Search

Background We previously reported that the ILVBL gene on chromosome 19p13.1 was associated with the risk for aspirin-exacerbated respiratory disease (AERD) and the percent decline of forced expired volume in one second (FEV1) after an oral aspirin challenge test. In this study, we confirmed the association between polymorphisms and haplotypes of the ILVBL gene and the risk for AERD and its phenotype. Methods We recruited 141 AERD and 995 aspirin-tolerant asthmatic (ATA) subjects. All study subjects underwent an oral aspirin challenge (OAC). Nine single nucleotide polymorphisms (SNPs) with minor allele frequencies above 0.05, which were present in the region from 2 kb upstream to 0.5 kb downstream of ILVBL in Asian populations, were selected and genotyped. Results In an allelic association analysis, seven of nine SNPs were significantly associated with the risk for AERD after correction for multiple comparisons. In a codominant model, the five SNPs making up block2 (rs2240299, rs7507755, rs1468198, rs2074261, and rs13301) showed significant associations with the risk for AERD (corrected P = 0.001–0.004, OR = 0.59–0.64). Rs1468198 was also significantly associated with the percent decline in FEV1 in OAC tests after correction for multiple comparisons in the codominant model (corrected P = 0.033), but the other four SNPs in hapblock2 were not. Conclusion To the best of our knowledge, this is the first report of an association between SNPs on ILVBL and AERD. SNPs on ILVBL could be promising genetic markers of this condition. Electronic supplementary material The online version of this article (10.1186/s12890-017-0556-6) contains supplementary material, which is available to authorized users.

BACKGROUND Aspirin-exacerbated respiratory disease (AERD) is characterized by a severe and sudden asthma attack after aspirin ingestion in patients with asthma. We studied associations with six common single nucleotide polymorphisms (SNP) of the gasdermin B gene (GSDMB). OBJECTIVE DNA obtained from 572 patients with asthma (with AERD, n = 165; and with aspirin-tolerant asthma, n = 407) and 391 normal controls was subjected to genotyping of six SNPs of GSDMB. METHODS An association analysis between GSDMB variants and AERD, with a fall rate of the forced expiratory volume in the first second of expiration (FEV1), was performed by using logistic and regression models. RESULTS Two SNPs in the intron (rs870830, rs7216389) showed significant associations with AERD (minimum p = 7.00 × 10-4 in the dominant model), even after Bonferroni correction (pcorr = 0.01 for the rs870830). Regression analysis of the genetic variants with FEV1 revealed significant associations with rs870830 and the haplotype 2 (pcorr = 4.71 × 10-4 for rs870830 and pcorr = 1.14 × 10-3 for haplotype 2, respectively). CONCLUSION We found strong associations among GSDMB polymorphisms and the presence of AERD and FEV1 in Korean patients with asthma. Our findings indicated that genetic variations of GSDMB may be associated with the development of AERD and aspirin-induced bronchospasm.

Background/Aims Mucosal immunoglobulin A (IgA) may prevent the entrance of allergens. This study examined the relationship between serum IgA levels (within the normal range) and sensitization to house dust mites (HDM) or airway hyper-responsiveness (AHR). Methods The clinical records of 1,136 adult patients with suspected asthma, for whom test data for serum IgA level and methacholine-AHR were available, were reviewed retrospectively. The AHR/allergy indices were compared among patient groups with low (

Purpose We previously reported that the skin prick test was sensitive and the serum specific immunoglobulin E test was specific for predicting positive airway responses to house dust mites (HDMs) in patients with asthma. Because the nose and bronchus are one airway, the nasal provocation test would be more specific for predicting the bronchial responses to HDM than the skin test. Methods The allergy skin prick test and nasal and bronchial provocation tests using HDM (Dermatophagoides farinae) were performed in 41 young men (age, 19-28 years) who wanted military certification for asthma. The nasal responses to HDM was scored according to the severity of rhinorrhea, sneezing, and nose itching. Results The prevalence of a positive skin prick test to HDM did not significantly differ between patients with (n=24) and without (n=17) an early airway reaction (EAR; 79.2% vs 70.6%, P=0.534). However, the prevalence of a positive nasal test was significantly higher in the airway responders than in the others (37.5% vs 0%, P=0.005). The concordance of a positive response to the nasal test (κ=0.332, P=0.004) but not to the skin prick test (κ=0.091, P=0.529) was significant with an EAR. The diagnostic sensitivity of the nasal test (37.5%) was lower than that of the skin prick test (79.2%), but the specificity was higher (100% vs 29.4%). Conclusions The skin prick test is more sensitive, whereas the nasal test is more specific and accurate, for predicting an EAR to HDM in patients with asthma.

We developed a genetic marker set of single nucleotide polymorphisms (SNPs) by summing risk scores of 14 SNPs showing a significant association with aspirin-exacerbated respiratory disease (AERD) from our previous 660 W genome-wide association data. The summed scores were higher in the AERD than in the aspirin-tolerant asthma (ATA) group (P=8.58 × 10(-37)), and were correlated with the percent decrease in forced expiratory volume in 1 s after aspirin challenge (r(2)=0.150, P=5.84 × 10(-30)). The area under the curve of the scores for AERD in the receiver operating characteristic curve was 0.821. The best cutoff value of the summed risk scores was 1.01328 (P=1.38 × 10(-32)). The sensitivity and specificity of the best scores were 64.7% and 85.0%, respectively, with 42.1% positive and 93.4% negative predictive values. The summed risk score may be used as a genetic marker with good discriminative power for distinguishing AERD from ATA.

PURPOSE Inhalant allergen sensitization is one of the major factors involved in the pathogenesis of allergic respiratory diseases. However, the sensitization is determined by interactions between genetic and environmental factors. Thus, testing panels of inhalant allergens may differ among geographical areas. Here we aimed to determine 10 common inhalant allergens in Korean adult patients with suspected respiratory allergies and to examine the variation between different geographical locations. METHODS A total of 28,954 patient records were retrieved for retrospective analysis, from 12 referral allergy clinics located in 9 different areas. Inclusion criteria were Korean adults (≥18 years old) who underwent the inhalant allergen skin prick test for suspected history of respiratory allergy. The primary outcome was inhalant allergen skin prick response. Demographic and clinical information were also collected. Positive skin prick responses to allergens were defined as allergen-to-histamine wheal ratio ≥1. Based on skin test results, the most prevalent aeroallergens were determined. RESULTS The overall prevalence of allergic sensitization was 45.3%. Dermatophagoides farinae and Dermatophagoides pteronyssinus were the most commonly sensitized allergens. Other common inhalant allergens were cat epithelium (8.1%), birch (7.7%), mugwort (6.9%), alder (6.7%), hazel (6.7%), beech (6.7%), oak (6.6%), and Tyrophagus putres (6.2%), in decreasing order frequency. These 10 inhalant allergens explained 90% of inhalant allergen sensitization in the study participants. However, distinct patterns of the 10 inhalant sensitization were observed in patients living in Chungnam and Jeju. American cockroach, Gernam cockroach, and Trichophyton metagrophytes were unique in Chungnam. Orchard, Japanese cedar, and Velvet were unique in Jeju. CONCLUSIONS The present analysis suggests a panel of 10 most common inhalant allergens in Korean adult patients with suspected respiratory allergies, which explained 90% of inhalant allergen sensitization. This panel can be utilized as a practical and convenient tool for primary practice and epidemiological surveys of respiratory allergic diseases.

