammation in asthma in the diagnosis and evaluation of the severity and bronchial hyperresponsiveness in childhood asthma. We studied 72 children with atopic asthma, 36 children with nonatopic asthma, and 43 healthy controls. Skin prick tests, pulmonary function tests, and methacholine challenge tests were performed, in addition to total eosinophil count, serum ECP, and EDN being measured in all subjects. EDN levels were significantly higher in the atopic asthma group than those in the nonatopic asthma group or control group (p < 0.001), as were ECP levels (p < 0.001). EDN levels differed more significantly among groups divided by asthma severity (p < 0.001) than did ECP levels for these groups (p < 0.05). For the groups divided according to bronchial hyperresponsiveness, both EDN and ECP levels were significantly different (p < 0.005 and p < 0.01, respectively). Significant correlations were found between EDN and PC(20) (gamma = -0.281; p < 0.001), between ECP and PC(20) (gamma = -0.274; p < 0.005), and between EDN and ECP (gamma = 0.443; p < 0.001). In conclusion, serum EDN, as another marker of eosinophilic inflammation together with ECP, may aid in the diagnosis of asthma, especially atopic asthma, and in the evaluation of the severity and bronchial hyperresponsiveness in childhood asthma.