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1.  The Usefulness of Component-Resolved Diagnostics in Food Allergy 
PMCID: PMC3936036  PMID: 24587944
2.  Prevalence of Allergic Rhinitis in China 
Allergic rhinitis (AR) is a serious systemic allergic disease, which together with comorbid asthma causes major illness and disability worldwide. Recent epidemiological studies have revealed wide variations in the increasing prevalence of AR and allergies globally, including in China. Despite a markedly higher population than western countries, and a landmass close to Europe in area, little epidemiological data is available on AR in China. Thus, the present study reviewed the prevalence, comorbid allergic diseases, trends and pattern of sensitizing allergens in adults and children suffering from AR in China. Available data indicated that despite variations in the prevalence of AR in different regions of the country, the prevalence of AR has increased in both adults and children over the last 2 decades. Similarly, there has been an increase in a "western"-type lifestyle, industrialization and air pollution over this period, which may have contributed to the increased prevalence of AR observed in China.
PMCID: PMC3936037  PMID: 24587945
Allergic rhinitis; prevalence; China; asthma; allergen; epidemiology; adult; children
3.  Integrating Evidence for Managing Asthma in Patients Who Smoke 
Cigarette smoking among asthma patients is associated with worsening symptoms and accelerated decline in lung function. Smoking asthma is also characterized by increased levels of neutrophils and macrophages, and greater small airway remodeling, resulting in increased airflow obstruction and impaired response to corticosteroid therapy. As a result, smokers are typically excluded from asthma randomized controlled trials (RCTs). The strict inclusion/exclusion criteria used by asthma RCTs limits the extent to which their findings can be extrapolated to the routine care asthma population and to reflect the likely effectiveness of therapies in subgroups of particular clinical interest, such as smoking asthmatics. The inclusion of smokers in observational asthma studies and pragmatic trials in asthma provides a way of assessing the relative effectiveness of different treatment options for the management of this interesting clinical subgroup. Exploratory studies of possible treatment options for smoking asthma suggest potential utility in: prescribing higher-dose ICS; targeting the small airways of the lungs with extra-fine particle ICS formulations; targeting leukotreines, and possibly also combinations of these options. However, further studies are required. With the paucity of RCT data available, complementary streams of evidence (those from RCTs, pragmatic trials and observational studies) need to be combined to help guide judicious prescribing decisions in smokers with asthma.
PMCID: PMC3936038  PMID: 24587946
Smoking; asthma; leukotriene receptor antagonists (LTRAs); small airways; inhaled glucocorticosteroids (ICS); extra-fine particle
4.  Usefulness of nBos d 4, 5 and nBos d 8 Specific IgE Antibodies in Cow's Milk Allergic Children 
The aim of study was to assess the value of recombinants in predicting the degree of symptoms in children with and without anaphylaxis to cow's milk.
The study included 79 children (70±40 months) referred to the Allergological Unit of the Pediatric Department between the years 2008-2012. Group A was composed of 17 children (78±49.6 months) with anaphylaxis after ingestion of milk. Group B was composed of 62 children (73.1±38.6 months) without a history of anaphylaxis, but with less severe symptoms (gastrointestinal and/or skin symptoms). All patients from Group B had a positive open challenge with cow's milk. All patients underwent an allergic evaluation and blood samples were collected to test for IgE to recombinans of milk (nBos d 4, 5, 8).
A significant difference in nBos d 8 emerged with higher levels in Group A (median [IQR]=2.80 [0.91-16.1]) than B (0.65 [0.24-1.67]; P=0.006), whereas there were no statistically significant differences for nBos d 4 and 5. The recombinants' sum was higher in Group A than B: 8.39 [2.72-41.39] vs 3.04 [1.85-7.31] kUA/L; P=0.044. The recombinant nBos d 8 was superior to the other recombinants in identifying children at risk for anaphylaxis, with an area under the curve of 0.718 (95% CI, 0.57-0.86, P=0.006). Considering a cutoff of 1.8 kUA/L, nBos d 8 had the most favorable sensitivity and specificity ratio (sensitivity=0.65, specificity=0.77) with an odd ratio of 6.02 (95% C.I: 1.89-19.23).
This study suggested 2 phenotypes of allergic children, "high-anaphylaxis-risk" and "milder-risk". These types can be differentiated through measuring the level of IgE to nBos d 8.
