When the Body’s Reaction to Protect Us Becomes the Problem
Inflammation is an important response to infection. It is part of the initial immune response that tries to control infection while the more complex antibody system is activating. Inflammation, however, can be a two-edged sword injuring the host of it is too aggressive or sustained.
The “too aggressive” example in COVID-19 has been those with severe infections who developed “cytokine storm” which caused extensive damage to the lungs often resulting in death. It was actually the host’s inflammatory response to the infection that resulted in severe lung damage. It now appears that long COVID-19 is related to “sustained inflammation” or inflammation that fails to turn off when it is not needed.
Long COVID-19, which is the persistence of symptoms well past when the acute infection was resolved, affects approximately 20%, or 1 in 5 patients who had milder disease. To give 20% perspective, the U.S. has had over 80 million infections during the 2 ½ years of the pandemic suggesting that those with some persisting symptoms may number in the 15 to 20 million range.
The first step in effectively treating any health problem is understanding what is causing it. New research into why those who had mild to moderate infections may develop longer term symptoms is providing some answers. Several research efforts have suggested that the initial inflammatory response to the infection does not resolve in those with long COVID-19.
A recent study looked at the behavior of macrophages in those with long COVID-19 symptoms following mild infections. Macrophages are the primary white blood cell that turn on inflammation in response to infection but also resolve inflammation when it is no longer needed. The monocytes in those with long COVID-19 were still behaving as if there was an acute infection stimulating inflammatory activation. When these cells are activated by an infection, they produce enzymes that convert omega-6 fatty acids from their cell membrane turning them into inflammatory activating eicosanoids. However, as the infection begins to resolve, these cells should then begin converting omega-3 fatty acids from the cell membrane. These are enzymatically converted to “specialized pro-resolving mediators”, or SPMs which resolve inflammation and promote healing.
The message to make this inflammatory to anti-inflammatory transition comes from activation of the vagus nerve which is the major parasympathetic communication between the body and the brain. The parasympathetic nervous system moves the body back into “rest, digest & repair” after activation of the sympathetic nervous system which activates “fight or flight” such as during infection. Extensive research has shown that stimulation of the vagus nerve with low frequency current is effective in programing macrophages to switch from inflammatory to anti-inflammatory activity as they circulate through the spleen.
The balance in intake of omega-6 to omega-3 fatty acids prior to infection is a critical factor in the balance between turning inflammation on as needed and being able to resolve or turn it off at the appropriate time. The ideal intake of omega-6 and omega-3 fatty acids for optimal functioning of the immune system is a 3:1 ratio. The western dietary pattern is very heavy in omega-6 rich foods such as grain and seed oils but very low in omega-3 rich foods such as seafood and green plant foods. The omega-6:omega-3 of the western diet is > 12:1 or very pro-inflammatory. Anything such as infection that triggers inflammation with a high omega-6:omega-3 will result in impaired ability to resolve it.
Similarly, an imbalance between sympathetic and parasympathetic nervous system activity will impair the ability to resolve inflammation at the appropriate time. This imbalance termed “sympathetic dominance”, is common with high levels of stress, excessive body fat and several other activators of the “fight or flight” system. Sympathetic dominance prevents the adequate parasympathetic activity which is needed to resolve inflammation. It is this relationship that largely explains the increased risk of a poor outcome with COVID-19 in those with significantly high body fat.
The resolution of long COVID-19 appears to require several steps. The first is using plant phytochemicals called phenolics to slow inflammatory activation. The most effective phenolics include curcumin, resveratrol, boswellia serrata and ginger. The balance of omega fatty acids can be restored with high dose omega-3 fatty acid supplementation. In the longer term it should be balanced with transitioning from a “inflammatory” diet to an “anti-inflammatory” diet.
The resolution of sympathetic dominance can be accomplished by procedures including photobiomodulation, heart rate variability biofeedback and transcutaneous vagus nerve stimulation. Major ongoing triggers of stress need also be addressed for optimal outcome.
Fortunately, we are understanding more of what drives long COVID-19 symptoms and this is leading to treatment solutions. This problem is new and has presented a major challenge. The pace of scientific investigation into both COVID-19 infections and in the long-term symptoms that so many end up with has been rapid and intense giving us answers about a path forward.