More of the vaccinated and boosted landing in hospital with COVID-19

Authors: By Ariel Hart Zachary Hansen May 19. 2022 – The Atlanta Journal-Constitution

Doctors say it’s caused by a combination of a variant that can escape the vaccine’s effects and the most vulnerable also being the most vaccinated

As summer once again brings signs of a coming COVID-19 wave, an unusual trend has emerged: The Georgians who are fully vaccinated and boosted are increasingly winding up in the hospital with serious COVID-19 symptoms.

The phenomenon points to two changes in the unpredictable pandemic battleground more than two years in. The circulating omicron variant has become better at evading the vaccine, which was designed on the first version of coronavirus to appear in China. And the people most likely to get boosted are those who were most vulnerable to begin with: the elderly, or patients with pre-existing conditions. Despite the extra vaccine protection, those people remain the most vulnerable.

Even in light of the unexpected hospitalizations of those vaccinated and boosted, doctors say it’s still true that boosted groups are the least likely to die.

“I’ve had several older patients who have been boosted and had the vaccine,” said Dr. William Cleveland, a nephrologist in southwest Atlanta. “They get hospitalized, and they had to have some significant medical attention, but they get discharged. And I know that just because of their frailty, without having had the vaccine they would not have survived.”

The rate of hospitalizations for boosted Georgians fell again this week, but still remains higher than the rate of hospitalizations for those with only the primary vaccine series (2 shots). The fact that boosted patients’ hospitalizations nearly outstripped all others even for one week was an unprecedent moment in the pandemic. In the past, hospitalization rates for unvaccinated groups have drastically outnumbered those who have taken the vaccine — sometimes tenfold.

The trend emerged at the tail-end of the omicron variant outbreak and has accelerated over the past two months, setting off alarm bells for state public health experts already expecting a surge in cases this summer.

Dr. Eva Lee, director of the Center for Operations Research in Medicine and Healthcare at Georgia Tech, agreed that the rate of hospitalizations among boosted people was on track to outpace other populations. However, she said it’s not a sign of vaccines losing all effectiveness — it has to do with who is choosing to get boosted.

“A big part of the people that are boosted are also the ones that are really at high risk already to begin with, right?” Lee said. “But what has remained and hasn’t changed is the following: The people that are at risk remain at risk. That means the people that are immune-compromised and the people that are like the elderly people, and people who have coexisting conditions, their risk is still higher.”

Growing number of breakthroughs

Overall, the number of people hospitalized with COVID remains at or near the lowest rate since the beginning of the pandemic. But state data shows that the most protected and least protected groups are starting to find themselves fighting for their lives in Georgia hospitals at nearly the same levels.

According to Georgia Department of Public Health data, unvaccinated groups were being hospitalized due to COVID at twice the rate of other populations at the beginning of March. By the end of April, there were 1.3 hospitalizations per 100,000 vaccinated and boosted Georgians compared to 1.6 hospitalizations for every 100,000 unvaccinated Georgians.https://datawrapper.dwcdn.net/qtaSR/1/

In addition to at-risk groups being more likely to get every shot available to them, omicron and its subvariants have presented a challenge for the U.S.’s current vaccines. Breakthrough cases of less serious illness are now common, and health experts warn they are a sign of the vaccines’ waning immunity.

“Prior to Omicron we could, with a booster, assume there was well over 90-95% vaccine effectiveness vs severe disease,” Eric Topol, founder and director of the Scripps Research Translational Institute in New York, wrote in a recent column sounding the alarm for a summer surge in COVID-19 infections. “It is clear, however, from multiple reports … that this level of protection has declined to approximately 80%, particularly taking account the more rapid waning than previously seen. That represents a substantial drop-off.”

The growing number of breakthrough cases has prompted national health officials to discuss reformulating the current vaccines to specifically target omicron and its subvariants. The U.S. Food and Drug Administration has a meeting scheduled for June 28 to evaluate vaccine efficiency and composition.

Georgia hasn’t seen any noticeable uptick in COVID-19 deaths, but death reports often lag behind increasing hospitalization rates by several weeks.

While health experts are troubled by the rising hospitalization rates, they emphasize that COVID’s death toll would already be on the rise if the most at-risk Georgians weren’t vaccinated and boosted.

Surprised to still be alive

Raymond Fain knew he couldn’t risk getting COVID-19. Given he has kidney disease, the 58-year-old made sure to not only get fully vaccinated but he took a Pfizer booster shot to boot.

Just two months later, during the onslaught of the omicron variant this winter, he was shocked to be told that in spite of his vaccinations he caught COVID. What followed was a bad sickness and two rounds of hospitalization that totaled nearly a month. But at the end of it, came another surprise: He lived.

“I was sort of shocked that that disease that I caught didn’t overcome me with, the failed kidneys. You know what I’m saying?” Fain said.

Cleveland works with Fain’s doctor, both of whom have pleaded with their kidney patients to get vaccinated. Cleveland is all too familiar with kidney patients who get COVID and don’t make it. He’s heard all the excuses, and he’s ready to counter them.

“I’ve seen so much of that (kidney patients succumbing to COVID) that I do not hesitate to try to explain to my patients that I’ve just seen this too many times to to be comfortable with them saying that they are afraid,” Cleveland said.

The percentage of Georgia residents who’ve been vaccinated is among the lowest in the country — the peach state currently ranks 45th. The state’s booster adoption rate is even worse, with less than half of all fully vaccinated people choosing to get one booster dose.

There’s also a large age disparity among those getting boosted. Nearly 60% of all Georgia seniors, people 65 and older, have gotten a booster dose, but there’s a stark drop-off for younger populations. Only about 15% of 25- to 34-year-old Georgians are boosted.

The low booster adoption rate for younger people, who are less likely to be at a high risk of life-threatening infections, is an explanation for why boosted groups seem to be hospitalized at higher rates, health experts said.https://datawrapper.dwcdn.net/KYHdI/1/

“All such people need to have vaccination and booster coverage but our (Centers for Disease Control and Prevention) has failed to convey their life-saving impact from the get go…” Topol wrote in his column. “That’s why we have 31% of Americans who had had 1 booster shot whereas most peer countries are double that proportion.”

For Fain, he’s surprised he was able to pull through his severe bout with COVID and get back on his feet, but his friends and loved ones haven’t let him forget how close he was to death.

“Everybody’s going to talk to me now, they say, ‘Boy when you started, we thought you was going to get gone. You sounded so bad,’” Fain said. “Yeah, but everything is okay now. I’m strong.”

Growing share of Covid-19 deaths are among vaccinated people, but booster shots substantially lower the risk

Authors: Deidre McPhillips, CNN Updated 7:58 AM ET, Wed May 11, 2022 CNN Health

Since Covid-19 vaccines became widely available, there has been a wide gap in deaths between the vaccinated and unvaccinated. But recent Covid deaths are much more evenly split as highly transmissible variants take hold, vaccine protection wanes and booster uptake stagnates. Breakthrough infections have become more common in recent months, putting vulnerable populations at increased risk of severe disease or death as more and more transmissible variants continue to spread. This seems to be especially true for seniors in the United States, who were among the first to get their initial vaccine series. In the second half of September — the height of the Delta wave — less than a quarter of all Covid-19 deaths were among vaccinated people, federal data shows. But in January and February, amid the Omicron surge, more than 40% of Covid-19 deaths were among vaccinated people.

Covid-19 vaccines have saved millions of lives in the United States since the first shot was administered in December 2020, and the unvaccinated are still far more likely to be hospitalized or die than people who are vaccinated with at least two doses of the Moderna or Pfizer/BioNTech mRNA vaccines or a single dose of the Johnson & Johnson vaccine.

But evidence continues to build around the critical importance of booster shots.

Why Covid-19 vaccine boosters may be more important than ever Of those vaccinated people who died from a breakthrough case of Covid-19 in January and February, less than a third had gotten a booster shot, according to a CNN analysis of data from the US Centers for Disease Control and Prevention. The remaining two-thirds had only received their primary series. Overall, the risk of dying from Covid-19 is still about five times higher for unvaccinated people than it is for those vaccinated with at least their primary series, CDC data shows.

But there’s a significant disparity by level of vaccination, too: When adjusted for age, people vaccinated with only their initial series faced about three times greater risk of dying than those who also have their booster shot.The CDC encourages people to be “up-to-date” on Covid-19 vaccinations — which includes getting boosters at the appropriate time — but still defines a person to be “fully vaccinated” if they’ve received at least their initial vaccination series.But this week, a senior Biden administration official was more direct: All adults need a third shot.Vaccination is the best way for individuals to protect themselves against Covid-19, and protection is most effective with at least three shots, the official said.Others have emphasized the importance of boosters to save lives, too.”Almost no one in this country should be dying from Covid” with up-to-date vaccinations and appropriate antiviral treatments, Dr. Robert Califf, commissioner of the US Food and Drug Administration, said Saturday on CNN Newsroom.”What we really should be worried about is getting the boosters that we need to stay up to date so with the new variants that we have, we don’t have unnecessary deaths and hospitalizations.”

Boosters benefit high-risk seniors most

In the first year of the pandemic, before vaccines were available, the vast majority of Covid-19 deaths — more than 80% — were among seniors age 65 and older.

In 2021, especially during the Delta surge, the average age of people dying of Covid-19 shifted younger. Less than 60% of those who died in September were 65 or older, according to provisional data from the CDC.

Covid-19’s full death toll is nearly three times higher than reported, WHO data suggests But 2022 has looked a lot more like 2020 and the first winter surge; so far this year, about three-quarters of all Covid-19 deaths have been among seniors. Studies have suggested that Covid-19 vaccine effectiveness wanes over time. Data from the CDC published in January found that getting boosted was 90% effective at preventing hospitalizations during a period when Omicron was the dominant variant. In comparison, getting two shots was 57% effective when it had been at least six months past the second shot.The vast majority of seniors completed their initial series more than a year ago now. And while booster uptake among seniors is better than other age groups, less than two-thirds of seniors have gotten a booster shot.The CDC now recommends a second booster shot for this age group, too, and uptake is even lower.CNN’s analysis of CDC data from recent months suggests that disparities in risk among vaccinated people who are boosted compared with those who only have their initial series are most prominent among this vulnerable age group.

Covid-19 deaths are preventable

Daily Covid-19 deaths in the US have fallen to a fraction of what they were in January and February amid the Omicron surge, but hundreds are still dying each day.Cases are rising in nearly all states right now, and the White House has warned that another wave in the coming fall and winter could cause 100 million new cases — both raising the potential for more severe disease and tragic loss. But experts say we have the tools to ensure infections don’t turn tragic.

Getting more Americans boosted against Covid-19 could make a big difference as the country heads into the fall and winter, Dr. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, said Monday.”It’s really important that we try to get the half — or a little bit more than a half — of Americans who have only received two doses to get that third dose,” he said. “That may make a difference moving forward here, and it may particularly make a difference now that we’re coming into yet another wave of Covid-19.”

Spectrum of neurological complications following COVID-19 vaccination

Authors: Ravindra Kumar Garg1 and Vimal Kumar Paliwal2 Neuro 2022; 43(1): 3–40.Published online 2021 Oct 31. doi: 10.1007/s10072-021-05662-9PMCID: PMC8557950PMID: 34719776

Abstract

COVID-19 vaccines have brought us a ray of hope to effectively fight against deadly pandemic of COVID-19 and hope to save lives. Many vaccines have been granted emergency use authorizations by many countries. Post-authorization, a wide spectrum of neurological complications is continuously being reported following COVID-19 vaccination. Neurological adverse events following vaccination are generally mild and transient, like fever and chills, headache, fatigue, myalgia and arthralgia, or local injection site effects like swelling, redness, or pain. The most devastating neurological post-vaccination complication is cerebral venous sinus thrombosis. Cerebral venous sinus is frequently reported in females of childbearing age, generally following adenovector-based vaccination. Another major neurological complication of concern is Bell’s palsy that was reported dominantly following mRNA vaccine administration. Acute transverse myelitis, acute disseminated encephalomyelitis, and acute demyelinating polyneuropathy are other unexpected neurological adverse events that occur as result of phenomenon of molecular mimicry. Reactivation of herpes zoster in many persons, following administration of mRNA vaccines, has been also recorded. Considering the enormity of recent COVID-19-vaccinated population, the number of serious neurological events is miniscule. Large collaborative prospective studies are needed to prove or disprove causal association between vaccine and neurological adverse events occurring vaccination.

SARS-CoV-2 is a novel coronavirus that can rapidly affect human beings and can result in coronavirus disease (COVID-19). COVID-19 is dominantly characterized by lung damage and hypoxia. The first case of COVID-19, in Wuhan, China, was reported on December 8, 2019. Later, the World Health Organization announced COVID-19 as a worldwide health emergency, on January 30, 2020. On March 11, 2020, COVID-19 was declared a pandemic. As per the latest World Health Organization report, there were 196,553,009 confirmed cases as on August 1, 2021 along with 4,200,412 deaths [1].

Early this year, COVID-19 vaccines has brought a ray of hope to effectively fight against this deadly pandemic and save precious human lives. Currently, four major vaccine types are being used. These vaccine types include viral vector-based vaccines, COVID-19 mRNA-based vaccines, inactivated or attenuated virus vaccine, and protein-based vaccines. In viral vector-based vaccines, adenovirus is used to deliver a part of SARS-COV-2 genome to human cells. Human cells use this genetic material to produce SARS-COV-2 spike protein. Human body recognizes this protein to start a defensive response. The mRNA-based vaccines consist of SARS-COV-2 RNA. Once introduced, genetic material helps in making SARS-COV-2-specific protein. This protein is recognized by human body to start defensive immune reaction. In inactivated or attenuated vaccines, killed or attenuated SARS-COV-2 virus triggers immune response. Protein-based vaccines use the spike protein or its fragments for inciting immune response. These COVID-19 vaccines have received emergency approvals in different countries for human use [2]. As per the latest World Health Organization report, until August 1, 2021, globally, a total of 3,839,816,037 COVID-19 vaccine doses have been globally administered [1].

In fact, all kinds of vaccines are associated with the risk of several serious neurological complications, like acute disseminated encephalomyelitis, transverse myelitis, aseptic meningitis, Guillain-Barré syndrome, macrophagic myofasciitis, and myositis. Influenza vaccine has been found associated with narcolepsy in young persons. Several pathogenic mechanisms, like molecular mimicry, direct neurotoxicity, and aberrant immune reactions, have been ascribed to explain these vaccines associated with neurological complications [3]. Even COVID-19 vaccines are not free from neurological complications. In this article, we have focused on the neurological complications following COVID-19 vaccination that were reported after their emergency use authorizations.

Search strategy

We reviewed available data regarding neurological complications (post-authorization) described following the World Health Organization–approved COVID-19 vaccination. We classified COVID-19 vaccination associated with neurological complications in two broad groups: (1) common but mild and (2) rare but severe. We searched PubMed, Google, and Google Scholar databases using the keywords “COVID‐19” or “SARS‐CoV‐2” and “vaccination” or “vaccine,” to identify all published reports on neurological complications of COVID‐19 vaccines. We in this review will focus on spectrum of published neurological adverse events following COVID-19 vaccination. Last search was done on August 1, 2021.

Mild neurological events

Neurological adverse events following COVID-19 vaccination are generally mild and transient, like fever/chills, headache, fatigue, myalgia and arthralgia, or local injection site effects like swelling, redness, or pain. These mild neurological symptoms are common following administration of all kinds of COVID-19 vaccines.

Anxiety-related events, like feeling of syncope and/or dizziness, are particularly common. For example, Centers for Disease Control and Prevention, in a report published on April 30, 2021, recorded 64 anxiety-related events (syncope in 17) among 8,624 Janssen COVID-19 vaccine recipients. None of the event was labeled as serious [4].

In Mexico (data available in form of preprint) among 704 003 subjects who received first doses of the Pfizer-BioNTech mRNA COVID-19 vaccine, 6536 adverse events following immunization were recorded. Among those, 4258 (65%) had at least one neurologic manifestation, mostly (99.6%) mild and transient. These events included headache (62·2%), transient sensory symptoms (3·5%), and weakness (1%). In this study, there were only 17 serious adverse events, seizures (7), functional syndromes (4), Guillain-Barré syndrome (3), and transverse myelitis (2) [5].

In South Korea, Kim and co-workers collected data of post-vaccination adverse events following first dose of adenovirus vector vaccine ChAdOx1 nCoV-19 (1,403 subjects) and mRNA vaccine BNT162b2 (80 subjects) vaccinations. Data were collected daily for 7 days after vaccination. Authors noted that 91% of adenovirus-vectored vaccine and 53% of mRNA vaccine recipients had mild adverse reactions, like injection-site pain, myalgia, fatigue, headache, and fever [6]. A mobile-based survey among healthcare workers (265 respondents) who received both doses of the BNT162b2 mRNA vaccine was conducted. The most common adverse effects were muscle ache, fatigue, headache, chills, and fever. Adverse reactions were higher after the second dose compared with that after the first dose [7].

Headache

Headache is one of the most frequent mild neurological complaints reported by a large number of COVID-19 vaccine recipients, soon after they receive vaccine.

A review of headache characteristic noted that among 2464 participants, headache begun 14.5 ± 21.6 h after AstraZeneca adenovirus vector vaccine COVID-19 vaccination and persisted for 16.3 ± 30.4 h. Headaches, in majority, were moderate to severe in intensity and generally localized to frontal region. Common accompanying symptoms were fatigue, chills, exhaustion, and fever [8]. In a multicenter observational cohort study, Göbel et al. recorded clinical characteristic of headache occurring after the mRNA BNT162b2 mRNA COVID-19 vaccination. Generally, headache started 18.0 ± 27.0 h after vaccination and persisted for 14.2 ± 21.3 h. In majority, the headaches were bifrontal or temporal, dull aching character and were moderate to severe in intensity. The common accompanying symptoms were fatigue, exhaustion, and muscle pain [8].

