Clinical significance of serum S100 calcium-binding protein A12 concentrations in patients with community-acquired pneumonia

Abstract

Objective

This study aimed to investigate the clinical significance of serum S100 calcium-binding protein A12 (S100A12) concentrations in patients with community-acquired pneumonia (CAP).

Methods

This was a case–control study. We selected 120 patients with CAP treated in Xichang People’s Hospital from January to June 2022 as the case group. Sixty healthy adults without a history of basic diseases were selected as the control group. The patients in the case group were divided into the low S100A12 and high S100A12 subgroups. Serum S100A12, C-reactive protein (CRP), and procalcitonin (PCT) concentrations, the leukocyte count, and other study parameters were compared.

Results

Serum S100A12, CRP, and PCT concentrations and the leukocyte count were higher in the case group than in the control group. The baseline confusion, urea, respiratory rate, blood pressure, and age ≥ 65 score, baseline pneumonia severity index score, and 30-day mortality rate were higher in the high S100A12 subgroup than in the low S100A12 subgroup. Serum CRP and PCT concentrations and the leukocyte count were higher in the high S100A12 subgroup than in the low S100A12 subgroup.

Conclusion

Patients with high serum S100A12 concentrations have more severe CAP, a more serious inflammatory reaction, and higher 30-day mortality.

Keywords

Community-acquired pneumonia S100 calcium-binding protein A12 (S100A12)C-reactive protein procalcitonin leukocyte mortality

Introduction

Community-acquired pneumonia (CAP) refers to pulmonary infection caused by bacteria, viruses, chlamydia, and mycoplasma outside the hospital.¹ How to effectively monitor the severity of CAP in patients to guide clinical treatment urgently needs to be determined. The confusion, urea, respiratory rate, blood pressure, and age ≥ 65 (CURB-65) score is a predictive assessment that may be implemented succinctly and conveniently.² The pneumonia severity index (PSI) is a sensitive index for judging whether patients with CAP should be hospitalized.³ The CURB-65 is a concise and easy-to-implement scoring method, whereas the PSI is a more comprehensive and sensitive index. However, neither of these scoring methods provide a comprehensive assessment of the severity of CAP.

In addition to these scoring methods, circulating biomarkers are effective tools for predicting the clinical outcome in patients with CAP. Despite their potential, the sensitivity and specificity of these biomarkers are limited. Consequently, determining clinically significant biomarkers for predicting the prognosis of patients with CAP remains is important. Moreover, the 30-day mortality rate is an important clinical outcome that is crucial in the diagnosis and treatment of CAP.

Some members of the S100 calcium-binding protein A (S100A) family are important in various physiological and pathological processes. S100A12 is an important member of the calcium-binding protein S100 family and may promote the inflammatory response.^4–6 The level of serum S100A12 is related to the prognosis of severe pneumonia in elderly people, and has the potential to become a new index for evaluating the prognosis of severe pneumonia within 28 days after admission.⁷ Elevated serum S100A12 concentrations may also predict the severity of mycoplasma pneumonia.⁸ Inflammatory factor C-reactive protein (CRP) may increase rapidly after lung infection; therefore, it has value for assessing disease severity.⁹ Some studies have shown that CRP is closely related to CAP.¹⁰ Procalcitonin (PCT) may be used for the diagnosis and differential diagnosis of bacterial infections, and it is a commonly used diagnostic index of inflammation in the clinic.^11–12 PCT concentrations may predict blood culture positivity in CAP cases.¹³ The leukocyte count is associated with inflammation and severity of CAP.¹⁴ However, little is known about the relationships between S100A12 and clinical characteristics, serum CRP concentrations, serum PCT concentrations, and the leukocyte count.

Therefore, this study aimed to investigate serum S100A12 concentrations in patients with CAP and to analyze their relationship with the patients’ clinical characteristics, serum CRP concentrations, serum PCT concentrations, and the leukocyte count.

