Effect of omalizumab as add-on therapy to Quality of Life Questionnaire for Korean Asthmatics (KAQLQ) in Korean patients with severe persistent allergic asthma

Background/Aims@#Omalizumab is the first biologic known to be effective in patients with severe allergic asthma. @*Methods@#This study was conducted as a multicenter, single-group, open trial to evaluate the improvement in the quality of life with the additional administration of omalizumab for 24 weeks in Korean patients with severe persistent allergic asthma. @*Results@#Of the 44 patients, 31.8% were men and the mean age was 49.8 ± 11.8 years. A score improvement of 0.5 points or more in the Quality of Life Questionnaire for Korean Asthmatics (KAQLQ) was noted in 50.0% (22/44) of the patinets. In the improved group, the baseline total immunoglobulin E (IgE) level and the amount of omalizumab used were higher, and the day and night asthma symptoms were more severe, compared to those in the non-improved group. According to the Global Evaluation of Treatment Effectiveness, favorable outcomes were found in 78.6% of patients. The Korean asthma control test (p < 0.005) and forced expiratory volume in 1 second % predicted (FEV1%; p < 0.01) improved significantly in patients who received omalizumab treatment, compared to that at week 0, and the total dose of rescue systemic corticosteroids significantly decreased (p < 0.05). The improved group on KAQLQ showed a significant improvement in FEV1% (p < 0.001). @*Conclusions@#Omalizumab can be considered a biological treatment for Korean patients with severe allergic asthma. It is recommended to consider omalizumab as add-on therapy in patients with high baseline total IgE levels and severe asthma symptoms.

Effect of omalizumab as add-on therapy to Quality of Life Questionnaire for Korean Asthmatics (KAQLQ) in Korean patients with severe persistent allergic asthma

Background/Aims@#Omalizumab is the first biologic known to be effective in patients with severe allergic asthma. @*Methods@#This study was conducted as a multicenter, single-group, open trial to evaluate the improvement in the quality of life with the additional administration of omalizumab for 24 weeks in Korean patients with severe persistent allergic asthma. @*Results@#Of the 44 patients, 31.8% were men and the mean age was 49.8 ± 11.8 years. A score improvement of 0.5 points or more in the Quality of Life Questionnaire for Korean Asthmatics (KAQLQ) was noted in 50.0% (22/44) of the patinets. In the improved group, the baseline total immunoglobulin E (IgE) level and the amount of omalizumab used were higher, and the day and night asthma symptoms were more severe, compared to those in the non-improved group. According to the Global Evaluation of Treatment Effectiveness, favorable outcomes were found in 78.6% of patients. The Korean asthma control test (p < 0.005) and forced expiratory volume in 1 second % predicted (FEV1%; p < 0.01) improved significantly in patients who received omalizumab treatment, compared to that at week 0, and the total dose of rescue systemic corticosteroids significantly decreased (p < 0.05). The improved group on KAQLQ showed a significant improvement in FEV1% (p < 0.001). @*Conclusions@#Omalizumab can be considered a biological treatment for Korean patients with severe allergic asthma. It is recommended to consider omalizumab as add-on therapy in patients with high baseline total IgE levels and severe asthma symptoms.

Relationship between serum IgA level and allergy/asthma

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 (<140 mg/dL, group I), intermediate (140 to 280 mg/dL, group II), or high (≥280 mg/dL, group III) IgA levels in serum. RESULTS: The HDM skin sensitization rate progressively decreased from 30.0% in group I (n = 139) to 26.8% and 18.5% in groups II (n = 684) and III (n = 313), respectively (p = 0.003). Although both the HDM sensitization degree and the IgA level were significantly related to age, the adjusted odds ratio (OR) of association of a high IgA level (≥ 280 mg/dL) with HDM sensitization was significant (0.617; 95% confidence interval [CI], 0.415 to 0.916; p = 0.017). Among younger subjects (≤ 45 years of age) with AHR, the prevalence of moderate/severe AHR progressively decreased (70.6%, 52.3%, and 47.1% in groups I, II, and III [n = 34, 149, and 51]), respectively (p = 0.045). The IgA < 140 mg/dL was a significant risk factor for moderate/severe AHR (OR, 2.306; 95% CI, 1.049 to 5.071; p = 0.038). CONCLUSIONS: Sensitization to HDM and methacholine-AHR were significantly associated with serum IgA levels in suspected asthmatics, even when those levels were normal.

