brain fog

The Long Haul, Part 4: The Cost of Long COVID In Terms Of Individual Health And Quality Of Life

Surviving COVID-19 is one thing, recovering is another.

My frustration with those who would minimize the impact of COVID-19 is reaching an apex. I constantly have to deal with their baseless rationalizations that “it is just a cold,” or “it only kills 0.01% of people” (actually the number is 2% around the world), etc. And I constantly reply to these iconoclasts that COVID has become, by far, the leading killer in the US. I also explain over and over that treating simple mortality percentage as the only relevant statistic to consider is falderal. For example, the Spanish flu also killed “only” 2% of those infected, but in just 24 weeks, that virus killed more people around the world than were killed in WWI AND WWII together! The percent figure is meaningless without considering the percent of what. Why do they continue to ignore the devisor and, hence, the total number of deaths?

A small percentage of a very large number is, in fact, another large number.

Those who wish to downplay the significance of the pandemic only focus on this mortality percent, but mortality is NEVER the whole story for any pandemic. A serious person will also consider the morbidity caused by the disease. In fact, the major CDC publication on health in the US is called the Morbidity and Mortality Weekly Report. Notice that it considers both morbidity and mortality, and further notice that morbidity is listed first in the title. I have made three prior posts in this series on Long COVID, about the significant lasting morbidity of COVID-19. You can see these posts here, here, and here. In those posts, I shared data showing that some ~10-30% of COVID survivors suffer serious health problems that last months.

In those posts, I mentioned the cases of a young, healthy MD, and of a young, healthy journalist, both of whom struggled with long COVID, and how it affected their careers and cost them thousands of dollars in out-of-pocket expenses for the dozens of tests and doctors they needed. In an article in Maclean’s magazine, a reporter interviewed many Canadian long COVID patients and heard how their lives have been turned upside down. They reported that they are unable to live like they used to and care for their families, do anything mildly strenuous, or even cook their meals. They spend long stretches of time in bed. Many of those interviewed had not returned to work several weeks after recovering from the acute disease.

Anecdotes like these have been repeated millions of times around a world that, according to the Johns Hopkins University COVID tracker, has seen more than 330 million cases of COVID (and this is a significant undercount since many countries do not record these data well). Research has corroborated these anecdotes.

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Common long-term symptoms include debilitating fatigue; respiratory problems; and “brain fog.”  Other common symptoms include compromised function of the heart, and kidneys, which sometimes require transplantation. Wide-spread clotting problems can cause significant illness and even limb amputation. There also are frequent neurological and neuropsychiatric symptoms as highlighted in Part 3 of this series. Surprising manifestations continue to emerge, such as new-onset diabetes.

Lung scarring often occurs in patients who experienced COVID-caused acute respiratory distress syndrome (ARDS), a common problem seen in acute COVID patients who required ICU care. ARDS is a serious respiratory problem that can be caused by different respiratory viruses and other things. About a third of patients with ARDS arising from any cause were unemployed 5-years later because of their lung damage. It is fully expected that patients with COVID-related ARDS will be found to fare similarly.

There also is the dysfunctional immune response common in many moderate to severe COVID cases that can cause long-term multi-organ damage, particularly in the liver and kidneys. It can also disrupt coagulation control of the blood, sometimes leading to amputations, mostly in patients in their 30s and 40s. It was reported that amputations due to vascular problems have doubled since the CoV-2 virus arrived. Compromised coagulation control in COVID patients can also precipitate adverse cardiovascular events such as heart failure, or hemiplegia due to strokes. Data from the COVID Infection Survey on long-COVID suggest that the risk of major adverse cardiovascular events and long-term illness is about ten times higher in COVID patients (even after mild COVID) compared to non-COVID matched controls. A Dutch study found that 31% of COVID ICU patients suffered thrombotic complications. These problems can unexpectedly pop up in people who had completely recovered from COVID.

A global survey tallied 205 different symptoms across 10 different organ systems that can persist after COVID infection has cleared. Typically, these manifold long COVID symptoms do not appear in isolation, but in multi-symptom clusters. A long hauler typically has several of these problems at a time.

