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Nutrition, Metabolism & Cardiovascular Diseases (2021) 31, 2619e2627

Available online at www.sciencedirect.com

Nutrition, Metabolism & Cardiovascular Diseases

journal homepage: www.elsevier.com/locate/nmcd

Low-density lipoprotein cholesterol levels are associated with poor

clinical outcomes in COVID-19
Álvaro Aparisi a, Carolina Iglesias-Echeverría a, Cristina Ybarra-Falcón a,
Iván Cusácovich c, Aitor Uribarri a, Mario García-Gómez a, Raquel Ladrón a,
Raúl Fuertes d, Jordi Candela a, Javier Tobar a, Williams Hinojosa a, Carlos Dueñas c,
Roberto González c, Leonor Nogales e, Dolores Calvo f, Manuel Carrasco-Moraleja a,
J. Alberto San Román a,b, Ignacio J. Amat-Santos a,b, David Andaluz-Ojeda g,*
a
Cardiology Department, Hospital Clínico Universitario, Valladolid, Spain
b
CIBERCV, Cardiology Department, Hospital Clínico Universitario, Valladolid, Spain
c
Internal Medicine Department, Hospital Clínico Universitario, Valladolid, Spain
d
Medicine School, University of Valladolid, Valladolid, Spain
e
Intensive Care Unit Department, Hospital Clínico Universitario, Valladolid, Spain
f
Clinical Analysis Department, Hospital Clínico Universitario, Valladolid, Spain
g
Intensive Care Unit Department, Hospital Universitario HM Sanchinarro, Madrid, Spain

Received 26 October 2020; received in revised form 8 June 2021; accepted 22 June 2021
Handling Editor: G. Chiesa
Available online 6 July 2021

KEYWORDS Abstract Background and aims: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
SARS-CoV-2; is the sole causative agent of coronavirus infectious disease-19 (COVID-19).
COVID-19; Methods and results: We performed a retrospective single-center study of consecutively admitted
Coronavirus; patients between March 1st and May 15th, 2020, with a definitive diagnosis of SARS-CoV-2 infec-
Inflammation; tion. The primary end-point was to evaluate the association of lipid markers with 30-days all-
High-density cause mortality in COVID-19.
lipoprotein; A total of 654 patients were enrolled, with an estimated 30-day mortality of 22.8% (149 pa-
Low-density tients). Non-survivors had lower total cholesterol (TC) and low-density lipoprotein cholesterol
lipoprotein; (LDL-c) levels during the entire course of the disease. Both showed a significant inverse correla-
tion with inflammatory markers and a positive correlation with lymphocyte count. In a multivar-
Total cholesterol;
iate analysis, LDL-c  69 mg/dl (hazard ratio [HR] 1.94; 95% confidence interval [CI] 1.14e3.31), C-
Triglycerides
reactive protein >88 mg/dl (HR 2.44; 95% CI, 1.41e4.23) and lymphopenia <1000 (HR 2.68; 95%
CI, 1.91e3.78) at admission were independently associated with 30-day mortality. This associa-
tion was maintained 7 days after admission. Survivors presented with complete normalization of
their lipid profiles on short-term follow-up.
Conclusion: Hypolipidemia in SARS-CoV-2 infection may be secondary to an immune-
inflammatory response, with complete recovery in survivors. Low LDL-c serum levels are inde-
pendently associated with higher 30-day mortality in COVID-19 patients.
ª 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian
Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II
University. Published by Elsevier B.V. All rights reserved.

Abbreviations: ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; AUROC, Area under the receiver operating characteristic
curve analysis; CoQ10, Coenzyme Q10; COVID-19, Coronavirus disease 2019; CRP, C-Reactive protein; HDL-c, High-density lipoprotein
cholesterol; IL6, Interleukin 6; LDH, Lactate dehydrogenase; LDL-c, Low-density lipoprotein cholesterol; PCT, Procalcitonin; RT-PCR,
Reverse transcription-polymerase chain reaction; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; TC, Total cholesterol; TG,
Triglycerides.
* Corresponding author. Intensive Care Department, Hospital Universitario HM Sanchinarro. Oña 3, 28050, Madrid. Spain.
E-mail address: davidandaluz78@yahoo.es (D. Andaluz-Ojeda).

https://doi.org/10.1016/j.numecd.2021.06.016
0939-4753/ª 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical
Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.
2620 Á. Aparisi et al.

