Nationwide Study of the Epidemiology, Diagnosis, and Treatment of Hypersensitivity Pneumonitis in Korea.

BACKGROUND: Hypersensitivity pneumonitis (HP) is a condition with an uncertain global incidence, and information on its diagnosis and management is limited. This study aimed to address these knowledge gaps. METHODS: This study utilized customized claims data from the Health Insurance Review and Assessment Service (HIRA) in South Korea from January 2010, to December 2021. Patients with HP were identified based on the diagnosis code (International Classification of Diseases, 10th Revision, J67) between 2011 and 2020. Incident HP cases were defined as new HP claims, excluding those with claims in the previous year. The study examined various factors such as age, sex, comorbidities, diagnostic methods, and treatment patterns. Additionally, multivariate logistic regression analysis was performed to identify risk factors associated with treatment initiation. RESULTS: A total of 8,678 HP incident cases were confirmed, with age- and sex-adjusted annual incidence rates ranging from 1.14/100,000 in 2020 to 2.16/100,000 in 2012. The mean age of patients with incident HP was 52 years, with a higher incidence observed among males. Additionally, the most common comorbidity was asthma. Bronchoscopy was performed on 16.9% of patients, and 25.4% of patients did not receive treatment within 1 year of diagnosis. Among those who received treatment, prednisone was the most used systemic steroid, and azathioprine was the most commonly used second-line immunosuppressant. Factors associated with treatment initiation included the female sex, having asthma or gastroesophageal reflux disease (GERD), and undergoing bronchoscopy. CONCLUSION: This study provides valuable insights into the incidence, diagnosis, and treatment patterns of HP in South Korea using nationwide medical claims data.

Patterns of inflammatory immune responses in patients with septic shock receiving vitamin C, hydrocortisone, and thiamine: clustering analysis in Korea.

BACKGROUND: Sepsis is characterized by heterogeneous immune responses that may evolve during the course of illness. This study identified inflammatory immune responses in septic patients receiving vitamin C, hydrocortisone, and thiamine. METHODS: This was a single-center, post-hoc analysis of 95 patients with septic shock who received the vitamin C protocol. Blood samples were drawn on days 1-2, 3-4, and 6-8 after shock onset. Group-based multi-trajectory modeling was used to identify immune trajectory groups. RESULTS: The median age was 78 years (interquartile range, 70-84 years), and 56% were male. Clustering analysis identified group 1 (n=41), which was characterized by lower interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-10 levels, and these levels remained stationary or mildly increased until day 7. Conversely, group 2 (n=54) expressed initially higher IL-6, TNF-α, and IL-10 levels that decreased rapidly by day 4. There was a nonsignificant increase in lymphocyte count and a decrease in C-reactive protein level until day 7 in group 2. The intensive care unit mortality rate was significantly lower in group 2 (39.0% vs. 18.5%, P=0.03). Group 2 also had a significantly higher decrease in the mean (standard deviation) vasopressor dose (norepinephrine equivalent: -0.09±0.16 µg/kg/min vs. -0.23±0.31 µg/kg/min, P<0.001) and Sequential Organ Failure Assessment score (0±5 vs. -4±3, P=0.002) between days 1 and 4. CONCLUSIONS: There may be different subphenotypes in septic patients receiving the vitamin C protocol.

Risk of venous thromboembolism in Korean patients with rheumatoid arthritis treated with Janus kinase inhibitors: A nationwide population-based study.

