Coronavirus Updates February 2024

[missy]

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State of Affairs: Feb 6​

Still a lot of sickness out there, marking the longest respiratory season since the beginning of the pandemic.​

KATELYN JETELINA FEB 6

After a few weeks of nosediving, things are, unfortunately, stabilizing. Does it feel like this respiratory season is never-ending? That’s because this is the longest respiratory season since the beginning of the pandemic.

Here is your state of affairs.

Influenza-like illnesses: High and plateauing​

The climate of respiratory health in the United States (coined “influenza-like illnesses” by CDC) remains above the epidemic threshold and has plateaued due to children returning to school after the holidays.

We are going into our 13th week of being above “epidemic” levels. Last year, our entire season was 11 weeks. (The year before was 7 weeks). It’s looking more and more like “pre-pandemic” times, where we had ~15-18 weeks of illness during the winter.

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Outpatient Respiratory Illness Visits (Source: CDC; Annotated by YLE)
Covid-19 still takes the cake for respiratory deaths. By how much? We don’t know yet. The data below are from death certificates, which are pretty accurate for Covid and RSV but not for flu. CDC annually adjusts flu deaths post-hoc to account for underreporting. We must wait to see how those calculations play out.

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Trends in Viral Respiratory Deaths in the United States (Source: CDC; Annotated by YLE)

Covid-19: High and… stabilizing? ​

Nationally, Covid-19 in wastewater is still “high.” Unfortunately, levels have stabilized in all regions except the South, where exponential growth started again. This could be a “noise” signal due to unstable reporting or a “real” signal due to, perhaps, it getting colder later in the South.

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Wastewater SARS-CoV-2 viral activity level on a national level (Source: CDC; Annotations by YLE)
Covid-19 hospitalizations are slowing down, too, after a few weeks of nosediving. Are Covid-19 hospitalizations higher than flu? Well… it depends on which CDC graph you look at, which is confusing. The top graph below shows Covid-19 hospitalizations winning while the bottom shows flu winning.

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(Top) Covid-19 and Influenza Hospitalization Rates (Source: CDC) (Bottom) Weekly Rates of Respiratory Virus-Associated Hospitalizations by Season (Source: CDC); Annotated by YLE
Why the different data stories? The sources are different. The top graph is from all hospitals mandated to report due to the pandemic, and the bottom is a few hospitals representing only 10% of the population from mostly urban areas. This is probably causing two things to happen:

1. Vaccine effect. Urban places have more Covid-19 vaccinated than rural; thus Covid-19 hospitalizations are lower on the bottom graph than the top.
2. Case definition differences may be happening. The data in the top graph is reported by hospitals, which may differ from the bottom graph, reported by a review of lab records.

I trust the top graph more. Unfortunately, this data story will stop in April because the reporting mandate is ending. Hospitals hate reporting this metric, but if you ask me, I don’t care. We need this data.

Flu: High and stabilizing​

Influenza is still surging. Emergency department visits for flu increased due to one particular group: 5-17 year olds.

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Percent of Emergency Department Visits for Flu, by age. (Source CDC; Annotated by YLE)

RSV: Moderate but nosediving​

RSV continues to go down and down. Good riddance.

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(Source: CDC)

Other things I’m paying attention to:​

• New CDC data show that the 2023 fall Covid-19 vaccines provide 54% increased protection against infection. In other words, fall Covid vaccines were a good call. A few more thoughts of mine are here.
• Norovirus (think throwing up and diarrhea) has been a rollercoaster, but is now increasing quickly. Historically, this is about the time that norovirus takes off. Wash those hands.

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(Source: CDC)

Bottom line​

We are still very much in the middle of the “feeling crappy” season. And, unfortunately, it’s already longer than last year’s. Hopefully we get a reprieve in the next month or two.

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[missy]

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Healthcare Workers Face Increased Risks During the Pandemic​

Fran Lowry
February 01, 2024
Healthcare workers have been at an increased risk for SARS-CoV-2 infection and mental distress such as anxiety and depression during the pandemic, according to new research.
In an analysis of administrative health records for about 3000 healthcare workers in Alberta, Canada, the workers were as much as twice as likely to become infected with SARS-CoV-2 compared with the overall population. The risk for infection was higher among healthcare workers in the first two waves of the pandemic and again during the fifth wave.
"Previous publications, including ours, suggested that the main problem was in the early weeks and months of the pandemic, but this paper shows that it continued until the later stages," senior author Nicola Cherry, MD, an occupational epidemiologist at the University of Alberta in Edmonton, Canada, told Medscape Medical News.

Nicola Cherry, MD
The findings were published on January 16, 2024, in the Canadian Journal of Public Health.

Wave Upon Wave​

In the current study, the investigators sought to compare the risk for SARS-CoV-2 infection and mental distress among healthcare workers and among community referents (CRs). They examined the following waves of the COVID-19 pandemic:

• Wave 1: From March to June 2020 (4 months)
• Wave 2: From July 2020 to February 2021 (8 months)
• Wave 3: From March to June 2021 (4 months)
• Wave 4: From July to October 2021 (4 months)
• Wave 5 (Omicron): From November 2021 to March 2022 (5 months)

Healthcare workers in Alberta were asked at recruitment for consent to match their individual records to the Alberta Administrative Health Database. As the pandemic progressed, participants were also asked for consent to be linked to COVID-19 immunization records maintained by the provinces, as well as for the results of all polymerase chain reaction (PCR) testing for the SARS-CoV-2 virus.

The investigators matched 2959 healthcare workers to 14,546 CRs according to their age, sex, geographic location in Alberta, and number of physician claims from April 1, 2019, to March 31, 2020.
Incident SARS-CoV-2 infection was examined using PCR testing and the first date of a physician consultation at which the code for SARS-CoV-2 infection had been recorded. Mental health disorders were identified from physician records. They included anxiety disorders, stress and adjustment reactions, and depressive disorders.
Most (79.5%) of the healthcare workers were registered nurses, followed by physicians (16.1%), healthcare aides (2.4%), and licensed practical nurses (2.0%). Most participants (87.5%) were female. The median age at recruitment was 44 years.

Healthcare workers were at a greater risk for COVID-19 overall, with the first SARS-CoV-2 infection defined from either PCR tests (odds ratio [OR], 1.96) or from physician records (OR, 1.33). They were also at an increased risk for anxiety (adjusted OR, 1.25; P < .001), stress/adjustment reaction (adjusted OR, 1.52; P < .001), and depressive condition (adjusted OR, 1.39; P < .001). Moreover, the excess risks for stress/adjustment reactions and depressive conditions increased with successive waves during the pandemic, peaking in the fourth wave and continuing in the fifth wave.
"Although the increase was less in the middle of the phases of the pandemic, it came back with a vengeance during the last phase, which was the Omicron phase," said Cherry.
"Employers of healthcare workers can't assume that everything is now under control, that they know what they're doing, and that there is no risk. We are now having some increases in COVID. It's going to go on. The pandemic is not over in that sense, and infection control continues to be major," she added.
The finding that mental health worsened among healthcare workers was not surprising, Cherry said. Even before the pandemic, studies had shown that healthcare workers were at a greater risk for depression than the population overall.
"There is a lot of need for care in mental health support of healthcare workers, whether during a pandemic or not," said Cherry.

Nurses Are Suffering​

Commenting on the research for Medscape Medical News, Farinaz Havaei, PhD, RN, assistant professor of nursing at the University of British Columbia in Vancouver, Canada, said, "This is a very important and timely study that draws on objective clinical and administrative data, as opposed to healthcare workers' subjective reports." Havaei did not participate in the research.

Farinaz Havaei
Overall, the findings are consistent with previous research that drew upon healthcare workers' reports. They speak to the chronic and cumulative impact of COVID-19 and its associated stressors on the mental health and well-being of healthcare workers, said Havaei.
"The likelihood of stress/adjustment reaction and depression showed a relatively steady increase with increasing COVID-19 waves. This increase can likely be explained by healthcare workers' depleting emotional reserves for coping with chronic workplace stressors such as concerns about exposure to COVID-19, inadequate staffing, and work overload," she said. Witnessing the suffering and trauma of patients and their families likely added to this risk.

Havaei also pointed out that most of the study participants were nurses. The findings are consistent with pre-pandemic research that showed that the suboptimal conditions that nurses increasingly faced resulted in high levels of exhaustion and burnout.
"While I agree with the authors' call for more mental health support for healthcare workers, I think prevention efforts that address the root cause of the problem should be prioritized," she said.

From Heroes to Zeros​

The same phenomena have been observed in the United States, said John Q. Young, MD, MPP, PhD, professor and chair of psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. In various studies, Young and his colleagues have reported a strong association between exposure to the stressors of the pandemic and subsequent development of depression, anxiety, and posttraumatic stress disorder (PTSD) among healthcare workers.

John Q. Young, MD
"The findings from Alberta are remarkably consistent. In the beginning of the pandemic, there was a lot of acknowledgment of the work healthcare workers were doing. The fire department clapping as you leave work at night, being called heroes, even though a lot of healthcare workers feel uncomfortable with the hero language because they don't feel like heroes. Yes, they're afraid, but they are going to do what they need to do and help," he said.
But as the pandemic continued, public sentiment changed, Young said. "They've gone from heroes to zeros. Now we are seeing the accumulated, chronic effects over months and years, and these are significant. Our healthcare workforce is vulnerable now. The reserves are low. There are serious shortages in nursing, with more retirements and more people leaving the field," he said.
As part of a campaign to help healthcare workers cope, psychiatrists at Northwell Health have started a program called Stress First Aid at their Center for Traumatic Stress Response Resilience, where they train nurses, physicians, and other healthcare staff to use basic tools to recognize and respond to stress and distress in themselves and in their colleagues, said Young.

"For those healthcare workers who find that they are struggling and need more support, there is resilience coaching, which is one-on-one support. For those who need more clinical attention, there is a clinical program where our healthcare workers can meet with a psychologist, psychiatrist, or a therapist, to work through depression, PTSD, and anxiety. We didn't have this before the pandemic, but it is now a big focus for our workforce," he said. "We are trying to build resilience. The trauma is real."
The study was supported by the College of Physicians and Surgeons of Alberta, the Canadian Institutes of Health Research, and the Canadian Immunology Task Force. Cherry and Havaei reported no relevant financial relationships. Young reported that he is senior vice president of behavioral health at Northwell.
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[missy]

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Supreme Court to weigh whether Covid misinformation is protected speech​

By Sarah Owermohle Feb. 6, 2024

MANDEL NGAN/AFP VIA GETTY IMAGES

































WASHINGTON — As social media sites were flooded with misleading posts about vaccine safety, mask effectiveness, Covid-19’s origins and federal shutdowns at the height of the pandemic, Biden officials urged platforms to pull down posts, delete accounts, and amplify correct information.
Now the Supreme Court could decide whether the government violated Americans’ First Amendment rights with those actions — and dictate a new era for what role, if any, officials can play in combating misinformation on social media.

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The Supreme Court is set to hear arguments next month in a case that could have sweeping ramifications for federal health agencies’ communications in particular. Murthy v. Missouri alleges that federal officials coerced social media and search giants like Facebook, Twitter, YouTube, and Google to remove or downgrade posts that questioned vaccine safety, Covid’s origins, or shutdown measures. Biden lawyers argue that officials made requests but never forced companies.
Government defenders say that if the Court limits the government’s power, it could hamstring agencies scrambling to achieve higher vaccination rates and other critical public health initiatives. Critics argue that federal public health officials — already in the throes of national distrust and apathy — never should have tried to remove misleading posts in the first place.
“The best way is to have a very vigorous offensive social media strategy, which we didn’t have,” said Paul Mango, a Trump deputy chief of staff for the Health and Human Services Department who worked closely on Operation Warp Speed, the effort to speed Covid-19 vaccines and treatments to market. “Rather than trying to keep bad information off by suppression, why don’t we have a strategy that really is very aggressive at propagating accurate information
Though the Association of State and Territorial Health Officials is not taking a stance on the case or the government’s argument that it can ask sites to take social media down, its chief medical officer Marcus Plescia also said the best use of federal public health resources is counter-messaging.
“We really are limited to the extent that we can control misinformation,” said Plescia. “The number one [request from state officials] is we need good messaging that’s been tested, and that’s shown to be effective.”
For their part, social media executives like Meta CEO Mark Zuckerberg have said in the past that they made and altered their content moderation policies on their own. But the tech executives are unlikely to weigh in now, considering they are in the midst of two other firestorms over moderation. One is a suit against a Florida law that would effectively diminish platforms’ abilities to moderate false and misleading posts. Another is last week’s very public battering by senators demanding more content moderation to protect childrens’ safety on their platforms.

The recent hearing before the Senate Judiciary Committee, which also called TikTok, Snap and Discord executives to testify, stands in stark contrast to the coronavirus misinformation lawsuit, as it conversely suggests tech companies aren’t doing enough to police their platforms. At one point, Sen. Josh Hawley (R-Mo.) urged Zuckerberg to stand up and apologize to families in the hearing room for damage caused by Facebook and Instagram use.

Senators from both parties seemed open to peeling back a federal protection of tech companies that host problematic or false content.

“It is now time to make sure that the people who are holding up the signs can sue on behalf of their loved ones. Nothing will change until the courtroom door is open to victims of social media,” South Carolina Republican Lindsay Graham said.

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Biden’s lawyers are set to argue that he, and his officials, can make the same type of demands.

A lower courts in this case ruled that the federal government can’t put any pressure on social media platforms to censor their content. Under that ruling, even public statements by the president about the teen mental health crisis could be construed as undue pressure, Solicitor General Elizabeth Prelogar argued in a legal filing.

