Could tiny blood clots cause long COVID’s puzzling symptoms?

Scientists debate evidence for a micro-clot hypothesis that has some people pursuing potentially risky treatments

Authors: Cassandra Willyard Nature 608, 662-664 (2022)doi: https://doi.org/10.1038/d41586-022-02286-7

When Lara Hawthorne, an illustrator in Bristol, UK, began developing strange symptoms after having COVID-19, she hoped that they weren’t due to the virus. Her initial illness had been mild. “I’ve been triple vaccinated. I felt quite protected,” she says. But months later, she was still sick with a variety of often debilitating symptoms: earaches, tinnitus, congestion, headaches, vertigo, heart palpitations, muscle pain and more. On some days, Hawthorne felt so weak that she could not get out of bed. When she finally saw her physician, the diagnosis was what she had been dreading: long COVID.

Unable to find relief, she became increasingly desperate. After reading an opinion piece in The Guardian newspaper about how blood clots might be to blame for long COVID symptoms, Hawthorne contacted a physician in Germany who is treating people with blood thinners and a procedure to filter the blood. She hasn’t heard back yet — rumour has it that people stay on the waiting list for months — but if she has the opportunity to head there for these unproven treatments, she probably will. “I don’t want to wait on my health when I’m feeling so dreadful,” she says.

Researchers are baffled by long COVID: hundreds of studies have tried to unpick its mechanism, without much success. Now some scientists, and an increasing number of people with the condition, have been lining up behind the as-yet-unproven hypothesis that tiny, persistent clots might be constricting blood flow to vital organs, resulting in the bizarre constellation of symptoms that people experience.

Heart disease after COVID: what the data say

Proponents of the idea (#teamclots, as they sometimes refer to themselves on Twitter) include Etheresia Pretorius, a physiologist at Stellenbosch University in South Africa, and Douglas Kell, a systems biologist at the University of Liverpool, UK, who led the first team to visualize micro-clots in the blood of people with long COVID. They say that the evidence implicating micro-clots is undeniable, and they want trials of the kinds of anticoagulant treatment that Hawthorne is considering. Pretorius penned the Guardian article that caught Hawthorne’s attention.

But many haematologists and COVID-19 researchers worry that enthusiasm for the clot hypothesis has outpaced the data. They want to see larger studies and stronger causal evidence. And they are concerned about people seeking out unproven, potentially risky treatments.

When it comes to long COVID, “we’ve now got little scattered of bits of evidence”, says Danny Altmann, an immunologist at Imperial College London. “We’re all scuttling to try and put it together in some kind of consensus. We’re so far away from that. It’s very unsatisfying.”

Cascade of clots

Pretorius and Kell met about a decade ago. Pretorius had been studying the role of iron in clotting and neglected to cite some of Kell’s research. When he reached out, they began chatting. “We had a Skype meeting and then we decided to work together,” Pretorius says. They observed odd, dense clots that resist breaking down for years in people with a variety of diseases. The research led them to develop the theory that some molecules — including iron, proteins or bits of bacterial cell wall — might trigger these abnormal clots.

Blood clotting is a complex process, but one of the key players is a cigar-shaped, soluble protein called fibrinogen, which flows freely in the bloodstream. When an injury occurs, cells release the enzyme thrombin, which cuts fibrinogen into an insoluble protein called fibrin. Strands of fibrin loop and criss-cross, creating a web that helps to form a clot and stop the bleeding.

Under a microscope, this web typically resembles “a nice plate of spaghetti”, Kell says. But the clots that the team has identified in many inflammatory conditions look different. They’re “horrible, gunky, dark”, Kell says, “such as you might get if you half-boiled the spaghetti and let it all stick together.” Research by Kell, Pretorius and their colleagues suggests that the fibrin has misfolded1, creating a gluey, ‘amyloid’ version of itself. It doesn’t take much misfolding to seed disaster, says Kell. “If the first one changes its conformation, all the others have to follow suit”, much like prions, the infectious misfolded proteins that cause conditions such as Creutzfeldt–Jakob disease.

Long-COVID treatments: why the world is still waiting

Pretorius first saw these strange, densely matted clots in the blood of people with a clotting disorder2, but she and Kell have since observed the phenomenon in a range of conditions1 — diabetes, Alzheimer’s disease and Parkinson’s disease, to name a few. But the idea never gained much traction, until now.

When the pandemic hit in 2020, Kell and Pretorius applied their methods almost immediately to people who had been infected with SARS-CoV-2. “We thought to look at clotting in COVID, because that is what we do,” Pretorius says. Their assay uses a special dye that fluoresces when it binds to amyloid proteins, including misfolded fibrin. Researchers can then visualize the glow under a microscope. The team compared plasma samples from 13 healthy volunteers, 15 people with COVID-19, 10 people with diabetes and 11 people with long COVID3. For both long COVID and acute COVID-19, Pretorius says, the clotting “was much more than we have previously found in diabetes or any other inflammatory disease”. In another study4, they looked at the blood of 80 people with long COVID and found micro-clots in all of the samples.

So far, Pretorius, Kell and their colleagues are the only group that has published results on micro-clots in people with long COVID.

But in unpublished work, Caroline Dalton, a neuroscientist at Sheffield Hallam University’s Biomolecular Sciences Research Centre, UK, has replicated the results. She and her colleagues used a slightly different method, involving an automated microscopy imaging scanner, to count the number of clots in blood. The team compared 3 groups of about 25 individuals: people who had never knowingly had COVID-19, those who had had COVID-19 and recovered, and people with long COVID. All three groups had micro-clots, but those who had never had COVID-19 tended to have fewer, smaller clots, and people with long COVID had a greater number of larger clots. The previously infected group fell in the middle. The team’s hypothesis is that SARS-CoV-2 infection creates a burst of micro-clots that go away over time. In individuals with long COVID, however, they seem to persist.

Dalton has also found that fatigue scores seem to correlate with micro-clot counts, at least in a few people. That, says Dalton, “increases confidence that we are measuring something that is mechanistically linked to the condition”.

In many ways, long COVID resembles another disease that has defied explanation: chronic fatigue syndrome, also known as myalgic encephalomyelitis (ME/CFS). Maureen Hanson, who directs the US National Institutes of Health (NIH) ME/CFS Collaborative Research Center at Cornell University in Ithaca, New York, says that Pretorius and Kell’s research has renewed interest in a 1980s-era hypothesis about abnormal clots contributing to symptoms. Pretorius, Kell and colleagues found amyloid clots in the blood of people with ME/CFS, but the amount was much lower than what they’ve found in people with long COVID5. So clotting is probably only a partial explanation for ME/CFS, Pretorius says.

Micro-clot mysteries

Where these micro-clots come from isn’t entirely clear. But Pretorius and Kell think that the spike protein, which SARS-CoV-2 uses to enter cells, might be the trigger in people with long COVID. When they added the spike protein to plasma from healthy volunteers in the laboratory, that alone was enough to prompt formation of these abnormal clots6.