Introduction carried out by following the guidelines of the Declaration

of Helsinki of the World Medical Association.
Severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) is a novel single-stranded RNA virus [1], and it is Outcome measure
considered the sole causative agent of Coronavirus
disease-2019 (COVID-19). According to the World Health The primary endpoint was to investigate any relationship
Organization, approximately 2,191,898 patients are between serum levels of lipid markers in the first hours of
currently dead after 101,406,059 confirmed cases world- admission and all-cause mortality at 30-days. Secondary
wide [2]. Initial reports have suggested that SARS-CoV-2 endpoints included the correlation between lipid and in-
binds to a human angiotensin-converting enzyme-2 re- flammatory markers (1) during hospitalization and (2)
ceptor to gain intracellular entry [1] after it causes some after discharge on the first-time follow-up as well as their
protein and lipid conformational changes at the edges of (3) association with disease prognosis.
cholesterol-rich lipid domains [3]. Following the institution’s protocols, a blood sample
Cholesterol is a precursor of steroid hormones and bile was drawn on the first 24 h and on the 7th day during
acids and is an essential constituent of cell membranes hospitalization according to medical criteria. We assessed
that facilitates signal transduction. Besides, membrane after overnight fasting total cholesterol (TC), high-density
cholesterol is a critical component to facilitate viral entry lipoprotein cholesterol (HDL-c), low-density lipoprotein
into host cells, and evidence suggests that inflammation cholesterol (LDL-c), triglycerides (TG), and inflammatory
can alter circulating levels of lipids [4e7]. Interestingly, markers as well as a complete blood count measurement.
COVID19 is associated with a great inflammatory burden Medical records were also used to identify baseline (per-
and inflammatory markers have been associated with an formed on the last eighteen months before the index
increased mortality rate [1,8]. Converseverly, studies in event) and follow-up lipid levels, excluding those per-
SARS-CoV patients showed long-term metabolic dysregu- formed in the hospital, to evaluate potential patterns
lations [9]. among COVID-19 patients.
This evidence led us to hypothesize that COVID-19 may
disrupt cholesterol homeostasis and mirror the lipid Clinical laboratory tests
changes observed in other inflammatory conditions.
Herein, we conducted a retrospective study involving We carried out all tests at our certified clinical laboratory
hospitalized SARS-CoV-2 infected patients to evaluate the (ISO 9001:2015). White blood cells, lymphocyte, and
relationship between COVID-19 and lipid profiles. For this monocyte counts were performed on Sysmex XN-1000
purpose, we also evaluated previous baseline and follow- analyzer using the manufacture’s reagents (Sysmex Cor-
up lipid profiles, as well as inflammatory profiles. poration, Japan). Alanine aminotransferase (ALT), aspartate
aminotransferase (AST), lactate dehydrogenase (LDH), LDL-
Methods c, HDL-c, TC, and TG were tested on Roche Cobas 8100
sampling system analyzer (Module Cobas c 702, Roche
Study design and population Diagnostics, Switzerland) using manufacture’s reagents.
The methodology for direct LDL-c, HDL-c, and TC methods
We conducted this retrospective single-center study at a are based on a standard homogeneous enzymatic colori-
Spanish tertiary hospital (Hospital Clínico Universitario de metric assay. We tested interleukin 6 (IL6) on IMMULITE
Valladolid, Spain, Valladolid). Between March 1st, 2020, 2000 immunoassay system using the manufacture’s
and May 15th, 2020, data from a total of 654 consecutive luminescent immunoassay reagents (IMMULITE 2000
patients with a definitive diagnosis of SARS-CoV-2 infec- IL6, Siemens Healthcare Diagnostic, Germany). Procalcito-
tion confirmed through positive reverse transcriptase- nin (PCT) measurement in plasma was performed by
polymerase chain reaction (RT-PCR). Exclusion criteria electrochemiluminescence immunoassay on a chemistry
were age <18 years old, pregnant women, and death in the analyzer (Cobas 6000, Roche Diagnostics) limit of detec-
first 24 h after admission. We retrospectively collected the tion, as below 0.02 ng/ml. We measured serum C-reactive
baseline clinical features, radiologic procedures, and lab- protein (CRP) by particle enhanced immunoturbidimetric
oratory tests. We also recorded ongoing treatment and (e501 Module Analyser, Roche Diagnostics). The limit of
clinical outcomes from the electronic medical records. detection was set below 0.3 mg/L.
Special attention was given to the accurate recording of
the prescribed therapy before admission and during hos- Statistical analysis
pital stay according to our institution’s protocols and the
discretion of the medical team. Follow-up continued We reported categorical variables as absolute values and
through until July 25th, 2020. percentages. Continuous variables were reported as me-
The local ethics committees approved the study pro- dian (interquartile range [IQR]). The normal distribution
tocol. Informed consent was waived, given the retrospec- of continuous variables was verified with the
tive and observational nature of the study. The work was KolmogoroveSmirnov test and qeq plot. Categorical
Dyslipidaemia in COVID-19 2621

