Covid-19:  How It Kills

This is Dr. Cal Shipley presenting COVID-19: How It Kills – the Pathophysiology of the Coronavirus.

Covid-19 Size

COVID-19 is a viral particle which is a mere 100 nanometers in diameter. By comparison, the diameter of a human hair is 1,000 times greater, and yet, in spite of its diminutive size, a single particle can infect a human being and result in death.

In this presentation, I’m going to examine the mechanism (or pathophysiology, as we call it in medicine) by which this virus wreaks such havoc.

Respiratory  Anatomy and Physiology

COVID-19’s primary target in the human body is the lung and so it is critically important that we understand a little bit about how the lungs work in order to understand how the virus causes its damage.

Shown here are the heart, the left and right lung, and in blue, the pulmonary arteries through which the heart pumps oxygen-poor blood which has returned from the venous system.

The pulmonary arterial system consists of an intricate web of blood vessels (simplified here for graphical presentation purposes).

The bronchial tree is an equally intricate system of airways distributed throughout both lungs. There is a physical interface between the airway system and the pulmonary arterial system, which we’ll take a closer look at in just a moment.

Oxygenation

To begin the process of blood oxygenation, air is inhaled into the bronchial tree. Let’s zoom in for a closer look to see how the process of oxygen transfer occurs.

The pulmonary arterial system and bronchial tree divide down into ever smaller branches. The smallest arterial branch is known as a pulmonary arteriole. Tiny airways known as terminal bronchioles give way to even smaller airways, known as respiratory bronchioles. At the end of the respiratory bronchioles are structures known as alveolar sacs. Each alveolar sac consists of a number of individual alveoli which we will take a closer look at in just a moment.

The smallest blood vessels, known as CAPillaries also (pronounced as caPILLary in Canada and the United Kingdom) originate from the pulmonary arterioles and interface directly with the alveolar sacs. Taken all together, the capillaries and alveolar sacs are termed the alveolar-capillary complex.

Just to give you some sense of the size of these structures, here is the shaft of a typical paperclip which is about one millimeter in diameter.

Moving in closer now, we can see the intimate physical relationship between the capillaries and the individual alveoli. I have made the capillaries semi-transparent exposing the individual red blood cells circulating through them. The capillary is in close contact with a single alveolus. As noted previously, a respiratory bronchiole is attached to the alveolar sac. Examining a single alveolus and capillary allows a more complete view of their anatomical relationship.

The diameter of a capillary is just greater than that of a red blood cell, which keeps the red blood cells in close proximity to the wall of the alveolus. Air enters the alveolus from the respiratory bronchiole. The walls of both the alveolus and the capillary are permeable to oxygen molecules and allow the movement of oxygen from one to the other. Oxygen molecules attach to red blood cells. Within each red blood cell is an iron-containing protein structure known as hemoglobin which binds the oxygen molecules.

Each red blood cell is typically capable of carrying about 1 billion molecules of oxygen. The freshly oxygenated blood flows into the left atrium and ventricle and is then pumped via the aorta to all organs and tissues in the body.

Ventilation of Carbon Dioxide

The alveoli of the lungs also act as receptacles for the removal of excess carbon dioxide from the bloodstream. We breathe out carbon dioxide with each exhalation. This ventilation of carbon dioxide by the alveoli plays a critical role in maintaining proper acid-base balance in the body.

Covid-19

Let’s move on now to an examination of the COVID-19 virus and Severe Acute Respiratory Syndrome (SARS). The structure of the COVID-19 is the key to understanding its lethal effects.

Covid-19 Structure

The overall shape of the COVID-19 virus is typically spherical or elliptical. The structure of the virus is designated as a nucleocapsid: an outer protein membrane which envelops an inner RNA strand. The RNA strand consists of 30,000 nucleic acid bases and is the largest viral RNA strand known.

Like DNA in human beings, the RNA strand contains the virus’s genome, the genetic information required for viral replication.

Viral Spikes

The envelope is studded with numerous spikes, which gives the virus its characteristic appearance, as well as its name, corona being the Latin root for crown.

The spikes contain a form of a protein called glycoproteins, and these are thought to play a prominent role in guiding the virus to target host cells in the body, as well as facilitating viral entry into the cells.

Scientists also suspect that it was a mutation in the spiked proteins that allowed the COVID-19 virus to jump from an animal to a human host.

Viral Proteins

The proteins contained in the envelope and spikes of COVID-19 are responsible for its ability to create adverse effects in a human host.

Proteins

Proteins are ubiquitous throughout all plant and animal life on the earth. They supply the building blocks for organs and tissues. They can function as chemical messengers, signaling cells when and how to act. Proteins also play a critical role in facilitating metabolic processes in organic life.

