Interstitial lung disease following COVID-19 vaccination: a disproportionality analysis using the Global Scale Pharmacovigilance Database (VigiBase).

BACKGROUND AND OBJECTIVE: Despite several case reports, population-based studies on interstitial lung disease (ILD) following COVID-19 vaccination are lacking. Given the unprecedented safety issue of COVID-19 vaccination, it is important to assess the worldwide patterns of ILD following COVID-19 vaccination. This study aimed to investigate the signals of COVID-19 vaccine-associated ILD compared with other vaccinations using disproportionality analysis. METHODS: We analysed the VigiBase database during the period between 13 December 2020 and 26 January 2023. We adopted the case/non-case approach to assess the disproportionality signal of ILD for COVID-19 vaccines via 1:10 matching by age and sex. We compared COVID-19 vaccines with all other vaccines as the reference group. RESULTS: Among 1 233 969 vaccine-related reports, 679 were reported for ILD. The majority of ILD cases were related to tozinameran (376 reports, 55.4%), Vaxzevria (129 reports, 19.0%) and elasomeran (78 reports, 11.5%). The reporting OR of ILD following COVID-19 vaccination was 0.86 (95% CI 0.64 to 1.15) compared with all other vaccines. CONCLUSION: No significant signal of disproportionate reporting of ILD was observed for COVID-19 vaccines compared with all other vaccines. Moreover, when compared with the influenza vaccines that are known to cause ILD, no signal was observed. This study results might help decision-making on the subsequent COVID-19 vaccination strategy of ILD. Further large and prospective studies are required for more conclusive evidence.

Cardiovascular outcomes between COVID-19 and non-COVID-19 pneumonia: a nationwide cohort study.

BACKGROUND: Previous studies that assessed the risk of cardiovascular outcomes in survivors of coronavirus disease 2019 (COVID-19) were likely limited by lack of generalizability and selection of controls nonrepresentative of a counterfactual situation regarding COVID-19-related hospitalization. This study determined whether COVID-19 hospitalization was associated with incident cardiovascular outcomes compared to non-COVID-19 pneumonia hospitalization. METHODS: Nationwide population-based study conducted using the Korean National Health Insurance Service database. A cohort of 132,784 inpatients with COVID-19 (October 8, 2020-September 30, 2021) and a cohort of 31,173 inpatients with non-COVID-19 pneumonia (January 1-December 31, 2019) were included. The primary outcome was the major adverse cardiovascular event (MACE; a composite of myocardial infarction and stroke). Hazard ratios (HRs) with 95% confidence intervals (CIs) of all outcomes of interest were estimated between inverse probability of treatment-weighted patients with COVID-19 and non-COVID-19 pneumonia. RESULTS: After weighting, the COVID-19 and non-COVID-19 pneumonia groups included 125,810 (mean [SD] age, 47.2 [17.6] years; men, 49.3%) and 28,492 patients (mean [SD] age, 48.6 [18.4] years; men, 47.2%), respectively. COVID-19 hospitalization was not associated with an increased risk of the MACE (HR, 0.84; 95% CI 0.69-1.03). However, the MACE (HR, 7.30; 95% CI 3.29-16.21), dysrhythmia (HR, 1.88; 95% CI 1.04-3.42), acute myocarditis (HR, 11.33; 95% CI 2.97-43.20), myocardial infarction (HR, 6.78; 95% CI 3.03-15.15), congestive heart failure (HR, 1.95; 95% CI 1.37-2.77), and thrombotic disease (HR, 8.26; 95% CI 4.06-16.83) risks were significantly higher in patients with COVID-19 aged 18-39 years. The findings were consistent after adjustment for preexisting cardiovascular disease. COVID-19 hospitalization conferred a higher risk of acute myocarditis (HR, 6.47; 95% CI 2.53-16.52) or deep vein thrombosis (HR, 1.97; 95% CI 1.38-2.80), regardless of vaccination status. CONCLUSIONS: Hospitalized patients with COVID-19 were not at an increased risk of cardiovascular outcomes compared to patients with non-COVID-19 pneumonia. Further studies are needed to evaluate whether the increased risk of cardiovascular outcomes is confined to younger patients.

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.

Vitamin C for ≥ 5 days is associated with decreased hospital mortality in sepsis subgroups: a nationwide cohort study.

BACKGROUND: Previous randomized trials of vitamin C, hydrocortisone, and thiamine on sepsis were limited by short-term vitamin C administration, heterogeneous populations, and the failure to evaluate each component's effect. The purpose of this study was to determine whether vitamin C alone for ≥ 5 days or in combination with corticosteroids and/or thiamine was associated with decreased mortality across the sepsis population and subpopulation. METHODS: Nationwide population-based study conducted using the Korean National Health Insurance Service database. A total of 384,282 adult patients with sepsis who were admitted to the intensive care unit were enrolled from January 2017 to December 2019. The primary outcome was hospital mortality, while the key secondary outcome was 90-day mortality. RESULTS: The mean [standard deviation] age was 69.0 [15.4] years; 57% were male; and 36,327 (9%) and 347,955 did and did not receive vitamin C, respectively. After propensity score matching, each group involved 36,327 patients. The hospital mortality was lower by - 0.9% in the treatment group (17.1% vs 18.0%; 95% confidence interval, - 1.3 to - 0.5%; p < 0.001), a significant but extremely small difference. However, mortality decreased greater in patients who received vitamin C for ≥ 5 days (vs 1-2 or 3-4 days) (15.8% vs 18.8% vs 18.3%; p < 0.001). Further, vitamin C was associated with a lower hospital mortality in patients with older age, multiple comorbidities, pneumonia, genitourinary infection, septic shock, and mechanical ventilation. Consistent findings were found for 90-day mortality. Moreover, vitamin C alone or in combination with thiamine was significantly associated with decreased hospital mortality. CONCLUSIONS: Intravenous vitamin C of ≥ 5 days was significantly associated with decreased hospital and 90-day mortality in sepsis patients. Vitamin C combined with corticosteroids and/or thiamine in specific sepsis subgroups warrants further study.

