Estimating the association between TNF inhibitors and Legionnaires' disease

项目总结/摘要 军团病（LD）是一种严重的细菌性肺炎，病死率高（约10%）。最近的公开 健康问题和资金已被用于了解LD发病率的增加。来 在过去的二十年中，发病率从<0.5例/100，000人增加到近2.5例/100，000人 人口对这一增长有多种假设，包括人口比例的增加， 对LD高度敏感的人群。虽然疾病负担可能是由于多种因素的综合作用 (e.g.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起关键作用，但研究不足。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。TNF 抑制剂（TNFi）（如阿达木单抗、依那西普、英夫利昔单抗）通常用于类风湿性关节炎 和其他自身免疫性疾病，并与所有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，以包括潜在的风险， 李斯特菌和军团菌感染。这一咨询是对有限数量的病例报告的回应， 观察性研究，缺乏能够调整归因于慢性基础疾病风险的正式分析。 疾病（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等因素将提供必要的信息，以潜在地遏制疾病的增加。重要的是， TNFi的摄取在与报告的LD增加相同的时间段内显著增加。我们 假设：1）TNF抑制剂使个体患军团病风险高于 常规疾病缓解抗风湿药物（cDMARD;例如甲氨蝶呤），以及2） TNFi摄取增加与军团病发病率之间的时间关系。稳健地 估计这些潜在的关联，我们将利用强大的丹麦国家登记数据。丹麦 2000年至2010年期间，约25，000人接受TNF或cDMARD治疗的国家医疗登记数据 到2020年，我们将探索。住院和门诊就诊信息，以及药品信息 处方将包括提供独特的能力，以确定危险窗口，调整基础 疾病，并检测处方摄入和LD发病率之间的纵向关联。以前的研究 TNFi和LD之间的关联还不能调整潜在疾病的严重程度， 需要新奇的研究设计次要分析将评估其他传染病结局， 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）影响军团病监测和预防措施，2）告知临床决策- 关于TNFi的研究，以及3）提供对未充分研究的LD免疫介导的风险因素的见解。

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.