Member RAS oncogene family (RAB1A), a member of the RAS oncogene family, cycles between inactive GDP-bound and active GTP-bound forms regulating vesicle transport in exocytosis. Thus, functional alterations of the RAB1A gene may contribute to aspirin intolerance in asthmatic sufferers. To investigate the relationship between single-nucleotide polymorphisms (SNPs) in the RAB1A gene and aspirin-exacerbated respiratory disease (AERD), asthmatics (n=1197) were categorized into AERD and aspirin-tolerant asthma (ATA). All subjects were diagnosed as asthma on the basis of the Global Initiative for Asthma (GINA) guidelines. AERD was defined as asthmatics showing 15% or greater decreases in forced expiratory volume in one second (FEV(1)) or naso-ocular reactions by the oral acetyl salicylic acid (ASA) challenge (OAC) test. In total, eight SNPs were genotyped. Logistic regression analysis identified that the minor allele frequency of +14444 TG and +41170 CG was significantly higher in the AERD group (n=181) than in the ATA group (n=1016) (p=0.0003-0.03). Linear regression analysis revealed a strong association between the SNPs and the aspirin-induced decrease in FEV(1) (p=0.0004-0.004). The RAB1A gene may play a role in the development of AERD in asthmatics and the genetic polymorphisms of the gene have the potential to be used as an indicator of this disease.

Aspirin-exacerbated respiratory disease (AERD) is characterized by the development of airway obstruction in asthmatic individuals following the ingestion of aspirin or other nonsteroidal anti-inflammatory drugs. TAPBP (TAP-binding protein, tapasin) is upregulated by eicosanoids, which act as potent inflammatory molecules in aspirin-related reactions. Thus, functional alterations in the TAPBP gene may contribute toward AERD.We examined the relationship between the single nucleotide polymorphisms on the TAPBP gene and AERD.A group of asthmatic patients (n=1252) underwent the oral aspirin challenge. Oral aspirin challenge reactions were categorized into two groups as follows: 15% or greater decreases in forced expiratory volume in 1 s or naso-ocular and skin reactions (AERD), or 15% or less decreases in forced expiratory volume in 1 s without naso-ocular and skin reactions (aspirin-tolerant asthma). Five single nucleotide polymorphisms of the TAPBP gene were genotyped.Logistic regression analysis showed that the minor allele frequencies of TAPBP rs2071888 CG (Thr260Arg) on exon 4 (P0.05), which was in absolute linkage disequilibrium with rs1059288 TC on 3'UTR, were significantly higher in the AERD group than in the aspirin-tolerant asthma group, and the P values remained significant after multiple comparisons (Pcorr=0.006, odds ratio: 1.37, 95% confidence interval: 1.11-1.69, additive model; Pcorr=0.009, odds ratio: 1.52, 95% confidence interval: 1.14-2.03, dominant model). Alpha-helical wheel plotting showed that 260Arg had greater hydrophilic helical property than 260Thr.TAPBP polymorphisms may play a role in the development of AERD.

Aim To investigate the association of single nucleotide polymorphisms (SNP) on IL17RA gene with Aspirin Exacerbated Respiratory Disease (AERD) and the functional effect of these variants on expression of IL17RA gene products. Material & methods 15 SNPs of IL17RA gene were analyzed in 825 normal controls and 143 subjects with AERD and 411 with aspirin-tolerant asthma (ATA) and functionally characterized using measurement of protein and m-RNA expression. Result Minor alleles frequencies of the three SNPs ( −1075 A > G, −947 A > G, −50 C > T) and one haplotype ( BL1_ht1 ) were significantly lower in AERD compared to those in ATA ( p corr = 0.002–0.03). IL17RA protein expression and mRNA amount in CD14 + peripheral blood monocytes and mononuclear cells were significantly increased in subjects carrying the common alleles homozygote compared with those carrying the minor alleles. Conclusions The minor alleles of the three SNPs may decrease the risk of AERD via attenuation of IL17RA gene expression.

Asthma is a global health problem which threatens approximately 300 million patients worldwide. Among them, up to 20 % of the asthma patients are classified as aspirin exacerbated respiratory disease (AERD). Interleukin-1 receptor associated kinase (IRAK2) is associated with necrosis factor kappa B (NF-кB) pathway via interleukin-1 (IL-1) signaling. NF-кB pathway is known to be involved in asthma development, and several interleukin and IRAK family members have also been reported to be associated with asthma or AERD. Since IRAK2 plays an important role in the asthma etiology, we hypothesized that the genetic variants of IRAK2 may be associated with AERD. This study genotyped a total of 25 common single nucleotide polymorphisms (SNPs) in 163 AERD cases and 429 aspirin-tolerant asthma (ATA) controls. As a result, no significant association was found between the genetic variants of IRAK2 and AERD (P > 0.05). In further regression analysis for the forced expiratory volume in 1 s (FEV1) decline, an important phenotype for diagnosing AERD, although one haplotype (BL1_ht3) showed a nominal association with FEV1 decline (P = 0.04), the significance disappeared after correction for multiple testing (P > 0.05). Despite limitations in our study and need for replications, our results suggest that the genetic variants of IRAK2 might not be associated with AERD and the obstructive symptoms in asthma.

The aim of the present study was to develop a diagnostic set of single-nucleotide polymorphisms (SNPs) for discriminating aspirin-exacerbated respiratory disease (AERD) from aspirin-tolerant asthma (ATA) using the genome-wide association study (GWAS) data; the GWAS data were filtered according to p-values and odds ratios (ORs) using PLINK software, and the 10 candidate SNPs most closely associated with AERD were selected, based on 100 AERD and 100 ATA subjects. Using multiple logistic regression and receiver-operating characteristic (ROC) curve analysis, eight SNPs were chosen as the best model for distinguishing between AERD and ATA. The relative risk for AERD in each subject was calculated based on the relative risk of each of the eight SNPs. Ten of the original 109,365 SNPs highly associated (filtered with p0.001 and ORs) with the risk for AERD were selected. A combination model of the eight SNPs among the 10 SNPs showed the highest area under the ROC curve of 0.9. The overall relative risk for AERD based on the eight SNPs was significantly different between the AERD and ATA groups (p=2.802E-21), and the sensitivity and specificity were 78% and 88%, respectively. The candidate set of eight SNPs may be useful in predicting the risk for AERD.

Aspirin-exacerbated respiratory disease (AERD) is a respiratory disease characterized by acute bronchial responses upon the administration of non-steroidal anti‑inflammatory drugs (NSAIDs) and the immune response by mast cells is regarded as one of the noteworthy causes of AERD pathogenesis. The complement cascade is regarded as a key mechanism for clearing pathogens from the host. CD55 is one of the proteins involved in self-recognition, a central component of the complement system and autoimmunity. To investigate the associations between CD55 single nucleotide polymorphisms (SNPs) and the risk of AERD, we carried out logistic analyses with three genetic models and further regression analysis was performed with the fall rate of forced expiratory volume in 1 sec (FEV1) by aspirin provocation. However, our results demonstrate that no CD55 polymorphisms are associated with the risk of AERD and the fall rate of FEV1 (P>0.05). Therefore, our results suggest that CD55 polymorphisms are not genetic markers of aspirin‑induced bronchospasm, including FEV1, in the population studied. Although the genetic role of CD55 has been found to be integral to human immunity, our results indicate that genetic variations of CD55 do not influence the risk of AERD and the fall rate of FEV1 in the population studied.

