New disease linked to long COVID - Introducing SARS-CoV-2 Persistent Intestinal Epithelial Syndrome (SPIES)

Medical News: A recent study conducted by researchers at SUNY Downstate Health Sciences University in Brooklyn, New York-USA, has identified a new condition linked to Long COVID, termed SARS-CoV-2 Persistent Intestinal Epithelial Syndrome (SPIES). This Medical News report explores this groundbreaking discovery, detailing the clinical, histologic, and RNA programmatic data used to identify SPIES as a novel disease entity.


New disease linked to long COVID - Introducing SARS-CoV-2 Persistent Intestinal Epithelial Syndrome (SPIES)
 
Unveiling SPIES
Long COVID has been a persistent issue, causing a myriad of symptoms that linger long after the acute phase of the infection has passed. One of the lesser-understood aspects of Long COVID is its impact on the gastrointestinal (GI) system. Researchers have now characterized a syndrome involving persistent SARS-CoV-2 viral material in the intestines, leading to ongoing GI symptoms.
 
The Study in Brief
The research team, including Dr. Thomas Wallach, Dr. Ahmed Soliman, Dr. John Agboola, Dr. Shagun Sharma, Dr. Lais Araujo-Coelho, Dr. Meredith Pittman, Dr. Christos Chatzinakos, and Dr. Sergios-Orestis Kolokotronis, focused on patients aged 5-22 who underwent esophagogastroduodenoscopy (EGD) for GI symptoms between June 2020 and June 2023. The study excluded patients with known histologic diseases. Biopsies from these patients were analyzed for the presence of the SARS-CoV-2 nucleocapsid antigen using immunohistochemical staining.
 
Key Findings
High Prevalence of Persistent SARS-CoV-2 Antigen
Out of 30 patients, 15 were found to have persistent SARS-CoV-2 nucleocapsid antigen (SC-NA) in their intestinal tissue. The presence of SC-NA was confirmed through immunohistochemical staining, which revealed that nine patients had duodenal positivity, two had terminal ileum positivity, and eight had colonic positivity. This indicates that the virus can persist in various parts of the intestinal tract long after the initial infection.
 
Symptoms and Clinical Manifestations
The symptoms observed in these patients included abdominal pain (86.6%), nausea (66.6%), and weight loss (60%). Notably, 37.5% of patients with colonic SC-NA exhibited hematochezia (bloody stool). Elevated ESR/CRP levels were observed in 33% of the positive cases, indicating an inflammatory response. A significant finding was the presence of large lymphoid aggregates (LLA) in 73.3% of SC-NA positive patients, compared to only 20% in the negative group.
 
These symptoms and clinical manifestations are similar to those seen in inflammatory bowel disease (IBD), suggesting that SPIES could be mistaken for other gastrointestinal disorders. The study also noted that some patients experienced constipation (40%) and arthralgia (joint pain) (13.3%), further complicating the clinical picture.
 
RNA Sequencing Insights
The RNA sequencing of duodenal tissue fro m SC-NA positive patients revealed gene expression patterns consistent with acute SARS-CoV-2 infection. The study identified HSPE1P2 as a central gene in the RNA expression network, with involvement from other known SARS-CoV-2 immune mediators like NEAT1. Comparative analysis with irritable bowel syndrome (IBS) and acute SARS-CoV-2 infection data indicated a stronger overlap with acute infection, highlighting the unique nature of SPIES.
 
Detailed Gene Expression Analysis
The differentially expressed genes (DEG) analysis revealed several genes significantly upregulated in the SPIES patients. These include genes like RPL24, RPL13, RPLP1, RPLP2, and APRT, which were found to have higher expression levels compared to control groups. Conversely, several genes were downregulated, including AL161891.1, TCTE3, PSMD6-AS2, RN7SKP9, AL080317.1, THRB, POC1B-AS1, TBILA, HCG18, and AC008625.1.
 