While it is estimated that overall, 10-30% of COVID patients become long haulers, reports on the number of people suffering long COVID vary widely. Depending on the report, anywhere from 30-90% of COVID survivors suffer long term health problems. And even at the lower end of that range, 30% of over 330 million people world-wide who have been infected is a very large number. It represents an enormous personal toll in terms of lost health and diminished quality of life. Some of these reports are summarized below.

  • Half of 70,000 hospitalized UK COVID-19 patients experienced long-term complications, according to a study published in July. Complications occurred regardless of age group: For instance, 25% of adults aged 19-29 developed complications, as did 33% of those aged 30-39. Complications affecting the kidneys and respiratory system, liver injury, anemia, and arrhythmia were the most common.
  • Many COVID-19 survivors require extensive and prolonged rehabilitation. An European study found about one-third of 1,837 non-hospitalized COVID patients (i.e., those with mild disease) needed a caregiver three months after their symptoms started.
  • In April the CDC reported in its Morbidity and Mortality Weekly Report that 69 percent of nonhospitalized adult COVID patients in Georgia required
  • one or more outpatient visits 28 to 180 days after their diagnosis.
  • A study published last February in the Journal of the American Medical Association found that roughly one-third of 177 people who had mild COVID disease not requiring hospitalization reported persistent symptoms and a decline in quality of life up to nine months after illness.
  • 70% of people hospitalized for COVID-19 in the UK had not fully recovered five months after hospital discharge. They averaged nine long COVID symptoms requiring continued medical care.
  • A study in South Korea found that 90% of patients who recovered from acute COVID experienced long-term side effects.
  • According to a report in the journal, Lancet, 75% of people hospitalized with COVID-19 in Wuhan early in the pandemic, reported continued problems with fatigue, weakness, sleep problems, anxiety and depression six months after being diagnosed with the disease. More than half also had persistent lung abnormalities.

Data like these have been commonly reported around the world, pointing to a more chronic and expensive health problem than seen with the flu or common cold, which often is caused by different coronaviruses. A July 2021 article in Scientific American talked about how all of this indicates that long COVID will cause a “tsunami of disability” that will affect individual lives as well as create enormous strain on the health system. Consider the numbers: More than 60 million Americans (this is an underestimate since many COVID cases are not reported) have been infected with the CoV-2 virus. Therefore, if only 30% of these suffer long COVID, we are talking about 20 million long haulers and counting.

The related health care and disability costs of all of this are also still being calculated. How many “long haulers” will not be able to return to work for months, or at all? How many will need short-term disability payments, and how many will become permanently dependent on disability programs? As increasing numbers of younger people become infected, will we see a generation of chronically ill? This then moves us to consider the economic and financial cost of long COVID, which will be the topic of the next installation in this series.

Stay tuned.

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The Long Haul, Part 3: Long Neurological COVID

As I have noted before in this series, acute COVID-19 often appears with neurological symptoms ranging from loss of smell to severe depression to stuttering to brain fog, mania and psychosis. It sometimes has been linked to suicidal ideation. In addition, long haulers often have cognitive symptoms and structural brain changes similar to those seen in aging brains and in those with Alzheimer’s disease. An early survey of 153 COVID-19 patients in the UK and a more recent study of people hospitalized with the acute disease in Italy both found that about a third had neurological symptoms of some kind ranging from sensory problems, motor impairment, and cognitive issues that persist after clearing the acute infection. Other estimates of neuro involvement in long COVID have trended even higher. Many people who survived earlier coronavirus infections such as SARS and MERS also experienced neurological impairments up to 3.5 years after acute infection. Obviously many of these symptoms of long COVID are very serious while others are more annoyances. So, what is going on? Researchers have pretty well cataloged the unusual range of long COVID’s neurological symptoms and now are at the very early stages of understanding their causes and how to treat the problems. Here, I label long COVID that primarily manifests itself with neurological symptoms as “long neuro COVID” in order to distinguish it from other long COVID problems that primarily involve the lungs, heart, or other organs.

