Effect of low high-density lipoprotein levels on mortality of septic patients: A systematic review and meta-analysis of cohort studies

doi:10.5847/wjem.j.1920-8642.2020.02.008

Abstract

Abstract:

BACKGROUND: An increase in high-density lipoprotein (HDL) is well associated with a decreased cardiovascular risk, especially atherosclerosis. Recent studies suggest that lower levels of HDL may also be associated with an increased risk of sepsis and an increased rate of mortality in septic patients. However, this conclusion remains controversial.

METHODS: MEDLINE, EMBASE, and CENTRAL databases were searched from inception to September 30, 2019. All studies were conducted to evaluate the correlation of lipoprotein levels and the risk and outcomes of sepsis in adult patients. The primary outcomes were the risk and mortality of sepsis.

RESULTS: Seven studies comprising 791 patients were included. Lower levels of HDL had no marked relevance with the risk of sepsis (odds radio [OR] for each 1 mg/dL increase, 0.94; 95% CI 0.86-1.02; P=0.078), whereas lower HDL levels were related to an increased mortality rate in septic patients (OR for below about median HDL levels, 2.00; 95% CI 1.23-3.24; P=0.005).

CONCLUSION: This meta-analysis did not reveal a significant association between lower HDL levels and an increase in the risk of sepsis, whereas it showed that lower HDL levels are associated with a higher mortality rate in septic adult patients. These findings suggest that HDL may be considered as a promising factor for the prevention and treatment of sepsis in the future.

Key words: High-density lipoprotein, Sepsis, Mortality, Meta-analysis

Shao-hua Liu, Huo-yan Liang, Hong-yi Li, Xian-fei Ding, Tong-wen Sun, Jing Wang. Effect of low high-density lipoprotein levels on mortality of septic patients: A systematic review and meta-analysis of cohort studies[J]. World Journal of Emergency Medicine, 2020, 11(2): 109-116.

Figures/Tables 8

Figure 1.

