Increased risk of venous and arterial thromboembolism in patients with colorectal cancer receiving cetuximab-based combination chemotherapy: A population-based study in Korea.

INTRODUCTION: Limited data exist on the risk of venous and arterial thromboembolisms (VTE and ATE) in patients receiving cetuximab plus chemotherapy. We aimed to determine the thromboembolic risk of patients with recurrent/metastatic colorectal cancer (CRC) treated with cetuximab plus chemotherapy compared to chemotherapy alone. METHODS: This population-based study used nationwide claims data from the Health Insurance Review and Assessment Service of South Korea from 2013 to 2020. Patients with recurrent/metastatic CRC treated with first-line oxaliplatin- or irinotecan-based doublets with or without cetuximab and no secondary prevention for VTE and ATE were included. Primary outcomes were the occurrence of any thromboembolic events, VTE, and ATE, which were determined using the cumulative incidence method incorporating death as a competing event. RESULTS: We identified 19,723 patients (cetuximab plus chemotherapy, N = 7630; chemotherapy alone, N = 12,093). The cumulative incidence of any thromboembolic events in patients with cetuximab plus chemotherapy was significantly higher than in those receiving chemotherapy alone (6-month, 5.62 % vs. 3.58 %, P < 0.0001). The rates of VTE (6-month, 5.11 % vs. 3.28 %, P < 0.0001) and ATE (6-month, 0.53 % vs. 0.32 %, P = 0.0218) were also higher in patients receiving cetuximab plus chemotherapy. In multivariable analysis, cetuximab plus chemotherapy was independently associated with developing any thromboembolic events (hazard ratio [HR], 1.63; 95 % confidence interval [CI], 1.42-1.87), VTE (HR, 1.62; 95 % CI, 1.40-1.87), and ATE (HR, 1.77; 95 % CI, 1.16-2.71). CONCLUSIONS: Cetuximab with irinotecan- or oxaliplatin-based doublet chemotherapy was associated with an increased risk of any thromboembolic events, VTE, and ATE; further studies are warranted to examine the underlying mechanisms.

Incidence of Pregnancy-Associated Venous Thromboembolism: Second Nationwide Study.

BACKGROUND: Pregnancy is a transient risk factor for venous thromboembolism (VTE). This second nationwide study aimed to inspect trend changes in the incidence rate of pregnancy-associated VTE (PA-VTE) during the study period (2014-2018) compared with that reported in a previous study (2006-2010). METHODS: Using the Korean Health Insurance Review and Assessment Service database, we retrospectively identified all PA-VTE events using both diagnostic and medication codes. RESULTS: Of the 124,228 VTE events, 510 (0.4%) cases of PA-VTE were identified in 499 women (median age: 34 years; range: 20-49 years). The incidence rate of PA-VTE/10,000 deliveries (PA-VTE/104D) in this second study (2.62) was 3.2 times higher than that in the first study (0.82). In the second study, the PA-VTE/104D ratio of women in their 40s (5.46) was three times higher than that of women in their 20s (1.80) (relative risk: 3.03; 95% confidence interval: 2.04-4.51; p < 0.01). The incidence rate for women in their 40s in the second study was 2.3 times higher than that in the first study. PA-VTE/104D cases occurred more frequently in multiparous than in primiparous women, in cesarean section cases compared with vaginal delivery, and in multiple rather than single pregnancies. Most PA-VTE cases occurred during the postpartum period (321/510, 62.9%), of which pulmonary embolism was the most frequently occurring type (231/321, 72%). CONCLUSION: Advanced maternal age, cesarean section, multiparity, and multifetal pregnancies increased the risk of PA-VTE. Obstetricians need to be cautious of VTE, particularly during the postpartum period, in high-risk pregnant patients.

Association of Underlying Comorbidities and Sites of tuberculosis: an analysis using surveillance data.