Materials and methods

Subjects

We performed a case–control study. One hundred twenty patients with CAP who were treated in Xichang People’s Hospital from January to June 2022 were selected as the case group. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.¹⁵

The inclusion criteria were as follows: (1) patients met the diagnostic criteria for CAP,¹⁶ and the symptoms began in the community and were confirmed by chest radiography or chest computed tomography; (2) age ≥ 18 years; (3) inpatients; (4) a history of basic diseases including chronic obstructive pulmonary disease, diabetes, and cardiovascular diseases (e.g., heart failure and myocardial infarction); (5) there was complete clinical data; and (6) the patients volunteered to participate in the study. The exclusion criteria were as follows: (1) < 18 years old; (2) patients with pulmonary diseases caused by tuberculosis, pulmonary interstitial diseases, pulmonary embolism, or pulmonary vasculitis; (3) patients with other types of infectious diseases; (4) patients with immunodeficiency diseases or hematological diseases; (5) patients with tumors; (6) patients with organ transplantation; (7) patients who took immunosuppressors within 4 weeks before the study; (8) patients with mental illness; and (9) pregnant patients. Sixty healthy adults without a history of basic diseases who underwent a physical examination in our hospital were selected as the healthy control group.

The study protocol was approved by the Research Ethical Committee of Xichang People’s Hospital, Sichuan Province, China (No. 2021-IRB-156). Written informed consent was obtained from all participants in the study. All of the subjects’ details had been de-identified.

Detection method of serum indices

Fasting elbow vein blood was collected within 24 hours after admission. In the control group, fasting elbow vein blood was collected on the day of the physical examination. The blood was centrifuged and the serum was used for further examination.

Serum S100A12 concentrations were detected by an enzyme-linked immunosorbent assay (Shanghai Pengke Industrial Co., Ltd., Shanghai City, China). Serum CRP and PCT concentrations were measured by scattering turbidimetry (Orion Diagnostica Ltd., Espoo, Finland) and electrochemiluminescence (MIC Biotechnology Co., Ltd., Chengdu City, China), respectively. The changes in the leukocyte count were detected and recorded by an automatic blood cell analyzer (MIC Biotechnology Co., Ltd.). According to the median level of serum S100A12 in the case group, the patients were divided into the low S100A12 subgroup and the high S100A12 subgroup, and the above-mentioned serum index levels were compared between the two groups.

Statistical analysis

Measurement data that conformed to a normal distribution are expressed as the mean ± standard deviation, and comparison between groups was performed by the independent sample t-test. Measurement data with a non-normal distribution are shown as the median (25th, 75th percentiles), and the Mann–Whitney U test was used for comparison between two groups. Count data are expressed by the number (%), and the chi-square test was used for comparison between two groups. The sample size was calculated by G Power software (https://www.psychologie.hhu.de/arbeitsgruppen/allgemeine-psychologie-und-arbeitspsychologie/gpower.html). IBM SPSS Statistics for Windows, Version 26.0 (IBM Corp., Armonk, NY, USA) was used for data analysis. P < 0.05 was considered statistically significant.

Results

There were 68 (56.67%) men and 52 (43.33%) women in the case group, the mean age was 63.07 ± 5.05 years, and the mean body mass index (BMI) was 22.75 ± 1.81 kg/m². In the control group, there were 35 (58.33%) men and 25 (41.67%) women, the mean age was 62.45 ± 5.11 years, and the mean BMI was 22.63 ± 1.86 kg/m². There were no significant differences in sex, age, or BMI between the case group and the control group (P = 0.831, P = 0.443, and P = 0.680, respectively). A flowchart of this study is shown in Figure 1.

Figure 1.

Flowchart of the study

Mean serum S100A12, CRP, and PCT concentrations and the mean leukocyte count in the case group were significantly higher than those in the control group (all P < 0.001) (Table 1).

Table 1.

Comparison of serum indices between the case group and control group.

Indices	Case group (n = 120)	Control group (n = 60)	P value
Serum S100A12 (ng/mL)	32.05 ± 2.23	3.84 ± 0.32	< 0.001
Serum CRP (mg/L)	51.43 ± 3.58	6.20 ± 0.51	< 0.001
Serum PCT (ng/mL)	2.36 ± 0.16	0.15 ± 0.01	< 0.001
Leukocyte count (× 10⁹/L)	7.74 ± 0.54	6.46 ± 0.57	< 0.001

Values are the mean ± standard deviation.

S100A12, S100 calcium-binding protein A12; CRP, C-reactive protein; PCT, procalcitonin.

The median serum S100A12 concentration in the case group was 32.01 ng/mL. The 55 patients in the case group with serum S100A12 concentrations below the median value were included in the low S100A12 subgroup, and 65 patients in the case group with serum S100A12 concentrations ≥ 32.01 ng/mL were included in the high S100A12 subgroup. There were no significant differences in age, BMI, days of intensive care unit hospitalization, or the proportions of systolic blood pressure, diastolic blood pressure, sex (men and women), hypertension, diabetes, coronary heart disease, hyperlipidemia, fever, cough, expectoration, shortness of breath, and chest pain between the low S100A12 subgroup and the high S100A12 subgroup (Table 2).