For instance, under that ruling, a White House statement condemning the role social media plays in teens’ mental health and calling for potential legislative reform “might be viewed as coercion or significant encouragement under the Fifth Circuit’s novel understanding of those concepts,” she wrote.

But this case didn’t start with mental health, and much of it will likely rest on private rather than public comments from federal officials.

The lawsuit, started by then-Missouri Attorney General Eric Schmitt, reflects a growing trend of state attorneys general mounting politically divisive cases against the federal government. Another state, Louisiana, joined the suit along with three doctors who co-signed a paper on herd immunity, an anti-lockdown activist in Louisiana, and a conservative news site, The Gateway Pundit.

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Federal officials began communicating with the social platforms in early 2021, according to court documents. Those communications included White House messages to one site saying to take a post down “ASAP” and “keep an eye out for tweets that fall in the same … genre” or instructions to another platform to “remove [an] account immediately.” CDC officials also regularly flagged posts to the companies and in one instance asked “what [was] being done on the amplification-side” to promote official messaging on coronavirus information.

Later, according to court documents, government officials began asking Facebook and others for data and the details of their moderation policies and standards. They held regular meetings, suggested changes and at least one company created a portal for government requests to be prioritized. After a Washington Post article detailing Facebook’s moderation struggle, an official wrote to the company that they felt Facebook was not “trying to solve the problem” and the White House was “nternally … considering our options on what to do about it.”

In July 2021, federal officials took their frustrations to the public. Surgeon General Vivek Murthy said in a press briefing that “modern technology companies have enabled misinformation to poison our information environment, with little accountability to their users. “

He added, “We’re asking them to operate with greater transparency and accountability. We’re asking them to monitor misinformation more closely.” The same day, he issued his first formal advisory as surgeon general — on confronting health misinformation.

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Despite a lower court ruling that those statements could be inappropriate pressure, experts who spoke to STAT said it’s hard to imagine the Supreme Court going that far.

“The government does, and should, have the ability to communicate with private entities about the dangers that exist,” said Clay Calvert, a senior fellow on technology policy at the American Enterprise Institute. “Why this case is so controversial is the inherently political divisiveness of the content in question — that divided Republicans and Democrats on matters like mask mandates and Covid vaccines.”

Where this leaves federal health officials​

The overarching question before the court is whether these actions count as government coercion of a private company, which would be an overstep of its authority. Justice Department lawyers argue that while officials “frequently suggested” removal or downgrade of posts, they didn’t force companies — nor did companies always oblige.

An appeals court deemed some officials’ actions — particularly those of the White House — potentially coercive, but vastly whittled down a district court’s broad prohibition of government officials’ correspondence with social media companies. In doing so, they laid the groundwork for some communications — particularly the CDC’s alerts on changing recommendations and explainers on true vs. false information — as valid dispatches.

But that does not mean the CDC is in the clear when the Supreme Court considers the case in March. Justice Samuel Alito already signaled some of his apprehension when he dissented from other justices on lifting the ban before they hear arguments.

“At this time in the history of our country, what the Court has done, I fear, will be seen by some as giving the Government a green light to use heavy-handed tactics to skew the presentation of views on the medium that increasingly dominates the dissemination of news,” Alito wrote.

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Even if the court rejects broader controls on federal communications with social media sites, the case could have extensive implications for effective messaging from federal health officials, legal experts say.

“It will have a chilling effect on the government … especially for the CDC,” said Dorit Reiss, a professor at UC Law San Francisco. “Because the line is fuzzy and because they don’t want to be accused of coercion, they’re not going to be sure when they can talk to social media.”


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[missy]

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Bivalent COVID Vaccine Protected Children, Adolescents​

Publish date: February 6, 2024
By
Marcia Frellick

FROM JAMA
Children and adolescents ages 5-17 who received a bivalent COVID-19 mRNA vaccine were less likely to become infected with SARS-CoV-2 compared with those who were unvaccinated or received only the monovalent COVID-19 vaccine, according to new data published February 6 in JAMA.
“All eligible children and adolescents should remain up to date with recommended COVID-19 vaccinations,” wrote the authors, led by Leora R. Feldstein, PhD, with the US Centers for Disease Control and Prevention (CDC) in Atlanta.
By the end of 2023, at least 911 youths ages 5-17 had died from COVID-related causes.
Researchers found that compared with participants who did not receive the COVID-19 vaccine or got monovalent-only doses 180 days or more before, the adjusted vaccine effectiveness of a bivalent COVID-19 vaccine dose against SARS-CoV-2 infection was 51.3% (95% confidence interval [CI], 23.6%-71.9%) 7-60 days after vaccination. Relative effectiveness was 62.4% (95% CI, 38.5%-81.1%) 61-150 days after vaccination. The researchers said the confidence intervals were wide because of the small sample size.
The information can help inform public health strategies, the authors noted, especially as new variants emerge.

Bivalent Dose Recommended in Fall of 2022​

Bivalent mRNA COVID vaccines were recommended in the United States for children and adolescents ages 12 years or older on Sept. 1, 2022, and for children ages 5-11 on Oct. 12, 2022, when Omicron BA.4/5 types were the predominant circulating variant.
The study included 2,959 participants who completed periodic surveys (answering questions on demographics, household details, chronic medical conditions, and COVID-19 symptoms) and submitted weekly self-collected nasal swabs (whether or not they had symptoms). Those in the study submitted additional nasal swabs if they developed any symptoms.
Median adherence to weekly upper respiratory specimen swabbing was high throughout the study period at 93.8%.
Data from Sept. 4, 2022, to Jan. 31, 2023, were combined from three prospective US cohort studies at six sites. In addition to the surveys, researchers used information from state immunization information systems and electronic medical records.

Most of the Infected Were Unvaccinated or Had Monovalent Vax​

Of the 426 participants (14.4% of the combined cohorts) infected with SARS-CoV-2, 383 (89.9%) were either unvaccinated or received monovalent vaccine doses only.
Calculations were adjusted for age, sex, race, ethnicity, health conditions, prior SARS-CoV-2 infections, geographic location, proportion of circulating variants by site, and local virus prevalence.
Participants living in Oregon, for example, had the highest uptake of bivalent COVID-19 vaccine (56.2%), whereas those in Texas had the lowest (2.4%). Participants reporting Hispanic ethnicity had lower bivalent uptake (17.1%) compared with non-Hispanic participants of all races (27.1%).
Of the 2,207 participants who did not receive a bivalent dose, 24.2% were unvaccinated and 1,672 (75.8%) received at least 1 monovalent dose.
The researchers said they saw no sign of waning effectiveness 61-150 days (the limit for this analysis) after receipt of the bivalent COVID-19 vaccine.
They wrote that continuation of the cohorts will allow study of waning patterns, which could help inform vaccine recommendations.
Among the limitations of the study are that testing methods and the COVID-19 symptoms surveyed varied among the three cohorts, so there may be some differences in defining infection or symptomatic COVID. In addition, the researchers were not able to account for the social vulnerability index and immunocompromised status, which could have affected vaccine uptake and risk of SARS-CoV-2 infection.
This study was supported by the National Center for Immunization and Respiratory Diseases, US Centers for Disease Control and Prevention, and by the National Institute of Allergy and Infectious Diseases. Coauthor Dr. Caban-Martinez reported grants from the Florida Firefighter Cancer Initiative and the Florida Department of Health. Coauthors Dr. Chu, Dr. Englund, Dr. Martin, and Dr. Monto reported receiving personal fees or grants from multiple pharmaceutical companies. Dr. Hegmann reported being the editor of the American College of Occupational and Environmental Medicine practice guidelines. Coauthor Dr. Gaglani reported serving as cochair of the infectious diseases and immunization committee and the respiratory syncytial virus task force lead for the Texas Pediatric Society and the Texas Chapter of the American Academy of Pediatrics. No other disclosures were reported.

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[missy]

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New Evidence Suggests Long COVID Could Be a Brain Injury

Long-COVID sufferers of brain fog and memory loss exhibit elevated biomarkers consistent with brain injury.

www.medscape.com

New Evidence Suggests Long COVID Could Be a Brain Injury​

Sara Novak
February 08, 2024


Brain fog is one of the most common, persistent complaints in patients with long COVID. It affects as many as 46% of patients who also deal with other cognitive concerns like memory loss and difficulty concentrating.
Now, researchers believe they know why. A new study has found that these symptoms may be the result of a viral-borne brain injury that may cause cognitive and mental health issues that persist for years.
Researchers found that 351 patients hospitalized with severe COVID-19 had evidence of a long-term brain injury a year after contracting the SARS-CoV-2 virus. The findings were based on a series of cognitive tests, self-reported symptoms, brain scans, and biomarkers.

Brain Deficits Equal to 20 Years of Brain Aging​

As part of the preprint study, participants took a cognition test with their scores age-matched to those who had not suffered a serious bout of COVID-19. Then a blood sample was taken to look for specific biomarkers, showing that elevated levels of certain biomarkers were consistent with a brain injury. Using brain scans, researchers also found that certain regions of the brain associated with attention were reduced in volume.
Patients who participated in the study were "less accurate and slower" in their cognition, and suffered from at least one mental health condition, such as depression, anxiety, or posttraumatic stress disorder, according to researchers.
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The brain deficits found in COVID-19 patients were equivalent to 20 years of brain aging and provided proof of what doctors have feared: that this virus can damage the brain and result in ongoing mental health issues.

"We found global deficits across cognition," said lead study author Benedict Michael, PhD,director of the Infection Neuroscience Lab at the University of Liverpool in Liverpool, England. "The cognitive and memory problems that patients complained of were associated with neuroanatomical changes to the brain."

Proof That Symptoms Aren't 'Figment' of Patients' Imaginations​

Cognitive deficits were common among all patients, but the researchers said they don't yet know whether the brain damage causes permanent cognitive decline. But the research provides patients who have been overlooked by some clinicians with proof that their conditions aren't a figment of their imaginations, said Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina School of Medicine's COVID Recovery Clinic.
"Even though we're several years into this pandemic, there are still a lot of providers who don't believe that their patients are experiencing these residual symptoms," said Thompson, "That's why the use of biomarkers is important, because it provides an objective indication that the brain has been compromised in some way."
Some patients with long COVID have said that getting their doctors to believe they have a physical ailment has been a persistent problem throughout the pandemic and especially as it relates to the sometimes-vague collection of symptoms associated with brain fog. One study found that as many as 79% of study respondents reported negative interactions with their healthcare providers when they sought treatment for their long-COVID symptoms.

How Do COVID-Related Brain Injuries Happen?​

Researchers are unsure what's causing these brain injuries, though they have identified some clues. Previous research has suggested that such injuries might be the result of a lack of oxygen to the brain, especially in patients who were hospitalized, like those in this study, and were put on ventilators.
Brain scans have previously shown atrophy to the brain's gray matter in COVID-19 patients, likely caused by inflammation from a heightened immune response rather than the virus itself. This inflammatory response seems to affect the central nervous system. As part of the new study, researchers found some neuroprotective effects of using steroids during hospitalization to reduce brain inflammation.
The results suggest that clinicians should overcome their skepticism and consider the possibility that their patients have suffered a brain injury and should be treated appropriately, said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University School of Medicine. "The old saying is that if it walks like a duck and talks like a duck, it's a duck," said Jackson.
He contends that treatments used for patients who have brain injuries have also been shown to be effective in treating long COVID–related brain fog symptoms. These may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for the treatment of related mental health concerns.

A New Path Forward​

Treating long-COVID brain fog like a brain injury can help patients get back to some semblance of normalcy, researchers said. "What we're seeing in terms of brain injury biomarkers and differences in brain scans correlates to real-life problems that these patients are dealing with on a daily basis," said Jackson. These include problems at work and in life with multitasking, remembering details, meeting deadlines, synthesizing large amounts of information, and maintaining focus on the task at hand, he said.
There's also a fear that even with treatment, the aging of the brain caused by the virus might have long-term repercussions and that this enduring injury may cause the early onset of dementia and Alzheimer's disease in those who were already vulnerable to it. One study, from the National Institute of Neurological Disorders and Stroke (NINDS), found that in those infected with COVID-19 who already had dementia, the virus "rapidly accelerated structural and functional brain deterioration."

"We already know the role that neuroinflammation plays in the brains of patients with Alzheimer's disease," said Thompson. "If long COVID is involved in prolonged inflammation of the brain, it goes a long way in explaining the mechanism underlying [the study's reported] brain aging."

Still More to Learn​

In some ways, this study raises nearly as many questions as it does answers. While it provides concrete evidence around the damage the virus is doing to the brains of patients who contracted severe COVID-19, researchers don't know about the impact on those who had less serious cases of the virus.
For Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System, the concern is that some long-COVID patients may be suffering from cognitive deficits that are more subtle but still impacting their daily lives, and that they're not getting the help they need.

What's more, said Al-Aly, it's unclear whether the impacts of the brain damage are permanent or how to stop them from worsening. Researchers and clinicians need a better understanding of the mechanism that allows this virus to enter the brain and do structural damage. If it's inflammation, will anti-inflammatory or antiviral medications work at preventing it? Will steroids help to offset the damage? "It's critical we find some answers," he said.
"SARS-CoV-2 isn't going anywhere. It will continue to infect the population, so if this is indeed a virus that damages the brain in the long term or permanently, we need to figure out what can be done to stop it," said Al-Aly.

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[missy]

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Long COVID: Another Great Pretender​

Has COVID replaced syphilis as the great imitator? At the turn of the 20th century, Sir William Osler was quoted as saying, “He who knows syphilis knows medicine.”
If you have any doubts about the “imitator” analogy, simply use any broad search engine or AI portal and enter “what is the differential diagnosis of primary syphilis, or secondary syphilis, or tertiary syphilis?” A plethora of diseases across many body systems appears.

