Young-Hee Nam

Effects of Omalizumab Treatment in Patients With Refractory Chronic Urticaria

Purpose Chronic urticaria (CU) is a common and debilitating disease, and the need for effective treatment has increased. Omalizumab may be an alternative regimen in patients with CU who do not respond to conventional treatments. The aim of this study is to investigate the efficacy and to observe the clinical results of omlizumab in patients with refractory CU. Methods We conducted a retrospective analysis of 26 patients with refractory CU who were treated with omalizumab. Omalizumab was administered every 2 or 4 weeks, depending on body weight and the total serum IgE level, for 24 weeks. Results Fourteen patients (53.8%) achieved remission after the treatment; they had a significantly higher prevalence of personal (P=0.033) and family history of allergic diseases (P=0.002) than those who did not achieve remission. During omalizumab treatment, the urticaria activity score declined significantly (12.11±1.97 to 2.7±4.23; P=0.001) and the CU-quality of life score improved significantly (34.65±13.58 to 60.88±11.11; P=0.004). There were significant decreases in the use of systemic steroids (42.3%-11.5%; P=0.027) and immunomodulators (65.4%-19.2%; P=0.002). The dose of antihistamines required to control CU also decreased significantly (215.66±70.06 to 60.85±70.53 mg/week of loratadine equivalents; P<0.001). No serious adverse event was noted. Conclusions These findings suggest that omalizumab can be an effective and safe treatment in patients with refractory CU.

Co-existence of Chronic Urticaria and Metabolic Syndrome: Clinical Implications

A systemic pro-inflammatory and pro-coagulating state occurs in subjects who have both chronic urticaria and metabolic syndrome. To investigate the prevalence and clinical impact of metabolic syndrome in Korean patients with chronic urticaria, a hospital-based cross-sectional study of 131 patients was performed. Metabolic syndrome was assessed by the criteria of the National Cholesterol Education Programs Adult Treatment Panel III. Urticaria disease activity was assessed by total urticaria activity score (range 0-15). Thirty-nine patients (29.8%) had metabolic syndrome compared to 17.8% in a matched control group (p=0.001). Patients with chronic urticaria and metabolic syndrome were older, had a higher mean urticaria activity score and serum levels of eosinophil cationic protein, tumour necrosis factor-α, and complements, and showed a higher rate of negative autologous serum skin tests compared with those with-out metabolic syndrome. Logistic regression analysis indicated that an urticaria activity score of ≥ 13 (p=0.025) and the presence of metabolic syndrome (p=0.036) were independent predictors of uncontrolled chronic urticaria. We conclude that patients with severe and uncontrolled chronic urticaria should be evaluated for metabolic syndrome in order to reduce cardiovascular risk and improve chronic urticaria outcomes.

The Predictors of Poorly Controlled Asthma in Elderly

Purpose To evaluate asthma control in elderly individuals and identify the factors that predict poor control. Methods A retrospective, observational study evaluating 108 elderly individuals with asthma (59 females: ≥60 years, mean age: 70.5 years) was conducted at Ajou University Hospital from October 2010 to March 2011. Subjects were classified into two groups according to scores on the asthma control test (ACT). Group I consisted of 38 patients with ACT scores ≤19 (poor controllers) and group II included 70 patients with ACT scores >19 (controllers). Clinical data was analyzed. Spirometry was performed, and the ACT and asthma quality-of-life survey were completed. Medication possession ratios were calculated to evaluate compliance. Results Of the 108 enrolled subjects, 54.6% were female, 7.5% were obese, and 49.0% were atopic. The mean age of the patients was 70.5, and the average of time patients had suffered from asthma was 15.5 years. Comorbid conditions were found in more than 80% of the patients. Allergic rhinitis was most common comorbid condition; this was followed by cardiovascular disease and degenerative arthritis (76.9%, 65.7%, and 51.9%, respectively). Many patients (35.2%) were in poorly controlled states characterized by significantly lower asthma quality of life scores (P<0.001) and higher admission rates (P=0.034). Multivariate logistic regression analysis showed that a history of pulmonary tuberculosis was a predictor of poorly controlled asthma in elderly individuals even after adjusting for age, sex, smoking, lung function and other comorbidities (OR=4.70, CI=1.06-20.81, P=0.042). Conclusions The asthma of more than one-third of elderly individuals with this condition was poorly controlled, and a history of pulmonary tuberculosis may have contributed to this outcome. Proper evaluation and management of comorbid conditions in elderly patients with asthma is essential for the achievement of better control of the disease and a higher quality of life for those who suffer from it.