variables were compared with the chi-square test and the respect to statins (7.4% vs. 7.4%; p Z 0.996) and cortico-
Fisher exact test when necessary. We compared contin- steroids (57.2% vs. 63.1%; p Z 0.202) in the two groups. The
uous variables with the ManneWhitney U test. A incidence of respiratory failure (92.5% vs. 43.3%; p < 0.001),
Spearman test was performed to analyze the correlation nosocomial infection (31.5% vs. 14.9%; p < 0.001) and ICU
between lipid variables with the rest of the serum admission (20.3% vs. 8.1%; p < 0.001) were more common
markers. We assessed the accuracy of analyzed variables to among non-survivors during hospitalization.
identify non-survivors patients by using the area under the
receiver operating characteristic curve analysis (AUROC). Lipid profile among COVID-19 patients
We determined the optimal operating point (OOP) in the
AUROC as the one that equaled sensitivity and specificity Lipid profiles were tracked from previous laboratory re-
regarding mortality, and we used it as the cut-off point in ports before SARS-CoV-2 infection (when available), at
the lipid profiles. We analyzed time to 30-day mortality by hospital admission, on the 7th day during hospitalization,
KaplaneMeier survival curves and compared using the and until first-time follow-up after discharge. In the
log-rank test. In a further step, we performed a multivar- overall population (including both groups), serological
iable Cox-regression analysis with a stepwise forward se- levels of all the analyzed lipid markers, except TG, dis-
lection to determine the predictors of 30-day mortality in played a significant decrease at the time of admission
the global study population. Proportional hazard as- concerning the previous baseline values. Besides, baseline
sumptions were verified by Shoenfeld residual test and serum TC and LDL-c levels were significantly higher in
check using the log(-log(survival)) plots. Sensitivity sub- survivors than non-survivors at any time; whereas, HDL-c
group analyses were performed to determine possible was comparable at admission but significantly lower in
differences in LDL-c levels as markers of poor prognosis by non-survivor before (47.2 vs. 52.6 mg/dL; p Z 0.004) and
age, sex, and plasma lipids. We performed the statistical in the 7th day (27 vs. 34 mg/dL; p Z 0.011) after hospital
analyses with the use of R software, version 3.6.1 (R Project admission.
for Statistical Computing) and IBM SPSS Statistics, Version The results of changes in the concentration of lipid and
25.0. Armonk, NY: IBM Corp. Differences were statistically inflammatory markers over time are summarized in Fig. 1
significant when the p-value was <0.05. and Table 2. Overall, non-survivors had a progressive
decline of TC, LDL-c, and HDL-c levels in comparison to
Results survivors, who presented with complete recovery to
previous baseline lipid levels and CRP (1.7 [1e3.2] mg/L)
Baseline and clinical characteristics after a median time to first-time follow-up of 73 days.