Severe neurological adverse events

Serious adverse reaction following immunization is defined as a post-vaccination event that are either life-threatening, requires hospitalization, or result in severe disability. The World Health Organization listed Guillain-Barré syndrome, seizures, anaphylaxis, syncope, encephalitis, thrombocytopenia, vasculitis, and Bell’s palsy as serious neurologic adverse events. Instances of serious adverse events following COVID-19 vaccinations are continuously pouring in the current scientific literature and are source of vaccine hesitancy in many persons [9] (Fig. 1).

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Fig. 1

A flow diagram depicts the spectrum of severe neurological complications following COVID-19 vaccinations (ADEM, acute disseminated encephalomyelitis; CVST, cerebral venous sinus thrombosis; LETM, longitudinally extensive transverse myelitis; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorders; PRES, posterior reversible encephalopathy syndrome; TIA, transient ischemic attacks)

Functional neurological disorders

Functional neurological disorders are triggered by physical/emotional stress following an injury, medical illness, a surgery, or vaccination. Functional neurological disorders often remain misdiagnosed despite extensive workup.

After availability of COVID-19 vaccine, many YouTube videos depicted continuous limb and trunk movements and difficulty walking immediately after COVID-19 vaccine administration. These videos were of concern as they were the source of “vaccine hesitancy” [10]. Kim and colleagues reviewed several such social media videos demonstrating motor movements consistent with functional motor symptoms occurring after administration of COVID-19 vaccine. Motor movements were bizarre asynchronous and rapidly variable in frequency and amplitude consistent with functional neurological disorder. The Functional Neurological Disorder Society has lately clarified that movement disorder is consistent with functional in nature. The spread of these videos are important because these functional disorders created concerns for vaccine hesitancy [11].

Several other kinds of functional neurological disorders have also been reported. Butler and colleagues described two young ladies, who presented with functional motor deficits mimicking stroke. Both these patients had variability in weakness and had many non-specific symptoms. A detailed workup and neuroimaging failed to demonstrate any specific abnormality [12]. Ercoli and colleagues described a middle-aged man who, immediately after vaccine administration, reported bilateral facial paralysis along with failure to blink. These manifestations resolved quickly within 40 min. Immediately after administration of second dose of vaccine, he complained of respiratory distress and swollen tongue. Again, all these symptoms resolved quickly following treatment with corticosteroids, however, he developed new symptoms in the form of right hemiparesis. Two weeks later, he developed facial hypoesthesia. A detailed workup of the patient failed to demonstrate any abnormality. A diagnosis of functional neurological disorder was, finally, made [13].

Cerebral vascular events

As a matter of concern, increasing number of reports about adenoviral vector vaccine-induced cerebral vascular adverse events, like cerebral venous thrombosis, arterial stroke, and intracerebral hemorrhage, is getting published in leading medical journals. These reports are alarming as post-vaccination vascular events culminate either in severe disability or death. Vaccine-induced cerebral vascular adverse events are generally associated with severe immune-mediated thrombotic thrombocytopenia. Thrombocytopenia generally clinically manifests within 5 to 30 days after administration of adenovirus vector-based vaccines. In post-vaccination thrombotic thrombocytopenia, a picture similar to that of heparin-induced thrombocytopenia is encountered. When heparin binds platelet factor 4, there is generation of antibodies against platelet factor 4. Antibodies against platelet factor 4 result in platelet destruction and trigger the intravascular blood clotting [14]. The post-mortem examination, in patients with vaccine-induced thrombocytopenia, demonstrated extensive involvement of large venous vessels. Microscopic findings showed vascular thrombotic occlusions occurring in the vessels of multiple body organs along with marked inflammatory infiltration [15]. The vector-based vaccines contain genetic material of SARS-COV-2 that is capable of encoding the spike glycoprotein. Possibly, leaked genetic material binds to platelet factor 4 that subsequently activates formation of autoantibodies. These autoantibodies destroy platelets [1617].

Cerebral venous thrombosis

Cerebral venous thrombosis is the one of the most feared devastating COVID-19 vaccine-associated neurological complication. Cerebral venous thrombosis should be suspected in all vaccinated patients, who has persistent headache. Headache is generally unresponsive to the analgesics, and some patients may have focal neurological deficits. Affected patients are generally females of younger ages (Table ​(Table1)1) [1846].

Table 1

Clinical, magnetic resonance imaging findings, and outcome details of patients who developed cerebral venous sinus thrombosis after vaccination against SARS-CoV-2

ReferenceNeurological complicationsCountryAge/sexVaccine typeDuration of onset after vaccinationClinical featuresNeuroimagingTreatment given
Castelli et al. [18]Cerebral venous sinus thrombosisItaly50/MCOVID-19 vaccine AstraZeneca10 daysSevere headache, right hemiparesis, unsteady gait, and visual impairment of 4 days Patient needed ICU care and mechanical ventilationIntra-parenchymal hemorrhage CT angiography = left transverse and sigmoid venous sinuses thrombosisFibrinogen concentrate (10 g total) and platelet (4 units total) a bilateral decompressive craniectomy
D’Agostino et al. [19Cerebral venous thrombosis and disseminated intravascular coagulationItaly54/FThe AstraZeneca vaccine12 daysAltered sensorium and hemiparesis Myocardial infarctionMultiple subacute lobar hemorrhages basilar artery thrombosis associated with the superior sagittal sinus thrombosis Bilateral adrenal hemorrhageIntensive care unit
Scully et al. (report of 23 patients) [20]Thrombocytopenia (23 patients) Cerebral venous thrombosis (13 patients)London12 years (Median)ChAdOx1 nCoV-19 vaccine (AstraZeneca)6 to 24 days13 patients with cerebral venous thrombosisNot availableNot available
Franchini et al. [21]Cerebral venous thrombosisItaly50/MCOVID-19 vaccine AstraZeneca7 daysComa thrombocytopeniaIntra-parenchymal hemorrhage Angiography cerebral venous sinus thrombosisIntensive care unit
Mehta et al. [22]Cerebral venous sinus thrombosisUK32/MVaxzevria vaccine9 daysThunderclap headache Left hemiparesis, left-sided incoordination Thrombocytopenia and rapidly evolving comaSuperior sagittal sinus and cortical vein thrombosis and significant cortical edema with small areas of parenchymal and subarachnoid hemorrhageIntensive care unit
25/MVaxzevria vaccine6 daysHeadache hemiparesis, left hemisensory loss Seizures, agitation, decerebrate posturing, reduced GCS ThrombocytopeniaSuperior sagittal sinus thrombosis with extension into the cortical veins and hemorrhage in lobar and sub-arachnoid locationsIntensive care unit
Bersinger et al. [23]Cerebral venous sinus thrombosisFrance21/FChAdOx1 nCoV-19 vaccine9 daysHeadaches, seizures, hemiplegia, expressive aphasia, and no pupillary abnormalities and altered sensorium The platelet count was 61,000 per cubic millimeterCT of the head showed massive thrombosis in the deep and superficial cerebral veins, thrombosis of the left jugular vein, and left frontoparietal venous hemorrhagic infarctionA selective arterial embolization was performed immediately after decompressive craniectomy IV immunoglobulin Fondaparinux
Ramdeny et al. [24]Cerebral venous sinus thrombosisUnited Kingdom54/MCOVID-19 Vaccine AstraZeneca21 daysWorsening headache, bruising and unilateral right calf swelling Thrombocytopenia D-dimer = 60,000 ng/ml Anti-platelet factor 4Cerebral venous sinus thrombosisIntravenous immunoglobulin
Zakaria et al. [25]Cerebral venous sinus thrombosisMalaysia49/MFirst dose of mRNA SARS-CoV-2 vaccine16 daysNew onset of mild to moderate headache and giddinessCT) of the brain showed cordlike hyperattenuation within the left transverse and sigmoid sinus suggestive of cord or dense clot sign CT cerebral venography a long segment-filling defect and empty delta sign within the superior sagittal sinus extending into the torcula Herophili, left transverse sinus, and sigmoid sinus to proximal internal jugular veinSubcutaneous Clexane improved
Ryan et al. [26]Cerebral venous sinus thrombosisIreland35/FAZD1222 (COVID-19 Vaccine AstraZeneca)10 daysHeadache thrombocytopenia bruising and petechiae Antibody to platelet factor 4MR venogram showed cerebral venous sinus thrombosisApixaban
Graf et al. [27]Cerebral venous sinus thrombosisGermany29/MChAdOx1 nCov-19, AstraZeneca9 daysSevere headache and hematemesis thrombocytopeniaComplete thrombosis of the left transverse and sigmoid sinus down to the left proximal jugular vein Temporo-parietal intracranial hemorrhage CT angiography revealed extensive thrombosis of the mesenteric and portal veinHigh-dose immunoglobulins Argatroban
George et al. [28]Cerebral venous sinus thrombosisUSA40/FChAdOx1 nCov-19, AstraZeneca7 daysHeadache thrombocytopenia Antibody to platelet factor 4Venous thrombosis involving the left transverse sigmoid sinus and internal jugular veinA direct thrombin inhibitor (bivalirudin) Intravenous immune globulin (IVIG)
Jamme et al. [29]Cerebral venous sinus thrombosisFrance69/FFirst dose of Oxford–AstraZeneca vaccine11 daysHeadache associated with behavioral symptomsBilateral frontal hemorrhage cerebral venous thrombosis of the left internal jugular vein, sigmoid sinus, and superior sagittal sinusNone
Tiede et al. (report of 5 patients) [30]Cerebral venous sinus thrombosisGermany41 and 67 years All femalesChAdOx1 COVID-19 vaccine (AZD1222, Vaxzevria)5 to 11 days after first vaccinationCerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), arterial cerebral thromboembolism, and thrombotic microangiopathy thrombocytopenia Autoantibodies against platelet factor 4Brain hematomas infarcts, presence of thrombi in major vesselsIntravenous immunoglobulin or corticosteroids Argatroban
Schulz et al. (report of 45 cases) [31]Cerebral venous thrombosisGermany46.5 years (mean)/35 femalesBNT162b2, ChAdOx1, and mRNA-1273Within 30 days of vaccinationThrombocytopenia in all patientsCerebral venous thrombosisIntravenous immunoglobulins, plasmapheresis, corticosteroids, anticoagulants
Bourguignon et al. [32]A report three patients one had cerebral venous sinus thrombosisCanada69/MChAdOx1 nCov-19, AstraZeneca12 daysDiabetes mellitus, hypertension, obstructive sleep apnea, recently diagnosed prostate cancer Headache and confusion left-sided weakness Thrombocytopenia Autoantibodies against platelet factor 4Right middle cerebral-artery stroke with hemorrhagic transformation Right cerebral transverse and sigmoid sinuses, right internal jugular vein, hepatic vein, and distal lower-limb vein; pulmonary embolismIntravenous immunoglobulin Plasmapheresis
Gattringer et al. [33]Cerebral venous sinus thrombosisAustria39/FThe first vaccination with ChAdOx1 nCov-19 (AstraZeneca)8 daysHeadache since 2 days thrombocytopenia (84 × 10 [8]/L)Left sigmoid/transverse sinus thrombosis without brain parenchymal involvementIntravenous immunoglobulin
Ikenberg et al. [34]Cerebral venous sinus thrombosisGermanyearly 30 s/FThe first dose of ChAdOx1 nCov-19 (AstraZeneca)Headache Gait ataxia, and amnestic difficulties as well as aphasia Thrombocytopenia of 37 000/µLCVST of the left transverse and sigmoidal sinus with a left-temporal and left-cerebellar intracerebral hemorrhageIntravenous immunoglobulin argatroban
Clark et al. [35]Cerebral venous sinus thrombosisUSA40/FThe Ad26.COV2.S (Johnson & Johnson/ Jansen) vaccine5 daysWorsening headaches thrombocytopeniaCerebral venous sinus thrombosis involving the left transverse and sigmoid sinuses, extending into the left internal jugular veinBivalirudin infusion Intravenous immunoglobulin
Bonato et al. [36]Cerebral venous sinus thrombosisItaly26/FChAdOx1 nCoV-19 vaccine14 daysheadache non-responsive to drugs right-sided weakness and visual disturbances rapidly deteriorated with decreased consciousnessMultifocal venous thrombosis with bilateral occlusion of parietal cortical veins, straight sinus, vein of Galen, internal cerebral veins, and inferior sagittal sinus. Right parietal and left frontoparietal lobes an extensive venous infarction with hemorrhagic transformation Platelet-factor 4 (PF4)–heparin IgG antibodies – elevated thrombocytopeniaDexamethasone Intravenous immunoglobulin argatroban
Wang et al. [37]Cerebral venous sinus thrombosisTaiwan41/FFirst vaccination with ChAdOx1 nCoV-197 daysFever and headache thrombocytopenia positive anti-PF4 antibodiesMR venography revealed cerebral venous sinus thrombosisIntravenous immunoglobulin
Dutta et al. [38]Cerebral venous sinus thrombosisIndia51/MFirst-dose of COVISHIELD6 daysHeadache double vision papilledema Platelet count was normalMR venography revealed thrombosis in superior sagittal sinus and transverse sinusLow-molecular-weight heparin
Aladdin et al. [39]Cerebral venous sinus thrombosisSaudi Arabia36/FFirst dose of the ChAdOx1 nCoV-19 vaccine14 daysVomiting and severe headache left upper limb weakness thrombocytopenia Disseminated intravascular coagulationBrain computed tomography (CT) scan showed superior sagittal thrombosis with thickened cortical veins and bilateral hypodensities in the parietal lobesLow-molecular-weight heparin ICU care
Lavin et al. (a series of 4 patients) [40]Cerebral venous sinus thrombosisIreland29/F 38/M 50/F 35/FVaxzevria vaccine (ChAdOx1 nCoV-19, AstraZeneca)10 days 16 days 23 days 14 daysVisual disturbance followed by a headache, nausea, vomiting, bruising and petechiae severe thunderclap headache, nausea and vomiting headache, persistent bruising and petechiae all had thrombocytopeniaDural venous sinus thrombosis in one patient only other had abdominal abnormalitiesIntravenous immunoglobulin
Tølbøll Sørensen et al. [41]Cerebral venous sinus thrombosisUK30/FChAdOx1 nCoV-19Headache and general malaise portal vein thrombosis thrombocytopenia and consumption coagulopathy Anti-platelet antibodies were detectedNormalTinzaparin
Fan et al. [42] (a series of 3 patients)Cerebral venous sinus thrombosisSingapore54/M 62/F 60/FBNT162b2 mRNA vaccination1 day 9 days 8 daysSevere headache and vomiting and acute left hemiparesis Headache and vomiting Right ataxic hemiparesis There was no thrombocytopeniaA large right temporo-parietal lobe intraparenchymal hemorrhage Acute right cerebral bleed involving occipital and temporal lobes associated with subarachnoid hemorrhage Venous infarct in bilateral perirolandic gyri Venogram confirmed cerebral venous sinus thrombosis in all threeLow-molecular-weight heparin decompressive craniectomy
Suresh and Petchey  [43]Cerebral venous sinus thrombosisUK27/MChAdOx1 nCOV-19 vaccine2 daysWorsening headache and new homonymous hemianopia Thrombocytopenia Anti-platelet antibodies were detectedAcute parenchymal bleed with subdural extension CT venogram confirmed significant cerebral venous sinus thrombosisDabigatran and intravenous immunoglobulins
Dias et al. (a series of 2 patients) [44]Cerebral venous sinus thrombosisPortugal47/F 67/FBNT162b2 mRNA SARS-CoV-2 vaccine6 days 3 daysHeadache, nausea and photophobia a sudden left motor deficit Sudden right lower limb clonic movements, followed by motor deficit, loss of consciousness and headache There was no thrombocytopenia Anti-platelet antibodies were not detectedMRI with venography revealed thrombosis of superior sagittal, right lateral, transverse, sigmoid sinuses, and jugular vein and left sigmoid sinus, together with right frontal subarachnoid hemorrhage and a cortical venous infarct Brain MRI showed thrombosis of high convexity cortical veins, superior sagittal, right transverse, and sigmoid sinus and jugular veinAcetazolamide and enoxaparin Levetiracetam 500 mg bid and enoxaparin
Guan et al. [45]Cerebral venous sinus thrombosisTaiwan52/MThe first dose of ChAdOx1 nCov-19 (AstraZeneca)10 daysNausea and thunderclap headache thrombocytopenia Platelet factor 4 antibodies detectedHyperdensity of the sinus, including cord sign and dense vein sign at the left transverse and sigmoid sinuses CT venogram revealed CVST at the left transverse sinus and sigmoid sinuses and thrombosis of the left internal jugular veinApixaban Outcome not provided
Varona et al. [46]Cerebral venous sinus thrombosis and primary adrenal insufficiencySpain47/MAdenoviral (ChAdOx1) vector-based COVID-19 vaccine10 daysHeadache, somnolence, and mild confusion Blateral segmentary pulmonary embolism Thrombocytopenia Anti-platelet antibodies were detectedConsistent with cerebral venous thrombosisIntravenous immunoglobulins and subcutaneous fondaparinux hydrocortisone Patient improved

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In Europe, since March 2021, cases of cerebral venous thrombosis started pouring in following COVID-19 vaccination, particularly after administration of viral vector based (AstraZeneca ChAdOx1 nCoV-19 and the Johnson and Johnson Ad26. COV2.S) vaccines [22]. Scully and colleagues recently reported findings of 23 patients, who presented with thrombosis and thrombocytopenia (platelet counts below 10 × 109/L). These patients developed thrombosis and thrombocytopenia 6 to 24 days after they received the first dose of the viral vector-based vaccines. In a significant observation, authors, in majority of patients, demonstrated the presence of autoantibodies against platelet factor 4. Additionally, D-dimer levels were found elevated [20]. Tiede and co-workers reported five German cases of prothrombotic immune thrombocytopenia after vaccination with viral vector-based vaccine (Vaxzevria). In these patients, acute vascular events clinically manifested as cerebral venous sinus thrombosis, splanchnic vein thrombosis, arterial cerebral thromboembolism, and/or thrombotic microangiopathy within 2 weeks post vaccination. All five patients had low platelet counts and markedly raised D-dimer. In all, autoantibodies against platelet factor 4 were also demonstrated [30].

