The Lazarus effect of very high-dose intravenous anakinra in severe non-familial CNS-HLH.
The Lazarus effect of very high-dose intravenous anakinra in severe non-familial CNS-HLH.
复制标题
严重的非家族中枢神经系统HLH中，非常高剂量静脉内Anakinra的Lazarus效应。
DOI：
10.1016/s2665-9913(20)30361-1
复制
发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Bailey K
中科院分区：
文献类型：
--
作者：
Kavirayani A;Charlesworth JEG;Segal S;Kelly D;Wilson S;Qureshi A;Blanco E;Weitz J;O'Shea D;Bailey K
《大脑血流代谢杂志》2011；31：439-47。显示出明显的恶魔可控制的脑脊液压力(相对于血浆浓度的1.6%)，并建议进行神经保护。3随后，Ana Kinra被提出作为蛛网膜下腔出血患者预防炎症和迟发性脑缺血的促进性治疗选择。我们利用这种原理，即大剂量静脉注射阿纳金纳是安全的，能够穿越血脑屏障，在治疗时间窗口内提供可能的神经保护，从而成功地治疗了我们的患者。因为她已经在服用大剂量的阿纳金纳(每天12毫克/公斤)，由于正在进行的中枢神经系统促黄体生成素，我们推断了蛛网膜下腔出血3和败血症2患者的现有证据，并将阿纳金纳的输注升级到每小时2毫克/公斤(每天48毫克/公斤)，持续72小时，随后逐渐减少。使用这种方案，我们的患者有效地表现出神经逆转，并最终恢复无缺陷，尽管神经极度迟钝。在我们的患者中，阿纳金拉的剂量从已经很高的输注剂量递增，以成功地达到这种神经治疗效果。近3年过去了，她仍然很好，神经学上也很正常。此外，我们在血液滤过时，尽管并发感染(这与先前研究中观察到的高安全性有共鸣)2和治疗剂量(尽管肾功能衰竭)，仍使用Anakinra。在新冠肺炎大流行的背景下，新冠肺炎的神经学联系被越来越多地描述，然而，继发性脑病(类似于中枢神经系统-促黄体生成素)尚未被描述为特征，在这些情况下，了解替代治疗方案可能是有益的。综上所述，我们报告了非常大剂量静脉注射阿纳金纳治疗非家族性CNS-HLH的成功。这可能是一种潜在的治疗选择，如果及时、合理和适当地使用，在8周后等待出院时，使用Anakinra、类固醇、环孢素和氟康唑预防，所有治疗最终都成功停止。对原发或遗传性HLH的调查均为阴性(附录pp 1-2)，确切的触发因素仍不清楚。继发性HLH的神经受累程度差异显著，往往预示着预后不良，难治性CNS-HLH的治疗是长期的。4由于缺乏临床试验，推荐的治疗方法包括类固醇(地塞米松)、免疫抑制(如依托泊西或环孢素)和鞘内治疗(如甲氨蝶呤或类固醇)。除非HLH是由Epstein-Barr病毒驱动的，其中利妥昔单抗可能是有益的，否则额外的治疗(包括alemtuzumab、抗胸腺细胞球蛋白、ruxolitinib、干扰素伽马阻滞剂或挽救实验疗法)是昂贵的、难以在紧急情况下获得、难以在实验中获得或充满副作用。造血干细胞移植在家族性、中枢神经系统-家族性和分离的中枢神经系统-HLH中被描述。对于需要时间紧迫干预的快速恶化的多器官功能障碍患者，这些治疗方法可能并不容易获得或可行。此前，阿纳金拉已被报道对发热感染相关癫痫综合征有效，5这是一种非促黄体生成素相关的难治性癫痫脑病，每天两次皮下注射5 mg/kg。我们的患者在无反应时已经每天静脉注射12毫克/公斤的阿纳金纳。对成人蛛网膜下腔出血的研究探索了IL-1抑制在减轻神经炎症效应中的作用。在…中静脉注射Anakinra(每小时2 mg/kg)的初步研究之后
J Cereb Blood Flow Metab 2011; 31: 439–47. showed significant demons trable CSF pene tra tion (1· 6% relative to plasma concentration) with proposed neuro protection. 3 Subsequently, ana kinra has been proposed as a promis ing therapeutic option for prevent ing inflammation and delayed cerebral ischaemia in subarachnoid haemorrhage patients. We used this rationale of very highdose intravenous anakinra infusion being safe and able to cross the blood–brain barrier, conferring possible neuroprotection within a therapeutic time window, to successfully treat our patient. Because she was already on high-dose anakinra (12 mg/kg per day), due to ongoing CNS-HLH, we extrapolated available evidence in subarachnoid haemorrhage3 and sepsis2 patients, and escalated anakinra infusion to 2 mg/kg per h (48 mg/kg per day) for 72 h, subsequently tapered. With this regimen, our patient effectively showed neurological reversal and eventually recovered without deficits, despite extreme neurological obtundation. The anakinra dose in our patient was escalated from an already high dose infusion to achieve this neurotherapeutic effect successfully. Almost 3 years on, she remains well and neurologically normal. Furthermore, we administered anakinra despite intercurrent infections (which resonates with the high safety profile observed in previous studies) 2 and therapeutic doses despite renal failure, while on haemofiltration. In the context of the COVID-19 pandemic, neurological associations of COVID-19 are increasingly described, however, encephalopathy secondary to severe HLH (akin to CNS-HLH) has not been characterised, where awareness of alternative therapeutic options might be beneficial. In summary, we report very highdose intravenous anakinra for success f ul treatment of non-familial CNS-HLH. This might be a potential therapeutic option and possibly neuroprotective if used promptly, rationally and appropriately, while awaiting discharged after 8 weeks, on anakinra, steroids, ciclosporin, and fluconazole prophylaxis, all therapy was eventually stopped successfully. Investigations for primary or genetic HLH were negative (appendix pp 1–2), the exact trigger remains unknown. Severity of neurological involvement in secondary HLH varies signifi cantly, often heralds poor prognosis, and treatment of refractory CNS-HLH is chal lenging. 4 Because of a paucity of clini cal trials, recommended manage ment includes steroids (dexamethasone), immunosuppression (eg, eto po side or ciclosporin) and intra thecal therapy (eg, methotrexate or steroids). Unless HLH is Epstein-Barr virus-driven, wherein rituximab might be beneficial, additional therapy (including alemtuzumab, anti-thymocyte globulin, ruxolitinib, interferon gamma blockers or salvage experimental therapy) is costly, difficult to procure in an emergency setting, experimental, or fraught with sideeffects. Haematopoietic stem cell transplantation is described in familial HLH, CNS-familial HLH, and isolated CNS-HLH. In patients with rapidly deteriorating multiorgan dysfunction requiring time-critical intervention, these therapies might not be readily accessible or practicable. Previously, anakinra has been reported to be effective in febrile infection-related epilepsy syndrome, 5 a non-HLH-related refractory epileptic encephalopathy in children, administered 5 mg/kg twice daily subcutaneously. Our patient was already on 12 mg/kg per day intravenous anakinra when she became unresponsive.Studies in adults with subarachnoid haemorrhage have explored the role of IL-1 inhibition in mitigating effects of neuroinflammation. After a pilot study of intravenous anakinra (2 mg/kg per h) in …