PMCID: PMC3936039  PMID: 24587947
child; symptoms; milk; allergy; recombinant proteins
5.  The Effects of Inhaled Albuterol in Transient Tachypnea of the Newborn 
Transient tachypnea of the newborn (TTN) is a disorder caused by the delayed clearance of fetal alveolar fluid. β-adrenergic agonists such as albuterol (salbutamol) are known to catalyze lung fluid absorption. This study examined whether inhalational salbutamol therapy could improve clinical symptoms in TTN. Additional endpoints included the diagnostic and therapeutic efficacy of salbutamol as well as its overall safety.
From January 2010 through December 2010, we conducted a prospective study of 40 newborns hospitalized with TTN in the neonatal intensive care unit. Patients were given either inhalational salbutamol (28 patients) or placebo (12 patients), and clinical indices were compared.
The duration of tachypnea was shorter in patients receiving inhalational salbutamol therapy, although this difference was not statistically significant. The duration of supplemental oxygen therapy and the duration of empiric antibiotic treatment were significantly shorter in the salbutamol-treated group. No adverse effects were observed in either treatment group.
Inhalational salbutamol therapy reduced the duration of supplemental oxygen therapy and the duration of empiric antibiotic treatment, with no adverse effects. However, the time between salbutamol therapy and clinical improvement was too long to allow definitive conclusions to be drawn. Further studies examining a larger number of patients with strict control over dosage and frequency of salbutamol inhalations are necessary to better direct the treatment of TTN.
PMCID: PMC3936040  PMID: 24587948
Transient tachypnea of the newborn; inhalation; albuterol
6.  Prevalence of Immediate-Type Food Allergy in Early Childhood in Seoul 
There are scanty epidemiologic data on the prevalence of food allergy (FA) among preschool children in Asia. We performed this study to determine the prevalence and causative foods of immediate-type FA in early childhood in Korea.
A questionnaire-based, cross-sectional study was performed between September and October 2011. Children aged 0-6 years were recruited from 301 public child care centers in Seoul. Parents were asked to complete a questionnaire on FA. Children with FA were classified into "perceived FA, ever," "immediate-type FA, ever," and "immediate-type FA, current" according to the algorithm.
A total of 16,749 children were included in this study. The prevalence of "perceived FA, ever," "immediate-type FA, ever," and "immediate-type FA, current" was 15.1%, 7.0%, and 3.7%, respectively. "Immediate-type FA, current" was reported by 182 (4.9%) out of 3,738 children aged ≤2 years, 262 (3.4%) of 7,648 children aged 3-4 years, and 177 (3.3%) of 5,363 children aged 5-6 years. Hen's egg (126/621) was the most frequent cause as the individual food item, followed by cow's milk (82/621) and peanut (58/621). Among the food groups, fruits (114/621), tree nuts (90/621) and crustaceans (85/621) were the most common offending foods. The three leading causes of food-induced anaphylaxis were hen's egg (22/47), cow's milk (15/47), and peanut (14/47).
The prevalence of immediate-type FA in early childhood is 3.7%, and is higher in younger children. The most common offending foods differed with age.
PMCID: PMC3936041  PMID: 24587949
Immediate hypersensitivity; child; food allergy; prevalence
7.  The Interaction Between Allelic Variants of CD86 and CD40LG: A Common Risk Factor of Allergic Asthma and Rheumatoid Arthritis 
Allergic asthma (AA) and rheumatoid arthritis (RA) are immune tolerance-related diseases, and immune tolerance is known to be influenced by costimulatory molecules. In this study, we sought to identify common genetic susceptibility in AA and RA.
Two hundred cases of AA, 184 cases of RA, and 182 healthy controls were recruited at the Seoul National University Hospital, Seoul, Korea. Eight single nucleotide polymorphisms (SNPs) in five genes coding costimulatory molecules, namely, -318C>T, +49A>G, and 6230G>A in CTLA4, IVS3+17T>C in CD28, -3479T>G and I179V in CD86, -1C>T in CD40, and -3458A>G in CD40LG were scored, and genetic interactions were evaluated by multifactor dimensionality reduction (MDR) analysis.
MDR analysis revealed a significant gene-gene interaction between -3479T>G CD86 and -3458A>G CD40LG for AA. Subjects with the T/T genotype of -3479T>G CD86 and the A/A genotype of -3458A>G CD40LG were found to be significantly more likely to develop AA than those with the T/T genotype of -3479T>G CD86 and A/- genotype of -3458A>G CD40LG (adjusted OR, 6.09; 95% CI, 2.89-12.98; logistic regression analysis controlled by age). Similarly those subjects showed a significant risk of developing RA (adjusted OR, 39.35; 95% CI, 15.01-107.00, logistic regression analysis controlled by age).