Bits of evidence hint that the protein might be involved. In a preprint7 posted in June, researchers from Harvard University in Boston, Massachusetts, reported finding the spike protein in the blood of people with long COVID. Another paper8 from a Swedish group showed that certain peptides in the spike can form amyloid strands on their own, at least in a test tube. It’s possible that these misfolded strands provide a kind of template, says Sofie Nyström, a protein chemist at Linköping University in Sweden and an author of the paper.

Micrographs of platelet poor plasma of a healthy volunteer showing few microclots,and post-COVID-19 infection showing microclots
Micro-clots (green) in a study participant before SARS-CoV-2 infection (left four panels) and in the same person after they developed long COVID (right four panels).Credit: E. Pretorius et al./Cardiovasc. Diabetol. (CC BY 4.0)

A California-based group found that fibrin can actually bind to the spike. In a 2021 preprint9, it reported that when the two proteins bind, fibrin ramps up inflammation and forms clots that are harder to degrade. But how all these puzzle pieces fit together isn’t yet clear.

If the spike protein is the trigger for abnormal clots, that raises the question of whether COVID-19 vaccines, which contain the spike or instructions for making it, can induce them as well. There’s currently no direct evidence implicating spike from vaccines in forming clots, but Pretorius and Kell have received a grant from the South African Medical Research Council to study the issue. (Rare clotting events associated with the Oxford–AstraZeneca vaccine are thought to happen through a different mechanism (Nature 596, 479–481; 2021).)

Raising safety concerns about the vaccines can be uncomfortable, says Per Hammarström, a protein chemist at Linköping University and Nyström’s co-author. “We don’t want to be over-alarmist, but at the same time, if this is a medical issue, at least in certain people, we have to address that.” Gregory Poland, director of the Mayo Clinic’s vaccine research group in Rochester, Minnesota, agrees that it’s an important discussion. “My guess is that spike and the virus will turn out to have a pretty impressive list of pathophysiologies,” he says. “How much of that may or may not be true for the vaccine, I don’t know.”

Dearth of data

Many researchers find it plausible and intriguing that micro-clots could be contributing to long COVID. And the hypothesis does seem to fit with other data that have emerged on clotting. Researchers already know that people with COVID-19, especially severe disease, are more likely to develop clots. The virus can infect cells lining the body’s 100,000 kilometres of blood vessels, causing inflammation and damage that triggers clotting.

Those clots can have physiological effects. Danny Jonigk, a pathologist at Hanover Medical School in Germany, and his colleagues looked at tissue samples from people who died of COVID-19. They found micro-clots and saw that the capillaries had split, forming new branches to try to keep oxygen-rich blood flowing10. The downside was that the branching introduces turbulence into the flow that can give rise to fresh clots.

How common is long COVID? Why studies give different answers

Several other labs have found signs that, in some people, this tendency towards clotting persists months after the initial infection. James O’Donnell, a haematologist and clotting specialist at Trinity College Dublin, and his colleagues found11 that about 25% of people who are recovering from COVID-19 have signs of increased clotting that are “quite marked and unusual”, he says.

What is less clear is whether this abnormal clotting response is actually to blame for any of the symptoms of long COVID, “or is it just, you know, another unusual phenomenon associated with COVID?” O’Donnell says.

Alex Spyropoulos, a haematologist at the Feinstein Institutes for Medical Research in New York City, says the micro-clot hypothesis presents “a very elegant mechanism”. But he argues that much more work is needed to tie the lab markers to clinical symptoms. “What’s a little bit disturbing is that these authors and others make huge leaps of faith,” Spyropoulos says.

Jeffrey Weitz, a haematologist and clotting specialist at McMaster University in Hamilton, Canada, points out that the method Pretorius’s team is using to identify micro-clots “isn’t a standard technique at all”. He adds: “I’d like to see confirmation from other investigators.” Micro-clots are difficult to detect. Pathologists can spot them in tissue samples, but haematologists tend to look for markers of abnormal clotting rather than the clots themselves.

Other, larger studies of long COVID have failed to find signs of clotting. Michael Sneller, an infectious-disease specialist, and his colleagues at the NIH in Bethesda, Maryland, thoroughly examined 189 people who had been infected with SARS-CoV-2, some with lingering symptoms and some without, and 120 controls12. They did not specifically look for micro-clots. But if micro-clots had been clogging the capillaries, Sneller says, they should have seen some evidence — tissue damage in capillary-rich organs such as the lungs and kidneys, for example. Micro-clots might also damage red blood cells, leading to anaemia. But Sneller and his colleagues found no signs of this in any of the lab tests.

The four most urgent questions about long COVID

Kell and Pretorius argue that just because this study didn’t find any evidence of micro-clots doesn’t mean they aren’t there. One of the key issues with long COVID is that “every single test comes back within the normal ranges”, Pretorius says. “You have desperately ill patients with no diagnostic method.” She hopes that other researchers will read their papers and attempt to replicate their results. “Then we can have a discussion,” she says. The ultimate causal proof, she adds, would be people with long COVID feeling better after receiving anticoagulant therapies.

There is some limited evidence of this. In an early version of a preprint, posted in December 2021, Kell, Pretorius and other researchers, including physician Gert Jacobus Laubscher at Stellenbosch University, reported that 24 people who had long COVID and were treated with a combination of two antiplatelet therapies and an anticoagulant experienced some relief13. Participants reported that their main symptoms resolved and that they became less fatigued. They also had fewer micro-clots. Pretorius and Kell are working to gather more data before they try to formally publish these results. But other physicians are already using these medications to treat people with long COVID. Some are even offering a dialysis-like procedure that filters fibrinogen and other inflammatory molecules from the blood. To O’Donnell, such treatment feels premature. He accepts that some people with long COVID are prone to clots, but leaping from a single small study to treating a vast number of people is “just not going to wash in 2022 in my book”, he says. Sneller agrees. “Anticoagulating somebody is not a benign thing. You basically are interfering with the blood’s ability to clot,” he says, which could make even minor injuries life-threatening.

Kell says he’s tired of waiting for a consensus on how to treat long COVID. “These people are in terrible pain. They are desperately unwell,” he says. Altmann understands that frustration. He gets e-mails almost daily, asking: “Where are the drug trials? Why does it take so long?” But even in the midst of a pandemic, he argues, researchers have to follow the process. “I’m not rubbishing anybody’s data. I’m just saying we’re not there yet,” he says. “Let’s join up the dots and do this properly.”

References

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COVID Can Cause Strange Eye and Ear Symptoms

From conjunctivitis to vertigo, coronavirus infections can affect disparate senses

Authors:  Emily Sohn SCIENTIFIC AMERICAN

Red eyes, ringing ears, sensitivity to light, trouble hearing: although a loss of taste and smell have become well-known sensory symptoms of COVID, accumulating research suggests that vision and hearing are also frequent targets of SARS-COV-2, the virus that causes the disease.

