Sang Heon Cho

Airway Exposure Levels of Lipopolysaccharide Determine Type 1 versus Type 2 Experimental Asthma

Allergic asthma is characterized by airway inflammation initiated by adaptive immune responses to aeroallergens. Recent data suggest that severe asthma may be a different form of asthma rather than an increase in asthma symptoms and that innate immune responses to LPS can modulate adaptive immune responses to allergens. In this study, we evaluated the hypothesis that airway exposure to different doses of LPS induces different form of asthma. Our study showed that neutrophilic inflammation and IFN-γ expression were higher in induced sputum from severe asthma patients than from mild to moderate asthmatics. Animal experiments indicated that allergen sensitization with low-dose LPS (0.1 μg) induced type 2 asthma phenotypes, i.e., airway hyperresponsiveness, eosinophilic inflammation, and allergen-specific IgE up-regulation. In contrast, allergen sensitization with high-dose LPS (10 μg) induced asthma phenotypes, i.e., airway hyperresponsiveness and noneosinophilic inflammation that were not developed in IFN-γ-deficient mice, but unaffected in the absence of IL-4. During the allergen sensitization period, TNF-α expression was found to be enhanced by both low- and high-dose LPS, whereas IL-12 expression was only enhanced by high-dose LPS. Interestingly, the asthma phenotypes induced by low-dose LPS, but not by high-dose LPS, were completely inhibited in TNF-α receptor-deficient mice, whereas the asthma phenotypes induced by high-dose LPS were abolished in the homozygous null mutation of the STAT4 gene. These findings suggest that airway exposure levels of LPS induces different forms of asthma that are type 1 and type 2 asthma phenotypes by high and low LPS levels, respectively.

Genome-Wide and Follow-Up Studies Identify CEP68 Gene Variants Associated with Risk of Aspirin-Intolerant Asthma

Aspirin-intolerant asthma (AIA) is a rare condition that is characterized by the development of bronchoconstriction in asthmatic patients after ingestion of non-steroidal anti-inflammatory drugs including aspirin. However, the underlying mechanisms of AIA occurrence are still not fully understood. To identify the genetic variations associated with aspirin intolerance in asthmatics, the first stage of genome-wide association study with 109,365 single nucleotide polymorphisms (SNPs) was undertaken in a Korean AIA (n = 80) cohort and aspirin-tolerant asthma (ATA, n = 100) subjects as controls. For the second stage of follow-up study, 150 common SNPs from 11 candidate genes were genotyped in 163 AIA patients including intermediate AIA (AIA-I) subjects and 429 ATA controls. Among 11 candidate genes, multivariate logistic analyses showed that SNPs of CEP68 gene showed the most significant association with aspirin intolerance (P values of co-dominant for CEP68, 6.0×10−5 to 4.0×10−5). All seven SNPs of the CEP68 gene showed linkage disequilibrium (LD), and the haplotype of CEP68_ht4 (T-G-A-A-A-C-G) showed a highly significant association with aspirin intolerance (OR  = 2.63; 95% CI  = 1.64–4.21; P = 6.0×10−5). Moreover, the nonsynonymous CEP68 rs7572857G>A variant that replaces glycine with serine showed a higher decline of forced expiratory volume in 1s (FEV1) by aspirin provocation than other variants (P = 3.0×10−5). Our findings imply that CEP68 could be a susceptible gene for aspirin intolerance in asthmatics, suggesting that the nonsynonymous Gly74Ser could affect the polarity of the protein structure.

The Current Status of Asthma in Korea

A systematic review of English and Korean articles published between 1990 and 2004 and a search of database and various online resources was conducted to determine the prevalences, mortality rates, socioeconomic burden, quality of life, and treatment pattern of asthma in Korean adults and children. Asthma morbidity and mortality in Korea are steadily increasing. The prevalence of asthma in Korea is estimated to be 3.9% and its severity is often underestimated by both physicians and patients. Mortality resulting from chronic lower respiratory diseases including asthma increased from 12.9 to 22.6 deaths per 100,000 of the population between 1992 and 2002. Disease severity, level of control, and symptom state were all found to negatively impact the quality of life of asthmatics. Although international and Korean asthma management guidelines are available, familiarity with and implementation of these guidelines by primary care physicians remain poor.

