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BACKGROUND: Several cases of renal complications, including acute kidney injury (AKI), after influenza vaccination have been reported, but the association remains unproven. We evaluated the association between influenza vaccination and AKI occurrence among the Korean elderly in the 2018-2019 and 2019-2020 seasons. METHODS: We used a large database combining vaccination registration data from the Korea Disease Control and Prevention Agency and claims data from the National Health Insurance Service. The study subjects were patients hospitalized with AKI for the first-time following vaccination among those who received one influenza vaccine in the 2018-2019 or 2019-2020 season. Only those aged 65 or older at the date of vaccination were included. We performed a self-controlled case series study, designating the risk period as 1 to 28 days post-vaccination and the observation period as each influenza season. The adjusted incidence rate ratio (aIRR) was calculated by adjusting for nephrotoxic drug use and influenza infection that may influence AKI occurrence using a conditional Poisson regression model. RESULTS: A total of 16 713 and 16 272 AKI events were identified during the 2018-2019 and 2019-2020 seasons, respectively. The aIRR for AKI was 0.83 (95% confidence interval [CI] = 0.79-0.87) in the 2018-2019 season. The aIRR for the 2019-2020 influenza season was similar to the 2018-2019 season (aIRR = 0.86; 95% CI = 0.82-0.90). CONCLUSIONS: Influenza vaccination is associated with a lower risk of AKI in the elderly over 65. This evidence supports the recommendation of annual influenza vaccination for the elderly. Further studies are needed to determine the biological mechanisms linking the influenza vaccine and AKI.
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Lesión Renal Aguda , Vacunas contra la Influenza , Gripe Humana , Humanos , Vacunas contra la Influenza/efectos adversos , Vacunas contra la Influenza/administración & dosificación , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/etiología , Anciano , Masculino , Femenino , Gripe Humana/prevención & control , Gripe Humana/epidemiología , República de Corea/epidemiología , Anciano de 80 o más Años , Incidencia , Vacunación/efectos adversos , Vacunación/estadística & datos numéricos , Bases de Datos Factuales , Hospitalización/estadística & datos numéricos , Estaciones del Año , Factores de RiesgoRESUMEN
OBJECTIVES: The prior event rate ratio is a recently developed approach for controlling confounding by measured and unmeasured covariates in real-world evidence research and observational studies. Despite its rising popularity in studies of safety and effectiveness of biopharmaceutical products, there is no guidance on how to empirically evaluate its model assumptions. We propose two methods to evaluate two of the assumptions required by the prior event rate ratio, specifically, the assumptions that occurrence of outcome events does not alter the likelihood of receiving treatment, and that earlier event rate does not affect later event rate. STUDY DESIGN AND SETTING: We propose using self-controlled case series (SCCS) and dynamic random intercept modelling (DRIM) respectively, to evaluate the two aforementioned assumptions. A non-mathematical introduction of the methods and their application to evaluate the assumptions are provided. We illustrate the evaluation with secondary analysis of de-identified data on pneumococcal vaccination and clinical pneumonia in The Gambia, West Africa. RESULTS: SCCS analysis of data on 12,901 vaccinated Gambian infants did not reject the assumption of clinical pneumonia episodes had no influence on the likelihood of pneumococcal vaccination. DRIM analysis of 14,325 infants with a total of 1,719 episodes of clinical pneumonia did not reject the assumption of earlier episodes of clinical pneumonia had no influence on later incidence of the disease. CONCLUSION: The SCCS and DRIM methods can facilitate appropriate use of the prior event rate ratio approach to control confounding.
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BACKGROUND: The role of children and staff in SARS-CoV-2 transmission outside and within households is still not fully understood when large numbers are in regular, frequent contact in schools. METHODS: We used the self-controlled case-series method during the alpha- and delta-dominant periods to explore the incidence of infection in periods around a household member infection, relative to periods without household infection, in a cohort of primary and secondary English schoolchildren and staff from November 2020 to July 2021. RESULTS: We found the relative incidence of infection in students and staff was highest in the 1-7 days following household infection, remaining high up to 14 days after, with risk also elevated in the 6--12 days before household infection. Younger students had a higher relative incidence following household infection, suggesting household transmission may play a more prominent role compared with older students. The relative incidence was also higher among students in the alpha variant dominant period. CONCLUSIONS: This analysis suggests SARS-CoV2 infection in children, young people and staff at English schools were more likely to be associated with within-household transmission than from outside the household, but that a small increased risk of seeding from outside is observed.
