Ivermectin disinformation leads to new kinds of chaos

BY JUSTINE COLEMAN – 09/29/21 06:00 AM EDT

An avalanche of misinformation about the antiparasitic drug ivermectin’s ability to treat COVID-19 has caused a series of national problems, from increased calls to poisoning centers to a shortage of the medicine itself. 

Patients have become desperate for a treatment that’s most commonly used for livestock and have taken their disputes over ivermectin with hospitals to court. 

Disinformation has flooded the internet, where dozens of Facebook groups centered around ivermectin remain active despite insufficient evidence that the medicine works in treating people for COVID-19. 

It’s also gone well beyond the internet to popular podcast hosts like Joe Rogan, who has touted the medicine to his millions of listeners. 

The Food and Drug Administration (FDA), other state health departments and even Merck, the drug’s main manufacturer, have all warned against using ivermectin for COVID-19. 

Still, online influences supporting the controversial COVID-19 treatment endure. 

It’s all raising questions about whether the government needs to do more to step in. 

“The promise that there are miracle solutions to an illness is really persuasive,” Jennifer Reich, a professor of sociology at the University of Colorado Denver. “And the idea that individuals can manage their own health, if they read a lot, gather information and make their own decisions is really powerful.”

Media Matters for America found 60 public and private Facebook groups dedicated to ivermectin last month, before the social media giant removed 25 of them after the liberal watchdog’s report. But the other groups still involve more than 70,000 combined users. 

Media Matters released a report on Tuesday concluding that Facebook users are getting around the platform’s moderation strategies by posting links and screenshots of misinformation in the comments of posts and by purposely misspelling keywords such as ivermectin and vaccines. 

“Unfortunately, due to Facebook’s lax moderation of the content on its platform, these evasion techniques are working, and misinformation is thriving on the social media site,” the report reads.

Kayla Gogarty, the associate research director for Media Matters, criticized Facebook for not adequately responding to such misinformation in groups.

“The fact that Facebook has not taken much action against these groups is definitely problematic,” she said.

A Facebook spokesperson told The Hill that the company has removed 20 million pieces of content from Facebook and Instagram for violating COVID-19 misinformation policies.  

“As we enforce our policies against COVID misinformation, we know people will keep trying new tactics to get around our policies and we are constantly evolving to stay ahead of them,” the spokesperson said. 

“We will continue to enforce against any account or group that violates our COVID-19 and vaccine policies,” the statement continued. 

A spokesperson also told The New York Times that the platform removes “content that attempts to buy, sell or donate for ivermectin” and any claims that the drug is “a guaranteed cure or guaranteed prevention.”

Ivermectin is not the first drug to gain traction online as a possible COVID-19 treatment despite lacking evidence. Several experts compared the dewormer’s popularity to that of antimalarial hydroxychloroquine that former President Trump promoted last year.

Yunkang Yang, a postdoctoral research scientist at the Institute for Data, Democracy and Politics at George Washington University, said that influential figures, including Republican politicians, have contributed to the discourse of ivermectin as a “miracle cure.”

For instance, Rogan declared to his millions of listeners that he was taking ivermectin following his COVID-19 diagnosis.

“It would be hard to imagine this information gaining any traction without [their] participation,” he said. 

Misinformation surrounding ivermectin specifically is also not new, as the drug was proposed as a possible treatment earlier in the pandemic, including in some studies retracted due to flawed or fabricated data.

But ivermectin-related calls to poison control centers this year have more than tripled compared to the same period last year, with 1,440 calls through Sept. 20, according to the American Association of Poison Control Centers. 

July, in particular, saw a five-fold increase in ivermectin calls compared to the “pre-pandemic baseline,” according to the Centers for Disease Control and Prevention. Some cases have been fatal, with New Mexico reporting this week two deaths from misusing ivermectin as a COVID-19 medication.

The spikes in ivermectin misuse sparked the FDA to issue an advisory against using the drug for the virus earlier this month. 

“You are not a horse. You are not a cow. Seriously, y’all. Stop it,” the agency said on Twitter. 

While the FDA has approved ivermectin to treat parasitic worms, lice and skin conditions like rosacea among humans, the drug is more often used to treat animals, including cattle and horses. 

In addition to taking unprescribed ivermectin, several cases have emerged where people have been using these animal products. 

“The issue happens when you have inappropriate use where you have a non-human product, for example, that is meant for cattle that has a different formulation composition,” said Ziad Kazzi, a professor of medical toxicology at Emory University.

“The strength of the formulation is different than what you would use in a human,” said Kazzi, who is also the secretary treasurer of the American College of Medical Toxicology,.

Tara Kirk Sell, a senior scholar at the Johns Hopkins Center for Health Security, said the government can always counter specific COVID-19 rumors such as ivermectin’s effectiveness, but it may not be perceived as a “trusted messenger.”

Instead, she said the government needs to develop a national strategy to fight against misinformation in general so Americans are “more resilient to future misinformation.”

“That can kind of be more of a role for government, rather than deciding what’s true, helping people have the tools to figure it out for themselves,” she said.  

“We’ll see this again with something else,” she added. “And we have to realize that we’re going to have to be pushing back against these rumors for a long time to come.”

Changing recommendations for boosters lead to confusion for the vaccinated and their doctors

Author: Carissa Wolf, Frances Stead Sellers, Ashley Cusick, Kim Mueller  1 day ago

Even in Idaho, which has one of the lowest coronavirus vaccination rates in the country, clinics have been gearing up for an onslaught of calls and emails requesting booster shots.

Administrators at the Primary Health Medical Group updated their website Thursday and then set about revising it Friday when government eligibility recommendations for boosters suddenly changed to include workers in high-risk jobs. Even then, the clinic’s chief executive had to figure out which occupations that meant.

“Who’s at high risk? I had to look it up. Is it firemen? I don’t know,” said David Peterman. “This is so confusing to the public and creates mistrust. And we can’t have that right now. Right now, we need the public to say, ‘Let’s get vaccinated.’ And for those that need boosters, we need to say that ‘This is safe, and this is what we need to do.’”

Confusion over boosters, which has been brewing for months, heightened over the past week as government regulators and advisers met to hash out the pros and cons of administering third doses.

Hours of meetings were followed by a dramatic decision Thursday: The Centers for Disease Control and Prevention’s advisory group narrowed the Food and Drug Administration’s recommendation for who should get a third Pfizer shot, only to be overruled in a late-night announcement by the CDC director: Along with Americans 65 and older, nursing home residents and people ages 50 to 64 with underlying medical conditions, who the advisory panel had suggested should get shots, Rochelle Walensky added the people in high-risk jobs.

“It’s a communications crisis,” said Robert Murphy, executive director of the Institute for Global Health at Northwestern University Feinberg School of Medicine, who said he received worried calls Thursday evening from health-care workers who thought they would not be eligible for the shots, followed by messages Friday from colleagues wondering when and where to go.The deluge of phone calls about booster shots to Primary Health clinics in Southwestern Idaho began weeks ago. On Friday morning, the group’s Garden City clinic, where Maddie Morris fields inquiries, saw an increase in calls, mostly from senior citizens.

“The calls seem pretty nonstop,” the customer service representative said. “It seems like a lot of people are anxious to get a booster.”

Doctors say confusion clouds patients’ willingness to receive boosters. In Idaho, the problem coincides with the primary health-care system’s struggle to meet the demands of the latest covid-19 crush, which earlier this month plunged the state into crisis standards of care — essentially the rationing of health care as demand overwhelms resources.Four patients, two dialysis machines: Rationing medical care becomes a reality in hospitals overwhelmed with covid patients

Peterman expects the new booster guidelines to prompt an increase in inquiries just as the number of providers out sick is at an all-time high.

“We went from 40,000 phone calls daily at 21 clinics to 80,000. Eighty thousand! On top of that, we went from maybe 20 of our employees being out a day to 30 to 40,” Peterman said.

“In the next 72 hours, I want [the CDC] to answer our phones,” he said.

Many newly eligible patients are over 65 and not comfortable using the Internet to find information. So the phones keep ringing at Morris’s desk.

“You really can’t take a breather. You just have to jump to the next call,” she said. And Peterman says he has had to ask staffers to take extra shifts and work long into the night to help close the staffing gap.

Much of the muddle stems from legacy systems at the FDA and CDC that were set up to handle routine drug approvals and childhood vaccinations, not a fast-moving public health crisis involving the entire population, said Jay A. Winsten, the founding director of the Center for Health Communications at the Harvard T.H. Chan School of Public Health.

The CDC’s Advisory Committee on Immunization Practices includes infectious-disease specialists, obstetricians and pediatricians who grappled Thursday with questions in which they have no expertise, such as whether offering boosters might undermine public confidence in the vaccines’ efficacy.

