No detectable differences in peripheral blood immune profiles between patients with prolonged severe long COVID and convalescent controls

Abstract Long COVID (LC) is characterized by persistent symptoms following acute SARS-CoV-2 infection. Common symptoms include post-exertional malaise (PEM), fatigue, cognitive impairments, and orthostatic intolerance. The underlying pathophysiological mechanism of LC remains poorly understood and studies involving patients affected for several years remain scarce. We analyzed a comprehensive panel of inflammation-associated immune markers and clinical features in LC patients with a median disease duration of three years, and compared them with convalescent controls (CC). LC was characterized using patient-reported outcome measures (PROMs), including assessments of recovery, symptoms, PEM, fatigue, cognitive failures, orthostatic intolerance, and health-related quality of life. Peripheral blood was analyzed for immune cell distributions, systemic interferon (IFN) pathway activation, monocyte transcriptional signatures, and circulating cytokine levels in serum. Immunologically, absolute numbers and frequencies of immune subsets did not differ significantly between LC and CC groups. Similarly, after correction for multiple testing, no significant differences were observed between patients with LC and CC in the expression of monocyte-associated genes, cytokine levels, or systemic IFN pathway activation. In the LC group, immunological markers were not significantly associated with illness duration or PROMs. Our findings contrast with earlier reports, predominantly conducted earlier in the disease course, describing subtle inflammatory differences in LC. In this study, we observed no detectable differences in the assessed immune markers in peripheral blood between patients with LC and controls under resting conditions. Consequently, these markers may have limited utility for diagnosis or stratification in long-term LC.