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COVID-19 , Composición Familiar , SARS-CoV-2 , Instituciones Académicas , Estudiantes , Humanos , COVID-19/epidemiología , COVID-19/transmisión , Niño , Inglaterra/epidemiología , Incidencia , Estudiantes/estadística & datos numéricos , Femenino , Masculino , Adolescente , Adulto , Adulto Joven , Persona de Mediana EdadRESUMEN
The self-controlled case-series (SCCS) research design is increasingly used in pharmacoepidemiologic studies of drug-drug interactions (DDIs), with the target of inference being the incidence rate ratio (IRR) associated with concomitant exposure to the object plus precipitant drug versus the object drug alone. While day-level drug exposure can be inferred from dispensing claims, these inferences may be inaccurate, leading to biased IRRs. Grace periods (periods assuming continued treatment impact after days' supply exhaustion) are frequently used by researchers, but the impact of grace period decisions on bias from exposure misclassification remains unclear. Motivated by an SCCS study examining the potential DDI between clopidogrel (object) and warfarin (precipitant), we investigated bias due to precipitant or object exposure misclassification using simulations. We show that misclassified precipitant treatment always biases the estimated IRR toward the null, whereas misclassified object treatment may lead to bias in either direction or no bias, depending on the scenario. Further, including a grace period for each object dispensing may unintentionally increase the risk of misclassification bias. To minimize such bias, we recommend 1) avoiding the use of grace periods when specifying object drug exposure episodes; and 2) including a washout period following each precipitant exposed period.
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BACKGROUND AND AIMS: Concerns about the safety of coronavirus disease 2019 (COVID-19) vaccines in patients with atrial fibrillation/flutter (AF/AFL) have arisen due to reports of thrombo-embolic events following COVID-19 vaccination in the general population. This study aimed to evaluate the risk of thrombo-embolic events after COVID-19 vaccination in patients with AF/AFL. METHODS: This was a modified self-controlled case-series study using a comprehensive nationwide-linked database provided by the National Health Insurance Service in South Korea to calculate incidence rate ratios (IRRs) of thrombo-embolic events. The study population included individuals aged ≥12 years who were either vaccinated (e.g. one or two doses) or unvaccinated during the period from February to December 2021. The primary outcome was a composite of thrombo-embolic events, including ischaemic stroke, transient ischaemic attack, and systemic thromboembolism. The risk period was defined as 0-21 days following COVID-19 vaccination. RESULTS: The final analysis included 124 127 individuals with AF/AFL. The IRR of thrombo-embolic events within 21 days after COVID-19 vaccination, compared with that during the unexposed control period, was 0.93 [95% confidence interval (CI) 0.77-1.12]. No significant risk variations were noted by sex, age, or vaccine type. However, patients without anticoagulant therapy had an IRR of 1.88 (95% CI 1.39-2.54) following vaccination. CONCLUSIONS: In patients with AF/AFL, COVID-19 vaccination was generally not associated with an increased risk of thrombo-embolic events. However, careful individual risk assessment is required when advising vaccination for those not on oral anticoagulant, as these patients exhibited an increased risk of thrombo-embolic events post-vaccination.
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Fibrilación Atrial , Vacunas contra la COVID-19 , COVID-19 , Tromboembolia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Fibrilación Atrial/epidemiología , Aleteo Atrial/epidemiología , COVID-19/prevención & control , COVID-19/epidemiología , COVID-19/complicaciones , Vacunas contra la COVID-19/efectos adversos , Incidencia , República de Corea/epidemiología , Tromboembolia/prevención & control , Tromboembolia/epidemiología , Tromboembolia/etiología , Vacunación/efectos adversosRESUMEN
Confounding by indication is a key challenge for pharmacoepidemiologists. Although self-controlled study designs address time-invariant confounding, indications sometimes vary over time. For example, infection might act as a time-varying confounder in a study of antibiotics and uveitis, because it is time-limited and a direct cause both of receiving antibiotics and uveitis. Methods for incorporating active comparators in self-controlled studies to address such time-varying confounding by indication have only recently been developed. In this paper we formalize these methods, and provide a detailed description for how the active comparator rate ratio can be derived in a self-controlled case series (SCCS): either by explicitly comparing the regression coefficients for a drug of interest and an active comparator under certain circumstances using a simple ratio approach, or through the use of a nested regression model. The approaches are compared in two case studies, one examining the association between thiazolidinediones and fractures, and one examining the association between fluoroquinolones and uveitis using the UK Clinical Practice Research DataLink. Finally, we provide recommendations for the use of these methods, which we hope will support the design, execution and interpretation of SCCS using active comparators and thereby increase the robustness of pharmacoepidemiological studies.