Our findings suggest that a genetic interaction between CD86 and CD40LG favors the development of both AA and RA.
PMCID: PMC3936042  PMID: 24587950
Asthma; rheumatoid arthritis; CD86; CD40 ligand; genetic polymorphism
8.  Polymorphisms of ATF6B Are Potentially Associated With FEV1 Decline by Aspirin Provocation in Asthmatics 
Endoplasmic reticulum (ER) stress has recently been observed to activate NF-kappaB and induce inflammatory responses such as asthma. Activating transcription factor 6β (ATF6B) is known to regulate ATFα-mediated ER stress response. The aim of this study is to investigate the associations of ATF6B genetic variants with aspirin-exacerbated respiratory disease (AERD) and its major phenotype, % decline of FEV1 by aspirin provocation.
Four common single nucleotide polymorphisms (SNPs) of ATF6B were genotyped and statistically analyzed in 93 AERD patients and 96 aspirin-tolerant asthma (ATA) as controls.
Logistic analysis revealed that 2 SNPs (rs2228628 and rs8111, P=0.008; corrected P=0.03) and 1 haplotype (ATF6B-ht4, P=0.005; corrected P=0.02) were significantly associated with % decline of FEV1 by aspirin provocation, whereas ATF6B polymorphisms and haplotypes were not associated with the risk of AERD.
Although further functional and replication studies are needed, our preliminary findings suggest that ATF6B may be related to obstructive phenotypes in response to aspirin exposure in adult asthmatics.
PMCID: PMC3936043  PMID: 24587951
ATF6B; aspirin exacerbated respiratory disease (AERD); single nucleotide polymorphism (SNP); haplotype
9.  Effects of Fungi and Eosinophils on Mucin Gene Expression in Rhinovirus-Infected Nasal Epithelial Cells 
Fungi, rhinoviruses (RVs), and eosinophils are associated with upper respiratory diseases. We evaluated the effects of fungal stimulation and eosinophil co-culture on the expression of mucin genes in RV-infected nasal polyp epithelial cells.
Nasal polyp epithelial cells were obtained from chronic rhinosinusitis patients. Cultured epithelial cells were stimulated with Alternaria and Aspergillus with or without RV-16 infection. The epithelial cells were co-cultured with eosinophils for 16 h. MUC4, MUC5AC, MUC5B, and MUC8 mRNA expressions in the epithelial cells were quantified using real-time RT-PCR. To determine the underlying mechanism, nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and mitogen-activated protein kinase (MAPK) inhibitors were used to inhibit mucin gene expression.
Fungi and RV-16 induced mucin gene expression in nasal polyp epithelial cells. However, there was no synergistic increase in mucin gene expression, with the exception of MUC4 mRNA expression stimulated by 25 µg/mL Aspergillus. When RV-16-infected epithelial cells were stimulated with fungi and then co-cultured with eosinophils, MUC4, MUC5B, and MUC8 mRNA expressions increased. Mucin gene expression was inhibited by NF-κB inhibitors.
RV-16, airborne fungi, and eosinophils may exacerbate the inflammatory process in nasal mucosal diseases by enhancing mucin gene expression.
PMCID: PMC3936044  PMID: 24587952
Rhinovirus; nasal epithelial cell; mucin gene; fungus; eosinophil; nuclear factor-κB
10.  Cross-reactivity to Acetaminophen and Celecoxib According to the Type of Nonsteroidal Anti-inflammatory Drug Hypersensitivity 
Identification of tolerable alternative analgesics is crucial for management in nonsteroidal anti-inflammatory drug (NSAID)-sensitive patients. We investigated cross-reactivity of acetaminophen and celecoxib according to the type of aspirin/NSAID hypersensitivity and aimed to determine the risk factors for cross-intolerance.
We retrospectively reviewed the medical records of patients intolerant to aspirin and NSAIDs who had undergone an acetaminophen and/or celecoxib oral provocation test. Aspirin/NSAID hypersensitivity was classified into 4 types according to a recently proposed classification: aspirin-exacerbated respiratory disease (AERD), aspirin-exacerbated chronic urticaria (AECU), aspirin-induced acute urticaria/angioedema (AIAU), and NSAID-induced blended reaction (NIRD).