OBJECTIVE: There was a safety concern about an increased risk of thromboembolic events in patients with rheumatoid arthritis (RA) treated with Janus kinase inhibitors (JAKis). This study aimed to determine the risk of venous thromboembolism (VTE) in Korean patients with RA treated with JAKis compared with tumour necrosis factor (TNF) inhibitors. METHODS: Using the National Health Insurance Service database between 2015 and 2019, patients with prevalent RA who started JAKi or TNF inhibitor were selected as the study population. All participants were naïve to targeted therapy. Patients that had experienced any VTE event or used anticoagulant agents within 30 days were excluded. Demographic and clinical characteristics were all balanced by stabilised inverse probability of treatment weighting (sIPTW) using propensity score. The Cox proportional hazard model considering death as a competing risk was used to evaluate the risk of VTE in JAKi users compared with TNF inhibitor users. RESULTS: A total of 4,178 patients were included: 871 JAKi users and 3,307 TNF inhibitor users were followed up for 1,029.2 person-years (PYs) and 5,940.3 PYs, respectively. With a balanced sample after sIPTW, the incidence rates (IR) of VTE were 0.06 per 100 PYs (95% confidence interval [CI] 0.00-1.23) in JAKi users and 0.38 per 100 PYs (95% CI 0.25-0.58) in TNF inhibitor users. The hazard ratio was 0.18 (95% CI 0.01-3.47) after adjusting for unbalanced variables after performing sIPTW. CONCLUSION: There is no increased risk of VTE in RA patients treated with JAKis compared with TNF inhibitors in Korea.

Risk of cardiovascular events according to the tricyclic antidepressant dosage in patients with chronic pain: a retrospective cohort study.

PURPOSE: We aimed to examine the risk of cardiovascular adverse events by tricyclic antidepressant (TCA) dosage among patients with chronic pain. METHODS: A retrospective cohort study was conducted using a nationwide sample cohort. Among patients aged ≥ 18 years with a chronic pain diagnosis and no history of cardiovascular events, we extracted users and non-users of TCAs through 1:1 propensity score matching. TCA users were categorized into three groups according to the mean defined daily dose (DDD): very low doses (< 0.15 DDD), low doses (0.15-0.34 DDD), and traditional doses (≥ 0.34 DDD). A 6-month follow-up was conducted with an intention-to-treat approach. We examined the hazard ratio of cardiovascular adverse events using Cox proportional hazards analysis. RESULTS: In total, 16,660 matched patients were followed up (8330 TCA users and 8330 non-users). TCA use did not significantly increase cardiovascular adverse events (hazard ratio [HR] 1.12, 95% confidence interval [CI] 0.94-1.33). Low-dose (0.15-0.34 DDD) TCAs (HR 1.37, 95% CI 1.08-1.74), particularly low-dose (0.15-0.34 DDD) nortriptyline (HR 2.11, 95% CI 1.44-3.08), was associated with an increased risk of cardiovascular adverse events. Administration of TCAs at the traditional dose (≥ 0.34 DDD) increased the risk of ischemic stroke (HR 2.08, 95% CI 1.11-3.88). CONCLUSION: Close monitoring of patients on long-term, low-dose use of TCAs should be conducted to avoid an increase in the cumulative dose, which increases the risk of cardiovascular adverse events.

Safety Profiles of mRNA COVID-19 Vaccines Using World Health Organization Global Scale Database (VigiBase): A Latent Class Analysis.

INTRODUCTION: Although messenger RNA (mRNA) vaccines have been developed and widely utilized to mitigate the coronavirus disease (COVID-19) pandemic, it is essential to describe the adverse events (AEs) following immunization. This study aimed to identify the patterns associated with serious AE reports after mRNA COVID-19 vaccination in the World Health Organization (WHO)'s global scale database (VigiBase). METHODS: This study performed a latent class analysis (LCA) of reports of serious AEs following mRNA COVID-19 vaccination from VigiBase between December 28, 2020 , and February 28, 2022 (N = 312878). The Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) terms were selected for LCA. The reporting characteristics in accordance with the cluster were described. We used a multinomial logistic regression model to estimate the association between potential factors and each cluster. RESULTS: Five clusters of AE reports were distinguished through LCA: infection AEs (cluster 1), cardiac AEs (cluster 2), respiratory/thrombotic AEs (cluster 3), systemic AEs (cluster 4), and nervous system AEs (cluster 5). Compared to cluster 4, cluster 2 had a higher proportion of males (OR 2.98; 95% confidence interval (CI) 2.87-3.09), and cluster 1 had a longer time to onset than other AEs (≥ 14 days) (OR 16.2; 95% CI 15.5-16.9). CONCLUSION: Using LCA, we found five clusters of serious AEs following mRNA COVID-19 vaccination. Each cluster was distinguished by potential factors such as age, gender, region, and time to onset. We suggest that monitoring should carefully consider the patterns of young males with cardiac AEs and elderly individuals with thrombosis after respiratory AEs. Our findings could contribute to enhancing understanding of safety profiles and establishing management strategies for serious AEs of special interest following mRNA COVID-19 vaccination.

