Risk factors for asthma-related healthcare use: longitudinal analysis using the NHI claims database in a Korean asthma cohort.

BACKGROUND: Though insurance claims data are useful for researching asthma, they have important limitations, such as a diagnostic inaccuracy and a lack of clinical information. To overcome these drawbacks, we used the novel method by merging the clinical data from our asthma cohort with the National Health Insurance (NHI) claims data. METHODS AND RESULTS: Longitudinal analysis of asthma-related healthcare use from the NHI claims database, merged with data of 736 patients registered in a Korean asthma cohort, was conducted for three consecutive years from registration of the cohort. Asthma-related asthma healthcare referred to outpatient and emergency department visits, hospitalizations, and the use of systemic corticosteroids. Univariate and multivariate logistic regression analysis was used to evaluate risk factors for asthma-related healthcare. Over three years after enrollment, many patients changed from tertiary to primary/secondary hospitals with a lack of maintenance of inhaled corticosteroid-based controllers. An independent risk factor for emergency visits was a previous history of asthma exacerbation. In hospitalizations, old age and Asthma Control Test (ACT) score variability were independent risk factors. An independent risk factor for per person cumulative duration of systemic corticosteroids was the FEV1 (Forced expiratory volume in one second)%. The use of systemic corticosteroids was independently associated with being female, the FEV1%, and ACT score variability. CONCLUSION: We found that old age, being female, long-standing asthma, a low FEV1%, asthma brittleness, asthma drug compliance, and a history of asthma exacerbation were independent risk factors for increased asthma-related healthcare use in Korea.

Clusterin expression level correlates with increased oxidative stress in asthmatics.

BACKGROUND: Oxidative stress is thought to play a role in the pathogenesis of asthma. Clusterin is a sensitive cellular biosensor of oxidative stress and has antioxidant properties. The function and expression of clusterin in patients with asthma have not been fully investigated. OBJECTIVE: To investigate whether the expression of clusterin in patients with asthma is regulated by increased oxidative burden and whether clusterin expression could be used to assess the response to inhaled corticosteroids. METHODS: Clusterin levels in serum, induced sputum, and peripheral blood mononuclear cells of patients with asthma were measured by enzyme-linked immunosorbent assay and western blotting and compared with pulmonary function and levels of expression of hyperoxidized peroxiredoxins. Serum concentrations of clusterin in treatment-naive patients were compared before and after inhaled corticosteroid use. RESULTS: Serum clusterin concentration was significantly elevated in patients with severe asthma and was inversely correlated with pulmonary function. The expression of hyperoxidized peroxiredoxins was greatly increased in peripheral blood mononuclear cells of patients with asthma and was strongly correlated with clusterin expression. Serum clusterin concentrations in treatment-naive patients with asthma were decreased significantly after initial treatment with inhaled corticosteroids. CONCLUSION: Clusterin may be a biomarker of asthma severity and the burden of oxidative stress in patients with asthma. Moreover, clusterin may be useful for the prompt assessment of airway inflammation.

Influence of initial treatment modality on long-term control of chronic idiopathic urticaria.

BACKGROUND: Chronic idiopathic urticaria (CIU) is a common cutaneous disorder but the influence of initial treatment modality on long-term control is not known. The aim of this study was to evaluate clinical features, and the influence of initial treatment modality on long-term control. METHODS AND RESULTS: 641 CIU patients were enrolled from the allergy clinic in a tertiary referral hospital. Disease duration, aggravating factors and treatment modality at each visit were evaluated. Times required to reach a controlled state were analyzed according to initial treatment modality, using Kaplan-Meier survival curves, the Cox proportional-hazards model, and propensity scores. Female to male ratio was 1.7: 1; mean age at onset was 40.5 years. The most common aggravating factors were food (33.5%), stress (31.5%) and fatigue (21.6%). Most patients (82.2%) used H1-antihistamines alone as initial treatment while 17% used a combination treatment with oral corticosteroids. There was no significant difference in the time taken to reach a controlled state between patients treated with single vs multiple H1-antihistamines or between those who received H1-antihistamine monotherapy vs. a combination therapy with oral corticosteroids. CONCLUSION: The time required to control CIU is not reduced by use of multiple H1-antihistamines or oral corticosteroids in the initial treatment.

The Effectiveness of Automatic Recommending System for Premedication in Reducing Recurrent Radiocontrast Media Hypersensitivity Reactions.