A total of 180 patients with hypersensitivity to aspirin and NSAIDs were enrolled; 149 acetaminophen provocation test results and 145 celecoxib provocation test results were analyzed. The overall cross-reaction rates to acetaminophen and celecoxib were 24.8% and 10.3%, respectively. There was a significant difference in the cross-reactivity to acetaminophen according to the type of NSAID hypersensitivity. Cross-reactivity to acetaminophen was highest in the AECU group (43.9%), followed by the AERD (33.3%), NIBR (16.7%), and AIAU (12.5%) groups. Underlying chronic urticaria was more prevalent in patients with cross-intolerance to both acetaminophen (P=0.001) and celecoxib (P=0.033). Intolerance to acetaminophen was associated with intolerance to celecoxib (P<0.001).
Acetaminophen and celecoxib may induce adverse reactions in a non-negligible portion of aspirin/NSAID-sensitive patients. Physicians should be aware of the possible cross-reactions of these alternative drugs and consider an oral challenge test to confirm their tolerability.
PMCID: PMC3936045  PMID: 24587953
Acetaminophen; celecoxib; cross reactions; hypersensitivity; intolerance; anti-inflammatory agents; non-steroidal
11.  Receptor Interacting Protein 2 (RIP2) Is Dispensable for OVA-Induced Airway Inflammation in Mice 
Asthma is a pulmonary chronic inflammatory disease characterized by airway obstruction and hyperresponsiveness. Pattern recognition receptors are known to play a key role in the development of allergic diseases as well as host defenses against microbial infection. Receptor interacting protein 2 (RIP2), a serine/threonine kinase, is an adaptor molecule of NOD1 and NOD2, and genetic variation in this receptor is known to be associated with the severity of allergic asthma in children. In this study, we examined the role of RIP2 in the development of allergic airway inflammation in a mouse model.
Airway inflammation was induced in mice through intranasal administration of ovalbumin (OVA) after 2 intraperitoneal immunizations with OVA. Lung inflammation and mucus hypersecretion were examined histologically and total cell infiltration in bronchoalveolar (BAL) fluids was determined. Levels of the Th2-related cytokines, IL-5 and IL-13, in lung extracts were measured by ELISA. Serum antigen-specific IgE and IgG1 levels were also assessed.
OVA-induced lung inflammation and mucus hypersecretion were not different between WT and RIP2-deficient mice. The IL-5 and IL-13 levels in the bronchoalveolar (BAL) fluids were also not impaired in RIP2-deficient mice compared to WT mice. Moreover, RIP2 deficiency did not affect serum OVA-specific IgG1 and IgE levels.
Our results suggest that RIP2 is not associated with the development of allergic airway inflammation.
PMCID: PMC3936046  PMID: 24587954
RIP2; ovalbumin; airway inflammation; Th2; IgE
12.  Reference Values and Determinants of Fractional Concentration of Exhaled Nitric Oxide in Healthy Children 
Measurement of the fractional concentration of exhaled nitric oxide (FeNO) is a quantitative, noninvasive, simple, safe method of assessing airway inflammation. While FeNO measurement has been standardized, reference values for elementary school children are scarce. The aim of this study was to establish reference values for FeNO in children.
FeNO was measured in elementary school children at 6-12 years of age in Seoul, Korea, following American Thoracic Society guidelines and using a chemiluminescence analyzer (NIOX Exhaled Nitric Oxide Monitoring System, Aerocrine, Sweden). A total of 1,252 children completed a modified International Study of Asthma and Allergy in Children (ISAAC) questionnaire; FeNO was measured in 1,063 children according to the protocol and in 808 children defined as healthy controls.
Mean FeNO were 10.32 ppb, 16.58 ppb, and 12.36 ppb in non-atopic, atopic, and all 808 healthy controls, respectively. FeNO was not associated with age and gender. The FeNO reference equations were determined by multiple linear regression analysis, taking into account the variables of age, height, weight, total IgE, eosinophil percent, and bronchial hyper-responsiveness (methacholine PC20). FeNO=0.776+0.003×total IgE+0.340×eosinophil percent; coefficient of determination (R2)=0.084 in the 501 healthy non-atopic controls. FeNO=-18.365+1.536×eosinophil percent, R2=0.183 in the 307 healthy atopic controls; and FeNO=-7.888+0.130×Height+0.004×total IgE+1.233×eosinophil percent, R2=0.209 in the 808 all healthy controls. Eosinophil percent was correlated with FeNO in all healthy controls. FeNO was not associated with BMI.
