Pathogenesis and Pathophysiology of COVID-19 and Long Term COVID-19 Health Consequences

We are well into my blog series dedicated to my mother (Hi Mom!) about the long-term health consequences that may face those who were infected by the SARS-CoV-2 virus and survived – a topic on which there is little discussion in the lay press and media. And, to some extent this is understandable, because frankly, there is much we don’t know, and much of what we do know just keeps raising more questions. Oftentimes, doctors and scientists are reluctant to wade into these areas where we have more questions than answers because they are worried about being proved wrong with time or being labelled a fear monger. I, too, share some of this reluctance, however, I believe that people need to understand all the risks and potential risks as we know them so that they can make their own risk calculations as to what precautions they feel they should take to protect themselves and others. Unfortunately, the focus only on hospitalizations and deaths has caused many people to take risks that they might not have had they fully understood the long-term consequences to their health that might be possible even with relatively mild infection. I also believe that my readers are capable of understanding the limits to the information that I am providing to them, and we will discuss some of those limits below.

We started with mini-tutorials on virology, immunology and clinical studies. This will help prepare you to understand the rest of this blog series at a deeper level. In the last blog piece, we discussed what is Long COVID and the potential magnitude of that problem. Now we are going to discuss the pathogenesis (how an infection results in disease and how that disease manifests itself) and pathophysiology (the biologic processes by which the virus is able to cause disease) of COVID-19. We will start with what we currently understand about how the SARS-CoV-2 virus causes COVID-19 and then in the next blog piece, we will turn to what goes wrong that appear to be factors in why some people develop long-term consequences to their health following what seems to be recovery from the initial infection, including Long COVID or PASC.

Before digging in, let’s cover my disclaimers:

  1. We are learning more every day about these subjects. I have trouble keeping up with all of the developments myself, even with all the time I dedicate to reading articles and clinical studies each and every day. So, keep in mind that new studies may provide more light on what I am going to cover below, which is based on what we know today, literally today. That new light may correct, modify or further elucidate the information below.
  2. I am going to do my best to assimilate huge amounts of data and clinical studies together for you below, but I cannot cover everything, and some of the information is just so complicated that I may choose to not cover it if I don’t think it will be of general interest, or I may have to simplify it a bit in order to not loose my audience, but as you can understand, when I simplify complicated material, there will be some lost nuances and risk for some technical inaccuracies. Afterall, my goal is not to make you experts, but rather to make you more informed with a much better grasp of this information for which there is little public awareness.
  3. When we discuss pathogenesis and pathophysiology, it is important to understand some of these disease processes are different in different aged people. I am a general internist- that means an expert in diagnosing and treating diseases in adults. I learned a long time ago that kids are not little adults, medically speaking. They are a completely different species. Most of what we know about pathogenesis and pathophysiology is from studying adults. Some of this information will apply to children; some will not. When I do not specify otherwise, the information below is what happens in adults, and it may or may not occur the same way in children.
  4. In addition, as you will learn, if you didn’t already know it, disease processes can also be different in the elderly compared to young adults in their 20s, 30s and 40s. One explanation for this is that the immune system ages- so-called immunosenescence – and this plays a huge role, though not the only role, in why we have seen the worst COVID-19 outcomes (hospitalization and death) impact the elderly disproportionately.
  5. Besides age, disease processes are also different in different people depending on their general health, the presence or absence of other chronic medical conditions, their pre-infection functional status, and can even be different based on which variant they have been infected with and how much virus they were infected with (a story largely missed is that one of the greatest benefits of wearing a mask may merely be the reduction in the amount of virus that you inhale, which appears to result in milder illness, at least for our earlier variants). Further, your prior exposures and your genetics may greatly influence the disease you get and the way it manifests for better or for worse. There are hundreds of proteins, cytokines, chemokines, receptors, and cells involved in the response to the entry of SARS-CoV-2 virus into your body. Many of these trigger genes that comprise your genetic make-up to be turned on or off, and a genetic defect that you would be unlikely to know about can impact how and how effectively your body reacts to the virus. We also must appreciate that there are millions of Americans who have an immune deficiency (e.g., their bodies may not make certain types of antibodies or immune cells) or who are otherwise immunocompromised (cannot mount a normal and effective immune response due to an underlying disease or because of medications used to treat the underlying disease). Their disease processes will also be very different, and I will not be going into depth on how those disease processes are different in this blog piece.
  6. Finally, a warning. In medical school, we joked about “sophomore-itis.” That is to say that in our second year of medical school, as we began to get much more into the study of diseases, it was not unusual for students to begin thinking they might have that disease we were studying. I know many readers are looking for understanding of their own health issues following COVID-19. I just want to be clear that what we will review may or may not apply to your individual situation. This will especially be true as we get further into this blog series where we are discussing specific conditions resulting from COVID-19. In a blog, I simply cannot provide you with the depth of information that a physician must use to make actual diagnoses. Please do not diagnose yourself, especially from merely reading my blog. Instead, use this to better inform yourself and better inform the questions that you want to discuss with your physician when you see him or her for evaluation and follow-up.

