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（约 10%）。最近公开 健康关注和资金已用于了解 LD 发病率的增加。超过 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 人口。对于这种增加有多种假设，包括增加 LD 高度易感人群。虽然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。高度 感兴趣的易感人群包括那些正在服用免疫抑制药物的人。肿瘤坏死因子 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 呼吸道感染。 2011 年，FDA 更新了 TNFi 的黑框警告，纳入了以下潜在风险： 李斯特菌和军团菌感染。本咨询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 等因子将提供必要的信息来潜在地遏制疾病的增加。重要的是， 在报告的 LD 增加的同一时期内，TNFi 的摄取急剧增加。我们 假设 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的时间关联。稳健地 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。丹麦语 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 并将于2020年进行探索。有关住院和门诊就诊以及药品的信息 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，并检测处方摄取与 LD 发生率之间的纵向关联。之前的研究 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 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 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。