What is "Long" COVID?
Should I be afraid of Long COVID?
I wrote an earlier entry on “COVID and Mental Health” When I thought COVID was at the zenith of epidemic proportions. At that time, the number of people who had contracted the virus was large, but not nearly as large as it is today. Some epidemiologists are now reporting that over a million deaths in the United States can be traced back to COVID, and the fact that a great many people have contracted the virus, not once, but twice, and sometimes more underlines its persistence. It is to the point where more people have contracted COVID than have not.
Over half of my clients have report contracting COVID. Sessions have been missed, some clients have persisted seeing me (via tele-video) when sick. Although I have yet to personally contract COVID (this statement could change should I contract it), I’ve seen some of the lingering mental health symptoms including brain fog, fatigue, depressed mood, anxiety, paranoia and the like. These are symptoms people report while recovering from COVID, and some are still experiencing them.
I’m asked frequently what I think about “Long COVID.” Is this a reliable description of a condition that follows from COVID? If so, how do you know you have long COVID? An important question related to post-COVID symptoms is: What are the mental health implication of Long COVID?
This is another one of those daunting entries because there is more we don’t know about mental health implications than we know.
In this entry I will:
Define Long COVID
Describe how and why Long COVID spreads and the scope of Long COVID
Discuss the interaction between biology and psychology in Long COVID
Identify whether there is a cure or a treatment for Long COVID
Defining Long COVID
The dictionary definition of Long COVID is: (noun, non-pathology): A condition characterized by symptoms or health problems that linger or first appear after supposed recovery from an acute phase of COVID-19 infection: Symptoms of long COVID can vary widely and include cough, low-grade fever, fatigue, chest pain, shortness of breath, headaches, and gastrointestinal upset.
One interesting feature of the layperson’s dictionary definition is that it completely leaves out mental health symptoms. It could be that because mental health is seen as separate from physical health in everyday language that this is reflected in the lay biological definition.
(from Nature Medicine, 22 march 2021)…The pathological definition of Long COVID (Post-acute Sequelae of COVID 19, PASC) is more comprehensive: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for coronavirus disease 2019 (COVID-19)… is evolving… long-term…which can affect multiple organ systems…long-term complications of SARS-CoV-2 infection beyond 4 weeks from the onset of symptoms…is divided into two categories: (1) subacute or ongoing symptomatic COVID-19…symptoms and abnormalities present from 4–12 weeks beyond acute COVID-19; and (2) chronic or post-COVID-19 syndrome, …symptoms and abnormalities persisting…beyond 12 weeks of the onset of acute COVID-19 and not attributable to alternative diagnoses…the presence…of symptoms (such as dyspnea, fatigue/muscular weakness and PTSD), reduction in health-related quality of life scores, pulmonary function abnormalities and radiographic abnormalities…(From Frontiers in Microbiology, 23 June 2021)…Long-term symptoms…may be due to consequences from organ or tissue injury caused by SARS-CoV-2, or associated clotting or inflammatory processes during acute COVID-19.
The Spread and the Scope of Long COVID
We know quite a bit now about how fast COVID is spreading especially across the United States. This spreading also relates its scope (or larger implications). Globally, over 6 million deaths are directly attributable to COVID. With regard to the United States, today, or June 26, 2022 approximately 86.7 million people report COVID infection. Approximately: 1,015,000 have died in the U.S. as a direct result of COVID infection. Roughly 60% of the U.S. population reports contracting COVID. In some ways, this latter statistic (60%) is remarkable because it underscore just how fast a viral pathogen can move through an entire world population to the point where more people report contracting COVID than not.
When it comes to Long COVID, not everyone infected by acute COVID has (or will) experience Long COVID. So, the statistic for Long COVID is smaller than 60%; that is, it is somewhere between 10 and 30% of persons who have contracted COVID. In the United States, Long COVID ranges between 7.7 and 23 million people. The Long COVID statistic is much less reliable than infection rate because people must decide when or how to declare they “might” have Long COVID. Researchers have estimated this number at about 30% of those infected. In other words, 30% of those people in the United States who have been infected with COVID also experience the biological or psychological effects of Long COVID.
How Does COVID Affect Mental Health?
