Portal de Periódicos da CAPES

The bidirectional link between HDL and COVID-19 infections

2021; Elsevier BV; Volume: 62; Linguagem: Inglês

10.1016/j.jlr.2021.100067

1539-7262

Kenneth R. Feingold,

Vitamin C and Antioxidants Research

It is well recognized that gram positive and negative bacterial infections, tuberculosis, fungal infections, and parasitic infections result in changes in plasma lipid levels (1Alvarez C. Ramos A. Lipids, lipoproteins, and apoproteins in serum during infection.Clin. Chem. 1986; 32: 142-145Crossref PubMed Scopus (245) Google Scholar, 2Cappi S.B. Noritomi D.T. Velasco I.T. Curi R. Loureiro T.C.A. Soriano F.G. Dyslipidemia: a prospective controlled randomized trial of intensive glycemic control in sepsis.Intensive Care Med. 2012; 38: 634-641Crossref PubMed Scopus (22) Google Scholar, 3Gallin J.I. Kaye D. O'Leary W.M. Serum lipids in infection.N. Engl. J. Med. 1969; 281: 1081-1086Crossref PubMed Scopus (282) Google Scholar, 4Gordon B.R. Parker T.S. Levine D.M. Saal S.D. Wang J.C.L. Sloan B.-J. Barie P.S. Rubin A.L. Low lipid concentrations in critical illness.Critical Care Medicine. 1996; 24: 584-589Crossref PubMed Scopus (154) Google Scholar, 5Kerttula Y. Weber T.H. Serum lipids in viral and bacterial meningitis.Scand. J. Infect. Dis. 1986; 18: 211-215Crossref PubMed Scopus (23) Google Scholar, 6Khovidhunkit W. Kim M.-S. Memon R.A. Shigenaga J.K. Moser A.H. Feingold K.R. Grunfeld C. Thematic review series: The Pathogenesis of Atherosclerosis. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host.J. Lipid Res. 2004; 45: 1169-1196Abstract Full Text Full Text PDF PubMed Scopus (1123) Google Scholar, 7Sammalkorpi K. Valtonen V. Kerttula Y. Nikkila E. Taskinen M.-R. Changes in serum lipoprotein pattern induced by acute infections.Metabolism. 1988; 37: 859-865Abstract Full Text PDF PubMed Scopus (240) Google Scholar, 8van Leeuwen H.J. Heezius E.C.J.M. Dallinga G.M. van Strijp J.A.G. Verhoef J. van Kessel K.P.M. Lipoprotein metabolism in patients with severe sepsis.Crit. Care Med. 2003; 31: 1359-1366Crossref PubMed Scopus (270) Google Scholar, 9Visser B.J. Wieten R.W. Nagel I.M. Grobusch M.P. Serum lipids and lipoproteins in malaria - a systematic review and meta-analysis.Malar. J. 2013; 12: 442Crossref PubMed Scopus (61) Google Scholar, 10Sahin F. Yildiz P. Distinctive biochemical changes in pulmonary tuberculosis and pneumonia.Arch. Med. Sci. 2013; 9: 656-661Crossref PubMed Scopus (23) Google Scholar, 11Gazi I.F. Apostolou F.A. Liberopoulos E.N. Filippatos T.D. Tellis C.C. Elisaf M.S. Tselepis A.D. Leptospirosis is associated with markedly increased triglycerides and small dense low-density lipoprotein and decreased high-density lipoprotein.Lipids. 2011; 46: 953-960Crossref PubMed Scopus (21) Google Scholar, 12Apostolou F. Gazi I.F. Kostoula A. Tellis C.C. Tselepis A.D. Elisaf M. Liberopoulos E.N. Persistence of an atherogenic lipid profile after treatment of acute infection with brucella.J. Lipid Res. 2009; 50: 2532-2539Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Of note, viral infections, such as HIV, Epstein-Barr virus, and Dengue fever, also similarly alter plasma lipid levels (13Grunfeld C. Pang M. Doerrler W. Shigenaga J.K. Jensen P. Feingold K.R. Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome.J. Clin. Endocrinol. Metab. 1992; 74: 1045-1052Crossref PubMed Scopus (0) Google Scholar, 14Marin-Palma D. Sirois C.M. Urcuqui-Inchima S. Hernandez J.C. Inflammatory status and severity of disease in dengue patients are associated with lipoprotein alterations.PLoS One. 2019; 14e0214245Crossref PubMed Scopus (15) Google Scholar, 15Apostolou F. Gazi I.F. Lagos K. Tellis C.C. Tselepis A.D. Liberopoulos E.N. Elisaf M. Acute infection with Epstein-Barr virus is associated with atherogenic lipid changes.Atherosclerosis. 2010; 212: 607-613Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). Typically, infections decrease total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels with either elevated triglyceride or inappropriately normal triglyceride levels for the decreased nutritional status that characteristically occurs with infections. As would be expected from the changes in lipid levels, apolipoprotein A-I, A-II, and B levels are also reduced (1Alvarez C. Ramos A. Lipids, lipoproteins, and apoproteins in serum during infection.Clin. Chem. 1986; 32: 142-145Crossref PubMed Scopus (245) Google Scholar, 7Sammalkorpi K. Valtonen V. Kerttula Y. Nikkila E. Taskinen M.-R. Changes in serum lipoprotein pattern induced by acute infections.Metabolism. 1988; 37: 859-865Abstract Full Text PDF PubMed Scopus (240) Google Scholar, 8van Leeuwen H.J. Heezius E.C.J.M. Dallinga G.M. van Strijp J.A.G. Verhoef J. van Kessel K.P.M. Lipoprotein metabolism in patients with severe sepsis.Crit. Care Med. 2003; 31: 1359-1366Crossref PubMed Scopus (270) Google Scholar). With recovery from infection, the alterations in plasma lipid levels return toward the baseline. The greater the severity of the infection, the greater the decrease in total cholesterol, LDL-C, and HDL-C levels (16Deniz O. Gumus S. Yaman H. Ciftci F. Ors F. Cakir E. Tozkoparan E. Bilgic H. Ekiz K. Serum total cholesterol, HDL-C and LDL-C concentrations significantly correlate with the radiological extent of disease and the degree of smear positivity in patients with pulmonary tuberculosis.Clin. Biochem. 