key: cord-0948253-vww8ypyz
authors: Wei, Xiuqi; Zeng, Wenjuan; Su, Jingyu; Wan, Huimin; Yu, Xinqin; Cao, Xiaoling; Tan, Wenbin; Wang, Hui
title: Hypolipidemia is associated with the severity of COVID-19
date: 2020-04-30
journal: J Clin Lipidol
DOI: 10.1016/j.jacl.2020.04.008
sha: d54ff8c4779d97fbf75cc7b535f840953ac37002
doc_id: 948253
cord_uid: vww8ypyz

Abstract Background Many patients with coronavirus disease 2019 (COVID-19) suffer multiple organ dysfunctions. However, whether patients develop dyslipidemia is unknown. Objective In this study, we aimed to investigate the pathological alterations of low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and total cholesterol (TC) in COVID-19 patients and their relationships with the disease severity. Methods A retrospective study was performed to examine serum levels of LDL-c, HDL-c, and TC on 597 COVID-19 patients (mild: 394; severe, 171; critical: 32) who were hospitalized in our center between February 1 and March 3, 2020. Age and gender-matched normal subjects (n=50) who had routine laboratory lipid tests between October 1 and November 1, 2019 in our center were included as the control group. Results LDL-c and TC levels were significantly lower in COVID-19 patients as compared with normal subjects (p<0.001). There were significant and gradual decreases in levels of LDL-c (median (IQR) in mg/dL, mild: 91 (76, 104); severe 86 (69, 102); critical: 69 (48, 81); p<0.02) and TC (mild: 173 (148, 203); severe 167 (138, 197); critical: 125 (95, 162); p<0.05) across all three groups. HDL-c levels only decreased significantly in critical cases as compared to levels in mild and severe cases. LDL-c and TC levels inversely correlated with C-reactive protein and IL-6, and positively correlated with the number of lymphocytes in patients. Conclusions Development of hypolipidemia starts in patients with mild symptoms. It progressively becomes worse in an association with the disease severity.

The pandemic of coronavirus disease 2019 (COVID-19) has become a big threat to global 57 public health system. 1 The disease is believed to be of zoonotic origin. 2,3 Snakes, pangolins, 58 and turtles are speculated to be intermediate host (s) . 4 Since the middle of December 2019, 59 person-to-person transmission of COVID-19 has been evident, becoming a strong propagating 60 force driving the spread of virus. 5 The estimated basic reproduction rate (R0) ranges from 2.24 61 to 3.58. 6 Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) is the causative 62 organism for COVID-19. 7 The SARS-COV2 Spike (S) protein, composed of subunits S1 and S2, 63 is considered for the virus entering host cells via surface angiotensin converting enzyme 2 64 (ACE2). 8, 9 The S2 subunits of SARS-COV-2 and SARS-COV are highly conserved with 99% 65 identity; the S1 subunit of SARS-COV-2 has an approximate 70% identity with SARS-COV, but 66 conserves a receptor-binding domain similar to that of SARS-COV, which may result in a high 67 affinity to ACE2. 10,11 COVID-19 patients can be asymptomatic or symptomatic. The incubation 68 period for symptomatic development in COVID-19 is approximately 4-7 days. 5 Many patients 69 with coronavirus disease 2019 (COVID-19) suffer multiple organ dysfunctions, suggesting a 70 systemic targeting by the SARS-COV-2. The mortality rate of COVID-19 is estimated to be 71 about 2.3%, with a range from 6 to 41 days from the onset of symptoms to death. 10,11 72

The dyslipidemia associated with SARS has been reported, although rarely. There was a 73

report showing a lower level of total cholesterol (TC) in SARS patients as compared to healthy 74 subjects. 12 Altered lipid metabolism was reported in recovered SARS patients 12 years after 75 infection. 13 These reports indicate that patients with coronavirus-related diseases may develop 76 dyslipidemia but have been underrated. We posit that dyslipidemia may occur in COVID-19 77 patients. In this study, we performed a retrospective investigation of lipid profiles on patients 78

with COVID-19. We found that COVID-19 patients showed hypolipidemia which positively 79 correlated with the severity of disease. 80

This retrospective study was carried out at the Cancer Center, Union Hospital of Tongji Medical 83

College, Wuhan, and was approved by the Institutional Review Board (IRB) at the Union 84

Hospital. The requirement for informed consent was waved by the IRB committee. A total of 597 85 COVID-19 patients admitted to the hospital between February 1 and March 3, 2020, were 86 included in this study. Electronic data regarding epidemiological, demographic, clinical 87 symptoms and diagnosis, laboratory tests, and treatments were extracted. All patients were 88 Table 1 . Patients were classified into three severity categories by two independent physicians 94 based on their symptoms on admission, e.g. mild (n=394), severe (n=171), and critical (n=32) 95 cases. Any disagreements were subjected to adjudications from a third independent physician. 96

