COVID-19 has taken the world by storm. First identified in December 2019 in Wuhan, China, this emerging respiratory disease rapidly spread beyond the borders and was declared a pandemic by the World Health Organization (WHO) on March 11, 2020.
According to the WHO Coronavirus Dashboard, there are over 223 million confirmed cases of COVID-19, including over 4.5 million deaths globally since its inception. Of these numbers, the United States is leading the world in the number of confirmed cases (with over 40 million) and deaths (approaching nearly 720,000) when this blog post was written.
What is COVID 19?
COVID-19 is a disease caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Coronaviruses are a family of spherical viruses with “crown-like” spikes that cover their surfaces. These viruses are widely distributed in nature and affect other species such as birds, cats, bats, rodents, pigs, and other mammals, as well as humans.
In fact, this is not the first time we have seen a virus like this threaten the human population. There are seven coronaviruses known to infect humans. Some reading this article may remember two other recent outbreaks in recent history — Severe Acute Respiratory Syndrome (SARS) outbreak in China in 2003 and the Middle East Respiratory Syndrome (MERS) outbreak in Saudi Arabia in 2012.
SARS-CoV-2 is primarily transmitted through direct person-to-person contact with respiratory droplets by cough or sneezing. Once contracted, it targets the lung tissue and likely other organs that express high amounts of the ACE2 receptor, such as the heart and kidney. This virus may cause a wide range of symptoms in humans.
While some people who test positive for COVID-19 display no symptoms at all, others may experience fever, fatigue, sore throat, dry cough, shortness of breath, body aches, and congestion. In its most severe form, COVID-19 leads to life-threatening pneumonia and acute respiratory distress syndrome (ARDS). The mortality rate from COVID-19 ARDS, the leading cause of COVID-19 death, can approach 40% to 50%.
The Cytokine Storm that follows COVID-19 infection
Inflammatory cytokines emerged early as critical players in COVID-19 disease progression. Cytokines are small proteins that are crucial in controlling the growth and activity of immune cells. When released, they signal the immune system to do its job. Cytokines are made by many different cells, but the predominant producers are T-cells and macrophages, both of which play a critical role in our immune response.
It’s important to understand that cytokines are a vital part of our immunity. Different cytokines play different roles in our immune response and are not innately “bad.” However, the term “cytokine storm,” which has become synonymous with the pathophysiology of COVID-19, seems to present serious problems.
A cytokine storm, also known as cytokine release syndrome (CRS), refers to an overly activated immune system’s uncontrolled and overwhelming release of pro-inflammatory mediators. This leads to widespread and unrestrained inflammation throughout the body systems. Severe COVID-19 disease and death are, in part, mediated by this rampant cytokine storm.
When it comes to COVID-19, there seems to be a triad of cytokines that are closely correlated with disease progression, interleukin (IL)-6, IL-10, and interferon (IFN)-gamma-induced protein 10 (IP-10). A study with 305 samples confirmed that the rise in this cytokine profile is correlated with the deterioration of patient health status. It’s been found that IL-6 levels, specifically, might serve as a predictive biomarker for COVID-19 disease severity. High levels of IL-6 are tied to respiratory failure and shock, and multi-organ dysfunction. Another large retrospective cohort study also found that blood levels of IL-6 were correlated with COVID-19 disease mortality.
The sharp increase in pro-inflammatory cytokines and its association to worse COVID-19 outcomes led to the idea that targeting and managing the cytokine storm may be essential for supporting COVID-19 patients.
What do Omega-3s Have to do With COVID-19?
The health benefits of Omega-3s cover a wide range of different systems, including cardiovascular health, brain health, vision, and neurodevelopment. Omega-3s are also well-known mediators of inflammation and can amplify anti-inflammatory responses.
Since accumulating evidence suggests inflammation-induced lung injury and dysregulated immune responses play roles in the pathophysiology of severe COVID-19, omega-3s may be an attractive approach to preventing and mitigating severe outcomes by resolving the cytokine storm.
