Vision Problems After COVID: Causes and Treatment

ATHER  |  BRAIN INJURY AWARENESS November 9, 2022Medically Reviewed by Dr. Alina Fong Cognitive FX

When most people think of COVID-19 symptoms, they often recall the most common acute symptoms: brain fog, sore throat, congestion, headaches, and the like. What many don’t know is that long COVID can affect your vision for months after contracting the illness.

Current studies show that 1 in 10 COVID patients experience at least one eye problem, such as dryness, redness, blurred vision, or sensitivity to light. Conjunctivitis is common in the early stages of the illness, and for some patients, it’s the first sign of a COVID-19 infection. 

However, as we’ll discuss in this article, the real number of patients experiencing eye issues is likely higher, and the range of symptoms is much broader. Red and watery eyes are easy to spot, but it can be challenging for patients to recognize symptoms that stem from gaze and focus abnormalities. Some examples of potentially vision-related symptoms are headaches, difficulty focusing while reading, feeling overwhelmed in crowded spaces, dizziness while in a moving vehicle, and more. Because most research studies (a) rely on asking patients about their symptoms and (b) don’t include all of the appropriate tests to diagnose vision problems, many post-COVID vision changes go unreported. 

We also know that COVID patients don’t just experience vision problems. They also have a wide range of symptoms, from cognitive issues to digestive problems. The best approach to recovery for these patients is one that considers the whole person. It’s key that post-COVID patients find a provider who can address the wide range of effects long COVID has throughout the body and who is willing to diagnose the root issue (rather than treating just symptoms).

At Cognitive FX, we look at how the virus has affected your brain and body, then devise a plan to restore normal function. Our approach involves a combination of aerobic exercise and multidisciplinary therapies to address specific issues that you’re experiencing, including problems with your vision if you have them.  

n this article, we’ll look at:

Our treatment was originally designed to help post-concussion patients recover from persistent symptoms. After just one week of treatment, over 90% of our patients show improvement. Thus far, we’ve seen similar results with long COVID patients who pass our current screening criteria. To discuss your specific symptoms of COVID-19 and determine whether you’re eligible for treatment at our clinic, schedule a consultation.

Can COVID-19 Cause Vision Problems?

Soon after the coronavirus pandemic started in 2020, ophthalmologists worldwide started reporting how patients infected with the virus were experiencing visual symptoms during their illness. Common symptoms identified during these early stages included conjunctivitis, dry and itchy eyes, blurry vision, and sensitivity to light.  

However, over the past two years, the medical community and ophthalmology experts spotted a wider range of symptoms than previously expected, such as issues with saccades (how your eye switches focus from point to point), control of eye movements, and communication issues between the vestibular and visual systems. These issues are difficult for patients themselves to recognize and many doctors are not trained to look for and diagnose them. As a result, there are some misconceptions about the impact of COVID-19 on vision. 

When you think of problems with vision, you might think of people who need to wear glasses. Some see well at a distance but need glasses to see images that are near (hyperopia), while others can see objects that are near clearly but need glasses to see distant objects (myopia). Someone with 20/20 vision can see both near and far objects clearly and thus does not need glasses.

However, it’s possible to have vision-related changes triggered by COVID-19 and to still have 20/20 vision. Many vision problems don’t affect visual acuity. Patients’ eyes may not converge or diverge correctly. They might struggle with certain types of eye movement, experience reduced peripheral vision, not see clearly when they’re moving… the list of possible problems with your eyes is quite long. 

This brings us to our first misconception: Many patients believe that just because they haven’t noticed any problems with their vision that their eyes and visual system are functioning normally. In reality, it can be quite difficult to detect problems in your own vision because your brain does its best to compensate. 

Instead of noticing your eye problems, you’re more likely to experience the symptoms those eye problems result in: headaches, dizziness, nausea, difficulty concentrating, fatigue, and more. Most people are not aware of how the visual system can cause these symptoms, and they never think to seek help from a vision specialist. 

A second misconception is that vision problems caused by COVID-19 are rare. This is somewhat supported by clinical studies. Studies over the past two years found ocular manifestations in patients with COVID-19 ranging from 2% to 32%, with most results hovering around 10%

However, we believe the real value is much higher. Most of these studies only followed participants for a few weeks and looked for obvious symptoms like red and itchy eyes, which are easy to detect. Symptoms like problems with divergence (the ability to focus on a distant object) and convergence (the ability to focus on a close object) require specialized tests.

In addition, symptoms may not develop immediately and might come and go in waves like many other long COVID symptoms. To get a more accurate understanding of the situation, we need clinical studies which follow patients for more extended periods and which test for a wider range of symptoms. 

Vision Symptoms Caused by COVID-19

One of the most commonly reported eye conditions caused by COVID-19 in both children and adults is conjunctivitis (colloquially called pink eye). Some studies found that 9 in 10 patients with eye symptoms experience this condition. These patients often experience red and itchy eyes, dry eyes, watery eye discharge, sensitivity to light, and eye pain. In some cases, this eye condition may also cause blurry vision and swollen eyes. 

In addition to conjunctivitis, vision symptoms caused by COVID-19 may include the following:

  • Ocular irritation
  • Red eyes
  • Eye soreness
  • Blurry vision
  • Tunnel vision
  • Double vision
  • Vision loss
  • Floaters in the eyes
  • Cotton wool spots
  • Loss of peripheral vision
  • Uveitis (inflammation of the eye)
  • Eye infection
  • Swollen eyelids
  • Sensitivity to light
  • Glaucoma
  • Divergent and convergent issues
  • Saccades problems
  • Gaze fixation issues
  • Problems with focus
  • Vestibular-ocular deficiencies
  • Retinal artery occlusion and retinal vein occlusion caused by hemorrhage or blood clots

Causes of Vision Problems After COVID-19

There are many possible ways to explain how COVID-19 can cause vision problems. For most patients, it’s likely a mixture of multiple factors. Some of the most important reasons include…

  • Disruption of the Autonomic Nervous System (ANS)
  • Neurovascular Coupling (NVC) dysfunction
  • Direct impact on brain function related to vision
  • Vestibular issues
  • Pre-existing visual dysfunction
  • Side effects of medication
  • Blood clots
  • Direct viral attack on the eyes
  • Ventilators

Disruption of the Autonomic Nervous System (ANS)

We’ve discussed in a previous post how COVID-19 can disrupt the normal functioning of the autonomic nervous system (ANS). 

Along with other important functions like controlling heart rate and blood pressure, this part of the nervous system is also involved in vision. Specifically, it controls the movement of the iris to fine-tune the amount of light that enters the eye, similar to a camera aperture. 

The ANS has two important components: the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS). Stimulation of the sympathetic branch, which triggers “fight or flight” responses when the body is under stress, induces pupil dilation. In contrast, stimulation of the parasympathetic system, known for “rest and digest” functions, causes the pupil to contract.

Under normal circumstances, SNS and PNS work in balance, and the size of the pupils change as needed. In COVID patients, however, the SNS tends to be dominant, which may cause some vision issues, such as light sensitivity and blurry vision. 

Neurovascular Coupling (NVC) Dysfunction

Vision problems can also occur if there’s a disruption in the way nerve cells receive the resources they need to function normally. Under normal circumstances, brain cells get nutrients and oxygen from a network of blood vessels. The dynamic relationship between blood vessels and the particular neuronal clusters they supply with resources is called neurovascular coupling (NVC). 

If this dynamic relationship is disrupted, affected regions of the brain may struggle to perform regular functions. Researchers have already established that COVID-19 can have a long-term impact on the brain. Recently, a study found damage in multiple brain regions over four months in elderly adults after they experienced a COVID infection. If you want to find out more, we have written about this important study in more detail in another post

It’s not unreasonable to think that if the virus affects function in the visual cortex — the primary region of the brain that receives and processes visual information — it can lead to vision problems such as poor visual acuity, loss of field of vision, and sensitivity to light.

If you notice that your vision gets worse during or after highly demanding cognitive tasks, it’s likely that you’re experiencing symptoms caused by NVC dysfunction. It’s also not unusual for the effects of NVC dysfunction to combine with ANS dysfunction. 

Vestibular Issues

Many COVID-19 patients also experience symptoms affecting the vestibular system, including dizziness, balance problems, and vertigo. A common complaint for these patients is that their vision is also affected. They can have problems focusing on objects or “seeing” objects moving from side to side. (There are evolving hypotheses linking COVID’s effect on the brainstem to these symptoms.)

This occurs because the vestibular system communicates with the eyes via an automatic function called the vestibulo-ocular reflex (VOR). The VOR is crucial to maintaining both balance and clear vision, controlling the position of the eyes so that when you move, you can keep your gaze stable and fixed on a certain point. However, if this system is not working properly due to a Sars-CoV-2 infection, patients may experience blurry or double vision, even though there’s nothing wrong specifically with the eyes. 

Pre-existing Visual Dysfunction

Some patients have vision problems they aren’t aware of which are then exacerbated by COVID-19. The brain does an amazing job of compensating for small problems in eye coordination and other visual issues. But if your brain is affected by COVID-19, it may not have enough bandwidth to compensate for those issues any longer. The result is a seemingly new set of vision problems when in reality, they just weren’t bad enough to cause symptoms until now.

Side-effects of Medication

Some commonly prescribed drugs can have adverse ocular effects. Some of these go away when the patient stops taking the medication, but others may cause irreversible vision loss.

This is particularly dangerous for COVID patients with diabetes, heart disease, and hypertension. For example, some medications for hypertension and diabetes cause abnormalities in pupil size, while some drugs for heart disease increase the risk of cataracts and cause eye irritation. The list of medications with a potential impact on vision includes steroids, antihistamines, antipsychotics, and any meds that affect blood flow. (Some research shows a large increase in the incidence of macular degeneration linked to blood pressure medication).

In addition, some antiviral medications can cause mild eye inflammation and redness, as well as blurry vision and ocular pain. However, there is no evidence that meds routinely used to treat most COVID-19 patients can cause vision problems. 

Our advice is to contact your physician or eye doctor if you experience any visual symptoms. Most symptoms are only mild, and you may feel that these problems are a reasonable trade-off for a potentially life-saving drug. Make sure you inform your doctor of all the medications you take, including prescription and over-the-counter, along with the dosages.

Other Possible Causes

Poor blood flow to the retina and corneaBlurred vision can result from the virus blocking, or at least restricting, the blood supply to the eye. This is known as retinopathy. Without nutrients and oxygen, the tissue in the retina may start to swell and die, making this area look white and fluffy, like cotton wool. These are commonly known as cotton wool spots and do not typically affect a person’s visual acuity, but may cause eye pain. 

Direct viral attack: The virus may be able to get into the body through the eyes. If SARS-CoV-2 reaches the surface of the eye, it can travel through the mucous membrane and eventually reach the retina all the way in the back of the eye. Expression of the ACE-2 receptor allows the virus to infect cells in the eye, which may explain many symptoms such as conjunctivitis, red and itchy eyes, and blurry vision. Given the connection between the eye and brain via the optic nerve, infection of the retina could be a way for the virus to reach the brain and cause further damage. 

Ventilators: It’s possible that COVID patients who suffered a severe COVID-19 infection develop vision problems after being on a ventilator. A study suggested that some patients on ventilators have nodules growing on the macula of the eye (this macular part processes what’s directly in front of the eyes), increasing the risk of conjunctivitis, vascular problems, and potential loss of vision. 

Treatment at Cognitive FX

Most long COVID patients who experience vision problems and eye disease also have a wide range of other symptoms, such as brain fog, difficulty sleeping, and headaches, to name just a few. Instead of looking at visual issues in isolation, our approach is to tackle the root of the problem and address multiple symptoms at the same time. 

Before treatment, you will undergo a detailed medical examination, allowing our doctors to find out more about your medical history and current symptoms. Part of our evaluation includes a functional Neurocognitive Imaging scan (fNCI) to identify which regions of the brain were affected by neurovascular coupling dysfunction and how well they’re communicating with other brain regions. The scan includes 56 areas of the brain. Using the information from the scan and the medical examination, our team will design a treatment plan custom-made for your needs. 

For example, this part of an fNCI report shows regions involved in reading comprehension, whether they are hypoactive (indicated a blue color on the report), and whether they’re communicating with each other as expected:

Results from a reading comprehension test and brain scan.

During our week-long treatment — called Enhanced Performance in Cognition, or EPIC for short— patients receive multidisciplinary therapy, including… 

  • Vision therapy
  • Neuromuscular therapy
  • Occupational therapy
  • Vestibular therapy
  • Cognitive therapy
  • Sensorimotor therapy
  • Neurointegration therapy
  • Psychotherapy
  • And more.

These therapies are appropriate therapeutic approaches for NVC dysfunction, autonomic dysfunction, vision problems, and vestibular issues. Some of the post-COVID symptoms these therapies can help resolve in addition to vision include…

All of our therapies have a visual component and will address some of your symptoms. However, we also have specific activities to rehabilitate your vision, such as the Brock string and Dynavision.

Our therapists use the Brock string for patients who are experiencing visual perception issues. This tool helps retrain the eyes to work together to focus on beads located at different distances along the string.

Dynavision is a computerized light board where patients push buttons as they light up, following different patterns on the board. The task may be as simple as hitting every button that lights up as quickly as possible, or it may be more challenging, where you only hit the green and avoid the red lights. This is a great tool to improve oculomotor coordination and for activating a number of brain regions involved in movement, cognition, and vision. 

Many of our patients experience significant improvements in just one week in many of their symptoms, but vision problems often need more than one week’s worth of therapy. It may take from six months to a year of vision therapy for your eyes to fully recover. We can refer you to a vision specialist in your hometown and show you how to do specific exercises at home. 

Our patients report a significant decrease in symptoms related to emotional function, sleep, concentration, clarity of thought, memory, and light sensitivity at the end of one week of treatment. 

While many other symptoms show direct improvement, they often require some rest at home or continuing therapy for a more marked improvement. Many patients are understandably tired after an intense week-long treatment protocol and experience less fatigue when they’re able to rest at home.

Percent symptom decrease based on 43 patient evaluations.

At the end of the week, you will receive a second fNCI scan to see how your brain is improving. Then, our clinicians will analyze your results and give you some homework, which typically includes aerobic exercise, cognitive games, and cognitive rest to help you continue your recovery journey at home.

Tips to Help You Cope With Vision Symptoms at Home

Not surprisingly, COVID long haulers with visual symptoms can experience difficulties with many activities during the day, including cooking, shopping, watching television, and reading. Here are a few tips to improve eye health and cope with your symptoms at home and work:

  • Follow the 20-20-20 rule: If your work involves long periods of the day in front of a computer or any other activities that rely heavily on your vision, you might suffer from mental fatigue, dry eyes, and headaches. Throughout the day, take a 20-second break away from the computer every 20 minutes and focus on an object about 20 feet away from you. This is a quick and easy exercise to reduce eye strain. Also, limit screen time as much as possible. 
  • Palming to relax your eyes: Cup your hands and apply gentle pressure over the sockets of your eyes for about 30 seconds. Close your eyes and breathe deeply. You can repeat this exercise throughout the day to relax your eyes. For your eye care routine, you may also find it helpful to apply eye drops (but avoid overuse). 

Coronavirus and the Nervous System

Authors: NIH What is SARS-CoV-2 and COVID-19?

What is SARS-CoV-2 and COVID-19?

Coronaviruses are common causes of usually mild to moderate upper respiratory tract illnesses like the common cold, with symptoms that may include runny nose, fever, sore throat, cough, or a general feeling of being ill. However, a new coronavirus called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) emerged and spread to cause the COVID-19 pandemic.

COVID-19, which means Coronavirus disease 2019, is an infectious disease that can affect people of all ages in many ways. It is most dangerous when the virus spreads from the upper respiratory tract into the lungs to cause viral pneumonia and lung damage leading to Acute Respiratory Distress Syndrome (ARDS). When severe, this impairs the body’s ability to maintain critical levels of oxygen in the blood stream—which can cause multiple body systems to fail and can be fatal.

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What do we know about the effects of SARS-CoV-2 and COVID-19 on the nervous system?

Much of the research to date has focused on the acute infection and saving lives. These strategies have included preventing infection with vaccines, treating COVID-19 symptoms with medicines or antibodies, and reducing complications in infected individuals.

Research shows the many neurological symptoms of COVID-19 are likely a result of the body’s widespread immune response to infection rather than the virus directly infecting the brain or nervous system. In some people, the SARS-CoV-2 infection causes an overreactive response of the immune system which can also damage body systems. Changes in the immune system have been seen in studies of the cerebrospinal fluid, which bathes the brain, in people who have been infected by SARS-CoV-2. This includes the presence of antibodies—proteins made by the immune system to fight the virus—that may also react with the nervous system. Although still under intense investigation, there is no evidence of widespread viral infection in the brain. Scientists are still learning how the virus affects the brain and other organs in the long-term. Research is just beginning to focus on the role of autoimmune reactions and other changes that cause the set of symptoms that some people experience after their initial recovery. It is unknown if injury to the nervous system or other body organs cause lingering effects that will resolve over time, or whether COVID-19 infection sets up a more persistent or even chronic disorder.

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What are the immediate (acute) effects of SARS-CoV-2 and COVID-19 on the brain?

Most people infected with SARS-CoV-2 virus will have no or mild to moderate symptoms associated with the brain or nervous system. However, most individuals hospitalized due to the virus do have symptoms related to the brain or nervous system, most commonly including muscle aches, headaches, dizziness, and altered taste and smell. Some people with COVID-19 either initially have, or develop in the hospital, a dramatic state of confusion called delirium. Although rare, COVID-19 can cause seizures or major strokes. Muscular weakness, nerve injury, and pain syndromes are common in people who require intensive care during infections. There are also very rare reports of conditions that develop after SARS-CoV-2 infection, as they sometimes do with other types of infections. These disorders of inflammation in the nervous system include Guillain-Barré syndrome (which affects nerves), transverse myelitis (which affects the spinal cord), and acute necrotizing leukoencephalopathy (which affects the brain).

Bleeding in the brain, weakened blood vessels, and blood clots in acute infection

The SARS-CoV-2 virus attaches to a specific molecule (called a receptor) on the surface of cells in the body. This molecule is concentrated in the lung cells but is also present on certain cells that line blood vessels in the body. The infection causes some arteries and veins—including those in the brain—to  become thin, weaken, and leak. Breaks in small blood vessels have caused bleeding in the brain (so-called microbleeds) in some people with COVID-19 infection. Studies in people who have died due to COVID-19 infection show leaky blood vessels in different areas of the brain that allow water and a host of other molecules as well as blood cells that are normally excluded from the brain to move from the blood stream into the brain. This leak, as well as the resulting inflammation around blood vessels, can cause multiple small areas of damage. COVID-19 also causes blood cells to clump and form clots in arteries and veins throughout the body. These blockages reduce or block the flow of blood, oxygen, and nutrients that cells need to function and can lead to a stroke or heart attack.

stroke is a sudden interruption of continuous blood flow to the brain. A stroke occurs either when a blood vessel in the brain becomes blocked or narrowed or when a blood vessel bursts and spills blood into the brain. Strokes can damage brain cells and cause permanent disability. The blood clots and vascular (relating to the veins, capillaries, and arteries in the body) damage from COVID-19 can cause strokes even in young healthy adults who do not have the common risk factors for stroke.