This study provides reference values for FeNO that can be used to evaluate airway inflammation in elementary school children. Determinants that could most accurately predict FeNO in healthy school-age children were assessed.
PMCID: PMC3936047  PMID: 24587955
FeNO; reference value; determinants; healthy; children
13.  Potential Masking of Airway Eosinophilic Inflammation by Combination Therapy in Asthma 
Long-acting β2 agonists (LABA) may mask ongoing bronchial inflammation, leaving asthmatic patients at greater risk of severe complications. The aim of this study was to compare the effect of combination therapy using low-dose inhaled corticosteroids (ICS) plus LABA on airway inflammation in asthma to the effect of medium-dose ICS alone.
Twenty-four patients with asthma not controlled by low-dose (400 µg per day) budesonide alone were enrolled in this prospective crossover study. Patients were randomized into 2 treatment phases: one receiving medium-dose (800 µg per day) budesonide (ICS phase), and the other receiving a combination therapy of low-dose budesonide/formoterol (360 µg/9 µg per day) delivered by a single inhaler (LABA phase). Each treatment phase lasted for 6 week, after which patients were crossed over. Asthma symptoms, lung function, and airway inflammation were compared between the 2 phases.
Twenty-three patients completed the study; adequate sputum samples were collected from 17 patients. Asthma symptoms and lung function remained similar between the 2 phases. However, the mean sputum eosinophil percentage was higher in the LABA phase than in the ICS phase (5.07±3.82% vs. 1.02±1.70%; P<0.01). Sputum eosinophilia (≥3%) was more frequently observed in the LABA phase than in the ICS phase (six vs. two).
Addition of LABA may mask airway eosinophilic inflammation in asthmatic patients whose symptoms are not controlled with low-dose ICS.
PMCID: PMC3936048  PMID: 24587956
Airway; inflammation; asthma; corticosteroids; beta2-agonists
14.  A Case of Eosinophilic Fasciitis Presenting as Pitting Edema of the Lower Extremities 
Eosinophilic fasciitis is a rare disease characterized by diffuse fasciitis with peripheral eosinophilia and progressive induration and thickening of the skin and soft tissues. We report a 19-year-old female who presented with pitting edema in both lower extremities. She had a history of excessive physical activity before her symptoms developed. Physical examination revealed 2+ pitting edema in both lower legs. She complained of mild pain in both knee joints and feet, with no tenderness or heating sensations. Laboratory results were unremarkable except for severe eosinophilia. Parasite infection, venous thrombosis, and cardiac and renal problems were excluded. A magnetic resonance imaging study of both lower extremities revealed increased signal intensity in the subcutaneous lesions, consistent with superficial inflammation of the fascia. Mixed perivenular lymphoplasmacytic and eosinophilic infiltration in the subcutaneous lesion were observed on biopsy. The patient was treated with corticosteroids, resulting in remarkable improvement in both edema and eosinophilia.
PMCID: PMC3936049  PMID: 24587957
Eosinophilia; eosinophilic fasciitis; pitting edema
15.  A Case of Serum Sickness-Like Reaction and Anaphylaxis - Induced Simultaneously by Rifampin 
Rifampin is commonly used as a first-line anti-tuberculosis drug, but it can induce a serum sickness-like reaction or anaphylaxis. However, it is possible for 1 drug antigen to induce 2 or more simultaneous immunologic reactions. Here, we report a case of a serum-sickness-like reaction and anaphylaxis induced concurrently by rifampin. A 25-year-old male presented with high fever and a maculopapular rash with vesicles on the hands, which developed 2 weeks following regular administration of anti-tuberculosis drugs for tuberculous meningitis, including rifampin. Elevated liver enzymes, peripheral neuropathy, and decreased serum C3 and C4 levels were found. Interestingly, these symptoms were accompanied by severe hypotension. A serum-sickness-like reaction was considered after excluding other potential causes for the fever. A drug provocation test showed that the fever developed after oral administration of rifampin, suggesting that rifampin was the cause of the allergic reaction. However, hypotension, epigastric discomfort, and diarrhea also accompanied these symptoms, indicating that IgE-mediated type I hypersensitivity could be part of the serum sickness-like reaction. An intradermal skin test clearly showed an immediate positive reaction to rifampin. This case was diagnosed as concurrent serum-sickness-like reaction and anaphylaxis induced by rifampin. One drug may therefore induce combined allergic reactions via 2 or more simultaneous hypersensitivity responses.