Evidence has recently become available that demonstrates this may be the case. A pilot study published in January of 2021 compared the associations between the Omega-3 Index (a measure of omega-3s EPA and DHA in the blood) and risk for death from COVID-19 in 100 patients. Researchers found that patients with an Omega-3 Index of >5.7% were at about 75% lower risk for death than those below that value. This was the first study to directly test the hypothesis that omega-3 fatty acids could benefit COVID-19 patients.
A follow-up study published in July 2021 confirmed these findings and found an inverse association between the Omega-3 Index and significant clinical outcomes of severe COVID-19. Subjects in the lowest Omega-3 Index quartile (<3.75%) had a 3.1-fold higher risk of dying from severe COVID-19 than patients in the highest Omega-3 Index quartile.
Moreover, those subjects in the highest quartile reduced the risk of mechanical ventilation by half. The authors concluded that Omega-3 status might profoundly influence the inflammation resolution and airway mucosal immunity needed in response to COVID-19.
The first randomized clinical trial to assess the effect of omega-3 fatty acid supplementation on ICU patients with COVID-19 was published in March 2021. Conducted on critically ill COVID-19 patients, it concluded that omega-3 supplementation improved the levels of several respiratory and renal function parameters and led to a significantly higher 1-month survival rate.
How do Omega-3s Help COVID-19 Patients? It’s the SPMs…
Omega-3 fatty acids EPA and DHA are the main precursors of a novel superfamily of molecules called specialized pro-resolving mediators (SPMs). These substances are critically important in the homeostasis of inflammation resolution and airway mucosal immunity.
The conversion of omega-3s to SPMs actively disrupts inflammatory circuits and skews the immune response toward a return to equilibrium. SPMs have also been found to inhibit viral replication and reduce the severity of viral pneumonia in experimental models.
Additionally, omega-3 fatty acids have been found to (1) inhibit the production of pro-inflammatory mediators like IL-6, and TNF-alpha, as well as mitigate cytokine storms; (2) dampen the inflammatory response through T-cell differentiation; and (3) enhance the anti-viral effect by boosting the activity of the innate immune system and inhibiting viral replication.
It is through these actions that omega-3s might present a safe and relatively inexpensive, protective approach for those who are at risk and have contracted the novel virus.
History can Help Guide Treatment and Prevention Strategies for COVID-19 Today.
While there is still limited research on COVID-19 patients due to the novelty of the disease, there is data from previous clinical studies supporting the beneficial role of omega-3s in certain aspects of the COVID-19 disease process. For one, research has found that an optimal Omega-3 Index is inversely associated with pro-inflammatory biomarkers and that omega-3s routinely lower cytokine levels.
A recent meta-analysis of 12 randomized controlled trials (including over 1200 patients in total) performed in patients with ARDS concluded that omega-3 supplementation was associated with improvements in lung function, shorter ICU stays, and shorter duration on mechanical ventilation, in addition to a significant reduction in mortality.
Furthermore, a study completed in 2009 found that treating airway epithelial cells with DHA and EPA 24 hours before rhinovirus infection significantly reduced the release of IL-6 and IP-10 – two of the three cytokines found to be responsible for the cytokine storm in COVID-19 patients.
More About the Omega-3 Index
The Omega-3 Index measures the amount of EPA and DHA in the red blood cell membranes. This test reflects long-term omega-3 intake and has historically been identified as a risk factor for death from cardiovascular disease.
Studies indicate that up to 90% of American people consume less than the recommended amounts of omega-3 fatty acids in their diet. Chronically low intake of omega-3 fatty acids leads to an average Omega-3 Index of around 5% in the United States.
Japan and South Korea, on the other hand, are well known for their high dietary intake of Omega-3s and have reported an Omega-3 Index of 8-12% and 7-11% on average. Interestingly, Japan and South Korea have also reported extremely low severity of COVID-19.
While more research is required to confirm and build upon these preliminary findings, it appears that increasing intake of omega-3 fatty acids and improving Omega-3 Index levels globally could have far-reaching implications on the evolution and survival rate of the COVID-19 pandemic.