In this study, we found the dyslipidemia in patients with severe COVID-19, and demonstrated that low levels of HDL-C and Apo-AI at admission were significantly associated with high levels of CRP, prolonged hospital stay, increased disease severity. Additionally, the analysis of the longitudinal changes of lipid profiles showed that non-survival COVID-19 patients persistent had hypolipidemia including TC, HDL-C, LDL-C, Apo-AI than the survival patients during the early period of hospitalization. Furthermore, hypertension, NLR, platelet count and high CRP/ HDL-C ratio (>62.543) could serve as independent factors to predict in-hospital mortality, especially, higher CRP/ HDL-C ratio was closely associated with increased hospital mortality.
Acute inflammation caused by viral infection may result in dyslipidemia in patients, and the lipid metabolism is known to play an important role in host immune response. Clinical observations have displayed that patients with acute Epstein-Barr virus(EBV) infection had lower levels of Apo-AI, HDL-C, TC, Apo B, LDL-C and LP-A compared with their controls[25]. Another study showed that cytomegalovirus(CMV) infection was associated with lower HDL-C in normal-weight females[26]. Compared with other febrile patients, dengue-positive patients had lower HDL-C and LDL-C levels[27]. In addition, SARS patients had lower levels of Apo-AI compared to their normal controls from the results of plasma proteomics [28]. Similarly, our study showed that non-survivors with severe COVID-19 showed lower HDL-C and Apo-AI concentrations at admission compared to those survivors. Additionally, the analysis of longitudinal changes of lipid profiles demonstrated that LDL-C, HDL-C, TC and Apo-AI remained persistent at low levels, or even further gradually decreased during disease progression in non-survivors, while in survivors, although initially decreased, aforementioned lipid profiles were shown to increase steadily during recovery. Several
possible hypotheses might explain the dynamic changes during the course of COVID-19. Firstly, Liver plays an critical role in lipid metabolism, and liver dysfunction caused by SARS-CoV2 infection or potential drugs will affect lipid synthesis. It was reported that 14%-53% of patients with COVID-19 had hepatic dysfunction, especially in those severe and critical patients[29]. Therefore, the synthesis of apolipoproteins and lipoproteins would be affected by hepatic dysfunction of patients with severe COVID-19. Secondly, acute inflammation caused by SARS-CoV-2 might alter lipid metabolism as well. Severe and critical patients with COVID-19 were commonly accompanied with largely excessive release of pro-inflammatory cytokines, such as IL-1, IL-6, IL-12, IFN - γ and TNF-α, as the disease progressed over time and gradually got worse[30]. It was shown that tumor necrosis TNF-α, IL-1β, and IL-6 could decrease synthesis and/or secretion of apolipoproteins in hepatic cell lines in dose-dependent way [31]. Additionally, severe inflammatory response could also cause capillary leakage, thus resulting in the leakage of lipoproteins and apolipoproteins particles from intravascular to extravascular compartment [32]. In our study, we found that HDL-C and Apo-AI were closely associated with inflammatory marker of CRP, which might partially explain the hypolipidemia was associated with inflammatory response in severe COVID-19 patients. Finally, a very recent study has showed that a rare missense variant in cholesteryl ester transfer protein gene (CETP, rs1800777-A) that was associated with marked reduction in HDL-C levels and adverse clinical outcome during sepsis[33]. COVID-19 patients who carry the A allele may have lower HDL level and worse prognosis compared with non-carriers[33]. Therefore, the genetic variation of CETP gene is a key regulator of HDL-C levels and clinical prognosis during sepsis. At present, the genetic variation of CETP gene in patients with COVID-19 has not been reported, and it may be a promising research direction in the treatment and evaluation of prognosis among patients with COVID-19.
