Evaluation of Plasma Sphingosine-1-Phosphate as A Diagnostic and Prognostic Biomarkers of Community-Acquired Pneumonia

Pneumonia is a major infectious cause of death worldwide and imposes a considerable burden on healthcare resources. Obstructive lung diseases (COPD and Asthma) are increasingly important causes of morbidity and mortality worldwide. The patients with community-acquired pneumonia (CAP), and acute exacerbations of obstructive lung diseases commonly present with similar signs and symptoms. For antibiotic use, the rapid and accurate differentiation of clinically relevant of bacterial lower respiratory tract infections from other mimics is essential. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid has both extracellular and intracellular effects in mammalian cells. S1P is involved in many physiological processes including immune responses and endothelial barrier integrity. In term of endothelial barrier integrity, S1P plays a crucial role in protecting lungs from the pulmonary leak and lung injury. Because of the involvement in lung injury, S1P would be the potential biomarker of pneumonia. Based on the above evidence, S1P plays an essential role in the pathobiology of pneumonia was hypothesized.

The study was a branch of our PM2.5 observational study (Acute Effects of Particulate Matter on Pulmonary Diseases) and mainly focus on lipid biomarker for the target diseases. Lower respiratory tract infections are the most frequent infectious cause of death worldwide\[1\] and impose a considerable burden on healthcare resources. Despite the advancement in treatment and diagnostic technique, the overall 30-day mortality rate of community-acquired pneumonia (CAP) is as high as 12.1% for patients who aged 65 years and older admitted to hospital\[2\]. Obstructive lung diseases (COPD and Asthma) are increasingly important causes of morbidity and mortality worldwide. The patients with CAP, and acute exacerbations of obstructive lung diseases commonly present with similar signs and symptoms.

The use of conventional diagnostic markers, such as complete blood count (CBC) with differential and C-reactive protein is the current mainstream method for differentiating clinically relevant to bacterial lower respiratory tract infections from other mimics. However, for patients with a clinical suspicion of infection, those conventional methods have suboptimal sensitivity and specificity\[3,4\] The limitations often cause the ambiguity of the initiation of antibiotic treatment. As a result, unnecessary use of antibiotics adversely affects patient outcomes. Also, inappropriate antibiotic therapy increases antibiotic resistance in patients, which poses a public health problem. Current strategies to reduce antibiotic usage have included the development of biomarker-directed treatment algorithms. However, a recent study suggested that procalcitonin-guided therapy has not been effective in reducing antibiotic use\[5\]. Therefore, developing new biomarkers may be the answer to the problems.

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid has both extracellular and intracellular effects in mammalian cells\[6-9\]. S1P is synthesized by two sphingosine kinases (SphK1 and SphK 2) and degraded by S1P lyase (S1PL)\[6\] S1P is a ligand for five G protein-coupled receptors, S1P receptors1-5\[6,7\], and also acts as an intracellular second messenger\[10,11\]. S1P is involved in many physiological processes including immune responses and endothelial barrier integrity\[12-15\]. In term of endothelial barrier integrity, S1P plays a crucial role in protecting lungs from the pulmonary leak and lung injury. \[16-19\] Previous research suggests that S1P signaling through S1PR1 is crucial for endothelial barrier function. \[20\] The S1P induces actin polymerization and then results in the spreading of endothelial cells which fills intercellular gaps. Also, the S1P-signaling can stabilize the endothelial cell-cell junctions such as adherens junction and tight junction. \[21-23\] Both actin-dependent outward spreading of endothelial cells and cell junction stabilization enhance the endothelial barrier function. Because of the involvement in lung injury and endothelial barrier function, S1P would be the potential biomarker of pneumonia.

For the study, a case-control design was utilized for collecting clinical samples. the investigators plan to enroll 150 individuals for each targeted disease (CAP, Asthma, Asthma with CAP, COPD, and COPD with CAP) and control. Peripheral blood will be collected from the patients presenting at the emergency department (ED) of Wan Fang Hospital for an acute event of the candidate diseases. Each recruited individual will fill out a specific questionnaire, which will include lifestyle, occupation, habits, and general dietary information. The initial peripheral blood sample will be obtained in the emergency department, and if the patients were admitted, the individual's blood sample would be collected one day before a planned discharge again. The following parameters will be recorded for each participant: sex, age, body weight, body temperature, vital signs at the ED, and clinical characteristics of the disease. The laboratory testing will include baseline analyses (hematocrit, white blood count with differential, serum sodium, and chloride), ALT, AST, CRP, BUN, and creatinine. The plasma S1P will also be tested and will be measured by ELISA. The questionnaire will provide the individual's basic information of living area, occupational environment, personal habits and family history for further analysis.

Eligibility Criteria:
Inclusion Criteria:

* Clinical diagnosis of chronic obstructive pulmonary disease (COPD; ICD-9 codes 490-492, 494, 496)
* Clinical diagnosis of Asthma (ICD-9 code 493),
* Clinical diagnosis of pneumonia (ICD-9 codes 480-488).

Exclusion Criteria:

* Underage incapacity
* Pregnant women,
* Psychiatric history
* Unfamiliar with Chinese