Plasma lipids in COVID-19: bystanders or players?
Recently, a report on SSRN and a rapid response on bmj.com suggest the role of reduced plasma cholesterol in worsening COVID-19 prognosis (1, 2). Subsequently, Pirro et al (3) in a rapid response on bmj.com argued the possible benefit of reducing low-density lipoprotein cholesterol (LDL-C) in this condition, irrespective of the infection-related hypocholesterolaemia. Moreover, these authors further suggested the possible beneficial role of statins during COVID-19 disease considering the high burden of cardiovascular complications observed in these patients.
We would like to invite everyone to be more cautious in interpreting the relationships between plasma lipids and COVID-19 disease, because the available evidence, as it has been collected, does not allow to draw any definitive conclusions about the causal role, if any, of plasma lipids or its treatment in influencing COVID-19 outcomes.
Support for this belief comes from a review of the literature we conducted to investigate the association between plasma lipids and SARS-CoV-2 infection. To this aim, we have recently searched in different electronic databases (Pubmed, SSNR, MedRixv) for any article reporting data on plasma lipids or hyperlipidaemia in COVID-19 patients. Lei Y et al (4) showed that there were no differences in plasma levels of total cholesterol and triglycerides (TGs) between symptomatic and asymptomatic patients with COVID-19. Similarly, comparable levels of blood lipids have been found in the 55 COVID-19 patients admitted to the Fifth Medical Center of PLA General Hospital (5). Moreover, in the 97 patients reported by Nie et al (6), authors have found no differences in levels of LDL-C and TGs between patients with severe or mild disease. Interestingly, in this report it was noted that plasma levels of high-density lipoprotein cholesterol (HDL-C) were lower in patients with the severe as compared to those with the milder form of pneumonia. These data may support the hypothesis that HDL particles may exert some protection against SARS-CoV-2 due to their well-known anti-microbial and anti-inflammatory actions (7).
A different picture emerges if we consider the prevalence of hyperlipidaemia. Though defined according to variable criteria, this condition appears to be largely represented in patients diagnosed with COVID-19. In a report including 1591 Italian patients with SARS-CoV-2 infection (8), hypercholesterolemia was the third most common (18%) comorbidity, after hypertension (49%) and cardiovascular diseases (21%). In the study considering 4,103 COVID-19 patients evaluated in New York City (9), hyperlipidaemia was found in 25% of hospitalized patients. Finally, in the recently published work (10) describing clinical characteristics of 8,910 COVID-19 patients collected in the observational database from 169 hospitals in Asia, Europe, and North America, the prevalence of hyperlipidaemia reached-up 30.2% among survivors and 35% among non-survivors.
Despite the increased prevalence of history of hyperlipidaemia in COVID-19 patients, its impact on disease prognosis appears weak. In 124 patients suffering with COVID-19, Simmonet et al (11) found that hyperlipidaemia was not able to predict the necessity of invasive mechanical ventilation. Similar results were reported by Zhang et al (12) who detected no association between hyperlipidaemia and severity of the disease. In the previously mentioned US study (9), authors found that hyperlipidaemia was a risk factor for hospitalization but not for critical illness (defined as a composite of care in the intensive care unit, use of mechanical ventilation, discharge to hospice, or death) and, finally, in the largest cohort of COVID-19 patients reported so far (10), the presence of hyperlipidaemia was not able to independently predict in hospital death.
A possible interpretation that might be helpful in clarifying this somewhat confusing picture is that plasma lipid levels or hyperlipidaemia should be considered as bystanders (or risk markers) rather than players directly involved in the pathogenesis of complications caused by SARS-CoV-2 infection. Indeed, it is well known that there is a strong link between plasma lipids or hyperlipidaemia and other comorbidities such as cardiovascular diseases, diabetes mellitus or obesity, which have been recognised to worsen the prognosis of COVID-19 (12). Similarly, the better chance of survival observed in SARS-CoV2 infected patients who reported previous use of statins (12,13), the most commonly used lipid-lowering medication, should be interpreted considering that statin use may be a proxy of increased cardio metabolic risk. On the other side, the low cholesterol levels observed in COVID patients with worst prognosis (1,2) can be well explained as the consequence of malnutrition that may occur in these patients (3,14) as well as the direct consequence of the more severe inflammation occurring in COVID-19 patients with poorest outcomes.
In summary, we are in favour of the idea that plasma lipids or hyperlipidaemia might have a neutral effect on COVID-19, but they can describe the metabolic status of patients, which may have a direct impact on disease’s prognosis. In this context, hyperlipidaemia may be eventually used as a clinical hallmark in identifying patients that may require more intensive care. However, further studies, including randomized clinical trials, are needed before any conclusion can be reached regarding a potential, direct role of lipids or its treatment in SARS-CoV-2 infection. We hope that these studies will focus mainly on evaluating those lipid fractions, e.g. TGs and HDL, which have the closest link with the immune system/meta-inflammation networking.
1. Hu X, Chen D, Wu L et al. Low Serum Cholesterol level among patients with COVID-19 infection in Wenzhou, China (February 21, 2020). Available at SSRN: https://ssrn.com/abstract=3544826.
2. Ravnskow U. Cholesterol-lowering treatment may worsen the outcome of a Covid-19 infection. https://www.bmj.com/content/368/bmj.m1182/rr-10
3. Pirro M, Bianconi V. Cholesterol and cholesterol-lowering in COVID-19: why we should not let our guard down (May 1, 2020). https://www.bmj.com/content/368/bmj.m1182/rr-18
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14. Laviano A, Koverech A, Zanetti M. Nutrition support in the time of SARS-CoV-2 (COVID-19). Nutrition. 2020 Apr 2:110834. doi: 10.1016/j.nut.2020.110834.
Competing interests: No competing interests