Another Great Pretender?​

Did you or do you now have long COVID? How do you know? Do you even know what long COVID is? How would you diagnosis it?
When asked about long COVID, this is what large language model source bard.google.com had to say:
Long COVID, also known as post-COVID conditions or PASC, is a complex condition that can occur in people who have had COVID-19, even if their initial illness was mild or even asymptomatic. It’s characterized by a wide range of symptoms that can last for weeks, months, or even years after the initial infection.
Symptoms of long COVID can include: fatigue, shortness of breath, brain fog (trouble thinking or concentrating), loss of smell or taste, sleep problems, muscle pain, joint pain, headache, dizziness, depression or anxiety, heart palpitations, gastrointestinal problems.
Duh!!! It reads much like a continuation of the symptoms of acute COVID. Bard continued:
The exact cause of long COVID is still unknown, but there are several theories. One possibility is that the virus itself can damage organs and tissues, leading to ongoing symptoms. Another possibility is that the immune system’s response to the virus can continue to cause inflammation even after the virus is gone.
Human intelligence source Wikipedia says this:
Long COVID or long-haul COVID is a group of health problems persisting or developing after an initial COVID-19 infection. Symptoms can last weeks, months or years and are often debilitating. The World Health Organization defines long COVID as starting three months after infection, but other definitions put the start of long COVID at four weeks.
Highly varied, including post-exertional malaise (symptoms made worse with effort), fatigue, muscle pain, shortness of breath, chest pain, and cognitive dysfunction (brain fog).

Acute COVID to Long COVID​

The World Health Organization estimates that 36 million people in the European region have developed long COVID in the first 3 years of the pandemic. That›s a lot.
We all know that the common signs and symptoms of acute COVID-19 include fever or chills, a dry cough and shortness of breath, feeling very tired, muscle or body aches, headache, loss of taste or smell, sore throat, congestion, runny nose, nausea, vomiting, and diarrhea. Except for the taste and smell findings, every one of these symptoms or signs could indicate a different virus infection or even some type of allergy. My point is the nonspecificity in this list.
Uncommon signs and symptoms of acute COVID include a flat skin rash covered with small bumps, discolored swollen areas on the fingers and toes (COVID toes), and hives. The skin of hands, wrists, or ankles also can be affected. Blisters, itchiness, rough skin, or pus can be seen.
Severe confusion (delirium) might be the main or only symptom of COVID-19 in older people. This COVID-19 symptom is linked with a high risk for poor outcomes, including death. Pink eye (conjunctivitis) can be a COVID-19 symptom. Other eye problems linked to COVID-19 are light sensitivity, sore eyes, and itchy eyes. Acute myocarditis, tinnitus, vertigo, and hearing loss have been reported. And 1-4 weeks after the onset of COVID-19 infection, a patient may experience de novo reactive synovitis and arthritis of any joints.
So, take your pick. Myriad symptoms, signs, diseases, diagnoses, and organ systems — still present, recurring, just appearing, apparently de novo, or after asymptomatic infection. We have so much still to learn.
What big-time symptoms, signs, and major diseases are not on any of these lists? Obviously, cancer, atherosclerotic cardiovascular diseases, obesity, bone diseases, and competitive infections. But be patient; the lingering effects of direct tissue invasion by the virus as well as a wide range of immunologic reactions may just be getting started. Mitochondrial damage, especially in muscles, is increasingly a pathophysiologic suspect.
Human diseases can be physical or mental; and in COVID, that twain not only meet but mix and mingle freely, and may even merge into psychosoma. Don’t ever forget that. Consider “fatigue.” Who among us, COVID or NOVID, does not experience that from time to time?
Or consider brain fog as a common reported symptom of COVID. What on earth is that actually? How can a person know they have brain fog, or whether they had it and are over it?
We need one or more lab or other diagnostic tests that can objectively confirm the diagnosis of long COVID.

Useful Progress?​

A recent research paper in Science reported intriguing chemical findings that seemed to point a finger at some form of complement dysregulation as a potential disease marker for long COVID. Unfortunately, some critics have pointed out that this entire study may be invalid or irrelevant because the New York cohort was recruited in 2020, before vaccines were available. The Zurich cohort was recruited up until April 2021, so some may have been vaccinated.

Then this news organization came along in early January 2024 with an article about COVID causing not only more than a million American deaths but also more than 5000 deaths from long COVID. We physicians don’t really know what long COVID even is, but we have to sign death certificates blaming thousands of deaths on it anyway? And rolling back the clock to 2020: Are patients dying from COVID or withCOVID, according to death certificates?Now, armed with the knowledge that “documented serious post–COVID-19 conditions include cardiovascular, pulmonary, neurological, renal, endocrine, hematological, and gastrointestinal complications, as well as death,” CDC has published clear and fairly concise instructions on how to address post-acute COVID sequelae on death certificates.

In late January, this news organization painted a hopeful picture by naming four phenotypes of long COVID, suggesting that such divisions might further our understanding, including prognosis, and even therapy for this condition. Among the clinical phenotypes of (1) chronic fatigue–like syndrome, headache, and memory loss; (2) respiratory syndrome (which includes cough and difficulty breathing); (3) chronic pain; and (4) neurosensorial syndrome (which causes an altered sense of taste and smell), overlap is clearly possible but isn›t addressed.

I see these recent developments as needed and useful progress, but we are still left with…not much. So, when you tell me that you do or do not have long COVID, I will say to you, “How do you know?”

I also say: She/he/they who know COVID know medicine.


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[missy]

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The C.D.C., ignored​

Much of the world has decided that most young children do not need to receive Covid booster shots. It’s true in Britain, France, Japan and Australia.

Some countries, like India, have gone further. They say that otherwise healthy children do not need even an initial Covid vaccination. In Germany, public health experts don’t recommend vaccines for any children, including teenagers, unless they have a medical condition.

Scientists in these countries understand that Covid vaccines are highly effective. But the experts have concluded that the benefits for children often fail to outweigh the costs.

The benefits are modest because children are extremely unlikely to become seriously ill from Covid and are less likely to transmit the virus than an adult is. The costs include the financial price of mass vaccination, the possibility that a shot’s side effects will make a child sick enough to miss school, the tiny chance of more serious side effects and the inherent uncertainty about long-term effects.

The U.S. — as American readers have probably realized by this point in the newsletter — is a global outlier. The C.D.C. urges booster shots for all childrensix months and older.

Yet the recommendation has failed to accomplish much. Instead, most American parents have chosen to overrule the C.D.C. Only about 40 percent of children under 12 have been vaccinated against Covid, and only about 5 percent are up to date on their boosters.

This situation makes for a case study of the shortcomings in U.S. Covid policy: A strict approach to a nuanced issue has backfired, fostering skepticism of scientific expertise while doing little to improve public health. Dr. Francis Collins, the retired head of the National Institutes of Health, acknowledged the larger problem last year when he said that experts erred during the pandemic by taking a “very narrow view of what the right decision is.”

Monthslong school closures that harmed student learning were one example. Extended mask mandates that many people ignored were another. A continuing C.D.C. recommendation that conflicts with international practice — and that most Americans have dismissed — has become yet another.

What’s reasonable?​

Dr. Sandro Galea, the dean of the Boston University School of Public Health, recently published a book making a detailed version of this argument. The book is titled, “Within Reason.” During the pandemic, as Galea told me, health experts sometimes adopted “an illiberal ideology.” This ideology imagined people as robots who existed merely to minimize the chances of contracting a virus.

In reality, as Galea pointed out, society regularly decides that some amount of additional safety isn’t worth it. Car drivers and passengers would be safer if they wore helmets, for instance, but who wears a helmet in a car?

In the case of Covid, there are indeed benefits to giving booster shots to children. Some of the benefits are probably greater for American children, too. They are more likely to be obese or lack health insurance than children elsewhere. “Even though kids are at a lower risk, they are not at zero risk,” Dr. Nirav Shah, the C.D.C.’s principal deputy director, told me when defending the booster recommendation.

But there are also downsides to urging health measures that most people oppose, Galea notes. Only when the benefits of doing so are large (as was the case with perceptions of smoking in the 20th century) should experts try to change people’s minds.

The scientific data — and the expert consensus in other countries — make it hard to argue that the benefits of boosting children are large. “I don’t think in the U.S.A. they have got the risk-benefit equation correct for children,” Dr. Peter Collignon of the Australian National University told me.

(C.D.C. data shows that the children at highest Covid risk are newborns, who aren’t eligible for vaccines even in the U.S. They can instead benefit from a mother’s prenatal vaccination.)

The value of candor​

Galea believes that the biggest drawback to the U.S. booster policy may be its effect on the C.D.C.’s credibility. When people who are already skeptical of expert advice, as many Americans are, see the C.D.C. insisting on a vaccine with a marginal benefit, they have more reason to question other C.D.C. guidance — such as the urgent importance of childhood vaccines against measles and diphtheria.

“There is a real cost to our not being honest,” Galea said.

When I’ve asked public health experts off the record what they are doing with their own children, they tend to be honest. Almost all have vaccinated their children, for the sake of both those children and other people. At the same time, some experts told me that they had not boosted their children.

Why? The benefits seem small, for everybody. The costs — like a child’s fear of needles or a missed day of school from side effects — also seem small. With such a close call, reasonable parents will make different decisions, and that’s OK.

Maybe the C.D.C. would have a bigger impact if it conveyed a similarly candid message.



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[missy]

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Immune Response May Cause Virus-Induced Neurologic Damage​

Gwendolyn Rak
February 14, 2024

Neurologic damage following acute viral infections may be attributed to an excessive immune response to the infection, according to a new study.
Many viral infections that don't directly infect the central nervous system (CNS) have been associated with severe neurologic disease. For these viruses, including newer viruses such as SARS-CoV-2 and Zika, the mechanism behind the association is poorly understood. To gain a better picture of how viruses may cause neurologic disease, researchers used a mouse model of Zika virus infection and identified a population of T cells that may be responsible for the damage.
Elizabeth Balint
"Our study ultimately finds that it isn't the virus itself alone that causes the damage. Instead, we find that it's a very excessive immune response to the virus," study author Elizabeth Balint, a PhD student at McMaster University in Hamilton, Ontario, Canada, told Medscape Medical News. Balint's research could serve as the first step toward eventually developing targeted therapies to prevent neurologic damage.

The study was published on February 5, 2024, in Nature Communications.

Cytotoxic T Cells​

Traditionally, experts have thought that a high viral load results in more severe damage to the CNS. But surprisingly, the investigators found that the viral load did not correspond with the severity of neurologic damage. This finding suggests that a dysregulated immune response is likely at fault.

The researchers then identified a specific population of cytotoxic T cells called CD8+ T cells that became overactivated during the infection and likely caused the damage. T cells are generally thought to be antigen-specific immune cells that only attack certain pathogens. "What we found, which was quite surprising, was that there were a number of T cells that seem to be nonspecifically activated," said Balint. The T cells appeared to be activated by a nonspecific receptor during a cytokine storm. "Lots of inflammation leads to excessive T cell activation, and then those T cells are what we're calling 'bystander activated' and able to kill nonspecifically," explained Balint.

The investigators chose to model Zika because of its status as an emerging virus that was linked to severe neurologic outcomes during the 2015-2016 epidemic. The disease is still circulating, and the mechanism for this association is poorly understood, said Balint. While the findings have yet to be tested in other models, Balint believes they may apply to viruses beyond Zika. She hopes to test other models in the future.

Specific Treatments​

With a better understanding of the basic science behind how viral infections cause neurologic damage, researchers may be able to begin developing therapies to prevent and treat disease. "We're really hoping that the more that we know about these T cells, the more specific treatments we can develop," said Balint.
In the study, for example, the investigators experimented with an antibody that blocked a particular receptor called NKG2D to avoid activating the cytotoxic T cells. The antibody reduced cell death and prevented Zika-associated paralysis in the mice that received treatment. This antibody has been tested in clinical trials for other uses, such as for the treatment of Crohn's disease, according to Balint.

She acknowledged that the research is in the early stages for such clinical implications but added that "it does show some promise for developing more targeted therapies."

Difficult to Isolate​

Commenting on the study for Medscape Medical News, Karl Weiss, MD, a professor of medicine at McGill University and chief of infectious diseases at Jewish General Hospital, Montreal, Quebec, Canada, said that the study advances basic science but may or may not produce applications for treatment in future research.
"In the past, whenever we tried to isolate one single element of a very complex immune system," said Weiss, "we never were able to isolate the culprits very effectively." That's because the immune system includes many connected pathways and redundancies in case of failure. "If we find a way of blocking this pathway, we will prevent neurologic problems. The problem with this is that you might block this pathway, but there is probably an alternative."
Preventing neurologic damage is an important goal, Weiss said. But because of these complexities, the research is still far from the development of any drug. Applying the science in clinical trials is a crucial next step and often the sticking point where potential treatments fail. Weiss also noted that further research using other viruses and models is needed before the findings can be generalized beyond Zika.
When considering clinical implications, Weiss said, "I think we have to be very prudent."
The study was supported by grants from the Canadian Institutes of Health Research. Balint and Weiss reported no relevant financial relationships.


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[missy]

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Changing Covid-19 isolation?​

My thoughts.​

KATELYN JETELINA FEB 16

What happened? The Washington Post leaked that CDC is considering replacing the Covid 5-day isolation guidance with “staying home until 24 hours fever free and improving symptoms.”

This is what we know and don’t know, and what this all means in the larger context.