Usefulness of House Dust Mite Nasal Provocation Test in Asthma

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.

Patterns of Inhalant Allergen Sensitization and Geographical Variation in Korean Adults: A Multicenter Retrospective Study

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.

Clinical outcomes after recovery from severe asthma exacerbation: the third report

PURPOSE: Up to 10% of the mortality rate of asthmatics within a year from the near-fatal attacks has been reported. We previously reported that not a few patients with acute severe asthma died after discharge from the hospital. This study investigated whether our efforts to improve clinical outcomes of patients after recovery from severe asthma exacerbation did work or not. METHODS: Follow-up data from asthmatic patients who had been hospitalized due to severe exacerbation between 2007 and 2014 (present) were compared with that the previous one (1998–2006) (previous). RESULTS: Sex, age, near-fatal asthma, and mortality (9.8% vs. 9.6%) were not significantly different between the previous (n=225) and present (n=397) studies. However, rehospitalization rate was significantly lower in the present study (29.3% vs. 52.4%, P=0.000). The patients in the present study used inhaled steroid more frequently (78.5% vs. 68.0%, P=0.006), had better asthma knowledge (P=0.000), and higher proportion of regular hospital visitors to total subjects (75.6% vs. 64.9%, P=0.004) than did the previous patients. The regular hospital visitors (n=300) showed a significantly lower mortality (3.3% vs. 28.9%, P=0.000), better knowledge (P=0.000) and higher inhaled steroid use (85.8% vs. 54.1%, P=0.000) than did the other group (n=97) in the present study. CONCLUSION: Clinical outcomes after recovery from severe asthma exacerbation in the present study were better than the previous one. Our efforts to educate patients might contribute to these better results.

ERRATUM: Table Correction. Suppressive effects of long-term treatment with inhaled steroids on hypothalamic-pituitary-adrenal axis in asthma

Some parts of Tables 1 and 2 in this paper was described incorrectly.

Suppressive effects of long-term treatment with inhaled steroids on hypothalamic-pituitary-adrenal axis in asthma

PURPOSE: Long-term treatment with inhaled steroids (ICS), especially fluticasone that developed lately, may suppress the hypothalamic-pituitary-adrenal (HPA) axis. This study investigated the relationship between ICS use and HPA axis suppression in asthmatics under ICS treatment for average 4.5 years. METHODS: The medical records of 129 adult asthmatics who received ICS treatment for 6 months or more and underwent a corticotropin stimulation test from January 2005 to August 2013 were retrospectively reviewed. RESULTS: The patients received ICS only (n=87) were found to have an abnormal response to the corticotropin test in as high as 32.2%, and those received ICS in combination with oral steroids (n=42) had a significantly higher prevalence of the response (71.4%, P<0.001). Abnormal responses to corticotropin occurred depending on ICS daily doses (low, n=8, 12.5%; medium, n=19, 36.8%; high, n=102, 49.0%; chi2=4.384, P=0.036). Among the subjects received ICS only, nasal steroid doses (P=0.016) but not ICS doses (P=0.159) were significantly higher in those with abnormal responses than the others. Among all the subjects, oral steroid use (odds ratio [OR], 4.27; 95% confidence interval [CI], 2.35-11.80; P<0.001) and nasal steroid dose (OR, 1.02; 95% CI, 1.00-1.04; P=0.015) were significant risk factors for HPA axis suppression. CONCLUSION: One-third of asthmatics under long-term treatment with ICS showed a suppression of the HPA axis in a dose-dependent manner. Oral or nasal steroid use may be a risk factor for the suppression. However, since our results may have been overestimated due to subject selection bias, further prospective case-control studies are warranted.

