INTRODUCTION
Severe Acute Respiratory syndrome-Coronavirus-2 (SARS-CoV-2), possibly leading to poor outcomes, is known as a single origin of coronavirus disease-19 (COVID-19) pandemic. Pneumonia, acute respiratory distress syndrome, and septic shock are observed as major complications of the disease, leading to death.
Previously, SARS-CoV-1 caused “SARS,” in 2002 (1). Thereafter, the “middle east respiratory syndrome coronavirus (MERS-CoV)” caused the second outbreak in the past two decades (2).
Some common features were found among SARS-CoV-1, MERS-CoV, and SARS-CoV-2 from the epidemiological, clinical, molecular, and infectious aspects (3).
The onset of infections starts with a viral entrance to the host cell. Coated viruses, including CoVs, initially activate the plasma membrane fusion or endocytosis processes for the entrance. SARS-CoV-2, similar to SARS-CoV-1, employs human angiotensin converting enzyme 2 (ACE2) as a receptor to successfully enter the cell (4). ACE2 molecules located in the lipid rafts are widely available in alveolar type II epithelial cells (5).
Studies confirmed that the lipoproteins served as the initial defense barrier against the invading microbes (6), whose levels change during viral infections (7). Cholesterol known as a major lipid in the cell membrane is also an important component within this context (8,9).
Some rare findings were reported that dyslipidemia arises from SARS. Specifically, patients with SARS were reported to have reduced total cholesterol (TC) levels compared with healthy participants (10). Alterations in lipoprotein levels during COVID-19 infection were also reported (11-15).
Lipid profiles of patients with COVID-19 and their possible relation with disease severity were retrospectively investigated in our study.
METHODS
Study Design and Cohort
A total of 1,509 adult patients with COVID-19 pneumonia diagnosed using the polymerase chain reaction technique and radiologic involvement of computed tomography (CT) scan and admitted to University of Health Sciences Turkey, Bakirköy Dr. Sadi Konuk Training and Research Hospital in Istanbul, level-3 pandemic, from September 01, 2020, to December 31, 2020, were retrospectively observed. The hospital electronic database was screened and patients without clinical or laboratory data or with pneumonia arising from other causes were excluded from the study. Other criteria for exclusion, to reduce the confounding effects, includes the existence of dyslipidemia, use of lipid-lowering therapy, end-stage renal failure, chronic dialysis, nephrotic syndrome, obesity, cholestatic liver disease, chronic use of corticosteroids, immunosuppressive conditions, human immunodeficiency virus (HIV) infection, hypothyroidism, diabetes mellitus, chronic alcoholism, terminal conditions due to cancer, serum albumin level measurement of <3 g/dL, and pregnancy or breastfeeding, as well as chemotherapy for cancer treatment.
After the exclusion, 817 patients were enrolled, all of whom were over 18 years old and none was taken to the intensive care unit (ICU). Demographic data, comorbidities, COVID-19-related examinations, respiratory rate, oxygen saturation by pulse oximetry (SpO2), and mean oxygen requirement during hospitalization were recorded. Our hospital has accredited laboratories standardized for internal and external quality assurance measures to monitor the precision and accuracy of the performed tests. In all cases, blood samples of fasting were obtained from the peripheral vein within 24 hours of hospitalization. Data were categorized as moderate or severe according to the severity classification of the “Chinese Guidelines for Diagnosis and Treatment of Novel Coronavirus Pneumonia (Trial Version 7)” (16). Patients with moderate COVID-19 had a fever (>37.3 °C) and respiratory symptoms identified with radiological findings for pneumonia. COVID-19 cases were considered severe with any of the following criteria: “(1) respiratory distress (≥30 breaths/min), (2) oxygen saturation of ≤93% at rest, (3) arterial partial pressure of oxygen/fraction of inspired oxygen of ≤300 mmHg (l mmHg=0.133 kPa).” All patients were scanned with spiral CT on admission. Radiologist-evaluated CT results were classified into three categories: mild, moderate, and severe involvement (17). All study participants were managed according to the “COVID 19 Treatment Protocol of Turkish Health Ministry” (18). The research was first registered in the data of the “Turkish Health Ministry Scientific Research Committee” and then reviewed and approved by the “Local Ethics Committee.”
Serum Lipids Measurement
The dataset consisting of TC, high-density lipoprotein cholesterol (HDL-C)-, and LDL-C were analyzed using the modular dual-phase extraction system “(COBAS-C 501, Roche Diagnostics, Basel, Switzerland).”
Statistical Analysis
Mean ± standard deviation values were estimated as descriptive statistics. Deviations from normality were assessed using the median and percentage values in the distributions. The Student’s t-test was used for continuous variables with normal distributions. Categorical data were analyzed using the chi-square test. Continuous variables having abnormal distribution were evaluated by the Mann-Whitney U test. A p-value of <0.05 was accepted as statistically significant. Commercially available “Statistical Package for the Social Sciences software v.21 (Statistical Package for the Social Sciences Inc., Chicago, IL, USA)” was used for all the statistical analyses.