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BACKGROUND: The self-controlled case series (SCCS) is often used to monitor vaccine safety. The evaluation of intussusception after the rotavirus vaccine is complicated because the baseline rate varies with age. Time-varying baseline risk adjustments with data from unexposed cohorts are utilised. Self-controlled risk interval (SCRI), with a shorter observation period, can also mitigate the problem by studying a control period close to the risk period. OBJECTIVE: An Indian rotavirus vaccine has previously been studied using SCCS. The risk of intussusception in the high-risk windows (21 days after vaccination) was comparable to the background risk. The aim was to re-analyse data of an existing SCCS study using alternate statistical methods to examine vaccine safety. METHODS: We examined the mean age of intussusception in the vaccinated and the unvaccinated. We performed an SCRI analysis of the surveillance data from the SCCS study, limiting the observation period to 180 days. We analysed the time-to-intussusception from the last vaccination. Finally, we performed an SCCS analysis, excluding unvaccinated cases from the analysis. RESULTS: We found that the mean age of intussusception was significantly lower in the vaccinated (205 days) compared to the unvaccinated (223 days) (p-value 0.0026). The Incident Risk Ratio (IRR) on SCRI analysis was 1.62 (95% CI 1.07-2.44). There were significantly more intussusceptions in the first 30 days after vaccination compared to the next 30-day window. (92 vs 63 p-value = 0.009). We found that excluding unvaccinated infants from the SCCS analysis demonstrated significantly increased risk for the risk period 1-21 days after the 3rd dose (IRR 2.47, 95% CI 1.70-3.59). The risks of intussusception were missed in traditional SCCS analysis using unvaccinated infants as controls. CONCLUSION: Traditional risk adjustments using data from unexposed cohorts in SCCS may not be appropriate for investigating the risk of intussusception where vaccination lowers the mean age of intussusception.
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Intususcepción , Vacunas contra Rotavirus , Humanos , Lactante , India/epidemiología , Intususcepción/inducido químicamente , Intususcepción/epidemiología , Infecciones por Rotavirus/prevención & control , Infecciones por Rotavirus/epidemiología , Vacunas contra Rotavirus/efectos adversos , Factores de TiempoRESUMEN
BACKGROUND: The potential association between bivalent COVID-19 vaccination and ischemic stroke remains uncertain, despite several studies conducted thus far. OBJECTIVE: This study aimed to evaluate the risk of ischemic stroke following bivalent COVID-19 vaccination during the 2022-2023 season. METHODS: A self-controlled case series study was conducted among members aged 12 years and older who experienced ischemic stroke between September 1, 2022, and March 31, 2023, in a large health care system. Ischemic strokes were identified using International Classification of Diseases, Tenth Revision codes in emergency departments and inpatient settings. Exposures were Pfizer-BioNTech or Moderna bivalent COVID-19 vaccination. Risk intervals were prespecified as 1-21 days and 1-42 days after bivalent vaccination; all non-risk-interval person-time served as the control interval. The incidence of ischemic stroke was compared in the risk interval and control interval using conditional Poisson regression. We conducted overall and subgroup analyses by age, history of SARS-CoV-2 infection, and coadministration of influenza vaccine. When an elevated risk was detected, we performed a chart review of ischemic strokes and analyzed the risk of chart-confirmed ischemic stroke. RESULTS: With 4933 ischemic stroke events, we found no increased risk within the 21-day risk interval for the 2 vaccines and by subgroups. However, risk of ischemic stroke was elevated within the 42-day risk interval among individuals aged younger than 65 years with coadministration of Pfizer-BioNTech bivalent and influenza vaccines on the same day; the relative incidence (RI) was 2.13 (95% CI 1.01-4.46). Among those who also had a history of SARS-CoV-2 infection, the RI was 3.94 (95% CI 1.10-14.16). After chart review, the RIs were 2.34 (95% CI 0.97-5.65) and 4.27 (95% CI 0.97-18.85), respectively. Among individuals aged younger than 65 years who received Moderna bivalent vaccine and had a history of SARS-CoV-2 infection, the RI was 2.62 (95% CI 1.13-6.03) before chart review and 2.24 (95% CI 0.78-6.47) after chart review. Stratified analyses by sex did not show a significantly increased risk of ischemic stroke after bivalent vaccination. CONCLUSIONS: While the point estimate for the risk of chart-confirmed ischemic stroke was elevated in a risk interval of 1-42 days among individuals younger than 65 years with coadministration of Pfizer-BioNTech bivalent and influenza vaccines on the same day and among individuals younger than 65 years who received Moderna bivalent vaccine and had a history of SARS-CoV-2 infection, the risk was not statistically significant. The potential association between bivalent vaccination and ischemic stroke in the 1-42-day analysis warrants further investigation among individuals younger than 65 years with influenza vaccine coadministration and prior SARS-CoV-2 infection. Furthermore, the findings on ischemic stroke risk after bivalent COVID-19 vaccination underscore the need to evaluate monovalent COVID-19 vaccine safety during the 2023-2024 season.