More than 10 percent of people who get COVID develop some type of eye or ear symptom, according to the latest data, and both categories are among the complaints that can end up persisting for a long time. As researchers work to understand how the virus infiltrates our senses, their findings suggest that people may need to broaden the scope of warning signs for when to get tested. Instead of just a fever, cough or changes in taste and smell, the first signs of illness might include irritated eyes, hearing problems or balance issues.

Nearly two years into the pandemic, research on COVID’s effects on the eyes and ears suggests that scientists have much more to learn about how the virus affects our bodies and nervous systems, experts say. “The data are growing to suggest that there are more neural consequences of this infection than we originally thought,” says Lee Gehrke, a molecular biologist at the Massachusetts Institute of Technology.

THE EYES HAVE IT

One of the first people who tried to warn the world about COVID was Li Wenliang, a Chinese ophthalmologist in Wuhan. He likely caught the virus from an asymptomatic glaucoma patient, according to Bhupendra Patel, of the University of Utah’s John A. Moran Eye Center, who co-authored a 2021 review of research on COVID’s ocular symptoms. Li died from his illness early in 2020, but his case was not the only early clue that eyes might play a role in the virus’s spread. From the beginning of the pandemic, reports included red eyes as a common symptom.

That was not surprising to scientists. During the 2003 SARS outbreak, researchers in Singapore detected the virus that causes that disease in patients’ tears. And in Toronto, the risk of infection was higher among health care workers who did not wear eye protection. But because COVID causes severe respiratory problems and other symptoms, and because most eye doctors closed their offices during lockdowns, eyes were overlooked at first, Patel says.

Over the pandemic’s first year and a half, accumulated data have established that about 11 percent of people with COVID develop some kind of eye issue, according to a review of multiple studies. The most common symptom is conjunctivitis, or inflammation of the eye lining. This condition affected nearly 89 percent of people with eye symptoms, researchers in Iran reported in a 2021 meta-analysis that included 8,219 COVID patients across 38 studies.

Other ocular symptoms can include dry eyes, redness, itching, blurry vision, sensitivity to light and the feeling that there is a foreign particle in the eye. People on ventilators often develop a type of eye irritation called chemosis, a swelling or bulging of the eye membranes and eyelids, Patel says. He suspects that as many as one third of people with COVID have some type of eye issue—even if it is just red eyes that do not bother them. And some eye issues are not visible. Patel and his colleagues are working on a study, not yet submitted for publication, that he says will be among the first to report that the virus can cause inflammation in the tissue behind the eyeball.

Eye symptoms can show up early or late in the illness, adds Shahzad Mian, an ophthalmologist at the University of Michigan. He and his colleagues reported ocular signs and symptoms in nearly 10 percent of 400 patients hospitalized in Michigan in March and April 2020.

A person who has COVID can shed the virus through their tears, sometimes long after they have recovered from the illness. One early COVID patient was a 65-year-old woman who travelled from Wuhan to Italy in January 2020 and was soon admitted to a hospital with a cough, sore throat and conjunctivitis in both eyes. Even though her eyes were better by 20 days after she was admitted, researchers detected viral RNA in eye swabs on day 27. In the Lombardy region of Italy, researchers found SARS-CoV-2 on the surface of the eyes in 52 out of 91 patients hospitalized with COVID in the spring of 2020, sometimes even when their nasal swab was negative.

The virus may also able to get into the body through the eyes, studies suggest—either from eye rubbing and the direct transfer of tears or from respiratory droplets that happen to land on the eye. When drops containing SARS-CoV-2 were put into the eyes of rhesus macaques in a 2020 study, the animals got sick. A monkey intervention study cannot reveal whether or how often people get infected through their eyes in real life, but the virus appears to be able to replicate in eye tissue and then make its way into the nasal passages, Mian says. Eye involvement “may be a portal for COVID in addition to being just a symptom,” he says.

As many as 6 percent of people will show symptoms in their eyes before any other signs of COVID, Mian says. Red eyes or irritation could be a sign that someone has the illness, especially if there is a known exposure or other symptoms. “As a parent or as a patient or as a community member, you should be aware that if you have conjunctivitis in this day and age, you want to make sure that it’s not COVID,” he says.

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INSIDE THE EARS

Hearing and balance changes can also be signs of SARS-CoV-2 infection, says Zahra Jafari, an audiologist and cognitive neuroscience at the University of Lethbridge in Alberta. In a 2021 meta-analysis, she and her colleagues found dizziness or vertigo in 12 percent of COVID patients, a ringing in the ear known as tinnitus in 4.5 percent and hearing loss in 3 percent. One hypothesis of how SARS-CoV-2 might affect the ears, she says, is that inflammation caused by the virus may directly impact the auditory system. The virus could also invade a barrier between the bloodstream and inner ear.

Confirming those mechanisms has been difficult because the inner ear is notoriously hard to study, Gehrke says. Encased in bone and located deep inside the head, it is inaccessible, and animal models do not always help. Mice are not natural hosts for RNA viruses, so the commonly used lab rodents do not work particularly well as a stand-in for SARS-CoV-2 infection.

To investigate what might be happening inside the ears of people with COVID, Gehrke teamed up with researchers at several other labs to grow human ear tissues using stem cells. With those tissues, the team was then able to show that two types of inner ear cells have the genes for making proteins—including ACE-2 receptors—that allow SARS-CoV-2 to get into cells.

Hair cells, which are important for both hearing and balance, can also be infected by the virus, the researchers reported in Nature in October. The team was able to confirm that inner ear infection with the virus is possible by studying human tissue that had been removed as part of surgeries that were scheduled as treatments for other disorders. The findings are “highly suggestive that, indeed, SARS-CoV-2 patients might have hearing loss associated with virus infection due to infection of the hair cells,” Gehrke says.

Most of the time, both eye and ear symptoms get better on their own, experts say. But research is starting to suggest that, in both cases, COVID-induced symptoms can become long-lasting. Patel knows of two cases in which COVID-patients have lost sensation in their corneas, which can cause those corneas to break down, even with minor trauma. That breakdown can lead to corneal infection, damage and ultimately blindness. Multiple case reports include ear-related symptoms that stick around even after people recover from the illness, Jafari says.

Although damage to sight and hearing still appear to be less common than loss of smell and taste—which can affect 40 percent or more of people with COVID—studies on eyes and ears lend insight into the many and often still mysterious ways that the virus can go to work inside the human body, experts say.

The research also illustrates how intertwined our sensory organs are. Nasal passages butt against Eustachian tubes and eyeballs. “The nerves that allow you to taste, the nerves that allow you to smell, and the nerves that allow you to feel corneal sensation—these are all part of the central nervous system where the brain connects to these different parts,” Patel says. Vision, smell and taste—“these are all connected.”

