To assess serum S100A9 levels as an inflammatory marker of adverse outcomes in patients with COVID-19

In a recent article published on Research Square* preprint server, researchers demonstrated that S100A9 was an inflammatory biomarker in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: S100A9 as an inflammatory marker in hospitalized COVID-19 patients. Image Credit: Beliphotos/Shutterstock


SARS-CoV-2-induced CoV disease 2019 (COVID-19) is a multisystem disease. The clinical manifestations of SARS-CoV-2 infections vary from mild flu-like symptoms to severe viral pneumonia.

SARS-CoV-2-induced tissue damage will result in the generation of damage-associated molecular patterns (DAMPs), which will then trigger the innate immune response by stimulating tumor necrosis factor-α (TNF-α), interleukin- 6 (IL-6), and other chemokines. Additionally, S100 family proteins are DAMPs found in the cytoplasm and nucleus of a wide range of myeloid lineage cells and play a role in cell differentiation and cell cycle progression.

S100A9 has been implicated as an inflammatory mediator in the pathogenesis of vascular and inflammatory diseases resulting in thrombotic events, a hallmark of COVID-19. According to recent studies, the S100A8/A9 complex produced by neutrophils is a hallmark of SARS-CoV-2 infection and may induce cytokine storms. However, only limited studies have focused on the role of S100A9 in innate immunity, especially in the context of COVID-19.

About the study

In the present cross-sectional investigation, scientists assessed whether serum S100A9 concentrations serve as an inflammatory indicator of adverse outcomes in hospitalized COVID-19 patients.

Blood samples were collected from COVID-19 negative healthcare workers, from quantitative reverse transcription-polymerase chain reaction (RT-qPCR) positive COVID-19 patients with various clinical signs of the disease and from patients convalescents with SARS-CoV-2. Overall, the study cohorts were divided into 1) 11 COVID-19 RT-qPCR-negative individuals, 2) 21 SARS-CoV-2 positive but not hospitalized, 3) 30 COVID-positive -19 and hospitalized, and 4) 25 patients recovered from SARS-CoV-2. These subjects were recruited from a referral unit for the diagnosis of COVID-19 in the western part of Bahia, Brazil, between May 2020 and June 2021.

Cytokines and inflammatory mediators, such as S100A9, IL-10, IL-6, IL-12p70, TNF-α and D-dimers, were analyzed by cytometric bead array (CBA)/enzyme immunoassay (ELISA) . Additionally, neutrophil counts in hospitalized COVID-19 positive patients were assessed. Additionally, to determine the predictive power of IL-6 and S100A9 parameters as indicators of SARS-CoV-2 infection severity, a receiving operating curve (ROC) analysis was performed. with COVID-19 positive patients (hospitalized and non-hospitalized).


Collectively, the study results showed that hospitalized SARS-CoV-2 patients had higher levels of D-dimer, S100A9, IL-10, IL-6, IL-12p70 and TNF-α compared to non-patients. hospitalized COVID-19, uninfected subjects and convalescent volunteers infected with the virus. Elevated levels of S100A9 in hospitalized COVID-19 patients compared to non-hospitalized SARS-CoV-2 positive patients suggested that S100A9 may be directly linked to adverse outcomes during COVID-19. Moreover, TNF-α and IL-12p70 levels remained elevated in recovered COVID-19 patients, likely due to late consequences of cytokine storm correlated with post-infection.

According to Spearman’s analysis, a positive association existed between S100A9 and inflammatory D-dimers/cytokines. The association between S100A9 production and plasma D-dimer indicated a high risk of incidence of thrombotic events due to the synergistic action between these markers. Additionally, in previous investigations, the S100A9 homodimer has demonstrated a critical role in thrombus generation in animal models. Furthermore, the specificity and sensitivity of IL-6 and S100A9 have been precisely demonstrated by ROC analyses.

Further, a significant correlation existed between the prevalence of COVID-19 symptoms like dyspnea and comorbidities like hypertension, diabetes, and age above 60 years, considering the breadth of clinical manifestations. Additionally, diabetes was a comorbid condition in more than 32% of SARS-CoV-2 positive hospitalized patients, a key risk factor for SARS-CoV-2 infection.


Study results showed that in COVID-19, elevated serum S100A9 levels were linked to poor outcomes and poor prognosis in hospitalized patients. Plasma S100A9 was associated with several severity markers established as indicators of poor prognosis in SARS-CoV-2 infection, such as D-dimer, cytokine IL-6, and TNF-α. Therefore, the authors mentioned that the combination of S100A9 with other predefined standards in clinical protocols could be a valuable tool in predicting key clinical developments of SARS-COV-2 infection.

Overall, the present work illustrated the potential relevance of the S100A9 protein as a perspective indicator of severity in the progression of SARS-CoV-2 infection. The team mentioned that in the context of the COVID-19 pandemic, where rapid clinical decision-making was essential to minimize risk and fatalities and where the availability of techniques capable of predicting adverse outcomes was becoming increasingly important, S100A9 could be a promising molecule to study.

*Important Notice

Preprints with Research Square publish preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.

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