Polymorphisms of ATF6B Are Potentially Associated With FEV1 Decline by Aspirin Provocation in Asthmatics

PURPOSE: Endoplasmic reticulum (ER) stress has recently been observed to activate NF-kappaB and induce inflammatory responses such as asthma. Activating transcription factor 6beta (ATF6B) is known to regulate ATFalpha-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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

ERRATUM: Spelling Correction. Suppressive effects of long-term treatment with inhaled steroids on hypothalamic-pituitary-adrenal axis in asthma

On page 289 of this paper, the x-axis title in Fig. 3A has been incorrectly spelled.

Immunomodulating Approach to Asthma Using Mycobacteria

No abstract available.

Association Analysis Between FILIP1 Polymorphisms and Aspirin Hypersensitivity in Korean Asthmatics

PURPOSE: Aspirin exacerbated respiratory disease (AERD) results in a severe asthma attack after aspirin ingestion in asthmatics. The filamin A interacting protein 1 (FILIP1) may play a crucial role in AERD pathogenesis by mediating T cell activation and membrane rearrangement. We investigated the association of FILIP1 variations with AERD and the fall rate of forced expiratory volume in one second (FEV1). METHODS: A total of 34 common FILIP1 single nucleotide polymorphisms (SNPs) were genotyped in 592 Korean asthmatic subjects that included 163 AERD patients and 429 aspirin-tolerant asthma (ATA) controls. RESULTS: This study found that 5 SNPs (P=0.006-0.01) and 2 haplotypes (P=0.01-0.03) of FILIP1 showed nominal signals; however, corrections for the multiple testing revealed no significant associations with the development of AERD (P corr>0.05). In addition, association analysis of the genetic variants with the fall rate of FEV1, an important diagnostic marker of AERD, revealed no significant evidence (P corr>0.05). CONCLUSIONS: Although further replications and functional evaluations are needed, our preliminary findings suggest that genetic variants of FILIP1 might be not associated with the onset of AERD.

Seasonal Variation in Skin Sensitivity to Aeroallergens

PURPOSE: We previously demonstrated seasonal variation in sensitization to aeroallergens in a small group of patients with exercise-induced asthma. This study was performed to confirm the relationship in a much larger population. METHODS: The charts of 1,891 patients who received allergy skin prick tests were reviewed retrospectively. The test results from subjects aged < or =60 years were compared between the groups classified according to the season when the patients received the tests (spring: March-May, summer: June-August, fall: September-November, winter: December-February). The data from 25 respiratory allergy patients who received the tests two or more times and showed a positive response at least once were analyzed longitudinally. RESULTS: The most prevalent among 29 tested aeroallergens were house dust mites (HDMs) Dermatophagoides pteronyssinus and D. farinae. The skin sensitization rates to D. pteronyssinus (23.2% vs. 32.1%, P=0.004) and D. farinae (22.2% vs. 30.2%, P=0.009) were significantly lower in the summer and higher in the fall (38.3% vs. 26.6% and 35.6% vs. 25.3%; P=0.001 respectively) than those in other seasons in patients with a respiratory allergy (n=1,102). The sensitization rates to weed pollens in the fall (13.9% vs. 8.3%, P=0.006) and to Aspergillus fumigatus in the winter (2.9% vs. 0.7%, P=0.005) were significantly higher. In patients with non-respiratory allergy such as urticaria/anaphylaxis (n=340), the D. farinae sensitization rate was significantly lower in the summer also but higher in the spring. The trend of the HDM sensitization rate being lower in the summer and higher in the fall was observed in the longitudinal study. CONCLUSIONS: Skin sensitivity to aeroallergens such as HDMs, pollens, and molds demonstrates seasonal variation in respiratory allergy patients. Non-respiratory allergy patients also showed seasonal variation in sensitivity to aeroallergens, which might be related to the "priming" effect of allergens.

Immune Tolerance by Induced Regulatory T Cells in Asthma

No abstract available.