Pottegård et al. in Denmark and Norway evaluated incidence of arterial events, venous thromboembolism, thrombocytopenia, and bleeding among vaccinated population. The vaccinated cohorts comprised of 148,792 Danish people and 132,472 persons from Norway. All has received their first dose of viral vector-based vaccine (ChAdOx1-S). An excess rate of venous thromboembolism (like cerebral venous thrombosis) was observed among vaccine recipients, within 28 days of vaccine administration. Authors estimated an increased rate for venous thromboembolism corresponding to 11 excess events per 100,000 vaccinations with 2.5 excess cerebral venous thrombosis events per 100,000 vaccinations [47].

Krzywicka et al., from the Netherlands, collected data of 213 cases with post-vaccination (187 after adenoviral vector vaccines and 26 after a mRNA vaccine) cerebral venous sinus thrombosis; they noted thrombocytopenia in 107/187 (57%) post-vaccination cerebral venous sinus thrombosis cases. Thrombocytopenia was not recorded in any of patients, who received an mRNA-based vaccine. Cerebral venous sinus thrombosis after adenoviral vector vaccines carried poorer prognosis. Approximately, 38% (44/117) patients in adenoviral vector vaccine group died, while in mRNA vaccine group, 20% (2/10) had died [48].

Recently published National Institute for Health and Care Excellence (NICE) guidelines recommend that the patients with clinical diagnosis of vaccine-induced immune thrombocytopenia and thrombosis should be treated with intravenous administration of human immunoglobulin, at a dose of 1 g/kg. If there is no response or there is further deterioration, second dose of human immunoglobulin should be given. In patients with insufficient response, methylprednisolone 1 g intravenously for 3 days or dexamethasone 20 to 40 mg for 4 days can be used [49].

Heparin needs to be avoided, instead alternative anticoagulants like argatroban, bivalirudin, fondaparinux, rivaroxaban, or apixaban should be used for anticoagulation [4951]. NICE guidelines further recommend that patients with very low platelet count should be treated either alone with a argatroban or a combination of argatroban and platelet transfusion [49].

Arterial events

Several acute arterial events, like arterial thrombosis, intracerebral hemorrhage, transient global amnesia, and spinal artery ischemia, have also been reported following vaccination [31].

Simpson and colleagues, in Scotland, estimated the incidence of vaccine-associated thrombocytopenia and vascular events following administration of first dose of viral vector-based vaccine (ChAdOx1) or mRNA (BNT162b2 Pfizer-BioNTech or mRNA-1273 Moderna) vaccination. First dose of viral vector-based vaccine was associated with small enhanced risk of idiopathic thrombocytopenic purpura; in addition, up to 27 days after vaccination, there was possibility of an increased risk for thromboembolic and hemorrhagic events. No such adverse associations were noted with mRNA vaccines [52]. The reports of COVID-19 vaccine-related intracerebral hemorrhage and ischemic stroke are summarized in Table ​Table22 [5361].

Table 2

Clinical, neuroimaging and outcome details of patients who suffered strokes (other than cerebral venous thrombosis) after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Athyros and Doumas [53]Intracerebral hemorrhageGreece71/FModerna anti-COVID-19 vaccine3 daysRight hemiplegia, aphasia, agnosia Acute hypertensive crisisLeft basal ganglia hemorrhageClonidine, furosemideDied
Bjørnstad-Tuveng [54]Intracerebral hemorrhageNorwayThirties/FAstraZeneca’s vaccine ChAdOx1 nCoV-199 daysSlurred speech, left hemiparesis, and reduced consciousnessRight intracerebral hemorrhage on CT, thrombosis in transverse sinus and pulmonary artery on postmortemICU managementDied
de Mélo Silva et al. [55]Intracerebral hemorrhage with intraventricular extensionBrazil57/FChAdOx1 nCoV-19 vaccine5 daysLeft hemiparesis, vomiting, and somnolenceA large right deep frontal lobe parenchymal hematomaICU management Decompressive craniectomySurvived with disabilities
Bayas et al. [56]Bilateral superior ophthalmic vein thrombosis, ischemic stroke, and immune thrombocytopeniaGermany55/FSARS-CoV-2— ChAdOx1 nCoV-1910 daysFlu-like illness, diplopia, vision loss, a transient, mild, right-sided hemiparesis, and aphasia, focal seizuresMRI showed superior ophthalmic vein thrombosis An MRI showed an ischemic stroke in the left parietal lobe, middle cerebral artery territory, with restricted diffusionIntravenous dexamethasone AnticoagulantsImproved
Al-Mayhani et al. [57Ischemic stroke with thrombocytopeniaLondon35/F 37/F 43/FChAdOx1 nCoV-19 vaccine ChAdOx1 nCoV-19 vaccine ChAdOx1 nCoV-19 vaccine11 days 12 days 21 daysLeft face, arm, leg weakness and drowsiness Headache, left visual field loss, confusion, left arm weakness DysphasiaRight middle-cerebral artery infarct Bilateral acute border zone infarcts Left middle-cerebral artery infarctDecompressive hemicraniectomy Intravenous immunoglobulin Intravenous immunoglobulinDied Improved Stable
Blauenfeldt et al. [58]Ischemic strokeDenmark60/MmRNA-based vaccine BNT162b2 (Pfizer/BIOTECH)7 daysBilateral adrenal hemorrhages A massive right sided ischemic stroke Thrombocytopenia Platelet factor 4 (PF‐4) reactive antibodiesAngiography showed occlusion of the right internal. Carotid arteryIntensive care unitPalliative care
Malik et al. [59]transient ischemic attackUSA43/FJohnson and Johnson COVID-19 Ad26.COV2.S vaccination10 daysHeadache, fever, body aches, chills, mild dyspnea and light-headedness thrombocytopenia numbness and tingling of her face and right armRight internal carotid artery (ICA) thrombusFondaparinuxImproved
Finsterer and Korn [60]AphasiaAustria52/MThe second dose of an mRNA-based SARS-CoV-2 vaccine7 daysSudden-onset reading difficulty and aphasia motor aphasia with paraphasiaA lobar bleeding in the left temporal lobeSupportiveImproved
Walter et al. [61]Ischemic stroke Main stem occlusion of middle cerebral arteryGermanyFirst dose ChAdOx1 nCov-19 vaccineacute headache, aphasia, and hemiparesis Platelet count and fibrinogen level were normalMain stem occlusion of middle cerebral artery A wall-adherent, non-occluding thrombus in the ipsilateral carotid bulb was notedWithin 1 h after start of IV thrombolysisThrombus dissolved and patient improved

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Intracerebral hemorrhage

Athyros and Doumas reported a 71-year-old female. who developed intracerebral hemorrhage after she received the first dose of the Moderna mRNA vaccine.

On the third post-vaccination day, the patient developed right hemiplegia, aphasia, and agnosia along with accelerated hypertension. Computed tomography revealed a hematoma in the left basal ganglia. On the 9th day, she died [53].

In another report, Bjørnstad-Tuveng et al. described a young woman, who had a fatal cerebral event following vaccination with AstraZeneca’s ChAdOx1 nCoV-19 vaccine. She was found to have severe thrombocytopenia. The patient died the next day of the event. Post-mortem examination revealed antibodies against platelet factor 4 and the presence of small thrombi in the transverse sinus, frontal lobe, and pulmonary artery [54].

Acute ischemic stroke

Bayas and co-workers described a case that presented with superior ophthalmic vein thrombosis, ischemic stroke, and immune thrombocytopenia, after administration of viral vector-based vaccine. Intravenous dexamethasone resulted in marked improvement in platelet count [56]. Al-Mayhani et al. described three cases of vaccine-induced thrombotic thrombocytopenia, all presented with arterial strokes. Authors opined that young patients with arterial stroke after receiving the COVID-19 vaccine should always be evaluated for vaccine-induced thrombotic thrombocytopenia. Other laboratory tests, like platelet count, D-dimers, fibrinogen level, and testing for platelet factor 4 antibodies, should also be performed [57].

Blauenfeldt et al. described a 60-year-old woman, who presented with intractable abdominal pain, 7 days after receiving the adenoviral (ChAdOx1) vector-based COVID-19 vaccine. Abdominal computed tomography revealed bilateral adrenal necrosis. Later, a massive right cerebral infarction, secondary to occlusion of the right internal carotid artery, occurred that led to death of the patient. Blood tests showed thrombocytopenia, elevated in D-dimer and platelet factor 4 antibodies [58].

Many reports of acute brain disorders like encephalopathy, seizures, acute disseminated encephalopathy, neuroleptic malignant syndrome, and post-vaccine encephalitis were described secondary to COVID-19 vaccine. These are summarized in Table ​Table33 [6275].

Table 3

Clinical, neuroimaging and outcome details of patients who presented with an acute brain disorder (other than cerebral venous thrombosis and arterial stroke) after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Baldelli et al. [62]Reversible encephalopathyItaly77/MThe first dose of ChAdOx1 nCoV-19 vaccine (AstraZeneca)1 dayDelirium A significant increase of interleukin (IL)-6 in both CSF and serumNormalCorticosteroids
Aladdin and Shirah [63]New-onset refractory status epilepticusSaudi Arabia42/FChAdOx1 nCoV-19 vaccine10 daysHeadache and fever first-ever generalized tonic–clonic seizure lorazepam, levetiracetam, and phenytoin failed to controlIncrease in the signal on FLAIR images at bilateral hippocampi and insulaMidazolam and propofol Plasma exchangeImproved
Ghosh et al. [64]SeizuresIndia68/MCovishield vaccine4 daysFocal onset non-motor seizurePeriventricular leukoaraiosis and cortical atrophybrivaracetamImproved
Liu et al. [65] (two cases)Associated with non-convulsive status epilepticusUSA86/F 73/MModerna COVID-19 vaccine7 days 21 daysDiastolic dysfunction, chronic kidney disease and diabetes mellitus with acute encephalopathy Acute confusion with visual hallucinations EEG demonstrated non-convulsive focal status epilepticus Acute encephalopathy with non-convulsive status epilepticusNormalAntiepileptic therapy and ICU careBoth improved
Naharci and Tasc [66]DeliriumTurkey88/Ffirst dose of CoronaVac–-an inactivated COVID-19 vaccineAcute confusion, hallucinations, agitation, and sleep disturbanceNoneHaloperidol and trazodoneImproved
Salinas et al. [67]Transient akathisiaUSA36/FPfizer-BioNTech vaccineWithin 24 h of second doseRestless body syndrome had fever after 5 h of motor restlessness resolved after 24 hNoneNoneImproved
Zavala-Jonguitud et al. [68]DeliriumMexico89/MThe first dose of BNT162b2 RNA vaccine24 hAcute confusion, fluctuating attention, anxiety and inversion of the sleep–wake cycle History of type 2 diabetes mellitus, hypertension, stage III‐b chronic kidney disease, prostatic hyperplasiaNot doneQuetiapineImproved
Alfishawy et al. [69]Neuroleptic malignant syndromeKuwait74/FBNT162b2 mRNA COVID-19 vaccine16 daysOld case of dementia and bipolar disorder and was receiving memantine, donepezil, and quetiapine presented with fever, delirium, rigidity, and elevated CPKNormalSymptomaticImproved
Ozen Kengngil et al. [70]Acute disseminated encephalomyelitis like MRI lesionsTurkey46/FInactivated SARS-CoV-2 vaccine of Sinovac1 MonthSeizures, normal examinationT2, FLAIR hyperintensity in thalamus, and corona radiataMethyl prednisoloneNo recurrence of seizures
Cao and Ren [71]Acute disseminated encephalomyelitisChina24/FSARS-CoV-2 Vaccine (Vero Cell), Inactivated2 weeksSomnolence and memory decline, MMSE-11 inflammatory changes in CSFT2/FLAIR white matter hyperintensity in both temporal lobesIV immunoglobulinImproved
Raknuzzaman et al. [72]Acute disseminated encephalomyelitisBangladesh55/MBNT162b2 mRNA COVID-19 vaccine3 weeksDelirium followed by loss of consciousnessT2/FLAIR white matter hyperintensities in periventricular regionMethyl prednisoloneImproved
Torrealba-Acosta et al. [73]Acute encephalitis, myoclonus and Sweet syndromeUSA77/MmRNA-1273 vaccine1 dayConfusion, fever and generalized rash; later headache, dizziness and double vision leading to severe encephalopathy Intermittent orofacial movements and upper extremity myoclonus CSF showed increased cells and protein. Skin biopsy showed vasculitis changesNormalMethylprednisoloneImproved
Vogrig et al. [74]Acute disseminated encephalomyelitisItaly56/FPfizer-BioMTech COVID-19 vaccine (Comirnaty)2 weeksHorizontal gaze-evoked nystagmus, Mild weakness on left upper limb, left hemi-ataxic gaitT2/FLAIR white matter hyperintensity in left cerebellar peduncle prednisone improved FLAIR sequences were observed, the largest in the left centrum semiovalePrednisoneImproved
Zuhorn et al. [75]Postvaccinal encephalitis Similar to autoimmune encephalitisGermany21/FChAdOx1 nCov-19 vaccine the first dose5 daysHeadache and progressive neurological symptoms including attention and concentration difficulties and a seizure CSF lymphocytic pleocytosis EEG slow delta rhythmNormalPrednisoneImproved
63/FChAdOx1 nCov-19 vaccine6 daysGait disorder, a vigilance disorder and a twitching all over her body Opsoclonus-myoclonus syndrome CSF lymphocytic pleocytosis EEG slow delta rhythmNormalMethylprednisoloneImproved
63/MChAdOx1 nCov-19 vaccine8 daysIsolated aphasia and fever CSF lymphocytic pleocytosis EEG normalNormalNoneMild improvement despite no treatment

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Encephalopathy

Some patients developed encephalopathy following administration of COVID-19 vaccines. Acute encephalopathy is defined as rapidly evolving disorder of the brain. Acute encephalopathy clinically manifests either with delirium, decreased consciousness, or coma.

Delirium

Delirium is characterized with fluctuating disturbance in attention and awareness. Zavala-Jonguitud and Pérez-García described an 89-year-old man, who developed delirium after mRNA vaccination. Within 24 h, patient developed confusion, fluctuating attention, anxiety, and inversion of the sleep–wake cycle. Patient had many comorbidities (diabetes mellitus, hypertension, and chronic kidney disease). Patient improved after he was treated with quetiapine [68].

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome is a life-threatening complication of many antipsychotic drugs characterized by fever, altered mental status, muscle rigidity, and autonomic dysfunction. In an isolated report, neuroleptic malignant syndrome, in a 74-year-old female with dementia and bipolar disorder 16 days after COVID-19 vaccination, has been described [69].

Acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is an acute inflammatory demyelinating disorder of the central nervous system. In the majority, ADEM is a post-infectious entity; in many cases, it even develops after vaccination [76]. In two cases, acute disseminated encephalomyelitis following COVID-19 vaccination has been reported. In first such case a 46-year-old woman received Sinovac inactivated SARS-CoV-2 vaccine before onset of clinical manifestations. Patient was presented with seizures, and magnetic resonance imaging revealed multiple, discrete T2/FLAIR periventricular. hyperintense lesions. Patient improved following methylprednisolone treatment [70] Another patient was a 24-year-old female who presented with encephalopathy along with limb weakness of 1-day duration. Two weeks prior, patient was vaccinated with inactivated SARS-CoV-2 vaccine. Magnetic resonance imaging revealed multiple, discrete T2/FLAIR hyperintense lesions in the brain. Patient improved following treatment with antiepileptics and intravenous immunoglobulins [71].

Post-vaccinal encephalitis

Zuhorn et al. reported a case series 3 patients, who presented with post-vaccinal encephalitis, akin to autoimmune encephalitis, 7 to 11 days after administration of adenovirus-based ChAdOx1 nCov-19 vaccine. All patients fulfilled the diagnostic criteria for possible autoimmune encephalitis. One interesting case had presented with opsoclonus-myoclonus syndrome. Two patients presented with cognitive decline, seizures, and gait disorder. Neuroimaging did not reveal any abnormality. CSF pleocytosis was noted in all three patients. All patients responded well to corticosteroids [75].

Transverse myelitis

Acute transverse myelitis is an inflammatory spinal cord disorder that clinically manifests with the paraparesis/quadriparesis, transverse sensory level, and bowel or bladder dysfunction. Acute transverse myelitis usually is a postinfectious disorder. Magnetic resonance imaging demonstrates T2/FLAIR hyperintensity extending several spinal cord segments. Autoimmunity via mechanism of molecular mimicry is usually responsible for spinal cord dysfunction. Adenoviral vector-based COVID-19 vaccines are more frequently associated with causation of transverse myelitis. In isolated cases, even inactivated virus vaccine and mRNA-based vaccines had precipitated acute demyelination spinal cord syndromes, like multiple sclerosis and neuromyelitis optica. Reports of myelitis associated with vaccination for SARS-CoV-2 are summarized in Table ​Table44 [7783].