Association between malignancy risk and Janus kinase inhibitors versus tumour necrosis factor inhibitors in Korean patients with rheumatoid arthritis: a nationwide population-based study.

OBJECTIVE: To determine the risk of malignancy in Korean patients with rheumatoid arthritis (RA) receiving Janus kinase inhibitors (JAKis) compared with tumour necrosis factor inhibitors (TNFis). METHODS: A retrospective cohort of patients with RA initiating their first JAKi or TNFi was established using the Korean National Health Insurance database between 2015 and 2019. They were followed up from treatment initiation to the occurrence of malignancy, drug discontinuation, death or until December 2019. Baseline features of the patients were balanced through inverse probability of treatment weighting (IPTW) using a propensity score. A Cox proportional hazard model was established to estimate the HR for malignancy risk in JAKi users compared with TNFi users. RESULTS: A total of 4929 patients (1064 JAKi-treated and 3865 TNFi-treated patients) were included, and the observation periods were 1288.6 person-years (PYs) for JAKi users and 6823.8 PYs for TNFi users. The incidence rates of overall malignancy were 0.54 per 100 PYs (95% CI 0.26 to 1.14) in JAKi users and 0.85 per 100 PYs (95% CI 0.66 to 1.10) in TNFi users. In IPTW analysis with a balanced sample (4101 JAKi-treated and 5131 TNFi-treated patients), HR was 0.83 (95% CI 0.55 to 1.27) for overall malignancy: 0.77 (95% CI 0.50 to 1.19) for solid malignancy and 2.86 (95% CI 0.41 to 20.00) for haematological malignancy. CONCLUSION: Malignancy risk in Korean patients with RA was not increased with JAKi use compared with TNFi use.

Longitudinal study of the impact of three major regulations on the Korean pharmaceutical industry in the last 30 years.

BACKGROUND: The pharmaceutical industry is heavily regulated. Partly for this reason, new drugs generally take over 10 years from the product development stage to market entry. Although regulations affect the pharmaceutical industry over a long period, previous studies investigating the impact of new regulatory policies have usually focused on the short period before and after implementing that policy. Therefore, the purpose of this study is to examine whether and how significantly regulatory policies affect long-term innovation in the pharmaceutical industry in Korea. METHODS: This study focused on three significant regulatory policies: the introduction of the product patent system, changes in the Good Manufacturing Practice (GMP) system, and the Drug Expenditure Rationalization Plan (DERP). The study used interrupted time series (ITS) analysis to investigate the long-term impacts of the policies before and after implementation. RESULTS: Our results show that introducing the product patent system in 1987 significantly increased the number of Korean patent applications. The effect of the revised GMP policies was also statistically significant, both before and after implementation and between pre-emptive companies and non-pre-emptive ones. However, due to the companies' negotiations with the regulatory authorities or the regulatory system that links drug approval and price evaluation, the DERP did not significantly delay new drug registration in Korea. CONCLUSION: This study showed that the policies of the product patent system, GMP policies, and DERP regulations have significantly encouraged pharmaceutical companies to strive to meet regulatory requirements and promote innovation in Korea. The study suggests that it is necessary for companies to pre-emptively respond to systemic changes in development and production strategies to deal with regulatory changes and achieve sustainable growth. Also, our study results indicate that since government policies motivate the innovative system of the pharmaceutical industry, governmental authorities, when formulating pharmaceutical policies, need to consider the impact on the long-term innovation of the industry.

