Bloomfield Marketa, Klocperk Adam, Zachova Radana, Milota Tomas, Kanderova Veronika, Sediva Anna
Department of Immunology, 2nd Faculty of Medicine, Charles University Hospital in Motol, Prague, Czechia.
Department of Pediatrics, 1st Faculty of Medicine, Charles University in Prague and Thomayer University Hospital, Prague, Czechia.
Front Pediatr. 2021 Jul 19;9:697706. doi: 10.3389/fped.2021.697706. eCollection 2021.
Activated phosphoinositide 3-kinase delta syndrome (APDS), caused by mutations in PI3Kδ catalytic p110δ () or regulatory p85α () subunits, is a primary immunodeficiency affecting both humoral and cellular immunity, which shares some phenotypic similarities with hyper-IgM syndromes and common variable immunodeficiency (CVID). Since its first description in 2013, over 200 patients have been reported worldwide. Unsurprisingly, many of the newly diagnosed patients were recruited later in life from previously long-standing unclassified immunodeficiencies and the early course of the disease is, therefore, often less well-described. In this study, we report clinical and laboratory features of eight patients followed for APDS, with particular focus on early warning signs, longitudinal development of their symptoms, individual variations, and response to therapy. The main clinical features shared by our patients included recurrent bacterial and viral respiratory tract infections, gastrointestinal disease, non-malignant lymphoproliferation, autoimmune thyroiditis, and susceptibility to EBV. All patients tolerated vaccination with both attenuated live and subunit vaccines with no adverse effects, although some failed to mount adequate antibody response. Laboratory findings were characterized by dysgammaglobulinaemia, elevated serum IgM, block in B-cell maturation with high transitional B cells, and low naïve T cells with CD8 T-cell activation. All patients benefited from immunoglobulin replacement therapy, whereas immunosuppression with mTOR pathway inhibitors was only partially successful. Therapy with specific PI3K inhibitor leniolisib was beneficial in all patients in the clinical trial. These vignettes, summary data, and particular tell-tale signs should serve to facilitate early recognition, referral, and initiation of outcome-improving therapy.
活化磷脂酰肌醇3激酶δ综合征（APDS）由PI3Kδ催化亚基p110δ（）或调节亚基p85α（）的突变引起，是一种影响体液免疫和细胞免疫的原发性免疫缺陷病，与高IgM综合征和常见变异型免疫缺陷病（CVID）有一些表型相似之处。自2013年首次描述以来，全球已报告200多名患者。不出所料，许多新诊断的患者是在晚年从以前长期未分类的免疫缺陷病中招募的，因此，疾病的早期病程往往描述得不够充分。在本研究中，我们报告了8例接受APDS随访患者的临床和实验室特征，特别关注预警信号、症状的纵向发展、个体差异以及对治疗的反应。我们患者共有的主要临床特征包括反复的细菌和病毒呼吸道感染、胃肠道疾病、非恶性淋巴增殖、自身免疫性甲状腺炎以及对EBV的易感性。所有患者对减毒活疫苗和亚单位疫苗接种均耐受，无不良反应，尽管有些患者未能产生足够的抗体反应。实验室检查结果的特征为γ球蛋白血症异常、血清IgM升高、高过渡性B细胞导致B细胞成熟受阻以及幼稚T细胞减少伴CD8 T细胞活化。所有患者均从免疫球蛋白替代治疗中获益，而mTOR通路抑制剂的免疫抑制仅部分成功。在临床试验中，特异性PI3K抑制剂来那度胺对所有患者均有益。这些病例、汇总数据以及特定的警示信号应有助于促进早期识别、转诊以及启动改善预后的治疗。