What is long neuro COVID like? In the early days of the pandemic, a newly minted English MD worked on the front lines in a COVID ward and soon became a patient herself. Being 35 and healthy she expected to quickly recover but underwent the long haul, which she has written about. The acute phase of the disease lasted about two weeks, but by 4-5 weeks, she was experiencing new persistent problems including tachycardia with a resting heart rate of 140 bpm (normal is 60-100) that would increase to 170 after minimal exertion such as getting a glass of water. She also was breathless with a resting respiratory rate of 20-24 (12-16 is normal), saying it felt like her “body forgot to breath.” She described cyclic bouts of pins and needles in all four extremities, and whole-body shaking as violent as if she were having a seizure. There were feelings of impending doom, and, despite extreme mental and physical exhaustion, she was unable to sleep, which eventually led to hallucinations. Those symptoms slowly subsided over a few months only to be replaced by intense pain very deep in one ear. This ultimately led to tinnitus and some hearing loss and a diagnosis of encephalitis. Ten months later, she wrote that  she was recovering but was far from normal. She suspected that these symptoms were driven by a dysfunctional autonomic nervous system, a condition called dysautonomia. The autonomic nervous system is what regulates your organs and allows you to breath, your heart to beat, your gut to move food through it, and controls your blood pressure without you having to think about it all. Since her experience in early 2020, it has been confirmed that long neuro COVID can wreak havoc with both the peripheral and central nervous systems.

 

After two years of long COVID, we now know that long neuro COVID symptoms are wide ranging; some are devastating, like stroke, encephalitis, and even psychosis or mania, or even suicide. Other neuro symptoms are more subtle such as cognitive decline, loss of smell, hearing loss, balance problems, fatigue, memory problems, and difficulty concentrating or brain fog. Others are bizarre, such as stuttering. This seemingly unrelated range of symptoms suggests that there might be several different subtypes of long neuro COVID, possibly arising from distinct pathologies.

Back in July 2020, one of the first studies was published describing neurological symptoms that appeared long after the initial COVID disease. This since has been followed by several other reports of neurological or neuropsychiatric problems long after recovering from acute COVID disease. One study by Oxford scientists published last February, found that about 33% of post-COVID patients are left with long term mental health or neurological symptoms including brain fog, headaches, dizziness, and cognitive problems such as difficulty doing simple math. Some studies have shown an elevated incidence of PTSD, and seizures or movement disorders  long after COVID recovery. Other post-COVID patients have new-onset depression, psychosis, and suicidal behavior as reported in JAMA Psychiatry by a Columbia University research team this past spring. In this large study investigators examined electronic health records of more than 236,000 COVID-19 patients, mostly in the US. The researchers compared their records with records from those who experienced non-COVID respiratory tract infections during the same time frame and found an increased incidence in anxiety and mood disorders in post-COVID patients. More than three months after diagnosis, these common psychiatric diagnoses were found in about 34% of COVID survivors. Other studies confirmed that having the disease led to doubled risk for anxiety, depression and sleep disorders.

Importantly, researchers did not see an increased incidence of other neurological problems such as Parkinson’s disease or Guillain-Barré syndrome in long COVID patients, both of which sometimes follow viral infection. This suggests that long neuro COVID involves a select subset of neurological problems rather than an indiscriminate neurological malady.

Similarities between long COVID and Alzheimer’s disease. The cognitive issues seen in many long neuro COVID patients share intriguing similarities with Alzheimer’s disease (AD) and normal aging. Thus, an international group of researchers found that more than half of patients 60 or older who had been infected with the CoV-2 virus showed acceleration of Alzheimer’s-like symptoms such as cognitive decline. Other researchers at the University of Texas Health Science Center, San Antonio studied more than 200 older adults from Argentina who had COVID-19. Those who had a persistent loss of smell were more likely to experience AD-like cognitive issues. Importantly, the area of the brain affected in AD overlaps with the area that processes smell. It also might be relevant that the sense of smell, which is often lost in COVID patients, is also often reduced in AD patients.

