In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered the global
coronavirus disease 2019 (COVID-19) pandemic. Although most
infections cause a self-limited syndrome comparable to other upper respiratory viral pathogens, a portion of individuals develop severe illness leading to substantial morbidity and mortality. Furthermore, an estimated 10%-20% of
SARS-CoV-2 infections are followed by
post-acute sequelae of COVID-19 (PASC), or
long COVID.
Long COVID is associated with a wide variety of clinical manifestations including cardiopulmonary complications, persistent
fatigue, and neurocognitive dysfunction. Severe acute
COVID-19 is associated with hyperactivation and increased
inflammation, which may be an underlying cause of
long COVID in a subset of individuals. However, the immunologic mechanisms driving
long COVID development are still under investigation. Early in the pandemic, our group and others observed immune dysregulation persisted into
convalescence after acute
COVID-19. We subsequently observed persistent immune dysregulation in a cohort of individuals experiencing
long COVID. We demonstrated increased SARS-CoV-2-specific CD4+ and CD8+ T-cell responses and antibody affinity in patients experiencing
long COVID symptoms. These data suggest a portion of
long COVID symptoms may be due to chronic immune activation and the presence of persistent SARS-CoV-2
antigen. This review summarizes the
COVID-19 literature to date detailing acute
COVID-19 and
convalescence and how these observations relate to the development of
long COVID. In addition, we discuss recent findings in support of persistent
antigen and the evidence that this phenomenon contributes to local and systemic
inflammation and the heterogeneous nature of clinical manifestations seen in
long COVID.