Incorporating a real-time automatic alerting system based on electronic medical records could improve rapid response systems: a retrospective cohort study.

BACKGROUND: Rapid response systems (RRSs) are essential components of patient safety systems; however, limited evidence exists regarding their effectiveness and optimal structures. We aimed to assess the activation patterns and outcomes of RRS implementation with/without a real-time automatic alerting system (AAS) based on electronic medical records (EMRs). METHODS: We retrospectively analyzed clinical data of patients for whom the RRS was activated in the surgical wards of a tertiary university hospital. We compared the code rate, in-hospital mortality, unplanned intensive care unit (ICU) admission, and other clinical outcomes before and after applying RRS and AAS as follows: pre-RRS (January 2013-July 2015), RRS without AAS (August 2015-November 2016), and RRS with AAS (December 2016-December 2017). RESULTS: In-hospital mortality per 1000 admissions decreased from 15.1 to 12.9 after RRS implementation (p < 0.001). RRS activation per 1000 admissions increased from 14.4 to 26.3 after AAS implementation. The severity of patients' condition calculated using the modified early warning score increased from 2.5 (± 2.1) in the RRS without AAS to 3.6 (± 2.1) (p < 0.001) in the RRS with AAS. The total and preventable code rates and in-hospital mortality rates were comparable between the RRS implementation periods without/with AAS. ICU duration and mortality results improved in patients with RRS activation and unplanned ICU admission. The data of RRS non-activated group remained unaltered during the study. CONCLUSIONS: Real-time AAS based on EMRs might help identify unstable patients. Early detection and intervention with RRS may improve patient outcomes.

Risk of Fractures in Older Adults with Chronic Non-cancer Pain Receiving Concurrent Benzodiazepines and Opioids: A Nested Case-Control Study.

OBJECTIVE: The aim of this study was to investigate the relationship between the concurrent use of benzodiazepines and opioids and the risk of fractures in older patients with chronic non-cancer pain. METHODS: Patients with osteoarthritis or low back pain (≥ 65 years of age) included in the Korean National Health Insurance Service-National Sample Cohort database of Korea and with an incident diagnosis of hip, humeral, or forearm fracture between 2011 and 2015 were identified as cases. For each case, four controls were matched for age (within 5 years), sex, and year of cohort entry. We estimated the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for fractures associated with concurrent use of benzodiazepines and opioids using a conditional logistic regression analysis, adjusting for comorbidities and comedications. RESULTS: The aOR (95% CI) for the concurrent use of benzodiazepines and opioids was 1.45 (1.22-1.71), compared with those of non-use within 30 days before the index date. The aOR was 1.65 (1.22-2.23) in patients who were continuously receiving benzodiazepines and were newly initiated with concurrent opioids. The aORs for concurrent use were 1.95 (1.39-2.74) and 1.27 (1.03-1.56) in the case of hip fracture and forearm fracture, respectively. CONCLUSION: The concurrent use of benzodiazepines and opioids was associated with an increased risk of fractures in older patients with chronic non-cancer pain. Therefore, patients continuously receiving benzodiazepines in whom opioids are newly initiated need careful monitoring, and such combined therapy should be limited to the shortest duration possible.

Change Point Analysis for Detecting Vaccine Safety Signals.

It is important to detect signals of abrupt changes in adverse event reporting in order to notice public safety concerns and take prompt action, especially for vaccines under national immunization programs. In this study, we assessed the applicability of change point analysis (CPA) for signal detection in vaccine safety surveillance. The performances of three CPA methods, namely Bayesian change point analysis, Taylor's change point analysis (Taylor-CPA), and environmental time series change point detection (EnvCpt), were assessed via simulated data with assumptions for the baseline number of events and degrees of change. The analysis was validated using the Korea Adverse Event Reporting System (KAERS) database. In the simulation study, the Taylor-CPA method exhibited better results for the detection of a change point (accuracy of 96% to 100%, sensitivity of 7% to 100%, specificity of 98% to 100%, positive predictive value of 25% to 85%, negative predictive value of 96% to 100%, and balanced accuracy of 53% to 100%) than the other two CPA methods. When the CPA methods were applied to reports of syncope or dizziness following human papillomavirus (HPV) immunization in the KAERS database, Taylor-CPA and EnvCpt detected a change point (Q2/2013), which was consistent with actual public safety concerns. CPA can be applied as an efficient tool for the early detection of vaccine safety signals.