First, what we do know​

• Contagiousness has not changed. If infected, you still spread Covid-19 to others for 5-12 days.
• Spreading Covid-19 is less consequential these days, though. Hospitalizations and deaths continue to decouple from infections. (This means ~300 deaths per day—which is still a lot—compared to the peak of 3,500.) Long Covid-19 prevalence is decreasing slowly, but millions still suffer.
• Testing is expensive. Innovation has not kept up. Antigen tests are not positive until days 3, 4, or 5 now.
• The number of paid sick days for Americans is abysmal—23% of Americans have zero (!) paid sick leave. Among those who do have it, the average American has 10 days.
• We are no longer in an emergency. The majority of Americans have put Covid-19 in the rearview mirror. Only 1 in 5 adults are vaccinated.

What we do not know ​

The actual proposed policy from the actual agency. This was a leak, which means it lacks justification, context, and details. We don’t have the full picture, like whether they will recommend masks, a cautionary period, or what to do for those at high risk.

A leak automatically puts CDC on the defense, which is disappointing as stakeholder engagement, gathering data, and conducting models takes time. Let’s give them time to line up their ducks.

One of the worst things CDC did throughout the emergency was change guidance without clear communication. I’m optimistic this will change.

What would be nice to know​

We are always working off incomplete data, but some rough answers would certainly help me, at least, craft an opinion:

• How many people follow the current isolation guidelines? In other words, will this impact community transmission? Data from the U.K., California, and Oregon can help answer this, as they have already implemented similar guidance. Oregon, for example, shared that dropping isolation did not impact community transmission.
• How many people get a fever with Covid-19 infection? Is a fever or improving symptoms correlated with contagiousness for Covid-19? How well does this align with the flu and RSV? Do people know what “symptoms improving” means?
• Is there a risk difference between a symptomatic person on Day X vs. asymptomatic case walking around (which is about 40% of Covid-19 cases)?

Even if we get answers to the science, health policy is also based on psychology, politics, economy, culture, and values:

• What is acceptable to the majority of Americans? 100% protection x 0% adherence = 0% benefit.
• How many sick days are people willing to cash in for Covid-19?How many missed school days is “worth it”?
• Does a 5-day isolation period disincentivize people from testing in the first place?
• How will institutions react? If someone needs to stay home longer, will their employer let them? What will happen at hospitals?
• What do key high-risk stakeholder organizations (i.e., nursing homes, AARP, immunocompromised, health departments, healthcare workers) think?

What is the purpose of public health? ​

Whether we get answers or not, all of this centers around one core question: What is the purpose of public health? Do we meet people where they are (e.g., people aren’t isolating anyways, so let’s drop), or provide a north star (e.g., this is ideal, although we know most people won’t follow it)?

Ideally, it’s a balance with a clear goal in mind. This has resulted in a tug-of-war throughout the pandemic.

This isn’t abnormal in public health, though. Take car safety. In the 1980s there was incredible pushback on seatbelt laws. But that didn’t stop guidance, and wearing a seatbelt was eventually normalized. Seatbelts had minimal (if any) tradeoffs, though. We don’t tell people not to drive, even though it’s the most dangerous thing people do daily. Instead, public health put in place interventions and recommendations to mitigate harm.

When recommending an intervention to a huge fraction of society, we’d better have strong justification of the benefits and risks, even if acting on the precautionary principle and limited data.

Ideally, guidance comes in tandem with background systematic change after an emergency—ventilation, free vaccines, paid sick leave, normalizing mask usage. I see it in Japan, but it is a fleeting pipedream in the U.S. Of course, a lot of this isn’t in the purview of CDC.

​

Air quality monitor in a Japanese taxi

Bottom line​

Health policy is messy and complex, involving weighing tradeoffs that change over time for very diverse 330 million people. We ultimately need guidance that is protective and actionable and feasible. I’m optimistic CDC will provide answers and clarity soon.

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[missy]

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When It Comes to Isolation, COVID Shouldn't Be Singled Out From the Pack​

— It's time for CDC to update its guidance​

by Amesh Adalja, MD February 20, 2024

News surfaced last week suggesting a potential shift in COVID-19 isolation guidancefrom the CDC. The planned guidance, which is expected to be released this spring for public comment, indicates a significant switch in how COVID-19 is conceptualized. The guidance would bring COVID-19 into line with how other common respiratory viruses are managed: with isolation recommended until the individual has mild and improving symptoms, and is fever-free (without pharmaceutical aid) for 24 hours.


With the news of the proposed guidance, many voices rose up to immediately attack the proposed guidance as a capitulation and not evidence-based. This was similar to the refrain from opponents when the federal or state governments dropped or loosened mask requirements or guidance.

I was not one of them.

Indeed, I welcome the proposed guidance change because it reflects the progress that has been made in the management of COVID-19. When evaluating this guidance, it is critical to understand that SARS-CoV-2, the cause of COVID-19, is situated among the myriad respiratory viruses that infect humans.

SARS-CoV-2, a virus unknown to humans before 2019, naturally began its foray into our species unopposed by diagnostic tests, antivirals, vaccinations, and knowledge. Today, in 2024, there are more tools for monitoring and managing COVID-19 than for any other respiratory virus: spanning from home tests, to wastewater monitoring, to potent antivirals, to highly effective vaccines, to a wealth of clinical guidance to manage cases and mitigate complications. All of these medical countermeasures are coupled with a high degree of immunity in the population from prior infections, vaccinations, and combinations of both. In short, the entire context of COVID-19 has changed for the better.


No longer are hospitals worried about capacity due to huge COVID surges -- cases may ebb and flow in the community and new variants appear, but no longer are these phenomena coupled to hospitals in crisis. While the raw numbers of hospital admissions and invasive mechanical ventilation or death were higher for COVID than for both respiratory syncytial virus (RSV) and the flu in 2022-2023, rates of ventilation or death were statistically no different for older adults hospitalized for either RSV or COVID (13.5% vs 10.2%), recent CDC data showed, both higher than for flu (7%). Furthermore, the highest rates of oxygen therapy and ICU admission in the study were among those with RSV (a virus for which no antiviral exists).


What is most baffling to me is that those who are critical of the proposed guidance change seemingly ignore the fact that most countries have already moved to this new paradigm without any evidence of major untoward impacts. Indeed, even California and Oregon -- two states not known for cavalier attitudes regarding COVID-19 mitigation -- have done the same. These states also advise that asymptomatic patients do not need to isolate at all; masking for 10 days is deemed sufficient. This is despite the fact that contagiousness remains in some individuals, even with improved clinical symptoms and a fever-free status.


What the new guidance reflects is that COVID-19, with the wealth of tools that were created to combat it, cannot be singled out from the pack of respiratory viruses (most of which we have zero countermeasures for) for special treatment in perpetuity.

When our ancestors chose to live among each other in cities and villages, it brought many advantages, but there was also the tradeoff of flourishing communicable diseases, as population density and attendant social interactions increased. Among these communicable diseases were respiratory virus infections, which I believe people implicitly consent to when they live among and interact with each other.

While certain respiratory viruses are above that consent threshold -- and COVID-19 was above that threshold for some time -- many are not. COVID no longer is. What that means is that it will remain important for those at high risk for severe COVID, severe RSV, and severe influenza -- or anyone who really wants to avoid infection – to keep in mind that these viruses are ever-present where there are people. They must also remember that humans have the tools to minimize their impact via masks, tests, vaccines, and antivirals; these are readily available if an individual's risk calculation favors employing them. COVID-19 hospitalizations and deaths are preventable with prompt antiviral use coupled with high-risk individuals staying up-to-date on vaccination.


COVID-19 guidance has long needed to embrace the paradigm of harm reduction as it does for sexually transmitted infections, injection drug use, and many other endeavors humans choose to engage in that have a non-zero risk. COVID-19 was always destined to be an endemic respiratory virus for which repeated infection would become a fact of life for humans. This is not capitulation but an embracing of the biology of the virus. Abstinence-only guidance -- as reflected by current guidelines that do not reflect the almost science fiction-like progress made against COVID-19 -- no longer has any place.

Amesh Adalja, MD, is a senior scholar at the Johns Hopkins Center for Health Security, and a practicing infectious disease, critical care, and emergency physician in Pittsburgh.


Disclosures
Adalja is currently a consultant, speaker, and/or advisory board member for GSK, Shionogi, and BD.
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[missy]

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Largest COVID Vax Safety Study; Kratom Deaths Rising; Gov. Threatens Hospital Chain​

— Health news and commentary from around the Web gathered by MedPage Today staff​

by Judy George, Deputy Managing Editor, MedPage Today February 21, 2024

An analysis based on 99 million people globally who received COVID-19 vaccinesopens in a new tab or windowconfirmed previously established safety signals for myocarditis, pericarditis, Guillain-Barré syndrome, and cerebral venous sinus thrombosis, and identified other areas that may need further research. (Vaccine)

Abstract​

Background​

The Global COVID Vaccine Safety (GCoVS) Project, established in 2021 under the multinational Global Vaccine Data Network™ (GVDN®), facilitates comprehensive assessment of vaccine safety. This study aimed to evaluate the risk of adverse events of special interest (AESI) following COVID-19 vaccination from 10 sites across eight countries.

Methods​

Using a common protocol, this observational cohort study compared observed with expected rates of 13 selected AESI across neurological, haematological, and cardiac outcomes. Expected rates were obtained by participating sites using pre-COVID-19 vaccination healthcare data stratified by age and sex. Observed rates were reported from the same healthcare datasets since COVID-19 vaccination program rollout. AESI occurring up to 42 days following vaccination with mRNA (BNT162b2 and mRNA-1273) and adenovirus-vector (ChAdOx1) vaccines were included in the primary analysis. Risks were assessed using observed versus expected (OE) ratios with 95 % confidence intervals. Prioritised potential safety signals were those with lower bound of the 95 % confidence interval (LBCI) greater than 1.5.

Results​

Participants included 99,068,901 vaccinated individuals. In total, 183,559,462 doses of BNT162b2, 36,178,442 doses of mRNA-1273, and 23,093,399 doses of ChAdOx1 were administered across participating sites in the study period. Risk periods following homologous vaccination schedules contributed 23,168,335 person-years of follow-up. OE ratios with LBCI > 1.5 were observed for Guillain-Barré syndrome (2.49, 95 % CI: 2.15, 2.87) and cerebral venous sinus thrombosis (3.23, 95 % CI: 2.51, 4.09) following the first dose of ChAdOx1 vaccine. Acute disseminated encephalomyelitis showed an OE ratio of 3.78 (95 % CI: 1.52, 7.7 following the first dose of mRNA-1273 vaccine. The OE ratios for myocarditis and pericarditis following BNT162b2, mRNA-1273, and ChAdOx1 were significantly increased with LBCIs > 1.5.

Conclusion​

This multi-country analysis confirmed pre-established safety signals for myocarditis, pericarditis, Guillain-Barré syndrome, and cerebral venous sinus thrombosis. Other potential safety signals that require further investigation were identified.

Keywords​

Vaccine safety surveillance
Pharmacovigilance
Adverse events following immunization
Adverse events of special interest
COVID-19
Observed vs. expected analysis

1. Introduction​

Since declaration of the COVID-19 pandemic by the World Health Organization (WHO) on March 11, 2020 [1] more than 13.5 billion doses of COVID-19 vaccines have been administered worldwide [2]. As of November 2023, at least 70.5 % of the world’s population had received at least one dose of a COVID-19 vaccine [2]. This unparalleled scenario underscores the pressing need for comprehensive vaccine safety monitoring as very rare adverse events associated with COVID-19 vaccines may only come to light after administration to millions of individuals.
In anticipation of this unprecedented global rollout of COVID-19 vaccines, the Safety Platform for Emergency vACcines (SPEAC) initiative formulated a list of potential COVID-19 vaccine adverse events of special interest (AESI) in 2020 [3]. AESI selection was based on their pre-established associations with immunization, specific vaccine platforms or adjuvants, or viral replication during wild-type disease; theoretical concerns related to immunopathogenesis; or supporting evidence from animal models using candidate vaccine platforms [3].
One flexible approach for assessing AESI is the comparison of observed AESI rates following the introduction of a vaccine program with the expected (or background) rates based on historical periods pre-vaccine roll out [4], [5]. Such comparisons can be executed rapidly and can play a key role in early detection of potential vaccine safety signals or when regulatory and public health agencies need rapid assessment of an emerging safety signal [4], [6]. Observed versus (vs.) expected (OE) analysis was integral in identifying thrombosis with thrombocytopenia syndrome (TTS) as a safety signal, prompting the suspension of use of the ChAdOx1 (AstraZeneca COVID-19 vaccine) on March 11, 2021, in Denmark and Norway [7], [8].
These evaluations are not only valuable early-on in large-scale vaccine deployment, but also as the vaccination program matures, especially if they can be conducted in a multi-country context. We conducted a global cohort study following the Observed vs. Expected Analyses of COVID-19 Adverse Events of Special Interest Study Protocol [9]with data from 10 sites across eight countries participating in the unique Global COVID Vaccine Safety (GCoVS) Project [10] of the Global Vaccine Data Network™ (GVDN®) [11]. The GCoVS Project, initiated in 2021, is a Centers for Disease Control and Prevention (CDC) funded global collaboration of investigators and data sources from multiple nations for the purpose of COVID-19 vaccine safety monitoring.

2. Methods​

2.1. Study design​

This retrospective observational study was designed to estimate the OE ratios of selected AESIs after COVID-19 vaccination in a multi-country population cohort.