Here we go. We are starting with the pathogenesis and pathophysiology behind the development of COVID-19 (the acute infection).

So, it all begins with someone being infected with the SARS-CoV-2 virus, whether they know it or not. Keep in mind that one of the reasons this pandemic has taken off and been so difficult to control is the fact that people can be infected and shedding infectious virus from their mouth and nose for up to several days prior to the development of symptoms or testing positive for COVID-19. The person who has infectious virus in their nose and throat will expel that virus into the air with breathing, talking, laughing, yelling, singing, coughing and/or sneezing. If a susceptible person is in a room, choir hall, auditorium, lecture hall, office, lunch or break room, restaurant, classroom, or other indoor area that is served by the same air supply and ventilation system, very small aerosols of the infectious virus will be suspended in air and carried across the room from the source (infected person) to the air return. When you have heard of super-spreader events, it is almost always this mechanism of transmission at play. (Super-spreader events can also occur outdoors when people are crammed closely together such as a sporting event, concert or rally.)

With very poor ventilation and air circulation, the virus can remain suspended in air for more than an hour. We can greatly mitigate this risk of so-called aerosol transmission by increasing the number of air exchanges per hour so that the virus is not allowed to remain suspended in the air so long. In addition, we can decrease the chances of infection by not recirculating the air, or if the air is recirculated, by adding filtration designed to trap virus particles, such as HEPA filters.

Another way to be infected is through larger respiratory droplets. This can occur when you are in close proximity to the infected person and this can be either indoors even with fairly good ventilation and filtration or outdoors. Obviously, the closer you are and the longer amount of time you are in contact, the higher the chance of transmission. However, do not get confused by the CDC definition of close contact, which is criteria (less than 6 feet for at least 15 minutes over a 24-hour period) for who would be subject to contact tracing – these are not the criteria for determining whether someone is at risk for being infected. You can be infected in far less than 15 minutes (the time can vary, but if someone has a high viral load [the amount of virus in their nose and throat] and you are indoors in the same room unmasked or not wearing a high-quality mask correctly or in close proximity to that person either indoors or outdoors, transmission may take place in less than a minute, especially with our more recent highly transmissible variants of concern). You also can be infected at a greater distance, especially if the infected person is coughing vigorously, yelling, singing, or otherwise projecting their voice.

As the virus enters a person’s nose or throat (and reportedly the conjunctivae of the eyes), the virus will seek out cells that have the appropriate receptor that will allow it access to the inner workings of the cell. We sometimes describe viruses by the tissues that contain the necessary receptors that will allow the virus cell entry and are targets for infection as tropism. For example, rabies, polio and California encephalitis viruses are neurotropic, in that they can infect the brain and cause disease with neurologic features. Some viruses have very limited tropism and cause characteristic diseases that are limited to a specific tissue or organ of the body. On the other hand, we shall see that SARS-CoV-2 has wide-reaching and varying tropism that allows it to infect many different tissues and organs resulting in a variety of disease manifestations. Of course, just because a virus has a number of tropisms, does not mean it will cause those infections and disease manifestations in everyone. For example, the polio virus enters the gastrointestinal system, and in most people causes asymptomatic or minor illness. However, in some unfortunate individuals, the poliovirus does make its way to the nervous system and can cause paralysis, weakness and disability. We will find that the same multi-tropism is true for SARS-CoV-2.

