I have written several articles on the coronavirus and on masks and healthcare issues. A series of links have been provided at the bottom of this article for your convenience. This article will, however address a different aspect of the virus or on Healthcare issues in general.
Table of Contents
-For millions of vulnerable people, COVID-19 is far from over
–Did Dr. Fauci Fund research in the Wuhan Institute of Virology Lab in China?
-How to Trace A Virus to Its Source
-Classification and Structure: Human Cornavirus Types
-Interlude: RNA vs DNA
-Making A Protein, Part 1: Transcription
-Making a Protein, Part 2: Translation
–Additional and Miscellaneous Information on the Virus
-Coronavirus in the U.S.: Where cases are growing and declining
-Modes of transmission of the Covid-19 virus
-Transmission by Function and Activities
-How the coronavirus infects cells — and why Delta is so dangerous
-Precautions to take to prevent transmission
-How is it detected
-Symptoms of Covid-19
-Comorbidities that increase the lethality of the disease
-Can COVID-19 alter your personality? Here’s what brain research shows
-COVID-19 in people with diabetes: understanding the reasons for worse outcomes
-How the coronavirus affects your body
-Here’s what coronavirus does to the body
-COVID and the brain: researchers zero in on how damage occurs
-How does COVID-19 affect the brain? A troubling picture emerges
-How COVID-19 harms the heart
-The real risk of heart inflammation to kids is from COVID-19—not the vaccine
-Can COVID-19 lead to diabetes? Here’s what you need to know
-Why some COVID-19 infections may be free of symptoms but not free of harm
-How COVID-19 can damage all five senses
-Therapeutics and Treatment Modalities
-The Heart and the QT interval
-Medications that can prolong the QT interval
-At Home Coronavirus Treatment
-COVID-19 is linked to new diabetes cases—but long-term problems could be more severe
-Therapeutics and treatment modalities revisited
-The shaky science behind ivermectin as a COVID-19 cure
-Post-acute Covid-19 Syndrome
-New Developments in Covid Research
-ICU NURSE: “You’re being lied to about COVID.”
-The world may need to learn to live with the virus.
-Will we ever know the real death toll of the pandemic?
-Here’s why the CDC reversed course on masks indoors—and how it might affect you
-Struggling to assess pandemic risks? You’re not alone.
-Why is Delta more infectious and deadly? New research holds answers.
-How will the pandemic end? The science of past outbreaks offers clues.
-Delta’s rise is fuelled by rampant spread from people who feel fine
-COVID-19 may impair men’s sexual performance
-Heart-disease risk soars after COVID — even with a mild case
-How Merck’s antiviral pill could change the game for COVID-19
-Common antidepressant slashes risk of COVID death
-Fact and fiction – myths and truths about COVID-19
-Two years later, coronavirus evolution still surprises experts. Here’s why.
Note: this article was written in the attempt to distill a massive amount of data on covid into a more manageable format. Since its first posting in July, I have updated it several times. Each time I update it I will move it up in the order of my postings to make it easier for you the reader to keep up to date. I will also post adjunct articles dealing with different aspects of the coronavirus, that would not necessarily fit in this article. This article covers a fairly extensive number of subjects on covid. You don’t not have to read the entire article in one sitting. Actually I would advise against it. I likewise did not write it in one sitting. One thing you will find if you have been reading my previous articles on covid, is that I am consistent in my presentation. I have never changed my opinion on how it is transmitted or how effective masks are, unlike all the other supposed experts have done. You may ask why I have been able to do this? I grew up with science and medicine as my bed fellows. My father groomed me for a career in medicine, He wanted me to be a doctor, but I ended up becoming an ICU nurse instead. He was somewhat disappointed, but he was still pleased and proud of my career choice. When children received comic books and Hardy Boy Books to read, I received medical books and scientific journals. So I had a bit of a strange childhood. I also had all the models of the human body and organs that were popular in the 70’s and 80’s. By the way, I tried to follow his dream for me, I did go to college and entered in a pre-med program and received a BS in Biology. Unfortunately my timing was poor and the competition was incredibly stiff for medical school positions during that period of time, and while my grades were good they did not match the 3.8 and higher GPA numbers they were looking for.