BACKGROUND: Non-ionic radiocontrast media (RCM) is rarely associated with hypersensitivity reactions. Premedication of patients who reacted previously to RCM with systemic corticosteroids and/or antihistamines can help reduce recurrent hypersensitivity reactions. However, premedication is still not prescribed in many cases for various reasons. This study aimed to determine the effectiveness of our novel RCM hypersensitivity surveillance and automatic recommending system for premedication. METHODS AND RESULTS: Hospitalized patients with a history of RCM hypersensitivity were identified in an electronic medical record system that included a mandatory reporting system for past adverse drug reactions. In 2009, a novel automatic prescription system was added that classified index RCM reactions by severity and dispensed appropriate corticosteroid and/or antihistamine pretreatment prior to new RCM exposures. The data from 12 months under the previous system and 12 months under the current system were compared. The two systems had similar overall premedication rates (91% and 95%) but the current system was associated with a significantly higher corticosteroid premedication rate (65% vs. 14%), which significantly reduced the breakthrough reaction rate (6.7% vs. 15.2%). The current system was also associated with increased corticosteroid and antihistamine premedication of patients with a mild index reaction (61% vs. 7%) and a reduction in their breakthrough reaction rate (6% vs. 15%). CONCLUSIONS: Premedication with corticosteroid and/or antihistamine, which was increased by our novel automatic prescription system, significantly reduced breakthrough reactions in patients with a history of RCM hypersensitivity.

Characteristics of liver injury in drug-induced systemic hypersensitivity reactions.

BACKGROUND: The liver is the most commonly involved internal organ in drug-induced systemic hypersensitivity. However, data obtained from these patients have yet to be analyzed in depth with respect to liver injury. METHODS: The medical records of 136 patients who developed delayed-type drug hypersensitivity were reviewed at a tertiary referral hospital. Culprit drugs, the pattern and degree of liver injury, and the effect of systemic corticosteroids were evaluated in the group of patients with drug-induced systemic hypersensitivity and liver dysfunction (aspartate aminotransferase or alanine aminotransferase ≥80 IU/L). Clinical characteristics of patients with drug-induced systemic hypersensitivity and liver injury were analyzed. RESULTS: Among the 61 patients with drug-induced systemic hypersensitivity and liver dysfunction, the clinical phenotypes were drug reaction with eosinophilia and systemic symptoms (n = 29, 48%), Stevens-Johnson syndrome/toxic epidermal necrolysis (n = 11, 18%), and maculopapular rash (n = 17, 28%). Antibiotics (n = 27, 44%) were the most common cause of drug-induced systemic hypersensitivity with liver dysfunction. Whereas patients with Stevens-Johnson syndrome/toxic epidermal necrolysis had mild hepatocellular-type liver injury of relatively brief duration, those with drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome had more severe and prolonged hepatocellular injury in addition to moderate to severe cholestatic-type liver injury. The use of systemic corticosteroids did not significantly affect either recovery from liver injury or mortality. LIMITATIONS: This study was retrospective and the number of subjects was small. CONCLUSION: The results suggest that the severity, pattern, and duration of liver injury differ according to the drug-hypersensitivity phenotype. Further studies are needed to evaluate the role of systemic corticosteroids in drug-induced systemic hypersensitivity and liver injury.

Clinical characteristics that distinguish eosinophilic organ infiltration from metastatic nodule development in cancer patients with eosinophilia.

BACKGROUND: When new space-occupying lesions are observed together with peripheral blood eosinophilia in patients diagnosed with cancer, the possibility of eosinophilic organ involvement should be differentiated from metastasis of primary cancer, since a misdiagnosis could lead to unnecessary chemotherapy. The aim of this study is to identify the clinical characteristics of eosinophilic organ involvement that distinguish it from distant metastasis in patients with primary cancer. METHODS: The medical records of 43 cancer patients who developed hepatic or pulmonary nodules with peripheral blood eosinophilia between January 2005 and February 2010 in the Asan Medical Center (Seoul) were reviewed. Eosinophilic infiltration and distant metastasis were identified on the basis of pathological findings and radiological features. Fisher's exact test, χ² test or Mann-Whitney test were used for statistical analysis. RESULTS: In total, 33 patients (76%) were diagnosed with eosinophilic infiltration, 5 (12%) with cancer metastasis and 5 (12%) had undetermined diagnoses. Compared to the patients with metastases, the patients with eosinophilic infiltration were significantly more likely to have serology indicating a parasitic infection, a history of eating raw food, high serum levels of total IgE, normal liver function, normal C-reactive protein levels, a normal erythrocyte sedimentation rate, and fewer and smaller nodules. The most common underlying malignancy in the eosinophilic organ infiltration group was stomach cancer. Physicians tended to neglect the eosinophilia in patients with a history of cancer. CONCLUSIONS: Several clinical characteristics of eosinophilic organ infiltration distinguish it from cancer metastasis. Physicians should make greater efforts to determine the causes of organ involvement with peripheral blood eosinophilia, especially in cancer patients.

