Table_4_Immune Dysregulation in Pediatric Common Variable Immunodeficiency: Implications for the Diagnostic Approach.DOCX

Infections and infectious complications are hallmarks of common variable immunodeficiency (CVID) and the leading cause of morbidity and mortality in affected patients at any age. However, the pediatric CVID is no longer perceived as a primary immunodeficiency associated solely with infectious manifestations; autoimmune, allergic, lymphoproliferative, and malignant disorders and organ-specific immunopathology also characterize the spectrum of non-infectious complications. In this study, we sought to determine the role of immune dysregulation and frequency of non-infectious sequelae in children affected with CVID. We also aimed at providing an insight into the pathogenesis of non-infectious complications and at delineating the diagnostic approach to pediatric CVID with immune dysregulation. An in-depth retrospective analysis of clinical manifestations and their correlations with selected immune parameters was performed in a group of 39 CVID children, followed by our pediatric immunology department. Whereas recurrent sinopulmonary infections were present in all (100%) of the children studied, an unexpectedly high rate of non-infectious disorders and immune dysregulation phenotypes were observed in as many as 32 (82.05%) patients, compared with infection-only phenotypes limited to 7 (17.95%) male patients. The most common inflammatory comorbidity was asthma, diagnosed in 21 (53.85%) patients. The second most frequent immune dysregulation group was autoimmune disorders, present in 18 (46.15%) of the children studied with a high rate of autoimmune thyroiditis in as many as 10 (25.64%) of the CVID-affected children. Lymphoproliferation was seen in 14 children (35.90%), and, among them, lymphadenopathy occurred in nine (23.08%) cases and granulomatous lymphocytic interstitial lung disease in seven (17.95%) cases. Finally, malignancies occurred in two female patients (5.13%), papillary thyroid cancer in the first one and T-cell lymphoblastic leukemia in the other one. The most prominent abnormalities in the B- and T-cell compartment contributing to complex immune deficiency and immune dysregulation phenotypes were seen in the autoimmunity group, showing significant reductions in the switched memory B cell, naive T helper cell, and regulatory T-cell subsets. Herein, we document the previously unreported high rate of immune dysregulation in pediatric CVID as a clinical and diagnostic challenge with the variability of defects in the humoral and cellular immune responses.

感染与感染性并发症是普通变异型免疫缺陷病（common variable immunodeficiency, CVID）的标志性表现，也是各年龄段受累患者发病与死亡的首要诱因。然而，儿童普通变异型免疫缺陷病不再被视为仅与感染性表现相关的原发性免疫缺陷病；自身免疫性疾病、变态反应性疾病、淋巴细胞增生性疾病、恶性肿瘤以及器官特异性免疫病理，同样构成了其非感染性并发症的谱系特征。本研究旨在明确免疫失调在儿童CVID患者中的作用，以及该人群中非感染性后遗症的发生频率，同时阐明非感染性并发症的发病机制，并明确伴免疫失调的儿童CVID的诊断路径。本研究对我科随访的39例儿童CVID患者开展了深入的回顾性分析，对其临床表现及与选定免疫参数的相关性进行了研究。尽管所有纳入研究的儿童（100%）均存在复发性呼吸道-鼻窦感染，但多达32例（82.05%）患者出现了非感染性疾病与免疫失调表型，发生率远超仅表现为感染表型的7例男性患者（17.95%）。最常见的炎症合并症为哮喘，共在21例（53.85%）患者中确诊。第二常见的免疫失调类别为自身免疫性疾病，纳入研究的儿童中有18例（46.15%）存在此类表现，其中自身免疫性甲状腺炎的发生率极高，多达10例（25.64%）CVID受累儿童罹患该病。淋巴细胞增生现象见于14例儿童（35.90%），其中9例（23.08%）出现淋巴结病，7例（17.95%）发生肉芽肿性淋巴细胞间质性肺疾病。最终，2例女性患者（5.13%）出现恶性肿瘤，分别为乳头状甲状腺癌与T细胞淋巴母细胞白血病。在自身免疫组中，B细胞与T细胞区室出现了最显著的异常，这些异常是引发复杂免疫缺陷与免疫失调表型的核心原因，具体表现为转换记忆B细胞、初始T辅助细胞及调节性T细胞亚群的显著降低。本研究证实了此前未被报道的儿童CVID患者高免疫失调发生率，该现象作为一项临床与诊断挑战，伴随体液免疫与细胞免疫应答缺陷的异质性。