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

• 批准号: 10386479
• 负责人: Kelsie Cassell
• 金额: $ 4.68万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2024-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386479
• 关键词: Address; Adverse event; Age; Aging; Antirheumatic Agents; Autoimmune Diseases; Bacterial Pneumonia; Case Fatality Rates; Case Study; Chronic; Chronic Kidney Failure; Climate; Collection; Combined Modality Therapy; Communicable Diseases; Country; Crohn' 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; Health Care Visit; Healthcare; Immune; Immune system; Immunologics; Immunomodulators; Immunosuppression; Incidence; Individual; Infection; Inhalation; Inpatients; Laboratory Research; Legionella; Legionnaires' 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 Factors; Role; Salmonella; Severity of illness; Source; Statistical Models; Steroids; TNF gene; Time; Time trend; Ulcerative Colitis; Update; Visit; Weather; adalimumab; base; 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; immunological status; immunosuppressed; infection risk; infliximab; inhibitor; insight; interest; long-term sequelae; member; modifiable risk; novel; older patient; overtreatment; response; secondary analysis; trend; uptake

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.

项目摘要/摘要 军团疾病（LD）是一种严重的细菌肺炎，病例死亡率很高（约10％）。最近的公众 健康关注和资金已致力于了解LD发病率的增加。在 在过去的二十年中，事件已从<0.5案例/100,000人口增加到近2.5箱/100,000例 人口。有多种增加的假设，包括增加的比例 高度容易受到LD的人口。虽然疾病的燃烧可能是由于多种因素而造成的 （例如，诊断测试强度，天气），我们认为人口比例的增加 高度容易受到影响可能在不断增长的发病率中起着至关重要的作用。高度 易感人群包括那些服用免疫抑制药物的人。 TNF 抑制剂（TNFI）（例如Adalimumab，etanercept，frisriximab）通常用于类风湿关节炎 和其他自身免疫性疾病，并且与全因的敏感性增加有关 呼吸道感染。 2011年，FDA对TNFI的盒装警告更新了，以包括 由于李斯特菌和军团菌引起的感染。该咨询是针对有限数量的案件报告和 观察性研究和缺乏正式分析可以调整归因于慢性潜在的风险 疾病（例如类风湿关节炎）。分析量化LD与可修改风险之间的关系 诸如TNFI之类的因素将提供所需的信息，以遏制疾病的增加。重要的是， 与报告LD的增加，TNFI的吸收在同一时期大幅增加。我们 假设1）TNF抑制剂使个人患军团疾病的风险更大 常规疾病修饰抗毒药（CDMARDS;例如Methodotrexate），并且2）有一个 增加TNFI吸收和军团疾病发病率之间的临时关联。坚固 估计这些潜在的关联，我们将利用强大的丹麦国家注册数据。丹麦语 2000年之间，大约25,000人或CDMARD的国家医疗注册数据 将探索2020年。有关住院和门诊就诊以及药物的信息 处方将包括在内，提供独特的识别危险窗口的能力 疾病，并检测处方摄取和LD事件之间的纵向关联。先前的研究 TNFI和LD之间的关联尚未适应潜在的疾病严重程度，并增加了 我们的研究设计所需的新颖性。次级分析将评估其他传染病结果 可能与TNFI使用有关（例如沙门氏菌，李斯特菌，全因肺炎）。这些研究的结果 威尔1）影响军团疾病的监测和预防措施，2）为临床决策提供信息 使TNFI和3）提供有关LD的免疫介导的危险因素的见解。