Rivalta Beatrice, Amodio Donato, Milito Cinzia, Chiriaco Maria, Di Cesare Silvia, Giancotta Carmela, Conti Francesca, Santilli Veronica, Pacillo Lucia, Cifaldi Cristina, Desimio Maria Giovanna, Doria Margherita, Quinti Isabella, De Vito Rita, Di Matteo Gigliola, Finocchi Andrea, Palma Paolo, Trizzino Antonino, Tommasini Alberto, Cancrini Caterina
Research Unit of Primary Immunodeficiencies, Immune and Infectious Diseases Division, Academic Department of Pediatrics (DPUO), Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Chair of Pediatrics, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
Front Pediatr. 2021 Aug 27;9:703853. doi: 10.3389/fped.2021.703853. eCollection 2021.
Activated PI3K-kinase Delta Syndrome (APDS) is an autosomal-dominant primary immunodeficiency (PID) caused by the constitutive activation of the PI3Kδ kinase. The consequent hyperactivation of the PI3K-Akt-mTOR pathway leads to an impaired T- and B-cells differentiation and function, causing progressive lymphopenia, hypogammaglobulinemia and hyper IgM. Patients with APDS show recurrent sinopulmonary and chronic herpes virus infections, immune dysregulation manifestations, including cytopenia, arthritis, inflammatory enteropathy, and a predisposition to persistent non-neoplastic splenomegaly/lymphoproliferation and lymphoma. The recurrence of the lymphoproliferative disorder and the difficulties in the proper definition of malignancy on histological examination represents the main challenge in the clinical management of APDS patients, since a prompt and correct diagnosis is needed to avoid major complications. Targeted therapies with PI3Kδ-Akt-mTOR pathway pharmacologic inhibitors (i.e., Rapamycin, Theophylline, PI3K inhibitors) represent a good therapeutic strategy. They can also be used as bridge therapies when HSCT is required in order to control refractory symptoms. Indeed, treated patients showed a good tolerance, improved immunologic phenotype and reduced incidence/severity of immune dysregulation manifestations. Here, we describe our experience in the management of four patients, one male affected with APDS1 (P1) and the other three, a male and two females, with APDS2 (P2, P3, P4) presenting with chronic EBV replication, recurrent episodes of immune dysregulation manifestations and lymphomas. These cases highlighted the importance of a tailored and close follow-up, including serial endoscopic and lymph nodes biopsies control to detect a prompt and correct diagnosis and offer the best therapeutic strategy.
活化的磷脂酰肌醇-3激酶δ综合征（APDS）是一种常染色体显性遗传的原发性免疫缺陷病（PID），由PI3Kδ激酶的组成性激活引起。PI3K-Akt-mTOR通路随之出现的过度激活会导致T细胞和B细胞分化及功能受损，进而引起进行性淋巴细胞减少、低丙种球蛋白血症和高IgM血症。APDS患者表现出反复的鼻窦肺部感染和慢性疱疹病毒感染、免疫失调表现，包括血细胞减少、关节炎、炎症性肠病，以及易患持续性非肿瘤性脾肿大/淋巴细胞增殖和淋巴瘤。淋巴细胞增殖性疾病的复发以及在组织学检查中正确定义恶性肿瘤的困难是APDS患者临床管理中的主要挑战，因为需要及时、正确的诊断以避免重大并发症。使用PI3Kδ-Akt-mTOR通路药理抑制剂（即雷帕霉素、茶碱、PI3K抑制剂）进行靶向治疗是一种很好的治疗策略。当需要进行造血干细胞移植（HSCT）以控制难治性症状时，它们也可作为过渡治疗。事实上，接受治疗的患者显示出良好的耐受性、改善的免疫表型以及免疫失调表现的发生率/严重程度降低。在此，我们描述了我们对四名患者的管理经验，一名患有APDS1的男性（P1），另外三名，一名男性和两名女性，患有APDS2（P2、P3、P），表现为慢性EB病毒复制、反复出现的免疫失调表现和淋巴瘤。这些病例突出了量身定制且密切随访的重要性，包括连续的内镜检查和淋巴结活检控制，以实现及时、正确的诊断并提供最佳治疗策略。