Table 2.

Comparison of clinical features between the low S100A12 subgroup and the high S100A12 subgroup.

Clinical baseline data	Low S100A12 subgroup (n = 55)	High S100A12 subgroup (n = 65)	P value
Age (years)	63.36 ± 4.90	62.82 ± 5.21	0.556
Male sex, n (%)	31 (56.36)	37 (56.92)	0.951
Female sex, n (%)	24 (43.64)	28 (43.08)	0.951
BMI (kg/m²)	22.87 ± 1.74	22.52 ± 1.81	0.287
Combined with hypertension, n (%)	26 (47.27)	32 (49.23)	0.831
Combined with diabetes, n (%)	14 (25.45)	17 (26.15)	0.931
Combined with coronary heart disease, n (%)	18 (32.73)	21 (32.31)	0.961
Combined with hyperlipidemia, n (%)	20 (36.36)	29 (44.62)	0.359
ICU hospitalization (days)	15.95 ± 1.21	16.38 ± 1.32	0.061
Systolic blood pressure (mmHg)	122.48 ± 9.38	123.06 ± 9.14	0.731
Diastolic blood pressure (mmHg)	77.50 ± 5.94	78.60 ± 4.95	0.270
Fever, n (%)	29 (52.73)	38 (58.46)	0.529
Cough, n (%)	18 (32.73)	24 (36.92)	0.631
Expectoration, n (%)	15 (27.27)	20 (30.77)	0.675
Shortness of breath, n (%)	12 (21.82)	19 (29.23)	0.355
Chest pain, n (%)	8 (14.55)	12 (18.46)	0.566
Baseline CURB-65 score	3 (2, 3)	5(5, 5)	< 0.001
Baseline PSI score	96 (88, 104)	130 (103.5, 136)	< 0.001
30-day mortality rate, n (%)	4 (7.27)	42(64.62)	< 0.001

Values are the mean ± standard deviation, median (range), or n (%).

S100A12, S100 calcium-binding protein A12; BMI, body mass index; ICU, intensive care unit; CURB-65, confusion, urea, respiratory rate, blood pressure, and age ≥ 65; PSI, pneumonia severity index.

The median baseline CURB-65 score, baseline PSI score, and 30-day mortality rate in the high S100A12 subgroup were significantly higher than those in the low S100A12 subgroup (all P < 0.001) (Table 2).

The mean serum CRP and PCT concentrations and the mean leukocyte count in the high S100A12 subgroup were significantly higher than those in the low S100A12 subgroup (all P < 0.001) (Table 3).

Table 3.

Comparison of serum indices between the low S100A12 subgroup and the high S100A12 subgroup.

Indices	Low S100A12 subgroup (n = 55)	High S100A12 subgroup (n = 65)	P value
Serum CRP (mg/L)	48.26 ± 1.74	54.12 ± 2.31	< 0.001
Serum PCT (ng/mL)	2.22 ± 0.09	2.48 ± 0.11	< 0.001
Leukocyte count (× 10⁹/L)	7.26 ± 0.26	8.14 ± 0.34	< 0.001

Values are the mean ± standard deviation.

S100A12, S100 calcium-binding protein A12; CRP, C-reactive protein; PCT, procalcitonin.

Discussion

Patients with CAP are prone to developing to sepsis and multiple organ failure if they are not treated in a timely manner, which seriously endangers the physical and mental health of patients. CAP is a common pulmonary infectious disease.¹⁷ The detection of serum biomarkers is a rapid method for distinguishing infectious diseases. The leukocyte count, CRP, and PCT are common indices to evaluate the severity of infected diseases and predict the prognosis of patients. In recent years, some new serum markers have been gradually applied to the differential diagnosis of clinical infectious diseases.

S100A12 is a marker of infection, and is mainly expressed in human peripheral blood cells, and its source is mainly neutrophils. After stimulation, neutrophils may produce a lot of S100A12, upregulate the expression of adhesion molecules in vascular endothelial cells, and then induce an inflammatory reaction.¹⁸ S100A12 is an effective marker of inflammatory diseases such as bacterial pneumonia.¹⁹ S100A12 may be involved in the pathophysiological process of CAP. In this study, we found that serum S100A12 concentrations in patients with CAP were higher than those in healthy controls. The findings in this study are basically consistent with those in previous studies.²⁰

Excessive inflammatory factors are released after viruses, bacteria, and other microorganisms invade the body, which cause an excessive inflammatory response and aggravate tissue damage. This study showed that serum CRP and PCT concentrations and the leukocyte count in patients with CAP were higher than those in controls. This finding suggested that there was an inflammatory reaction and an abnormal leukocyte count in patients with CAP.

