Triglyceride/High-Density Lipoprotein Cholesterol Ratio is associated with the mortality of COVID-19: An Observational Study

(1) Background: Triglyceride to high density lipoprotein cholesterol (TG/HDL-c) ratio is crucial when researching metabolic and vascular diseases, and its involvement in COVID-19 was sparsely elaborated on. The purpose of the study was to explore if there were any associations between the TG/HDL-c ratio and COVID-19 prognosis; (2) Methods: A total of 262 COVID-19 patients were retrospectively investigated. The clinical features and baseline hematological parameters were recorded and analyzed; (3) Results: Compared with the survivors, the non-survivors of COVID-19 had signicantly higher levels of white blood cells (4.7 vs. 13.0 ×10 9 /L; P < 0.001), neutrophils (3.0 vs. 11.6×10 9 /L; P < 0.001), C-reactive proteins (15.7 vs. 76.7 mg/L; P < 0.001) and TG/HDL-c ratio (1.4 vs. 2.5; P = 0.001). The receiver operating characteristics curve [area under the curve, 0.731; 95% condence interval, 0.609–0.853; P = 0.001] suggested that the TG/HDL-c ratio could predict the mortality of COVID-19. Moreover, the TG/HDL-c ratio was positively correlated with white blood cells (r = 0.255, P < 0.001), neutrophils (r = 0.243, P < 0.001) and C-reactive proteins (r = 0.170, P < 0.006); (4) Conclusions: Our study demonstrated that TG/HDL-c ratio may potentially be a predictive marker for mortality in COVID-19 patients.


Background
As is generally known, the Coronavirus disease 2019 (COVID- 19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has already become a serious threat to the global public health system 1 . As of May 21, 2021, there were already 160 million con rmed cases of COVID-19 which has resulted in more than 3.4 million deaths worldwide 2 . Although most cases reported mild, severe cases can progress rapidly, culminating in respiratory failure, septic shock, or a fatal outcome. Consequently, being able to identify risk factors early is very important for COVID-19 progression. Dyslipidemia is common in strokes 3 , insulin resistance 4 , metabolic syndromes 5 and cardiovascular diseases 6 .
Increases in TG and decreases in HDL-c may be caused by in ammatory cytokines, and triglyceride (TG), and a high density lipoprotein cholesterol (HDL-c) ratio (TG/ HDL-c) was strongly correlated with in ammation 7 . Idiopathic pulmonary arterial hypertension (IPAH) patients with a higher TG/ HDL-c ratio were more likely to suffer from systemic in ammation 7 . Type B acute aortic dissection (AAD) patients with higher TG/ HDL-c ratio had greater mortality that might be explained by higher levels of in ammatory factors 8 . Nevertheless, the correlation between TG/HDL-c ratio and viral infections is still not clear. And this study seeks to clarify the relationship of TG/HDL-c ratio and the mortality of COVID-19 patients. Based on their survival status, the enrolled patients were divided into a survivor and non-survivor group.

Data Collection
All medical records of the patients were carefully collected and reviewed by two members of our team.
We recorded the demographics, baseline characteristics, and blood test parameters when admitting patients. The medical records with incomplete information were excluded. The primary end point in this study was the occurrence of death among patients with COVID-19.

Statistical Analysis
The Mann-Whitney test and Fisher's exact test (or χ 2 test) were used to analyze the continuous and categorical variables, respectively. To detect which variables best predicted the nal outcome for COVID-19 patients, we performed univariate and multivariate logistic regression analyses. To evaluate how variables can predict COVID-19 prognoses, the receiver operating characteristics (ROC) were calculated.
The Spearman's rank correlation coe cients were used to measure the correlation between two variables. IBM SPSS version 26 software was conducted during all analyses.