As I have stated I am not a doctor. I am not trying to prescribe any medication, make any diagnoses. Any comments I may make about treatments are my opinion only and should not be taken as recommendations. If I was infected with covid-19 I would certainly push for them, though. As I stated already, I am an ICU nurse. I have been on the front lines since day one in the Coronavirus pandemic. I have also done a lot of research on the matter, since I care for these patients every day, I wanted to be safe. With proper precautions the Coronavirus need not be feared, but it should be respected. Whether it kills by itself or pushes people over the brink with comorbidities, it is very dangerous. I have seen many people die from it and assorted complications. This article is an attempt to dispel a lot of misconceptions on the subject and to present unbiased data, so you can make up your own mind on the matter. But if you take anything from this article please take the importance of the following; be careful, be considerate and be safe.
As I have stated when new information becomes available I would update this article. One area that little new information has come about is the origin of the virus and when did it actually arrive on the world arena. Until now that is. Recently blood samples from the American Red Cross have been tested from last year. Don’t let the name fool you, they do good work around the world. Well in this study they found out that there were asymptomatic cases in Italy as early as September 2019 and in South America November of 2019 as well. That certainly changes the picture a little. However, we still do not have the initial host species. It has also been almost completely dispelled that the virus originated from bats and the Wuhan wet market in China. It is more likely that it originated in the virology clinic in the Wuhan Province. I also have an update on masks and goggles and vaccines which I will add to the addendum section. (Update 12/5/2020)
Since my last update on 12/5/2020 there has been more data that point to a lab leak from Wuhan as the location for the virus. Top aide to President Trump Matthew Pottinger says leaders in China are “admitting” there is a chance theories suggesting Covid-19 started in a “wet market” are false.
The Mail on Sunday 1/4/2021 reports how Deputy National Security Adviser Matthew Pottinger told politicians from around the world that intelligence points to the likelihood of the virus leaking from China’s biggest lab, the Wuhan Institute of Virology.
“There is a growing body of evidence that the lab is likely the most credible source of the virus”, Pottinger said in a statement.
He told leaders during the call that the incident could we have been a “leak or an accident”.
“Even establishment figures in Beijing have openly dismissed the wet market story,” he added.
In the UK, former Conservative Party leader Iain Duncan-Smith, who was present at the meeting, said the comments helped to “stifen” the arguments surrounding the theory.
The news also comes amid reports US authorities are said to be talking to a “whistleblower” from the Wuhan institute.
Mr Duncan-Smith said: “I was told the US have an ex-scientist from the laboratory in America at the moment.
“That was what I heard a few weeks ago.
“I was led to believe this is how they have been able to stiffen up their position on how this outbreak originated.”
There have long been theories that coronavirus was accidentally leaked from the Institute, something that has been claimed by President Trump several times.
In May last year the president claimed the coronavirus outbreak was the result of a “horrible mistake” in China after claiming he’d seen evidence the virus originated in a Wuhan lab.
The president added the Chinese communist regime then tried to cover up their Covid-19 blunder — but “couldn’t put out the fire”.
In December a journalist who bravely exposed the “cover up” of Wuhan’s deadly coronavirus outbreak was jailed for four years for “trouble making”.
Zhang Zhan, 37, was found guilty of “picking quarrels and provoking trouble” after a brief hearing in Shanghai, according to her legal team.
The Pudong New Area Peoples Court claimed she spread false information, gave interviews to foreign media, disrupted public order and maliciously manipulated the pandemic.
Ms Zhang travelled to Wuhan to collect first hand accounts of life under lockdown and posted videos of crematoriums working at midnight that cast doubt on the official death toll.
Damning leaked filed also allege China hid its true Covid-19 infection rate to “protect” its image.
The explosive secret data, from China’s own health chiefs, appeared to expose a catalogue of cover-ups and blunders which hid the true scale of the killer disease that has since killed more than 1.8 million people.