“What’s missing from the equation are communication experts,” said Winsten, including specialists in public-opinion polling and behavior change. “They need a seat at the table.”

Health-care providers across the nation have been helping patients for weeks to filter through not just misinformation and disinformation about boosters but also a surfeit of real-time information.

“That’s the biggest problem,” said Clay Marsh, a pulmonary critical care doctor and executive dean for health sciences at West Virginia University. “The amount of information is dizzying,” Marsh said, “It creates chaos.”

Across the New Orleans metropolitan area, new CDC guidelines had failed to trickle down to many administration sites by Friday morning.

The Louisiana National Guard, which helps to run testing and vaccination sites, was still awaiting clarity.

“We are just administering the first and second doses,” said Sgt. Gaynell Leal, a guard spokeswoman. “As far as the booster part of it, that hasn’t come our way yet.”

“The biggest thing is gaining people’s confidence in science,” Leal said. “My civilian job is I’m a funeral director. So I’ve seen this on both sides.”

On the ground, some National Guard-run sites did offer booster shots Friday, but the eligibility benchmarks they used had not yet caught up with the CDC’s latest guidelines.Tracking the coronavirus vaccine

At a drive-through testing and vaccine site in Meraux, La., just east of New Orleans, medics offered booster shots to those who met the requirements laid out on a “self-risk attestation form” issued in mid-August by the Louisiana Department of Health. That form offered a checklist of reasons one might qualify for a third dose, including active cancer treatment, HIV infection, immunodeficiency issues or the use of immunosuppressants. The form did not account for the age or job-related eligibility factors the CDC announced late this week.

In the French Quarter, Tara Thompson, 53, enjoyed a drink in Pirate’s Alley with her husband.

Thompson said that although she took the vaccine to spend time with her elderly parents, she hoped this week’s guidelines would not lead to booster shots soon being pushed on the public.

“I personally don’t want it if I don’t have to have it,” she said. “It’s a matter of trusting the science that seems to be skewed toward the benefit of certain political mind-sets.”

Thompson said she could change her mind if the shots help with travel.

“Or, if the booster shots help Mardi Gras to happen,” she said. “I might consider it then.”

In Chalmette, La., Kerissa Fernandez, 37, wanted more clarity on how the new booster shot guidelines applied to her.

Fernandez, a family nurse practitioner, said she and the staff at the small urgent care clinic she runs with her husband all meet the front-line worker requirement for booster shots. But none of the staffers at the Bayou Urgent Care Clinic had received the Pfizer vaccine, she said.

“I had Moderna. We all got Moderna,” she said. But when the delta variant reached record numbers in Louisiana, she and her husband both ended up with breakthrough infections.

Knowing firsthand the virus’s ability to shape-shift, Fernandez said she and her staff are all eager to get booster shots.

Many newly eligible people say they aren’t waiting for the rules and recommendations to change again. Ann Mackey, 66, qualifies for a booster shot.

“I have a doctor’s appointment next week, so I might see if they can jab me then,” she said from her high-rise apartment in downtown Kansas City, Mo.

The former FDA employee said the government’s conflicting messages have been confusing. She doesn’t understand why she can receive a Pfizer booster, but her friends and family can’t get their third Moderna shot. She is confused about how the government defines “high risk” and who will enforce the newest set of recommendations. And she worries that public confusion will provide another excuse for people to avoid getting their first dose.

“There already is a lot of vaccine hesitancy, and they are just looking for reasons not to get vaccinated,” Mackey said.Americans are sneaking extra coronavirus shots as officials weigh who should get them

Others are considering creative ways to get boosters.

Derek Hoetmer has been following the news closely, hoping he and his wife, a nurse who worked on a covid response team, could get a booster before the Missouri winter.

The problem is that the rules keep changing — and not in the Hoetmers’ favor. They were pleased to wake Friday morning to find the vaccination door had been opened to people in high-risk jobs.

But not wide enough for the Hoetmers, who won’t qualify because their first two doses were Moderna jabs.

With the Missouri winter only two months away, Hoetmer is considering his options. He has heard that other Americans who do not qualify are secretly getting boosters, anyway.

n situation in letter to opposition

Even in Idaho, which has one of the lowest coronavirus vaccination rates in the country, clinics have been gearing up for an onslaught of calls and emails requesting booster shots.© Scott Olson/Getty Images HINES, ILL. – SEPTEMBER 24: Lalain Reyeg administers a coronavirus booster vaccine and an influenza vaccine to Army veteran William Craig at the Edward Hines Jr. VA Hospital on September 24, 2021 in Hines, Ill. (Photo by Scott Olson/Getty Images)

Administrators at the Primary Health Medical Group updated their website Thursday and then set about revising it Friday when government eligibility recommendations for boosters suddenly changed to include workers in high-risk jobs. Even then, the clinic’s chief executive had to figure out which occupations that meant.

“Who’s at high risk? I had to look it up. Is it firemen? I don’t know,” said David Peterman. “This is so confusing to the public and creates mistrust. And we can’t have that right now. Right now, we need the public to say, ‘Let’s get vaccinated.’ And for those that need boosters, we need to say that ‘This is safe, and this is what we need to do.’”

Confusion over boosters, which has been brewing for months, heightened over the past week as government regulators and advisers met to hash out the pros and cons of administering third doses.

Hours of meetings were followed by a dramatic decision Thursday: The Centers for Disease Control and Prevention’s advisory group narrowed the Food and Drug Administration’s recommendation for who should get a third Pfizer shot, only to be overruled in a late-night announcement by the CDC director: Along with Americans 65 and older, nursing home residents and people ages 50 to 64 with underlying medical conditions, who the advisory panel had suggested should get shots, Rochelle Walensky added the people in high-risk jobs.

“It’s a communications crisis,” said Robert Murphy, executive director of the Institute for Global Health at Northwestern University Feinberg School of Medicine, who said he received worried calls Thursday evening from health-care workers who thought they would not be eligible for the shots, followed by messages Friday from colleagues wondering when and where to get them.

“Everyone is kind of confused,” he said. The current discontent has deep roots. In April, Pfizer chief executive Albert Bourla said a third coronavirus dose was “likely” to be needed. In late July, Pfizer-BioNTech announced that their vaccine’s efficacy waned over time. Data from Israel confirmed a drop. Then, last month, as the delta variant of the coronavirus surged and the World Health Organization decried the distribution of third shots in wealthy countries while poor countries were lacking first doses, President Biden announced that most Americans could begin getting boosters of the Pfizer and Moderna vaccines Sept. 20 — subject to the government’s regulatory processes, which unfolded in recent days and focused only on Pfizer. R22egulators already allowed third shots for the immunocompromised who have received Pfizer or Moderna shots but have not yet made recommendations for all recipients of the Moderna and Johnson & Johnson vaccines.People who got Johnson & Johnson’s coronavirus shot feel left behind in push for boosters

The deluge of phone calls about booster shots to Primary Health clinics in Southwestern Idaho began weeks ago. On Friday morning, the group’s Garden City clinic, where Maddie Morris fields inquiries, saw an increase in calls, mostly from senior citizens.

“The calls seem pretty nonstop,” the customer service representative said. “It seems like a lot of people are anxious to get a booster.”

Doctors say confusion clouds patients’ willingness to receive boosters. In Idaho, the problem coincides with the primary health-care system’s struggle to meet the demands of the latest covid-19 crush, which earlier this month plunged the state into crisis standards of care — essentially the rationing of health care as demand overwhelms resources.Four patients, two dialysis machines: Rationing medical care becomes a reality in hospitals overwhelmed with covid patients

Peterman expects the new booster guidelines to prompt an increase in inquiries just as the number of providers out sick is at an all-time high.

“We went from 40,000 phone calls daily at 21 clinics to 80,000. Eighty thousand! On top of that, we went from maybe 20 of our employees being out a day to 30 to 40,” Peterman said.

“In the next 72 hours, I want [the CDC] to answer our phones,” he said.

Many newly eligible patients are over 65 and not comfortable using the Internet to find information. So the phones keep ringing at Morris’s desk.

“You really can’t take a breather. You just have to jump to the next call,” she said. And Peterman says he has had to ask staffers to take extra shifts and work long into the night to help close the staffing gap.

Much of the muddle stems from legacy systems at the FDA and CDC that were set up to handle routine drug approvals and childhood vaccinations, not a fast-moving public health crisis involving the entire population, said Jay A. Winsten, the founding director of the Center for Health Communications at the Harvard T.H. Chan School of Public Health.

The CDC’s Advisory Committee on Immunization Practices includes infectious-disease specialists, obstetricians and pediatricians who grappled Thursday with questions in which they have no expertise, such as whether offering boosters might undermine public confidence in the vaccines’ efficacy.