Inhaled Corticosteroids and COVID-19 Risk and Mortality: A Nationwide Cohort Study.

Inhaled corticosteroids (ICS) could increase both the risk of coronavirus disease 2019 (COVID-19) and experiencing poor outcomes. To compare the clinical outcomes between ICS users and nonusers, COVID-19-related claims in the Korean Health Insurance Review and Assessment database were evaluated. To evaluate susceptibility to COVID-19 among patients with COPD or asthma, a nested case-control study was performed using the same database. In total, 7341 patients were confirmed to have COVID-19, including 114 ICS users and 7227 nonusers. Among 5910 patients who were hospitalized, death was observed for 9% of ICS users and 4% of nonusers. However, this association was not significant when adjusted for age, sex, region, comorbidities, and hospital type (aOR, 0.94; 95% CI, 0.43-2.07). The case-control analysis of COPD compared 640 cases with COVID-19 to 2560 matched controls without COVID-19, and the analysis of asthma compared 90 cases with COVID-19 to 360 matched controls without COVID-19. Use of ICS was not significantly associated with COVID-19 among patients with COPD (aOR, 1.02; 95% CI, 0.46-2.25) or asthma (aOR, 0.38; 95% CI, 0.13-1.17). Prior ICS use was not significantly associated with COVID-19 in patients with COPD or asthma, nor with clinical outcomes among patients with COVID-19.

Concomitant Use of NSAIDs or SSRIs with NOACs Requires Monitoring for Bleeding.

PURPOSE: Non-vitamin K antagonist oral anticoagulants (NOACs) are widely used in patients with atrial fibrillation (AF) because of their effectiveness in preventing stroke and their better safety, compared with warfarin. However, there are concerns for an increased risk of bleeding associated with concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) or selective serotonin reuptake inhibitors (SSRIs) with NOACs. In this study, we aimed to evaluate the risk of bleeding events in individuals taking concomitant NSAIDs or SSRIs with NOACs after being diagnosed with AF. MATERIALS AND METHODS: A nested case-control analysis to assess the safety of NSAIDs and SSRIs among NOAC users with AF was performed using data from Korean National Health Insurance Service from January 2012 to December 2017. Among patients who were newly prescribed NOACs, 1233 cases hospitalized for bleeding events were selected, and 24660 controls were determined. RESULTS: The risk of bleeding events was higher in patients receiving concomitant NSAIDs [adjusted odds ratio (aOR) 1.41; 95% confidence interval (CI) 1.24-1.61] or SSRIs (aOR 1.92; 95% CI 1.52-2.42) with NOACs, compared to no use of either drug, respectively. The risk of upper gastrointestinal bleeding was higher in patients receiving concomitant NSAIDs or SSRIs without proton pump inhibitors (PPIs) (NSAIDs: aOR 2.47; 95% CI 1.26-4.83, SSRI: aOR 10.8; 95% CI 2.41-2.48) compared to no use. CONCLUSION: When NSAIDs or SSRIs are required for NOAC users with AF, physicians need to monitor bleeding events and consider the use of PPIs, especially for combined use of both drugs or when initiating NOACs treatment.

Association of Renin-angiotensin-aldosterone System Inhibitors With Coronavirus Disease 2019 (COVID-19)- Related Outcomes in Korea: A Nationwide Population-based Cohort Study.

