key: cord-0690902-e3m7djzf
authors: Mahat, Roshan Kumar; Rathore, Vedika; Singh, Neelima; Singh, Nivedita; Singh, Sanjeev Kumar; Shah, Rakesh Kumar; Garg, Chanchal
title: Lipid Profile as an Indicator of COVID-19 Severity: A Systematic Review and Meta-analysis
date: 2021-07-31
journal: Clin Nutr ESPEN
DOI: 10.1016/j.clnesp.2021.07.023
sha: 231cb7e65c49cf46d8cbe6997dc3252eadb6baf2
doc_id: 690902
cord_uid: e3m7djzf

Background Coronavirus disease-2019 (COVID-19) is now becoming a global threat. Studies reported dyslipidemia in patients with COVID-19. Herein, we conducted a systematic review and meta-analysis of published articles to evaluate the association of lipid profile with the severity and mortality in COVID-19 patients. Methods PubMed/Medline, Europe PMC, and Google Scholar were searched for studies published between January 1, 2020 and January 13, 2021. Random or Fixed effects models were used to calculate the mean difference (MD) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using Cochran’s Q test and I2 statistics. Results This meta-analysis included 19 studies. Of which, 12 studies were categorized by severity, 04 studies by mortality, and 03 studies by both severity and mortality. Our findings revealed significantly decreased levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in the severe group when compared with the non-severe group in a random effect model. Similarly, random effect model results demonstrated significantly lower levels of HDL-C and LDL-C in the non-survivor group when compared with the survivor group. The level of TC was also found to be decreased in the non-survivor group when compared to the survivor group in a fixed-effect model. Conclusion In conclusion, lipid profile is associated with both the severity and mortality in COVID-19 patients. Hence, a lipid profile may be used for assessing the severity and prognosis of COVID-19. PROSPERO registration Number CRD42021216316.

dysregulation of lipid metabolism may promote the progression of COVID-19 [23, 24] . In addition, a study reported that hypolipidemia begins in patients with mild COVID-19 and escalates with the progression and severity of the disease [25] .

To the best of our knowledge, no systematic review and meta-analysis has been conducted to date concerning the association of lipid profile with the severity and mortality in COVID-19.

Therefore, we conducted a systematic review and meta-analysis of published articles from January 1, 2020 to January 13, 2021 to evaluate the association of lipid parameters (total cholesterol, HDL-cholesterol, LDL-cholesterol, and triacylglycerols) with the severity and mortality in COVID-19 patients.

This systematic review and metaanalysis was prospectively registered on PROSPERO-The International Prospective Register of Systematic Reviews (Registration No. CRD42021216316)

[26] and adheres to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [27] .

Studies that meet the following criteria were included in the meta-analysis: a) representation for clinical questions (Population: laboratory-confirmed COVID-19 patients; Exposure: severe COVID-19 patients or patients who died due to COVID-19 (non-survivors); Comparator: non- Review articles, conference papers, non-research letters, editorials, commentaries, case reports, research articles with samples below 10, articles not written in English language, and studies that have been conducted exclusively on children or pregnant women were excluded. If two or more studies were conducted at the same place during the same or overlapping period, a study with a larger sample size was included in the present meta-analysis.

For the relevant studies, a comprehensive systematic literature search of PubMed/Medline, Europe PMC, and Google Scholar was performed from January 1, 2020 to January 13, 2021 using the following search terms: ("COVID-19" OR "2019-nCOV" OR "SARS-COV-2" OR "novel coronavirus disease" OR "novel coronavirus 2019" OR "coronavirus disease-2019") AND ("lipid profile" OR "lipid parameters" OR "dyslipidemia"). After the initial search, duplicates were removed and two authors (RKM and VR) independently screened titles and abstracts for potentially relevant articles. The full text of relevant articles was reviewed for the eligibility criteria. The reference list of eligible studies and relevant systematic reviews were also reviewed to reduce the literature omissions. We have also included unpublished and preprint articles in our meta-analysis. Disagreements on which studies to include during both title and abstract screen, and the subsequent full-text analysis, were resolved through discussion until consensus was reached.

Two reviewers (RKM and VR) independently extracted the following data from each included study: first author's name, country, publication year, hospital, study type, data collection date, gender, age, grouping situation, number of cases in each group, and lipid parameters measured.

A third reviewer (NS) checked the article list and extracted data to ensure there were no duplicate articles or duplicate information.

The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of included studies [28] . For every original study included, the quality assessment was carried out independently by two reviewers (RKM and VR) and the disagreements were resolved through a panel discussion with other reviewers.