Three to six months after they were infected, more than half of these patients still struggled with AD-like cognitive challenges including persistent forgetfulness, difficulty sequencing tasks, and forgetting words and phrases. How sick a patient was with acute COVID-19 was not an indicator of whether they would experience this cognitive decline. In other words, AD-like symptoms also occurred in people who only had mild COVID.

COVID-19, of course begins as a respiratory disease and investigators have long been tuned in to the potential links between respiratory diseases and the brain. For example, AD-like changes in cognition and behavior were also observed in people with Severe Acute Respiratory Syndrome (SARS) and with Middle East Respiratory Syndrome (MERS). Infection with other respiratory viruses can also increase the risk of Alzheimer’s.

Together, these findings suggest that some patients with long neuro COVID might have an acceleration of Alzheimer’s-related symptoms and pathology, but it is too soon to conclude that long neuro COVID causes AD, or even that AD and COVID-related cognitive dysfunction are even related. A major distinction between classical AD and AD-like long COVID is that the latter do not show the amyloid brain plaques which are pathognomonic of AD, which suggests that these could be distinct cognitive maladies with overlapping symptoms. Furthermore, other studies showed that worse cognitive scores in long COVID patients correlated with patients who had lower oxygen saturation during a 6-minute walk test. This makes it possible that persistent oxygen deprivation in the brain due to lung compromise during COVID could cause cognitive difficulties in these patients.

At this point, these observations simply raise many unanswered questions on whether there is a real overlap with COVID and Alzheimer's disease. But, it is too soon to say that COVID-19 increases a person's risk for Alzheimer's vs causes a different neurological problem symptomatically related to AD.

What causes long neuro COVID? Long COVID represents a broad category of over 200, often unrelated symptoms encompassing 10 organ systems. It likely consists of multiple different maladies with manifold causes, of which long neuro COVID is at least one broad category. Based on its biology and range of symptoms, long neuro COVID also likely entails more than one specific problem. It makes sense then that the many different manifestations of long neuro COVID would arise from different causes. Such seems to be the case. Researchers have cataloged several genetic, structural, inflammatory, and infectious correlates to the various symptoms, painting a complicated picture. Then things get really confusing since viral infection of neurological tissues and/or the attendant inflammatory responses could cause the observed structural changes and all this could be predisposed or mitigated by genetics. In other words, things are as clear as mud right now about what causes long neuro COVID. Investigators are just now making basic observational correlates between the neurological changes and long neuro COVID symptoms, and these correlations will be followed by the harder studies to learn just how these changes might cause the plethora of symptoms that have been documented.

On the genetic front, a Stanford U team found that long neuro patients manifest widespread changes in gene expression in the region of the brain involved in complex processing of human thought. These genetic changes affected genetic pathways that play a role in mental illnesses such as schizophrenia and depression. Although these results were made in the brains of patients who died of acute COVID disease, such fundamental changes in gene expression in the brains of patients with acute COVID would plausibly lead to long-lasting post-COVID effects. Similar changes in gene expression were not found in the brains of people who died from flu or from nonviral causes, which strengthens a possible cause and effect relationship of gene expression changes to some long neuro COVID symptoms.

But, what causes changes in brain gene expression? Is it directly due to viral infection in the brain or secondarily due to the immune inflammatory response to the virus? Maybe both? Or is something else involved? Evidence exists for all these possibilities.

One report on 111 unvaccinated patients from the Chicago area showed that 56 who had long neuro COVID cognitive problems showed a particular immunological signature that was not found in people who cleared the acute infection without long term problems. The severity of cognitive deficits correlated with reduced memory T cell responses to certain parts of the virus, and with enhanced antibody (or B cell) responses to one of the viral proteins. Furthermore, it has been observed that females are more prone to devleop long neuro COVID. Since women also are more likely to get autoimmune disease, some have put these observations together to suggest that there might be an autoimmune component to some long neuro COVID symptoms.

