Role of diesel exhaust particle-induced cellular senescence in the development of asthma in young and old mice.

BACKGROUND: Although it has been reported that cellular senescence is important in the pathogenesis of asthma, the differential effects of diesel exhaust particle (DEP)-induced cellular senescence on the development of asthma according to age have not been thoroughly studied. METHODS: We first confirmed that DEP induced cellular senescence in mouse lungs, and then that DEP-induced cellular senescence followed by intranasal instillation of a low-dose house dust mite (HDM) allergen resulted in murine asthma. Second, we examined age-dependent differential effects using 6-week-old (young) and 18-month-old mice (old), and tested whether the mammalian target of the rapamycin (mTOR) pathway plays an important role in this process. Finally, we performed in vitro experiments using human bronchial epithelial cells (HBEC) originating from young and elderly adults to identify the underlying mechanisms. RESULTS: DEP induced cellular senescence in the airway epithelial cells of young and old mice characterized by increased senescence-associated beta-galactosidase, S100A8/9, and high mobility group box 1 (HMGB1) expressions. DEP-induced cellular senescence with subsequent exposure to a low-dose HDM allergen resulted in asthma in young and old mice. Rapamycin (mTOR pathway inhibitor) administration before DEP instillation significantly attenuated these asthmatic features. In addition, after treatment with a low-dose HDM allergen, S100A9 and HMGB1 over-expressed HBEC originating from young and elderly adults greatly activated co-cultured monocyte-derived dendritic cells (DCs). CONCLUSIONS: This study showed that DEP-induced senescence made both young and old mice susceptible to allergic sensitization and resultant asthma development by enhancing DC activation. Public health efforts to reduce DEP exposure are warranted.

Inhibition of glutaminase 1 activity reverses airway hyperresponsiveness and decreases IL-1ß+ M1s and IL-17 producing ILC3s in high-fat diet-fed obese mice.

In obesity, disturbed glutamine metabolism contributes to enhanced inflammation by inducing alterations in immune cells. As macrophages and innate lymphoid cells (ILCs) are known to be involved in the pathogenesis of obesity-related asthma, we tested our hypothesis that altered glutamine metabolism may link obesity to airway hyperresponsivenss (AHR), a cardinal feature of asthma, focusing on these innate immune cells. Four-week-old male C57BL/6 mice were fed a high-fat diet (HFD) for 13 wk in the presence or absence of BPTES [Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide, a selective inhibitor of glutaminase 1 which converts glutamine to glutamate] and their blood, lung, and adipose tissues were analyzed. We then conducted in vitro experiments using bone marrow-derived macrophages (BMDMs) and mouse alveolar macrophage cell line. Furthermore, we investigated plasma glutamine and glutamate levels in obese and nonobese asthmatics. BPTES treatment prevented HFD-induced AHR and significantly decreased IL-1ß+ classically activated macrophages (M1s) and type 3 ILCs (ILC3s) which increased in the lungs of HFD-fed obese mice. In in vitro experiments, BPTES treatment or glutamine supplement significantly reduced the proportion of IL-1ß+NLRP3+ M1s in lipopolysaccharide-stimulated BMDMs and mouse alveolar macrophage cell line. BPTES treatment also significantly reduced the IL-17 producing ILC3s differentiated from ILCs in naïve mouse lung. In addition, plasma glutamate/glutamine ratios were significantly higher in obese asthmatics compared to nonobese asthmatics. Inhibition of glutaminolysis reverses AHR in HFD-induced obese mice and decreases IL-1ß + NLRP3+ M1s and IL-17 producing ILC3s, which suggests altered glutamine metabolism may have a role in the pathogenesis of obesity-related AHR.

Rapamycin Restores Different Patterns of Cytokine Expression to Dexamethasone Treatment on CD14++CD16+ Monocytes from Steroid-Resistant Asthma Patients.