BACKGROUND: Tuberculosis (TB) is a highly heterogeneous disease that can affect any organ. Extrapulmonary TB (EPTB) is more difficult to diagnose due to various clinical presentations. Depending on the characteristics of the patient, the involved site of TB may vary. However, data on clinical characteristics of EPTB are inconsistent and insufficient. This study aimed to identify the characteristics of patients with pulmonary TB (PTB) and EPTB and describe characteristic differences for each involved site. METHODS: We systemically collected data of TB patients included in the national surveillance system in South Korea from July 2018 to June 2019 and compared the characteristics of patients with EPTB with that of PTB. RESULTS: A total of 7674 patients with a mean age of 60.9 years were included. Among them, 6038 (78.7%) patients were diagnosed with PTB and 1636 (21.3%) with EPTB. In PTB group, the mean age (61.7 ± 18.7 vs. 57.8 ± 19.9) and proportion of male sex (63.3% vs. 50.1%) were higher, but the body mass index was lower (21.2 ± 3.4 vs. 22.7 ± 3.5) than that of the EPTB group. Prevalence of diabetes (20.5% vs. 16.9%) and chronic lung disease (5.1% vs. 2.9%) were higher in PTB group, meanwhile, those of chronic kidney disease (CKD) (2.7% vs. 5.4%) and long-term steroid use (0.4% vs. 1.0%) were higher in EPTB group. Abdominal TB was more prevalent in patients with chronic liver disease (odds ratio [OR]: 2.69, 95% CI: 1.52-4.74), and urogenital TB was more prevalent in patients with CKD (OR: 2.75, 95% CI: 1.08-6.99). CONCLUSIONS: We found that underlying comorbidities were closely associated with the location of TB development, and therefore, the possibility of EPTB should be carefully evaluated while monitoring for underlying disease in TB-endemic areas.

Treatment and Bleeding Complications of Cancer-Associated Venous Thromboembolism: A Korean Population-Based Study.

OBJECTIVES: This study investigated the treatment pattern and the rate of bleeding complications in real-world practice in cancer-associated venous thromboembolism (CT) patients. METHODS: We used the Korean Health Insurance Review and Assessment Service database (2014-2018). Among patients with venous thromboembolism, patients with concomitant malignancy diagnostic codes were categorized as CT, while all others were categorized as non-CT. Treatments were categorized as direct oral anticoagulant (DOAC), parenteral anticoagulant (PAC), warfarin, and mixed anticoagulants. RESULTS: We identified 27,205 CT and 57,711 non-CT patients. DOACs were the most frequently used anticoagulants. The proportion of patients treated with PAC was higher in CT than in non-CT patients (35.7 vs. 19.5%; p < 0.01). In CT, the cumulative incidence of any/major bleeding was higher with DOAC (8.1%/3.9%) than with PAC (7.5%/3.2%; p = 0.04 and 0.01, respectively). However, there was no difference in major bleeding when compared with warfarin (p = 0.11) or mixed anticoagulants (p = 0.94). Overall, gastrointestinal (GI) cancer patients showed higher risks of bleeding. The cumulative incidence of major GI bleeding was higher with DOAC than with PAC (4.9 vs. 3.0%; p < 0.01), while there was no difference compared with warfarin (p = 0.59) or mixed anticoagulants (p = 0.80). Major bleeding with each DOAC showed no difference among entire CT (p = 0.94), GI cancer (p = 0.27), and genitourinary cancer (p = 0.88) patients. CONCLUSION: Five years after their introduction into clinical practice, DOACs have become the most prescribed anticoagulant in Korea. In our patient population, bleeding complications occurred more frequently in CT than in non-CT, especially in patients treated with DOACs.

Incidence of Venous Thromboembolism: The 3rd Korean Nationwide Study.