Table 4

Clinical, neuroimaging, and outcome details of patients who presented with spinal cord involvement after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Malhotra et al. [77]Transverse myelitisIndia36/MViral-vectored, recombinant ChAdOX1 nCoV-19 Covishield vaccine (AstraZeneca vaccine by Serum Institute of India)On the 8th post-vaccination dayAbnormal sensations in lower limbs with truncal levelT2-hyperintense lesion in the dorsal aspect of spinal cord at C6 and C7 vertebral levelsMethylprednisoloneImproved
Fitzsimmons and Nance [78]Transverse myelitisUSA63/MSecond dose of the Moderna vaccineWithin 1 dayLower back pain, paresthesia in both feet, and pain in lower extremities difficulty in walking and urinary retentionIncreased T2 cord signal seen in the distal spinal cord and conusIntravenous immunoglobulin and methylprednisoloneImproved
Tahir et al. [79]Transverse myelitisUSA44/FAd26.COV2.S (Johnson & Johnson) vaccine10 daysCervical cord transverse myelopathy CSF increased cellsIncreased T2 cord signal seen in the spinal cord extending from the C2-3 segment into the upper thoracic regionPlasma exchange and methylprednisoloneImproved
Pagenkopf and Südmeyer [80]Longitudinally extensive transverse myelitisGermany45/MFirst dose COVID-19-vaccine (AZD1222, AstraZeneca)11 daysThoracic back pain and urinary retentionT2 hyperintense signal of the spinal cord with wide axial and longitudinal extent reaching from C3 to Th2PrednisoloneImproved
Helmchen et al. [81]Optic neuritis with longitudinal extensive transverse myelitis in stable multiple sclerosisGermany40/FAstra Zeneca, COVID19 Vaccine®; Vaxzevria2 weeksBlindness paraplegia, with absent tendon reflexes in the legs, incontinence, and a sensory deficit for all qualities below Th5. CSF showed severe pleocytosis and elevated proteinIncreased longitudinal centrally located signal intensities throughout the thoracic spinal cordCorticosteroids and plasmapheresisImproved
Havla et al. [82]First manifestation of multiple sclerosisGermany28/FPfizer-BioNTech COVID-19 vaccine6 days first doseMyelitis oligoclonal bandsMRI revealed multiple (> 20), partially confluent lesions with spatial dissemination but no gadolinium enhancement. Contrast-enhancing lesion at the T6 level, suggestive of myelitisMethylprednisolone and plasma exchangeImproved
Chen et al. [83]Neuromyelitis optica spectrum disorderChinaMiddle-aged femaleThe first dose of inactivated virus vaccine3 daysDizziness and unsteady walking AQP4-positiveMRI scanning of the brain revealed area postrema and bilateral hypothalamus lesionsMethylprednisoloneImproved

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Malhotra and colleagues reported a 36-year-old patient, who had short-segment myelitis 21 days after first dose of adenoviral vector-based (Oxford/AstraZeneca, COVISHIELD™) vaccine. Patient recovered completely after treatment with methylprednisolone [77]. Fitzsimmons and Nance reported another patient of acute transverse myelitis following Moderna vaccine (an mRNA vaccine). The 63-year-old patient developed symptoms of acute myelopathy within 24 h of vaccination. MRI revealed increased T2 cord signal seen in the distal spinal cord and conus. Patient improved considerably following treatment with methylprednisolone and intravenous immunoglobulin [78].

Earlier, in phase III trial of Oxford/AstraZeneca vaccine, 2 patients had developed transverse myelitis. One of the case of transverse myelitis was reported 14 days after booster vaccination. The expert committee considered that this case was the most likely an idiopathic, short segment transverse myelitis. The second case was reported 68 days post-vaccination. Experts believed that in this case, transverse myelitis was not likely to be associated with vaccination. This patient was earlier diagnosed as a case of multiple sclerosis [8485].

The pathogenesis of acute transverse myelitis following COVID-19 vaccination remains unknown. Possibly, SARS-CoV-2 antigens present in the COVID-19 vaccine or its adenovirus adjuvant induce immunological reaction in the spinal cord. The occurrence of 3 reported acute transverse myelitis adverse effects among 11,636 participants in the vaccine trials was considered high and a cause of concern [86].

Bell’s palsy

Several cases of Bell’s palsy have occurred following COVID-19 vaccination. (Table ​(Table5)5) [8795]. The instances of Bell’s palsy are most often associated with mRNA vaccines [96]. Vaccine-associated Bell’s palsy generally responds very well to the oral corticosteroids. The exact pathogenesis remains speculative.

Table 5

Summary of reported patients, who suffered from Bell’s palsy after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Shemer et al. (a report of 9 cases) [87]Bell’s palsyIsrael35–86 (M = 5 and F = 4)BNT162b2 SARS-CoV-2 vaccine4–30 days after first dose 3 received 2nd doseAcute facial weakness One had herpes zoster ophthalmicus and herpes zoster oticusNoneCorticosteroidsNot given
Repajic et al. [88]Bell’s palsyUSA57/FPfizer-BioNTech COVID-19 A messenger RNA (mRNA) vaccine36 h after second dose3 previous episodes of Bell’s palsy ageusia Facial weaknessNonePrednisoneImproved
Colella et al. [89]Bell’s palsyItaly37/MmRNA vaccine BNT162b25 days after first doseAcute facial weaknessNot doneCorticosteroidsImproved
Martin-Villares et al. [90]Bell’s palsySpain34/FModerna COVID-19 vaccine2 daysGrade III facial palsy She developed a right Bell’s palsy in 2012 during pregnancy (5th month)NoneCorticosteroidsImproved
Nishizawa et al. [91]Bell’s palsyJapan62/FAd26.COV2.S vaccination20 daysHouse-Brackmann score 4 Bell’s PalsyNormalNoneNone
Gómez de Terreros et al. [92]Bell’s palsySpain50/MPfizer-BNT162b2 mRNA vaccine9 daysMuscle weakness on the left side of his faceNormalCorticosteroidsImproved
Burrows et al. [93]Sequential contralateral facial nerve palsiesUKFirst and second doses of the Pfizer-BioNTech COVID-19 vaccineRight palsy, 5 h Left palsy after 2 daysTwo discrete contralateral episodes of Bell’s palsyNormalPrednisoloneImproved both the time
Obermann et al. [94]Bell’s palsyGermany21/FFirst dose of SARS-CoV-2 mRNA vaccine Comirnaty (BNT162b2, BioNTech/Pfizer)2 dayFacial muscle paralysis SARS-CoV-2 antibodies were present in blood and CSFNormalPrednisoloneImproved
Iftikhar et al. [95]Bell’s palsyQatar36/MSecond dose of the mRNA-1273 vaccine1 dayFacial palsyNormalPrednisoloneImproved

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In a case–control study, Shemer et al. compared clinical parameters of patients with Bell’s palsy following mRNA vaccination with that of patients with Bell’s palsy without vaccination. Out of 37 patients, 21 had received vaccination. Bell’s palsy developed within 2 weeks following first dose of COVID-19 vaccination. There was no difference in any of the clinical parameter between vaccinated or unvaccinated groups [97].

Earlier, in the Pfizer-BioNTech clinical trial, which included 44,000 participants, 4 people had Bell’s palsy. No case of Bell’s palsy was reported in the placebo arm. In the Moderna trial, which included 30,400 participants, 3 vaccine recipients reported Bell’s palsy. One person was in the placebo arm [98]. An article, published in the Lancet, analyzed the combined phase 3 data of Pfizer and Moderna trials and noted that the rate of Bell’s palsy was higher than expected [98].

Other cranial nerve involvement

In isolated instances, mRNA vaccines were found associated with olfactory dysfunction and sixth cranial nerve palsy (Table ​(Table6)6) [99104].

Table 6

Summary of reported patients, who suffered from cranial nerve involvement (other than Bell’s palsy) after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Konstantinidis et al. [99] Report of 2 patientsOlfactory dysfunctionGreeceBoth femalePfizer-BioNTech BNT162b23 and 5 days after second doseHyposmia after their second doseNoneOlfactory trainingImproved
Keir et al. [100]PhantosmiaUSA57/FPfizer-BioNTech COVID-19 vaccination Second doseNoneFeeling weak, fatigued, with random episodes of ‘‘smelling smoke’’ associated with hyposmiaPostcontrast CT demonstrates faint enhancement left olfactory tract MRI enhancement of the left greater than right olfactory bulb and bilateral olfactory tractsNoneNone
Reyes-Capo et al. [101]Acute abducens nerve palsyUSA59/FPfizer-BioNTech COVID-19 vaccine2 daysFever for 1 day followed by diplopiaNormal MRI of brain and orbitsNot availableSensory-motor examination remained unchanged in recent follow-up
Parrino et al. [102]TinnitusItaly37/F 63/ 30/MBNT162b2 mRNA-vaccine7-h first dose 20 h 7 daysSudden unilateral tinnitusNormal MRICorticosteroids, in twoImproved all
Tseng et al. [103 ] PMID: 34,297,133Reversible tinnitus and cochleopathyTaiwan32/MFirst dosage of the AstraZeneca COVID-19 vaccine5 hHigh-pitch tinnitus and disturbed the normal hearing high fever with chills and myalgiaNot doneCorticosteroidsImproved
Narasimhalu et al. [104]Trigeminal and cervical radiculitisSingapore52/FPfizer-BioNTech vaccination (tozinameran)3 h first doseNumbness, swelling and pain over the left face and neckMRI of trigeminal nerve revealed thickening and perineural sheath enhancement of the V3 segment of the left trigeminal nerve The MRI of the cervical spine revealed spondylotic changesPregabalinImproved

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Olfactory dysfunction

Olfactory dysfunction is the most frequent neurological complication of COVID-19. Konstantinidis and colleagues reported two cases of smell impairment after second dose of the BioNTechBNT162b2 vaccine (Pfizer) administration [51].

Keir and colleagues reported phantosmia following administration of Pfizer COVID-19 vaccine. Patient complained of constantly “smelling smoke” and headaches. MRI of brain of the patient showed enhancement of the olfactory bulbs and bilateral olfactory tracts [100].

Abducens nerve palsy

Reyes-Capo et al. reported a 59-year-old lady, who presented with an abducen nerve palsy 2 days post-vaccination (Pfizer-BioNTech mRNA vaccine). Neuroimaging in this patient was normal..

Otologic manifestations

A variety of otologic manifestations has been noted following COVID-19 vaccination. Parrino and colleagues described three patients with sudden unilateral tinnitus following BNT162b2 mRNA vaccine administration. Tinnitus rapidly resolved in 2 cases. Wichova and colleagues in a retrospective review recorded 30 patients, who either had significantly exacerbated otologic symptoms or had a new symptom after getting mRNA vaccine. Post-vaccination otologic manifestations included hearing loss with tinnitus, dizziness, or with vertigo. In some patients, with Menière’s disease or autoimmune inner ear disease, vaccine led to exacerbation of the pre-existing otologic symptoms [102,105].

Acute vision loss

Santovito and Pinna reported an unusual patient, who developed acute visual impairment following the 2nd dose of the Pfizer-BioNTech COVID-19 vaccine. Prior to visual symptoms, patient experienced unilateral headache. He also reported mild confusion, asthenia, and profound nausea. His symptoms got relieved after taking analgesics. Possibly, patient had an acute attack of migraine with aura that got precipitated by the vaccine [106].

Guillain-Barré syndrome

Guillain-Barré syndrome is a post-infectious disorder of peripheral nerve manifesting with lower motor neuron type of sensory-motor quadriparesis. Acute motor weakness is frequently preceded by an antecedent microbial infection. There are numerous reports indicating that COVID-19 infection can trigger Guillain-Barré syndrome. The US Food and Drug Administration has recently expressed its concern regarding a possible association between the Johnson and Johnson COVID-19 vaccine with Guillain-Barré syndrome [107].

After emergency use approvals, all kinds of COVID-19 vaccines were found associated with Guillain-Barré syndrome. Adenovector-based vaccines were more frequently associated with Guillain-Barré syndrome. Earlier, in phase 3 trial of Johnson and Johnson adenovirus vector-based COVID-19 vaccine, 2 patients developed Guillain-Barré syndrome. One patient belonged to vaccine group and other to placebo group. Both patients had Guillain-Barré syndrome within 2 weeks of receiving injections. The Guillain-Barré syndrome in the vaccine arm was preceded by chills, nausea, diarrhea, and myalgia [108109].

Post-vaccination Guillain-Barré syndrome generally affects older adults within 2 weeks of vaccine administration. Clinical presentation is similar to acute demyelinating neuropathy; nerve conduction studies show demyelinating pattern, and CSF examination shows cyto-albuminic dissociation. Many patients present only with facial diplegia. Response to immunotherapy is generally good. (Table ​(Table7)7) [110126].

Table 7

Summary of reported patients, who developed an acute peripheral nerve disorder after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Waheed et al. [110]Guillain-Barré syndromeUSA82/FPfizer-BioNTech COVID-19 A messenger RNA (mRNA) vaccine2 weeksAreflexic paraparesis with distal sensory loss CSF showed albuminocytologic dissociationenhancement of cauda equina nerve rootsIV immunoglobulinImproved
Márquez Loza et al. [111]Guillain-Barré syndromeUSA60/FJohnson & Johnson, d26.COV2.S, a recombinant adenovirus serotype 26 (Ad26) vector vaccine2 weeksOphthalmoplegia, facial diplegia and Areflexic quadriparesis CSF showed albuminocytologic dissociationEnhancement of cauda equina nerve rootsIV immunoglobulinImproved
Patel et al. [112]Guillain-Barré syndromeUK37/MCOVID-19 ChAdOx1 vaccine adenovirus-vectored vaccine Oxford AstraZeneca2 weeksSymmetrical, progressive ascending muscle weakness areflexic bilaterally in the lower limbsCauda equina nerve root enhancementIntravenous immunoglobulinImproved
Razok et al. [113]Guillain-Barré syndromeQatar73/MPfizer-BioNTech COVID-19 vaccine20 days Second doseAcute bilateral lower limb weaknessNoneIVIGImproved
Ogbebor et al. [114]Guillain-Barré syndromeUS86/3FPfizer-BioNTech COVID-19 vaccine1 dayWeakness in her bilateral lower extremities and by day 6, she could no longer walk CSF = a protein 162 mg/dL and glucose (49 mg/dL)NoneIntravenous immunoglobulinImproved
Finsterer  [115]Exacerbating Guillain-Barré syndromeAustria32/MA vector-based COVID-19 vaccine8 daysParesthesia and dysphagia bilateral frontal and nuchal headacheNoneIntravenous immunoglobulinImproved
Marammatom et al. [116] Report of 7 casesGuillain-Barré syndromeIndiaChAdOx1-S/nCoV-19 adenovector-based vaccineWithin 2 weeks of the first doseAll patients progressed to areflexic quadriplegia 2 cases required mechanical ventilation All 7 cases had bilateral facial paresis Four patients (57%) also developed other cranial neuropathies (4th and 5th)In two patients, MRI brain and spine were normalIntravenous immunoglobulinOne recovered Rest six still bed bound
Allen et al. [117] Report of 4 casesGuillain-Barré syndrome variantUK20–57 all malesOxford-AstraZeneca SARS-CoV2 vaccineWithin 3 weeksFacial weakness in 1 facial diplegia in 3 areflexic quadriparesis in 1 Cyto-albuminic dissociation in allMRI of the brain and whole spine with contrast showed enhancement of the facial nerve within the right internal auditory canalIntravenous immunoglobulin, oral steroids, or no treatmentAll improved
Kohli et al. [118]Guillain-Barré syndromeIndia71/MCovishield, AstraZeneca, University of Oxford6 daysAreflexic quadriparesis with bulbar palsy NCV- demyelinating patternNoneIntravenous immunoglobulin and mechanical ventilationImproved
Azam et al. [119]Guillain-Barré syndromeUK67/MThe first dose of the AstraZeneca COVID-1915 daysAreflexic quadriparesis with facial diplegiaNCV- demyelinating patternNormalIntravenous immunoglobulinImproved
Hasan et al. [120]Guillain-Barré syndromeUK62/FFirst dose of the Oxford/AstraZeneca COVID-19 vaccineWeakness of bilateral lower limbs preceded by paresthesia and numbness a flaccid-type paraplegia NCV- demyelinating pattern CSF-albumin-cytological dissociationNormalIntravenous immunoglobulinThe patient remains in the ICU
Theuriet et al. [121]Guillain-Barré syndromeFrance72/MFirst dose of ChAdOx1 nCoV-19 vaccine (VaxZevria/Oxford-AstraZeneca)3 weeksAreflexic quadriparesis with facial diplegia NCV- demyelinating patternNoneIntravenous immunoglobulinThe patient remains in the ICU
Bonifacio et al. [122] (A series of 5 cases)Guillain-Barré syndromeUK43/M 51 M 53/M 66/m 71/fVaxzevria AstraZeneca, University of Oxford COVID-19 vaccine11 days 7 days 7 days 8 days 12 daysBilateral facial weakness with paresthesia variant of Guillain-Barré syndrome NCV- demyelinating pattern in 4 patientsBilateral contrast enhancement along whole facial nerve in 3 patientsIntravenous immunoglobulin Was given in 2 patientsAll improved
Nasuelli et al. [123]Guillain-Barré syndromeItaly59/MChAdOx1 nCoV-19 vaccine10 daysAreflexic quadriparesis with facial diplegia NCV- demyelinating pattern in 4 patients CSF-albumin-cytological dissociationNormalIntravenous immunoglobulinImproved
Jain et al. [124]Guillain-Barré syndromeUSA65/FAd26.COV2.S (Johnson & Johnson) vaccine19 daysFacial diplegiaNormalIntravenous immunoglobulin And plasmapheresisImproved
McKean and Chircop [125]Guillain-Barré syndromeMalta48/MVaxzevria AstraZeneca, University of Oxford COVID-19 vaccine First dose10 daysFacial diplegia and severe back pain ascending paresthesia and bilateral progressive areflexic lower limb weakness. CSF-albumin-cytological dissociation NCV multifocal sensorimotor demyelinating polyneuropathyNormalIntravenous immunoglobulin and oral prednisoloneImproved
Bonifacio et al. [126] (a report of 5 cases)Guillain-Barré syndromeUK
Waheed et al. [127]Small fiber neuropathyUSA57/FPfizer-BioNTech COVID-19 A messenger RNA (mRNA) vaccine (Second dose)Subacute onsetIntense burning dysesthesias in the feet gradually spreading to the calves and minimally into the hands (Nerve biopsy proved small fiber neuropathy)NoneGabapentinSymptomatic improvement

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Proposed pathogenesis of Guillain-Barré syndrome is an autoantibody-mediated immunological damage of peripheral nerves via mechanism of molecular mimicry between structural components of peripheral nerves and the microorganism. Lately, several cases of Guillain-Barré syndrome following COVID-19 vaccination have also been reported.