It is without question that Long COVID occurs when the COVID virus enters the brain or more broadly, the central nervous system. The pathway is most commonly through the nasal cavity (Word of Advice: When you are around someone with COVID, don’t pick your nose afterwards). Based on what we know so far about COVID, its systemic inflammation may unleash chemicals that trigger symptoms in the brain such as hallucinations, anxiety, depression, and suicidal thinking, depending on which part of the brain is contaminated. It is difficult, if not impossible, for the brain, once infected by COVID, to ameliorate this pathogen. The transmission of blood across the blood brain barrier is too slow to move out pathogens, so this may partly explain how the virus stays in the neurological system for such an extended period. As many as 1 in 3 patients recovering from Covid-19 will experience neurological or psychological after-effects beyond the 4-week disease cycle.
One study I reviewed evaluated nearly 4,000 long COVID patients and found that 45 percent reduced their work hours for more than six months while recovering. For some people, a major change in job status can affect health insurance, which can further complicate treatment options. Individuals have also said their symptoms interfere with childcare, exercise, and social activities. This disruption of daily lives can cause a range of mental health issues in and of itself that interact with the biological features of the COVID virus. Another study I reviewed used electronic health records of more than 200,000 COVID-19 survivors and found that within 6 months following initial infection, one-third experienced neurological or psychological symptoms such as anxiety, depression, post-traumatic stress disorder, and even psychosis.
The figure above highlights symptoms of long COVID in a visual way by connecting symptoms to organs and organ systems. This underscores the fact that COVID is a systemic disease. The Figure below summarizes long COVID symptoms.
Note: Sjögren's syndrome is: A chronic autoimmune disease affecting salivary glands and tear glands. (dry mouth and dry eyes).
How Does Biology Interact with Mental Health Symptoms in Long COVID?
Of the most obvious interactions, chronic stress appears to weaken resistance to COVID infection via an increased inflammatory response. Stress is a reason COVID remains persistent (or long) within a body due to relatively low host immune resistance.
In one of the largest studies to date conducted with the “23andMe” genetic data, it found that Long COVID disproportionately impacts women, and being diagnosed with depression or anxiety is associated with a more than a two-fold increase in risk for Long COVID (following the contraction of COVID). Half of those with persistent symptoms experienced those symptoms for six months or longer.
In a study published in BMJ (British Medical Journal) on a gigantic sample of millions of Veterans who used the U.S. Department of Veterans Affairs (VA) health system early in the pandemic the consequence - 1 year later - of being diagnosed with COVID was evaluated. Veterans contracting the COVID-19 virus were 46% more likely than controls (non-infected but psychiatrically vulnerable Veterans) diagnosed with any of 14 neuropsychiatric disorders. These included depression, suicidal thoughts, anxiety, sleep disturbance, opioid use disorder, and neurocognitive decline or “brain fog.” The risk of brain fog, in this group, was 80% higher than in controls. Veterans hospitalized with COVID infections had the highest risk for developing any of the psychiatric disorders—343% more than controls. This was is in contrast to non-COVID infected hospital outpatients who faced a 40% higher risk of developing a psychiatric ailment.
This study was based on Veterans’ who by and large are older, White, lower SES, and usually more physically and psychiatrically frail than the general population. But still, the study size and the percentages are staggering.
The Central Nervous System Gets the Brunt of COVID
When there is direct CNS involvement in COVID infection it depends on: 1. How much viral load (the amount of virus) gets into the CNS and 2. How well (and quickly) the person’s immune system responds to it. These two factors determine whether the consequences are mild and temporary or severe and long-term. Most 2022 literature estimates that 36% of patients will develop neurological symptoms associated with COVID. An infected person has a one in three chance of developing a neurological condition following COVID infection. This includes: Headache, Loss of Fine Muscle Control, Diminished Stamina, Less Muscle Strength, Poor Vision, Memory and Attention Deficits. and on and on. A frequent symptom people report is memory deficit. Memory deficit is predictable and a common neurological symptom of COVID and particularly Long COVID.
I present this case below because it represents an otherwise normal, high functioning young person who would not be suspected to develop neurological symptoms from sources other than COVID. Fortunately for him, his symptoms probably improved, but the case is evidence that COVID can impact the brain and CNS in otherwise healthy people.