2007; 40: 162-166Crossref PubMed Scopus (62) Google Scholar, 17Deniz O. Tozkoparan E. Yaman H. Cakir E. Gumus S. Ozcan O. Bozlar U. Bilgi C. Bilgic H. Ekiz K. Serum HDL-C levels, log (TG/HDL-C) values and serum total cholesterol/HDL-C ratios significantly correlate with radiological extent of disease in patients with community-acquired pneumonia.Clin. Biochem. 2006; 39: 287-292Crossref PubMed Scopus (30) Google Scholar, 18El-Sadr W. Mullin C. Carr A. Gibert C. Rappoport C. Visnegarwala F. Grunfeld C. Raghavan S. Effects of HIV disease on lipid, glucose and insulin levels: results from a large antiretroviral-naive cohort.HIV Med. 2005; 6: 114-121Crossref PubMed Scopus (227) Google Scholar). Numerous studies have shown that the degree of reduction in total cholesterol, HDL-C, and apolipoprotein A-I predict mortality in patients with severe sepsis (19Barlage S. Gnewuch C. Liebisch G. Wolf Z. Audebert F.-X. Glück T. Fröhlich D. Krämer B.K. Rothe G. Schmitz G. Changes in HDL-associated apolipoproteins relate to mortality in human sepsis and correlate to monocyte and platelet activation.Intensive Care Med. 2009; 35: 1877-1885Crossref PubMed Scopus (107) Google Scholar, 20Chien J.-Y. Jerng J.-S. Yu C.-J. Yang P.-C. Low serum level of high-density lipoprotein cholesterol is a poor prognostic factor for severe sepsis∗.Crit. Care Med. 2005; 33: 1688-1693Crossref PubMed Scopus (248) Google Scholar, 21Gruber M. Christ-Crain M. Stolz D. Keller U. Muller C. Bingisser R. Tamm M. Mueller B. Schuetz P. Prognostic impact of plasma lipids in patients with lower respiratory tract infections - an observational study.Swiss Med. Wkly. 2009; 139: 166-172PubMed Google Scholar, 22Chien Y.-F. Chen C.-Y. Hsu C.-L. Chen K.-Y. Yu C.-J. Decreased serum level of lipoprotein cholesterol is a poor prognostic factor for patients with severe community-acquired pneumonia that required intensive care unit admission.J. Crit. Care. 2015; 30: 506-510Crossref PubMed Scopus (53) Google Scholar, 23Lekkou A. Mouzaki A. Siagris D. Ravani I. Gogos C.A. Serum lipid profile, cytokine production, and clinical outcome in patients with severe sepsis.J. Crit. Care. 2014; 29: 723-727Crossref PubMed Scopus (89) Google Scholar, 24Cirstea M. Walley K.R. Russell J.A. Brunham L.R. Genga K.R. Boyd J.H. Decreased high-density lipoprotein cholesterol level is an early prognostic marker for organ dysfunction and death in patients with suspected sepsis.J. Crit. Care. 2017; 38: 289-294Crossref PubMed Scopus (87) Google Scholar, 25Trinder M. Genga K.R. Kong H.J. Blauw L.L. Lo C. Li X. Cirstea M. Wang Y. Rensen P.C.N. Russell J.A. Walley K.R. Boyd J.H. Brunham L.R. Cholesteryl ester transfer protein influences high-density lipoprotein levels and survival in sepsis.Am. J. Respir. Crit. Care Med. 2019; 199: 854-862Crossref PubMed Scopus (59) Google Scholar). Toward the end of 2019, a deadly new viral infection emerged caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which resulted in coronavirus disease 2019 (COVID-19) (26Gandhi R.T. Lynch J.B. Del Rio C. Mild or moderate Covid-19.N. Engl. J. Med. 2020; 383: 1757-1766Crossref PubMed Scopus (900) Google Scholar). This virus rapidly spread throughout the world, leading to a worldwide pandemic. It is estimated that approximately 80% of COVID-19 infections are either asymptomatic or result in only mild symptoms, but in a significant percentage of patients, the infection leads to a severe respiratory illness requiring hospital care and respiratory support (26Gandhi R.T. Lynch J.B. Del Rio C. Mild or moderate Covid-19.N. Engl. J. Med. 2020; 383: 1757-1766Crossref PubMed Scopus (900) Google Scholar, 27Berlin D.A. Gulick R.M. Martinez F.J. Severe Covid-19.N. Engl. J. Med. 2020; 383: 2451-2460Crossref PubMed Scopus (916) Google Scholar). As of January 20, 2021, there have been over 2 million deaths worldwide according to the John Hopkins Coronavirus Resource Center. Older age, obesity, diabetes, cardiovascular disease, hypertension, and male gender are some of the factors that increase the risk of severe infection and death (26Gandhi R.T. Lynch J.B. Del Rio C. Mild or moderate Covid-19.N. Engl. J. Med. 2020; 383: 1757-1766Crossref PubMed Scopus (900) Google Scholar, 27Berlin D.A. Gulick R.M. Martinez F.J. Severe Covid-19.N. Engl. J. Med. 2020; 383: 2451-2460Crossref PubMed Scopus (916) Google Scholar). As observed with other infections, numerous studies have reported a decrease in total cholesterol, LDL-C, and HDL-C levels and variable changes in triglycerides in patients with COVID-19 infections (28Fan J. Wang H. Ye G. Cao X. Xu X. Tan W. Zhang Y. Letter to the Editor: Low-density lipoprotein is a potential predictor of poor prognosis in patients with coronavirus disease 2019.Metabolism. 