Data Sheet 1_Markers of T cell activation and exhaustion in plasma are associated with persistent symptoms up to 18 months following mild SARS-CoV-2 infection.docx

BackgroundPersistent symptoms following SARS-CoV-2 is an increasing problem after COVID-19 disease. The pathogenesis of this persistent post Covid-19 Condition (PCC) is, however, largely unknown. We hypothesized that persistent T cell activation and exhaustion play a role in PCC development.
MethodsWe examined plasma levels of soluble (s) CD25, TIM-3 and LAG-3, all markers of T cell activation/exhaustion, by enzyme immunoassays in 170 home-isolated and 53 hospitalized patients for up to 18 months after COVID-19 in relation to persistent symptomatology.
ResultsOur major findings were: (i) Cases with persistent dyspnea and fatigue had markedly higher sCD25 at 6–18 months with a more modest increase in sTIM-3. (ii) Cases with memory problems at 12–18 months had increased sLAG-3 iii) sCD25 correlated with SARS-CoV-2 antibody titers and microneutralization titers only in cases with PCC while sTIM-3 correlated with these parameters irrespectively of symptoms. iv) Although hospitalized patients had markedly elevated levels of T cell activation/exhausting markers during follow-up, there was no relation to PCC symptoms.
ConclusionOur study indicates a role for T cell activation/exhaustion in PCC following home isolated COVID-19 infection, with somewhat different patterns of sCD25, sTIM-3 and sLAG-3, but not in hospitalized COVID-19 patients where disease severity may be more important.

研究背景：新型冠状病毒（SARS-CoV-2）感染后出现的持续症状已成为新型冠状病毒肺炎（COVID-19）康复后日益突出的临床问题。然而，新冠后持续症状（Post COVID-19 Condition, PCC）的发病机制目前尚未完全明确。本研究推测，持续的T细胞活化（T cell activation）与耗竭（T cell exhaustion）在PCC的发生发展中发挥了关键作用。
研究方法：本研究采用酶免疫分析法（enzyme immunoassays），检测了170名居家隔离患者与53名住院患者在感染COVID-19后最长18个月内的血浆可溶性CD25（soluble CD25, sCD25）、TIM-3及LAG-3水平——上述分子均为T细胞活化/耗竭的标志性指标，并分析其与患者持续症状的相关性。
研究结果：本研究主要发现如下：(1) 存在持续性呼吸困难与乏力的患者，在感染后6~18个月时的血浆sCD25水平显著升高，同时sTIM-3水平仅出现轻度上升；(2) 在感染后12~18个月存在记忆障碍的患者，其sLAG-3水平显著升高；(3) 仅在PCC患者中，sCD25水平与SARS-CoV-2抗体滴度及微量中和滴度呈显著正相关，而sTIM-3水平与上述参数的相关性不受症状状态的影响；(4) 尽管住院患者在随访期间的T细胞活化/耗竭标志性分子水平显著升高，但该类指标与PCC症状并无关联。
研究结论：本研究表明，T细胞活化与耗竭在居家隔离感染COVID-19后发生的PCC中发挥了一定作用，且该过程伴随sCD25、sTIM-3及sLAG-3的差异化表达模式；但在住院COVID-19患者中并未观察到该关联，此类患者的疾病严重程度可能是影响预后的更关键因素。