In some patients, remnants of the coronavirus in the gut may stifle production of serotonin, an important neurotransmitter, researchers suggest.
The News
A team of scientists is proposing a new explanation for some cases of long Covid, based on their findings that serotonin levels were lower in people with the complex condition.
In their study [*], published on Monday in the journal Cell, researchers at the University of Pennsylvania suggest that serotonin reduction is triggered by remnants of the virus lingering in the gut. Depleted serotonin could especially explain memory problems and some neurological and cognitive symptoms of long Covid, they say.
Why It Matters: New ways to diagnose and treat long Covid.
This is one of several new studies documenting distinct biological changes in the bodies of people with long Covid — offering important discoveries for a condition that takes many forms and often does not register on standard diagnostic tools like X-rays.
The research could point the way toward possible treatments, including medications that boost serotonin. And the authors said the biological pathway that their research outlines could unite many of the major theories of what causes long Covid: lingering remnants of the virus, inflammation, increased blood clotting and dysfunction of the autonomic nervous system.
“All these different hypotheses might be connected through the serotonin pathway,” said Christoph Thaiss, a lead author of the study and an assistant professor of microbiology at the Perelman School of Medicine at the University of Pennsylvania.
“Second of all, even if not everybody experiences difficulties in the serotonin pathway, at least a subset might respond to therapies that activate this pathway,” he said.
“This is an excellent study that identifies lower levels of circulating serotonin as a mechanism for long Covid,” said Akiko Iwasaki, an immunologist at Yale University. Her team and colleagues at the Icahn School of Medicine at Mount Sinai recently published a study that identified other biological changes linked to some cases of long Covid, including levels of the hormone cortisol. These studies could point to specific subtypes of long Covid or different biological indicators at different points in the condition.
The Back Story: A series of disruptions set off by bits of virus in the gut.
Researchers analyzed the blood of 58 patients who had been experiencing long Covid for between three months and 22 months since their infection. Those results were compared to blood analysis of 30 people with no post-Covid symptoms and 60 patients who were in the early, acute stage of coronavirus infection.
Maayan Levy, a lead author and assistant professor of microbiology at the Perelman School of Medicine, said levels of serotonin and other metabolites were altered right after a coronavirus infection, something that also happens immediately after other viral infections.
But in people with long Covid, serotonin was the only significant molecule that did not recover to pre-infection levels, she said.
The team analyzed stool samples from some of the long Covid patients and found that they contained remaining viral particles. Putting the findings in patients together with research on mice and miniature models of the human gut, where most serotonin is produced, the team identified a pathway that could underlie some cases of long Covid.
Here’s the idea: Viral remnants prompt the immune system to produce infection-fighting proteins called interferons. Interferons cause inflammation that reduces the body’s ability to absorb tryptophan, an amino acid that helps produce serotonin in the gut. Blood clots that can form after a coronavirus infection may impair the body’s ability to circulate serotonin.
Depleted serotonin disrupts the vagus nerve system, which transmits signals between the body and the brain, the researchers said. Serotonin plays a role in short-term memory, and the researchers proposed that depleted serotonin could lead to memory problems and other cognitive issues that many people with long Covid experience.
“They showed that one-two-three punch to the serotonin pathway then leads to vagal nerve dysfunction and memory impairment,” Dr. Iwasaki said.
There are caveats. The study was not large, so the findings need to be confirmed with other research. Participants in some other long Covid studies, in which some patients had milder symptoms, did not always show depleted serotonin, a result that Dr. Levy said might indicate that depletion happened only in people whose long Covid involves multiple serious symptoms.
What’s Next: A clinical trial of Prozac.
Scientists want to find biomarkers for long Covid — biological changes that can be measured to help diagnose the condition. Dr. Thaiss said the new study suggested three: the presence of viral remnants in stool, low serotonin and high levels of interferons.
Most experts believe that there will not be a single biomarker for the condition, but that several indicators will emerge and might vary, based on the type of symptoms and other factors.
There is tremendous need for effective ways to treat long Covid, and clinical trials of several treatments are underway. Dr. Levy and Dr. Thaiss said they would be starting a clinical trial to test fluoxetine, a selective serotonin reuptake inhibitor often marketed as Prozac, and possibly also tryptophan.
