University Of Virginia Study Finds That Sars-Cov-2 Infections Triggers Reduction In Circulating Monocytes That Leads To Persistent Post-COVID Pulmonary Fibrosis
A new study led by researchers from the Department of Medicine, University of Virginia, Charlottesville-USA has found that as a result of SARS-CoV-2 infections causing a reduction in circulating monocytes, the condition of persistent Post-COVID pulmonary fibrosis
Researchers from the Division of Pulmonary and Critical Medicine, Department of Medicine, Mayo Clinic, Rochester-USA also contributed towards the study.
To date, it has been found that up to 30% of COVID-19 patients experience persistent sequelae, including dyspnea, restrictive physiology, and early radiographic signs of pulmonary fibrosis (PF).
However, the detailed mechanisms that induces post-COVID progressive pulmonary fibrosis or PF are poorly understood, and biomarkers to identify at-risk patients are urgently needed.
The study team evaluated a cohort of 14 symptomatic COVID survivors with impaired respiratory function and imaging worrisome for developing PF, including bilateral reticulation, traction bronchiectasis and/or honeycombing, and compared these to Idiopathic Pulmonary Fibrosis (IPF) patients and age-matched controls without respiratory disease.
The study team also performed single-cell RNA-sequencing and multiplex immunostaining on peripheral blood mononuclear cells collected at the COVID-19 patients’ first visit after ICU discharge.
It was found six months later, symptoms, restriction and PF improved in some (Early-Resolving COVID PF), but persisted in others (Late-Resolving COVID PF).
The study findings showed that circulating monocytes were significantly reduced in Late-Resolving COVID PF patients compared to Early-Resolving COVID PF and non-diseased controls.
Monocyte abundance correlated with pulmonary function tests FVC and DLCO. Differential expression analysis revealed MHC-II class molecules were upregulated on the CD8 T cells of Late-Resolving COVID PF patients but downregulated in monocytes.
Interestingly, IPF patients had a similar decrease in monocyte abundance and marked decrease in monocyte HLA-DR protein expression compared to Late-Resolving COVID PF patients.
The study findings conclude that circulating monocyte abundance may distinguish between patients whose post-COVID PF resolves or persists. Furthermore, fibrotic progression coincided with decreases in HLA-DR expression on monocytes, a phenotype previously associated with dampened antigen stimulation and severe respiratory failure.
The study findings were published on a preprint server and are currently being peer reviewed.
The study team utilized a multi-omic approach to analyze blood samples collected more than one-month post-infection but before these two cohorts clinically diverged, and the researchers uncovered that immune cell composition and gene expression significantly differed between ER (early resolving) and LR (late resolving) COVID PF patients.
The key finding of this study is that LR COVID PF patients had significantly fewer monocytes than ER COVID PF patients and controls.
The study is the first to identify that decreased monocyte abundance correlates with impaired pulmonary function in COVID-associated pulmonary fibrosis.
The study findings are consistent with reports that severe COVID patients exhibit a decrease in monocytes but demonstrate monocyte depletion is a distinguishing characteristic within severe COVID.
The study team also found that monocytes of LR COVID PF patients expressed lower levels of MHC class II molecules. CD16+ monocytes are more mature and express more HLA-DR in comparison to CD14+ monocytes, therefore reductions in HLA-DR+ CD14+ monocytes have been associated with mobilization of immature monocytes from the bone marrow for emergency myelopoiesis which was observed here and others reported as a marker of severe COVID-19.
Importantly, loss of HLA-DR on monocytes is also an established marker of immunosuppression, so these findings may also suggest dampening of antigen-mediated stimulation and inhibition of antigen-specific T cell responses as has been shown in sepsis.
Another previous study reported functional suppression of COVID-19 monocytes compared to healthy controls.
Typically, decreases in the MHC class II molecule HLA-DR on monocytes are also associated with severe respiratory failure in COVID-19 pneumonia, immunosuppression, and decreased oxygen saturation in severe COVID-19.