On Fox News HHS Secretary in an live interview on Fox and Friends Alex Azar, stated that only approximately 5% of the antibody therapies touted by President Trump and that have been provided to the medical facilities free of charge and at great cost to the tax payers are being administered to patients. Apparently the Infectious Disease Society is not pushing the use of these treatments and are stating that there is no proof of their efficacy. I guess blocking the use of Hydroxychloroquine in the early spring was not enough, now they are standing in the way of more treatments. The FDA has released these antibody treatments by Lilly and Regneron for emergency use. They are both currently in phase 3 testing. Thousands of people are still dying every week and over 300,000 people have died in the U.S. so far and millions have been infected. When will people in power stop playing games with our lives and well being? Apparently people have to tell the doctors what medicine we need. If the doctors are afraid of lawsuits, simply have the patients sign waiver forms. I am sure they would have no problem with this. (Update 12/22/2020)
Dr. Tedros Director-General of World Health Organization obtained his position from support China. He lives in Switzerland, and pays no income tax. He also enjoys all expenses paid travel. He and his team just wrapped up their “investigation” of the Wuhan Virus crisis in Wuhan, China. They totally exonerated China of any culpability. They set up a faulty theory that the virus came from frozen food shipped to China from Australia. During their investigation they only visited one of the three virology labs in the Wuhan Province, where they only spent 3 hours there. The only thing the experts said was that the virus originated from Bats. Something we already knew. The most logical origins were from bats that they were feeding and breeding in the labs. This research was in fact funded by Dr. Fauci. The virus spread to lab workers, who spread it to their local residents. Will we ever know the entire facts behind the outbreak, most likely the answer is no. This is mainly due to the fact that China destroyed all the original data and specimens. (Updated 2/15/2021)
Coronaviruses are a family of viruses that can cause illnesses such as the common cold, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). In 2019, a new coronavirus was identified as the cause of a disease outbreak that originated in China.
The virus is now known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease it causes is called coronavirus disease 2019 (COVID-19). In March 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a pandemic.
Public health groups, including the U.S. Centers for Disease Control and Prevention (CDC) and WHO, are monitoring the pandemic and posting updates on their websites. These groups have also issued recommendations for preventing and treating the illness.
Origins of the Virus:
I have come across a seminal article on the origins of the virus by the magazine entitled Nature. The article is both well written and appears to be an impartial coverage of the subject matter. So I have decided to copy it in its entirety:
The biggest mystery: what it will take to trace the coronavirus source
SARS-CoV-2 came from an animal but finding which one will be tricky, as will laying to rest speculation of a lab escape.
Since the pandemic began, the question of where the coronavirus came from has been one of the biggest puzzles. It almost certainly originated in bats, and a new study out this week — the most comprehensive analysis of coronaviruses in China — adds further weight to that theory.
But the lack of clarity around how the virus passed to people has meant that unsubstantiated theories — promoted by US President Donald Trump — that it escaped from a laboratory in China persist.
By contrast, most researchers say the more likely explanation, given what is known so far about this virus and others like it, is that bats passed it to an intermediate animal, which then spread it to people.
In mid-May, the World Health Assembly, the World Health Organization’s key decision-making body, passed a resolution that calls on the agency to work with other international organizations to identify the animal source.
That the WIV, a laboratory highly regarded for its work on bat coronaviruses, is located in the city where the outbreak first emerged is probably just a coincidence. But the leading work its researchers are doing to unravel the origin of the pandemic, as well as the unsubstantiated speculation about its possible role in the outbreak, has thrust it into the spotlight: several of the authors of the latest bat study work there.
An independent investigation at the facility is probably the only way to convincingly rule out the lab as a possible source of the outbreak, but scientists think such a probe is unlikely, given the delicate geopolitics that surround the issue.
In the latest study, researchers analysed partial sequences for some 1240 coronaviruses found in bats in China. They report that the virus fuelling the pandemic, SARS-CoV-2, is most closely related to a group of viruses found in horseshoe bats (Rhinolophus).
Their finding adds to an earlier report that a coronavirus called RATG13, which some of the authors found in intermediate horseshoe bats (Rhinolophus affinis) in Yunnan province, shares 96% of its genetic sequence with SARS-CoV-2.
The authors of the latest analysis note that the viral group to which both viruses belong seems to have originated in Yunnan province. But as the team only collected viruses from sites in China, they cannot rule out that a SARS-CoV-2 ancestor might have come from neighbouring Myanmar and Laos, where horseshoe bats also live.
A co-author of the study, posted on bioRxiv, is Shi Zheng-Li, the WIV virologist whose extensive work surveying coronaviruses in China has drawn particular attention during the pandemic. Shi has refuted suggestions that the lab has ever had a virus similar to SARS-CoV-2, and has previously cautioned about the risks of another SARS-like disease emerging from animals. “She had actually warned us that there are bat viruses in nature that can spill over to humans,” says Volker Thiel, a virologist at the University of Bern.
