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Long COVID Clues Found in Acute SARS-CoV-2 Infection Blood Samples

NEW YORK – A team from the US and Switzerland has identified cell type-specific gene expression signatures in blood samples from individuals with acute SARS-CoV-2 infections that appeared to predict the risk and types of long-term symptoms they may experience, pointing to the possibility of understanding the biological processes at play when such symptoms persist.

"[T]he work presented here demonstrates the need to consider the acute phase to better understand the development of long-term symptoms," co-senior and co-corresponding authors Noam Beckmann and Alexander Charney, both from the Icahn School of Medicine at Mount Sinai, and their colleagues wrote in Nature Medicine on Thursday, adding that "knowledge of symptom-specific mechanisms will present opportunities to investigate precision treatment and prevention strategies."

Using RNA sequencing, the researchers tracked the transcriptomic profiles of blood samples collected over time from 495 Mount Sinai COVID-19 Biobank Study participants hospitalized with acute SARS-CoV-2 infections, comparing them with blood transcriptomes for 72 healthy individuals or individuals hospitalized with non-COVID-19 conditions.

By bringing in ELISA-based serum antibody titers and self-reported long-term, or post-acute sequelae of COVID-19 (PASC), symptoms for 232 patients followed for at least six months after being discharged, the team tracked down blood cell type-specific gene expression signatures that corresponded with patients' risk of PASC. PASC, commonly known as "Long COVID," is marked by the presence of ongoing symptoms ranging from fatigue or shortness of breath to problems smelling or tasting and affects more than half of people who have had COVID-19.

The findings pointed to the possibility of developing predictive biomarkers for PASC.

In 50 participants with documented vaccination dates, the team did not see ties between vaccine doses and any of the PASC features considered. Likewise, the presence of ongoing symptoms months after hospitalization did not reflect disease severity during the acute infection stage.

"Although additional studies will be required to determine if our findings generalize to mild COVID-19 and asymptomatic infections, this lack of dependence on disease severity is consistent with the reported occurrence of PASC across the range of severity for SARS-CoV-2 infection," the authors noted.

With RNA-seq data for 361 acute blood samples from 165 patients with six months to a year of follow-up data, the team uncovered cell type and molecular clusters that appeared to coincide with distinct long-term symptoms.

Along with ties between post-infection pneumonia and antibody-producing plasma cell levels in acute samples, and links found for ongoing muscle pain and reduced acute infection levels of follicular helper T cell levels, the researchers uncovered symptom-related gene shifts in specific cell types.

While differentially expressed plasma cell genes were associated with skin, lung, sleep, gastrointestinal, and other symptoms, for example, the researchers linked memory resting CD4-positive T-cell gene expression changes to long-term tooth or cavity troubles. Still other cell type-specific gene differences coincided with ongoing thought or memory problems and quality of life changes.

Their results also pointed to two informative plasma cell-related molecular clusters coinciding with half a dozen long-term symptoms. A group of COVID-19 cases in the "plasma cell miscellaneous" cluster had enhanced immunoglobulin-related gene expression and antibodies targeting the SARS-CoV-2 spike protein, along with long-term symptoms related to pneumonia or lung function.

Meanwhile, cases in the so-called "plasma cell pulmonary" cluster involving PASC symptoms such as sleep, skin, smell/taste, or nausea/diarrhea/vomiting problems were marked by anti-spike antibody-independent molecular features, including diminished immunoglobulin gene expression and reduced nonspecific antibody representation.

"The discovery of the association of gene expression during acute COVID-19 with PASC symptoms one year after discharge establishes the existence of direct connections between the acute and post-acute phases," the authors wrote in their paper, noting that "future studies of the relationship between acute infection and PASC will define additional symptom clusters with common underlying mechanisms."