It should be noted that the cohorts in these studies included patients who were acutely infected, whereas this new study shows that HLA-DR downregulation can be prolonged months after infection.
One study found that monocyte HLA-DR in COVID-19 patients began to recover four weeks into hospital admission.
Hence, expression of HLA-DR on monocytes may indicate recovery, as the LR COVID PF cohort appeared to have low HLA-DR expression more than 1-month post-infection, while patients with ER COVID PF maintained or recovered HLA-DR expression.
Importantly, peripheral blood samples from patients with IPF also display decreased monocyte abundance and expression of MHC-II molecules on monocytes relative to age-matched controls.
It should be noted that monocyte depletion has been suggested to contribute to pathogenesis of IPF53.
The study team recruited a clinically stable, outpatient IPF population, therefore, it may not reflect shifts in circulating monocyte populations during acute exacerbations or active progression of IPF.
The study findings indicate that HLA-DR expression is decreased exclusively on CD16+ monocytes in IPF, while conversely CD14+ and intermediate monocytes are the key populations affected in LR COVID PF.
It is possible that the study findings in IPF indicate immunoparesis, while in COVID PF, enhanced migration of monocytes to the lung during COVID PF may evoke emergency myelopoiesis and eventually promote a state of exhaustion.
Whether the observed decrease in HLA-DR+ monocytes in IPF and LR COVID PF arise from the same mechanism remains unknown, but further review of monocyte dysfunction in pulmonary fibrosis will require careful consideration of which monocyte subpopulations are affected.
To date, severe COVID-19 infection has been associated with an increase in CD8+ T cell activation as well as suppression of naïve CD4 T cells.
The study findings found evidence of each of these in T cell phenotypes in the LR COVID PF cohort. Compared to ER COVID PF patients, controls, and IPF patients, LR COVID PF patients had fewer naïve CD4+ T cells, and their CD8+ T cells expressed significantly greater levels of activation markers (HLA-DR and CD38).
Hence the study team posit that the T cell response in LR COVID PF patients is polarized toward an effector or memory phenotype rather than naïve state, similar to that described in another past study.
Such as chronic inflammatory state may lead to senescence of CD8+ T cells, a state common in IPF.
Though the study did not observe gene expression changes suggestive of T cell senescence in the LR COVID PF cohort at the measured time point, a previous study found that shortened telomere length, a defining characteristic of cellular senescence and feature associated with worse survival in IPF, is an independent risk factor for developing fibrotic-like radiographic abnormalities after severe COVID-19.
The study team noted limitations to the study which included them is restricting the age of their COVID PF study cohort (Mean (SD) age = 58±9 years old. While this prevented age-associated changes from becoming a co-variant, it was necessary to properly compare their cohort to IPF patients.
Similarly, their COVID PF cohort was majority male (13/16 patients) and sample size was limited.
Future further studies with a larger clinical cohort comprising young and old COVID PF patients as well as identifying immune signature changes in the lung are necessary to validate whether our findings apply to a broader population in the circulation and tissue.
It should be noted that Post-COVID fibrosis is an emerging cause of restrictive lung disease, and longitudinal studies are needed to evaluate the disease course in these patients.
The study findings imply the peripheral immune response of LR COVID PF is distinct from IPF.
The study findings suggest that in LR COVID PF patients, monocytes are either systemically depleted or alternatively recruited to the lung or other tissues.
Past research confirmed increased infiltration of monocyte-derived macrophages in the bronchoalveolar lavage fluid of severe COVID-19 patients and lungs of fatal COVID-19.
Such an observation presents the opportunity to investigate inhibiting monocyte recruitment as a method to improve recovery from COVID PF.
The study team proposes that relative monocyte abundance may be a useful and simple prognostic indicator for determining whether long-haul COVID patients will resolve or have persistent pulmonary complications early in their disease course.
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