“What’s missing from the equation are communication experts,” said Winsten, including specialists in public-opinion polling and behavior change. “They need a seat at the table.”

Health-care providers across the nation have been helping patients for weeks to filter through not just misinformation and disinformation about boosters but also a surfeit of real-time information.

“That’s the biggest problem,” said Clay Marsh, a pulmonary critical care doctor and executive dean for health sciences at West Virginia University. “The amount of information is dizzying,” Marsh said, “It creates chaos.”

Across the New Orleans metropolitan area, new CDC guidelines had failed to trickle down to many administration sites by Friday morning.

The Louisiana National Guard, which helps to run testing and vaccination sites, was still awaiting clarity.

“We are just administering the first and second doses,” said Sgt. Gaynell Leal, a guard spokeswoman. “As far as the booster part of it, that hasn’t come our way yet.”

“The biggest thing is gaining people’s confidence in science,” Leal said. “My civilian job is I’m a funeral director. So I’ve seen this on both sides.”

On the ground, some National Guard-run sites did offer booster shots Friday, but the eligibility benchmarks they used had not yet caught up with the CDC’s latest guidelines.Tracking the coronavirus vaccine

At a drive-through testing and vaccine site in Meraux, La., just east of New Orleans, medics offered booster shots to those who met the requirements laid out on a “self-risk attestation form” issued in mid-August by the Louisiana Department of Health. That form offered a checklist of reasons one might qualify for a third dose, including active cancer treatment, HIV infection, immunodeficiency issues or the use of immunosuppressants. The form did not account for the age or job-related eligibility factors the CDC announced late this week.

In the French Quarter, Tara Thompson, 53, enjoyed a drink in Pirate’s Alley with her husband.

Thompson said that although she took the vaccine to spend time with her elderly parents, she hoped this week’s guidelines would not lead to booster shots soon being pushed on the public.

“I personally don’t want it if I don’t have to have it,” she said. “It’s a matter of trusting the science that seems to be skewed toward the benefit of certain political mind-sets.”

Thompson said she could change her mind if the shots help with travel.

“Or, if the booster shots help Mardi Gras to happen,” she said. “I might consider it then.”

In Chalmette, La., Kerissa Fernandez, 37, wanted more clarity on how the new booster shot guidelines applied to her.

Fernandez, a family nurse practitioner, said she and the staff at the small urgent care clinic she runs with her husband all meet the front-line worker requirement for booster shots. But none of the staffers at the Bayou Urgent Care Clinic had received the Pfizer vaccine, she said.

“I had Moderna. We all got Moderna,” she said. But when the delta variant reached record numbers in Louisiana, she and her husband both ended up with breakthrough infections.

Knowing firsthand the virus’s ability to shape-shift, Fernandez said she and her staff are all eager to get booster shots.

Many newly eligible people say they aren’t waiting for the rules and recommendations to change again. Ann Mackey, 66, qualifies for a booster shot.

“I have a doctor’s appointment next week, so I might see if they can jab me then,” she said from her high-rise apartment in downtown Kansas City, Mo.

The former FDA employee said the government’s conflicting messages have been confusing. She doesn’t understand why she can receive a Pfizer booster, but her friends and family can’t get their third Moderna shot. She is confused about how the government defines “high risk” and who will enforce the newest set of recommendations. And she worries that public confusion will provide another excuse for people to avoid getting their first dose.

“There already is a lot of vaccine hesitancy, and they are just looking for reasons not to get vaccinated,” Mackey said.Americans are sneaking extra coronavirus shots as officials weigh who should get them

Others are considering creative ways to get boosters.

Derek Hoetmer has been following the news closely, hoping he and his wife, a nurse who worked on a covid response team, could get a booster before the Missouri winter.

The problem is that the rules keep changing — and not in the Hoetmers’ favor. They were pleased to wake Friday morning to find the vaccination door had been opened to people in high-risk jobs.

But not wide enough for the Hoetmers, who won’t qualify because their first two doses were Moderna jabs.

With the Missouri winter only two months away, Hoetmer is considering his options. He has heard that other Americans who do not qualify are secretly getting boosters, anyway.

“I won’t lie. I’ve thought about that option,” Hoetmer said. “I would rather go about it the right way and not take away someone’s booster shot.”

FDA Issues Warning About Increased Risk Of Heart Inflammation Caused By Moderna Jab

Authors: BY TYLER DURDENMONDAY, AUG 30, 2021 – 02:14 P

Earlier this month, we reported on leaked data from a Canadian study which arrived at a disturbing conclusion: the risk of rare side effects like myocarditis and pericarditis – types of heart inflammation that are potentially deadly in some patients – was at least 2.5x higher in the Moderna jab than in its main competitor, produced by Pfizer-BioNTech.

The leaking of the data to the press was an embarrassment for the FDA and CDC, and so they pledged to investigate. Now, less than two weeks later, the FDA has just announced that it has updated its “fact sheet” to reflect the higher risk of heart inflammation in male patients under the age of 40.

For all patients, the “post-marketing” data examined by the FDA show that the risk of experiencing these side effects is highest within 7 days of receiving the second dose.

Only Pfizer has received full approval from the FDA; the Moderna jab is still technically under the emergency authorization. Whether this will delay or in any way impact the FDA’s approval of the Moderna jab remains unclear.

Here’s the full updated text:

Myocarditis and Pericarditis Postmarketing data demonstrate increased risks of myocarditis and pericarditis, particularly within 7 days following the second dose. The observed risk is higher among males under 40 years of age than among females and older males. The observed risk is highest in males 18 through 24 years of age. Although some cases required intensive care support, available data from short-term follow-up suggest that most individuals have had resolution of symptoms with conservative management. Information is not yet available about potential long-term sequelae. The CDC has published considerations related to myocarditis and pericarditis after vaccination, including for vaccination of individuals with a history of myocarditis or pericarditis

Questions about the link between the mRNA jabs and heart inflammation have been circulating since these side effects were first uncovered in a group of American soldiers reporting acute chest pain after their vaccinations.

The news is weighing on Moderna’s share price, which has fallen substantially since its Aug. 9 peak. It was down more than 3% on Monday afternoon.

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

Authors: Bryant, Andrew MSc1,*; Lawrie, Theresa A. MBBCh, PhD2; Dowswell, Therese PhD2; Fordham, Edmund J. PhD2; Mitchell, Scott MBChB, MRCS3; Hill, Sarah R. PhD1; Tham, Tony C. MD, FRCP4 American Journal of Therapeutics: July/August 2021 – Volume 28 – Issue 4 – p e434-e460doi: 10.1097/MJT.0000000000001402

Abstract

Background: 

Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials.

Areas of uncertainty: 

We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection.

Data sources: 

We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion.

Therapeutic Advances: 

Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19–0.73; n = 2438; I2 = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian–Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff–Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%–91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for “need for mechanical ventilation,” whereas effect estimates for “improvement” and “deterioration” clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty.

Conclusions: 

Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.

For More Information:https://journals.lww.com/americantherapeutics/Fulltext/2021/08000/Ivermectin_for_Prevention_and_Treatment_of.7.aspx

Further evidence supports controversial claim that SARS-CoV-2 genes can integrate with human DNA

Authors: By Jon CohenMay. 6, 2021 , 2:45 PM

Science’s COVID-19 reporting is supported by the Heising-Simons Foundation.

A team of prominent scientists has doubled down on its controversial hypothesis that genetic bits of the pandemic coronavirus can integrate into our chromosomes and stick around long after the infection is over. If they are right—skeptics have argued that their results are likely lab artifacts—the insertions could explain the rare finding that people can recover from COVID-19 but then test positive for SARS-CoV-2 again months later.

Stem cell biologist Rudolf Jaenisch and gene regulation specialist Richard Young of the Massachusetts Institute of Technology, who led the work, triggered a Twitter storm in December 2020, when their team first presented the idea in a preprint on bioRxiv. The researchers emphasized that viral integration did not mean people who recovered from COVID-19 remain infectious. But critics charged them with stoking unfounded fears that COVID-19 vaccines based on messenger RNA (mRNA) might somehow alter human DNA. (Janesich and Young stress that their results, both original and new, in no way imply that those vaccines integrate their sequences into our DNA.)

Researchers also presented a brace of scientific criticisms, some of which the team addresses in a paper released online today by the Proceedings of the National Academy of Sciences (PNAS). “We now have unambiguous evidence that coronavirus sequences can integrate into the genome,” Jaenisch says.

