Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune system activation largely driven by high levels of interferon gamma. The clinical HLH presentation 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 simultaneous presentation of complement mediated thrombotic microangiopathy (TMA). Figure 1 contains the diagnostic criteria for both HLH and TMA.

Objectives

• Recognize presenting symptoms of HLH

• Recognize presenting symptoms of TMA

• Recognize that HLH and TMA can present concurrently

Methods

Patients of any age with frontline therapy refractory hemophagocytic lymphohistiocytosis (HLH) who were treated at our institution from January 2012 through December 2018 were identified by retrospective chart review after Institutional Review Board (IRB) approval. All patients were prospectively screened for TMA as part of clinical care as previously described. Patient demographics, disease characteristics, HLH and TMA targeted therapy, complications, intervention and laboratory assessment were captured from the electronic medical record.

Results

Sixteen of 23 patients with HLH met high risk TMA criteria (Figure 2). 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 ventilatory support mainly due to CNS symptoms, such as status epilepticus, while those with HLH and TMA had respiratory failure predominantly associated with pulmonary hypertension, a known presentation of pulmonary TMA (Figure 2).

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 (Figure 2).

Conclusion

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 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 early institution of a brief course of complement blocking therapy in addition to HLH targeted therapy may improve clinical outcomes in these patients (Figure 3).

中文翻译：

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HLH之外的思考：兼有吞噬性淋巴细胞增多和血栓性微血管病患者的临床特征

介绍

吞噬性淋巴细胞组织细胞增生症（HLH）是免疫系统过度激活的综合症，很大程度上是由高水平的干扰素γ驱动的。HLH的临床表现可能与其他炎性疾病有相当多的重叠。我们介绍了一组转诊至我们中心的难治性HLH治疗患者，发现他们同时出现了补体介导的血栓性微血管病（TMA）。图1包含HLH和TMA的诊断标准。

目标

•认识到HLH的症状

•识别出现TMA症状

•认识到HLH和TMA可以同时出现

方法

在机构审查委员会（IRB）批准后，通过回顾性图表审查确定了2012年1月至2018年12月在我们机构接受治疗的任何年龄的一线治疗难治性噬血细胞性淋巴细胞增多症（HLH）患者。如前所述，对所有患者均进行了TMA筛查，作为临床护理的一部分。电子病历记录了患者的人口统计资料，疾病特征，HLH和TMA靶向治疗，并发症，干预措施和实验室评估。

结果

23例HLH患者中有16例符合高风险TMA标准（图2）。仅在伴有补体介导的TMA的HLH患者中记录了需要肾替代疗法，严重高血压，浆膜炎和胃肠道出血的肾衰竭。HLH和无TMA的患者需要通气支持，主要是由于中枢神经系统症状，例如癫痫持续状态，而HLH和TMA的患者的呼吸衰竭主要与肺动脉高压相关，这是已知的肺部TMA表现（图2）。

10名患者接受依库丽单抗治疗补体介导的TMA，同时接受HLH治疗。除干扰素γ受体阻滞剂依帕珠单抗外，所有接受补体受体阻滞剂依库丽单抗的患者均已完全消退其TMA并存活（图2）。

结论

我们的观察结果表明，干扰素和补体途径的共同激活是诸如HLH等炎症性疾病患者血栓性微血管病发展的潜在元凶，并可能为这些重症患者提供新颖的治疗方法。对于HLH和多器官功能衰竭的儿童应考虑TMA，因为除HLH靶向治疗外，早期实施补体阻断治疗的短期疗程可能会改善这些患者的临床结局（图3）。