Summary Aspirin-exacerbated respiratory disease (AERD) is prevalent in about 10% of asthma patients and is characterized by a severe decline in forced expiratory volume in 1-s (FEV1), an important phenotype for total lung capacity, upon ingestion of aspirin. The general transcription factor IIH subunit 4 (GTF2H4) is positioned at 6p21.33, a part of the major histocompatibility complex (MHC) class II region that contains a number of genes that play an important role in the immune system. In addition, genetic variants in another general transcription factor IIH gene have revealed significant association with lung disease. To investigate whether GTF2H4 genetic variants could be a causative factor for AERD development and FEV1 decline by aspirin provocation, five common single-nucleotide polymorphisms (SNPs) were genotyped in 93 patients with AERD and 96 aspirin-tolerant asthma (ATA) controls. As a result, when adjusted for age, gender, smoking status and atopy as covariates, the rs1264307 variant and two haplotypes showed nominal signals in the association with AERD (P = 0.02–0.04), but the significances disappeared after corrections for multiple testing (corrected P > 0.05). In further multiple regression analysis, no genetic variants of GTF2H4 showed significant associations with FEV1 decline by aspirin provocation in asthmatics (P > 0.05). Despite the need for replications in larger cohorts, our preliminary findings suggest that GTF2H4 variants may not be associated with susceptibility to AERD and obstructive symptoms in asthmatics.

Background Nasal polyps, part of the aspirin triad symptoms, are edematous protrusions arising from the mucosa of the nasal sinuses. Although the causative factors and pathogenesis of the polyps are unknown, the significant effect of human leukocyte antigen-DR (HLA-DR) expression in nasal polyps and genetic associations of the major histocompatibility complex class II, DR alpha (HLA-DRA) with immune-mediated diseases have been revealed. Methods To investigate the associations of HLA-DRA polymorphisms with nasal polyposis in asthmatic patients and in aspirin-hypersensitive subgroups, 22 single nucleotide polymorphisms (SNPs) were genotyped in a total of 467 asthmatic patients including 158 nasal polyp-positive and 309 polyp-negative subjects. Results Statistical analysis showed that four SNPs (p = 0.0005-0.02; Pcorr = 0.009-0.033) and one haplotype (p = 0.002; Pcorr = 0.029) were significantly associated with the presence of nasal polyposis in asthmatic patients. In further analysis, although significant signals disappeared after corrections for multiple testing, two HLA-DRA polymorphisms (rs9268644C>A, rs3129878A>C) were found to be potential markers for nasal polyp development in aspirin-tolerant asthma (p = 0.005 and 0.007, respectively) compared with the aspirin-exacerbated respiratory disease (p > 0.05) subgroup. In silico analysis predicted major “C” allele of rs14004C>A in 5’ -untranslated region as a potential binding site for regulatory glucocorticoid receptor. In addition, sequence nearby rs1051336G>A is suspected to be a pyrimidine-rich element that affects mRNA stability. Conclusion Despite the need for replication in larger cohorts and/or functional evaluations, our findings suggest that HLA-DRA polymorphisms might contribute to nasal polyposis susceptibility in patients with asthma

Aspirin exacerbated respiratory disease (AERD) induces bronchoconstriction in asthmatic patients characterized with a clinical condition of severe decline in forced expiratory volume in one second (FEV1) after ingestion of aspirin. Two genes consisting a heterodimer, transporter 1 and 2, ATP-binding cassette, sub-family B (MDR/TAP) (TAP1 and TAP2) within the major histocompatibility complex (MHC) region, have been implicated in immunodeficiency and bronchiectasis development. To investigate the associations of TAP1 and TAP2 genetic polymorphisms with AERD and phenotypic FEV1 decline, a total of 43 common single-nucleotide polymorphisms (SNPs) including 12 SNPs of TAP1 and 31 SNPs of TAP2 were genotyped in 93 AERD patients and 96 aspirin-tolerant asthma controls. Interestingly, regression analysis revealed that polymorphisms and haplotypes of TAP2 were associated with FEV1 decline by aspirin provocation (P=0.002-0.04), with about twofold decline rate of FEV1 in most of minor homozygotes compared with major homozygotes. In addition, nominal evidences of association between TAP2 and AERD development were observed (P=0.02-0.04). However, TAP1 polymorphisms showed no relations to both AERD and FEV1 decline after aspirin challenge (P0.05). Although further functional evaluations and replications are required, our preliminary findings provide supporting information that variants of TAP2 might be predisposing factors for FEV1 decline-related symptoms.

Aspirin exacerbated respiratory disease (AERD) is a clinical condition characterized by severe decline in forced expiratory volume in one second (FEV1) following the ingestion of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin. The exacerbated inflammatory response in Fancc-deficient mice has been reported to be associated with hemopoietic responses that are also related to AERD pathogenesis. To investigate associations of FANCC polymorphisms with AERD and related phenotypes, this study genotyped 25 common single nucleotide polymorphisms (SNPs) in a total of 592 Korean asthmatics including 163 AERD and 429 aspirin-tolerant asthma (ATA) subjects. Logistic analysis revealed that genetic polymorphisms of the FANCC gene might not be directly related to AERD development and nasal polyposis (P > 0.05). However, the FEV1 decline by aspirin provocation showed significant associations with FANCC polymorphisms (P = 0.006-0.04) and a haplotype (unique to rs4647416G > A, P = 0.01 under co-dominant, P = 0.006 under recessive model). In silico analysis showed that the "A" allele of rs4647376C > A, which was more prevalent in AERD than in ATA, could act as a potential branch point (BP) site for alternative splicing (BP score = 4.16). Although replications in independent cohorts and further functional evaluations are still needed, our preliminary findings suggest that FANCC polymorphisms might be associated with the obstructive symptoms in allergic diseases.

Purpose Bacille Calmette-Guérin (BCG) vaccination has been reported to be an effective treatment for asthma in several animal models. This study investigated whether the response to BCG treatment in asthma depends on subject clinical characteristics. Methods Stable asthma patients were vaccinated with BCG. One month later, alterations in pulmonary function after vaccination and their relationships with subject clinical characteristics were determined. Results Of 149 patients with asthma, 54 (36.2%) showed a good or fair response to BCG. The ΔFEV1 after vaccination was significantly related to age (r=-0.348, P0.05). A good/fair response was highly prevalent in atopic females compared with atopic males, especially among those aged ≤50 years (90.9% vs. 40.0%, P=0.024). Age (P

Aim: Thromboxane A synthase (TBXAS1) converts prostaglandin H to thromboxane A, a potent constrictor of smooth respiratory muscle. Thus, functional alterations of the TBXAS1 gene may contribute to aspirin-intolerant asthma (AIA). Materials & methods: We investigated the relationship between SNPs in the TBXAS1 gene and AIA. Asthmatics (n = 470) were categorized into AIA (20% or greater decreases in forced expiratory volume in 1 s [FEV1], or 15% to 19% decreases in FEV1 with naso-ocular or cutaneous reactions) and aspirin-tolerant asthma (ATA). A total of 101 SNPs were genotyped. mRNA expression of the TBXAS1 gene by peripheral blood mononuclear cells and plasma thromboxane B2 (TXB2) concentrations were measured by reverse transcriptase (RT)-PCR and ELISA. Results: Logistic regression analysis showed that the rare allele frequency of rs6962291 in intron 9 was significantly lower in the AIA group (n = 115) than in the ATA group (n = 270) (pcorr = 0.04). The linear regression analysis revealed a strong association of rs6962291 with the aspirin challenge-induced FEV1 fall (p = 0.003). RT-PCR revealed an exon-12-deleted splice variant. We measured TBXAS1 mRNA levels in peripheral blood mononuclear cells. The mRNA levels of the full-length wild-type and splice variant were significantly higher in the TT homozygotes than in the AA homozygotes of rs6962291 (1.00 ± 0.18 vs 0.57 ± 0.03 and 1.00 ± 0.18 vs 0.21 ± 0.05, p = 0.047 and 0.001, respectively). The plasma TXB2 level was significantly lower in rs6962291 AA carriers than in rs6962291 TT (p = 0.016) carriers. Conclusion: The rare allele of rs6962291 may play a protective role against aspirin hypersensitivity via a lower catalytic activity of the TBXAS1 gene, attributed to the increase of a nonfunctioning isoform of TBXAS1. Original submitted 26 August 2010; Revision submitted 29 October 2010.