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Vacunas contra la COVID-19 , COVID-19 , Accidente Cerebrovascular Isquémico , Humanos , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/etiología , Persona de Mediana Edad , Masculino , Femenino , Adulto , Anciano , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/administración & dosificación , Adulto Joven , Adolescente , COVID-19/prevención & control , COVID-19/epidemiología , Niño , Anciano de 80 o más Años , IncidenciaRESUMEN
The assumption that serious adverse events (SAEs) do not affect subsequent exposure might not hold when evaluating 2-dose vaccine safety through a self-controlled case series (SCCS) design. To address this, we developed: 1) propensity score SCCS (PS-SCCS) using a propensity score model involving SAEs during the risk interval after dose 1 (${R}_1\Big)$, and 2) partitioned SCCS (P-SCCS) estimating relative incidence (RI) separately for doses 1 and 2. In simulations, both provided unbiased RIs. Conversely, standard SCCS overestimated RI after dose 2. We applied these approaches to assess myocarditis/pericarditis risks after 2-dose mRNA COVID-19 vaccination in 12-39-year-olds. For BNT162b2, PS-SCCS yielded RIs of 1.85 (95% CI, 0.75-4.59) and 11.05 (95% CI, 6.53-18.68) 14 days after doses 1 and 2 respectively; standard SCCS provided similar RI after dose 1 and RI of 12.92 (95% CI, 7.56-22.09) after dose 2. For mRNA-1273, standard SCCS showed RIs of 1.96 (95% CI, 0.56-6.91) after dose 1 and 7.87 (95% CI, 3.33-18.57) after dose 2. As no mRNA-1273 recipients with SAEs during ${R}_1$ received dose 2, P-SCCS was used, yielding similar RI after dose 1 and RI of 6.48 (95% CI, 2.83-14.83) after dose 2. mRNA vaccines were associated with elevated myocarditis/pericarditis risks following dose 2 in 12-39-year-olds.
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BACKGROUND: Cancer patients have an increased risk of cardiovascular outcomes and are susceptible to coronavirus disease 2019 (COVID-19) infection. We aimed to assess the cardiovascular safety of COVID-19 vaccination for cancer patients in South Korea. METHODS: We conducted a self-controlled case series study using the K-COV-N cohort (2018-2021). Patients with cancer aged 12 years or older who experienced cardiovascular outcomes were identified. Cardiovascular outcomes were defined as myocardial infarction, stroke, venous thromboembolism (VTE), myocarditis, or pericarditis, and the risk period was 0-28 days after receiving each dose of COVID-19 vaccines. A conditional Poisson regression model was used to calculate the incidence rate ratio (IRR) with 95% confidence interval (CI). RESULTS: Among 318,105 patients with cancer, 4,754 patients with cardiovascular outcomes were included. The overall cardiovascular risk was not increased (adjusted IRR, 0.99 [95% CI, 0.90-1.08]) during the whole risk period. The adjusted IRRs of total cardiovascular outcomes during the whole risk period according to the vaccine type were 1.07 (95% CI, 0.95-1.21) in the mRNA vaccine subgroup, 0.99 (95% CI, 0.83-1.19) in the ChAdOx1 nCoV-19 vaccine subgroup, and 0.86 (95% CI, 0.68-1.10) in the mix-matched vaccination subgroup. However, in the analysis of individual outcome, the adjusted IRR of myocarditis was increased to 11.71 (95% CI, 5.88-23.35) during the whole risk period. In contrast, no increased risk was observed for other outcomes, such as myocardial infarction, stroke, VTE, and pericarditis. CONCLUSION: For cancer patients, COVID-19 vaccination demonstrated an overall safe profile in terms of cardiovascular outcomes. However, caution is required as an increased risk of myocarditis following COVID-19 vaccination was observed in this study.