BACKGROUND: The incidence of venous thromboembolism (VTE) has gradually increased in the Korean population. This study aimed to evaluate the annual age- and sex-adjusted incidence rates (ASR) of VTE and anticoagulation trends between 2014 and 2018. METHODS: Using the Korean Health Insurance Review and Assessment Service database, we retrospectively identified VTE patients between 2014 and 2018 using both diagnostic and medication anticoagulant codes assigned within 6 months of the initial index event. Anticoagulant patterns were classified as follows: direct oral anticoagulants (DOAC), parenteral anticoagulants, warfarin, and mixed anticoagulation regimens. RESULTS: We identified 95,205 patients with VTE (female, 56.8%). The ASR for VTE per 100,000 person-years increased from 32.8 in 2014 to 53.7 cases in 2018 (relative risk of 1.63; 95% confidence interval, 1.6-1.67). The VTE incidence rates were 25 times higher in the ≥ 80 group than in the 30s group. VTE occurred 1.29 times more often in women than in men. The proportion of DOAC prescriptions increased from 40.5% to 72.8%, whereas warfarin prescriptions decreased from 27% to 5.6% in 2014 and 2018. CONCLUSION: In Korea, the ASRs of VTE continued to increase since 2014, but the rate of increase slowed in 2018. The VTE occurred more often in the elderly and in women. Five years after the introduction of DOACs in 2013, they accounted for 73% of all anticoagulants used to treat VTE.

Decline in Carbon Monoxide Transfer Coefficient in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Although a reduced carbon monoxide transfer coefficient (Kco) is an important feature in chronic obstructive pulmonary disease (COPD), how it changes over time and its relationship with other clinical outcomes remain unclear. This study evaluated longitudinal changes in Kco and their relationship with other clinical outcomes. METHODS: We evaluated patients with COPD from the Korean Obstructive Lung Disease cohort, followed up for up to ten years. Random coefficient models were used to assess the annual change in Kco over time. Participants were categorized into tertiles according to Kco decline rate. Baseline characteristics and outcomes, including changes in FEV1 and emphysema index, incidence of exacerbations, and mortality, were compared between categories. RESULTS: A decline in Kco was observed in 92.9% of the 211 enrolled participants with COPD. Those with the most rapid decline (tertile 1) had a lower FEV1/FVC% (tertile 1: 43.8% ± 9.7%, tertile 2: 46.4% ± 10.5%, tertile 3: 49.2% ± 10.4%, p = 0.008) and a higher emphysema index at baseline (27.7 ± 14.8, 22.4 ± 16.1, 18.1 ± 14.5, respectively, p = 0.001). Tertile 3 showed a lower decline rate in FEV1 (16.3 vs. 27.1 mL/yr, p = 0.017) and a lower incidence of exacerbations (incidence rate ratio = 0.66, 95% CI = 0.44-0.99) than tertile 1. There were no differences in the change in emphysema index and mortality between categories. CONCLUSION: Most patients with COPD experienced Kco decline over time, which was greater in patients with more severe airflow limitation and emphysema. Decline in Kco was associated with an accelerated decline in FEV1 and more frequent exacerbations; hence, this should be considered as an important outcome measure in further studies.

Impact of gender on chronic obstructive pulmonary disease outcomes: a propensity score-matched analysis of a prospective cohort study.

BACKGROUND/AIMS: Despite increasing awareness of the burden of chronic obstructive pulmonary disease (COPD) in women, knowledge regarding gender differences in COPD outcomes is limited. Therefore, we aimed to evaluate whether COPD outcomes, including exacerbations, lung function, and symptoms differ by gender. METHODS: We recruited patients with COPD from two Korean multicenter prospective cohorts. After propensity score matching, the main outcome, the incidence of moderate or severe exacerbations was analyzed using a negative binomial regression model. We also assessed changes in lung function and symptom scores including the St. George's respiratory questionnaire for COPD (SGRQ-C), COPD assessment test (CAT), and the modified Medical Research Council (mMRC) dyspnea score. RESULTS: After propensity score matching, 74 women and 74 men with COPD were included. The incidence rates of exacerbations in women and men were not significantly different (incidence rate ratio, 1.49; 95% confidence interval [CI], 0.88 to 2.54). There was no significant difference in the incidence rates adjusted for medication possession ratios of long-acting muscarinic antagonists, long-acting ß-agonists, and inhaled corticosteroids during the follow-up period (incidence rate ratio, 1.47; 95% CI, 0.86 to 2.52). Rates of decline in post-bronchodilator forced expiratory volume in 1 second and forced vital capacity did not differ between women and men during 48 months of follow-up. The changes in scores on the SGRQ-C, CAT, and mMRC Questionnaire in women were also similar to those in men. CONCLUSION: We observed no gender differences in the rate of exacerbations of COPD in a prospective longitudinal study. Further studies are needed to confirm these findings in the general COPD population.