SARS-CoV-2 vaccine-associated-tinnitus: A review

Authors: Syed HassanAhmedaSummaiyyaWaseemaTaha GulShaikhaNashwa AbdulQadiraSarush AhmedSiddiquiaIrfanUllahbAbdulWarisbZohaibYousafc

Annals of Medicine and Surgery Volume 75, March 2022, 103293

Abstract

The global vaccination drive against severe acute respiratory syndrome coronavirus-2 is being pursued at a historic pace. Unexpected adverse effects have been reported following vaccination, including thrombotic thrombocytopeniamyocarditis, amongst others. More recently, some cases of tinnitus are reported post-vaccination. According to the Vaccine Adverse Events Reporting System (VAERS), 12,247 cases of coronavirus post-vaccination tinnitus have been reported till September 14, 2021. To the best of our knowledge, this is the first review evaluating any otologic manifestation following vaccine administration and aims to evaluate the potential pathophysiologyclinical approach, and treatment. Although the incidence is infrequent, there is a need to understand the precise mechanisms and treatment for vaccine-associated-tinnitus.

1. Introduction

The SARS-CoV-2 virus has infected approximately 225 million people globally, resulting in 4.6 million deaths [1]. It commonly manifests as fever, dry cough, shortness of breath, fatigue, and myalgias. However, it can also lead to severe complications like pneumonia, leukopenia, kidney failure, myocardial involvement, and central nervous system (CNS) disorders [2].

Vaccinations are arguably the most effective preventive tool against SARS-CoV-2. In August 2020, Russia became the first country to register Sputnik V, a coronavirus vaccine based on human adenovirus vectors rAd26 and rAd5 developed by the Gamaleya national center of epidemiology and microbiology. However, this vaccine was approved without phase III trials, raising concerns over its safety [3].

The currently available vaccines underwent clinical trials and were approved after demonstrating an acceptable safety profile and efficacy [4]. To date, 5.5 billion vaccine doses have been administered [1]. The adverse effects of vaccines are mostly mild and transient, commonly including pain at the injection site, pyrexia, headache, myalgias, fatigue, chills [5] and dermatologic manifestations like Pityriasis Rosea [6]. However, severe complications like anaphylaxis [7], vaccine-induced immune thrombotic thrombocytopenia [8], myocarditis [9] have also been reported. The adverse effects of vaccine are markedly outweighed by their beneficial effects, in decreasing hospital admissions and deaths due to the SARS-CoV-2 [10,11].

Investigations of the otologic manifestations of the SARS-CoV-2 suggest the incidence of tinnitus, hearing loss, sensorineural hearing loss (SNHL), otalgia, amongst others. However, only association with tinnitus and hearing loss were statistically significant [12]. More recently, cases of tinnitus presented following both vector-based and mRNA SARS-CoV-2 vaccines [13,14]. According to the Vaccine Adverse Event Reporting System (VAERS), 12,247 cases of tinnitus post-coronavirus vaccination have been reported [15].

Tinnitus is an otologic symptom characterized by a conscious perception of sound without an external auditory stimulus. The prevalence varies from one population subset to another [16]. The study by Jong Kim et al., which employed data from the Korean National Health and Nutrition Examination survey, reported tinnitus prevalence to be 20.7% among adults, i.e., 20- to 98-year-old [17]. The National Health and Nutritional Examination survey data indicated a prevalence of 16.5% among the overall population and 6.6% among Asian Americans [18]. Along with varying prevalence, it has also been associated with a wide range of risk factors including male gender, hearing impairment, ear infections, stress, unemployment, military services, dyslipidemiaosteoarthritisrheumatoid arthritis, asthma, depression, thyroid disease, noise exposure, history of head injury and numerous others [17,19].

Herein, we review the association between SARS-CoV-2 vaccines and tinnitus. This review aims to evaluate the potential pathophysiologyclinical approach to diagnosis and management of post-vaccination tinnitus.

2. Literature search, data extraction, and results

Two independent authors (SHA, TGS) conducted a thorough literature search over PubMed, Cochrane Library, and Google Scholar from inception till September 12, 2021, without any language restriction. To achieve comprehensive results, search string comprised of keywords, “SARS-CoV-2 Vaccine”, “Coronavirus Vaccine,” “Corona Vaccine,” “COVID-19 Vaccine”, “Tinnitus,” “Ear Ringing,” “Otologic Manifestations,” and separated by BOOLEAN operators “OR” and “AND.” All relevant case reports, case series, cohort studies, editorials, and correspondences were reviewed. Grey literature and bibliographies of the relevant articles were also screened. Results of the literature search are summarized in Fig. 1. The work has been reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 criteria [20].

Fig. 1

Ultimately, two studies [13,14] (case report and case series) were retrieved for inclusion in the review. The studies comprised data from four patients (three males and one female) with a mean age of 41.8 ± 12.6 years. The following figure (Fig. 2) demonstrates the geographical locations where these cases were reported. Out of the four reported cases, three presented in Italy, while one was reported from Taiwan. Along with these findings, future research may enable us to predict the gender, age groups, and geographical locations that may leave certain individuals more susceptible to COVID-19 vaccine-associated tinnitus than others.

Fig. 2

Following studies selection, two independent authors (SW, NAQ) retrieved all the relevant data comprising of author’s name, patient’s age, and sex, past medical history, vaccine administered, time from dose administration till the onset of symptoms, presenting complaint, laboratory findings, treatment interventions, and outcome into a table. All significant findings are summarized in Table 1. Any discrepancies were resolved by discussion with a third reviewer (SS).

Table 1. A tabulation of the outcomes of literature review.

AuthorAge
Sex
Past Medical HistoryVaccine AdministeredTime from Vaccination to Onset of symptomsPresenting ComplaintInvestigationsTreatmentOutcome
Tao-Tseng et al. [14]37 y/o MaleGlaucoma is treated with latanoprost and brimonidine eye dropsChAdOx1 nCoV-19 AstraZeneca (1st dose)5 hIntermittent, high pitch, right ear tinnitus, high fever with chills and myalgias. It progressed to continuous high pitch and intermittent low pitch tinnitus.THI = 28 (5 h post vaccination)
THI = 46 (after visiting emergency)
Audiometry test on 1st May revealed normal PTA and short SiSi
THI (post-treatment) = 0
Single-dose of 10 mg IV dexamethasone and 3 × 5 mg oral prednisone daily for 3 days.Recovered on day 4
Parrino et al. [13]37 y/o FemaleGlaucoma, undifferentiated connective tissue disease, and transient tinnitus due to acute otitis media 20 years previouslyBNT162b2 mRNA-vaccine Pfizer (1st dose)7 hRight ear tinnitus, short-term dizziness, pain at the injection site.Otoscopy investigation was normal.
PTA revealed normal bilateral hearing with slight asymmetry on the right ear
THI = 90/100
Psychoacoustic Measures of Tinnitus = 20 dB pure tone at 10,000 Hz
THI (post-treatment) = 78/100
30 mg Deflazacort daily given orally for first 5 days followed by 15mg/daily dose for next 5 days.Recovering
Parrino et al. [13]63 y/o MaleBilateral symmetrical mild high frequencies SNHL, chronic gastritis, extrinsic asthma, and reactive depression for which he had undergone psychotherapyBNT162b2 mRNA-vaccine Pfizer (1st dose)20 hLeft tinnitus associated with hyperacusis and dysacusis and local pain at the injection siteOtoscopy examination was normal.
PTA revealed slight threshold worsening on the left ear
Psychoacoustic Measures of Tinnitus = white noise of 25 dB intensity
THI = 76/100
THI (after 7 days) = 36/100
Corticosteroid therapy was proposed, but the patient refused.Recovering
Parrino et al. [13]30 y/o MaleHashimoto thyroiditisBNT162b2 mRNA-vaccine Pfizer (2nd dose)6 daysLeft tinnitus, hyperacusis, dysacusis. Reported fever, nausea, and local pain after dose administration that was treated with 1 × 1000 mg acetaminophenOtoscopy was normal
PTA showed normal bilateral hearing.
THI = 78/100
THI (post-treatment) = 6/100
10 days course of oral prednisone at 50 mg/day for first 4 days followed by 25 mg/day for the next 3 days and 12.5 mg/day for the last 3 days.Recovered

THI: Tinnitus Handicap Inventory, PTA: Pure Tone Average, SiSi: Short increment Sensitivity index, SNLH: sensorineural hearing loss.