As we discussed in the virology and immunology tutorials, when we encounter a new virus for the first time, it is our innate immune system that does the heavy lifting in trying to fight the virus, providing the adaptive immune system (humoral [antibodies] and cellular) time to develop and design precision weapons. Recall that it takes 1 – 2 weeks to generate the full range of antibody response. Also recall that the antibodies cannot enter cells to combat the viruses that have already entered cells (we have to rely on our cellular immunity for that).

This is where vaccinated individuals have a huge advantage when they are encountering the SARS-CoV-2 virus for the first time. Vaccinated individuals already have a range of antibodies, including neutralizing antibodies, that can bind to the virus. In the case of the neutralizing antibodies, they target the receptor binding domain on the spike protein making it difficult, if not impossible, for the virus to attach to the ACE-2 receptor on a cell in order to enter the cell. In addition, you have heard a lot about T-cells, but there is another part of the cellular immune system called B-cells, cells that can be turned on to produce huge amounts of antibodies to a specific invader. When vaccinated, some of these B-cells become memory B-cells that will then already be primed with the instructions and machinery to produce large amounts of these specific antibodies, so while it can take a week or 10 days for an unvaccinated person to make these new antibodies in response to encountering the virus, these memory B-cells can crank out these specific antibodies in just a few days to augment what antibodies are already circulating.

Now when the virus is breathed in your nose or throat and does reach cells that have the ACE-2 receptors in your airways, the receptor binding domain on the spike protein will align itself with the ACE-2 receptor on the cell surface (imagine a space shuttle docking to the international space station). We believe that the better the fit and the stronger the binding between the virus’ receptor binding domain and the cell’s surface ACE-2 receptor (we call this binding affinity), the more the newly infected person will be able to infect others and the more severe disease the infected person is likely to get. Once attached, the membrane of the SARS-CoV-2 virus will fuse to the membrane of the cell and the cell will essentially engulf and swallow the virus. Think of a cell like an egg that you have cracked open and poured into a skillet. The yellow part of the egg would be the analogy to the nucleus of the cell. The white part of the egg is the analogy to the cytoplasm of the cell. The virus is now in the cytoplasm of the cell. This is where the cell keeps its machinery to produce proteins, in ordinary conditions according to instructions that originate in the DNA in the nucleus of the cell that are copied by RNA and then the cell’s messenger RNA (mRNA) will take that message from the nucleus to the cytoplasm to the cell’s machinery (ribosomes, endoplasmic reticulum and Golgi apparatus) that will produce proteins needed by the cell according to those instructions.

However, once the cell is infected, the virus takes control of the cell’s protein-making equipment and instructs it according to the RNA of the virus, to make viral proteins and particles. As these come off of the production line of the cell’s machinery, the pieces are assembled to create new complete viruses that can be released from the cell to go out and infect other cells. Since each time a virus successfully enters a cell, it results in the production of many progeny, you can begin to see why minimizing the time we are in proximity to someone who is infected and shedding infectious virus, being outdoors or having good ventilation indoors to minimize the number of virus particles suspended in air that we might breathe in and wearing a well-fitting high grade mask will all serve to help protect us from getting infected, but even if we do get infected, it will minimize the number of invading viruses (the viral dose). With a lower viral dose, we have a better fighting chance. Our tears, our nasal secretions and saliva all play roles in decreasing the numbers of virus particles that get through to invade our bodies. Then, our innate immune system kicks in, and you can see how we are advantaged if we have already been vaccinated and have antibodies at the ready that can attach to the spike protein and prevent or impede the ability of the virus particles to successfully bind to the cell surface ACE-2 receptors. The more virus particles that are prevented from entering cells, the fewer new virus particles produced. Remember from above, even if the antibodies don’t completely block the virus from entering the cell, if they just make the fit less tight between the spike protein (receptor binding domain) and the ACE-2 receptor on the cell due to the physical interference from the attached antibody, it appears that the newly infected person will be less likely to transmit the virus to others and is likely to have milder disease.

