A proportion of patients surviving acute coronavirus disease 2019 (COVID-19) infection develop post-acute COVID syndrome (long COVID (LC)) lasting longer than 12 weeks. Here, we studied individuals with LC compared to age- and gender-matched recovered individuals without LC, unexposed donors and individuals infected with other coronaviruses. Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection. Using a log-linear classification model, we defined an optimal set of analytes that had the strongest association with LC among the 28 analytes measured. Combinations of the inflammatory mediators IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with LC with 78.5–81.6% accuracy. This work defines immunological parameters associated with LC and suggests future opportunities for prevention and treatment.
Acute COVID-19, caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by a broad spectrum of clinical severity, from asymptomatic to fatal1,2. The immune response during acute illness contributes to both host defense and pathogenesis of severe COVID-19 (ref. 3). Pronounced immune dysregulation with lymphopenia and increased expression of inflammatory mediators3,4 have been described in the acute phase. Following acute COVID-19 infection, a proportion of patients develop physical and neuropsychiatric symptoms lasting longer than 12 weeks (known as Long COVID, chronic COVID syndrome or post-acute sequelae of COVID-19 (ref. 5)), henceforth denoted as LC. Although similar syndromes have been described following infection with SARS-CoV-1 (ref. 6) and Middle East respiratory syndrome–related coronavirus7, LC often develops after mild-to-moderate COVID-19 (refs. 8,9). Symptoms persisting 6 months were observed in 76% of hospitalized patients, with muscle weakness and fatigue being most frequently reported10,11. LC affects between 10% and 30% of community-managed COVID-19 cases 2 to 3 months after infection12,13 and can persist >8 months after infection14. LC symptoms include severe relapsing fatigue, dyspnea, chest tightness, cough, brain fog and headache15. The underlying pathophysiology of LC is poorly understood.