“If we supplement serotonin or prevent the degradation of serotonin, maybe we can restore some of the vagal signals and improve memory and cognition and so on,” Dr. Levy said.
As updated COVID-19 vaccines are rolled out across the country, fresh evidence confirms that the vaccines are overwhelmingly safe, with only a small percentage of people reporting serious reactions.
More than 38 million COVID-19 vaccine doses have been administered in Ontario alone as of Oct. 8, with 23,002 reports of adverse reactions, an incidence of 0.06 per cent, according to a report from Public Health Ontario.
The report, published earlier this month, is based on surveillance data collected from patients since the start of COVID-19 vaccinations in December, 2020.
It found that 94.5 per cent of those adverse reactions were not serious, with allergic skin reactions and redness or pain at the injection site among the most common complaints.
Just 5.5 per cent of adverse events linked to the vaccines were considered serious and included conditions that required an admission to hospital or resulted in death.
But Public Health Ontario says that doesn’t mean the vaccines were the cause. The surveillance program captures all medical events that occur after vaccination, so those that would have happened anyway are included in the report, even if there’s a small likelihood of a link.
“I see this very positively – that there’s been 38 million doses in arms, very small numbers of adverse events reported, less than 0.1 per cent of doses, and the vast majority of those, close to 95 per cent, are non-serious,” said Reed Morrison, a public health physician with Public Health Ontario who has expertise in vaccine-preventable diseases.
There have been 821 reports of myocarditis or pericarditis, which involve inflammation of the heart, after COVID-19 vaccination, according to the PHO report, for a rate of 22.2 per million mRNA doses administered. Young males aged 12-24 appear to have the highest risk. Previous research has shown the vast majority of cases are mild, patients recover quickly and risks can be averted by extending the time between doses.
Similar data published by British Columbia earlier this year also confirms the strong safety profile of COVID-19 vaccines. There, the vast majority of reported adverse events were allergic reactions or pain at the injection site, with about 8 per cent of events considered serious.
That report provides extensive details about the serious cases, which included people who required a hospital admission or died, making it clear the vaccine was likely not the cause. For instance, several people died after receiving a vaccine, but investigations revealed they had extensive medical conditions, such as an individual with metastatic cancer.
B.C. Health Minister Adrian Dix said in an interview that the evidence is clear: Vaccines are safe.
“We’re transparent about those adverse events,” he said. “I think it’s important not to say there are none, but it’s a tiny number.”
Meanwhile, COVID-19 continues to cause serious outcomes and death, particularly among the elderly and other high-risk groups. According to the Public Health Agency of Canada, 3,786 people were in hospital as a result of COVID-19 for the week ending Oct. 17, a slight decrease from the week before.
At the same time, a new study published by Canadian researchers found that babies whose mothers had been vaccinated against COVID-19 during pregnancy were less likely to experience serious health complications, be admitted to the neonatal intensive care unit or die. The study, published this week in the journal JAMA Pediatrics, looked at data from more than 142,000 births in Ontario and followed infants for six months to determine their outcomes.
Researchers found that 7.3 per cent of infants whose mothers had received at least one COVID-19 vaccination experienced a serious event, such as a seizure, in the first month of life, compared with 8.3 per cent of those whose mothers were unvaccinated; neonatal death occurred in 0.09 per cent of babies exposed to the vaccine in utero, compared with 0.16 of those who were not; and 11.4 per cent of vaccine-exposed babies required admission to a neonatal intensive care unit, compared with 13.1 per cent of babies born to unvaccinated mothers.
Sarah Jorgensen, one of the study’s authors, said the findings should provide reassurance to pregnant women that the vaccines are safe and can help protect their babies.
“Pregnant women and really young infants in the first couple of months, they’re also high-risk,” said Ms. Jorgensen, who is a pharmacist and a PhD candidate in the Temerty Faculty of Medicine’s Institute for Medical Science at the University of Toronto.
Some experts have expressed concern over what they describe as confusing or inadequate messaging about the importance of getting an updated COVID-19 vaccine this fall. In B.C., Mr. Dix said the province’s Get Vaccinated system, built during the pandemic, is helping ensure people get timely information about when and where to get their vaccine. Last year, the province vaccinated a record number of people against influenza, which Mr. Dix credits to the success of the new system.