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Vacunas contra la COVID-19 , COVID-19 , Neoplasias , SARS-CoV-2 , Humanos , Masculino , Femenino , República de Corea/epidemiología , Vacunas contra la COVID-19/efectos adversos , COVID-19/prevención & control , COVID-19/epidemiología , Persona de Mediana Edad , Anciano , SARS-CoV-2/aislamiento & purificación , Adulto , Infarto del Miocardio/etiología , Infarto del Miocardio/epidemiología , Enfermedades Cardiovasculares/etiología , Vacunación/efectos adversos , Miocarditis/etiología , ChAdOx1 nCoV-19 , Tromboembolia Venosa/etiología , Tromboembolia Venosa/prevención & control , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/epidemiología , Adulto Joven , Adolescente , Pericarditis/etiología , Pericarditis/epidemiologíaRESUMEN
Proton-pump inhibitors (PPI) are empirically used to treat asthma symptoms such as cough; however, the effectiveness of PPI on asthma exacerbation has not been well studied. We aimed to evaluate the relationship between PPI use and asthma exacerbation using a large administrative claims database in Japan. We conducted a self-controlled case series using the JMDC Claims Database (JMDC, Inc., Tokyo, Japan). The cases included adult patients with asthma who were prescribed PPI and experienced at least one outcome event between January 2015 and December 2019. The primary outcome was the composite outcome of hospital admissions and unscheduled outpatient clinic visits due to asthma exacerbation. We also conducted stratified analyses based on PPI generation, the presence of gastroesophageal reflux disease (GERD), asthma severity, and the number of allergic comorbidities. A total of 7379 eligible patients were included in the study. PPI prescription was associated with a decrease in the composite outcomes (incidence rate ratio, 0.90; 95% confidence interval, 0.87-0.93). However, PPI prescriptions did not affect the outcomes of hospital admissions (incidence rate ratio, 1.34; 95% confidence interval, 0.86-2.10). Stratified analyses based on PPI generation, the presence of GERD, asthma severity (except for severe asthma), and the number of allergic comorbidities yielded consistent results. PPI use was associated with a moderate decrease in asthma exacerbation, regardless of the patient profile. However, this effect was not as strong as the prevention of hospital admissions, and outcome events were not prevented in patients with severe asthma.
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The author believes that the principles of statistical methods for vaccine safety can be divided into three categories: comparison of adverse event incidence rates between vaccinated and unvaccinated groups, analysis of incidentality in the vaccinated group, and a combination of both. The first category includes the cohort study; the second, the self-controlled risk interval design (SCRI); and the third, the self-controlled case series method. A single p-value alone should not determine a scientific conclusion, and analysis should be performed using multiple statistical methods with different principles. The author believes that using both the cohort study and the SCRI for analysis is the best method to assess vaccine safety. When the cohort study may not detect a significant difference owing to a low incidence rate of an adverse event in the vaccinated group or a high one in the unvaccinated group, the SCRI may detect it. Because vaccines must have a higher level of safety than the pharmaceuticals used for treatment, vaccine safety is advisable to be assessed using methods that can detect a significant difference even for any value of the incidence rate of an adverse event. The author believes that the analyses of COVID-19 vaccine safety have areas for improvement because the proportion of papers that used the cohort study and the SCRI was negligible.
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BACKGROUND: Despite publications assuring no increased risk for acute cardiovascular events (excluding myocarditis) and sudden death following administration of COVID19 vaccines, these issues still stir much public ado. We assessed the risk for acute cardiovascular events that require hospitalization (excluding myocarditis) and for mortality in the short-term following administration of the second dose of the Pfizer COVID19 vaccine in Israel. METHODS: Using a self-controlled case series (SCCS) study design and national databases, all second-dose vaccinees, who had not been diagnosed with COVID19 and who had an acute cardiovascular event (acute myocardial infarction/acute stroke/acute thromboembolic event) that required hospitalization in the 60 days following vaccine administration between Jan 11th, 2021 and Oct 31st 2021, were included. A similar analysis was carried out for mortality. The first 30 days following vaccination were defined as risk period while the next 30 days were defined as control period. The probability for an event between these periods was compared using a conditional logistic regression model, accounting for sex, age group, background morbidity and seasonal risk. RESULTS: Out of 5,700,112 second dose vaccinees, 4,163 had an acute cardiovascular event in the 60 days following vaccine administration. Following exclusion of 106 due to technical considerations, 1,979 events occurred during the risk period and 2,078 during the control period: Odds ratio, OR = 0.95, 95% confidence interval, CI 0.90-1.01, p = 0.12. Adjusted OR was similar (OR = 0.88, 95%CI 0.72-1.08). Stratifying by age showed no increased risk in any age group. Mortality assessment indicated low number of events in both periods. These results were consistent in sensitivity analyses. CONCLUSIONS: There was no increased risk for acute cardiovascular events (excluding myocarditis) in the risk period compared to the control period following administration of the second dose of Pfizer COVID19 vaccine. Mortality data raised no concerns either, but may have been biased.