Incidence and Risk Factors of Recurrent Venous Thromboembolism after Pulmonary Embolism.

BACKGROUND: Information about the epidemiology of venous thromboembolism (VTE) recurrence in Korea is lacking. The purpose of this study was to investigate VTE cumulative recurrence rates and identify risk factors for VTE recurrence among Korean adults. METHODS: A retrospective cohort study was conducted on adult patients (≥18 years) admitted to a university teaching hospital for pulmonary embolism (PE) from 2005 to 2013. The main outcome of interest was a recurrence of VTE. We used Cox proportional hazard regression analyses to calculate the relative risk of VTE recurrence. RESULTS: Five-year cumulative incidence of recurrent VTE events was 21.5% (95% confidence interval [CI], 17.7-25.4) in all cases of PE; 17% after provoked and 27% after unprovoked PE. Multivariate analysis showed that body mass index (BMI) of ≥25 (hazard ratio [HR], 2.02; 95% CI, 1.17-3.46; p=0.01) and longer anticoagulation therapy duration (HR, 0.90; 95% CI, 0.84-0.96; p<0.01) were independently associated with risk of VTE recurrence. Risk factors not found to be statistically significant at the <0.05 level included history of VTE (HR, 1.81; 95% CI, 0.84-3.88; p=0.12), unprovoked PE (HR, 1.70; 95% CI, 0.89-3.25; p=0.10), symptomatic deep vein thrombosis (HR, 1.62; 95% CI, 0.89-2.94; p=0.10), and female sex (HR, 1.42; 95% CI, 0.78-2.55; p=0.24). We found that age, history of cancer, and other co-morbidities did not significantly affect the risk of VTE recurrence. CONCLUSION: Recurrence of VTE after PE is high. Patients with BMI ≥25 or reduced anticoagulation therapy duration have a higher risk of recurrent VTE.

Resting hyperinflation and emphysema on the clinical course of COPD.

The aim of this study is to clarify whether the combined evaluation of resting hyperinflation and emphysema confers any additional advantages in terms of predicting clinical outcomes in chronic obstructive pulmonary disease (COPD) patients. We included COPD patients from the Korean Obstructive Lung Disease (KOLD) cohort. Patients with a residual volume/total lung capacity (RV/TLC) over the upper limit of normal were defined as having resting hyperinflation, and those with an emphysema index >10% were defined as having emphysema. We investigated the impacts of resting hyperinflation and emphysema on exacerbations and mortality. A total of 310 COPD patients were analyzed over a mean of 61.1 months. After adjustment for covariates, resting hyperinflation was an independent predictor of earlier exacerbation (HR = 1.66, CI = 1.24-2.22), more frequent exacerbation (IRR = 1.35, CI = 1.01-1.81), and higher mortality (HR = 2.45, CI = 1.16-5.17) risk. Emphysema was also significantly associated with earlier exacerbation (HR = 1.64, CI = 1.15-2.35), and higher mortality (HR = 3.13, CI = 1.06-9.27) risk. Participants with both resting hyperinflation and emphysema had an additively higher risk of earlier exacerbations (HR = 1.71, 95% CI = 1.26-2.33) and mortality (HR = 3.75, 95% CI = 1.81-7.73) compared with those in other groups. In conclusion, resting hyperinflation and emphysema had additional worse impacts on exacerbations and mortality in COPD patients.

Long-term rivaroxaban for the treatment of acute venous thromboembolism in patients with active cancer in a prospective multicenter trial.