SARS-CoV-2, the virus that causes COVID-19, has genes composed of RNA, and Jaenisch, Young, and co-authors contend that on rare occasions an enzyme in human cells may copy the viral sequences into DNA and slip them into our chromosomes. The enzyme, reverse transcriptase, is encoded by LINE-1 elements, sequences that litter 17% of the human genome and represent artifacts of ancient infections by retroviruses. In their original preprint, the researchers presented test tube evidence that when human cells spiked with extra LINE-1 elements were infected with the coronavirus, DNA versions of SARS-CoV-2’s sequences nestled into the cells’ chromosomes.

Many researchers who specialize in LINE-1 elements and other “retrotransposons” thought the data were too thin to support the claim. “If I would have had this data, I would have not submitted to any publication at that point,” says Cornell University’s Cedric Feschotte, who studies endogenous retrovirus chunks in the human genome. He and others also said they expected higher quality work coming from scientists of the caliber of Jaenisch and Young. In two subsequent studies, both posted on bioRxiv, critics presented evidence that the supposed chimeras of human and viral DNA traces are routinely created by the very technique the group used to scan for them in chromosomes. As one report concluded, the human-virus sequences “are more likely to be a methodological product, [sic] than the result of genuine reverse transcription, integration and expression.”

In their new paper, Jaenisch, Young, and colleagues acknowledge that the technique they used accidentally creates human-viral chimeras. “I think it’s a valid point,” Jaenisch says. He adds that when they first submitted the paper to a journal, they knew it needed stronger data, which they hoped to add during the review process. But the journal, like many, requires authors to immediately post all COVID-19 results to a preprint server. “I probably should have said screw you, I won’t put it on bioRxiv. It was a misjudgment,” Jaenisch says.

In the new PNAS paper, the team provides evidence that artifacts alone can’t explain the detected levels of virus-human chimeric DNA. The scientists also show that portions of LINE-1 elements flank the integrated viral genetic sequence, further supporting their hypothesis. And they have collaborated with one of the original skeptics, Stephen Hughes of the National Cancer Institute, who suggested an experiment to clarify whether the integration was real or noise, based on the orientation of the integrated viral sequences relative to the human ones. The results support the original hypothesis, says Hughes, a co-author of the new paper. “That analysis has turned out to be important,” he says.

“The integration data in cell culture is much more convincing than what was presented in the preprint, but it’s still not totally clean,” says Feschotte, who now calls Jaenisch’s and Young’s hypothesis “plausible.” (SARS-CoV-2, he notes, can also persist in a person for months without integrating its genes.)

The real question is whether the cell culture data have any relevance to human health or diagnostics. “In the absence of evidence of integration in patients, the most I can take away from these data is that it is possible to detect SARS-CoV-2 RNA retroposition events in infected cell lines where L1 is overexpressed,” Feschotte says. “The clinical or biological significance of these observations, if any, is a matter of pure speculation at this point.”

Jaenisch’s and Young’s team do report hints of SARS-CoV-2 integration in tissue from living and autopsied COVID-19 patients. Specifically, the researchers found high levels of a type of RNA that is only produced by integrated viral DNA as the cell reads its sequence to make proteins. But, Young acknowledges, “We do not have direct evidence for that yet.”

Harmit Malik, a specialist in ancient viruses in the human genome at the Fred Hutchinson Cancer Research Center, says it’s a “legitimate question” to ask why people who should have cleared the virus sometimes have positive polymerase chain Reaction tests for its sequences. But he also remains unconvinced that the explanation is integrated virus. “Under normal circumstances, there is so little reverse transcription machinery available” in human cells, Malik says.

The controversy has grown decidedly more civil since December. Both Young and Jaenisch say they received more intense criticism for their preprint than any studies in their careers, in part because some researchers worried it played into the hands of vaccine skeptics spreading false claims about the newly authorized mRNA vaccines. “If there ever was a preprint that should be deleted, it is this one! It was irresponsible to even put it up as a preprint, considering the complete lack of relevant evidence. This is now being used by some to spread doubts about the new vaccines,” Marie-Louise Hammarskjöld, a microbiologist at the University of Virginia, posted in a comment on bioRxiv at the time.

And what of the original journal submission? “They rejected it,” Jaenisch says.

Role of proteolytic enzymes in the COVID-19 infection and promising therapeutic approaches

Authors: Magda Gioia,a,⁎ Chiara Ciaccio,a,⁎ Paolo Calligari,b Giovanna De Simone,c Diego Sbardella,d Grazia Tundo,dGiovanni Francesco Fasciglione,a Alessandra Di Masi,cD onato Di Pierro,a Alessio Bocedi,b Paolo Ascenzi,c,e and Massimo Colettaa,⁎ Biochem Pharmacol. 2020 Dec; 182: 114225.Published online 2020 Sep  doi: 10.1016/j.bcp.2020.114225PMCID: PMC7501082PMID: 32956643

Abstract

In the Fall of 2019 a sudden and dramatic outbreak of a pulmonary disease (Coronavirus Disease COVID-19), due to a new Coronavirus strain (i.e., SARS-CoV-2), emerged in the continental Chinese area of Wuhan and quickly diffused throughout the world, causing up to now several hundreds of thousand deaths.

As for common viral infections, the crucial event for the viral life cycle is the entry of genetic material inside the host cell, realized by the spike protein of the virus through its binding to host receptors and its activation by host proteases; this is followed by translation of the viral RNA into a polyprotein, exploiting the host cell machinery. The production of individual mature viral proteins is pivotal for replication and release of new virions.

Several proteolytic enzymes either of the host and of the virus act in a concerted fashion to regulate and coordinate specific steps of the viral replication and assembly, such as (i) the entry of the virus, (ii) the maturation of the polyprotein and (iii) the assembly of the secreted virions for further diffusion. Therefore, proteases involved in these three steps are important targets, envisaging that molecules which interfere with their activity are promising therapeutic compounds.

In this review, we will survey what is known up to now on the role of specific proteolytic enzymes in these three steps and of most promising compounds designed to impair this vicious cycle.Go to:

1. Introduction

Over the past twenty years, β-Coronaviruses (CoV)s have caused three epidemics/pandemics, namely SARS-CoV in 2002, MERS-CoV in 2013 and SARS-CoV-2 in 2019, which have been associated with acute severe respiratory illnesses. As of September 8, SARS-CoV-2 virus, responsible for the global COVID-19 pandemic, has been causing more than 27 millions of contagions and around 900.000 deaths worldwide (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports). The scientific community has come together to understand the mechanisms underlying the infection and the virulence of SARS-CoV-2 virus, as well as all symptoms and risk factors for subsequent mortality. Currently, there is neither antiviral nor vaccine for the severe acute respiratory syndrome induced by SARS-CoV-2. Its alarming spread and its severity across most countries elicited an effort for the elucidation of the pathogenetic features of this novel viral infection in search for effective therapeutic approaches [1].

Little is known about the pathobiology of SARS-CoV-2, even though the availability of the virus genome sequence (GenBank ID: MN908947.3) has demonstrated crucial similarities between SARS-CoV-2 and other members of the same viral order (i.e.Nidovirales[2]. Hence, to rapidly gain insights on molecular mechanism of SARS-CoV-2 it is worth exploiting what we have learned from several medicinal chemistry studies on viral spreading to help us in finding promising targets for the development of anti-viral strategies for SARS-CoV-2.

1.1. Host and viral proteases involved in viral life-cycle

As for common viral infections, the crucial event for the viral life cycle is the entry of genetic material inside the host cell for replication and release of new virions. During its life-cycle, SARS-CoV-2 is internalized in the host cell where the viral RNA is translated, exploiting the host cell machinery and giving rise to virus-encoded proteins of different open reading frames (ORF)s. The ORF1, which encompasses about 75% of the viral genome, is translated into two viral replicase polyproteins (i.e., pp1a and pp1ab) (Fig. 1 ). Sixteen mature non-structural proteins (nsp) arise from further processing of these two pps, which are autocatalytically processed by two proteases (also auto-processed), namely (a) the papain-like protease (PLpro), which cleaves the first two non-structural proteins (nsp1 and nsp2) at the N-terminal region of the polyprotein, and (b) the main protease (Mpro, also known as a chymotrypsin-like cysteine protease, 3CLpro), which recognizes cleavage sites at the C-terminus and brings to the production of about 11 individual mature non-structural proteins [5][3][4]. The remaining ORFs encode accessory and structural proteins, like spike surface glycoprotein (S), small envelope protein (E), matrix protein (M), nucleocapsid protein (N) (see Fig. 1).

