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Review 2: "Serum Sphingosine-1-Phosphate as Novel Prognostic and Predictive Biomarker for COVID-19 Severity and Morbidity and Its Implications in Clinical Management"

This potentially informative article with some methodological flaws suggests that serum Sphingosine-1-Phosphate (S1P) is associated with COVID-19 severity. Further research is needed to understand if serum S1P could be provided therapeutically to reduce COVID-19 severity.

Published onSep 22, 2020
Review 2: "Serum Sphingosine-1-Phosphate as Novel Prognostic and Predictive Biomarker for COVID-19 Severity and Morbidity and Its Implications in Clinical Management"

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



In this paper, Marfia et al. aimed to evaluate the prognostic power of circulating sphingosine 1-phosphate (S1P), a bioactive lipid mediator in blood involved in the regulation of vascular integrity and inflammatory responses, for COVID-19 severity. Their major claims are that the drop of serum S1P level in COVID patients is strongly associated with the decrease of red blood cells and two major S1P carrier proteins, apoM and albumin, and that S1P is the most important predictor for the outcomes of COVID-19 patients.

Although the study is overall well designed and conducted, there are two major drawbacks in the methods they adopted. The first point is that they measured S1P in serum, not in plasma. As they described in the Discussion section, circulating S1P levels in blood are best-reflected by plasma S1P levels. During the serum preparation, coagulation proceeds, which results in massive release of S1P from platelets. However, the circulating S1P is mostly supplied by RBC and endothelial cells. As such, the drop of serum S1P levels they observed can be attributed to the decreases in RBC levels, in S1P carrier proteins levels (apoM and albumin) due to liver malfunction, or deficits somewhere in the coagulation processes. They claim that S1P is a good prognostic marker, but RBC and apoM/albumin also show significant differences, which might serve as easier and more straight-forward biomarkers. Ideally, the authors could show S1P levels in plasma as well, and compare the correlation with COVID severity.

The second drawback is that they used ELISA assay kit from Echelon for the measurement of S1P. This ELISA kit recognizes mostly albumin-bound S1P, but not apoM-bound S1P very well, probably due to strong interaction of S1P with apoM. Therefore, the S1P levels shown in this paper might not reflect the total S1P levels properly. Currently, S1P measurement by LC-MS is the most reliable method.

Nonetheless, if serum S1P levels serve as a good prognostic and predictive biomarker for COVID-19 severity, whatever the mechanism is, it would contribute to stimulating further investigation, and eventually to better understanding and prognosis of COVID-19. Hopefully, administration of S1P or S1P-receptor agonists to COVID patients can ameliorates the outcomes, as observed in experimental septic animals.

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