Pulmonary function of healthy Korean children from three independent birth cohorts: Validation of the Global Lung Function Initiative 2012 equation.

BACKGROUND AND OBJECTIVE: Global Lung Function Initiative (GLI) 2012 equations were developed to resolve the age-related disparity in interpreting spirometry results. Local validation of the equation is needed, especially in Northeast Asian children. This study evaluated the GLI equation in Korean children. METHODS: Spirometry indices (FEV1, FVC, FEV1/FVC, and FEF25%-75%) and clinical information were gathered from three population-based birth cohorts. Predicted GLI reference values and z scores of spirometry results were calculated for 1239 healthy children. The mean, standard deviation of z scores were compared with the expected 0 and 1. Probabilities of falling below the lower limit of normal (LLN) (z score: -1.64) were compared with the expected value 5%. GLI z scores were assessed according to low (<-2), normal (≥-2 and ≤2), and high (>2) BMI z score groups. RESULTS: Mean z scores significantly differed from 0 for FEV1/FVC in males (mean [95% confidence interval]: 0.18 [0.08, 0.27]) and forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) in females (-0.23 [-0.31, -0.15] and -0.26 [-0.36, -0.16], respectively). The standard deviation was larger than 1 for all variables in males and FVC and FEV1/FVC in females. The probability of falling below the LLN was significantly larger than 5% for FEV1 (12.13% [9.64, 14.77]), FVC (15.86% [13.06, 18.81]), and forced expiratory flow at 25%-75% of forced vital capacity (FEF25%-75%) (7.31% [5.29, 9.49]) in males and FVC (11.91% [9.40, 14.60]) in females. FEV1 and FVC z scores increased across low to high body mass index (BMI) groups, and FEV1/FVC decreased from low to high BMI groups. CONCLUSION: GLI equations marginally differ from real-world values, which should be considered by pulmonologists in practice or research.

Intertrochanteric fracture with low-energy trauma in a young woman with anorexia nervosa: A case report.

RATIONALE: Anorexia nervosa is a chronic psychiatric disease defined by severe weight loss, due to fear of obesity, and self-imposed semi-starvation. Of the many complications following anorexia nervosa, low bone mineral density (BMD) is a significant risk factor for fractures. Anorexia nervosa is associated with higher risk of incident fracture in females across all age groups, and in males >40 years old. Sites at highest risk of fracture include the hip/femur and pelvis in females, and vertebrae in males with anorexia nervosa. PATIENT CONCERNS: A 29-year-old woman known to have suffered from anorexia nervosa 15 years ago visited the emergency department due to right hip pain after falling while getting out of a taxi. During the period of anorexia nervosa, she had a body mass index (BMI) of 14.06 kg/m (weight, 36 kg; height, 1.60 m) and suffered from amenorrhea. At the time of presentation, she had a BMI of 19.53 kg/m (weight, 50 kg; height, 1.60 m) and had regular menstrual periods, indicating clinical recovery from anorexia nervosa. DIAGNOSES: Plain radiography, computed tomography, and bone scintigraphy revealed AO 31-A2.2 type right hip proximal femur intertrochanteric fracture. The BMD showed a T score of -3.9 in the hip and -3.6 at the lumbar level, indicating severe osteoporosis. INTERVENTIONS: Osteosynthesis was performed with proximal femoral nail antirotation (PFNA) and wiring. OUTCOMES: There were no specific symptoms, such as trauma or infection, during postoperative rehabilitation and postoperative management, and she was discharged after 2 weeks. After 1 year of follow-up at our outpatient clinic, she had no complications. LESSONS: Here, we describe an unusual case of unilateral femoral intertrochanteric fracture that occurred after clinical recovery from anorexia nervosa. This case indicated that the risk of fracture remains even after recovery of BMI. We propose that women who have clinically recovered from anorexia nervosa should be advised to undergo annual osteodensitometric analyses after consulting with specialists in other areas (psychiatry, endocrinology, eating disorders).

Profiles and characteristics of bronchial responsiveness in general 7-year-old children.