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Fig. 1

SARS-CoV-2 polyproteins encoded by ORF1a and ORF1ab. Schematic representation of the open reading frames 1a and 1ab, which encode for polyproteins pp1a and pp1ab. Proteins composing each polyprotein are shown: (ns) indicates non-structural proteins; RNA dependent RNA polymerase and Helicase are indicated by (RdRp) and (Hel), respectively. Proteolytic sites cleaved by PLpro and Mpro are reported in yellow and green arrows, respectively. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Since proteolytic enzymes are the major actors of the various events described in this review and although knowledge about their role is continuously expanding, it may be worth recalling that they can be roughly classified into seven broad groups (from the type of aminoacid involved as proton donor for the activation of the peptide bond to be cleaved), namely (a) serine protease, (b) cysteine protease, (c) threonine protease, (d) aspartic protease, (e) glutamic protease, (f) metalloproteases (usually employing Zn++), and (g) asparagine peptide lyases [6][7]. Within each group, a further differentiation can be applied according to whether the peptide bond cleaved by the specific enzyme corresponds to a terminal residue (i.e., exoprotease) or else to one of aminoacids within the sequence (i.e., endoprotease).

1.2. Endoproteases targeted for the development of anti-viral strategies

The activity of several endoproteases ensures viral infection, involving host and viral proteases which belong to the classes of serine- and cysteine-proteases, respectively. Both proteases of the host cell (which are supposed to assist the virus during the intracellular and extracellular phases of its cycle) and those of the virus act in a concerted fashion to regulate and coordinate specific steps of the viral propagation, such as (i) the entry and the replication of the virus, (ii) the maturation of the polyprotein and (iii) the assembly of the secreted virions for further diffusion [5] (Fig. 2 ).

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Fig. 2

Diagram of the involvement of host and viral proteases in SARS-CoV-2 life cycle. Activation of coronavirus spike proteins by host cell proteases occurs at different stages in the viral life cycle and in different cell localizations. The ACE2-dependent infectious entry at the cell membrane is triggered through the S protein cleavage by host proteases: furin (1) and/or TMPRSS2 (2). Intracellular activation of S protein is mediated by cathepsin in lysosomes (3) and/or by Furin in trans-Golgi network (TGN) (4). After the receptor recognition, the viral genome is released into the cytoplasm of the host cell (5), RNA attaches directly to the host ribosome for translation of two polyproteins (not shown). Polyprotein (pp) maturation into mature fragments is catalysed by viral Cys proteases (Mpro and PL pro) (6). RNA is translated into DNA and inside the nucleus (N) replication amplifies the number of virus genome copies (7). The viral genome produces pps, which help to take command over host ribosomes for their own translation process; protein biosynthesis starts at the endoplasmic reticulum (ER) and follows the constitutive secretory pathway along Golgi compartments (8). The virion assembly occurs (9) and the newly packed viral particles can egress (10).

The spike glycoproteins are responsible for the crown-like appearance of Coronavirus particles (Fig. 3 A), playing a crucial role for the entry of the viral genome inside the host cell (Fig. 2). The first critical step is the binding of the homotrimeric S protein with its specific cellular receptor, which triggers a cascade of proteolytic events leading to the fusion of cell and viral membranes. Similarity in structure and sequence with SARS-CoV and in vitro binding measurements indicate that SARS-CoV-2 S protein shows an improved binding for the receptor of angiotensin converting enzyme2 (ACE2), identifying it as the main host receptor [8]. The S protein is synthesized as an uncleaved precursor which includes two functionally distinct domains (i.e., S1 and S2 domains) that are responsible for receptor binding and triggering of the fusion event, respectively (Fig. 3B).

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Open in a separate windowFig. 3

(A): Schematic representation of coronavirus particle. Spike proteins are highly glycosylated type I transmembrane protein, which assemble into trimers on the virion surface to form the distinctive “corona” (crown-like) appearance. (B): Domain organization and cleavage sites of the coronavirus Spike monomer (S). The ectodomain of all CoV spike proteins share the same organization in two domains, that is a N-terminal domain, named S1 and responsible for receptor binding, and a C-terminal S2 domain responsible for fusion. The domain organization of the S monomer consists of a signal peptide (SP), the N-terminal domain (NTD), the receptor-binding domain (RBD), the fusion peptide (FP), the internal fusion peptide (IFP), the heptad repeat 1/2 (HR1/2), and the transmembrane domain (TM).The region between the two domain is termed S1/S2 site. (C): Sequence of S1/S2 cleavage site of S protein from SARS-CoV-2. The four amino acid insertion (SPRRs), unique to SARS-CoV-2, is marked in yellow, the conserved S1/S2 cleavage site is marked in grey. (D): Comparative sequences of S protein cleavage sites. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

The inactive CoV S protein acquires both cellular receptor binding and fusion function upon cleavage events at different sites, which can be carried out by multiple proteases at multiple sites in different cell compartments [10][9] (see Fig. 2). Importantly, depending on CoV strain and cell type, CoV S protein is activated at a specific cell localization by one or several host proteases, including furin, trypsin, cathepsin L, transmembrane protease serine protease2 (TMPRSS2), TMPRSS4, or human airway trypsin-like protease (HAT) [11] (see Fig. 2). Exploiting redundant pathways to activate surface glycoproteins, the activating cleavage is mediated by multiple host membrane proteases via two distinct pathways, namely either (i) the late endosomal pathway, using cathepsins, and/or (ii) the cell-surface or early endosome pathway, using transmembrane serine proteases (e.g., TMPRSS2 and pro-protein convertase furin) (Fig. 2).

It has been suggested that the surface route is preferred under natural conditions, while repeated passages in cultured cells in vitro appears to exert a selective pressure in favour of virions bearing a greater capacity to invade the target cell via late endosomes [12][9][13]. Thus, to activate the fusion machinery of the viral S protein the cooperation in space and in time of multiple membrane proteases is demanded; the actually involved pool depends on both the virus strain and the specific host cell type expression profile of proteases (thus changing for each cell type).

Among host proteases, involved in the viral infection, furin is the one most widely present, being constitutively expressed in a variety of cell types. It cycles from the trans Golgi network (TGN)/endosomal compartments and cell surface, and it is known to accumulate in the TGN (where it is supposed to fulfil its proteolytic activity) [14](Fig. 2). Nevertheless, recently it has been also detected linked to the membrane of oral and airway epithelial cells [16][15].

Unlike close relatives, SARS-CoV-2 can promptly infect a broad spectrum of human cell types, spanning from lung cells to endothelial, conjunctival and gut cells, with the respiratory district being the main target, displaying the peculiar ability to infect even the upper respiratory tract. The efficient spreading of virus relies on the protease arsenal of host cells which mediate the propagation of viral infection. The expression profile of furin and ACE2 in human cells could explain why SARS-CoV-2 is so efficient in spreading virus particles, since they are present throughout the body in endothelial cells with particularly increased levels in cells lying in alveoli and small intestine[17]. Moreover, SARS-CoV-2 S protein possesses a peculiar insertion of four amino acids (i.e., Ser-Pro-Arg -Arg-Ala-Arg689↓, see [18] and Fig. 3C), which has been identified as an additional cleavage site for the specificity of furin activity, strengthening the idea that this enzyme plays a dominant relevance in SARS-CoV-2 viral infection [13][19][20][21].

Therefore, furin may play either (a) a role in the first entry of the virus, thanks to its topological location at the outer membrane (which would allow the formation of the ternary complex with ACE2, i.e., furin:SARS-CoV-2S:ACE2), and/or (b) during the transport of virions along the secretory pathway, further facilitating the virus diffusion (Fig. 2). This co-expression has been detected in airway epithelia, cardiac tissues and enteric canals [16], envisaging the possibility that in these districts the role of furin in favouring the virus cell entry is relevant, providing a cellular and molecular basis for the comprehension of the major clinical effects of COVID-19 in the tissues where these cell types are located.

A key discovery in understanding the mechanism of SARS-CoV-2 infection concerns the role of the androgen-responsive transmembrane serine protease 2 (TMPRSS2), that is expressed by specific epithelial tissues (including those of the respiratory and digestive tracts), facilitating the SARS-CoV-2 entry in the human airways by cleaving the viral spike (S) protein [22][23][19] (Fig. 2).

Beside host proteolytic enzymes, two viral proteases, namely Mpro and PLpro (involved in the maturation of viral polyprotein) are also recognized as important drug target(s). In particular, Mpro has been found to play a prominent role in the viral gene expression and replication, thus becoming an attractive target for anti-CoV-2 drugs. Notably, its quaternary structure renders Mpro ideal for rational drug design strategies against SARS-CoV-2, as there is a correlation between homodimer formation and the enzyme catalytic activity. Each protomer contains an antiparallel β-barrel structure, which has a folding scaffold similar to other viral chymotrypsin-like proteases. However, unlike chymotrypsin, the active site of SARS-CoV-2 Mpro contains a catalytic cysteinyl residue instead of a serine residue.

It must be stressed that although the endoprotease classes show a variety of catalytic sites (see above) and distinct protein folding, functional similarity can be found across evolutionary distant species (from viruses to humans) [6], thus representing a caveat in the development of effective COVID-19 therapeutic strategies.

