What does SARS-CoV-2 tell us about our health?

SARS-CoV-2 may exploit our autoimmune issues through inflammatory mechanisms. After spending considerable time in the literature some interesting correlations exist, although, for discussion here, I would like to mention age as a risk factor separately from the underlying conditions and comorbidities like heart disease, diabetes, pulmonary disease and obesity. Age risk factors are listed in table 1, where you might notice that the fatality rates related to age groups, are uniquely telling. In contrast to many viral infections that put younger populations at risk, SARS-CoV-2 appears to be quite different in that its greatest impact appears to be on the older populations. Nevertheless, it is important to note that since the total number of COVID-19 cases remains unknown, the fatality rates are skewed. It is expected that we will have a more accurate picture as more statistical information comes in. A higher priority is our understanding of the underlying immunological risk factors.   

Table 1. United States: Hospitalization, intensive care unit (ICU) admission, and case–fatality percentages for reported COVID–19 cases, by age group —United States, February 12–March 16, 2020.
Age group (yrs) (no. of cases) %*
Hospitalization ICU admission Case-fatality
0–19 (123) 1.6–2.5 0 0
20–44 (705) 14.3–20.8 2.0–4.2 0.1–0.2
45–54 (429) 21.2–28.3 5.4–10.4 0.5–0.8
55–64 (429) 20.5–30.1 4.7–11.2 1.4–2.6
65–74 (409) 28.6–43.5 8.1–18.8 2.7–4.9
75–84 (210) 30.5–58.7 10.5–31.0 4.3–10.5
≥85 (144) 31.3–70.3 6.3–29.0 10.4–27.3
Total (2,449) 20.7–31.4 4.9–11.5 1.8–3.4

 

*The CDC has a broad estimated fatality risk range of 0.25%–3.0% for COVID-19, while saying that "lower estimates might be closest to the true value"

 

First, this means more testing because COVID-19 can look alot like other illnesses or remain asymptomatic. Testing also tracks infectious rates, lethality, differential infectivity, identifies carriers and allows us to project more accurate outcomes. Perhaps most importantly, testing identifies those people who need to be isolated. Clinical reviews of mild cases were found to have an early viral clearance, with 90% of these patients repeatedly testing negative by day 10 post-onset. In contrast, all severe cases still tested positive at or beyond day 10 post-onset. This means the viral load of severe cases was around 60 times higher than that of mild cases, suggesting that critically ill people are not clearing the viral load.  
Analysis of the critically ill cases of COVID-19 has been startling and has led researchers to identify comorbidities, (see Table 2), related to critically infected COVID-19 patients. Professor Micheal Osterholm, director of the Center for Infectious Disease Research and Policy (CIDRAP), predicted the obesity risk factor before SARS-CoV-2 had reached the United States. His hypothesis was based on the similar inflammatory physiology of obesity to smokers, who were a high risk group in China. In fact, research on critically ill patients in Kirkland, WA, have identified the highest risk characteristics including: pulmonary disease, diabetes, kidney disease and obesity among other immune related chronic issues. 

 

Table 2.

WHO China and Our World in Data Coronavirus: early-stage case fatality rates by underlying health condition
Underlying Risk Factors Crude Fatality Rate (CFR)
Elderly over 80 years of age 21.9%
Cardiovascular Disease 13.2%
Diabetes 9.2%
Chronic Respiratory Disease 8.0%
Obesity 7.0%
Hypertension 7.9%
Cancer 7.6%

  

By digging deeper into the mechanism of the infective cycle of  SARS-CoV-2, a relationship begins to emerge between chronic inflammation and autoimmune conditions that helps explain how they create a greater risk in humans. Conceptually, comorbid conditions like obesity and diabetes increase risk because immune system function and dysfunction is significantly impacted by insulin response, glucose metabolism, inflammation and lipid metabolism. Therefore, people with these conditions often have compromised innate and acquired immunity, placing them directly on the path for developing serious COVID-19 symptoms. Currently, the CDC lists people with severe obesity, defined as a BMI of at least 40 kg/m2, and diabetes as being at high risk for developing severe illness from COVID-19. A case study in China showed that from the beginning of the outbreak through Feb. 11, 2020, the death rate among patients with COVID-19 who had diabetes was 7.3% compared to 0.9% for those without it. Conversely, better controlling diabetes, obesity, and heart disease, or otherwise reversing these chronic inflammatory-autoimmune conditions, reimagines how we can decrease SARS-CoV-2 risk in uninfected people. 

Moreover, other comorbid data may be explained by the fact that people with obesity often have sleep apnea and other lung abnormalities that can result in hypoxia even before any infection occurs. This leaves an already exasperated lung at risk for further injury if infected with SARS-CoV-2. Saskia Smits et.al. published research on SARS-CoV, which showed that an increase in differential expression of genes, associated with inflammation, could lead to a deficiency in control of viral replication. In turn, this led to prolonged proinflammatory responses, potentially leading to poor outcome clinically. Reflecting on the etiology of risk factors among the critically ill COVID-19 patients, there are comorbid conditions that have been the focus of alternative clinical practice for years. There are significant bodies of research, clinical indications and education regarding the environmental, emotional, nutritional, phytochemical and microbiome impacts on achieving healthy immune and metabolic functions. Therefore, as cornerstones of our alternative model, these datasets represent an important opportunity we cannot and should not overlook now and for future viral interactions.  

1.Arentz, Matt, Eric Yim, Lindy Klaff, Sharukh Lokhandwala, Francis X. Riedo, Maria Chong, and Melissa Lee. "Characteristics and Outcomes of 21 Critically Ill Patients with COVID-19 in Washington State." Jama (2020).