The meta-analysis of included studies was performed using Review Manager Version 5.4 and STATA (version 16; Stata Corporation, College Station, TX). When the results of the included studies were present in median and interquartile range (IQR), the mean and standard deviation of lipid parameters were extrapolated from sample size, median and interquartile range (IQR) according to Luo et al [29] and Wan et al [30] . Some studies included in our systematic review and metaanalysis reported lipid parameters in mg/dl. In that case, the units were converted to mmol/L to standardize all data. Values in mg/dl were divided by the following conversion factors: 38.67 for total cholesterol, LDL-cholesterol, and HDL-cholesterol; and 88.57 for triacylglycerol [31] . To assess the difference of lipid parameters between severe and non-severe COVID-19 groups or COVID-19 patients who survived (survivor group) and those who died due to COVID-19 (non-survivor group), a pooled mean difference (MD) with 95% confidence interval (CI) was used. To assess statistical heterogeneity among included studies, Cochran's Q test and I 2 statistics were used. A Cochran's Q value of <0.10 shows significant heterogeneity between studies while I 2 statistic was interpreted as 25%, 50%, and 75% representing low, moderate, and high degrees of heterogeneity, respectively. The random-effect model was used if heterogeneity existed; otherwise, the fixed-effect model was used. Sensitivity analysis was J o u r n a l P r e -p r o o f carried out by omitting individual studies to assess the stability of the meta-analysis. Funnel plots were constructed for lipid parameters and Egger's test was adopted to statistically assess the potential publication bias (a p-value <0.1 indicated significant bias). Except for Egger's test and Cochran's Q test, a p-value <0.05 was considered statistically significant.

Outcome of database search:

A total of 2681 articles could be initially identified from PubMed/Medline, Europe PMC, Google Scholar, and other sources. After removing duplicates, 2091 articles remained, of which, 41 articles were selected for full-text assessment after screening the title and abstract. Eventually, 19 studies with a total sample of 5690 confirmed COVID-19 patients were finally selected for qualitative synthesis and metaanalysis after excluding 22 ineligible studies. The PRISMA flow diagram for the study selection process is shown in Figure 1 .

All the 19 studies were hospital-based, conducted between January 1, 2020 to January 13, 2021.

Of 19 studies, 17 were retrospective and 02 were prospective studies. 

The methodological quality of included studies was assessed by Newcastle-Ottawa Scale (NOS).

A score of 0-9 was allocated to each study with higher scores indicating a lower risk of bias. The quality results are shown in Table 1 .

For the patients grouped by severity of COVID-19, the analysis of the random effect model 

To evaluate the stability of results, sensitivity analysis was carried out. We found that the combined results could not change significantly after excluding any one specific study in TC, HDL-C, LDL-C, and TG between severe and non-severe groups or survivor and non-survivor groups (Supplement 1 and 2) . Funnel plots were constructed for TC, HDL-C, LDL-C, and TG since these parameters were retrieved from ≥10 studies, and to examine whether there was evidence for statistically significant asymmetry, we had performed Egger's test. Egger's test indicated that there was no evidence of substantial publication bias for TC (p=0.9159), HDL-C (p=0.8344), LDL-C (p=0.2082), and TG (p=0.3491) in studies grouped by severity (Supplement J o u r n a l P r e -p r o o f 3). Since less than 10 studies were included in the meta-analysis of lipid profile in studies grouped by mortality, funnel plots could not be constructed and Egger's test could not be carried out.

To the best of author's knowledge, this is the first systematic review and meta-analysis that investigated the association of lipid profile with the severity and mortality in COVID-19 patients.

The findings of the present meta-analysis revealed significantly decreased levels of TC, HDL-C, and LDL-C are associated with severity and mortality in COVID-19 patients. However, no significant difference was observed in the level of TG between severe and non-severe groups or survivor and non-survivor groups.

