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Fungal infection risks associated with the use of cytokine antagonists and immune checkpoint inhibitors.
Experimental Biology and Medicine ( IF 3.2 ) Pub Date : 2020-07-08 , DOI: 10.1177/1535370220939862
Xin Li 1 , Susanna Kp Lau 1, 2, 3 , Patrick Cy Woo 1, 2, 3
Affiliation  

The revolutionary success of biologic agents in treating various malignant and autoimmune conditions has been met with increased risk of opportunistic infections due to perturbations in immunity. In patients receiving biologic-containing regimens, the risk of fungal infection is less well-understood, and there is a lack of established guideline on the standard of care in terms of screening and prophylaxis. In this article, we reviewed the risk of fungal infections associated with cytokine antagonists, including anti-tumor necrosis factor (TNF) agents and interleukin (IL) antagonists, and immune checkpoint inhibitors. The risk of fungal infection in this group of patients is drug-, pathogen-, host-, and context-dependent. Among the biologic agents reviewed, anti-TNF agents are associated with highest number of reported cases of fungal infection, especially histoplasmosis. In fact, infection due to all dimorphic fungi except Talaromyces marneffei have been reported in patients receiving TNF-α inhibitors, despite their widespread use in T. marneffei-endemic regions. The risk is higher with TNF-α inhibitors that block both the membrane-bound and soluble forms of TNF-α, i.e., infliximab and adalimumab, compared with etanercept which inhibits the soluble form only. In addition to the preferential suppression of Th1 pathway and granuloma formation leading to genuinely higher risk of infection, the longer history and extensive use of infliximab coupled with the endemicity of histoplasmosis in the United States lead to an apparent increase in reported cases. IL-17 antagonists lead to a moderate increase in mucocutaneous candidiasis, but not the risk of life-threatening mycosis, consistent with the essential role of Th17 cells in mucosal defense. Immune checkpoint inhibitors, on the other hand, do not significantly increase the risk of invasive fungal infections when used alone and may even be of therapeutic value in the treatment of severe and refractory mycosis.

Impact statement

The risk of opportunistic infections due to fungi is relatively less well addressed in patients receiving biologic agents, compared with other opportunistic bacterial and viral infections. There is a lack of consensus guideline on the screening, prophylaxis, and management of fungal infection in patients anticipated to receive or actively receiving biologic therapy. In addition, invasive mycosis in immunocompromised patients is associated with high mortality and morbidity. This review highlighted the risk of fungal infection in patients receiving cytokine antagonists and immune checkpoint inhibitors, two big categories of biologic agents that are widely used in the treatment of various autoimmune and malignant conditions, often in combination with other immunomodulatory or immunosuppressive agents but also as standalone therapy. The adverse outcomes of opportunistic fungal infection in these patients can be reduced by heightened awareness, active case finding, and prompt treatment.



中文翻译:

与使用细胞因子拮抗剂和免疫检查点抑制剂相关的真菌感染风险。

由于免疫紊乱,生物制剂在治疗各种恶性和自身免疫性疾病方面取得了革命性的成功,并且增加了机会性感染的风险。在接受含生物制剂治疗方案的患者中,真菌感染的风险了解得较少,并且缺乏有关筛查和预防方面护理标准的既定指南。在本文中,我们回顾了与细胞因子拮抗剂相关的真菌感染的风险,其中包括抗肿瘤坏死因子(TNF)试剂和白介素(IL)拮抗剂以及免疫检查点抑制剂。在这组患者中,真菌感染的风险取决于药物,病原体,宿主和背景。在所审查的生物制剂中,抗TNF制剂与报道的真菌感染病例最多有关,特别是组织胞浆菌病。实际上,除所有双态真菌外,其他所有感染马尔尼菲篮状菌已报道在接受TNF-α抑制剂的患者,尽管他们在广泛使用T.马尔尼菲流行地区。与依那西普仅抑制可溶形式的依那西普相比,可阻断膜结合形式和可溶形式的TNF-α(英夫利昔单抗和阿达木单抗)的风险更高。除了优先抑制Th1途径和肉芽肿形成会导致感染的真正风险增加之外,英夫利昔单抗的悠久历史和广泛使用再加上美国组织胞浆菌病的流行,导致报告病例明显增加。IL-17拮抗剂导致粘膜皮肤念珠菌病轻度增加,但没有威胁生命的真菌病风险,这与Th17细胞在粘膜防御中的重要作用相一致。另一方面,免疫检查点抑制剂

影响陈述

与其他机会性细菌和病毒感染相比,在接受生物制剂治疗的患者中,由真菌引起的机会性感染的风险相对较差。对于预期接受或积极接受生物治疗的患者,在真菌感染的筛查,预防和管理方面缺乏共识性指南。此外,免疫受损患者的浸润性真菌病与高死亡率和高发病率有关。这篇综述强调了接受细胞因子拮抗剂和免疫检查点抑制剂的患者中真菌感染的风险,这是两大类生物试剂,广泛用于治疗各种自身免疫和恶性疾病,通常与其他免疫调节剂或免疫抑制剂联合使用,但也作为独立疗法。

更新日期:2020-07-09
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