Since COVID-19 is a global pandemic with a high mortality rate, it will be helpful to determine several early markers to predict the disease severity and prognosis of COVID-19. Previous studies showed that low levels of Apo-AI and HDL-C have been used as prognostic biomarkers in patients with pneumonia, sepsis and other infections. An observational study indicated that a low level of Apo-AI was an indicator for poor prognosis in cirrhotic patients with severe sepsis[16]. Similarly, gradually-declined HDL-C level from day 1 to day 7 after admission could serve as a poor prognostic indicator among patients with severe community-acquired pneumonia[34]. Consistently, our data suggested that both HDL-C and Apo-AI levels were inversely correlated with disease severity scored (SOFA score and NEWS2 score), length of stay of survivors and inflammatory marker of CRP in patients with severe COVID-19. Additionally, our data also reported the low power of HDL-C and Apo-AI levels at admission to predict the in-hospital mortality. HDL and Apo-AI display pleiotropic properties including antioxidant and anti-inflammatory functions[9]. CRP is a common inflammatory marker. Thus, the ratio of CRP/HDL-C or CRP/ Apo-AI may reflect the balance between pro-inflammatory and anti-inflammatory factors. It is noteworthy that severe COVID-19 patients usually have an imbalance between anti-inflammatory and pro-inflammatory processes. Clinical and experimental studies have shown that patients with severe COVID-19 may exhibit features of systemic hyper-inflammation and inflammatory cytokine storm, which releases pro-inflammatory cytokines excessively and uncontrollably including IL-6 and TNF-α[19, 35]. And clinical reports showed that anti-inflammation therapies (such as glucocorticoids, immunosuppressants and inflammatory cytokines antagonists), which may help in preventing further injury in severe and critical COVID-19 patients, is an effective treatment to improve the clinical outcome[36]. Similarly, we found that the ratios of CRP/HDL-C and CRP/Apo-AI were significantly higher in survival COVID-19 patients compared to those non-survivors, and these ratios had strong negative correlation with SOFA score, length of stay of survivors and CRP. Moreover, high CRP/ HDL-C ratio (>62.543) was proved to be independent factor to predict in-hospital mortality among patients with severe COVID-19. Based on these findings, high CRP/ HDL-C ratio not only shows the imbalance of inflammation in patients with severe COVID-19, but also correlate with deteriorating disease severity and worsening prognosis, and might be serve as a potential indicator for poor outcome among COVID-19.
HDL and its major protein, Apo-AI, display pleiotropic protective functions, which include anti-infectious, anti-inflammatory, anti-oxidative, anti-thrombotic and Anti-diabetic properties[9]. An increasing number of evidences showed that HDL, particularly its major protein, Apo-AI, played protective effects in a variety of lung disease, including ALI, ARDS, chronic obstructive pulmonary disease(COPD), asthma, pulmonary fibrosis and viral pneumonia[6]. However, there are no clinical and experimental studies on the protective effect of HDL and Apo-AI in COVID-19. In severe and critical COVID-19 patients, clinical outcome can be significantly worsened by excessive release of pro-inflammatory cytokines[30]. HDL and Apo-AI may help in preventing inflammatory injury and improving the clinical outcome with anti-inflammatory and anti-oxidative properties. Then, a systematic review and meta-analysis showed that bacterial co-infection occurred in 7% of hospitalized COVID-19 patients and 14% of ICU patients, and the bacterial co-infection would lead to a higher mortality of COVID-19 [37]. Studies showed that HDL was capable to bind and neutralize Gram-negative LPS and Gram-positive lipoteichoic acid (LTA), thus reducing LTA and LPS-induced inflammatory injury[38, 39], thus providing the conception that HDL-based therapies might be promising in severe COVID-19 patients with bacterial co-infection. Diabetes was a common comorbidity in patients with COVID-19, and associated with greater disease severity and higher mortality of COVID-19[40], especially in those population with poorly-controlled glycemia [41]. Several experimental studies have demonstrated that HDL particles displayed anti-diabetic properties by improving insulin sensitivity and β cell insulin secretion[9, 42, 43]. The evidence suggested that HDL or Apo-AI might improve glycemic control and promote a better prognosis in severe COVID-19 patients. Although no clinical and experimental studies were conducted to determine the role of HDL and Apo-AI-based therapy in COVID-19, it would be a promising direction in searching novel treatment for severe patients with COVID-19.
Our study was subject to a few limitations that should not go unnoticed. Firstly, this study was a retrospective study with a relatively small sample size, large cohort study would be required to further confirm our conclusion. Secondly, asymptomatic patients and those with mild symptoms were not be enrolled, thus the conclusions drew by the study might not be applicable to asymptomatic and mild patients. Thirdly, a large number of factors could affect the lipid metabolism in COVID-19, the specific mechanism about the dyslipidemia could not be concluded, and would be required further powerful investigation.