Further, structural and evolutionary analyses indicate that SARS-CoV-2 Mpro is a highly conserved viral protein, which recognizes the sequence Leu-Met-Phe-Gln↓Ser-Gly-Ala while no human proteases share the same specificity [24]. This unique feature makes Mpro an even more attractive target for a broad inhibition of multiple stages in the viral life cycle (such as viral formation, progression of the viral infection and reproduction of virions).

Overall, two very attractive processes (which indeed represent important targets for designing anti-viral drugs), will be discussed here: (a) the proteolytic activation of the S protein (by furin and TMPRRS2), impairing the entry of viral genetic material inside the host cell, and (b) the activity of viral proteases (in particular Mpro), impairing the formation of mature viral proteins, which are required for the progression of the viral infection and replication of viruses.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501082/

Japan probes two deaths after jabs from tainted Moderna batch

Sat, August 28, 2021, 6:10 AM

Japan is investigating the death of two men who received jabs from batches of Moderna’s Covid-19 vaccine suspended from use due to contamination, the health ministry said Saturday.

The men aged 30 and 38 died earlier this month after getting their second Moderna doses from one of three manufacturing lots suspended by the government on Thursday after several vials were found to be contaminated, the ministry said in a statement.

The ministry said the cause of death was still being investigated and “currently, causal relations with the vaccinations are unknown”.- ADVERTISEMENT –

Both men contracted fever after receiving their vaccinations and neither had underlying health conditions or allergic history, the ministry said.

The suspension affects 1.63 million doses of Moderna Covid vaccines, which have been reportedly shipped to over 800 vaccination centres across Japan.

Takeda, which is in charge of sales and distribution of the Moderna shot in Japan, said it received reports from several vaccination centres that “foreign substances” have been found inside unopened vials.

Around 44 percent of Japan’s population has been fully vaccinated, as the country battles a record surge of virus cases driven by the more contagious Delta variant.

Over 15,700 people have died from Covid-19 in the country, and large parts of Japan are under strict virus restrictions.

Long COVID’s daunting toll seen in study of pandemic’s earliest patients

Authors: Melissa Healy   6 hrs ago

COVID-19 patients in Wuhan were among the pandemic’s first victims, and a comprehensive new study finds that a year after shaking the coronavirus, survivors were more likely than their uninfected peers to suffer from mobility problems, pain or discomfort, anxiety and depression.

detailed accounting of 1,276 people hospitalized for COVID-19 in the pandemic’s opening months reveals that a full year later, almost half continued to report at least one lingering health problem that is now considered a symptom of “long COVID.”

One out of five said they had continued fatigue and/or muscle weakness, and 17% said they were still experiencing sleep difficulties. Just over one in four said they were suffering anxiety or depression in the wake of their bout with the SARS-CoV-2 virus.

For the growing number of patients who identify themselves as COVID “long haulers,” the new accounting offers cause for optimism — and concern. The period from six to 12 months after infection brought improvement for many. But most patients struggling with symptoms at the six-month mark were not yet well six months later.

The findings, catalogued by a team of Chinese researchers, were published late Thursday in the medical journal Lancet.

“This is not good news,” said David Putrino, a rehabilitation specialist who works with COVID long haulers at Mount Sinai Hospital in New York. “If you run the numbers here, about one-third of the group that had persistent symptoms are getting better after 12 months, while two-thirds are not.”

Putrino also called the findings a “wake-up call” to public health officials that even when the pandemic is over — a distant enough prospect in the midst of a fourth wave of infections — its downstream consequences will not be.

“We’re going to need resources for many years to come to deal with these patients,” he said.

There will be a lot of them. More than 87,000 COVID-19 patients are being hospitalized each day in the United States, and 2.7 million have receiving hospital care in the past year alone.

The half who contend with persistent symptoms will show up in doctors’ offices with clusters of vague and perplexing complaints including brain fog, heart palpitations, pain and exhaustion. And despite emerging evidence that time and specialized treatment can help many to improve, few will have the wherewithal to spend months in intensive rehabilitation for their symptoms, Putrino said.

An editorial published alongside the new study noted that only 0.4% of COVID long haulers are receiving rehabilitative treatment for their symptoms.

Even as scientists puzzle over the common biological mechanisms of long COVID’s diverse symptoms, healthcare providers “must acknowledge and validate the toll of the persistent symptoms of long COVID on patients, and health systems need to be prepared to meet individualised, patient-oriented goals, with an appropriately trained workforce,” Lancet’s editors wrote.

The new research also offered some glimmers of hope.

When the study’s COVID-19 patients were examined at six months, 68% said they had at least one of 15 symptoms considered hallmarks of long COVID, which is also known as Post-Acute Sequelae of COVID, or PASC. At one year, 49% were still afflicted by at least one of those symptoms.

The proportion of patients with ongoing muscle weakness and fatigue dropped from 52% to 20% during that time. Patients experiencing loss of smell dropped from 11% to 4%, and those afflicted with sleep problems fell from 27% to 17%. The 22% who reported hair loss at six months dwindled to 11% a full year out.

At the same time, the numbers of patients reporting breathing difficulties saw a slight increase, rising from 26% at six months to 30% after a year. Likewise, patients who reported new depression or anxiety increased from 23% to 26% during that period.

Study co-author Xiaoying Gu from the China-Japan Friendship Hospital in Beijing said the slight uptick in anxiety and depression was, like all of long COVID’s symptoms, hard to explain.

The psychiatric symptoms “could be caused by a biological process linked to the virus infection itself, or the body’s immune response to it,” he said. “Or they could be linked to reduced social contact, loneliness, incomplete recovery of physical health or loss of employment associated with illness.”

Patients who required mechanical ventilation were more likely than those with less severe illness to have measurable lung impairment and abnormal chest X-rays at both six and 12 months.

But in the tally of more subjective long COVID symptoms, the difference between the most severely ill and those who required no supplemental oxygen at all was very small.

That finding underscores the fact that even patients who are only mildly ill are at risk of developing a range of persistent symptoms.

Of the study population’s 479 patients who held jobs when the pandemic struck, 88% had returned to work a year after their illness. Most of the 57 who did not return said they either could not or were unwilling to do the tasks required of them.

The findings from the Wuhan patients also tracked with the widespread observation that persistent post-COVID infection symptoms are more common in women than in men. Women who had been hospitalized for COVID-19 were twice as likely as their male counterparts to report depression or anxiety 12 months later. In addition, they were close to three times as likely to show evidence of impaired lung function, and 43% more likely to report symptoms of fatigue and muscle weakness.

All of the study’s participants were treated at a single hospital in Wuhan, where reports of a mysterious new form of pneumonia first surfaced in December 2019. The researchers followed a large group of patients sickened in the first five months that the outbreak.

That makes the Lancet report one of the earliest and largest accounts of lingering COVID-19 symptoms to be tallied and vetted by other researchers, and the only one to compare such patients to a group of uninfected peers matched on a wide range of demographic and health attributes.

One thing is already clear, the journal editors noted: “Long COVID is a modern medical challenge of the first order.”

This story originally appeared in Los Angeles Times.

“Inescapable” COVID-19 Antibody Discovery – Neutralizes All Known SARS-CoV-2 Strains

Authors: By LAWRENCE BERKELEY NATIONAL LABORATORY AUGUST 26, 2021

An antibody therapy that appears to neutralize all known SARS-CoV-2 strains, and other coronaviruses, was developed with a little help from structural biologist Jay Nix.

Lifesaving COVID-19 vaccines are allowing us to feel optimistic again, after more than a year of anxiety and tragedy. But vaccines are only one side of the coin – we also need treatments that can prevent severe disease after someone has been infected. In the past year, there has been significant progress in developing effective antibody-based therapies, and three drugs are currently available through emergency use authorization (EUA) by the Food and Drug Administration.

Sotrovimab, the newest antibody therapy, was developed by GlaxoSmithKline and Vir Biotechnology after a large collaborative study by scientists from across the nation discovered a natural antibody (in the blood of a SARS survivor, back in 2003) that has remarkable breadth and efficacy.

Experiments showed that this antibody, called S309, neutralizes all known SARS-CoV-2 strains – including newly emerged mutants that can now “escape” from previous antibody therapies – as well as the closely related original SARS-CoV virus.

Jay Nix, leader of the Molecular Biology Consortium based at Berkeley Lab’s Advanced Light Source (ALS), used beamlines at the ALS and beamlines at SLAC’s Stanford Synchrotron Radiation Lightsource to perform X-ray crystallography on samples of survivor-derived antibodies during an early phase of the study. His work, alongside other crystallography and cryo-electron microscopy findings, helped generate detailed structural maps of how these antibodies bind to the SARS-CoV-2 spike protein, allowing the wider team to select the most promising contenders and advance them to cell culture- and animal-based studies. Following exciting lab results, the developers designed sotrovimab based on the structure of S309, and evaluated it in clinical trials.