PMCID: PMC3936050  PMID: 24587958
Rifampin; serum sickness, anaphylaxis
16.  Embarking on a New Journey With the Allergy, Asthma & Immunology Research 
PMCID: PMC3881393  PMID: 24404385
17.  Molecular Genetic Mechanisms of Chronic Urticaria 
Chronic urticaria (CU) is a common allergic skin disease that requires long-term pharmacological treatment. Some patients with severe CU suffer a poor quality of life. Although the pathogenic mechanisms of CU are not clearly understood, several groups have suggested that genetic mechanisms are involved in various CU cohorts. To further understand the molecular genetic mechanisms of CU, we summarize recent genetic data in this review. Although a few HLA alleles were suggested to be candidate markers in different ethnic groups, further replication studies that apply the recent classification are needed. Genetic polymorphisms in histamine-related genes, including FcεRI and HNMT, were suggested to be involved in mast cell activation and histamine metabolism. Several genetic polymorphisms of leukotriene-related genes, such as ALOX5, LTC4S, and the PGE2 receptor gene PTGER4, were suggested to be involved in leukotriene overproduction, a pathogenic mechanism. Further investigations using candidate gene approaches and genome-wide association studies (GWAS) will provide new insights into the molecular genetic mechanisms of CU, which will provide new marker genes for differentiation of CU phenotypes and identification of potential therapeutic targets.
PMCID: PMC3881394  PMID: 24404388
Chronic urticaria; genetic association; leukotriene; mast cell
18.  Effects of Methylprednisolone Pulse Therapy on Refractory Mycoplasma pneumoniae Pneumonia in Children 
Mycoplasma pneumoniae (M. pneumoniae) is one of the most common causes of community-acquired pneumonia in children. The clinical course is typically self-limited and benign; however, rare cases of severe pneumonia can develop despite appropriate antibiotic therapy. We studied the effects of methylprednisolone pulse therapy on severe refractory M. pneumoniae pneumonia in children.
The clinical effects of methylprednisolone therapy were evaluated retrospectively in 12 children with severe refractory M. pneumoniae pneumonia, which was diagnosed serologically. All patients developed respiratory distress, high fever, and initial lobar pneumonic consolidation based on radiological findings. All clinical symptoms deteriorated despite appropriate antibiotic therapy. Thus, children were treated with intravenous methylprednisolone pulse therapy in addition to antibiotics.
The average febrile period before admission was 4.9±1.7 days, and fever persisted in all children until steroid administration. Methylprednisolone pulse therapy (30 mg/kg) was given 5.4±2.5 days after admission. After methylprednisolone pulse therapy, clinical symptoms improved in all patients without adverse events. The fever subsided 0-2 h after initiation of corticosteroid therapy. The abnormal radiological findings resolved within 2.6±1.3 days, and the high C-reactive protein levels (6.7±5.9 mg/dL) on admission decreased to 1.3±1.7 mg/dL within 3.0±1.1 days after starting corticosteroid therapy.
Three-day methylprednisolone pulse therapy could be applied to treatment of refractory M. pneumoniae pneumonia despite appropriate antibiotic therapy and appeared to be efficacious and well-tolerated.
PMCID: PMC3881395  PMID: 24404389
Children; methylprednisolone; Mycoplasma pneumoniae; pneumonia
19.  Fractional Exhaled Nitric Oxide and Impulse Oscillometry in Children With Allergic Rhinitis 
Airway inflammation, bronchial hyper-responsiveness (BHR), and bronchodilator response (BDR) are representative characteristics of asthma. Because allergic rhinitis (AR) is a risk factor for asthma development, we evaluated these 3 characteristics in AR using measurement of fractional exhaled nitric oxide (FeNO), a methacholine challenge test (MCT), and impulse oscillometry (IOS).
This study included 112 children with asthma (asthma group), 196 children with AR (AR group), and 32 control subjects (control group). We compared pulmonary function parameters and FeNO levels among the 3 groups. The AR group was subdivided into 2 categories: the AR group with BHR and the AR group without, and again pulmonary function and FeNO levels were compared between the 2 subgroups.
FeNO levels were more increased in the AR and asthma groups than in the control group; within the AR group, FeNO was higher in the AR group with BHR than in the AR group without. The BDR was more increased in the AR group than in the control group when percent changes in reactance at 5 Hz (Δ X5) and reactance area (Δ AX) were compared. In the AR group, however, there was no difference in Δ X5 and Δ AX between the AR group with BHR and the AR group without.