RESULTS
A total of 817 patients with COVID-19 pneumonia participated in this study, wherein 347 were moderate and 470 were severe. Baseline parameters and comorbidities showed no difference in sex. Patients with severe conditions were older than those with moderate ones. Hypertension and heart failure were more frequent (p=0.003, p<0.001, respectively) in patients in severe condition than those in moderate condition. SpO2, in baseline and under oxygen support, was lower in severe than in the moderate group. The respiratory rate was higher in the severe group (Table 1). Lymphopenia was lower, whereas neutrophil and platelet counts were higher in the severe than in the moderate group. Glucose, urea, transaminases (alanine aminotransferase and aspartate transaminase), magnesium, and potassium levels were also higher in the severe than in the moderate group. In addition, patients in severe conditions were linked with stronger inflammatory responses, which yielded poor prognostic laboratory findings, such as lactate dehydrogenase, C-reactive protein, troponin I, D-dimer, fibrinogen, and ferritin. Albumin and calcium were lower in patients with severe conditions; however, no difference was found in the procalcitonin between groups. CT revealed a severe involvement in the severe than the moderate group. Thyroid-stimulating hormone and free triiodothyronine values were lower in the severe than in the moderate group, within the reference range. No difference was found in the free thyroxine value between groups. The hospitalization duration was higher in the severe than in the moderate group. TC and LDL-C levels were lower in the severe group than in the moderate group (p=0.02, p=0.03, respectively). A total of 48 patients who died from respiratory failure were all from the severe group. The mortality rate was 10.2% in the severe group (Table 2). TC and LDL-C have a negative correlation with the hospitalization duration (r=-0.163, p=0.02; r=-0.154, p=0.03, respectively) (Figure 1, 2).
DISCUSSION
Lipid profiles of patients hospitalized with COVID-19 pneumonia were retrospectively analyzed based on the clinical laboratory reports of lipid measurements on a large patient population.
Previous studies showed that patients with community-acquired pneumonia had a higher risk of death with reduced LDL-C levels (19). Thus, the risk of sepsis for patients who are hospitalized also increased (20,21). One particular study showed that reduced levels of LDL-C were followed by a higher likelihood of future sepsis, which implied a direct influence of LDL-C on sepsis risk (22).
Contrarily, altered lipid profiles in patients arise from the inflammation due to viral infection. For instance, patients with HIV have reduced HDL-C and increased LDL-C levels (23,24). Patients with dengue fever disease have reduced LDL-C serum (25), and patients with cirrhotic hepatitis B also have reduced HDL-C and LDL-C levels (26).
Lipid metabolism changes 12 years after recovery in patients infected with SARS (27), thus dyslipidemia is possible to develop in patients with COVID-19-related diseases. However, several published investigations in the literature that examine the cholesterol levels with COVID-19 were reported.
Generally, published studies reported a reduced level of TC, triglyceride, HDL-C, and LDL-C (11). The severity level in both hypolipidemia and COVID-19 showed a positive correlation (12). In addition, severe consequences emerge more likely in reduced levels of HDL-C in COVID-19 (13). Contrarily, ApoCOVID study showed that HDL-C and LDL-C concentrations upon ICU admission are low in patients with severe COVID-19 pneumonia but are not associated with poor outcomes. However, low lipoprotein concentrations in the case of bacterial superinfection during ICU hospitalization are associated with mortality, which reinforces the potential role of these particles during bacterial sepsis (14). Another recent study demonstrated that LDL-C levels declined perpetually until death in patients hospitalized for COVID-19, though the cohort had a small sample size, which makes one think that LDL-C could potentially predict the disease progress and poor prognosis (15).
Various plausible mechanisms are responsible for dyslipidemia. COVID-19 gave possible harm to liver functions thereby reducing the LDL-C biosynthesis. An acute severe inflammation triggered by COVID-19 changes lipid metabolism or vascular permeability, which in turn leads to the entrance of cholesterol molecules into the alveoli forming exudate and causing a deficit in the plasma LDL-C and cholesterol (28). Another possibility is that the COVID-19-activated sterol regulatory element-binding protein-2 disturbs the cholesterol biosynthesis, which usually ends up with a cytokine storm (29).
As lipopolysaccharide creates a reaction with systemic viral infection and/or entrance of a toxic substance, the cholesterol counters the emerging toxic disturbance under selective interaction.
Moreover, LDL-C levels are assumed to be linked to the interplay between dyslipidemia and vasculopathy during a pathological process in patients with COVID-19 (30).
Our results showed that reduced levels of TC and LDL-C were linked with the severity of patients hospitalized with COVID-19 pneumonia. Reduced concentrations of TC and LDL-C most likely resulted from complicated biological and pathological processes caused by COVID-19. Obtained data suggested a decreased LDL-C concentration in patients with COVID-19 is related to disease severity.
Study Limitations
Several exclusion criteria were used to reduce the confounding effect; however, our findings, showing a correlation between the inferior LDL-C concentrations and poor outcomes of patients hospitalized with COVID-19 pneumonia, had its limitations. The baseline cholesterol levels before the start of the infection were unavailable, which made the precise emergence of reduced LDL-C concentrations uncertain. In addition, the LDL-C level during the recuperation was unrecorded due to the retrospective nature of our design, which resulted in a more pronounced account of the link between the variability of LDL-C concentrations and COVID-19 outcomes.
CONCLUSION
The variability of LDL concentrations in the vascular system of patients with COVID-19 indicated a strong relationship with the disease severity. Several researchers already demonstrated the strong link between lipid metabolism and COVID-19 in a way that corroborates our observations. Therefore, a foreseeable LDL as a marker for predicting COVID-19 severity is not fortuitous.
ETHICS
Ethics Committee Approval: The study were approved by the University of Health Sciences Turkey, Bakirköy Dr. Sadi Konuk Training and Research Hospital of Local Ethics Committee (no: 2021/127-2021-06-05 date: 15.03.2021).
Informed Consent: Retrospective study.
Authorship Contributions
Surgical and Medical Practices: M.B., Concept: M.B., Design: M.B., Data Collection or Processing: M.B., I.K.A., Analysis or Interpretation: M.B., I.K.A., Literature Search: M.B., I.K.A., Writing: M.B.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.