Identification of SARS-CoV-2 Persistent Intestinal Epithelial Syndrome (SPIES) as a Novel Disease Entity using Clinical, Histologic, and RNA Programmatic Data

Thomas Wallach, Ahmed Soliman, John Agboola, Shagun Sharma, Lais Araujo Coelho, Meredith Pittman, Christos Chatzinakos, Sergios-Orestis Kolokotronis
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Abstract

Abstract Long COVID (LC) remains an ongoing issue and one which has created a substantial burden of disease. Gastrointestinal LC is relatively poorly understood. In this study we characterize a syndrome of persistent SARS-CoV2 viral material via clinical and histologic data, and RNA sequencing Methods We reviewed patients aged 5-22 years with an esophagogastroduodenoscopy (EGD) for gastrointestinal (GI) symptoms from 6/2020-6/2023, excluding patients with known histologic disease. Biopsies were sent for immunohistochemical staining. Clinical data was collected. Duodenal, ileal, cecal, and sigmoid colon samples were stained for SARS-CoV-2 using a SARS-CoV-2 nucleocapsid antibody. Slides were reviewed by a blinded pathologist. 8 patients with known duodenal SARS-CoV-2 nucleocapsid antigen (SC-NA) positivity and 8 demographically matched IBS matched patients from prior to 2020 were identified for RNA sequencing comparison. Results were compared with public data from the Gene Expression Omnibus (GEO) data repository for intestinal tissue with IBS and epithelial tissues with active SARS-CoV2 infection. Results Of 30 patients, fifteen (50%) were identified to have positive SC-NA . 3 (20%) had received at least a single SARS-CoV2 vaccine in the + cohort, and 8 (53.3%) in the - (P=0.05). Primary symptoms were pain (86%, nausea (66.6%), and weight loss (60%). 37.5% of patients with colonic SC-NA displayed hematochezia. 33% of + patients showed elevated ESR/CRP. Mean + calprotectin was 317.3 vs. 156.4 (p=0.2). 11/15 (73.3%) +SC-NA had large lymphoid aggregates (LLA) (p = 0.00338). RNA expression was consistent with known acute SARS-CoV2 infection. Hub network analysis showed a tight shift in RNA expression centered around HSPE-1p26, with involvement of known SARS-CoV2 immune mediators like NEAT1. DGE comparative analysis with IBS and acute SARS-CoV2 infection showed higher overlap with acute infection vs. IBS. FGSEA analysis with the same source data demonstrated the same. Conclusions Our findings establish a syndrome mediated by persistent viral infection (SARS-CoV2 Persistent Intestinal Epithelial Syndrome (SPIES)). We hypothesize that persistent sparse infection drives ongoing immune signaling altering movement and function, creating epithelial and movement effects overlapping with DGBI and IBD
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利用临床、组织学和 RNA 程序数据将 SARS-CoV-2 肠上皮细胞持续综合征 (SPIES) 鉴定为一种新型疾病实体
摘要 长期慢性胆囊炎(LC)仍然是一个持续存在的问题,它造成了巨大的疾病负担。人们对胃肠道 LC 的了解相对较少。在本研究中,我们通过临床和组织学数据以及 RNA 测序,描述了一种持续性 SARS-CoV2 病毒物质综合征的特征。方法 我们回顾了 2020 年 6 月至 2023 年 6 月期间因胃肠道(GI)症状而接受食管胃十二指肠镜检查(EGD)的 5-22 岁患者,排除了已知有组织学疾病的患者。活组织切片被送去进行免疫组化染色。收集临床数据。使用 SARS-CoV-2 核壳抗体对十二指肠、回肠、盲肠和乙状结肠样本进行 SARS-CoV-2 染色。切片由盲法病理学家审阅。确定了 8 名已知十二指肠 SARS-CoV-2 核头状抗原 (SC-NA) 阳性的患者和 8 名 2020 年以前的人口统计学匹配的 IBS 患者进行 RNA 测序比较。结果 在 30 例患者中,15 例(50%)被确定为 SC-NA 阳性。在 "+"组群中有 3 人(20%)至少接种过一次 SARS-CoV2 疫苗,在"-"组群中有 8 人(53.3%)至少接种过一次 SARS-CoV2 疫苗(P=0.05)。主要症状为疼痛(86%)、恶心(66.6%)和体重减轻(60%)。37.5%的结肠 SC-NA 患者出现血尿。33%的 + 患者出现 ESR/CRP 升高。平均 + calprotectin 为 317.3 对 156.4(P=0.2)。11/15(73.3%)+SC-NA 有大淋巴细胞聚集(LLA)(p=0.00338)。RNA 表达与已知的急性 SARS-CoV2 感染一致。枢纽网络分析显示,以 HSPE-1p26 为中心的 RNA 表达发生了紧密的变化,已知的 SARS-CoV2 免疫介质(如 NEAT1)也参与其中。与肠易激综合征和急性 SARS-CoV2 感染的 DGE 比较分析显示,急性感染与肠易激综合征的重叠率更高。结论我们的研究结果确定了一种由持续病毒感染介导的综合征(SARS-CoV2 肠上皮细胞持续综合征 (SPIES))。我们假设,持续的稀疏感染会驱动持续的免疫信号改变运动和功能,产生与 DGBI 和 IBD 重叠的上皮和运动效应。
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