Case from: Front. Neurol., 28 January 2022
a 23-year-old man who contracted COVID-19 in February 2021. The diagnosis was made by rRT-PCR on a nasopharyngeal swab performed after contact with an infected individual. The patient was asymptomatic at the time of test positivity and started a period of quarantine. He was alone, abroad for study reasons, and the notification of the infection, together with self-isolation, was a reason for intense stress. In the following days he began to complain of fatigue, episodic shortness of breath, nocturnal tachycardia, and chest pain; an electrocardiogram and chest x-ray were negative. After his return to Italy, the symptoms persisted. In addition, he developed attention and memory difficulties, and a fluctuating limb dysesthesia (dysesthesia=Chronic pain that may involve itchiness, burning, electric shock, or a general tightening in any part of the body). Physical examination and an extensive diagnostic work-up including ECG, echocardiogram, and chest CT were normal. In April 2021, the patient underwent his first neurological examination, reporting weakness and clumsiness of his left arm. He was diagnosed with a functional movement disorder… (brain MRI, nerve conduction studies, electromyography, and evoked potentials were negative). Arm weakness was characterized by extreme slowness and drift without pronation (he could rotate his hand and arm), and deep tendon reflexes were normal. Importantly, weakness has been reported as one of the most common functional motor symptoms, being frequently associated with non-motor disturbances such as anxiety and fatigue The patient was then referred to our center for FND [Functional Neurological Disorders]. The patient had no history of psychiatric disturbances or mood disorders, and no pathological personality traits were identified. Stress related to social expectations and isolation, along with health concerns related to SARS-CoV-2 infection may be considered as precipitating factors. Neuropsychological evaluation showed a normal cognitive profile, presence of depression, and elevated anxiety levels. After carefully discussing the diagnosis of FND with the neurologist, a course of psychoanalytic psychotherapy and targeted physical therapy was planned. A few weeks later, the patient was evaluated at a post-COVID center of another hospital. After an additional diagnostic assessment with negative results, he received a diagnosis of a post-COVID-19 syndrome. After 4 months, dysesthesia and motor symptoms had resolved, and the subjective cognitive complaints had improved. The patient returned to his studies and social activities but had not fully resumed the physical activity, as post-exertional malaise and chest pain, and a fluctuating muscle tension in his back and left arm persisted.
Will this young man experience lingering symptoms of Long COVID for the rest of his life? It’s hard to know, but this is a good description of a direct neurological consequence of Long COVID.
Is There a Cure for Long Covid?
The short and simple answer is NO. At this point in time we don’t have a cure for COVID or long COVID, we don’t even fully know what the entire scope of the problem or issue is. There are lingering questions:
Can the COVID virus be completely removed from someone who has contracted COVID?
Is there a way to know what organ systems COVID will damage the most?
Will there be specific neurological conditions that emerge from this COVID Pandemic? Like, for example, the condition of encephalitis lethargica that emerged directly from the Spanish Flue in 1918.
There is research investigating long lasting antibodies that could create an extra layer of protection for people, but once COVID enters a body, it appears that it is impossible to irradicate it.
How Does COVID Actually Impact the Brain?
This is a critical question because drug therapy or other forms of treatment are dependent on knowing how COVID infiltrates the brain and once it does what aspects of brain function or structure gets impacted. Certainly, during the course of our lives we are accosted by all kinds of viruses and diseases. For example, if you happen to fall ill to Shingles, you can expect to have a few mental health and neurological consequences from the infection. Especially in older adults, shingles can evolve into a painful, emotionally traumatic set of long-term symptoms that takes a few weeks to many months to resolve. Approximately 20 percent of people aged 60 to 65 who get shingles will develop post-herpetic neuralgia (PHN), a nerve pain syndrome that can last for years, and that is after just one shingles outbreak. Complicated PHN can cause depression, anxiety, sleeplessness, and weight loss. It can be so severe as to impact daily living such as dressing, cooking, and eating.
Back to COVID. Brain fog is a common consequence from the COVID virus. Is this due to COVID or is brain fog a result of the body putting stress on cognitive capabilities that are otherwise entirely intact. Who knows? Right?
Can I eventually recover from the depression, suicidal thoughts, paranoia, brain fog, memory deficits associated with COVID.
The answer is a qualified, Yes. One statistic that has yet to appear in the literature is the mental health recovery time from Long COVID. This is probably because we haven’t had enough time to study the long-term pathways of recovery that people who have contracted Long COVID take as part of a return to full health. But, clearly, some people do return to normal mental health very quickly, but for others, mental health recover from a bout of Long COVID takes more time.
Back to the question of the brain. How does COVID infiltrate and attack the brain? A lot of research is focusing on this question. This is what we know so far.