BACKGROUND: Although bronchial responsiveness (BR) is usually categorized as normal or hyperresponsive to aid the diagnosis of asthma, it exists on a continuous spectrum, not in a dichotomous manner. We aimed to evaluate the distribution profile of BR in a general population of 7-year-olds. METHODS: In 2015, 7-year-old Korean children from a nationwide birth cohort study visited regional study hospitals for skin prick test, standard spirometry, and bronchial provocation to establish reference values for the general population. Their BR degrees were categorized into five ordered groups: hyperresponsive BRs were classified into group 1 (provocative concentration (PC) of methacholine causing a 20% fall in forced expiratory volume in 1 second [FEV1], PC20 of <4 mg/mL) and group 2 (PC20 of ≥4 mg/mL and <16 mg/mL), and nonresponsive BRs were categorized into group 3 (final FEV1 percentage fall after inhaling 16 mg/mL of methacholine [FEV1%fall] of >15% and ≤20%), group 4 (FEV1%fall of >10% and ≤15%), and group 5 (FEV1%fall of ≤10%). RESULTS: In total, 559 subjects finished all tests reliably. Groups 1 and 2 comprised 10.0% and 15.7% of the total population, respectively. Groups 3, 4, and 5 comprised 14.7%, 18.4%, and 41.1%, respectively. As the group number increased, the proportion of those with recent wheezing and those with indoor allergen sensitization decreased (P for trend = 0.001 and P for trend < 0.001, respectively), and the baseline FEV1/FVC increased (P for trend < 0.001) CONCLUSION: BR of the 7-year-olds in the general population, while showing a wide distribution across phenotypes, is associated with allergic symptoms, negatively correlated with baseline lung function and positively correlated with indoor allergen sensitization.

Impact on Bisphosphonate Persistence and Compliance: Daily Postprandial Administration.

BACKGROUND: Bisphosphonate (BP) is an effective drug for the prevention and treatment of osteoporosis. However, gastrointestinal distress caused by BP is a well-known side effect for low compliance. The aim of our study was to compare the 1-year persistence, compliance and T-scores between the aperitif medication group and the postprandial medication group. METHODS: Three hundred patients were included in this study to determine their persistence and compliance with the prescribed daily BP (Maxmarvil®, alendronate 5 mg and calcitriol 0.5 µg; YuYu Pharm) following distal radius fractures. Patients in Group 1 (aperitif medication) were asked to adhere to the general guidelines for BPs before breakfast. Patients in Group 2 (postprandial medication) were recommended medication after breakfast. We compared the persistence and compliance of this daily BP therapy using the medication possession ratio (MPR) and T-scores between the 2 groups after 1 year. RESULTS: Bone mineral density in hip and lumbar spine was improved significantly in 2 groups (P<0.001). Significant differences existed between 2 groups, including 73 of 150 patients (48.7%) in Group 1, and 111 of 150 patients (73.3%) in Group 2 for 1-year persistence (P=0.001). The mean MPR is 0.66 in Group 1 (range, 0.50-0.86) and 0.71 in Group 2 (range, 0.54-0.87). A significant difference was detected between the 2 groups (P=0.002). CONCLUSIONS: Postprandial administration improved persistence and compliance with daily BP therapy, resulting in better clinical outcomes.

Association between obesity and the prevalence of allergic diseases, atopy, and bronchial hyperresponsiveness in Korean adolescents.

BACKGROUND: Although several mechanisms underlying the asthma-obesity connection have been proposed, debates still remain. This study was to determine whether overweight is associated with a higher prevalence of atopy, asthma symptoms, airway obstruction, bronchial hyperresponsiveness (BHR) or biomarkers of inflammation in a sample of Korean adolescents. METHODS: We conducted a cross-sectional survey involving questionnaires, skin tests, spirometry and methacholine challenge tests among 717 adolescents from Seoul (South Korea). Overweight status was defined as a BMI greater than the local age- and gender-specific 85th percentile. RESULTS: Overweight subjects more frequently reported ever having wheezing (24.6 vs. 14.0%, p = 0.001) and wheezing in the previous 12 months (11.5 vs. 6.3%, p = 0.02) than normal-weight subjects, especially in boys. Atopy was more common among overweight adolescents than among those of normal weight (61.5 vs. 49.2%, p = 0.002), especially in boys (65.0 vs. 52.8%, p = 0.005). Overweight subjects had higher total WBC counts and eosinophil counts, especially boys. The presence of BHR was more common only among overweight girls (32.8 vs. 18.0%, p = 0.028). Overweight status was a significant risk factor for the presence of atopy (odds ratio = 1.49; 95% CI 1.06-2.10), after adjusting for various confounders by logistic regression analysis. CONCLUSIONS: An association was found between overweight status and both atopy and an increased prevalence of wheezing in adolescent Korean boys. These findings suggest that being overweight in puberty may be one of several risk factors responsible for atopy, BHR, and asthma symptoms.