No bat viruses found so far are similar enough to SARS-CoV-2 to be a direct ancestor. So while the new virus could have been spread to people directly from bats, researchers think it’s more likely that it passed through an intermediate animal. Evidence suggests that the related coronavirus that causes severe acute respiratory syndrome (SARS) passed to people from bats by way of civets, and that camels were the intermediate source of another related virus that causes Middle East respiratory syndrome (MERS). Those species were found to host versions of the viruses almost identical to those seen in humans.
Finding a virus nearly identical to SARS-CoV-2 in an animal would provide the most persuasive evidence for how it passed to people. It would require extensive sampling of coronaviruses in wildlife and livestock in China, says Rob Grenfell, the director of the Commonwealth Scientific and Industrial Research Organisation’s Health and Biosecurity unit in Melbourne, Australia. China has reportedly started such investigations, but little information on their status has been released.
Similar investigations happened after the original SARS outbreak. The first cases emerged in November 2002, but the cause wasn’t identified as a coronavirus until April 2003. By then, authorities already suspected that animals were involved, because more than 30% of the early cases in Guangdong province, China, where the outbreak started, were in workers at a live animal market. A month later, researchers found the virus in civets at live animal markets. Researchers later linked civets to cases of SARS in people — a waitress and customer at a restaurant serving palm civets (Paradoxurus hermaphroditus) tested positive for the virus, along with six of the animals.
But it took nearly 15 years and extensive animal sampling to find a closely related virus in bats. It was Shi Zheng-Li who led the team that sampled thousands of bats in remote caves in China. And even though they found all the genetic components of the SARS virus, they did not find one virus with the same genetic make-up.
Scientists say that pinpointing the animal source of SARS-CoV-2 could take just as long. Groups around the world are already using computational models, cell biology and animal experiments to investigate species that are susceptible to the virus — and so possibly the source — but so far it remains elusive.
Dr. Richard Ebright on Coronavirus Zoonotic Origins Theory. “The outbreak occurred in Wuhan, a city that does not contain horsehoe-bat colonies., that is tens of kilometers from, and that is outside the flight range of, the nearest known horsehoe-bat colonies. Furthermore, the outbreak occurred at a time of year when horsehoe bats are in hibernation and do not leave colonies.” (Update 3/28/2021)
The WIV hosts a maximum-security lab that is one of a few dozen biosafety-level-4 (BSL-4) labs around the world. Although there’s no evidence to support the suggestion that the virus escaped from there, scientists say that completely ruling it out will be tricky and time consuming.
For millions of vulnerable people, COVID-19 is far from over
Immunocompromised patients remain frightened and frustrated that vaccines aren’t offering enough protection as everyone else moves on. Scientists are racing to figure out what will work.
Janet Handal was feeling optimistic when she booked her flight to Texas in early 2021. The 71-year-old New York City resident had just scheduled her first COVID-19 vaccine appointment amid news that the mRNA vaccines available in the U.S. were highly effective. She carefully counted the days until she would be safe to travel, eager to see family for the first time in over 18 months.
But that optimism was short-lived.
A blood sample taken a month after her second shot revealed that Handal had developed nearly no antibodies against COVID-19. The two vaccine doses being recommended for mRNA shots didn’t confer the same robust immunity as they had for tens of thousands of vaccine trial participants. That’s because she has been on immune-suppressing drugs due to a kidney transplant she received in 2010.
“It was really a punch to the gut,” she says. “I never imagined that I was not going to be protected [in the same way].”
Handal is among the estimated 10 million people in the U.S. with a compromised immune system. Unlike everyone else, they mount a much weaker immune response to several vaccines. But when pharmaceutical companies first began testing COVID-19 vaccines in 2020 and 2021, the clinical trials excluded immunocompromised individuals and issued the same vaccination recommendations for them without conducting separate trials.
“When a new vaccine comes out, the recommendation for an immunocompromised patient is the same as that for everyone else,” says Deepali Kumar, a transplant infectious diseases physician at the University of Toronto. It isn’t until later that those recommendations are adjusted, in part because the burden of providing data for immunocompromised individuals falls on the shoulders of independent scientists, not the vaccine makers, and it can take months to years to conduct the studies. “It’s a long-standing issue,” she says.
Even now it remains unclear whether more vaccine doses will help protect the severely immunocompromised. The U.S. Food and Drug Administration authorized a third dose in August 2021 for certain immunocompromised people. Some transplant recipients have since been vaccinated with a fourth shot and a smaller subset have secured a fifth dose. But Kumar says more may not always be better, and additional studies are needed to prove that further doses are effective.
