Botta Cirino, Indrieri Alessia, Garofalo Eugenio, Biamonte Flavia, Bruni Andrea, Pasqua Pino, Cesario Francesco, Costanzo Francesco Saverio, Longhini Federico, Mendicino Francesco
Hematology Unit, Department of Hemato-Oncology, "Annunziata" Hospital of Cosenza, Cosenza, Italy.
Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
Front Oncol. 2021 Jan 8;10:599502. doi: 10.3389/fonc.2020.599502. eCollection 2020.
Since SARS-CoV-2 outbreak in December 2019, world health-system has been severely impacted with increased hospitalization, Intensive-Care-Unit (ICU) access and high mortality rates, mostly due to severe acute respiratory failure and multi-organ failure. Excessive and uncontrolled release of proinflammatory cytokines (cytokine release/storm syndrome, CRS) have been linked to the development of these events. The recent advancements of immunotherapy for the treatment of hematologic and solid tumors shed light on many of the molecular mechanisms underlying this phenomenon, thus rendering desirable a multidisciplinary approach to improve COVID-19 patients' outcome. Indeed, currently available therapeutic-strategies to overcome CRS, should be urgently evaluated for their capability of reducing COVID-19 mortality. Notably, COVID-19 shares different pathogenic aspects with acute graft-versus-host-disease (aGVHD), hemophagocytic-lymphohistiocytosis (HLH), myelofibrosis, and CAR-T-associated CRS. Specifically, similarly to aGVHD, an induced tissue damage (caused by the virus) leads to increased cytokine release (TNFα and IL-6) which in turn leads to exaggerated dendritic cells, macrophages (like in HLH) and lymphocytes (as in CAR-T) activation, immune-cells migration, and tissue-damage (including late-stage fibrosis, similar to myelofibrosis). Janus Kinase (JAK) signaling represents a molecular hub linking all these events, rendering JAK-inhibitors suitable to limit deleterious effects of an overwhelming inflammatory-response. Accordingly, ruxolitinib is the only selective JAK1 and JAK2-inhibitor approved for the treatment of myelofibrosis and aGVHD. Here, we discuss, from a molecular and hematological point of view, the rationale for targeting JAK signaling in the management of COVID-19 patients and report the clinical results of a patient admitted to ICU among the firsts to be treated with ruxolitinib in Italy.
自2019年12月新型冠状病毒肺炎（SARS-CoV-2）疫情爆发以来，全球卫生系统受到严重冲击，住院人数增加、重症监护病房（ICU）使用率上升且死亡率居高不下，主要原因是严重急性呼吸衰竭和多器官功能衰竭。促炎细胞因子的过度和不受控制释放（细胞因子释放/风暴综合征，CRS）与这些事件的发生有关。血液系统和实体瘤免疫治疗的最新进展揭示了这一现象背后的许多分子机制，因此需要采取多学科方法来改善COVID-19患者的预后。事实上，目前可用的克服CRS的治疗策略，应紧急评估其降低COVID-19死亡率的能力。值得注意的是，COVID-19与急性移植物抗宿主病（aGVHD）、噬血细胞性淋巴组织细胞增生症（HLH）、骨髓纤维化和嵌合抗原受体T细胞（CAR-T）相关CRS有不同的致病方面。具体而言，与aGVHD类似，病毒引起的组织损伤会导致细胞因子释放增加（TNFα和IL-6），进而导致树突状细胞、巨噬细胞（如HLH中）和淋巴细胞（如CAR-T中）过度活化、免疫细胞迁移和组织损伤（包括晚期纤维化，类似于骨髓纤维化）。Janus激酶（JAK）信号代表连接所有这些事件的分子枢纽，使JAK抑制剂适合限制过度炎症反应的有害影响。因此，鲁索替尼是唯一被批准用于治疗骨髓纤维化和aGVHD的选择性JAK1和JAK2抑制剂。在此，我们从分子和血液学角度讨论在COVID-19患者管理中靶向JAK信号的基本原理，并报告意大利首例接受鲁索替尼治疗的ICU住院患者的临床结果。
