The Long Haul, Part 2: What Is Long COVID?
In the 1890s one of the biggest pandemics in recorded history, known then as the “Russian flu”, swept the world and killed one million people (for perspective, that is out of a world population about ¼ of today’s population). That “flu” is now thought to have been a novel coronavirus. Like the current coronavirus, SARS-CoV-2, the Russian “flu” was a new human pathogen so few people had any natural immunity to it and it was quite lethal. Not only that, but as the pandemic waned, it left in its wake a global wave of long-lasting neurological problems in the survivors. A similar long-lasting post-acute disease wave followed the next big pandemic, the “Spanish” flu of 1918 (which really was due to the influenza virus). The common symptom following the Spanish flu was lethargy so bad that in Tanganyika (modern-day Tanzania), for example, it caused a famine because people were too debilitated to pick the harvest. Other viral outbreaks, including SARS, MERS, and Ebola, also have been associated with long-term sequelae in survivors. However, today’s long COVID complications are far more common and far more variable than the persistent symptoms following these other viral pandemics. The variety of unrelated long COVID symptoms has flummoxed doctors hard pressed to diagnose and, hence, treat the constellation of chronic problems that appear in each patient.
As I wrote in Part 1 of this series, a wave of what has become known as “long COVID” is emerging in many people who have recovered from the acute disease. A recent review chronicling the effects of long COVID reported that “long haulers” commonly experience fatigue, sleep problems, and joint and muscle pain long after their bodies cleared the virus. Other symptoms range from the mundane to the bizarre: brain fog, shortness of breath, fatigue, tremors, tooth loss, racing heart, glaucoma, and diabetes among others. Long haulers are also at a significantly increased risk of dying months after infection. A large study found that after surviving acute COVID-19, patients had a 59% increased risk of dying within six months after their initial diagnosis. This translates into an extra eight deaths per 1000 patients. Thus, the consequences of the acute disease itself are just the tip of the iceberg.
Because the official definition of the chronic problem is fluid, we are still learning what this new malady is. A UK study published last December simply defined the syndrome as a collection of symptoms lasting for more than 28 days after initial diagnosis. However, another British study as well as Britain’s National Institute for Health and Care Excellence vaguely and broadly define long COVID as “signs and symptoms that develop during or after an infection consistent with COVID-19, and that continue for more than 12 weeks and are not explained by an alternative diagnosis”. It does not specify a list of what the symptoms are.
But, there are many. A global survey tallied 205 different symptoms across 10 different organ systems that can persist after COVID infection has cleared, including those affecting the heart, lungs, gastrointestinal system, muscles, and joints. There also are frequent neurological and neuropsychiatric symptoms as highlighted in Part 1 of this series. A sufferer typically has several of these problems at a time (14 different symptoms on average), with the most debilitating usually being one of three: severe breathlessness, fatigue, or “brain fog”. Other common symptoms included compromised function of the lungs, heart, and kidneys sometimes requiring transplantation. There also have been skin rashes, and newly diagnosed diabetes.
What exactly is long COVID? About the only thing we can say with any certitude at this time is that long COVID exists but is not easy to describe, possibly because it really is more than one malady. The only constant between different long COVID patients with different symptoms is that the conditions are a collection of varied symptoms that persist long after the acute disease subsides, which sounds as vague as the British definitions described above. Long COVID clearly represents a new health malady or maladies since it is not generally found in uninfected people, but is common in COVID survivors; yet not all COVID patients experience it. Long COVID can affect any post-COVID patient at any age, but it mostly presents in middle-aged people and seems to slightly prefer women. Even people with asymptomatic CoV-2 infection can have late arising effects that fit the profile of long COVID. Multiple studies have shown that infected people who do not get acutely ill can still show irregular lung scans, for example. One such study found that nearly 60% of people with asymptomatic infection showed some lung inflammation in CT scans. Other studies have shown that young people with asymptomatic or mild infections can have long lasting cardiac issues, while others show signs of small blood vessel damage.
Some of these symptoms can be similar to other recognized, if not fully understood chronic problems, such as chronic fatigue syndrome (CFS), which is one of the most common complaints that long haulers have. CFS remains a mystery malady with an unknown cause, but it often follows a viral or bacterial infection. It is, therefore, possible that long-COVID CFS-like problems might be no different from classic CFS. It also is possible that CFS-like long COVID symptoms are not at all related to what is recognized as classic CFS, and they are simply different illnesses with similar symptoms. Time and research will tell.