2020; 107: 154243Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 29Hu X. Chen D. Wu L. He G. Ye W. Declined serum high density lipoprotein cholesterol is associated with the severity of COVID-19 infection.Clin. Chim. Acta. 2020; 510: 105-110Crossref PubMed Scopus (100) Google Scholar, 30Tanaka S. De Tymowski C. Assadi M. Zappella N. Jean-Baptiste S. Robert T. Peoc'h K. Lortat-Jacob B. Fontaine L. Bouzid D. Tran-Dinh A. Tashk P. Meilhac O. Montravers P. Lipoprotein concentrations over time in the intensive care unit COVID-19 patients: Results from the ApoCOVID study.PLoS One. 2020; 15e0239573Crossref PubMed Scopus (50) Google Scholar, 31Wei X. Zeng W. Su J. Wan H. Yu X. Cao X. Tan W. Wang H. Hypolipidemia is associated with the severity of COVID-19.J. Clin. Lipidol. 2020; 14: 297-304Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 32Wang D. Li R. Wang J. Jiang Q. Gao C. Yang J. Ge L. Hu Q. Correlation analysis between disease severity and clinical and biochemical characteristics of 143 cases of COVID-19 in Wuhan, China: a descriptive study.BMC Infect. Dis. 2020; 20: 519Crossref PubMed Scopus (75) Google Scholar, 33Wang G. Zhang Q. Zhao X. Dong H. Wu C. Wu F. Yu B. Lv J. Zhang S. Wu G. Wu S. Wang X. Wu Y. Zhong Y. Low high-density lipoprotein level is correlated with the severity of COVID-19 patients: an observational study.Lipids Health Dis. 2020; 19: 204Crossref PubMed Scopus (92) Google Scholar, 34Zhang Q. Wei Y. Chen M. Wan Q. Chen X. Clinical analysis of risk factors for severe COVID-19 patients with type 2 diabetes.J. Diabetes Complications. 2020; 34: 107666Crossref PubMed Scopus (52) Google Scholar, 35Lv Z. Wang W. Qiao B. Cui X. Feng Y. Chen L. Ma Q. Liu X. The prognostic value of general laboratory testing in patients with COVID-19.J. Clin. Lab. Anal. 2020; 35e23668PubMed Google Scholar, 36Zhang B. Dong C. Li S. Song X. Wei W. Liu L. Triglyceride to high-density lipoprotein cholesterol ratio is an important determinant of cardiovascular risk and poor prognosis in coronavirus disease-19: a retrospective case series study.Diabetes Metab. Syndr. Obes. 2020; 13: 3925-3936Crossref PubMed Scopus (24) Google Scholar, 37Lin L. Zhong C. Rao S. Lin H. Huang R. Chen F. Clinical characteristics of 78 cases of patients infected with coronavirus disease 2019 in Wuhan, China.Exp. Ther. Med. 2021; 21: 7PubMed Google Scholar, 38Turgay Yildirim O. Kaya S. The atherogenic index of plasma as a predictor of mortality in patients with COVID-19.Heart Lung. 2021; 50: 329-333Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 39Begue F. Tanaka S. Mouktadi Z. Rondeau P. Veeren B. Diotel N. Tran-Dinh A. Robert T. Vélia E. Mavingui P. Lagrange-Xélot M. Montravers P. Couret D. Meilhac O. Altered high-density lipoprotein composition and functions during severe COVID-19.Sci. Rep. 2021; 11: 2291Crossref PubMed Scopus (58) Google Scholar). As expected, apolipoprotein A-I and B were also decreased (39Begue F. Tanaka S. Mouktadi Z. Rondeau P. Veeren B. Diotel N. Tran-Dinh A. Robert T. Vélia E. Mavingui P. Lagrange-Xélot M. Montravers P. Couret D. Meilhac O. Altered high-density lipoprotein composition and functions during severe COVID-19.Sci. Rep. 2021; 11: 2291Crossref PubMed Scopus (58) Google Scholar, 40Kimhofer T. Lodge S. Whiley L. Gray N. Loo R.L. Lawler N.G. Nitschke P. Bong S.-H. Morrison D.L. Begum S. Richards T. Yeap B.B. Smith C. Smith K.G.C. Holmes E. Nicholson J.K. Integrative modeling of quantitative plasma lipoprotein, metabolic, and amino acid data reveals a multiorgan pathological signature of SARS-CoV-2 infection.J. Proteome Res. 2020; 19: 4442-4454Crossref PubMed Scopus (107) Google Scholar, 41Ressaire Q. Dudoignon E. Moreno N. Coutrot M. Depret F. Low total cholesterol blood level is correlated with pulmonary severity in COVID-19 critical ill patients.Anaesth. Crit. Care Pain Med. 2020; 39: 733-735Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar). With recovery from COVID-19 infection, the lipid levels return toward levels present before infection (28Fan J. Wang H. Ye G. Cao X. Xu X. Tan W. Zhang Y. Letter to the Editor: Low-density lipoprotein is a potential predictor of poor prognosis in patients with coronavirus disease 2019.Metabolism. 2020; 107: 154243Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 29Hu X. Chen D. Wu L. He G. Ye W. Declined serum high density lipoprotein cholesterol is associated with the severity of COVID-19 infection.Clin. Chim. Acta. 2020; 510: 105-110Crossref PubMed Scopus (100) Google Scholar, 30Tanaka S. De Tymowski C. Assadi M. Zappella N. Jean-Baptiste S. Robert T. Peoc'h K. Lortat-Jacob B. Fontaine L. Bouzid D. Tran-Dinh A. Tashk P. Meilhac O. Montravers P. Lipoprotein concentrations over time in the intensive care unit COVID-19 patients: Results from the ApoCOVID study.PLoS One. 2020; 15e0239573Crossref PubMed Scopus (50) Google Scholar, 42Qin C. Minghan H. Ziwen Z. Yukun L. Alteration of lipid profile and value of lipids in the prediction of the length of hospital stay in COVID-19 pneumonia patients.Food Sci. Nutr. 2020; 8: 6144-6152Crossref PubMed Scopus (20) Google Scholar, 43Ouyang S.M. Zhu H.Q. Xie Y.N. Zou Z.S. Zuo H.M. Rao Y.W. Liu X.Y. Zhong B. Chen X. Temporal changes in laboratory markers of survivors and non-survivors of adult inpatients with COVID-19.BMC Infect. Dis. 2020; 20: 952Crossref PubMed Scopus (39) Google Scholar). As expected, the greater the severity of the illness, the greater the reduction in LDL-C and/or HDL-C levels (29Hu X. Chen D. Wu L. He G. Ye W. Declined serum high density lipoprotein cholesterol is associated with the severity of COVID-19 infection.Clin. Chim. Acta. 2020; 510: 105-110Crossref PubMed Scopus (100) Google Scholar, 31Wei X. Zeng W. Su J. Wan H. Yu X. Cao X. Tan W. Wang H. Hypolipidemia is associated with the severity of COVID-19.J. Clin. Lipidol. 