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A Hallmark of Covid-19: Cytokine Storm/Oxidative Stress and its Integrative Mechanism
by Richard Z. Cheng, M.D., Ph.D.
OMNS (Jan. 22, 2022) Cytokine storm has recently been recognized as the key pathology responsible for the severe symptoms of Covid-19 and other viruses and non-viral agents. The underlying biochemical cause of cytokine storm is excessive oxidative stress. Cytokine storm and its associated oxidative stress appears to be a universal non-specific mechanistic pathway common among many causative agents, for example viruses, that leads to severe clinical disease.
A biochemical sequence known as "lipid peroxidase chain reaction" (LPCR) plays a critical role in oxidative stress and cytokine storm. Prevention and blocking the occurrence of cytokine storm/oxidative stress appears to be a logically sound and effective strategy to prevent the severe symptoms of Covid-19. If this could be performed world-wide, it could reduce the devastating medical, economic and societal impact of the Covid-19 pandemic. Preventing or blocking LPCR and the excessive oxidative stress requires intact antioxidant systems, especially the antioxidant vitamins and nutrients, including vitamins C, E, CoQ10, alpha lipoic acid, glutathione and niacin (to promote NADP+/NADP), selenium and others. Insufficiency or absence of any of these antioxidant agents may render these antioxidant systems ineffective, which may be responsible for the inconsistent results of antioxidant therapies in the literature.
Here we propose an integrative and systematic therapy that includes these antioxidant vitamins, minerals, and nutrients. The "universal and non-specific nature" of cytokine storm/oxidative stress makes possible a pre-emptive treatment to prevent or block cytokine storm/oxidative stress induced by severe diseases, even before full recognition of the underlying causative agent. This is very significant because it allows us to potentially prevent and block a pandemic of a new virus or a new viral mutant when it happens without requiring the extended time needed to develop a specific drug or vaccine treatment. With the seemingly endless mutations of SARS-Cov-2, we may still have time to apply this strategy to break the Covid-19 pandemic.
A key hallmark of Covid-19: Cytokine storm/oxidative stress
Cytokine storm with the underlying elevated oxidative stress is a key hallmark of severe Covid-19. [1-12] Cytokine storm was first described 28 years ago [13,14] and is a common mechanism leading to severe symptoms, not only in Covid-19, but also in other respiratory viral infections [15,16], HIV-related infections [17,18], sepsis , SARS , tick-borne SFTS syndrome , autoimmune and viral hepatitis [22,23], Ebola , yellow fever , and Coronaviral encephalitis , immunotherapies [27,28], as well as systemic diseases and anaphylaxis. 
Cytokine storm describes the explosive and excessive release of free radicals and cytokines (signaling molecules) in a short period of time, overwhelming the body's innate antioxidant/anti-inflammatory mechanisms, leading to significant oxidative damage of biologically important molecules such as DNA, proteins and lipids, and severe cellular and organ damage. This can rapidly progress to multi-organ failure with a very high mortality rate. Hence, it is very important to recognize the early clinical signs of cytokine storm and prevent it from developing. If we can interrupt the cytokine storm/oxidative stress before it causes significant cellular and tissue damage, this will provide a way to prevent severe Covid-19 and other severe viral syndromes. One exciting possibility is to administer early and sufficient doses of antioxidants to strengthen the body's antioxidant defenses. This can play a major role in prevention and intervention of cytokine storm/oxidative stress. [5,6] Antioxidant vitamins and nutraceuticals have been used for this purpose in the management of Covid-19. Some of these nutrients showed significant effectiveness in treating Covid-19 [30-33], and "Long Covid" symptoms. 
Lipid peroxidation plays a central and an important role in cytokine storm. Unlike oxidation of DNA and protein, lipid peroxidation is unique in that it usually happens rapidly, damaging many of the lipid molecules in a local cellular environment through a lipid peroxidation chain reaction (LPCR). It can continue until all the unsaturated lipid molecules in cell membranes are damaged or until LPCR is terminated by antioxidants, usually the body's main lipophilic antioxidant, vitamin E. [35-38] The prevention of lipid peroxidation and termination of LPCR requires a series of antioxidants to work together in a systematic manner, like a cogwheel. Lacking or insufficiency of any one component may render the entire antioxidant cascade ineffective. There is little recognition of this "integrative or systematic" working relationship in the literature.  This lack of recognition may be responsible for the failure of some antioxidant studies to show clinical effectiveness.
The main purpose of this article is to analyze and present this "Integrative Antioxidant Therapies" concept.