3. COVID-19 vaccines and their characteristics

Most of the current COVID-19 vaccines use the genetic code of spike protein to stimulate a protective immune reaction against coronavirus. The viral vector vaccines (AstraZeneca, sputnik, Janssen) incorporate spike protein gene into adenovirus DNA, which induces spike protein formation and hence antibodies, conferring protection against the virus. Conversely, mRNA vaccines (Pfizer, Moderna) deliver messenger RNA for spike protein into the host cells, stimulating a protective response [21]. Another category of COVID-19 vaccines (Sinopharm, Sinovac) employs a weakened or attenuated virus, capable of replication but not potent enough to cause the disease itself [22].

Moreover, research done after SARS-CoV-1 indicated the protective and long-lasting effect of T-cell immunity. The transfer of T-cells led to a swift viral clearance and disease elimination [23,24] Unlike antibody response, T cell memory can last longer as seen in SARS-CoV-1 when the immunity was even detected 4 years after the infection. Especially, Regulatory T cells play a vital role in resolving the infection, confirmed from the fact that they were found to be risen in COVID-19 patients [25]. Along with them, circulating follicular T helper cells have been seen in individuals with COVID-19. They play a major role in representing antibody response to infection. Hence, despite no vaccine currently offering the T-cell response to COVID-19, there is a room to further investigations.

Listed in Table 2 are some of the most common vaccines currently used to counter the pandemic and their characteristics including mechanism of action, dosage, time between dosages, efficacy, general and serious adverse effects. What is of immense concern is the fact that despite a vast previous knowledge on T-cell immunity, none of the marketed vaccine is using it as a mechanism of their action. Hence, leaving room for further investigations.

Table 2. Table 2: Characteristics of COVID-19 vaccines.

VaccineManufacturer & CountryMechanism of ActionDoses – Time Between DosesEfficacyAdverse EffectsSerious Adverse Effects
BNT162b2BioNTech, Fosun Pharma, Pfizer – America and GermanyRNA vaccine [26,27]Two doses – 3 weeks [26]100% against severe disease as per CDC, 93% against severe disease as per FDA [26]Redness, Swelling, Headache, Muscle pain, Chills, Fever, Nausea, Tiredness [28]Lymphadenopathy, paroxysmal ventricular arrhythmia, syncope, and right leg paresthesia [29], heart inflammation in young adults [26]
mRNA-1273Moderna- U.S. and SwitzerlandRNA vaccine [26]Two doses – 4 weeks [26]>90% [26]Pain, swelling, redness, fever, fatigue, headache, vomiting, arthralgia, myalgia, urticaria [28]Bell’s Palsy, facial swelling [27]
ChAdOx1 nCoV-19/AZD1222AstraZeneca (University of Oxford) – U.K.Viral vector vaccine [27]Two doses −4 to 12 weeks [26]76% (phase III trials) [26]Redness, myalgias, arthralgias, and headache [27]Pulmonary embolism, Thromboembolism [27]
Ad26.COV2.SJohnson & Johnson -U.S.Viral vector vaccine [26]A single dose [26]72% [26]Pain, redness, and swelling at the injection site [27]Rare and Severe blood clots [27]
Ad5-nCoVCansino – ChinaViral vector vaccine [30]A single dose [30]65.7% [30]Fever, redness, and pain [30]Not reported [30]
CoronavacSinovac – ChinaInactivated Virus [31]Two doses – 2 to 4 weeks [32]51% [32]Pain on injection [31]Acute hypersensitivity with the manifestation of urticaria [31]
BBIBP-CorVSinopharm – ChinaInactivated Virus [33]Two doses – 2 to 3 weeks apart, followed by a booster dose in Age group >18 years [33].79% [33]Pain at the vaccination site, fatigue, lethargy, headache, and tenderness [34]
Gam-COVID-Vac/Sputnik VGamaleya Research Institute of Epidemiology and Microbiology – RussiaViral Vector Vaccine [35]2 doses, 3 weeks apart [35]91.6% [35]Mild pain at the injection site, fever, headache, fatigue, and muscle aches [36]

WHO: World Health Organization; CDC: Center for Disease Control and Prevention; FDA: U.S. Food and Drug Administration.

Moreover, all the listed vaccines include the ones currently, accepted in many countries throughout the world. With frequent introduction of numerous vaccines in the market to combat the pandemic, there is a definite need to evaluate their characteristics in comparison and the better ones shall be publicly made available.

4. Pathophysiology

Tinnitus is defined as intermittent or continuous, unilateral or bilateral, pulsatile or non-pulsatile, acute or chronic, and subjective or objective [37,38]. There are several classifications categorizing tinnitus into numerous types, with each type associated with multiple potential etiologies. It can result from a lesion in the auditory pathway. Potential etiologies may include otitis externacerumen impactionotosclerosis, otitis media, cholesteatomavestibular schwannomaMeniere’s diseasecolitisneuritis, and ototoxic drugs [37,38]. The character of tinnitus can vary based on etiology. Furthermore, certain non-otologic conditions like vascular anomalies, myoclonus, and nasopharyngeal carcinoma can also contribute. Despite several cases of tinnitus being reported post-SARS-CoV-2 vaccination, the precise pathophysiology is still not clear.

4.1. Molecular mimicry

Based on the mechanisms behind other COVID-19 vaccine-induced disorders (38, 39) and the phenomenon of molecular mimicry [41], a cross-reactivity between anti-spike SARS-CoV-2 antibodies and otologic antigens is a possibility. The heptapeptide resemblance between coronavirus spike glycoprotein and numerous human proteins further supports molecular mimicry as a potential mechanism behind such vaccine-induced disorders [41]. Several autoimmune conditions, including vaccine-induced thrombotic thrombocytopenia (VITT) [8] and Guillain-Barré syndrome (GBS) [40], have been reported following coronavirus vaccination. Anti-spike antibodies may potentially react with antigens anywhere along the auditory pathway and initiate an inflammatory reaction involving the tympanic membrane, ossicular chain, cochlea, cochlear vessels, organ of Corti, etc. Therefore, understanding the phenomenon of cross-reactivity and molecular mimicry may be helpful in postulating potential treatment behind not only tinnitus but also the rare events of vaccination associated hearing loss and other otologic manifestations [42]. Moreover, serologic investigations may play a role in understanding the underlying mechanism. Specific findings, such as raised anti-platelet factor 4, have been reported in cases of VITT post-COVID-19 vaccination [39].