2.2. Data source and study population​

The GCoVS Project compiled electronic healthcare data on AESI related to COVID-19 vaccines from participants across multiple sites within the GVDN network, including Argentina, Australia – New South Wales, Australia – Victoria, Canada – British Columbia, Canada – Ontario, Denmark, Finland, France, New Zealand, and Scotland [10]. The healthcare data comprised of either individual- or population-level data, depending on the availability in the study sites (Supplementary Table 1).
Immunization registers containing individual-level vaccination data were utilized by the majority of study sites. These registers covered the same population and geographic region as the data sets used to calculate background rates. We also examined population-level data on vaccination uptake using regularly updated dashboards from the study sites. If the number of individuals vaccinated in specific age and gender groups was available, we converted those numbers into person-years based on the post-vaccination risk period. Unlike the registers with individual-level data, the age and sex strata used in this approach might not have matched the strata used in the background rates calculations.
Participants were individuals vaccinated with COVID-19 vaccines in the populations represented by the sites. To the extent possible, standardized methods were applied across sites. Patient types included hospital inpatients (Australia – New South Wales, France, New Zealand, Scotland), and combinations of inpatient and outpatient emergency department patients (Argentina, Australia – Victoria, Canada, Denmark, Finland). In countries without clearly defined patient types, hospital contact duration was used as a proxy for patient types. As an example, a contact duration of five hours or longer was used as a proxy for inpatients in Denmark. Site-specific characteristics of data sources and data are presented in Supplementary Table 1.

2.3. Study period and follow-up​

The study periods varied across countries, commencing on the date of the site-specific COVID-19 vaccination program rollout, and concluding at the end of data availability (Table 1). In general, the study periods spanned from December 2020 until August 2023. The shortest study period observed occurred in Australia – New South Wales, including 11 months from February 2021 to December 2021. Argentina had the longest study period, from December 2020 to August 2023, encompassing a total of 32 months.
Table 1. Population summary by site. (Only Pfizer/BioNTech BNT162b2, Moderna mRNA-1273, and Oxford/Astra Zeneca/Serum Institute of India ChAdOx1 vaccines and doses 1–4 included).

Vaccines: Pfizer/BioNTech (BNT162b2), Moderna (mRNA-1273), and Oxford/Astra Zeneca/Serum Institute of India (ChAdOx1).

The risk intervals used after each dose were 0–7 days, 8–21 days, 22–42 days, and 0–42 days. For each vaccination dose, day 0 was denoted the day of vaccine receipt. For this manuscript, we present results for the risk interval of 0–42 days only. More data are presented on the GVDN dashboard with all latest updates from participating sites [12]. Outcome events that occurred outside the study period were not included. A 365-day washout period for outcome events was used to define incident outcomes. Outcome events were considered incident if there was no record of the same outcome event during the preceding 365-day washout period. An individual may have contributed several outcome events on the condition they were separated in time by at least the washout period of 365 days.

2.4. Study variables and outcomes​

2.4.1. Adverse events of special interest (AESI)​

Thirteen conditions representing AESI of specific relevance to the current landscape of real-world vaccine pharmacovigilance were selected from the list compiled by the Brighton Collaboration SPEAC Project [3] and in response to the safety signals of thrombosis with thrombocytopenia syndrome [7], [8] (Supplementary Table 2). The conditions chosen matched the AESI for which background rates were recently generated by GVDN sites [13]. AESI were identified using harmonized International Classification of Diseases 10th Revision (ICD-10) codes. Neurological conditions selected included Guillain-Barré syndrome (GBS), transverse myelitis (TM), facial (Bell’s) palsy, acute disseminated encephalomyelitis (ADEM), and convulsions (generalized seizures (GS) and febrile seizures (FS)) as potential safety signals have been identified for some of these conditions [14], [15], [16]. Hematologic conditions included cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT) and pulmonary embolism (PE); the unusual site thromboses (CVST and SVT) were selected as markers of potential TTS that could be accurately identified using diagnostic codes [17], [18]. Thrombocytopenia and immune thrombocytopenia (ITP) were also included due to their association with TTS and reports of ITP as an independent safety signal [7], [19], [20]. Myocarditis and pericarditis were included as cardiovascular conditions and the OE ratios were evaluated separately for each condition [21], [22], [23].

2.4.2. COVID-19 vaccines​

As of November 2023, multiple vaccines against COVID-19 were in use by the GCoVS sites representing multiple platform types such as inactivated, nucleic acid-based (mRNA), protein-based, and non-replicating viral vector platforms (Table 2). For this manuscript, we focused on three vaccines that recorded the highest number of doses administered, Pfizer/BioNTech BNT162b2, Moderna mRNA-1273, and Oxford/Astra Zeneca/Serum Institute of India ChAdOx1 vaccines. The cumulative number of doses of other vaccines administered (n) across study sites were relatively low, with exceptions for the inactivated Sinopharm (n = 134,550) and Sinovac (n = 31,59 vaccines, the protein-based Novavax (n = 66,856) vaccine, and the adenovirus-vector Janssen/Johnson & Johnson (n = 1,137,505) and Gamaleya Research Institute/Sputnik (n = 84,460) vaccines. The total number of doses of each vaccine brand administered are outlined in Table 2. Exposure to COVID-19 vaccine by platform/type, brand, and dose data were available at the individual level to determine the number of observed cases by vaccine type/brand and dose profile and within the 0–42 days post-vaccination risk interval.
Table 2. Total number of vaccinations by brand.

Vaccine platform	Vaccine brand	Total doses
Inactivated	Covilo or SARS-CoV-2 Vaccine (Vero Cell) [Sinopharm (Beijing)]	134,550
Covaxin [Bharat Biotech]	1,660
CoronaVac or Sinovac [Sinovac Biotech]	31,598
Inactivated (Vero cell) [Sinopharm (Wuhan)]	623
Nucleic acid-based	Comirnaty or Riltozinameran or Pfizer/BioNTech COVID-19 Vaccine Bivalent [Pfizer/BioNTech]	3,516,963
Comirnaty or Tozinameran [Pfizer/BioNTech or Fosun-BioNTech]	183,677,660
Comirnaty or Tozinameran Paediatric [Pfizer/BioNTech or Fosun-BioNTech]	2,439,086
Spikevax bivalent Original/Omicron [Moderna]	2,750,476
Elasomeran or Spikevax or TAK-919 Half Dose [Moderna or Takeda]	400,395
Elasomeran or Spikevax or TAK-919 [Moderna or Takeda]	36,222,514
Protein-based	MVC-COV1901 [Medigen]	16
Covovax or Nuvaxoid [Novavax or Serum Institute of India]	66,856
Non-replicating viral vector	Convidecia or Convidence [CanSino]	3,938
Covishield or Vaxzevria [AstraZeneca or Serum Institute of India]	23,094,620
Sputnik Light or Gam-COVID-Vac [Gamaleya Research Institute]	26
Sputnik V [Gamaleya Research Institute]	84,460
Janssen [Janssen/Johnson & Johnson]	1,137,505

2.5. Statistical analysis​

2.5.1. Calculation of observed vs. expected ratios for each site​

For each site, we calculated the observed number of events for each AESI in the risk interval after introduction of COVID-19 vaccination. To calculate the expected number of cases, we used pre-COVID-19 vaccination background rates data from 2015 to 2019 (2019–2020 for Denmark) collected in the GCoVS Background Rates of AESI Following COVID-19 vaccination study [13]. The observed follow-up period in person-years for a given vaccination profile and post-vaccination period was stratified according to age group and sex. Each of the age-sex stratified person-years were multiplied by the corresponding age-sex stratified background rate. This resulted in the expected number of cases in each stratum, which were then summed to give the total number of expected cases during the observed follow-up period.
The aggregated OE ratios by last dose were calculated by dividing the observed number of cases by the expected number of cases in the post-vaccination period, 95 % confidence intervals (CI) were derived using the exact Poisson distribution. We also calculated OE ratios for homologous schedules for BNT162b2, mRNA-1273, and ChAdOx1 vaccines up to four doses. Both the aggregated OE ratios and those specific to homologous schedules are presented.
We considered an OE ratio a potential safety signal of concern where the lower bound of the 95 % CI (LBCI) was greater than one and reached statistical significance [5]. However, we prioritised potential safety signals of concern for further evaluation where the LBCI was greater than 1.5, due to increased statistical evidence and the higher likelihood of being a true signal, based on expert opinion from the CDC and GVDN collaborators.

2.5.2. Combining results across sites​

The results were aggregated across sites by summing the observed number of events for each AESI and the age-sex stratified person-years for a given vaccination profile and post-vaccination period. For each AESI, individual vaccine profiles were reported if the cumulative amount of follow up (in person-years) in the 0–42 days post-vaccination period was 10,000 or greater. The combined numbers of events and the OE ratio was calculated with 95 % CIs derived using the exact Poisson distribution. No event (i.e., zero) observed for a vaccine brand and dose profile was reported separately without CI.

2.5.3. Sensitivity analysis​

Firstly, we conducted site-specific sensitivity analyses to further explore potential associations of the most significant safety signals identified in the main analysis. The observed rates reported by sites were considered in the analysis based on the following constraints. For each vaccine brand and dose profile, and post-vaccination period combination, the OE ratios and 95 % CI were suppressed if fewer than five events were observed. Secondly, we conducted supplemental analysis including other vaccines and doses administered across sites. The person-years threshold for reporting was lowered from 10,000 to 1,000 person-years compared to the main aggregated OE ratios analysis, allowing for broader scope of vaccines to be analysed.

2.6. Ethical approval​

Approval from the relevant Human Research Ethics Committees was either acquired or an exemption obtained for all participating sites (Supplementary Table 3).

3. Results​

The total vaccinated population across all sites comprised 99,068,901 individuals. Most vaccine recipients were in the 20–39 and 40–59-year age groups (Table 1). In total, 183,559,462 doses of BNT162b2, 36,178,442 doses of mRNA-1273, and 23,093,399 doses of ChAdOx1 were administered across all the sites in the study periods. The highest numbers of doses were administered in France (120,758,419), followed by Canada – Ontario (32,159,817) and Australia – Victoria (15,617,627). In total, 23,168,335 person-years contributed to the OE ratios for the AESI following homologous schedules. The population summary is presented in Table 1, and more detailed information on the other administered vaccines are presented in Supplementary Table 4. In the results sections below, we provide both aggregated OE ratios (Table 3, Table 4, Table 5) and detailed OE ratios for homologous schedules (Fig. 1, Fig. 2, Fig. 3), including the number of events and person-years. Overall, 95.8 % and 86.6 % of vaccinations were included in the aggregated and the homologous schedules analysis, respectively (Supplementary Table 5). The primary results from the individual sites as well as additional risk periods and meta-analyses for each AESI are available in the interactive GVDN Observed vs Expected (OE) Dashboard [12].
Table 3. Aggregated OE Ratios by last dose, neurological conditions, period 0–42 days.

AESI: GBS = Guillain-Barré syndrome, TRM = Transverse myelitis, BP = Facial (Bell’s) palsy, ADEM = Acute disseminated encephalomyelitis, FSZ = Febrile seizures,
GSZ = Generalised seizures.
Vaccines: Pfizer/BioNTech (BNT162b2), Moderna (mRNA-1273), and Oxford/Astra Zeneca/Serum Institute of India (ChAdOx1).

Table 4. Aggregated OE Ratios by last dose, haematologic conditions, period 0–42 days.

AESI: THR = Thrombocytopenia, ITP = Idiopathic thrombocytopenia, PEM = Pulmonary embolism, CVST = Cerebral venous sinus thrombosis, SVT = Splanchnic vein thrombosis.
Vaccines: Pfizer/BioNTech (BNT162b2), Moderna (mRNA-1273), and Oxford/Astra Zeneca/Serum Institute of India (ChAdOx1).

Table 5. Aggregated OE Ratios by last dose, cardiovascular conditions, period 0–42 days.

3.1. Neurological conditions​

There was a statistically significant increase in GBS cases within 42 days after a first ChAdOx1 dose (OE ratio = 2.49; 95 % CI: 2.15, 2.87), indicating a prioritised safety signal (Table 3). Seventy-six GBS events were expected, and 190 events were observed (Fig. 1). The OE ratio for ADEM within 42 days after a first mRNA-1273 dose also fulfilled the significance threshold of a prioritised safety signal (3.78; 95 % CI: 1.52, 7.7, with two expected events compared with seven observed events (Fig. 1).
Statistically significant differences were also found for transverse myelitis (OE ratio = 1.91; 95 % CI: 1.22, 2.84) and ADEM (OE ratio = 2.23; 95 % CI: 1.15, 3.90) after a first ChAdOx1 dose. Bell’s palsy had an increased OE ratio after a first dose of BNT162b2 (1.05; 95 % CI: 1.00, 1.11) and mRNA-1273 (1.25; 95 % CI: 1.11, 1.39). There were also increased OE ratios for febrile seizures following a first and second dose of mRNA-1273 (1.36, 95 % CI: 1.02, 1.77 and 1.44, 95 % CI: 1.04, 1.95, respectively), and for generalised seizures following a first mRNA-1273 dose (1.15, 95 % CI: 1.10, 1.20) and a fourth BNT162b2 dose (1.09, 95 % CI: 1.04, 1.14). No increased OE ratios were identified following a third dose of any vaccine. The results are concordant with the OE ratios of homologous schedules; however, an increased OE ratio for generalized seizures following a homologous schedule of four doses of mRNA-1273 (1.33; 95 % CI: 1.07, 1.63) was identified (Fig. 1). These outcomes did not meet the threshold for a prioritised safety signal following vaccination.