Correlation between the Korean Version of Asthma Control Test and Health-Related Quality of Life in Adult Asthmatics

The Asthma Control Test (ACT) is a patient-completed questionnaire developed to assess asthma control. Health-related quality of life (HRQL) in asthmatics has shown relatively low correlations with parameters of asthma control and the relationship between the ACT and HRQL in asthmatics is yet unclear. Because revalidations of translated versions of questionnaires are critical for its utilization, we first sought to validate the Korean version of ACT and then to evaluate the relationship between the ACT and HRQL. Patients (n=117) completed the ACT and asthma-related quality of life questionnaire (AQLQ) at 3 physician visits. Pulmonary function was measured and an asthma specialist rated asthma control. The Korean version of ACT was found to be reliable, valid, and responsive to changes in asthma control over time up to three consecutive visits. ACT scores correlated significantly (p=0.001) with symptoms domain (r=0.72), activity domain (r=0.65), emotional domain (r=0.69), and environmental domain (r=0.67) of AQLQ. In conclusion, the Korean version of the ACT was found to be a reliable and valid tool for measuring asthma control, and to correlate well with AQLQ scores. Moreover, the ACT was responsive to changes in AQLQ scores over time.

Effect of single nucleotide polymorphisms within the interleukin-4 promoter on aspirin intolerance in asthmatics and interleukin-4 promoter activity.

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=270) were genotyped and functional promoter assays were performed. Results Of 15 SNPs 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 (Pcorr=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 &bgr; 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.

Allergic Diseases in Preschoolers Are Associated With Psychological and Behavioural Problems

Purpose The aim of the present study was to investigate the relationship between three major allergic diseases, asthma, allergic rhinitis (AR), and atopic dermatitis (AD), and psychological and behavioural problems in preschoolers based on a community survey. Methods A cross-sectional survey was conducted using a modified International Study of Asthma and Allergies in Childhood questionnaire to determine the prevalence of symptoms and diagnosed allergic diseases, and a Korean version of the Child Behaviour Checklist to assess internalizing, externalizing, and sleep problems among 780 preschoolers. Five-hundred and seventy-five preschoolers with valid data were included in this study. Results The prevalence of lifetime diagnosis and treatment in the past 12 months was 8.7% and 4.4% for asthma, 24.4% and 19.2% for AR, and 35.1% and 16.6% for AD, respectively. Scores for internalizing and sleep problems were significantly higher in those diagnosed with AR. Preschoolers who had been treated for AD in the past 12 months had higher attention problem and attention-deficit/hyperactivity disorder scores. Sleep problems were more severe in moderate to severe AD compared to control and mild AD groups, categorised according to SCOring index of AD. The severity of sleep problems correlated positively with the percentage of eosinophils in peripheral blood. Conclusions Psychological and behavioural problems differed among the three major allergic diseases, weaker association for asthma and stronger association for AR and AD. The results of this study may lead to the identification of potential underlying shared mechanisms common to allergic diseases and psychological and behavioural problems.

Challenges in the Management of Asthma in the Elderly

Recent literature has emphasized the clinical and socio-epidemiological significance of asthma in the elderly. However, why the disease burden remains high in this group is unclear. Elderly subjects usually have multiple chronic illnesses, and the role played by comorbidities in the context of asthma has been underappreciated. This review aims to summarize the literature associations between comorbidities and asthma in elderly patients. In addition, we discuss patient management issues.

