Decreased serum level of sphingosine-1-phosphate: a novel predictor of clinical severity in COVID-19

Abstract

The severity of coronavirus disease 2019 (COVID-19) is a crucial problem in patient treatment and outcome. The aim of this study is to evaluate circulating level of sphingosine-1-phosphate (S1P) along with severity markers, in COVID-19 patients. One hundred eleven COVID-19 patients and forty-seven healthy subjects were included. The severity of COVID-19 was found significantly associated with anemia, lymphocytopenia, and significant increase of neutrophil-to-lymphocyte ratio, ferritin, fibrinogen, aminotransferases, lactate dehydrogenase (LDH), C-reactive protein (CRP), and D-dimer. Serum S1P level was inversely associated with COVID-19 severity, being significantly correlated with CRP, LDH, ferritin, and D-dimer. The decrease in S1P was strongly associated with the number of erythrocytes, the major source of plasma S1P, and both apolipoprotein M and albumin, the major transporters of blood S1P. Not last, S1P was found to be a relevant predictor of admission to an intensive care unit, and patient's outcome. Circulating S1P emerged as negative biomarker of severity/mortality of COVID-19 patients. Restoring abnormal S1P levels to a normal range may have the potential to be a therapeutic target in patients with COVID-19.

Keywords: COVID-19; Coronavirus; intensive care unit; prognostic biomarker; sphingosine-1-phosphate.

Figure 1. Serum levels of S1P and apoM in HLT and COV patients

1. A, B

   Serum levels of S1P (A) and apoM (B) in HLT (n = 47) and COV (n = 111) patients. The box plots represent the interquartile range with median value (central line); the whiskers represent the measured range of HLT and COV. Each measurement was run in triplicate, and performed at least twice. Two‐tailed Student’s t‐test was used for statistical analysis. P < 0.0001 is reported.

2. C–F

   Pearson correlation between S1P and apoM (C), RBC number (D), HGB concentration (E), HCT value (F). Scatter plots, together with the fitted regression line, are shown. Pearson correlation was performed for statistical analysis. Exact P values or P < 0.0001 are reported.

Figure 2. Correlations between S1P/apoM and their transporters

1. A, B

   Correlations between S1P and HDL‐C (A), and albumin (B).

2. C, D

   Correlations between apoM and HDL‐C (C) and albumin (D).

Data information: Scatter plots and fitted regression line are shown in each figure. Each S1P and apoM measurement was run in triplicate, and performed at least twice in independent assays. Pearson correlation was performed for statistical analysis. Exact P values or P < 0.0001 are reported.

Figure 3. Serum levels of S1P and its blood transporters in noICU and ICU patients

1. A–D

   The serum concentrations of S1P (A), apoM (B), albumin (C), and HDL‐C (D) in noICU (n = 89) and ICU (n = 22) patients are shown. The box plots represent the interquartile range with median (central line); the whiskers represent the measured range of noICU and ICU patients. Each S1P and apoM measurement was run in triplicate, and performed at least twice in independent assays. Two‐tailed Student’s t‐test was used for statistical analysis. P < 0.0001 is reported.

Figure 4. Correlation between S1P/apoM and COVID‐19 infection severity

1. A–F

   Pearson correlation between S1P (A–C) or apoM (D–F) and PSI (A, D), days from admission (B, E), and NLR (C, F) in COV (n = 111). Scatter plots and fitted regression line are shown in each figure. Exact P values or P < 0.0001 are reported.

Figure 5. Prognostic value of S1P in COV patients

1. A, B

   Cumulative risk for ICU admission (A) and cumulative survival (B) in COV patients (n = 111), grouped for cutoff value of S1P serum level of 0.60 μM. Statistical analysis was performed by Cox regression. Exact P values are reported.

Figure 6. Overview of the proposed mechanisms underlying S1P involvement in COVID‐19 pathophysiology and severity

After SARS‐CoV‐2 infection, a local inflammation occurs, with increased pro‐inflammatory cytokines (1). This promotes an interstitial increase of S1P, which in turn potentiates cytokine secretion by different cells (2). The exuberant local cytokine levels result in a systemic cytokine storm (3). This gives on to different alterations (4), including anemia (with impaired S1P synthesis/export) and acute‐phase response in the liver (with decrease in the negative acute‐phase proteins albumin and apoM, which act as S1P transporters). These alterations lead to a progressive drop of circulating S1P, with decrease in both apoM/S1P and albumin/S1P (5). The reduction of S1P in the systemic circulation correlates with COVID‐19 severity and patient outcome (6).