Seasonal Factors Influencing Exercise-Induced Asthma

PURPOSE: Exercise-induced bronchoconstriction (EIB) in patients with asthma occurs more frequently in winter than in summer. The concentration of house dust mite (HDM) allergens in beds also shows seasonal variation. This study examined the relationship between seasonal differences in the prevalence of EIB and sensitization to HDMs in patients with asthma. METHODS: The medical records of 74 young adult male patients with asthma-like symptoms who underwent bronchial challenge with methacholine, 4.5% saline and exercise, and allergen skin prick tests, were reviewed. The subjects were divided into summer (n=27), spring/fall (n=26) and winter (n=21) groups according to the season during which they underwent testing. RESULTS: The positive responses to exercise differed according to season (48.1% in summer, 73.1% in spring/fall, and 90.5% in winter; P0.05). CONCLUSIONS: Positive skin test reactions to HDMs and EIB occurred in winter, spring/fall, and summer in decreasing order of frequency. Seasonal variation in the prevalence of EIB may be related to seasonal variation in sensitization to HDMs, accompanied by differences in indirect, but not direct, AHR.

Therapeutic Effects of Mycobacterial Secretory Proteins Against Established Asthma in BALB/c Mice

PURPOSE: Live/killed mycobacteria and culture supernatants can suppress asthmatic reactions. This study investigated whether mycobacterial secretory proteins have therapeutic effects on asthma. METHODS: Mycobacterium bovis bacille Calmette-Guerin (BCG; 2x105 CFUs) and mycobacterial secretory proteins (Ag85 complex, 38-kDa protein or MPB70; 4 or 20 microg) were administered intraperitoneally to female BALB/c mice with established airway hyperresponsiveness. One week after treatment, the mice underwent a methacholine challenge test, and then inflammatory cell numbers in bronchoalveolar lavage fluid (BAL) and around bronchi (<500 microm), and cytokine levels in splenocyte supernatants, were assessed. RESULTS: BCG and all of the tested secretory proteins significantly improved airway sensitivity compared to baseline values (P<0.05). The secretory protein Ag85 complex significantly suppressed airway reactivity also (P<0.05), while 38-kDa protein significantly suppressed reactivity and maximal narrowing (P<0.05). The number of eosinophils in BAL and around bronchi, and the goblet cell proportion, were also significantly reduced in mice in both the BCG and secretory protein groups compared to the asthma control group. IFN-gamma/IL-5 ratios were significantly higher in mice treated with BCG, 4 microg MPB70 or 4 microg 38-kDa protein than in asthma control mice (P<0.05), and were negatively associated with airway hyperresponsiveness, peribronchial eosinophil numbers and goblet cell proportion (all P<0.05). IL-17A was positively correlated with IL-5 (r=0.379, P<0.001), maximal airway narrowing, peribronchial eosinophil numbers and goblet cell proportion (all P<0.05). CONCLUSIONS: Secretory proteins from BCG and M. tuberculosis and live BCG were effective against established asthma, their effects being accompanied by increased IFN-gamma/IL-5 ratios. Thus, allergic asthma could be effectively treated with mycobacterial secretory proteins.

Potential Association of DCBLD2 Polymorphisms with Fall Rates of FEV1 by Aspirin Provocation in Korean Asthmatics

Aspirin exacerbated respiratory disease (AERD) is a clinical syndrome characterized by chronic rhinosinusitis with nasal polyposis and aspirin hypersensitivity. The aspirin-induced bronchospasm is mediated by mast cell and eosinophilic inflammation. Recently, it has been reported that the expression of discoidin, CUB and LCCL domain-containing protein 2 (DCBLD2) is up-regulated in lung cancers and is regulated by transcription factor AP-2 alpha (TFAP2A), a component of activator protein-2 (AP-2) that is known to regulate IL-8 production in human lung fibroblasts and epithelial cells. To investigate the associations between AERD and DCBLD2 polymorphisms, 12 common variants were genotyped in 163 AERD subjects and 429 aspirin tolerant asthma (ATA) controls. Among these variants, seven SNPs (rs1371687, rs7615856, rs828621, rs828618, rs828616, rs1062196, and rs8833) and one haplotype (DCBLD2-ht1) show associations with susceptibility to AERD. In further analysis, this study reveals significant associations between the SNPs or haplotypes and the percentage of forced expiratory volume in one second (FEV1) decline following aspirin challenge using multiple linear regression analysis. Furthermore, a non-synonymous SNP rs16840208 (Asp723Asn) shows a strong association with FEV1 decline in AERD patients. Although further studies for the non-synonymous Asp723Asn variation are needed, our findings suggest that DCBLD2 could be related to FEV1-related phenotypes in asthmatics.