2020; 14: 297-304Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 32Wang D. Li R. Wang J. Jiang Q. Gao C. Yang J. Ge L. Hu Q. Correlation analysis between disease severity and clinical and biochemical characteristics of 143 cases of COVID-19 in Wuhan, China: a descriptive study.BMC Infect. Dis. 2020; 20: 519Crossref PubMed Scopus (75) Google Scholar, 33Wang G. Zhang Q. Zhao X. Dong H. Wu C. Wu F. Yu B. Lv J. Zhang S. Wu G. Wu S. Wang X. Wu Y. Zhong Y. Low high-density lipoprotein level is correlated with the severity of COVID-19 patients: an observational study.Lipids Health Dis. 2020; 19: 204Crossref PubMed Scopus (92) Google Scholar, 34Zhang Q. Wei Y. Chen M. Wan Q. Chen X. Clinical analysis of risk factors for severe COVID-19 patients with type 2 diabetes.J. Diabetes Complications. 2020; 34: 107666Crossref PubMed Scopus (52) Google Scholar, 35Lv Z. Wang W. Qiao B. Cui X. Feng Y. Chen L. Ma Q. Liu X. The prognostic value of general laboratory testing in patients with COVID-19.J. Clin. Lab. Anal. 2020; 35e23668PubMed Google Scholar, 36Zhang B. Dong C. Li S. Song X. Wei W. Liu L. Triglyceride to high-density lipoprotein cholesterol ratio is an important determinant of cardiovascular risk and poor prognosis in coronavirus disease-19: a retrospective case series study.Diabetes Metab. Syndr. Obes. 2020; 13: 3925-3936Crossref PubMed Scopus (24) Google Scholar, 38Turgay Yildirim O. Kaya S. The atherogenic index of plasma as a predictor of mortality in patients with COVID-19.Heart Lung. 2021; 50: 329-333Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 42Qin C. Minghan H. Ziwen Z. Yukun L. Alteration of lipid profile and value of lipids in the prediction of the length of hospital stay in COVID-19 pneumonia patients.Food Sci. Nutr. 2020; 8: 6144-6152Crossref PubMed Scopus (20) Google Scholar, 44Huang W. Li C. Wang Z. Wang H. Zhou N. Jiang J. Ni L. Zhang X.A. Wang D.-W. Decreased serum albumin level indicates poor prognosis of COVID-19 patients: hepatic injury analysis from 2,623 hospitalized cases.Sci. China Life Sci. 2020; 63: 1678-1687Crossref PubMed Scopus (84) Google Scholar, 45Sun J.T. Chen Z. Nie P. Ge H. Shen L. Yang F. Qu X.L. Ying X.Y. Zhou Y. Wang W. Zhang M. Pu J. Lipid profile features and their associations with disease severity and mortality in patients with COVID-19.Front. Cardiovasc. Med. 2020; 7: 584987Crossref PubMed Scopus (41) Google Scholar). LDL-C and HDL-C levels are inversely correlated with C-reactive protein levels, that is, the higher the CRP levels, the lower the LDL-C or HDL-C level (28Fan J. Wang H. Ye G. Cao X. Xu X. Tan W. Zhang Y. Letter to the Editor: Low-density lipoprotein is a potential predictor of poor prognosis in patients with coronavirus disease 2019.Metabolism. 2020; 107: 154243Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 29Hu X. Chen D. Wu L. He G. Ye W. Declined serum high density lipoprotein cholesterol is associated with the severity of COVID-19 infection.Clin. Chim. Acta. 2020; 510: 105-110Crossref PubMed Scopus (100) Google Scholar, 31Wei X. Zeng W. Su J. Wan H. Yu X. Cao X. Tan W. Wang H. Hypolipidemia is associated with the severity of COVID-19.J. Clin. Lipidol. 2020; 14: 297-304Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 45Sun J.T. Chen Z. Nie P. Ge H. Shen L. Yang F. Qu X.L. Ying X.Y. Zhou Y. Wang W. Zhang M. Pu J. Lipid profile features and their associations with disease severity and mortality in patients with COVID-19.Front. Cardiovasc. Med. 2020; 7: 584987Crossref PubMed Scopus (41) Google Scholar). Low LDL-C and/or HDL-C levels at admission to the hospital predict an increased risk of developing a severe disease. Increased mortality was observed in patients with low total cholesterol, LDL-C, and/or HDL-C levels at admission to the hospital, and in these very ill patients, lipid levels continued to decline during the hospitalization (28Fan J. Wang H. Ye G. Cao X. Xu X. Tan W. Zhang Y. Letter to the Editor: Low-density lipoprotein is a potential predictor of poor prognosis in patients with coronavirus disease 2019.Metabolism. 