The FDA granted an EUA for sotrovimab in late May after trials showed that people with mild to moderate COVID-19 infections who received an infusion of the therapy had an 85% reduction in rates of hospitalization or death, compared with placebo.

But the team didn’t stop there.

Understanding that new mutations could arise and that a novel pathogenic coronavirus could emerge from an animal-human crossover event, the scientists began a follow-up study to deeply explore what factors make antibodies resistant to viral escape and how certain antibodies are also broadly reactive against diverse, related viruses. Using biochemical and structural analysis, deep mutational scanning, and binding experiments, they identified one antibody with unparalleled universal potency.

“This antibody, which binds to a previously unknown site on the coronavirus spike protein, appears to neutralize all known sarbecoviruses – the genus of coronaviruses that cause respiratory infections in mammals,” said Nix, who is an affiliate in Berkeley Lab’s Biosciences Area. “And, due to the unique binding site on mutation-resistant part of the virus, it may well be more difficult for a new strain to escape.”

Subsequent tests in hamsters suggest that this antibody could even prevent a COVID-19 infection if given prophylactically. The new work was published in Nature.

Reference: “SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape” by Tyler N. Starr, Nadine Czudnochowski, Zhuoming Liu, Fabrizia Zatta, Young-Jun Park, Amin Addetia, Dora Pinto, Martina Beltramello, Patrick Hernandez, Allison J. Greaney, Roberta Marzi, William G. Glass, Ivy Zhang, Adam S. Dingens, John E. Bowen, M. Alejandra Tortorici, Alexandra C. Walls, Jason A. Wojcechowskyj, Anna De Marco, Laura E. Rosen, Jiayi Zhou, Martin Montiel-Ruiz, Hannah Kaiser, Josh Dillen, Heather Tucker, Jessica Bassi, Chiara Silacci-Fregni, Michael P. Housley, Julia di Iulio, Gloria Lombardo, Maria Agostini, Nicole Sprugasci, Katja Culap, Stefano Jaconi, Marcel Meury, Exequiel Dellota, Rana Abdelnabi, Shi-Yan Caroline Foo, Elisabetta Cameroni, Spencer Stumpf, Tristan I. Croll, Jay C. Nix, Colin Havenar-Daughton, Luca Piccoli, Fabio Benigni, Johan Neyts, Amalio Telenti, Florian A. Lempp, Matteo S. Pizzuto, John D. Chodera, Christy M. Hebner, Herbert W. Virgin, Sean P. J. Whelan, David Veesler, Davide Corti, Jesse D. Bloom and Gyorgy Snell, 14 July 2021, Nature.
DOI: 10.1038/s41586-021-03807-6

The Advanced Light Source and SLAC’s Stanford Synchrotron Radiation Lightsource are Department of Energy Office of Science User Facilities.

The Epidemiology, Transmission, and Diagnosis of COVID-19

Authors: By: Neesha C. Siriwardane & Rodney Shackelford, DO, Ph.D. April 15, 2020

Introduction to COVID-19

Coronaviruses are enveloped single-stranded RNA viruses of the Coronaviridae family and order Nidovirales (1). The viruses are named for their “crown” of club-shaped S glycoprotein spikes, which surround the viruses and mediate viral attachment to host cell membranes (1-3). Coronaviruses are found in domestic and wild animals, and four coronaviruses commonly infect the human population, causing upper respiratory tract infections with mild common cold symptoms (1,4). Generally, animal coronaviruses do not spread within human populations, however rarely zoonotic coronaviruses evolve into strains that infect humans, often causing severe or fatal illnesses (4). Recently, three coronaviruses with zoonotic origins have entered the human population; severe acute respiratory syndrome coronavirus-2 (SARS) in 2003, Middle Eastern respiratory syndrome (MERS) in 2012, and most recently, coronavirus disease 2019 (COVID-19), also termed SARS-CoV-2, which the World Health Organization declared a Public Health Emergency of International Concern on January 31st, 2020 (4,5). 

COVID19 Biology, Spread, and Origin

COVID-19 replicates within epithelial cells, where the COVID-19 S glycoprotein attaches to the ACE2 receptor on type 2 pneumocytes and ciliated bronchial epithelial cells of the lungs. Following this, the virus enters the cells and rapidly uses host cell biochemical pathways to replicate viral proteins and RNA, which assemble into viruses that in turn infect other cells (3,5,6). Following these cycles of replication and re-infection, the infected cells show cytopathic changes, followed by various degrees of pulmonary inflammation, changes in cytokine expression, and disease symptoms (5-7). The ACE2 receptor also occurs throughout most of the gastrointestinal tract and a recent analysis of stool samples from COVID-19 patients revealed that up to 50% of those infected with the virus have a COVID-19 enteric infection (8).

COVID-19 was first identified on December 31st, 2020 in Wuhan China, when twenty-seven patients presented with pneumonia of unknown cause. Some of the patients worked in the Hunan seafood market, which sold both live and recently slaughtered wild animals (4,9).  Clusters of cases found in individuals in contact with the patients (family members and healthcare workers) indicated a human-to-human transmission pattern (9,10). Initial efforts to limit the spread of the virus were insufficient and the virus soon spread throughout China. Presently COVID-19 occurs in 175 countries, with 1,309,439 cases worldwide, with 72,638 deaths as of April 6th, 2020 (4). Presently, the most affected countries are the United States, Italy, Spain, and China, with the United States showing a rapid increase in cases, and as of April 6th, 2020 there are 351,890 COVID-19 infected, 10,377 dead, and 18,940 recovered (4).  In the US the first case presented on January 19th, 2020, when an otherwise healthy 35-year-old man presented to an urgent care clinic in Washington State with a four-day history of a persistent dry cough and a two-day history of nausea and vomiting.  The patient had a recent travel history to Wuhan, China. On January 20th, 2020 the patient tested positive for COVID-19.  The patient developed pneumonia and pulmonary infiltrates, and was treated with supplemental oxygen, vancomycin, and remdesivir. By day eight of hospitalization, the patient showed significant improvement (11). 

Sequence analyses of the COVID-19 genome revealed that it has a 96.2% similarity to a bat coronavirus collected in Yunnan province, China. These analyses furthermore showed no evidence that the virus is a laboratory construct (12-14). A recent sequence analysis also found that COVID-19 shows significant variations in its functional sites, and has evolved into two major types (termed L and S). The L type is more prevalent, is likely derived from the S type, and may be more aggressive and spread more easily (14,15). 

Transmission

While sequence analyses strongly suggest an initial animal-to-human transmission, COVID-19 is now a human-to-human contact spread worldwide pandemic (4,9-11). Three main transmission routes are identified; 1) transmission by respiratory droplets, 2) contract transmission, and 3) aerosol transmission (16). Transmission by droplets occurs when respiratory droplets are expelled by an infected individual by coughing and are inhaled or ingested by individuals in relatively close proximity.  Contact transmission occurs when respiratory droplets or secretions are deposited on a surface and another individual picks up the virus by touching the surface and transfers it to their face (nose, mouth, or eyes), propagating the infection. The exact time that COVID-19 remains infective on contaminated surfaces is unknown, although it may be up to several days (4,16). Aerosol transmission occurs when respiratory droplets from an infected individual mix with air and initiate an infection when inhaled (16). Transmission by respiratory droplets appears to be the most common mechanism for new infections and even normal breathing and speech can transmit the virus (4,16,17). The observation that COVID-19 can cause enteric infections also suggests that it may be spread by oral-fecal transmission; however, this has not been verified (8). A recent study has also demonstrated that about 30% of COIVID-19 patients present with diarrhea, with 20% having diarrhea as their first symptom. These patients are more likely to have COVID-19 positive stool upon testing and a longer, but less severe disease course (18).  Recently possible COVID-19 transmission from mother to newborns (vertical transmission) has been documented. The significance of this in terms of newborn health and possible birth defects is currently unknown (19). 

The basic reproductive number or R0, measures the expected number of cases generated by one infection case within a population where all the individuals can become infected. Any number over 1.0 means that the infection can propagate throughout a susceptible population (4). For COVID-19, this value appears to be between 2.2 and 4.6 (4,20,21). Unpublished studies have stated that the COVID10 R0 value may be as high as 6.6, however, these studies are still in peer review. 

