Immuno-proteomic profiling reveals abundant airway CD8 T cells and ongoing epithelial injury in prolonged post-COVID19 respiratory disease

Abstract

Some patients hospitalized with acute COVID19 suffer respiratory symptoms that persist for many months. To characterize the local and systemic immune responses associated with this form of long COVID, we delineated the immune and proteomic landscape in the airway and peripheral blood of normal volunteers and patients from 3 to 6 months after hospital discharge. The bronchoalveolar lavage (but not peripheral blood) proteome was abnormal in patients with post-COVID19 lung disease with significantly elevated concentration of proteins associated with apoptosis, tissue repair and epithelial injury. This correlated with an increase in cytotoxic lymphocytes (especially tissue resident CD8+ T cells), lactate dehydrogenase and albumin (biomarkers of cell death and barrier integrity). Follow-up of a subset of these patients greater than 1-year post-COVID19 indicated these abnormalities resolved over time. Collectively, these data indicate that COVID-19 results in a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to ongoing activation of cytotoxic T cells.

Targeted proteomics identifies circulating biomarkers associated with active COVID-19 and post-COVID-19

“…The acute effects of SARS-CoV-2 are mainly marked by dysregulation of inflammatory markers and complement factors, as has been described before ( 9 , 35 ). Consistent with earlier research in COVID-19 patients after the infection phase ( 12 ), our results suggest that a substantial proportion of proteins (109/220, ~50%) return to normal levels as they do not show statistical difference compared to controls in the post-infection phase. A note of caution for this conclusion is that we cannot completely exclude that for some proteins this may be caused by other factors such as a lack of statistical power to detect differences.…”

“…Taken together, there is an urgent need for understanding the mechanisms underlying COVID-19 and establishing biomarkers for patient stratification, to be able to identify patients who will progress to severe disease or take more time to recover. Targeted proteomics has proven successful in identifying key mediators of disease, also in COVID-19 ( 7 – 12 ). However, most of these studies are confined to smaller sample sizes, and few studies include individuals after the initial phase of the disease.…”

A persistent neutrophil-associated immune signature characterises post-COVID19 pulmonary sequelae

“…Our data suggests that this transition may be delayed in severe COVID19 since pro-in ammatory signatures remained elevated compared to mild disease. This is supported by other studies in the literature that have shown increased systemic in ammation-associated markers in individuals recovering from acute severe COVID19 when compared to healthy control subjects 17,28 .…”

“…Having identi ed persistent immune activation following severe COVID19, we sought to determine whether components of this pro-in ammatory signature, or alternative pathways, are selectively upregulated in subjects with persistent morphologic abnormalities following COVID-19 compared to those showing radiographic resolution. Such comparisons have the potential to offer clearer discrimination of key mechanistic drivers than comparisons to healthy uninfected subjects, as has been the case in other studies 17,18 . The present study has identi ed a range of selectively increased plasma proteins in individuals with post-COVID interstitial lung changes predominantly consistent with a neutrophil-associated in ammatory signature.…”

“…Whether post-COVID lung pathology is driven by persistence of this initial heightened in ammatory response or activation of alternative pathways that develop subsequent to recovery from the acute illness is unknown. Recent immunopro ling studies have compared individuals with post-COVID19 lung parenchymal abnormalities to healthy controls and identi ed increases in airway CD8+ and CD4+ T lymphocytes with gene expression associated with myeloid cell in ammation 17,18 . These studies provide information about the immunological landscape after recovery from acute SARS-CoV-2 but lack an appropriate control group, namely individuals with resolution of lung changes post-COVID19 and so do not provide meaningful insight to distinguish the critical pathways dictating susceptibility to, or protection against, development of persistent interstitial lung changes.…”