BACKGROUND/AIMS: Limited data are available regarding the efficacy of rivaroxaban for the treatment of cancer-associated venous thromboembolism (VTE). The aim of this study was to evaluate the effectiveness and safety of rivaroxaban for the treatment of VTE in active cancer patients. METHODS: In this prospective, multicenter, open-label trial (NCT01989845), we enrolled patients with active cancer and objectively diagnosed lower-extremity deep vein thrombosis, pulmonary embolism (PE), or both from November 2013 to June 2016. Active cancer was defined as a histologically confirmed malignancy, which was diagnosed or treated within the previous 6 months, or as a recurrent/ metastatic cancer. Patients received oral rivaroxaban 15 mg twice daily for first 3 weeks, followed by 20 mg once daily for 6 months. The primary outcome was the symptomatic recurrent VTE and the secondary outcomes included any recurrent VTE, major or clinically relevant non-major (CRNM) bleeding events, and overall mortality. All study outcomes were validated by blinded central adjudication. RESULTS: Of 124 patients enrolled, 110 (88.7%) had solid cancer, 93 (75.0%) had metastatic disease, and 110 (88.7%) were receiving chemotherapy or radiotherapy. During the 6-month study period, seven patients experienced symptomatic recurrent VTE (cumulative incidence, 5.9%), and two patients experienced incidental recurrent PE (cumulative incidence of any recurrent VTE, 7.6%). Major bleeding events occurred in six patients (cumulative incidence, 5.3%) and CRNM bleeding events in 11 patients (cumulative incidence, 10.2%). Twenty-eight patients (overall mortality, 24.0%) died. CONCLUSION: Rivaroxaban is effective and safe for the treatment of VTE in patients with active cancer.

Sputum bacteriology and clinical response to antibiotics in moderate exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: Presence of purulent sputum during an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is considered sufficient indication for starting empirical antibiotics. We investigated the relationship between detection of potentially pathogenic bacteria (PPB) using sputum culture or polymerase chain reaction (PCR) and clinical response and sought the risk factors for PPB growth. METHODS: In 342 outpatients with AECOPD, we compared detection rates of H. influenzae (HI) and S. pneumoniae (SP) using conventional sputum culture versus PCR. The utility of either technique to predict clinical cure or failure after effective antibiotics was assessed. The factors predicting positive sputum cultures were evaluated using logistic regression. RESULTS: Using sputum culture, 132 PPB were detected. The predominant bacteria were HI (40.9%) and SP (19.7%). Detection of HI or SP in sputum was higher using PCR than culture growth (60.8% vs 18.6%; P < .001). Clinical response was not affected by the results of either technique. Independent risk factors for PPB isolation were Gram-negative bacteria on sputum smear (OR 15.78, 95% CI 6.38-39.06; P < .001), sputum purulence (OR 2.31, 95% CI, 1.05-5.11; P = .04), body temperature (OR 0.16, 95% CI 0.05-0.54; P = .003), albumin level (OR 0.29, 95% CI 0.09-0.88; P = .03) and dyspnea grade (OR 0.51, 95% CI 0.27-0.96; P = .04). CONCLUSIONS: Neither culture growth nor PCR positivity for HI or SP in sputum predicted clinical response to antibiotics; therefore, these tests are not necessary for outpatients with AECOPD. Examining Gram-staining and purulence on sputum smear, however, was significant to predict PPB growth in sputum.

Determinants of Nicotine Dependence in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Smoking cessation is the most powerful intervention to modify progress of chronic obstructive pulmonary disease (COPD), and nicotine dependence is one of the most important determinants of success or failure in smoking cessation. We evaluated nicotine dependence status and investigated factors associated with moderate to high nicotine dependence in patients with COPD. METHODS: We included 53 current smokers with COPD in the Korean Obstructive Lung Disease II cohort enrolled between January 2014 and March 2016. Nicotine dependence was measured by using Fagerstrom test for nicotine dependence (FTND). Cognitive function was assessed by Korean version of Montreal Cognitive Assessment. RESULTS: The median FTND score was 3, and 32 patients (60%) had moderate to high nicotine dependence. The median smoking amount was 44 pack-years, which was not related to nicotine dependence. Multiple logistic regression analysis revealed that high education status (odds ratio, 1.286; 95% confidence interval, 1.036-1.596; p=0.023), age <70 (odds ratio, 6.407; 95% confidence interval, 1.376-29.830; p=0.018), and mild to moderate airflow obstruction (odds ratio, 6.969; 95% confidence interval, 1.388-34.998; p=0.018) were related to moderate to high nicotine dependence. CONCLUSION: Nicotine dependence does not correlate with smoking amount, but with education level, age, and severity of airflow obstruction. Physicians should provide different strategies of smoking cessation intervention for current smokers with COPD according to their education levels, age, and severity of airflow obstruction.