Background: Aspirin-intolerant asthma (AIA) is a clinical syndrome characterized by acute bronchoconstriction following the ingestion of aspirin. Solute carrier family 22, member 2 (SLC22A2), also known as organic cation transporter 2 (OCT2), is predominantly expressed in the luminal membrane of airway epithelial cells and has been shown to mediate the transport of prostaglandins on the cyclooxygenase pathway which is regulated by aspirin blockage. Recently, SLC22A2-mediated uptake inhibition by several nonsteroidal anti-inflammatory drugs and decreased SLC22A2 transport activity by its genetic variants have been elucidated in asthma. Methods: To investigate the associations between AIA and genetic polymorphisms of the SLC22A2 gene, 18 variants were genotyped in 163 AIA subjects and 429 aspirin-tolerant asthma (ATA) controls. Logistic analyses were used to evaluate p values for the associations of SLC22A2 polymorphisms with AIA. Results: One common polymorphism in intron 5, i.e. rs316021, was significantly associated with susceptibility to AIA (p = 0.004, Pcorr = 0.05, OR = 0.60, 95% CI = 0.43–0.85 in a codominant model). The minor allele frequency of rs316021 in the AIA group was significantly lower than that in the ATA controls. In addition, a polymorphism in intron 4 (rs3912161) and a haplotype (SLC22A2-ht3) showed significantly stronger association signals with the FEV1 fall rate induced by aspirin provocation in AIA subjects compared with ATA controls (p = 0.004, Pcorr = 0.05). Conclusion: Our findings suggest that SLC22A2 could be a susceptibility gene for aspirin intolerance in asthmatics.

Objective Aspirin affects interleukin-4 (IL-4) synthesis; however, the genetic role of IL-4 has not been evaluated in asthmatics with aspirin hypersensitivity. The objective of the study was to examine the influence of single nucleotide polymorphisms (SNPs) in IL-4 gene on aspirin hypersensitivity in asthmatics at the genetic and molecular levels. Methods Aspirin-intolerant (AIA, n= 103 ) and aspirin-tolerant asthmatics (n=2 70 ) were genotyped and functional promoter assays were performed. Results Of 15 S N Ps tested, seven (- 589T > C (rs2243250) in promoter, -33T>C (rs2070874) in the 5'-untranslated region, +4047A>G (rs2243266), + 4144C> G (rs2243267), + 4221C> A (rs2243268), +4367G>A (rs2243270), and +5090A>G (rs2243274) in introns) were significantly associated with AIA risk. The frequency of the rare allele (C) of -589T>C was higher in the AIA group than in the aspirin-tolerant asthmatic group (P corr =0.016), and a gene dose-dependent decline in forced expiratory volume in 1 s was noted after an aspirin challenge (P=0.0009). Aspirin unregulated IL-4 mRNA production in Jurkat T and K562 leukemia cells. A reporter plasmid assay revealed that aspirin augmented IL-4 promoter transactivation with the -589T>C C and -33T>C C alleles, compared with that bearing the -589T> C T and -33T > C T alleles. Further, electrophoretic mobility shift assay showed the formation of nuclear complexes with -33T>C and - 589T > C allele-containing probes; this was augmented by aspirin. The complexes formed with the -33T>C and -589T>C probes were shifted by treatment with anti-CCAAT-enhancer-binding proteins β and anti-nuclear factor of activated T-cells antibodies, respectively, indicating the inclusion of these transcription factors. Conclusion Aspirin may regulate IL4 expression in an allele-specific manner by altering the availability of transcription factors to the key regulatory elements in the IL4 promoter, leading to aspirin hypersensitivity.

Aspirin-intolerant asthma (AIA) is an asthma phenotype characterized by the development of bronchoconstriction following ingestion of aspirin. Despite the well-defined pathological trigger, the underlying mechanisms of AIA are still unclear. With the biophysical characteristics of the human EMI domain-containing protein 2 (EMID2) gene in relation to the extracellular matrix deposition and epithelial-mesenchymal transition as pivotal characteristics of airway remodeling in asthma, we hypothesized that genetic polymorphisms of EMID2 might affect the development of AIA. In this study, the allelic associations of 49 single-nucleotide polymorphisms (SNPs) of the human EMID2 gene were evaluated from 163 AIA patients and 429 aspirin-tolerant asthma (ATA) subjects as controls in a Korean population. Logistic analysis showed that five SNPs (P = 0.01–0.04, but P corr > 0.05) and EMID2_BL2_ht2 haplotype (unique to the minor alleles of rs4727494 and rs13233066; P = 0.02; P corr = 0.02) were significantly associated with AIA. More interestingly, regression analysis of the decline of forced expiratory volume in one second (FEV1) by aspirin provocation revealed that 10 SNPs (P = 0.003–0.04) and four relevant haplotypes (P = 0.002–0.02) were significantly associated with the fall rate of FEV1 by aspirin provocation, indicating that genetic polymorphisms of EMID2 could cause meaningful deficits in the upper and lower airways among AIA patients. These findings provide evidence that EMID2 may be a susceptible genetic factor for aspirin hypersensitivity among asthmatics in Korean population.

Aspirin-intolerant asthma (AIA), as a clinical syndrome caused by aspirin, is characterized by lung inflammation and reversible bronchoconstriction. Recently, the altered trafficking and diminished airway reactivity have been implicated in allergic airway remodeling. The stromal membrane-associated protein 1-like (SMAP1L) exerts common and distinct functions in vesicle trafficking including endocytosis. The disturbance of pulmonary surfactant synthesis has been elucidated to be associated with asthma experimentally. Moreover, in alveolar type II (ATII) cells that synthesize pulmonary surfactant, alterations of clathrin-dependent endocytosis cause disturbance at the surfactant function, suggesting that SMAP1L, which directly interacts with clathrin, could be associated with asthma and related phenotypes.To verify our hypothesis that SMAP1L could play a role in the development of AIA, this study investigated associations between single-nucleotide polymorphisms (SNPs) of the SMAP1L gene and AIA.We conducted an association study between 19 SNPs of the SMAP1L gene and AIA in a total of 592 Korean subjects including 163 AIA and 429 aspirin-tolerant asthma (ATA) patients. Associations between polymorphisms of SMAP1L and AIA were analyzed with sex, smoking status, atopy, and body mass index as covariates.Logistic analyses revealed that three common polymorphisms, rs2982510, rs2294752, and rs446738, were putatively associated with the increased susceptibility to AIA (p = .003, p(corr) = .004, OR = 0.24, 95% CI = 0.09-0.62 for rs2982510 and rs2294752; p = .008, p(corr) = .03, OR = 0.44, 95% CI = 0.24-0.80 for rs446738, in the recessive model). In addition, rs2982510 and rs2294752 were significantly associated with the fall of forced expiratory volume in 1 s (FEV₁) by aspirin provocation (p = .001, p(corr) = .04 in the recessive model for both SNPs).Our findings suggest that SMAP1L might be a susceptible gene to AIA, providing a new strategy for the control of aspirin intolerance.

