Supplementary file 1_Granulomatous lymphocytic interstitial lung disease in common variable immune deficiency: an in-depth clinical, immunological, functional and radiological exploration with a focus on its management, challenged by chronic CMV infection.docx

BackgroundCommon variable immune deficiency (CVID) is the most prevalent inborn error of immunity (IEI), marked by diverse clinical-immunological phenotypes and significant immune-dysregulation, including granulomatous lymphocytic interstitial lung disease (GLILD). GLILD is a severe manifestation of CVID, contributing to reduced life expectancy and a challenging diagnosis due to its insidious and non-specific clinical course. Current management strategies for GLILD rely on expert opinion due to a lack of randomized controlled trials (RCTs).
ObjectivesThis study aims to provide a comprehensive immunophenotypical characterization of CVID patients with and without GLILD, investigate predictive biomarkers for GLILD development, and explore therapeutic strategies, particularly during concomitant SARS-CoV-2 and chronic cytomegalovirus (CMV) infections.
SourcesPrimary data were collected from a cohort of 25 patients with CVID who underwent high-resolution computed tomography (HRCT), immunophenotyping, and serum immunoglobulin analysis at diagnosis and after immunoglobulin replacement therapy. Existing literature on CVID and GLILD biomarkers, immunological profiles, and therapeutic interventions informed comparative analyses.
ContentPatients with GLILD exhibited distinct immunophenotypical features, including reduced regulatory T-cells, CD8+ naïve, central memory T-cells, and B-cell subsets (memory and switched memory), alongside increased CD21low B-cells and naïve B-cells, indicative of chronic inflammation-driven immune activation. IgA and IgG4 concentrations were significantly lower in patients with GLILD at diagnosis. Immunosuppressive therapy, predominantly mycophenolate mofetil (MMF), demonstrated favorable clinical and functional outcomes, though radiological progression persisted in some cases. CMV infection in patients with GLILD on immunosuppressants resulted in favorable outcomes, underscoring the importance of personalized treatment strategies.
ImplicationsThis study highlights novel immunological markers and clinical-radiological patterns as potential predictors for GLILD, advocating for their integration into diagnostic and monitoring frameworks to reduce reliance on invasive histopathology. Future research should focus on validating biomarkers and conducting RCTs to establish evidence-based guidelines for GLILD management.

背景：普通变异型免疫缺陷病（Common Variable Immune Deficiency, CVID）是最常见的原发性免疫缺陷病（Inborn Error of Immunity, IEI），其特征为多样的临床-免疫表型及显著的免疫失调，可并发肉芽肿性淋巴细胞性间质性肺疾病（Granulomatous Lymphocytic Interstitial Lung Disease, GLILD）。GLILD是CVID的严重并发症，可导致患者预期寿命缩短，且因其起病隐匿、临床过程无特异性，诊断颇具挑战性。由于缺乏随机对照试验（Randomized Controlled Trial, RCTs）证据，当前GLILD的治疗策略均基于专家经验制定。
研究目的：本研究旨在对伴或不伴GLILD的CVID患者开展全面的免疫表型特征分析，探索GLILD发生的预测生物标志物，并探究其治疗策略，尤其是在合并新型冠状病毒（Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2）与慢性巨细胞病毒（Cytomegalovirus, CMV）感染场景下的治疗方案。
数据来源：本研究的原始数据来自25例CVID患者队列，所有患者在确诊时及接受免疫球蛋白替代治疗后均接受了高分辨率计算机断层扫描（High-Resolution Computed Tomography, HRCT）、免疫表型分析及血清免疫球蛋白检测。本研究的比较分析参考了现有关于CVID与GLILD生物标志物、免疫谱及治疗干预的相关文献。
研究内容：伴GLILD的CVID患者呈现独特的免疫表型特征：调节性T细胞（Regulatory T Cells, Tregs）、CD8+初始T细胞、中枢记忆T细胞及记忆B细胞、转换记忆B细胞亚群比例降低，而CD21低表达B细胞与初始B细胞比例升高，提示慢性炎症驱动的免疫活化。确诊时，GLILD患者的血清免疫球蛋白A（IgA）与免疫球蛋白G4（IgG4）浓度显著降低。以霉酚酸酯（Mycophenolate Mofetil, MMF）为主的免疫抑制治疗可取得良好的临床与功能转归，但部分患者仍存在影像学进展。合并GLILD且接受免疫抑制治疗的患者若发生CMV感染，亦可获得良好预后，这凸显了个体化治疗策略的重要性。
研究意义：本研究揭示了新型免疫标志物与临床-影像学模式可作为GLILD的潜在预测指标，建议将其整合至诊断与监测体系中，以减少对侵入性组织病理学检查的依赖。未来研究应聚焦于生物标志物的验证，并开展随机对照试验以制定基于证据的GLILD管理指南。