The Prevalence of Serum Specific IgE to Superantigens in Asthma and Allergic Rhinitis Patients.

Staphylococcus aureus is the most common bacterium present in upper respiratory tract, and the toxins it produced are involved in allergic inflammation pathogenesis. In this study, we investigated the clinical significance of IgE in association with staphylococcal superantigens in allergic asthma with rhinitis (BAwAR) and allergic rhinitis alone (AR). We recruited 100 patients with BAwAR (group I), 100 patients with AR (group II), and 88 healthy controls (group III). Patients were clinically diagnosed by physicians, and were sensitized to house dust mites. Specific IgE antibodies to staphylococcal superantigen A (SEA), B (SEB), and toxic shock syndrome toxin-1 (TSST-1) were measured using the ImmunoCAP system. Other clinical parameters were retrospectively analyzed. All specific IgE antibodies to SEA, SEB, and TSST-1 were detected most frequently in group I (22%, 21%, and 27%), followed by group II (11%, 14%, and 21%) and group III (4.5%, 3.4%, and 2.3%). Absolute values of serum specific IgE to SEA, SEB, and TSST-1 were also significantly higher in group I (0.300±1.533 kU/L, 0.663±2.933 kU/L, and 0.581±1.931 kU/L) and group II (0.502±2.011 kU/L, 0.695±3.337 kU/L, and 1.067±4.688 kU/L) compared to those in group III (0.03±0.133 kU/L, 0.03±0.14 kU/L, and 0.028±0.112 kU/L). The prevalence of serum specific IgE to SEA was significantly higher in group I compared to group II (P=0.025). Blood eosinophil counts were significantly higher in patients with specific IgE to SEA or SEB, and higher serum levels of specific IgE to house dust mites were noted in patients with specific IgE to TSST-1. In conclusion, the present study suggested that IgE responses to staphylococcal superantigens are prevalent in the sera of both BAwAR and AR patients. This may contribute to an augmented IgE response to indoor allergens and eosinophilic inflammation.

Role of vitamin D-binding protein in isocyanate-induced occupational asthma

The development of a serological marker for early diagnosis of isocyanate-induced occupational asthma (isocyanate-OA) may improve clinical outcome. Our previous proteomic study found that expression of vitamin D-binding protein (VDBP) was upregulated in the patients with isocyanate-OA. In the present study, we evaluated the clinical relevance of VDBP as a serological marker in screening for isocyanate-OA among exposed workers and its role in the pathogenesis of isocyanate-OA. Three study groups including 61 patients with isocyanate-OA (group I), 180 asymptomatic exposed controls (AECs, group II), 58 unexposed healthy controls (NCs, group III) were enrolled in this study. The baseline serum VDBP level was significantly higher in group I compared with groups II and III. The sensitivity and specificity for predicting the phenotype of isocyanate-OA with VDBP were 69% and 81%, respectively. The group I subjects with high VDBP (≥ 311 µg/ml) had significantly lower PC20 methacholine levels than did subjects with low VDBP. The in vitro studies showed that TDI suppressed the uptake of VDBP into RLE-6TN cells, which was mediated by the downregulation of megalin, an endocytic receptor of the 25-hydroxycholecalciferol-VDBP complex. Furthermore, toluene diisocyanate (TDI) increased VEGF production and secretion from this epithelial cells by suppression of 1,25-dihydroxycholecalciferol [1,25(OH)2D3] production. The findings of this study suggest that the serum VDBP level may be used as a serological marker for the detection of isocyanate-OA among workers exposed to isocyanate. The TDI-induced VEGF production/secretion was reversed by 1,25(OH)2D3 treatment, which may provide a potential therapeutic strategy for patients with isocyanate-OA.