Airway hyperresponsiveness is associated with total serum immunoglobulin E and sensitization to aeroallergens in Korean adolescents.

BACKGROUND: Allergen sensitization and airway hyperresponsiveness (AHR) are the most important characteristics of bronchial asthma and their correlation has been speculated. OBJECTIVE: We attempted to investigate the relationship between sensitization to allergens and AHR to methacholine in Korean high school students. METHODS: A questionnaire survey, methacholine bronchial provocation tests, and skin-prick tests for 16 major allergens were performed on 724 students. The mean age of participants was 15.79 ± 0.40 years old. Serum total immunoglobulin E (IgE) and the fraction of blood eosinophils were measured. RESULTS: AHR (PC(20) < 16 mg/ml) was present in 12.3%. Log total IgE was higher in AHR-positive group than negative group (4.22 ± 1.55, 3.70 ± 1.33, P = 0.001). Three hundred eighty-four students (53.0%) were sensitized to more than one allergen, and among them Dermatophagoides pteronyssinus (Der p, 295 students, 40.7%) and Dermatophagoides farinae (Der f, 301 students, 41.6%) were most common. The risk of AHR development was high in the group who had sensitization to one allergen (adjusted odds ratio [aOR] = 1.97, 95% confidence interval [CI]: 1.13-3.44, P = 0.018) and to more than two allergens (aOR = 2.94, 95% CI: 1.32-6.57, P = 0.009). Among the specific allergens, AHR was developed in those who were sensitized to Der f (aOR = 1.73, 95% CI: 1.04-2.86, P = 0.033), dog dander (aOR = 3.97, 95% CI: 1.67-9.51, P = 0.002), and Alternaria (aOR = 3.19, 95% CI: 1.24-6.41, P = 0.016). In the groups with high IgE (>300 IU/ml) and high eosinophil fraction (>4%), AHR was more developed than groups who were low in each (aOR = 2.73, 95% CI: 1.15-6.51, P = 0.023; aOR = 10.82, 95% CI: 3.33-35.08, P = 0.001). CONCLUSION: The risk of AHR development was closely linked with allergen sensitization itself, and the number or types of sensitized allergens such as indoor and fungal allergens in Korean young adolescents.

TNF-alpha (-308 G/A) and CD14 (-159T/C) polymorphisms in the bronchial responsiveness of Korean children with asthma.

BACKGROUND: TNF-alpha is a pivotal proinflammatory cytokine increased in asthmatic airways. The TNF-alpha gene family might be linked to asthma or bronchial hyperresponsiveness (BHR), and TNF-alpha production might be modulated by CD14(+) cells. OBJECTIVE: We investigated the association between asthma susceptibility or asthma-related phenotypes and TNF-alpha (-308G/A) polymorphism and examined the combined effect with CD14 (-159T/C) polymorphism in Korean children. METHODS: Asthmatic (n = 788) and control (n = 153) children were evaluated for asthma phenotypes. Genotypes were determined by using the single-base extension method and PCR-restriction fragment length polymorphism. RESULTS: There was no difference between asthmatic children and control subjects in terms of the allele frequencies of TNF-alpha (-308G/A) and CD14 (-159T/C). Significantly lower PC(20) values were seen in asthmatic (P = .016) children with the TNF-alpha risk allele (-308A). Higher frequencies of 1 or 2 copies of the risk allele were found in asthmatic children with moderate-to-severe BHR to methacholine and exercise compared with control children (adjusted odds ratio of 2.57 [95% CI, 1.30-5.08] and adjusted odds ratio of 2.04 [95% CI 0.99-4.20], respectively). In addition, asthmatic children with risk alleles at both loci had significantly greater BHR than those homozygous for the common alleles (P = .018). CONCLUSION: The TNF-alpha promoter polymorphism (-308G/A) might be associated with severe BHR in Korean children with asthma. In addition, these children show a synergistic effect between the TNF-alpha promoter (-308A) and CD14 promoter (-159C) polymorphisms in terms of BHR. CLINICAL IMPLICATIONS: The TNF-alpha polymorphism might be a disease-modifying gene in asthma and modulated by the CD14 gene.

