Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune system activation driven mainly by high levels of interferon gamma. The clinical presentation of HLH can have considerable overlap with other inflammatory conditions. We present a cohort of patients with therapy refractory HLH referred to our center who were found to have a simultaneous presentation of complement-mediated thrombotic microangiopathy (TMA). Twenty-three patients had therapy refractory HLH (13 primary, 4 EVB-HLH, 6 HLH without known trigger). Sixteen (69.6%) met high-risk TMA criteria. Renal failure requiring renal replacement therapy, severe hypertension, serositis, and gastrointestinal bleeding were documented only in patients with HLH who had concomitant complement-mediated TMA. Patients with HLH and without TMA required ventilator support mainly due to CNS symptoms, while those with HLH and TMA had respiratory failure predominantly associated with pulmonary hypertension, a known presentation of pulmonary TMA. Ten patients received eculizumab for complement-mediated TMA management while being treated for HLH. All patients who received the complement blocker eculizumab in addition to the interferon gamma blocker emapalumab had complete resolution of their TMA and survived. Our observations suggest co-activation of both interferon and complement pathways as a potential culprit in the evolution of thrombotic microangiopathy in patients with inflammatory disorders like refractory HLH and may offer novel therapeutic approaches for these critically ill patients. TMA should be considered in children with HLH and multi-organ failure, as an early institution of a brief course of complement blocking therapy in addition to HLH-targeted therapy may improve clinical outcomes in these patients.

中文翻译：

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超越 HLH 的思考：同时出现噬血细胞性淋巴组织细胞增生症和血栓性微血管病的患者的临床特征。

噬血细胞性淋巴组织细胞增生症 (HLH) 是一种主要由高水平干扰素 γ 驱动的过度免疫系统激活综合征。HLH 的临床表现可能与其他炎症状况有相当大的重叠。我们介绍了一组转诊至我们中心的治疗难治性 HLH 患者，这些患者被发现同时出现补体介导的血栓性微血管病 (TMA)。23 名患者患有治疗难治性 HLH（13 名原发性、4 名 EVB-HLH、6 名无已知触发因素的 HLH）。16 个 (69.6%) 符合高风险 TMA 标准。仅在伴有补体介导的 TMA 的 HLH 患者中记录到需要肾脏替代治疗的肾功能衰竭、严重高血压、浆膜炎和胃肠道出血。HLH 和 TMA 患者需要呼吸机支持，主要是由于 CNS 症状，而 HLH 和 TMA 患者的呼吸衰竭主要与肺动脉高压有关，这是肺 TMA 的已知表现。10 名患者在接受 HLH 治疗的同时接受了依库珠单抗进行补体介导的 TMA 管理。除了干扰素 γ 阻滞剂 emapalumab 外，所有接受补体阻滞剂依库珠单抗的患者的 TMA 完全消退并存活。我们的观察表明，干扰素和补体通路的共同激活是炎症性疾病（如难治性 HLH）患者血栓性微血管病演变的潜在罪魁祸首，并可能为这些危重患者提供新的治疗方法。