The immunology of long COVID

Long COVID is the patient-coined term for the disease entity whereby persistent symptoms ensue in a significant proportion of those who have had COVID-19, whether asymptomatic, mild or severe. Estimated numbers vary but the assumption is that, of all those who had COVID-19 globally, at least 10% have long COVID. The disease burden spans from mild symptoms to profound disability, the scale making this a huge, new health-care challenge. Long COVID will likely be stratified into several more or less discrete entities with potentially distinct pathogenic pathways. The evolving symptom list is extensive, multi-organ, multisystem and relapsing-remitting, including fatigue, breathlessness, neurocognitive effects and dysautonomia. A range of radiological abnormalities in the olfactory bulb, brain, heart, lung and other sites have been observed in individuals with long COVID. Some body sites indicate the presence of microclots; these and other blood markers of hypercoagulation implicate a likely role of endothelial activation and clotting abnormalities. Diverse auto-antibody (AAB) specificities have been found, as yet without a clear consensus or correlation with symptom clusters. There is support for a role of persistent SARS-CoV-2 reservoirs and/or an effect of Epstein-Barr virus reactivation, and evidence from immune subset changes for broad immune perturbation. Thus, the current picture is one of convergence towards a map of an immunopathogenic aetiology of long COVID, though as yet with insufficient data for a mechanistic synthesis or to fully inform therapeutic pathways. SARS-CoV-2 infection can lead to a diverse array of chronic symptoms, collectively termed 'long COVID'. In this Review, Altmann and colleagues explore current thinking about the pathophysiology of long COVID and discuss potential immunological mechanisms.

Automated summary

Long COVID is a condition where persistent symptoms occur in a significant number of individuals who have had COVID-19, regardless of the severity of their initial infection. It is estimated that at least 10% of global COVID-19 patients have long COVID. The symptoms of long COVID can range from mild to severe, affecting multiple organs and systems, and can relapse and remit over time. There are radiological abnormalities observed in various body sites of individuals with long COVID, suggesting possible endothelial activation and clotting abnormalities. Autoantibodies and immune subset changes are also found in individuals with long COVID. The current understanding suggests an immunopathogenic etiology of long COVID, but more research is needed for a mechanistic synthesis and effective therapeutic approaches.