COVID-19 can cause blood clots in other parts of the body, too. A blood clot in or near the heart can cause a heart attack. A heart attack or Inflammation in the heart, called myocarditis, can cause heart failure, and reduce the flow of blood to other parts of the body. A blood clot in the lungs can impair breathing and cause pain. Blood clots also can damage the kidneys and other organs.

Low levels of oxygen in the body (called hypoxia) can permanently damage the brain and other vital organs in the body. Some hospitalized individuals require artificial ventilation on respirators. To avoid chest movements that oppose use of the ventilator it may be necessary to temporarily “paralyze” the person and use anesthetic drugs to put the individual to sleep. Some individuals with severe hypoxia require artificial means of bringing oxygen into their blood stream, a technique called extra corporeal membrane oxygenation (ECMO). Hypoxia combined with these intensive care unit measure generally cause cognitive disorders that show slow recovery.

Diagnostic imaging of some people who have had COVID-19 show changes in the brain’s white matter that contains the long nerve fibers, or “wires,” over which information flows from one brain region to another. These changes may be due to a lack of oxygen in the brain, the inflammatory immune system response to the virus, injury to blood vessels, or leaky blood vessels. This “diffuse white matter disease” might contribute to cognitive difficulties in people with COVID-19. Diffuse white matter disease is not uncommon in individuals requiring intensive hospital care but it not clear if it also occurs in those with mild to moderate severity of COVID-19 illness.

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What is the typical recovery from COVID-19?

Fortunately, people who have mild to moderate symptoms typically recover in a few days or weeks. However, some  people who have had only mild or moderate symptoms of COVID-19 continue to experience dysfunction of body systems—particularly in the lungs but also possibly affecting the liver, kidneys, heart, skin, and brain and nervous system—months after their infection. In rare cases, some individuals may develop new symptoms (called sequelae) that stem from but were not present at the time of initial infection. People who require intensive care for Acute Respiratory Distress Syndrome, regardless of the cause, usually have a long period of recovery. Individuals with long-term effects, whether following mild or more severe COVID-19, have in some cases self-identified as having “long COVID” or “long haul COVID.” These long-term symptoms are included in the scientific term, Post Acute Sequelae of SARS-CoV-2 Infection (PASC).

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What are possible long-term neurological complications of COVID-19?

Researchers are following some known acute effects of the virus to determine their relationship to the post-acute complications of COVID-19 infection. These post-acute effects usually include fatigue in combination with a series of other symptoms. These may include trouble with concentration and memory, sleep disorders, fluctuating heart rate and alternating sense of feeling hot or cold, cough, shortness of breath, problems with sleep, inability to exercise to previous normal levels, feeling sick for a day or two after exercising (post-exertional malaise), and pain in muscle, joints, and chest. It is not yet known how the infection leads to these persistent symptoms and why in some individuals and not others.

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Nerve damage, including peripheral neuropathy

Fatigue and post-exertional malaise

Cognitive impairment/altered mental state

Muscle, joint, and chest pain

Prolonged/lingering loss of smell (anosmia) or taste

Persistent fevers and chills

Prolonged respiratory effects and lung damage

Headaches

Sleep disturbances

Anxiety, depression, and stress post-COVID

 How do the long-term effects of SARS-CoV-2 infection/COVID-19 relate to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)?

Some of the symptom clusters reported by people still suffering months after their COVID-19 infection overlap with symptoms described by individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). People with a diagnosis of ME/CFS have wide-ranging and debilitating effects including fatigue, PEM, unrefreshing sleep, cognitive difficulties, postural orthostatic tachycardia, and joint and muscle pain. Unfortunately, many people with ME/CFS do not return to pre-disease levels of activity. The cause of ME/CFS is unknown but many people report its onset after an infectious-like illness. Rest, conserving energy, and pacing activities are important to feeling better but don’t cure the disease. Although the long-term symptoms of COVID-19 may share features with it, ME/CFS is defined by symptom-based criteria and there are no tests that confirm an ME/CFS diagnosis.

ME/CFS is not diagnosed until the key features, especially severe fatigue, post-exertional malaise, and unrefreshing sleep, are present for greater than six months. It is now becoming more apparent that following infection with SARS-CoV-2/COVID-19, some individuals may continue to exhibit these symptoms beyond six months and qualify for an ME/CFS diagnosis. It is unknown how many people will develop ME/CFS after SARS-CoV-2 infection. It is possible that many individuals with ME/CFS, and other disorders impacting the nervous system, may benefit greatly if research on the long-term effects of COVID-19 uncovers the cause of debilitating symptoms including intense fatigue, problems with memory and concentration, and pain.

Am I at a higher risk if I currently have a neurological disorder?

Much is still unknown about the coronavirus but people having one of several underlying medical conditions may have an increased risk of illness. However, not everyone with an underlying condition will be at risk of developing severe illness. People who have a neurological disorder may want to discuss their concerns with their doctors.

Because COVID-19 is a new virus, there is little information on the risk of getting the infection in people who have a neurological disorder. People with any of these conditions might be at increased risk of severe illness from COVID-19:

  • Cerebrovascular disease
  • Stroke
  • Obesity
  • Dementia
  • Diabetes
  • High blood pressure

There is evidence that COVID-19 seems to disproportionately affect some racial and ethnic populations, perhaps because of higher rates of pre-existing conditions such as heart disease, diabetes, and lung disease. Social determinants of health (such as access to health care, poverty, education, ability to remain socially distant, and where people live and work) also contribute to increased health risk and outcomes.

Can COVID-19 cause other neurological disorders?

In some people, response to the coronavirus has been shown to increase the risk of stroke, dementia, muscle and nerve damage, encephalitis, and vascular disorders. Some researchers think the unbalanced immune system caused by reacting to the coronavirus may lead to autoimmune diseases, but it’s too early to tell.

Anecdotal reports of other diseases and conditions that may be triggered by the immune system response to COVID-19 include para-infectious conditions that occur within days to a few weeks after infection:

  • Multi-system infammatory syndrome – which causes inflammation in the body’s blood vessels
  • Transverse myelitis – an inflammation of the spinal cord
  • Guillain-Barré sydrome (sometimes known as acute polyradiculoneuritis) – a rare neurological disorder which can range from brief weakness to nearly devastating paralysis, leaving the person unable to breathe independently
  • Dysautonomia – dysfunction of the autonomic nerve system, which is involved with functions such a breathing, heart rate, and temperature control
  • Acute disseminating encephalomyelitis (ADEM) – an attack on the protective myelin covering of nerve fibers in the brain and spinal cord
  • Acute necrotizing hemorrhagic encephalopathy – a rare type of brain disease that causes lesions in certain parts of the brain and bleeding (hemorrhage) that can cause tissue death (necrosis)
  • Facial nerve palsies (lack of function of a facial nerve) such as Bell’s Palsy
  • Parkinson’s disease-like symptoms have been reported in a few individuals who had no family history or early signs of the disease

Does the COVID-19 vaccine cause neurological problems?

Almost everyone should get the COVID-19 vaccination. It will help protect you from getting COVID-19. The vaccines are safe and effective and cannot give you the disease. Most side effects of the vaccine may feel like flu and are temporary and go away within a day or two. The U.S. Food and Drug Administration (FDA) continues to investigate any report of adverse consequences of the vaccine. Consult your primary care doctor or specialist if you have concerns regarding any pre-existing known allergic or other severe reactions and vaccine safety.

A recent study from the United Kingdom demonstrated an increase in Guillain-Barré Syndrome related to the Astra Zeneca COVID-19 vaccine (virally delivered) but not the Moderna (messenger RNA vaccine). Guillain-Barré syndrome (a rare neurological disorder in which the body’s immune system damages nerve cells, causing muscle weakness and sometimes paralysis) has also occurred in some people who have received the Janssen COVID-19 Vaccine (also virally delivered). In most of these people, symptoms began within weeks following receipt of the vaccine. The chance of having this occur after these  vaccines is very low, 5 per million vaccinated persons in the UK study. The chance of developing Guillain-Barré Syndrome was much higher if one develops COVID-19 infection (i.e., has a positive COVID test) than after receiving the Astra Zeneca vaccine. The general sense is that there are COVID-19 vaccines that are safe in individuals whose Guillain-Barré syndrome was not associated with a previous vaccination and that actual infection is the greater risk for developing Guillain-Barré Syndrome. 

The U.S. Centers for Disease Control and Prevention (CDC) site offers information on vaccine resources. The National Institutes of Health (NIH) has information on vaccines for the coronavirus. The CDC  has make public its report on the association of Guillain-Barré Syndrome with the Janssen COVID-19 Vaccine and no increased incidence occurred after vaccination with the Moderna or Pfizer vaccines.

More information about Guillain-Barré Syndrome here.

There have been reports of  neurological complications from other SARS-CoV-2 vaccinations. Visit the FDA COVID-19 Vaccines webpage for information about coronavirus vaccines and fact sheets for recipients and caregivers that outline possible neurological and other risks.

Peripheral facial nerve palsy associated with COVID-19

Journal of NeuroVirology volume 26, pages941–944 (2020)Cite this article

Authors: Marco A. LimaMarcus Tulius T. SilvaCristiane N. SoaresRenanCoutinhoHenrique S. OliveiraLivia AfonsoOtávio EspíndolaAna Claudia Leite & Abelardo Araujo 

Abstract

COVID-19 pandemic revealed several neurological syndromes related to this infection. We describe the clinical, laboratory, and radiological features of eight patients with COVID-19 who developed peripheral facial palsy during infection. In three patients, facial palsy was the first symptom. Nerve damage resulted in mild dysfunction in five patients and moderate in three. SARS-Cov-2 was not detected in CSF by PCR in any of the samples. Seven out of eight patients were treated with steroids and all patients have complete or partial recovery of the symptoms. Peripheral facial palsy should be added to the spectrum of neurological manifestations associated with COVID-19.

Introduction

The ongoing COVID-19 pandemic has affected millions of people worldwide and revealed several neurological syndromes related to this infection. Anosmia/ageusia, encephalitis, encephalopathy, cerebrovascular complications, myelitis, and Guillain-Barré syndrome, among other neurological complications, occur in a significant proportion of patients (Ellul et al. 2020; Paterson et al. 2020).

Acute facial nerve palsy commonly occurs in clinical practice and is associated with considerable distress due to possible functional and esthetic sequelae (Jowett 2018). There are many potential mechanisms implicated in its occurrence, including viral infections. Herein, we review the clinical and laboratory features of eight patients with COVID-19 who developed peripheral facial palsy during the clinical course of the infection or as its first symptom.

Methods

Case series of eight patients seen from May to July 2020 with a diagnosis of COVID-19 based on positive SARS-CoV-2 RNA RT-qPCR in nasal and oropharyngeal swabs (Biomanguinhos kit (E+P1), FIOCRUZ, Brazil).

Data about the onset of facial palsy, associated clinical conditions, brain imaging, cerebrospinal fluid parameters, treatment, and outcome were recorded. Facial palsy was graded according to the House-Brackmann scale (House and Brackmann 1985). This study was approved by the Local Ethical Committee at INI/FIOCRUZ.

Results

Among the eight patients, seven were women. All had COVID-19 diagnosis based on positive SARS-CoV-2 RNA RT-qPCR in nasal and oropharyngeal swabs. The mean age was 36 years (range 25–50 years). In three patients, facial palsy was the first symptom of COVID-19, while in the remaining five, it appeared from 2 to 10 days after onset of other clinical manifestations. All patients had mild respiratory and systemic COVID-19 symptoms, and none required hospitalization. According to the House-Brackmann grading system, nerve damage resulted in mild (grade 2) dysfunction in five patients and moderate (grade 3) in three (Table 1). The neurological examination disclosed no abnormalities in all but one patient, who had an associated ipsilateral abducent nerve palsy. Deep tendon reflexes were preserved, and no sensory abnormalities were present. Six patients underwent lumbar puncture with normal opening pressure in all cases. CSF analysis showed no inflammatory changes except for a mild protein elevation in one patient (50 mg/dl) (Table 1). SARS-Cov-2 was not detected in CSF by PCR in any of the samples. Imaging (CT scan or MRI) was normal in seven patients. In one patient, MRI showed contrast enhancement in the distal intracanalicular portion in the tympanic and mastoid segments of the left facial nerve (Fig. 1).Table 1 Clinical and laboratory manifestations of COVID-19 patients with facial palsy

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Fig. 1

Six out of seven patients were treated with oral steroids (prednisone 40–60 mg/day for 5–7 days) and one received intravenous methylprednisolone. One patient with mild manifestations received only supportive care (eye lubricant) with complete recovery 2 days later. Two patients received oral acyclovir concomitant to steroids due to possible Herpes simplex virus infection. Complete recovery occurred in five patients, while the other three still had some degree of facial weakness at the last follow-up 30 days after onset of neurological symptoms.

Discussion

Infections such as HSV-1, VZV, and Lyme disease are common causes of facial paralysis (Owusu et al. 2018). The rapid expansion of COVID-19 pandemics led to the development of a growing number of neurological syndromes. Our study shows that peripheral facial palsy can occur during the clinical course of COVID-19 or anticipate other typical manifestations such as fever and respiratory symptoms.

Interestingly, all but one of our patients were women. Idiopathic facial palsy does not have a gender preference (Katusic et al. 1986). Indeed, our sample is too small to assume any conclusion, and the two other cases of isolated facial palsy in association with COVID-19 described by Goh and Casas were men (Casas et al. 2020; Goh et al. 2020).

Most patients in this study had isolated facial palsy with mild or moderate dysfunction and no other neurological findings. Except for the two described above by Goh and Casas (Casas et al. 2020; Goh et al. 2020), in all other studies, facial paralysis in COVID-19 patients occurred unilaterally or bilaterally in association with other manifestations of Guillain-Barré syndrome (Manganotti et al. 2020; Ottaviani et al. 2020; Juliao Caamaño and Alonso Beato 2020; Paybast et al. 2020; Sancho-Saldaña et al. 2020; Bigaut et al. 2020).

CSF basic parameters (cellularity, protein, and glucose levels) are usually normal in patients with idiopathic facial paralysis as observed in our series (Bremell and Hagberg 2011). SARS-CoV2 was not detected in any five cases who underwent lumbar puncture, which is consistent with a recent study that failed to show viral RNA in the CSF of COVID-19 patients with different neurological syndromes (Espíndola et al. 2020).

Possible mechanisms related to nerve damage in idiopathic facial nerve paralysis include ischemia of vasa nervorum and demyelination induced by an inflammatory process (Zhang et al. 2020). Microthrombi and other vascular changes have been consistently reported in several postmortem studies (Silberzahn et al. 1988; Nunes Duarte-Neto et al. 2020) and may be implicated in the development of facial nerve ischemia in COVID-19 patients. Direct viral damage or an autoimmune reaction toward the nerve producing inflammation would be alternative or contributing mechanisms to dysfunction.

Supportive care and oral steroids are the mainstays of treatment (Sullivan et al. 2007). Our patients had complete recovery or significant improvement in few weeks after treatment as the patient reported by Casas et al. (2020), suggesting a good outcome when peripheral facial palsy occurs in association with COVID-19.

In conclusion, peripheral facial palsy should be added to the spectrum of neurological manifestations associated with COVID-19. Most patients had an uncomplicated course with good outcome, and SARS-CoV-2 RNA could not be detected in CSF of any patient.

References

COVCOG 1: Factors Predicting Physical, Neurological and Cognitive Symptoms in Long COVID in a Community Sample. A First Publication From the COVID and Cognition Study

Authors: Panyuan Guo1Alvaro Benito Ballesteros1Sabine P. Yeung1Ruby Liu1Arka Saha1Lyn Curtis2Muzaffer Kaser3,4Mark P. Haggard1 and Lucy G. Cheke1*

Since its first emergence in December 2019, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has evolved into a global pandemic. Whilst often considered a respiratory disease, a large proportion of COVID-19 patients report neurological symptoms, and there is accumulating evidence for neural damage in some individuals, with recent studies suggesting loss of gray matter in multiple regions, particularly in the left hemisphere. There are a number of mechanisms by which COVID-19 infection may lead to neurological symptoms and structural and functional changes in the brain, and it is reasonable to expect that many of these may translate into cognitive problems. Indeed, cognitive problems are one of the most commonly reported symptoms in those experiencing “Long COVID”—the chronic illness following COVID-19 infection that affects between 10 and 25% of patients. The COVID and Cognition Study is a part cross-sectional, part longitudinal, study documenting and aiming to understand the cognitive problems in Long COVID. In this first paper from the study, we document the characteristics of our sample of 181 individuals who had experienced COVID-19 infection, and 185 who had not. We explore which factors may be predictive of ongoing symptoms and their severity, as well as conducting an in-depth analysis of symptom profiles. Finally, we explore which factors predict the presence and severity of cognitive symptoms, both throughout the ongoing illness and at the time of testing. The main finding from this first analysis is that that severity of initial illness is a significant predictor of the presence and severity of ongoing symptoms, and that some symptoms during the initial illness—particularly limb weakness—may be more common in those that have more severe ongoing symptoms. Symptom profiles can be well described in terms of 5 or 6 factors, reflecting the variety of this highly heterogenous condition experienced by the individual. Specifically, we found that neurological/psychiatric and fatigue/mixed symptoms during the initial illness, and that neurological, gastrointestinal, and cardiopulmonary/fatigue symptoms during the ongoing illness, predicted experience of cognitive symptoms.

Introduction

Manifestations of coronavirus 2 (SARS-CoV-2) infection vary in severity ranging from asymptomatic to fatal. In the acute stage, symptomatic patients—at least in the early variants—typically experience respiratory difficulties that can result in hospitalization and require assisted ventilation (Baj et al., 2020Heneka et al., 2020Jain, 2020). While COVID-19 is primarily associated with respiratory and pulmonary challenge, 35% of patients report neurological symptoms including headache and dizziness (e.g., Mao et al., 2020). In severe illness, neurological symptoms can be seen in 50–85% of patients (e.g., Pryce-Roberts et al., 2020Romero-Sánchez et al., 2020). Indeed, alteration in taste or smell (anosmia/dysgeusia) is reported in over 80% of cases (e.g., Lechien et al., 2020), is often the first clinical symptom (Mao et al., 2020Romero-Sánchez et al., 2020) and regularly persists beyond resolution of respiratory illness (Lechien et al., 2020).

Accumulating evidence suggests that many COVID-19 patients experiencing severe illness show evidence of neural damage (Helms et al., 2020Kandemirli et al., 2020) and unusual neural activity (Galanopoulou et al., 2020). There are a number of postulated mechanisms linking COVID-19 infection with neurological problems (Bougakov et al., 2021). For example, based on the behavior of previous SARS viruses, SARS-CoV-2 may attack the brain directly perhaps via the olfactory nerve (Lechien et al., 2020Politi et al., 2020) causing encephalitis. Severe hypoxia from respiratory failure or distress can also induce hypoxic/anoxic-related encephalopathy (Guo et al., 2020). There is considerable evidence that COVID-19 is associated with abnormal blood coagulation, which can increase risk of acute ischemic and hemorrhagic cerebrovascular events (CVAs) (Beyrouti et al., 2020Li et al., 2020Wang et al., 2020Kubánková et al., 2021) leading to more lasting brain lesions. Indeed, ischemic or hemorrhagic lesions have been found in COVID-19 patients in multiple studies (Le Guennec et al., 2020Matschke et al., 2020Moriguchi et al., 2020Poyiadji et al., 2020). A recent study using the United Kingdom Biobank cohort comparing structural and functional brain scans before and after infection with COVID-19 identified significant loss of gray matter in the parahippocampal gyrus, lateral orbitofrontal cortex and insula, notably concentrated in the left hemisphere in patients relative to controls (Douaud et al., 2021).

A key candidate mechanism is dysfunctional or excessive immune response to infection. For example, excessive cytokine release (“cytokine storm”) and immune-mediated peripheral neuropathy (e.g., Guillain-Barre syndrome) are both linked with neurological and sensory-motor issues (Alberti et al., 2020Das et al., 2020Poyiadji et al., 2020Whittaker et al., 2020Zhao et al., 2020). In addition to acute effects, chronic inflammation has also been associated with neural and cognitive dysfunction, particularly in the hippocampus—a key area responsible for memory (Ekdahl et al., 2003Monje et al., 2003Jakubs et al., 2008Belarbi et al., 2012). Considerable rodent evidence links inflammatory cytokines with cognitive impairments (e.g., IL-1β: Thirumangalakudi et al., 2008Beilharz et al., 20142018Che et al., 2018Mirzaei et al., 2018; TNF-α: Thirumangalakudi et al., 2008Beilharz et al., 2014Almeida-Suhett et al., 2017). These findings are broadly reflected in human studies, wherein circulating cytokines have been associated with reduced episodic memory (e.g., Kheirouri and Alizadeh, 2019) and chronic neuroinflammation has been heavily implicated in the pathophysiology of neurodegenerative diseases (McGeer and McGeer, 2010Zotova et al., 2010Chen et al., 2016Bossù et al., 2020). Given the volume of reports of excessive immune response to COVID-19 infection (Mehta et al., 2020Tay et al., 2020), and evidence for neuroinflammation from postmortem reports (Matschke et al., 2020) research into cognitive sequalae is highly implicated.

Given the evidence for widespread neural symptoms and demonstrable neural damage, it could be expected that COVID-19 infection would be associated with cognitive deficits. Indeed, there is some early evidence linking neural changes following COVID-19 and cognitive deficits. Hosp et al. (2021) found that evidence of frontoparietal hypometabolism in older patients presenting with post-COVID-19 neurological symptoms via positron emission tomography (PET) was associated with lower neuropsychological scores, particularly in tests of verbal memory and executive functions.

Many forms of neuropathology would be unlikely to be present uniquely as cognitive deficits, but would be associated with a range of related symptoms. Some of these symptoms may be neurological (e.g., disorientation, headache, numbness) while others may reflect systemic/multisystem involvement (e.g., reflecting the symptom profile of chronic inflammatory or autoimmune diseases). It may therefore be possible to gain information as to the mechanism of neurological involvement via investigation of symptomatology. If it is possible to identify groups of symptoms (such as neurological, respiratory, systemic) during either the acute or post-acute phase of illness that predict cognitive problems, this may aid in the identification of patients that are at risk of developing cognitive deficits. In a highly heterogenous condition, in which up to 200 symptoms have been suggested (Davis et al., 2021), reduction of dimensionality is essential to allow meaningful associations to be drawn between experienced symptoms and relevant outcomes.

The United Kingdom Office for National Statistics [ONS] (2021) has estimated that around 21% of those experiencing COVID-19 infection still have symptoms at 5 weeks, and that 10% still have these symptoms at 12 weeks from onset. These figures may not tell the full story, being based on a list of 12 physical symptoms which does not include neurological or cognitive manifestations (e.g., Alwan and Johnson, 2021Ziauddeen et al., 2021). Other calculations suggest that around 1 in 3 non-hospitalized COVID-19 patients have physical or neurological symptoms after 2–6 weeks from disease onset (Sudre et al., 2020Tenforde et al., 2020Nehme et al., 2021) and that 11–24% still have persisting physical, neurological or cognitive symptoms 3 months after disease onset (Cirulli et al., 2020Ding et al., 2020). A community-based study reported that around 38% symptomatic people experienced at least one physical or neurological symptom lasting 12 weeks or more from onset and around 15% experienced three or more of these symptoms (Whitaker et al., 2021). Ongoing symptoms seem to occur regardless of the severity of the initial infection, with even asymptomatic patients sometimes going on to develop secondary illness (FAIR Health, 2021Nehme et al., 2021), however, initial severity may impact severity of ongoing issues (e.g., Whitaker et al., 2021).

The National Institute for Health and Care Excellence (NICE) guidelines describe “post-COVID-19 syndrome” as “Signs or symptoms that develop during or after infection consistent with COVID-19, continue for more than 12 weeks and are not explained by an alternative diagnosis” (National Institute for Health and Care Excellence [NICE], 2020). One difficulty with this definition is that the “signs or symptoms” that qualify for the diagnosis are not specified (e.g., Alwan and Johnson, 2021Ziauddeen et al., 2021) thus many patients could go uncounted and unrecognized clinically, or conversely over-liberal inclusion may lead to overcounting. The patient-created term “Long COVID” has increasingly been used as an umbrella term to describe the highly heterogenous condition experienced by many people following COVID-19 infection (Callard and Perego, 2021).

Emerging evidence suggests that Long COVID is a debilitating multisystem illness that affects multiple organ systems and there have been some attempts to characterize “phenotypes.” An online survey involved in 2,550 non-hospitalized participants detected two clusters within both initial and ongoing symptoms. Initial symptoms showed a majority cluster with cardiopulmonary symptoms predominant, and a minority cluster with multisystem symptoms that did not align specifically with any one organ system. Similarly, ongoing symptoms were clustered into a majority cluster with cardiopulmonary, cognitive symptoms and exhaustion, and a minority cluster with multisystem symptoms. Those with more related symptoms in the initial major cluster were more likely to move into ongoing multisystem cluster, and this movement can be predicted by gender and age, with higher risk in women, those younger than 60, and those that took less rest during the initial illness (Ziauddeen et al., 2021).

“Long COVID” research has repeatedly identified cognitive dysfunction as one of the most common persistent symptoms (after fatigue), occurring in around 70% of patients (Cirulli et al., 2020Bliddal et al., 2021Davis et al., 2021Ziauddeen et al., 2021). Indeed, brain fog and difficulty concentrating are more common than cough is at many points in the Long COVID time course (Assaf et al., 2020). Ziauddeen et al. (2021) report nearly 40% of participants endorsing at least one cognitive symptom during the initial 2 weeks of illness, with this persisting in the long term. However around 30% of participants also reported developing cognitive symptoms—particularly brain fog and memory problems—later. Indeed, Davis et al. (2021) demonstrate that brain fog, memory problems and speech and language problems were more commonly reported at week 8 and beyond than they were during initial infection. Furthermore, strenuous cognitive activity was found to be one of the most common triggers leading to relapse/exacerbation of existing symptoms (Davis et al., 2021Ziauddeen et al., 2021). Crucially, 86% of participants indicated that cognitive dysfunction and/or memory impairment was impacting their ability to work, with nearly 30% reporting being “severely unable to work” and only 27% working as many hours as they had pre-COVID-19 (Davis et al., 2021). These figures suggest that the cognitive sequelae of COVID-19 have the potential for long-term consequences not just for individuals but also—given the prevalence of Long COVID—for the economy and wider society.

Here we report on the first stage of a mixed cross-sectional/longitudinal investigation—The COVID and Cognition Study (COVCOG)—aimed at understanding cognition in post-acute COVID-19. The aims of this current paper are threefold: First, to provide a detailed demographic profile of our sample, comparing those who had experienced COVID-19 infection to those who had not, and those who recovered to those who continued to experience COVID-19 symptoms after acute phase of illness. Second, we aim to contribute to the understanding of phenotypes of Long COVID by using a rigorous factor analytic approach to identify groups of symptoms that tend to co-occur. We investigate symptom profiles both during and following initial infection in those that had experienced COVID-19. This allows investigation of symptoms during initial illness that may be predictive of ongoing symptoms, as well as exploring the nature of those ongoing symptoms themselves. These phenotypes may, through future studies, be directly linked to disease profiles and mechanisms. In an application of this second aim, a third objective is to use the symptom factors extracted (such as those incorporating neurological symptoms) to investigate predictors of self-reported cognitive deficits. Due to the novel character of both the virus and the subsequent ongoing illness at the time of study creation, this study was designed not to test specific hypotheses but to map the terrain, generating hypotheses for future, more targeted investigation.

Materials and Methods

Participants

A total of 421 participants aged 18 and over were recruited through word of mouth, student societies and online/social media platforms such as the Facebook Long COVID Support Group (over 40K members). Of these, 163 participants were recruited through the Prolific recruitment site, targeting participants with demographic profiles otherwise underrepresented in our sample. Specifically, recruitment through Prolific was limited to those with low socioeconomic status and levels of education below a bachelor’s degree. As the study was conducted in English, participants were recruited from majority English speaking countries (the United Kingdom, Ireland, United States, Canada, Australia, New Zealand, or South Africa). Informed consent to use of anonymized data was obtained prior to starting.

Data collection for this stage of the study took place between October 2020 and March 2021, and recorded data on infections that occurred between March 2020 and February 2021. As such, all participants with experience of COVID-19 infection were likely to have been infected with either Wild-Type or Alpha-variant SARS-CoV-2, as the later-emerging variants (e.g., Delta, Omicron) were not common in the study countries at that time. Study recruitment started before the roll out of vaccinations, thus we do not have confirmed vaccination status for all participants. Once vaccination became available, the questionnaire was revised to ask about vaccination status. Of the 33 participants who were tested after this point, 11 (2 in the No COVID group, 9 in the COVID group) reported being vaccinated. Among them, 8 had received the first dose and 3 had had two doses. The majority (over 80%) had the vaccine within the last 7 days to last month. All received Pfizer (BNT162b2) except 1 (COVID group) who received AstraZeneca (AZD1222).

Procedure

The study was reviewed by University of Cambridge Department of Psychology ethics committee (PRE.2020.106, 8/9/2020). The current paper is part of a larger, mixed cross-sectional/longitudinal online study (“COVCOG”) conducted using the online assessment platform Gorilla.1 The COVCOG study consists of a baseline assessment of characteristics and cognition in samples of individuals who had or had not experienced COVID-19 infection. Both groups completed questionnaire and a range of cognitive tasks and were then followed up at regular intervals. The results reported here are for the questionnaire section of the baseline session only. The questionnaire covered demographics, previous health and experience of COVID-19.

Participants answered questions relating to their age, sex, education level, country of permanent residence, ethnicity, and profession. They were then asked a series of questions relating to their medical history and health-related behaviors. These included self-reporting their height and weight—which were used to calculate body mass index (BMI), and their usual diet intake, use of tobacco and alcohol, and physical activity (before the illness if infected) on a 6-point frequency scale from “Never” to “Several times daily.” Following this, they were asked for details of their experience of COVID-19. Because many of the participants in this study contracted COVID-19 before confirmatory testing of infection state was widely available, both those with (“Confirmed”) and without test confirmation (“Unconfirmed”) were included in the “COVID” group. Those that didn’t think they had had COVID-19 but had experienced an illness that could have been COVID-19 were assigned an “Unknown” infection status. Those that confirmed that they had not had COVID-19, nor any illness that might have been COVID-19, were included in the “No COVID” group. The procedure for grouping and progression through the baseline session is detailed in Figure 1.FIGURE 1

Figure 1. Study procedural flow.

Participants in the “COVID” group indicated the number of weeks since infection on a drop-down menu. Those that reported being within the first 3 weeks of infection proceeded straight to debriefing and were followed up 2 weeks later, once the initial infection was passed. Apart from this delay, they proceeded with the experiment in the same way as the rest of the COVID group. Participants then answered questions on the severity of the initial illness and whether they were experiencing ongoing symptoms. Finally, participants were asked to give details on a large number of individual symptoms during three time periods: initial illness (first 3 weeks), ongoing illness (“since then,” i.e., the time since initial infection), and currently (past 1–2 days). When reporting on initial symptoms, participants gave an indication of severity on a scale of 1–3 from “Not at all” to “Very severe.” When reporting symptoms over the period “since then” they reported on both severity and regularity of symptoms on a scale of 1–5 from “Not at all” to “Very severe and often.” When reporting on symptoms in the past 1–2 days, they reported the presence or absence of the symptoms dichotomously (i.e., check the box of the symptom if present). These symptom lists were developed based on currently available medical literature reporting symptoms experienced by COVID-19 patients and through consulting medical doctors and COVID-19 patients from the Long COVID Support Group. Participants in the “No COVID” Group were not asked their experience of COVID-19.

Data Processing and Analysis

Analyses were conducted using IBM SPSS Statistics for Windows, Version 23.0. We describe quantitative variables using means and standard deviations, and numbers and percentages for qualitative variables. Sidak’s correction for multiple comparisons was employed. All p-values are reported uncorrected, and the Sidak-corrected alpha is quoted where appropriate.

We investigated differences in the first group of variables: sociodemographic, medical history, and health behaviors, concerning two COVID group classifications. First dividing the sample into two groups (COVID/No COVID), second subdividing the COVID group by symptom longevity and severity (Recovered, Ongoing mild infection, and Ongoing severe infection). Where parametric analysis was not appropriate, we employed the Pearson’s chi-square (χ2) test for categorical variables and the Mann-Whitney and Kruskal-Wallis test for continuous variables depending on the number of COVID groups. To investigate differences between groups (COVID/No COVID; Recovered/Ongoing mild/Ongoing severe), we employed Mann-Whitney and ANOVA/Kruskal-Wallis. To examine whether these variables and initial symptoms predicted degrees of ongoing illness, we ran independent multinomial logistic regression, using forward stepwise method to identify what items within these variables were significant predictors while controlling for demographics including sex, age, education, and country of residence. Next, to determine suitable groups of symptoms, we employed exploratory principal component analysis (PCA) with varimax rotation. Based on our high number of items (Nunnally, 1978) and the novelty of the subject (Henson and Roberts, 2006), we performed two PCAs, one for the initial symptoms and another one symptoms experienced since the initial phase. We then used the high-loading items on the “since then” symptom factors to calculate profiles for currently experienced symptoms. To explore what symptom factors were associated with infection or ongoing symptoms, we employed various independent multinomial logistic regression with backward elimination of variables p > 0.05 to identify the best fitted models. Data analyzed in relation to our study aims are depicted in Figure 2.FIGURE 2

Figure 2. Data analyzed in relation to our study aims.

Results

Sample Characteristics

No COVID (NCn = 185) vs. COVID (Cn = 181)

Distributions of demographics including sex, age, education level, country, and ethnicity of the two groups (NC/C) are shown in Table 1. The majority of participants were from the United Kingdom and were of White (Northern European) ethnicity (over 70% in both groups). Pearson’s chi-square tests showed that the groups did not significantly differ in sex, but differed in age [χ2(5) = 19.08, p = 0.002, V = 0.228] and level of education [χ2(5) = 56.86, p < 0.001, V = 0.394], with the COVID group tending to fall into the older age ranges and higher education level more than the No COVID group.TABLE 1

Table 1. Distribution of demographics in No COVID and COVID groups.

Employment

Supplementary Table 1 shows the distributions of pre-pandemic profession and employment status. To adjust for multiple comparisons, Sidak corrections were applied and alpha levels were adjusted to 0.003 for profession and 0.007 for employment status. The COVID group had significantly more people working in healthcare [χ2(1) = 12.77, p < 0.001, V = 0.187] and engaging in full-time work before the pandemic [χ2(1) = 21.19, p < 0.001, V = 0.241]. In contrast, the No COVID group were more likely not to be in paid work [Profession “Not in paid work” χ2(1) = 27.72, p < 0.001, V = 0.275; Employment status “Not Working” χ2(1) = 13.18, p < 0.001, V = 0.190], and they were more likely to be students [χ2(1) = 8.91, p = 0.003, V = 0.156].

Health and Medical History

Supplementary Table 2 compares medical history and health behaviors across the COVID and No COVID groups, which may be informative as to vulnerabilities. Sidak correction adjusted the alpha level to 0.003 for medical history and 0.008 for health behaviors. Pearson’s chi-square tests showed that inflammatory or autoimmune diseases [χ2(1) = 9.81, p = 0.002, V = 0.164] were found more commonly in the COVID group than the No COVID group. Mann-Whitney U-tests showed that the COVID group consumed more fruit and vegetables (U = 13,525, p = 0.001) and had higher level of physical activity (U = 13,752, p = 0.002) than the No COVID group, while the No COVID group consumed sugary (U = 14168.5, p = 0.008) food more than the COVID group. ANOVA showed that the COVID group (M = 26.71, SD = 7.26) had higher BMI than the No COVID group (M = 25.15, SD = 5.64), [F(1, 361) = 5.24, p = 0.023]. However this effect was not significant after controlling for sex, age, education and country [F(1, 357) = 1.57, p = 0.211].

Characteristics of Those Experiencing Ongoing Symptoms

To understand the potential association between the progression of COVID-19 and various potential risk factors at baseline, including demographics, medical history and health behaviors, and the severity of initial illness and initial symptoms, we further divided the COVID group into three duration subgroups: (i) those who, at the time of test, had recovered from COVID-19 (“Recovered group,” Rn = 42), (ii) those who continued to experience mild or moderate ongoing symptoms [“Ongoing (Mild/Moderate) group,” C + ; n = 53], and (iii) those who experienced severe ongoing symptoms [“Ongoing (Severe) group,” C + + ; n = 66]. Those who were still at their first 3 weeks of COVID-19 infection (n = 17) or those who reported “it is too soon” to comment on their ongoing symptoms (n = 3) were not included in the following analyses. Participants in all groups ranged between 3 and 31 + weeks since symptom-onset, and a majority (81.5%) of those with ongoing symptoms reporting after more than 6 months since infection.

Figure 3 shows the distribution of demographic variables across the COVID-19 duration subgroups (further details available in Supplementary Table 3). In each, more than half of the participants were from the United Kingdom (54.8–92.4%) and were of White (Northern European) ethnicity (69–93.9%). Pearson’s chi-square tests suggested that age [χ2(10) = 53.41, p < 0.001, V = 0.407] and education level [χ2(10) = 20.03, p = 0.029, V = 0.249], but not sex, significantly differed between subgroups. In terms of age, the R subgroup tended to fall more in the younger age ranges (see Figure 3A). In terms of education level, the R subgroup tended to have lower education level (GCSE or below and A level), but the C + + (Severe) subgroup clustered more in higher education level (bachelor’s degree) (see Figure 3B). The subgroups also differed in the time elapsed since infection at the time of completing the study [χ2(6) = 19.64, p = 0.003, V = 0.247]. The R subgroup were more likely to be in their first 10 weeks of infection, while the C + + (Severe) subgroup were more likely to be at their 31 weeks or above (Figure 3C).FIGURE 3

Figure 3. Distributions of (A) age, (B) education level, (C) weeks since infection, and (D) severity of initial illness in Recovered, Ongoing (Mild/Moderate) and Ongoing (Severe) subgroups.

A multinomial logistic regression indicated that only age, but not sex or education, was significantly associated with COVID-19 progression [χ2(10) = 43.6, p < 0.001]. People in the age ranges of 18–20 and 21–30 years were more likely to recover from COVID-19 than to progress into mild/moderate (ps = 0.02–0.03) or severe (p = 0.002) ongoing symptoms.

We examined whether medical history and health behaviors were different between COVID-19 duration subgroups. Table 2 shows the descriptive statistics of these factors in RC +, and C + + subgroups for medical history and pre-pandemic health behaviors. None of the listed health conditions significantly differed between subgroups (against Sidak α = 0.003). There were, however, significant group differences (Sidak α = 0.008) in fruit and vegetables consumption [H(2) = 15.92, p < 0.001] and fatty food consumption [H(2) = 36.54, p < 0.001]. Both ongoing symptom subgroups ate more fruit and vegetables (C + + : U = 810, p < 0.001; C + : U = 808, p = 0.016) and less fatty food (C + : U = 773.5, p = 0.005; C + + : U = 552.5, p < 0.001) than the R subgroup. The C + (Mild/Moderate) subgroup also consumed more fatty food than the C + + (Severe) subgroup (U = 1142, p < 0.001). The subgroups did not significantly differ in BMI [F(2, 157) = 0.085, p = 0.919].TABLE 2

Table 2. Distribution of medical history and health behaviors (1 = Never–6 = Several times daily; higher scores indicating higher frequency) in COVID subgroups: Recovered (R), Ongoing (Mild/Moderate) (C+) and Ongoing (Severe) (C++).

After controlling for sex, age, education, and country, a forward stepwise multinomial logistic regression indicated that no medical history variables were associated with COVID-19 progression, however, health behaviors including fatty food consumption [χ2(2) = 23.25, p < 0.001], physical activity [χ2(2) = 10.31, p = 0.006], and alcohol consumption [χ2(2) = 8.18, p = 0.017] were all significantly associated with COVID-19 progression. In our sample, people consuming more fatty food had a higher chance of having recovered from COVID-19 (p < 0.001) or having developed mild/moderate ongoing symptoms (p < 0.001) than progressing into severe ongoing symptoms. Higher levels of physical activity were associated with reduced chance of recovery relative to progression onto mild/moderate (p = 0.002) or severe ongoing symptoms (p = 0.034). Those drinking alcohol more frequently were more likely to recover from COVID-19 than to develop severe ongoing symptoms (p = 0.007).

Severity of Initial Illness

The severity of illness in the first 3 weeks of infection was associated with subsequent symptom longevity. Multinomial logistic regression showed that severity of initial illness was significantly associated with COVID-19 progression [χ2(2) = 24.44, p < 0.001], with higher initial severity associated with more severe subsequent ongoing symptoms (ps < 0.001–0.02). This effect was maintained after controlling for sex, age, education, and country [χ2(2) = 12.28, p = 0.002; C + + > C + : p = 0.048; C + + > Rp = 0.001]. Those with severe ongoing symptoms experienced more severe initial illness than those whose ongoing symptoms were mild/moderate (U = 1,258, p = 0.005, Figure 3D) and those who were fully recovered (U = 658.5, p < 0.001). The severity difference between the C + (Mild/Moderate) subgroup and the R subgroup was also significant (U = 842, p = 0.034).

Supplementary Table 4 shows the relative frequencies of particular diagnoses received during the initial illness. Of the 109 participants who sought medical assistance, the most common diagnoses received were hypoxia (14.7%), blood clots (5.5%), and inflammation (4.6%).

Symptoms During Initial Illness

Symptoms that appeared in less than 10% of participants were excluded. Kruskal-Wallis H-tests (Sidak α = 0.001) showed significant duration-group differences in 11/33 symptoms in terms of the severity experienced (see Figure 4, more information in Supplementary Table 5). In post hoc analysis (Sidak α = 0.017), muscle/body pains, breathing issues and limb weakness showed gradation, with the C + + (Severe) subgroup having experienced the most severe symptoms, followed by the C + (Mild/Moderate) subgroup, and the R subgroup experiencing the least (p ranges < 0.001–0.012). Some symptoms did not show gradation with severity of ongoing symptoms, but were reliably higher in those with ongoing symptoms. Both the ongoing symptoms subgroups reported more severe symptoms of fatigue, brain fog and chest pain/tightness during the initial illness than those that recovered (ps < / = 0.001) but did not differ from one another. Those with severe ongoing symptoms experienced more severe nausea and blurred vision than those with mild/moderate or who recovered (p ranges < 0.001–0.009). Finally, the C + + (Severe) subgroup experienced more abdominal pain, altered consciousness and confusion during the initial illness than the R subgroup (ps < / = 0.001).FIGURE 4

Figure 4. Severity of different symptoms during the initial (left) and ongoing (right) illness among those who recovered or had ongoing mild or severe illness. Higher scores indicate higher severity.

After controlling for sex, age, education, and country, a forward stepwise multinomial logistic regression suggested that six initial symptoms were significantly associated with COVID-19 progression. These were: limb weakness [χ2(2) = 25.92, p < 0.001], brain fog [χ2(2) = 13.82, p = 0.001], chest pain or tightness [χ2(2) = 10.81, p = 0.005], dizziness [χ2(2) = 7.82, p = 0.02], cough [χ2(2) = 7.74, p = 0.021], and breathing difficulties [χ2(2) = 6.98, p = 0.031]. People initially experiencing more severe limb weakness were more likely to experience severe ongoing symptoms than to recover (p < 0.001) or develop mild/moderate ongoing symptoms (p < 0.001). More severe initial breathing issues (p = 0.014) and dizziness (p = 0.037) were associated with greater likelihood of severe than mild/moderate ongoing symptoms, but people with more severe initial dizziness (p = 0.02) and cough (p = 0.009) were more likely to recover rather than to develop mild/moderate ongoing symptoms. More severe initial brain fog and chest pain/tightness were associated with more progression into mild/moderate than either severe ongoing symptoms (brain fog: p = 0.029; chest pain: p = 0.026) or recovery (brain fog: p = 0.001; chest pain: p = 0.007).

Symptoms During Ongoing Illness

Excluding those who reported being totally asymptomatic throughout or feeling completely better very quickly after initial illness (who did not report on ongoing symptoms, n = 15), the COVID subgroups were asked to report on their ongoing experience of a list of 52 symptoms. Symptoms that appeared in less than 10% of participants were excluded. The duration-groups differed significantly in 27/47 symptoms (Sidak α = 0.001; see Figure 4 and Supplementary Table 6). Post hoc tests (Sidak α = 0.017) showed that the C + + (Severe) subgroup reported higher levels of severity than the R subgroup in all 27 symptoms (ps < 0.001–0.017) and then the C + (Mild/Moderate) subgroup in all except two (altered consciousness and eye-soreness; ps < 0.001–0.017). The C + (Mild/Moderate) subgroup also reported experiencing higher severity in 16 symptoms (including fatigue, difficulty concentrating, brain fog, and forgetfulness) than the R subgroup (ps < 0.001–0.016; see Figure 4 and Supplementary Table 6; see also Supplementary Table 7 for similar analysis of current symptoms).

Symptoms in Those With Confirmed or Suspected COVID-19 vs. “Other” Illnesses

As much of our sample experienced infection early in the pandemic before widespread testing was available, not all cases included in our COVID group were confirmed by a polymerase chain reaction (PCR) test (infection statuses: “Confirmed” COVID, “Unconfirmed” COVID). Meanwhile, a significant minority of participants had an illness during the pandemic period that they did not think was COVID-19 (infection status: “Unknown”) (see Figure 1). We compared symptom prevalence across these three groups (Unknown, n = 55; Unconfirmed, n = 96; Confirmed, n = 65) for both the initial 3 weeks of illness, and the time since then. Those who were still at their first 3 weeks of COVID-19 infection (n = 17) and who reported “it is too soon” to comment on their ongoing symptoms (n = 3) were not included in this analysis.

The groups significantly differed in 14 out of 31 symptoms during the initial illness (Sidak α = 0.0016; Supplementary Table 8). Both Confirmed and Unconfirmed groups reported higher severity than the Unknown group on 13 symptoms (including fatigue, muscle/body pains and loss of smell/taste; p ranges < 0.001–0.014; Sidak α = 0.017). Additionally, the Unconfirmed group reported more severe blurred vision than the Unknown group (p < 0.001), and the Unknown group reported more severe sore throat/hoarseness than the Confirmed group (p < 0.001). As for the differences within those with COVID-19, the Confirmed group experienced greater loss of smell/taste than the Unconfirmed group (p = 0.002), while the Unconfirmed group reported higher levels of breathing issues, chest pain/tightness, sore throat/hoarseness, and blurred vision than the Confirmed group (ps = 0.004–0.015).

Of these participants, 177 (Unknown group: n = 31; Unconfirmed group: n = 88; Confirmed group: n = 58) reported experiencing ongoing symptoms after the 3 weeks of illness. Significant group differences were found in 11/47 ongoing symptoms (Sidak α = 001; see Figure 5 and Supplementary Table 9). Post hoc tests (Sidak α = 0.017) showed that, compared with the Unknown group, both the Confirmed and Unconfirmed groups reported higher levels of fatigue, difficulty concentrating, brain fog, tip-of-the-tongue (ToT) problems, muscle/body pains, fast/irregular pulse, semantic disfluency, chest pain/tightness, limb weakness, and loss of smell/taste (ps < / = 0.001). The Unconfirmed group also experienced higher level of night waking (p = 0.001) than the Unknown group. There were no significant differences in ongoing symptoms between the Confirmed and the Unconfirmed groups.FIGURE 5

Figure 5. Experience of ongoing symptoms in Unknown, Unconfirmed COVID, and Confirmed COVID groups.

Characterizing Symptom Profiles

While data on individual symptoms are useful in identifying highly specific predictors, these are too numerous for more systematic analysis, which require data-reduction. A stated aim of this study was to identify symptom profiles that may be informative as to underlying pathology.

Initial Symptom Factors

To group the initial symptoms, we included 34 symptoms in the PCA after excluding paralysis and seizures (experienced by less than 10% of the participants). A total of 164 participants reported on their symptoms during the first 3 weeks of illness (the factor analysis coded here as 1 = Very severe, 3 = Not at all). The Kaiser-Meyer-Olkin (KMO) test (value 0.861) and Bartlett’s test of sphericity [χ2(528) = 2,250, p < 0.001] showed the data were suitable for factor analysis. We employed the varimax rotation. Initially, nine factors were obtained with eigenvalue > 1.0, which was reduced to five via Cattell’s Scree test (Kline, 2013). Assessments were conducted of 4, 5, and 6 factor solutions for interpretability and robustness. The ratio of rotated eigenvalue to unrotated eigenvalue was higher for the 5-factor solution than for the 4- or 6-factor solutions, and this structure was also the most interpretable. We thus proceeded with a 5-factor solution, which explained 50.59% of item variance with last rotated eigenvalue of 1.998.

We labeled the new components as “F1: Neurological/Psychiatric,” “F2: Fatigue/Mixed,” “F3: Gastrointestinal,” “F4: Respiratory/Infectious,” and “F5: Dermatological” (see Table 3 for factor loadings). We computed the factor scores using the regression method (see Supplementary Table 10 for factor scores).TABLE 3

Table 3. Factors and loadings from the “Initial Symptoms” PCA.

People who went on to experience ongoing symptoms showed higher factor scores in the Fatigue/Mixed symptom factor during the initial illness [F(2, 158) = 23.577, p < 0.001], but did not differ in any other initial symptom factor. Pairwise analysis revealed that those who recovered were significantly less likely to experience Fatigue/Mixed symptoms than those with mild/moderate (p < 0.001) or severe (p < 0.001) ongoing symptoms (Figure 6).FIGURE 6

Figure 6. Severity of Fatigue/Mixed symptom factor during initial illness among those who went on to full recover, or have ongoing mild or severe symptoms.

Ongoing Symptom Factors

We performed a second PCA using the symptoms experienced since the initial phase (after the first 3 weeks), including 45 symptoms. Paralysis and seizures were excluded (experienced by less than 10% of the participants). A total of 149 participants reported on their symptoms over the time since the first 3 weeks of illness (the factor analysis coded here as 1 = Very severe and often, 5 = Not at all). The KMO test (value 0.871) and Bartlett’s test of sphericity [χ2(861) = 3,302, p < 0.001] showed suitability for factor analysis. We employed the varimax rotation. PCA showed 11 components with eigenvalues > 1.0, and this was reduced to 6 via inspection of the eigenvalue gradient (scree plot). The ratio of rotated eigenvalue to unrotated eigenvalue was higher for the 7-factor solution, followed by the 6-factor. The 6- and 7-factor solutions were differentiated by subdivision of the second factor, reducing the degree of cross-loading. However, the 7-factor solution was less interpretable and less robust to removal to cross-loaders (the presence of which can be accepted from a pathology perspective, given that multiple mechanisms can produce the same symptom). As such, we proceeded with the 6-factor solution, which explained 54.17% of item variance and had a last rotated eigenvalue of 2.227.

We labeled the new components as “F1: Neurological,” “F2: Gastrointestinal/Autoimmune,” “F3: Cardiopulmonary/Fatigue,” “F4: Dermatological/Fever,” “F5: Appetite Loss,” and “F6: Mood” (see Table 4 for factor loadings). We computed the factor scores using the regression method (see Supplementary Table 11 for factor scores).TABLE 4

Table 4. Factors and loadings from the exploratory factor analysis of ongoing “since then” symptoms PCA.

In order for cognitive symptoms [brain fog, forgetfulness, tip-of-the-tongue (ToT) problems, semantic disfluency and difficulty concentrating] to be used as a dependent variable, these were isolated and a PCA run separately. A single component emerged, with all the cognitive symptoms loading homogeneously highly (see Supplementary Table 12). The KMO test (value 0.886) and Bartlett’s test of sphericity [χ2(10) = 564, p < 0.001] indicated suitability for factor analysis, and the single 5-item factor explained 76.86% of variance.

Current Symptoms

The current symptoms assessed were the same as the ongoing symptoms, but rated dichotomously as either currently present or absent. To estimate the degree to which current symptoms aligned with the factors established for the ongoing period, we generated a quasi-continuously distributed variable according to how many of the high loading (> / = 0.5) items from the ongoing factors were recorded as present currently. Using this sum scores by factor method (Tabachnick et al., 2007Hair, 2009), each score was subsequently divided by the number of items in that factor producing quasi “factor scores” that were comparable and indicative of “degree of alignment” of current symptoms to established factors.

To assess the stability and specificity of symptom profiles between these periods, serial correlations were conducted for corresponding and non-corresponding factors. Correlations of the same factor across time points were materially higher (> 0.2) from the next highest correlation among the 5 non-corresponding factors, with Williams tests (Steiger, 1980) giving the narrowest gap at p = 0.003 (Neurological: r = 0.676, t = 5.712; Gastrointestinal/Autoimmune: r = 0.531, t = 3.778; Cardiopulmonary/Fatigue: r = 0.678, t = 7.272; Dermatological/Fever: r = 0.523, t = 3.364; Appetite Loss: r = 0.591, t = 5.017; Mood: r = 0.490, t = 4.803). This consistency suggests that while particular symptoms may fluctuate, the profile of symptoms—once grouped into an adequately supported factor—is moderately stable for individuals, and can be relatively well represented by a “snapshot” of current symptoms. For completeness, an additional factor analysis was conducted on the current symptoms, which are reported in Supplementary Table 13.

One symptom factor showed change over time since infection, suggesting higher severity in those who had been ill for longer: Number of weeks since infection (positive test/first symptoms) was positive correlated with severity of ongoing severity of Cardiopulmonary/Fatigue symptoms [r(147) = 0.271, p < 0.001; Figure 7] and, to a weaker extent, current alignment with the same factor [r(147) = 0.206, p = 0.012], however, only the former association survived correction for multiple comparisons (Sidak α = 0.0085).FIGURE 7

Figure 7. Association between number of weeks since infection and severity of (top) Cardiopulmonary/Fatigue Symptoms and (bottom) cognitive symptoms in the entire period since the initial infection (left) and the past 1–2 days (right). Higher scores indicate higher symptom severity.

Cognitive Symptoms

Within those currently experiencing symptoms (n = 126), 77.8% reported difficulty concentrating, 69% reported brain fog, 67.5% reported forgetfulness, 59.5% reported tip-of-the-tongue (ToT) word finding problems and 43.7% reported semantic disfluency (saying or typing the wrong word).

Symptoms experienced during the initial illness significantly predicted both ongoing and current cognitive symptoms (Figure 8). A linear regression with backward elimination found that the best model contained the Neurological/Psychiatric, Fatigue/Mixed, Gastrointestinal, and Respiratory/Infectious symptom factors and explained 20% of variance (Radj2 = 0.2, p < 0.001). Table 5 shows that the Fatigue/Mixed symptoms factor (η′p2 = 0.129) was the better predictor followed by the Neurological/Psychiatric symptom factor (η′p2 = 0.092). For current cognitive symptoms, the best model contained both the Neurological/Psychiatric and Fatigue/Mixed symptom factors, together explaining 13.9% of variance (p < 0.001). Of the two, the Fatigue/Mixed factor was the better predictor (η′p2 = 0.110). No interactions between factors contributed significantly and were thus not included in the final models.FIGURE 8

Figure 8. Association between combined regression model predicted value for (A) initial symptom factors and ongoing cognitive symptoms; (B) initial symptom factors and current cognitive symptoms; (C) ongoing symptom factors and ongoing cognitive symptoms; (D) ongoing symptom factors and current cognitive symptoms; and (E) current symptom factors and current cognitive symptoms.TABLE 5

Table 5. Regression models predicting variation in the cognitive symptom factor (ongoing and current) from non-cognitive symptom factors (initial, ongoing, and current).

A similar, but much stronger, pattern emerged when considering the predictive value of ongoing (non-cognitive) symptoms (Figure 8). Using backward elimination to factors with significance (p < 0.05), all factors except Dermatological/Fever remained in the model, which explained over 55% of variance (Radj2 = 0.558, p < 0.001). The effect size (η′p2) for each factor is given in Table 5. The Gastrointestinal/Autoimmune and Cardiopulmonary/Fatigue factors were the biggest contributors to the model. Indeed, in an extreme elimination model in which contributing factors were limited to two or fewer, these two factors alone explained 38% of variance retaining strong significance (p < 0.001). No interactions between factors contributed significantly and were thus not included in the final models. Ongoing symptoms also predicted current cognitive symptoms. The best model explained 36% of the variance (p < 0.001) and included the Neurological, Gastrointestinal/Autoimmune and Cardiopulmonary/Fatigue factors and an interaction between the Gastrointestinal/Autoimmune and Cardiopulmonary/Fatigue factors. Of these, Cardiopulmonary/Fatigue symptoms were the strongest predictor (η′p2 = 0.208), with Neurological (η′p2 = 0.118) and Gastrointestinal/Autoimmune (η′p2 = 0.115) being relatively equal.

Current symptom factors also strongly predicted current cognitive symptoms (Figure 8). The backward elimination model left three contributing factors: Neurological, Cardiopulmonary/Fatigue and Appetite Loss. Together these explained around 50% of variance (Radj2 = 0.494). Of these, Cardiopulmonary/Fatigue was the stronger predictor (η′p2 = 0.306). Indeed, when the model was limited to just this factor, this model still explained 43% of the variance.

There was a significant association between degree of cognitive symptoms and duration of illness. Those who had been ill for longer were more likely to report having had cognitive symptoms throughout the ongoing illness [r(147) = 0.262, p = 0.001] and to be experiencing them at the time of test [r(147) = 0.179, p = 0.03] (Figure 7).

Experiences and Impact of Long COVID

Here we limited analysis to all those who reported some degree or period of ongoing symptoms following COVID-19 [i.e., excluding those who reported being totally asymptomatic throughout or feeling completely better very quickly after initial illness (n = 15)]. Of the remaining 146 participants, 108 (74%) self-identified as experiencing or having experienced “Long COVID.”

We examined the impact and experiences of ongoing illness (Table 6). In most cases, the nature and degree of negative experience of ongoing symptoms scaled with perceived severity. The change in symptoms over time differed between severity subgroups [χ2(6) = 37.52, p < 0.001, V = 0.367]. The C + + (Severe) subgroup were more likely to report that symptoms were consistent over time, while those with mild/moderate ongoing symptoms were more likely to report improvement in symptoms. As might be expected, the R subgroup were alone in reporting complete resolution of symptoms after recovery from the initial illness (Supplementary Table 14).TABLE 6

Table 6. Experiences and impact of Long COVID in different ongoing symptom severity groups.

Long COVID has significant impact on individuals’ lives. Over 54.6% of those with ongoing symptoms had experienced long periods unable to work and 34.5% had lost their job due to illness, 63.9% reported difficulty coping with day-to-day activities, 49.6% had had difficulty getting medical professionals to take their symptoms seriously, and 43.7% felt that they had experienced a trauma, while 17.6% had experienced financial difficulty as a result of illness. These impacts scaled with symptom severity. Those with severe ongoing symptoms were more likely to report being unable to work for a long period due to illness [χ2(2) = 46.42, p < 0.001, V = 0.564], having difficulty coping with day-to-day requirements [χ2(2) = 20.23, p < 0.001, V = 0.372], having difficulty getting medical professionals to take their symptoms seriously [χ2(2) = 23.05, p < 0.001, V = 0.397], and losing their job due to illness [χ2(2) = 24.39, p < 0.001, V = 0.409]. In contrast, the R subgroup tended to report experiencing none of the above [χ2(2) = 52.73, p < 0.001, V = 0.601].

We further compared job-loss with the No COVID group (n = 185). Those with ongoing symptoms were more likely to have lost their job than those who had not experienced COVID-19 [χ2(1) = 26.74, p < 0.001, V = 0.297]. The most common reason for job-loss among those with ongoing symptoms was illness [χ2(1) = 56.85, p < 0.001, V = 0.432], while the most common reason in the No COVID group was economy [χ2(1) = 7.67, p = 0.006, V = 0.159].

Discussion

Nature of Illness and Symptom Profiles

Here we report the initial findings from a cross-sectional/longitudinal study investigating cognition post-COVID-19. One aim of this first publication was to characterize the “COVID and Cognition Study” (COVCOG) sample. Within the COVID group, we recruited specifically to get good representation of those who were experiencing or had experienced ongoing symptoms. Indeed, 74% identified with the term “Long COVID.” Our final sample had a relatively even spread of those that had fully recovered at the time of test (42), or had mild/moderate (53) or severe (66) ongoing symptoms. Medical history did not differ between those experiencing ongoing symptoms and those who recovered. However, in terms of health behaviors, those with ongoing symptoms were in general “healthier,” being more likely to have previously been consuming less fatty food and more fruits and vegetables. This result is counterintuitive and may reflect insufficient controls for confounding demographic variables relating to socio-economic status. Nonetheless potential links between lifestyle and nutrition and COVID-19 recovery warrant further investigation.

The nature of the initial illness was found to have a significant impact on the likelihood and severity of ongoing symptoms. Despite this sample almost entirely comprised of non-hospitalized patients, those with more severe initial illness were more likely to have ongoing symptoms, and for those symptoms to be more severe. This suggests even in “community” cases, initial infection severity is a predictor of vulnerability to Long COVID. In an analysis of all symptoms experienced during the initial illness, there were several that were predictive of presence or severity of ongoing symptoms. In particular, individuals with severe ongoing symptoms were significantly more likely to have experienced limb weakness during the initial illness than those that recovered. However, some differences in severity ratings between ongoing subgroups were small despite being statistically significant, which warrant caution in interpreting the results.

We asked participants to retrospectively report on symptoms over three time periods: initial illness, ongoing illness, and currently experienced. Given the highly heterogenous nature of Long COVID, we used principal component analysis (PCA) with the aim to ascertain whether there may be different phenotypes of the condition within our sample—that is to say, that there may be certain types of symptoms that tend to (or not to) co-occur. For both the initial and ongoing illness, the symptom factors resemble those found in previous studies (e.g., Davis et al., 2021Whitaker et al., 2021Ziauddeen et al., 2021), with some quite coherent cardiopulmonary clusters, and other less specific “multisystem” profiles which may reflect more systemic issues such as inflammation, circulation, or endocrine function.

Predictors of Cognitive Difficulties

A large proportion of our sample reported cognitive difficulties. We isolated the cognitive symptoms for the ongoing and current illness and computed a single factor including only these. Using this, we investigated which (non-cognitive) symptom factors during both the initial and ongoing illness explained significant variance in severity of cognitive symptoms.

Together, the Fatigue/Mixed, Neurological/Psychiatric, Gastrointestinal and Respiratory/Infectious symptom factors during the initial illness explained around 20% of variance in ongoing (“since then”) cognitive symptoms, and a similar model (containing only Neurological/Psychiatric and Fatigue/Mixed symptom factors) explained nearly 14% of variance in current cognitive symptoms. These findings strongly suggest that experience of neurological symptoms during the initial illness are significant predictors of self-reported cognitive impairment. While only one factor is named “Neurological” both this and the Fatigue/Mixed factor contain clear elements of neurological involvement. Indeed, headache, dizziness, and brain fog all loaded more highly on the Fatigue/Mixed factor than on the Neurological/Psychiatric factor (which was more characterized by disorientation, visual disturbances, delirium, and altered consciousness). This suggests different types of neurological involvement, potentially reflecting neuroinflammation (the Fatigue/Mixed factor) and encephalitis (the Neurological/Psychiatric factor), respectively. It is of note then that both these factors independently predicted subjective cognitive problems. Both inflammation and encephalitis have been proposed as mechanisms through which COVID-19 may impact the brain (Bougakov et al., 2021) and the presence of indications of neuro-inflammation have been found in post-mortem studies (Matschke et al., 2020). It will be an important next step in the investigation to explore whether the neurological and (possible) inflammatory symptom factors explain variance in performance in cognitive tests.

Participants’ experience of ongoing Neurological, Cardiopulmonary/Fatigue, Gastrointestinal/Autoimmune, Mood and Appetite Loss symptom factors all predicted current cognitive symptoms, together explaining around over 55% of variance. Unlike the initial symptom factors, the vast majority of neurological symptoms were contained within the Neurological factor for ongoing symptoms, with only headache and dizziness loading more strongly into the Gastrointestinal/Autoimmune factor. This latter factor was instead more characterized by symptoms associated with systemic illness—potentially endocrine, or reflecting thyroid disruption—including diarrhea, hot flushes and body pains. An additional predictor here was Cardiopulmonary/Fatigue symptoms, a factor which was quite narrowly characterized by symptoms associated with breathing difficulties. Alone, the Gastrointestinal/Autoimmune and Cardiopulmonary/Fatigue factors explained a large proportion of the variance (36%), suggesting these were the biggest contributor to individual differences in cognitive symptoms. These findings suggest that the symptoms linked with cognitive issues are not so specifically neurological as during the initial illness, but may also incorporate problems with heart and lung function (potentially implying hypoxia, which can induce hypoxic/anoxic-related encephalopathy; Guo et al., 2020) and with other ongoing ill health that is harder to label (resembling symptoms of the menopause, Crohn’s disease, hypothyroidism, and a number of other conditions), but may imply systemic inflammation. Again, these associations align with previous findings, in which cardiopulmonary and cognitive systems clustered in the same factor (Ziauddeen et al., 2021).

In terms of current symptoms, the Cardiopulmonary/Fatigue factor again emerged as a significant predictor, this time paired with Neurological and Appetite Loss symptom factors and explaining nearly 50% of variance. It is potentially notable that both the cognitive and Cardiopulmonary/Fatigue factors showed positive correlation with length of illness, suggesting either that the same disease process underpinning both increases in severity over time, or that the relationship between the two may be the result of both being symptoms more commonly still experienced in those with longer-lasting illness. Longitudinal investigation within individuals would be necessary to disambiguate this.

Impact of Long COVID

Of those experiencing Long COVID, more than half (and 75% of those with severe symptoms) reported long periods unable to work due to illness. These findings chime with evidence from other studies on Long COVID (e.g., Davis et al., 2021Ziauddeen et al., 2021). Notably, Davis et al. (2021) found that in their sample 86% of participants reported that it was the cognitive dysfunction in particular that was impacting their work (30% severely so). The reported experiences of those with Long COVID—many of whom were at least 6 months into their illness at the time of completing the study—suggest that in addition to broader economic challenges associated with the pandemic, society will face a long “tail” of workforce morbidity. It is thus of great importance—not just for individuals but for society—to be able to prevent, predict, identify and treat issues associated with Long COVID, and including treatment for cognitive symptoms as part of this policy.

A major roadblock to progress in management and treatment of Long COVID is that clinicians do not have the appropriate information or experience. A significant number (over 50% of those with severe symptoms) of our sample reported struggling to get medical professionals to take their symptoms seriously. Part of this issue will be the nature of the symptoms experienced. Patients whose symptoms cannot be, or are not routinely, clinically measured (such as cognitive symptoms; Kaduszkiewicz et al., 2010) are at greater risk of “testimonial injustice”—that is, having their illness dismissed by medical professionals (De Jesus et al., 2021). The novel and heterogenous nature of Long COVID also provides a particular challenge for clinicians dealing with complex and undifferentiated presentations and “medically unexplained symptoms” (Davidson and Menkes, 2021). The data presented here demonstrate that cognitive difficulties reported by patients can be predicted by severity and pattern of symptoms during the initial stages of infection, and during the ongoing illness. These findings should provide the foundation for clinicians to assess the risk of long-term (6 months +) cognitive difficulties, as well as for researchers to investigate the underlying mechanism driving these deficits. In our next paper, we will explore the association between general and cognitive symptoms and performance on cognitive tasks, with the aim of establishing whether self-reported cognitive issues translate into “objective” deficits on cognitive evaluations.

Some have argued that cognitive changes following COVID-19 infection may reflect changes related to experience of lockdown or social isolation (perhaps via development of depression or anxiety). There is indeed some evidence that pandemic-related changes in lifestyle impact cognition (e.g., Fiorenzato et al., 2021Okely et al., 2021). However, many of these studies did not record COVID-19 infection history (Okely et al., 2021Smirni et al., 2021) so it is difficult to ascertain to what degree these findings may have been related to COVID-19 infection. One study that did control for this (Fiorenzato et al., 2021) identified significant declines in self-reported attention and executive function, however, showed reduced reports of forgetfulness compared with pre-lockdown. Our results show that, compared to individuals who experienced a (probable) non-COVID-19 illness during the pandemic, those with suspected or confirmed COVID-19 infection experienced greater levels of fatigue, difficulty concentrating, brain fog, tip-of-the-tongue (ToT) word finding problems and semantic disfluency, but did not differ in levels of anxiety and depression. Meanwhile there was little difference between those that did and did not have biological confirmation of their COVID-19 infection. This strongly suggests that self-reported cognitive deficits reported in our sample are associated with COVID-19 infection, rather than the experience of illness, or pandemic more generally.

Limitations and Future Research

While the findings of this study are notable, there are a number of limitations in design and execution which warrant caution in interpreting the results.

Being unable to bring participants into the lab for clinical assessment, this study relied on online retrospective self-report of symptoms sometimes experienced some months previously. We thus must be cognizant of potential issues of misremembering and that questionnaires may not have been completed in an environment conducive to concentration and reflection. The manner of reporting symptoms differed between different reporting times, with a longer list and more reporting options (reflecting both severity and regularity) for the “ongoing” period. In particular, our binary present/absent reporting approach for currently experienced symptoms was not able to reflect current severity and did not lend itself to factor analysis. Using the sum scores by factor method (Tabachnick et al., 2007Hair, 2009) to calculate alignment of currently experienced symptoms with the symptom factors got around some of these issues, future studies should keep lists consistent to allow for direct comparison of symptom profiles at the different time points. A similar issue is that symptoms information was not collected for the “No COVID” group, or (in terms of current symptoms) for those that reported having recovered. This would have been highly useful in order to establish the degree to which symptoms (particularly those which might be expected to be exacerbated by lockdowns, such as depression, anxiety, fatigue) were more common in those that had previously experienced COVID-19 than those that had not. It would also be useful to ask both the COVID and No COVID groups about their living situation at the time of completing the study, such as whether lockdown or any social restrictions were taking place and how much these measures were affecting their physical and psychological health. It would also have been useful to assess whether people who reported having “recovered” showed symptomatology similar to the “No COVID” group, or remained distinct.

Due to the intensive performance focus of the current investigation, our study had a relatively smaller sample size than is feasible in an epidemiological cohort. Characterizing the sample, we found that those who had experienced COVID-19 infection—and within these, those with more severe ongoing symptoms—tended to be older and more educated. We do not believe that these features reflect vulnerabilities toward COVID-19 or Long COVID, but rather the biases in our recruitment and target populations. Our sample was recruited from English speaking countries (the United Kingdom, Ireland, United States, Canada, Australia, New Zealand, or South Africa) and the majority were from the United Kingdom, which may not be representative of people from other parts of the world. Where possible, we controlled for age, sex, education, and country of residence, which should mitigate some of these biases, however, these sampling discrepancies should be kept in mind. We furthermore specifically targeted our recruitment to those self-identifying as experiencing Long COVID, and we advertised the study as investigating memory and cognition in this group. Our sample may thus have been biased toward those individuals with more severe symptoms and cognitive symptoms in particular (as these individuals may be more motivated to take part). Overrepresentation of Long COVID sufferers is not a serious issue outside of prevalence studies, however, our reported rates of cognitive symptoms within the Long COVID cohort should be treated with caution. It is reassuring, however, that the figures for these symptoms within our cohort are comparable to those seen in much larger studies not explicitly investigating cognition (e.g., Davis et al., 2021Ziauddeen et al., 2021).

Finally, much of the analysis in this study was necessarily exploratory, as too little was known at the time of study design to form many clear hypotheses. To handle this, multiple comparisons were conducted, for which the alpha adjustments entailed that only the very strongest effects survived at conventional statistical thresholds. This high type 2 error rate means that it is likely that more than just these findings would be confirmed on replication, and because a stated aim of this study was to generate hypotheses that could be tested in later, more targeted research, we have additionally reported the uncorrected results. Similarly, in terms of investigating symptom profiles, we did not aim to present a “definitive” set of factors, but to provide stratifiers and covariates for future analysis, particularly of cognitive test performance, and changes over time. While this study is not able to identify a specific mechanism, it may be able to lay the groundwork with sufficient breadth and detail to inform future mechanistic investigation.

Conclusion

The COVID and Cognition study is a cross-sectional/longitudinal study assessing symptoms, experiences and cognition in those that have experience COVID-19 infection. Here we present the first analysis in this cohort, characterizing the sample and investigating symptom profiles and cognitive symptoms in particular. We find that particular symptom-profiles—particularly neurological symptoms—during both the initial infection and ongoing illness were predictive of experience of cognitive dysfunction. The symptoms and experiences reported by our sample appear to closely resemble those reported in previous work on Long COVID (e.g., Davis et al., 2021Ziauddeen et al., 2021) which suggests that our, smaller, sample might be generally representative of the larger Long COVID patient community. The participants in this study are being followed up over the course of the next 1–2 years, and it is hoped that future publications with this sample will provide valuable information as to the time-course of this illness.

The severity of the impact of “Long COVID” on everyday function and employment reported in our sample appear to reflect previous studies (e.g., Davis et al., 2021) and is notable, particularly given the large proportion of healthcare and education staff in our sample. All of these issues should be of interest to policy makers, particularly when considering the extent to which large case numbers should be a concern in the context of reduced hospitalizations and deaths due to vaccination. While we do not yet know the impact of vaccination on Long COVID numbers, there are reasons to believe that high levels of infection among relatively young, otherwise healthy individuals may translate into considerable long-term workforce morbidity.

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

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COVID-19 and cerebrovascular diseases: a comprehensive overview

Authors: Georgios TsivgoulisLina PalaiodimouRamin Zand

First Published December 8, 2020 Review Article Find in PubMed https://doi.org /10.1177/1756286420978004

Abstract

Neurological manifestations are not uncommon during infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A clear association has been reported between cerebrovascular disease and coronavirus disease 2019 (COVID-19). However, whether this association is causal or incidental is still unknown. In this narrative review, we sought to present the possible pathophysiological mechanisms linking COVID-19 and cerebrovascular disease, describe the stroke syndromes and their prognosis and discuss several clinical, radiological, and laboratory characteristics that may aid in the prompt recognition of cerebrovascular disease during COVID-19. A systematic literature search was conducted, and relevant information was abstracted. Angiotensin-converting enzyme-2 receptor dysregulation, uncontrollable immune reaction and inflammation, coagulopathy, COVID-19-associated cardiac injury with subsequent cardio-embolism, complications due to critical illness and prolonged hospitalization can all contribute as potential etiopathogenic mechanisms leading to diverse cerebrovascular clinical manifestations. Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been described in case reports and cohorts of COVID-19 patients with a prevalence ranging between 0.5% and 5%. SARS-CoV-2-positive stroke patients have higher mortality rates, worse functional outcomes at discharge and longer duration of hospitalization as compared with SARS-CoV-2-negative stroke patients in different cohort studies. Specific demographic, clinical, laboratory and radiological characteristics may be used as ‘red flags’ to alarm clinicians in recognizing COVID-19-related stroke.

Introduction

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and has been declared as a Public Health Emergency of International Concern by the World Health Organization.1 Since its outbreak in December 2019, SARS-CoV-2 has spread in more than 235 countries, and as of 25 September 2020, it has infected 32,029,704 patients.2 Characteristically, COVID-19 affects the respiratory system, producing symptoms ranging from mild upper-airway manifestations to pneumonia and severe acute respiratory distress syndrome.3 COVID-19 is increasingly recognized as a multi-system disease with apparent involvement of other organ systems and clinical gastrointestinal, cardiological, dermatological and other extrapulmonary manifestations.48

COVID-19 affection of the nervous system has also been reported, including both the central nervous system (CNS) and peripheral nervous system (PNS).9 A growing number of case series and cohort studies have been published identifying neurological symptoms associated with COVID-19. CNS manifestations may include headache, dizziness, seizures, confusion, delirium, and coma. PNS involvement may be presented as hypogeusia, hyposmia, other cranial neuropathies or generalized weakness due to Guillain–Barré and intensive-care-unit-acquired polyneuropathy or myopathy.

In the first case series reporting on the neurological manifestations of COVID-19, cerebrovascular disease was reported with a higher prevalence in COVID-19 patients who were more seriously infected.10 Since then, multiple studies have been published, arguing whether there is a causal or coincidental relationship between COVID-19 and cerebrovascular disease.

In this narrative review, we present the possible pathophysiological mechanisms linking cerebrovascular disease and COVID-19, describe the clinical syndromes and their prognosis and provide a ‘red flag’ system to alert clinicians for prompt recognition of cerebrovascular disease during COVID-19.

Methods

We systematically searched the literature through MEDLINE and EMBASE, using the following keywords and their combination: SARS-CoV-2, COVID-19, cerebrovascular disease, stroke, ischemic stroke, intracranial hemorrhage, subarachnoid hemorrhage, cerebral venous thrombosis, cerebral sinus, and vein thrombosis. We evaluated only peer-reviewed articles that had been published or had been officially accepted for publication. References of retrieved articles were also screened. Case reports, case series, editorials, reviews, case-control, and cohort studies were evaluated, and relevant information was abstracted. The literature search protocol was conducted by three independent authors (GT, LP, and AHK). The last literature search was conducted on 1 September 2020. Characteristic images of cerebrovascular disease manifestations in COVID-19 patients have been provided by co-authors using previously unpublished data from COVID-19 tertiary care referral centers from Europe, North America, and Asia.

Results

Possible pathophysiological mechanisms linking cerebrovascular disease and COVID-19

Several common cerebrovascular risk factors have been associated with severe COVID-19 as well, including cardiovascular disease, diabetes mellitus, hypertension, smoking, advanced age, and previous history of stroke.11 This raises the question whether their relationship is causal or if they just coincide. Several possible pathophysiological mechanisms have been recently described (Figure 1).

Figure 1. Potential pathophysiological mechanisms underlying cerebrovascular involvement in COVID-19.

SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptors, leading to the receptors’ inactivation. ACE2 dysregulation contributes to the post-ischemic inflammation cascade, resulting in decreased perfusion in the ischemic zone and the development of larger infarct volume in the case of ischemic stroke (IS). In addition, ACE2 dysfunction may subsequently cause hypertensive peaks and impairment of cerebrovascular endothelium, contributing to the pathogenesis of intracerebral hemorrhage (ICH). Virus-related cardiac injury, including myocardial ischemia and cardiac arrhythmias such as atrial fibrillation, may cause cardio-embolism and subsequently, IS. COVID-19-related hypercoagulability may determine in situ arterial thrombosis and IS. Another potential IS mechanism related to hypercoagulability is paradoxical emboli of generated venous thrombi through right-to-left shunts. Cerebral venous thrombosis may also be caused by hypercoagulability and in situ thrombosis. Furthermore, COVID-19-related coagulopathy may present as dysfunctional hemostasis and predispose to ICH, especially when therapeutic anticoagulation is administered. Cytokine storm-mediated endotheliitis and vasculitis of the CNS due to SARS-CoV-2 infection causes vessel remodeling, leading to vessel occlusion or injury and IS or ICH, respectively. Finally, a primarily immune-mediated critical illness during COVID-19, hypoxemia, and systemic hypotension may induce hypoxic/ischemic encephalopathy or cerebral microbleeds with or without leukoencephalopathy.

CNS, central nervous system; COVID-19, coronavirus disease 2019; DVT, deep venous thrombosis; PE, pulmonary embolism; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Targeting angiotensin-converting enzyme 2 (ACE2) receptor

SARS-CoV-2 is known to bind to the ACE2 receptor, causing the inactivation of the receptor and leading to dysfunction in blood pressure regulation.12,13 In turn, this could lead to hypertensive peaks that could be particularly important in the pathogenesis of intracerebral hemorrhage (ICH). However, data to date have suggested that patients with ICH and COVID-19 present with lower systolic blood pressure, relative to spontaneous ICH.14 Furthermore, ACE2 dysregulation may also contribute to the post-ischemic inflammation cascade through the accumulation of angiotensin 2, resulting in decreased perfusion in the ischemic zone and the development of larger infarct volumes.15,16 The impaired endothelial function in cerebral arteries caused by ACE2 inactivation has also been implicated in the pathogenesis of cerebrovascular events, including both ischemic and hemorrhagic stroke.17,18

Cardiovascular complications associated with COVID-19

Virus-related cardiac injury in patients with COVID-19 has been associated with ACE2 dysregulation, imbalanced immune response leading to cytokine storm, hypoxia related to respiratory dysfunction and treatment-adverse events.6 Specifically, SARS-CoV-2 infection can be complicated with decompensated heart failure, myocarditis, acute myocardial infarction and cardiac arrhythmias, including incident atrial fibrillation.6,19,20 The aforementioned cardiac manifestations of COVID-19 may lead to subsequent cardio-embolism and cerebral infarction.

Coagulopathy associated with COVID-19

Various reports have been published regarding hypercoagulability associated with severe COVID-19 illness, due to immobilization, dehydration, inflammation, elevated fibrinogen, endothelial cell injury, and platelet activation.2124 The hypercoagulability may further add to the risk of developing cerebral venous thrombosis (CVT) or ischemic stroke (IS).2325 The COVID-19-associated prothrombotic state is accompanied by high D-dimer levels, elevated ferritin, and in some cases, detectable lupus anticoagulant, anticardiolipin immunoglobulin A (IgA), and antiphospholipid IgA and immunoglobulin M (IgM) autoantibodies directed against β2-glycoprotein-1.22,26 On the other hand, it is well established that such autoantibodies appear in many conditions characterized by profound immune activation with no apparent pathogenic role.

Hypercoagulability due to SARS-CoV-2 infection has also been associated with a higher incidence of deep vein thrombosis.27,28 Right-to-left shunt and paradoxical embolism of generated venous thrombi through a patent foramen ovale might act as an etiopathogenic mechanism in younger patients with cryptogenic cerebral ischemia without any vascular risk factors for stroke. In addition to intracardiac shunts, the right-to-left shunt may be associated with intrapulmonary causes, such as pulmonary vascular dilatations or pulmonary arteriovenous malformations. In a recently published study, contrast-enhanced transcranial Doppler was performed in mechanically ventilated patients with COVID-19 pneumonia and detected microbubbles in 83% of the patients.29 The detection of microbubbles was attributable to pulmonary vasodilatations which may also explain the disproportionate hypoxemia seen in COVID-19 patients.29

On the other hand, coagulopathy associated with COVID-19 may present as dysfunctional hemostasis, prolonged prothrombin time and bleeding disorder, especially in severely infected patients. The characteristics of COVID-19 coagulopathy are similar but not perfectly matched to those of disseminated intravascular coagulopathy.30 Characteristically, COVID-19 coagulopathy manifests with significantly elevated D-dimers, but only mild thrombocytopenia and slightly prolonged prothrombin time, and rarely meets the diagnostic criteria of disseminated intravascular coagulopathy according to the International Society on Thrombosis and Haemostasis.31,32 Nevertheless, the disruption of hemostasis in COVID-19 may contribute to an increased risk of secondary intracranial hemorrhage, especially when therapeutic anticoagulation is also administered.

Triggering CNS vasculitis and endotheliitis

SARS-CoV-2 viral-like particles may be detected in brain capillary endothelium, as was recently noted in an autopsy study.33 This finding supports the viral neurotropism and potentially implicates SARS-CoV-2 in a direct effect on cerebral vessels with subsequent endothelium dysfunction and degeneration.34 SARS-CoV-2 has also been implicated in triggering CNS vasculitis, possibly through an inflammatory response mediated by the cytokine storm and specifically interleukin-6.3538 This is not new for viral infections, since other viruses (e.g. varicella zoster, human immunodeficiency virus, hepatitis C virus, hepatitis B, cytomegalovirus, parvovirus b19) may trigger such a response.39 Inflammation of cerebral vasculature may lead to arterial remodeling with either stenosed or dilated, fragile vessels with subsequent ischemic or hemorrhagic stroke, respectively. Reversible cerebral vasoconstriction syndrome and posterior reversible encephalopathy syndrome may mimic primary angiitis of the CNS and have been recently described in COVID-19 patients.4042 IS, ICH, and convexal subarachnoid hemorrhage are common manifestations of reversible cerebral vasoconstriction syndrome.43

Critical illness due to COVID-19

A significant percentage of patients with SARS-CoV-2 infection present with serious manifestations and may need intubation, mechanical ventilation, and prolonged hospitalization in intensive care units, mostly due to pulmonary complications. Hypoxemia and systemic hypotension due to primarily immune-mediated critical illness may further induce hypoxic/ischemic encephalopathy and contributes to IS, mostly in watershed territories or presenting as cortical laminar necrosis.44 Additionally, prolonged hypoxemia and respiratory failure have been associated with cerebral microbleeds and/or leukoencephalopathy.45

Cerebrovascular manifestations associated with COVID-19

Reports of cerebrovascular complications associated with COVID-19 are continuously increasing.

Ischemic stroke

A recently published, prospective, multinational study reported 123 patients who presented with acute IS out of a total of 17,799 SARS-CoV-2-infected patients.46 This result corresponds to a non-weighted risk of 0.7% for IS among patients hospitalized for COVID-19. Other cohort studies reporting IS risk among hospital admissions for COVID-19 also presented similar results (Table 1). These data underscore that COVID-19 may be associated with a small but non-negligible risk for IS. Another important fact is that IS is reported as the initial manifestation and reason for hospitalization in 26% of COVID-19-confirmed patients.47

Table 1. Cohort studies reporting cerebrovascular events in COVID-19 patients during general hospital admission.

Table 1. Cohort studies reporting cerebrovascular events in COVID-19 patients during general hospital admission.View larger version

Regarding the IS subtype according to Trial of ORG 10172 in Acute Stroke Treatment classification, COVID-19 was reported to be associated with a higher incidence of cryptogenic stroke.47,48,56,60 According to a retrospective cohort study performed in a major health system in New York, cryptogenic stroke was twice more prevalent in COVID-19 positive patients compared with both a contemporary control group consisting of COVID-19 negative patients and a historical control group derived from patients treated in the same period in 2019.48 The presented high rates of cryptogenic stroke could further alarm clinicians regarding hypercoagulability state, in situ arterial thrombosis from endothelitis and occult cardioembolism or paradoxical embolism, both of which require deeper investigation and consideration of therapeutic anticoagulation.6163 Other studies, which also included hospitalized COVID-19 patients, reported an incidence of up to 35% for cryptogenic stroke among IS patients.51,52,64 Finally, it should be noted that different case series of stroke complicating COVID-19 patients have reported a decreased prevalence of lacunar infarction (⩽10%) among IS patients.46,48 This observation indicates the potential lack of association between COVID-19 and intrinsic small-vessel disease. However, since lacunar strokes are generally associated with less severe symptoms compared with large-vessel occlusion (LVO) strokes, the patients may have not undergone neuroimaging evaluation with brain MRI and ascertainment of acute cerebral ischemia mechanism leading to the under-representation of lacunar strokes in patient cohorts.

Another important observation regarding IS incidence in patients with COVID-19 is the report of younger patients without known risk factors presenting with stroke due to LVO.65 Also, COVID-19 patients with LVO were younger compared with both contemporary controls of COVID-19-negative patients and historical controls, as investigated in different studies.66,67 In another case series, it was shown that among patients hospitalized for stroke due to LVO, more than half tested positive for SARS-CoV-2.67 Almost a quarter of COVID-19 patients admitted for acute IS is reported to be due to LVO.52,68 An illustrative case of a patient with LVO stroke and concurrent COVID-19 is presented in Figure 2. Multifocal LVOs is another matter of concern in those patients, since multivessel obstruction is presented significantly more frequently in SARS-CoV-2 positive patients.66,68

Figure 2. Imaging evaluation of a patient with acute proximal occlusion of the right middle cerebral artery during hospitalization for COVID-19.

A 65-year-old man with a history of hypertension and diabetes mellitus presented with acute left-sided hemiplegia, dysarthria, neglect, and right-gaze deviation. He had minimal respiratory symptoms. Emergency brain CT and CTA scanning were performed. Acute proximal right middle cerebral artery (MCA) occlusion was demonstrated on CTA (panel A, arrow) with evolving right MCA infarction. Right MCA occlusion was also confirmed on CTA 3D reconstruction (panel B, dotted circle). At that time, D-dimer levels were 2.8 ng/ml (normal values <500 ng/ml). The patient was not eligible for either intravenous thrombolysis due to delayed presentation or mechanical thrombectomy due to an unfavorable perfusion profile. Brain MRI was subsequently performed, showing restricted diffusion in right MCA territory, confirmative of large right MCA infarct (panel C). SARS-CoV-2 infection was confirmed at day 9 of hospitalization. On the 3-month follow up, the patient had modified Rankin Scale score of 4 with persistent severe left hemiparesis.

COVID-19, coronavirus disease 2019; CT, computed tomography; CTA, computed tomography angiography; MRI, magnetic resonance imaging; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

In patients admitted with acute IS during the period of COVID-19 restrictions, significant concern has been raised regarding the delivery of acute reperfusion treatments. This gains even more importance, especially in the aforementioned patients with LVO, who may need mechanical thrombectomy. Initially, patients were thought to be reluctant to seek medical help for stroke symptoms due to their fear of contracting COVID-19, and subsequently presented with substantial delay to the emergency department, outside the time window for available acute reperfusion therapies.69,70 Different cohort studies evaluated the management in the acute phase of stroke patients during COVID-19 restrictions compared with historical controls treated in the same periods before the pandemic. Several of them have underscored the negative effect of lockdown on the management of IS, depicting reductions of stroke admissions, the total number of thrombolysis and/or thrombectomy and significant increases in treatment times.7175

However, the American Heart Association/American Stroke Association Stroke Council Leadership responded promptly with emergency guidance to the need of addressing those issues and securing the delivery of acute stroke treatments.70 A ‘protected code stroke’ was recommended and a focused framework was provided with the aim of COVID-19-specific screening, personal protective equipment, and crisis resource management during acute stroke treatment.76 In addition, the European Society of Neurosonology and Cerebral Hemodynamics issued practice recommendations for neurovascular investigations of acute stroke patients during the COVID-19 pandemic aiming to highlight the utility of ultrasound as a non-invasive, easily repeatable bedside real-time examination of cerebral vessels.77 Finally, the European Stroke Organization and other organizations addressed to the public and underscored that patients with stroke symptoms should seek medical help as soon as possible, despite COVID-19 restrictions.78 Hopefully, such measures will contribute to the stabilization of stroke treatment delivery despite those unprecedented times.

Cerebral hemorrhage

Several case reports and cohort studies have recently been published presenting COVID-19 patients with parenchymal hemorrhage,58,59,7985 subarachnoid hemorrhage,14,58,59,86 and subdural hematoma.59 A retrospective case series of five patients showed that COVID-19 patients with ICH were younger than expected and mostly suffered from lobar ICH.85 One of the patients described in this report had multifocal ICH without any underlying vascular abnormality.85 Similar results were presented in a retrospective cohort study, that showed 0.5% of hospitalized COVID-19 patients to be diagnosed with hemorrhagic stroke, with coagulopathy being the most common etiology.58 A large, deep intracerebral hematoma with an irregular, multi-lobular shape identified in a COVID-19 patient is presented in Figure 3.

Figure 3. Imaging evaluation of a COVID-19 patient with large, multi-lobular intracerebral hemorrhage.

A 55-year-old woman with a history of diabetes mellitus and hypertension was quarantined at home due to SARS-CoV-2 infection with mild respiratory symptoms. At 12 days later, she deteriorated, presenting dyspnea and respiratory failure. She was admitted to the ICU for mechanical ventilation. On day 11 of hospitalization, she became apneic on the ventilator, with fixed, dilated pupils. An emergent brain CT scan was performed showing a large, left-sided intracerebral hemorrhage causing compression of the ipsilateral lateral ventricle and midline shift to the right (panel A). The hematoma had an irregular, multi-lobular shape (panel A and B). No hypertensive spike was confirmed. The patient expired 1 day after neurological worsening.

COVID-19, coronavirus disease 2019; CT, computed tomography; ICU, intensive care unit; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

However, among general hospital admissions of COVID-19 patients, only a minor proportion exhibited ICH (Table 1). Similarly, COVID-19 patients who were hospitalized in neurological wards did not have significantly more cerebral hemorrhagic events compared with non-COVID-19 patients.87 Based on these observations, it remains unknown whether COVID-19 has a causal association with ICH through ACE2 inactivation, endothelial dysfunction/degeneration, coagulopathy or hypocoagulability, or rather, whether secondary effects of COVID-19 such as renal failure/cirrhosis with concomitant therapeutic anticoagulation in a critically ill older population is the culprit. The atypical multifocal nature of many of the reported ICH cases to date would suggest some form of underlying vasculopathy which likely acts synergistically with the aforementioned factors in causing ICH. One pathological report to date has confirmed underlying endothelial reactivity, as well as endothelial and neuropil degeneration in a COVID-19 patient with ICH.34

Cerebral microbleeds have also been demonstrated in critically ill COVID-19 patients and can present with or without leukoencephalopathy.45,88 The atypical location of cerebral microbleeds in the corpus callosum and juxtacortical region may raise the suspicion of SARS-CoV-2 infection in critically ill patients.42 However, a very similar pattern has previously been presented in critically ill non-COVID-19 patients with respiratory failure.89,90 These neuroimaging findings are associated with worse neurological status and longer hospitalization in COVID-19, and likely reflect a more advanced stage of critical illness.45

Cerebral venous thrombosis

Venous thromboembolic events, such as pulmonary embolism and deep venous thrombosis, are detected with high frequency in COVID-19 patients hospitalized in intensive care units, even despite anticoagulation treatment.91 The risk of thrombosis associated with COVID-19 may also be responsible for CVT. Numerous case reports have been published about COVID-19 patients presenting with CVT.9299 In addition, cases with more atypical presentations, such as cortical or deep cerebral venous thrombosis, have been described.100,101 Six patients were diagnosed with CVT among 17,799 hospitalized SARS-CoV-2 patients.46 Headache and impaired consciousness may complicate or even be the presenting symptoms of both COVID-19 and CVT (Figure 4). For that reason, clinicians should be quite vigilant in order to timely diagnose CVT-complicating COVID-19.102 Clinicians should also be able to differentiate COVID-19 patients with primary ICH and hemorrhagic infarction due to CVT, since the latter requires anticoagulant treatment in therapeutic dosage.103 Finally, CVT involving the internal cerebral veins may be challenging to differentiate from acute hemorrhagic necrotizing encephalitis (Weston–Hurst syndrome), which is another COVID-19 CNS complication that may symmetrically affect basal ganglia and thalami with hemorrhagic lesions.104

Figure 4. Imaging evaluation of a COVID-19 patient with cerebral venous thrombosis.

A 59-year-old woman presented with a thunderclap headache followed by a severe progressive headache. Her neurological examination revealed bilateral papilledema. In the brain CT scan, she had an ischemic occipital lesion (panel A). Brain MRV demonstrated lack of flow in the left transverse and sigmoid sinuses, confirming the diagnosis of cerebral venous sinus thrombosis (panel B). In addition, the patient reported she had a fever, cough, and sore throat 10 days before her neurological symptoms. Chest CT showed diffuse ground-glass opacification (panel C). A positive SARS-CoV2 PCR confirmed the diagnosis of COVID-19.

COVID-19, coronavirus disease 2019; CT, computed tomography; MRV, magnetic resonance venography; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Red flags for COVID-19-associated stroke diagnosis

Prompt diagnosis and treatment of acute cerebrovascular disease complicating COVID-19 are essential since co-existing stroke appears to negatively influence the outcome in patients with SARS-CoV-2 infection.50,105 Several clinical and neuroimaging characteristics are present and can raise suspicion in COVID-19 associated stroke diagnosis. The adjunctive use of artificial intelligence may expedite an accurate diagnosis and is already developing in the field of COVID-19-related brain injury.106

Ischemic strokes in COVID-19 patients often present with multi-territorial arterial distribution, embolic pattern, and hemorrhagic transformation.64,107114 A COVID-19 patient diagnosed with multi-territorial arterial infarctions of an embolic pattern in the absence of vascular risk factors is shown in Figure 5. Large cerebral vessel occlusions with significant thrombus burden and a propensity for clot fragmentation is well documented in the literature.46,65,67,68,108,110,115 Characteristically, LVO may affect younger patients without known risk factors for stroke, it is associated with higher in-hospital mortality and may represent the initial manifestation leading to hospitalization during SARS-CoV-2 infection.65,67,115,116 Hypercoagulable state, cardioembolism, or paradoxical embolism due to COVID-19 may be potential reasons for such a stroke presentation. Furthermore, unexpected IS locations, such as in the corpus callosum or a frequent involvement of posterior circulation, have been associated with COVID-19.117119 Increased incidence of hemorrhagic transformation of ischemic infarcts has also been observed in COVID-19 stroke patients.56,111 Whether the dysfunctional hemostasis or the increased use of anticoagulants could be associated with the likelihood of hemorrhagic transformation remains currently unknown. Finally, level of consciousness was recently reported as an important component in a risk stratification score related to severe COVID-19.120 Confusion may not only be an important parameter relating to the severity of a multisystem disease like COVID-19, but in addition, it may underlie the presence of cerebrovascular disease. Unsuccessful recovery after ventilation weaning should alarm clinicians about the possibility of cerebrovascular disease development, and mandates appropriate neuroimaging studies.111

Figure 5. Imaging evaluation of a COVID-19 patient with multi-territorial ischemic infarcts.

An 83-year-old man with a history of hypertension, diabetes, hyperlipidemia, and prior ischemic stroke with no residual symptoms, presented to the emergency department with seizure-like activity and acute respiratory failure, likely due to aspiration. Brain MRI was performed showing restricted diffusion in the territories of both the right middle cerebral artery (MCA; panel A) and the right posterior cerebral artery (PCA; panel B), indicating right MCA and PCA acute ischemic stroke. He was intubated in the emergency department for decreased level of consciousness, hypoxia, and airway protection and initially admitted to the medical ICU. On presentation and the day after presentation, nasopharyngeal swab tests were performed and were both negative for SARS-CoV-2. At 10 days after initial presentation, a third nasopharyngeal swab was performed and found positive, confirming SARS-CoV-2 infection. Despite initial hypoxia and multiorgan failure, the patient improved systematically and was eventually weaned off the ventilator after 1 month of ICU hospitalization. However, the neurological examination did not improve accordingly, and the patient did not fully regain his level of consciousness. For that reason, a brain MRI was repeated and disclosed acute left MCA (panel C and D) and additional right MCA (panel D) territory recurrent ischemic infarcts. The patient was finally discharged to a long-term nursing facility and expired approximately 2.5 months after his initial presentation.

COVID-19, coronavirus disease 2019; ICU, intensive care unit; MRI, magnetic resonance imaging; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

ICH may complicate in COVID-19 patients that are younger than expected for conventional ICH.85 Coagulopathy was reported as the most common etiology of ICH, whereas COVID-19-negative patients most often suffered from hypertension-related ICH.58 Coagulopathy is reflected by the significantly higher levels of D-dimers, which may be considered as a ‘red flag’ for COVID-19-associated ICH.58 Furthermore, although spontaneous ICH most typically presents as deep hemorrhage in patients with negative COVID-19 history, lobar and multi-focal hematomas without underlying macrovascular abnormalities are commonly reported in COVID-19 patients.58,85 Cerebral microbleeds represent a recently described neuroimaging finding in COVID-19 patients, which is associated with critical illness.45,88 In addition, anticoagulation treatment prior to the manifestation of hemorrhagic stroke in COVID-19 patients has been consistently reported in a recent case series from New York City.75

Development of CVT in patients without other risk factors of hypercoagulability should alert clinicians to the possibility of SARS-CoV-2 infection, especially in the presence of excessively high (>2.0 ng/ml) D-dimer levels. Persisting headache and altered consciousness with confusion and/or agitation, coupled with high levels of D-dimers, may be a hint for CVT complication that should be promptly diagnosed and anticoagulated.103

Prognosis of cerebrovascular events associated with COVID-19

Data regarding the long-term prognosis of COVID-19 patients with cerebrovascular events are scarce. Most studies report clinical outcomes at discharge. In a single-center study, it was shown that positive patients had higher National Institutes of Health Stroke Scale score and were less likely to achieve functional independency at discharge.87 Moreover, the mortality rate in COVID-19 stroke patients was higher compared with contemporary SARS-CoV-2-negative stroke patients.87 Similar results are confirmed in other cohort studies investigating cerebrovascular disease in COVID-19 patients compared with COVID-19-negative patients (Table 2). A high mortality rate was also reported in a multinational cohort study, for both ischemic and hemorrhagic COVID-19 stroke patients.56 Additionally, in the same study it was shown that 17.4% of COVID-19 IS patients suffered from a hemorrhagic transformation of the infarction.56

Table 2. Cohort studies reporting clinical outcomes at discharge of COVID-19 patients with cerebrovascular disease compared with COVID-19-negative patients.

Table 2. Cohort studies reporting clinical outcomes at discharge of COVID-19 patients with cerebrovascular disease compared with COVID-19-negative patients.View larger version

Irrespective of SARS-CoV-2 positivity, the COVID-19 pandemic and the subsequently imposed restrictions had a negative influence on mortality and functional outcomes in stroke patients in general. Higher incidence of mortality and worse functional outcomes at discharge were reported in different cohort studies evaluating stroke patients who were admitted during the COVID-19 pandemic, compared with historical controls of the pre-COVID-19 period.60,64,71,72,122125 These alarming results may be attributable to delays in the presentation of stroke patients and subsequent lower rates of recanalization therapies. Furthermore, longer hospitalization stay was needed for the acute management of stroke patients during COVID-19 pandemic.60,64,71,72,122 Severe neurological impairment of the stroke patients, limited medical and laboratory resources, assignment, and transfer of medical personnel from stroke wards to COVID-19 designated wards might explain the need for the extension of hospitalization.

Apart from the observation that SARS-CoV-2 is a risk factor of mortality in stroke patients, it has also been shown that COVID-19 patients who experienced an acute IS during the infection had significantly lower rates of survival compared with those without a stroke.50,105 In addition, a previous history of stroke was an independent risk factor for severe pneumonia leading to critical illness, the need for ventilation, and mortality in COVID-19 patients.126,127

In ICH patients, COVID-19 was negatively associated with prognosis. A higher mortality rate was observed in COVID-19 patients compared to both contemporary and historical negative controls with ICH.58 In another cohort, all COVID-19 patients with hemorrhagic lesions on brain MRI suffered from acute respiratory distress syndrome and were hospitalized in intensive care units.88 A total of 20% patients with hemorrhagic lesions died during hospitalization, compared with 6% of COVID-19 patients with other non-hemorrhagic lesions.88

Impact of COVID-19 pandemic on stroke management

The COVID-19 pandemic and the imposed restrictions severely impacted stroke management.9,69 Since the first weeks of the outbreak, declining numbers of stroke admissions have been reported in the literature.128,129 Patients with transient or minor stroke symptoms are more likely to avoid seeking medical help due to their fear of contracting the virus.130 Moreover, the availability of acute reperfusion therapies, including both intravenous thrombolysis and mechanical thrombectomy has been limited, according to recent reports from North America and Europe.7175 When administered, treatment time metrics are prolonged, negatively impacting the effectiveness of the treatments.131 The performance of the more time-consuming, multiparametric stroke neuroimaging techniques is reported to have also declined, which, in turn, impedes the recognition of eligible patients for acute reperfusion therapies.132

In order to safely implement acute stroke management during the COVID-19-imposed restrictions, a ‘protected code stroke’ has been proposed.76 When a stroke patient presents to the emergency department, the clinicians should specifically ask for signs and symptoms compatible with COVID-19 infection, such as a history of fever, cough, dyspnea, diarrhea, hyposmia, or hypogeusia.133 History taking regarding COVID-19 should not be limited to the stroke patient, but should also include patients’ close contacts. Temperature checks can be used as an initial, feasible, and inexpensive screening tool upon patient presentation. In cases of positive COVID-19 history or confirmed fever, a nasopharyngeal swab should be tested for SARS-CoV-2 and repeated if negative and clinical suspicion is high, according to local COVID-19 protocols. Rapid antigen tests with high sensitivity and specificity can be used while in triage and may be a game changer in this regard. However, in cases of acute stroke, the management should not be delayed, and the patient should be treated as suspected COVID-19 by the minimum number of medical personnel and appropriate infection control measures, in order to minimize exposure.134

When indicated, intravenous thrombolysis with bolus tenecteplase might be considered as an alternative to alteplase bolus, and 1 h infusion to reduce the acute treatment duration and staff exposure.135 In addition, a minimum number of medical personnel, who should be experienced in donning and doffing personal protective equipment with safety, should perform mechanical thrombectomy procedures. If possible, mechanical thrombectomy under conscious sedation should be considered as the first line if the patient is stable.136 If general anesthesia and endotracheal intubation are needed, extreme caution is mandatory, since the latter is an aerosol and airborne-generating procedure. Ideally, intubation, mechanical ventilation, and extubation of the patient should be performed in negative-pressure rooms.136 Finally, acute stroke care should be provided by experienced stroke teams and the involved specialized personnel should not be redeployed to other hospital departments due to COVID-19-specific demands.137

During further hospitalization, transcranial ultrasound may be used to monitor intracranial vessel patency in IS patients who have received recanalization treatments, since it is a feasible, bedside test and can limit patient transportation.77 If further neuroimaging is needed, brain MRI may be performed for the differential diagnosis of COVID-19 patients with neurological manifestations.138 Moreover, regarding secondary prevention treatment in the subacute phase, prophylactic anticoagulant treatment is indicated in COVID-19 stroke patients.139,140 Finally, possible underlying mechanisms and deteriorating factors, such as hypoxia, coagulation disorder, and electrolyte imbalance should be managed, and cardiac function should be supported if needed during stroke hospitalization.

As for the long-term management and functional improvement, the COVID-19 stroke patients will not only require rehabilitation for their stroke, but also for the long-term consequences associated with a severe COVID-19 infection. The multidisciplinary stroke rehabilitation team needs to adapt to cater for both needs. It is of importance to initiate and maintain an inpatient rehabilitation program for the most severely affected patients.141 Tele-rehabilitation through electronic communication technologies may be a viable procedure for milder cases and their caregivers, limiting unnecessary transportation and close contacts, and providing protection against SARS-CoV-2 transmission.142,143 Finally, mental health should also be preserved. Stroke patients may often experience depression and anxiety, while anxiety itself may act as an additional trigger factor for acute stroke.144,145 Psychiatric support becomes even more important during the COVID-19 pandemic, since self-isolation, physical distancing, imposed restrictions and the fear of contracting the virus may pose additional emotional threats.146

Discussion

The causative versus incidental relationship between SARS-CoV-2 and stroke may still be debatable. Our narrative review presents the potential underlying mechanisms of the association between COVID-19 and cerebrovascular disease. ACE2 receptor dysregulation, excessive immune response, coagulation disorders, cardiac complications, and critical illness can lead to the development of different cerebrovascular disease manifestations during SARS-CoV-2 infection. However, stroke incidence in COVID-19 patients appears to be lower (0.5–1.5%) than what was originally reported from the Wuhan outbreak (5–6%).10,4648 This discrepancy might partially be explained by the fact that during the first weeks of the pandemic, prophylactic anticoagulation treatment was not administered as a standard of care in every COVID-19 patient.

Several key aspects should be summarized based on the presented review. Cryptogenic ischemia due to LVO appears to be the most common manifestation of acute cerebral ischemia, while lacunar stroke is rarely reported to complicate SARS-CoV-2 infection. Coagulation disorders, in situ arterial thrombosis, paradoxical embolization through right-to-left shunts, and occult paroxysmal atrial fibrillation should be scrutinized as indicated. Lobar or subcortical ICH that may be temporally associated with the initiation of anticoagulation therapy appears to be the most prevalent hemorrhagic CNS manifestation of COVID-19. CVT may also present as a hemorrhagic transformation of the cerebral venous infarction and should be included in the differential diagnosis of hemorrhagic lesions in COVID-19 patients. Importantly, CVT may seldom (≈0.5%) represent the initial manifestation of COVID-19 in patients with underlying hypercoagulability.

The adverse outcomes of COVID-19 patients with co-existing cerebrovascular disease mandate physician alertness for timely diagnosis and swift delivery of available acute stroke therapies. Several clinical and neuroimaging characteristics may be utilized as red flags to promote diagnosis. Younger age of patients, the absence of known stroke risk factors, difficulties in weaning from mechanical ventilation, high D-dimer levels, spontaneously prolonged international normalized ratio (INR)/partial thromboplastin time (PTT), multi-territorial acute infarctions, unexpected stroke locations (e.g. splenium of the corpus callosum), and LVOs should alarm clinicians about the co-existence of stroke and SARS-CoV-2 infection. Despite COVID-19-imposed restrictions, acute treatment should be offered as indicated through a safe pathway for both the patients and the medical personnel. Tele-neurology and remote imaging access may minimize exposure of vascular neurologists during the management of SARS-CoV-2 infected patients and should be used when feasible.147,148

The limitations of the present review should be acknowledged. First, this is a narrative review of the literature with the aim of discussing the association between COVID-19 and stroke. Cohort studies and case series included in this review are highly heterogenous regarding stroke diagnostic work-up, acute management, study populations, and use of contemporary versus historical controls. Furthermore, we did not review studies that have been submitted but not accepted to international medical journals. Ideally, an up-to-date systematic review and meta-analysis of included cohort studies may be conducted, investigating the incidence, treatment, and outcomes of cerebrovascular disease in COVID-19 patients and providing future directions in stroke diagnosis and management in the COVID-19 era.

Conclusion

Neurological manifestations are not uncommon during SARS-CoV-2 infection. Among those, cerebrovascular disease was initially reported with an alarming incidence of 6% in a small Chinese cohort.10 However, recent studies in the international larger dataset report a smaller but non-negligible risk of stroke (0.5–1.5%) in infected patients.4648 Whether this smaller risk could be attributed to the standard prophylactic anticoagulation given in every hospitalized patient is not known. ACE2 receptor dysregulation, inflammation, coagulopathy, COVID-19-associated cardiac involvement with subsequent cardio-embolism, and critical illness may all act as pathogenetic mechanisms for developing IS, hemorrhagic stroke, and CVT. Longer duration of hospitalization, worse functional outcomes at discharge, and higher in-hospital mortality are reported in COVID-19 associated stroke. For that reason, prompt stroke diagnosis and preservation of high-quality acute stroke treatment should be emphasized. Several clinical characteristics, such as younger age of patients and lack of known stroke risk factors, as well as neuroimaging (multi-territorial cerebral ischemia of embolic pattern due to underlying LVO) and laboratory (excessive elevation of D-dimer levels and spontaneously prolonged INR/PTT at hospital admission) caveats could further assist clinicians in diagnosing cerebrovascular disease in patients with SARS-CoV-2 infection.

Funding
The authors received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest statement
The authors declare that there is no conflict of interest.

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COVID virus linked with headaches, altered mental status in hospitalized kids

Authors: UNIVERSITY OF PITTSBURGH Peer-Reviewed Publication

PITTSBURGH, Jan. 21, 2022 – Of hospitalized children who tested or were presumed positive for SARS-CoV-2, 44% developed neurological symptoms, and these kids were more likely to require intensive care than their peers who didn’t experience such symptoms, according to a new study led by a pediatrician-scientist at UPMC and the University of Pittsburgh School of Medicine

The most common neurologic symptoms were headache and altered mental status, known as acute encephalopathy. Published in Pediatric Neurology, these preliminary findings are the first insights from the pediatric arm of GCS-NeuroCOVID, an international, multi-center consortium aiming to understand how COVID-19 affects the brain and nervous system. 

“The SARS-CoV-2 virus can affect pediatric patients in different ways: It can cause acute disease, where symptomatic illness comes on soon after infection, or children may develop an inflammatory condition called MIS-C weeks after clearing the virus,” said lead author Ericka Fink, M.D., pediatric intensivist at UPMC Children’s Hospital of Pittsburgh, and associate professor of critical care medicine and pediatrics at Pitt. “One of the consortium’s big questions was whether neurological manifestations are similar or different in pediatric patients, depending on which of these two conditions they have.” 

To answer this question, the researchers recruited 30 pediatric critical care centers around the world. Of 1,493 hospitalized children, 1,278, or 86%, were diagnosed with acute SARS-CoV-2; 215 children, or 14%, were diagnosed with MIS-C, or multisystem inflammatory syndrome in children, which typically appears several weeks after clearing the virus and is characterized by fever, inflammation and organ dysfunction. 

The most common neurologic manifestations linked with acute COVID-19 were headache, acute encephalopathy and seizures, while youths with MIS-C most often had headache, acute encephalopathy and dizziness. Rarer symptoms of both conditions included loss of smell, vision impairment, stroke and psychosis.  

“Thankfully, mortality rates in children are low for both acute SARS-CoV-2 and MIS-C,” said Fink. “But this study shows that the frequency of neurological manifestations is high—and it may actually be higher than what we found because these symptoms are not always documented in the medical record or assessable. For example, we can’t know if a baby is having a headache.” 

The analysis showed that neurological manifestations were more common in kids with MIS-C compared to those with acute SARS-CoV-2, and children with MIS-C were more likely than those with acute illness to have two or more neurologic manifestations. 

According to Fink, the team recently launched a follow up study to determine whether acute SARS-CoV-2 and MIS-C—with or without neurologic manifestations—have lasting effects on children’s health and quality of life after discharge from hospital.  

“Another long-term goal of this study is to build a database that tracks neurological manifestations over time—not just for SARS-CoV-2, but for other types of infections as well,” she added. “Some countries have excellent databases that allow them to easily track and compare children who are hospitalized, but we don’t have such a resource in the U.S.” 

This study was partly funded by the Neurocritical Care Society Investing in Clinical Neurocritical Care Research (INCLINE) grant. 

Other researchers who contributed to the study include Courtney L. Robertson, M.D., Johns Hopkins Children’s Center; Mark S. Wainwright, M.D., Ph.D., University of Washington and Seattle Children’s Hospital; Juan D. Roa, M.D., Universidad Nacional de Colombia and Fundación Universitaria de Ciencias de la Salud; Michelle E. Schober, M.D., University of Utah, and other GCS-NeuroCOVID Pediatrics investigators who are listed in the paper. 

To read this release online or share it, visit http://www.upmc.com/media/news/012122-Fink-COVID-Children.  


JOURNAL

Pediatric Neurology

DOI

10.1016/j.pediatrneurol.2021.12.010 

METHOD OF RESEARCH

Observational study

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Prevalence and Risk Factors of Neurologic Manifestations in Hospitalized Children Diagnosed with Acute SARS-CoV-2 or MIS-C

ARTICLE PUBLICATION DATE

21-Jan-2022

Post-COVID ‘brain fog’ could be result of virus changing patients’ spinal fluid

Authors: by John Andere JANUARY 19, 2022

Cases of “brain fog” among COVID patients are becoming more and more common, even among people recovering from mild infections. Now, new research is finally providing some potential answers to why people have difficulty concentrating, thinking clearly, and completing easy daily tasks after battling COVID. A team from the University of California-San Francisco say brain fog may result from how the virus alters a person’s spinal fluid — just like other diseases which attack the brain.

Their study finds certain patients who develop cognitive symptoms following a mild case of COVID-19 display abnormalities in their cerebrospinal fluid, similar to the kinds which appear in patients with diseases like Alzheimer’s. While this is only a start, study authors are optimistic this work is an important first step toward understanding what exactly SARS-CoV-2 can do to the human brain.

“They manifest as problems remembering recent events, coming up with names or words, staying focused, and issues with holding onto and manipulating information, as well as slowed processing speed,” explains senior study author Joanna Hellmuth, MD, MHS, of the UCSF Memory and Aging Center, in a university release.

Post-COVID brain fog is likely much more common than most people realize. One recently released study focusing on a post-COVID clinic in New York found that a staggering 67 percent of 156 recovered COVID-19 patients experienced some form of brain fog.

Brain fog patients experience more brain inflammation

This latest research featured 32 adults. All participants had recovered from a COVID-19 infection but did not require hospitalization. Twenty-two exhibited genuine cognitive symptoms, while the rest served as a healthy control group.

Among the entire group, 17 (including 13 with brain fog symptoms) agreed to have their cerebrospinal fluid analyzed. Scientists extracted the fluids from the lower back, on average, about 10 months after each patient’s first COVID symptoms.

Those tests showed 10 of the 13 participants with cognitive symptoms had anomalies within their cerebrospinal fluid. Importantly, the other four cerebrospinal fluid samples collected from people without brain fog showed no anomalies whatsoever. Participants experiencing cognitive issues tended to be older, with an average age of 48, while the control group’s average age was younger: 39 years-old.

All of the patients come from the Long-term Impact of Infection with Novel Coronavirus (LIINC) study, which tracks and assesses adults recovering from SARS-CoV-2.

Further analyses performed on the cerebrospinal fluid samples showed higher-than-normal protein levels and the presence of some unexpected antibodies usually found in an activated immune system. Researchers say these observations suggest a high level of inflammation. Some of these antibodies were seen in the blood and cerebrospinal fluid, implying a systemic inflammatory response. Some antibodies, however, were unique to the cerebrospinal fluid, which hints at brain inflammation specifically.

Study authors don’t know the intended target of these antibodies yet, but theorize they may attack the body itself, like an autoimmune disease.

“It’s possible that the immune system, stimulated by the virus, may be functioning in an unintended pathological way,” explains Dr. Hellmuth, who is the principal investigator of the UCSF Coronavirus Neurocognitive Study. “This would be the case even though the individuals did not have the virus in their bodies.”

Pre-existing conditions raise the risk of COVID brain fog

Notably, patients dealing with brain fog symptoms had an average of 2.5 cognitive risk factors, such as diabetes, high blood pressure, or a history of ADHD, in comparison to an average of less than one average risk factor for participants without brain fog symptoms.

These cognitive risk factors are relevant because they potentially raise an individual’s risk of stroke, mild cognitive impairment, vascular dementia, and generally make the mind more susceptible to executive functioning issues. Additional risk factors include drug use, learning disabilities, anxiety, and depression.

Additionally, all participants underwent a series of cognitive tests with a neuropsychologist modeled after the criteria used for HIV-associated neurocognitive disorder (HAND). To the research team’s surprise, 59 percent of patients dealing with brain fog met HAND criteria, while 70 percent of the control subjects did the same.

“Comparing cognitive performance to normative references may not identify true changes, particularly in those with a high pre-COVID baseline, who may have experienced a notable drop but still fall within normal limits,” Dr. Hellmuth concludes. “If people tell us they have new thinking and memory issues, I think we should believe them rather than require that they meet certain severity criteria.”

The study is published in the journal Annals of Clinical and Translational Neurology.

13 ways that the SARS-CoV-2 spike protein causes damage

Authors: Posted on January 13, 2022 by Jesse Santiano, M.D.

The SARS-CoV-2 virus has four structural proteins. The spike, membrane, envelop, and nucleocapsid proteins. The spike protein protrudes from the middle of the coronavirus and attaches to the ACE2 receptor of cells to start the process of cell entry, replication, and infection. The two major parts of the spike protein are the S1 and S2 subunit. The S1 has the receptor-binding domain.

For easier reading, this review starts with what happens after the COVID jabs, soluble spike proteins, and what it takes to have a normal blood vessel. Then I will enumerate how the spike protein damages the body.

What happens after the COVID shots?

COVID vaccination aims to produce an immune response against the spike protein in the form of neutralizing antibodies so that in future SARS-CoV-2 exposures, COVID-19 will be prevented.

The injected messenger RNA provides instructions to the cells on making the spike proteins. Once the spike protein is produced, it migrates to the outside of the cell to be anchored on the cells’ outer surface, where the immune system will recognize it and develop an immune response to it. (antibodies, T cells, B cells).

Soluble spike proteins

Ideally, the whole spike protein should stay attached to the outside of the cells. Sometimes incomplete spike proteins are produced in the form of spike peptides. As shown below, they are also presented to the immune system by cells outside the surface with an anchoring protein called the Major Histocompatibility Complex (MHC).

Anchoring to the cells is critical because once the spike protein or its pieces in the form of peptides become soluble or float in the bloodstream, they induce inflammation and clot formation in the arteries and capillaries. Scientists have found several ways that it happens.

First is that enzymes called metalloproteinases can cut the MHC1 at their bases.[1] Free-floating MHCs are found in patients with systemic lupus erythematosus SLE and cancers.[4][5]

The second is that errors can happen while RNA splicing occurs inside the nucleus. This results in variant spike proteins that are soluble.[2] Soluble S1 subunits were observed among recipients of the Moderna shots.[3

You can read more about it in this article: SARS-CoV-2 spike proteins detected in the plasma following Moderna shots.

Third, are exosomes released from cells containing MHCs with the spike proteins. [6] T-cells can interact with the spike proteins in the exosomes and cause inflammation [7]. Immunogenic spike proteins inside exosomes were demonstrated after Pfizer injection[8].

 Donor Blood Can Have Spike Protein Exosomes

The normal blood vessel

All organs in the body need an adequate blood supply, and blood vessels have to be in pristine working conditions for that to happen. They should be distensible to allow greater blood flow during exertion, smooth inside to prevent blood clot formation, and have working mechanisms to repair themselves and dissolve blood clots that may form.

All that work falls on the endothelial cells that line the inner wall of the blood vessels, andI talked about them at The Magical Endothelium. Any injury to the endothelium can elicit an inflammatory response and clot formation leading to organ dysfunctions like heart attacks, strokes, and deaths. 

Blood clots always start small, and once they develop, they initiate a chain reaction that promotes a more extensive clot. The good thing is that the body can do fibrinolysis, a built-in mechanism to dissolve clots.

13 ways Spike Proteins cause disease

The following are how the spike proteins and their S1 subunit can cause damage. They can work together and have four results, inflammationthrombosis or clot formation, auto-immunity, and amyloid formation.

Any foreign protein inside the body can elicit inflammation. That is why parts of the spike proteins in the form of their S1 subunits or shorter fragments are enough to cause damage.[9][10].

Inflammation and thrombosis

The S1 subunit activates Toll-like receptor 4 (TLR4) signaling to induce pro-inflammatory responses. It happens with the spike protein in COVID-19 [10] and the S1 subunits.[12]

The spike protein triggers cell signaling events that promote pulmonary vascular remodeling and pulmonary arterial hypertension (PAH), and other cardiovascular complications [13]Source: Suzuki and Gychka. Vaccines 2

The spike S1 initiates inflammatory responses from tumor-necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) to initiate a cytokine storm syndrome in the lungs. [14].

Spike proteins cause vascular leaks by degrading the barrier of the endothelium. [15] The leak may explain the proliferation of lymphocytes seen by German pathologists in the organs of deceased patients who died after the shots.

Spike proteins affect the cardiac pericytes, the cells that “supervise” the endothelial cells responsible for maintaining the smoothness of the blood vessels. [16]. Study shows spike proteins affect cardiac pericytes and explain why soccer players collapse

Spike proteins downregulate the ACE2 and impair endothelial function [17]

The S1 produces blood clots resistant to the body’s fibrinolysis and hospital clot-buster medications [18]. That’s why some have their limbs amputated after the shots. One woman had both legs and hands amputated. There’s a list here.

The spike protein can cause inflammation by activating the alternate complement pathway. [20]

Long COVID-Syndrome

  1. The S1 Proteins can persist in CD16+ Monocytes up to 15 Months Post-Infection and vaccination to induce chronic inflammation. This explains the symptoms of the Long COVID Syndrome. [19]

Amyloids formation and interaction

  1. Amyloids are fibrillar proteins. They are most commonly associated with neurodegenerative diseases like dementia. However, they can also form in the heart and lungs and make them rigid and form blood clots resistant to dissolution. [21The SARS-CoV-2 spike protein can form amyloids seen in lung, blood, and nervous system disorders
  2. The S1 protein contains heparin-binding sites that attract amyloids to initiate amyloid protein aggregation. Amyloid formation leads to neurodegeneration like Parkinson’s Disease, Alzheimer’s’ disease, and Frontal lobe dementia. [22]

Molecular mimicry

12. Molecular mimicry happens if protein sequences in the spike protein and peptides have similarities to human proteins. Antibodies made for those viral proteins may also attack the host proteins.[24][25][26].

This leads to several autoimmune diseases like immune thrombocytopenia (low platelet counts) [23], autoimmune liver diseasesGuillain-Barré syndromeIgA nephropathyrheumatoid arthritis, and systemic lupus erythematosus[27]

Cancer and Immune Deficiency

  1. Spike proteins impair DNA damage repair and result in ineffective antibodies and damaged tumor-suppressor genes like the BRCA1 and 53BP1 that lead to cancers. BRCA1 damage is associated with breast, ovarian, and prostate cancers.

53BP1 loss of function in tumor tissues is elated to tumor occurrence, progression, and poor prognosis in human malignancies.[30]

Parting thoughts

The disease-causing part of the SARS-CoV-2 virus is the spike protein, and it is present in COVID-19 and the COVID injections. Prevention and early treatment are possible for COVID-19. Once you have the shot, there is no way to control the spike protein.

It is unclear why not all have the adverse effects or die. What is sure is that there are over one million reported adverse effects on VAERS, and more than one hundred thousand have been killed. Vaccine-induced deaths in the U.S. and Europe are way higher than the VAERS reports!

This list is not all-inclusive, and I probably missed some. Indeed, more will be discovered in the future, and I don’t want my body to find out. Do you?

Don’t Get Sick!

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Related:

  1. Blood Vessel Damaging Proteins of the SARS-CoV-2
  2. Cerebral Thrombosis after the Pfizer Covid-19 Vaccine
  3. The High Risk of Deadly Brain Clots in the J & J COVID Vaccine
  4. This Study shows a Ten-Fold Risk of Developing Blood Clots after the COVID Vaccines.
  5. You got the COVID shot and found that others developed blood clots. Now what?
  6. Platelet Changes Causes Blood Clots in COVID-19
  7. Unidentified Foreign Bodies in the Vaccines Form Clots
  8. Retinal complications after COVID shots
  9. U.K. Study of COVID-19 shots and Excess Rates of Guillain-Barré Syndrome
  10. mRNA Vaccination Increases the Risk of Acute Coronary Syndrome
  11. German Analysis: The Higher the Vaccination Rate, the Higher the Excess Mortality
  12. Anti-Idiotype Antibodies against the Spike Proteins may Explain Myocarditis

References:

  1. Rijkers GT, Weterings N, Obregon-Henao A, et al. Antigen Presentation of mRNA-Based and Virus-Vectored SARS-CoV-2 VaccinesVaccines (Basel). 2021;9(8):848. Published 2021 Aug 3. doi:10.3390/vaccines9080848
  2. Kowarz E, Krutzke L, Reis J, et al. “Vaccine-Induced Covid-19 Mimicry” Syndrome: Splice reactions within the SARS-CoV-2 Spike open reading frame result in Spike protein variants that may cause thromboembolic events in patients immunized with vector-based vaccines. Research Square; 2021. DOI: 10.21203/rs.3.rs-558954/v1
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Long covid—mechanisms, risk factors, and management

Authors: Harry Crook, research assistant1,  Sanara Raza, research assistant1,  Joseph Nowell, research assistant1,  Megan Young, clinical research officer1,  Paul Edison, clinical senior lecturer, honorary professor12

Abstract

Since its emergence in Wuhan, China, covid-19 has spread and had a profound effect on the lives and health of people around the globe. As of 4 July 2021, more than 183 million confirmed cases of covid-19 had been recorded worldwide, and 3.97 million deaths. Recent evidence has shown that a range of persistent symptoms can remain long after the acute SARS-CoV-2 infection, and this condition is now coined long covid by recognized research institutes. Studies have shown that long covid can affect the whole spectrum of people with covid-19, from those with very mild acute disease to the most severe forms. Like acute covid-19, long covid can involve multiple organs and can affect many systems including, but not limited to, the respiratory, cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. The symptoms of long covid include fatigue, dyspnea, cardiac abnormalities, cognitive impairment, sleep disturbances, symptoms of post-traumatic stress disorder, muscle pain, concentration problems, and headache. This review summarizes studies of the long term effects of covid-19 in hospitalized and non-hospitalized patients and describes the persistent symptoms they endure. Risk factors for acute covid-19 and long covid and possible therapeutic options are also discussed.

Introduction

Coronavirus disease 2019 (covid-19) has spread across the world. As of 4 July 2021, more than 183 million confirmed cases of covid-19 have been recorded worldwide, and more than 3.97 million deaths have been reported by the World Health Organization .1 The clinical spectrum of covid-19 ranges from asymptomatic infection to fatal disease.23 The virus responsible for causing covid-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), enters cells via the angiotensin-converting enzyme 2 (ACE2) receptor.4 Once internalized, the virus undergoes replication and maturation, provoking an inflammatory response that involves the activation and infiltration of immune cells by various cytokines in some patients.5 The ACE2 receptor is present in numerous cell types throughout the human body, including in the oral and nasal mucosa, lungs, heart, gastrointestinal tract, liver, kidneys, spleen, brain, and arterial and venous endothelial cells, highlighting how SARS-CoV-2 can cause damage to multiple organs.67

The impact of covid-19 thus far has been unparalleled, and long term symptoms could have a further devastating effect.8 Recent evidence shows that a range of symptoms can remain after the clearance of the acute infection in many people who have had covid-19, and this condition is known as long covid. The National Institute for Health and Care Excellence (NICE) defines long covid as the symptoms that continue or develop after acute covid-19 infection and which cannot be explained by an alternative diagnosis. This term includes ongoing symptomatic covid-19, from four to 12 weeks post-infection, and post-covid-19 syndrome, beyond 12 weeks post-infection.9 Conversely, The National Institutes of Health (NIH) uses the US Centers for Disease Control and Prevention (CDC) definition of long covid, which describes the condition as sequelae that extend beyond four weeks after initial infection.10 People with long covid exhibit involvement and impairment in the structure and function of multiple organs.11121314 Numerous symptoms of long covid have been reported and attributed to various organs, an overview of which can be seen in fig 1. Long term symptoms following covid-19 have been observed across the spectrum of disease severity. This review examines the long term impact of symptoms reported following covid-19 infection and discusses the current epidemiological understanding of long covid, the risk factors that may predispose a person to develop the condition, and the treatment and management guidelines aimed at treating it.

Multi-organ complications of covid-19 and long covid. The SARS-CoV-2 virus gains entry into the cells of multiple organs via the ACE2 receptor. Once these cells have been invaded, the virus can cause a multitude of damage ultimately leading to numerous persistent symptoms, some of which are outlined here.

For More Information: https://www.bmj.com/content/374/bmj.n1648