As of February 2022, about 100 million people worldwide suffer from long COVID, and, considering that we likely haven’t tested and detected every case, that number is bound to rise dramatically. But according to new scientific research, we might have a promising new way to combat long COVID.
What is Long Disease?
Long COVID sufferers often experience extended brain fog, general weakness and fatigue, sleep difficulties and anxiety or depression, as outlined by the CDC. Some “long haulers” who partially or completely lost their sense of smell during their illness might also experience an alteration of smell in the long term – in some cases, permanently. In fact, according to a 2021 study, somewhere between 700,000 to 1.6 million Americans who had COVID-19, lost their sense of smell for six months or longer, which equates to approximately 43.75% of cases becoming long haulers.
But what is “long disease”? Does it essentially mean having a disease or illness for a “long” time? Although many of us may not have heard of long disease before, the concept is not new. Polio, once a threatening and infectious disease, includes symptoms such as sore throat, vomiting, fever and headache, which last about two to five days. In fact, polio is incredibly similar to the flu. However, when we think of polio, we think of a person who has lost the use of their limbs and experiences paralysis. This is because many polio survivors develop Post Polio Syndrome — the long form of the disease, which includes symptoms like muscle weakness, paralysis and meningitis. These long symptoms can last somewhere between 15–40 years. We see a similar long disease in other recent breakouts, such as Ebola. Many Ebola survivors have developed long-term impairments in their colour vision and inflammation in the uvea layer of their eyes. Even a sizable number of SARS survivors from the 2003 outbreak experienced debilitating fatigue for 13-36 months after their initial infection. As such, in the context of COVID-19, authorities such as the CDC, define it as symptoms that last more than four weeks to months after infection.
The Mechanism of Long COVID
So why does long COVID happen? The answer boils down to the fact that the COVID virus overwhelms your body systematically. The virus enters a cell by binding to a receptor on the cell’s surface called the angiotensin-converting enzyme 2 (ACE2) receptor, and it begins wreaking havoc by replicating itself and setting off inflammatory responses from your immune system . The ACE2 receptor is found on the surface of many types of cells in your body, including your oral and nasal mucosal linings, lungs, heart, gastrointestinal tract, liver, kidneys, spleen, brain and even in the endothelial cells that make up your arteries and veins. This means that the virus can enter all of these cell types.
While the virus is replicating and spreading throughout your body, it enters cells in almost all of your tissues and sets off a chain reaction of inflammatory reactions from your immune system, which secretes proteins called “cytokines”. Cytokines effectively kill off pathogens that infect your body, but they can also damage your tissues and organs if they are stimulated systemically. Suddenly, you have chest pains, heart palpitations, lung dyspnea, cough, brain fog, delirium, pancreatitis, liver injury, kidney stresses, diarrhea, nausea, sore throat and a major inflammatory response — all at once. They also eventually degrade your lymphoid follicles in the spleen; normally, the lymphoid follicles function to produce B and T cells which help you fight infections, so the degradation or “atrophy” of the follicles makes you produce fewer of these B and T cells, and thus become more prone to infections.
And of course, there is the classic loss of smell or “anosmia” that seems to be a common long COVID symptom in patients. Interestingly, the olfactory neurons in our nose that detect smell do not express ACE2 receptors – so the virus cannot directly infect them or damage the brain. Rather, the virus infects the nearby support cells lining the nasal cavity and triggers an inflammatory response which damages the smell receptors on the neurons by proximity. This effect can be dangerous enough to cause a loss of smell. Although the resulting anosmia doesn’t permanently kill the olfactory neurons, it can persist, and long COVID patients have reported a continuing loss of smell.
Where the Microclots Come In
There is still a great deal of debate behind the risk factors that might make you more likely to experience long COVID. The usual risk factors include being 50 or older and having pre-existing medical conditions. However, this is not the full picture, as many young people, including children, have long COVID. About 30% of adults have long COVID symptoms, while somewhere between 2–10% of young teens and children (as young as nine) have long symptoms. This will inevitably impact them for the rest of their lives. We must try to better understand the mechanisms behind long COVID and how we can treat this chronic condition.
Recently, a research lab in South Africa has discovered an interesting new aspect of COVID infections: Not only does the infection affect the lungs, but it also significantly affects our body’s coagulation system. The coagulation system normally functions to produce blood clots and help you heal from injuries or wounds. The clots are made up of platelets and several clotting proteins, including plasminogen, fibrinogen, alpha-2 antiplasmin and Von Willebrand factor (VWF). The body normally breaks down the clots by a process called “fibrinolysis.” However, upon examining the blood of COVID patients, researchers observed the presence of microclots that persisted and resisted fibrinolysis. The researchers found that long COVID patients had nine times the levels of microclots in the delicate branches of their lungs compared to influenza patients.