Discussion
Our study primarily contributed to three ndings. First, TG/HDL-c ratio of non-survivors had risen when compared with the survivors. Furthermore, TG/HDL-c ratio levels at admission positively correlated with in ammatory indicators, such as WBC, neutrophils, and CRP. Finally, TG/HDL-c ratio at admission might be able to predict and measure COVID-19 mortality.
TG/HDL-c ratio integrates predictive risks of two parameters into a single risk factor, and it is simple, noninvasive, and easily measured. Previous studies revealed that higher TG/HDL-c ratio was frequently seen in insulin resistance 4 and cardiovascular diseases 6 . Studies have supported that TG/HDL-c ratio might serve as an in ammatory factor in IPAH and type-B AAD patients 7,8 . However, there is little literature investigating the function of TG/HDL-c ratio on viral infections. It was discovered that the expression of TG levels rose during the period of infection and in ammation 9,10 . In ammatory cytokines contribute to TG synthesis and reduce TG hydrolysis under septic conditions 11 and also increase the angiopoietin-like protein 4 expressions which suppress the TG-rich lipoprotein metabolism 12 . The tumor necrosis factor (TNF)-α was reported to produce a rapid rise in TG concentrations through increasing hepatic production 12 . Without doubt, due to social isolation and long periods at home, people were more likely to have an imbalanced diet and be less active, which worsened their metabolic and lipid les and led to hypertriglyceridemia 13 . Hypertriglyceridemia induces endothelial dysfunctionality, causing COVID-19 patients to become more susceptible to complications related to cardiovascular diseases 14 . It was reported that TG levels signi cantly increased in COVID-19 patients with poor prognoses 15 .
The most striking function of HDL was participating in reverse cholesterol transport from tissues to the liver 16 . HDL particles are crucial to the immune system and ghting infectious diseases, which mitigate in ammatory responses during sepsis 17,18 , and function against RNA and DNA viruses 19 . In addition, HDL has the greatest a nity for binding and neutralizing lipopolysaccharides and lipoteichoic acid 20 and exert antithrombotic 21 and antioxidant effects 22 . Previous studies using genetic variants as risk factors showed that increasing genetically determined levels of HDL-c exhibited an association with reduced mortality from sepsis 9 . Other studies suggested that cholesteryl ester transfer protein (CETP) variant rs1800777 was related to the degree of HDL-C in septic patients 23 , and CETP inhibitors might be a potential therapy for sepsis 24 . Some viral infections causing in ammation also resulted in dyslipidemia, in which human immunode ciency virus (HIV) patients had a decreased HDL-c levels 25,26 , and patients with hepatitis B in the cirrhosis phase showed lower HDL-c levels 27 . Recent studies demonstrated that COVID-19 patients with declined HDL-c concentrations had longer viral nucleic acid turning negative time than normal 28 , and lower HDL-c levels exhibited an association with the severity of COVID-19 in patients 29 . A marked decrease in HDL-c concentrations during the acute phase response is well documented, however, the mechanisms underlying this decrease are not clearly de ned. Apolipoprotein-1 (ApoA-1), a major structural protein of HDL-c, reportedly decreased together with lower HDL-c when proin ammatory cytokines, such as interleukin-6 (IL-6) and CRP inhibited the activity of apolipoprotein synthesis enzymes 15,17 . Serum amyloid A (SAA)-enriched HDL displaced and decreased ApoA-1 levels and scavenged HDL more rapidly which was signi cantly higher in patients with a severe COVID-19 diagnosis 11,15 . Paraoxonase 1 (PON1), an antioxidant enzyme of HDL, could be inactivated under oxidative stresses and further weaken HDL functions 30 . Moreover, hemodilution, consumption of HDL particles, and capillary leaks explain the decreased HDL concentration might be applicable to COVID-19 patients as well 17,31 . Impaired antioxidant properties of HDL cause lipid oxidation inducing in ammation and accentuating tissue damage 14 . Consequently, HDL-c de ciency induces cytokine overproduction, in turn, cytokine can prime the depletion of HDL-c, which promotes a vicious cycle in severe patients.
Overall, systemic in ammatory responses can cause hypertriglyceridemia and decreased HDL-c, resulting in an increase in levels of TG/HDL-c ratio.
In ammatory cells release a large amount of cytokines in the pathophysiological processes during SARS-CoV-2 infection, thus leading to a cytokine storm which induces rapid development in multiple organ dysfunctions or even death 32 . Abundant evidence indicates that compromised immune functions and an excessive in ammatory response are closely related with mortality from COVID-19 33-35 . In the current study, the TG/HDL-c ratio was positively related to the levels of WBC, neutrophils, and CRP, similar to the study mentioned, within which IPAH patients with elevated TG/HDL-c ratio had elevated levels of interleukin-1β, monocyte chemoattractant protein-1, and IL-6 7 . Zhang et al. 36 also reported that the levels of IL-6 in non-survivors of COVID-19 were higher than that of the survivors, and increasing IL-6 concentrations were accompanied by increasing TG/HDL-c ratio. In our further analysis, we generated a ROC curve and found that TG/HDL-c ratio was probably a choice of prognostic predictors for COVID-19. Based on the ndings presented above, we can speculate that in ammation might serve a bene cial role in predicting the poor outcomes of COVID-19 patients who had elevated TG/HDL-c ratio, but further investigations are required for speci c mechanisms.
The study has some limitations. First, due to the retrospective analysis, we were unable to identify variables, such as BMI which might cause bias. Next, TG and HDL-c levels haven't been detected over hospitalization stays, while dynamic monitoring might be a better characterization for dyslipidemia.
Finally, the lipid metabolism can be affected by various factors, such as dietary preferences and habits, and the mechanisms should be further studied.

Conclusions
In conclusions, this study demonstrated that higher TG/HDL-c ratio might help identify patients who have a high likelihood of developing a poor outcome.  Figure 1