4.2. Autoimmune reactions

Antibodies can form complexes with one or more antigens leading to a type III hypersensitivity reaction. Deposition of circulating immune complexes and vestibule-cochlear antibodies can play a role in autoimmune inner ear disease [43,44]. Incidence of pre-existing autoimmune conditions like Hashimoto thyroiditis and gastritis in patients, as shown in Table 1, further leaves patients prone to immune dysfunction and thus abnormal immune responses [13]. However, future research should investigate the incidence of post-vaccination tinnitus in individuals with autoimmune diseases with a suitable control as all the currently reported patients were known cases of such conditions. Moreover, several potential genes, including Glial cell Derived Neurotrophic Factor (GDNF), Brain Derived Neurotrophic Factor (BDNF), potassium recycling pathway genes, 5-Hydroxytryptamine Receptor 7 (HTR7), Potassium Voltage Gated Channel Subfamily E Regulatory Subunit 3 (KCNE3), and a few others, have been studied to understand the underlying mechanism. However, the evidence is still insufficient to draw any conclusion [45]. Therefore, genetic predisposition and immunologic pathways may play a role in post-vaccination-tinnitus.

4.3. Past medical history

Literature suggests a relationship between glaucoma and tinnitus, with glaucoma patients having 19% increased odds for tinnitus than in patients without it [46]. The mechanism linking these disorders is ambiguous, but vascular dysregulation may play a significant role in causing both disorders. Nitric oxide (NO) production inhibition is a potential mechanism [46]. NO is a regulator of intraocular pressure (IOP), thus linking defects in the nitric oxide guanylate cyclase (NO-GC) pathway with glaucoma [47]. Furthermore, diminished jugular vein NO levels have been reported in tinnitus patients, leading to the reduced blood supply to the ears [46]. As shown in Table 1, two of the reported cases had pre-existing glaucoma. Therefore, any potential association between vaccines and NO dysregulation should be investigated. Certain COVID-19 vaccines have been associated with vaccine-induced thrombotic thrombocytopenia [8]. Developing thrombus can reduce the blood supply to the ear and increase the probability of developing tinnitus. The existing literature lacks articles investigating associations between vaccines and NO levels. Therefore, the association of vaccines with NO deficiency in genetically susceptible patients should be investigated. Lastly, the association between vaccines and other vascular dysregulations must also be evaluated, as such abnormalities can disrupt laminar blood flow and cause pulsatile tinnitus [48].

4.4. Ototoxicity

Numerous drugs and chemical substances have been reported as ototoxic, causing damage to the auditory pathway and cochlear hair cells. Exposure to such agents, including aminoglycosidesvancomycin, platinum-based anticancer drugsloop diureticsquinine, toluene, styrene, lead, trichloroethylene, and others, may lead to tinnitus, hearing loss, and other otologic manifestations [37,49]. The mechanisms behind ototoxicity are not fully understood but may involve chemical and electrophysiological alterations in the inner ear structures and the eighth cranial nerve. Certain agents, including loop diuretics, incite such symptoms by inhibiting endolymph production from stria vascularis, whereas drugs like aminoglycosides and cisplatin are directly toxic to the hair cells the organ of Corti. Meanwhile, Non-Steroidal Anti-Inflammatory Drugs (NSAID) induce ototoxicity by reducing cochlear blood flow and alterations in the sensory cell functions [50]. Hence, the possibility of one or more vaccine components exerting ototoxic effects cannot be written off and requires attention.

Furthermore, the current literature also proposes certain risk factors associated with drug-induced ototoxicity. For example, age, hypoalbuminemia, and uremia significantly increase the risk of developing NSAIDs induced ototoxicity. Similarly, erythromycin-related ototoxicity is more commonly associated with hepatic and renal failure, increasing age and female gender [50]. Therefore, genetic predispositions and associated conditions may also play a significant role in determining the development of vaccine-induced tinnitus. As shown in Table 1, most of the cases reported till now were transient, which may be accountable to past administration of offending agents as seen in cases of erythromycin, aminoglycosides, vancomycin, and NSAIDs associated ototoxicity, which resolved upon early discontinuation of the inciting agent [50].

4.5. Psychological conditions

Anxiety-related adverse events (AEFI) following vaccination, defined by WHO, “a range of symptoms and signs that may arise around immunization that are related to anxiety and not to the vaccine product, a defect in the quality of the vaccine or an error of the immunization program” [51], have been witnessed in around 25% COVID-19 vaccination cases in India, as reported by Government of India, Ministry of health and family welfare, immunization division [52]. These responses may include vasovagal mediated reactions, hyperventilation mediated reactions, and stress-related psychiatric reactions or disorders [53]. Loharikar et al. [54], in their systematic review, reported common symptoms of it to be dizziness, headache, and fainting with rapid onset after vaccination. There are several speculations on the causative agents behind AEFIs after immunization. Since most of the vaccines are delivered through needles, it may be possible that trypanophobia, affecting at least 10% of the population around the globe [55], may trigger stress, hence leading to a stress-mediated response. Moreover, hearing or witnessing someone else’s sickness can lead to reporting similar symptoms, known as psychogenic illness, as reported by Blaine Ditto et al. [56]. Hence, a possible connection can exist between people’s presumption and social media misinformation, leading to anxiety and possible adverse reaction.

Vaccine hesitancy, defined as a “delay in acceptance or refusal of vaccination despite the availability of vaccination services” [57], is a complex behavior, and the most common cause of it usually includes perceived risks vs. benefits, religious beliefs, and lack of knowledge [58]. People with vaccine hesitancy may have pre-assumed beliefs. Hence, after getting vaccinated, there is a chance of facing AEFIs, with symptoms constellating stress. Numerous studies have demonstrated anxiety and stress as risk factors for tinnitus [17,19]. In one of the reported cases [13], the patient had a history of reactive depression. Therefore, the incidence of anxiety and stress disorders also need to be explored, with a particular emphasis on vaccine-related anxiety, as a potential cause of tinnitus developing post-vaccination.

4.6. Overview

While several suggested hypotheses exist, the precise mechanism behind vaccine-induced tinnitus remains undetermined, leaving room for future studies. Furthermore, as shown in Table 1, two reported cases had a medical history of otologic conditions involving recovered tinnitus and SNHL. Therefore, the possibility of vaccines aggravating underlying otologic disorders and exacerbating any morphologic damage also needs to be explored. Lastly, the character of tinnitus, including subjective or objective, intermittent or continuous, and pulsatile or non-pulsatile, can also give beneficial insight into understanding the involved sights and underlying mechanisms.