Eosinophils play a major role in the severity of exercise-induced bronchoconstriction in children with asthma.

Exercise-induced bronchoconstriction (EIB) was associated with eosinophilic airway inflammation, bronchial hyperresponsiveness (BHR), atopy and airway obstruction. To understand the pathogenesis of EIB, we determine whether eosinophil is more related to the mechanism of EIB than atopy, BHR and airway obstruction. This study comprised 268 asthmatic children who underwent lung function test, methacholine challenge test, exercise challenge test, and blood tests for total IgE levels and total eosinophil counts (TEC). Urine eosinophil protein X (EPX) levels after exercise were measured by using ELISA method. EIB was observed in 195 of 268 asthmatics (72.8%). Asthmatics with EIB showed significantly increased TEC (P < 0.01) and decreased log PC(20) as compared with asthmatics without EIB. Maximal percent fall in FEV(1) after exercise was significantly correlated with TEC, log IgE, FEF(25-75%), log PC(20) (P < 0.001, respectively) and FEV(1) (P = 0.013). When the same study was carried out in nonatopic asthmatics, those with EIB showed significantly increased TEC (P = 0.01) compared with those without EIB; however, log PC(20), FEV(1), and FEF(25-75%) showed no significant differences between the two groups of nonatopic asthmatics. In addition, there was a significant correlation between the severity of EIB and TEC in nonatopic asthmatics. Urine EPX/Cr levels after exercise were correlated with the severity of EIB (r = 0.238, P = 0.014). Blood eosinophils and urine EPX/Cr after exercise correlate significantly with the maximal percent fall in FEV(1) after exercise, therefore EIB may reflect a state of eosinophilic inflammation in the airway of asthmatic children.

Familial interstitial lung disease in two young Korean sisters.

Most of the interstitial lung diseases are rare, chronic, progressive and fatal disorders, especially in familial form. The etiology of the majority of interstitial lung disease is still unknown. Host susceptibility, genetic and environmental factors may influence clinical expression of each disease. With familial interstitial lung diseases, mutations of surfactant protein B and surfactant protein C or other additional genetic mechanisms (e.g. mutation of the gene for ATP-binding cassette transporter A3) could be associated. We found a 21 month-old girl with respiratory symptoms, abnormal radiographic findings and abnormal open lung biopsy findings compatible with nonspecific interstitial pneumonitis that is similar to those of her older sister died from this disease. We performed genetic studies of the patient and her parents, but we could not find any mutation in our case. High-dose intravenous methylprednisolone and oral hydroxychloroquine were administered and she is still alive without progression during 21 months of follow-up.

IL-5 and thromboxane A2 receptor gene polymorphisms are associated with decreased pulmonary function in Korean children with atopic asthma.