Small fiber neuropathy

Waheed et al. described a 57-year-old female, who presented with painful neuropathy following administration of the mRNA COVID-19 vaccine. Patient subacutely presented with intense peripheral burning sensations. Electrodiagnostic studies were normal. Skin biopsy proved small fiber neuropathy. Patient responded to gabapentin.(Table ​gabapentin.(Table7)7) [127].

Parsonage-Turner syndrome

Parsonage-Turner syndrome or neuralgic amyotrophy is clinically manifested with acute unilateral shoulder pain followed by brachial plexopathy. Parsonage-Turner syndrome is usually triggered by any infection, surgery, or rarely vaccination. In many reports, Parsonage-Turner syndrome has been described following COVID-19 vaccination.(Table ​vaccination.(Table8)8) [128130].

Table 8

Summary of reported patients, who developed neuralgic amyotrophy after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Mahajan et al. [128]Parsonage-Turner syndromeUSA50/MCOVID-19 BNT162b2 vaccination7 daysSudden onset of severe left periscapular pain after first dose One week after the second dose, the patient developed left hand grip and left wrist extension weakness. Electromyography showed decreased motor unit recruitmentNormalCorticosteroidsImproved
Diaz-Segarra et al. [129]Painless idiopathic neuralgic amyotrophyUSA35/FPfizer-BioNTech COVID-19 vaccine9 daysNew-onset painless left arm weakness, numbness, and paresthesiasCervical spine computed tomography showed mild degenerative changes without foraminal narrowingHigh-dose prednisoneImproved
Antonio Crespo Burillo et al. [130]Parsonage-Turner syndromeSpain38/MVaxzevria (AstraZeneca)4 daysShoulder and arm pain Electrophysiology suggested brachial plexopathyMRI of the shoulder revealed a mild left subacromial tendinopathyMethylprednisoloneImproved

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Herpes zoster

Herpes zoster occurs following reactivation of varicella zoster virus. Patients with herpes zoster present with the classic maculopapular rash, which is unilateral, confined to a single dermatome. The rash disappears in 7 to 10 days. Postherpetic neuralgia is the frequent complication of herpes zoster, which is noted in 1 in 5 patients. McMahon and co-workers recorded 414 cutaneous reactions to mRNA COVID-19 vaccines, and 5 (1.9%) were diagnosed with herpes zoster [131]. Other types of COVID-19 vaccines are infrequently associated with post-vaccination reactivation of herpes zoster. It has been suggested that vaccine-induced immunomodulation, resulting in dysregulation of T cell function, is responsible for reactivation of herpes zoster virus [132133]. Reports of herpes zoster reactivation after vaccine against SARS-CoV-2 are summarized in Table ​Table99 [134142].

Table 9

Summary of reported patients, who developed Herpes zoster after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Tessas and Kluger [134]Herpes zosterFinland44/MBNT162b2 mRNA COVID-19 vaccine7 daysHerpetiform vesicular and erythematous rash on the left upper backNoneOral valacyclovirImproved
Rodríguez-Jiménez et al. [135] A report of 5 casesHerpes zosterSpain39–58 F = 3BNT162b2 mRNA COVID-19vaccine (Pfizer)1–16 (4 less than 7 days)Painful herpetiform dermatomal rashNoneNoneNone
Eid et al. [136]Herpes zosterLebanon79/MmRNA COVID vaccine6 daysPainful herpetiform dermatomal rashNoneAntiviral treatmentImproved
Bostan and Yalici-Armagan [137]Herpes zosterTurkey78/MInactivated COVID-19 vaccineErythematous, painful, and pruritic lesions on chest
Furer et al. [138] (a report of 6 cases)Herpes zosterIsrael36–61 All femalesBNT162b2 mRNA vaccination3 -14 daysAll had autoimmune inflammatory rheumatic diseases Herpes zoster ophthalmicus in one Truncal herpes zoster in othersNot doneNANA
Aksu and Öztürk et al. [139]Herpes zosterTurkey68/MThe inactivated COVID-19 vaccine5 daysmultiple pinheaded vesicular lesions upon an erythematous base occupying an area on his right mammary region and back corresponding to T3–T5 dermatomesNot doneValacyclovir paracetamolImproved
Chiu et al. [140] (a report of 3 cases)Herpes zosterTaiwan71/M 46/M 42/MPfizer-BNT162b2 mRNA and Moderna mRNA-12732 days 7 days 2 daysErythematous papules and vesicle in dermatomal patternNot doneOral acyclovirAll improved
Alpalhão and Filipe et al. [141] (a report of 4 cases)Herpes zosterPortugalNAPfizer’s Comirnaty™ vaccine AstraZeneca Vaxzevria™ vaccine3–6 daysErythematous papules and vesicle in dermatomal patternNot doneValacyclovirAll improved
Channa et al. [142]Herpes zosterUSA81/MmRNA-1273 (Moderna) Covid-19 vaccine3 daysA dermatomal rashNot doneNot availableNot available

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Myositis and rhabdomyolysis

There are reports, which have indicated that COVID-19 vaccines have potential to damage the skeletal muscles as well (Table ​(Table10)10) [143147]. Tan and colleagues described a patient with a known carnitine palmitoyltransferase-II deficiency disorder, who developed fever, vomiting, shortness of breath, frank haematuria, myalgia and muscle weakness within four hours of receiving AstraZeneca COVID-19 vaccine [143]. Theodorou and colleagues described a 56-year-old woman who, 8 days after a second dose of vaccine administration, developed severe left upper arm pain along restricted shoulder movements. Her serum creatine kinase was elevated suggesting skeletal muscle damage. MRI revealed severely edematous deltoid muscles. Contrast-enhanced imaging demonstrated enhancement of deltoid muscles suggestive of myositis [146].

Table 10

Summary of reported patients, who developed an acute muscular disorder following vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Tan et al. [143]Rhabdomyolysis in a patient with Carnitine palmitoyltransferase II deficiencyUK27/MCOVID-19 vaccine AstraZeneca5 hFever, vomiting, shortness of breath, frank hematuria, and myalgia CK concentration of 105,000 U/L and deranged liver function tests (ALT 300 U/L and AST 1496 U/L)NoneContinuous intravenous dextrose 10% and a high carbohydrate dietImproved
Mack et al. [144]RhabdomyolysisUSA80/MSecond dose of Moderna COVID-19 vaccine2 daysGeneralized body aches, nausea, and vomiting elevated CKNoneIV fluidsImproved
Nassar et al. [145]RhabdomyolysisUSA21/MFirst Pfizer/BioNTech COVID-19 vaccine1 daySevere back pain with radiation to his left lateral thigh Creatinine phosphokinase (CPK) level more than 22,000 U/LNormalIV fluidsImproved
Theodorou et al. [146]MyositisGreece56/FModified mRNA COVID-19 vaccine8 days after second doseThere was tenderness over the deltoid muscle, guarding, and decreased abduction of the shoulder and arm along with elevated CPKOn MRI, the deltoid muscle was edematous. On contrast enhancement, muscle exhibited enhancement indicating inflammationSymptomaticImproved
Godoy et al. [147]Myositis ossificansBrazil51/M3 monthsRight upper arm pain, soreness and palpable massIntramuscular nodule n the proximal fibers of the brachii muscle with perilesional muscle edema One week later, CT showed a hypoattenuating intramuscular nodule with internal calcificationsNSAIDsImproved

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Conclusion

Post-authorization, a wide spectrum of serious neurological complications has been reported following COVID-19 vaccination. The most devastating neurological complication is cerebral venous sinus thrombosis that has been reported in females of childbearing age following adenovector-based vaccines. Another major neurological complication of concern is Bell’s palsy that was reported dominantly following mRNA vaccine administration. Transverse myelitis, acute disseminated encephalomyelitis, and Guillain-Barré syndrome are other severe unexpected post-vaccination complications that can occur as result of molecular mimicry and subsequent neuronal damage. Most of other serious neurological complications are reported in either in form of isolated case reports or small cases series. A causal association of these adverse events is controversial; large collaborative prospective studies are needed to prove causality.

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Second COVID booster shot extends protection for just a few weeks, study shows

Authors: Joseph Wilkinson, New York Daily NewsWed, April 6, 2022, 9:23 PM·2 min read

A fourth shot of the Pfizer COVID-19 vaccine increased protection against viral infection for only four to seven weeks, according to a massive study published Tuesday.

The study included 1.25 million people age 60 and over in Israel who received their fourth dose between January and March. Israel uses only the Pfizer vaccine.

People who got the fourth dose were half as likely to test positive for COVID-19 four weeks later when compared to people who only had three doses, according to the study.

But by the eighth week, the groups were almost equally likely to catch COVID-19, researchers found.

The fourth shot was the subject of much debate before U.S. regulators approved it last week for people age 50 and older. The second booster had already been approved for immunocompromised people. President Joe Biden, 79, got his on March 30.

While increased protection against infection was short-lived, the fourth booster continued to protect against severe illness for at least six weeks, the study found. The research period actually ended before the protection did, leading researchers to suggest future studies.

The study compared only people with the fourth dose to people with a third dose. Previous research had suggested that the third dose provided a significant bump in infection protection over zero, one or two doses.

Only about 30% of the U.S. population, 98 million people, has received a third dose, according to Centers for Disease Control data.

“For confirmed infection, a fourth dose appeared to provide only short-term protection and a modest absolute benefit,” the study’s authors wrote.

“Overall, these analyses provided evidence for the effectiveness of a fourth vaccine dose against severe illness caused by the omicron variant, as compared with a third dose administered more than 4 months earlier.”

This New COVID Variant Is the Most Unpredictable One Yet

Authors: David Axe Published Apr. 03, 2022 10:47PM ET 

After spreading across Asia and Europe, the BA.2 subvariant of the novel coronavirus is now dominant in the United States, according to the U.S. Centers for Disease Control and Prevention.

Right now, U.S. COVID cases are at a six-month low. But what happens next in the U.S. and nearby countries is hard to predict. Looking to Europe for hints isn’t enormously helpful because, on that continent, BA.2 has behaved… unpredictably. Indeed, unpredictability might be exactly what Americans—and everyone else—should expect as the pandemic enters its 28th month.

A patchwork of public health rules, varying vaccination rates, and differing amounts of natural immunity from past infections mean that no two countries are the same. But even those differences don’t fully explain BA.2’s uneven impact.

“The bottom line is that it is not predictable what BA.2 will do,” John Swartzberg, a professor emeritus of infectious diseases and vaccinology at the University of California-Berkeley’s School of Public Health, told The Daily Beast.

Amid this confusion, at least one thing remains true, however. As volatile as BA.2 is when it comes to countries and populations, you can still protect yourself by getting vaccinated.

Usually, there’s a pattern with new COVID lineages. An uptick in positive tests from clinics, hospitals, and wastewater samples correlates with a proportional increase in symptomatic infections.

But when it comes to BA.2, “something different seems to be occurring,” Peter Hotez, an expert in vaccine development at Baylor College, told The Daily Beast. “BA.2 is going up everywhere in terms of percentage of virus isolated” in tests, Hotez explained, “yet this translates into many different scenarios in terms of rise in cases.”“I can’t say with any certainty that this can be chalked up to their vaccine policies or vaccine politics alone.”

BA.2 is a highly mutated cousin of the previously dominant BA.1 subvariant of Omicron, the latest major variant—“lineage” is the scientific term–of the SARS-CoV-2 virus. Changes to the spike protein, which helps the virus to grab onto and infect our cells, make BA.1 and BA.2 extremely transmissible.

BA.1, which first appeared last fall and quickly drove record infections across much of the world, was the most contagious respiratory virus many virologists had ever seen—until BA.2 showed up a few weeks after its older cousin. BA.2 could be as much as 80 percent more transmissible than BA.1, Swartzberg said.

That’s why BA.2 eventually has outcompeted BA.1 and become the dominant sublineage in a steadily growing number of countries. It happened first in China, which for more than two years managed to avoid major COVID outbreaks through a combination of travel restrictions, business closures, careful contact-tracing and strict quarantine rules.

BA.2 blew right through China’s so-called “zero-COVID” strategy, causing cases to spike in Hong Kong then neighboring Shenzen then Shanghai. Authorities locked down each city in turn but still failed to stop the sublineage’s march across the country.

Europe was next. Health officials in the Americas watched nervously as BA.2 became dominant in one European country after another. After all, Europe tends to catch a particular coronavirus lineage or sublineage a month or six weeks before the U.S. and its neighbors do.

But BA.2 hasn’t sent clear signals. The first confusing datapoint actually wasn’t in Europe—it was in Africa. Weirdly, BA.2 was a virtual no-show in South Africa. That country logged a big surge in BA.1 cases in December, and then… nothing. A steady decline in cases even as BA.2 was ravaging other big, rich countries.

Some European countries likewise have escaped significant harm from BA.2. Others are reeling.

The United Kingdom and France caught BA.1 big-time in December and January. Both countries reported record numbers of cases that, owing to the vaccines, fortunately didn’t lead to record hospitalizations and deaths. Austria, by contrast, muddled through BA.1 before taking a huge hit from BA.2.

The U.K. reported a weekly average of 183,000 new daily cases in early January. Three weeks later, France counted a staggering weekly average of 354,000 daily new cases. The U.K.’s worst day for BA.1 deaths was Feb. 2, when authorities reported 535 COVID fatalities. On France’s worst day of BA.1, Feb. 8, 691 people died of COVID.

Comparing the two countries is natural. Not only are they neighbors, they also have roughly the same number of people–around 67 million. Both have managed to fully vaccinate around three-quarters of their populations. Both have wound down all major domestic COVID restrictions.

It makes sense that BA.2 would affect France and the U.K. similarly. And there, at least, the sublineage made some sense. The BA.2 wave that rolled across the U.K. and France starting in February has been relatively minor compared to the BA.1 wave—in both countries.

France’s daily new BA.2 cases seem to be leveling off at a weekly average of 126,000 infections. The U.K.’s weekly average of daily new cases peaked at 125,000 on March 21. Deaths tend to lag cases by a few weeks, so it’s not clear how fatal BA.2 will be in either country, but so far the worst daily death toll is much lower than it was for BA.1.

Now consider Austria. With just 8.9 million people, it’s smaller than the U.K. and France. But it’s equally well-vaccinated—and even came close to having a nationwide vaccine mandate before canceling the planned mandate back in early March, days before it was due to take effect. Austria, like most countries in Europe, has ended domestic restrictions on businesses and travel.

But unlike the U.K. and France, Austria caught BA.2 worsethan BA.1. Daily new case rates from BA.1 swelled to a weekly average of 34,000 and stayed there for a month and a half. Then BA.2 arrived in early March and, without much respite from BA.1, added another 10,000 daily new cases on top of the existing weekly average.“I don’t see a consistent thread between countries.”

Aside from a tiny dip in mid-March, the daily death rate has been going up and up on a weekly basis since January in Austria. BA.2 is claiming 40 lives a day, day after day on average.

It’s difficult to determine which policies make the difference—assuming differences in public health strategy matter at all against a virus as contagious as BA.2. Yes, Austria almost had a vaccine mandate, but it didn’t actually take force. And it’s very hard to say what the proposed mandate’s impact was, or would have been.

“Even if no additional people got vaccinated after a mandate was introduced, this doesn’t mean it didn’t ‘work,’ as the purpose of the mandate may have been to simply ensure that the only people you encounter when out at a restaurant or concert are vaccinated,” Maxwell Smith, a bioethicist at Western University in Ontario, told The Daily Beast.

“In that case, the vaccination mandate ‘working’ would mean reducing levels of transmission of the virus in the settings to which it applied,” Smith added. “Or, in the case of preserving critical infrastructure, it would mean something like fewer cases of severe illness or hospitalizations among those to whom the mandate applied.”

There are lots of ways Austria’s vaccine mandate might have improved outcomes for millions of Austrians at risk of catching COVID. But that didn’t stop Austria as a whole from suffering worse from BA.2 than other nearby countries.

“There are many factors that may have led to the case numbers we’re seeing both in Austria and its neighboring countries, so I can’t say with any certainty that this can be chalked up to their vaccine policies or vaccine politics alone,” Smith said.