COVID-19-related outcomes in immunocompromised patients: A nationwide study in Korea.

BACKGROUND: Given the rapid increased in confirmed coronavirus disease 2019 (COVID-19) and related mortality, it is important to identify vulnerable patients. Immunocompromised status is considered a risk factor for developing severe COVID-19. We aimed to determine whether immunocompromised patients with COVID-19 have an increased risk of mortality. METHOD: The groups' baseline characteristics were balanced using a propensity score-based inverse probability of treatment weighting approach. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated for the risks of in-hospital mortality and other outcomes according to immunocompromised status using a multivariable logistic regression model. We identified immunocompromised status based on a diagnosis of malignancy or HIV/AIDS, having undergone organ transplantation within 3 years, prescriptions for corticosteroids or oral immunosuppressants for ≥30 days, and at least one prescription for non-oral immunosuppressants during the last year. RESULTS: The 6,435 COVID-19 patients (≥18 years) included 871 immunocompromised (13.5%) and 5,564 non-immunocompromised (86.5%). Immunocompromised COVID-19 patients were older (60.1±16.4 years vs. 47.1±18.7 years, absolute standardized mean difference: 0.738). The immunocompromised group had more comorbidities, a higher Charlson comorbidity index, and a higher in-hospital mortality rate (9.6% vs. 2.3%; p < .001). The immunocompromised group still had a significantly higher in-hospital mortality rate after inverse probability of treatment weighting (6.4% vs. 2.0%, p < .001). Multivariable analysis adjusted for baseline imbalances revealed that immunocompromised status was independently associated with a higher risk of mortality among COVID-19 patients (adjusted odds ratio [aOR]: 2.09, 95% CI: 1.62-2.68, p < .001). CONCLUSIONS: Immunocompromised status among COVID-19 patients was associated with a significantly increased risk of mortality.

Early Vitamin C, Hydrocortisone, and Thiamine Treatment for Septic Cardiomyopathy: A Propensity Score Analysis.

This study investigated the effectiveness of early vitamin C, hydrocortisone, and thiamine among patients with septic cardiomyopathy. In total, 91 patients with septic cardiomyopathy received a vitamin C protocol in September 2018-February 2020. These patients were compared to 75 patients with septic cardiomyopathy who did not receive a vitamin C protocol in September 2016-February 2018. Relative to the control patients, the treated patients were older and more likely to require mechanical ventilation. The vitamin C protocol was associated with a lower risk of intensive care unit mortality in the propensity score (PS)-matched cohort (aHR: 0.55, 95% CI: 0.30-0.99) and inverse probability of treatment weighting-matched cohort (aHR: 0.67, 95% CI: 0.45-1.00). In the PS-matched cohort (59 patients per group), the vitamin C protocol was associated with decreased values for vasopressor dosage, C-reactive protein concentration, and the Sequential Organ Failure Assessment score during the 4-day treatment period. Patients who started the vitamin C protocol within 2 h after diagnosis (vs. 2-8 h or ≥8 h) had the highest vasopressor weaning rate and the lowest mortality rate. These results suggest that early treatment using a vitamin C protocol might improve organ dysfunction and reduce mortality among patients with septic cardiomyopathy.

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.

Characterizing tramadol users with potentially inappropriate co-medications: A latent class analysis among older adults.

BACKGROUND: Although tramadol is an effective weak opioid analgesic, careful monitoring of potential central nervous system adverse reactions in older adults is needed, especially when used with concomitant medications which may trigger the adverse effects. We aimed to characterize tramadol users with potentially inappropriate co-medications in older adults using a latent class analysis (LCA). METHOD: Patients aged 65 years or older using tramadol and receiving potentially inappropriate co-medications were included from a nationwide healthcare claims database. We defined antidepressants, first-generation antihistamines, and anxiolytics as potentially inappropriate co-medications. We applied an LCA for grouping tramadol users based on the common characteristics of medication use and healthcare utilization, and each patient was probabilistically assigned to a class. Patients' characteristics in different latent classes were compared. Potential adverse drug reactions (ADRs) was defined as the any visits for emergency department after the occurrence of potentially inappropriate co-medications. Logistic regression analysis was used to examine the association between latent classes and potential ADRs. RESULTS: We identified four distinct latent classes of tramadol users representing different patterns of co-medications: multiple potential drug-drug interaction (pDDI) combination users, antihistamines-tramadol users, antidepressants-tramadol users, and anxiolytics-tramadol users. Multiple pDDI combination users showed high proportion of regular tramadol use, tended to visit more medical institutions, and had a high Charlson comorbidity score. The duration of use of potentially inappropriate co-medications with tramadol was the longest in multiple pDDI combination users and the shortest in antihistamines-tramadol users. When compared with antihistamines-tramadol users, increased potential ADR risk was observed in multiple pDDI combination users (adjusted odds ratio (OR), 1.81; 95% confidence interval (CI), 1.75-1.88), antidepressants-tramadol users (1.24; 1.19-1.29), and anxiolytics-tramadol users (1.04; 1.00-1.08). CONCLUSIONS: Four distinct classes were identified among older adults using tramadol and potentially inappropriate co-medications. Differences in potential ADR risk were observed between these classes. These findings may help to identify patients at a high risk for ADRs owing to potentially inappropriate co-medications with tramadol.

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.

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.