Table 1

Table 2

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

References 42

1	Shankar-Hari M, Phillips G, Levy M, Seymour C, Liu V, Deutschman C, et al. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8):775-87.
2	Czupryna P, Garkowski A, Moniuszko A, Pancewicz S, Ciemerych A, Zajkowska J. Patients with sepsis in infectious diseases department in years 1997-2010 - epidemiology and clinical features. Przegl Epidemiol. 2013; 67(3):429-34,535-8.
3	Vincent JL, Pereira AJ, Gleeson J, Backer D. Early management of sepsis. Clin Exp Emerg Med. 2014; 1(1):3-7.
4	Dendoncker K, Libert C. Glucocorticoid resistance as a major drive in sepsis pathology. Cytokine Growth Factor Rev. 2017; 35:85-96.
5	Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016; 37(29):2315-81.
6	Shor R, Wainstein J, Oz D, Boaz M, Matas Z, Fux A, et al. Low HDL levels and the risk of death, sepsis and malignancy. Clinical Research in Cardiology. 2008; 97(4):227-33.
7	Roveran Genga K, Lo C, Cirstea M, Zhou G, Walley KR, Russell JA, et al. Two-year follow-up of patients with septic shock presenting with low HDL: the effect upon acute kidney injury, death and estimated glomerular filtration rate. Journal of Internal Medicine. 2017; 281(5):518-29.
8	Murch O, Collin M, Hinds CJ, Thiemermann C. Lipoproteins in inflammation and sepsis. I. Basic science. Intensive Care Med. 2007; 33(1):13-24.
9	Walley KR, Thain KR, Russell JA, Reilly MP, Meyer NJ, Ferguson JF, et al. PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci Transl Med. 2014; 6(258):258ra143.
10	Guo L, Zheng Z, Ai J, Huang B, Li XA. Hepatic scavenger receptor BI protects against polymicrobial-induced sepsis through promoting LPS clearance in mice. J Biol Chem. 2014; 289(21):14666-73. pmid: 24719333
11	Levels JH, Abraham PR, van den Ende A, van Deventer SJ. Distribution and kinetics of lipoprotein-bound endotoxin. Infect Immun. 2001; 69(5):2821-8.
12	Levels JH, Abraham PR, van Barreveld EP, Meijers JC, van Deventer SJ. Distribution and kinetics of lipoprotein-bound lipoteichoic acid. Infect Immun. 2003; 71(6):3280-4.
13	Kon V, Yang H, Fazio S. Residual Cardiovascular risk in chronic kidney disease: role of high-density lipoprotein. Arch Med Res. 2015; 46(5):379-91.
14	Jones T, Wong H, Meyer N. HDL cholesterol: A “pathogen lipid sink” for sepsis? Am J Respir Crit Care Med. 2019; 199(7):812-4.
15	Barlage S, Gnewuch C, Liebisch G, Wolf Z, Audebert FX, Gluck T, et al. Changes in HDL-associated apolipoproteins relate to mortality in human sepsis and correlate to monocyte and platelet activation. Intensive Care Med. 2009; 35(11):1877-85.
16	Chien YF, Chen CY, Hsu CL, Chen KY, Yu CJ. 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(3):506-10. doi: 10.1016/j.jcrc.2015.01.001 pmid: 25702844
17	Lagrost L, Girard C, Grosjean S, Masson D, Deckert V, Gautier T, et al. Low preoperative cholesterol level is a risk factor of sepsis and poor clinical outcome in patients undergoing cardiac surgery with cardiopulmonary bypass. Crit Care Med. 2014; 42(5):1065-73.
18	Lekkou A, Mouzaki A, Siagris D, Ravani I, Gogos CA. Serum lipid profile, cytokine production, and clinical outcome in patients with severe sepsis. J Crit Care. 2014; 29(5):723-7. pmid: 24891152
19	Shor R, Wainstein J, Oz D, Boaz M, Matas Z, Fux A, et al. Low serum LDL cholesterol levels and the risk of fever, sepsis, and malignancy. Ann Clin Lab Sci. 2007; 37(4):343-8.
20	Chien JY, Jerng JS, Yu CJ, Yang PC. Low serum level of high-density lipoprotein cholesterol is a poor prognostic factor for severe sepsis. Crit Care Med. 2005; 33(8):1688-93.
21	Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009; 62(10):1006-12. pmid: 19631508
22	Wells GSB, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm. Accessed 2019.
23	Grion CMC, Cardoso LTQ, Perazolo TF, Garcia AS, Barbosa DS, Morimoto HK, et al. Lipoproteins and CETP levels as risk factors for severe sepsis in hospitalized patients. European Journal of Clinical Investigation. 2010; 40(4):330-8.
24	Cirstea M, Walley KR, Russell JA, Brunham LR, Genga KR, Boyd JH. 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; 38:289-94. pmid: 28013095
25	Lee SH, Park MS, Park BH, Jung WJ, Lee IS, Kim SY, et al. Prognostic implications of serum lipid metabolism over time during sepsis. Biomed Res Int. 2015; 2015:789298.
26	Lekkou A, Mouzaki A, Siagris D, Ravani I, Gogos CA. Serum lipid profile, cytokine production, and clinical outcome in patients with severe sepsis. J Crit Care. 2014; 29(5):723-7. doi: 10.1016/j.jcrc.2014.04.018 pmid: 24891152
27	Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21(11):1539-58.
28	Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003; 327(7414):557-60.
29	Guo L, Ai J, Zheng Z, Howatt DA, Daugherty A, Huang B, et al. High density lipoprotein protects against polymicrobe-induced sepsis in mice. J Biol Chem. 2013; 288(25):17947-53. pmid: 23658016
30	McDonald M, Dhadly P, Cockerill G, Cuzzocrea S, Mota-Filipe H, Hinds C, et al. Reconstituted high-density lipoprotein attenuates organ injury and adhesion molecule expression in a rodent model of endotoxic shock. Shock. 2003; 20(6):551-7.
31	Netea MG, Demacker PN, Kullberg BJ, Boerman OC, Verschueren I, Stalenhoef AF, et al. Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe gram-negative infections. J Clin Invest. 1996; 97(6):1366-72. pmid: 8617867
32	Birjmohun RS, van Leuven SI, Levels JH, van’t Veer C, Kuivenhoven JA, Meijers JC, et al. High-density lipoprotein attenuates inflammation and coagulation response on endotoxin challenge in humans. Arterioscler Thromb Vasc Biol. 2007; 27(5):1153-8.
33	Pajkrt D, Doran JE, Koster F, Lerch PG, Arnet B, van der Poll T, et al. Antiinflammatory effects of reconstituted high-density lipoprotein during human endotoxemia. J Exp Med. 1996; 184(5):1601-8. doi: 10.1084/jem.184.5.1601 pmid: 8920850
34	Mackness MI, Durrington PN, Mackness B. How high-density lipoprotein protects against the effects of lipid peroxidation. Curr Opin Lipidol. 2000; 11(4):383-8.
35	Chung DW, Chen J, Ling M, Fu X, Blevins T, Parsons S, et al. High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion. Blood. 2016; 127(5):637-45.
36	Kitchens RL, Wolfbauer G, Albers JJ, Munford RS. Plasma lipoproteins promote the release of bacterial lipopolysaccharide from the monocyte cell surface. J Biol Chem. 1999; 274(48):34116-22. doi: 10.1074/jbc.274.48.34116 pmid: 10567381
37	Green P, Theilla M, Singer P. Lipid metabolism in critical illness. Curr Opin Clin Nutr Metab Care. 2016; 19(2):111-5.
38	Osborn TM, Phillips G, Lemeshow S, Townsend S, Schorr CA, Levy MM, et al. Sepsis severity score: an internationally derived scoring system from the surviving sepsis campaign database. Crit Care Med. 2014; 42(9):1969-76.
39	Zou Q, Wen W, Zhang XC. Presepsin as a novel sepsis biomarker. World J Emerg Med. 2014; 5(1):16-9. pmid: 25215141
40	Dellinger RP, Tomayko JF, Angus DC, Opal S, Cupo MA, McDermott S, et al. Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: results of a phase II multicenter, randomized, placebo-controlled, dose-finding clinical trial. Crit Care Med. 2009; 37(11):2929-38.
41	Musher DM, Longo DL, Abers MS, Corrales-Medina VF. Acute infection and myocardial infarction. N Engl J Med. 2019; 380(2):171-6. pmid: 30625066
42	Willeit P, Ridker PM, Nestel PJ, Simes J, Tonkin AM, Pedersen TR, et al. Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet. 2018; 392(10155):1311-20.

The first author (year)	Country	Study design	No. of population (case/control)	Mean age of patients population	Mean age of control population	Sample source	Source divided into case/control group	Levels of HDL in case/control group (mg/dL)	Study period	Reported outcomes	Source of definition of sepsis/severe sepsis /septic shock
Shor (2008)^[6]	Israel	RC	108/96	66.6	66.3	Serum	Levels of serum HDL	<20 /≥65	01/2005- 12/2005	Risk of sepsis	ACCP/SCCM consensus conference definitions
Genga (2017)^[7]	Canada	OC	11/24	55.8	53.7	Plasma	Levels of serum HDL	<33.06 /≥33.06	01/2011- 07/2013	2-year mortality	Institutional Sepsis Protocol
Chien (2005)^[16]	China	PC	30/33	72.5	72	Serum	Levels of serum HDL	<20 /≥20	10/2002- 01/2003	30-day mortality	ACCP/SCCM consensus conference definitions
Lekkou (2014)^[18]	Greece	PC	28/22	64.8	66.2	Serum	Levels of serum HDL	<25 /≥25	NA	Mortality	SIRS
Grion (2010)^[23]	Brazil	PC	51/71	65.81	65.12	Serum	Levels of serum HDL	33.07 /40.33	05/2005- 12/2005	Risk of sepsis	ACCP/SCCM consensus conference definitions
Cirstea (2017)^[24]	Canada	OC	68/132	56.5	55.9	Serum	Levels of serum HDL	<25.1 /≥25.1	01/2011- 06/2014	28-day mortality	Suspected sepsis protocol
Lee (2015)^[25]	South Korea	PC	65/52	63	62.3	Serum	Survivors/non-survivors	21 /21	08/2008- 12/2008	Mortality	The identification of an infection site + three or four SIRS

Author	Selection			Comparability			Assessment of outcome			Total quality score
Author	Representativeness of exposure arm(s)	Selection of the comparative arm(s)	Origin of exposure source	Demonstration that outcome of interest was not present at start of study	Studies controlling the most important factors	Studies controlling the other main factors	Assessment of outcome with independency	Adequacy of follow-up length (to assess outcome)	Lost to follow-up acceptable (less than 10% and reported)	Total quality score
Shor (2008)^[6]	*	*	*	*	*	*	-	*	-	7
Genga (2017)^[7]	*	*	*	*	*	-	*	*	-	7
Chien (2005)^[16]	*	*	*	*	*	*	-	*	-	7
Lekkou (2014)^[18]	*	*	*	*	*	-	*	*	-	7
Grion (2010)^[23]	*	*	*	*	*	*	*	*	-	8
Cirstea (2017)^[24]	*	-	*	*	*	*	*	*	-	7
Lee (2015)^[25]	*	*	*	*	*	*	*	*	-	8

[1]	Ahammed Mekkodathil, Ayman El-Menyar, Talat Chughtai, Ahmed Abdel-Aziz Bahey, Ahmed Labib Shehatta, Ali Ayyad, Abdulnasser Alyafai, Hassan Al-Thani. Initial serum electrolyte imbalances and mortality in patients with traumatic brain injury: a retrospective study [J]. World Journal of Emergency Medicine, 2025, 16(4): 331-339.
[2]	Carlos del Pozo Vegas, Ancor Sanz-García, Antonio Dueñas-Ruiz, Pedro de Santos Castro, Ana Gil Contreras, María Blanco González, Alberto Correas Galán, Joan B. Soriano, Raúl López-Izquierdo, Francisco Martín-Rodríguez. Prehospital oxygen-therapy and mortality in patients treated by emergency medical services: a prospective, observational multicenter study [J]. World Journal of Emergency Medicine, 2025, 16(4): 357-366.
[3]	Quan Li, Yun Qu, Jinfang Xue, Hai Kang, Chuanzhu Lyu. Exploring lipid-modifying therapies for sepsis through the modulation of circulating inflammatory cytokines: a Mendelian randomization study [J]. World Journal of Emergency Medicine, 2025, 16(3): 256-261.
[4]	Peili Chen, Yan Ge, Huiqiu Sheng, Wenwu Sun, Jiahui Wang, Li Ma, Enqiang Mao. The role of early changes in routine coagulation tests in predicting the occurrence and prognosis of sepsis [J]. World Journal of Emergency Medicine, 2025, 16(2): 136-143.
[5]	Chunxue Wang, Dianyin Yang, Yuxin Zhu, Qian Yang, Tong Liu, Xiandong Liu, Dongyang Zhao, Xiaowei Bao, Tiancao Dong, Li Shao, Lunxian Tang. Circulating circular RNAs act as potential novel biomarkers for sepsis secondary to pneumonia: a prospective cohort study [J]. World Journal of Emergency Medicine, 2025, 16(2): 144-152.
[6]	Azzah S Alharbi, Raghad Hassan Sanyi, Esam I Azhar. Bacteria and host: what does this mean for sepsis bottleneck? [J]. World Journal of Emergency Medicine, 2025, 16(1): 10-17.
[7]	Jesús Jurado-Palomo, José Luis Martín-Conty, Begoña Polonio-López, Cristina Rivera Picón, Raúl López-Izquierdo, Carlos del Pozo Vegas, Pedro Ángel de Santos Castro, Ancor Sanz-García, Francisco Martín-Rodríguez. Prehospital critical care drug-therapy and 30-day mortality in patients with acute respiratory disease [J]. World Journal of Emergency Medicine, 2025, 16(1): 43-50.
[8]	Chao Gong, Shengyong Xu, Youlong Pan, Shigong Guo, Joseph Harold Walline, Xue Wang, Xin Lu, Shiyuan Yu, Mubing Qin, Huadong Zhu, Yanxia Gao, Yi Li. Effects of probiotic treatment on the prognosis of patients with sepsis: a systematic review [J]. World Journal of Emergency Medicine, 2025, 16(1): 18-27.
[9]	Jingyuan Xie, Jiandong Gao, Mutian Yang, Ting Zhang, Yecheng Liu, Yutong Chen, Zetong Liu, Qimin Mei, Zhimao Li, Huadong Zhu, Ji Wu. Prediction of sepsis within 24 hours at the triage stage in emergency departments using machine learning [J]. World Journal of Emergency Medicine, 2024, 15(5): 379-385.
[10]	Juexian Wei, Hengzong Mo, Yuting Zhang, Wenmin Deng, Siqing Zheng, Haifeng Mao, Yang Ji, Huilin Jiang, Yongcheng Zhu. Evolutionary trend analysis and knowledge structure mapping of endothelial dysfunction in sepsis: a bibliometrics study [J]. World Journal of Emergency Medicine, 2024, 15(5): 386-396.
[11]	Rex Pui Kin Lam, Zonglin Dai, Eric Ho Yin Lau, Carrie Yuen Ting Ip, Ho Ching Chan, Lingyun Zhao, Tat Chi Tsang, Matthew Sik Hon Tsui, Timothy Hudson Rainer. Comparing 11 early warning scores and three shock indices in early sepsis prediction in the emergency department [J]. World Journal of Emergency Medicine, 2024, 15(4): 273-282.
[12]	Zeyu Yang, Huiruo Liu, Dazhou Lu, Shengchuan Cao, Feng Xu, Chuanbao Li. Effects of high-dose glucose-insulin-potassium on acute coronary syndrome patients receiving reperfusion therapy: a meta-analysis [J]. World Journal of Emergency Medicine, 2024, 15(3): 181-189.
[13]	Huixin Zhao, Yiming Dong, Sijia Wang, Jiayuan Shen, Zhenju Song, Mingming Xue, Mian Shao. Comparison between sepsis-induced coagulopathy and sepsis-associated coagulopathy criteria in identifying sepsis-associated disseminated intravascular coagulation [J]. World Journal of Emergency Medicine, 2024, 15(3): 190-196.
[14]	A-ling Tang, Yan Li, Li-chao Sun, Xiao-yu Liu, Nan Gao, Sheng-tao Yan, Guo-qiang Zhang. Xuebijing improves intestinal microcirculation dysfunction in septic rats by regulating the VEGF-A/PI3K/Akt signaling pathway [J]. World Journal of Emergency Medicine, 2024, 15(3): 206-213.
[15]	Qing Zhao, Jinfu Ma, Jianguo Xiao, Zhe Feng, Hui Liu. Data driven analysis reveals prognostic genes and immunological targets in human sepsis-associated acute kidney injury [J]. World Journal of Emergency Medicine, 2024, 15(2): 91-97.