Which bronchodilator reversibility criteria can predict severe acute exacerbation in chronic obstructive pulmonary disease patients?

BACKGROUND: It is unclear whether various bronchodilator reversibility (BDR) criteria affect the prognosis of chronic obstructive pulmonary disease (COPD). The aim of this study is to evaluate the impact of positive BDR defined according to various BDR criteria on the risk of severe acute exacerbation (AE) in COPD patients. METHODS: Patients from four prospective COPD cohorts in South Korea who underwent follow-up for at least 1 year were enrolled in this study. The assessed BDR criteria included the Global Initiative for Chronic Obstructive Lung Disease (GOLD), American Thoracic Society (ATS), American College of Chest Physicians, (ACCP), major criteria of the Spanish definition of asthma-COPD overlap syndrome (ACOS), criteria compatible with ACOS in the Global Initiative for Asthma (GINA), and European Respiratory Society (ERS). The rate of patients with severe AE who required hospitalization within 1 year due to BDR results according to each set of criteria was analyzed using logistic regression models. RESULTS: Among a total of 854 patients, the BDR-positive cases varied according to the criteria used. There was a 3.5% positive BDR rate according to GINA and a 29.9% rate according to the ATS criteria. Positive BDR according to the GOLD criteria was significantly associated with a decreased risk of severe AE (adjusted odds ratio (aOR) = 0.38; 95% Confidence interval (CI) = 0.15-0.93). This result remained statistically significant even in a sensitivity analysis that included only participants with a smoking history of at least 10 pack-years and in the analysis for the propensity score-matched participants. CONCLUSIONS: Among different criteria for positive BDR, the use of the GOLD ones was significantly associated with a decreased risk of severe AE in COPD patients. Increase use of ICS/LABA may have affected this relationship.

The Perioperative Management of Antithrombotic Therapies Using Enoxaparin.

Oral anticoagulant therapy is frequently and increasingly prescribed for patients at risk of arterial or venous thromboembolism (VTE). Although elective surgical or invasive procedures have necessitated temporary interruption of anticoagulants, managing these patients has been performed empirically and been poorly investigated. This study was designed to evaluate the adequacy of perioperative anticoagulation using enoxaparin. This was a retrospective, single-center study that evaluated the efficacy and safety of therapeutic-dose enoxaparin for bridging therapy in patients on long-term warfarin at Soonchunhyang University Hospital in Korea between August 2009 and July 2011. Warfarin was discontinued 5 days before surgery, and enoxaparin was administered twice daily by subcutaneous injection at a dose of 1 mg per kg from 3 days before the procedure to the last dose 24 hours before the procedure. Anticoagulation was restarted if proper hemostasis had been confirmed. There were 49 patients, of whom 25 (51%) were men, and the mean age was 63 years. Thirty-four (69%) received warfarin therapy for VTE, and 9 (18%) for atrial fibrillation. Twenty-nine patients (59%) underwent major surgery and 20 (41%) minor surgery. The mean postoperative duration of enoxaparin was 4 days. No patients had thromboembolic complications through 30 days after the procedure. The overall 30-day mortality rate was 0%. In conclusion, our findings demonstrate that bridging therapy with therapeutic-dose enoxaparin is feasible and associated with a low incidence of major bleeding and no thromboembolic complications. However, the optimal approach to managing patients perioperatively is uncertain and requires further evaluation.

Factors associated with plasma IL-33 levels in patients with chronic obstructive pulmonary disease.