Now, we are going to back and fill in some more details, because in many cases, it appears that the hyper-inflammatory and dysregulated immune response to the infection may be causing more of the damage to the body than the direct viral infection of cells. This likely helps to explain why we see such a range in illness from those who are asymptomatic or mildly ill to those who end up on ventilators in the ICU and even die. Of note, though co-infections have been reported (e.g., infection with both SARS-CoV-2 and influenza virus or SARS-CoV-2 with Respiratory Syncytial Virus), we will not be discussing the impact of co-infection in this pathophysiology review. Further, another complication of severe COVID-19 and its treatment can be superinfection (i.e., a subsequent bacterial or fungal infection that occurs during the treatment of the COVID-19 infection – the latter was a big problem in India), and similarly, this pathophysiology review will not explore the implications of such an additional infection.

To further understand how SARS-CoV-2 infection can result in severe COVID-19 in some people, we must examine more closely the hyper-inflammatory state that can be induced and the immune dysregulation that can occur. First, we examine the innate immune system reaction to the virus.

Our innate immune system is on guard for either bacterial or viral invaders. You likely have experienced the consequences of the former if you have ever had an infected cut or strep throat – pain, swelling, and soreness – evidence of our body’s innate immune system reacting to the bacterial invader and trying to stop it. We have already discussed the ACE-2 receptor on the cell surface to which the SARS-CoV-2 virus binds in order to enter cells. Humans have at least 10 different “toll-like” receptors (TLRs) that bind to various types of molecules that are commonly associated with bacteria, viruses, fungi and protozoal parasites. One in particular (TLR 4), binds to lipopolysaccharide (LPS) (a common structural component of bacterial cell walls made up of a fat and a sugar), and when LPS binds to it, it signals the release of inflammatory chemicals (cytokines – a wide variety of pro- and anti-inflammatory factors such as interleukins (I will refer to those as IL followed by a number to indicate which specific interleukin), tumor necrosis factor (TNF), and interferons (I will refer to those as IFN followed by a Greek letter to indicate the specific interferon) and chemokines – a subset of cytokines that have the special function of “chemotaxis” – attracting specific white blood cells to come to the site of invasion to assist in killing the invaders). Keep in mind that the SARS-CoV-2 virus enters the body at sites that already have bacteria lining the surfaces (nose, throat, and perhaps the gastrointestinal tract), and as I mentioned above, some people, especially when they require treatment in the hospital with steroids can develop superinfections with bacteria. Further, there can be LPS in the blood due to the fact that our bodies are constantly fending off bacterial would-be invaders. It turns out that the spike protein of the SARS-CoV-2 virus can bind to LPS and together this can interact with TLR 4 to cause release of cytokines and chemokines that can cause inflammation and recruitment of certain white blood cells that cause further damage to the cells and tissues where the virus is invading. and

As you will see with this blog series, the immune system is made up of many components that under normal circumstances, strive to maintain a balance between responding enough to successfully thwart an invader, but not too much that an overexuberant response will harm the host (the body’s effort to ensure that the “cure” is not worse than the disease). There are many ways in which the SARS-CoV-2 virus can tip the scales in terms of promoting overreaction by the immune system, and this binding of the SARS-CoV-2 virus with LPS that stimulates an exuberant reaction is just one example. The one good thing that comes from this release of cytokines is that they specifically activate helper T-cells (CD4+), which enable the development and production of more and better SARS-CoV-2 specific antibodies.