Bottom line, it’s the protein makeup of COVID-19 that makes it more contagious and more lethal than comparable viruses such as influenza A or B.

While many important aspects of COVID-19’s pathophysiology have already been uncovered, much scientific research still lies ahead in determining how the complex of proteins and its structure facilitate its mechanism of harm.

Severe Acute Respiratory Syndrome (SARS)

When COVID-19 kills, it does so by causing Severe Acute Respiratory Syndrome (SARS) in the infected individual.

First SARS Outbreak

The first notable outbreak of SARS occurred in 2003 in Southeast Asia. This outbreak was caused by a different version of the coronavirus than today’s COVID-19 and sickened about 8,000 people worldwide with over 700 deaths.

MERS Outbreak

Another form of SARS known as MERS for Middle East Respiratory Syndrome occurred in 2012. There were 2,500 confirmed cases of MERS worldwide with over 700 deaths.

As of the recording of this presentation, over 400,000 cases of Covid-19 invfection have been confirmed in the United States alone, with over 12,000 deaths, and so COVID-19 has already far outpaced its viral cousins.

Covid-19 Transmission

The primary mode of transmission for the COVID-19 virus is via droplet infection. The virus attaches itself to molecules of water vapor in the infected individual’s airways. These droplets are then expelled via coughing, sneezing, laughing, singing, and even talking. These viral droplets then land in the nasal passages or mouth of another individual and are inhaled into the lungs.

There has been much discussion among researchers as to how far a droplet may remain airborne, and thus pose a risk to another individual. Early data indicated a range of three to six feet. Others now suspect that the airborne viability of the viral droplets may be much greater than just six feet. So the CDC has now recommended that all individuals wear a mask for self-protection when out in public.

Covid-19 In The Airway

Once inhaled, the virus moves into the airways of the lung. Ultimately, some virus particles will reach the alveoli. Some researchers believe that proteins in the viral spikes help to direct the virus to alveolar epithelial cells. Here is an alveolar epithelial cell shown in cross section. Depicted are the nucleus of the cell as well as a ribosome which is responsible for synthesizing protein. The virus enters the epithelial cell with the assistance of spike proteins, which bind to ACE-2, angiotensin converting enzyme-2.

ACE-2 is an enzymatic protein which is embedded in the outer surface of pulmonary epithelial cells. Spike proteins in the COVID-19 virus specifically recognize the ACE-2 receptor in humans. In the absence of the ACE-2 receptor, the COVID-19 virus would not be able to target and penetrate human epithelial cells and therefore the virus would be unable to infect humans. One intriguing question for researchers then is whether or not manipulation of the ACE-2 levels might prevent COVID-19 viral infections in humans. You can read much more about the ACE-2 enzyme in a couple of the articles in my citation list at trialimage.com.

Covid-19 Replication

Once the COVID-19 virus has bound itself to the ACE-2 receptors, it enters the epithelial cell. Once in the cell, the virus migrates to the cell’s protein synthesis machinery, and utilizing its RNA strand as a template, begins to replicate itself. This ability to use the host machinery to replicate itself is common to all infectious viruses and represents the real genius of their design. Why lug around all the biological overhead required to reproduce yourself when all you need is a good strand of RNA and a strong set of proteins to run the show?

Spread

The newly minted viruses, in turn, infect other epithelial cells, and the cycle goes on and on so that in a relatively short space of time, a single virus particle can be responsible for millions of infected host cells. Theoretically, inhalation of just a single viral particle of COVID-19 can result in SARS-related fatality. In the majority of most fatal cases, however, it is likely that at least hundreds or thousands of inhaled viral particles have penetrated epithelial cells to begin the progression to SARS.

Covid-19 SARS

To demonstrate the progression of the disease from this point, I’m going to depict the alveolar capillary which directly abuts the epithelial cells of the alveolus. Here’s a zoomed-out view just to reorient you to the relationship between the alveolus and the capillary. Once the presence of COVID-19’s foreign protein is detected by the body, an immune response is triggered. Initially, this response will consist of white blood cells migrating to the site of infection.

Chemotaxis

Responding to chemical signals, the white blood cells migrate from their home in the bloodstream through blood vessel walls and into the tissue around the area of infection, a process known as chemotaxis. The white blood cells shown here are called neutrophils. Neutrophils are the most abundant white blood cell in the human body and usually act as first responders when a foreign agent is detected. White cells are capable of killing both viruses and bacteria, primarily by the physical ingestion of the foreign agent.