The main baseline and clinical characteristics at admission Correlation of lipid markers with other inflammatory
are listed in Table 1. A total of 654 patients were admitted markers
due to COVID-19 with an estimated 30-day fatality rate of
22.8%. Non-survivors were older (82 vs. 66 years old; A Spearman correlation analysis assessed the relationship of
p < 0.001) and had a greater prevalence of hypertension lipid parameters with all the gathered analytical parame-
(74.5% vs. 46.7%; p < 0.001), diabetes mellitus (31.5% vs 17%; ters. Interestingly, LDL-c and TC levels at admission were
p < 0.001), dyslipidemia (52.3% vs. 34.3%; p < 0.001) as well inversely correlated with the levels of CRP (r Z 0.217 and
as other comorbidities such as chronic kidney disease (19.5% 0.209, respectively; p < 0.001), PCT (r Z 0.313 and
vs. 5.7%; p < 0.001) or ischemic heart disease (14.8% vs. 0.229; p < 0.001) and IL6 (r Z 0.334 and 0.301;
8.1%; p Z 0.016). In accordance, non-survivors were more p < 0.001) with a positive correlation with lymphocytes
commonly treated prior to admission with antihypertensive (r Z 0.179 and 0.191; p Z 0.001), which was maintained
drugs, oral antidiabetics, antiplatelets, and statins. throughout hospitalization and until recovery (see Table S1
Time interval from symptom onset to admission (4 vs. 7 in the Supplementary appendix). LDL-c did show a very
days; p < 0.001) and baseline oxygen saturation levels at strong positive correlation with TC (r Z 0.937; p < 0.001) as
admission (91% vs 95%; p < 0.001) were smaller among opposed to HDL-c (r Z 0.201; p < 0.001). We also observed
non-survivors. They also displayed greater levels parame- a significant mild correlation of TC (R Z 0.287; p < 0.001)
ters of organ damage and inflammation such as creatinine and LDL-c (R Z 0.273; p < 0.001) with age at the time of
(1.16 vs. 0.81 mg/dL; p < 0.001), D-dimer (1394 vs. 664 ng/ admission.
mL; p < 0.001), CRP (128.4 vs. 54.5 mg/L; p < 0.001),
procalcitonin (0.33 vs. 0.08 ng/mL; p < 0.001), LDH (357 AUROC curve analysis and threshold values
vs. 265 U/L; p < 0.001) and IL6 (52.1 vs. 18.4 pg/mL;
p < 0.001) levels. In contrast, non-survivors had lower We analyzed the diagnostic performance accuracy of lipid
blood count of haemoglobin (12.4 vs. 13.3 g/dL; p < 0.001) profiles to predict 30-day mortality using the area under
lymphocytes (805 vs. 1130 cells/mm3; p < 0.001) and the receiver operating characteristic curve analysis
platelets (183 vs. 218 cells/mm3 x103; p < 0.001). (AUROC). The best estimated threshold values for LDL-c
Specific COVID-19 treatment was more commonly pre- and TC were those calculated by the optimal operating
scribed in survivors with comparable prescription rate in point (OOP) in the AUROC as the one that equaled
2622 Á. Aparisi et al.

Table 1 Baseline Characteristics and main features during admission in hospitalized patients due to Coronavirus Disease 2019 according to
mortality.

