An inflammatory cytokine signature predicts COVID-19 severity and survival

Abstract

COVID-19 disease, caused by SARS-CoV-2 infection, has resulted in more than 15.5 million infections and 634,000 deaths worldwide. A recent study of hospitals in New York City, at the initial epicenter of the COVID-19 pandemic in the United States, reported that, during March 2020, 21% of patients hospitalized with confirmed COVID-19 died 1 . These findings are aligned with outcomes observed in the Mount Sinai Health System 2,3 . There are currently no curative or preventive therapies for COVID-19, highlighting the need to enhance current understanding of SARS-CoV-2 pathogenesis for the rational development of therapeutics.Recent studies have suggested that, in addition to direct viral damage, uncontrolled inflammation contributes to disease severity in 5 ). Consistent with this hypothesis, high levels of inflammatory markers, including C-reactive protein (CRP), ferritin and D-dimer, high neutrophil-to-lymphocyte ratio [6][7][8][9] and increased levels of inflammatory cytokines and chemokines 6,8-11 have been observed in patients with severe diseases. Pathogenic inflammation, also referred to as cytokine storm, shares similarities with what was previously seen in patients infected with other severe coronaviruses, including SARS-CoV and Middle East respiratory syndrome coronavirus 12 , and bears similarities to cytokine release syndrome (CRS) observed in patients with cancer treated with chimeric antigen receptor-modified (CAR) T cells 13 . Tocilizumab, an IL-6 receptor inhibitor, is a US Food and Drug Administration (FDA)-approved treatment for CRS in patients receiving CAR T cells 14 . Several single-center studies have used IL-6 inhibitors to treat patients with COVID-19 with some clinical benefits 15 and reported failures 14 . Beyond IL-6, several cytokines have been shown to be elevated in CRS and to contribute to tissue damage. TNF-α is important in nearly all acute inflammatory reactions, acting as an amplifier of inflammation. TNF-α blockade has been used to treat more than ten different autoimmune inflammatory diseases, suggesting that this might be a potential therapeutic approach to reduce organ damage in patients with ). IL-1 is also a highly active pro-inflammatory cytokine, and monotherapy blocking

Prognostic factors in patients admitted to an urban teaching hospital with COVID-19 infection

“…Indeed, the role of dexamethasone is endorsed by the recent positive report from the RECOVERY trial that showed a significant survival benefit at 28-days among patients who required either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support [27]. Furthermore, there is emerging evidence of the importance of pro-inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor (TNF-alpha) as predictors of mortality in patients with COVID-19 [28] and that IL-6 blockade appears to be beneficial [29]. Biran et alhave recently reported in a retrospective multi-centre observational study of 764 patients with severe SARS-CoV-2 infection requiring ICU support that treatment with a recombinant monoclonal antibody against the interleukin (IL)-6 receptor, Tocilizumab ® , was associated with a 25% reduction in hospital-related mortality [29].…”

A 21st Century Evil: Immunopathology and New Therapies of COVID-19

“…Furthermore, even higher levels of these mediators were found in patients of critical COVID-19 cases, suggesting that the severity of the disease may be associated with this huge amount of inflammatory mediators, called cytokine storm, which overloads the immune system with information, preventing the establishment of an effective immune response (26). For example, a study published by Valle et al showed that COVID-19 patients have higher levels of IL-6, IL-8, and TNF-alpha than healthy individuals on hospital admission; moreover, when they stratified the population by low versus high cytokine levels and applied a risk competition model, it was found that each cytokine is an independent predictive factor of the patients' overall survival and is significantly associated with worse clinical outcomes (145).…”

The bumpy road to achieve herd immunity in COVID-19

“…TNF-α, indicating organ damage, could predict poor outcome of the disease. [84] IL-8 was found associated with survival time. These findings point out that the inflammatory status of the individual is yet again a measure of the disease outcome.…”

“…[87] Early cytokine measurements could predict patient's clinical evolution and hence could rapidly orient therapy. [84] Another overlooked issue is that cytokine pattern is sexdependent [88] and that data gather upon differences in soluble IL-2 R, IL-6, ferritin, procalcitonin, LDH, and hsCRP in males versus female patients, and independently associated with disease severity in COVID-19 patients. [89]…”