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COVID-19 , Enfermedades Cardiovasculares , Humanos , Masculino , Femenino , Israel/epidemiología , Persona de Mediana Edad , Adulto , Anciano , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/epidemiología , COVID-19/prevención & control , COVID-19/epidemiología , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/efectos adversos , Vacuna BNT162 , Miocarditis/epidemiología , Infarto del Miocardio/epidemiología , Estudios de Casos y Controles , Hospitalización/estadística & datos numéricosRESUMEN
INTRODUCTION: The aim of this study was to assess the possible extent of bias due to violation of a core assumption (event-dependent exposures) when using self-controlled designs to analyse the association between COVID-19 vaccines and myocarditis. METHODS: We used data from five European databases (Spain: BIFAP, FISABIO VID, and SIDIAP; Italy: ARS-Tuscany; England: CPRD Aurum) converted to the ConcePTION Common Data Model. Individuals who experienced both myocarditis and were vaccinated against COVID-19 between 1 September 2020 and the end of data availability in each country were included. We compared a self-controlled risk interval study (SCRI) using a pre-vaccination control window, an SCRI using a post-vaccination control window, a standard SCCS and an extension of the SCCS designed to handle violations of the assumption of event-dependent exposures. RESULTS: We included 1,757 cases of myocarditis. For analyses of the first dose of the Pfizer vaccine, to which all databases contributed information, we found results consistent with a null effect in both of the SCRI and extended SCCS, but some indication of a harmful effect in a standard SCCS. For the second dose, we found evidence of a harmful association for all study designs, with relatively similar effect sizes (SCRI pre = 1.99, 1.40 - 2.82; SCRI post 2.13, 95 %CI - 1.43, 3.18; standard SCCS 1.79, 95 %CI 1.31 - 2.44, extended SCCS 1.52, 95 %CI = 1.08 - 2.15). Adjustment for calendar time did not change these conclusions. Findings using all designs were also consistent with a harmful effect following a second dose of the Moderna vaccine. CONCLUSIONS: In the context of the known association between COVID-19 vaccines and myocarditis, we have demonstrated that two forms of SCRI and two forms of SCCS led to largely comparable results, possibly because of limited violation of the assumption of event-dependent exposures.
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COVID-19 , Miocarditis , Vacunas , Humanos , Vacunas contra la COVID-19/efectos adversos , COVID-19/prevención & control , Proyectos de Investigación , Vacunación/efectos adversosRESUMEN
AIM: Myocarditis is a recognized safety concern following COVID-19 mRNA vaccination. However, there is limited research quantifying the risk associated with the third dose or comparing the risk between the three doses. The US Vaccine Adverse Event Reporting System (VAERS) is a passive surveillance system that monitors rare adverse events after US-licensed vaccination. However, studies analyzing VAERS data have often faced criticism for underreporting cases and lacking a control group to assess the increase in baseline risk. METHODS: The temporal association between myocarditis onset and COVID-19 vaccination was studied. To overcome limitations, a novel modified self-controlled case series method was employed, explicitly modeling the case reporting process in VAERS data. RESULTS: We found an increased risk of myocarditis during the 1- to 3-day period following the second and third doses of both the BNT162b2 vaccine and the mRNA-1273 vaccine. Following the second dose, the relative incidence (RI) was 4.89 (95% confidence interval (CI), 2.39-10.08) for the BNT162b2 vaccine and 2.86 (95% CI: 1.18-7.03) for the mRNA-1273 vaccine. Similarly, following the third dose, the RI was 9.04 (95% CI: 2.79-40.99) for the BNT162b2 vaccine and 4.71 (95% CI: 1.42-19.09) for the mRNA-1273 vaccine. No significant increase in risk was observed during other periods. Notably, our analysis also identified a similar increased risk of myocarditis among individuals aged below 30. CONCLUSIONS: These findings raise safety concerns regarding COVID-19 mRNA vaccines, provide insights into the quantification of myocarditis risk at different postvaccination periods, and offer a novel approach to interpreting passive surveillance system data.