Variable All population Survivors Non-survivors p-value

N Z 654 N Z 505 (77.2) N Z 149 (22.8)
Demographics
Female sex 278 (42.5) 223 (44.6) 55 (36.9) 0.116
Age (years) 70 [58e81] 66 [55e76] 82 [72e87] <0.001
Cancer 117 (17.9) 81 (16) 36 (24.2) 0.023
CKDa 58 (8.9) 29 (5.7) 29 (19.5) <0.001
Diabetes 133 (20.3) 86 (17) 47 (31.5) <0.001
Dyslipidemia 251 (38.4) 173 (34.3) 78 (52.3) <0.001
Hypertension 347 (53.1) 236 (46.7) 111 (74.5) <0.001
Hypothyroidism 81 (12.4) 51 (10.1) 22 (13.4) 0.252
IHD 63 (9.6) 41 (8.1) 22 (14.8) 0.016
Obesity 62 (9.5) 47 (9.3) 15 (10.1) 0.781
Prior pulmonary disease 143 (21.9) 106 (21) 37 (24.8) 0.319
Prior rheumatic disease 48 (7.3) 34 (6.7%) 14 (9.4) 0.273
Prior stroke/TIA 41 (6.3) 29 (5.9%) 12 (8.1) 0.306
Treatment prior to admission
Antiplatelets 106 (16.2) 70 (13.9) 36 (24.3) 0.002
ACEI/ARB 266 (40.7) 182 (36) 84 (56.8) <0.001
Levothyroxine 71 (10.9) 52 (10.3) 19 (12.8) 0.383
Oral anticoagulation 79 (12.1) 40 (8.3) 37 (25) <0.001
Oral antidiabetics 106 (16.2) 73 (14.5) 33 (22.3) 0.023
Statins 210 (32.2) 151 (29.9) 59 (39.9) 0.022
Main findings at admission
Time from onset (days) 7 [3e10] 7 [4e10] 4 [2e7] <0.001
Pathological Chest X-ray 597 (91.8) 462 (91.8) 135 (91.8) 0.996
Positive RT-PCRb 638 (97.6) 489 (96.8) 149 (100) 0.030
Basal O2 saturation 94 [91e96] 95 [92e97] 91 [86e94] <0.001
Sat:FiO2 447 [433e457] 452 [438e462] 433 [409e448] <0.001
Laboratory findings at admission
Haemoglobin (g/dL) 13.1 [12e14.4] 13.3 [12.2e14.5] 12.4 [11e14] <0.001
CK (mmol/L) 80 [49e134] 78 [49e123] 101 [53e221] 0.016
C-Reactive protein (mg/L) 67.7 [26.75e134.05] 54.5 [21e105.6] 128.4 [72.2e191.5] <0.001
Creatinine (mg/dL) 0.87 [0.7e1.15] 0.81 [0.7e1.02] 1.16 [0.88e1.63] <0.001
D-Dimer (ng/mL) 756 [449e1386] 664 [414e1134] 1394 [747e2576] <0.001
Ferritin (ng/mL) 609 [294e1134] 605 [290e1100] 640 [302e1298] 0.205
ALT (U/L) 24 [17e43] 25 [17e44] 22 [15e37] 0.004
AST (U/L) 36 [24e52] 34 [24e49] 41 [25e60] 0.022
Interleukin-6 (pg/mL) 20.9 [10e47] 18.4 [9.3e40.5] 52.1 [22.5e115] <0.001
LDH (U/L) 283 [215e359] 265 [206e331] 357 [303e460] <0.001
Lymphocytes (cells/mm3) 1050 [720e1470] 1130 [820e1570] 805 [580e1215] <0.001
Neutrophils (cells/mm3) 4600 [3020e6830] 4260 [2840e5920] 6125 [4035e9805] <0.001
Platelets (cells/mm3x103) 213 [163e274] 218 [169e284] 183 [137e260] <0.001
Procalcitonin (ng/ml) 0.11 [0.06e0.29] 0.08 [0.05e0.16] 0.33 [0.13e0.82] <0.001
Troponin (pg/mL) 15.04 [7.91e22.28] 9.3 [7e17.2] 33.6 [16e148.1] <0.001
Specific COVID-19 treatment
Azithromycin 588 (94.2) 470 (95.3) 118 (90.1) 0.022
Betaferon 244 (39.1) 182 (36.9) 62 (47.3) 0.03
Hydroxychloroquine 605 (97) 483 (98) 122 (93.1) 0.008
Lopinavir/Ritonavir 590 (94.4) 473 (95.7) 117 (89.3) 0.004
Non-specific COVID-19 treatment
Antibiotics 551 (84.4) 424 (84.1) 127 (85.2) 0.743
Anticoagulationc 545 (83.8) 434 (86.3) 111 (75.5) 0.002
Corticosteroids/Glucocorticoids 383 (58.6) 289 (57.2) 94 (63.1) 0.202
Statins 48 (7.4) 37 (7.4) 11 (7.4) 0.996
Main in-hospital outcomes
LOS (days) 9 [5e15] 10 [6e16] 7 [4e14] <0.001
ICU admission 71 (10.9) 41 (8.1) 30 (20.3) <0.001
Mechanical ventilation 77 (9.7) 33 (6.6) 34 (22.1) <0.001
Nosocomial infection 122 (18.7) 75 (14.9) 47 (31.5) <0.001
Respiratory failured 354 (54.5) 218 (43.3) 136 (92.5) <0.001
Abbreviations: ACEi: Angiotensin-converting enzyme inhibitors; ALT: alanine aminotransferase; ARB: angiotensin receptor blocker; AST:
aspartate aminotransferase CKD: Chronic kidney disease; ICU: Intensive care unit; IHD: Ischemic heart disease; LDH: Lactate dehydrogenase;
LOS: Length of stay; RT-PCR: Reverse transcription-polymerase chain reaction.
Values are reported as median (IQR) or n (%). Significant values (p < 0.05) are bold.
a
Chronic kidney disease was defined as a glomerular filtration rate of <60 ml/min or need for dialysis.
b
At hospital admission.
c
Includes prophylactic, intermediate and complete anticoagulation doses.
d
Defined as pO2 < 60 mmHg, SO2 <92% or need for non-invasive or mechanical ventilation.
Dyslipidaemia in COVID-19 2623

Figure 1 Temporal changes in lipid profile levels in COVID-19 patients according to the clinical course of the disease: A) Total cholesterol; B) LDL-c;
C) HDL-c. The horizontal lines represent the median value in each group. HDL-c: High-density lipoprotein cholesterol; LDL-c: Low-density lipo-
protein cholesterol; TC: Total cholesterol.