The kinesin family number 3A (KIF3A) gene on the human chromosomal 5q31-33 region, which is known as a susceptibility locus for immune diseases including asthma, plays a crucial role in generation of cilia.A treatment with aspirin in the human bronchial epithelial cells increased the mRNA expression level of KIF3A compared to that of the untreated control (P ≤ 0.01), and nasal polyp epithelia from aspirin-intolerant asthma (AIA) patients also showed a higher expression of KIF3A protein than aspirin-tolerant asthma controls. Further logistic analyses revealed that most polymorphisms of KIF3A were significantly associated with AIA (P = 0.0004-0.02; P(corr) = 0.004-0.04) and the decline of forced expiratory volume at 1 s (FEV(1))% by aspirin provocation (P = 0.004-0.04; P(corr) = 0.03).Our findings suggest that the KIF3A gene and/or its polymorphisms might have a susceptibility effect on AIA, providing a new step toward controlling aspirin intolerance in asthmatics.

Aims: Cysteinyl leukotrienes are inactivated by acetyl coenzyme A-dependent N-acetyltransferase (NAT). Thus, functional alterations of the NAT gene may contribute to the risk of aspirin-intolerant asthma. Materials & methods: Asthmatics (n = 438) were categorized into aspirin-intolerant asthma (15% or greater decrease in the forced expiratory volume in 1 s or cutaneous reactions, n = 170) or aspirin-tolerant asthma (n = 268) groups. In total, 14 polymorphisms of the NAT2 gene were genotyped by a single-base extension method. Results: The distributions of all loci of the 14 SNPs were in Hardy–Weinberg equilibrium (p > 0.05). Among the 14 SNPs, six common SNPs (minor allele frequency >5%) in a Korean population were used for haplotype construction and further statistical analysis. The logistic regression analysis demonstrated that NAT2 -9246G>C and haplotype 2 (TCACGG) were significantly associated with the risk of aspirin-intolerant asthma. The rare allele frequencies of the SNP and Ht2 were significantly higher in the aspirin-intolerant asthma group than in the aspirin-tolerant asthma group (pcorr = 0.03 and pcorr = 0.02 in codominant model). Conclusion: In a large genetic epidemiology study of aspirin-intolerant asthma in a Korean population, genetic polymorphisms of NAT2 were found to be related to a risk of aspirin hypersensitivity among asthmatics.

Summary Aspirin-intolerant asthma (AIA) occurs from asthma exacerbation after exposure to aspirin. However, the underlying mechanisms of AIA occurrence are still unclear. The critical role of the solute carrier family 6 (neurotransmitter transporter, betaine/GABA) member 12 (SLC6A12) gene in GABAergic transmission, which is associated with mucus production in asthma, makes it a candidate gene for AIA association study. Eight single nucleotide polymorphisms (SNPs) in SLC6A12 were genotyped in 163 aspirin-intolerant asthma (AIA) and 429 aspirin-tolerant asthma (ATA) patients of Korean ethnicity. Associations between polymorphisms of SLC6A12 and AIA were analysed using multivariate logistic analysis. Results showed that two polymorphisms and a haplotype in SLC6A12, rs499368 (P= 0.005; Pcorr= 0.03), rs557881 (non-synonymous C10R, P= 0.007; Pcorr= 0.04), and SLC6A12_BL1_ht1 (P= 0.009; Pcorr= 0.05) respectively, were significantly associated with AIA after multiple testing corrections. In addition, SNPs of SLC6A12 were significantly associated with the fall rate of FEV1 by aspirin provocation suggesting that SLC6A12 could affect reversibility of lung function abnormalities in AIA patients. Although these results are preliminary and future replications are needed to confirm these findings, this study showed evidence of association between variants in SLC6A12 and AIA occurrence among asthmatics in a Korean population.

The recent Global Initiative for Asthma guideline states that inhaled corticosteroids (ICSs) may induce osteoporosis as a systemic adverse effect. New ICSs, such as fluticasone propionate, have a high topical potency and may therefore induce tooth problems as a result of direct exposure without hepatic metabolism more frequently than older ICSs.We evaluated asthma patients who underwent long-term treatment with a new ICS to determine if they had tooth problems that were related to osteoporosis of the mandible.When the conventional bone mineral density (BMD) of asthmatics that received the ICS treatment for at least one year was measured using dual-energy X-ray absorptiometry, the BMD of the mandible was also measured. The T-score of the mandible BMD was then determined based on the mean BMD +/- the standard deviation of normal young adults.Asthma patients with tooth loss (n = 36) and with caries or other tooth problems (n = 28) were found to have a significantly higher prevalence of osteoporosis in the mandible than those without tooth problems (n = 17; 22.2%, 7.1%, 0%, respectively; chi(2) = 6.34, p0.05). In addition, the presence of mandibular osteoporosis (odds ratio: 6.14, p = 0.02) and a T-score of-1.0 for the femoral neck (odds ratio: 3.25, p = 0.01) were found to be significant risk factors for tooth loss in the asthma patients. Finally, the T-score of the mandible was found to be correlated with age (r = -0.316, p0.01), and with the T-scores of the lumbar spine (r = 0.413, p0.001) and femoral neck (r = 0.446, p0.001).Tooth loss in asthma patients undergoing long-term treatment with a topically potent ICS was found to be related to a decrease in BMD, especially in the mandible. Therefore, patients using these types of ICS should have their mandibular BMD checked regularly, especially if they have any risk factors for osteoporosis. In addition, it would be wise for such patients to reduce their ICS dose.

Both BCG and dehydroepiandrosterone (DHEA) induce Th1 immune responses and suppress Th2 allergic reactions. To investigate whether the combination of BCG and DHEA has an additive effect on asthma prevention, BALB/c mice (n = 10 per group) were given an intraperitoneal injection of BCG at the beginning of sensitization, and fed mice chow containing DHEA throughout the study. In female mice, the combined administration of 2 x 10(4) CFUs BCG and 0.01% DHEA effectively suppressed the ovalbumin-induced increase in airway sensitivity to methacholine (56.5 vs. 8.2 mg/mL, p0.01), while BCG (13.9 mg/mL) or DHEA (17.9 mg/mL) alone did not. However, the addition of high dose (0.1%) DHEA decreased the efficacy of high dose (2 x 10(5) CFUs) BCG in suppressing the airway responsiveness and eosinophilia. In male mice, the treatments with BCG and/or DHEA were less effective, and the interferon-gamma/interleukin-4 ratio in the splenocyte supernatant was significantly higher and the ovalbumin-specific IgE concentration in the serum was significantly lower as compared to female mice. In conclusion, the combination of low doses of BCG and DHEA had an additive effect in suppressing the development of airway hypersensitivity. Androgens in males and DHEA overdose might reduce the efficacy of BCG.