Reversible airway obstruction on IOS and elevated FeNO levels were observed in children with AR. Because elevated FeNO levels can indicate airway inflammation and because chronic inflammation may lead to BHR, FeNO levels may be associated with BHR in AR. IOS can be a useful tool for detecting lower airway involvement of AR independent of BHR assessed in the MCT.
PMCID: PMC3881396  PMID: 24404390
Asthma; allergic rhinitis; bronchial hyper-responsiveness; bronchodilator effect; child; nitric oxide
21.  Can Fecal Calprotectin Level Be Used as a Markers of Inflammation in the Diagnosis and Follow-Up of Cow's Milk Protein Allergy? 
Calprotectin is a cytosolic protein with immunomodulatory, antimicrobial, and antiproliferative actions. The concentration of calprotectin increases in infection, inflammation, and malignancy. We determined if calprotectin can be used as a marker for the diagnosis and follow-up of bowel inflammation in cow's milk protein allergy (CMPA).
In total, 32 patients newly diagnosed with CMPA were included (24 IgE-mediated, 8 non-IgE-mediated). In all subjects, a complete blood count, total IgE, cow's milk-specific IgE, and fecal calprotectin (FC) were assessed before and after a cow's milk protein (CMP) elimination diet was started. The results were compared with those of 39 healthy children.
The mean FC value before the CMP elimination diet was 516±311 µg/g in the 32 patients with CMPA and 296±94 µg/g in the control group (P=0.011). The mean FC value after the diet in these patients was 254±169 µg/g, which was significantly different from the mean value before the CMP elimination diet (P<0.001). When we compared FC levels before the CMP elimination diet in the IgE-mediated group with the control group, we found no significant statistical difference (P=0.142). The mean FC value before the CMP elimination diet was 886±278 µg/g in the non-IgE-mediated group and 296±94 µg/g in the control group; this difference was statistically significant (P<0.001). In the IgE-mediated and non-IgE-mediated groups, FC values after CMP elimination diet were 218±90 µg/g and 359±288 µg/g, respectively, and FC values before CMP elimination diet were 392±209 µg/g and 886±278 µg/g, respectively; these differences were statistically significant (P=0.001 and P=0.025, respectively).
FC levels may be a useful marker for follow-up treatment and recurrence determination in CMPA.
PMCID: PMC3881398  PMID: 24404391
Milk hypersensitivity; milk protein; fecal calprotectin
22.  Eosinophilic Airway Inflammation and Airway Hyperresponsiveness According to Aeroallergen Sensitization Pattern in Patients With Lower Airway Symptoms 
Sensitization to specific allergens may be important in the development of allergic airway inflammation and airway hyperresponsiveness (AHR). We evaluated the effect of specific aeroallergen sensitization on eosinophilic airway inflammation and AHR.
We reviewed retrospectively the clinical data of subjects who underwent skin prick tests to aeroallergens, induced sputum analysis, and methacholine bronchial provocation tests to evaluate lower airway symptoms as well as analyzed the associations between the pattern of aeroallergen sensitization and sputum eosinophilia or AHR.
Of the 1,202 subjects be enrolled, 534 (44.4%) were sensitized to at least one aeroallergen in skin tests. AHR was demonstrated in 23.5% and sputum eosinophilia in 38.8%. Sputum eosinophilia was significantly associated with sensitization to perennial allergens (OR, 1.9; 95% CI, 1.4-2.5), house dust mite (OR, 1.7; 95% CI, 1.3-2.3), dog (OR, 1.9; 95% CI, 1.1-3.3), and cat (OR, 2.1; 95% CI, 1.4-3.4). AHR was associated with sensitization to perennial allergens (OR, 2.7; 95% CI, 2.0-3.7), house dust mite (OR, 2.2; 95% CI, 1.6 3.2), Alternaria (OR, 2.3; 95% CI, 1.2-4.7), and cat (OR, 2.7; 95% CI, 1.7-4.3). Sensitization to more perennial allergens increased the risk for sputum eosinophilia and AHR. There was no relationship with individual seasonal allergens.
The development of airway eosinophilic inflammation and AHR in an adult Korean population was associated with sensitization to perennial allergens rather than seasonal allergens.
PMCID: PMC3881399  PMID: 24404392
Aeroallergen; airway eosinophilia; airway hyperresponsiveness
23.  Variability of Offending Allergens of Allergic Rhinitis According to Age: Optimization of Skin Prick Test Allergens 
This study evaluates offending allergens in patients with allergic rhinitis (AR) according to age that establish a minimal panel for skin prick test (SPT) allergens required to identify if a patient is sensitized.