Experts are at a loss to explain what other factors might be at work. If nearby countries have vaccinated roughly the same percentage of their populations and have also reopened their borders, businesses and schools—thus allowing for a certain level of natural immunity from past infection—then they should be equally prepared for a new viral lineage.

Clearly, they’re not. “I don’t see a consistent thread between countries,” Swartzberg said.

There are serious implications for the rest of the world as it braces for BA.2. Even strong vaccine uptake and lingering natural immunity might not spare you a big bump in infections. By the same token, BA.2 might just bypass a country for reasons no one fully understands, like it did with South Africa.

But the experiences of whole countries aren’t the experiences of individuals. Yes, BA.2 might have unpredictable effects on populations. But the science is clear on how people can reduce their personal risk. Favor well-ventilated indoor spaces. Wear an N95 mask when local case rates are high.

Most importantly, get vaccinated and boosted.

What You Should Know About Treating Covid-19

Some therapies have been shown to work in clinical studies and other research

Authors: Jared S. Hopkins Mar. 21, 2022 4:47 pm ET The Wall Street Journal

The Food and Drug Administration authorized the first antiviral pills to treat Covid-19 from Pfizer Inc. and Merck & Co. and partner Ridgeback Biotherapeutics LP in December. The authorizations came after each drugmaker’s pill received a positive recommendation from a panel of experts advising the FDA, and weeks after the emergence of the Omicron variant.

Public-health experts say the best preventive measure to decrease the likelihood of contracting Covid-19 is to get vaccinated. The Centers for Disease Control and Prevention has recommended that everyone 12 and older get an additional shot after completing a primary series of Covid-19 vaccination.

Here’s what public-health and infectious-disease experts say about how to treat Covid-19.

I’ve contracted Covid-19; what should I do? How can I treat mild symptoms from home?

Doctors say an initial step is to monitor symptoms to determine whether infected people could be considered at low or high risk for developing severe disease. Individuals who are typically considered to be at low risk for severe disease include people who are young and healthy. They should stay at home away from others, drink plenty of fluids to stay hydrated and take over-the-counter medicines such as acetaminophen or ibuprofen to reduce fevers, according to physicians and the CDC. Physicians say people who are young, otherwise healthy and at low risk of developing severe disease should recover if they take the right steps. 

People who are at high risk include those with underlying health conditions and the elderly, according to doctors. These individuals should pay close attention to any change in their health, including symptoms of fever, cough, fatigue or difficulty breathing. If high-risk individuals need medical attention, they should seek it right away.

“The management of Covid continues to depend on what your risk of progression is,” said Carlos del Rio, a professor of global health at Emory University. “Treatment has to be individualized.” 

Additionally, people who are vaccinated and become infected—what is known as a breakthrough case—are unlikely to develop severe disease or need hospitalization, according to doctors and studies.

What are Covid-19 antiviral pills? When can I get one to treat myself?

Antivirals are treatments designed to impede a virus’s replication cycle, allowing people to recover from the illness, and they are most effective if they are taken by patients early in the course of disease. 

Merck and partner Ridgeback say their oral antiviral, molnupiravir, reduced the risk of hospitalization and death by about 30%. Pfizer said in December a late-stage study confirmed its oral antiviral, called Paxlovid, which is taken with another antiviral called ritonavir, was 89% effective at reducing the risk of hospitalization and death in adults at high risk of severe Covid-19. A separate, preliminary analysis found that the drug may also help people at low risk of severe Covid-19. The company said lab tests showed Paxlovid works against the Omicron variant. 

Both drugs are authorized by the FDA, and have been cleared for use. 

The pills carry some safety risks and limitations. A component of Pfizer’s Paxlovid regimen, ritonavir, can interact with other drugs in dangerous or life-threatening ways. Drugs that interact with Paxlovid include common ones such as the cholesterol-lowering pill simvastatin, the antipsychotic lurasidone and the sedative triazolam. Patients should make sure to tell their doctor or pharmacist of any medications they take before starting an antiviral regimen from Pfizer, according to physicians. The Merck-Ridgeback drug isn’t authorized for children because of its potential effect on bone and cartilage growth. It isn’t recommended for pregnant women because of the potential for fetal harm, a safety signal seen in animal studies of the drug.

The Merck-Ridgeback drug can be prescribed by doctors to adults at high risk of severe disease shortly after they develop mild to moderate symptoms. Pfizer’s drug permits doctors to prescribe the medicine to high-risk patients age 12 and older early in the course of disease, shortly after they develop symptoms.

The companies studied their drugs in people who are at high risk of developing severe disease. They excluded certain people from their tests: Both left out pregnant women while Pfizer excluded people who take certain common medications such as heart drugs. 

The pills are also being tested in people for preventive use with results expected by mid-2022.

Both treatments are taken over five days, with Pfizer’s totaling 30 pills and Merck-Ridgeback clocking in at 40 capsules. 

The U.S. has purchased 20 million courses of treatment of Pfizer’s pill, although supply has been limited as the company increases manufacturing. The government purchased about 3.1 million courses of the Merck-Ridgeback pill, and Merck said all of it has been supplied.

Will antiviral pills be effective against the Omicron variant?

The antiviral manufacturers say they expect the treatments to be effective against Omicron, although they plan to conduct tests to verify. Both drugs target different parts of the virus than vaccines and other treatments, which are targeting the spike protein that plays a key role in infecting cells. 

Pfizer has said so far its researchers haven’t seen any changes in the variant that suggests Paxlovid, which is given with the antiviral ritonavir, is less effective than against previous strains. The company said in January that three separate lab tests showed Paxlovid is effective against the Omicron.

Merck said last year that it was working to collect samples of Omicron to study whether molnupiravir is effective against Omicron and expected results by the end of the year. It has not announced results from any internal testing

Molnupiravir targets machinery the virus uses to replicate, rather than the spike protein, the structure that helps the virus infiltrate cells.

Merck expects molnupiravir to be effective against Omicron because testing has found the drug to be effective against other circulating variants. “Molnupiravir retains activity across all of these variants of concern, and there’s no difference in its antiviral activity,” said Daria Hazuda, vice president of infectious disease discovery at Merck. “There shouldn’t be any more or less concern about its effectiveness against Omicron versus any other variants.”

Merck and partner Ridgeback said in January that molnupiravir was active against Omicron in laboratory tests, pointing to six preclinical studies performed by researchers outside the company.

Are there any drugs approved or authorized for administration in clinics?

Monoclonal antibody treatments are available for people who develop symptoms and are considered to be at high risk of severe disease. As many as 75% of U.S. adults are eligible to take the drugs under FDA guidelines, according to experts. The drugs are lab-engineered molecules that mimic the natural antibodies produced by the immune system to fight off viruses. They are usually administered by infusion or injection at hospitals or clinics.

“It’s a lot easier to access one of these if you happen to live in a more populous area,” said Erica Johnson, chair of the Infectious Disease Board of the American Board of Internal Medicine and assistant professor of infectious diseases at Johns Hopkins University School of Medicine.

The FDA is permitting use of antibody treatments from Eli Lilly & Co., and from GlaxoSmithKline PLC and partner Vir Biotechnology. In January the agency restricted use of older antibody drugs from Lilly and Regeneron Pharmaceuticals because tests found they lost potency against the Omicron variant.

The Glaxo-Vir drug, sotrovimab, has retained effectiveness against Omicron. Regulators cleared for use in February a new drug from Lilly called bebtelovimab that retains effectiveness against Omicron, for the treatment of mild to moderate Covid-19 in nonhospitalized individuals 12 and older who are at high risk of getting severely sick.

In some parts of the U.S., the antibody treatments may be available for administration at home or through mobile clinics. Some states are also allowing low-risk patients to receive monoclonal antibodies, but it is not recommended by the National Institutes of Health. “The juice is not worth the squeeze,” Dr. del Rio said. 

Evusheld, a preventive antibody cocktail from AstraZeneca PLC, which has shown strong efficacy in reducing risk of symptomatic Covid-19, was authorized by the FDA on Dec. 8. Evusheld is delivered as two shots and aims to offer an alternative to vaccines primarily for a minority of adolescents and adults age 12 and older with moderate to severely compromised immune systems. That includes those who have cancer, another illness, or take medications or undergo treatments such as chemotherapy that inhibit an immune response to Covid-19 vaccines.

The FDA in January permitted the use of Veklury, also known as remdesivir, for treatment of people who are not hospitalized with Covid-19. The antiviral was first developed for treating Ebola

For patients with mild to moderate symptoms but who are at high risk of developing severe disease and becoming hospitalized, the National Institutes of Health says the first option should be Paxlovid. If the drug is unavailable, or the patient can’t take it for some reason, sotrovimab should be administered. Veklury is the third option, followed by molnupiravir.

My loved one is hospitalized. Are there any FDA-approved treatments for hospitalized Covid-19 patients?

Most research has found that monoclonal antibodies aren’t effective once people become hospitalized and they are currently not recommended at that point.

Veklury is fully approved for treatment of people who are hospitalized with Covid-19.

Patients who may be at risk of advancing to severe disease may also be given dexamethasone, a steroid first approved in the 1950s that is successful at treating inflammation. The steroid has been found in studies of hospitalized Covid-19 patients to reduce the risk of death. It is recommended for treatment by the NIH and the Infectious Diseases Society of America. 

Patients who don’t respond to dexamethasone may be given an immune-suppressing rheumatoid arthritis drug called Olumiant, which received an emergency-use authorization from the FDA after a study showed it helped hospitalized patients recover more quickly.

A similar rheumatoid arthritis drug, Actemra, made by Roche Holding AG, is also used to tamp down the potentially lethal inflammation seen in some hospitalized patients.

Doctors sometimes administer blood-thinners to hospitalized patients, which can reduce blood clots and inflammation that develop in some Covid-19 patients. Some studies have found that such treatments can also reduce the risk of patients needing mechanical ventilation and could help them leave the hospital sooner.

Which Covid-19 treatments are being tested?

Bristol-Myers Squibb Co. is testing a monoclonal antibody and expects Phase 2 results in the coming months, according to the company.

Researchers studying the antidepressant fluvoxamine recently reported in the Lancet, a peer-reviewed medical journal, that patients who took the widely available drug were significantly less likely to require hospitalization than those who didn’t. The drug is still being studied, and isn’t yet recommended by the NIH or IDSA. 

Some research has suggested steroid inhalers are helpful at reducing symptoms early in the course of the disease, said David Boulware, an infectious-diseases specialist at the University of Minnesota. He said it is unlikely manufacturers would seek an emergency use authorization because they are widely available, although the NIH and IDSA hasn’t recommended them.

An oral antiviral from Japanese drugmaker Shionogi & Co. is also in clinical trials.

Is ivermectin effective in treating Covid-19?

In the latest trial, researchers testing the antiparasitic drug ivermectin against Covid-19 found that the drug didn’t reduce hospital admissions. The trial, with nearly 1,400 Covid-19 patients at risk of severe disease, is the largest to show that those who received ivermectin as a treatment didn’t fare better than those who received a placebo.

Most prior research hasn’t shown that ivermectin is an effective Covid-19 treatment, physicians say, and the drug isn’t authorized for that use. The FDA has approved ivermectin to treat some parasitic worms, as well as a topical treatment for head lice and skin conditions such as rosacea. It is also used in the U.S. to treat or prevent parasites in animals.

The drug, which was developed years ago by Merck, has been used to prevent river blindness and other diseases in Africa and other places where parasites are common. Prescriptions of the drug have shot up in recent months, and federal health regulators have warned doctors and veterinarians against the unauthorized use of ivermectin to treat Covid-19. 

Can my doctor treat me with hydroxychloroquine?

Numerous studies have found that hydroxychloroquine and chloroquine, approved decades ago to treat and prevent malaria, don’t reduce the severity of Covid-19 symptoms or provide a benefit to patients. Doctors, however, are permitted to write so-called off-label prescriptions, to treat ailments that the FDA hasn’t approved, and some doctors have done so with hydroxychloroquine and chloroquine. 

The drugs, which are also used to treat ailments such as lupus and rheumatoid arthritis, initially received emergency-use authorization, although the FDA later revoked it after concluding the therapies were unlikely to help fight the disease. 

Early in the pandemic hospitals and doctors around the world began treating Covid-19 patients with hydroxychloroquine after several small studies suggested a benefit.

The NIH recommends against the use of hydroxychloroquine in hospitalized or nonhospitalized people, as does the IDSA, which also recommends against it as a prophylactic. 

I’m vaccinated but I contracted Covid-19. Can I use any of the approved treatments?

“Vaccination remains one of the most important factors for us to consider,” said Dr. Abhijit Duggal, a staff ICU physician and director for critical care research for the medical ICU at the Cleveland Clinic. “Anything that we do after that is really trying to minimize the damage associated with the viral infection.”

He said factors that affect treatment decisions in vaccinated people included whether someone has any underlying immunity as well as any comorbidities. Doctors say that while it remains unlikely that vaccinated people will end up in the hospital, those who do will likely be eligible for similar treatments. 

“Once you get hospitalized in breakthrough cases you will get all the usual therapies,” Dr. Duggal said. “Vaccination not only prevents the disease but also ameliorates the severity of disease.” He said some doctors in the U.S. have administered antibody treatments but it isn’t standard treatment and may not be appropriate since the virus infected the patient despite the presence of antibodies from the vaccines. 

What if I am immunocompromised and become infected?

Most of the hospitalized patients who were previously vaccinated are immunocompromised, according to doctors. Hospitalized patients who are immunocompromised are eligible to receive convalescent plasma, a highly concentrated solution of antibodies taken from recovered Covid-19 patients. There is limited data that suggests monoclonal antibody treatments will benefit the immunocompromised, even if they are vaccinated, said Dr. Duggal. 

—Joseph Walker contributed to this article.

Bone Marrow Suppression Secondary to the COVID-19 Booster Vaccine: A Case Report

Authors: Toral Shastri 1Navkiran Randhawa 2Ragia Aly 3Masood Ghouse 3

PMID: 35210894 PMCID: PMC8863340DOI: 10.2147/JBM.S350290

Abstract

As of September 2021, SARS-CoV-2 booster shots became widely available in the US to ensure continued protection against the virus. A temporal relationship has been previously reported between the first or second dose of the COVID-19 vaccine and the development of thrombocytopenia. However, adverse events related to the third COVID-19 vaccine are still being reported and studied. We report a 74-year-old male who developed bone marrow suppression and pancytopenia recorded seven days after receiving the Pfizer SARS-CoV-2 vaccine. During his hospital stay, the patient’s hemoglobin, white blood cell, and platelet levels continued to trend downwards. However, all three levels showed improvement one week after discharge without robust intervention. Global vaccination is of utmost importance, as is understanding and documenting post-vaccination reactions including bone marrow suppression. Prompt evaluation and patient education are imperative to improve patient outcomes and combat hesitancy against vaccine administration.

Introduction

Since its emergence in December of 2019, the rapid spread of severe acute respiratory syndrome coronavirus (SARS-CoV-2) has quickly affected millions of lives across every continent.1 This highly transmittable and pathogenic viral infection has led to massive mitigation efforts and allocation of resources to prevent the spread of transmission and high mortality related to complications.2 The establishment of higher levels of community (herd) immunity and protection against SARS-CoV-2 via the widespread deployment of effective vaccines has become a global effort.3 In December of 2020, the FDA issued an Emergency use Authorization for the Pfizer-BioNTech and Moderna COVID-19 Vaccine as a two-dose series.4 In September 2021, booster vaccines became widely administered in the US due to waning immunity of the COVID-19 vaccines against variants of SARS-CoV-2 along with ensuring continued protection against the virus.5

Serious adverse events such as anaphylaxis, Guillain-Barre Syndrome, myocarditis, pericarditis, thrombocytopenia, and death have been previously reported following the first and/or second dose of vaccine.6 To our knowledge, no cases have been reported regarding bone marrow suppression related to the third COVID-19 vaccine. Adverse events reported between August 12-September 19, 2021 from the COVID-19 booster vaccine supported similar reactions to those after dose two.7 According to the Centers for Disease Control and Prevention (CDC), these initial findings indicate no unexpected patterns of adverse reactions after an additional dose of COVID-19 vaccination.7 However, adverse events related to the COVID-19 booster are still being reported and studied.6 This report presents a case of bone marrow suppression occurring after the third COVID-19 vaccine without a similar reaction after the first or second dose.Go to:

Case Report

A 74-year-old male with a history of polychondritis and hypothyroidism presented to the hospital after falling out of his chair and inability to ambulate. The patient was found to be mildly confused upon arrival to the emergency room, limiting our ability to obtain a full verbal history. Chart review revealed the patient had received his third Pfizer Covid vaccine shot seven days before admission followed by fatigue, decreased appetite, fever, and chills. The patient had received the second Pfizer Covid-19 shot nine months before the booster. No reactions to the previous two shots were noted.

Upon initial evaluation, vital signs were within normal limits and a physical exam revealed significant tenderness in the upper arm and no gross bleeding (Figure 1). Computed tomography (CT) imaging (Figure 2) was significant for enhancement of the left axillary lymph node. The patient’s initial complete blood count (CBC) was remarkable for a hemoglobin count of 9.9 g/dl and platelet count of 84 x 109/L; both values lower than his prior hemoglobin count of 13.7 g/dl and platelet count of 180 x 109/L from December of 2020. His mean corpuscular volume (MCV) was elevated at 101.3 femtolitres from his prior MCV value of 95.8 femtolitres in December of 2020. His white blood cell (WBC) count was recorded at 7.6 x 109/L.

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Figure 1

The patient’s upper arm showed erythema with no gross bleeding near the injection site

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Figure 2

The patient’s CT imaging of the thoracic region showed enhancement of the left axillary lymph node.