It sends messages to people based on their risk status, age or other information, allowing them to book vaccine appointments instantly. As of this week, the province had already vaccinated more than 250,000 people with the updated XBB.1.5 COVID-19 vaccine, Mr. Dix said, with another 276,000 appointments booked. Nearly 600,000 people have received flu shots this year, he added.
Abstract
How people recall the SARS-CoV-2 pandemic is likely to prove crucial in future societal debates on pandemic preparedness and appropriate political action. Beyond simple forgetting, previous research suggests that recall may be distorted by strong motivations and anchoring perceptions on the current situation1,2,3,4,5,6. Here, using 4 studies across 11 countries (total n = 10,776), we show that recall of perceived risk, trust in institutions and protective behaviours depended strongly on current evaluations. Although both vaccinated and unvaccinated individuals were affected by this bias, people who identified strongly with their vaccination status—whether vaccinated or unvaccinated—tended to exhibit greater and, notably, opposite distortions of recall. Biased recall was not reduced by providing information about common recall errors or small monetary incentives for accurate recall, but was partially reduced by high incentives. Thus, it seems that motivation and identity influence the direction in which the recall of the past is distorted. Biased recall was further related to the evaluation of past political action and future behavioural intent, including adhering to regulations during a future pandemic or punishing politicians and scientists. Together, the findings indicate that historical narratives about the COVID-19 pandemic are motivationally biased, sustain societal polarization and affect preparation for future pandemics. Consequently, future measures must look beyond immediate public-health implications to the longer-term consequences for societal cohesion and trust.
It's winter, that cozy season that brings crackling fireplaces, indoor gatherings — and a wave of respiratory illness. Nearly four years since the pandemic emerged, people are growing weary of dealing with it, but the virus is not done with us.
Nationally, a sharp uptick in emergency room visits and hospitalizations for COVID-19, influenza, and respiratory syncytial virus, or RSV, began in mid-December and appears to be gaining momentum.
Here are a few things to know this time around:
What's circulating now?
The COVID virus is continually changing, and a recent version is rapidly climbing the charts. Even though it appeared only in September, the variant known as JN.1, a descendant of omicron, is rapidly spreading, representing between 39% to half of the cases, according to pre-holiday stats from the Centers for Disease Control and Prevention.
Highlights
• Hydroxychloroquine was prescribed in hospitalised patients with Covid-19 despite of the low-level evidence.
• Subsequently, HCQ use was associated with an 11% increase in the mortality rate in a meta-analysis of randomized trials.
• The number of hydroxychloroquine related deaths in hospitalised patients is estimated at 16,990 in six countries.
• These findings illustrate the hazard of drug repurposing with low-level evidence for the management of future pandemics.
Abstract
Background
During the first wave of COVID-19, hydroxychloroquine (HCQ) was used off-label despite the absence of evidence documenting its clinical benefits. Since then, a meta-analysis of randomised trials showed that HCQ use was associated with an 11% increase in the mortality rate. We aimed to estimate the number of HCQ-related deaths worldwide.
Methods and findings
We estimated the worldwide in-hospital mortality attributable to HCQ use by combining the mortality rate, HCQ exposure, number of hospitalised patients, and the increased relative risk of death with HCQ. The mortality rate in hospitalised patients for each country was calculated using pooled prevalence estimated by a meta-analysis of published cohorts. The HCQ exposure was estimated using median and extreme estimates from the same systematic review. The number of hospitalised patients during the first wave was extracted from dedicated databases. The systematic review included 44 cohort studies (Belgium: k = 1, France: k = 2, Italy: k = 12, Spain: k = 6, Turkey: k = 3, USA: k = 20). HCQ prescription rates varied greatly from one country to another (range 16–84%). Overall, using median estimates of HCQ use in each country, we estimated that 16,990 HCQ-related in-hospital deaths (range 6267–19256) occurred in the countries with available data. The median number of HCQ-related deaths in Belgium, Turkey, France, Italy, Spain, and the USA was 240 (range not estimable), 95 (range 92–128), 199 (range not estimable), 1822 (range 1170–2063), 1895 (range 1475–2094) and 12739 (3244− 15570), respectively.