sensitivity and specificity regarding mortality. These cut CI, 1.41e4.23; p Z 0.001) at admission were independent
offs were 69 mg/dl on admission and 75 mg/dl in the 7th variables associated with a greater risk of 30-day mortal-
day of hospitalization for LDL-c. For TC estimated cut-off ity. However, statins were not independently associated
were 132 mg/dL and 147 mg/dL (see Fig. S1). Threshold with mortality. A sensitivity subgroup analysis was per-
values for LDL-c and TC were also calculated from the formed to identify potential differences at the time of
quartiles, but had a worse balance between sensitivity and admission for LDL-c (See Fig. S2). Overall, when we
specificity, so they were not selected for multivariate repeated the multivariate analysis including analytics
analysis. values on 7th day of admission, the results remained
consistent. In fact, age, presence of lymphopenia, CRP
Association between mortality and lipid profile levels> 33 mg/dL and LDL-c levels <75 mg/dL determined
on the 7th day of admission, were the only variables
Independent predictors of mortality were estimated associated with 30-day mortality (See Table 3).
through a Cox uni- and multivariate regression analysis. The unadjusted survival KaplaneMeier curves for 30-
The variables included in the multivariate model were day global mortality were performed and shown in Fig. 2.
those with a p-value <0.05 on the univariate analysis (age, Those patients with LDL-c levels <69 mg/dl at the time of
hypertension, diabetes, dyslipidemia, ischemic heart dis- admission and <75 mg/dl on the 7th day showed a 20%
ease, chronic renal disease, angiotensin receptor antago- higher 30-day mortality rate than the rest of the patients.
nist, angiotensin-converting enzyme inhibitors, statins, On the other hand, it was observed that the lower the LDL-
lymphopenia, CRP, antiviral treatment, anticoagulation, c levels, the higher the mortality on day 30, represented by
total cholesterol, and LDL-c). KaplaneMeier curves (Suppl. Figure 3).
Multivariate adjusted models showed that age ([hazard
ratio [HR] 1.08; 95% confidence interval [CI], 1.05e1.11]; Discussion
p < 0.001), lymphopenia <1000 cells/ml (HR 2.68; 95% CI,
1.91e3.78; p < 0.001), LDL-c <69 mg/dL (HR 1.94; 95% CI, Lipoproteins play a vital role in innate immunity and
1.14e3.31; p Z 0.014) and CRP >88 mg/dL (HR 2.44; 95% perform different functions against infection: receptor
2624 Á. Aparisi et al.

Table 2 Lipid and inflammatory profile of patients with Coronavirus Disease 2019 in the global study population and according to mortality
during the full course of the disease.

Variable All population Survivors Non-survivors p-value

N Z 654 N Z 505 (77.2) N Z 149 (22.8)
Lipid laboratory profile before admission
Total cholesterol (mg/dL) 187.5 [155e214] 191 [164.5e215] 167.5 [133e200] <0.001
HDL-c (mg/dL) 51.6 [41.7e62.1] 52.6 [43e64] 47.2 [37.5e60] 0.004
LDL-c (mg/dL) 108.4 [84.6e129.6] 113.2 [91.3e134.3] 93 [66.4e112.6] <0.001
Triglycerides (mg/dL) 109.5 [82.0e146.0] 108 [79e146] 116.5 [91e145] 0.122
TC/HDL-c 3.5 [2.9e4.3] 3.5 [3e4.3] 3.5 [2.8e4] 0.328
Lipid laboratory profile at admission
Total cholesterol (mg/dL) 137 [117e163] 142 [120e165] 121 [101.5e146.5] <0.001
HDL-c (mg/dL) 34 [28e43] 34 [28.3e43] 33.5 [27e44] 0.278
LDL-c (mg/dL) 77 [59e97] 80 [63e98] 61.1 [41e84.2] <0.001
Triglycerides (mg/dL) 118 [91e163] 119 [92e163] 114 [86.5e157] 0.240
TC/HDL-c 3.9 [3.11e4.84] 3.9 [3.2e4.9] 3.39 [2.9e4.6] 0.012
Lipid laboratory profile during 7th day of hospitalization
Total cholesterol (mg/dL) 157 [126e192] 163 [130.5e197] 134 [106.5e158] <0.001
HDL-c (mg/dL) 33 [26.5e41.6] 34 [28e41.8] 27 [19.1e37] 0.011
LDL-c (mg/dL) 79.7 [55e107.5] 85.7 [62e115.5] 56.4 [39.3e75.1] 0.001
Triglycerides (mg/dL) 184 [130e257] 189 [132e261.5] 161.5 [124e226] 0.057
TC/HDL-c 4.54 [3.73e5.95] 4.5 [3.7e5.9] 4.4 [3.6e6.1] 0.965
Lipid laboratory profile during follow-upa
Total cholesterol (mg/dL) 196 [168e223.5] 196 [168e223.5] NA NA
HDL-c (mg/dL) 52.8 [44.1e64] 52.8 [44.1e64] NA NA
LDL-c (mg/dL) 117.3 [99.3e144.7] 117.3 [99.3e144.7] NA NA
Triglycerides (mg/dL) 111 [83e156] 111 [83e156] NA NA
TC/HDL-c 3.7 [3.2e4.3] 3.7 [3.2e4.3] NA NA
Abbreviations: HDL-c: High-density lipoprotein cholesterol: LDL-c: Low-density lipoprotein cholesterol; NA: Not applicable; TC: Total choles-
terol: TG Triglycerides.
Values are reported as median (IQR) or n (%). Significant values (p < 0.05) are bold.
a
Only in survivors.

