未接种疫苗的有持续症状的新冠病毒感染者的多层深度免疫分析、新冠病毒血症和炎症
Multi-layered deep immune profiling, SARS-CoV-2 RNAemia and inflammation in unvaccinated COVID-19 individuals with persistent symptoms.
作者信息
Rovito Roberta, Bono Valeria, Coianiz Nicolò, Cazzetta Valentina, Franzese Sara, Mikulak Joanna, Di Vito Clara, Bai Francesca, Beaudoin-Bussières Guillaume, Tauzin Alexandra, Augello Matteo, Tincati Camilla, Santoro Andrea, Borghi Elisa, Marozin Sabrina, Finzi Andrés, Della Bella Silvia, Mavilio Domenico, Marchetti Giulia
机构信息
Clinic of Infectious Diseases and Tropical Medicine, Department of Health Sciences, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy.
Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy.
出版信息
Commun Med (Lond). 2025 May 5;5(1):155. doi: 10.1038/s43856-025-00832-8.
BACKGROUND
Long-COVID immunopathogenesis involves diverse factors. We longitudinally characterize hospitalized COVID-19 patients, examining the role of SARS-CoV-2 RNAemia and inflammation in immune dysregulation.
METHODS
Hospitalized patients are evaluated during acute infection (T0), 3 months post-symptom onset (T1), and 3 years if symptoms persisted (T2). Immune profile includes characterization of SARS-CoV-2-specific/non-specific T/B cells (flow cytometry) and antibodies (ELISA, neutralization, ADCC). RNAemia and cytokines are quantified (RT-PCR, cytometric beads array) and correlated.
STATISTICS
non-parametric cross-sectional, longitudinal and correlation analyses.
RESULTS
Here we show 48 hospitalized individuals during acute COVID-19, 38 exhibit early persistent symptoms (EPS+) 3 months post-symptoms onset, 10 do not (EPS-). Groups are comparable for age, sex, co-morbidities. The EPS+ shows fatigue, dyspnoea, anosmia/dysgeusia, diarrhea, chronic pain, mnestic disorders. Over time, they show a reduction of neutralization ability and total SARS-CoV-2-specific CD4 T cells, with increased total CD4 T, and failure to increase RBD-specific B cells and IgA+ MBCs. EPS+ patients show higher levels of T0-IFN-γ + CD4 T, T1-IL-2 + CD4 T and T1-TNF-α + CD4 cTfh. In EPS+, baseline SARS-CoV-2 RNAemia positively correlates with CD4 T, follow-up SARS-CoV-2 RNAemia with ADCC. Among 38 EPS+ individuals at T1, 33 are evaluated 3 years after infection, 5 are lost at follow-up. 10/33 EPS+ show long-term symptoms (late persistent symptoms, EPS + LPS+), whereas 23/33 fully recover (EPS + LPS-). Antibodies, RNAemia, and cytokines show no differences between/within groups at any time point.
CONCLUSIONS
Early persistent symptoms are associated with multi-layered SARS-CoV-2-specific/non-SARS-CoV-2-specific immune dysregulation. The shift towards non-Ag-specific T and ADCC trigger in EPS+ may relate to SARS-CoV-2 RNAemia. Early immune dysregulation does not associate with long-term persistent symptoms. Further research on SARS-CoV-2 RNAemia and early immune dysregulation is needed.
背景
新冠后综合征的免疫发病机制涉及多种因素。我们对住院的新冠患者进行纵向研究，探讨严重急性呼吸综合征冠状病毒2（SARS-CoV-2）病毒血症和炎症在免疫失调中的作用。
方法
对住院患者在急性感染期（T0）、症状出现后3个月（T1）以及若症状持续则在3年后（T2）进行评估。免疫特征包括对SARS-CoV-2特异性/非特异性T/B细胞（流式细胞术）和抗体（酶联免疫吸附测定、中和试验、抗体依赖性细胞介导的细胞毒性）的特征分析。对病毒血症和细胞因子进行定量（逆转录聚合酶链反应、细胞计数微珠阵列）并进行相关性分析。
统计学方法
非参数横断面、纵向和相关性分析。
结果
我们展示了48例急性新冠感染期住院患者的数据，其中38例在症状出现后3个月表现出早期持续症状（EPS+），10例未出现（EPS-）。两组在年龄、性别、合并症方面具有可比性。EPS+组表现出疲劳、呼吸困难、嗅觉丧失/味觉障碍、腹泻、慢性疼痛、记忆障碍。随着时间推移，他们的中和能力和SARS-CoV-2特异性总CD4 T细胞减少，总CD4 T细胞增加，且RBD特异性B细胞和IgA+记忆B细胞未能增加。EPS+患者在T0期IFN-γ+CD4 T、T1期IL-2+CD4 T和T1期TNF-α+CD4 cTfh水平较高。在EPS+组中，基线SARS-CoV-2病毒血症与CD4 T细胞呈正相关，随访时SARS-CoV-2病毒血症与抗体依赖性细胞介导的细胞毒性呈正相关。在T1期的38例EPS+个体中，33例在感染后3年接受评估，5例失访。10/33例EPS+个体表现出长期症状（晚期持续症状，EPS+LPS+），而23/33例完全康复（EPS+LPS-）。在任何时间点，抗体、病毒血症和细胞因子在组间/组内均无差异。
结论
早期持续症状与多层次的SARS-CoV-2特异性/非SARS-CoV-2特异性免疫失调有关。EPS+组向非抗原特异性T细胞和抗体依赖性细胞介导的细胞毒性的转变可能与SARS-CoV-2病毒血症有关。早期免疫失调与长期持续症状无关。需要对SARS-CoV-2病毒血症和早期免疫失调进行进一步研究。
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