OBJECTIVE: We aimed to investigate the differences in interleukin (IL)-10, IL-1ß, IL-6, and tumor necrosis factor (TNF)-α expression in lipopolysaccharide (LPS)-stimulated CD14++CD16+ monocytes obtained from asthmatics after dexamethasone or dexamethasone plus rapamycin treatments between clinical steroid responders (R) and non-responders (NR). METHODS: Cytokine expressions in LPS-stimulated CD14++CD16+ p-mammalian target of rapamycin (mTOR) monocytes from R and NR were determined using flow cytometry. RESULTS: IL-10high CD14++CD16+ p-mTOR population following LPS stimulation increased in the R group although decreased in the NR group with dexamethasone treatment. IL-1ßhigh population decreased in the R group although increased in the NR group. Rapamycin treatment after LPS and dexamethasone resulted in a significant increase in the IL-10high population and a significant decrease in the IL-1ßhigh population in the NR group. CONCLUSION: Dexamethasone treatment resulted in different patterns of change in cytokine expressions in LPS-stimulated CD14++CD16+ p-mTOR monocytes between the R and NR. mTOR inhibition can restore steroid responsiveness involving IL-10 and IL-1ß in CD14++CD16+ p-mTOR monocytes.

IL-23 plays a significant role in the augmentation of particulate matter-mediated allergic airway inflammation.

It has been recently that particulate matter (PM) exposure increases the risk and exacerbation of allergic asthma. However, the underlying mechanisms and factors associated with increased allergic responses remain elusive. We evaluated IL-23 and IL-23R (receptor) expression, as well as changes in the asthmatic phenotype in mice administered PM and a low dose of house dust mite (HDM). Next, changes in the phenotype and immune responses were evaluated after intranasal administration of anti-IL-23 antibody during co-exposure to PM and low-dose HDM. We also performed in vitro experiments to investigate the effect of IL-23. IL-23 expression was significantly increased in Epcam+CD45- and CD11c+ cells, while that of IL-23R was increased in Epcam+CD45- cells only in mice administered PM and low-dose HDM. Administration of anti-IL-23 antibody led to decreased airway hyperresponsiveness, eosinophils, and activation of dendritic cells, reduced populations of Th2 Th17, ILC2, the level of IL-33 and granulocyte-macrophage colony-stimulating factor (GM-CSF). Inhibition of IL-23 in PM and low-dose HDM stimulated airway epithelial cell line resulted in decreased IL-33, GM-CSF and affected ILC2 and the activation of BMDCs. PM augmented the phenotypes and immunologic responses of asthma even at low doses of HDM. Interestingly, IL-23 affected immunological changes in airway epithelial cells.

Treatment patterns and cost of exacerbations in patients with chronic obstructive pulmonary disease using multiple inhaler triple therapy in South Korea.

BACKGROUND: Multiple inhaler triple therapy (MITT), comprising inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA), has been used as an escalation treatment for patients with chronic obstructive pulmonary disease (COPD). However, real-world use of MITT has not been investigated in Asia, including South Korea. This study reports baseline characteristics of patients with COPD initiated on MITT in South Korea, and their treatment patterns. Healthcare resource utilization (HRU) and costs associated with COPD exacerbations following MITT initiation were also assessed. METHODS: This was a retrospective cohort study using the South Korea National Health Insurance database (2014-2018). Included patients were ≥ 40 years, had a COPD diagnosis, were newly initiated on MITT and had ≥ 12 months' data both before (baseline) and after index date (the first day with overlapping supply of all MITT components). Treatment immediately before initiation and immediately following discontinuation of MITT were identified, and proportion of days covered (PDC) by MITT was calculated. HRU and costs (per person per year [PPPY]) associated with exacerbations were identified following MITT initiation; costs were calculated using the average 2020 exchange rate (0.0008 USD/KRW). RESULTS: Among 37,400 patients, the mean age was 69 (SD 10) years and 73% were males; 56% had ≥ 1 COPD exacerbation during the baseline period, with a mean of 2 (SD 5) events/year. ICS/LABA was the most frequent regimen prescribed immediately before initiation (37%) and immediately following discontinuation (41% of 34,264 patients) of MITT. At 3, 6, and 12 months from treatment initiation, mean PDC was 81%, 63% and 49%, respectively; median treatment duration was 102 days. The mean (95% confidence interval [CI]) number of total visits for severe COPD exacerbations was 0.77 PPPY (0.75-0.78); mean PPPY total healthcare costs were 2093 USD. CONCLUSIONS: Patients with COPD in South Korea experienced frequent exacerbations prior to MITT, and PDC by MITT was low. Patients may benefit from early optimization of COPD therapy, and greater emphasis on adherence to inhaled COPD therapy. Severe exacerbations were found to incur substantial costs; treatment alternatives that can reduce the rate of severe exacerbations are likely to minimize healthcare costs.

