# Immunological dysfunction persists for 8 months following initial mild-moderate SARS-CoV-2 infection

## TL;DR

This study shows that people with long COVID have lasting immune system changes, including elevated inflammation and missing immune cells, even 8 months after infection.

## Contribution

The study identifies persistent immune dysfunction in long COVID patients, including a unique cytokine profile and reduced naive T/B cells.

## Key findings

- Long COVID patients had elevated levels of 15 correlated inflammatory cytokines for 8 months post-infection.
- Long COVID patients showed a persistent absence of un-activated naive T and B cells in peripheral blood.
- Interferon and T cell activation markers were elevated in SARS-CoV-2 survivors but not higher in long COVID patients.

## Abstract

A proportion of patients surviving acute COVID-19 infection develop post-COVID syndrome (long COVID) encompassing physical and neuropsychiatric symptoms lasting longer than 12 weeks. Here we studied a prospective cohort of individuals with long COVID compared to age/gender matched subjects without long COVID (from the ADAPT study), healthy donors and individuals infected with other non-SARS CoV2 human coronaviruses (the ADAPT-C study). We found highly activated innate immune cells and an absence of subsets of un-activated naïve T and B cells in peripheral blood of long COVID subjects, that did not reconstitute over time. These activated myeloid cells may contribute to the elevated levels of type I (IFN-β) and III interferon (IFN-λ1) that remained persistently high in long COVID subjects at 8 months post-infection. We found positive inter-analyte correlations that consisted of 18 inflammatory cytokines in symptomatic long COVID subjects that was not observed in asymptomatic COVID-19 survivors. A linear classification model was used to exhaustively search through all 20475 combinations of the 29 analytes measured, that had the strongest association with long COVID and found that the best 4 analytes were: IL-6, IFN-γ, MCP-1 (CCL2) and VCAM-1. These four inflammatory biomarkers gave an accuracy of 75.9%, and an F1 score of 0.759, and have also previously been associated with acute severe disease. In contrast, plasma ACE2 levels, while elevated in the serum of people previously infected with SARS-CoV-2 were not further elevated in subjects with long COVID symptoms. This work defines immunological parameters associated with long COVID and suggests future opportunities to prevention and treatment.