This retrospective study examined the association between blood lipid status and mortality of COVID-19 patients. While previous studies have established the frequency of dyslipidemia among individuals with COVID-19, our focus was on the predictive value of dynamic changes in lipid levels for mortality. Our results indicate that non-surviving COVID-19 patients exhibit persistent dyslipidemia, characterized by reduced levels of HDL-C, LDL-C and TC, along with increased levels of TG. By comparing the changes in lipid parameters between surviving and non-surviving patients during the early stages of hospitalization, we observed that both the levels and fluctuations in TC, HDL, and LDL were strongly associated with mortality, with AUCs values exceeding 0.7. Notable, in the third week of hospitalization, the AUCs for TC, HDL, and LDL were 0.891, 0.895, and 0.879, respectively, while the AUCs for changes in these parameters were even higher, at 0.975, 0.950, and 0.925, respectively. Our findings shed light on the dynamic evolution of lipidology in COVID-19 patients and offer insights into predicting outcomes and understanding the mechanism underlying dyslipidemia.
There have been several observational studies that have shown a significant correlation between blood lipid parameters and mortality. The available evidence suggests that non-survivals of COVID-19 patients exhibited decreased LDL, HDL and TC than survivors, with or without elevated TG levels(12, 14). Additionally, HDL has been identified as a predictor for one-year mortality after COVID-19 (15). Consequently, it appears that the lipid profile may play a crucial role in determining the prognosis of patients with COVID-19, both in the long-term and the short-term. Therefore, there is a significant need to investigate the evolution of the lipid parameters in COVID-19 patients. One of the pertinent questions to address is the underlying causes of dyslipidemia in patients with COVID-19.
There were several possible explanations for the changes in lipid profile during COVID-19 infection. Firstly, SARS-CoV-2 induced acute inflammation may lead to dyslipidemia. Studies have shown that inflammatory mediators, such as interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis-alpha (TNF-α), can dose-dependently reduce the production and/or release of apolipoproteins in hepatic cell lines (16). This suggests that a more pronounced dyslipidemia may result from a stronger inflammatory response. Our study found that non-surviving COVID-19 patients exhibited a robust inflammatory response, as indicated by higher levels of WBC, neutrophil count, and CRP, which is consistent with previous studies (7, 13, 15, 17–19). In sepsis patients, TC and HDL decreased during the acute phase and slowly increased within 28 days (20). Similarly, our repeated measurement data demonstrated that lipid levels gradually recovered during the first four weeks in surviving COVID-19 patients, while hypolipidemia persisted in the non-survivors. Lipid metabolism and inflammatory response interact and regulate each other. Our study found that CRP were significantly correlated with TC, HDL and LDL at all four time points. Secondly, COVID-19 may impair liver function and affect lipid metabolism. The liver is essential for lipid synthesis and metabolism, and virus infections may damage hepatocytes, thereby altering the synthesis of TG and cholesterol. Consistent with previous studies (6, 7, 13, 18), our data revealed that non-surviving COVID-19 patients exhibited significant abnormal liver function, as evidenced by increased levels of ALT, AST, and TBil. Impaired liver function also led to abnormal coagulation function, with significantly prolonged PT and APTT in non-survivals. Pro-inflammatory cytokines IL-6, IL-1b and TNF-a and regulate lipid metabolism though altering liver synthesis and decomposition functions and reducing cholesterol transport (21). Thirdly, medication side effects may generate dyslipidemia. For instance, tocilizumab has a significant correlation to high TG in COVID-19 patients (22). In the present study, the non-survival group had a higher proportion of received the treatment of immunoglobulin, with a higher level of TG. Fourthly, the massive replication of the virus may consume lipids, leading to dyslipidemia (23). Fifthly, increased free radicals in host cells infected by the virus may rapidly degrade lipids leading the decreased levels of LDL, HDL, and total cholesterol (24). Finally, vascular permeability may be easily altered by virus infection in critical patients with COVID-19 so that exudates could be formed in tissues, such as alveolar spaces, accumulated by a series of leaked cholesterol particles (25).
There is indeed a link between lipid abnormalities and poor outcomes in COVID-19 patients. Our research has shown that dyslipidemia can predict a worst prognosis, which in line with previous reports that it is an independent risk factor of for a bad outcome. Dyslipidemia may also exacerbate both the disease severity and mortality of patients with COVID-19 (10). The role of cholesterol in immunity is increasingly recognized in multiple observational studies. It has been suggested that low cholesterol levels could be regarded as a marker for a worse prognosis in sepsis patient (26). COVID-19 patients with lower LDL levels are more likely to experience immunological and inflammatory dysfunction, renal dysfunction, hepatic dysfunction, and cardiac dysfunction (9). Decreased LDL level indicates poor prognosis of severe and critical COVID-19 patients (9). In the present study, LDL levels of non-survivals were significantly decreased from W1 to W3 than those of survivals, though survivals had higher levels of LDL than non-survivals at W1, W2 and W3. Conversely, a recent meta-analysis of retrospective cohort reported raised LDL is a risk factor for severe COVID-19 infection (27). Both high and low levels of LDL were markedly related with bad outcome of COVID-19 (28). Thus, the role of LDL in COVID-19 is complex and remained controversial. TC, HDL and LDL were significantly correlated with organ dysfunction (eg. BUN, CK, BNP) in this study. Furthermore, the endothelium may suffer from an elevation of TG and a drop of HDL in COVID-19 patients (13), which can contribute to endothelial dysfunction and coagulopathy, both of which are severe and potentially fatal risk factors for COVID-19 (29). Our data showed that TC, HDL and LDL were significantly associated with D-dimer.
It also reported that D-dimer levels greater than 1ug /ml can help identify COVID-19 patients with poor prognosis (30). Our results have confirmed that the D-dimer levels of non-surviving patients were significantly higher than 11ug /ml and significantly associated with levels of TC, HDL and LDL at all four time points. Dynamic monitoring of D-dimer is more useful than cross-sectional studies because it can help track the evolution of the disease and facilitate the study of its pathogenesis (19),(31).
In contrast to traditional markers of severity, such as CRP, PCT, and cytokines, which have short half-lives and unpredictable peaks that are only briefly associated with disease severity, HDL has a greater predictive value because of its immediate decline and long-term stability (32). Therefore, our study of dynamic lipid profile, which are relatively stable parameters, is significance for predicting poor prognosis. This is a supplementary finding to a previous study that suggested a correlation between HDL and a higher risk of developing severe events in COVID-19 patients (33).
Limitations:
There are several limitations to this study. Firstly, it is a retrospective analysis conducted in a single center. Not all patients in the study had blood lipid measurements at each time point, and as the time point increased, there were fewer instances of blood lipid results available. Meanwhile, we lack the information regarding the lipid levels and lipid-regulating medication use of the study population prior to disease onset. Secondly, we lack information regarding the lipid levels and lipid-lowering medication use of the study population prior to disease onset. Therefore, considering the intricate nature of dyslipidemia in COVID-19 patients, it is imperative to conduct extensive prospective studies with a substantial sample size to gain a thorough comprehension of the condition.