key: cord-0706542-8oy95q0x
authors: Fan, Junli; Wang, Hui; Ye, Guangming; Cao, Xiaoling; Xu, Xianqun; Tan, Wenbin; Zhang, Yongxi
title: Low-density lipoprotein is a potential predictor of poor prognosis in patients with coronavirus disease 2019
date: 2020-04-19
journal: Metabolism
DOI: 10.1016/j.metabol.2020.154243
sha: 9f27ec4714710fa2e9add31ee5668ebb98fa1e46
doc_id: 706542
cord_uid: 8oy95q0x

Abstract Background The pandemic of coronavirus disease 2019 (COVID-19) has become a global threat to public health. The lipid pathophysiology in COVID-19 is unknown. Methods In this retrospective longitudinal study, we monitored the serum lipids in 17 surviving and 4 non-surviving COVID-19 cases prior to their viral infections and duration the entire disease courses. Results In surviving cases, the low-density lipoprotein (LDL) levels decreased significantly on admission as compared with the levels before infection; the LDL levels remained constantly low during the disease progression and resumed to the original levels when patients recovered (pre-infection: 3.5 (3.0–4.4); on admission: 2.8 (2.3–3.1), p < .01; progression: 2.5 (2.3–3.0); discharge: 3.6 (2.7–4.1); median (IQR), in mmol/L). In non-surviving patients, LDL levels showed an irreversible and continuous decrease until death (1.1 (0.9–1.2), p = .02 versus the levels on admission). The ratio changes of LDL levels inversely correlated with ratio changes of high-sensitivity C-reactive protein levels. Logistic regression analysis showed increasing odds of lowered LDL levels associated with disease progression (odds ratio: 4.48, 95% IC: 1.55–12.92, p = .006) and in-hospital death (odds ratio: 21.72, 95% IC: 1.40–337.54, p = .028). Conclusions LDL levels inversely correlated to disease severities, which could be a predictor for disease progress and poor prognosis.

The pandemic of coronavirus disease 2019 , caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global threat to public health [1] .

SARS-COV-2 is a single-strand RNA virus with 96.3% sequence identity the bat coronavirus RaTG13 [2] [3] [4] . The spike protein of SARS-COV-2 is responsible for entry of the host cells via binding to surface angiotensin converting enzyme 2 [2, 5] . The estimated mortality rate for COVID-19 is about 2.3%, with a range of 6 to 41 days from the onset of symptoms to death [6, 7] . The prominent pathological changes in lungs include edema, proteinaceous exudate, and multinucleated pneumocytes [8, 9] . We here first report the lipid pathophysiology in COVID-19.

We performed a retrospective longitudinal analysis of COVID-19 patients (n=21) who were admitted between January 18 and February 8, 2020, into the department of infectious diseases at Zhongnan Hospital of Wuhan University in Wuhan, China. The study was approved by the Institutional Review Board at the hospital (No. 2020011). The patients who had a routine laboratory test including lipids in our hospital between January 9 and 17, 2020 prior to their SARS-CoV2 infection and tested positive for SARS-CoV-2 during the COVID-19 epidemic were included in this study. All patients were admitted to our hospital between January 18 and February 8, 2020, and were either discharged or died by March 15, 2020. Healthy subjects (n=31) and patients with chronic obstructive pulmonary disease (COPD, n=21) who had lipid tests in our hospital between September, 2019 to October, 2019 were included as normal and non-COVID-19 controls. Electronic medical records including demographic, clinical treatment, and laboratory data, were extracted. Detailed methods were described in the supplementary J o u r n a l P r e -p r o o f 5 materials. Data were presented as median (interquartile range, IQR) and a Mann-Whitney U test was used to compare differences between groups.

The average age of the patients was 62.5±12.6 years; 52% were male and 48% were female.