Grape seed proanthocyanidin extract attenuates allergic inflammation in murine models of asthma.

BACKGROUND: Antioxidants have been suggested to alleviate the pathophysiological features of asthma, and grape seed proanthocyanidin extract (GSPE) has been reported to have powerful antioxidant activity. PURPOSE: This study was performed to determine whether GSPE has a therapeutic effect on allergic airway inflammation in both acute and chronic murine model of asthma. METHODS: Acute asthma model was generated by intraperitoneal sensitization of ovalbumin (OVA) with alum followed by aerosolized OVA challenges, whereas chronic asthma model was induced by repeated intranasal challenges of OVA with fungal protease twice a week for 8 weeks. GSPE was administered by either intraperitoneal injection or oral gavage before OVA challenges. Airway hyperresponsiveness (AHR) was measured, and airway inflammation was evaluated by bronchoalveolar lavage (BAL) fluid analysis and histopathological examination of lung tissue. Lung tissue levels of various cytokines, chemokines, and growth factors were analyzed by quantitative polymerase chain reaction and ELISA. Glutathione assay was done to measure oxidative burden in lung tissue. RESULTS: Compared to untreated asthmatic mice, mice treated with GSPE showed significantly reduced AHR, decreased inflammatory cells in the BAL fluid, reduced lung inflammation, and decreased IL-4, IL-5, IL-13, and eotaxin-1 expression in both acute and chronic asthma models. Moreover, airway subepithelial fibrosis was reduced in the lung tissue of GSPE-treated chronic asthmatic mice compared to untreated asthmatic mice. Reduced to oxidized glutathione (GSH/GSSG) ratio was increased after GSPE treatment in acute asthmatic lung tissue. CONCLUSION: GSPE effectively suppressed inflammation in both acute and chronic mouse models of asthma, suggesting a potential role of GSPE as a therapeutic agent for asthma.

The role of nitrosative stress in the pathogenesis of unexplained chronic cough with cough hypersensitivity.

BACKGROUND: Unexplained chronic cough is a common condition without specific causes. A hyperreactivity of the cough reflex has been suggested as a mechanism for inducing chronic cough. We hypothesized that nitrosative stress in the upper airway might play a role in cough hypersensitivity by causing neurochemical abnormalities. METHODS: Fifty-one patients with unexplained chronic cough and 27 controls were enrolled. A capsaicin cough provocation test was performed to determine cough sensitivity. Nitrosative stress in the upper airway was assessed by quantifying 3-nitrotyrosine (3-NT) immunostaining in nasal epithelial cells (NECs) and measuring nasal nitric oxide (nNO). The effect of NO on airway epithelium was investigated by measuring the levels of substance P (SP) in nasal lavage fluid and evaluating SP expression in airway epithelial cells. RESULTS: Based on the results of the capsaicin test, patients were divided into two groups: a cough hypersensitivity (CHS) group and a normal cough sensitivity (NCS) group. The levels of 3-NT immunoreactivity in NECs were significantly higher in CHS (49 ± 2.9%) than in NCS (27 ± 3.3%) and controls (12 ± 1.6%), a pattern that was also reflected in the values of nNO (350 ± 43, 215 ± 23, and 138 ± 23 ppb in CHS, NCS, and controls, respectively). SP concentration was also elevated in nasal lavage fluids from CHS (746 ± 28 pg/mL) compared with that from NCS (624 ± 40 pg/mL) and controls (526 ± 41 pg/mL). SP expression in airway epithelial cells was greatly enhanced by exposure to NO donor, which was attenuated by pretreatment with either NO scavenger or NO synthase inhibitor. CONCLUSION: Increased nitrosative stress in the upper airway may play a role in the pathogenesis of unexplained chronic cough with CHS through enhanced secretion of SP.

Chlamydophila pneumoniae inhibits corticosteroid-induced suppression of metalloproteinase-9 and tissue inhibitor metalloproteinase-1 secretion by human peripheral blood mononuclear cells.