Potential Association of DCBLD2 Polymorphisms with Fall Rates of FEV1 by Aspirin Provocation in Korean Asthmatics

Aspirin exacerbated respiratory disease (AERD) is a clinical syndrome characterized by chronic rhinosinusitis with nasal polyposis and aspirin hypersensitivity. The aspirin-induced bronchospasm is mediated by mast cell and eosinophilic inflammation. Recently, it has been reported that the expression of discoidin, CUB and LCCL domain-containing protein 2 (DCBLD2) is up-regulated in lung cancers and is regulated by transcription factor AP-2 alpha (TFAP2A), a component of activator protein-2 (AP-2) that is known to regulate IL-8 production in human lung fibroblasts and epithelial cells. To investigate the associations between AERD and DCBLD2 polymorphisms, 12 common variants were genotyped in 163 AERD subjects and 429 aspirin tolerant asthma (ATA) controls. Among these variants, seven SNPs (rs1371687, rs7615856, rs828621, rs828618, rs828616, rs1062196, and rs8833) and one haplotype (DCBLD2-ht1) show associations with susceptibility to AERD. In further analysis, this study reveals significant associations between the SNPs or haplotypes and the percentage of forced expiratory volume in one second (FEV1) decline following aspirin challenge using multiple linear regression analysis. Furthermore, a non-synonymous SNP rs16840208 (Asp723Asn) shows a strong association with FEV1 decline in AERD patients. Although further studies for the non-synonymous Asp723Asn variation are needed, our findings suggest that DCBLD2 could be related to FEV1-related phenotypes in asthmatics.

Personal Factors Affecting Therapeutic Responses to BCG Vaccination in Asthmatics

PURPOSE: Bacille Calmette-Guerin (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 DeltaFEV1 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 < or =50 years (90.9% vs. 40.0%, P=0.024). Age (P<0.001, odds ratios (OR)=0.92, confidence interval (CI)=0.88-0.96) and atopy (P<0.01, OR=4.95, CI=1.70-14.44) were significant predictors for a good/fair response in females. However, blood eosinophil counts (P<0.05, OR=1.18, CI=1.01-1.39) and FEV1 % best (P<0.001, OR=0.86, CI=0.79-0.94), but not age or atopy, were significant predictors in males. Approximately three-quarters of the males were smokers. CONCLUSIONS: The therapeutic effect of BCG in asthma may differ according to patient clinical characteristics. The greatest benefit occurred in young atopic females. Asthma activity indices, such as eosinophilia and FEV1 % best, were more predictive of a good/fair response in males; this may have been related to cigarette smoking.

Gender-Specific Asthma Treatment

Because genetic characteristics vary among subjects, the therapeutic effects of a certain drug differ among patients with the same disease. For this reason, special interest has focused on tailored treatments. Although it is well known that sex is genetically determined, little attention has been paid to sex differences in the clinical features and treatment of asthma. Females are more likely to suffer allergic asthma, to have difficulty controlling asthma symptoms, and to show adverse effects to drugs. As asthma symptoms show cyclic changes depending on female hormone levels in many women of child-bearing age, the use of contraceptives may specifically help to treat female patients with asthma such as those with perimenstrual asthma and severe asthma. Generally, testosterone seems to suppress asthma, and dehydroepiandrosterone (DHEA), a less virilizing androgen, may be effective for treating asthma. Evidence exists for a therapeutic and steroid-sparing effect of DHEA. However, further studies on the optimal dose and route of DHEA for each sex are needed. Monitoring of the serum DHEA-S level is necessary for patients with asthma on inhaled steroid treatment, and at minimum, replacement therapy for patients with a low level of DHEA may be helpful for treating their asthma.