Association of hyperlipidemia and statin use with severity of COVID-19

Background and Aims: We aim to study the association of hyperlipidemia and statin use with COVID-19 severity. Methods: We analysed a retrospective cohort of 717 patients admitted to a tertiary centre in Singapore for COVID-19 infection. Clinical outcomes of interest were oxygen saturation ≤ 94% requiring supplemental oxygen, intensive-care unit (ICU) admission , invasive mechanical-ventilation and death. Logistic regression models were used to study the association between hyperlipidemia and clinical outcomes adjusted for age, gender and ethnicity. Statin treatment effect was determined , in a nested case-control design, through logistic treatment models with 1:3 propensity matching for age, gender and ethnicity. All statistical tests were two-sided, and statistical signicance was taken as p < 0.05. Results: One hundred fty-six (21.8%) patients had hyperlipidemia and 97% were on statins. There were no signicant associations between hyperlipidemia and clinical outcomes. Logistic treatment models showed a lower chance of ICU admission for statin users when compared to non-statin users (ATET: b-0.12(-0.23,-0.01); p=0.028). There were no other signicant differences in other outcomes. Conclusion: Treated hyperlipidemia was not an independent risk factor for severe COVID-19. Statin use independently associated with lower ICU admission. This supports current practice to continue prescription of statins in COVID-19 patients.


Introduction
The COVID-19 pandemic continues to grow around the world, with total number of cases around the crossing the 10 million mark on 30 June 20 [1]. Recent studies suggested that COVID-19, like SARS and MERS, are associated with dysregulated immune and in ammatory processes. Severe cases of COVID-19 had high levels of circulating pro-in ammatory cytokines, as well as high neutrophil counts and lymphopenia [2][3][4]. COVID-19 has been associated with hyperin ammatory states in children, cardiovascular disease and venous thromboembolism [5][6][7].
Hyperlipidemia is part of the metabolic syndrome associated with a pro-in ammatory state [8]. Statins are commonly used to treat hyperlipidemia and its pleiotropic effects have been shown to reduce cytokines in various non-infective conditions [9][10]. Patients on statin therapy who developed pneumonia in the setting of bacterial infections [11][12] and in uenza [13] are known to have better outcomes.
Medical comorbidities such as diabetes, hypertension and cardiovascular diseases have been identi ed as risk factor for severe COVID-19 in numerous large case series from China, Italy and the United States [14][15][16]. Hyperlipidemia has not been identi ed as an independent risk factor [17], although it is associated with diabetes and hypertension, and contributes to cardiovascular diseases. We aimed to study the association of hyperlipidemia with COVID-19 severity and the effects of the use of statin in COVID-19 patients.

Methods
We carried out a retrospective cohort study of patients with con rmed COVID-19 hospitalized at the National Centre of Infectious Diseases, Singapore, which has managed more than 60% of COVID-19 patients in Singapore. Patients may be identi ed by primary care and emergency doctors based on case de nitions informed by evolving epidemiological risk factors, case detection from active contact tracing, enhanced pneumonia surveillance and diagnostic testing based on doctors' discretion [18]. Patients were included if they were hospitalized from 22 January 2020 to 4 April 2020. Inclusion criteria were: age ≥50 years old, presence of comorbidities and hyperlipidemia, or presence of pneumonia on chest radiography.
Electronic medical records of hospitalised patients with COVID-19 con rmed by PCR performed on respiratory samples were reviewed to extract information on demographic data on age, gender and ethnicity, presence of comorbidities and concomitant medications, laboratory investigations including full blood count, renal and liver function tests, C-reactive protein (CRP) and lactate dehydrogenase (LDH) and clinical outcomes of COVID-19. Clinical outcomes of interest were: hypoxia with oxygen saturation ≤94% requiring supplemental oxygen, intensive care unit (ICU) admission and invasive mechanical ventilation (IMV) and death. All study procedures and data collections were performed in accordance with institutional guidelines. Waiver of informed consent for data collection was provided by the Ministry of Health under provision of the Infectious Disease Act.
Continuous and categorical variables are presented as median (interquartile range) and frequency (%), respectively. We used the logistic regression models to study the association between hyperlipidemia and outcomes of hypoxia, ICU admission, IMV and death, adjusted for age, gender and ethnicity. Linear regression models to assess the association between each of the complete blood count variables and in ammatory markers, and hyperlipidaemia with adjustment for age, gender and ethnicity were built. To assess the possible treatment effect of statin use on these outcomes we used a nested case control design, wherein after excluding patients with diabetes and hypertension, we estimated the statin treatment effect through logistic treatment models with 1:3 propensity matching for age, gender and ethnicity. All statistical tests were two-sided, and statistical signi cance was taken as p < 0.05. All statistical analyses were performed using Stata version 15.