Intranasal bacille Calmette-Guérin (BCG) vaccination causes greater suppression of ovalbumin-induced airway eosinophilia in mice than does subcutaneous vaccination. Coadministration of ovalbumin with interleukin (IL)-18 induces an ovalbumin-specific Th1 immune reaction. The purpose of this study was to examine whether the suppressive effect of BCG is dependent on the inoculation method, using various murine asthma models. Female BALB/c mice (n = 7 per group) were immunized with BCG subcutaneously or intranasally, then sensitized with ovalbumin or Dermatophagoides farinae either immediately or one week later. After provocation with one of the allergens, the mice were tested by methacholine bronchial challenge, and analyses of the inflammatory cell numbers in the airways and cytokine levels in the supernatant of concanavalin A-stimulated splenocytes were conducted. Overall, the airway responses to the allergens were significantly lower and the interferon (IFN)-gamma level was significantly higher in BCG-treated mice than in untreated mice, and the number of airway eosinophils was significantly related to the IFN-gamma/IL-5 ratio (r = -0.444, p0.001). Subcutaneous BCG inoculation tended to have a greater suppressive effect on the development of airway hyperresponsiveness and eosinophilia than did intranasal inoculation. Concurrent BCG vaccination and D. farinae sensitization one week before ovalbumin sensitization tended to have a greater suppressive effect on airway responsiveness to methacholine induced by D. farinae aerosols than did that induced by ovalbumin aerosols. Subcutaneous BCG inoculation suppressed asthmatic reactions more remarkably than did intranasal inoculation, and concurrent BCG vaccination and allergen sensitization induced allergen-specific suppression of asthmatic reactions.

The choice of BCG vaccine strain may play an important role in vaccination efficiency.To investigate whether the suppressive effects of BCG on asthma depend on the strain of BCG.Female BALB/c mice were injected intraperitoneally with 1 of 4 different strains of BCG (1 X 10(6) CFU): Pasteur F1173P2, Tokyo 172, Tice, and Connaught. Seven days later, the animals were sensitized by 2 injections of ovalbumin (20 microg) at 2-week intervals before being provoked with 1% ovalbumin aerosols on 3 successive days. Thereafter, the mice underwent a methacholine bronchial challenge and were killed to quantify the inflammatory cells and cytokines in bronchoalveolar lavage fluid and the supernatant of cultured splenocytes.The eosinophil proportion in the bronchoalveolar lavage fluid was significantly lower and the concentration of interferon-gamma and the interferon-gamma-interleukin 5 (IL-5) ratio in the supernatant of cultured splenocytes were significantly higher in each of the BCG-treated groups (n=10 per group) than in the asthma control group (n=15). However, the methacholine sensitivity (P.05) and IL-5 concentration (P.01) in the supernatant of cultured splenocytes were significantly lower only in the group treated with the Tokyo strain of BCG. There was a significant positive correlation between IL-5 and IL-10 concentrations (r = 0.79; P.001).The 4 strains of BCG suppressed asthma to different degrees, but all strains induced a shift in the T(H)1/T(H)2 balance toward T(H)1 without increasing IL-10-related regulatory T-cell activity.

Allergic airway diseases are related to exposure to atmospheric pollutants, which have been suggested to be one factor in the increasing prevalence of asthma. Little is known about the effect of ozone and diesel exhaust particulates (DEP) on the development or aggravation of asthma. We have used a mouse asthma model to determine the effect of ozone and DEP on airway hyperresponsiveness and inflammation. Methacholine enhanced pause (P(enh)) was measured. Levels of IL-4 and IFN-gamma were quantified in bronchoalveolar lavage fluids by enzyme immunoassays. The OVA-sensitized-challenged and ozone and DEP exposure group had higher P(enh) than the OVA-sensitized-challenged group and the OVA-sensitized-challenged and DEP exposure group, and the OVA-sensitized-challenged and ozone exposure group. Levels of IFN-gamma were decreased in the OVA-sensitized-challenged and DEP exposure group and the OVA-sensitized-challenged and ozone and DEP exposure group compared to the OVA-sensitized-challenged and ozone exposure group. Levels of IL-4 were increased in the OVA-sensitized-challenged and ozone exposure group and the OVA-sensitized-challenged and DEP exposure group, and the OVA-sensitized-challenged and ozone and DEP exposure group compared to OVA-sensitized-challenged group. Co-exposure of ozone and DEP has additive effect on airway hyperresponsiveness by modulation of IL-4 and IFN-gamma suggesting that DEP amplify Th2 immune response.

It has been suggested that dendritic cells (DCs) are critical antigen presenting cells for eosinophilic airway inflammation in a mouse model of asthma, and cysteinyl leukotrienes may play a role in DC trafficking in asthmatics. We investigated whether the number of DCs is increased in the induced sputum of both atopic and nonatopic asthmatics and is related to activated eosinophil count in the sputum. Sputum was induced by inhalation of hypertonic saline in 9 atopic and 12 nonatopic asthmatics and 10 nonatopic normal controls, and differential cell counts were performed. DCs and activated eosinophils were identified by immunocytochemistry with monoclonal antibodies (anti-CD1a and EG2, respectively). There were significantly higher percentages of eosinophils, EG2+ cells, and CD1a+ DC in the sputum of atopic and nonatopic asthmatics compared with normal controls, respectively. In asthmatics, the percentage of CD1a+ DC was significantly correlated with that of EG2+ cells (Rs=0.62, p=0.004). We demonstrated that the increased number of DCs was evident in the induced sputum of both atopic and nonatopic asthmatics, and the DC number was related to the activated eosinophil count, which suggests that DCs may contribute to the ongoing eosinophilic inflammation in asthmatic airways, and vice versa.

Background. The concept that asthma diagnosis based on allergen-specific IgE levels in serum is more accurate than diagnosis based on skin test reactivity is controversial. Objective. To determine the atopy parameter that correlates most closely with airway reactivity to house dust mites in asthma. Methods. Forty-three asthma cases were examined retrospectively for data on Dermatophagoides farinae-specific bronchoprovocation, serum-specific IgE, and skin prick tests. Results. The maximal decreases in FEV1 following bronchoprovocation were correlated significantly with both the IgE levels and skin test scores. The accuracies of the tests were highest at a cutoff value of class 4 or higher for the IgE and of 3 + or higher for the skin test. At the cutoff values, the accuracies of both tests were similar (70% vs. 70%). The sensitivity of the skin test (81%) was higher than that of the IgE test (67%), whereas the specificity of the IgE test (71%) was higher than that of the skin test (52%). The sensitivity of...

Background: A single, acute exposure to ozone has been shown to modify the antioxidant defense mechanism in the respiratory tract. Objective: The aim of this study was to evaluate the effects of ozone exposure on antioxidant response in BALB/c mice. Methods: We measured enhanced pause of breathing (Penh) as a marker of airway obstruction using barometric whole-body plethysmography before and after ozone exposure [groups (n = 6): filtered air, 0.12 ppm, 0.5 ppm, 1 ppm, 2 ppm] for 3 h. Antioxidant levels were measured using high-performance liquid chromatography with electrochemical detection in bronchoalveolar lavage (BAL) fluid and lung tissue homogenates. Results: Malondialdehyde concentrations in lung tissue homogenates were significantly increased in the group exposed to 2-ppm ozone compared to the filtered air group. Uric acid and γ-tocopherol concentrations in BAL fluid were significantly increased in the ozone exposure group compared to the filtered air group (p < 0.01). Uric acid concentrations were increased in a concentration-dependent manner according to ozone concentration to which the animals were exposed. Increases in Penh after ozone exposure were significantly higher in an ozone concentration-dependent manner. The proportion of neutrophils in BAL fluid was significantly higher in the group exposed to 2 ppm than in the filtered air and the group exposed to 0.12 ppm (p < 0.01, respectively). The level of ascorbate correlated with the level of γ-tocopherol. Conclusion: These findings suggest that antioxidant responses may serve as a protective mechanism against a range of oxidants in BALB/c mice exposed to ozone.

