Metabolic, viral, and immune phenotypes in Long COVID

• August 2026
• Frontiers in Endocrinology

Publication Details

DOI: 10.3389/fendo.2026.1899115

Abstract

Context: Long COVID is characterized by persistent symptoms ≥ 3 months after acute SARS-CoV-2 infection. To date, the underlying pathophysiology is unclear.

Objective: To characterize the immune and metabolic features of Long COVID and the potential role of viral persistence in adipose tissue.

Design: Case-control, cross-sectional study under the RECOVER Initiative.

Setting: Maine, Louisiana, and Kentucky.

Participants: Adults from the RECOVER study with high or low symptom burden assessed by the PROMIS scoring system or the Long COVID RECOVER Index (LCRI), matched by age, sex, and BMI, comparing post-infected individuals with Long COVID vs those without sequelae.

Main outcome measures: The primary outcome was a difference in T cell mitochondrial respiration by symptom severity. Secondary outcomes included glucose tolerance, body composition, T cell surface markers, and subcutaneous adipose biopsy.

Results: There were 54 participants, 80% female; mean age was 51.7 years, mean BMI 31. Time from initial infection was 894 days. The participant cohort by symptom burden was elucidated using a PROMIS symptom score subdivided by the following: High Symptom Burden (HSB) >15:n=25, Intermediate Symptom Burden (ISB) 10-15:n=14 and Low Symptom Burden (LSB) <10:n=15. Using the LCRI, n=15 were Long COVID+ (LC+) and n=39 were Indeterminate. The primary outcome, T cell oxidative phosphorylation, did not differ between LC+ and Indeterminate nor by PROMIS scores. BMI and fat mass did not differ but T cell glycolytic activity was greater in those with LC+ vs Indeterminate. Lean mass and femoral BMD trended lower in the HSB vs LSB by both classifications. Prevalence of Type 2 diabetes did not differ by symptom scores, but HOMA-IR was higher and HOMA-B was lower in LC+ vs Indeterminate. SARS-CoV-2 viral RNA was not detectable in subcutaneous adipose tissue biopsies. CD26+ T cell number and DPP-4 (CD26) activity were higher in the HSB and correlated significantly with symptom scores (r=0.52, p<0.01); plasma cytokines and stimulated T cell cytokines did not differ by symptom group in either classification.

Conclusions: Individuals with Long COVID symptoms show subtle impairments in glucose tolerance, serum leptin, lean mass and enhanced T cell DPP-4 activity. Participants with Long COVID have subtle changes in glucose metabolism that are not driven by SARS-CoV-2 virus in subcutaneous adipose tissue.

Authors

Ivette F Emery, Seynt Jiro Sahagun, Elizabeth R M Zunica, Christopher Axelrod, Robbie A Beyl, Eunhan Cho, Guillaume Spielmann, Samantha Costa, Joanne T DeKay, Carolyn Chlebek, Shinya Amano, Katherine Stevens, Philipp E Scherer, Dawei Bu, Aida Javidan, Brian S Finlin, Xiaohua D Zhang, Barbara Nikolajczyk, Catherine Blish C, Carolyn Bramante, Tracey McLaughlin, Soneida DeLine-Caballero, Kalani Ratnasiri, Uma Mangalanathan, Jonathan Z Li, Brooke M Leeman, Gregory Edelstein, Elizabeth W Karlson, John P Kirwan, Philip A Kern, Sergei Ryzhov, Clifford J Rosen

Keywords

T cells; glucose metabolism; glucose metabolism glycolysis; glycolysis; leptin; leptin T cells