blocking, lysis, chemotaxis, and neutralization of bacterial also SARS-CoV-2-mediated dyslipidemia. We observed a
endotoxins. Lipids are essential for the replication and paradoxical lipid metabolism with a U-shaped curve of
pathogenicity of enveloped viruses [10,11]. The main lipid levels among survivors with similar findings previ-
findings of this research are: (1) The observed dyslipide- ously described in inflammatory diseases [14]. There are a
mia and mortality in COVID-19 patients was mainly driven number of possible explanations from an immunological
by a stronger inflammatory response; (2) inflammatory point of view.
markers inversely correlated with lipid levels, with com- HDL-c might become pro-inflammatory under specific
plete resolution among survivors during short-term conditions that increase reactive oxygen species and
follow-up after the resolution of inflammation; and (3)
low LDL-c levels might be a potential prognostic marker in
COVID-19 and septic patients.
Table 3 Multivariate Cox regression analysis for evaluating the risk
The mechanism underlying the observed altered
of 30-day mortality in the COVID-19 study population.
cholesterol homeostasis is likely multifactorial and com-
plex. Serum ALT, AST, and LDH levels were moderately Variable Multivariate
increased in non-surviving patients, indicating mild liver- HR (95% CI) p value
function impairment, which could be a contributing fac- At admission
tor by disrupting uptake and biosynthesis of lipoproteins Age 1.08 (1.05e1.11) <0.001
[12]. Nonetheless, a specific type of viral infections can CRP > 88 mg/dL 2.44 (1.41e4.23) 0.001
lead to alteration of lipid metabolism in the acute and LDL-c < 69 mg/dL 1.94 (1.14e3.31) 0.014
Lymphocytes < 1000 cells/mm3 2.68 (1.91e3.78) <0.001
chronic phases as a response to an ongoing inflammatory
7th day
state [6,7]. Age 1.06 (1.03e1.1) <0.001
Although COVID-19 pathophysiology is not fully un- CRP > 33 mg/dL 3.91 (1.9e8.06) <0.001
derstood, COVID-19 severity and death are associated with LDL-c < 75 mg/dL 2.12 (1.06e4.23) 0.033
a hyperinflammatory state due to a dysregulated immune Lymphocytes < 1000 cells/mm3 3.97 (1.87e8.4) <0.001
system [8,13]. The clinical profile of the patients included CI: Confidence interval; CRP: C-Reactive protein; LDL-c: Low-den-
in this study shows a similar trend, with systemic sity lipoprotein cholesterol; HR: Hazard ratio.
Significant values (p < 0.05) are bold.
inflammation being a major contributor to mortality, but
Dyslipidaemia in COVID-19 2625

Figure 2 KaplaneMeier estimates of mortality in the total COVID-19 population according to LDL-c A) at admission and B) at the 7th day of
hospitalization based on their optimal cut-off point. ) Time scale takes place between day 0 (day of admission) to 30 )) Day 0 represents the
seventh day of admission.