Nitric oxide (NO) and aquaporins (AQPs) are believed to play an important role in the pathogenesis of pulmonary inflammation and edema. The aim of this study was to investigate the role of NO synthase (NOS) and AQP in acute lung injury (ALI) lung following bleomycin inhalation in rats. A prospective controlled trial in a university research laboratory. Sprague-Dawley rats were treated by inhalation of 10 U/kg bleomycin hydrochloride in 5 ml of normal saline. Control rats were treated with 5 ml normal saline alone. The animals (6–8 rats per group) were killed on days 4, 7 or 14. We analyzed the change in expression of inducible NOS (iNOS), neuronal NOS (nNOS), endothelial NOS (eNOS), aquaporin 1 (AQP1) and aquaporin 5 (AQP5) over time by Western blot. Nitrate and nitrite concentrations were measured in bronchoalveolar lavage fluid (BALF) using a modified Griess reaction. The nitrite and nitrate concentrations in BALF from rats 4 days after bleomycin exposure were greater than those from saline-treated rats. Immunoblotting studies demonstrated increased levels of eNOS in the rat lung at 4, 7 and 14 days and iNOS at 7 and 14 days after bleomycin inhalation. However, nNOS expression was unaltered. Although AQP1 expression was decreased in rats at 4 days, AQP5 expression was increased at 4, 7 and 14 days. This study demonstrates that NO metabolites increase along with eNOS and iNOS expression during the acute exudative phase in ALI, and that AQP and NOS are regulated independently in bleomycin-induced pulmonary edema.

Background : Airway hyperresponsiveness (AHR) to direct stimuli, such as methacholine (MCh), is observed not only in asthma but other diseases. AHR to indirect stimuli is suggested to be more specific for asthma. The purpose of this study was to determine whether asthmatic airway inflammation is more closely related to AHR to hypertonic saline (HS), an indirect stimulus, than to MCh. Methods : Sixty-four consecutive adult patients with suspected asthma (45 asthma and 19 non-asthma) performed a combined bronchial challenge and sputum induction with 4.5% saline, and MCh challenge on the next day. Results : Both HS-PD15 and MCh-PC20 were significantly lower in asthma patients than in non-asthma patients. However, the sensitivity / specificity for asthma was 48.9%/100%, respectively, in the HS test and 82.2% / 84.2%, respectively, in the MCh test. There was a significant relationship between HS-PD15 and MCh-PC20 and only 52.9% of patients with MCh-PC20≤4 mg/mL showed HS-AHR, but 4 patients with HS-AHR showed MCh-PC20>4 mg/mL. There were significant correlations between both HS-PD15 and MCh-PC20 and FEV1, or sputum eosinophils, but FEV1 was more closely related to MCh-PC20 (r=0.478, p

Background Airway responsiveness after acute inhalation of ozone is related to the concentration and duration of ozone exposure. Using barometric whole-body plethysmography and increase in enhanced pause (Penh) as an index of airway obstruction, we measured the response of BALB/c mice to acute ozone inhalation to study the time course change of pulmonary function after ozone exposure. Methods Penh was measured before and after exposure to filtered air or 0.12, 0.5, 1, or 2 ppm ozone for 3 hr (n=6/group). In addition, Penh was measured 24, 48 and 72 hr after ozone exposure. Bronchoalveolar lavage (BAL) and histopathologic examinations were performed. Results The increase in Penh after ozone exposure was significantly higher in the 0.12, 0.5, 1 and 2 ppm groups compared with the control group (all p

Summary Background Cytokines production by T helper lymphocytes (Th cells), which orchestrate the interplay of the different cells involved in airway inflammation of asthma, may be reflected in peripheral blood. Some studies have suggested that the Th cell cytokines by peripheral blood T cells correlate with asthma severity. Objective To investigate the relationship between changes in IFN-γ production by peripheral blood T cells and changes in lung function in chronic stable asthmatics. Methods Sixteen patients with chronic stable moderate asthma aged 35–65 years (nine women) were recruited. Morning and evening peak expiratory flow rates (PEFR) monitoring and blood sampling for peripheral blood T cell culture, total IgE and blood eosinophils were performed at baseline and week 12. Levels of IFN-γ, IL-4 and IL-5 in culture supernatants of peripheral blood T cell were determined by using enzyme-linked immunosorbent assay (ELISA) kits. Results Patients with increased IFN-γ changes from baseline showed significantly increased changes in morning (P = 0.02) and evening (P

Background: Several investigators have demonstrated a considerable disagreement between FEV1 and PEFR to assess the severity of airflow obstruction. The purpose of this study was to examine whether the discrepancy between the two measurements affects the assessment in the severity of acute asthma. Methods : Thirty-five consecutive asthma patients measured both FEV1 and PEFR at 0, Ihr, 1, 3, 5, 7 days of an emergency room admission using a spirometer and a Ferraris PEFR meter. The degree of discrepancy between FEV1 and PEFR expressed as % predicted values was determined. Results : When predictive equations that recommended by the instrument manufacturers were used, PEFR measured with the PEFR meter (f-PEFR) was significantly higher than FEV1 at all time points, with 16.1% mean difference and unacceptable wide limits of agreement (−20.0–52.3%). The classification in severity was significantly different between FEV1 and f-PEFR (p

Background Bacille Calmette-Guerin (BCG) vaccination in humans induces Th1 immune responses. Th1 and Th2 cells are reciprocally regulated. Objective To examine whether BCG vaccination of adult patients with asthma, a Th2-associated allergic disease, is clinically effective. Methods Forty-three moderate-to-severe asthma patients were randomly assigned into groups that received percutaneous injection of 58.2×10 7 CFUs BCG (n = 22) or placebo (n = 21) in a double-blinded fashion, on the first day of a 12-week treatment period. Medications were adjusted every 4 weeks to maintain optimal asthma control. Spirometric measurements were performed before treatment and at weeks 4, 8, and 12 after vaccination. The daily peak expiratory flow rate values, asthma symptoms, and medications were also recorded. Tuberculin skin tests, and sputum inflammatory cell and cytokine analyses were carried out before treatment and 12 weeks after vaccination. Results BCG vaccination significantly increased forced expiratory volume in 1 second and forced expiratory flow rate 25% to 75% at weeks 4, 8, and 12. Morning peak expiratory flow rate was significantly increased only during the first 4 weeks. Although the asthma symptom scores were not significantly changed, the weekly medication scores were significantly decreased. Tuberculin skin reactivities were significantly increased without significant alterations in induced sputum profiles. In contrast, medication scores and sputum eosinophils were significantly increased, and the interferon-γ:interleukin-4 ratio in sputum was significantly decreased in the placebo group. Conclusions BCG vaccination improved lung function and reduced medication use in adults with moderate-to-severe asthma. This amelioration was accompanied by a suppressed Th2-type immune response, suggesting that BCG vaccination might be an effective therapeutic modality against asthma.