Characteristics of Specialist-Diagnosed Asthma-COPD Overlap in Severe Asthma: Observations from the Korean Severe Asthma Registry (KoSAR).

BACKGROUND: While the clinical characteristics and outcomes of asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) have been frequently compared with those of COPD or asthma, the prevalence and features of ACO in patients with severe asthma are unclear. OBJECTIVES: Evaluation of the prevalence and clinical features of ACO using the Korean severe asthma registry. METHODS: At the time of registration, ACO was determined in patients with severe asthma by attending specialists. Patients were classified into ACO and non-ACO groups, and the demographic and clinical characteristics of these two groups were compared. RESULTS: Of 482 patients with severe asthma, 23.7% had ACO. Patients in the ACO group were more likely to be male (P < .001), older (P < .001), and ex- or current smokers (P < .001) compared with those in the non-ACO group. Patients in the ACO group had lower mean forced expiratory volume in 1 second (P < .001) and blood eosinophil percentage (P = .006), but higher blood neutrophil percentage (P = .027) than those in the non-ACO group. The ACO group used more inhaled long-acting muscarinic antagonist (P < .001), methylxanthine (P = .001), or sustained systemic corticosteroid (P = .002). In addition, unscheduled emergency department visits due to exacerbation were more frequent in the ACO group (P = .006). CONCLUSION: Among patients with severe asthma, those with ACO were older, predominantly male, and were more likely to have a smoking history than those with asthma only. Patients with ACO used more systemic corticosteroid and had more frequent exacerbations related to emergency department visits than those with severe asthma only.

Incidence rates of severe cutaneous adverse reactions due to antiseizure medication: A nationwide study using health claims data in Korea.

OBJECTIVE: Antiseizure medications (ASMs) can rarely result in severe, sometimes fatal, cutaneous adverse reactions. To date, few studies have reported on the incidence rates (IRs) of severe cutaneous adverse reactions (SCARs) due to ASM use. This study aimed to determine the IRs of SCAR resulting from the use of seven commonly prescribed ASMs, carbamazepine (CBZ), phenytoin (PHT), oxcarbazepine (OXC), lamotrigine (LMT), zonisamide (ZNS), levetiracetam (LVT), and topiramate (TPM), and to compare the associated risks among the drugs. METHODS: Using a nationwide health claims database, we selected all the patients prescribed with one of the target ASMs. We defined a SCAR case as the first hospitalization with one of three specific codes provided by the International Classification of Diseases, 10th revision (L511, L512, and L27). We then calculated the IR of SCARs according to each target ASM. RESULTS: The IR of SCARs for each ASM was as follows: 870/1 000 000 person-years (PYs) for CBZ, 5750/1 000 000 PYs for PHT, 1490/1 000 000 PYs for OXC, 3860/1 000 000 PYs for LMT, 1540/1 000 000 PYs for ZNS, 830/1 000 000 PYs for LVT, and 400/1 000 000 PYs for TPM. Concomitant use of antibiotics and nonsteroidal anti-inflammatory drugs significantly increased the risk of SCARs with OXC, LVT, or TPM use. Comorbid skin disease was associated with a significantly higher IR of SCARs from CBZ, PHT, OXC, LMT, or LVT use. SIGNIFICANCE: This is the first study in Asia to determine the IRs of SCARs for various ASMs and compare the rates across drugs using a large dataset. The results from this study should help clinicians select safer ASMs in practice.

