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Some COVID-19 patients go on to develop severe infection with organ failure, potentially leading to death, and one of the contributing factors appears to be toxicity from the release of stored unsaturated fatty acids (UFAs), according to a small study in .

Vijay P. Singh, MBBS, a gastroenterologist at the Mayo Clinic in Scottsdale, Arizona, and colleagues retrospectively looked at mortality and dietary and other factors in 15 COVID-19 patients, one of of whom died and seven of whom needed intensive care (ICU group). The rest were discharged home. They found that the ICU group had an early drop in serum calcium and albumin several days before ICU admission. Separately, on analyzing global COVID-19 mortality data and comparing it with 12 risk factors for mortality, they found unsaturated fat intake to be associated with increased mortality. This was based on the dietary fat patterns of 61 countries in the United Nations' Food and Agricultural Organization . Surprisingly, they found saturated fats to be protective.

In experimental studies, UFAs were seen to cause hypocalcemia and hypoalbuminemia. Since calcium and albumin can bind and neutralize UFA toxicity only when given early, this led the investigators to conclude that the simple low-cost intervention of maintaining adequate calcium and albumin levels early in the disease could bind UFAs, reduce injury, and help prevent death.

Singh explained these connections in the following interview.

How were you first alerted to the possible connection between UFAs and COVID-19 severity?

Singh: It was the similar patterns between COVID-19, a new disease with no treatment, and pancreatitis, an old disease, which we're currently studying. For example, obesity is a risk factor for both, and multi-organ failure can occur in both, although one disease starts in the lungs and the other in the digestive tract. And in either disease, severity is preceded by hypoalbuminemia and hypocalcemia. In addition, lipase elevation is linked to severity in COVID-19 and also mediates severity in pancreatitis.

The resemblances of the dietary patterns, clinical features, and autopsy findings for severe COVID-19 to those for severe acute pancreatitis were astounding!

What are the links between UFAs and the injury you noted in these patients?

Singh: We found epidemiologic links correlating high UFA intake with higher mortality, and clinically we found that unbound fatty acids, predominantly unsaturated, were elevated in patients with worse organ failure. Furthermore, UFAs bind to calcium and albumin, resulting in deficiencies. UFAs cause multi-system organ failure in a way very similar to severe COVID-19, and UFAs are also used as a model for acute respiratory distress syndrome (ARDS), similar to that caused by severe COVID-19.

Furthermore, mechanistically, UFAs can rapidly depolarize mitochondria, inhibit mitochondrial complexes I and V, and decrease levels of adenosine triphosphate. They also trigger the release of calcium from an endoplasmic reticulum and increase cytokines and inflammatory markers.

How are these fats potentially lethal?

Singh: Humans have 1 to 5 kilograms of linoleic acid stored in fat. In this stored form it's safe, but it's released by lipases in pancreatitis and in COVID-19. The lethal dose of is 280 milligrams per kilogram -- just 23 grams for a person weighing 80 kilos. Similarly, in the case of oleic acid, only very low doses are needed for lethality.

Which dietary sources contain high levels of UFAs?

Singh: It's all related to composition based on double bonds in a long fatty acid chain with more than 12 carbons. Linoleic and oleic acid are the two most abundant UFAs in the human body, and linoleic acid has increased to now comprise more than 20% of our stored fat. Commonly consumed vegetable oils such as safflower, sunflower, and corn are all quite high in linoleic acid, while oleic acid makes up a large part of olive, canola, and peanut oil.

What is the course of UFA toxicity?

Singh: As mentioned, UFA toxicity is very relevant to several acute diseases such as COVID-19, pancreatitis, and ARDS. All these progress rapidly over days or even hours, in contrast to chronic diseases like hypertension and diabetes, which progress over months to decades.

UFAs also affect obesity, and not all obesity is the same. It is the UFA component in obesity that determines the degree of harm in the event of acute lipolysis as in severe COVID-19 or acute pancreatitis. A larger proportion of UFA accumulation in adipose fat -- even when the overall fat amount is lower, as in a leaner person -- may be more harmful during acute lipolysis than a greater proportion of saturated fat.

In light of the pandemic, should people at large be adjusting their intake of these fats in a precautionary way?

Singh: It has been known for a long time that the composition of the fat we store in adipose tissue takes several years to change in response to changes in diet. Dietary habits, that is, the fats we cook in such as butter and different types of oil, as well as the foods we eat, are strongly determined by culture, region, tradition, and what we're taught is good or bad, though there is little evidence for the latter. In the long term, avoiding high UFA intake may help with future pandemics like COVID-19, and severe pancreatitis or similar disease scenarios.

What about prophylactically upping calcium intake or supplementing with albumin?

Singh: Patients who develop severe COVID-19 have an early drop in serum calcium. Our study shows that prevention of this early drop, and staying "total calcium-albumin normal" may help keep the infection mild. Calcium is cheap and available over the counter. When treating early COVID-19 patients, physicians should consider checking total calcium and albumin levels, apart from other relevant blood tests. Short-term oral calcium carbonate supplementation for 3 to 4 weeks might be appropriate for patients while they fight the infection, as well as intravenous albumin if needed.

There is no indication for healthy individuals who do not have COVID-19 to take supplemental calcium and albumin to prevent infection.

You can read the abstract of the study here, and about the clinical implications of the study here.