Summary Background Recent studies suggest that atopy may be associated with exercise-induced bronchospasm (EIB) in asthma. However, it is not clear whether atopy is related to EIB, regardless of airway hyper-responsiveness (AHR) to methacholine, because asthmatic subjects often show AHR to exercise and methacholine simultaneously. Objective To investigate whether atopy is related to EIB in asthmatic subjects, independently of AHR to methacholine. Methods Fifty-eight male asthmatic subjects were studied. Initial spirometry was performed. Skin prick test was carried out, using 53 common allergens including mites dust antigen. Atopy score was defined as a sum of mean weal diameters to all allergens tested. Methacholine bronchial provocation testing was performed. Twenty-four hours later, free running test was performed. Positive EIB was defined as a 15% reduction or more in FEV1 from baseline after exercise. Results All subjects had AHR to methacholine. The degree of AHR to methacholine in asthmatics with EIB was similar to that in asthmatics without EIB. However, atopy score and skin reaction to Dermatophagoides pteronyssinus significantly increased in asthmatics with EIB compared with those without EIB (P

Background: Most studies on the effects of temperature and humidity on exercise-induced bronchospasm (EIB) in asthmatics have been carried out under indoor conditions. However, any asthmatic patient is exposed to varying climatic conditions. Objective: To investigate whether temperature or relative humidity plays a more important role in determining the degree of EIB in asthmatics under naturally exposed climate conditions. Methods: To exclude the effects of pollen on EIB, we enrolled 69 subjects with perennial asthma (mean ± SD: 20.1 ± 1.5 years). The subjects performed outdoor free running tests. They were divided into winter (n = 25), spring/autumn (n = 22), and summer (n = 22) groups according to the season when they performed the tests. Initial spirometry and skin prick tests were performed. Methacholine bronchial challenge testing and, one day later, the free running tests were done. Results: There were significant differences in temperature and relative humidity among the three groups: However, the relative humidity in winter did not differ from that in spring/autumn. There were no differences in pulmonary functions, airway responsiveness, and atopy score among the three groups. The percentage of cases of positive EIB – fall in forced expiratory volume in 1s FEV1 of >15% from baseline – in winter (84%, p < 0.05) or spring/autumn (86.4%, p < 0.05) was higher than that in summer (50%). However, the percentage of subjects with a positive EIB in winter did not differ from that in spring/autumn. The maximal percent fall in FEV1 after exercise in winter did not differ from that in spring/autumn. Conclusions: The occurrence of EIB is associated with environmental temperature and humidity. Under such climatic conditions as in Korea, relative humidity may be a more important factor than temperature in contributing to EIB in patients with perennial asthma.

Cigarette smoking may reduce the production of endogenous nitric oxide (NO), which plays an important role in inflammation of the asthmatic airway. NO metabolites in sputum were measured in 11 cigarette smokers and five nonsmokers, all with acute asthma. NO metabolite levels reflected the severity of asthmatic exacerbation, as they were significantly higher in patients with "severe," or "respiratory arrest imminent" asthma than in patients with "mild" to "moderate" asthma. There were no significant differences in sputum NO metabolite levels between smokers and nonsmokers with asthma, nor were any differences observed in NO metabolite levels for relative cigarette pack-years in smokers. These findings suggest that severe airway inflammation outweighs the effect of smoking on NO in the sputum of patients with asthma.

Aspirin-exacerbated respiratory disease (AERD) is one phenotype of asthma, often occurring in the form of a severe and sudden attack. Due to the time-consuming nature and difficulty of oral aspirin challenge (OAC) for AERD diagnosis, non-invasive biomarkers have been sought. The aim of this study was to identify AERD-associated exonic SNPs and examine the diagnostic potential of a combination of these candidate SNPs to predict AERD. DNA from 165 AERD patients, 397 subjects with aspirin-tolerant asthma (ATA), and 398 normal controls were subjected to an Exome BeadChip assay containing 240K SNPs. 1,023 models (2(10)-1) were generated from combinations of the top 10 SNPs, selected by the p-values in association with AERD. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves was calculated for each model. SNP Function Portal and PolyPhen-2 were used to validate the functional significance of candidate SNPs. An exonic SNP, exm537513 in HLA-DPB1, showed the lowest p-value (p = 3.40x10(-8)) in its association with AERD risk. From the top 10 SNPs, a combination model of 7 SNPs (exm537513, exm83523, exm1884673, exm538564, exm2264237, exm396794, and exm791954) showed the best AUC of 0.75 (asymptotic p-value of 7.94x10(-21)), with 34% sensitivity and 93% specificity to discriminate AERD from ATA. Amino acid changes due to exm83523 in CHIA were predicted to be "probably damaging" to the structure and function of the protein, with a high score of '1'. A combination model of seven SNPs may provide a useful, non-invasive genetic marker combination for predicting AERD.

Background Urine-derived gonadotropins have been used to treat infertility but may cause allergic reactions. IgE-mediated hypersensitivity reactions can be treated with desensitization, especially when new therapies such as recombinant human gonadotropins are unavailable. Objective This case is described to highlight a successful intervention with desensitization in a woman with a complicated history of secondary infertility. She had been treated with ovulation-induction regimens, such as IVF-M (in vitro fertilization-human menopausal gonadotropin [hMG]) and IVF-C (human chorionic gonadotropin [hCG]), for intrauterine insemination. During treatment, however, she experienced reactions to IVF-M and IVF-C. Because she strongly wanted a baby and no alternative preparation was available, desensitization was attempted. Methods Intradermal tests with IVF-M and IVF-C using both negative and positive controls were performed on the patient and four normal control subjects. Immediate wheal-and-flare reactions occurred only in the patient. ELISA and ELISA inhibition tests showed positive responses to IVF-M and IVF-C, but not to highly purified hMG, hCG, or d-mannitol, a preservative in IVF-M and IVF-C. Desensitization to IVF-M and IVF-C was done with a protocol used for parenteral desensitization to penicillin. Results During the IVF-M desensitization, the intramuscular injections were well tolerated. For the next 2 days, daily administration of IVF-M was uneventful. Thirty-six hours later, desensitization to IVF-C was performed successfully. The patient had two intrauterine inseminations and became pregnant. Conclusions Nongonadotropin proteins in urine-derived gonadotropins cause IgE-mediated hypersensitivity reactions. Acute desensitization to urine-derived gonadotropins can be performed effectively, as shown in our current case.

Hypertonic saline aerosols are being used increasingly for bronchial provocation testing and induction of sputum. The aims of this study were to assess the response to challenge with 3% hypertonic saline administered via a ultrasonic nebulizer in patients with asthma, and to evaluate relationship between % fall of FEV1 during induction of sputum (osmotic airway hyperresponsiveness; osmotic AHR) and biochemical markers of induced sputum. We investigated changes in FEV1 in response to inhaling ultrasonically nebulized 3% saline in 25 patients with asthma and 10 control subjects. FEV1 was measured before, during, and after induction of sputum. We used fluoroimmunoassay to detect eosinophil cationic protein (ECP), immunohistochemical staining to detect EG2+ (secretory form of ECP) eosinophils, and a sandwich ELISA to detect interleukin (IL)-5. Protein concentration was determined by using bicinchoninic acid protein assay reagent. Asthmatics, compared with controls, had significantly higher osmotic AHR. Moderate to severe asthmatics had significantly higher osmotic AHR compared to mild asthmatics. Osmotic AHR was significantly correlated with the proportion of eosinophils, the levels of ECP, EG2+ eosinophils, IL-5, and proteins. These data suggest that osmotic AHR is closely related to the clinical status and biochemical markers of sputum supernatant in asthmatic patients.