The COVID virus contains a spike protein called the S1 subunit, which can interact with clotting proteins such as fibrinogen and prothrombin, as well as an inflammatory molecule in our body called complement 3 . Through a series of molecular changes, this can cause them to form microclots containing inflammatory molecules. These persistent microclots activate platelets to continue coagulating and thickening the blood, leading to adverse effects such as inefficient delivery of oxygen to cells and hypoxia (lack of adequate oxygen) in tissues and organs.
Thus, we see the continuous presence of inflammatory molecules in the body, and exhaustion and fatigue ensues. Not to mention, the inflammatory cytokines in your body can actually cross the blood brain barrier (BBB) and increasingly activate your sympathetic nervous system. The sympathetic nervous system normally activates your fight-or-flight instinct through a series of physiological pathways; although long COVID is not severe enough to trigger your fight-or-flight response, a mild constant activation of sympathetic nerves can keep you trapped in a sustained stress response. It can negatively impact your cardiac output, blood sugar, blood pressure, and it can even increase the intensity with which you feel pain.
Strangely, a long COVID patient will test negative for COVID, because the inflammatory molecules that blood tests typically measure will be “trapped” within the clots and thus many clinicians will miss the very real molecular signature of long COVID. This results in the patient being told that they’re healthy, despite feeling unwell or not quite back to normal, and it can be highly discouraging and frustrating.
The Recovery Process
Going forward, clinicians can look specifically at platelet counts or “plate-poor plasma” to measure coagulation levels in a patient’s blood and gain a better understanding of whether the patient has long COVID. As the number of cases continues to rise, and as we experience increasing incidences of long COVID, this will surely become a more common practice. Furthermore, the same researchers also found that anticoagulant treatments show enormous promise in reducing hypercoagulation in human subjects to restore oxygen delivery to tissues and organs. That being said, there’s still more research to do, including learning more about what factors predispose some people to form these persistent microclots and develop long COVID. With more clinical trials to test anticoagulant drugs and replicate positive results, we can eventually begin to prescribe these treatments to long haulers and help them recover from these chronic long-term impacts. Researchers should also explore other mechanisms that could be involved in long COVID, including a theoretical prediction from some immunologists that the virus persists in the body long after the illness, triggering small sustained inflammatory reactions.
But that will take time. In the meantime, what can we do? According to Gavin Francis, a GP in Edinburgh, the most important duty we have is to respect and guide patients through recovery. Certainly, a great deal of recovery from an illness has to do with receiving medication and physical care, but another important aspect is how we culturally perceive and cope with illness. Many people feel physically weakened and absolutely exhausted following a systemic viral infection. Instead of imposing a rigid time limit in which we expect them to immediately bounce back into the rhythm of their previous life, we should embrace the fact that recovery is different for every individual.
This means acknowledging that long COVID is a very real entity that has hindered many people’s ability to exercise, work, and simply concentrate on a task. Researchers and clinicians have to work with long haulers, listening to their symptoms and informing the public to better educate them on long COVID.
Our Perception of Long COVID
Our perception of COVID can significantly impact the outcomes for many people. According to demographics studies, minorities and people of colour are disproportionately affected by COVID. Researchers from McGill University looked at the COVID cases and census data across 16 metropolitan areas within BC, Manitoba, Ontario and Quebec. They found that COVID cases were substantially higher in areas with people who had lower income and areas with a higher population of visible minorities, recent immigrants, high-density housing and essential workers. With significantly higher COVID numbers among minorities, this is likely to be the case for long COVID cases too. This startling pattern is not unique to only Canada, as studies in other countries, including the United States and Sweden, have found similar disproportionate cases.
Additionally, one Georgia study found that when US media regularly covered racial disparities, it actually impacted their perception of COVID. White US residents appeared to have a “reduced fear of COVID-19” when they learned that it impacts racial minorities more. Their reduced fear also correlated with reduced empathy and lessened support for restrictions and safety precautions. These findings reflect the systemic racism experienced by marginalized communities and the occupational barriers that substantially decrease the health outcomes of many minorities. They also suggest that focusing public awareness on the racial disparities in cases of COVID and long COVID could create a “vicious cycle” of reduced support for policies that mitigate inequality and perpetuate the current disparities. Thus, these studies show time and time again that knowing or being informed about systemic racism is not enough to adequately combat it. It is therefore important for public health discussions to not centre around racial disparities, as that may lead some to perceive that ethnic groups may have an inherent genetic vulnerability to COVID. We have already seen this bias take shape before, as many North Americans and Western Europeans believe that Ebola is an “African problem”. Instead, education must focus on the more accurate message that COVID infection and long COVID could affect anyone.
COVID will influence our lives for years, or maybe decades. We don’t know yet if a person can ever fully recover from long COVID. We are expecting COVID survivors to immediately bounce back into work without accommodating long COVID or even discussing the wave of grief people are suffering as they reckon with the deaths of their loved ones who didn’t survive this devastating pandemic. We are also seeing a disproportionate number of long COVID in communities of already disenfranchised people. The research behind identifying and treating long COVID is promising but while we’re waiting to find out, we owe long haulers a warm and compassionate helping hand.