Identification of soluble biomarkers that associate with distinct manifestations of long COVID

Long COVID is a heterogeneous clinical syndrome of uncertain etiology triggered by infection with SARS-CoV-2. We employed ultrasensitive approaches to profile the immune system and plasma proteome in healthy convalescent individuals and patients with long COVID. Symptomatic disease was not consistently associated with quantitative differences in immune cell lineage composition or antiviral T cell immunity. Healthy convalescent individuals nonetheless exhibited higher titers of neutralizing antibodies against SARS-CoV-2 than patients with long COVID, and extensive phenotypic analyses revealed a subtle increase in the expression of some coinhibitory receptors, most notably PD-1 and TIM-3, among SARS-CoV-2 nonspike-specific CD8 ⁺ T cells in patients with long COVID. We further identified a plasma biomarker signature of disease linking breathlessness with apoptotic inflammatory networks centered on the hub protein TRAF2 and dysregulated pathways associated with lung injury, cell cycle progression, and platelet activation, which could potentially inform the diagnosis and treatment of long COVID.