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Vacunas contra la COVID-19 , COVID-19 , Miocarditis , Humanos , Vacuna nCoV-2019 mRNA-1273 , Vacuna BNT162 , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Vacunas de ARNm , Miocarditis/epidemiología , Miocarditis/etiología , Proyectos de Investigación , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Several neurological manifestations shortly after a receipt of coronavirus infectious disease 2019 (COVID-19) vaccine have been described in the recent case reports. Among those, we sought to evaluate the risk of encephalitis and meningitis after COVID-19 vaccination in the entire South Korean population. METHODS: We conducted self-controlled case series (SCCS) analysis using the COVID-19 immunization record data from the Korea Disease Control Agency between February 2021 and March 2022, linked with the National Health Insurance Database between January 2021 and October 2022. We retrieved all medical claims of adults aged 18 years or older who received at least one dose of COVID-19 vaccines (BNT162b2, mRNA-1273, ChAdOx1-S, or Ad26.COV2.S), and included only those who had a diagnosis record for encephalitis or meningitis within the 240-day post-vaccination period. With day 0 defined as the date of vaccination, risk window was defined as days 1-28 and the control window as the remainder period excluding the risk windows within the 240-day period. We used conditional Poisson regression to estimate the incidence rate ratios (IRR) with 95% confidence intervals (CI), stratified by dose and vaccine type. RESULTS: From 129,956,027 COVID-19 vaccine doses administered to 44,564,345 individuals, there were 251 and 398 cases of encephalitis and meningitis during the risk window, corresponding to 1.9 and 3.1 cases per 1 million doses, respectively. Overall, there was an increased risk of encephalitis in the first 28 days of COVID-19 vaccination (IRR 1.26; 95% CI 1.08-1.47), which was only significant after a receipt of ChAdOx1-S (1.49; 1.03-2.15). For meningitis, no increased risk was observed after any dose of COVID-19 vaccine (IRR 1.03; 95% CI 0.91-1.16). CONCLUSIONS: Our findings suggest an overall increased risk of encephalitis after COVID-19 vaccination. However, the absolute risk was small and should not impede COVID-19 vaccine confidence. No significant association was found between the risk of meningitis and COVID-19 vaccination.
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COVID-19 , Enfermedades Transmisibles , Encefalitis , Meningitis , Adulto , Humanos , Vacunas contra la COVID-19/efectos adversos , Ad26COVS1 , Vacuna BNT162 , COVID-19/epidemiología , COVID-19/prevención & control , Meningitis/epidemiología , Meningitis/etiología , República de Corea/epidemiología , Vacunación/efectos adversos , ChAdOx1 nCoV-19RESUMEN
The self-controlled case series (SCCS) is a commonly adopted study design in the assessment of vaccine and drug safety. Recurrent event data collected from SCCS studies are typically analyzed using the conditional Poisson model which assumes event times are independent within-cases. This assumption is violated in the presence of event dependence, where the occurrence of an event influences the probability and timing of subsequent events. When event dependence is suspected in an SCCS study, the standard recommendation is to include only the first event from each case in the analysis. However, first event analysis can still yield biased estimates of the exposure relative incidence if the outcome event is not rare. We first demonstrate that the bias in first event analysis can be even higher than previously assumed when subpopulations with different baseline incidence rates are present and describe an improved method for estimating this bias. Subsequently, we propose a novel partitioned analysis method and demonstrate how it can reduce this bias. We provide a recommendation to guide the number of partitions to use with the partitioned analysis, illustrate this recommendation with an example SCCS study of the association between beta-blockers and acute myocardial infarction, and compare the partitioned analysis against other SCCS analysis methods by simulation.