Clinical Features and the Diagnostic Value of Component Allergen-Specific IgE in Hymenoptera Venom Allergy

Purpose Although patient history is vital for the diagnosis of hymenoptera venom allergy, specific IgE detection is also important to identify the culprit insect and monitor the effect of immunotherapy. We evaluated the diagnostic value of serum-specific IgE detection of hymenoptera venom component allergens and documented changes in allergen-specific IgE after immunotherapy. Methods Fifty-six hymenoptera venom allergy patients receiving venom immunotherapy were recruited from Ajou University Hospital, Korea. The clinical manifestations of the patients were noted, and serum-specific IgE detection was performed, using conventional venom extracts as well as component allergens. Data were analyzed retrospectively. Results A total of 35 (62.5%) patients were male, and 33 (73.3%) patients were atopic. The mean patient age was 44.9±13.8 years. Localized reactions occurred in 23.2% of patients, and systemic reactions occurred in 76.8%. The most common clinical manifestations included skin involvement, such as urticaria and angioedema, and respiratory involvement. Yellow jackets were the most frequent culprit insect, followed by yellow hornets, white-faced hornets, honeybees, and paper wasps, as determined at the time of diagnosis. Double sensitization to both Apidae and Vespidae species was detected in 70.9% of patients. The positive predictive values (PPV) of rVes v 5-specific and rPol d 5-specific IgE detection were 85.7% and 87.5%, respectively, which correlated well with conventional venom extract-specific IgE detection (r=0.762 and r=0.757, respectively). In contrast, the PPV of rApi m 1-specific IgE detection at the time of diagnosis was 34.8%. Three years of venom immunotherapy resulted in decreased venom-specific IgE, particularly IgE specific for Vespidae venom components. Conclusions Stings by yellow jackets and male sex may be risk factors for hymenoptera venom allergy in Korea. Vespidae component-specific IgE, but not Apidae component-specific IgE, had diagnostic and monitoring value in hymenoptera venom allergy comparable to that of conventional hymenoptera venom extract-specific IgE.

Genetic Mechanisms in Aspirin-Exacerbated Respiratory Disease

Aspirin-exacerbated respiratory disease (AERD) refers to the development of bronchoconstriction in asthmatics following the exposure to aspirin or other nonsteroidal anti-inflammatory drugs. The key pathogenic mechanisms associated with AERD are the overproduction of cysteinyl leukotrienes (CysLTs) and increased CysLTR1 expression in the airway mucosa and decreased lipoxin and PGE2 synthesis. Genetic studies have suggested a role for variability of genes in disease susceptibility and the response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLA-DPB1, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10, ACE, IL13, KIF3A, SLC22A2, CEP68, PTGER, and CRTH2 and a four-locus SNP set composed of B2ADR, CCR3, CysLTR1, and FCER1B. Future areas of investigation need to focus on comprehensive approaches to identifying biomarkers for early diagnosis.

Polymorphisms of Aspirin-Metabolizing Enzymes CYP2C9, NAT2 and UGT1A6 in Aspirin-Intolerant Urticaria

