Evaluating serum levels of S100A9 as an inflammatory marker of unfavorable outcomes in patients with COVID-19

In a recent article posted to the Research Square* preprint server, investigators demonstrated S100A9 as an inflammatory biomarker among hospitalized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients.

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

Background

CoV disease 2019 (COVID-19) induced by SARS-CoV-2 is a multisystemic illness. 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 then trigger the innate immune response by stimulating tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and other chemokines. Further, the S100 family proteins are DAMPs found in the cytoplasm and nucleus of a broad array 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 illnesses resulting in thrombotic events, a characteristic of COVID-19. According to recent studies, the S100A8/A9 complex produced by neutrophils is a hallmark of SARS-CoV-2 infection and could induce cytokine storms. However, only limited studies have focused on the role of S100A9 in innate immunity, particularly in the COVID-19 context. 

About the study

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

Blood samples were procured from COVID-19-negative healthcare personnel, quantitative reverse transcription-polymerase chain reaction (RT-qPCR)-positive COVID-19 patients with various clinical signs of the illness, and convalescent SARS-CoV-2 patients. 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-19-positive and hospitalized, and 4) 25 recovered SARS-CoV-2 patients. These subjects were recruited from a referral unit for diagnosing COVID-19 in the western part of Bahia, Brazil, between May 2020 and June 2021.  

Cytokines and inflammatory mediators, like S100A9, IL-10, IL-6, IL-12p70, TNF-α, and D-dimer, were analyzed by cytometric beads array (CBA)/enzyme-linked immunosorbent assay (ELISA). Additionally, neutrophil counts in the hospitalized COVID-19-positive patients were assessed. Besides, to determine the predictive efficacy of IL-6 and S100A9 parameters as indicators of severity in SARS-CoV-2 infection, a receiving operating curve (ROC) analysis was conducted with COVID-19-positive patients (hospitalized and non-hospitalized).

Results

Collectively, the study results showed that hospitalized SARS-CoV-2 patients displayed superior levels of D-dimer, S100A9, IL-10, IL-6, IL-12p70, and TNF-α relative to non-hospitalized COVID-19 patients, non-infected subjects, and convalescent virus-infected volunteers. The heightened S100A9 levels in hospitalized COVID-19 patients versus SARS-CoV-2-positive non-hospitalized patients suggested that S100A9 could be linked directly to unfavorable outcomes during COVID-19. Furthermore, TNF-α and IL-12p70 levels remained high in recovered COVID-19 patients, possibly due to the late consequences of the cytokine storm correlated with post-infection.

According to the Spearman analysis, a positive association existed between S100A9 and D-dimer/inflammatory cytokines. The association between S100A9 production and plasma D-dimer indicated an elevated risk for incidence of thrombotic events because of the synergistic action among these markers. Moreover, in previous investigations, the S100A9 homodimer demonstrated a critical role in thrombus generation in animal models. Besides, the specificity and sensitivity of IL-6 and S100A9 were demonstrated precisely 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. In addition, diabetes was a comorbid condition in over 32% of hospitalized SARS-CoV-2-positive patients, a key risk factor for SARS-CoV-2 infection.

Conclusions

The study findings illustrated that in COVID-19, high S100A9 serum concentrations were linked to poor outcomes and prognosis in hospitalized patients. The plasmatic S100A9 was associated with several severity markers established as indicators of poor prognosis in SARS-CoV-2 infection, such as the D-dimer, cytokine IL-6, and TNF-α. Therefore, the authors mentioned that combining S100A9 with other predefined standards in clinical protocols might be a valuable tool for predicting key clinical developments in SARS-COV-2 infection.

On the whole, the present work illustrated the potential relevance of the S100A9 protein as a prospect for severity indicator in the progression of SARS-CoV-2 infection. The team mentioned that in the COVID-19 pandemic context, where swift clinical decision-making was critical for minimizing risks and deaths and the availability of techniques capable of forecasting unfavorable outcomes was becoming increasingly important, S100A9 might be a promising molecule to investigate. 

*Important notice

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

Journal reference:
Shanet Susan Alex

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.

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