BACKGROUND: Renin-angiotensin-aldosterone system (RAAS) inhibitors may facilitate host cell entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or attenuate organ injury via RAAS blockade. We aimed to assess the associations between prior use of RAAS inhibitors and clinical outcomes among Korean patients with coronavirus disease 2019 (COVID-19). METHODS: We performed a nationwide population-based cohort study using the Korean Health Insurance Review and Assessment database. Claim records were screened for 69 793 individuals who were tested for COVID-19 until 8 April 2020. Adjusted odds ratios (ORs) were used to compare the clinical outcomes between RAAS inhibitor users and nonusers. RESULTS: Among 5179 confirmed COVID-19 cases, 762 patients were RAAS inhibitor users and 4417 patients were nonusers. Relative to nonusers, RAAS inhibitor users were more likely to be older, male, and have comorbidities. Among 1954 hospitalized patients with COVID-19, 377 patients were RAAS inhibitor users, and 1577 patients were nonusers. In-hospital mortality was observed for 33 RAAS inhibitor users (9%) and 51 nonusers (3%) (P < .001). However, after adjustment for age, sex, Charlson comorbidity index, immunosuppression, and hospital type, the use of RAAS inhibitors was not associated with a higher risk of mortality (adjusted OR, 0.88; 95% confidence interval, 0.53-1.44; P = .60). No significant differences were observed between RAAS inhibitor users and nonusers in terms of vasopressor use, modes of ventilation, extracorporeal membrane oxygenation, renal replacement therapy, and acute cardiac events. CONCLUSIONS: Our findings suggest that prior use of RAAS inhibitors was not independently associated with mortality among COVID-19 patients in Korea.

Conducting and Reporting a Clinical Research Using Korean Healthcare Claims Database.

An increasing number of studies are using healthcare claims databases to assess healthcare intervention utilization patterns or outcomes in real-world clinical settings. However, methodological issues affecting study design or data analysis can make conducting and reporting these types of studies difficult. This review presents an overview of the types of information contained in claims data, describes some advantages and limitations of using claims data for research purposes, and outlines steps for utilizing the Korea Health Insurance Review and Assessment and National Health Insurance Service databases. The study also reviews epidemiological approaches utilizing healthcare claims databases (including cross-sectional, case-control, case-crossover, and cohort designs) with respect to protocol development, analysis, and reporting of results, and introduces relevant guidelines and checklists, including the Guidelines for Good Pharmacoepidemiology Practices, the Strengthening the Reporting of Observational Studies in Epidemiology checklist, and the Risk of Bias in Nonrandomized Studies of Interventions tool.

Duplicated tramadol use in chronic low back pain: A nationwide cross-sectional study.

Tramadol is a weak opioid that is commonly used for chronic low back pain (LBP). Despite its effectiveness, duplicated use of tramadol, which may indicate abuse or dependence, may exacerbate potential adverse reactions. This population-based, cross-sectional study aimed to investigate the prevalence of duplication of tramadol and its associated factors among patients with LBP. From a Korean nationwide claims database, non-hospitalized patients aged 40-99 years with LBP without malignancy were prescribed tramadol during 2014-2016. Duplication of tramadol was defined as overlapping of prescription days. Among them, we defined "extensive duplication (ED)" when days of tramadol duplication cover 10% or more of the days prescribed tramadol. Patient and healthcare utilization factors associated with ED were examined using a logistic regression model. The study population was 6 417 503 patients. Of these, 13.7% were ED users. The age- and sex-standardized prevalence of using tramadol twice or more a year was 14.06 per 100 people in 2014, 13.74 per 100 people in 2015 and 13.52 per 100 people in 2016. ED occurred more in those in the group aged 70-79 years (OR 1.12, 95% CI 1.11-1.13) than 40-49 years and in those with comorbidities, such as drug abuse (OR 2.99, 95% CI 2.05-4.36) or depression (OR 1.75, 95% CI 1.72-1.77). Based on the results of this study, a proper management system is needed to avoid tramadol duplication among older people and patients with drug abuse or depression.