Stroke is a common acute cerebrovascular disease, which is the second leading cause of death and the third-leading cause of death and disability combined globally (1). The high mortality rate of stroke is largely attributable to its complications. Stroke-associated pneumonia (SAP) is the most common complication of stroke, occurring most often within the first week in 8.6% to 14.3% of stroke patients (2–4). Stroke activates inflammatory cascades in the brain, such as the excessive release of cytokines, then stimulates the central immune system to produce anti-inflammatory signals. Subsequently, the efferent vagus nerve is activated and inhibits cytokine production, ultimately leading to the suppression of systemic immunity. Stroke-induced immunosuppression increases the susceptibility of stroke patients to infection, accompanied by decreased pulmonary clearance and impaired secretion drainage caused by the alteration in tracheal endothelia after stroke, ultimately leading to the occurrence of SAP (5–7). At the same time, risk factors such as stroke severity, advanced age, hypertension, and smoking history also contribute to the occurrence of SAP (8, 9). SAP further increases the severity of the stroke, lengthens hospital stay, increases financial burden, worsens the functional outcome, and increases patient mortality (9, 10). Prevention and early diagnosis or prediction of SAP is an important clinical strategy. However, current methods are less specific and sensitive, making the early diagnosis of SAP become a big difficulty (3, 11). There is still great value in exploring the early markers of SAP.

Prostaglandin E2 (PGE2) is a key mediator of inflammation, its elevation is a response to inflammation (12). 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is the sole degradation enzyme of PGE2 by oxidizing it to inactive 15-keto PGE2 (13). The decrease of 15-PGDH can lead to an increase in PGE2, which has been observed in stroke (14). Meanwhile, 15-PGDH is generally identified as a tumor suppressor, such as lung cancer, breast cancer, colorectal cancer, etc (15–17). In addition, 15-PGDH is also involved in lipopolysaccharide-induced acute kidney injury, pulmonary fibrosis, tissue repair, and other pathological processes (18–20). Interestingly, a previous study reported that in pulmonary infection caused by pseudomonas aeruginosa, inhibition of PGE2 overproduction shows a protective effect, in part by raising the level of 15-PGDH (21). However, no report has revealed the level of 15-PGDH in SAP and the relationship between 15-PGDH and SAP. Therefore, we will determine the relationship between 15-PGDH and SAP, and determine whether it can be used as an early marker to predict SAP and provide a basis for early diagnosis of SAP.

Two important findings are presented in this study. First, lower serum 15-PGDH increases the risk of SAP in stroke patients. Second, there is an L-shaped relationship between 15-PGDH and SAP risk. Once 15-PGDH is lower than the critical value, SAP risk will be significantly increased.

Stroke is an acute neurovascular disease with high morbidity, mortality and disability. SAP is the most common complication of stroke, usually manifests within 7 days after the onset of stroke (3). The complication of SAP further aggravates the severity of stroke, prolonged hospitalization, worsen the prognosis, and increase mortality (6, 10). The occurrence of SAP increases the difficulty of stroke treatment. Therefore, the prevention and early prediction or diagnosis of SAP should not be ignored in the treatment of stroke patients. Our study demonstrates that advanced age, smGoking, higher WBC and neutrophils, and lower GCS, thrombocytes, and lymphocytes are all risk factors for SAP. In addition, previous studies have found that dysphagia (25), aspiration (26), invasive treatments, antacids, hypertension, diabetes, pulmonary diseases and so on are also risk factors for SAP (27). Prevention and early diagnosis of so many risk factors are an important part of stroke and SAP management.

Inflammation-related indicators are the most important predictive markers of SAP and contribute greatly to the early diagnosis of SAP. Monocyte to lymphocyte ratio (28), neutrophil to lymphocyte ratio (24) and platelet to lymphocyte ratio (29) have been proven to be valuable predictors of SAP markers. PGE2 is an important inflammatory mediator involved in many inflammatory processes. As the degradation enzyme of PGE2, 15-PGDH is potential to become one predictive marker of SAP. In our study, serum 15-PGDH level in patients with SAP were significantly lower than those without SAP. Binary logistic regression analysis proved that low 15-PGDH was a risk factor for SAP. With an AUC of 0.836, 15-PGDH is undoubtedly a valuable predictor of SAP. Furthermore, RCS visualizes the relationship between 15-PGDH and SAP risk as L-shaped, which may contribute significantly to the prediction and treatment of SAP. It should be noted that the 15-PGDH concentration of 0.37 ng/mL is a critical threshold. When 15-PGDH is lower than 0.37 ng/mL, its decrease will sharply increase the risk of SAP, while when higher than 0.37 ng/mL, this trend is very gentle. Therefore, when assessing the risk of SAP, on the premise of avoiding the reduction of 15-PGDH, it is more important to ensure that 15-PGDH should not be lower than 0.37 ng/mL, which may be critical for SAP prevention.

Admittedly, there are some limitations to our research. First, since our study is a retrospective study, it is difficult to draw a causal relationship between 15-PGDH and SAP, which requires further verification by subsequent studies. Second, we did not collect enough patients, which may lead to partial results bias. For example, the incidence of SAP was higher than previously reported. Third, although we compared the characteristics of SAP patients in the severe group and mild group, it is unclear whether the level of 15-PGDH is predictive of the severity of SAP. Furthermore, we did not analyze patients with different stroke types separately, and there may be some different findings.

In stroke patients, serum 15-PGDH is a valuable biomarker for predicting SAP. There is an L-shaped relationship between the level of 15-PGDH and the risk of SAP. Once lower than 0.37 ng/mL, the risk of SAP will increase rapidly.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Ethics Committee of the Xiangya Hospital of Central South University. The patients/participants provided their written informed consent to participate in this study.

DY, YL, and JZ designed and directed the project. SY collected clinical samples. HQ collected baseline demographic and clinical data. YX, LZ, YZ, and QX performed the experiments. YX wrote the manuscript.

This work was supported by the National Natural Science Foundation of China (Nos. 82172147, 81571880, 81373147, 30901555, 30972870, and 81360080), Natural Science Foundation of Hunan Province (2021JJ30900 and 2016JJ2157), and the Fundamental Research Funds for the Central Universities of Central South University (2020zzts222). All funding bodies were involved in the study design, collection, analysis, interpretation of data, and writing the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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