Cytokine storm/oxidative stress is a pathobiological response that can be induced by various pathogens and by nature is non-pathogen-specific. Thus therapeutic strategies to prevent or block cytokine storm/oxidative stress may be a very effective general method to prevent/treat diseases involving cytokine storm/oxidative stress. This point may have a wide-reaching clinical significance, especially in the current global management of Covid-19 pandemic. Despite the various causes that may induce a cytokine storm and the varied cytokine responses that may happen in a cytokine storm, the associated elevated oxidative stress response for any particular causative agent is very likely similar. This makes it possible to develop an antioxidant therapy to prevent or block the severe diseases that result from the cytokine storm, including severe Covid-19 pneumonia. One of the difficulties in developing preventive treatments for pandemics like Covid-19 is the rapid mutations of these RNA viruses. But with cytokine storm as the common feature of such severe diseases, it may be possible to prevent these severe diseases with integrative antioxidant therapies to prevent or block the cytokine storm, even without detailed studies of new virus mutants. This applies not only to Covid-19; it may be applicable to other future epidemics, and other severe viral diseases. The clinical, societal and economic impact of this strategy is so profound that further research is urgently needed with top priority.
One of the key problems dealing with Covid-19 and other epidemic/pandemic-causing viruses is their rapid mutation rates, which can often obviate the few available virus specific vaccines and/or drugs. We propose an integrative viricidal and antioxidant therapy that may be universally applicable to Covid-19 and other viral infections, including various Covid-19 mutants and future mutants.
Lipid peroxidation chain reaction (LPCR), a key cascade of events in cytokine storm:
LPCR is well studied and established in the field of biochemistry. LPCR has 3 stages: the Initiation stage, the Propagation stage, and the final Termination stage.  LPCR not only damages lipid molecules, which make up the cell membrane, but the LPCR process also causes a number of very toxic oxidation products including lipid hydroperoxides (LOOH) and aldehydes such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). MDA is the most mutagenic product of lipid peroxidation and is commonly used as a biomarker for oxidative deterioration in omega-3 and omega-6 fatty acids. 4-HNE is the most toxic secondary product of lipid peroxidation.
Lipid peroxidation chain reaction (LPCR) is at the center of the cytokine storm, producing free radicals. [36,40-43] In turn, free radicals oxidize and damage DNA, proteins and lipids. The oxidation of lipids is biochemically called peroxidation. Once a lipid molecule is oxidized (this is called initiation), it becomes a lipid radical. The lipid radical can oxidize the next lipid molecule in the neighborhood very readily and rapidly until this chain event is terminated by antioxidants, especially vitamin E. Lipid peroxidation has been implicated in the development and progression of critical illnesses.  High levels of lipid peroxidation are associated with severe Covid-19 symptoms. [44-46] Protein adducts of lipid peroxidation products (4-HNE) were found to be higher in patients who died of severe Covid-19 symptoms than in those who survived Covid-19. 
Excessive oxidative stress is common in many, if not all, acute and chronic diseases, including Covid-19.
Oxidative stress describes biochemical reactions involving reactive molecules, including reactive oxygen species (ROS) and reactive nitrogen species (RNS), sometimes collectively abbreviated as RONS. Oxidative stress is an important part of redox signaling inherent in cell physiology. [48-50] Lipid peroxidation is also implicated in many chronic diseases, such as cardiovascular disease [51-56], cancer [57-60], Alzheimer's, liver diseases, lung diseases (COPD), diabetes mellitus [61-68], autoimmune diseases [69-73], and also Covid-19, chronic Covid-19 symptoms (so-called "Long Covid") and even Covid vaccine related injuries. [5,34,47,74-84] More advanced atherosclerosis is found to be associated with increased oxidized linoleic acid (LA) than with non-oxidized LA. 
Polyunsaturated fatty acids (PUFAs) are the targets of LPCR:
LPCR primarily targets the double bonds in lipid molecules. PUFAs are the fatty acids with unsaturated double bonds between the carbon molecules in their backbone. Hence PUFAs are the primary targets of LPCR. All fatty acids can be oxidized, but with increasing difficulty from PUFAs to MUFAs (monounsaturated fatty acids) to saturated fats. 
The double bonds in PUFAs are relatively unstable and can be readily broken by oxidative free radicals, causing damage to these lipids. Cell membranes, and the membrane of subcellular organelles such as mitochondria are made up mostly of lipids. Once these lipids are damaged, their functions are also impaired. Cardiolipin, e.g., an abundant lipid on the mitochondria membrane, plays a critical role in cellular energy production. Peroxidation of PUFAs in cardiolipin may contribute to age-related decline in the mitochondrial function.  Cardiolipin is found to be damaged in many cancer cells as well. [87-90]
Saturated fatty acids don't have these double bonds, and MUFAs have only one such double bond. Hence saturated fats and MUFAs are more stable and less readily oxidized by free radicals.
