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If you’ve been keeping up with my blogs this year, you may have learned that coronaviruses (i.e. what causes the common cold and the novel SARS-CoV-2 or “COVID-19” infection) are RNA viruses that infect both humans and animals with their main focus of damage on the respiratory, gastrointestinal, and central nervous systems (Cui et al., 2019).
You may have also learned that we’ve faced adversity before during two separate, but related, coronavirus epidemics: Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Although they were not as infectious or lethal as COVID-19, these past public health events nevertheless caused thousands of deaths in their own right.
The outbreak in Wuhan, China certainly rocked our world in 2020, and although antiviral therapy, corticosteroid therapy, and mechanical respiratory support have been applied to treat those infected, there is a lack of targeted treatments for COVID-19 (Huang et al., 2020) which actually works. Hence, there is a TON of interest in finding resources already available to us which can both prevent the infection and accelerate its recovery process. And one of those is the Anti-inflammatory Melatonin, the hormone released by the pineal gland inside of the brain which regulates our sleep–wake cycle.
Melatonin (scientific name N-acetyl-5-methoxytryptamine) is a bioactive molecule with a wide variety of health-promoting properties. Notably, it has been successfully used to treat sleep disorders, delirium, digestive problems, vascular and respiratory disease, other viral infections, and so much more (Reiter et al., 2020a). Earlier studies have documented the positive effects of melatonin in alleviating acute respiratory stress induced by a virus, bacteria, and radiation, among other ailments (Huang et al., 2010; Yip et al., 2013; Wu et al., 2019).
There is unquestionable evidence today which indicates that melatonin is critical for both supporting optimal human physiology, for preventing and fighting infections, like COVID-19.
What’s the Rationale for Melatonin Use?
To understand the power of melatonin, you need to understand the damage that COVID-19, or any chronic infection, causes. People who are infected by SARS-CoV-2 chiefly present with fever, dry cough, myalgia, fatigue, diarrhea, and loss of taste, with symptoms varying somewhat with the patients' age. Although rare, in some patients, there is a severe progression of the disease, which results in acute lung injury and acute respiratory distress syndrome (ALI/ARDS), respiratory failure, heart failure, sepsis, and even sudden cardiac arrest within a few days (Chen et al., 2020; Huang et al., 2020).
Upon closer look of pathogenic lung specimens from mild COVID-19 individuals (who were retrospectively found to have COVID-19 at the time of their lung cancer surgery), examination showed significant edema, proteinaceous exudate with globules, patchy inflammatory cellular infiltration, and moderate formation of hyaline membranes (Tian et al., 2020). In a postmortem assessment of another infected patient with severe ARDS, specimens of infected lungs demonstrated bilateral diffuse alveolar damage with edema, pneumocyte desquamation, and hyaline membrane formation (Xu et al., 2020). These findings indicate rampant underlying immune system activation and subsequent inflammatory damage to tissue.
While these pathological reports were made in only a small number of cases, the findings are quite similar to the pathological features found in SARS- and MERS-induced pneumonia (Liu et al., 2020).
SARS-CoVs, MERSCoVs and SARS-CoV-2 are classified in beta- coronavirus family members (Chen, 2020). Recent published research indicates that SARS-CoV-2 shares 79.0% nucleotide identity to the earlier SARS-CoV strain and 51.8% identity to MERS-CoV (Ren et al., 2020), suggesting a high genetic homology among SARS-CoV-2, MERS-CoV, and SARS-CoV. This means that they all kind of create the same damage, but in slightly different ways from one another. This is an important consideration.
In SARS-CoV and MERS-CoV infected animal models, significant inflammatory and immune responses activate what you may have heard as “a cytokine storm”, the event that is like a tornado created by the immune system, wreaking havoc wherever it travels. In addition to the cytokine storm, cellular death (i.e. apoptosis) of epithelial and endothelial cells takes place similar to what occurs when a tornado rips through and aggressively damages home and all other structures in its way. The subsequent blood vessel damage and abnormal T cell and macrophages responses can quickly lead to ALI/ARDS or even death (Channappanavar & Perlman, 2017). This is similar to how dams break and fires erupt after a severe storm.
Based on genetic homology and pathologic features of the infected lung, most scientists agree that the cytokine storm likely rages on in patients infected with COVID-19.
In the blood of people infected with COVID-19, there appears to be a high level of problematic cytokines: interleukin 1β (IL-1β), interferon γ (IFN-γ), interferon-inducible protein 10 (IP-10), and monocyte chemoattractant protein 1 (MCP-1), as well as IL-4 and IL-10 when compared to that of SARS patients. With the exception of IL-10, these molecules of the immune system are powerful. So powerful that they can actually kill an array of infections with ease. However, when they spin out of control as in the cytokine storm, it causes catastrophic damage. Again, while SARS-CoV-2, MERS-CoV, and SARS-CoV are all related, the cytokine profile of SARS-CoV-2 suggests some potential difference from SARS- and MERS-CoV in the pathogenesis of coronavirus (Huang et al., 2020).
We also have to consider that many COVID-19 patients have some underlying health conditions (i.e., metabolic syndrome, obesity, diabetes, high blood pressure, cancer, chronic fatigue, asthma, etc) which they may or may not be aware of. Their immune function is already suppressed with hypo-albuminemia, lymphopenia, neutropenia, and decreased percentage of T-helper cells (CD8+ T cells) (Chen et al., 2020; Huang et al., 2020). Read more about that in a previous post. Bottom line, they are ill-prepared to fight off an infection since their poor immune system has already been overdrive even before they became infected with COVID-19.