Conclusions
Although our estimates are limited by their imprecision, these findings illustrate the hazard of drug repurposing with low-level evidence.
CDC to ease Covid-19 isolation guidance
The US Centers for Disease Control and Prevention is expected to shift its Covid-19 isolation guidance this spring
to say that people no longer need to isolate once they have been fever-free for 24 hours and their symptoms are
mild or improving, according to the Washington Post.
Since 2021, the agency has said people should isolate for at least five days if they tested positive for Covid-19,
and then continue to mask. The updated guidance would bring Covid-19 in line with guidance for other respiratory
viruses, such as flu.
Abstract
Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood–brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog. Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.
Two years ago, German doctors stumbled across news reports of a man being investigated for receiving scores of coronavirus vaccines with no medical explanation.
Then followed a flurry of speculation about what he had been up to. As it turned out, prosecutors were looking into whether he had been receiving so many extra doses as part of a scheme to collect stamped immunization cards that he could later sell to people who wanted to skirt vaccine mandates.
But to the doctors, the man was a medical anomaly, someone who had defied official recommendations and turned himself into a guinea pig for measuring the outer limits of an immune response. Last year, they asked prosecutors investigating his vaccine splurge to pass along a request: Would he like to join a research project?
Once prosecutors closed their fraud investigation without criminal charges, the man agreed.
By the time the doctors first saw him, the 62-year-old man had received 215 doses of coronavirus vaccine, they said. Flouting their pleas to stop, he received another two shots in the next months, expanding his immunological stockpile to a combined 217 doses of eight different Covid vaccine types over two and a half years.
After months of studying him, the doctors, led by Dr. Kilian Schober, an immunologist at the University of Erlangen-Nuremberg in the German state of Bavaria, reported their findings this week in The Lancet Infectious Diseases, a medical journal.
The man had seemingly never been infected with the coronavirus. He reported no vaccine side effects. And, most interestingly to the researchers, his repertoire of antibodies and immune cells was considerably larger than that of a typical vaccinated person, even if the precision of those immune responses remained effectively unchanged.
The researchers found that even the 217th shot boosted the man’s immune response. And while they were carefully looking for signs of a progressive weakening in his immune reactions over time — an unwelcome type of immune tolerance that sometimes develops during long-term viral infections — they reported seeing no such drop-off in responses.
“This indicates really how robust the immune system’s response is to such repetitive immunization,” Dr. Schober said. “Even 200 vaccinations are not nearly as much of a challenge to the immune system as a chronic infection.”
The researchers said the man was from Magdeburg, a city in central Germany, but offered few other details and said his reasons for the vaccination spree were private.
The prosecutors had collected evidence of 130 vaccinations over nine months, the researchers wrote. The man’s first vaccination, with a shot made by Johnson & Johnson, came in June 2021. Most of his subsequent shots were mRNA vaccines made by Moderna or Pfizer-BioNTech. He also received several of Pfizer-BioNTech’s updated vaccines.
In addition to their own testing, the scientists relied on the man’s routine medical tests from before and during the pandemic. But because they had no access to other vaccine hoarders, the researchers said their findings could not be used to predict how other people would react to repeated inoculations.
Other patients who are given so many doses could experience side effects, Dr. Schober said, making it unwise for people to defy medical advice to receive more than the recommended number of shots. And while the study suggested both that the vaccines were generally very safe and could continue to boost immune responses, the benefits of being repeatedly vaccinated did not necessarily outweigh the small risk of an additional shot.
For instance, Dr. Schober said, the man’s antibody levels dropped off in the periods after his most recent recorded shots, as they generally do in patients receiving the usual number of doses. The finding suggested that the man’s elevated immune response could only be kept aloft by revaccinating all the time.
“These super-high levels are not sustainable,” Dr. Schober said. “They would drop off to the normal level.”
Still, the two-and-a-half-year vaccine binge created a type of immune system stress test that doctors never would have allowed to happen on their watch. And while the results were far from conclusive, at least this one man’s immune system looked remarkably resilient.
“Two hundred vaccinations may seem like a lot,” Dr. Schober said. But immune cells capable of reacting to chronic viruses, he added, “are basically laughing” at the imitation viral particles that they have to deal with, even over the course of hundreds of shots.
