Metabolic, viral, and immune phenotypes in long COVID

Document Type

Article

Publication Date

8-11-2026

Institution/Department

Center for Clinical and Translational Science

Journal Title

Frontiers in endocrinology

MeSH Headings

Humans; Female; COVID-19 (immunology, metabolism, virology); Middle Aged; Male; Case-Control Studies; Post-Acute COVID-19 Syndrome; SARS-CoV-2; Cross-Sectional Studies; T-Lymphocytes (metabolism, immunology); Symptom Burden; Phenotype; Body Composition; Adult; Adipose Tissue (metabolism, virology); Mitochondria (metabolism)

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, 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, 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.

ISSN

1664-2392

First Page

1899115

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