5. Clinical approach and management

To start the treatment regimen, it is crucial to determine a well-established diagnosis for Tinnitus. For this purpose, a well-focused and detailed history and examination are necessary [38]. In case of vaccine-induced tinnitus, vaccine administered, days since dose administered to the onset of symptoms, and any other adverse effects experienced must be further added. Additionally, a particular emphasis must be placed on pre-existing health conditions, specifically autoimmune diseases like Hashimoto thyroiditis, otologic conditions like SNHL, glaucoma, and psychological well-being. All the reported patients presented with a history of one or more of the aforementioned disorders, as shown in Table 1. However, any such association has not yet been established and requires further investigation to be concluded as potential risk factors for vaccine-induced tinnitus. Routine cranial nerve examinationotoscopyWeber’s test, and Rinne test, that are used for tinnitus diagnosis in general [38], may also be used for confirmation of the disorder post-vaccination. Due to the significant association between tinnitus and hearing impairment [59], audiology should be performed as well.

Tinnitus handicap inventory (THI), a reliable and valid questionnaire to evaluate tinnitus-related disability [60], is recommended by the tinnitus research initiative (TRI) [61]. To date, it has been translated into numerous languages and is being used across the globe. In THI, the scores of 0, 2, and 4 are assigned to no, sometimes, and yes, respectively, to answer a subset of questions. The scores can vary from 0 to 100, with higher scores indicating a more significant disability. Based on scores, the patients can be classified into five categories: Scores ranging between (1) 0 to 16 indicate no handicap, (2) 18 to 36 indicate mild handicap, (3) 38 to 56 indicate moderate, (4) 58 to 76 indicate severe handicap and (5) 78 to 100 indicate catastrophic handicap [62]. This scale can be employed to evaluate both the severity of the condition and therapeutic response, as reported in the included studies [13,14].

While the treatment options for non-vaccine-induced tinnitus show a significant degree of variance, corticosteroids were the lead treatment choice for SARS-CoV-2 vaccine-induced tinnitus, as reported in both the included studies [13,14]. Based on the results, Tseng et al. [14] recommend immediate use of steroids for sudden onset tinnitus post-coronavirus vaccination. The reason may lie in their underlying immunosuppressive mechanism. After entering the cell, Corticosteroid forms a steroid-receptor complex in the cytoplasm, which then modifies transcription by incorporating itself into DNA. Hence playing their role in synthesizing or inhibiting certain proteins. A well-known protein synthesized by them is lipocortin, which inhibits Phospholipase A2, ultimately inhibiting arachidonic acid (AA) which leads to hampered Leukotrienes and Prostaglandins production. It also impedes mRNA that plays role in interleukin-1 formation [63] as well as sequestrate CD4+ T-lymphocytes in the reticuloendothelial system, all building up and leading to immunosuppression [64].

Although two out of four patients showed improvement following drug administration, the efficacy of steroid therapy is yet to be investigated in larger populations.

There is also a dire need to perform trials for other pharmacological interventions that can be administered in post-vaccine tinnitus. Numerous non-pharmacological (counseling, tinnitus retraining therapy, sound therapy, auditory perceptual training) as well pharmacological interventions (sodium channel blockers, anti-depressants, anti-convulsant, benzodiazepines, and several others) for treatment of tinnitus have been evaluated [16,65], however, there is insufficient data for tinnitus following vaccination, despite that vaccine-induced tinnitus have also been reported after hepatitis B, rabies, measles and (influenza A virus subtype) H1N1 vaccines, associated to Sensorineural hearing loss (SNHL) [66].

Thereby, deeming high-quality trials evaluating the efficacy of conventional treatment necessary. Lastly, the transient nature also requires special attention, as one of the patients recovered without any medication [13].

6. Adverse effects monitoring

Although the COVID-19 vaccines were approved after rigorous testing and trials, the center for disease control and prevention (CDC) has taken numerous initiatives to ensure a highly intensive safety monitoring program to determine potential adverse effects that may not be reported during clinal trials. Several vaccine safety monitoring systems are being employed, including the VAERS, v-safe, clinical immunization safety assessment (CISA) program, vaccine safety datalink (VSD), and a few others. This wide range of systems allows patients, attendants, and healthcare workers to report any side effects they have been experiencing following SARS-CoV-2 vaccination. CDC and vaccine safety experts evaluate all the reports regularly and assess vaccines safety on their basis [67]. Investigations into reported side effects are conducted to ensure vaccines safety, as was observed following cases of thrombotic thrombocytopenia, which led to a temporary ban on two vaccines and were only lifted once the vaccines demonstrated an acceptable safety profile. With already established benefits and such critical safety monitoring, the COVID-19 global vaccination program must be supported and appreciated for prioritizing public safety. However, such reporting systems may be more useful if there was a way to determine if the reported adverse events were vaccine-induced, exacerbated following vaccination, or due to some underlying pathology.

7. Conclusion

This review scrutinizes the currently available literature and highlights potential pathophysiology and clinical approaches to diagnose and manage vaccine-induced tinnitus. Although the incidence of COVID-19 vaccine-associated tinnitus is rare, there is an overwhelming need to discern the precise pathophysiology and clinical management as a better understanding of adverse events may help in encountering vaccine hesitancy and hence fostering the COVID-19 global vaccination program. Despite the incidence of adverse events, the benefits of the SARS-CoV-2 vaccine in reducing hospitalization and deaths continue to outweigh the rare ramifications.

8. Limitations

This study carries some limitations. Firstly, given the limited number of cases reported, there is an imperative need to overcome the paucity of data and evaluate the impact of different COVID-19 vaccines, type of tinnitus, response to conventional treatment options, and reversible nature of the condition. Secondly, all the patients evaluated reported substantial past medical history and carried a high risk of immune dysregulation; therefore, the role of genetic predisposition and underlying conditions requires special surveillance, which can help redefine vaccine administration criteria to avoid any further cases.

Department of Internal Medicine, Hamad Medical Corporation, Doha, Qatarzohaib.yousaf@gmail.com

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Here’s what we know so far about the long-term symptoms ofCOVID-19

July 26, 2020 3.56pm EDT

We’re now all too familiar with the common symptoms of COVID-19: a fever, dry cough and fatigue. Some people also experience aches and pains, a sore throat, and loss of taste or smell.

Sufferers with mild illness might expect to get better after a few weeks. But there’s mounting evidence this isn’t the case, and COVID-19 may leave a long-lasting impression on its victims – not just the most severely affected or the elderly and frail.

It’s not just an infection of the lungs

On the surface, COVID-19 is a lung disease. The SARS-CoV-2 coronavirus infects cells of the respiratory tract and can cause life-threatening pneumonia.

However, the full range of symptoms affects multiple parts of the body. An app that records daily symptoms developed at King’s College London has tracked the progress of more than 4 million COVID-19 patients in the United Kingdom, Sweden and the United States.

Besides the well-described symptoms of fever, cough and loss of smell are other effects, including fatigue, rash, headache, abdominal pain and diarrhoea. People who develop more severe forms of the disease also report confusion, severe muscle pains, cough and shortness of breath.

