Why some patients get long haul COVID

Causes of long COVID remain murky, but researchers continue to discover possible explanations

It’s estimated that some 10-30 percent of COVID cases result in long-haul COVID. Even a mild SARS-CoV-2 infection can cause long COVID. The high transmissibility of the Omicron variant means this number could continue to increase.

Research by Dr. Bruce Patterson et. al. shows that chronic COVID-19 symptoms termed post-acute sequelae SARS-CoV-2 infection (PASC) may affect up to 30 percent of all infected individuals.  

Dr. Mobeeen Syed, CEO of Drbeen Corp, a modern online medical education marketplace, says, “That is a pandemic in itself.”

Whether it’s brain fog, loss of smell, fatigue, heart palpitations or many other combinations of ailments, the symptoms of long COVID are disruptive and even debilitating. In some cases, they can last for months or more.

With so many patients affected, doctors and researchers are trying to identify the reasons some patients develop long haul COVID and determine the best course of treatment to help them.

 

Chronic disease doctors now treating long COVID

Those physicians who are already managing chronic diseases are now seeing a significant influx of new patients dealing with symptoms of long COVID that resemble symptoms of other chronic diseases. 

Syed says, “These patients are now part of our daily life, and they’re suffering. The misery just continues.” 

 

What causes long COVID

Those physicians who are already managing chronic diseases are now seeing a significant influx of new patients dealing with symptoms of long COVID that resemble symptoms of other chronic diseases. 

Syed says, “These patients are now part of our daily life, and they’re suffering. The misery just continues.”

 

What causes long COVID

Researchers are still studying what causes some COVID patients to recover while others suffer from long haul COVID. However, there are some theories about the cause of long COVID. 

Following are some theories why some patients suffer from long COVID:

• Viral “hit and run” that leads to immune dysregulation
• S1 protein segments in monocytes
• Blood cell morphology change
• Auto-antibodies to ACE2
• Blood supply interruption to the vestibulocochlear system
• RNA-less virion persistence in other tissue 
• Mast cell activation syndrome (MCAS)
• Macrophage activation syndrome (MAS)

 

The “hit and run” theory for long COVID

Dr. Syed describes the first hypothesis for the cause of long COVID in some patients based on a theory in immunology of a virus “hit-and-run” mechanism. This theory proposes that a virus can trigger a chronic disease, resulting in lasting immune abnormalities that cause some pathology. Even once the virus is wiped out by the immune system response, the immune system itself remains dysregulated. As this continues, it becomes the basis for a chronic disease. 

“I think the hit and run theory is very much possible with COVID,” says Dr. Syed.

 

S1 protein segments in monocytes theory for long COVID

The second possibility is that the spike protein piece remains in the monocyte. Monocytes are a type of white blood cell (leukocytes) that reside in the blood and tissues to find and destroy germs. The monocytes carry pieces of spike protein for a long period of time. 

Here’s how the spike protein works in normal immune function: 

1. On the SARS-CoV-2 virus, the spike protein is divided for its functional pieces. It has a receptor binding domain (RBD). This is where it binds to ACE2. 
2. The remaining part of the spike protein is made up of two parts, an S1 unit and an S2 unit. When the virus docks with the ACE2, the surface protein cleaves a part of the S1 from S2, which causes the spike protein to become separated. 
3. S1 remains stuck to the ACE2. It gets recycled or downregulated and brought into the cell for digestion. The S1 part is sitting in the monocyte.
4. The S2 portion acts as a fusion protein, connecting with the cell membrane. Then, it allows the virus to fuse and send the RNA in. 

This is the normal immune function. However, for some people with long COVID, the S1 part ends up in monocytes for months. One study found persistence of SARS CoV-2 S1 protein in monocytes in patients for up to 15 months post-acute infection compared to healthy controls.

Having this antigen inside the monocyte causes the cells to become dysregulated. It continues to be triggered and make cytokines, which causes continuous inflammation.  

Monocytes normally have a short lifespan. This study discusses the possibility that the continuous irritation of the monocyte keeps it from becoming cleared out. Or as one monocyte is eaten up by another, in some cases, perhaps the spike protein just transfers from cell to cell. 

 

Blood cell morphology change theory for long COVID

Another theory of what causes long COVID is a blood cell morphology change. This is where the shape of blood cells change, especially the red blood cells (RBD). Researchers in this study were able to observe that COVID-19 infection causes significant changes in the size and stiffness of red and white blood cells, sometimes lasting several months. 

Findings show there is a change in the membrane lipids, which makes the cell a little more rigid. There may be microtubular changes as well. The exact pathology is still not clear, but researchers observed the shape changes. 

The end result is that the cells become a little more rigid, and their shapes become dysmorphic. This makes it harder for blood cells to move around in the blood vessels, instead getting stuck and causing issues. Dysmorphic cells have a propensity toward clotting as well. 

These findings may help to explain why some patients suffer from long haul COVID symptoms caused by inflammation, long after first contracting the virus.