COVID-19 Prevention

There is no vaccine available to prevent COVID-19 infection, and thus prevention presently centers on limiting COVID-19 exposures as much as possible within the general population (22). Recommendations to reduce transmission within community include; 1) hand hygiene with simultaneous avoidance of touching the face, 2) respiratory hygiene, 3) utilizing personal protective equipment (PPE) such as facemasks, 4) disinfecting surfaces and objects that are frequently touched, and 5) limiting social contacts, especially with infected individuals  (4,9,17,22). Hand hygiene includes frequent hand-washing with soap and water for twenty seconds, especially after contact with respiratory secretions produced by activities such as coughing or sneezing. When soap and water are unavailable, hand sanitizer that contains at least 60% alcohol is recommended (4,17,22). PPE such as N95 respirators are routinely used by healthcare workers during droplet precaution protocols when caring for patients with respiratory illnesses. One retrospective study done in Hunan, China demonstrated N95 masks were extremely efficient at preventing COVID-19 transfer from infected patients to healthcare workers (4,22-24). It is also likely that wearing some form of mask protection is useful to prevent COVID19 spread and is now recommended by the CDC (25). 

Although transmission of COVID-19 is primarily through respiratory droplets, well-studied human coronaviruses such as HCoV, SARS, and MERS coronaviruses have been determined to remain infectious on inanimate surfaces at room temperature for up to nine days. They are less likely to persist for this amount of time at a temperature of 30°C or more (26). Therefore, contaminated surfaces can remain a potential source of transmission. The Environmental Protection Agency has produced a database of appropriate agents for COVID-19 disinfection (27). Limiting social contact usually has three levels; 1) isolating infected individuals from the non-infected, 2) isolating individuals who are likely to have been exposed to the disease from those not exposed, and 3) social distancing. The later includes community containment, were all individuals limit their social interactions by avoiding group gatherings, school closures, social distancing, workplace distancing, and staying at home (28,29). In an adapted influenza epidemic simulation model, comparing scenarios with no intervention to social distancing and estimated a reduction of the number of infections by 99.3% (28). In a similar study, social distancing was estimated to be able to reduce COVID-19 infections by 92% (29). Presently, these measured are being applied in many countries throughout the world and have been shown to be at least partially effective if given sufficient time (4,17,30). Such measures proved effective during the 2003 SARS outbreak in Singapore (30). 

Symptoms, Clinical Findings, and Mortality 

On average COVID-19 symptoms appear 5.2 days following exposure and death fourteen days later, with these time periods being shorter in individuals 70-years-old or older (31,32). People of any age can be infected with COVID-19, although infections are uncommon in children and most common between the ages of 30-65 years, with men more affected than women (32,33). The symptoms vary from asymptomatic/paucisymptomatic to respiratory failure requiring mechanical ventilation, septic shock, multiple organ dysfunction, and death (4,9,32,33). The most common symptoms include a dry cough which can become productive as the illness progresses (76%), fever (98%), myalgia/fatigue (44%), dyspnea (55%), and pneumoniae (81%), with less common symptoms being headache, diarrhea (26%), and lymphopenia (44%) (4,32,33). Rare events such as COVID-19 acute hemorrhagic necrotizing encephalopathy have been documented and one paper describes conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, or increased secretions in 30% of COVID-19 patients (34,35). Interestingly, about 30-60% of those infected with COVID-19 also experience a loss of their ability to taste and smell (36). 

The clinical features of COVID-19 include bilateral lung involvement showing patchy shadows or ground-glass opacities identified by chest X-ray or CT scanning (34). Patients can develop atypical pneumoniae with acute lung injury and acute respiratory distress syndrome (33). Additionally, elevations of aspartate aminotransferase and/or alanine aminotransferase (41%), C-reactive protein (86%), serum ferritin (63%), and increased pro-inflammatory cytokines, whose levels correlate positively with the severity of the symptoms (4,31-33,37-39).

About 81% of COVID-19 infections are mild and the patients make complete recoveries (38). Older patients and those with comorbidities such as diabetes, cardiovascular disease, hypertension, and chronic obstructive pulmonary disease have a more difficult clinical course (31-33,37-39). In one study, 72% of patients requiring ICU treatment had some of these concurrent comorbidities (40). According to the WHO 14% of COVID-19 cases are severe and require hospitalization, 5% are very severe and will require ICU care and likely ventilation, and 4% will die (41). Severity will be increased by older age and comorbidities (4,40,41). If effective treatments and vaccines are not found, the pandemic may cause slightly less than one-half billion deaths, or 6% of the world’s population (41). Since many individuals infected with COVID-19 appear to show no symptoms, the actual mortality rate of COIVD-19 is likely much less than 4% (42). An accurate understanding of the typical clinical course and mortality rate of COVID-19 will require time and large scale testing.         

COVID-19 Diagnosis

COVID-19 symptoms are nonspecific and a definitive diagnosis requires laboratory testing, combined with a thorough patient history.  Two common molecular diagnostic methods for COVID-19 are real-time reverse polymerase chain reaction (RT-PCR) and high-throughput whole-genome sequencing.  RT-PCR is used more often as it is cost more effective, less complex, and has a short turnaround time. Blood and respiratory secretions are analyzed, with bronchoalveolar lavage fluid giving the best test results (43). Although the technique has worked on stool samples, as yet stool is less often tested (8,43). RT-PCR involves the isolation and purification of the COVID-19 RNA, followed by using an enzyme called “reverse transcriptase” to copy the viral RNA into DNA. The DNA is amplified through multiple rounds of PCR using viral nucleic acid-specific DNA primer sequences. Allowing in a short time the COVID-19 genome ti be amplified millions of times and then easily analyzed (43). RT-PCR COVID-19 testing is FDA approved and the testing volume in the US is rapidly increasing (44,45). The FDA has also recently approved a COVID-19 diagnostic test that detects anti-COVID-19 IgM and IgG antibodies in patient serum, plasma, or venipuncture whole blood (43). As anti-COVID-19 antibody formation takes time, so a negative result does not completely preclude a COVID-19 infection, especially early infections. Last, as COVID-19 often causes bilateral pulmonary infiltrates, correlating diagnostic testing results with lung chest CT or X-ray results can be helpful (4,31-33,37-39).  

Testing for COVID-19 is based on a high clinical suspicion and current recommendations suggest testing patients with a fever and/or acute respiratory illness. These recommendations are categorized into priority levels, with high priority individuals being hospitalized patients and symptomatic healthcare facility workers. Low priority individuals include those with mild disease, asymptomatic healthcare workers, and symptomatic essential infrastructure workers. The latter group will receive testing as resources become available (41,46,47). 

COVID-19 Possible Treatments

Presently research on possible COVIS-19 infection treatments and vaccines are underway (48). At the writing of this article many different drugs are being examined, however any data supporting the use of any specific drug treating COVID-19 is thin as best. A few drugs that might have promise are:  

Hydroxychloroquine

Hydroxychloroquine has been used to treat malarial infections for seventy years and in cell cultures it has anti-viral effects against COVID-19 (49). In one small non-randomized clinical trial in France, twenty individuals infected with COVID-19 who received hydroxychloroquine showed a reduced COVID-19 viral load, as measured on nasopharyngeal viral carriage, compared to untreated controls (50). Six individuals who also received azithromycin with hydroxychloroquine had their viral load lessened further (50). In one small study in China, a similar drug (chloroquine) was superior in reducing COVID-19 viral levels in treated individuals compared to untreated control individuals (51).  These results are preliminary, but promising. 

Remdesivir

Remdesivir is a drug that showed value in treating patients infected with SARS (52). COVID-19 and SARS show about 80% sequence similarity and since Remdesivir has been used to treat SARS, it might have value in treating COVID-19 (52). These trials are underway (48). Remdesivir was also used to treat the first case of COIVD-19 identified within the US (11). There are many other drugs being examined to treat COVID-19 infections, however, the data on all of them is presently slight to none, and research has only begun. There is an enormous research effort underway, and progress should be rapid (48). 

Conclusion

Our understanding of COVID-19 is changing extremely rapidly and new findings come out daily. Combating COVID-19 effectively will require multiple steps; including slowing the spread of the virus through socially isolating and measures such as hand washing. The development of effective drug treatments and vaccines is already a priority and rapid progress is being made (48). Additionally, many areas of the world, such as South American and sub-Saharan Africa, will be affected by the COVID-19 pandemic and are likely to have their economies and healthcare systems put under extreme stress. Dealing with the healthcare crisis in these countries will be very difficult. Lastly, several recent viral pandemics (SARS, MERS, and COVID-19) have come from areas where wildlife is regularly traded, butchered, and eaten in conditions that favor the spread of dangerous viruses between species, and eventually into human populations. The prevention of new viral pandemics will require improved handling of wild species, better separation of wild animals from domestic animals, and better regulated and lowered trade in wild animals, such as bats, which are known to be a risk for carrying potentially deadly viruses to human populations (53). 

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