BACKGROUND: Asthmatic airways undergo chronic inflammatory cell infiltration by T cells and eosinophils, which results in sustained airway hyperresponsiveness. IL-5 is important for eosinophil-induced airway inflammation and airway hyperresponsiveness. Thromboxane A2 and its receptor, TBXA2R, are involved in constriction of respiratory smooth muscles and may play a role in thickening and remodeling of airways, which contributes to the severity of asthma. The relationship between IL-5 and TBXA2R gene polymorphisms and pulmonary function in children with asthma has rarely been examined. OBJECTIVE: To determine whether IL-5 (T-746C) and TBXA2R (T924C) gene polymorphisms are associated with asthma phenotype and pulmonary function in Korean children with atopic and nonatopic asthma. METHODS: We conducted an association study between known polymorphisms of IL-5 (T-746C) and TBXA2R (T924C) and asthma phenotype and the parameters of atopy and pulmonary function in atopic and nonatopic Korean children with asthma. The subjects were 240 atopic children with asthma, 70 nonatopic children with asthma, and 106 nonatopic healthy children. Asthma phenotypes and bronchial responsiveness to methacholine were determined by a physician. IL-5 and TBXA2R gene polymorphisms were determined by genotyping by using PCR-RFLP assays. RESULTS: The genotype frequencies of IL-5 and TBXA2R polymorphisms did not differ between healthy controls and atopic or nonatopic children with asthma. A significant association was observed between the IL-5 polymorphism and forced expiratory flow at 25% to 75% of forced vital capacity (FEF 25-75% ; %; P = .002), and between the TBXA2R polymorphism and FEV 1 (%; P = .035) and FEF 25-75% (%; P = .042) in children with atopic asthma, whereas no such association between the polymorphisms and lung function was observed in nonatopic or control children. In atopic children with asthma, we identified a significant gene-gene interaction in that the combination of the IL-5 (T-746C) and TBXA2R (T924C) mutant alleles was shown to be associated with reduced pulmonary function as determined by FEF 25-75% (%) measurement. CONCLUSION: The current study indicates that IL-5 (T-746C) and TBXA2R (T924C) polymorphisms alone are associated with spirometric markers of asthma severity, whereas they are not associated with presence of asthma per se. In addition, the data suggest that an interaction between IL-5 and TBXA2R genes may contribute to the severity of asthma, especially atopic asthma. These results suggest that IL-5 and TBXA2R genes may be disease-modifying genes in Korean children with atopic asthma.

Prolonged effect of montelukast in asthmatic children with exercise-induced bronchoconstriction.

Accumulating evidence shows that cysteinyl leukotrienes are the most important mediators in exercise-induced bronchoconstriction (EIB). In contrast to several studies in adults, there are few long-term studies of leukotriene receptor antagonists (LTRAs) in children with EIB. The aim of this study was to assess the prolonged clinical and bronchoprotective effects of montelukast in asthmatic children with EIB. We randomly assigned 64 asthmatic children with EIB. Forty subjects received montelukast (5 mg/day), and 24 subjects received placebo once daily for 8 weeks. Exercise challenge was performed before and after 8 weeks of treatment. Of the 40 patients in the montelukast group, 28 patients crossed over after 8 weeks. The response was measured as asthma symptom score, maximum percent fall in forced expiratory volume in 1 sec (FEV(1)) from pre-exercise baseline, and time to recovery of FEV(1) to within 10% of pre-exercise baseline (time to recovery). Following 8 weeks of treatment with montelukast, the montelukast group compared with placebo showed significant improvements in all endpoints, including asthma symptom score, maximum percent fall in FEV(1) after exercise, and time to recovery. In the cross-over group, even 8 weeks after stopping montelukast treatment, all endpoints were significantly and persistently improved. These results indicate that montelukast provides clinical protection from airway hyperresponsiveness in asthmatic children with EIB, and suggest that LTRAs may be useful for the long-term management of asthmatic children with EIB.

Different IL-5 and IFN-gamma production from peripheral blood T-cell subsets in atopic and nonatopic asthmatic children.

Defective Th1 and enhanced Th2-type cytokine responses have been implicated in the development of atopic disease. However, the immunopathology of nonatopic asthma, especially in children, remains unclear, and there have been few studies to compare the cytokine profile in peripheral blood T-cell subsets between atopic and nonatopic asthmatic children. To document whether atopic asthmatic children have a cytokine imbalance and to compare the cytokine profile between atopic and nonatopic asthmatic children, we investigated the interleukin (IL)-5-producing and interferon (IFN)-gamma-producing T-cell subsets from peripheral blood mononuclear cells (PBMC). The percentages of IFN-gamma-producing CD4+ and CD8+ T cells from atopic asthmatic children were decreased, but those in nonatopic asthmatic children were not decreased. In both groups of asthmatic children, the percentages of IFN-gamma-producing CD4+ T cells were inversely correlated with the peripheral blood eosinophils and had a significant correlation with airway responsiveness (PC20). Thus, we found that the mechanism underlying allergic inflammation of nonatopic asthma is not simple a Th1/Th2 cytokine imbalance. Considering the inverse relationship between IFN-gamma-producing CD4+ T cells and eosinophilia or airway hyperresponsiveness, IFN-gamma from CD4+ T cells may play an important role in allergic inflammation and airway hyperresponsiveness in asthmatic children.