Acetyl salicylic acid (ASA) is metabolized by UDP-glucuronosyltransferase 1A6 (UGT1A6), cytochrome P4502C9 (CYP2C9), and N-acetyl transferase 2 (NAT2). Variations in the activities of these enzymes may modulate adverse ASA-related symptoms such as urticaria. We examined whether polymorphisms in the UGT1A6, CYP2C9, and NAT2 genes are related to ASA-intolerant urticaria (AIU). The genotypes of 148 subjects with AIU (AIU group) and 260 normal healthy control subjects (NC group) were analyzed with respect to the following single nucleotide polymorphisms: CYP2C9 -1188T>C and CYP2C9*3A1075C; UGT1A6 T181A A>G and UGT1A6 R184S A>C; and NAT2 9796A>T, NAT2 197G>A, NAT2 286G>A, NAT2 9601A>G, and NAT2 9306A>G. There were significant differences in the allele frequencies for the CYP2C9 polymorphisms between the two groups. The frequency of the minor allele CYP2C9 -1188T>C was significantly higher in the AIU group than in the NC group (P=0.005). The frequency of the variant genotype CC was higher in the AIU group compared with the controls in both the co-dominant (P=0.007) and recessive models (P=0.012). The frequency of haplotype 2 [CA] was also significantly higher in the AIU group in both the co-dominant (P=0.006) and dominant models (P=0.012). There was no significant difference in genotype frequencies for any of the UGT1A6 or NAT2 polymorphisms between the two groups. Clinical parameters did not differ according to genotype. These results suggest that the C allele of CYP2C9 -1188T>C may be associated with AIU.

Predictors of Asthma Control by Stepwise Treatment in Elderly Asthmatic Patients

The geriatric population is increasing, and asthma severity increases with age. We determined the predictors of asthma control, exacerbation, and the factors that affect asthma-specific quality of life (A-QOL) in elderly asthmatic patients. This was a prospective, multicenter, real-life study for 6 months with stepwise pharmacologic treatment based on the Global Initiative for Asthma (GINA) guideline. A total of 296 asthmatic patients aged ≥ 60 yr were recruited from 5 university centers in Korea. The improved-asthma control group was defined as the group of patients who maintained well-controlled or improved disease and the not-improved asthma control group was defined as the remaining patients. Fewer number of medications for comorbidities (2.8 ± 3.3 in the improved vs. 4.5 ± 4.4 in the control) and higher physical functioning (PF) scale (89.8 ± 14.2 in the improved vs. 82.0 ± 16.4 in the control) were significant predictors in the improved-asthma control group (OR = 0.863, P = 0.004 and OR = 1.028, P = 0.018, respectively). An asthma control test (ACT) score of ≤ 19 at baseline was a significant predictor of asthma exacerbation (OR = 3.938, P = 0.048). Asthma duration (F = 5.656, P = 0.018), ACT score (F = 12.237, P = 0.001) at baseline, and the presence of asthma exacerbation (F = 5.565, P = 0.019) were significant determinants of changes in A-QOL. The number of medications for comorbidities and performance status determined by the PF scale may be important parameters for assessing asthma control in elderly asthmatic patients. Graphical Abstract

Identifying genetic susceptibility to sensitization to cephalosporins in health care workers.

Exposure to cephalosporins could cause occupational allergic diseases in health care workers (HCWs). We evaluated the prevalence of serum specific IgE and IgG antibodies to cephalosporin-human serum albumin (HSA) conjugate and to identify potential genetic risk factors associated with sensitization to cephalosporins in exposed HCWs. The study population consisted of 153 HCWs who had been exposed to antibiotics in a single university hospital and 86 unexposed healthy controls. A questionnaire survey of work-related symptoms (WRS) was administered. A skin-prick test (SPT) was performed, and serum-specific IgE and IgG antibodies to 3 commonly prescribed cephalosporins were measured by ELISA. Four single-nucleotide polymorphisms of the candidate genes related to IgE sensitization were genotyped. The prevalence of WRS to cephalosporins was 2.6%. The prevalence rates of serum-specific IgE and IgG antibodies to cephalosporins were 20.3% and 14.7%, respectively. The FcεR1β-109T > C polymorphism was significantly associated with IgE sensitization to cephalosporins in HCWs (P = 0.036, OR = 3.553; CI, 1.324-9.532). The in vitro functional assay demonstrated that the T allele of FcεR1β-109T had greater promoter activity than did the C allele (P < 0.001). The FcεR1β-109T > C polymorphism may be a potential genetic risk factor for increased IgE sensitization to cephalosporins.