Discontinuation of inhaled corticosteroids in patients with controlled asthma: The DISCO (Discontinuation of Inhaled Steroid in Controlled asthmatics Over 6 months) study.

BACKGROUND: Although inhaled corticosteroids (ICSs) are the recommended first-line therapy for asthma, determining whether to continue or discontinue ICS treatment in patients with mild asthma remains challenging for clinicians. Several studies have revealed that patients with mild-persistent asthma maintained a well-controlled state after ICS withdrawal. However, the long-term outcomes of ICS withdrawal have not yet been determined. OBJECTIVE: To determine the possible clinical outcomes of the discontinuation of ICS in patients with well-controlled mild asthma. METHODS: We investigated the clinical outcomes of discontinuing ICSs in patients with well-controlled mild asthma and compared the time to loss of control (LOC) between patients who stopped ICS treatment (ICS withdrawal group, IWG) and those who continued treatment for 3 years (continuous ICS group, CIG). RESULTS: A significant difference in the time to LOC was observed between the IWG and CIG (hazard ratio, 2.56; 95% confidence interval, 1.52-4.33; P < .001). Increasing fractional exhaled nitric oxide levels (P = 0.008) and sputum eosinophil counts (%) (P = 0.015) revealed a weak but significant association with LOC risk in the CIG. The sputum eosinophil counts (P = 0.039) and serum total immunoglobulin E levels (P = 0.014) were significantly higher in the LOC group than in the non-LOC group of the CIG. CONCLUSION: Our results suggest that the maintenance of ICS treatment may help keep patients' asthma under control. Furthermore, patients with LOC had significantly higher sputum eosinophil counts in the CIG than those in the non-LOC group. Therefore, continuous ICS use by patients with mild, well-controlled asthma could be associated with good clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: KCT0002234.

Cough persistence in adults with chronic cough: A 4-year retrospective cohort study.

BACKGROUND: There is very limited evidence regarding long-term prognosis of chronic cough. We examined longitudinal outcomes among patients with chronic cough, and explored predictors of cough persistence. METHODS: A retrospective cohort was constructed of adults who had newly visited a specialist cough clinic in 2012-2013. All had undergone systematic investigation for chronic cough. The Hull Airway Reflux Questionnaire (HARQ) was administered to assess reflux cough symptoms. A follow-up survey was conducted in 2016-2017 to assess cough persistence. RESULTS: From 418 candidates, 323 participated in the follow-up study; main analyses focused on patients with chronic persistent cough (n = 64; 19.8%) and remitted cough (n = 193; 59.8%). Compared with remitted cough group, chronic persistent cough group had more family history of chronic cough (17.2% vs. 4.7%, p = 0.001) and cold air-sensitive cough (62.5% vs. 44.6%, p = 0.013). The total HARQ score did not differ; however, two items (cough with eating and cough with certain foods) scored significantly higher in chronic persistent cough. In multivariate analyses, a family history of chronic cough (adjusted odds ratio 4.27 [95% confidence interval 1.35-9.89]), cold air-sensitive cough (2.01 [1.09-3.73]), and cough with eating (1.22 [1.02-1.45]) were associated with chronic persistent cough at 4 years. CONCLUSIONS: Cough persists in about 20% of patients after 4 years following systematic assessment and treatments. Several cough characteristics, such as family history, cold air-sensitivity, or reflux cough, may be associated with cough persistence. Larger cohort studies are warranted to further understand long-term prognosis and confirm predictors of persistence in patients with chronic cough.

