The post-acute sequelae of SARS-CoV-2 infection (PASC) refers to a broad spectrum of symptoms and signs that are persistent, exacerbated or newly incident in the period after acute SARS-CoV-2 infection. Most studies have examined these conditions individually without providing evidence on co-occurring conditions. In this study, we leveraged the electronic health record data of two large cohorts, INSIGHT and OneFlorida+, from the national Patient-Centered Clinical Research Network. We created a development cohort from INSIGHT and a validation cohort from OneFlorida+ including 20,881 and 13,724 patients, respectively, who were SARS-CoV-2 infected, and we investigated their newly incident diagnoses 30–180 days after a documented SARS-CoV-2 infection. Through machine learning analysis of over 137 symptoms and conditions, we identified four reproducible PASC subphenotypes, dominated by cardiac and renal (including 33.75% and 25.43% of the patients in the development and validation cohorts); respiratory, sleep and anxiety (32.75% and 38.48%); musculoskeletal and nervous system (23.37% and 23.35%); and digestive and respiratory system (10.14% and 12.74%) sequelae. These subphenotypes were associated with distinct patient demographics, underlying conditions before SARS-CoV-2 infection and acute infection phase severity. Our study provides insights into the heterogeneity of PASC and may inform stratified decision-making in the management of PASC conditions.

SARS-CoV-2感染后急性后遗症（PASC）是指在急性SARS-CoV-2感染后持续、加剧或新出现的一系列症状和体征。大多数研究都单独检查了这些病症，但没有提供同时发生的病症的证据。在这项研究中，我们利用了来自国家以患者为中心的临床研究网络的两个大型队列 INSIGHT 和 OneFlorida+ 的电子健康记录数据。我们从 INSIGHT 创建了一个开发队列，从 OneFlorida+ 创建了一个验证队列，分别包括 20,881 名和 13,724 名感染 SARS-CoV-2 的患者，并且我们在记录的 SARS-CoV-2 感染后 30-180 天调查了他们的新诊断病例。通过对超过 137 种症状和病症的机器学习分析，我们确定了四种可重复的 PASC 亚表型，主要是心脏和肾脏（包括开发和验证队列中 33.75% 和 25.43% 的患者）；呼吸、睡眠和焦虑（32.75%和38.48%）；肌肉骨骼和神经系统（23.37%和23.35%）；以及消化系统和呼吸系统后遗症（10.14%和12.74%）。这些亚表型与不同的患者人口统计数据、SARS-CoV-2 感染前的基础状况以及急性感染阶段的严重程度相关。我们的研究提供了对 PASC 异质性的见解，并可能为 PASC 状况管理中的分层决策提供信息。