The amount of dietary omega-6 polyunsaturated fatty acids (N6 PUFAs) has increased significantly over the past few decades:
Due to decades of widespread misinformation that saturated fats are unhealthy, the intake of unsaturated fats, especially in the form of N-6 rich seed oils has significantly increased in modern diets. [91-93] Although both N-3 and N-6 are essential fatty acids, N-6 PUFA has a pro-inflammation effect, while N-3 PUFA is anti-inflammatory. The N-6 to N-3 fatty acid ratio has increased significantly from a ratio of ~1:1 during prehistoric evolution to 20:1 or even higher in recent decades. The increased N6/N3 ratio has been found to be correlated with various chronic diseases. [39,91,93,94] Although the recent abnormally high N6/N3 ratio may not have a direct impact on LPCR and cytokine storm, the increased total PUFA in our body is a setup for potentially more explosive LPCR. These PUFAs are enriched in cell membranes  which allows the membranes to be more readily attacked by the free radicals. This happens especially in a cytokine storm, with a huge outburst of free radicals in a short period of time, which overwhelms the antioxidant capacity of cells, leading to the initiation and propagation of the lipid peroxidation chain reaction. This increase of dietary N-6 PUFA intake is especially found among those with metabolic diseases such as diabetes. [91-93] This may explain why patients with metabolic diseases are prone to severe Covid-19 diseases with a high risk of multiorgan failure and mortality.
Termination of LPCR:
Once LPCR is initiated, it can propagate until all the lipids are oxidized or until it is terminated by antioxidants, especially vitamin E (VE). [35,96-98] VE is the chief LPCR chain-breaking antioxidant. VE is a lipid soluble antioxidant vitamin and is located on cell membranes, sitting among the lipid molecules. These features make VE the key antioxidant vitamin to protect cell membranes from oxidation. Other antioxidants, such as vitamin C, the primary extracellular antioxidant, do not have this LCPR termination effect. 
Cascade of Antioxidants:
Vitamin E appears to be required to block the propagation of LPCR and to terminate LPCR. The oxidized VE will not in turn oxidize other lipid molecules, but instead, oxidized VE needs to be reduced by other antioxidants, especially vitamin C (VC). The oxidized VC needs to be reduced by alpha lipoic acid, CoQ10, glutathione, selenium and NADP+/NADP. The free radicals will be passed down onto NADP/NADPH cascade to be disposed of in water. These antioxidants work in a systematic manner (Fig. 2).
Systematic and integrative nature of the antioxidant systems:
It should be noted that these antioxidants work in an integrative and systematic manner like a system of cogwheels. Each and every one of the components is required.
It's been shown that in the absence of VE, VC is not able to prevent lipids from being attacked by LPCR. Sato et al. described in their study of LDP cholesterol that VE and VC together can prevent LDL oxidation. However, in the absence of VE, VC is unable to prevent the LDL oxidation.  A recent national survey found alarming high rates of vitamin deficiency among American adults: 45% of American adults are deficient in vitamin A, vitamin C (46% deficient), vitamin D (95% deficient), vitamin E (84% deficient) and zinc (15% deficient).  It is conceivable that when individuals deficient in antioxidant vitamins and nutrients are hit by cytokine storm, their innate LPCR prevention and termination mechanisms are severely impaired so they will suffer high rates of cytokine storm/oxidative stress damages, leading to severe diseases and death.
Antioxidation therapies of various single antioxidants or a combination of a selected few antioxidants have been used to clinically treat various diseases. The results have been mixed. Lack of understanding of this "integrative and systematic" nature of antioxidant cascade may be responsible for at least some of the failures observed in those clinical antioxidant studies.
The contribution of N-6 PUFA, LPCR, and the integrative nature of antioxidants in the prevention and termination of LPCR has not been previously addressed. To the best of my knowledge, this is the first time this concept is described. In fact, clinical attention of oxidation has been mostly given to DNA mutation, but hardly any attention has been given to the peroxidation of lipids and ways to prevent this life-threatening condition.
Systematic Antioxidant Therapy
The terms cytokine storm and oxidative stress are associated with many viral syndromes and other non-viral infections. Systematic Antioxidants Therapy may have wide clinical application, and deserves further clinical studies.