2020; 107: 154243Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 36Zhang B. Dong C. Li S. Song X. Wei W. Liu L. Triglyceride to high-density lipoprotein cholesterol ratio is an important determinant of cardiovascular risk and poor prognosis in coronavirus disease-19: a retrospective case series study.Diabetes Metab. Syndr. Obes. 2020; 13: 3925-3936Crossref PubMed Scopus (24) Google Scholar, 38Turgay Yildirim O. Kaya S. The atherogenic index of plasma as a predictor of mortality in patients with COVID-19.Heart Lung. 2021; 50: 329-333Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 41Ressaire Q. Dudoignon E. Moreno N. Coutrot M. Depret F. Low total cholesterol blood level is correlated with pulmonary severity in COVID-19 critical ill patients.Anaesth. Crit. Care Pain Med. 2020; 39: 733-735Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 43Ouyang S.M. Zhu H.Q. Xie Y.N. Zou Z.S. Zuo H.M. Rao Y.W. Liu X.Y. Zhong B. Chen X. Temporal changes in laboratory markers of survivors and non-survivors of adult inpatients with COVID-19.BMC Infect. Dis. 2020; 20: 952Crossref PubMed Scopus (39) Google Scholar, 44Huang W. Li C. Wang Z. Wang H. Zhou N. Jiang J. Ni L. Zhang X.A. Wang D.-W. Decreased serum albumin level indicates poor prognosis of COVID-19 patients: hepatic injury analysis from 2,623 hospitalized cases.Sci. China Life Sci. 2020; 63: 1678-1687Crossref PubMed Scopus (84) Google Scholar, 45Sun J.T. Chen Z. Nie P. Ge H. Shen L. Yang F. Qu X.L. Ying X.Y. Zhou Y. Wang W. Zhang M. Pu J. Lipid profile features and their associations with disease severity and mortality in patients with COVID-19.Front. Cardiovasc. Med. 2020; 7: 584987Crossref PubMed Scopus (41) Google Scholar). A single study reported that the time to develop a negative RT-PCR test for SARs-CoV-2 was increased in patients with low HDL-C levels (46Ding X. Zhang J. Liu L. Yuan X. Zang X. Lu F. He P. Wang Q. Zhang X. Xu Y. Li X. Liu Y. Li Q. Tan X. Zheng Y. Lin X. Liu Y. High-density lipoprotein cholesterol as a factor affecting virus clearance in covid-19 patients.Respir. Med. 2020; 175: 106218Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). Finally, HDL isolated from patients with COVID-19 infections displayed a blunted ability to protect against TNF-alpha–induced increases in endothelial cell permeability, vascular endothelial–cadherin disorganization, and apoptosis (39Begue F. Tanaka S. Mouktadi Z. Rondeau P. Veeren B. Diotel N. Tran-Dinh A. Robert T. Vélia E. Mavingui P. Lagrange-Xélot M. Montravers P. Couret D. Meilhac O. Altered high-density lipoprotein composition and functions during severe COVID-19.Sci. Rep. 2021; 11: 2291Crossref PubMed Scopus (58) Google Scholar). A large number of observational studies have found that low total cholesterol, LDL-C, and/or HDL-C levels are associated with an increased risk of developing infections and sepsis (47Delgado-Rodriguez M. Medina-Cuadros M. Martínez-Gallego G. Sillero-Arenas M. Total cholesterol, HDL-cholesterol, and risk of nosocomial infection: a prospective study in surgical patients.Infect. Control Hosp. Epidemiol. 1997; 18: 9-18Crossref PubMed Scopus (50) Google Scholar, 48Rodriguez-Sanz A. Fuentes B. Martinez-Sanchez P. Prefasi D. Martinez-Martinez M. Correas E. Díez-Tejedor E. High-Density Lipoprotein: A Novel Marker for Risk of In-Hospital Infection in Acute Ischemic Stroke Patients?.Cerebrovasc. Dis. 2013; 35: 291-297Crossref PubMed Scopus (23) Google Scholar, 49Claxton A.J. Jacobs Jr., D.R. Iribarren C. Welles S.L. Sidney S. Feingold K.R. Association between serum total cholesterol and HIV infection in a high-risk cohort of young men.J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 1998; 17: 51-57Crossref PubMed Scopus (16) Google Scholar, 50Grion C.M.C. Cardoso L.T.Q. Perazolo T.F. Garcia A.S. Barbosa D.S. Morimoto H.K. Matsuo T. Carrilho A.J.F. Lipoproteins and CETP levels as risk factors for severe sepsis in hospitalized patients.Eur. J. Clin. Invest. 2010; 40: 330-338Crossref PubMed Scopus (73) Google Scholar, 51Guirgis F.W. Donnelly J.P. Dodani S. Howard G. Safford M.M. Levitan E.B. Wang H.E. Cholesterol levels and long-term rates of community-acquired sepsis.Crit. Care. 2016; 20: 408Crossref PubMed Scopus (47) Google Scholar, 52Iribarren C. Jacobs Jr., D.R. Sidney S. Claxton A.J. Feingold K.R. Cohort study of serum total cholesterol and in-hospital incidence of infectious diseases.Epidemiol. Infect. 1998; 121: 335-347Crossref PubMed Scopus (72) Google Scholar, 53Kaysen G.A. Grimes B. Dalrymple L.S. Chertow G.M. Ishida J.H. Delgado C. Segal M. Chiang J. Dwyer T. Johansen K.L. Associations of lipoproteins with cardiovascular and infection-related outcomes in patients receiving hemodialysis.J. Clin. Lipidol. 2018; 12: 481-487.e14Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 54Kaysen G.A. Ye X. Raimann J.G. Wang Y. Topping A. Usvyat L.A. Stuard S. Canaud B. van der Sande F.M. Kooman J.P. Kotanko P. Lipid levels are inversely associated with infectious and all-cause mortality: international MONDO study results.J. Lipid Res. 2018; 59: 1519-1528Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 55Canturk N. Canturk Z. Okay E. Yirmibesoglu O. Eraldemir B. Risk of nosocomial infections and effects of total cholesterol, HDL cholesterol in surgical patients.Clin. Nutr. 2002; 21: 431-436Abstract Full Text PDF PubMed Scopus (35) Google Scholar, 56Madsen C.M. Varbo A. Tybjærg-Hansen A. Frikke-Schmidt R. Nordestgaard B.G. U-shaped relationship of HDL and risk of infectious disease: two prospective population-based cohort studies.Eur. Heart J. 2018; 39: 1181-1190Crossref PubMed Scopus (112) Google Scholar, 57Shor R. Wainstein J. Oz D. Boaz M. Matas Z. Fux A. Halabe A. Low serum LDL cholesterol levels and the risk of fever, sepsis, and malignancy.Ann. Clin. Lab. Sci. 2007; 37: 343-348PubMed Google Scholar, 58Shor R. Wainstein J. Oz D. Boaz M. Matas Z. Fux A. Halabe A. Low HDL levels and the risk of death, sepsis and malignancy.Clin. Res. Cardiol. 