myeloperoxidase activity. It can also modify their levels recent work by Walley et al. proposed that low LDL-c levels
and Apoprotein-AI concentration; hence, altered reverse are merely an indicator of the disease severity in septic
cholesterol transport [4,15]. LDL-c can be oxidized when its patients, without a contributing role to mortality [29].
HDL-c counterpart loses its antioxidative properties, or if The observed associated mortality in this cohort of
oxidized phospholipids accumulate. They are identified as COVID-19 patients may be explained by other mechanism.
damaged-associated molecular patterns (DAMPs) by In this sense, LDL-c transports a large percentage of plasma
scavenger receptors, activate the inflammasome [4] and Coenzyme Q10 (CoQ10), which has a significant antioxi-
the immune system [13]. Low LDL-c levels may also be the dant capacity, avoiding peroxidative damage to the cellular
consequence of an increased vascular leakage in the lung membranes [30,31]. Low LDL-c levels can cause a decrease
parenchyma as a result of endothelial damage [12,13]. in plasma CoQ10 levels, which can lead to endothelial
Finally, an increased concentration of pro-inflammatory dysfunction, organ damage and death, as observed in
cytokines may be responsible for a drastic decrease in COVID-19 patients [32]. Furthermore, the incidence of se-
plasma LDL-c levels during the acute-phase response. vere COVID-19 among elderly has been the greatest. Aging
Direct effects of cytokines might explain the altered lipid is associated with increased circulating levels of ox-LDL;
concentrations [14] by up-regulating ox-LDL uptake or thus, it could trigger a vicious cycle due to higher basal
overriding suppression of LDL-c receptor through the levels [33]. All these mechanisms justify that patients with
expression of scavenger receptors. These changes observed low LDL-c levels have a reduced defensive, energetic and
with inflammation can increase the odds of cardiovascular metabolic reaction capacities to be able to properly
disease through the formation of foam cells and endo- manage a situation of aggression and organ stress such as
thelial damage [15,16]. COVID-19.
Sepsis is defined as the presence of infection with a Overall, low LDL-c levels may reflect a pro-inflammatory
detrimental host response with organ damage [17]. Low phenotype of severe SARS-CoV-2 infection, but they may
HDL-c levels have been associated before with an also induce multiple systemic reactions through a complex
increased risk of sepsis [18,19] and adverse outcomes interplay. Therefore, in the appropriate scenario, we might
[20e23]. In fact, Maile et al. [24] or Guirgis et al. [25] also hypothetically consider low LDL-c levels as a plausible
suggested that low baseline LDL-c levels are associated candidate as a routine risk marker during admission and
with an increased risk of mortality and sepsis, respectively. disease progression. Nevertheless, we did not explore role of
By analogy, similar findings should be identified in SARS- statins given the lack of association with mortality despite
CoV-2 patients. their pleiotropic properties [34]. Additionally, we cannot
In particular, low HDL-c levels in SARS-CoV-2 patients rule out a catabolic state or high immune cell turnover as a
have been associated with disease severity [26,27], but our cause of low LDL-c levels in COVID-19 patients. The presence
results are in agreement with those recently published in in our study of a statistically significant positive correlation
which low LDL-c levels were associated with COVID-19 between LDL-c levels and blood lymphocyte count, the
severity [12,28]. However, we also observed an association latter being an independent variable associated with 30-day
with an increased risk of mortality with low LDL-c levels mortality together with LDL-c in multivariate regression
after the adjusted multivariate analyses. In contrast, a analysis, can support this theory.
2626 Á. Aparisi et al.

Our work presents certain limitations. These observa- [6] Funderburg NT, Mehta NN. Lipid abnormalities and inflammation in
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This work was partially funded by Gerencia Regional de [17] Singer M, Deutschman CS, Seymour CW, Shankar-Hari M,
Annane D, Bauer M, et al. The third international consensus defi-
Salud de Castilla y León under grant number GRS COVID nitions for sepsis and septic shock (Sepsis-3). Jama 2016;315(8):
111/A/20 and GRS COVID 108/A/20. 801e10.
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Ethics of protocol fectious disease: two prospective population-based cohort studies.
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According to the Declaration of Helsinki, the local ethics [19] Feng Q, Wei W-Q, Chaugai S, Leon BGC, Mosley JD, Leon DAC, et al.
Association between low-density lipoprotein cholesterol levels
committee approved this study. and risk for sepsis among patients admitted to the hospital with
infection. Jama Netw Open 2019;2(1):e187223.
Declaration of competing interest [20] Kaysen GA, Ye X, Raimann JG, Wang Y, Topping A, Usvyat LA, et al.
Lipid levels are inversely associated with infectious and all-cause
mortality: international MONDO study results. J Lipid Res 2018;
None. 59(8):1519e28.
[21] Tanaka S, Couret D, Tran-Dinh A, Duranteau J, Montravers P,
Schwendeman A, et al. High-density lipoproteins during
Appendix A. Supplementary data sepsis: from bench to bedside. Crit Care 2020;24(1):134.
[22] Tanaka S, Diallo D, Delbosc S, Genève C, Zappella N, Yong-Sang J,
Supplementary data to this article can be found online at et al. High-density lipoprotein (HDL) particle size and concentra-
tion changes in septic shock patients. Ann Intensive Care 2019;
https://doi.org/10.1016/j.numecd.2021.06.016.
9(1):68.
[23] Cirstea M, Walley KR, Russell JA, Brunham LR, Genga KR, Boyd JH.
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