The hemoglobin, WBC, and platelet count further down trended from his baseline (Figures 3​5).5). Anemia labs including ferritin levels (554 ng/mL), vitamin B12 (253 pg/mL), total bilirubin (0.5 mg/dL), and reticulocyte count (0.8%) were nonsignificant during the patient’s hospital stay. The patient’s left shoulder presented with extensive bruising, erythema, papular rash, warmth, and tenderness on palpation during the hospitalization. An improvement in WBC and platelet levels was noted on day 4 of hospitalization.

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Figure 3

The patient’s hemoglobin count throughout his hospital course and 6 days after discharge.

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Figure 4

The patient’s WBC count throughout his hospital course and 6 days after discharge.

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Figure 5

The patient’s platelet count throughout his hospital course and 6 days after discharge.

Before discharge, the patient was fully alert and oriented and reported improvement in his symptoms. Examination of his lateral left arm showed decreased erythema and bruising with slight petechiae. The patient was discharged due to stabilization of labs and encouraged to take oral vitamin B12 supplements. During his outpatient follow-up six days after hospitalization, his hemoglobin increased to 10.5 g/dl, WBC count increased to 4.9 x 109/L, and platelets increased to 101 x 109/L.

Discussion

This paper presents a patient with pancytopenia recorded seven days after receiving the Pfizer booster vaccine. Interestingly, this patient did not report any reactions after the first or second dose of the Pfizer vaccine against SARS-CoV-2. Pancytopenia refers to a decrease in all peripheral bloodlines and is present when all three cell lines are below the normal reference range.8 The patient’s physical exam showed no signs of active bleeding along with his labs indicating no evidence of hemolysis. The patient’s hemoglobin, platelet, and white blood cell count presented below baseline followed by a decrease and slight improvement during his hospital stay. Six days after hospitalization, all three cell lines showed improvement. The temporal association with the booster vaccine and negative infectious disease workup raised suspicion for vaccine-induced bone marrow suppression. In addition, the patient’s reticulocyte count and lactate dehydrogenase value were consistent with hypoproliferation within the bone marrow.

Currently, there is a gap in knowledge of adverse events specific to the third vaccine against SARS-CoV-2 due to the recent initiation of administration and ongoing reporting of events.6 To our knowledge, bone marrow suppression after any dose of vaccine against SARS-CoV-2 has not been previously reported. However, a prior case of pancytopenia after the third vaccination with a recombinant hepatitis B vaccine has previously been reported.9 The patient’s bone marrow biopsy within this case displayed a paucity of late myeloid elements and CD8+ T cells.9 It was believed the patient’s CD8+T cells were causing excessive production of IFN-γ; a stimulant of negative regulators of hematopoiesis such as tumor necrosis factor and lymphotoxin.10 IFN-γ has also previously been reported to create immunological effects comprising an upregulation of histocompatibility gene transcription and alteration in class I and II antigen expression at the cell surface.11 It was predicted these changes resulted in an autoimmune reaction causing suppression of maturation of hematopoietic progenitor cells and pancytopenia.9 Via a similar mechanism, we believe that our patient’s pancytopenia was immune-mediated, potentially triggered by the vaccination.

Vaccines against SARS-CoV-2 (first or second dose) and the induction of Idiopathic Thrombocytopenic Purpura (ITP) have also been recently acknowledged in multiple cases.12 Our patient presented with low platelet levels and associated petechiae and purpura at the site of the vaccination. However, the patient’s presentation of low hemoglobin and white blood cells along with normal reticulocyte levels was more indicative of pancytopenia secondary to bone marrow suppression. In patients presenting with pancytopenia, the history and the physical exam should help assess the severity of the pancytopenia and comorbid illnesses that may complicate the disorder.13 In addition, suspicious medications and exposure to toxic agents should be ruled out.13 Initial screening laboratory evaluation should include the patient’s complete blood count, peripheral blood smear examination, reticulocyte count, complete metabolic panel, prothrombin time/partial thromboplastin time, and blood type and screen. Common interventions to alleviate bone marrow suppression and pancytopenia include treating the underlying cause and utilizing supplements to boost red blood cell production if indicated.

Vaccines against SARS-CoV-2 undergo continuous safety monitoring; adverse events are very rare.14 However, vaccine hesitancy remains a barrier towards full population inoculation against SARS-CoV-2 and is influenced by misinformation regarding vaccine safety.15 One study using an anonymous online questionnaire found a person’s trust in the effectiveness of the vaccine was a major facilitative factor affecting willingness to vaccinate.16 The same study also found that 66.7% of unvaccinated participants thought the vaccine’s safety was not enough, making it the main reason for reluctance or hesitance to be vaccinated.16 Therefore, education of adverse events and available interventions post-vaccination is imperative to prevent the spread of misinformation and combat hesitancy towards vaccination.15

As of September 19, 2021, about 2.2 million people in the United States received a third vaccine against SARS-CoV-2.17 Among those who received the vaccine, 22,000 people reported the effects of the vaccine with no unexpected patterns of adverse reactions.17 Our patient demonstrates abnormal pancytopenia first recorded seven days after receiving the booster vaccine, possibly indicating a rare adverse event from the vaccination given the temporal relationship. While additional studies and observations are indicated to verify bone marrow suppression as an adverse reaction, this case report provides an opportunity for patient education and treatment planning before symptoms arise.

Conclusion

Our case report highlights pancytopenia secondary to bone marrow suppression following Pfizer vaccination against SARS-CoV-2. It is important to consider the possibility of bone marrow suppression following the third vaccine against SARS-CoV-2. Although additional studies are indicated to determine the risk factors and pathogenesis of vaccine-induced bone marrow suppression, prompt evaluation and initiation of interventions can improve patient outcomes

Consent for Publication

Institutional approval was not required to publish the case details. The publication of this study has been consented to by the patient.

Disclosure

The authors report no conflicts of interest in this work.

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Protection against Covid-19 by BNT162b2 Booster across Age Groups

Authors. Yinon M. Bar-On, M.Sc., Yair Goldberg, Ph.D., Micha Mandel, Ph.D., Omri Bodenheimer, M.Sc., Laurence Freedman, Ph.D., Sharon Alroy-Preis, M.D., Nachman Ash, M.D., Amit Huppert, Ph.D., and Ron Milo, Ph.D.

Abstract

BACKGROUND

After promising initial results from the administration of a third (booster) dose of the BNT162b2 messenger RNA vaccine (Pfizer–BioNTech) to persons 60 years of age or older, the booster campaign in Israel was gradually expanded to persons in younger age groups who had received a second dose at least 5 months earlier.

METHODS

We extracted data for the period from July 30 to October 10, 2021, from the Israel Ministry of Health database regarding 4,696,865 persons 16 years of age or older who had received two doses of BNT162b2 at least 5 months earlier. In the primary analysis, we compared the rates of confirmed coronavirus disease 2019 (Covid-19), severe illness, and death among those who had received a booster dose at least 12 days earlier (booster group) with the rates among those who had not received a booster (nonbooster group). In a secondary analysis, we compared the rates in the booster group with the rates among those who had received a booster 3 to 7 days earlier (early postbooster group). We used Poisson regression models to estimate rate ratios after adjusting for possible confounding factors.

RESULTS

The rate of confirmed infection was lower in the booster group than in the nonbooster group by a factor of approximately 10 (range across five age groups, 9.0 to 17.2) and was lower in the booster group than in the early postbooster group by a factor of 4.9 to 10.8. The adjusted rate difference ranged from 57.0 to 89.5 infections per 100,000 person-days in the primary analysis and from 34.4 to 38.3 in the secondary analysis. The rates of severe illness in the primary and secondary analyses were lower in the booster group by a factor of 17.9 (95% confidence interval [CI], 15.1 to 21.2) and 6.5 (95% CI, 5.1 to 8.2), respectively, among those 60 years of age or older and by a factor of 21.7 (95% CI, 10.6 to 44.2) and 3.7 (95% CI, 1.3 to 10.2) among those 40 to 59 years of age. The adjusted rate difference in the primary and secondary analyses was 5.4 and 1.9 cases of severe illness per 100,000 person-days among those 60 years of age or older and 0.6 and 0.1 among those 40 to 59 years of age. Among those 60 years of age or older, mortality was lower by a factor of 14.7 (95% CI, 10.0 to 21.4) in the primary analysis and 4.9 (95% CI, 3.1 to 7.9) in the secondary analysis. The adjusted rate difference in the primary and secondary analyses was 2.1 and 0.8 deaths per 100,000 person-days.

CONCLUSIONS

Across the age groups studied, rates of confirmed Covid-19 and severe illness were substantially lower among participants who received a booster dose of the BNT162b2 vaccine than among those who did not.

VISUAL ABSTRACTProtection against Covid-19 by BNT162b2 Booster across Age Groups

After a resurgence of confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and severe coronavirus disease 2019 (Covid-19) illness in Israel,1 Israeli authorities approved on July 30, 2021, the administration of a booster dose of the BNT162b2 messenger RNA vaccine (Pfizer–BioNTech) for persons 60 years of age or older who had received a second dose of vaccine at least 5 months earlier. Initial reports have indicated that the booster dose was effective in reducing the rates of confirmed infection and severe disease against the currently dominant B.1.617.2 (delta) variant in the elderly population.2,3 Consequently, the booster campaign was extended to younger age groups in a stepwise manner: on August 13 for those 50 to 59 years of age, on August 20 for those 40 to 49 years of age, on August 24 for those 30 to 39 years of age, and on August 29 for all persons 12 years of age or older.

Although observational studies suggest that the booster dose is effective against both confirmed infection and severe disease in the elderly population, the extent of protection of an additional dose in younger age groups requires further clarification. Here, we quantified the booster effect on the adult population (≥16 years of age) relying on the analytical framework used to estimate the effectiveness of the booster dose in the population 60 years of age or older.2 The results also extend our previous analysis of the effect of the booster dose among those 60 years of age or older with a longer follow-up time and with Covid-19–associated death as an outcome.

Methods

GENERAL APPROACH

Our methods are similar to those applied by Bar-On et al.2 with minor modifications. Full details are provided in the Methods section in Bar-On et al.2 and in the protocol of that study, available with the full text of that article at NEJM.org.

Our analysis is based on data from the Israel Ministry of Health database; details about the database are provided in the Supplementary Methods 1 section in the Supplementary Appendix, available with the full text of this article at NEJM.org. Following the methods of Bar-On et al.,2 we extracted on October 12, 2021, data regarding Israeli residents 16 years of age or older who had been fully vaccinated (i.e., received two doses of BNT162b2) at least 5 months before the end of the study and were alive on the date that their age group became eligible for the booster dose, totaling 5,065,502 persons. Similarly to Bar-On et al.,2 we excluded from the analysis persons whose data did not include information regarding sex or area of residence; who had tested positive for SARS-CoV-2 on a polymerase-chain-reaction (PCR) assay before the date that their age group became eligible; who had received a booster dose before July 30, 2021; who had been abroad during the entire study period (persons were considered as being abroad in the period from 10 days before to 10 days after their return to Israel); or who had been fully vaccinated before January 16, 2021. A total of 4,696,865 persons met the inclusion criteria for the analysis (Figure 1).

The extracted data included vaccination dates (first, second, and third doses); information regarding PCR testing (sampling dates and results); the date of any Covid-19–related hospitalization; demographic variables, such as age, sex, and area of residence; demographic group (general Jewish, Arab, or ultra-Orthodox Jewish population), as determined by the participant’s statistical area of residence (similar to a census block)4; clinical status (mild or severe disease); and vital status. Severe disease was defined according to the National Institutes of Health Covid-19 treatment guidelines5 as a resting respiratory rate of more than 30 breaths per minute, an oxygen saturation of less than 94% while breathing ambient air, or a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of less than 300.6

STUDY DESIGN

Each participant’s study period started on the date of becoming eligible to receive the booster dose — that is, when the booster became available for that participant’s age group and more than 5 months had passed since receipt of the second dose (the latter of these two events). The end dates were chosen as October 10, 2021, for confirmed infection; October 5, 2021, for severe illness; and September 7, 2021, for death. The dates for confirmed infection, severe illness, and death were chosen to allow at least 2 days for the PCR result, 7 days for the development of severe illness, and 35 days for death. For participants who were abroad during part of the study period, we excluded days at risk and Covid-19 outcomes during the period from 10 days before to 10 days after their return to Israel.

As in our previous study,2 we calculated the rates of confirmed infection, severe illness, and death due to Covid-19 per person-days at risk in different dynamic groups: participants who had received a booster dose at least 12 days earlier (booster group) were compared with those who had not yet received the booster dose (nonbooster group) and, in a secondary analysis, with participants who had received a booster dose 3 to 7 days earlier (early postbooster group). The times of onset of severe Covid-19 and death were designated as the test date of confirmed infection.

OVERSIGHT

The study was approved by the institutional review board of the Sheba Medical Center. All the authors contributed to the writing and critical review of the manuscript, approved the final version, and made the decision to submit the manuscript for publication. The Israel Ministry of Health and Pfizer have a data-sharing agreement, but only the final results of this study were shared with Pfizer.

STATISTICAL ANALYSIS

We used the methods implemented by Bar-On et al.2 with several modifications (details and comparisons with the original methods are provided in the Supplementary Analysis 2 section in the Supplementary Appendix). Briefly, we performed Poisson regression to estimate the rate of a specific outcome in a specific vaccination group, using the function for fitting generalized linear models in R statistical software.7 These analyses were adjusted for the following covariates: sex, age group (16 to 29 years, 30 to 39 years, 40 to 49 years, 50 to 59 years, 60 to 69 years, 70 to 79 years, and ≥80 years), demographic group (general Jewish, Arab, and ultra-Orthodox Jewish population),4 and the date of the second vaccine dose (in half-month intervals). In addition, we accounted for environmental risk by including, as a time-varying covariate, a daily exposure risk index similar to that used by Goldberg et al.8 based on the number of confirmed infections in the participant’s area of residence during the past 7 days per 1000 residents. We categorized this quantity into 10 risk groups using the deciles of the variable. The 7-day moving average was chosen because the number of PCR tests typically drops on weekends.

We estimated adjusted rate ratios for confirmed infection, severe disease, and death due to Covid-19 between the booster group and the nonbooster group in different age groups by including interaction terms between age category and study group. The age categories for estimating the rate ratio were 16 to 29 years, 30 to 39 years, 40 to 49 years, 50 to 59 years, and 60 or more years for confirmed infection; 40 to 59 years and 60 or more years for severe disease; and 60 or more years for death due to Covid-19. Grouping those 60 years of age or older allowed comparison with our previous estimates2 (see the Supplementary Analysis 3 section and Tables S13 and S14 in the Supplementary Appendix for results involving a finer age subdivision). We restricted estimation of rate ratios to more limited age groups for severe disease (40 to 59 years and ≥60 years) and death (≥60 years) owing to smaller numbers of cases. Besides rate ratios, adjusted rate differences9 were estimated between the various age groups (see the Supplementary Methods 2 section in the Supplementary Appendix). Uncertainty around rate ratio estimates was calculated by the exponent of the 95% confidence interval for the regression coefficient without adjustment for multiplicity.

In an additional analysis, we calculated the rate ratio of confirmed infection as a function of time after receipt of the booster dose. To this end, for each age group (16 to 29 years, 30 to 39 years, 40 to 49 years, 50 to 59 years, and ≥60 years), we fitted a Poisson regression that included days after receipt of the booster dose as factors in the model. Each day until 12 days after receipt of the booster dose was considered as a separate factor, and days from day 12 onward were binned into intervals of 3 days (12 to 14 days, 15 to 17 days, and so on). The reference category comprised person-days before receipt of the booster dose.

As a sensitivity analysis, we analyzed the data using an alternative statistical method that relies on matching, similar to the method used by Dagan et al.10 (see the Supplementary Analysis 1 section and Table S15 in the Supplementary Appendix). Briefly, each person who received a booster dose was matched with a person who had not yet received the booster and who shared a similar risk profile (on the basis of personal characteristics). The probabilities of confirmed infection during the period from day 12 after the booster dose until the end of the study were estimated for those receiving and those not receiving the booster dose with the use of the Kaplan–Meier method10 and were compared.

Results

STUDY POPULATION

Demographic and Clinical Characteristics of the Study Population.

Table 1 presents the characteristics of the participants in the booster, early postbooster (days 3 to 7), and nonbooster groups in terms of person-days at risk. We provide details on all model covariates in Table S3 and the same information within each age group in Tables S4 through S8.

The nonbooster group included approximately 98 million person-days, with 83,481 confirmed infections, 1171 cases of severe illness, and 298 deaths. The booster group included approximately 104 million person-days, with 6160 confirmed infections, 175 cases of severe illness, and 35 deaths. The early postbooster group included approximately 17 million person-days, with 8880 confirmed infections, 136 cases of severe illness, and 46 deaths. The percentage of person-days at risk was higher in the booster group than in the nonbooster group with respect to the general Jewish population (88.8% vs. 70.8%), an age of 70 years or older (28.6% vs. 11.2%), and receipt of a second vaccination dose in January 2021 (42.2% vs. 12.7%), and the percentage was lower in the booster group than in the nonbooster group with respect to an age younger than 40 years (18.5% vs. 46.9%). The early postbooster group was closer in its characteristics to the booster group, but the percentage of person-days at risk was higher in the booster group than in the early postbooster group with respect to an age of 70 years or older (28.6% vs. 18.6%) and receipt of a second vaccination dose in January 2021 (42.2% vs. 29.6%), and the percentage was lower in the booster group than in the early postbooster group with respect to an age younger than 40 years (18.5% vs. 32.9%). We adjusted for these substantial between-group differences by including these variables as covariates in the Poisson regression model.