3.2. Hematologic conditions​

The OE ratio of CVST was 3.23 (95 % CI: 2.51–4.09) within 42 days after a first dose of ChAdOx1, fulfilling the threshold of a prioritised safety signal (Table 4). In total, 21 events were expected, while 69 events were observed (Fig. 2).
Increased OE ratios were also identified for thrombocytopenia after a first dose of ChAdOx1 (1.07; 95 % CI: 1.03, 1.12), BNT162b2 (1.11; 95 % CI: 1.08, 1.14), and mRNA-1273 (1.33; 95 % CI 1.25, 1.42), as well as after a third dose of ChAdOx1 (1.95; 95 % CI: 1.29, 2.84). Immune thrombocytopenia also demonstrated increased OE ratios after a first dose of ChAdOx1 (1.40; 95 % CI: 1.24, 1.5 and BNT162b2 (1.08; 95 % CI: 1.01, 1.16). Pulmonary embolism OE ratios were increased following first doses of ChAdOx1 (1.20; 95 % CI: 1.16, 1.24), BNT162b2 (1.29; 95 % CI: 1.26, 1.32), and mRNA-1273 (1.33, 95 % CI: 1.26, 1.40), as well as after a third dose of ChAdOx1 (1.88; 95 % CI: 1.32, 2.5. The OE ratio of CVST was 1.49 (95 % CI: 1.26, 1.75) after a first dose and 1.25 (95 % CI: 1.06, 1.46) after a second dose of BNT162b2. An increased OE ratio for SVT was found after a first dose of BNT162b2 (1.25; 95 % CI: 1.17, 1.34) and mRNA-1273 (1.23; 95 % CI: 1.03, 1.47); a second dose of mRNA-1273 (1.17; 95 % CI: 1.01, 1.36); and a fourth dose of BNT162b2 (1.30, 95 % CI: 1.06, 1.59) and mRNA-1273 (1.53, 95 % CI: 1.05, 2.16). These outcomes did not meet the threshold for a prioritised safety signal following vaccination.

3.3. Cardiovascular conditions​

Increased OE ratios fulfilling the threshold of prioritised safety signals for myocarditis were consistently identified following a first, second and third dose of mRNA vaccines (BNT162b2 and mRNA-1273) (Table 4). The highest OE ratio was observed following a first and second dose of mRNA-1273 (3.48; 95 % CI: 3.00, 4.01 and 6.10; 95 % CI: 5.52, 6.72, respectively). The OE ratio following a third dose of mRNA-1273 was 2.01 (95 % CI: 1.60, 2.49). The numbers of events for up to four doses of homologous schedules are shown in Fig. 3. The OE ratios of homologous schedules align with the aggregated OE ratios. The homologous OE for myocarditis following four doses of mRNA-1273 vaccine could not be estimated due to a lack of observed events.
Similarly, the OE ratio for pericarditis fulfilled the threshold of a prioritised safety signal following a first and fourth dose of mRNA-1273, with OE ratios of 1.74 (95 % CI: 1.54, 1.97) and 2.64 (95 % CI: 2.05, 3.35) respectively. An increased ratio of 6.91 (95 % CI: 3.45, 12.36), fulfilling the threshold of a prioritised safety signal, was also observed following a third dose of ChAdOx1. The aggregated OE ratios for pericarditis were increased following all doses of all the three vaccines presented (Table 4). The results are very similar to the ratios of homologous schedules (Fig. 3), except for the OE ratio of 1.23 (95 % CI: 0.45–2.69) after receipt of the fourth mRNA-1273 dose, which did not meet the threshold for a safety signal. The homologous OE ratio following a third dose of ChAdOx1 was not reported as only a small number of third doses of ChAdOx1 were given across study sites (Table1).

3.4. Sensitivity analysis​

Secondary analyses were conducted to further explore GBS, ADEM, CVST, myocarditis, and pericarditis at the site-specific level. We report the aggregated OE ratios by last dose and site in the period 0–42 days after vaccination in Supplementary Tables 6–10. It was not possible to report results for all sites and study outcomes due to insufficient person-years or less than five events observed by site privacy criteria. The majority of identified safety signals following specific vaccine brand and dose combinations from the main analysis were, however, confirmed by individual sites where data were available. The supplementary analysis with person-years threshold of 1,000 and including other vaccines and doses administered within the GVDN sites, showed an increased OE ratio for some outcomes, e.g. for generalized seizures following a first dose of Gamaleya Research Institute/Sputnik vaccine (5.50, 95 % CI: 2.74, 9.84) (Supplementary Tables 11–13).

4. Discussion​

This multi-country cohort study was conducted in the unique setting of the GVDN. To date, the number of such large systematically coordinated studies across diverse geographical locations and populations is limited. However, several studies have previously assessed the risks of the identified safety signals following COVID-19 vaccination, primarily in single site settings. We investigated the association between COVID-19 vaccination and 13 AESIs comprising neurological, haematological, and cardiovascular conditions across 10 sites in eight countries including Europe, North America, South America, and Oceania. In this study including more than 99 million people vaccinated against SARS-CoV-2, the risk up to 42 days after vaccination was generally similar to the background risk for the majority of outcomes; however, a few potential safety signals were identified. We observed potential safety signals for GBS and CVST after the first dose of ChAdOx1 based on more than 12 million doses administered.
Overall, studies of the vector-based vaccines such as the ChAdOx1, have observed a higher incidence of GBS after vaccination compared with the background incidence; whereas, most studies of the mRNA vaccines, such as BNT162b2 and mRNA-1273, have not observed increases of GBS [15], [24], [14], [25], [26], [27]. Atzenhoffer et al. [24]reported an elevated OE ratio > 2.0 for adenovirus-vectored COVID-19 vaccines, across countries contributing to VigiBase, an international database of adverse drug events and Patone et al. [27] reported 38 excess cases of GBS per 10 million exposed in the 1–28 days risk period following vaccination with ChAdOx1 in England. The authors did not observe an increased risk in those who received BNT162b2. In contrast, a study by Li et al. [28] showed no increased risk of GBS for ChAdOx1, while only SARS-CoV-2 infection was associated with a higher risk. The discrepancy, compared with the results of Patone et al. [27], could however be explained by a smaller sample size and different outcome measures. Overall, this evidence supports our findings of a GBS safety signal following ChAdOx1 vaccination. Although rare, this association was acknowledged by the WHO, the European Medicines Agency (EMA), and Therapeutic Goods Administration (TGA) of Australia, resulting in GBS being listed as a rare side effect following exposure to ChAdOx1 [15], [29], [30].
The identified increased risk of CVST following ChAdOx1 vaccination in this study is corroborated by multiple studies. An increased OE ratio was observed in a nationwide cohort study from Denmark and Norway, with increased rates of venous thromboembolic events, including CVST with an excess rate of 2.5 events per 100,000 vaccinations following ChAdOx1 [7]. Based on a variety of methodologies, other studies have also reported increased incidence of CVST after vaccination [31], [32]. Ultimately, this rare but concerning safety signal led to the withdrawal of the ChAdOx1 vaccine from COVID-19 vaccine programs or implementation of age-based restrictions in multiple countries [8].
It is crucial to acknowledge the significance threshold of prioritised safety signals applied in this study (LBCI > 1.5). This threshold was selected based on expert opinion within the GVDN and at CDC, to focus on those outcomes most likely to be true signals. Some observed events, although not fulfilling this threshold, may still hold clinical importance and require further investigation. For instance, ITP with an OE ratio > 1.0 and LBCI of 1.2 following vaccination with ChAdOx1 aligns with findings reported in the literature as a potential signal. This concurrence is highlighted in a study conducted in Victoria, Australia, which observed a substantially higher than expected rate of ITP following ChAdOx1 vaccination [33].
Moreover, we observed significantly higher risks of myocarditis following the first, second and third doses of BNT162b2 and mRNA-1273 as well as pericarditis after the first and fourth dose of mRNA-1273, and third dose of ChAdOx1, in the 0–42 days risk period. The elevated rates of pericarditis following ChAdOx1 vaccination identified in this study rely on a limited number of observed counts in the meta-analysis. The wide confidence interval underscores the substantial uncertainty of characterizing pericarditis as a safety signal following ChAdOx1 vaccination. However, our study confirms findings of previously identified rare cases of myocarditis and pericarditis following first and second doses of mRNA vaccines [21], [22], [23], [34]. A large cohort study of 23.1 million residents across four Nordic countries revealed an increased risk of myocarditis among young males aged 16–24 years, based on 4–7 excess events in 28 days per 100,000 vaccinees after a second dose of BNT162b2, and between 9 and 28 per 100,000 vaccinees after a second dose of mRNA-1273 [22]. Similarly, studies from British Columbia, Canada reported cases of myocarditis to be higher among those receiving a second dose compared with a third dose, and for those who received a second dose of the mRNA-1273 vaccine compared with the BNT162b2 vaccine [35], [36]. Patone et al. [37] estimated extra myocarditis events to be between one and 10 per million persons in the month following vaccination, which was substantially lower than the 40 extra events per million persons observed following SARS-CoV-2 infection period. A systematic review by Alami et al. [38] concluded that mRNA vaccinated individuals were twice as likely to develop myocarditis/pericarditis compared with unvaccinated individuals, with a rate ratio of 2.05 (95 % CI 1.49–2.82). Given the evidence, WHO issued updated guidance regarding these safety signals and mRNA COVID-19 vaccination, and EMA provided updates to the Product Information for BNT162b2 and mRNA-1273 vaccines [21], [23]. TGA as well as the CDC continue to monitor and review data on myocarditis and pericarditis following COVID-19 vaccination [39], [40].
Another potential safety signal was identified for ADEM after the first dose of mRNA-1273 vaccine, with five more observed than expected events based on 1,035,871 person-years and 10.5 million doses administered; however, the number of cases of this rare event were small and the confidence interval wide, so results should be interpreted with caution and confirmed in future studies. Although some case reports have suggested a possible association between COVID-19 vaccination and ADEM, there was no consistent pattern in terms of vaccine or timing following vaccination, and larger epidemiological studies have not confirmed any potential association [41], [42], [43], [44]. Moreover, case reports may report on coincidental events and do not establish association nor indicate causality, thus larger observational studies are warranted to further investigate our finding. To address this, a follow-up study is currently being undertaken within the GVDN, focusing on a demographic not included in our analysis. Based on reports of rare ADEM cases to the European Database of Suspected Adverse Drug Reaction, EMA assessed the potential association of ADEM following vaccination with ChAdOx1 [45]. Frontera et al. [46] concluded that chances of having a neurological event following acute SARS-CoV-2 infection were up to 617-fold higher than following COVID vaccination, suggesting that the benefits of vaccination substantially outweigh the risks. A safety signal for generalized seizures was identified following Gamaleya Research Institute/Sputnik vaccination, however the number of vaccinations was relatively low compared with other vaccines in this study. Further studies are warranted to explore this potential safety signal.
Conducting a cohort analysis in the unique multi-country context of the GVDN leverages a vast and diverse data pool. Aggregating data from multiple countries on more than 99 million vaccine recipients has significantly increased the sample size and the statistical power compared with many previous safety studies. This enhances the ability to detect safety signals, especially for extremely rare adverse events, as the larger sample size provides greater precision in estimating observed rates.
Results based on data across Europe, North and South America and Oceania offer stronger external validity, enabling findings to be more generalizable to a broader range of populations and healthcare settings participating in the global COVID-19 vaccination programme. Moreover, multi-country analyses facilitate comparisons between countries with varying vaccination strategies, population demographics, and healthcare systems, yielding insights into how these factors may influence vaccine safety profiles. Data used in our analysis were drawn from multiple databases, including healthcare databases, national immunization registries, and vaccination dashboards, allowing the identification of potential safety signals from various sources.
The results from our study should, however, be interpreted considering multiple limitations. Our analyses inherently involve heterogeneity in data collection, quality, and reporting standards across countries. These differences in healthcare infrastructure and surveillance systems can introduce bias and affect the comparability of results. The participating sites across the eight countries implemented varied vaccination strategies, including vaccine types, dosing schedules, and prioritization of vaccine recipients. Moreover, the multi-country analyses are susceptible to population confounding factors, such as differences in pre-existing health conditions, genetic factors, ethnic profiles, and behavioural patterns, which was not possible to adjust for in our analysis. We consider our approach suitable for application in large datasets representing average populations. However, age- and sex-specific historic background rates that are not adjusted for factors like prior disease may not provide a suitable comparison, for example, in the early stages of a vaccination campaigns where people with co-morbidities were vaccinated prior to other population groups.
Potential underreporting across countries may have led to an underestimation of the significance of potential safety signals. It is important to recognize the potential for false negatives, especially when detecting associations with lower confidence intervals below 1.5 that maintain statistical significance. The safety signals identified in this study should be evaluated in the context of their rarity, severity, and clinical relevance. Moreover, overall risk–benefit evaluations of vaccination should take the risk associated with infection into account, as multiple studies demonstrated higher risk of developing the events under study, such as GBS, myocarditis, or ADEM, following SARS-CoV-2 infection than vaccination. Finally, the use of ICD-10 codes is subject to considerations about specificity and sensitivity, and application may vary by country.

5. Conclusion​

Observed vs. expected analyses in a multi-country context of the GVDN and the GCoVS Project offers a larger and more diverse dataset, enhanced generalizability, and improved statistical power over single site or regional studies. It also presents challenges related to data heterogeneity, population confounding factors, and variations in vaccination strategies and reporting systems. The involvement of researchers and data sources from diverse regions of the world promotes inclusivity, reduces potential biases, and fosters collaboration in the pursuit of a shared public health goal. While our study confirmed previously identified rare safety signals following COVID-19 vaccination and contributed evidence on several other important outcomes, further investigation is warranted to confirm associations and assess clinical significance. This could be addressed by conducting association studies specific to individual outcomes by applying methodologies such as the self-controlled case series (SCCS) to validate the associations [6].