The study also conducted a Fast Gene Set Enrichment Analysis (FGSEA), revealing several pathways with significant false discovery rate (FDR) values, mostly upregulated. Notably, pathways like "BUSSLINGER DUODENAL_TRANSIT_AMPLIFYING_CELLS," "REACTOME EUKARYOTIC TRANSLATION INITIATION," and "GOCC CYTOSOLIC RIBOSOME" indicate enhanced protein synthesis and stress responses, reflecting the cellular response to persistent viral replication.
 
Weighted Gene Correlation Network Analysis (WGCNA)
The WGCNA revealed several modules of gene expression with statistical significance. The most significant module identified HSPE1P2 as the hub gene, which is linked to T cell activation, a crucial component of the immune response to SARS-CoV-2. This aligns with the histologic evidence of lymphoid aggregates and the observed clinical data, suggesting that T cell activation plays a central role in SPIES.
 
The study also found significant transcription factor binding enrichment, with factors like MYC, CTCF, and XRN2 showing notable changes in expression. These transcription factors are involved in regulating various cellular functions and responses to infection, further highlighting the complex molecular landscape of SPIES.
 
Histologic Evidence
Histologic review of the biopsy samples from SC-NA positive patients showed a notable presence of large lymphoid aggregates (LLA) in 11 out of 15 cases. These aggregates were primarily found in the ileocolonic region, with fewer instances in the duodenum. This finding is significant as it suggests a localized immune response to the persistent viral presence.
 
Patients with positive duodenal immunohistochemistry and completed colonoscopy showed that 20% had duodenal LLA, 100% had ileal LLA, and 80% had colonic LLA. This distribution pattern supports the hypothesis that persistent SARS-CoV-2 infection drives lymphoid expansion in the gut, contributing to the observed symptoms.
 
Clinical Implications
The study suggests that SPIES could be a significant cause of post-COVID GI symptoms, which might have previously been misdiagnosed as IBS. The presence of persistent viral material in the intestine leads to ongoing immune activation, resulting in symptoms similar to inflammatory bowel disease (IBD). The researchers propose that SPIES is characterized by GI symptoms lasting over two months, enlarged lymphoid aggregates, and the presence of SARS-CoV-2 in intestinal tissue.
 
A New Diagnostic Criterion
SPIES is defined by:
-Persistent GI symptoms (abdominal pain, weight loss, nausea, hematochezia) lasting over two months.
 
-Endoscopic evaluation showing enlarged lymphoid aggregates.
 
-Immunohistochemical evidence of persistent SARS-CoV-2.
 
Pathophysiology and Treatment
The study postulates that the persistent presence of SARS-CoV-2 in the gut triggers a local inflammatory response, which affects intestinal function and leads to symptoms. This condition appears to be distinct from typical IBS, with SPIES patients showing specific histological and molecular markers indicative of ongoing viral infection.
 
The treatment approach for SPIES remains symptomatic, with therapies like laxatives, low-dose SSRIs, mirtazapine, and 5-ASA showing some efficacy. However, more research is needed to develop targeted treatments for this newly identified condition.
 
Future Directions
The findings highlight the need for further research into the prevalence and long-term impact of SPIES. Understanding the full spectrum of symptoms and the duration of the condition will be crucial. The potential protective role of SARS-CoV-2 vaccination against SPIES also warrants further investigation.
 
The study underscores the importance of recognizing SPIES as a distinct clinical entity. With more patients experiencing long-term GI symptoms post-COVID, accurate diagnosis and appropriate treatment are essential for improving patient outcomes.
 
Conclusion
The identification of SPIES marks a significant advancement in understanding the long-term effects of COVID-19 on the gastrointestinal system. This novel condition, driven by persistent SARS-CoV-2 infection in the intestines, opens new avenues for diagnosis and treatment.
 
The study's findings were published on a preprint server and is currently being peer reviewed.
https://www.medrxiv.org/content/10.1101/2024.07.18.24310647v2
 
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https://www.thailandmedical.news/news/breaking-news-florida-study-shows-that-sars-cov-2-causes-histological-changes-to-the-gastrointestinal-tract