We retrospectively analyzed SPT results according to age to determine the minimum test battery panel necessary to screen at least 93%-95% of AR patients. Allergic skin tests (common airborne indoor and outdoor allergens) were performed on 7,182 patients from January 2007 to June 2011. All patients were classified into 9 groups according to age; subsequently, we investigated offending allergens by age group.
A total of 5,032 (70.1%) patients were found sensitized to at least one of the 55 aeroallergen extracts tested. The annual ranking of offending allergens was not significantly different from each other over the past 5 years. House dust mites (HDM) were the most prevalent allergens ranked from first to third for all 5 years. The allergens in the minimum test panel differed slightly among all age groups; in addition, the types of sensitized allergen sources were more diverse in the older versus younger age group. HDM covered a larger proportion of the sensitized allergens in the younger age group versus the older age group. Testing with 5 allergens (Dermatophagoides farinae, Tetranychus urticae, oak, mugwort and cockroach) adequately identified over 90% of the sensitized patients.
A SPT with around 5-7 allergens adequately detected most of the sensitization in the majority of the age groups in Korea. However, this study suggests that physicians perform the SPT with appropriately selected allergens in each age category for the screening of AR.
PMCID: PMC3881400  PMID: 24404393
Allergic rhinitis; aeroallergen; skin prick test; sensitization
24.  Gene-Gene Interaction Between CCR3 and Eotaxin Genes: The Relationship With Blood Eosinophilia in Asthma 
Eosinophils function as an effector cell in the development of asthma and allergic disease. Eotaxins are cytokines that promote pulmonary eosinophilia via the receptor CCR3. Single-nucleotide polymorphisms (SNPs) in CCR3 and eotaxin genes are associated with asthma. In this study, genetic interactions among SNPs of several eotaxin genes and CCR3 were assessed and their relationship with blood eosinophilia in asthma was examined.
A total of 533 asthmatics were enrolled in this study. Asthmatics with eosinophilia (>0.5×109/L) were compared with those without eosinophilia (≤0.5×109/L). Chi-square tests were used to compare SNP frequencies. Two different models were used to evaluate gene-gene interactions: logistic regression and generalized multifactor dimensionality reduction (GMDR).
EOT2+304C>A (29L>I) was significantly associated with 3 of the 4 CCR3 SNPs among asthmatics with eosinophilia (P=0.037-0.009). EOT2+304C>A (29L>I) and the CCR3 SNPs were also significantly associated with blood eosinophilia in an interaction model constructed by logistic regression (P=0.0087). GMDR analysis showed that the combination of EOT2+304C>A (29L>I) and CCR3-174C>T was the best model (accuracy=0.536, P=0.005, CVC 9/10).
The epistatic influence of CCR3 on eotaxin gene variants indicates that these variants may be candidate markers for eosinophilia in asthma.
PMCID: PMC3881401  PMID: 24404394
Asthma; epistasis; polymorphisms; CCR3; eotaxin
25.  Histamine-Releasing Factor and Immunoglobulins in Asthma and Allergy 
Factors that can induce the release of histamine from basophils have been studied for more than 30 years. A protein termed histamine-releasing factor (HRF) was purified and molecularly cloned in 1995. HRF can stimulate histamine release and IL-4 and IL-13 production from IgE-sensitized basophils and mast cells. HRF-like activities were found in bodily fluids during the late phase of allergic reactions, implicating HRF in allergic diseases. However, definitive evidence for the role of HRF in allergic diseases has remained elusive. On the other hand, we found effects of monomeric IgE on the survival and activation of mast cells without the involvement of a specific antigen, as well as heterogeneity of IgEs in their ability to cause such effects. The latter property of IgE molecules seemed to be similar to the heterogeneity of IgEs in their ability to prime basophils in response to HRF. This similarity led to our recent finding that ~30% of IgE molecules can bind to HRF via their Fab interactions with two binding sites within the HRF molecule. The use of peptide inhibitors that block HRF-IgE interactions revealed an essential role of HRF to promote skin hypersensitivity and airway inflammation. This review summarizes this and more recent findings and provides a perspective on how they impact our understanding of allergy pathogenesis and potentially change the treatment of allergic diseases.
PMCID: PMC3881402  PMID: 24404387
Asthma; allergy; histamine-releasing factor; IgE; mast cell; basophil

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