Introduction
Pneumonia is a primary cause of morbidity and mortality all over the world, especially in children and in adults more than 60 years. Every year, 450 million people suffered from pneumonia and 1.3 million cases died of pneumonia [
1‐
3].
Streptococcus pneumoniae (pneumococcus) is one of the commonest bacterial pathogens-inducing community-acquired pneumonia (CAP), which results in substantial health and economic burden [
4,
5]. Previous studies found that CAP accounts for more than 60,000 deaths, 1.2 million hospitalizations, 2.3 million emergency department visits and $10 billion in hospital costs in United States yearly [
6,
7]. In order to reduce the mortality and prevent CAP clinical deterioration, it is very necessary to diagnose the disease and evaluate the severity of CAP at the time of disease onset. Nevertheless, early recognition and evaluation the risk of CAP are difficult. The sensitivity and specificity of different biochemical markers and laboratory testing are variable and largely limited [
8]. Therefore, additional new biomarkers are essentially needed to evaluate the severity and simplify the diagnosis progress.
S100A9, a small Ca
2+ binding protein recognized as an alarmin, is released by stressed cells: an endogenous danger signal, which promotes and exacerbates the inflammatory response [
9]. S100A9 forms a complex with S100A8 (S100A8/S100A9 heterodimer) to exhibit different inflammatory effects via toll-like receptor 4 (TLR4) [
10,
11], scavenger receptor CD36 [
12] and receptor of advanced glycated end products (RAGE) [
13]. Released of S100A9 activates several signaling pathways and exerts important functions in a great deal of cellular processes [
10,
14‐
16]. The previous studies found that S1009A9 is elevated in several diseases, such as neutrophilic inflammation in asthma, insulin deficiency, atopic dermatitis and Parkinson’s disease [
17‐
20]. In addition, our previous study found that S100A8/S100A9 is increased in COPD patients and positively associated with inflammatory cytokines [
21]. Therefore, these results indicate that S100A9 may be used as a biomarker for the diagnosis of disease.
An early study revealed that S100A9 was increased in the lung of patients with non-small cell carcinoma [
22]. Perinatal inflammation exposure modified lung morphogenesis, elevated the level of S100A9 in fetal mice [
23]. TLR4/RAGE signaling was activated and S100A9 was increased under endotoxemia-induced pulmonary inflammation [
24]. These data indicated that S100A9 may play an important role in the pulmonary diseases. However, the role of S100A9 protein remains unknown in CAP patients. Therefore, the main purpose of current research was to analyze the correlations of serum S100A9 with the severity and prognosis in CAP patients based on a prospective cohort study.
Discussion
This study mainly analyzed the associations between serum S100A9 with the severity and the prognosis in CAP patients based on a prospective cohort study. The present study mainly found that: (1) Serum S100A9 was elevated in CAP patients; (2) Serum S100A9 on admission was positively associated with CAP severity scores; (3) Serum S100A9 on admission was positively associated with inflammatory cytokines; (4) Serum higher S100A9 on admission elevates mortality and hospital stay in CAP patients.
Earlier studies found that S100A9 is elevated in several diseases, such as neutrophilic inflammation in asthma, insulin deficiency, atopic dermatitis and Parkinson’s disease [
17‐
20]. Moreover, a report from our laboratory indicated S100A8/S100A9 is increased in COPD patients and positively associated with inflammatory cytokines [
21]. However, the role of S100A9 in CAP and the associations between serum S100A9 and the severity of CAP were unknown. In the present study, we found that serum S100A9 was elevated in CAP patients. Moreover, serum S100A9 was gradually increased in parallel with the severity of CAP. Further logistic regression analysis found that serum S100A9 was positively associated with the severity of CAP. These results reveal that S100A9 may take part in the pathophysiology process of CAP.
Previous research found that inflammation is increased in CAP patients [
30]. In this study, we also found that several inflammatory cytokines were elevated in CAP patients. Not only that, serum S100A9 was positively associated with inflammatory cytokines in CAP patients. Besides, some earlier studies revealed that blood routine indices were changed in CAP patients compared with control subjects [
31,
32]. This research found that WBC and neutrophil were increased, lymphocyte was reduced in CAP patients. The ratios of PLR, MON and NLR were increased in patients with CAP. Further correlation analysis demonstrated that serum S100A9 was positively correlated with WBC, NLR and MON. These results suggested that the level of serum S100A9 may reflect the pathophysiologic conditions for CAP in a certain extent.
The association between serum S100A9 and the severity of CAP has been explored. However, the influence of S100A9 on the prognosis of CAP patients remains unclear. The present study analyzed the effect of S100A9 on the death of risk among CAP patients. These results found that the level of serum S100A9 was increased in dead patients on admission. Univariate and multivariate logistic regression analysis verified that serum higher S100A9 on admission elevated the risk of death of CAP patients. Moreover, we found that the higher serum S100A9 was, the longer hospital stay was. Univariate logistic regression analysis suggested that serum S100A9 on admission was positively related with hospital stay in CAP patients. These results proved that serum higher S100A9 on the early stage always indicated a serious prognosis for CAP patients. In order to confirm the predictive capacity, the ROC curve was analyzed. The AUC value of serum S100A9 for CAP was 0.788 (95% CI: 0.699, 0.878). In addition, the predictive quality of serum S100A9 and CAP severity scores for severity were similar. Besides, the predictive power of serum S100A9 was superior to several known biomarkers though literature review [
31,
33]. Hence, these results provide additional evidence that serum S100A9 can be used as a better diagnostic biomarker for CAP.
This study mainly explored the relationships between serum S100A9 on the early stage with the severity and prognosis in CAP patients. However, there are several potential flaws in this study. Firstly, all CAP patients and control subjects were recruited from one hospital rather than from multicenter in China. The sample size was relatively small. So, the larger sample size and multicenter studies are needed in the future clinical research. Secondly, this was only a clinical epidemiology research, the mechanism of S100A9 elevation in CAP patients is needed to further clarify with in vitro experiments. Thirdly, S100A9 was only detected in serum, the local levels of S100A9 in sputum, lungs and bronchoalveolar lavage fluid are unknown in CAP patients. Fourthly, S100A9 was only detected in CAP patients. The levels and changes of S100A9 in patients with other pneumonias are unclear. The difference of S100A9 will be compared between CAP patients and other pneumonias’ patients in the next work.
Conclusion
In summary, this study mainly analyzed the associations between serum S100A9 on admission with the severity and prognosis among CAP patients based on a prospective cohort study. Our results reveal that serum S100A9 is elevated in CAP patients on admission. In addition, serum S100A9 is positively associated with the severity of CAP on admission. We provide evidence that serum higher S100A9 at the early stage elevates the risk of death and hospital stay of CAP patients. Therefore, S100A9 may be regarded as a diagnostic biomarker and useful for the clinical management of CAP in the future clinical practice.
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