About 20% of those infected with COVID-19 require hospitalisation to treat their pneumonia, and many need assistance with oxygen. In about 5% of cases the pneumonia becomes so severe patients are admitted to intensive care for breathing support.

It trips the immune system

People with severe COVID-19 seem to show an altered immune response even in the disease’s early stages. They have fewer circulating immune cells, which fail to efficiently control the virus, and instead suffer an exaggerated inflammatory response (the “cytokine storm”).

This is increasingly recognised as one of the main factors that makes the disease so serious in some patients. Suppressing this exaggerated response with the immunosuppressant dexamethasone remains the only treatment that reduces death rates in those who require oxygen support or intensive care.


Read more: Dexamethasone: the cheap, old and boring drug that’s a potential coronavirus treatment


Patients with severe COVID-19 describe a far more complex range of symptoms than would normally be seen with pneumonia alone. This can include brain inflammation (encephalitis), causing confusion and reduced consciousness. Up to 6% of severe sufferers may have a stroke.

Pathology studies and autopsies of patients who died from COVID-19 reveal the expected features of severe pneumonia or acute respiratory distress syndrome (ARDS), with extensive inflammation and scarring. ARDS occurs when there’s sudden and widespread inflammation in the lungs, resulting in shortness of breath and blueish skin.

Uniquely, however, they also reveal the virus seems to directly cause inflammation of the small capillaries or blood vessels, not just in the lungs but in multiple organs, leading to blood clots and damage to the kidney and heart.

Persistent symptoms ‘deeply frustrating’

Anyone with a severe disease would be expected to suffer long-lasting consequences. But COVID-19 seems to have persistent symptoms even in those with milder forms of the illness.

Social media is replete with stories of survivors afflicted by ongoing symptoms. Support groups have emerged on Slack and Facebook hosting thousands of people, some still suffering more than 60 days after infection. They call themselves “long-termers” or “long-haulers”.

One of the most well-known sufferers is Paul Garner, an infectious disease specialist at the Liverpool School of Tropical Medicine in the UK. He was infected in late March and his symptoms continue. In a blog post published by the British Medical Journal he describes having a:

…muggy head, upset stomach, tinnitus (ringing in the ears), pins and needles, breathlessness, dizziness and arthritis in the hands.

These symptoms have waxed and waned but not yet resolved. He says this is:

…deeply frustrating. A lot of people start doubting themselves… Their partners wonder if there is something psychologically wrong with them.

So far, only one peer-reviewed study has reported results on the long-term symptoms of COVID-19 infection: a single group of 143 survivors from Rome. Most of them did not need hospitalization and all were assessed at least 60 days after infection. They reported a worsened quality of life in 44.1% of cases, including symptoms of persistent fatigue (53.1%), breathlessness (43.4%), joint pain (27.3%), and chest pain (21.7%).

Covid-19 Vaccine Analysis: The most common adverse events reported so far

Authors: DATED: AUGUST 6, 2021 BY SHARYL ATTKISSON 

As of July 19, 2021 there were 419,513 adverse event reports associated with Covid-19 vaccination in the U.S., with a total of 1,814,326 symptoms reported. That’s according to the federal Vaccine Adverse Event Reporting System (VAERS) database.

Report an adverse event after vaccination online here.

Each symptom reported does not necessarily equal one patient. Adverse event reports often include multiple symptoms for a single patient.

Reporting of illnesses and symptoms that occur after Covid-19 vaccination does not necessarily mean they were caused by the vaccine. The system is designed to collect adverse events that occur after vaccination to uncover any patterns of illnesses that were not captured during vaccine studies.

Read CDC info on Covid-19 vaccine here.

Scientists have estimated that adverse events occur at a rate many fold higher than what is reported in VAERS, since it is assumed that most adverse events are not reported through the tracking system. Reports can be made by doctors, patients or family members and/or acquaintances, or vaccine industry representatives. 

Read: Exclusive summary: Covid-19 vaccine concerns.

Some observers claim Covid-19 vaccine adverse events are not as likely to be underreported as those associated with other medicine, due to close monitoring and widespread publicity surrounding Covid-19 vaccination.

Approximately 340 million doses of Covid-19 vaccine have been given in the U.S. Slightly less than half of the U.S. population is fully vaccinated.

According to the Centers for Disease Control (CDC) and Food and Drug Administration (FDA), the benefits of Covid-19 vaccine outweigh the risks for all groups and age categories authorized to receive it.

Watch: CDC disinformation re: studies on Covid-19 vaccine effectiveness in people who have had Covid-19.

The following is a summary of some of the most frequent adverse events reported to VAERS after Covid-19 vaccination. (It is not the entire list.)

Most common Covid-19 vaccine adverse events reported as of July 19, 2021

Yellow highlighted adverse events are subjects of investigations, warnings or stated concerns by public health officials. For details, click here.

128,370 Muscle, bone, joint pain and swelling including:

  • 39,902 Pain in extremity
  • 37,819 Myalgia, muscle pain, weakness, fatigue, spasms, disorders, related
  • 30,138 Arthralgia, joint pain or arthritis, swelling, joint disease, bone pain, spinal osteoarthritis
  • 14,682 Back pain, neck pain
  • 5,829 Muscle and skeletal pain, stiffness, weakness

119,866 Injection site pain, bleeding, hardening, bruising, etc.

105,332 Skin reddening, at injection site or elsewhere, rash, hives

100,564 Fatigue, lethargy, malaise, asthenia, abnormal weakness, loss of energy

89,302 Headache, incl. migraine, sinus

68,252 Vomiting, nausea

68,064 Fever

63,133 Chills

60,913 Pain

49,574 Dizziness

34,076 Flushing, hot flush, feeling hot, abnormally warm skin

31,785 Lung pain or abnormalities, fluid in lung, respiratory tract or lung congestion or infection, wheezing, acute respiratory failure including:

  • 23,005 Dyspnoea, difficulty breathing
  • 1,398 Pneumonia
  • 1,128 Respiratory arrest, failure, stopped or inefficient breathing, abnormal breathing
  • 563 Covid-19 pneumonia
  • 265 Mechanical ventilation
  • 217 Bronchitis

30,909 Skin swelling, pain, tightness, face swelling, swelling under skin, hives, angioedema including:

  • 7,579 Skin pain, sensitivity, burning, discoloration, tenderness

25,319 Heart failure, heart rhythm and rate abnormalities, atrial fibrillation, palpitations, flutter, murmur, pacemaker added, fluid in heart, abnormal echocardiogram including:

  • 3,105 Heart attack or cardiac arrest, sudden loss of blood flow from failure to pump to heart effectively, cardiac failure, disorder

22,085 Itchiness

29,861 Sensory disturbance including:

  • 8,236 Tinnitus, hearing noise
  • 7,951 Abnormal vision, blindness
  • 6,349 Ageusia, loss of taste, altered taste, disorders
  • 2,249 Anosmia, loss of smell, parosmia (rotten smell)
  • 2,075 Hypersensitivity
  • 1,560 Sensitivity or reaction to light 
  • 890 Hearing loss, deafness