Chlamydophila pneumoniae infection has been suggested to be associated with severe asthma characterized by persistent airway limitation, which may be related to airway remodelling. We investigated whether C. pneumoniae infection affected the secretion of metalloproteinase-9 (MMP9) and tissue inhibitor metalloproteinase-1 (TIMP1), and altered the responsiveness of inflammatory cells to corticosteroids. Human peripheral blood mononuclear cells (PBMCs) were cultured in vitro in the presence or absence of C. pneumoniae. Secretion of both MMP9 and TIMP1 was strongly suppressed by dexamethasone treatment in uninfected cells. MMP9 secretion was also significantly inhibited by dexamethasone in C. pneumoniae-infected cells, but TIMP1 secretion was not; hence the MMP9 to TIMP1 ratio decreased. Interestingly, expression of human glucocorticoid receptor ß, which is believed to confer resistance to corticosteroids, was enhanced by dexamethasone treatment in C. pneumoniae-infected PBMCs. We conclude that C. pneumoniae infection may promote airway remodelling by decreasing the ratio of MMP9 to TIMP1 secreted by inflammatory cells, and by altering cellular responsiveness to corticosteroids.

Hyperoxidized peroxiredoxins in peripheral blood mononuclear cells of asthma patients is associated with asthma severity.

AIMS: Oxidative stress is involved in the pathogenesis of asthma, and peroxiredoxins (PRDX) may be critical in controlling intracellular oxidative stress. The aim of this study was to evaluate expressions of PRDX and their hyperoxidized forms in asthmatic individuals. MAIN METHODS: The levels of expression of PRDX1, PRDX2, PRDX3, and PRDX6 and their hyperoxidized forms (PRDX-SO(3)) were measured in PBMCs from asthma patients and control subjects. In addition, cells from these subjects were treated with hydrogen peroxide (H(2)O(2)) and their intracellular concentrations of reactive oxygen species (ROS) were measured. KEY FINDINGS: The ratios of hyperoxidized to total PRDX (PRDX-SO(3/)PRDX) in PBMCs were significantly higher in asthma patients than in normal subjects and were correlated with disease severity, with the highest ratio seen in patients with severe asthma. Furthermore, H(2)O(2) treatment of PBMCs, particularly lymphocytes, increased intracellular ROS concentrations with greater and more persistent increases observed in cells from asthmatic than from control subjects. SIGNIFICANCE: Hyperoxidation of PRDX may serve as a biomarker of asthma severity and may predict enhanced susceptibility to oxidative stress load in PBMCs of asthmatics.

Smoking, longer disease duration and absence of rhinosinusitis are related to fixed airway obstruction in Koreans with severe asthma: findings from the COREA study.

BACKGROUND: The clinical manifestations of severe asthma are heterogeneous. Some individuals with severe asthma develop irreversible fixed airway obstruction, which is associated with poor outcomes. We therefore investigated the factors associated with fixed airway obstruction in Korean patients with severe asthma. METHODS: Severe asthma patients from a Korean adult asthma cohort were divided into two groups according to the results of serial pulmonary function tests. One group had fixed airway obstruction (FAO) [forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio < 0.7, n = 119] and the other had reversible airway obstruction (RAO) [FEV1/FVC ratio ≥ 0.7, n = 116]. Clinical and demographic parameters were compared between the two groups. RESULTS: Multivariate analysis showed that longer duration of disease, greater amount of cigarette smoking and absence of rhinosinusitis were significantly related to the development of FAO in severe asthmatics. Other parameters, including atopic status, pattern of airway inflammatory cells in induced sputum, and frequency of asthma exacerbations did not differ between the FAO and RAO groups. CONCLUSION: Severe asthma patients with longer disease duration and the absence of rhinosinusitis are more likely to develop FAO. This study also demonstrates the importance of quitting smoking in order to prevent irreversible airway obstruction. Further investigation is required to determine the mechanism by which these factors can modify the disease course in Korean patients with severe asthma.

Central pontine myelinolysis in a patient with acute lymphoblastic leukemia after hematopoietic stem cell transplantation: a case report.

We describe a 37-yr-old man who developed central pontine myelinolysis (CPM) after allogeneic hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia. After HSCT, desquamation developed on the whole body accompanied by hyperbilirubinemia. The liver biopsy of the patient indicated graft-versus-host disease- related liver disease, and the dose of methylprednisolone was increased. Then, the patient developed altered mentality with eye ball deviation to the left, for which electroencephalogram and magnetic resonance imaging (MRI) scans were done. Brain MRI scan demonstrated the imaging findings consistent with central pontine myelinolysis and extrapontine myelinolysis. He did not have any hyponatremia episode during hospitalization prior to the MRI scan. To the best of our knowledge, presentation of CPM after allogeneic HSCT is extremely rare in cases where patients have not exhibited any episodes of significant hyponatremia. We report a rare case in which hepatic dysfunction due to graft-versus-host disease has a strong association with CPM after HSCT.