The present study demonstrated the association of plasmatic S100A9 with other severity markers described in the literature, such as the cytokine IL-6 and D-dimer, both considered markers of poor prognosis in COVID-19. In addition, other cytokines of clinical importance such as IL-10, TNF-α and IL-12p70 were also measured and compared with the production of S100A9, where a positive association was found in the production of such markers.
In our study, increased S100A9 levels was found in COVID-19 hospitalized patients compared to positive not hospitalized patients, which suggests that S100A9 can be directly related to unfavorable outcomes during SARS-COV-2 infection. In a recent work, increased S100A9 gene expression were found in SARS-CoV-2 infected lung epithelial cells suggesting a potential therapeutic role for S100A9 blocking . These same blocking perspective, the Paquinimod, a specific inhibitor of S100A8/A9, can rescue the pneumonia with substantial reduction of viral loads in SARS-CoV-2-infected mice .
Several studies have shown remarkably high levels of serum calprotectin (S100A8/S100A9) in patients admitted with COVID-19 , , . In addition, elevated serum calprotectin levels on day 1 or 2 of hospitalization are associated with the requirement for mechanical ventilation during admission, a finding that should be evaluated in expanded prospective cohorts .
Moreover, due to its function as an inflammatory marker, S100 family proteins may also have a direct role in the auto-amplifying thrombo-inflammatory storm in COVID-19, through the mobilization and activation of innate immune sensors such as TLR4 . In the same way, hyperactivity of the coagulation system is a common finding in severe COVID-19 . Many patients exhibit a prothrombotic profile, including high levels of fibrin degradation products (D-dimer), high levels of fibrinogen and low levels of antithrombin . In our study, S100A9 production was correlated with plasma D-dimer. This data suggests an increased risk for the development of thrombotic events due to synergistic action between such markers since S100A9 homodimer has also been described as playing an important role in thrombus formation in animal models .
As a major cytokine in the “cytokine storm” and hyperinflammation during SARS-CoV-2 infection, IL-6 presented increased levels in plasma from severe patients as described in other studies , , . In addition, cytokines such as IL-10, TNF- α, IL-12p70, also were augmented in hospitalized patients compared to patients with not hospitalized patients. Interestingly, patients cured of COVID-19 remained with high levels of IL-12p70 and TNF-α. This could be related to late effects of cytokine storm associated with post-infection .
Increased blood levels of IL-10 is also correlated with disease severity in patients with COVID-19 , . The cellular source and specific effects of increased IL-10 in patients with severe COVID-19 remain undefined . However, it is interesting to note that IL-10 inhibits the expression of HLA class II molecules and a similar event is described in patients with severe COVID-19 . It is also possible that increased IL-10 may suppress antiviral immune responses dampening resistance to bacterial infections in patients with COVID-19 .
For range of clinical manifestations, we found a positive association between the occurrence of symptoms, such dyspnea, with comorbidities, like diabetes, hypertension and age over 60 years, data that corroborate previously published studies . A recent work described that, both chronic and intermittent hyperglycemia, which leads to increased production of inflammatory monocytes and neutrophils through enhanced S100A8 and S100A9 signaling on RAGE (receptor for advanced glycation end-products), in an NF-κB dependent pathway . In our study, more than 32% of positive hospitalized patients had diabetes as a co-morbidity, one of the main risk factors in COVID-19.
The pathogenesis of COVID-19 involves the production of inflammatory mediators that will determine the response pattern and consequently the patient's clinical evolution. The infection is characterized by a broad inflammatory signature, with increased levels of soluble biomarkers indicative of immune cell activation, including monocytes/macrophages, neutrophils, T and B lymphocytes and epithelial cells, with an important role in homeostasis imbalance . Providing new insights into the immunological effectors that may contribute to the immunopathogenesis of COVID-19 suggest that certain immune-based biomarkers, identified at the beginning of patient admission or during hospitalization, may indicate an increased risk of mortality in infected patients. The identification of these biomarkers is particularly important for the decision of early interventions, such as treatment with new drugs that are in the clinical study phase, such as molnupiravir .
In our study, we demonstrated the potential role of the S100A9 protein as a candidate of severity biomarker in the evolution of SARS-CoV-2 infection. In the context of a pandemic, where quick decision-making in the clinical environment is a crucial factor to minimize risks and reduce mortality, the availability of tools capable of predicting unfavorable outcomes is increasingly necessary. Thus, S100A9 can be a molecule to be explored within this perspective.