Unfortunately, this is not the only mechanism whereby pro-inflammatory cytokines are released, and in fact, when excessive, we refer to this as cytokine storm, a condition of excessive inflammation that renders patients critically ill. This “cytokine storm” or similar phenomenon is common in our COVID-19 ICU patients and in children that develop MIS-C (Multi-System Inflammatory Syndrome – Children), except that it occurs with the acute infection in those in the ICU and occurs weeks to months following the acute infection in children.

I made reference to certain white blood cells above. There are many kinds of white blood cells and they have differing functions, but there are four types that are important for our discussion in this blog series – lymphocytes (these include, among others, T-cells and B-cells), monocytes (specialized cells that play a large role in attacking invading viruses, bacteria, fungi and protozoal parasites, breaking them down and ridding the body of them), neutrophils (white blood cells that we typically associate with bacterial infections, but ones that get recruited to the scene of infection with SARS-CoV-2 in certain instances in response to specific chemokines and then wreak havoc) and macrophages (cells that detect, engulf [phagocytose] invaders and present the antigens of the invader to T-cells to assist with the cellular immune response to the invading would-be pathogen).

We all have macrophages in our lungs to clean up debris and to go after any bacteria or viruses that get past our upper airway defenses to settle into our lungs and attempt to cause infection of the lungs. Within the cytoplasm (remember, that is the white of the egg in our analogy of a cell) of the macrophages are inflammasomes – sensors that trigger the release of pro-inflammatory cytokines and proteases (enzymes that degrade certain proteins, such as elastase, collagenase, cathepsin and metalloproteinase).

Initially, we focused on the cells in our nose, throat, nasopharynx, airways and lungs as sites of infection where the SARS-CoV-2 virus was entering and causing all this damage directly or indirectly. Then we became aware that the virus was invading many other cells, including those of many of our organs, but also endothelial cells (the cells that line our blood vessels). Most recently, we have learned that the virus can even infect the immune cells that are responding to fight the virus! Few other viruses do this. (I hope you are beginning to see that COVID-19 is not just like a cold or the flu).

This is likely difficult for you to understand (but I will help you over the course of the remainder of the blog series), but as a consequence of all of this, in some patients with COVID-19 (and it appears that parts of this are not just limited to those who get severely ill), there are paradoxically two things going on at the same time – the immune system goes into overdrive trying to fight off the invading virus, while the immune system also becomes somewhat dysfunctional resulting in potential harm to the body. (more on this latter)

Now, back to our macrophages (these are those scavenger white blood cells that are attracted to sites of infection by chemokines ( As mentioned above, there are some macrophages that take up residence in our lungs and stay on duty, cleaning up debris and fighting any infection that can bypass the defenses of our upper airways.

A recent study ( describes a cascade of events that begins with infection of these lung macrophages by the SARS-CoV-2 (this was very surprising to me), but fortunately little replication of the virus within macrophages occurs (probably because unlike lung cells that can efficiently produce virus when infected; macrophages are designed to engulf and destroy viruses and the inflammasome pathway is a critical piece of this ability to do so). However, the viral replication that does occur within the macrophages activates inflammasomes within the macrophages (remember, these are the sensors that in turn trigger the release of pro-inflammatory cytokines (including IL-1β and IL-18, the latter has been associated with severe COVID-19) and proteases (enzymes that degrade certain proteins). Another unfortunate consequence of this exuberant response to infection is that this kind of inflammation actually triggers a programmed cell death of the macrophages (pyroptosis) – in essence, the cell being pre-wired with explosives to blow itself up if the enemy takes it over. While the inflammasome activation is important to fighting viruses that get down to the lungs, the excessive inflammation that results may be one of the keys to the excessive inflammation that typifies Long COVID as well as the lung damage that can result in lung scarring (fibrosis) and has resulted in so much damage that some people have even required lung transplantation following their recovery from the acute infection.