BACKGROUND: Interleukin (IL)-33 promotes T helper (Th)2 immunity and systemic inflammation. The role of IL-33 in asthma has been widely investigated. IL-33 has also been suggested to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). This study investigated the clinical significance and usefulness of plasma IL-33 level in patients with COPD. METHODS: A total of 307 patients with stable COPD from 15 centers, who were in the Korean Obstructive Lung Disease cohort, were enrolled in this study. Plasma IL-33 levels were measured by enzyme-linked immunosorbent assay. We analyzed the association between IL-33 level and other clinical characteristics related to COPD. We also examined the features of patients with COPD who exhibited high IL-33 levels. RESULTS: IL-33 levels varied, but were very low in most patients. Eosinophil count was significantly correlated with a plasma IL-33 level. In addition, old age and current smoking were related to a low IL-33 level. Significantly more patients with a higher IL-33 level had chronic bronchitis compared with those with a low IL-33 level. CONCLUSION: Plasma IL-33 level in patients with stable COPD was related to eosinophil count and chronic bronchitis phenotype. Further studies are needed to identify the precise mechanisms of IL-33/ST2 pathway in patients with COPD.

Association of interleukin-25 levels with development of aspirin induced respiratory diseases.

BACKGROUND: Aspirin-exacerbated respiratory diseases (AERD) are caused by ingestion of non-steroidal anti-inflammatory drugs and are characterized by acute bronchospasms and marked infiltration of eosinophils, the latter being attributable to altered synthesis of cysteinyl leukotrienes (LT) and prostaglandins (PG). Recently, the innate Th2 response is revealed to induce eosinophil infiltration in allergic inflammation, however the role of the innate Th2 response has not been studies in AERD. Thus, we evaluated the relationship between the innate Th2 cytokines including IL-25, thymic stromal lymphopoietin (TSLP) and IL-33 and the development of AERD. METHODS AND MATERIALS: Plasma IL-25, IL-33, and TSLP levels were measured before and after aspirin challenge in subjects with AERD (n = 25) and aspirin-tolerant asthma (ATA, n = 25) by enzyme-linked immunosorbent assay (ELISA). Pre and post-aspirin challenge levels of LTC4 and PGD2 were measured using ELISA. RESULTS: Basal plasma IL-25 levels were significantly higher in AERD group than in normal controls and in ATA group (p = 0.025 and 0.031, respectively). IL-33 and TSLP levels were comparable in the AERD and ATA groups. After the aspirin challenge, the IL-25 levels were markedly decreased in the ATA group (p = 0.024), while not changed in the AERD group. The post-challenge IL-25 levels of all asthmatic subjects were significantly correlated with aspirin challenge - induced declines in FEV1 (r = 0.357, p = 0.011), but not with basal and post challenge LTC4 and PGD2 levels. CONCLUSIONS: IL-25 is associated with bronchospasm after aspirin challenge, possibly via mechanisms other than altered LTC4 and PGD2 production.

Effectiveness and outcome of management strategies for dabigatran- or warfarin-related major bleeding events.

BACKGROUND: Strategies used for the management of dabigatran-related major bleeding events (MBEs), and their effectiveness have not been systematically evaluated. METHODS: Reports on 1034 individuals experiencing 1121 MBEs (696 on dabigatran, and 425 on warfarin) in 5 phase III randomized controlled trials were assessed independently by two investigators. RESULTS: MBEs were managed either by drug discontinuation only (37%), or drug discontinuation with either transfusion of only red cell concentrates (38%), or plasma (23%). Few MBEs (2%) were treated with coagulation factor concentrates. The effectiveness of the management was assessed as good in significantly larger proportion of MBEs on dabigatran (91%) than on warfarin (84%, odds ratio [OR] 1.68; 95% confidence interval [CI], 1.14-2.49), which was consistent with the lower 30-day mortality (OR (OR 0.66; 95% CI, 0.44-1.00)). The effectiveness of bleeding management in non-traumatic bleeding was better in patients with dabigatran than with warfarin (OR 1.82; 95% CI, 1.18-2.79) but was similar in traumatic bleeding (OR 0.75; 95% CI, 0.25-2.30). The relative effectiveness of management of bleeding and 30-day mortality rates across other key subgroups of patients or sites of bleeding, the use of platelet inhibitors, age-, sex- and renal function subgroups, were comparable in MBEs on dabigatran or warfarin. CONCLUSION: Despite the unavailability of a specific antidote at the time of these studies, bleeding in patients receiving dabigatran was managed in the overwhelming majority of patients without coagulation factor concentrates, with comparable or superior effectiveness and lower 30-day mortality rates versus those who bleed while receiving warfarin.