  1. Bialek, Stephanie, Ellen Boundy, Virginia Bowen, Nancy Chow, Amanda Cohn, Nicole Dowling, Sascha Ellington, et al. "Severe Outcomes among Patients with Coronavirus Disease 2019 (COVID-19) - United States, February 12-March 16, 2020." MMWR. Morbidity and Mortality Weekly Report 69, no. 12 (2020): 343-346.
  2. 3. "Coronavirus Pandemic Reaching Critical Tipping Point in America, Analysis shows." USNews.Com,2020. https://ourworldindata.org/coronavirus
  3. Harold Bays, MD, chief science officer of the obesity medical association and the medical director and president of Louisville Metabolic and Atherosclerosis Research Center 
  4. Smits, Saskia, Anna Lang, Judith Brand, Lonneke Leijten, Wilfred IJcken, René Eijkemans, Geert Amerongen, et al. "Exacerbated Innate Host Response to SARS-CoV in Aged Non-Human Primates." PLoS Pathogens 6, no. 2 (2010): e1000756.
  5. Wu, Yuntao. "Compensation of ACE2 Function for Possible Clinical Management of 2019-nCoV-Induced Acute Lung Injury." Virologica Sinica (2020).

 

Coronavirus Mechanism of Infection Underlies its Impact on Inflammation.

Like SARS-CoV, SARS-CoV-2 has been shown to target the angiotensin converting enzyme 2 (ACE2) receptors found on the surface of epithelial cells in the mucous membranes that line the respiratory tract, gastrointestinal tract, kidney tubules, and the oral cavity. This virus gains access into cells by binding to ACE2 receptors with their spike (S) proteins that protrude from the outer lipid layer of the virion. Once the virus binds to an ACE2 receptor it is brought into the cell via endocytosis where it can then release its RNA to be replicated, packaged, and released from the cell as new virions to initiate further infection of neighboring cells. ACE2 and its homologue, angiotensin-converting enzyme (ACE), are involved in the renin-angiotensin system (RAS) that regulates fluid volume, blood pressure, aldosterone secretion, vasoconstriction/vasodilation, and vascular permeability. In this system ACE2 is responsible for balancing out the actions initiated by ACE, thus, creating a delicate ratio of ACE/ACE2 that must be maintained for the body to function properly. 

When the RAS cascade is initiated, the liver produces angiotensinogen which is subsequently cleaved by renin, an enzyme produced by the kidneys, to produce angiotensin I (Ang I). ACE then converts Ang I to angiotensin II (Ang II), which is often referred to as the active form of angiotensin because when Ang II binds to its type I (AT1) or type II (AT2) receptors it activates the physiological processes that increase activity of the sympathetic nervous system (fight-or-flight response) and cause water retention, systemic vasoconstriction, high blood pressure, vascular permeability, inflammatory cytokine production, and cell proliferation. ACE2 comes into play to reduce Ang II concentrations and minimize these effects by hydrolyzing Ang I to Ang(1-9) before ACE can convert it to Ang II and by hydrolyzing Ang II to Ang(1-7) so that Ang II can no longer bind to its receptors. Instead Ang (1-7) can then bind to G protein-coupled MAS receptors to initiate its antagonistic effects against Ang II such as vasodilation, anti-inflammatory cytokine production, and anti-proliferative mechanisms to name a few.

This balance between ACE/Ang II and ACE2/Ang(1-7) becomes very important as we try to better understand how SARS-CoV-2 causes acute respiratory distress syndrome (ARDS) so that we may be able to develop better treatment options for those suffering from lung failure caused by COVID-19. Previous research on SARS-CoV has shown that as these viruses bind to ACE2 receptors in the lungs they significantly reduce the expression of ACE2, consequently increasing the levels of Ang II which has been associated with worse symptoms of ARDS, including pulmonary edema, and increased lung injury. Since both viruses have been shown to interact with ACE2 receptors, it has been suggested that they may also follow the same pathogenic mechanisms that cause lung failure in patients with COVID-19. From this information we can assume that by rebalancing the ratio of ACE2/Ang(1-7) to ACE/Ang II in COVID-19 patients we may be able to treat or reduce the severity of lung injury caused by SARS-CoV-2. In addition, angiotensin converting enzyme 2 is expressed on myocytes and vascular endothelial cells, so there is at least theoretical potential of direct cardiac involvement by the virus. 

 

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  1. Jordan, Rachel E., Peymane Adab, and K. K. Cheng. "Covid-19: Risk Factors for Severe Disease and Death." BMJ (Clinical Research Ed.) 368, (2020): m1198.
  2. Kuba, Keiji, Arthur S. Slutsky, Yi Huan, Bin Guan, Chi-Chung Hui, Josef M. Penninger, Lutz Hein, et al. "Angiotensin-Converting Enzyme 2 Protects from Severe Acute Lung Failure." Nature 436, no. 7047 (2005): 112-116.
  3. Simões e Silva, AC, KD Silveira, AJ Ferreira, and MM Teixeira. "ACE2, Angiotensin‐(1‐7) and Mas Receptor Axis in Inflammation and Fibrosis." British Journal of Pharmacology 169, no. 3 (2013): 477-492.
  4. Wu, Yuntao. "Compensation of ACE2 Function for Possible Clinical Management of 2019-nCoV-Induced Acute Lung Injury." Virologica Sinica (2020).
  5. Yan, Renhong, Yuanyuan Zhang, Yaning Li, Lu Xia, Yingying Guo, and Qiang Zhou. "Structural Basis for the Recognition of SARS-CoV-2 by Full-Length Human ACE2." Science (New York, N.Y.) 367, no. 6485 (2020): 1444-1448.