Age and gender-matched normal healthy subjects (n=50, age: 62 (53, 69)) who had routine 97 laboratory lipid tests between October 1 and November 1, 2019 in our center were included in 98 this study as the control group. De-identified electronic data including only age, gender and 99 values of lipid profiles were extracted. One additional dataset from normal subjects (n=1574, were from the blood samples drawn fasting on admission. 119

Statistical analyses were performed with the SPSS software (IBM, Armonk, NY, USA). Data 121 were presented as median (interquartile range, IQR), or "median ± 95% confidence interval (CI)". 122

Kruskal-Wallis test was used to compare variables among multiple groups and a Mann-Whitney 123 U test was used to compare differences between two groups. A Pearson correlation analysis 124 was used to calculate the correlation coefficiency. p<0.05 was considered as statistical 125 significance. 126 127 Results 128

A total of 597 COVID-19 cases were included in this study: 394 mild, 171 severe, and 32 critical 130 cases. The age for all patients was 66 (59, 72) (median (IQR)) years. The ages for the critical 131 and severe cases were 69 (61, 83) and 69 (64, 77), respectively; the patients in these groups 132 were significantly older than those with mild cases (64 (53, 69)) (p<0.05) ( Clinical laboratory results showed that lymphocytes and CD8 + T cell subpopulation decreased 142 significantly in patients across all three categories ( Table 2) . Levels of WBC and CRP increased 143 gradually and significantly during the disease progression (Table 2) . IL-6 levels increased 144 dramatically in all subgroups of patients with a peak in severe cases (Table 2) . Changes in 145 number of monocytes and levels of ALT, AST, ALP and GGT were not in evidence (Table 2) . TC (p<0.05) in patients across all three categories (Fig 2, Table 2 ). HDL-c levels decreased 152 significantly in critical cases as compared to levels in mild and severe cases (p<0.05) (Fig 2,  153 Table 2). TG levels in COVID-19 patients were significantly higher than the levels in normal 154 subjects (p<0.01), but significantly decreased in critical cases as compared with mild and 155 severe cases (p<0.01, Table 2 ). The age and gender-matched normal control group (n=50; age: 156 62 (53, 69)) showed almost the same median values of LDL-c, HDL-c and TC, but slightly 157 narrow IQRs, as compared with that from adult healthy population (n=1574, age: 40 (32, 52)) 158 (Fig 2) . 159

CRP levels inversely correlated with the levels of LDL-c (R= -0.290, p<0.001, Fig 3A) , TC (R= -161 0.332, p<0.001, Fig 3B) , and HDL-c (R= -0.351, p<0.001, Fig 3C) , respectively. The number of 162 lymphocytes positively correlated with the levels of LDL-c (R= 0.236, p<0.001, Fig 3D) , TC (R= 163 0.277, p<0.001, Fig 3E) , and HDL-c (R= 0.158, p<0.001, Fig 3F) and diminishing cholesterol efflux and transport. 21 We found that IL-6 was dramatically elevated 203 in 96% of all patients. This strongly suggests that pro-inflammatory cytokines such as IL-6 are a 204 major contributor to the lipid abnormality in patients. Third, lipids are highly vulnerable to 205 degradation by free radicals, whose levels are generally elevated in host cells with a viral permeability. 27,28 Therefore, one possible mechanism underlying our data is that during the 214 disease progression, severer inflammation and worse vascular permeability are, more plasma 215 cholesterol and lipids leak into alveolar space, and less LDL-c and cholesterol remain in the 216 plasma. We also posit that the dyslipidemia plays an important role in pathological development 217 of COVID-19, which mechanism needs an urgent investigation. 218

There are several limitations of this study. First, the time from the onset of symptoms to the 219 time of serum sample collection when patients were admitted to the hospital was varying among 220 patients. Therefore, the data might represent heterogeneous stages of the disease course. 221

Second, many patients might had been treated with various remedies at home, such as Chinese 222 traditional medicine, before on admission. Whether and how these factors interfered with our 223 data are unknown. Third, monitoring the dynamics of lipid profiles before and during the entire 224 disease course in a large cohort of COVID-19 patients will be needed for better characterization 225 of this hypolipidemia, which will be our future research goal. 226

Collectively, our data demonstrate that the development of hypolipidemia can start in patients 227 with mild symptoms. The degree of hypolipidemia positively correlates with the disease severity. Table 1 ) and patients with mild (n=394), severe (n=171), or critical (n=32) COVID-19, 243

respectively. Whiskers are presented as median ± 95% (CI) with the diamond boxed range of 244 IQR in the plots. A Mann-Whitney U test was used to compare differences between two groups. 245

The dotted lines indicate the median values of LDL-c (109 (92, 128) ), HDL-c (52 (41, 65) ) and 246 TC (182 (158, 206) ) that were measured from normal adult population in Wuhan city, Hubei 247 province (n=1574, age: 40 (32, 52)) in 2019 at our hospital. 248 

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*110 (96, 147) mg/dL 91

HDL-c *52 (40, 65) mg/dL 50

TC *184 (166, 221) mg/dL 173

176) mg/dL 150

51) 37 (15, 48) n.s. AST 8-40 U/L 27