2008; 97: 227-233Crossref PubMed Scopus (49) Google Scholar). For example, in a cohort of men (55,300) and women (65,271) in the Kaiser Permanente Medical Care Program who were followed up for 15 years, total cholesterol levels were inversely associated with infections requiring hospitalization or acquired in the hospital (52Iribarren C. Jacobs Jr., D.R. Sidney S. Claxton A.J. Feingold K.R. Cohort study of serum total cholesterol and in-hospital incidence of infectious diseases.Epidemiol. Infect. 1998; 121: 335-347Crossref PubMed Scopus (72) Google Scholar). It should be recognized that confounding factors could explain the association of low LDL-C and/or HDL-C with an increased risk of infection. Unrecognized disease, for example, pulmonary or gastrointestinal disorders, could decrease HDL-C and LDL-C levels and independently also increase the risk of infections and sepsis. In fact, in a recent study that found that low LDL-C levels were significantly associated with an increased risk of sepsis and admission to the ICU, the authors found that this association could be accounted for by comorbidities (60Feng Q. Wei W.Q. Chaugai S. Leon B.G.C. Mosley J.D. Leon D.A.C. Jiang L. Ihegword A. Shaffer C.M. Linton M.F. Chung C.P. Stein C.M. Association between low-density lipoprotein cholesterol levels and risk for sepsis among patients admitted to the hospital with infection.JAMA Netw. Open. 2019; 2e187223Crossref PubMed Scopus (29) Google Scholar). Thus, more sophisticated studies, beyond observational studies, are necessary to demonstrate a causal relationship between low LDL-C and/or HDL-C levels with infections. Several studies have taken a genetic approach, which reduces the risk of confounding variables, to determine if there is a causal relationship between lipoprotein levels and infections. Madsen et al using two common variants in the genes encoding hepatic lipase and cholesteryl ester transfer protein that regulate HDL-C levels found in 97,166 individuals from the Copenhagen General Population Study that low HDL-C increased the risk of infection (56Madsen C.M. Varbo A. Tybjærg-Hansen A. Frikke-Schmidt R. Nordestgaard B.G. U-shaped relationship of HDL and risk of infectious disease: two prospective population-based cohort studies.Eur. Heart J. 2018; 39: 1181-1190Crossref PubMed Scopus (112) Google Scholar). It was also noted in this study that high HDL-C levels were also associated with an increased risk of infection. Trinder et al using polygenic scores for LDL-C, HDL-C, and triglycerides in 407,558 individuals from the UK BioBank found that an increasing HDL-C polygenic score reduced the risk of hospitalizations for infections and sepsis induced mortality while LDL-C and triglyceride polygenic scores were not associated with the risk of hospitalization for infections or sepsis-induced mortality (61Trinder M. Walley K.R. Boyd J.H. Brunham L.R. Causal inference for genetically determined levels of high-density lipoprotein cholesterol and risk of infectious disease.Arterioscler. Thromb. Vasc. Biol. 2020; 40: 267-278Crossref PubMed Scopus (56) Google Scholar). This study did not find an increased risk of infection with high HDL-C levels. Finally, Walley and colleagues also reported that HMGCoA reductase and PCSK9 genetic variants that decrease LDL-C levels were not associated with an increase in mortality because of sepsis (59Walley K.R. Boyd J.H. Kong H.J. Russell J.A. Low low-density lipoprotein levels are associated with, but do not causally contribute to, increased mortality in sepsis.Crit. Care Med. 2019; 47: 463-466Crossref PubMed Scopus (24) Google Scholar). Taken together, these studies suggest that low HDL-C levels may play a causal role in infections. In the current issue of the Journal of Lipid Research, Hilser et al. (62Hilser J.R. Han Y. Biswas S. Gukasyan J. Cai Z. Zhu R. Tang W.H.W. Deb A. Lusis A.J. Hartiala J.A. Allayee H. Association of serum HDL-cholesterol and apolipoprotein A1 levels with risk of severe SARS-CoV-2 infection.J. Lipid. Res. 2021; 62: 100061Abstract Full Text Full Text PDF PubMed Google Scholar) utilized the UK BioBank to examine the association of HDL-C measured between 2006 and 2010 and the development of COVID-19 infections in 2020. They compared hospitalized patients who tested positive for COVID-19 (n = 1,117) (ie, individuals with severe COVID-19 infections) with patients who tested negative for COVID-19 infections in either in-patient or out-patient hospital settings (n = 3,544). Results in the overall group were analyzed and an additional analysis comparing matched hospital-based controls (n = 1,438) to cases (n = 719) at a ratio of 2:1 based on age, sex, obesity, hypertension, type 2 diabetes, and coronary artery disease. The major finding of this study was that increased HDL-C