The above study assessed the anti-CoV-2 immune responses of T and B cells from the peripheral blood but not from the brains of the patients. In other words, it did not address whether the immune response in the body affects brain function or whether an antiviral immune response directly occurs in the brain affecting cognitive function. Other researchers have shown that the virus can indeed enter the brain via the nose and spread from the olfactory lobe to the frontal and temporal lobes of the brain. Other confirmatory studies have found viral protein expression in cortical neurons of autopsied brain tissues, and have directly shown that the virus can infect neurons in tissue culture. While these findings are consistent with direct infection of the brain and the possibility of immunological damage to the organ, they do not settle the question of whether viral infection itself might directly damage the central nervous system, or whether it is the immune reaction to the virus that causes the problems.

Perhaps confounding all of this are the results of a large study on gross brain structure conducted by researchers at the University of Oxford and at the NIH. In this study, researchers used the UK Biobank, an existing database, which contains brain imaging data from >45,000 people in the UK going back to 2014. This means that there was pre-COVID baseline imaging data the researchers could compare to post-COVID brain images. New images were collected from 394 of these patients who caught COVID and compared to their pre-COVID images and to 388 controls who did not catch COVID-19. The groups were otherwise matched based on age, sex, common disease risk factors, etc. The results showed that those who caught COVID suffered significant loss of gray matter in the frontal and temporal lobes on the left side of the brain. This brain loss was found regardless of COVID disease severity. Those who were COVID-free had no brain tissue loss. Interestingly, these regions of the brain are responsible for smell, taste, memory, and emotion, all of which can be affected in long neuro COVID patients. We also often talk about the left temporal lobe in the context of aging and Alzheimer’s disease because that is where the hippocampus is located, which plays a key role in memory and other cognitive processes associated with aging and AD. While it is normal to see reduction in gray matter with age, the COVID-linked changes were greater than that typically seen during normal aging. All of this raises questions about how COVID might affect the natural aging process in the brain.

In addition to these genetic, immunological, and structural changes in the central nervous system of COVID patients, autopsies also have revealed clotting in multiple organs including the brains of many patients. About one in 50 COVID brains showed evidence for an ischemic stroke, which is when a blood clot interrupts blood flow to a region of the brain downstream from the clot. Ischemic strokes in COVID patients tended to be more severe and more likely to result in severe disability or death than stroke in non-COVID individuals. Again, while these findings were made on autopsies of patients suffering from acute COVID, these ischemic strokes would have caused long term manifestations presenting as long neuro COVID.

There are other, very specific and very peculiar neurological symptoms that might arise from more specific neurological abnormalities. For example, some long COVID patients display hearing loss and or balance problems which suggest vestibular involvement that could be due to CoV-2 infection of the inner ear. Scientists at MIT and Stanford found that the ACE2 protein, which is the cell receptor for the CoV-2 virus, is expressed on certain inner ear cells obtained from surgery patients. Since inner ear tissue is difficult to obtain, the researchers directed stem cells to develop into inner ear cell precursors or that could assemble into primitive inner ear  organoids in tissue culture and showed that the CoV-2 virus could infect them. Together, these observations support, but do not prove, that infection of the inner ear is a cause of hearing and balance issues in some long neuro COVID patients. It is relevant to note that it is not unusual for hearing loss and balance disorders to be caused by other viral infections of the inner ear.

Then there also are the rare long COVID patients who develop an odd stuttering problem. Typically, stuttering originates in the complex circuity of the brain that controls speech and this speech disruption usually appears when children are learning to talk. However, “neurogenic stuttering” can arise in adults after brain trauma. Since only a few researchers are investigating long COVID-associated stutter, the cause is not well understood, but, the link between neurogenic stuttering and brain injury raises the possibility that inflammation and/or micro-clotting caused by the virus or by the immune response to the virus in the brain microvasculature could lead to the neurological damage that causes stuttering.

Bottom line. These many new findings, while provocative, do not yet fully tell us how long neuro COVID arises, or how to treat it. But, they raise many new questions: What do these COVID-related brain changes mean for the process and pace of brain aging in long COVID patients? Over time does the brain recover? How do we medically deal with these patients? Can we prevent long neuro COVID? Etc.

Stay tuned, we will see.

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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.