Broadly speaking, there are three types of long COVID patients, according to one NIH scientist. The first are generally characterized by “exercise intolerance”, meaning they feel out of breath and exhausted from even mild physical activity. The second are characterized by cognitive complaints like brain fog and/or memory problems. The third type experiences problems with the autonomic nervous system, which controls things like heartbeat, breathing and digestion. Patients in this group suffer from symptoms such as heart palpitations and dizziness. Impairments of the autonomic nervous system are known as dysautonomia, which is an umbrella term for a variety of syndromes. Physicians treating long-COVID patients say there has been a marked increase in dysautonomia since the pandemic began. A rehabilitation doctor at Mount Sinai Hospital, in New York, says that roughly 80% of people who show up at his long COVID clinic have dysautonomia of one type or another.
Not only do long COVID patients suffer chronic debilitation, they also are at increased risk of dying. One of the largest studies of Covid-19 “long haulers” found that COVID survivors had a 59% increased risk of dying within six months after contracting the SARS-CoV-2 virus. The excess mortality translates into about 8 extra deaths per 1,000 patients. Thus, the pandemic’s hidden toll is that many patients require readmission, and some die, weeks after the viral infection abates.
What causes long COVID? What causes the myriad of symptoms lumped under the long COVID umbrella are being studied, but it seems that not all are actually caused by the CoV-2 virus. Based on what we have gleaned from observations of a few million long COVID patients around the world, the focus is on three possible biological explanations. One is that long COVID is due to a persistent viral infection. A second possible cause could be an autoimmune disorder. The third possibility is that it is a lingering consequence of tissue damage caused by inflammation during the initial, acute infection.
Supporting the first hypothesis that the infection persists even after COVID disease has passed is that some patients very slowly clear the virus completely. The virus or its remnants persist along with the long lasting symptoms. These patients are not infectious so it could be that they harbor some altered form or fragment of the bug which does not replicate, but is nevertheless making some viral product that their bodies are responding to. This is known to occur with other viruses, including measles, dengue and Ebola. RNA viruses are particularly prone to this phenomenon, and CoV-2 is an RNA virus. Direct proof of this hypothesis is lacking, but pertinent clues abound. A study published recently in Nature showed that some people had traces of CoV-2 proteins in their intestines four months after they had recovered from acute COVID-19. Viral products from CoV-2 have also been found in people’s urine several months after their recovery. All this is circumstantial evidence, to be sure, but viral persistence is consistent with long COVID in certain patients.
The second hypothesis, that long COVID is an autoimmune disease, holds that the virus causes something to go awry with the immune system inciting it to attack some of the body’s own tissues. Some evidence backs this idea, too. The immune system is a complex, tightly regulated machine designed to discriminate between your own cells and foreign entities such as viruses. Sometimes this ability to distinguish self from non-self fails and an immune response is generated to one’s own tissues. Some patients suffering from long COVID have badly behaving macrophages, which are immune cells responsible for gobbling up foreign invaders and displaying them to immune cells inciting them to make antibodies or to kill infected cells. Other long COVID patients exhibit abnormal activation of their B-cells, which churn out antibodies against the pathogen that can sometimes cross-react with the body’s own cells causing complications. Since antibodies circulate for several months after an infection, it makes sense that this could cause problems months after recovery from the disease. Again, this evidence is circumstantial, but consistent with the observations in some long haulers.
The third hypothesis about the cause of long COVID holds that the body’s inflammatory response during the acute illness causes long-term damage to cells and tissues leading to chronic inflammation. This sometimes happens with other viral diseases, but it could be particularly likely with COVID-19 since out-of-control inflammation, caused by a cytokine “storm” is a common hallmark of severe cases of acute illness. One guess is that the inflammation damages parts of the autonomic nervous system, or that the virus might damage the cells that line blood vessels, either by infecting them directly and/or via inflammation from the immune response. This could change the way blood flows to the brain and other organs, and may thus explain the brain fog and other organ failure that is sometimes seen. This too remains circumstantial, but consistent with current observations in certain patients.
Bottom line: Long COVID probably embraces several different chronic conditions with different causes. Studies to investigate each of these possibilities are under way.
We will see.