Alveolar macrophages modulate allergic inflammation in a murine model of asthma

The role of alveolar macrophages (AMs) in the pathogenesis of asthma is still unknown. The aim of the present study was to investigate the effects of AM in the murine model of asthma. AMs were selectively depleted by liposomes containing clodronate just before allergen challenges, and changes in inflammatory cells and cytokine concentrations in bronchoalveolar lavage (BAL) fluid were measured. AMs were then adoptively transferred to AM-depleted sensitized mice and changes were measured. Phenotypic changes in AMs were evaluated after in vitro allergen stimulation. AM-depletion after sensitization significantly increased the number of eosinophils and lymphocytes and the concentrations of IL-4, IL-5 and GM-CSF in BAL fluid. These changes were significantly ameliorated only by adoptive transfer of unsensitized AMs, not by sensitized AMs. In addition, in vitro allergen stimulation of AMs resulted in their gaining the ability to produce inflammatory cytokines, such as IL-1β, IL-6 and TNF-α, and losing the ability to suppress GM-CSF concentrations in BAL fluid. These findings suggested that AMs worked probably through GM-CSF-dependent mechanisms, although further confirmatory experiments are needed. Our results indicate that the role of AMs in the context of airway inflammation should be re-examined.

A Case of Hypersensitivity Syndrome to Both Vancomycin and Teicoplanin

Drug hypersensitivity syndrome to both vancomycin and teicoplanin has not been previously reported. We describe here a 50-yr-old male patient with vertebral osteomyelitis and epidural abscess who developed hypersensitivity syndrome to both vancomycin and teicoplanin. Skin rash, fever, eosinophilia, interstitial pneumonitis, and interstitial nephritis developed following the administration of each drug, and resolved after withdrawing the drugs and treating with high dose corticosteroids. The vertebral osteomyelitis was successfully treated with 6-week course of linezolid without further complications. Skin patch tests for vancomycin and teicoplanin was done 2 months after the recovery; a weak positive result for vancomycin (10% aq.,+at D2 and +at D4 with erythema and vesicles; ICDRG scale), and a doubtful result for teicoplanin (4% aq.-at D2 and±at D4 with macular erythema; ICDRG scale). We present this case to alert clinicians to the hypersensitivity syndrome that can result from vancomycin and teicoplanin, with possible cross-reactivity, which could potentially be life-threatening.

Cross-reactivity to Acetaminophen and Celecoxib According to the Type of Nonsteroidal Anti-inflammatory Drug Hypersensitivity

Purpose Identification of tolerable alternative analgesics is crucial for management in nonsteroidal anti-inflammatory drug (NSAID)-sensitive patients. We investigated cross-reactivity of acetaminophen and celecoxib according to the type of aspirin/NSAID hypersensitivity and aimed to determine the risk factors for cross-intolerance. Methods We retrospectively reviewed the medical records of patients intolerant to aspirin and NSAIDs who had undergone an acetaminophen and/or celecoxib oral provocation test. Aspirin/NSAID hypersensitivity was classified into 4 types according to a recently proposed classification: aspirin-exacerbated respiratory disease (AERD), aspirin-exacerbated chronic urticaria (AECU), aspirin-induced acute urticaria/angioedema (AIAU), and NSAID-induced blended reaction (NIRD). Results A total of 180 patients with hypersensitivity to aspirin and NSAIDs were enrolled; 149 acetaminophen provocation test results and 145 celecoxib provocation test results were analyzed. The overall cross-reaction rates to acetaminophen and celecoxib were 24.8% and 10.3%, respectively. There was a significant difference in the cross-reactivity to acetaminophen according to the type of NSAID hypersensitivity. Cross-reactivity to acetaminophen was highest in the AECU group (43.9%), followed by the AERD (33.3%), NIBR (16.7%), and AIAU (12.5%) groups. Underlying chronic urticaria was more prevalent in patients with cross-intolerance to both acetaminophen (P=0.001) and celecoxib (P=0.033). Intolerance to acetaminophen was associated with intolerance to celecoxib (P<0.001). Conclusions Acetaminophen and celecoxib may induce adverse reactions in a non-negligible portion of aspirin/NSAID-sensitive patients. Physicians should be aware of the possible cross-reactions of these alternative drugs and consider an oral challenge test to confirm their tolerability.