​

"

 

[dk168]

I went with 24 others from the service charity club for a weekend away, and 4 of them reported being tested positive for Covid on Tuesday.

2 of them shared a car there and back - 2.5h each way. One of them attended some sort of event before the trip and was informed some attendees had been tested positive.

3 of 4 tested positive attended a club social events Monday evening and I too was there myself.

Luckily, all the ones tested positive reported mild flu like symptoms, all of them are up to date with their vaccination.

I am Covid-free so far.

Covid has not gone away, so please stay safe!

DK

 

[missy]

I went with 24 others from the service charity club for a weekend away, and 4 of them reported being tested positive for Covid on Tuesday.

2 of them shared a car there and back - 2.5h each way. One of them attended some sort of event before the trip and was informed some attendees had been tested positive.

3 of 4 tested positive attended a club social events Monday evening and I too was there myself.

Luckily, all the ones tested positive reported mild flu like symptoms, all of them are up to date with their vaccination.

I am Covid-free so far.

Covid has not gone away, so please stay safe!

DK

I'm sorry @dk168 and sending you many well wishes that you remain Covid free

My dh and I have so far managed to avoid getting Covid but unfortunately his family insists on social gatherings and this June his cousin is throwing a 70th party bash and darn it we have to go. His brothers who live in other states are flying in for this and I have to just suck it up because I don't feel right telling Greg we cannot go. We hardly see his family (and his mom died June 2020) but these events are super spreaders. If my immune system was healthy and robust I would have no qualms but it isn't and neither is Greg's. There will be well over 200 people there and you know no one is testing before they go. Drat. Darn. Boo. I have a feeling we will be catching Covid sooner rather than later. My very risk adverse self does not like this at all

 

[dk168]

I'm sorry @dk168 and sending you many well wishes that you remain Covid free

My dh and I have so far managed to avoid getting Covid but unfortunately his family insists on social gatherings and this June his cousin is throwing a 70th party bash and darn it we have to go. His brothers who live in other states are flying in for this and I have to just suck it up because I don't feel right telling Greg we cannot go. We hardly see his family (and his mom died June 2020) but these events are super spreaders. If my immune system was healthy and robust I would have no qualms but it isn't and neither is Greg's. There will be well over 200 people there and you know no one is testing before they go. Drat. Darn. Boo. I have a feeling we will be catching Covid sooner rather than later. My very risk adverse self does not like this at all

Can Greg go on his own, for him to isolate in one of your rooms in your house for 5 days when he comes back?

DK

 

[missy]

Can Greg go on his own, for him to isolate in one of your rooms in your house for 5 days when he comes back?

DK

Thanks dk. We discussed that option but he feels he’d infect me if he went and got it and came back. We don’t really have space to separate in the house. It’s mainly all open space. Few rooms. Plus he wants me there and I want to be there for him. I am curious if my sisters in law are coming. Since it’s long distance. They’re not concerned about Covid. If they go I’m definitely going because I haven’t seen them since before covid. We’ve seen his middle brother who visited us this summer/fall. But no one else in the family


From his visit September 2023

 

[missy]

"
Oncology/Hematology>Other Cancers

Another COVID Toll: Over 134,000 Undiagnosed Cancers During Height of Pandemic​

— Diagnosis rates remained low throughout 2020, with mortality increase projected​

by Charles Bankhead, Senior Editor, MedPage Today February 22, 2024

More than 134,000 cancers might have gone undiagnosed during the first 10 months of the COVID-19 pandemic, according to a study of national trends in cancer incidence.

Annual cancer incidence fell almost 30% short of the expected rate from March through December 2020. The difference represented potentially 134,395 undiagnosed cancers during that period. Diagnosis of early- and late-stage cancers declined. Prostate, breast, and lung cancers accounted for the most potential missed cases. Overall, rates of "screenable" cancers decreased by 13.9% versus expected rates.



Rates of breast cancer began returning to norms after the first 3 months of the pandemic, but the incidence of colorectal, cervical, and lung cancers remained low, reported Krystle A. Lang Kuhs, PhD, MPH, of the University of Kentucky Markey Cancer Center in Lexington, and co-authors in JAMA Oncologyopens in a new tab or window.

"To our knowledge, this is the first study to offer a nationwide analysis using U.S. cancer registry data on the cancer case deficit experienced during the COVID-19 pandemic in 2020," the authors wrote. "The findings from this analysis can inform the U.S. healthcare system as decisions are made to recover the deficit through focused cancer screening and detection. These findings may also assist with planning for any future disruptions that would otherwise affect the timeliness of cancer diagnosis."

Actionable Information

Co-author Todd Burus, MA, MAS, also of the University of Kentucky Markey Cancer Center, told MedPage Today that the study highlights the impact of a disruption in routine healthcare visits and cancer screening on cancer detection and suggests potential action to offset or mitigate the effects.



"It is important to increase messaging and promotion of the screening guidelines among eligible populations to help re-establish good health-seeking behaviors," he wrote via email. "Our analysis of which cancer sites and population subgroups were most affected can help better target this messaging."

"We believe strong, consistent health messaging is crucial to helping establish (or re-establish) appropriate screening patterns," he continued. "We noted in the article how such strong messaging around female breast cancer screening likely contributed to the rapid recovery of female breast cancer incidence observed following the initial pandemic period."

The results also highlight a need for investment in technology and processes to increase the speed of cancer data reporting.

"Nationwide cancer incidence data for 2020 were not available until June 2023, at which point many of the best options for 'catching up' on missed cancer diagnoses from 2020 were off the table," Burus noted.


While the world focused on the threat posed by COVID-19, the threat of cancer remained ever present, the authors pointed out in their introduction. A decrease in observed cancer incidence during the period gives cause for concern. A decline in new cancer diagnoses in 2020 did not mean that the occurrence of cancer decreased, but that new cancers went undetected, an observation confirmed by multiple reports.



For this study, the authors analyzed data from the U.S. Cancer Statistics 2001-2020 Public Use Database, which included data from the CDC's National Program of Cancer Registries and the National Cancer Institute's Surveillance, Epidemiology, and End Results program. The records encompassed 99.7% of all cancer cases in the 50 states and the District of Columbia.

Lang Kuhs and colleagues calculated cancer incidence by month of diagnosis from Jan. 1, 2018 through Dec. 31, 2020, capturing cancer diagnoses before and during the pandemic. They also collected patient demographics and cancer stage at diagnosis. The analysis excluded Indiana and Nevada, due to the unavailability of 2020 data.

National Impact

The results showed that 1,297,874 new cancers were reported from March 1 through Dec. 31, 2020. Male-female distribution was essentially 50/50, individuals 65 or older accounted for 58.3% of the cases, and 82% of the cancers occurred in white patients.

The total number of new cancer diagnoses translated into an incidence of 326.5 cases per 100,000 population, reflecting a 13% decrease from the expected rate of 375.4 per 100,000. In absolute terms, the difference amounted to 134,395 potentially missed cancer diagnoses from March through December 2020.



The disruption in healthcare had the biggest impact from March to May 2020, when total cancer diagnoses decreased by 28.6% from the expected rate. Rates recovered slightly from June to December but remained significantly below estimates.

Prostate cancer accounted for the largest number of potentially missed cases (22,950), followed by breast (16,870) and lung (16,333) cancers. Diagnosis rates for breast cancer showed evidence of recovery after the first 3 months of the pandemic, but this was not the case for colorectal, cervical, and lung cancers. The investigators found that states with the most restrictive COVID-19 responses had the greatest disruption in cancer diagnoses, but differences were nonsignificant by the end of 2020, with the exception of lung, kidney, and pancreatic cancers.

From March through May 2020, diagnoses of melanoma had the largest decrease from expected (43.4%). Statistically significant reductions persisted from June through December for all cancer sites except breast and pancreatic cancers.

An analysis of stage at cancer diagnosis showed that early-stage diagnoses were 38% lower than expected for March through May 2020, 6.3% lower for June through December, and 15.8% lower than expected for the full study period of March through December. Somewhat surprisingly, rates of late-stage diagnoses also decreased: 26.7% from March-May, 4.7% for June-December, and 11.5% for March-December.



"It is important that we continue to evaluate the trends identified in this study as U.S. cancer incidence data for years after 2020 become available," the authors wrote. "Pandemic-associated disruptions will continue to affect rates of cancer incidence, and how long it will be until we fully recover is still unknown."

"Beyond incidence, it is important that we measure the pandemic's contribution to future trends in cancer mortality and survival," they added. "With a near 10% reduction from expected rates in overall late-stage incidence from March to December 2020, there will undoubtedly -- and unfortunately -- be a subsequent rise in cancer mortality. How substantial a rise and for how long will provide a more complete picture of the consequences of COVID-19 disruptions on the burden of cancer in the U.S."

Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007.

"

 

[missy]

Treating just 20% of symptomatic COVID patientsopens in a new tab or window with nirmatrelvir-ritonavir (Paxlovid) would avert hundreds of thousands of hospitalizations and save the U.S. billions of dollars, a modeling study suggested. (Emerging Infectious Diseases)

People with long COVIDopens in a new tab or window may have greater permeability of their blood-brain barrier, a small study suggested. (Nature Neuroscience)

Public Health Impact of Paxlovid as Treatment for COVID-19, United States

Paxlovid as Treatment for COVID-19, United States

wwwnc.cdc.gov

Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment - Nature Neuroscience

Long COVID is a major public health issue since 2020 and exhibits frequent neurological symptoms. Greene et al. propose that brain fog results from leaky brain blood vessels and a hyperactive immune system, shedding light on this phenomenon.

www.nature.com

 

[diamondringlover]

I work in a health insurance company and I am definitely seeing an increase in covid claims..so it is on the rise again

 

[missy]

I work in a health insurance company and I am definitely seeing an increase in covid claims..so it is on the rise again

Here are the most current statistics fyi

Coronavirus Disease (COVID-19) Situation Reports

The Weekly Epidemiological Update provides an overview of the global, regional and country-level COVID-19 cases and deaths, highlighting key data and trends; as well as other pertinent epidemiological information concerning the COVID-19 pandemic.

www.who.int

COVID-19 cases | WHO COVID-19 dashboard

The latest data for coronavirus (COVID-19) cases from the WHO COVID-19 dashboard.

data.who.int

 

[MamaBee]

My mom’s nursing home is in the middle of a Covid breakout. Yesterday they had six more cases..three staff and three residents. They are doing serial testing every three days. After every single test a bunch of new positive cases come out. Covid cases aren’t reported like they used to be..especially since home testing. Of course in medical settings I would think they still report them. I’m not sure. It’s definitely in an uptick in Pa.

 

[missy]

My mom’s nursing home is in the middle of a Covid breakout. Yesterday they had six more cases..three staff and three residents. They are doing serial testing every three days. After every single test a bunch of new positive cases come out. Covid cases aren’t reported like they used to be..especially since home testing. Of course in medical settings I would think they still report them. I’m not sure. It’s definitely in an uptick in Pa.

Yes, I am seeing covid everywhere. And my entire family and Greg's entire family have already had Covid. Some more than once. We are the only two so far who have not yet been infected. But I know it is only a matter of time. We wear our N95 masks when visiting hospitals, rehab centers and doctors offices but I am sure our luck is running out...

 

[missy]

"

Study IDs Immune Abnormality Possibly Causing Long COVID​

Publish date: February 23, 2024
Publish date: February 23, 2024
By
Tinker Ready

Swiss scientists have identified immune system abnormalities in patients with long COVID that might open the door to new diagnostic tests and treatments.
The researchers found that a group of proteins in the blood that are part of the body’s immune response called the “complement system” are not working properly in patients with long COVID.
Blood samples turned up important differences between those who recovered from COVID and those who did not. These differences might be used as biomarkers to diagnose long COVID and might even point the way to new treatments for the condition, the researchers said.

By testing for 6500 blood proteins in about 300 patients, the Swiss researchers found that dysfunctional complement system proteins could possibly explain fatigue and “smoldering inflammation,” said Onur Boyman, MD, a professor of immunology from University Hospital Zurich in Zurich, Switzerland.
Long COVID has been linked to hundreds of symptoms including brain fog, chronic fatigue, pain, and digestive issues. Various factors drive the condition and likely work with one another other, said David Putrino, PhD, from the Icahn School of Medicine at Mount Sinai in New York City. The Swiss study is useful because “we’re trying to best understand how we can explain all of this far-reaching pathobiology,” he said.

Testing Across Continents​

Dr. Boyman’s team collected blood samples from people with COVID in Europe and New York and tracked them. They compared those who developed long COVID with those who did not. One protein that was most unique to patients with long COVID is a blood complement that activates the immune system, Dr. Boyman said. But in people with long COVID, the immune response stays activated after the virus is gone. He described the response as “smoldering inflammation” in multiple organs, including the lungs and the gastrointestinal system.
The complement system also plays a role in clearing the body of dead cells. If the cells “lie around too much,” they can trigger an immune response, he said.
That may explain exercise intolerance in people with long COVID, Dr. Boyman said. Some people with long COVID have inflammation in the epithelium — the inner layer of their blood vessels. This would make it harder for the circulatory systems to recover from exercise, Dr. Boyman said.
“We think this regulated complement system is actually quite a central piece of the puzzle,” he said.