62% had morbidities such as diabetes, hypertension, cardiovascular disorders, hyperlipidemia, or kidney diseases. The onset symptoms of the patients were: fever (86%), cough (95%), fatigue (71%), shortness of breath (43%) and diarrhea (10%) ( Table 1a ). The severities of the admitted patients were 62% of mild, 19% of severe, and 19% of critical, a classification according to Chinese Center for Disease Control (CDC) guidelines [1] . Patients received standard treatments based on the guidelines of Chinese CDC, including antiviral remedies (arbidol, lopinavir and ribonavir, interferon α inhalation), anti-inflammatory treatments (corticosteroid), and immune-modulator (thymalfasin, immunoglobulin) (Table 1a) . Severe and critical cases were given high-flow oxygen, non-invasive or invasive ventilation, depending on their morbidities. Seventeen patients recovered and were discharged, while four patients did not survive.

In the stage of disease progression, there were significantly higher levels of C-reactive protein (CRP) (78 (28-134) versus 15 , in mg/L, p=0.042) and interleukin-6 (IL-6) (195 (127-280) versus 12 (4-18), in pg/ml, p<0.001), but lower levels of CD8 + subpopulation T cells (Table 1b) . Furthermore, in surviving patients, increases in levels of high-sensitivity CRP (hsCRP) were significantly associated with the disease severity (preinfection: 1.2 (0.7-5.9); on admission: 11 (5.9-26), p<0.02; progression: 9.8 (5.3-45); discharge: Table S1 ). Table S1 ). In patients did not survive, there was a continuous increase in hsCRP level or lymphopenia until death (Supplementary Table S1 ).

We next analyzed the serum lipid levels (in mmol/L) of the patients before they were infected by SARS-CoV-2 and during their entire courses of the disease. The average timeline of disease course was shown in Figure 1 Table S1 ).

The LDL, HDL and TC levels in the patients that did not survive (n=4) decreased continuously until death (Fig. 1, Supplementary Table S1 ). Particularly, LDL levels showed an irreversible 40-337.54, p=0.028) . The ratio changes of LDL, HDL and TC inversely correlated with the ratio changes of hsCRP during the disease course (Fig.1 ).

In this study, we report the dyslipidemia in COVID-19 patients and demonstrate that the degrees of decreased LDL levels have high odds associated with severity and mortality of the disease. Table 1 ), whether lipid biogenesis has been impaired is yet to be determined. Second, viral infection induced pro-inflammatory cytokines modulate lipid metabolism including oxidation of LDL by reactive oxygen species singling to facilitate LDL clearance [11] [12] [13] . A measurement of oxidized LDL in patient's serum will aid in determining this mechanism. Third, COVID-19 patients may have an increased vascular permeability caused by viral-induced inflammation. Exudates have been found evidently in the early phase of COVID-19 lung pathology [8] . Exudative fluids, containing high levels of protein and cholesterol, are caused by inflammation-related vascular permeability [14, 15] , which may be one possible mechanism underlying our data. The major limitations of this study include a small size of patients and lack of information of specific lipoproteins and oxidized LDLs. Another limitation is Journal Pre-proof J o u r n a l P r e -p r o o f 8 lack of a data set with lipids monitoring on a hospitalized non-COVID-19 disease group to further address the specificity between LDL levels and COVID-19 severity. We also posit that the dyslipidemia plays an important role in pathological development of COVID-19, which mechanism needs an urgent investigation. In conclusion, our results demonstrate that LDL decrease is associated with pathological course of COVID-19, which can serve a factor to access the disease progression and mortality. 

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Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding

The species severe acute respiratory syndrome-related coronavirus: Classifying 2019-ncov and naming it sars-cov-2

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Receptor recognition by novel coronavirus from wuhan: An analysis based on decade-long structural studies of sars

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Pulmonary pathology of early phase 2019 novel coronavirus (covid-19) pneumonia in two patients with lung cancer

Pathological findings of covid-19 associated with acute respiratory distress syndrome

Clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: A retrospective cohort study

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Leptin in congenital and hiv-associated lipodystrophy

Altered relationship of plasma triglycerides to hdl cholesterol in patients with hiv/haart-associated dyslipidemia: Further evidence for a unique form of metabolic syndrome in hiv patients

Pleural effusions: The diagnostic separation of transudates and exudates

Multilevel likelihood ratios for identifying exudative pleural effusions(*)

CD4 + (cells/µl)

CD8 + (cells/µl)

CD16+/CD56+(cells/µl) 210 to 1