Macrophages are not the only immune cell that can be infected by the SARS-CoV-2 virus I mentioned above in the short list of types of white blood cells that we will discuss because of their role in the pathogenesis of COVID-19 – monocytes. Monocytes are another type of white blood cell that plays an important role in innate immunity, being on the prowl for evidence of an invading virus. They, too, form inflammasomes that signal infection, trigger pyroptosis and lead to the release of potent cytokines, but rather than being stationed in tissues, like the lungs, monocytes circulate in the blood. The authors of this study demonstrated that up to 10% of monocytes were infected with SARS-CoV-2 in patients presenting to the emergency room for evaluation of their COVID-19.

The mechanism by which the virus enters monocytes is different than the mechanism by which it infects cells lining the airways and lungs (monocytes do not have ACE-2 receptors on their cell surface). Monocytes have different receptors that recognize antibodies attached to the virus, which causes the monocytes to attach to the virus-antibody complex in their effort to kill the virus and clear it from the body. However, with SARS-CoV-2, this binding could result in the monocytes themselves becoming infected. This is a form of antibody-mediated disease enhancement (ADE). Ironically, some physicians who spread disinformation have alleged that ADE is a significant risk with COVID-19 vaccination (which it is not), but in fact, we do see this phenomenon in these cases of infection.

This may be important not only for its role in further aggravating the inflammatory state by triggering the release of many more cytokines, but we have wondered how the SARS-CoV-2 virus gets to so many internal organs once it enters the lungs. Some viruses have a viremic phase (transient period of actual virus circulating in the blood). That may be the case for SARS-CoV-2, but as far as I am aware, we have never identified that. An alternative explanation may be that the virus is being carried by these infected immune cells that do circulate in the blood, do travel to various organs and in some cases, do take up residence in lymphoid tissues (such as your tonsils, gut and lymph nodes).

There is another remarkable thing these investigators discovered. The monocytes only took up the virus that was attached to antibodies from infection (the range of antibodies resulting from infection and from vaccination are very different); not when the antibodies were generated by the mRNA vaccines. This may be another reason why those who develop severe COVID-19 tend to be the unvaccinated. I have a relative who told me that his antibodies resulting from infection were much better than mine resulting from vaccination. Turns out, he may be wrong for several reasons.

Cytokines, and especially IL-8, attract neutrophils, a type of white blood cell that we typically see attack and kill bacteria. In the case of the cytokine storm, we see many neutrophils attracted to the sites of infection, like the lungs. IL-17 then activates the neutrophils. Activated neutrophils can release proteins that promote programmed cell death of the lung cells (apoptosis) and that contribute to immunological stimulation of blood clotting.

There are other changes to immune cells that we will discuss later in this blog series, but the direct infection of certain immune cells, as well as the resulting pyroptosis, may contribute to decreases in white blood cell counts that have been associated with more severe disease and worse outcomes. Lymphopenia (low lymphocyte count) is particularly associated with these worse outcomes and recall that lymphocytes encompass T-cells, B-cells and natural killer cells, among others.

Another key mediator of the body’s defense in fighting invading viruses is interferon. Interferon is very important to controlling the spread of the virus. Entry into certain cells by the virus will induce genes within the cell to produce and release this chemical messenger to surrounding cells. In essence, imagine thieves breaking into a house with the intent to go house-by-house up the street in the neighborhood to break into them, as well. When the first house (cell in this case) gets broken into (entered by the virus), an alarm system is triggered (release of Interferon) that notifies all its neighbors to lock their doors and windows, secure all entry points and put the deadbolts on. It doesn’t mean that those other houses (cells) can’t be entered, but it makes it much more difficult and slows the thieves (virus) down.

In addition, interferons can also interfere (get it?) with viral replication in the infected cell, this being a good thing to reduce the viral load that a patient is dealing with. Interferons, a type of cytokine, can also activate macrophages, cytotoxic T-cells (CD8+, these are the T-cells that attack and kill infected cells to prevent further replication of the virus as part of the cellular immune response) and natural killer cells (we haven’t discussed these yet. They are a specialized type of white blood cells – a subset of lymphocytes – that kill infected cells as part of the innate immune response. They do not need to be pre-programmed like the CD8+ cells of the cellular immune response by having seen and processed the antigens (the proteins that antibodies are designed to attach to) of the virus (e.g., the spike protein in the case of SARS-CoV-2). The natural killer cells recognize that cells are infected and they in essence puncture the cell wall of the infected cell and introduce a powerful enzyme causing the infected cell to implode.)

