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Abstract Background The association between lipoprotein levels and late-onset neonatal sepsis has shown controversial results. The aims are to assess lipid profile, cytokines, and Monocyte-to-HDL (M/H) ratio as diagnostic and prognostic markers for late-onset neonatal sepsis. Methods This prospective study included 49 septic neonates and 17 controls. Cholesterol (CT), Triglyceride (TG), Very-Low-Density (VLDLc), Low-Density (LDLc), and High-Density Lipoproteins (HDLc) were measured at admission (D0) and on days 3, 7 and 10 to evaluate septic shock outcomes. Cytokines and monocytes were evaluated by flow cytometry. Results Septic newborns showed higher IL-6 and IL-8 at D0 and CT levels on D7 and on D10, which also presented higher TG, VLDLc and non-HDL cholesterol concentrations than controls. The septic shock group (n = 22) revealed a higher number of male subjects, CRP, IL-6, IL-8 and IL-10 levels, while lower TG, HDLc, monocyte numbers and M/H ratio at admission compared to the non-shock group (n = 27). M/H ratio and non-HDL cholesterol on D0 were risk factors for septic shock (OR = 0.70, 0.49‒0.99; OR = 0.96, 0.92‒0.99, respectively). Decreasing levels from D0 to D3 of CT (OR = 0.96, 0.93‒0.99), VLDLc (OR = 0.91, 0.85‒0.98), and non-HDL cholesterol (OR = 0.92, 0.87‒0.98) were also predictors of septic shock. Conclusions Lower M/H ratios and non-HDL cholesterol at admission and decreasing levels of cholesterol, VLDLc and non-HDL cholesterol during a hospital stay are associated with the development of septic shock in newborns with late-onset neonatal sepsis. lateonset late onset results profile cytokines MonocytetoHDL Monocyte HDL MH M H (M/H 4 1 controls CT, , (CT) TG (TG) VeryLowDensity Very Low Density VLDLc, (VLDLc) LowDensity LDLc, LDLc (LDLc) HighDensity High HDLc (HDLc D (D0 3 outcomes cytometry IL6 IL 6 IL- IL8 8 D10 nonHDL non n 22 subjects CRP IL6, 6, IL10 IL-1 nonshock 27. 27 . 27) 070 0 70 0.70 0.49‒0.99 049099 99 096 96 0.96 092099 92 0.92‒0.99 respectively. respectively respectively) 0.93‒0.99, 093099 0.93‒0.99 93 0.93‒0.99) 091 91 0.91 0.85‒0.98, 085098 0.85‒0.98 85 98 0.85‒0.98) 092 0.92 0.87‒0.98 087098 87 (CT (TG (VLDLc (LDLc (D D1 2 IL1 07 0.7 0.49‒0.9 04909 9 09 0.9 09209 0.92‒0.9 09309 0.93‒0.9 08509 0.85‒0.9 0.87‒0.9 08709 0. 0.49‒0. 0490 0920 0.92‒0. 0930 0.93‒0. 0850 0.85‒0. 0.87‒0. 0870 0.49‒0 049 0.92‒0 093 0.93‒0 085 0.85‒0 0.87‒0 087 0.49‒ 04 0.92‒ 0.93‒ 08 0.85‒ 0.87‒ 0.49 0.93 0.85 0.87 0.4 0.8