Gene expression changes in lymphoblastoid cell lines and primary B cells by dexamethasone.

BACKGROUND: Human Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) have been thought to be a useful model system for pharmacogenomics studies. The purpose of this study was to determine the effect of Epstein-Barr virus transformation on gene expression changes by dexamethasone (Dex) in LCLs and primary B cells (PBCs) derived from the same individuals. PATIENTS AND METHODS: We prepared LCLs and purified PBCs from the same six male donors participating in the Childhood Asthma Management Program clinical trial, and compared mRNA profiles after 6 h incubation with Dex (10 mol/l) or sham buffer. We assessed differential expression and put the list of differentially expressed genes into the web interface of ConsensusPathDB to find the pathway-level interpretation of our genes specified. As a supplementary analysis, we looked at the expression of the Dex-regulated (inducing or repressing) genes in treatment-naive PBCs and LCLs (pre-Dex treatment) from the GSE30916 dataset. RESULTS: By hierarchical clustering, we found clustering of probes by cell types but not by individuals irrespective of Dex treatment. We observed that the Dex-regulated genes significantly overlapped in PBCs and LCLs. In addition, the expression of these genes showed significant correlations between treatment-naive PBCs and LCLs. Common genes showing significantly decreased expressions by the Dex treatment in both cells were enriched in immune responses and proinflammatory signaling pathways. CONCLUSION: Taken together, these results suggest the uses of LCLs are representative of the primary biologic effects of corticosteroids treatment.

Different upper airway microbiome and their functional genes associated with asthma in young adults and elderly individuals.

BACKGROUND: Microbes in the airway have been shown to be associated with the pathogenesis of asthma. The upper airway microbiome influences the dysbiosis of the lower airway microbiome. However, to date, the influence of upper airway microbiome for adult and elderly asthma has not been fully elucidated. Here, the metagenome of upper airway microbiome of young adults and elderly was analyzed to identify their association with adult asthma. METHODS: Nasopharyngeal swabs were collected from young adult and elderly asthma patients and non-asthmatic subjects. The compositions and functional genes of airway microbiome were analyzed by high-throughput sequencing. RESULTS: The composition of microbiota differed between young adult and elderly, and it was different between asthmatics and non-asthmatics in each age group. Different bacteria were related to FEV1% predicted in each age group. Genes related to lysine degradation, N-glycan biosynthesis, caprolactam degradation, and PPAR signaling pathway, which could be related to the reduction in inflammation and degradation of air pollutants, were higher in non-asthmatics. Genes related to pentose phosphate pathway, lipopolysaccharide biosynthesis, flagella assembly, and bacterial chemotaxis-which may all be related to increased inflammation and colonization of pathogenic bacteria-were higher in young adult asthmatic patients. However, the functional genes of airway microbiome in elderly patients were not significantly different according to asthma morbidity. CONCLUSIONS: These results suggest that the composition and function of upper airway microbiome could influence asthma pathogenesis, and the microbiome could play various roles depending on the age group.

Pharmacogenomics in asthma therapy: where are we and where do we go?

The response to drug treatment in asthma is a complex trait and is markedly variable even in patients with apparently similar clinical features. Pharmaco-genomics, which is the study of variations of human genome characteristics as related to drug response, can play a role in asthma therapy. Both a traditional candidate-gene approach to conducting genetic association studies and genome-wide association studies have provided an increasing list of genes and variants associated with the three major classes of asthma medications: ß2-agonists, inhaled corticosteroids, and leukotriene modifiers. Moreover, a recent integrative, systems-level approach has offered a promising opportunity to identify important pharmacogenomics loci in asthma treatment. However, we are still a long way away from making this discipline directly relevant to patients. The combination of network modeling, functional validation, and integrative omics technologies will likely be needed to move asthma pharmacogenomics closer to clinical relevance.

Oral Allergy Syndrome in Birch Pollen-Sensitized Patients from a Korean University Hospital.