When you got a fever in the past with a viral infection, you probably have your interferons to thank for it. (In case you are interested, fever is itself a defense against many organisms that cannot survive higher temperatures or are slowed down in their replication by higher temperatures).

Interferons also play a major role in modulating the immune response (i.e., tying to make sure we kill the bad guy with the attack, but not all the surrounding innocent people and buildings). But, like most everything else we have discussed or will discuss, when anything in the immune response is too little or too late, we are in danger of the infection being uncontrolled; and when anything in the immune response is too much or too long, we are in danger of the immune response harming us. In fact, one of the hallmarks of severe COIVD-19 is a delayed, and then sustained interferon response. The delayed interferon response appears to be due to the replicating virus being packaged in membrane covered vesicles and spherules that prevent the innate immune sensors in the infected cells from recognizing the virus and also due to proteins on the virus, but not associated with the spike protein that suppress interferon production and hamper signaling to other cells. An appropriate interferon response is critical to limiting viral replication and dissemination and to limiting the programmed destruction of infected cells (apoptosis) in order to protect the host. So, the next time you hear someone tell you that they think they are building up their immunity to COVID-19 by repeatedly getting infected with SARS-CoV-2 variants, you can now cringe like I do!

We still have a few more concepts we need to cover on COVID-19 pathogenesis. We will save the discussion about the pathogenesis of Long COVID and other health consequences of infection for the next blog piece, as all of this lays the ground work for that discussion.

We have discussed how the SARS-CoV-2 virus can trigger the release of an excessive amount of pro-inflammatory cytokines (e.g., IL-6, IL-8, IL-17, TNF-α and IFNϒ). These levels (as well as IL-2, IL-7, IL-10, granulocyte colony stimulating factor (G-CSF), have correlated with disease severity in COVID-19 and even death. Unfortunately, in those who develop severe illness, we find that some of the cytokines that are anti-inflammatory (IFNα/β) and IFNϒ are diminished and delayed in their release. Another marker in the blood of severe COVID-19 patients that we commonly test for in hospitalized patients is lactate dehydrogenase (LDH). LDH is commonly elevated when cells are destroyed and it can be evidence of pyroptosis that we discussed above.

Another element of the pathology of COVID-19 that has been vexing and unlike what we have generally seen with viral infections has been the development of both microclots (microthrombosis) and large blood clots that have in some cases blocked arteries (when you hear about a friend or family member having blood clots prior to COVID-19, these are almost always clots in veins. The difference is that if you block a vein, in many cases, your body will build redundancy around it so that it doesn’t threaten the viability of the extremity, but in the case of a clot to an artery, these can threaten the loss of the extremity in a matter of hours. Unfortunately, this has caused the need for amputation of limbs in some young adults with severe COVID-19). These larger blood clots have caused strokes, heart attacks, pulmonary emboli (blood clots that travel to the lungs) and even sudden death (often a massive pulmonary embolus).

When we have looked at lungs from patients who have died of COVID-19, it is not just the infection of the lung cells and the eventual destruction of the cells and resultant scarring (fibrosis) of the lungs, we see these very unusual microclots throughout the lungs. This is really important because your lungs are designed to breathe in oxygen from the air and then have that oxygen cross the thin air sacs of the lungs (called alveoli) into the blood vessels that abut them in order to oxygenate your blood. But, these microclots impede that oxygenation of the blood and this in turn can pose the risk that the organs of your body don’t get enough oxygen and are harmed.

We have covered a lot, but we need to explore one more concept and then we can move on in the next blog piece to discuss what may be the pathogenesis and pathophysiology leading to Long COVID and other post-COVID health consequences.