Cytokines

Once at the site of infection, the neutrophils will produce signaling proteins called cytokines, depicted as the streams of yellow dots in this graphic. The cytokines, in turn, will recruit additional white blood cells to the site of infection, including T lymphocytes and macrophages. Macrophages are also capable of ingesting bacteria and viruses, a process known as phagocytosis. T lymphocytes are capable of directly killing viruses and bacteria through secretions of toxic proteins, and also play a key role in modulating the production of antibodies directed towards a specific virus or bacteria.

The Inflammatory Response

The body’s overall response to the presence of the virus, including the chemotaxis of white blood cells to the site of infection, the production of cytokines and the activation of antibody production is known as an inflammatory response. The initial inflammatory response in individuals infected with COVID-19 represents a critical juncture for the progression of the disease.

A strong initial inflammatory response may result in the death of most of the virus resulting in only mild symptoms in the infected individual or even no symptoms at all. However, in older individuals or others who may have underlying diseases which impair immune response, the virus may persist with the progression of disease. Left to its own devices by a weak immune response, COVID-19 uses its proteins to signal white blood cells to produce massive quantities of cytokines.

Cytokine Storm

Autopsies on patients who have died of COVID-19-related SARS have revealed the presence of COVID virus within white blood cells. The significance of this finding is currently unknown, but it’s possible that the virus infects the white blood cells in order to stimulate the cytokine production. Whether from within or outside of the white blood cells, the COVID-19 virus stimulates a massive production of cytokines. These abnormally elevated levels of cytokines are known as a cytokine storm.

The storm consists primarily of a cytokine named interleukin-6 or IL6. High levels of IL6 result in a much exaggerated inflammatory response. This hyper-inflammation damages epithelial cells in the wall of capillary surrounding the alveoli. The connections between the epithelial cells become unstable and separate, resulting in leakage of serum into the alveoli. Fluid also accumulates in the tissues which lie outside of the airways and alveoli, the so-called interstitial spaces. The alveoli fill with fluid, blocking oxygen transfer from the airways to the bloodstream. The filling of alveoli, other airways and the interstitial spaces with fluid is known as pulmonary edema and is a key feature of COVID-related SARS.

Blockage of Oxygen Transfer

Oxygen can enter the upper airways but cannot be transferred to the bloodstream through the fluid-filled alveoli. Progressive pulmonary edema, such as can occur in COVID-19-related SARS, results in a critical loss of oxygen flow to all organs and tissues of the body, ultimately resulting in death.

Hyperinflammatory Response: Additional Effects

The cytokine storm induced by COVID-19 can also result in the death of epithelial cells in the walls of the alveoli. This damage to the alveolar walls in combination with pulmonary edema results in the collapse of alveoli.

In addition, the alveoli in patients who have died from COVID-19-related SARS exhibit hyaline membrane formation within the alveolar sacs. Hyaline membranes consist or ropes of a protein known as fibrinogen interspersed with dead alveolar epithelial cells. Fibrinogen is a key component of blood clot formation, and is very helpful when you cut yourself, but simply gets in the way of oxygenation when it is present in alveolar sacs.

Diffuse Alveolar Damage (DAD)

Widespread damage to the alveoli and the formation of alveolar hyaline membranes is known as diffuse alveolar damage, and is characteristic of Coronavirus-related SARS. The combination of diffuse alveolar damage and progressive pulmonary edema as seen in COVID-19-based SARS makes effective treatment of these individuals extremely difficult. The survival rate of patients who require ventilator support is only about 20%.

Susceptibility to Covid-19 SARS

Finally, I’d like to make a comment about patients with underlying medical conditions and susceptibility to COVID-19-related SARS.

Certainly, the elderly who generally have an age lessened immune response, as well as those who have immunodeficiency diseases, are among the groups most prone to develop SARS. Individuals with heart disease, cerebrovascular disease  (that is vascular disease involving the brain), diabetes, and high blood pressure, technically termed hypertension, are also in the high-risk group.

None of these conditions by themselves are associated with weakened immune systems per se. How do we explain the increase susceptibility of these groups to COVID-19-related SARS? It turns out that these conditions are associated with chronically elevated baseline levels of bodily inflammation. As I hope I’ve made clear in this presentation, COVID-19 does its damage by inducing a hyper-inflammatory state, so when the COVID-19 virus enters the body of an individual who already has a chronically elevated baseline inflammatory state, it’s job in driving the body to hyper-inflammation and SARS is that much easier.

What about then the 35-year-old otherwise healthy individual who dies of SARS from COVID-19 infection, or the 80-year-old who only develops mild disease? These cases are unexplainable given our current state of knowledge. The overwhelming odds are that these are not simply fluke events and that they have a scientific explanation if only we can find it, or perhaps I should say when we find it.

You can find a full list of the scientific papers I referred to in producing this presentation by clicking on the citations link on this web page. In the meantime, please be safe and stay well.

Cal Shipley, M.D. copyright 2020