Grey Matter Destruction
Grey Matter: We’ve discussed Brain Grey Matter before. Grey Matter is: Brain tissue that makes up the outermost layer of the brain and is pinkish grey in tone. The “grey” tone is from the high concentration of neuronal cell bodies that are part of this tissue. Grey matter also contains unmyelinated (uncovered) axons. It is abundant in the cerebrum, cerebellum, brain stem, and the spinal cord. The sheet of grey matter that constitutes the cerebrum varies in thickness from about 2 to 5mm. The grey matter surrounding the cerebrum is the cortex of the brain. See the figure below:
An article in BMJ reports data from 785 persons (aged 51-81) versus 384 control persons matched for age, brain images before and after they had COVID-19, This study found loss of grey matter in COVID infected persons across several areas of the cerebral cortex. This corresponded, in their study, to small losses in cognitive function for the COVID infected versus control participants. Two brain regions were specifically affected: orbitofrontal cortex and parahippocampal gyrus.
One way COVID might be accessing the brain is by passing through the olfactory mucosa, the lining of the nasal cavity, which borders the brain. This is essentially the nasal cavity which is a wide-open pathway to brain infections of all types.
Astrocyte Infection
A second way COVID impacts the brain is by infiltrating and damaging what are called astrocytes. What are these?
Astrocytes are small star-shaped cells (note the yellow cell above with the green nucleus) that perform nutrient transfer between neurons. In laboratory testing with live brain tissue where COVID is introduced directly into the tissue, the virus almost exclusively infects astrocytes over other cells. One research group in Brazil that analyzed 26 deceased COVID victim’s brains and then isolated brain tissue found that the virus almost exclusively attached to these astrocyte cells. When these astrocytes fail to act, or start acting haywire, then the neurons lose their nutrient base and begin to selectively fail.
When this happens (COVID is depicted in the yellow cell with the red dot - note the black neurons - black is damage - with the blue dot one is dying and one is dead - the astrocyte (yellow) with the black dot is a COVID-infected astrocyte), and if the failure is large enough, the neural net is impacted and then the person experiences declines in function associated with the neural net which controls motor behavior, attention, memory, and even organ function.
Blood Flow Restriction
The third pathway is blood flow restriction. Reduced blood flow to the brain impairs neuron function and ultimately kills them. This pathway is not restricted to COVID. An excellent example of this is COPD (Chronic Obstructive Pulmonary Disease). When nutrients like Oxygen that are carried by the blood are restricted by a Disease that impacts the lungs (blood to oxygen transfer), neurons are starved of oxygen and die. There is study after study documenting cognitive decline in patients with COPD. This is the pathway.
David Attwell, a neuroscientist at University College London published a preprint showing evidence that COVID impacts pericyte behavior. What are pericytes?
Pericytes are cells along the walls of capillaries. (note the figure on the right, the blue ring (pericyte) tightens like a band decreasing the diameter of the capillary. Note the green astrocyte - it stops transferring nutrients, further damaging the capillary wall). In the CNS, pericytes help blood vessel formation, maintain the blood–brain barrier, and regulate of immune cell entry to the CNS. Most important, pericytes control of brain blood flow. In hamster brains, the researchers observed that COVID blocks the functioning of receptors on pericytes, causing them to go haywire. This means that they start tightening or constricting capillaries in brain tissue. Capillary constriction limits blood flow, limited blood flow limits oxygen transfer and cells die, permanently.
In the figure below, here is an actual microscopic picture of a pericyte around the exterior of a capillary, so they do exist.
The final way that COVID impacts brain function is by stimulating the body’s own immune system to overreact and misfire due to the virus infiltration. Autoantibodies in the immune system easily pass through the blood-brain barrier and when this happens as the immune symptoms starts over-reacting, symptoms immediately start to occur including loss of vision, and weakness in limbs.
Abstracted from Nature 595, 484-485 (2021)
Science, and the scientific method is extremely good at pinpointing cause and effect. It can be daunting to read about how COVID impacts the body, and particularly the brain. It’s easy to get overly concerned because the picture I’m creating is such a negative, but realistic portrait of just how damaging COVID can be. However, what is important to realize is that I’m presenting information at a very microanalytic level. There is substantial redundancy and resilience in the brain as a whole, so should COVID damage some parts of the brain, the brain is capable of re-wiring itself and replacing damaged structures to maintain a certain level of functioning. But, this underscores that during the transition of physiological resistance innumerable symptoms can occur and there is good reason to believe that a lot of symptom will linger, and some for a very long time. This is where coping and adaptation comes in. How does one adapt to a COVID infection?
This Entry is Continuing, July 4, 2022