Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Università Vita-Salute San Raffaele, Milan, Italy.
Front Immunol. 2023 Jun 26;14:1187959. doi: 10.3389/fimmu.2023.1187959. eCollection 2023.
Hemophagocytic inflammatory syndrome (HIS) is a rare form of secondary hemophagocytic lymphohistiocytosis caused by an impaired equilibrium between natural killer and cytotoxic T-cell activity, evolving in hypercytokinemia and multiorgan failure. In the context of inborn errors of immunity, HIS occurrence has been reported in severe combined immunodeficiency (SCID) patients, including two cases of adenosine deaminase deficient-SCID (ADA-SCID). Here we describe two additional pediatric cases of ADA-SCID patients who developed HIS. In the first case, HIS was triggered by infectious complications while the patient was on enzyme replacement therapy; the patient was treated with high-dose corticosteroids and intravenous immunoglobulins with HIS remission. However, the patient required HLA-identical sibling donor hematopoietic stem cell transplantation (HSCT) for a definitive cure of ADA-SCID, without HIS relapse up to 13 years after HSCT. The second patient presented HIS 2 years after hematopoietic stem cell gene therapy (GT), secondarily to Varicella-Zoster vaccination and despite and lymphocytes' reconstitution in line with other ADA SCID patients treated with GT. The child responded to trilinear immunosuppressive therapy (corticosteroids, Cyclosporine A, Anakinra). We observed the persistence of gene-corrected cells up to 5 years post-GT, without HIS relapse. These new cases of children with HIS, together with those reported in the literature, support the hypothesis that a major dysregulation in the immune system can occur in ADA-SCID patients. Our cases show that early identification of the disease is imperative and that a variable degree of immunosuppression could be an effective treatment while allogeneic HSCT is required only in cases of refractoriness. A deeper knowledge of immunologic patterns contributing to HIS pathogenesis in ADA-SCID patients is desirable, to identify new targeted treatments and ensure patients' long-term recovery.
噬血细胞性炎症综合征（HIS）是一种罕见的继发性噬血细胞性淋巴组织细胞增生症，由自然杀伤细胞和细胞毒性 T 细胞活性之间的平衡失调引起，表现为细胞因子过度分泌和多器官功能衰竭。在先天性免疫缺陷中，HIS 已在严重联合免疫缺陷（SCID）患者中报道，包括两例腺苷脱氨酶缺乏-SCID（ADA-SCID）患者。本文描述了另外两例 ADA-SCID 患者发生 HIS 的病例。在第一个病例中，HIS 是在患者接受酶替代治疗时发生感染并发症时触发的；患者接受了大剂量皮质类固醇和静脉注射免疫球蛋白治疗，HIS 缓解。然而，该患者需要 HLA 匹配的同胞供体造血干细胞移植（HSCT）来根治 ADA-SCID，在 HSCT 后 13 年内没有 HIS 复发。第二个患者在造血干细胞基因治疗（GT）后 2 年发生 HIS，继发于水痘-带状疱疹疫苗接种，尽管与其他接受 GT 治疗的 ADA SCID 患者一样，淋巴细胞得以重建。该患儿对三线免疫抑制治疗（皮质类固醇、环孢素 A、阿那白滞素）有反应。我们观察到 GT 后 5 年内持续存在基因校正细胞，没有 HIS 复发。这些伴有 HIS 的儿童新病例，以及文献报道的病例，支持了一个假设，即 ADA-SCID 患者的免疫系统可能会发生重大失调。我们的病例表明，早期识别疾病至关重要，而一定程度的免疫抑制可能是有效的治疗方法，仅在难治性病例中才需要异基因 HSCT。深入了解导致 ADA-SCID 患者 HIS 发病机制的免疫模式是可取的，以便确定新的靶向治疗方法并确保患者的长期康复。
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