What I see all the time in practice is now being confirmed in the scientific literature. Recent studies highlight that in some COVID-19 patients (although being negative for the viral nucleic acid test), can still present with marked inflammation. This is why we see that clinical trials which use certolizumab pegol (a powerful tumor necrosis factor (TNF) cytokine blocker), along with other anti-virus therapies, have beneficial effects in COVID-19 patients. The drugs are calming down inflammation in the background. Thus, it would behoove all of us to find ways to keep inflammation at bay since we know, without a doubt, that inflammation is a major feature in COVID-19 patients.
Thus, excessive inflammation, depressed immune system function, and an activated cytokine storm all substantially contribute to the pathogenesis of COVID-19 and serious consequences from infection.
In the beginning stages of coronavirus infections, dendritic cells and epithelial cells are altered of the encroaching infection and pump out a cluster of pro-inflammatory cytokines and chemokines including IL-1β, IL-2, IL-6, IL-8, both IFN-α/β, TNF, CeC motif chemokine 3 (CCL3), CCL5, CCL2, and IP-10, etc. Once more, these are under complete control of the immune system, and overproduction of these cytokines and chemokines contributes to the development of disease (Cheung et al., 2005; Law et al., 2005; Chu et al., 2016). Our body is doing the damage with the molecules produced above.
Note, IL-10, produced by T-helper-2 (Th2), is actually a helpful cytokine we want because it is antiviral, but it appears that an infection of coronaviruses leads to a decrease in this cytokine (Chien et al., 2006; Fehr et al., 2016). Interestingly, COVID-19 patients can have a rise in the level of IL-10 floating around (Huang et al., 2020); whether this is a hallmark of COVID-19 infection or the result of medical treatment is to be determined. In theory, the amplification of the inflammatory response would drive cellular apoptosis or necrosis of the affected cells, which would further intensify inflammation, followed by increasing permeability of blood vessels and the aberrant accumulation of inflammatory monocytes, macrophages, and neutrophils in the lung alveoli (Channappanavar et al., 2016).
Bottom line: The vicious cycle intensifies the situation as the regulation and balance of immune response is lost and the cytokine storm is further activated. This results in dire consequences.
The cytokine storm pathology associated with coronaviruses is well supported by experimental SARS-CoV models. In fact, one research team found that the severity of ALI was accompanied with an increased expression of inflammation-related genes rather than increased viral titers (Channappanavar et al., 2016). This means that the virus was less damaging than the cytokines made by immune cells. Talk about some power we possess! And in another report, the elimination of IFN-α/β receptors or the depletion of inflammatory monocytes/macrophages lead to a significant rise in the survival rate of coronaviruses host without a change in viral load (Smits et al., 2010).
Both of the aforementioned situations point to a potential amplifying mechanism involved in CoV-induced ALI/ARDS, regardless of the viral load. If a similar pathology also exists in COVID-19, which it likely does, then the attenuation of the cytokine storm by targeting several key steps in the process could bring about improved outcomes. This is where melatonin comes in.
Even though melatonin is not viricidal per se, it has indirect antiviral actions (Reiter et al., 2020a) due to its anti-inflammatory, anti-oxidative, and immune enhancing effects (Boga et al., 2012; Anderson et al., 2015; Junaid et al., 2020; Reiter et al., 2020b). Most people, including physicians, do not know that in addition to sleep, melatonin is an essential anti-inflammatory agent the body uses to fight infection and subsequent inflammation.
Melatonin suppresses the features of viral infections. In animal studies whose central nervous system is infected by virus (i.e., inducing encephalitis), the supplementation of melatonin into the diet led to a decrease in viral activity, reduced paralysis and death, and lowered the total viral load (Ben-Nathan et al., 1995). In other respiratory syncytial virus models, melatonin caused downregulation of:
Taken together, these basic findings, support the rationale for melatonin use in many viral diseases we face. Not to mention, melatonin's anti-inflammatory, anti-oxidative, and immune supporting actions support it as a potential agent for the fight against COVID-19 infection (as summed up in Figure 1).
Figure 1. Development of COVID-19 and adjuvant use of melatonin. When a suppressed immune system encounters SARS-CoV-2 infection in the lungs, we see a marked rise in inflammation and an excessive amount of oxidation stress. They proceed unabated, resulting in cytokine storm. ALI/ARDS may ensue, accompanied by a series of complications, the outcomes of which vary according to the severity of the disease. Here, melatonin likely plays a therapeutic role in the regulation of immune system, inflammation, and oxidation stress, thereby providing support for patients with ALI/ARDS and related complications (Zhang et al., 2020).
Check back next week as I will dive further into melatonin’s anti-inflammatory, anti-oxidative, and immunomodulatory role in health and illness. And the following week I will talk about how to put all of this information into practice, as well as other supportive adjuvant agents. I promise it’s simpler than you think. Until then, rest up!
Dr. Bhandari and the Advanced Health Team Are Here to Support Your Health.
Our expert team of integrative holistic practitioners work with patients suffering from chronic health concerns. We help our patients reverse disease by better understanding how the body optimally functions and providing personalized treatment plans. To learn more and book an appointment, contact Advanced Health or call 1-415-506-9393.
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