Scoring methods, such as the PSI and CURB-65 score, are important for risk stratification management of patients with CAP, although the PSI and CURB-65 are equally sensitive in predicting death due to CAP.²¹ However, accurately assessing the mortality rate of patients with CAP is difficult.²² In this study, there were significant differences in the baseline CURB-65 score, baseline PSI score, and 30-day mortality rate between the low S100A12 subgroup and the high S100A12 subgroup. Patients with high S100A12 concentrations had more serious pneumonia, a higher 30-day mortality rate, and a worse prognosis than those with low serum S100A12 concentrations. We also found that serum S100A12, CRP, and PCT concentrations and the leukocyte count in the high S100A12 subgroup were higher than those in the low S100A12 subgroup. These findings suggested that serum S100A12 concentrations may play an important role in the progression of disease and the inflammatory response in the body. Additionally, S100A12 concentrations may complement CRP and PCT concentrations for evaluating the inflammatory response and severity of CAP, and thus more accurately predicting mortality. Therefore, S100A12 could be a useful index to evaluate the diagnosis and severity of CAP and the degree of the inflammatory reaction in the body.

The small number of samples in this study is a limitation of this study. The clinical significance of S100A12 needs to be confirmed by a large sample size and a multicenter study. Further research may be required to determine if low S100A12 concentrations have any clinical significance in the management and prognosis of CAP.

Conclusions

Patients with high serum S100A12 concentrations have more severe CAP, a more serious inflammatory reaction, and higher 30-day mortality. Therefore, serum S100A12 concentrations may reflect the severity of CAP and the degree of the inflammatory reaction in the body, and help evaluate 30-day mortality.

Supplemental Material

sj-jpg-1-imr-10.1177_03000605231191021 - Supplemental material for Clinical significance of serum S100 calcium-binding protein A12 concentrations in patients with community-acquired pneumonia

Supplemental material, sj-jpg-1-imr-10.1177_03000605231191021 for Clinical significance of serum S100 calcium-binding protein A12 concentrations in patients with community-acquired pneumonia by Haoling Wang, Dongqiong Li, Youli Wang, Guangjian Mao, Guozhou Lu, Qiqin Lan, Lianchun Xiao, Wenjuan Tang and Yiqi Liu in Journal of International Medical Research

Supplemental Material

sj-pdf-2-imr-10.1177_03000605231191021 - Supplemental material for Clinical significance of serum S100 calcium-binding protein A12 concentrations in patients with community-acquired pneumonia

Supplemental material, sj-pdf-2-imr-10.1177_03000605231191021 for Clinical significance of serum S100 calcium-binding protein A12 concentrations in patients with community-acquired pneumonia by Haoling Wang, Dongqiong Li, Youli Wang, Guangjian Mao, Guozhou Lu, Qiqin Lan, Lianchun Xiao, Wenjuan Tang and Yiqi Liu in Journal of International Medical Research

Supplemental Material

sj-pdf-3-imr-10.1177_03000605231191021 - Supplemental material for Clinical significance of serum S100 calcium-binding protein A12 concentrations in patients with community-acquired pneumonia

Supplemental material, sj-pdf-3-imr-10.1177_03000605231191021 for Clinical significance of serum S100 calcium-binding protein A12 concentrations in patients with community-acquired pneumonia by Haoling Wang, Dongqiong Li, Youli Wang, Guangjian Mao, Guozhou Lu, Qiqin Lan, Lianchun Xiao, Wenjuan Tang and Yiqi Liu in Journal of International Medical Research

Footnotes

Acknowledgements

We thank all of the participants for their contributions to this study.

Author contributions

H W and D L: Methodology, investigation, data curation, and writing the original draft.

Y W: Methodology, data curation, and supervision.

G M: Methodology and supervision.

G L: Methodology and investigation.

Q L, L X, and W T: Investigation and editing.

Y L: Supervision, writing, review, and editing.

Availability of data and materials

The dataset of this article is not openly available. However, it can be accessed upon reasonable request from the corresponding author.

Declaration of conflicting interest

The authors declare that there is no conflict of interest.

Funding

This study was funded by Key Research and Development Projects in Liangshan Prefecture, Sichuan Province, China (No. 22ZDYF0070).

ORCID iD

Yiqi Liu

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