The Microclot Connection​

The findings also support past research linking blood clots to long COVID. He suggested that clinicians and researchers consider testing drugs that regulate or inhibit the complementary system as a treatment of long COVID. Dr. Boyman said they are currently used for rare immune diseases.
Resia Pretorius, PhD, a professor of physiological sciences at Stellenbosch University in Stellenbosch, South Africa, said scientists studying the role of microclots in patients with long COVID often see complementary proteins inside the clots, so it has already been associated with long COVID. But she likened this clotting process to a garbage can that “just rolls along and collects everything that gets in its way. I think they are actively driving inflammation and disease.”
One factor complicating long COVID diagnosis and treatment is that it is a complex condition that involves multiple organ systems. That’s why the latest research suggests an underlying driver for the multiple symptoms of long COVID, Dr. Putrino said.
“Not every person has every symptom; not every person has every organ system affected,” Dr. Putrino said. “Whatever is happening is decided across the whole body.”

Research Offers New Direction​

The Swiss paper contributes to the effort to identify systemic issues contributing to long COVID. It gives researchers one more thing to test for and link to specific, long COVID symptoms, opening the door to new treatments, Dr. Putrino said.

He doesn’t think the study supports treating the complement dysfunction if researchers don’t know what’s driving it. It may be complicated by the body’s failure to clear the virus completely, he said.

Dr. Pretorius recommended doctors test patients with long COVID for specific symptoms that may be treated using existing therapies. “If you think your patient had vascular pathology, you can test for it,” she said.


Some patients have found certain supplements and over-the-counter products helpful, she said. Among them: Coenzyme Q 10 and clot-busters such as streptokinase and Nattokinase (though she noted some doctors may not be comfortable with supplements).

“It’s the only thing we have until we’ve got trials,” she said.

Dr. Putrino said more research is needed to identify potential root causes and symptoms. A common refrain, but the only thing that will lead to specific treatments.




"

 

[missy]

"
Yes, Covid shots are safe

Largest Covid Vaccine Study Yet Finds Links to Health Conditions

Vaccines that protect against severe illness, death and lingering long Covid symptoms from a coronavirus infection were linked to small increases in neurological, blood, and heart-related conditions in the largest global vaccine safety study to date.

www.bloomberg.com

A recent study found that Covid vaccines were linked to small increases in neurological, blood and heart-related conditions. That made panic over the safety of the shots, which had died down significantly, jump back up. This study, though, wasn’t the bombshell it might appear to be.

“After three years of administration, data shows that the vast majority of vaccinated people globally experience either no vaccine reactions, or reactions that are mild and self-limiting (fever, chills, tiredness, and headache, etc),” says Katrine Wallace, an epidemiologist at University of Illinois at Chicago.

Side effects, like the type covered in this study, are a normal and expected risk of any vaccine or medication, whether it’s aspirin or a Covid shot.

“Any time a medicine or a vaccine is approved and introduced into wider use, rare adverse events are found in the population that would be impossible to find in clinical trials,” says Wallace.

In the real world, more than 13.5 billion doses of Covid vaccines have now been administered globally. That’s more than you can include in a study.

And the findings don’t discount the fact that these vaccines protect against severe illness, death and lingering long Covid symptoms.

There are systems in place, like the US Vaccine Adverse Event Reporting System, or VAERS, that are designed to keep an eye out for potential side effects. The rollout of the Johnson & Johnson Covid shot was paused, for example, after just six cases of blood clots were reported to VAERS out of nearly 7 million doses administered. It was ultimately de-prioritized for use, even though the clots were very rare.

The study that came out recently, published online in the journal Vaccine, was the largest Covid safety study to date. It included data on more than 99 million vaccinated individuals across 10 sites in eight countries. It was spearheaded by the Global Vaccine Data Network and funded by the US Centers for Disease Control and Prevention, looking at the two mRNA shots and AstraZeneca’s viral vector vaccine. It examined how many people reported a group of specific adverse events after vaccination, and compared that to how frequently those events would occur normally in the population.

“The main, statistically significant findings from this study really only served to confirm safety signals that had already been already found in other databases around the world,” says Wallace.

For example, researchers found 190 cases of Guillain-Barre syndrome following the first dose of Astra-Zeneca’s shot, when 66 cases would be expected in the normal population.

The reality is that no medication or vaccine is 100% effective, and everything has risks and benefits, according to Wallace.

“Covid has killed over a million people in the US and has led to permanent disability in many others,” she says. “The vaccines are very safe overall, and the benefit of the vaccine still definitely outweighs the risks.” — Kristen V. Brown

"

 

[pearlsngems]

Gift link to WaPo article that appeared today:

CDC recommends older adults get 2nd updated coronavirus shot

 

[missy]

"

The Misleading Headlines Behind the New COVID Vaccine Safety Study​

— The study just confirms what we already knew​

by Katrine Wallace, PhD February 28, 2024



The largest COVID-19 safety studyopens in a new tab or window to date was published online earlier this month in the journal Vaccine. The study, which was spearheaded by the Global Vaccine Data Networkopens in a new tab or window and funded by the CDC, included data on over 99 million vaccinated individuals across 10 sites in eight countries.

Sensational headlines immediately began cropping up across news sites:

• "New study links COVID-19 vaccine to possible health issues" -- News Nation
• "Largest-ever COVID vaccine study links shot to small increase in heart and brain conditions" -- Fox News
• "Largest multicountry COVID study links vaccines to potential adverse effects" -- The Hill

At first glance, these stories appear to be reporting something new and differentabout the COVID vaccines. But when we step back, we realize this information is not new at all. The study is simply confirming what we've known for years now: there is a small risk of adverse events from the COVID vaccines but the benefits still far outweigh any risks.

Monitoring the Safety of the COVID-19 Vaccines

The COVID-19 vaccines were introduced globally in 2020, accompanied by the most intensive vaccine safety monitoring program the world has ever seen. After 3 years of administration, data show that for the vast majority of the 13.6 billion dosesopens in a new tab or windowadministered globally, recipients experienced either no vaccine reactions or reactions that were mild and self-limitingopens in a new tab or window (fever, chills, tiredness, headache, etc.).

Anytime a medicine or a vaccine is approved and introduced into wider use, rare adverse events are found in the population that would be impossible to find in clinical trials. The U.S. government constantly monitors different databases like the Vaccine Adverse Event Reporting System (VAERSopens in a new tab or window) for rare adverse events and potential safety signals that may arise, and then analyzes whether the number of events among vaccinated individuals is greater than what would be seen normally in the population. While some rare side effects of the COVID-19 vaccines have been shown to occur more frequently than in the background rate of the population, the number of these events represents a tiny percentage of the billions of people overall who received the vaccines.



Before this new study was published, healthcare professionals like yourself and the public were already aware of safety signals of a few very rare adverse events detected in databases (i.e. rare allergic reactions, myocarditis and pericarditis mostly detected in young men after mRNA and Novavax vaccines, or rare but serious cases of thrombosis with thrombocytopenia syndrome [TTS] after the Johnson & Johnson and AstraZeneca vaccines). Even though TTS cases linked to the J&J vaccine were extremely rare, use of this product was quickly pausedopens in a new tab or window and eventually deprioritizedopens in a new tab or windowas a result, proof that the safety surveillance system is very sensitive to detect the rarest events, and that the system does work to make vaccines safer.

Digging Deeper Into the Vaccine Safety Study


The purpose of the study was to get more precise estimates of the risk of adverse events following COVID-19 across several countries. Three vaccines were examined in the study: two were mRNA vaccines (Pfizer/BioNTech and Moderna) and the other was AstraZeneca's viral vector vaccine, which was never authorized in the U.S. but is the same vaccine type as the J&J shot.



It is important to note that the results of this study are not odds ratios or relative risks (which would be comparing vaccinated to unvaccinated people), but instead the study methodology examined the observed versus expected (OE) ratios: observed post-vaccination rates from a pre-specified list of adverse events to the expected rates, or the historical, background rate of the same events calculated from the same populations during 2015-2019, before the vaccines were available. Any event where the lowest end of the observed rate range was estimated to be at least more than 1.5 times the expected/background rate (using the lower bound of the confidence interval) was flagged as a potential safety signal. Because there is no direct comparison, studies like these are not used for causality assessment, but only for detecting potential safety signals.

So, what did the study find?

Despite headlines that may have suggested there was some kind of bombshell finding in this study, the main, statistically significant findings from this study really only served to confirm safety signals that already had been found in other databases around the world. The following are the events that were identified as safety signals:

• Guillain-Barré syndrome (OE 2.49, 95% CI 2.15-2.87) following the first dose of AstraZeneca's viral vector vaccine
• Cerebral venous sinus thrombosis (OE 3.23, 95% CI 2.51-4.09) following the first AstraZeneca dose (these are the TTS blood clots also linked to the J&J shot)
• Acute disseminated encephalomyelitis (OE 3.78, 95% CI 1.52-7.7 following the first dose of Moderna's mRNA vaccine -- this was not found in a more rigorous follow-up study done by this same group
• Myocarditis and pericarditis following Pfizer and Moderna's mRNA vaccines and AstraZeneca's viral vector vaccine were >1.5

All of the other findings of lower magnitude from the study were deemed to be "hypothesis generating" and should be followed-up on with more rigorous designs.

This was the conclusion from the authors: "This multi-country analysis confirmed pre-established safety signals for myocarditis, pericarditis, Guillain-Barré syndrome, and cerebral venous sinus thrombosis. Other potential safety signals that require further investigation were identified."

Don't Let the Headlines Halt Prevention Efforts

The bottom line is that no medication or vaccine is 100% effective or 100% safe, and everything has risks and benefits. But any risks from medications and vaccines need to be balanced against the risks of the disease you are trying to prevent. For example, the risk of myocarditis/pericarditis from COVID-19 is six to 11 times higheropens in a new tab or windowand is associated with a more severe clinical presentationopens in a new tab or window than the risk from the COVID-19 vaccine.

COVID-19 has killed over a million people in the U.S. and has led to permanent disability in many others. The vaccines are very safe overall, and the benefit of the vaccine still definitely outweighs the risks. Fear mongering headlines serve only to harm, not help, public health.

Katrine Wallace, PhD,opens in a new tab or window is an epidemiologist and adjunct assistant professor in the Division of Epidemiology and Biostatistics & Division of Community Health Sciences in the School of Public Health at the University of Illinois at Chicago.




"

 

[missy]

"

Older Adults Should Get Another COVID Booster, CDC Advisors Say​

— High hospitalization rates, low vaccine uptake behind decision​

by Katherine Kahn, Staff Writer, MedPage Today February 28, 2024

Adults ages 65 and older should receive an additional dose of the 2023-2024 COVID-19 vaccine this spring, according to CDC's Advisory Committee on Immunization Practices (ACIP).
Eleven members of the committee voted in favor of the recommendation, one member voted no, and one abstained from voting.
Shortly after the meeting, CDC Director Mandy Cohen, MD, MPH, endorsed the recommendation.
"There are still roughly 20,000 people a week hospitalized for COVID and about 2,000 deaths a week caused by the disease," Megan Wallace, DrPH, MPH, of the CDC's National Center for Immunization and Respiratory Diseases (NCIRD), told committee members on Wednesday, during the first of a 2-day ACIP meeting.

Over the past year, new COVID hospitalizations have never fallen below 6,000 a week, she noted. Persons ages 65 and older have the highest COVID hospitalization rates, and those ages 75 and older have the highest COVID mortality rates.
Christopher Taylor, PhD, also of the NCIRD, highlighted the fact that patients ages 65 and older made up about two-thirds of the population who were hospitalized for COVID from March 2020 to January 2024. Notably, the vast majority of patients hospitalized were unvaccinated or had not received the most up-to-date vaccine.
Another area of concern was that 2023-2024 COVID vaccination coverage has remained low. "While most Americans still consider COVID-19 vaccines to be safe and important, vaccine confidence has declined," said Kevin Chatham-Stephens, MD, MPH, of the NCIRD.
He reported that just 21% of adults had received the latest monovalent booster: 24% were white, 16% were Black, 13% were Hispanic, 11% were American Indian/Alaska Native, and 14% were Native Hawaiian or other Pacific Islander. Adults with health insurance, higher levels of income, and those living in urban areas were all more likely to be vaccinated, he noted.

The vote came after a prolonged discussion among ACIP members about the original language of the recommendation -- that adults ages 65 and older "may" get an additional 2023-2024 booster dose. Ultimately, committee members voted to change the language to read that those ages 65 and older "should" get an additional vaccine dose, a key nuance that struck a chord with committee members.

"I'm wrestling with this 'should' versus 'may' because I'm thinking that there's actually a fair amount of benefit here" to giving an additional dose of the vaccine, said ACIP member Jamie Loehr, MD, of Cayuga Family Medicine in Ithaca, New York. "I can see lots of reasons why the 'may' [recommendation] makes sense, including cost-effectiveness, seasonality ... but if you're asking my personal opinion, I would probably give [another dose] again in February or March for those people who are particularly high risk, those over 75, those who are immunocompromised, those who have high-risk conditions."

Camille Kotton, MD, of Massachusetts General Hospital in Boston, pointed out that only a minority of adults had received the first 2023-2024 COVID-19 vaccine. "From my perspective, as an active clinician in the field, many people did not even know that they should have had an updated vaccine" last fall, she said. "If we say 'may' -- for me, that's too soft."
Oliver Brooks, MD, of Watts Healthcare Corporation in Los Angeles, had a differing opinion. "We still have to get the population vaccinated. We're having more vaccine hesitancy," he said. "And there is concern about vaccine fatigue ... I think that allowing the flexibility of 'may' versus 'should' in the end may get more people vaccinated."
The ACIP COVID Vaccines Work Group presented key evidence to support the recommendation that included the latest data on COVID hospitalizations, vaccination status, cost-effectiveness of the vaccines, and next steps for the COVID vaccine program.




"