BACKGROUND: Oral allergy syndrome (OAS) is a type of allergic reaction that mainly occurs on oral contact with raw fruit, vegetables, or nuts. The most common type of OAS is birch pollen-related food allergy. Although OAS is a common food allergy in adults, only few epidemiologic studies have been reported in Korea. Here we investigate the prevalence and triggers of birch pollen-related food allergy. METHODS: We conducted a retrospective chart review of 1,427 patients who underwent a skin prick test for inhalant allergens at the Asthma and Allergy Clinic in Seoul National University Bundang Hospital from January 2011 to December 2016. RESULTS: Of 1,427 patients, 125 (8.7%) were sensitized to birch pollen. Among them, 20.0% developed OAS, which was the most common food allergy (96.2%). The prevalence of OAS was higher in females, and was 18.2% in birch pollen-sensitized allergic rhinoconjunctivitis patients. Further, 72.0% OAS patients had rhinoconjunctivitis, 20.0% had asthma, and 12.0% had chronic urticaria. Apple (68.0%), peach (56.0%), nuts (36.0%), kiwi (20.0%), persimmon (20.0%), plum (16.0%), and cherry (16.0%) were frequent triggers; however, Chinese yam, kudzu vine, bellflower root, codonopsis, and ginseng were also revealed as triggers. Patients (60.0%) showed OAS with ≥ 3 foods at the same time. Only 3 patients showed mono-sensitivity to birch pollen, while others were multi-sensitized to trees, grasses, weed, or house dust mite allergens. CONCLUSION: OAS was the most common food allergy in birch pollen-sensitized patients. This study revealed the unique triggers of OAS in Korea in addition to well-known triggers.

Diagnostic accuracy of fractional exhaled nitric oxide measurement in predicting cough-variant asthma and eosinophilic bronchitis in adults with chronic cough: A systematic review and meta-analysis.

BACKGROUND: Individual studies have suggested the utility of fractional exhaled nitric oxide (Feno) measurement in detecting cough-variant asthma (CVA) and eosinophilic bronchitis (EB) in patients with chronic cough. OBJECTIVE: We sought to obtain summary estimates of diagnostic test accuracy of Feno measurement in predicting CVA, EB, or both in adults with chronic cough. METHODS: Electronic databases were searched for studies published until January 2016, without language restriction. Cross-sectional studies that reported the diagnostic accuracy of Feno measurement for detecting CVA or EB were included. Risk of bias was assessed with Quality Assessment of Diagnostic Accuracy Studies 2. Random effects meta-analyses were performed to obtain summary estimates of the diagnostic accuracy of Feno measurement. RESULTS: A total of 15 studies involving 2187 adults with chronic cough were identified. Feno measurement had a moderate diagnostic accuracy in predicting CVA in patients with chronic cough, showing the summary area under the curve to be 0.87 (95% CI, 0.83-0.89). Specificity was higher and more consistent than sensitivity (0.85 [95% CI, 0.81-0.88] and 0.72 [95% CI, 0.61-0.81], respectively). However, in the nonasthmatic population with chronic cough, the diagnostic accuracy to predict EB was found to be relatively lower (summary area under the curve, 0.81 [95% CI, 0.77-0.84]), and specificity was inconsistent. CONCLUSIONS: The present meta-analyses indicated the diagnostic potential of Feno measurement as a rule-in test for detecting CVA in adult patients with chronic cough. However, Feno measurement may not be useful to predict EB in nonasthmatic subjects with chronic cough. These findings warrant further studies to validate the roles of Feno measurement in clinical practice of patients with chronic cough.

IL-23 secreted by bronchial epithelial cells contributes to allergic sensitization in asthma model: role of IL-23 secreted by bronchial epithelial cells.