Patients may experience dyslipidemia due to chronic inflammation caused by a viral Another study showed that patients with hepatitis B had decreased levels of HDL-C and LDL-C in the cirrhosis phase [53] . In addition, human immunodeficiency virus (HIV) patients had decreased HDL and increased LDL levels [54, 55] . Similarly, a study revealed that cytomegalovirus infection was linked to lower HDL-C in normal-weight females [56] . Lima et al. conducted a systematic review and meta-analysis of nine studies that evaluated 1953 patients and reported that circulating total cholesterol and LDL were inversely and significantly correlated with the severity of dengue fever [57] . The results of the International MONDO study also showed that lipid levels were inversely associated with infectious and all-cause mortality [58] . In patients with severe acute respiratory syndrome (SARS), the findings of dyslipidemia are rare. One study showed a lower level of total cholesterol in SARS patients when compared with healthy controls [59] . Another study reported altered lipid metabolism in recovered SARS Hepatic dysfunction has been seen in 14-53% of COVID-19 patients, particularly in severe and critical patients [60] . This hepatic dysfunction in severe COVID-19 patients would affect the synthesis of lipoproteins. Second, one of the significant features of COVID-19 patients is excessive inflammation, particularly in patients with severe cases or in those who have died [61] [62] [63] [64] , which causes alteration in lipid metabolism. Proinflammatory cytokines such as IL-6, TNFα, and IL-1β have been reported to modulate lipid metabolism by altering liver function and decreasing cholesterol efflux and transport in HIV patients [65] . IL-6, TNF-α, and IL-1β may also decrease the synthesis and/or secretion of apolipoproteins in hepatic cell lines in a dosedependent manner [66] . Moreover, in HIV-1 infection, decreased HDL-C is linked with the impairment of ATP-binding cassette transporter A1-dependent cholesterol efflux from J o u r n a l P r e -p r o o f macrophages, and the activation of endothelial lipase and phospholipase A2 by inflammation [67, 68] . Inflammation has been found to affect the expression of the hepatic apolipoprotein gene and strengthens the binding of the pro-inflammatory serum amyloid protein A (SAA) which, in turn, displaces and reduces the levels of ApoA-I in HDL [69, 70] . HDL particles loaded with SAA have been shown to clear more rapidly from circulation than normal HDL [22] . During inflammatory setting, reduced plasma levels of lecithin cholesterol acyltransferase (LCAT) can also impair HDL function and further worsen the inflammatory response [71] . Third, the virusinduced inflammatory response could also cause altered vascular permeability resulting in leakage of cholesterol molecule into tissues, such as alveolar spaces to form exudates. Exudates contain high levels of protein and cholesterol [72, 73] . Exudates are seen in lung autopsies from SARS patients, in cynomolgus macaques infected with SARS-COV [74] [75] [76] 

In conclusion, this systematic review and meta-analysis showed decreased levels of TC, HDL-C, and LDL-C in severe COVID-19 patients as compared to non-severe COVID-19. Furthermore, reduced levels of TC, HDL-C, and LDL-C were found in non-survivors compared to survivors, indicating lipid profile is associated with both the severity and mortality in COVID-19 patients.

Hence, a lipid profile may be used for assessing the severity and prognosis of COVID-19. Since lipid profile is cost-effective and easily accessible in all laboratories, it could help the physician in assessing the severity and prognosis of COVID-19 in resource-limited areas.

The authors declare that there is no conflict of interest. J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia

Indirect Virus Transmission in Cluster of COVID-19 Cases

COVID-19 indirect contact transmission through the oral mucosa must not be ignored

COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses

Serum Lipid Metabolic Derangement is Associated with Disease Progression During Chronic HBV Infection

High-density lipoprotein particles and markers of inflammation and thrombotic activity in patients with untreated HIV infection

HIV infection and high density lipoprotein metabolism

The association between cytomegalovirus infection, obesity, and metabolic syndrome in U.S. adult females. Obesity (Silver Spring)

Serum lipid profile as a predictor of dengue severity: A systematic review and meta-analysis

Lipid levels are inversely associated with infectious and all-cause mortality: international MONDO study results

COVID-19 and the liver

Cytokine storms in COVID-19 cases? Tidsskr Nor Laegeforen

Immunosuppression for hyperinflammation in COVID-19: a double-edged sword?

COVID-19: consider cytokine storm syndromes and immunosuppression

The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China

Lipid Abnormalities and Inflammation in HIV Inflection

Cytokines decrease apolipoprotein accumulation in medium from Hep G2 cells

Human immunodeficiency virus impairs reverse cholesterol transport from macrophages

Molecular regulation of HDL metabolism and function: implications for novel therapies

Reciprocal and coordinate regulation of serum amyloid A versus apolipoprotein A-I and paraoxonase-1 by inflammation in murine hepatocytes

Serum amyloid A impairs the antiinflammatory properties of HDL

Cholesterol efflux by acute-phase high density lipoprotein: role of lecithin: cholesterol acyltransferase

Pleural effusions: the diagnostic separation of transudates and exudates

Multilevel likelihood ratios for identifying exudative pleural effusions(*)

Pulmonary pathology of severe acute respiratory syndrome in Toronto

Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome