IF you’ve had Covid-19 then you could be plagued by memory issues, researchers have warned.
Experts at Hull York Medical School said memory function can improve over time, but that those with ongoing Covid symptoms could continue to experience issues.
This is also known as long Covid, with many Brits suffering with the condition, which includes symptoms such as anxiety, brain fog and severe fatigue.
Medics said that it’s widely known the virus can cause respiratory issues, but that memory issues aren’t as well researched.
The experts used an online anonymous survey which included a memory quiz.
Over 5,400 people took part between December 2020 and July 2021, with around 31 per cent having had one Covid infection during that time.
The factors which significantly affected memory scores were found to be Covid-19 status, age, time post-Covid and whether individuals were experiencing ongoing symptoms.
Experts also looked at memory scores and found that those over the age of 25 had a decline in function.
Writing in Plos One, they said that memory scores gradually increased over a period of 17 months post-Covid.
However, those with ongoing symptoms continued to show a reduction in memory scores.
Dr Heidi Baseler, senior lecturer in imaging sciences at Hull York Medical School, University of York, who was first author on the study, said: “Although it is well known that Covid-19 affects the respiratory system, it is perhaps less well known that it can also have neurological consequences and affect cognitive function, such as memory.”
It’s important to note that the study was conducted at a time when Covid variants such as Alpha and Delta were in circulation.
The current strain doing the rounds, Omicron, has proven to be milder than those that came before it.
Millions of Brits also now have protection from the bug in the form of vaccines or prior infection.
Dr Baseler added: “What the study demonstrates is that Covid-19 negatively impacts working memory or short-term memory function, but only in adults aged 25 years and over.
“While the survey suggests that memory function with Covid-19 can recover over time, our findings indicate that those with ongoing symptoms may continue to experience difficulty with short-term memory.”
A study published earlier this week also revealed that the illness can impact the brain up to six months after you have recovered from the bug.
Experts at the Indian Institute of Technology in Delhi found that those who had the virus had a significantly higher chance of abnormal changes in the brain.
Changes were mostly seen in the frontal lobe and medics said this region is mostly linked to fatigue, insomnia, anxiety, depression, headaches and cognitive problems,
Co-author Sapna S. Mishra, a PhD. candidate at the Indian Institute of Technology in Delhi said: “Our study highlights this new aspect of the neurological effects of Covid-19 and reports significant abnormalities in Covid survivors.”
Previous studies have shown that the virus can increase your risk of developing seizures or epilepsy within six months of being infected, medics in Oxford found.
Writing in the journal Neurology, the team at the University of Oxford said Covid poses a greater risk of the complication than flu – but added the overall risk is still low.
The increased risk was more noticeable in children than in adults and was also more common in those who had not been hospitalised with a Covid-19 infection, they found.
In July, medics in Denmark found that those who have the bug are more at risk of developing brain complications.
They found that 43,375 people who tested positive had a 3.5 times increased risk of being diagnosed with Alzheimer’s.
Evidence of “long COVID” may be present in a patient’s eyes, according to a small study published online this week in the British Journal of Ophthalmology.
The researchers found that nerve fiber loss and an increase in dendritic or key immune cells on the cornea may help identify long COVID.
Gulfidan Bitirgen, MD, of the Department of Ophthalmology of the Necmettin Erbakan University Meram Medical Faculty Hospital in Konya, Turkey, and colleagues found the link was particularly strong in the study of 40 patients when patients had lost a sense of smell or taste or had dizziness, numbness, or neuropathic pain after they contracted COVID-19.
“The fact that physicians will be able to objectively identify patients with Long COVID will enable us to identify those with a definite problem and also paves the way towards assessing the effect of therapies which may help nerve repair,” senior author Rayaz A. Malik, , PhD, with the Department of Medicine, Weill Cornell Medicine Qatar in Doha, Qatar, says.
At least 1 in 10 people who become infected with COVID will develop long COVID, what the researchers in this paper defined as having symptoms that last more than 4 weeks after the acute phase has passed. The symptoms aren’t readily explained by an alternative diagnosis.
Previous researchers had suggested nerve fiber damage may play a role in long COVID development.
Bitirgen’s team investigated that hypothesis with a real-time, noninvasive, high-resolution imaging laser technique known as corneal confocal microscopy (CCM) to look for nerve damage in the cornea and the density of dendritic cells. These cells have a key role in the primary immune system response.
CCM has been used to identify nerve damage and inflammatory changes in other diseases including diabetic neuropathy, multiple sclerosis, and fibromyalgia.
“COVID has affected so many parts of the body, it’s no surprise that it affects the eye,” says Angie Wen, MD, assistant professor of ophthalmology, cornea, cataract and refractive surgery at New York Eye & Ear Infirmary of Mount Sinai in New York City.
Checking the cornea through CCM could serve as another piece of information to support a long COVID diagnosis for people who have had, for instance, pulmonary symptoms and unexplained neuropathic pain.
“But it seems we’re unable to draw that conclusion yet from these results,” she says.
Malik says, “Our technique is not specific for long COVID, as it detects nerve fiber damage and there are potentially many causes for this. However, if other causes of nerve damage are excluded then we can be fairly confident that it is due to Long COVID.
“Also, I think CCM is particularly useful in a patient with Long COVID symptoms who does not have corneal nerve damage, where we can reassure them that there is no serious underlying problem.”
As far as access to the CCM technology, Malik says most large ophthalmic centers worldwide will have the equipment.
“Since we pioneered this technique in diabetic neuropathy over 20 years ago interest has grown exponentially and there are over 300 centers using this technique to assess a range of peripheral neuropathies including diabetic neuropathy, inflammatory neuropathy, HIV neuropathy, chemotherapy-induced neuropathy and central neurodegenerative diseases like multiple sclerosis, Parkinson’s and dementia,” he says.
However, Wen notes that outside large academic centers, the equipment is not generally readily available and that probably limits its use as a diagnostic tool, “but it is an avenue for research.”
More Work Needed
Limitations of the study include the small number of participants and the single-site scope as well a use of a questionnaire to define the severity of neurological symptoms rather than more objective measures.
“Further studies of larger cohorts of patients using additional measures of neuropathy and CCM are required,” the authors wrote.
Participants in the study had recovered from confirmed COVID-19 between 1 and 6 months earlier. They completed a 28-item National Institute of Health and Clinical Excellence (NICE) questionnaire to find out if they had symptoms consistent with long COVID.
The questionnaire responses that suggested long COVID correlated strongly with corneal nerve damage.
Neurological symptoms were present at 4 and 12 weeks in 22 out of 40 (55%) and 13 out of 29 (45%) patients, respectively.
Participants’ corneas were then scanned using CCM to look for small nerve fiber damage and the density of dendritic cells. These cells have a key role in the primary immune system response by capturing and presenting antigens from invading organisms.
The corneal scans were compared with those of 30 healthy people who hadn’t had COVID-19 infection.
The scans indicated that patients with neurological symptoms 4 weeks after they had recovered from acute COVID-19 had greater corneal nerve fiber damage and loss, with higher numbers of dendritic cells, than those who hadn’t had COVID-19 infection.
Those without neurological symptoms had comparable numbers of corneal nerve fibers as those who hadn’t been infected with COVID-19, but more dendritic cells.
“To the best of our knowledge, this is the first study reporting corneal nerve loss and an increase in [dendritic cell] density in patients who have recovered from COVID-19, especially in subjects with persisting symptoms consistent with long COVID,” the authors said.
Patients with long COVID-19 have corneal small nerve fiber damage and increased dendritic cells (DCs), investigators found in a study published in British Journal of Ophthalmology.
An estimated 80% of patients who recover from COVID-19 continue to have at least 1 symptom, sign, or abnormal laboratory parameter, beyond 2 weeks after initial diagnosis and at least 10% will go on to develop long COVID. The researchers used corneal confocal microscopy (CCM) to identify whether small nerve fiber damage is a biomarker of long COVID.
The study included 40 patients who had contracted COVID 1 to 6 months previously and 30 control individuals in the study. They reviewed the COVID-19 patients’ blood test results and identified persisting symptoms at 4- and 12-weeks after diagnosis using the National Institute for Health and Care Excellence (NICE) long COVID, Douleur Neuropathique 4 (DN4) and Fibromyalgia (FM-Q) questionnaires. The researchers used CCM to compare subbasal corneal nerve morphology and DC density in patients with and without long COVID. They manually quantified corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and DC density.
The 55% of COVID patients who had neurological symptoms at 4 weeks following diagnosis tended to have lower CNFD (mean difference -4.85 (1.88); P =.032), CNBD (mean difference -14.62; P =.020), and CNFL (mean difference -3.35; P =.012) compared with the control individuals. They had increased total (median 35.1 vs 12.7) cells/mm2; P =.046) and mature (median 7.3 vs 0 cells/mm2; P =.003) DC densities compared with the control individuals.
Patients without neurological symptoms had higher total median 53.5 vs 12.7 cells/mm2; P =.003), mature (median 7.3 vs 0 cells/mm2; P =.010) and immature (median 33.5 vs 12.7) cells/mm2; P =.007) DC densities, compared with control individuals.
Coronavirus disease 2019 (COVID-19) causes a wide range of symptoms, including several unexpected symptoms such as loss of taste, skin changes, and eye problems. We recently observed patients with documented COVID-19 develop de novo severe genitourinary symptoms, most notably urinary frequency of ≥ 13 episodes/24 h and nocturia ≥ 4 episodes/night. We call these associated urinary symptoms COVID-19 associate cystitis (CAC). COVID-19 severity is associated with inflammation. We collected urine samples from COVID-19 patients, including patients with CAC, and found elevation of proinflammatory cytokines also in the urine. It has been previously shown that patients with urinary incontinence and ulcerative interstitial cystitis/bladder pain syndrome have elevated urinary inflammatory cytokines compared to normal controls. We therefore hypothesize that CAC, with presentation of de novo severe urinary symptoms, can occur in COVID-19 and is caused by increased inflammatory cytokines that are released into the urine and/or expressed in the bladder. The most important implications of our hypothesis are: 1) Physician caring for COVID-19 patients should be aware of COVID-19 associate cystitis (CAC); 2) De novo urinary symptoms should be included in the symptom complex associated with COVID-19; and 3) COVID-19 inflammation may result in bladder dysfunction.
There is scarce literature regarding genitourinary symptoms in COVID-19, especially post-acute disease otherwise known as Long COVID. We identified recovered COVID-19 patients presenting with new or worsening overactive bladder symptoms, known as COVID-19-associated cystitis (CAC).
We used the American Urological Association Urology Care Foundation Overactive Bladder (OAB) Assessment Tool to screen COVID-19 recovered patients presenting with urological complaints at our urban-located institution from 5/22/2020 to 12/31/2020. Patients 10–14 weeks post-discharge responded to 5 symptom and 4 quality-of-life (QoL) questions. We reported median symptom scores, as well as QoL scores, based on new or worsening urinary symptoms, and by sex.
We identified 350 patients with de novo or worsening OAB symptoms 10–14 weeks after hospitalization with COVID-19. The median total OAB symptom score in both men and women was 18. The median total QoL score for both men and women was 19. Patients with worsening OAB symptoms had a median pre-COVID-19 symptom score of 8 (4–10) compared to post-COVID-19 median symptom score of 19 (17–21). Median age was 64.5 (range 47–82). Median hospital length-of-stay was 10 days (range 5–30).
We report survey-based results of patients suffering from new or worsening OAB symptoms months after their hospitalization from COVID-19. Future studies with larger sample sizes and more extensive testing will hopefully elucidate the specific pathophysiology of OAB symptoms in the context of long COVID so urologists can timely and appropriately treat their patients.
The online version contains supplementary material available at 10.1007/s11255-021-03030-2.
Keywords: COVID-19, Bladder, SARS-CoV-2, Overactive bladder, Long COVID, COVID-19-associated cystitis
Common symptoms in Coronavirus Disease 2019 (COVID-19), the disease caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), have been well-reported and can include fever, dry cough, difficulty breathing, and tiredness. Although many patients infected with the virus develop mild symptoms, a small percentage of individuals can progressively develop acute respiratory distress syndrome and ultimately multiple organ dysfunction syndrome resulting in demise . Additionally, there is an emergence of patients who experience new symptoms that involve nearly all organ systems, some more subtle than others. As these symptoms may overlap with other common disease processes and due to the preponderance of retrospective observational population studies, it has been difficult to establish any causation links between the various symptoms and COVID-19 as the underlying cause .
Although less-identified, but becoming increasingly reported, are patients with COVID-19 developing new onset or an exacerbation of baseline urinary symptoms, most notably overactive bladder (OAB) [3, 4]. This has been referred to as COVID-19-associated cystitis (CAC) [5, 6]. The underlying pathophysiology of urinary symptoms in COVID-19 patients is not clearly understood but hypotheses have begun to emerge from smaller, single-center studies [3, 5, 6] which are currently elucidating the impact of COVID-19 on the genitourinary system. Furthermore, whether urinary symptoms and any associated bother occur in long COVID or post-acute COVID-19 syndrome (PACS) patients has not been thoroughly investigated. In our study, we identified confirmed COVID-19 patients who also showed new or worsening urinary symptoms consistent with OAB 10–14 weeks after hospital discharge. Our aim is to find an association between the urinary symptoms, notably OAB, and COVID-19 using questionnaires.
This study had full IRB approval from Wayne State University’s IRB (IRB#20–04-2126-M1) and full written consent was provided by all research participants. Patients were admitted to Detroit Medical Center (Detroit, MI) for treatment of COVID-19 and discharged. Discharged patients who complained of urological symptoms were referred for urology follow-up and surveyed regarding their current urinary symptoms, and if applicable, how their symptoms changed after recovering from COVID-19. This was done in an office setting during a scheduled appointment 10–14 weeks post-discharge. Respondents were informed that they would be asked questions regarding their urinary wellness, in addition to information regarding age, race, history of OAB or benign prostatic hyperplasia (BPH), and current medications to control urinary symptoms. When possible, the patient’s hospital admission and discharge dates were confirmed to establish length-of-stay (LOS). Patients were given the option to decline participation or stop the survey at any time. Responses were collected from 5/22/2020 to 12/31/2020.
Our primary outcome variable was the American Urological Association’s Urology Care Foundation Overactive Bladder Assessment Tool (Supplemental Table Table1)1) . The five individual symptom scores for frequency (range from 0 to 5; 0 being ‘not at all’ and 5 being ‘almost always’) of the following symptoms: urgency, urge incontinence, incontinence, frequency, and nocturia. The total symptom score ranges from 0 (no symptoms) to 25 (most severe symptoms). Additionally, there are four QoL questions regarding symptom bother (range from 0 to 5; 0 being ‘I am not bothered at all’ and 5 being ‘I am bothered a great deal’) for urgency, urge incontinence, frequency, nocturia, and overall satisfaction with their current urinary condition. This score ranged from 0 representing “not bothered at all” to 5 representing “bothered a great deal”. Patients with history of OAB symptoms were asked to score their pre-COVID-19 symptoms compared to post-COVID-19 symptoms. Lastly, a final QoL question asks, ‘How have your symptoms changed your life?’ Patients could then select all of the eight associated questions pertaining to specific life activities that are affected by their OAB (e.g. Keeping you from getting a good night’s sleep?; Causing you to stay home more than you would like?; Causing you to exercise less or limit your physical activity?; Causing problems with friends or loved ones?; Keeping you from social activities or entertainment?; Keeping you from traveling, taking trips, or using public transit?; Making you plan trips around your knowledge of public restroom location?; Causing problems at work?), including a free-response option.
We identified 350 confirmed COVID-19 patients, including 140 females and 210 males, who developed either new or worsening symptoms associated with OAB 10–14 weeks following SARS-CoV-2 infection (Table (Table1).1). These were all patients that were referred to a urologist post-discharge due to their urology symptoms. There were 100 patients with prior OAB history, while 250 presented with new-onset OAB symptoms. The median age of patients was 64.5 years old (range 47–82 years old). Median LOS was 10 days (range 5–30 days). The majority of the COVID-19 patients identified as black (n = 305; 87%), as expected for the clinical population of this medical system (Table (Table1).1). BPH was identified in 110 men (52.4% of all males).
All 350 patients completed the symptom score and QoL surveys (Supplemental Table 1). The median total OAB symptom score in both men and women was 18 (ranges 12–20 and 15–21, respectively). In patients with new onset OAB symptoms, the median symptom score was 18 (12–21), while patients with worsening OAB symptoms had a median pre-COVID-19 symptom score of 8 (4–10) compared to post-COVID-19 median symptom score of 19 (17–21). The median QoL score for both men and women was 19 (16–20 and 16–21, respectively). In patients with new onset OAB symptoms, the median QoL score was 19 (16–24). In patients with worsening OAB, median pre-COVID-19 QoL score was 9 (8–10) compared to median post-COVID-19 QoL score of 20 (19–20). All patients indicated nocturia had impacted their QoL. Primary outcomes are reported in Table Table22.
Primary outcomes for symptom & quality-of-life scores
The results of the present investigation bring awareness to symptoms of OAB in recovered COVID-19 patients and the gaps in knowledge hereby identified. Symptoms of OAB are an important factor in patients’ QoL, but one that can be addressed when identified in a timely manner. In our cohort, the temporal aspect with the change in urinary symptoms suggests an impact from COVID-19 and a possible symptom to be included in long COVID or post-acute COVID-19 syndrome (PACS). Although causation cannot be established, several possibilities are currently considered. The pathophysiology of SARS-CoV-2 involves the binding of the viral spike protein to angiotensin converting enzyme 2 (ACE2) receptors located on pneumocytes, but are also present in the bladder and other organs . It is therefore plausible that the de novo or worsening OAB symptoms observed in the current study are a downstream effect of cellular cascade resulting from activation of the bladder specific ACE2 receptors. SARS-CoV, a related virus, has been found to be shed in the urine , however, SARS-CoV-2 has been reported by multiple groups to only be detectable in a small subset of COVID-19 patients by molecular detection [10–13] or detection of the spike protein . Another hypothesis in the literature suggests a direct insult to the bladder or urothelium causing viral cystitis . Lastly, increased pro-inflammatory cytokines have been detected in COVID-19 patients with de novo severe urinary symptoms, suggesting that COVID-19 associated inflammation may result in bladder dysfunction . Future studies are needed to clarify if these symptoms are associated with alterations in bladder pathology.
Other viruses, including human immunodeficiency viruses (HIV) that can lead to acquired immunodeficiency syndrome (AIDS), are known to cause bladder control issues. In HIV, the underlying cause of urinary symptoms includes opportunistic pathogens (i.e. toxoplasmosis) as well as direct neurogenic insult from the virus itself. HIV has the potential to cross the blood–brain-barrier and causes various peripheral neurologic diseases, and studies of HIV/AIDS patients confirmed neurogenic bladder as the culprit through urodynamic testing [15, 16]. Although data are preliminary, there is evidence that infection with SARS-CoV-2 can lead to neurocognitive symptoms post-infection, possibly due to insult to the nervous system .
This study is the first to look at lower urinary tract symptoms by survey consistent with OAB in a large cohort of patients recovering from COVID-19 after hospitalization. All these patients were referred to urology for follow-up. Interestingly, 71% of patients reported new onset of urinary symptoms after COVID-19 infection, and 29% of patients who had previous OAB symptoms reported worsening of their symptoms after COVID-19 infection. Given that all these patients were hospitalized for COVID-19, these findings may be representative of those patients who had severe acute disease and may not be seen in COVID-19 patients that had asymptomatic, mild, or moderate disease not requiring hospitalization. Our cohort was primarily composed of elderly patients, who often have pre-existing genitourinary (GU) symptoms, and therefore presents a confounding variable in the study. However, this is consistent with a prospective study where lower urinary tract symptoms (LUTS) were increased in elderly men during COVID-19 hospitalization as measured by the International Prostate Symptom Score (IPSS) . Future studies will evaluate GU symptoms in younger adult patients to see if this is related to age in addition to SARS-CoV-2 infection, and at later time points post SARS-CoV-2 infection. A smaller study comprised of younger patients (mean and standard deviation of age of female and male patients was 32.3 ± 8.9 and 38.9 ± 13 years old, respectively) found that LUTS, especially storage symptoms, were more prevalent during acute COVID-19 . Our cohort demographic was primarily composed of patients identifying as Black, which is expected given our urban location and typical clinical population. While COVID-19 has been reported to disproportionately impact Black and Hispanic/Latino populations , other studies have demonstrated that there is no difference by race for in-hospital mortality, intubation, or ICU days [21–23] and that socioeconomic vulnerability, independent of race, predicted in-hospital mortality [22, 23]. The cohort was also recruited from a urology clinic and therefore more likely to report GU symptoms regardless of COVID-19 status. Even though they had not previously reported OAB symptoms until after hospitalization, 21 men were previously confirmed to have BPH, which may have had confounding effects in the development of their symptom post-COVID-19. A report by Luciani et al. suggests that the urinary tract was severely impacted in three men with symptomatic COVID-19 infection during hospitalization that had a history of previous urological conditions (i.e. BPH and radiation cystitis); the authors hypothesize that the previous urological conditions made the patients especially vulnerable to damage to the urinary tract by COVID-19, including hematuria . Interestingly, Welk and colleagues have reported that there was no increase in urology consultation, cystoscopy, or overactive bladder medication prescription among patients who had COVID-19, compared to the matched cohort . However, their study was limited in that it did not contain patient reported outcome measures, or direct measures of urinary symptoms. It is possible that their patient population did not seek medical care or receive treatment related to their urologic symptoms during the time period studied. Furthermore, their study investigated all patients who had a positive nasopharyngeal swab for SARS‐CoV‐2, whereas this study was focused only on patients who were hospitalized for COVID-19 and referred to urology. One limitation of our study is the lack of a comparison group of OAB patients that were COVID-19 negative to see if their OAB symptoms changed during the same time frame in response to pandemic related stress or changes in lifestyle.
Currently, it is not clear if symptoms of OAB in the setting of COVID-19 are reversible or irreversible without longer follow-up. Future testing, including urodynamic studies, could help determine the underlying pathophysiology. Ultimately, future prospective multi-center studies with long-term follow-up are necessary to address these issues. The findings of our study indicate that worsening or de novo urinary symptoms in COVID-19 patients may be secondary to the disease. Most importantly, management of the urinary symptoms in COVID-19 recovered patients may be possible with medications and surgical interventions; these treatments may differ from those indicated for patients not affected by COVID-19. Therefore, it may be important to differentiate the diagnosis as either an independent urinary disease or as a sequela of COVID-19.
We report survey-based results of a cohort of 350 patients suffering from new or worsening OAB symptoms 10–14 weeks after their hospitalization from COVID-19. This supports that urinary urgency, frequency, and nocturia can be long COVID-19 symptoms that can significantly impact a patient’s QoL. Future prospective, multi-center studies will be necessary to elucidate the specific pathophysiology of OAB symptoms in the context of COVID-19 such that urologists can appropriately treat these patients in a timely fashion.
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What is currently known about COVID-19’s effect on the bladder? What symptoms have been reported?
In the initial stages of the pandemic, the main symptom appeared to be a painful bladder, but over time, we have seen more and more patients with urinary frequency, pain if they do not pass urine, or a desperate need to pass urine.
Another key element of what is now known as ‘COVID bladder’ is that patients will wake at night to pass urine. Patients who would only generally have one to two urine infections per year are now suddenly suffering from continuous and frequent infections.
COVID bladder has also resulted in patients arriving home with an intense urgency to pass urine, and they will often leak due to not being able to wait when unlocking their front door. Associated with that are long-COVID symptoms that generally include the following:
Interestingly, important data and research on this has shown that there are certainly abnormalities in white blood cells. These white blood cells seem to decline in people who have long COVID. We have looked at the bladder and we have found declining white cells living in the bladder.
So, the reason why there seems to be less of these white blood cells when we carry out blood tests is that they are going into the tissues, causing inflammation and making everything very irritated.
Another thing that people find quite distressing with COVID bladder is that they will often feel quite anxious. Studies have really shown that COVID bladder can actually affect all parts of the body. Interestingly, the vast majority of patients who have reported these COVID bladder-related symptoms have only suffered from a mild bout of COVID-19.
What is the connection between these symptoms and the COVID-19 virus?
The key thing about these symptoms is that, first of all, what has happened is that doctors who have been investigating have been doctors dealing with the lungs or blood pressure. It is only when we look at the areas which are affected, that, on one hand, there are lung-related symptoms such as difficulty breathing when walking up the stairs.
In terms of the heart, often people will have POTS. This means the person will feel very dizzy when standing, and their heart beats very fast to try and keep the blood pressure up. Both the lungs and heart are related to something called the autonomic nervous system, which is the part of the nervous system that gets involved when people have infections.
We have all experienced a cold before and thought to ourselves “I should be able to sit at my desk and work”, but people suffering from COVID bladder have said that they just feel so ill that they have got to go to bed. Now, the reason they have to go to bed is that their blood pressure is low, the pulse is high, and they have to, by lying down, correct the blood pressure, and as a result, they feel much better.
This is a very normal response to infection, and patients should not be concerned when the body causes these symptoms which affect the heart and the breathing. All of these symptoms are actually responses of the immune system to an infection. What is interesting about COVID-19, however, is that it makes one part of the immune system very angry.
This angry part of the immune system is typically also seen when someone gets a mosquito bite. Nothing much happens in terms of the bite itself, but 24 hours later we see swelling, redness, and pain. We see a similar thing in patients with long COVID, who report muscle pain. It is almost as if the body is experiencing a mosquito bite. People will also describe a feeling of being poisoned, but this is a normal feeling as the body is trying to fight off the virus, even if the virus may not be there anymore.
If a person has these symptoms, what should they do?
There are long COVID clinics where patients can be assessed. Patients will often have a low-grade bladder infection. The body has decided that the virus is in the body, the body has then produced inflammation, and this inflammation has then affected the inside of the bladder. We have now looked at over 60 patients with this, and we find that the inside of the bladder starts to bleed due to this inflammation.
When the wall of the bladder becomes inflamed, the lining becomes very fragile. We keep bacteria out primarily through the skin, so within the bladder, the lining keeps bacteria away. However, when inflammation occurs, that protective skin layer breaks down. As the lining of the bladder has become disrupted, bacteria start to live inside the bladder.
Interestingly, the bacteria that we are finding now inside patients’ bladder is very different to what we found before the outbreak of COVID-19. So, it is a completely different organism because the environment of the bladder has become very different.
Is the course of treatment the same as it would be without the patient also suffering from long COVID?
Treatment of a patient with COVID-19 is normally very acute, with the main aim being to reduce one’s temperature. Usually, patients would be assessed to see if they had a chest infection, and whether this chest infection was caused by bacteria or a left-over of the COVID-19 infection. Patients’ bowel will also be examined.
The long COVID symptoms, however, are present for 12 weeks after the initial infection, so this is something that has an entirely different aspect to it, when compared with acute, “standard” if you like, treatment.
We are not treating a virus or the effects of the virus acutely, but we are trying to calm the immune system that has become angry.
What is your advice for people suffering from long COVID?
The majority of patients that I have seen have had bladder problems, and that I happened to notice that they had other symptoms in the body. We have found that these symptoms really improve with treatment.
One of the crucial things is that vigorous exercise, or trying to beat long COVID does not work, and people end up a lot worse. Try to avoid intense levels of exercise when you are recovering. It is important to exclude other infections as well, such as chest infections and bowel infections. So, it is very important to get these infections under control as quickly as possible because if there is an infection in the body, the immune system is not going to stop, as its job is to protect us at all costs.
Authors: Robert M. DiSogra Audiology Today American Academy of Audiology
Johns Hopkins University’s Center for Systems Science and Engineering (CSSE) in the United States reported over seven million documented cases of COVID-19 and over 212,000 deaths since the virus was first identified in this country in January 2020 (2020).
Early in the pandemic, the medical profession, the Centers for Disease Control and Prevention (CDC), the National Institute of Health (NIH), and both federal and state governments worked 24/7 to develop testing protocols and intervention strategies (pharmacological management and vaccines).
Until a scientifically proven intervention strategy is identified along with a vaccine, the public continues to be advised by the CDC to wear face masks, socially distance from each other, wash their hands regularly, and avoid crowds/indoor events. This major change in our lifestyle/behavior and the associated economic impact is still with us today.
As a novel virus, no assumptions can be made about treatment or management strategies or prediction of late onset of new symptoms. Within a few months after the pandemic was declared, a variety of pharmacological interventions were proposed by the federal government—all without scientific evidence. The most popular unproven intervention strategy in the United States was the combined use of two known ototoxic drugs: hydroxychloroquine and azithromycin (Bortoli and Santiago, 2007; FDA, 2017; Prayuenyong. et al, 2020).
DiSogra (2020a) provides a detailed review of this strategy from an audiologist’s perspective. In Europe, hydroxychloroquine and chloroquine were prescribed for almost 12 percent of COVID-19 patients (Lechien et al, 2020).
Researchers attempted to determine if other FDA-approved drugs could be repurposed as an intervention strategy. A summary of several FDA-approved drugs that were being repurposed for COVID-19 patients appears in DiSogra (2020b).
A self-organized group of COVID-19 “long-haul” patients, who are researchers in relevant fields (e.g., participatory design, neuroscience, public policy, data collection and analysis, human-centered design, health activism) and have intimate knowledge of COVID-19, have been working on patient-led research around the COVID experience and prolonged recoveries (Assaf et al, 2020).
To capture and share the experiences of patients suffering from prolonged or long-haul COVID-19 symptoms, survivor/researchers used a data-driven participatory-type survey and patient-centric analysis. With 640 survey respondents, many participants experienced fluctuations in the type (70 percent reporting) and intensity (89 percent reporting) of symptoms over the course of being symptomatic.
For approximately 10 percent who had recovered, the average length of time of being symptomatic was 27 days. Unrecovered respondents experienced symptoms for an average of 40 days, with a large proportion experiencing symptoms for five to seven weeks. The chance of full recovery by day 50 was smaller than 20 percent.
Most common auditory/vestibular symptoms were earaches and vertigo lasting up to eight weeks after the diagnosis. Sixty percent of the respondents reported balance issues that peaked by second week and subsided over the next four weeks. Earaches (~32 percent) and vertigo/motion sickness (~25 percent) persisted over six weeks. One patient reported hearing loss that recovered after three weeks. Subjects listed tinnitus as the second highest complaint on a write-in list of symptoms.
All patients experienced a full recovery after 90 days except for patients with pre-existing asthma. The majority of survey respondents were not hospitalized; however, a large number of participants (37.5 percent) had visited the emergency rooms or urgent care but were not admitted for further testing or overnight observation.
Auditory Symptoms After COVID-19 Treatment
For this manuscript, “auditory symptoms” is defined as hearing loss (any degree/type), earache, subjective tinnitus, or vertigo/balance problems.
Sensorineural Hearing Loss
Almufarrij et al (2020) conducted a rapid systematic review investigated audio-vestibular symptoms associated with coronavirus. They found five case reports and two cross-sectional studies that met the inclusion criteria (N=2300). No records of audio-vestibular symptoms were reported with the earlier types of coronavirus (i.e., severe-acute respiratory syndrome [SARS] and Middle East respiratory syndrome [MERS]).
Reports of hearing loss, tinnitus, and vertigo were rarely reported in individuals who tested positive for the SARS-CoV-2. They opined that reports of audio-vestibular symptoms in confirmed COVID-19 cases are few “with mostly minor symptoms, and the studies are of poor quality.”
Munro et al (2020) concluded that it was unclear which cases of hearing loss [and tinnitus] can be directly attributed to SARS-CoV-2 or perhaps related to the many possible causes of hearing loss associated with critical care including ototoxic mediations (Ciorba et al. 2020), local, or systematic infections, vascular disorders and auto-immune disease.
Elbiol (2020) reported only one case (N=121) of sudden hearing loss (0.6 percent). A case report of sudden hearing loss that occurred one week after hospitalization was also published by Koumpa et al (2020).
Conductive Hearing Loss
Fiden (2020) reported one COVID-19 patient with a unilateral otitis media. The conductive hearing loss was mild to moderate.
Tinnitus was reported in four studies in 2020 (N = 8 patients; Cui et al, Fidan, Lechien et al, and Sun et al). The characteristics of the tinnitus and the impact on the individual were not reported.
Munro, et al (2020) followed 121 COVID-19 patients eight weeks after discharge. Sixteen (13.2 percent) patients reported a change in hearing and/or tinnitus after diagnosis of COVID-19. However, there was no pattern for the duration of the recovery.
Some patients showed no changes in tinnitus while one patient reported no tinnitus after eight weeks. There was self-reported tinnitus in eight cases with three reporting a pre-existing hearing loss. Another patient reported that their tinnitus resolved. Elibol (2020) noted that tinnitus is rarely seen in COVID-19 patients.
Liang et al (2020) attempted to identify and describe neurosensory dysfunctions (including tinnitus) of COVID-19 patients. A total of 86 patients were screened but only three (3.5 percent) were identified as having tinnitus. The average interval from onset of tinnitus was one day; while the average interval from onset of tinnitus to admission was 6 ± 5.29 days; the average duration of tinnitus was 5 ± 0 days. Finally, a non-organic component of the tinnitus (i.e., anxiety) cannot be ruled out (Xia et al, 2020). Although the current studies indicate a low incidence of tinnitus in these patients, development of tinnitus management protocol may be beneficial.
The Munro study (2020) identified one patient with hearing loss that also reported vertigo, which the authors concluded may have been vestibular in origin. TABLE 1 summarizes the earliest case reports and cross-sectional study designs that identified auditory/vestibular problems.
TYPE OF STUDY
Asaaf et al, 2020
Earaches (32 %) Vertigo (60%) Hearing Loss (0.15%)
Ciu et al, 2020
Tinnitus (N=1) Otitis media (N=1)
Tinnitus Otitis media
Han et al, 2019
Lechien et al, 2019
Ear pain (N=358 or 25%) Rotary vertigo (N=6 or 0.4%) Tinnitus (N=5 or 0.3%)
Sriwijitalai and Wiwanitkit, 2020
Sensorineural HL (N=1 or 1.2%)
Sun et al, 2020
TABLE 1. Summary of published case reports and cross-sectional research that identified some type of auditory/vestibular problems (adapted from Almufarrij et al, 2020).
The Mustafa study (2020) compared two groups of patients (asymptomatic SARS-CoV-2 vs. control), and the results found that the asymptomatic SARS-CoV-2 group had significantly poorer hearing thresholds at 4-8 kHz and lower amplitude transient evoked otoacoustic emissions (Mustafa, 2020). Almufarrij et al (2020) concluded that high-quality studies are required in different age groups to investigate the acute effects of coronavirus. These studies include temporary effects from medications as well as studies on long-term risks on the audio-vestibular system.
Some Intervention Strategies
Aside for re-purposed pharmaceuticals, dietary supplements are proposed as a treatment option (DiSogra, 2020c). In the Aasaf study (2020), Tylenol® (followed by an inhaler) were the top medications taken by respondents in their survey to treat symptoms. Supplements, such as vitamin C, vitamin D, zinc and electrolytes, were taken by many of the respondents over several weeks. Hot liquids were also very popular with the respondents.
Other popular entries for medications, supplements and treatments reported by participants included Mucinex®, prednisone, steroids, ginger, magnesium, steam, probiotics, oregano oil/supplements, Flonase®, and other nasal sprays.
The majority of respondents never consumed any of the following substances: smoke/vape nicotine, edible or liquid cannabis, smoke/vape recreational cannabis, consume or smoke cannabidiol-only products or consume recreational drugs. Many of the respondents said they occasionally or frequently consumed alcoholic beverages.
The auditory-vestibular side effects of any illness, or from a pharmaceutical, nutraceutical, noise, or trauma, as well as any psychogenic component, will always be a concern for audiologists. With COVID-19, it is still too early to predict auditory-vestibular side effects, although several studies have attempted to do so or at least guide us in our short and long-term management.
If these “long-hauler” patients can be followed more closely, a body of knowledge should emerge that will help audiologists better manage COVID-19 survivors when their auditory/vestibular symptoms result in a referral for testing. It would appear that conductive and sensorineural hearing loss, tinnitus (including its non-organic origin) and vertigo can be expected but with no predictable pattern.
Protocols for management will need to be developed; however, in the interim, an ototoxic drug monitoring protocol can serve as a reference (American Academy of Audiology, 2009). The duration of these symptoms (after the diagnosis) can last from one day to eight weeks but, again, it is still too early in the life of this pandemic to state definitively if these symptoms are temporary or permanent. Although no formal protocols have been developed, audiologists must keep in mind that the more severe, life-threatening side effects of COVID-19 will continue to get researcher’s attention.
Bortoli R, Santiago M. (2007) Chloroquine ototoxicity. Clin Rheumatol 26 (11):1809–1810
Ciorba A, Corazzi V, Skarzynski PH, Skarzynska MB, Bianchini C, Pelucchi S, Hatzopoulos S. (2020) Don’t forget ototoxicity during the SARS-CoV-2 (Covid-19) pandemic. Int J Immunopath Pharmacol 34:1–3.
Cui C, Yao Q, Zhang D, Zhao Y, Zhang K, Nisenbaum E, Liu X, Cao P, Zhao K, Huang X, Leng D,Liu C, Li N, Luo Y, Chen B, Casiano R,Weed D, Sargi Z, Telischi F, Lu H, Denneny III JC, Shu Y, Liu X. (2020) Approaching otolaryngology patients during the COVID-19 pandemic. Otolaryngol Head Neck Surg 163(1):121–131
Han W, Quan B, Guo Y, Zhang J, Lu Y, Feng G, Wu Q, Fang F, Cheng L, Jiao N, Li X, Chen Q. (2019) The course of clinical diagnosis and treatment of a case infected with coronavirus disease. J Med Virol 2(5):461–463
Koumpa FS, Forde CT, Manjaly JG. (2020) Sudden irreversible hearing loss post COVID-19. BMJ Case Reports 13(11):e238419.
Lechien JR, Chiesa-Estomba CM, Place S, Van Laethem Y, Cabaraux P, Mat Q, Saussez S. (2019) Clinical and epidemiological characteristics of 1,420 European patients with mild-to-moderate coronavirus disease. J Intern Med 288:3, 1–10
Liang Y, Xu J, Chu M, Mai J, Lai N, Tang W, Yang T, Zhang S, Guan C, Zhong F, Yang L, Liao G. (2020) Neurosensory dysfunction: A diagnostic marker of early COVID-19. Int J Infect Dis. 98:347–352.
Mustafa MWM. (2020) Audiological profile of asymptomatic Covid-19 PCR-positive cases. AmerJ Otolaryngol 41:3.
Coronavirus disease 2019 (COVID-19) mRNA vaccines induce robust immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), yet their cellular/molecular mode of action and the etiology of the induced adverse events (AEs) remain elusive.
Lipid nanoparticles (LNPs) probably have a broad distribution in human tissues/organs; they may also (along with the packaged mRNA) exert a proinflammatory action.
COVID-19 mRNA vaccines encode a transmembrane SARS-CoV-2 spike (S) protein; however, shedding of the antigen and/or related peptide fragments into the circulation may occur.
Binding of circulating S protein to angiotensin-converting enzyme 2 (ACE2) (that is critical for the renin–angiotensin system balance) or to other targets, along with the possibility of molecular mimicry with human proteins, may contribute to the vaccination-related AEs.
The benefit–risk profile remains in favor of COVID-19 vaccination, yet prospective pharmacovigilance and long-term monitoring of vaccinated recipients should be a public health priority.
Vaccination is a major tool for mitigating the coronavirus disease 2019 (COVID-19) pandemic, and mRNA vaccines are central to the ongoing vaccination campaign that is undoubtedly saving thousands of lives. However, adverse effects (AEs) following vaccination have been noted which may relate to a proinflammatory action of the lipid nanoparticles used or the delivered mRNA (i.e., the vaccine formulation), as well as to the unique nature, expression pattern, binding profile, and proinflammatory effects of the produced antigens – spike (S) protein and/or its subunits/peptide fragments – in human tissues or organs. Current knowledge on this topic originates mostly from cell-based assays or from model organisms; further research on the cellular/molecular basis of the mRNA vaccine-induced AEs will therefore promise safety, maintain trust, and direct health policies.
Fighting the COVID-19 pandemic with SARS-CoV-2 S protein-encoding mRNA vaccines
COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Box 1) and has resulted in millions of deaths worldwide. Nevertheless, for the majority of SARS-CoV-2-infected individuals, COVID-19 will remain asymptomatic or only mildly symptomatic [12.]. Although SARS-CoV-2 may also circulate in the gastrointestinal tract[3.
], being a respiratory virus, the virus itself or its related antigens will not, in most cases, impact tissues and organs other than the respiratory system (RS) (Box 1) [4.56.
]. In patients with severe disease, infection of airway and lung tissues may cause pneumonia and excessive inflammation which can lead to acute respiratory distress syndrome (ARDS) (see Glossary) (Box 1) [.8.9.0.. ARDS may then lead to organ damage beyond the RS because of micro-/macro-thromboembolism, hyperinflammation, aberrant complement activation, or extended viremia184.108.40.206.12.
. This may be due to the broad expression of its receptor angiotensin-converting enzyme 2 (ACE2) in several cell types and tissues [14.15.16.] which results in an expanding tropism of SARS-CoV-2 for various critical organs (heart, pancreas, kidneys, etc.). If systemic collapse and death are avoided, the postulated direct virus ‘attack’ – or indirect effects due to cytokine storm [13.] or imbalance of the renin–angiotensin system (RA13.
] – causing multiorgan damage, possibly foster systemic defects which cause a chronic condition (referred to as long COVID-19) which is independently associated with the severity of the initial illness17.].Box 1
Following an unprecedented effort of biomedical research and mobilization of resources, two mRNA vaccines – namely BNT162b2 (ComirnatyTM) from Pfizer-BioNTech and the mRNA-1273 of Moderna (encoded antigen: SARS-CoV-2 S protein of the Wuhan-Hu-1 strain) [18., 1920.] – were the first to receive FDA emergency use authorization. In mRNA vaccines, which are characterized by relatively rapid prototyping and manufacturing on a large scale, the S protein-encoding mRNA is delivered via lipid nanoparticles (LNPs) to human cells that produce the mature viral protein or related antigens (Figure 1, Key figure), which can exhibit a rather wide tissue/organ distribution (discussed later) [202122.]. In addition to the plausible proinflammatory role of LNPs (evidenced also from reported immediate allergic reactions) [23.4.] and of packaged mRNA – which has nonetheless been engineered by a replacement of uridine with pseudo uridine [20.25.6.
] so as not to trigger innate immunity through pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) receptors – we surmise that vaccination-mediated adverse effects (AEs) can be attributed to the unique characteristics of the S protein itself (antigen) either due to molecular mimicry with human proteins or as an ACE2 ligand.
As delivered mRNAs can theoretically trigger the production of distinct antigens that can distribute systemically [
], they are radically different from conventional platforms (i.e., inactivated whole-virus vaccines or even protein-subunit nanoparticle vaccines) (Box 2) where the produced antigen and its distribution are more predictable. As all COVID-19 vaccines rely on the S protein of the original Wuhan-Hu-1 strain [19.20.
], the differences across different vaccination platforms thus far reported (Box 2) may relate to the various vectors and formulations and/or the S protein constructs employed. Box 2
Anti-SARS-CoV-2 mRNA vaccines and their reported adverse effects
Both the BNT162b2 and mRNA-1273 vaccines are administered intramuscularly and mobilize robust and likely durable innate, humoral, and cellular adaptive immune responses [27.282, 30.
]. Existing data on the available mRNA vaccines are mostly limited to serological analyses. Nonetheless, beyond the assessment of immune responses, the understanding of the safety profile of these vaccines is critical to ensure safety, maintain trust, and inform policy. Reportedly, mRNA vaccines are in general well tolerated, with very low frequencies of associated severe postimmunization AEs. Although rare, AEs include serious clinical manifestations such as acute myocardial infarction, Bell’s palsy, cerebral venous sinus thrombosis, Guillain–Barré syndrome, myocarditis/pericarditis (mostly in younger ages), pulmonary embolism, stroke, thrombosis with thrombocytopenia syndrome, lymphadenopathy, appendicitis, herpes zoster reactivation, neurological complications, and autoimmunity (e.g., autoimmune hepatitis and autoimmune peripheral neuropathies [220.127.116.11.
]) (see Clinician’s corner). Apart from AEs documented in clinical trials, most of the syndromes or isolated manifestations have been reported in multicenter or even nationwide retrospective observational studies and case series. Although correlation does not necessarily mean causation, active monitoring and awareness regarding reported postvaccination AEs are essential. Importantly, these associated AEs are significantly less frequent than analogous or additional serious AEs induced after severe COVID-19 [31.3234.
]. Some vaccine-induced AEs (e.g., myocardial infarction, Guillain–Barré syndrome) were found to increase with age, while others (e.g., myocarditis, anaphylaxis, appendicitis) were more common in younger people [35.36.
]. Although myocarditis cases are rather rare, in a study of US military personnel the number was higher than expected among males after a second vaccine dose 37.
]; similarly, the rate of postvaccination cardiac AEs was higher in young boys following the second dose [38.9.. Finally, a recent study showed an increased risk of neurological complications in COVID-19 vaccine recipients (which was nevertheless lower than the risk in COVID-19 patients) [
]. The molecular basis of these AEs remains largely unknown. We postulate that, since most (if not all) of them are also apparent in severe COVID-19 [31., they may be related to acute inflammation caused by both the virus and the vaccine, as well as in the common denominator between the virus and the vaccine, namely, the SARS-CoV-2 S protein (Box 1). The vaccine-encoded antigen (S protein) is stabilized in its prefusion form in the BNT162b2 and mRNA-1273 vaccines [1920.
]; it is therefore plausible that, if entering the circulation and distributing systemically throughout the human body (Figure 2), it can contribute to these AEs in susceptible individuals.
There is also evidence that ionizable lipids within LNPs can trigger proinflammatory responses by activating Toll-like receptors (TLRs) [40.
]. A recent report showed that LNPs used in preclinical nucleoside-modified mRNA vaccine studies are (independently of the delivery route) highly inflammatory in mice, as evidenced by excessive neutrophil infiltration, activation of diverse inflammatory pathways, and production of various inflammatory cytokines and chemokines [41.
]. This finding could explain the LNPs’ potent adjuvant activity, supporting the induction of robust adaptive immune responses [24.
]. Interestingly, inflammatory responses can be exacerbated on a background of pre-existing inflammatory conditions, as was recently shown in a mouse model after administration of mRNA–LNPs [42.
]; this effect was proven to be specific to the LNP, acting independently of the mRNA cargo.Although chemical modifications in the RNA molecules used in vaccines (detailed earlier) are intended to decrease TLR sensing of external single-stranded RNAs (and thus proinflammatory signals), there is some evidence that modified uracil residues do not completely abrogate TLR detection of the mRNA; also, while efforts are made to reduce double-stranded (ds) RNA production, there may be small amounts of dsRNA that can occasionally get packaged within mRNA vaccines [26.].
In this context, frequent booster immunizations may increase the frequency and/or the severity of the reported AEs.
Vaccine-encoded antigen distribution in the human body and possible interactions with human proteins
Following vaccination, a cell may present the produced S protein (or its subunits/peptide fragments) to mobilize immune responses or be abolished by the immune system (e.g., cytotoxic T cells) [25.
]. Consequently, the debris produced, or even the direct secretion (including shedding) of the antigen by the transfected cells, may release large amounts of the S protein or its subunits/peptide fragments to the circulation (Figure 1) [19.20.
]. The anti-SARS-CoV-2 vaccine mRNA-containing LNPs are injected into the deltoid muscle and exert an effect in the muscle tissue itself, the lymphatic system, and the spleen, but can also localize in the liver and other tissues [21.2243.44.
] from where the S protein or its subunits/peptide fragments may enter the circulation and distribute throughout the body. It is worth mentioning that liver localization of LNPs is not a universal property of carrier nanoparticles, as specific modifications in their chemistry can retain immunogenicity with minimal liver involvement [43.45.
]. In line with a plausible systemic distribution of the antigen, it was found that the S protein circulates in the plasma of the BNT162b2 or mRNA-1273 vaccine recipients as early as day 1 after the first vaccine injection [46.
]. Reportedly, antigen clearance is correlated with the production of antigen-specific immunoglobulins or may remain in the circulation (e.g., in exosomes) for longer periods [4748. ], providing one reasonable explanation (among others) for the robust and durable systemic immune responses found in vaccinated recipients [49.50.
]. Therefore, there is likely to be an extensive range of expected interactions between free-floating S protein/subunits/peptide fragments and ACE2 circulating in the blood (or lymph), or ACE2 expressed in cells from various tissues/organs (Figure 2) [14.15.
,16. This notion is further supported by the finding that in adenovirus-vectored vaccines (Box 2), the S protein produced upon vaccination has the native-like mimicry of SARS-CoV-2 S protein’s receptor binding functionality and prefusion structure [51.].
Additional interactions with human proteins in the circulation, or even the presentation to the immune system of S protein antigenic epitopes [52. mimicking human proteins (molecular mimicry) may occur [18.104.22.168.
]. Reportedly, some of the near-germline SARS-CoV-2-NAbs against S receptor-binding domain (RBD) reacted with mammalian self-antigens [57.
], and SARS-CoV-2 S antagonizes innate antiviral immunity by targeting multiple pathways controlling interferon (IFN) production [58.
]. Also, a sustained elevation in T cell responses to SARS-CoV-2 mRNA vaccines has been found (data not yet peer-reviewed) in patients who suffer from chronic neurologic symptoms after acute SARS-CoV-2 infection as compared with healthy COVID-19 convalescents [59.
]. Given the reported (rare) neurological AEs following vaccination, it was suggested that further studies are needed to assess whether antibodies against the vaccine-produced antigens can cross-react with components of the peripheral nerves [34.
]. Further concerns include the possible development of anti-idiotype antibodies against vaccination-induced antibodies as a means of downregulation; anti-idiotype antibodies – apart from binding to the protective neutralizing SARS-CoV-2 antibodies – can also mirror the S protein itself and bind ACE2, possibly triggering a wide array of AEs [60.
]. Worth mentioning is a systems vaccinology approach (31 individuals) of the BNT162b2 vaccine (two doses) effects, where anticytokine antibodies were largely absent or were found at low levels (contrary to findings in acute COVID-19 [61.62.
]), while two individuals had anti-interleukin-21 (IL-21) autoantibodies, and two other individuals had anti-IL-1 antibodies [63.
]. In this context, anti-idiotypic antibodies can be particularly enhanced after frequent boosting doses that trigger very high titers of immunoglobulins [64.
]. Frequent boosting doses may also become a suboptimal approach as they can imprint serological responses toward the ancestral Wuhan-Hu-1 S protein, minimizing protection against novel viral S variants [65.66.].
The potential interaction at a whole-organism level of the native-like S protein and/or subunits/peptide fragments with soluble or cell-membrane-attached ACE2 (Figure 2) can promote ACE2 internalization and degradation 67.68.]. In support of this, soluble ACE2 induces receptor-mediated endocytosis of SARS-CoV-2 via interaction with proteins related to the RAS [69.
]. Prolonged loss or reduced ACE2 activity may result in extensive destabilization of the RAS which may then trigger vasoconstriction, enhanced inflammation, and/or thrombosis due to unopposed ACE and angiotensin-2 (ANG II)-mediated effects (Figure )[13.. Indeed, decreased ACE2 expression and/or activity contributes, among other things, to the development of ANG II-mediated hypertension in mice, indicating vasculature dysfunction [67.]. The baseline expression levels of ACE2 in endothelial cells, or its induced expression levels upon stimulation from other tissue-resident cells, along with the potential of endothelial cells to shed ACE2 to the circulation, or their sensitivity to SARS-CoV-2 infection is debatable [0.71.72.73.]. Nonetheless, even relatively low ACE2 expression levels in endothelial cells (e.g., compared to levels in epithelial cells) [22.214.171.124.
], along with the high expression levels of ACE2 in other cell types of the vasculature (e.g., heart fibroblasts/pericytes) [
], indicate that the vasculature can be sensitive to free-floating S protein or its subunits/peptide fragments (Figure 2). These effect(s), especially in capillary beds, and the prolonged antigen presence in the circulation [
], along with the systemic excessive immune response to the antigen, can then trigger sustained inflammation (discussed later) which can injure the endothelium, disrupting its antithrombogenic properties in multiple vascular beds.
The SARS-CoV-2 S protein-induced effects in mammalian cells or model organisms
Reportedly, intravenous (i.v.) injection of the S1 subunit in mice results in its localization in endothelia of mice brain microvessels showing colocalization with ACE2, caspase-3, IL-6, tumor necrosis factor α (TNF-α), and C5b-9; it was thus suggested that endothelial damage is a central part of SARS-CoV-2 pathology which may be induced by the S protein alone [75.
]. Also, the S1 subunit (or recombinant S1 RBD) impaired endothelial function via downregulation of ACE2 [76.
] and induced degradation of junctional proteins that maintain endothelial barrier integrity in a mouse model of brain microvascular endothelial cells or cerebral arteries; this latter effect was more enhanced in endothelial cells from diabetic versus normal mice [7.]. Similarly, the S1 subunit decreased microvascular transendothelial resistance and barrier function in cultured human pulmonary cells [78.]. Further, S protein disrupted human cardiac pericytes function and triggered increased production of proapoptotic factors in pericytes, causing endothelial cells death [79.
]. In support of this, administration of the S protein promoted dysfunction of human endothelial cells as evidenced by, for example, increased expression of the von Willebrand factor [80.
]. Other reports indicate that S1 can directly induce coagulation by competitive binding to both soluble and cellular heparan sulfate/heparin (an anticoagulant) [126.96.36.199.
], while cell-free hemoglobin, as a hypoxia counterbalance, cannot attenuate disruption of endothelial barrier function, oxidative stress, or inflammatory responses in human pulmonary arterial endothelial cells exposed to S1 [85.
]. Consistently, S protein binds fibrinogen (a blood coagulation factor), and S protein virions have been found to enhance fibrin-mediated microglia activation (data not yet peer-reviewed) and induce fibrinogen-dependent lung pathology in mice [86.
], while S1 binding to platelets’ ACE2 triggers their aggregation [84.
]. Interestingly, both the ChAdOx1 (AstraZeneca) and BNT162b2 vaccines can elicit antiplatelet factor 4 (anti-PF4) antibody production even in recipients without clinical manifestation of thrombosis [87.].Intriguingly, the S protein increases human cell syncytium formation [88.89.], triggering pyroptosis of syncytia formed by fusion of S and ACE2-expressing cell90.
]. Also, in cells or mouse experimental models, it was shown that S removes lipids from model membranes and interferes with the capacity of high-density lipoprotein to exchange lipids [91.], inhibits DNA damage repair processes [92.
], and induces Snail-mediated epithelial–mesenchymal transition marker changes and lung metastasis in a breast cancer mouse model [93.].
In support of the possibility that there is a wide range of S protein binders, Aβ1–42 (the 42 amino acid form of amyloid β in cerebrospinal fluid) was found to bind with high affinity to the S1 subunit and ACE2 [
. Aβ1–42 strengthened the binding of S1 to ACE2 and increased viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection mouse model. Data from this surrogate mouse model with IV inoculation of Aβ1–42 showed that the clearance of Aβ1–42 in the blood was dampened in the presence of the extracellular domain of the S protein trimers [94.
]. Given the wide ACE2 expression in human brain [95.
], a study of particular interest showed that IV-injected radioiodinated S1 (I-S1) readily crossed by adsorptive transcytosis the blood–brain barrier in male mice, was taken up by brain regions, and entered the parenchymal brain space. I-S1 was also taken up by the lung, spleen, kidney, and liver; intranasally administered I-S1 also entered the brain, although at lower levels than after i.v. administration [96.
]. Similarly, S1 was found to disrupt the blood–brain barrier integrity at a 3D blood–brain barrier microfluidic model [97.
]. In support of this, biodistribution studies of the mRNA–LNP platform by Moderna in Sprague Dawley rats revealed the presence of low levels of mRNA in the brain, indicating that the mRNA–LNPs can cross the blood–brain barrier [22.].
Finally, it was recently reported that human T cells express ACE2 at levels sufficient to interact with the S protein [98.
], while it had been shown previously that SARS-CoV-2 uses CD4 to infect T helper lymphocytes, and that S promotes a proinflammatory activation profile on the most potent antigen-presenting cells (APCs) (i.e., human dendritic cells) [99.
]. If these observations are confirmed, they may explain a SARS-CoV-2 vaccination-mediated AE, namely, reactivation of varicella zoster virus [100101..
S protein-induced proinflammatory responses and unique gene expression signatures following vaccination
Reportedly, S protein (apart from the LNP–mRNA platform discussed earlier) mediates proinflammatory and/or injury (of different etiology) responses in various human cell types [102.103.104.
, and ACE2-mediated infection of human bronchial epithelial cells with S protein pseudovirions induced inflammation and apoptosis [105.
]. Also, S protein promoted an inflammatory cytokine IL-6/IL-6R-induced trans signaling response and alarmin secretion in human endothelial cells, along with increased oxidative stress, induction of inflammatory paracrine senescence, and higher levels of leucocyte adhesion [106.
]. Other reports indicate that S protein triggers an inflammatory response signature in human corneal epithelial cells [107.
], increases oxidative stress and DNA ds breaks in human peripheral-blood mononuclear cells (PBMCs) postvaccination [108.
], and binds to lipopolysaccharide, boosting its proinflammatory activity [109.110.
]. Furthermore, S protein induces neuroinflammation and caspase-1 activation in BV-2 microglia cells [111.] and blocks neuronal firing in sensory neurons [112.
]. The S protein-induced systemic inflammation may proceed via TLR2-dependent activation of the nuclear factor κB (NF-κB) pathway [113.
], while structure-based computational models showed that S protein exhibits a high-affinity motif for binding T cell receptors (TCRs), and may form a ternary complex with histocompatibility complex class II molecules; indeed, analysis of the TCR repertoire in COVID-19 patients showed that those with severe hyperinflammatory disease exhibit TCR skewing consistent with superantigen (S protein) activation [114.
]. In in vivo mouse models, S protein activated macrophages and contributed to induction of acute lung inflammation [115.
], while intratracheal instillation of the S1 subunit in transgenic mice overexpressing human ACE2 induced severe COVID-19-like acute lung injury and inflammation. These effects were milder in wild-type mice, indicating the phenotype dependence on human ACE2 expression [78.
]. Consistently, the S1 subunit has been found to act as a PAMP that, via pattern recognition receptor engagement, induces viral infection-independent neuroinflammation in adult rats [116..
These observations correlate with the finding of a systemic inflammatory signature after the first BNT162b2 vaccination which was accompanied by TNF-α and IL-6 upregulation after the second dose [117.
]; these effects may also relate to a proinflammatory action of the mRNA–LNP platform (see earlier). In a thorough systems vaccinology study of the BNT162b2 mRNA vaccine effects, younger participants tended to have greater changes in monocyte and inflammatory modules 1 day after the second dose, whereas older individuals had increased expression of B and T cell modules. Moreover, single-cell transcriptomics analysis at the same time point revealed the emergence of a unique myeloid cell cluster out of 18 cell clusters identified in total. This cell cluster does not represent myeloid-derived suppressor cells, it expressed IFN-stimulated genes and was not found in COVID-19 infection; also, it was similar to an epigenetically reprogrammed monocyte population found in the blood of donors being vaccinated with two doses of an influenza vaccine [63.
. Whether epigenetic reprogramming underlies the enhanced IFN-induced gene response in C8 cells after secondary BNT162b2 vaccination remains to be clarified. Finally, a comparison between the BNT162b2 vaccine-induced gene expression signatures at day 7 post-prime (d7PP) and post-boost (d7PB) doses and that of other vaccine types (e.g., inactivated or live-attenuated vaccines) exhibited weak correlation both between d7PP and d7PB as well as with other vaccines [63.]. These findings suggest the evolution of novel genomic responses after the second dose and, more importantly, the unique biology of mRNA vaccines versus other more conventional platforms. Of particular interest is also the report of a cytokine release syndrome (CRS) – an extremely rare immune-related AE of immune checkpoint inhibitors – post-BTN162b2 vaccination in a patient with colorectal cancer on longstanding anti-programmed death 1 (PD-1) monotherapy; the anti-PD1 blockade-mediated CRS was evidenced by increased inflammatory markers, thrombocytopenia, elevated cytokine levels, and steroid responsiveness [118.]. These proinflammatory effects could be particularly pronounced in the elderly, since recent data revealed that senescent cells become hyperinflammatory in response to the S1 subunit, followed by increased expression of viral entry proteins and reduced antiviral gene expression in nonsenescent cells through a paracrine mechanism [119.].
The need to investigate the molecular basis of vaccination-induced AEs
Anti-SARS-CoV-2 mRNA vaccines induce durable and robust systemic immunity, and thus their contribution in mitigating the COVID-19 pandemic and saving thousands of lives is beyond doubt. This technology has several advantages over conventional vaccines [120.
] and opens a whole new era for the development of novel vaccines against various infectious and other diseases, including cancer. Based on currently available molecular insights (mostly in cell-based assays and model organisms), we hypothesize that the rare AEs reported following vaccination with S protein-encoding mRNA vaccines may relate to the nature and binding profile of the systemically circulating antigen(s) (Figure 1, Figure 2), although the contribution of the LNPs and/or the delivered mRNA is likely also significant [ 24.26,41.
]. Therefore, the possibility of subclinical organ dysfunction in vaccinated recipients which could increase the risk, for example, of future (cardio)vascular or inflammatory diseases should be thoroughly investigated. Given that severe COVID-19 correlates with older age, hypertension, diabetes, and/or cardiovascular disease, which all share a variable degree of ACE2 signaling deregulation, additional ACE2 downregulation induced by vaccination may further amplify an unbalanced RAS. Regarding localization of LNPs in the liver and consequent antigen expression, it is worth mentioning that the liver is continuously exposed to a multitude of self and foreign antigens and can mount efficient immune responses against pathogens as it hosts convectional APCs (e.g., dendritic cells, B cells, and Kupfer cells). Additional liver cell types – such as liver sinusoidal endothelial cells, hepatic stellate cells, and hepatocytes – also have the capacity to act as APCs [121.
]. It is plausible, though as yet unproven, that as the S protein is produced in liver cells, both conventional and unconventional APCs may prime adaptive but also innate immune responses in the liver’s immunological niche. Despite the liver’s major tolerogenic role [
], the sustained expression of S protein-related antigens (Figure 1) can potentially skew the immune response towards autoimmune-like tissue damage, as in the observed cases of autoimmune hepatitis following vaccination
]. It therefore merits further investigation whether LNPs can transfect any other nonimmunological body tissues bearing cells that can act as unconventional APCs, thus inducing a sustained immune response but also a self-response, as in cases of chronic viral infections [
Although the benefit–risk profile remains strongly in favor of COVID-19 vaccination for the elderly and patients with age-related or other underlying diseases, an understanding of the molecular–cellular basis of the anti-SARS-CoV-2 mRNA vaccine-induced AEs is critical for the ongoing and future vaccination and booster campaigns. In parallel, the prospective pharmacovigilance and long-term monitoring (clinical/biochemical) of vaccinated recipients versus matched controls should evolve in well-designed clinical trials. Moreover, the use of alternative chemistries for LNPs, and of S protein in its closed form (not prone to ACE2 binding) [126.
], along with the use of SARS-CoV-2 nucleocapsid protein or solely the S RDB, may be valuable alternatives for refined, next-generation mRNA vaccines. Finally, as we essentially do not know for how long and at what concentration the LNPs and the antigen(s) remain in human tissues or the circulation of poor vaccine responders, the elderly, or children (see Outstanding questions), and given the fact that cellular immunity likely persists despite reduced in vitro neutralizing titers [28.
], boosting doses should be delivered only where the benefit–risk profile is clearly established.
Overall, parallel to the ongoing research on the most challenging topics of SARS-CoV-2 biology, evolving dynamics and adaptation capacity to human species (i.e., transmission–infection rate and disease severity), the basic and clinical research (see Outstanding questions) aiming to understand the molecular–cellular basis of the rare AEs of the existing first-generation mRNA vaccines should be accelerated as an urgent and vital public health priority.
Individual and community-level risk for COVID-19 mortality in the United States.Nat. Med. 2021; 27: 264-269View in Article
If you’ve had COVID-19, it may still be messing with your brain. Those who have been infected with the virus are at increased risk of developing a range of neurological conditions in the first year after the infection, new research shows. Such complications include strokes, cognitive and memory problems, depression, anxiety and migraine headaches, according to a comprehensive analysis of federal health data by researchers at Washington University School of Medicine in St. Louis and the Veterans Affairs St. Louis Health Care system.
Additionally, the post-COVID brain is associated with movement disorders, from tremors and involuntary muscle contractions to epileptic seizures, hearing and vision abnormalities, and balance and coordination difficulties as well as other symptoms similar to what is experienced with Parkinson’s disease.
The findings are published Sept. 22 in Nature Medicine.
“Our study provides a comprehensive assessment of the long-term neurologic consequences of COVID-19,” said senior author Ziyad Al-Aly, MD, a clinical epidemiologist at Washington University. “Past studies have examined a narrower set of neurological outcomes, mostly in hospitalized patients. We evaluated 44 brain and other neurologic disorders among both nonhospitalized and hospitalized patients, including those admitted to the intensive care unit. The results show the devastating long-term effects of COVID-19. These are part and parcel of long COVID. The virus is not always as benign as some people think it is.”
Overall, COVID-19 has contributed to more than 40 million new cases of neurological disorders worldwide, Al-Aly said.
Other than having a COVID infection, specific risk factors for long-term neurological problems are scarce. “We’re seeing brain problems in previously healthy individuals and those who have had mild infections,” Al-Aly said. “It doesn’t matter if you are young or old, female or male, or what your race is. It doesn’t matter if you smoked or not, or if you had other unhealthy habits or conditions.”
Few people in the study were vaccinated for COVID-19 because the vaccines were not yet widely available during the time span of the study, from March 2020 through early January 2021. The data also predates delta, omicron and other COVID variants.
A previous study in Nature Medicine led by Al-Aly found that vaccines slightly reduce—by about 20%—the risk of long-term brain problems. “It is definitely important to get vaccinated but also important to understand that they do not offer complete protection against these long-term neurologic disorders,” Al-Aly said.
The researchers analyzed about 14 million de-identified medical records in a database maintained by the U.S. Department of Veterans Affairs, the nation’s largest integrated health-care system. Patients included all ages, races and sexes.
They created a controlled data set of 154,000 people who had tested positive for COVID-19 sometime from March 1, 2020, through Jan. 15, 2021, and who had survived the first 30 days after infection. Statistical modeling was used to compare neurological outcomes in the COVID-19 data set with two other groups of people not infected with the virus: a control group of more than 5.6 million patients who did not have COVID-19 during the same time frame; and a control group of more than 5.8 million people from March 2018 to December 31, 2019, long before the virus infected and killed millions across the globe.
The researchers examined brain health over a year-long period. Neurological conditions occurred in 7% more people with COVID-19 compared with those who had not been infected with the virus. Extrapolating this percentage based on the number of COVID-19 cases in the U.S., that translates to roughly 6.6 million people who have suffered brain impairments associated with the virus.
Memory problems—colloquially called brain fog—are one of the most common brain-related, long-COVID symptoms. Compared with those in the control groups, people who contracted the virus were at a 77% increased risk of developing memory problems. “These problems resolve in some people but persist in many others,” Al-Aly said. “At this point, the proportion of people who get better versus those with long-lasting problems is unknown.”
Interestingly, the researchers noted an increased risk of Alzheimer’s disease among those infected with the virus. There were two more cases of Alzheimer’s per 1,000 people with COVID-19 compared with the control groups. “It’s unlikely that someone who has had COVID-19 will just get Alzheimer’s out of the blue,” Al-Aly said. “Alzheimer’s takes years to manifest. But what we suspect is happening is that people who have a predisposition to Alzheimer’s may be pushed over the edge by COVID, meaning they’re on a faster track to develop the disease. It’s rare but concerning.”
Also compared to the control groups, people who had the virus were 50% more likely to suffer from an ischemic stroke, which strikes when a blood clot or other obstruction blocks an artery’s ability to supply blood and oxygen to the brain. Ischemic strokes account for the majority of all strokes, and can lead to difficulty speaking, cognitive confusion, vision problems, the loss of feeling on one side of the body, permanent brain damage, paralysis and death.
“There have been several studies by other researchers that have shown, in mice and humans, that SARS-CoV-2 can attack the lining of the blood vessels and then then trigger a stroke or seizure,” Al-Aly said. “It helps explain how someone with no risk factors could suddenly have a stroke.”
Overall, compared to the uninfected, people who had COVID-19 were 80% more likely to suffer from epilepsy or seizures, 43% more likely to develop mental health disorders such as anxiety or depression, 35% more likely to experience mild to severe headaches, and 42% more likely to encounter movement disorders. The latter includes involuntary muscle contractions, tremors and other Parkinson’s-like symptoms.
COVID-19 sufferers were also 30% more likely to have eye problems such as blurred vision, dryness and retinal inflammation; and they were 22% more likely to develop hearing abnormalities such as tinnitus, or ringing in the ears.
“Our study adds to this growing body of evidence by providing a comprehensive account of the neurologic consequences of COVID-19 one year after infection,” Al-Aly said.
Long COVID’s effects on the brain and other systems emphasize the need for governments and health systems to develop policy, and public health and prevention strategies to manage the ongoing pandemic and devise plans for a post-COVID world, Al-Aly said. “Given the colossal scale of the pandemic, meeting these challenges requires urgent and coordinated—but, so far, absent—global, national and regional response strategies,” he said.