or apolipoprotein A1 levels measured many years before the onset of COVID-19 infections was associated with a reduced risk of developing COVID-19 infection. A 10 mg/dl increase in HDL-C or apolipoprotein A1 levels was associated with ∼10% reduced risk of COVID-19 infection. In addition, an increased risk of death from COVID-19 infections was also inversely related to HDL-C and apolipoprotein A1 levels. In some analyses, increased triglyceride levels were also associated with an increased risk of COVID-19 infections. In contrast, increased LDL-C and apolipoprotein B levels were not associated with an increased risk of COVID-19 infections. To determine if this HDL-C protection from COVID-19 infections was the causal link, this study also evaluated the genetic effects of increased HDL-C using a genetic risk score based on SNPs and Mendelian Randomization but did not find an association of increased HDL-C levels and a decreased risk of COVID-19 infections. This failure to demonstrate an association could be due to the relatively small number of individuals in this study compared with the studies of Madsen and Trinder described above, which found a causal relationship between HDL-C and infections but studied a much larger number of individuals. Larger studies or meta-analyses of several smaller studies are needed to more definitively determine if there is a causal link between HDL-C levels and the risk of COVID-19 infections. Finally, Hilser et al. (62Hilser J.R. Han Y. Biswas S. Gukasyan J. Cai Z. Zhu R. Tang W.H.W. Deb A. Lusis A.J. Hartiala J.A. Allayee H. Association of serum HDL-cholesterol and apolipoprotein A1 levels with risk of severe SARS-CoV-2 infection.J. Lipid. Res. 2021; 62: 100061Abstract Full Text Full Text PDF PubMed Google Scholar) also confirmed prior studies that individuals with homozygosity for apolipoprotein E4 have a 2- to 3-fold increased risk of severe COVID-19 infections (63Kuo C.-L. Pilling L.C. Atkins J.L. Masoli J.A.H. Delgado J. Kuchel G.A. Melzer D. ApoE e4e4 genotype and mortality with COVID-19 in UK Biobank.J. Gerontol. A Biol. Sci. Med. Sci. 2020; 75: 1801-1803Crossref PubMed Scopus (66) Google Scholar, 64Kuo C.-L. Pilling L.C. Atkins J.L. Masoli J.A.H. Delgado J. Kuchel G.A. Melzer D. APOE e4 genotype predicts severe COVID-19 in the UK Biobank community cohort.J. Gerontol. A Biol. Sci. Med. Sci. 2020; 75: 2231-2232Crossref PubMed Scopus (246) Google Scholar) and that this was not due to dementia or Alzheimer's disease. Studies have shown that patients who are apolipoprotein E3/4 have an increased inflammatory response to toll receptor ligands compared with patients who are apolipoprotein E3/3, which could result in an increased risk of a more severe response to COVID-19 infections (65Gale S.C. Gao L. Mikacenic C. Coyle S.M. Rafaels N. Murray Dudenkov T. Madenspacher J.H. Draper D.W. Ge W. Aloor J.J. Azzam K.M. Lai L. Blackshear P.J. Calvano S.E. Barnes K.C. et al.APOε4 is associated with enhanced in vivo innate immune responses in human subjects.J. Allergy Clin. Immunol. 2014; 134: 127-134Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). African Americans have an increased frequency of the E4 allele, which could be one factor that contributes to the increased severity of COVID-19 infections in this group (66Howard B.V. Gidding S.S. Liu K. Association of apolipoprotein E phenotype with plasma lipoproteins in African-American and White young adults: The CARDIA study.Am. J. Epidemiol. 1998; 148: 859-868Crossref PubMed Scopus (67) Google Scholar). In addition, in patients with HIV, apolipoprotein E4/4 is associated with an accelerated disease progression and death compared with apolipoprotein E3/3 (67Burt T.D. Agan B.K. Marconi V.C. He W. Kulkarni H. Mold J.E. Cavrois M. Huang Y. Mahley R.W. Dolan M.J. McCune J.M. Ahuja S.K. Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE 4/ 4 genotype accelerates HIV disease progression.Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 8718-8723Crossref PubMed Scopus (166) Google Scholar). Several other studies using the UK BioBank have also demonstrated that low HDL-C were associated with an increased risk of COVID-19 infections (68Ho F.K. Celis-Morales C.A. Gray S.R. Katikireddi S.V. Niedzwiedz C.L. Hastie C. Ferguson L.D. Berry C. Mackay D.F. Gill J.M. Pell J.P. Sattar N. Welsh P. Modifiable and non-modifiable risk factors for COVID-19, and comparison to risk factors for influenza and pneumonia: Results from a UK Biobank prospective cohort study.BMJ Open. 2020; 10e040402Crossref PubMed Scopus (73) Google Scholar, 69Aung N. Khanji M.Y. Munroe P.B. Petersen S.E. Causal inference for genetic obesity, cardiometabolic profile and COVID-19 susceptibility: A Mendelian Randomization Study.Front. Genet. 2020; 11: 586308Crossref PubMed Scopus (44) Google Scholar, 70Scalsky R.J. Chen Y.J. Desai K. O'Connell J.R. Perry J.A. Hong C.C. Baseline cardiometabolic profiles and SARS-CoV-2 infection in the UK Biobank.PLoS One. 2021; 16: e0248602Crossref PubMed Scopus (22) Google Scholar, 71Zhang Y. Yang H. Li S. Li W.