Estimating the association between TNF inhibitors and Legionnaires' disease

项目摘要/摘要 军团菌病是一种病死率高(~10%)的严重细菌性肺炎。最近的公众 对健康的关注和资金用于了解学习障碍发病率的增加。超过了 在过去的20年里，发病率从0.5例/10万人上升到近2.5例/10万人。 人口。对这一增长有多种假设，包括增加 对腰椎病高度易感的人群。虽然疾病的负担很可能是由多种因素共同造成的 (例如，诊断检测强度、天气)，我们认为人口比例的增加 是高度易感的，可能在发病率上升中起关键作用，但还没有得到充分的研究。高度的 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 抗类风湿性关节炎的药物(TNFi)(如阿达利姆单抗、依那西普、英夫利昔单抗)通常是处方药物。 以及其他自身免疫性疾病，并与全因易感性增加有关 呼吸道感染。2011年，FDA更新了针对TNFi的盒装警告，将潜在的风险包括在内 李斯特氏菌和军团菌引起的感染。这一咨询是针对数量有限的案例报告和 观察性研究，缺乏能够对慢性潜在风险进行调整的正式分析 疾病(如类风湿性关节炎)。关于LD与可修改风险之间关系的量化分析 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 在报告的LD增加的同一时期内，TNFi的摄取量显著增加。我们 假设1)肿瘤坏死因子抑制剂使个人患退伍军人病的风险比 传统的抗风湿药物(cDMARDS；例如甲氨蝶呤)和2)有 不断增加的TNFi摄入量与退伍军人病发病率之间的时间关联。顽强地 估计这些潜在的关联，我们将利用强劲的丹麦国家登记数据。丹麦语 2000年间约25,000人的国家医疗登记数据表明患有TNFis或cDMARDS 并将探索2020年。住院和门诊就诊信息以及药品信息 将包括处方，提供独特的能力来识别危险窗口，根据潜在的情况进行调整 疾病，并检测处方摄取和LD发病率之间的纵向联系。以前的研究 他补充说，TNFi和LD之间的关联尚未能够根据潜在的疾病严重程度进行调整 我们的书房设计需要新奇的东西。二次分析将评估其他传染病的结果 可能与使用TNFi有关(例如沙门氏菌、李斯特氏菌、全因肺炎)。这些研究的结果 1)是否会影响退伍军人的疾病监测和预防措施；2)是否会影响临床决策- 关于TNFi的研究，以及3)洞察未被充分研究的免疫介导的LD危险因素。

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.