IL-23 has been postulated to be a critical mediator contributing to various inflammatory diseases. Dermatophagoides pteronyssinus (Der p) is one of the most common inhalant allergens. However, the role of IL-23 in Der p-induced mouse asthma model is not well understood, particularly with regard to the development of allergic sensitization in the airways. The objective of this study was to evaluate roles of IL-23 in Der p sensitization and asthma development. BALB/c mice were repeatedly administered Der p intranasally to develop Der p allergic sensitization and asthma. After Der p local administration, changes in IL-23 expression were examined in lung tissues and primary epithelial cells. Anti-IL-23p19 antibody was given during the Der p sensitization period, and its effects were examined. Effects of anti-IL-23p19 antibody at bronchial epithelial levels were also examined in vitro. The expression of IL-23 at bronchial epithelial layers was increased after Der p local administration in mouse. In Der p-induced mouse models, anti-IL-23p19 antibody treatment during allergen sensitization significantly diminished Der p allergic sensitization and several features of allergic asthma including the production of Th2 cytokines and the population of type 2 innate lymphoid cells in lungs. The activation of dendritic cells in lung-draining lymph nodes was also reduced by anti-IL-23 treatment. In murine lung alveolar type II-like epithelial cell line (MLE-12) cells, IL-23 blockade prevented cytokine responses to Der p stimulation, such as IL-1α, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-33, and also bone marrow-derived dendritic cell activation. In conclusion, IL-23 is another important bronchial epithelial cell-driven cytokine which may contribute to the development of house dust mite allergic sensitization and asthma.

Stratified premedication strategy for the prevention of contrast media hypersensitivity in high-risk patients.

BACKGROUND: Although the severity of hypersensitivity reactions to iodinated contrast media varies, it is well correlated with the severity of recurrent reactions; however, prophylaxis protocols are not severity-stratified. OBJECTIVE: To assess the outcomes of tailored prophylaxis according to the severity of hypersensitivity reactions to iodinated contrast media. METHODS: Our premedication protocols were stratified based on the severity of previous reactions: (1) 4 mg of chlorpheniramine for mild reactions, (2) adding 40 mg of methylprednisolone for moderate reactions, and (3) adding multiple doses of 40 mg of methylprednisolone for severe index reactions. Cases of reexposure in patients with a history of hypersensitivity reactions were routinely monitored and mandatorily recorded. RESULTS: Among a total of 850 patients who underwent enhanced computed tomography after severity-tailored prophylaxis, breakthrough reactions occurred in 17.1%, but most breakthrough reactions (89.0%) were mild and did not require medical treatment. Additional corticosteroid use did not reduce the breakthrough reaction rate in cases with a mild index reaction (16.8% vs 17.2%, P = .70). However, underpremedication with a single dose of corticosteroid revealed significantly higher rates of breakthrough reaction than did double doses of corticosteroid in cases with a severe index reaction (55.6% vs 17.4%, P = .02). Changing the iodinated contrast media resulted in an additional reduction of the breakthrough reaction rate overall (14.9% vs 32.1%, P = .001). CONCLUSION: In a total severity-based stratified prophylaxis regimens and changing iodinated contrast media can be considered in patients with a history of previous hypersensitivity reaction to iodinated contrast media to reduce the risk of breakthrough reactions.

Bronchodilator response following methacholine-induced bronchoconstriction predicts acute asthma exacerbations.

Methacholine bronchial provocation test provides the concentration of methacholine causing a 20% decrease in forced expiratory volume in 1 s (FEV1) from baseline (PC20). The dose-response slope (DRS), and other continuous indices of responsiveness (CIR; the percentage decline from the post-diluent baseline FEV1 after the last dose of methacholine), and per cent recovery index (PRI; the percentage increase from the maximally reduced FEV1 after bronchodilator inhalation) are alternative measures. The clinical relevance of these indices in predicting acute asthma exacerbations has not been fully evaluated.In two prospective cohorts of childhood and elderly asthmatics, baseline PC20, DRS, CIR and PRI were measured and evaluated as predictors of acute asthma exacerbations.We found that PRI was significantly related to the presence of asthma exacerbations during the first year of follow-up in both cohorts of childhood (p=0.025) and elderly asthmatics (p=0.003). In addition, PRI showed a significant association with the total number of steroid bursts during 4.3 years of follow-up in the cohort of childhood asthmatics (p=0.04).We demonstrated that PRI, an index of reversibility following methacholine-induced bronchoconstriction, was a good clinical predictor of acute exacerbations of asthma in both childhood and elderly asthmatics.