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Proyectos de Investigación , Vacunas , Humanos , Simulación por Computador , Sesgo , ProbabilidadRESUMEN
OBJECTIVES: To quantify the associations between invasive group A streptococcal disease (iGAS) incidence and influenza, varicella, and chronic hepatitis C virus (HCV). METHODS: We used individual-level linked data of iGAS cases from Victoria, Australia (2007-2017) to assess associations between these viral infections and iGAS. A self-controlled case series method was used to estimate the relative incidence of iGAS following an influenza or varicella infection, while the relative incidence of iGAS among HCV cases, and HCV cases who inject drugs, was estimated using population-level data and a negative binomial regression model. RESULTS: Of the 1949 individuals with at least one iGAS diagnosis, 82 were diagnosed with influenza at least once, 30 with varicella, and 118 with HCV during the study period. The relative incidence of iGAS increased substantially following infection with influenza (incidence rate ratio [IRR]: 34.5, 95% confidence interval [CI]: 21.3-55.8) or varicella (IRR: 22.4, 95% CI: 10.3-48.8). iGAS incidence was higher among HCV cases (IRR: 5.7, 95% CI: 4.4-7.3) compared to individuals without HCV. iGAS incidence was also higher among HCV cases who inject drugs (IRR: 17.9, 95% CI: 13.0-24.4) compared to individuals without HCV who did not inject drugs. CONCLUSIONS: We found a significantly higher risk of iGAS following an influenza or varicella infection and for chronic HCV cases, particularly those who inject drugs. These findings are relevant to public health practice and support the timely identification of iGAS cases.
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Varicela , Hepatitis C Crónica , Hepatitis C , Gripe Humana , Infecciones Estreptocócicas , Abuso de Sustancias por Vía Intravenosa , Humanos , Victoria/epidemiología , Hepacivirus , Gripe Humana/complicaciones , Gripe Humana/epidemiología , Varicela/complicaciones , Varicela/epidemiología , Infecciones Estreptocócicas/complicaciones , Infecciones Estreptocócicas/epidemiología , Streptococcus pyogenes , Incidencia , Hepatitis C/complicaciones , Hepatitis C/epidemiologíaRESUMEN
This study explores the relationship between influenza infection, both clinically diagnosed in primary-care and laboratory confirmed in hospital, and atherothrombotic events (acute myocardial infarction and ischemic stroke) in Spain. A population-based self-controlled case series design was used with individual-level data from electronic registries (n = 2,230,015). The risk of atherothrombotic events in subjects ≥50 years old increased more than 2-fold during the 14 days after the mildest influenza cases in patients with fewer risk factors and more than 4-fold after severe cases in the most vulnerable patients, remaining in them more than 2-fold for 2 months. The transient increase of the association, its gradient after influenza infection and the demonstration by 4 different sensitivity analyses provide further evidence supporting causality. This work reinforces the official recommendations for influenza prevention in at-risk groups and should also increase the awareness of even milder influenza infection and its possible complications in the general population.
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BACKGROUND: In January 2018, Afghanistan introduced the monovalent oral rotavirus vaccine (Rotarix) nationwide, administered as a 2-dose series at six and ten weeks of age. We describe characteristics of intussusception cases and assess potential intussusception risk associated with Rotarix vaccination in Afghan infants. METHODS: Multi-center prospective active hospital-based surveillance for intussusception was conducted from May 2018 to March 2022 in four sentinel sites in Afghanistan. We applied the Brighton Level 1 criteria for intussusception and verified vaccination status by reviewing vaccine cards. We used the self-controlled case series (SCCS) methodology to compare intussusception incidence in the 1 to 21 days after each dose of Rotarix vaccination against non-risk periods. RESULTS: A total of 468 intussusception cases were identified in infants under 12 months, with 264 cases aged between 28 and 245 days having confirmed vaccination status contributing to the SCCS analysis. Most case-patients (98 %) required surgery for treatment, and over half (59 %) of those who underwent surgery required intestinal resection. Nineteen (7 %) case-patients died. Eighty-six percent of case-patients received the first dose of Rotarix, and 69 % received the second dose before intussusception symptom onset. There was no increased risk of intussusception in the 1-7 days (relative incidence: 0.9, 95 % CI: 0.1, 7.5), 8-21 days (1.3, 95 % CI: 0.4, 4.2), or 1-21 days (1.1, 95 % CI: 0.4, 3.4) following receipt of the first dose or in the 1-7 days (0.2, 95 % CI: 0.3, 1.8), 8-21 days (0.7, 95 % CI: 0.3, 1.5), or 1-21 days (0.6, 95 % CI: 0.3, 1.2) following the second dose. CONCLUSION: Rotarix vaccination was not associated with an increased intussusception risk, supporting its continued use in Afghanistan's immunization program. However, there was a high level of death and resection due to intussusception among Afghan infants.