-D. Wang J. Wang Y. Association analysis framework of genetic and exposure risks for COVID-19 in middle-aged and elderly adults.Mech. Ageing Dev. 2021; 194: 111433Crossref PubMed Scopus (14) Google Scholar). Aung et al. additionally reported that LDL-C and triglycerides levels were not associated with COVID-19 infections (69Aung N. Khanji M.Y. Munroe P.B. Petersen S.E. Causal inference for genetic obesity, cardiometabolic profile and COVID-19 susceptibility: A Mendelian Randomization Study.Front. Genet. 2020; 11: 586308Crossref PubMed Scopus (44) Google Scholar), whereas Scalsky and colleagues observed that elevated apolipoprotein A1 levels were associated with a reduced risk of testing positive for SARS-CoV-2 while LDL-C, apolipoprotein B, and triglyceride levels were not found to be significantly associated with an increased risk (70Scalsky R.J. Chen Y.J. Desai K. O'Connell J.R. Perry J.A. Hong C.C. Baseline cardiometabolic profiles and SARS-CoV-2 infection in the UK Biobank.PLoS One. 2021; 16: e0248602Crossref PubMed Scopus (22) Google Scholar). However, Zhang et al. found that increased triglyceride levels were associated with an increased risk of COVID-19 infection (71Zhang Y. Yang H. Li S. Li W.-D. Wang J. Wang Y. Association analysis framework of genetic and exposure risks for COVID-19 in middle-aged and elderly adults.Mech. Ageing Dev. 2021; 194: 111433Crossref PubMed Scopus (14) Google Scholar). Thus, there is consistent evidence that baseline HDL-C and apolipoprotein A1 levels play a role in determining the risk of developing COVID-19 infections. The effect of baseline triglyceride levels requires additional study. Two studies have used a genetic approach to determine if lipoproteins play a causal role in COVID-19 infections. Ponsford et al using the UK BioBank (10,154 cases and 452,764 controls) and HUNT Study (Trøndelag Health Study—2,301 cases and 67,121 controls) databases reported that there was no evidence supporting an association of genetically induced LDL-C with the risk for severe COVID-19 infections (72Ponsford M.J. Gkatzionis A. Walker V.M. Grant A.J. Wootton R.E. Moore L.S.P. Fatumo S. Mason A.M. Zuber V. Willer C. Rasheed H. Brumpton B. Hveem K. Kristian Damås J. Davies N. et al.Cardiometabolic traits, sepsis, and severe COVID-19.Circulation. 2020; 142: 1791-1793Crossref PubMed Scopus (66) Google Scholar). In contrast, Aung et al. also using the UK BioBank (1,211 cases and 387,079 controls) reported that genetically higher exposure to LDL-C was associated with an increased risk of COVID-19 (69Aung N. Khanji M.Y. Munroe P.B. Petersen S.E. Causal inference for genetic obesity, cardiometabolic profile and COVID-19 susceptibility: A Mendelian Randomization Study.Front. Genet. 2020; 11: 586308Crossref PubMed Scopus (44) Google Scholar). Clearly additional studies are required to determine if there is a causal relationship between LDL-C, HDL-C, or triglycerides with the risk of COVID-19 infections. The potential HDL-C–mediated protection from COVID-19 could be due to HDL-C levels having beneficial effects on the host's immune response to infection and/or to HDL-C levels having an inhibitory effect on viral replication. Studies have shown that HDL-C can modulate innate and adaptive immunity that could increase resistance to viral infections (73Catapano A.L. Pirillo A. Bonacina F. Norata G.D. HDL in innate and adaptive immunity.Cardiovasc. Res. 2014; 103: 372-383Crossref PubMed Scopus (174) Google Scholar). Moreover, studies have shown that HDL-C and apolipoprotein A1 have antiviral properties (74Singh I.P. Chopra A.K. Coppenhaver D.H. Ananatharamaiah G.M. Baron S. Lipoproteins account for part of the broad non-specific antiviral activity of human serum.Antivir. Res. 1999; 42: 211-218Crossref PubMed Scopus (62) Google Scholar, 75Srinivas R.V. Birkedal B. Owens R.J. Anantharamaiah G.M. Segrest J.P. Compans R.W. Antiviral effects of apolipoprotein A-I and its synthetic amphipathic peptide analogs.Virology. 1990; 176: 48-57Crossref PubMed Scopus (83) Google Scholar, 76Kane J.P. Hardman D.A. Dimpfl J.C. Levy J.A. Apolipoprotein is responsible for neutralization of xenotropic type C virus by mouse serum.Proc. Natl. Acad. Sci. U.S.A. 1979; 76: 5957-5961Crossref PubMed Scopus (29) Google Scholar). Furthermore, a recent study has shown that HDL has antiviral activity against SARS-CoV-2 (77Cho K.H. Kim J.R. Lee I.C. Kwon H.J. Native high-density lipoproteins (hdl) with higher paraoxonase exerts a potent antiviral effect against SARS-CoV-2 (COVID-19), while glycated HDL lost the antiviral activity.Antioxidants (Basel). 2021; 10: 209Crossref PubMed Scopus (34) Google Scholar). In addition, D-4F, an apolipoprotein A-I mimetic peptide, reduced the severity of influenza in an animal model providing further evidence of potential benefits of HDL and apolipoprotein A-I in viral infections (78Van Lenten B.J. Wagner A.C. Anantharamaiah G.M. Garber D.W. Fishbein M.C. Adhikary L. Nayak D.P. Hama S. Navab M. Fogelman A.M. Influenza infection promotes macrophage traffic into arteries of mice that is prevented by D-4F, an Apolipoprotein A-I mimetic peptide.Circulation. 2002; 106: 1127-1132Crossref PubMed Scopus (167) Google Scholar).