TNF-α enhance Th2 and Th17 immune responses regulating by IL23 during sensitization in asthma model.

BACKGROUND: TNF-α has been postulated to be a critical mediator contributing to airway inflammation. The purpose of this study was to evaluate the role of TNF-α in the induction of Th17 and Th2 cells related to asthma pathogenesis. OBJECTIVE: To evaluate detailed mechanisms for the modulation of IL-23 by TNF-α in sensitization period. METHODS: During sensitization period, 10µg of rat anti-mouse TNF-α mAb was intravenously administrated one hour before the application of OVA and 0.1µg of LPS. To see the relation between TNF-α and associated effectors cytokine, we replenished TNF-α KO mice with IL-23 during sensitization period. To assess cellular resources, CD11c+ cells isolated from lung tissue after sensitization were treated with anti-TNF-α Ab. RESULTS: Treatment of anti-TNF-α mAb during sensitization period significantly reduced airway eosinophilia, serum OVA-specific IgE levels and methacholine AHR compared to isotype Ab. Anti-TNF-α mAb treated mice showed significant reduction in the levels of IL-23 after sensitization in bronchoalveolar lavage fluid (BALF) as well as IL-17A, IL-4 levels in BALF after challenge compared with isotype Ab treated mice. Supplementation of IL-23 in TNF-α KO mice resulted in complete restoration of eosinophilic airway inflammation, AHR, and IL-17A and IL-4 expression in CD4+ T cells. Anti-TNF-α mAb treatment after sensitization significantly diminished the population of IL-23p19-secreting CD11c+ cells in lung. CONCLUSION: TNF-α plays an important role in the development of airway inflammation by enhancing IL-23/Th17 and Th2 immune responses.

Outcomes of corticosteroid prophylaxis for hypersensitivity reactions to low osmolar contrast media in high-risk patients.

BACKGROUND: Corticosteroid prophylaxis has been widely adopted for the prevention of acute allergic-like reactions to iodinated contrast media, but its use is still controversial because there is no strong evidence supporting its efficacy before administration of nonionic low osmolar contrast media (LOCM). OBJECTIVE: To assess the outcomes of premedication in patients with previous acute allergic-like reactions to LOCM in clinical practice. METHODS: A retrospective study was performed on 322 high-risk patients who were reexposed to LOCM after premedication composed of antihistamines and/or systemic corticosteroids because of a previous history of acute allergic-like reactions to LOCM. RESULTS: After premedication, 275 patients (85.4%) did not experience any reaction, but 47 patients (14.6%) still experienced a breakthrough reaction. The premedication rate and amount of corticosteroid administered were significantly higher in the nonrecurrence group than in the recurrence group (P = .04 and P = .04, respectively), and a linear trend was observed in the use of corticosteroid premedication and the efficacy of prevention (P for trend = .02). Multivariate binary logistic regression revealed that corticosteroid premedication was effective in preventing recurrence (odds ratio, 0.284; 95% confidence interval, 0.103-0.784). Nonetheless, despite corticosteroid premedication, 3.4% of high-risk patients still experienced moderate to severe reactions, and 14.3% of patients with a severe index reaction again had a severe reaction. CONCLUSION: Premedication with corticosteroids seems to be helpful in reducing the overall rate of recurrence of acute allergic-like reactions to LOCM in high-risk patients, but patients with severe index reactions are still at risk of developing severe reactions despite corticosteroid premedication.