Results
Within our cohort of 717 patients, one hundred fty-six (21.8%) patients had hyperlipidemia. Individuals with hyperlipidemia were older (62.5 years, IQR 55-68 years versus 37 years, IQR 27-52 years) and more likely to be of Malay ethnicity (18.6% versus 8.9%). There were more patients with concomitant cardiovascular risk factors with 24 to 59% of patients having coexisting diabetes, hypertension and cardiovascular disease. In terms of in ammatory markers, those with hyperlipidemia were more likely to have higher CRP, LDH, procalcitonin, white cell count and neutrophil count but lower lymphocyte count.
Patients with hyperlipidemia were more likely to require supplemental oxygen, ICU admission and IMV. The risk of death was higher (P <0.05). See Table 1 and 2.
After adjusting for age, gender and ethnicity, there were no signi cant associations between hyperlipidemia and clinical outcomes of hypoxia, ICU admission, IMV and death. Hyperlipidemia was associated with higher white cell count and neutrophil count but not the other in ammatory markers. See Table 2 and 3.
Of those who had hyperlipidemia, 151 (96.7%) were on statins, 11 (7.1%) were on brates and 9 (5.8%) were on ezetimibe. In the nested case control analysis after excluding patients with diabetes and hypertension, 40 patients were on statins and 509 were non-statin users. Logistic treatment models using propensity matching showed a lower chance of ICU admission for statin users when compared to nonstatin users (Average treatment effect of statins (ATET): -0.12(-0.23,-0.01); p = 0.028). There were no other signi cant differences in other outcomes (Table 4).

Discussion
While comorbidities such as diabetes, hypertension and cardiovascular disorders are associated with poorer outcomes with COVID-19, we did not nd hyperlipidemia which is part of the metabolic syndrome to be independently associated with severe COVID-19. Most of the patients in this cohort were already treated with statins (97%) and this maybe a reason for these non-signi cant results. Cholesterol has been implicated to have a possible role in the increased risk of infection in the elderly patients wherein higher tissue cholesterol has been shown to increase the endocytic entry of SARS-CoV-2 along with increased tra cking of angiotensin converting enzyme-2 (ACE-2) in a preprint [19]. However, this increased transmission is more related to tissue cholesterol concentrations rather than the blood concentrations [19].
In our small observational cohort, we did see a signi cant trend towards a signi cantly higher white cell counts and neutrophil counts in hyperlipidemia status. Statin use was associated with a lower chance of requiring ICU admission. A key pathological process that leads to cardiovascular disease is in ammation. [20][21][22][23][24][25][26] in patients with hyperlipidemia, independent of its ability to reduce low-density lipoprotein [27]. Even in rheumatological disease statins are known to modulate the in ammatory response [28]. Additional to its bene cial effects in cardiovascular disease, statins may be bene cial in patients with bacterial sepsis [29-30], community acquired pneumonia [31] and in uenza [13]. Hence, we suggest that statins should not be discontinued in those who require them. This is especially important in COVID-19 as severe disease is related to cardiovascular comorbidities [14][15][16].

Statins have been shown to have anti-in ammatory and immunomodulatory effects
Our study has several limitations. We did not have the quantitative lipid pro le on admission to study detailed correlations with the lipid phenotype. Our cohort was small and adverse outcome rates, especially that of mortality, were low. This will affect the generalisability of our ndings. Lastly, there was a risk of channelling bias as patients on statins were more likely to have more severe cardiovascular disease than those without.

Conclusion
We found that treated hyperlipidemia was not an independent risk factor for severe COVID-19. There was a signi cant trend towards a higher innate immune response shown by higher white cell counts and neutrophil counts. Statin use was independently associated with lower requirement for ICU admission. This supports current practice to continue prescription of statins in hyperlipidemia and other metabolic disorders in COVID-19 patients. The effect of statin use on COVID-19 disease severity needs to be studied in larger observational studies or ideally in randomised controlled trials.

Declarations
The study protocol was reviewed and approved by the Singapore, Ministry of health who provided a waiver of informed consent from study participant for data collection under the Infectious Disease Act as part of national public health research. Author contributions: RD, WT conceptualized the study, performed data analysis, data interpretation, literature review and wrote the manuscript. DEKC : data interpretation and critical review of manuscript. DCL and BEY conceptualized the study, data interpretation and critical review of manuscript. All authors reviewed the nal manuscript.
Declaration of Interest: All authors state that they have no con ict of interest with regards to this manuscript.
Data Availability : The datasets are available from the corresponding author upon reasonable request.
[30] Ma Y, Wen X, Peng J, Lu Y, Guo Z, Lu J. Systematic review and meta-analysis on the association between outpatient statins use and infectious disease-related mortality. PLoS One. 2012;7:e51548.