Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning

Abstract

Expression of CCR5 and its cognate ligands have been implicated in COVID-19 pathogenesis, consequently therapeutics directed against CCR5 are being investigated. Here, we explored the role of CCR5 and its ligands across the immunologic spectrum of COVID-19. We used a bioinformatics approach to predict and model the immunologic phases of COVID so that effective treatment strategies can be devised and monitored. We investigated 224 individuals including healthy controls and patients spanning the COVID-19 disease continuum. We assessed the plasma and isolated peripheral blood mononuclear cells (PBMCs) from 29 healthy controls, 26 Mild-Moderate COVID-19 individuals, 48 Severe COVID-19 individuals, and 121 individuals with post-acute sequelae of COVID-19 (PASC) symptoms. Immune subset profiling and a 14-plex cytokine panel were run on all patients from each group. B-cells were significantly elevated compared to healthy control individuals (P<0.001) as was the CD14+, CD16+, CCR5+ monocytic subset (P<0.001). CD4 and CD8 positive T-cells expressing PD-1 as well as T-regulatory cells were significantly lower than healthy controls (P<0.001 and P=0.01 respectively). CCL5/RANTES, IL-2, IL-4, CCL3, IL-6, IL-10, IFN-γ, and VEGF were all significantly elevated compared to healthy controls (all P<0.001). Conversely GM-CSF and CCL4 were in significantly lower levels than healthy controls (P=0.01). Data were further analyzed and the classes were balanced using SMOTE. With a balanced working dataset, we constructed 3 random forest classifiers: a multi-class predictor, a Severe disease group binary classifier and a PASC binary classifier. Models were also analyzed for feature importance to identify relevant cytokines to generate a disease score. Multi-class models generated a score specific for the PASC patients and defined as S1 = (IFN-γ + IL-2)/CCL4-MIP-1β. Second, a score for the Severe COVID-19 patients was defined as S2 = (IL-6+sCD40L/1000 + VEGF/10 + 10*IL-10)/(IL-2 + IL-8). Severe COVID-19 patients are characterized by excessive inflammation and dysregulated T cell activation, recruitment, and counteracting activities. While PASC patients are characterized by a profile able to induce the activation of effector T cells with pro-inflammatory properties and the capacity of generating an effective immune response to eliminate the virus but without the proper recruitment signals to attract activated T cells.

Stellate ganglion block reduces symptoms of Long COVID: A case series

“…Conditions that “preload” the sympathetic nervous system toward inflammation, (e.g., hypertension, obesity, diabetes) predispose catastrophic failure of this feedback loop, resulting in damaging cytokine levels seen in severe COVID-19 ( Porzionato et al, 2020 ). The dysregulated neuroinflammatory state observed in Long COVID ( Patterson et al, 2021 ) represents a subtler form of dysautonomia that appears to be responsive to SGB.…”

“…Time to resolution of symptoms may be prolonged in cases with organ damage, but generally correlates with severity of disease course. However, approximately 30% of symptomatic and 5% of asymptomatic individuals who recover from acute infection develop a distinct proinflammatory cytokine/chemokine profile ( Patterson et al, 2021 ) and experience a range of symptoms that persist indefinitely ( Logue et al, 2021 ). The constellation of symptoms, which can range from mild to debilitating, is known colloquially as “Long COVID” and formally as Post-Acute Sequelae of SARS-CoV-2 infection (PASC).…”

The Immunology of SARS-CoV-2 Infection and Vaccines in Solid Organ Transplant Recipients

“…Patients who succumb to severe COVID-19 often present an imbalanced immune response with exacerbated inflammation and dysregulated T cell activation and other counteracting activities [ 86 ]. Thus, the use of anti-cytokine and immunomodulatory medication was postulated to diminish inflammatory-mediated organ damage in the general population and SOT recipients.…”

Post-acute COVID-19 syndrome: a new tsunami requiring a universal case definition

“…However, female sex, high numbers of symptoms and antibodies to SARS-CoV-2 may play a role in pathogenesis, although some studies have found no significant differences. New lines of research investigate specific biomarkers to establish clusters for both severe COVID-19 and PACS using machine learning techniques to resolve the discrepancies addressed above ( 23 ). We must ensure the follow up of these patients, with a view to finding out how long these symptoms persist and whether they develop into chronic disorders.…”