Millions of Americans were exposed to SARS-CoV-2 early in the pandemic but could not get diagnosed with COVID-19 due to testing limitations. Many have developed a postviral syndrome (PVS) including neurologic manifestations similar to those with postacute sequelae of SARS-CoV-2 infection (Neuro-PASC). Owing to those circumstances, proof of SARS-CoV-2 infection was not required for evaluation at Northwestern Medicine's Neuro COVID-19 clinic. We sought to investigate clinical and immunologic findings suggestive of SARS-CoV-2 exposure in patients with PVS.

We measured SARS-CoV-2–specific humoral and cell-mediated immune responses against Nucleocapsid and Spike proteins in 29 patients with PVS after suspected COVID-19, 32 confirmed age-matched/sex-matched Neuro-PASC (NP) patients, and 18 unexposed healthy controls. Neurologic symptoms and signs, comorbidities, quality of life, and cognitive testing data collected during clinic visits were studied retrospectively.

Of 29 patients with PVS, 12 (41%) had detectable humoral or cellular immune responses consistent with prior exposure to SARS-CoV-2. Of 12 PVS responders (PVS⁺), 75% harbored anti-Nucleocapsid and 50% harbored anti-Spike responses. Patients with PVS⁺ had similar neurologic symptoms as patients with NP, but clinic evaluation occurred 5.3 months later from the time of symptom onset (10.7 vs 5.4 months; p = 0.0006). Patients with PVS⁺ and NP had similar subjective impairments in quality of life measures including cognitive function and fatigue. Patients with PVS⁺ had similar results in objective cognitive measures of processing speed, attention, and executive function and better results in working memory than patients with NP.

Antibody and T-cell assays showed evidence of prior SARS-CoV-2 exposure in approximately 40% of the PVS group. Three-quarters of patients with PVS⁺ had detectable anti-Nucleocapsid and one-half anti-Spike responses, highlighting the importance of multitargeted COVID-19 immunologic evaluation and the limitations of commercially available diagnostic tests. Despite their persistent symptoms, lack of COVID-19 diagnosis likely delayed clinical care in patients with PVS. Our data suggest that millions of Americans presenting with PVS resembling Neuro-PASC were indeed exposed to SARS-CoV-2 at the beginning of the pandemic, and they deserve the same access to care and inclusion in research studies as patients with NP with confirmed COVID-19 diagnosis.

数以百万计的美国人在大流行初期就接触过 SARS-CoV-2，但由于检测限制而无法诊断出感染了 COVID-19。许多人出现了病毒后综合症 (PVS)，包括与 SARS-CoV-2 感染急性后遗症 (Neuro-PASC) 类似的神经系统表现。鉴于这些情况，西北医学中心 Neuro COVID-19 诊所的评估不需要 SARS-CoV-2 感染证明。我们试图调查提示 PVS 患者暴露于 SARS-CoV-2 的临床和免疫学结果。

我们测量了 29 名疑似 COVID-19 后患有 PVS 的患者、32 名确诊的年龄匹配/性别匹配的 Neuro-PASC (NP) 患者和18 个未暴露的健康对照。对临床就诊期间收集的神经系统症状和体征、合并症、生活质量和认知测试数据进行了回顾性研究。

在 29 名 PVS 患者中，12 名 (41%) 具有可检测到的体液或细胞免疫反应，与之前接触 SARS-CoV-2 的情况一致。在 12 个 PVS 反应者 (PVS ⁺ ) 中，75% 具有抗核衣壳反应，50% 具有抗尖峰反应。PVS ⁺患者与 NP 患者具有相似的神经系统症状，但临床评估发生在症状出现后 5.3 个月后（10.7 个月 vs 5.4 个月；p = 0.0006）。^{PVS +}和 NP患者在生活质量测量方面有相似的主观损伤，包括认知功能和疲劳。PVS ⁺患者在处理速度、注意力和执行功能等客观认知测量方面具有相似的结果，并且在工作记忆方面比 NP 患者有更好的结果。

抗体和 T 细胞检测显示，PVS 组中约 40% 的人之前曾暴露于 SARS-CoV-2。四分之三的 PVS ⁺患者具有可检测到的抗核衣壳反应和二分之一的抗尖峰反应，凸显了多靶点 COVID-19 免疫学评估的重要性以及市售诊断测试的局限性。尽管症状持续存在，但缺乏 COVID-19 诊断可能会延迟 PVS 患者的临床护理。我们的数据表明，数以百万计的患有类似 Neuro-PASC 的 PVS 的美国人确实在大流行开始时接触过 SARS-CoV-2，他们应该获得与确诊为新冠肺炎的 NP 患者相同的护理和纳入研究的机会-19诊断。