EFFECT OF THE BOOSTER DOSE ACROSS AGE GROUPS

Poisson Regression Analysis of Severe Illness and Death Due to Coronavirus Disease 2019 in the Older Age Groups.

The detailed results of the Poisson regression analysis for confirmed infection, severe illness, and death are provided in Tables S9 through S12 and are summarized in Table 2 and Table 3. The rate of confirmed infection was lower in the booster group than in the nonbooster group by a similar factor across age groups: 12.3 (95% confidence interval [CI], 11.8 to 12.8) among those 60 years of age or older, 12.2 (95% CI, 11.4 to 13.0) among those 50 to 59 years of age, 9.7 (95% CI, 9.2 to 10.3) among those 40 to 49 years of age, 9.0 (95% CI, 8.4 to 9.7) among those 30 to 39 years of age, and 17.2 (95% CI, 15.4 to 19.2) among those 16 to 29 years of age. The adjusted difference in the rate of confirmed infection between the nonbooster group and the booster group was 57.0 infections per 100,000 person-days among those 60 years of age or older, 69.0 among those 50 to 59 years of age, 81.7 among those 40 to 49 years of age, 89.5 among those 30 to 39 years of age, and 72.2 among those 16 to 29 years of age. The rate of confirmed infection at least 12 days after receipt of the booster dose was also substantially lower than the rate 3 to 7 days after receipt of the booster. The infection rate was lower by a factor of 7.4 (95% CI, 7.0 to 7.8) among those 60 years of age or older, by 7.2 (95% CI, 6.7 to 7.9) among those 50 to 59 years of age, by 5.4 (95% CI, 5.0 to 5.8) among those 40 to 49 years of age, by 4.9 (95% CI, 4.5 to 5.3) among those 30 to 39 years of age, and by 10.8 (95% CI, 9.6 to 12.2) among those 16 to 29 years of age.

The rate of severe illness was lower in the booster group than in the nonbooster group across the two age groups studied: by a factor of 17.9 (95% CI, 15.1 to 21.2) among those 60 years of age or older and by a factor of 21.7 (95% CI, 10.6 to 44.2) among those 40 to 59 years of age. The adjusted difference in the rate of severe illness between the nonbooster group and the booster group was 5.4 cases per 100,000 person-days among those 60 years of age or older and 0.6 cases per 100,000 person-days among those 40 to 59 years of age. In the secondary analysis, the rate of severe illness 12 or more days after the booster was lower than the rate 3 to 7 days after the booster by a factor of 6.5 (95% CI, 5.1 to 8.2) among those 60 years of age or older and by a factor of 3.7 (95% CI, 1.3 to 10.2) among those 40 to 59 years of age. The rate of severe disease in the youngest age groups (16 to 29 and 30 to 39 years of age) was very low, and there were not enough cases to estimate the rate ratio reliably (26 cases in the nonbooster group, 1 case in the booster group, and no cases in the early postbooster group).

Among participants 60 years of age or older, the rate of Covid-19–associated death in the booster group was lower than in the nonbooster group by a factor of 14.7 (95% CI, 10.0 to 21.4). The adjusted rate difference between the nonbooster group and the booster group was 2.1 cases per 100,000 person-days. The rate of Covid-19–associated death 12 or more days after receipt of the booster dose was lower than the rate 3 to 7 days after receipt of the booster by a factor of 4.9 (95% CI, 3.1 to 7.9). Reduction in Rate of Confirmed Infection in the Booster Group as Compared with the Nonbooster Group.

We also estimated the reduction in the rate of confirmed infection in the booster group as compared with the nonbooster group as a function of time after booster vaccination across the different age groups. As shown in Figure 2, a similar temporal pattern was seen in the different age groups: the rate of confirmed infection was lower in the booster group than in the nonbooster group by a factor of approximately 10. Of note, in all age groups, the rate of confirmed infection was lower in the early postbooster group than in the nonbooster group. We provide details on the possible source for this effect in the Discussion section.

The sensitivity analysis that used matching resulted in the following estimates (summarized in Table S15) for the factor by which the rate of confirmed infection in the booster group was lower than that in the nonbooster group: 9.5 (95% CI, 7.8 to 11.4) among those 60 years of age or older, 9.4 (95% CI, 5.2 to 13.0) among those 50 to 59 years of age, 8.4 (95% CI, 6.2 to 10.6) among those 40 to 49 years of age, 7.3 (95% CI, 5.7 to 8.7) among those 30 to 39 years of age, and 13.3 (95% CI, 5.9 to 18.8) among those 16 to 29 years of age. For severe illness, this approach yielded an estimated factor of 12.4 (95% CI, 4.3 to 30.4) among those 60 years of age or older.

Discussion

We sought to determine whether the booster dose had a similar effect across different age groups and have indeed found that the booster dose reduced the rate of confirmed infection and severe illness by a similar factor in the age groups studied (although in the youngest age group, a larger reduction factor against confirmed infections was observed). The temporal pattern of the rate ratio between the booster group and the nonbooster group after booster vaccination was also similar across age groups. These findings are consistent with those of the phase 2–3 clinical trial of the BNT162b2 vaccine,11 in which vaccine efficacy was similar across age groups.

Although in our primary analysis we attempted to address confounding and detection bias, some sources of bias may not have been measured or corrected adequately. These biases might include differences between booster recipients and those who chose not to receive the booster with respect to risk-avoidance behaviors and coexisting conditions, neither of which are recorded in the national database. Moreover, participants’ risk-avoidance behavior and propensity to perform PCR tests are probably modified after receipt of the booster dose. In our secondary analysis, we tried to reduce the extent of confounding bias between the booster group and the nonbooster group by focusing solely on persons who received the booster dose and comparing rates during a period in which the booster was expected to have a small effect (days 3 to 7 after vaccination) with those during a period in which it had become effective (≥12 days after vaccination).

Although this type of analysis reduces confounding bias, because all participants potentially contribute days at risk to both groups, estimates of the rate ratio during the first days after vaccination could include the effect of transient biases. These potential biases include the “healthy vaccinee” bias,12 in which people who feel ill tend not to get vaccinated in the following days, leading to a lower number of infections in the booster group during the first days after vaccination. Moreover, one would expect that detection bias due to behavioral changes such as the tendency to perform fewer PCR tests after booster vaccination is more pronounced just after receiving the dose (days 3 to 7) and that this bias declines over time. Thus, potential behavioral biases under this approach are expected to underestimate the true rate ratio. The secondary analysis showed a decrease in the rate of confirmed infection across age groups by a factor of approximately 5. Although the primary and secondary analyses were exposed to different biases and resulted in somewhat different estimates, both suggested a notable reduction in the rate of confirmed infections. With respect to severe illness in the booster group as compared with the nonbooster group (Table 3), the analysis shows decreased rates of severe Covid-19 in both age groups considered, but with wider confidence intervals owing to the lower number of cases of severe illness in those 40 to 59 years of age.

As compared with our previous analysis of the elderly population,2 we made two methodologic modifications in the current analysis. First, instead of including indicators for calendar dates in order to adjust for exposure risk, we calculated a spatial–temporal index of risk according to the number of infections in each area of residence. This method better measures the exposure risk for each participant. Second, in our secondary analysis, we compared the rates 12 or more days after receipt of the booster with the rates 3 to 7 days after its receipt, instead of 4 to 6 days. This change was made to increase the number of person-days at risk in the early postbooster group and enabled us to apply the secondary analysis to severe Covid-19 as well.

Understanding the protective effect of the booster dose in younger age groups is key for forming public health policy. Booster vaccination programs may provide a way to control transmission without costly social-distancing measures and quarantines. Our findings provide evidence for the short-term effectiveness of the booster dose against the currently dominant delta variant in persons 16 years of age or older. Future studies will help determine the longer-term effectiveness of the booster dose against current and emerging variants.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Mr. Bar-On and Dr. Goldberg and Drs. Huppert and Milo contributed equally to this article.

This article was published on December 8, 2021, at NEJM.org.

COVID-19 vaccine surveillance report Week 3

Latest UK Data Shows Covid Infection RATE Among the Triple Jabbed (Boosted) Is HIGHER And RISING FASTER Than The Unvaccinated Across ALMOST EVERY Age Group

20 January 2022

Executive summary
Four coronavirus (COVID-19) vaccines have now been approved for use in the UK. Rigorous
clinical trials have been undertaken to understand the immune response, safety profile and
efficacy of these vaccines as part of the regulatory process. Ongoing monitoring of the vaccines
as they are rolled out in the population is important to continually ensure that clinical and public health guidance on the vaccination program is built upon the best available evidence. UK Health Security Agency (UKHSA), formerly Public Health England (PHE), works closely with the Medicines and Healthcare Regulatory Agency (MHRA), NHS England, and other government, devolved administration and academic partners to monitor the COVID-19 vaccination program. Details of the vaccine surveillance strategy are set on the page COVID-19: vaccine surveillance strategy (1). As with all vaccines, the safety of COVID-19 vaccines is continuously being monitored by the MHRA. They conclude that overall, the benefits of COVID-19 vaccines outweigh any potential risks (2).

Vaccine effectiveness

Several studies of vaccine effectiveness have been conducted in the UK against different
COVID-19 variants. Vaccine effectiveness against symptomatic disease with the Omicron
variant is substantially lower than against the Delta variant, with rapid waning. However,
protection against hospitalisation remains high, particularly after 3 doses.

Population impact

The impact of the vaccination program on the population is assessed by taking into account
vaccine coverage, evidence on vaccine effectiveness and the latest COVID-19 disease surveillance indicators. Vaccine coverage tells us about the proportion of the population that have received 1, 2 and 3 doses of COVID-19 vaccines. By 16 January 2022, the overall vaccine uptake in England for dose 1 was 68.9% and for dose 2 was 63.6%. Overall vaccine uptake in England in people with at least 3 doses was 48.4%. In line with the program rollout, coverage is highest in the oldest age groups.

We present data on COVID-19 cases, hospitalizations and deaths by vaccination status. These
raw data should not be used to estimate vaccine effectiveness as the data does not take into account inherent biases present such as differences in risk, behavior and testing in the
vaccinated and unvaccinated populations. Vaccine effectiveness is measured in other ways as
detailed in the ‘Vaccine Effectiveness’ section. Based on antibody testing of blood donors, 98.7% of the adult population now have antibodies to COVID-19 from either infection or vaccination compared to 24.1% that have antibodies from infection alone.

COVID-19 vaccine surveillance report – week 3- 4

Vaccine effectiveness

Large clinical trials have been undertaken for each of the COVID-19 vaccines approved in the
UK which found that they are highly efficacious at preventing symptomatic disease in the
populations that were studied. The clinical trials have been designed to be able to assess the
efficacy of the vaccine against laboratory confirmed symptomatic disease with a relatively short follow up period so that effective vaccines can be introduced as rapidly as possible. Post implementation real world vaccine effectiveness studies are needed to understand vaccine effectiveness against different outcomes (such as severe disease and onwards transmission), effectiveness in different subgroups of the population and against different variants as well as to understand the duration of protection. Vaccine effectiveness is estimated by comparing rates of disease in vaccinated individuals to rates in unvaccinated individuals.

Below we outline the latest real-world evidence on vaccine effectiveness from studies in UK
populations. Where available we focus on data related to the Omicron variant which is currently dominant in the UK. The findings are also summarized in Table 2.

Effectiveness against symptomatic disease

Vaccine effectiveness against symptomatic COVID-19 has been assessed in England based on
community testing data linked to vaccination data from the National Immunisation Management
System (NIMS), cohort studies such as the COVID Infection Survey and GP electronic health
record data. After 2 doses of AstraZeneca vaccine, vaccine effectiveness against the Omicron
variant starts at 45 to 50% then drops to almost no effect from 20 weeks after the second dose.
With 2 doses of Pfizer or Moderna effectiveness dropped from around 65 to 70% down to
around 10% by 20 weeks after the 2nd dose. 2 to 4 weeks after a booster dose of either the
Pfizer or Moderna vaccine, effectiveness ranges from around 65 to 75%, dropping to 55 to 65%
at 5 to 9 weeks and 45 to 50% from 10+ weeks after the booster. Vaccine effectiveness
estimates for the booster dose are very similar, irrespective of the primary course received (3).
Vaccine effectiveness is generally slightly higher in younger compared to older age groups.

SEE FULL REPORT by selecting link below:

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1049160/Vaccine-surveillance-report-week-3-2022.pdf

Experts said that in people who had been vaccinated five months earlier, the booster increased vaccine efficacy tenfold compared with vaccinated patients who didn’t receive it.

By ILAN BEN ZIONyesterday

JERUSALEM (AP) — Israel is pressing ahead with its aggressive campaign of offering coronavirus boosters to almost anyone over 12 and says its approach was further vindicated by a U.S. decision to give the shots to older patients or those at higher risk.

Israeli officials credit the booster shot, which has already been delivered to about a third of the population, with helping suppress the country’s latest wave of COVID-19 infections. They say the differing approaches are based on the same realization that the booster is the right way to go, and expect the U.S. and other countries to expand their campaigns in the coming months.

“The decision reinforced our results that the third dose is safe,” said Dr. Nadav Davidovitch, head of the school of public health at Israel’s Ben-Gurion University and chairman of the country’s association of public health physicians. “The main question now is of prioritization.”

The World Health Organization has called for a moratorium on boosters until at least the end of the year so that more people in poor countries can get their first two doses, but Israeli officials say the booster shot is just as important in preventing infections.

“We know for sure that the current system of vaccine nationalism is hurting all of us, and it’s creating variants,” said Davidovitch, who is also a member of an Israeli government panel of experts. But he added that the problem is “much broader than Israel.”

Israel raced out of the gate early this year to vaccinate most of its adult population after striking a deal with Pfizer to trade medical data in exchange for a steady supply of doses. It has also purchased large quantities of the Moderna and AstraZeneca vaccines.

Most adults had received two doses of the Pfizer vaccine by March, causing infection levels to plummet and allowing the government to lift nearly all coronavirus restrictions.

But in June, the highly infectious delta variant began to spread. After studying the matter, experts concluded that the vaccine remained effective against the virus, but that its efficacy waned roughly five months after the second shot.

In late July, Israel began distributing booster shoots to at-risk citizens, including those over 60. Within weeks, it expanded the campaign to the general population.

More than 3 million of Israel’s 9 million citizens have gotten a third dose of the Pfizer vaccine, according to the Health Ministry.

In a study published last week in the New England Journal of Medicine, Israeli experts said that in people who had been vaccinated five months earlier, the booster increased vaccine efficacy tenfold compared with vaccinated patients who didn’t receive it.

That study tracked about 1 million people 60 and older and found that the booster was “very effective at reducing the rate of both confirmed infection and severe illness,” the Health Ministry said.

A senior Israeli health official, Dr. Sharon Alroy Preiss, was among the experts testifying before the U.S. Food and Drug Administration panel last week in favor of the booster shot. But the regulator decided against boosters for the general population, opting only to authorize it for people aged 65 or older and those in high-risk groups.

Experts cited a lack of safety data on extra doses and also raised doubts about the value of mass boosters, rather than ones targeted to specific groups. The U.S. Centers for Disease Control and Prevention made a similar endorsement Thursday.

The Israeli Health Ministry said the FDA decision “gave validity to the third vaccine operation” underway in Israel, which “decided to act responsibly and quickly in order to treat growing infections.” It said statistics show the booster dose has “restored protection.”

Recent weeks have seen “a declining rate of new infections among the elderly,” the vast majority of whom have received booster shots, and “a continuous increase in the proportion of unvaccinated individuals within the new severe cases,” Dr. Ran Balicer, head of the government’s expert advisory panel on COVID-19, told The Associated Press.

In recent weeks, as the booster campaign has been rolled out, the percentage of unvaccinated among serious COVID-19 cases has climbed, and the overall new cases among people with at least two shots has dropped.

As of Friday, around 70% of Israel’s 703 serious cases of COVID-19 were among the unvaccinated, and about 20% had not received a booster. A month earlier, after Israel vaccinated 1.5 million people with a third dose, those two groups were equally represented among the serious cases.

Over 60% of Israelis — the overwhelming majority of the adult population — have received at least two doses of the coronavirus vaccine.

Some experts noted that the U.S. and Europe were several months behind Israel’s vaccination campaign and predicted those countries would follow suit in the months ahead.

“We are experiencing first a phenomenon that will become apparent likely in many other countries in the coming months and create a similar challenge there,” Balicer said. “Few, if any at all, other countries are walking in our shoes right now.”

The U.K. already is rolling out a booster campaign, with third doses to be offered to anyone over 50 and other vulnerable groups.

The WHO has called on rich countries to refrain from exhausting vaccine stockpiles on boosters while much of the world has yet to receive any. A third shot may be necessary for people with certain health conditions, but “boosters for the general public are not appropriate at this stage of the pandemic,” it said.

“The longer vaccine inequity persists, the more the virus will circulate and change, the longer social and economic disruptions will continue, and the higher the chances that more variants will emerge that render vaccines less effective,” it said in a statement Friday.

Balicer said that Israel, as a small country, has little effect on global supplies and that its role as the world’s laboratory provides “a very important source of knowledge” for other countries.

Israeli Prime Minister Naftali Bennett has exhorted the public to get vaccine boosters as part of his aggressive public relations campaign since taking office in June.

“Israel is the only country in the world that is giving its citizens this gift of the possibility — both legally and in terms of supply — of a booster,” he said last week.

Balicer said other states should ready national plans for the rollout of booster shots.

“Countries that vaccinated more recently should be prepared for the impact of waning vaccine immunity manifesting in midwinter, further intensifying the challenge,” he said.

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