Estimating the association between TNF inhibitors and Legionnaires' disease

评估 TNF 抑制剂与退伍军人病之间的关联

基本信息

批准号：
10598462
负责人：
Kelsie Cassell
金额：
$ 3.74万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-15 至 2023-08-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10598462
关键词：
Address Adverse event Age Aging Autoimmune Diseases Bacterial Pneumonia Case Fatality Rates Case Study Chronic Chronic Kidney Failure Climate Collection Combined Modality Therapy Communicable Diseases Country Crohn&apos s disease Crossover Design Data Denmark Diabetes Mellitus Diagnosis Diagnostic tests Disease Disease Outcome Disease Surveillance Disease-Modifying Second-Line Drugs Drug usage Elderly Epidemiology Etanercept Funding Gender Goals Hazard Identification Health Care Visit Healthcare Immune Immune system Immunologics Immunomodulators Immunosuppression Incidence Individual Infection Inhalation Inpatients Laboratory Research Legionella Legionnaires&apos Disease Link Listeria Logistic Regressions Mediating Medical Methotrexate Nature Observational Study Outcome Outpatients Persons Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Play Pneumonia Population Population Sizes Predisposition Prevention Measures Public Health Recommendation Reporting Research Design Respiratory Tract Infections Rheumatoid Arthritis Risk Risk Adjustment Risk Factors Role Salmonella Seasons Severity of illness Source Statistical Models Steroids TNF gene Time Time trend Ulcerative Colitis Update Visit Weather adalimumab burden of illness climate change clinical decision-making cohort comorbidity comorbidity Index contaminated water disease diagnosis disorder prevention epidemiology study fighting hazard high risk high risk population human old age (65+)immunological status immunosuppressed infection risk infliximab inhibitor insight interest long-term sequelae member modifiable risk novel older patient response secondary analysis trend uptake

项目摘要

Project Summary/Abstract Legionnaires’ disease (LD) is a severe bacterial pneumonia with a high case fatality rate (~10%). Recent public health concern and funding has been directed towards understanding the increasing incidence of LD. Over the past two decades, incidence has increased from <0.5 cases/100,000 population to almost 2.5 cases/100,000 population. There are multiple hypotheses for the increase, including an increase in the proportion of the population that is highly susceptible to LD. While the burden of disease is likely due to a combination of factors (e.g. diagnostic testing intensity, weather), we believe that an increase in the proportion of the population that is highly susceptible may play a critical, and understudied, role in the increasing incidence. The highly susceptible population of interest includes those who are taking immunosuppressing medications. TNF inhibitors (TNFi) (e.g. adalimumab, etanercept, infliximab) are commonly prescribed for rheumatoid arthritis and other autoimmune disorders and have been associated with increased susceptibility to all-cause respiratory infections. In 2011, the FDA updated the Boxed Warning for TNFi to include potential risk of infection due to Listeria and Legionella. This advisory was in response to a limited number of case reports and observational studies and lacked formal analyses able to adjust for risk attributed to the chronic underlying illness (e.g. rheumatoid arthritis). An analysis quantifying the relationship between LD and a modifiable risk factor, such as TNFi, would provide needed information to potentially curb the increase in disease. Importantly, uptake of TNFi increased dramatically during the same time period as the increase in reported LD. We hypothesize that 1) TNF inhibitors place individuals at greater risk for Legionnaires’ disease compared to conventional disease modifying anti-rheumatic drugs (cDMARDs; e.g. methotrexate) and that 2) there is a temporal association between increasing uptake of TNFi and Legionnaires’ disease incidence. To robustly estimate these potential associations, we will take advantage of robust Danish national register data. Danish national medical register data for approximately 25,000 people indicated for TNFis or cDMARDs between 2000 and 2020 will be explored. Information on inpatient and outpatient visits, as well as pharmaceutical prescriptions will be included which offers the unique ability to identify hazard windows, adjust for underlying disease, and detect longitudinal associations between prescription uptake and LD incidence. Previous studies of the association between TNFi and LD have not been able to adjust for underlying disease severity, adding needed novelty to our study design. Secondary analyses will assess other infectious disease outcomes that may be associated with TNFi use (e.g. Salmonella, Listeria, all-cause pneumonia). The results of these studies will 1) influence Legionnaires’ disease surveillance and prevention measures, 2) inform clinical decision- making regarding TNFi, and 3) provide insight on understudied immune-mediated risk factors for LD.

项目概要/摘要退伍军人病 (LD) 是一种严重的细菌性肺炎，病死率很高（~10%）。健康关注和资金已用于了解 LD 发病率的增加。过去二十年，发病率从 <0.5 例/100,000 人增加到近 2.5 例/100,000 人对于人口的增加有多种假设，包括人口比例的增加。 LD 高度易感人群，而疾病负担可能是由多种因素造成的。（例如诊断测试强度、天气），我们认为人口比例的增加高度易感可能在发病率增加中发挥关键且尚未得到充分研究的作用。感兴趣的易感人群包括那些正在服用免疫抑制药物的人。抑制剂 (TNFi)（例如阿达木单抗、依那西普、英夫利昔单抗）通常用于治疗类风湿性关节炎和其他自身免疫性疾病，并与各种原因的易感性增加有关 2011 年，FDA 更新了 TNFi 的黑框警告，纳入了潜在的风险。由于李斯特菌和军团菌感染，本公告是针对数量有限的病例报告和。观察性研究，缺乏能够调整慢性潜在风险的正式分析疾病（例如类风湿性关节炎）。量化 LD 与可改变风险之间关系的分析。 TNFi 等因子将提供可能抑制疾病增加所需的信息。在报告的 LD 增加的同一时期，TNFi 的摄取急剧增加。 1) 与其他人相比，TNF 抑制剂使个体患军团病的风险更大传统疾病缓解抗风湿药物（cDMARD；例如甲氨蝶呤），并且 2) TNFi 摄取增加与军团病发病率之间存在显着的时间关联。估计这些潜在的关联，我们将利用可靠的丹麦国家登记数据。 2000 年期间约 25,000 名接受 TNFis 或 cDMARD 治疗的人的国家医疗登记数据 2020 年将探讨住院和门诊以及药品的信息。将包括处方，它提供了识别危险窗口、调整潜在风险的独特能力疾病，并检测处方摄入与 LD 发生率之间的纵向关联。 TNFi 和 LD 之间的关联无法根据潜在疾病的严重程度进行调整，补充道我们的研究设计需要新颖性，二次分析将评估其他传染病的结果。可能与 TNFi 的使用有关（例如沙门氏菌、李斯特菌、全因肺炎）。将 1) 影响军团的疾病监测和预防措施，2) 为临床决策提供信息- 3) 提供有关 TNFi 的研究，以及 3) 提供有关 LD 的未充分研究的免疫介导危险因素的见解。