This last concept relates to the fact that there is a sequence of amino acids in the spike protein of the SARS-CoV-2 virus that functions as a “superantigen.” Antigens are the structural components of a foreign substance or pathogen that are recognizable by our immune system and that trigger the development of antibodies that are specific to those antigens. Normally, an antigen will stimulate the development of a single clone of B-cells and T-cells, and these clones will represent only a small fraction of all the B-cells or T-cells. However, “superantigens” stimulate 5 – 20% or more of all the T-cells. This large-scale T-cell activation and proliferation results in hyperinflammation and cytokine storm. Unfortunately, superantigens are also implicated in the development of autoimmunity (the production of an immune response against parts of the patient’s own body) by triggering self-reactive T-cells.


  1. COVID-19 can manifest itself differently in different people due to age, underlying health conditions, the particular variant involved, the viral dose, prior infection history and genetics.
  2. The infection is transmitted by aerosols and respiratory droplets.
  3. The virus first tries to make its way into the cells lining the nose, throat and nasopharynx by attaching to the ACE-2 receptors on the cell surface. If not stopped, the virus can move down the airways into the lungs. Vaccination plays a huge role in limiting the replication and dissemination of the SARS-CoV-2 virus, and thus, helping protect against severe disease.
  4. Infected immune cells prompt a massive inflammatory response that helps contain the SARS-CoV-2 infection, but can inflict harm on the host at the same time. Antibodies generated in response to prior infection, but not vaccination, can facilitate the entry of virus into monocytes, and these cells may play a role in transporting the virus to other parts of the body.
  5. We have known that hospitalization lags infection by about a week since early in the pandemic. The association of worsening clinical progression during a time in which we generally see declining viral loads, and the development of critical illness occurring at the time we generally see the adaptive immune response kicking into full gear and a significant increase in inflammatory markers (cytokines, chemokines, LDH and C-reactive protein) all support an exuberant immune response and inflammation as playing a significant role in the pathogenesis of severe COVID-19.
  6. Another key factor in the development of severe COVID-19 and organ damage is the development of blood clots, both large and small. These blood clots can be life threatening (heart attacks, strokes and pulmonary emboli) when larger, but lead to organ damage when small by blocking small vessels that are important for delivering oxygen to the organs or other parts of the body.
  7. SARS-CoV-2 is different from many viruses, and all the previous coronaviruses that we have known to infect humans in that it contains a superantigen. This superantigen can trigger massive amounts of the body’s T-cells further contributing to hyperinflammation, an overly exuberant immune response to infection, and potentially to the development of autoimmunity.

6 thoughts on “Pathogenesis and Pathophysiology of COVID-19 and Long Term COVID-19 Health Consequences

  1. Dr. Pate, one question I have is: I know that Vitamin C is great against colds/flu, I normally use “Airborne/EmergencyC” when I first start getting a cold or flu or something of that sort. Does the increased use of these types of vitamins actually make C-19 worst? Thanks!


      1. Dr. Pate,
        Thanks much for the summary, seems that the evidence can go one way or the other according to the case facts, but need more trials it seems. Looks like I can continue to use my Vitamin C supplementals for now.


      2. I think that is right, Greg. Very unlikely it would hurt. Studies on vitamins and supplements for any condition have always been difficult when it comes to trying to prove a benefit.


  2. “Unfortunately, this is not the only mechanism whereby pro-inflammatory cytokines are released, and in fact, when excessive, we refer to this as cytokine storm, a condition of excessive inflammation that renders patients critically ill.”

    This is something that happens in a tiny minority of those infected with SARS-COV-2. Why only in them? Perhaps the following article will give us a clue.

    “The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.”


  3. Doesn’t it seem that vascular endothelial cells are prime targets for infection by covid virus? If so, then wouldn’t virus be produced heavily in those cells and released into the blood?

    Surely, we see lots of microvascular damage from the immune response to infected vascular endothelial cells (especially capillaries).


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