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Background: Since 1920, a decrease in serum cholesterol has been identified as a marker of severe pneumonia. We have assessed the performance of serum apolipoprotein-A1, the main transporter of HDL-cholesterol, to identify the early spread of coronavirus disease 2019 (Covid-19) in the general population and its diagnostic performance for the Covid-19., Methods: We compared the daily mean serum apolipoprotein-A1 during the first 34 weeks of 2020 in a population that is routinely followed for a risk of liver fibrosis risk in the USA (212,297 serum) and in France (20,652 serum) in relation to a local increase in confirmed cases, and in comparison to the same period in 2019 (266,976 and 28,452 serum, respectively). We prospectively assessed the sensitivity of this marker in an observational study of 136 consecutive hospitalized cases and retrospectively evaluated its specificity in 7,481 controls representing the general population., Results: The mean serum apolipoprotein-A1 levels in the survey populations began decreasing in January 2020, compared to the same period in 2019. This decrease was highly correlated with the daily increase in confirmed Covid-19 cases in the following 34 weeks, both in France and USA, including the June and mid-July recovery periods in France. Apolipoprotein-A1 at the 1.25 g/L cutoff had a sensitivity of 90.6% (95%CI84.2-95.1) and a specificity of 96.1% (95.7-96.6%) for the diagnosis of Covid-19. The area under the characteristics curve was 0.978 (0.957-0.988), and outperformed haptoglobin and liver function tests. The adjusted risk ratio of apolipoprotein-A1 for survival without transfer to intensive care unit was 5.61 (95%CI 1.02-31.0; P = 0.04)., Conclusion: Apolipoprotein-A1 could be a sentinel of the pandemic in existing routine surveillance of the general population. NCT01927133, CER-2020-14., Competing Interests: TP has several USPTO patents related to the performance of Apoa1 in patients with liver disease, including #10,198,552 Method of diagnosis of fibrotic diseases, #7,860,656 Diagnosis method of hepatic steatosis using biochemical markers, 7,856,319, Diagnosis method of alcoholic steato-hepatitis using biochemical markers, #7,225,080 Diagnosis method of inflammatory, fibrotic or cancerous disease using biochemical markers, and # 6,631,330 Diagnosis method of inflammatory, fibrotic or cancerous disease using biochemical markers, and applications pending: #20200011879 Method of diagnosis of drug induced liver injury, 20190265241 Method of diagnosis of non-alcoholic fatty liver diseases, #3 20140329260 Method of diagnosis of fibrotic diseases, and #20090111132 Diagnosis method of hepatic steatosis using biochemical markers. The data underlying the findings described in the manuscript are fully detailed including the confounding factors, without restriction, in the numerous supplementary files. The commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials.