Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is currently the leading cause of death due to a single infectious agent (1). While the majority of patients infected with COVID-19 are in the asymptomatic or mild category, a considerable proportion develop severe illness, presenting with acute respiratory distress syndrome, renal or hepatic dysfunction, requiring respiratory and multiorgan support in critical care settings (2, 3). Cholesterol is an important component of the membranes of host cells and enveloped viruses and has been shown to play an important role in the entry of SARS-CoV-2 virus into cells (4). Serum lipids, especially low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). are in constant interaction with the lipid rafts in the host cell membranes (5, 6) and can modify the interaction of virus with host cells and the resultant disease severity.

Several studies have reported an association between COVID-19 severity and low serum levels of HDL-C (7, 8), but the magnitudes of the association between COVID-19 and total cholesterol (TC), LDL-C, and triglycerides (TG) are inconsistent. This finding is in agreement with similar observations in patients with other infections, such as HIV, dengue, and tuberculosis (9, 10). The precise mechanism underlying the relationship between COVID-19 infection and low serum lipid levels is unclear, but the low serum lipid levels have been hypothesized to reflect an acute phase response during inflammation (11). Increased secretory phospholipase and serum amyloid A (SAA), and decreased reverse cholesterol transport have been attributed to low HDL-C levels following inflammation (12–14).

Multiple cardiovascular and metabolic risk factors have been shown to be associated with the risk of severe COVID-19 disease (2). We hypothesized that serum lipid levels may serve as biomarkers predicting disease severity and mortality and provide insight into the pathogenesis of COVID-19. We performed a systematic review of the literature and meta-analysis to determine differences in serum lipid levels, such as TC, LDL-C, HDL-C, and TG, between patients with COVID-19 and healthy controls, and to assess the association of these lipid levels at admission with severity and mortality among patients with COVID-19.

In the current study, we found that patients with COVID-19 had lower mean serum TC and HDL-C levels at the time of testing compared to healthy controls (Figure 2 and Table 1). There was no difference in mean LDL-C and TG levels among all patients with and without COVID-19. Lower serum TC, LDL-C, and HDL-C levels at admission were observed in patients with severe COVID-19, as well as in those who died relative to the respective comparison groups. Serum TG levels showed no relationship with COVID-19 severity or mortality. We did not find statistically significant publication bias for any of the analyses.

Lipids play a significant role in respiratory infections. The composition of pulmonary surfactant, which is an integral part of the innate and adaptive immune systems (23, 24), is 90% lipids (25). Moreover, more than 80% of total lung cholesterol is derived from the plasma (26). Of note, lower HDL-C was associated with COVID-19 infection, severity, and mortality in our meta-analysis. HDL-C plays a significant role in host resistance to bacterial, viral and parasitic infections (27, 28) and exhibits multiple properties, such as anti-inflammatory, anti-thrombotic, and anti-oxidative activities (28, 29). HDL-C and its structural protein, apoA-1, have been shown in pre-clinical studies to directly exert anti-inflammatory effects (30, 31) by neutralizing lipopolysaccharide and lipoteichoic acid, and preventing activation of peripheral blood monocytes, thereby decreasing TNF-α and IL-1β synthesis and secretion (32–34).

Oster et al. reported one of the first associations of hypocholesterolemia with increased in-hospital mortality (35). Multiple recent studies have found that patients with various infections, such as cytomegalovirus (36), Epstein-Barr virus (37), and tuberculosis (38), had lower levels of serum lipoprotein compared to non-infected controls. Several studies have established that plasma lipid levels are inversely associated with infection-related and all-cause mortality (10, 39), and have defined the role of lipid levels in acute infectious processes (40). In line with these reports, our meta-analysis highlights the association between COVID-19 infection and lower TC, LDL-C and HDL-C levels.

Recent systematic reviews have also noted findings similar to ours (41, 42), but they have not compared the lipid levels between infected patients and uninfected controls. Additionally, these reviews (41, 42) have only included studies up to January, 2021 while our study included articles up to September, 2021. Meta-regression analysis for the cofounder variables was not performed in the review by Mahat et al. (41), and thus did not account adequately for these variables. In the review by Zinellu et al. (42), the outcomes, namely severe disease and mortality, were combined into a composite outcome, thus the control group for the patients who survived may also contain patients with severe disease leading to a higher degree of heterogeneity in the analysis. Consistent with our findings, the meta-analysis by Ulloque-Badaracco et al. (43) found that serum levels of apoproteins Apo-A1 and Apo-B, which are major apoproteins of HDL-C and LDL-C, respectively, were lower in patients with severe COVID-19.

Several potential mechanisms explaining the altered serum lipid levels observed during COVID-19 infection have been postulated (Figure 4). Firstly, increased secretory phospholipase and SAA, together with decreased reverse cholesterol transport, have been attributed to low HDL-C levels following inflammation (12–14, 23). SAA-enriched HDL-C is known to be cleared more rapidly from circulation than regular HDL-C through scavenging mechanisms (23). Secondly, the liver plays a critical role in lipid metabolism, and liver dysfunction occurs frequently (in up to 53% cases) in severely ill patients with COVID-19 (44). Furthermore, severe COVID-19 is associated with excessive release of pro-inflammatory cytokines, such as IL-1, IL-6, IFN-γ, and TNF-α, which were shown to decrease the synthesis and secretion of apolipoproteins in hepatic cell lines in a dose-dependent manner (11, 28, 45). Thirdly, severe inflammation can cause leakage of lipoproteins and apolipoproteins in the capillaries (46). Lower serum levels of HDL-C result in a decrease in the anti-inflammatory activities of this molecule, leading to cytokine overproduction and further reduction of HDL-C levels (23). The net effect of this vicious cycle is a more profound depletion of serum HDL-C in the setting of inflammation (8, 34, 47). In vitro studies have reported that SARS-CoV-2 can bind to HDL particles via the spike protein of the virus (48), but whether this is an important mechanism for lowering HDL cholesterol that is specific to COVID-19 is unclear. Additionally, there are no currently available studies directly comparing the effect of COVID-19 and non-COVID-19 acute respiratory illness on serum lipid levels.

Although LDL-C levels appear to correlate with disease activity in other infections, such as dengue (49) and tuberculosis (10), a similar consistent correlation has not been observed with COVID-19 (50). The studies reporting low LDL-C levels attribute this finding to COVID-19-induced liver injury (44), and increased uptake by monocyte-derived macrophages in patients with COVID-19 (51). We observed a significant association between low serum LDL-C levels and severe COVID-19 infection and mortality. A systematic review noted that patients with dyslipidemia or hyperlipidemia were associated with higher risk of COVID-19 severity and mortality, but the study did not report the precise numerical values of plasma lipids (52).

Although some studies have reported an association between elevated serum TG levels and mortality in COVID-19 (53, 54), our meta-analysis showed that TG levels were not associated with COVID-19 infection, or disease severity or mortality. Of note, TG and its breakdown products, namely fatty acids, activate the NF-κB pathway, with increased expression of pro-inflammatory cytokines, including TNFα, IL-1β, IL-6, and MCP-1 (monocyte chemoattractant protein-1) (55). Also, TG-rich particles in the serum can increase local inflammation, activate the complement pathway and promote endothelial dysfunction (56, 57).

Our study has several strengths. This is the first systematic review to examine the association between lipid levels and the presence, severity, and mortality in COVID-19 infections and assess the robustness of our conclusions through meta-regression for common confounding variables, such as age, sex, diabetes, hypertension, and coronary artery disease. Our systematic review of studies from nine countries with variable healthcare access, allow for generalizability of our results. Our study also has some limitations. First, the information on COVID-19 is highly dynamic, and this is a summary of the currently published articles. Although a pooled analysis of adjusted estimates is desirable, most studies do not give uniform estimates adjusted for similar parameters. Time points of assessment of lipid levels were taken at admission to maintain uniformity but the lipid levels were observed to be dynamic during the time of hospital admission in multiple studies. The included studies did not clearly report whether these lipid levels were taken in the fasting or non-fasting state. The use of lipid modifying agents by the patients in the cohorts were not recorded well in most included studies. Lasty, very few of the studies that assessed changes in serum lipid levels presented data on inflammation and liver injury markers.

Our analysis demonstrated lower lipid levels in patients with COVID-19 compared to healthy controls. Among COVID-19 patients, lower TC, LDL-C and HDL-C levels at admission were associated with disease severity and mortality. Our results might spur further interest in probing the association and interaction of lipid levels and inflammation in atherosclerotic cardiovascular diseases. Current evidence suggests that reduced lipoprotein levels are secondary to systemic inflammation and hepatic dysfunction, but the causal relationship between circulating lipid levels and COVID-19 disease requires further study. Finally, whether low lipid levels prior to hospital admission contribute directly to increased COVID-19 incidence and severity requires additional study.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

VC and PK conceived the idea for the review. VC, AK, MM, and PK designed and undertook the literature review. VC, HS, MM, AK, and RS screened the articles and extracted the data. VC and MM performed the statistical analysis, figures, and appendix and analyzed and interpreted the data. VC, HS, AK, MM, RS, DV, JM, and PK wrote the first draft of the manuscript. VC, AK, HS, DV, JM, and PK revised the subsequent drafts of the manuscript. All authors reviewed the final draft of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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