In summary, cytokine storm and associated oxidative stress appear to be a common mechanistic pathway leading to severe clinical diseases caused by viruses and other non-viral agents, including Covid-19. Lipid peroxidation is a central part of the cytokine storm. Prevention of the lipid peroxidation chain reaction and its termination requires an integrative and systematic antioxidant cascade including sufficient doses of vitamin C, vitamin E, CoQ10, alpha lipoic acid, glutathione and NAD+/NADP+ and others. Lacking or insufficiency of any of these components may render the antioxidant cascade ineffective, resulting in failure to prevent/block cytokine storm/oxidative stress. This mechanism is universal and non-specific to causative agents. Epidemics and pandemics are on the rise, despite the significantly improved global economy and technology.  This "universal and non-specific nature" makes it possible for preemptive therapy to prevent or block cytokine storm induced severe diseases from happening, even before full recognition of the underlying causative agent. This is important, because it potentially allows us to prevent and block a pandemic of a new virus or a new viral mutant when it occurs, without spending the long time needed for specific drug or vaccine research and development. With the seemingly endless mutations of SARS-Cov-2, we may still have time to apply this strategy to break the Covid-19 pandemic.
Based on the biochemistry and pathology, we recommend high doses and early administration of antioxidants. We recommend vitamin C; vitamin E , alpha lipoic acid, CoQ10, glutathione and other vitamins and nutrients such as B vitamins and mitochondrial nutrients. Vitamin B3 (niacin) is critical in NAD+ biogenesis. NAD+ is involved in the final step of scavenging of free radicals. The rapid recovery in the case presented below highlights this approach.
We recently consulted on a case of severe Covid-19 in a patient who rapidly recovered after the administration of this Integrative Antioxidant Therapy, based on the above understanding and analysis. Robert from Manila, the Philippines, was of advanced age with multiple comorbidities including type 2 diabetes mellitus, hypertension, obesity and history of chronic hepatitis B. Robert was diagnosed of Covid-19 in September 2021, admitted to ICU and received standard Covid-19 care in the hospital for a week without improvement. Instead, his symptoms deteriorated with decrease of oxygen saturation progressed down to as low as 90-92% and rapidly rising cytokine storm markers of CRP, D. Dimer and ferritin (Fig. 3-5). The family requested my consultation and I recommended Integrative Antioxidant Therapy (Fig. 6). However, due to policy restrictions of the hospital, Robert did not receive my recommended protocol. His clinical conditions worsened with continued rise of cytokine storm markers (Fig. 3-5) and I was consulted again 4 days later. At that time, Robert was on a verge of or already in a cytokine storm and his risks of developing multiorgan failure were very high. I strongly urged the attending physician to implement the Integrative Antioxidant Therapy Protocol. Finally, Robert received the recommended protocol (Fig. 6). He rapidly improved on Day 2 after the implementation of the Protocol. He didn't need the supplemental oxygen on Day 3 to maintain adequate blood oxygen saturation. On Day 5, he was discharged to home care. I recommended continued integrative antioxidant therapy to ensure maximal repair of cellular and tissue oxidative damages and to prevent long term Covid-19 symptoms.
Fig. 3. Robert's ferritin levels during his hospitalization. Orange line: upper limit of normal range. Blue line: patient's ferritin values. Blue arrow: my recommendation of Integrative Antioxidant Therapy on my first consultation. Red arrow: implementation of Integrative Antioxidants Therapy. Black Arrow: discharge from hospital.
Fig. 4. Robert's CRP levels during his hospitalization. Orange line: upper limit of normal range. Blue line: patient's CRP values. Blue arrow: my recommendation of Integrative Antioxidant Therapy on my first consultation. Red arrow: implementation of Integrative Antioxidants Therapy. Black Arrow: discharge from hospital.
Fig. 5. Robert's D. Dimer levels during his hospitalization. Orange line: upper limit of normal range. Blue line: patient's D. Dimer values. Blue arrow: my recommendation of Integrative Antioxidant Therapy on my first consultation. Red arrow: implementation of Integrative Antioxidants Therapy. Black Arrow: discharge from hospital.
Fig. 6. Integrative Antioxidant Therapy Protocol
(The following recommendations should be implemented under the supervision of a qualified healthcare provider):
In conclusion, oxidative stress plays a central role in severe Covid-19 diseases and other diseases involving cytokine storm and oxidative stress. Lipid peroxidation is a central part of the cytokine storm. The prevention and termination of the lipid peroxidation chain reaction requires an integrative and systematic antioxidant cascade including vitamin C, vitamin E, CoQ10, alpha lipoic acid, glutathione and NAD+/NADP+ and others. Lacking or insufficiency of any of these components may render the antioxidant cascade ineffective, resulting in failure to prevent/block cytokine storm/oxidative stress. This mechanism is universal and non-specific to pathogens. Recognition of this mechanism may have a wide clinical implication to many viral and non-viral diseases. Clearly further clinical studies are warranted.
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