The researchers found that the red blood cells and white blood cells can lose their morphological structure during COVID, becoming a little rigid. When this happens, red blood cells can get stuck in various blood vessels, causing clotting and blood flow disruptions.

Dr. Syed explains two simultaneous problems for the blood vessels that is a possible mechanism for what is happening in long COVID:

1. Inside the blood vessels, there are issues with the clotting because the blood cell shape changes. 
2. Outside of the blood vessel, there are monocytes that are dysregulated. 

“The blood vessel is attacked from both sides, it’s inflamed, the blood flow is disrupted and clotting is occurring,” says Dr. Syed.

 

Auto-antibodies to ACE2 theory for what causes long COVID

The auto-antibodies to ACE2 is another mechanism that may be leading to long COVID. ACE2 is angiotensin converting enzyme-2, which has been identified as the receptor for the SARS-CoV-2 viral entry. 

According to this theory, the body produces anti-idiotypic antibodies as it tries to return to homeostasis. Anti-idiotypic antibodies bind to the variable region of another antibody, working against it. This is because this antibody’s binding region looks like the spike protein’s binding region. When it starts binding to the ACE2 receptor, this causes dysregulation.

This is how the homeostatic mechanism normally works: 

1. A pathogen enters the body
2. The body produces antibodies to the pathogen 
3. The body produces auto-antibodies to the antibodies 
4. The pathogen leaves
5. The antibodies to the pathogen leave 
6. The auto antibodies leave. 

That is the normal sequence. But in some people, the sequence fails, and the auto-antibodies remain, binding to ACE2 and causing dysregulation. 

Researchers in this study, Development of ACE2 autoantibodies after SARS-CoV-2 infection, found an abundance of Ang II, which causes a proinflammatory state that triggers symptoms of PASC, or long COVID. 

Researchers found that 93 percent of hospitalized patients had these auto-antibodies, and 40 percent of outpatients had them. Most of them got cleared out within a couple of months, but for some people, these auto-antibodies persisted.

Some percentage of people cannot eliminate those anti-antibodies, or anti-idiotype antibodies. They instead continue to attack the body because they look like the original antigen. 

Dr. Syed says, “ACE2 has a hugely important function in our body to manage inflammation. As soon as we disrupt ACE2, we put the body in a chronic inflammatory state. And that is the underlying problem with chronic diseases.”

 

RNA-less virion persistence in other tissue theory for long COVID

There are studies like this one that indicate that debris of the virus can continue to stick in the gastrointestinal tract cells for up to 59 days after the virus symptoms have subsided, says Dr. Syed. 

Broken RNA pieces inside the cells help build the immune system’s strength against future exposure by affinity maturation. This is a process where the antigen is exposed through follicular dendritic cells to B and T cells, making them more capable of attacking this antigen in the future. 

Some studies say that this continuous presence of messenger pieces of RNA are actually disrupting the local immune system, and causing local inflammation, says Dr. Syed. “This creates a lot of GIT-related long COVID symptoms. So far, the studies have not shown viable virus, but they have shown invisible pieces of virus, which may be immune dysregulating.”

 

MCAS theory for long COVID

One possible reason patients experience long COVID is because mast cell activation syndrome (MCAS) could be unmasked by dysregulation of the immune system. Mast cells are allergy cells responsible for immediate allergic reactions. 

With long COVID, a patient who actually has allergies and is not aware of it, may suddenly start experiencing MCAS. Some people who already have MCAS prior to contracting COVD may get flare ups post acute infection. 

 

Long COVID symptoms can persist for months

Whatever the cause of long COVID, it’s clear that millions of people deal with the aftermath of COVID for weeks, months and even more.

Long COVID can affect whole systems, including any one or combination of the following: 

• Gastrointestinal (GI)
• Respiratory
• Musculoskeletal
• Cardiovascular
• Autonomic
• Neurological

Dr. Syed says the course of the disease has hills and valleys where a patient feels better and then they feel worse. “They just keep going through that process. There’s persistent low intensity, persistent relapse to high intensity, temporary improvement with intervention and eventually permanent improvement.” 

 

Loss of smell in long COVID

One particularly frustrating symptom of long COVID for those who otherwise recover from all other symptoms is anosmia. Anosmia, or loss of smell, was first recognized as an indicator of COVID and now is also known as a common outcome of long COVID. 

Anosmia or hyposmia, which is reduced smell, are both common symptoms of long COVID. Researchers have shown that the epithelium of the olfactory bulb and the supporting cells – not the neurological pieces or the olfactory nerve – become infected. That local inflammation presses on the olfactory neurons and causes them to dysfunction. Plus, because there is an inflammation of the epithelium. If there is damage to the epithelium, that damages the whole system’s function. 

Like every other symptom of long COVID, anosmia gradually goes away on its own for many people. Others can recover with medical intervention. But for some patients, loss of smell persists for months or more.

Doctors, scientists and patients themselves who suffer from long COVID will continue to seek answers both for what causes long COVID and what cures it.

Dr. Mobeen Syed, “Dr. Been,” is CEO of drbeen.com, and host of DrBeen Med Ed, medical lectures on YouTube.