The irony is that the third dose may not have been authorized if not for people like Handal taking matters into their own hands.
Without robust protection from two shots, Handal knew her weak immune system meant greater chances of severe disease or death from exposure to the SARS-CoV-2 virus. So she and some others like her got a third COVID-19 shot—well before the FDA authorized its use. But not all immunocompromised people did, making things tricky in May 2021 as the Centers for Disease Control and Prevention was saying “no masks for the fully vaccinated.”
“I know three people myself who were transplant recipients who’ve died because they listened to the message of take your masks off,” Handal says. “Many, many, many, of us just decided we were going to get our [additional] vaccines early because we knew we weren’t protected.”
Why COVID-19 vaccines don’t work well in immunocompromised people
When our bodies receive a COVID-19 shot, the immune system springs into action. It stimulates the production of antibodies—which can bind to the virus and prevent it from infecting cells. It also activates specialized immune cells called T cells, as well as memory cells that “remember” how to respond when a COVID-19 infection occurs.
But those immune responses are blunted in immunocompromised people, including those taking immunosuppressive drugs for autoimmune diseases, organ transplants, cancers, HIV infections, and other conditions.
When a transplant patient receives an organ from another human, their immune system sees it as foreign and immediately tries to reject it. To counter these attacks doctors use immunosuppressants to dial down the activity of the patient’s immune system and stop it from attacking the new organ. “It’s always this really careful balance in leaving some of the immune system intact, obviously, and wanting to leave it suppressed enough so it doesn’t cause harm,” says Dorry Segev, a transplant surgeon at Johns Hopkins University. “But it also reduces the ability to respond to the vaccine.”
Several studies have suggested that two shots of an mRNA vaccine were grossly inadequate for several immunocompromised individuals, particularly kidney transplant recipients. One study published in May 2021 found that 46 percent of 658 kidney, lung, liver, and heart transplant individuals in the U.S. had no antibody response after receiving one or two doses of the mRNA vaccines. Compared to everyone else, transplant patients vaccinated with two doses had an 82-fold higher risk of breakthrough infections and 485-fold increased risk of hospitalization or dying.
Following a third shot, one study found that 77 out of 197 people with kidney transplants developed COVID-19-specific antibodies after producing none from two doses. In another study, 26 out of 60 organ transplant recipients who were given the third dose produced antibodies at levels nearly equivalent to those seen in people with healthy immune systems who’d gotten two doses.
But for some immunocompromised people, such as those who are older or taking certain immunosuppression drugs or high doses of it, even the third or fourth vaccine dose has proven limited.
“I have two patients who’ve had the fourth dose critically ill with COVID-19 because they didn’t mount a sufficient antibody response even with the fourth dose,” says Ayelet Grupper, a nephrologist at Israel’s Tel Aviv Medical Center. “And it’s getting more complicated—I’m not sure what level of antibodies are needed to fight against Omicron and new variants that might come.”
Like living under house arrest
Segev has been measuring post-vaccination antibody responses among organ transplant recipients, including Handal, since last year. While her blood work indicated an increase in antibody levels following a third dose in April 2021, the response was still weak compared to that seen in people with healthy immune systems.
So in October 2021—six months after her third dose—Handal got a fourth. Some of Segev’s patients still didn’t mount a robust immune response and needed a fifth shot. In a recent study, he recorded an increase in antibodies at dose five among some patients who didn’t have a sufficient response at four. “There are people out there who need two doses, there are people out there who need five doses, and there people in between,” Segev says.
But, theoretically, too many doses of the same vaccine could create a “problem of tolerance,” he says, meaning a potential lukewarm immune response following multiple vaccine doses. “Your body can say, I know this vaccine, I don’t need to do anything.”
Feeling unprotected, several of his patients have lived far more isolated lives during the pandemic than everyone else. “Essentially you’ve been living under house arrest,” Handal says. “You haven’t been able to participate in your family’s lives or be with your friends.” Getting additional shots hasn’t been easy either. It created dissonance for almost everyone who chose to do it, Handal says, especially if the shots were not yet officially authorized by the CDC and FDA.
“We are building the plane as we fly it,” Segev says, “and we’ve been doing that through the entire pandemic.”
Clinical trials spark hope
Scientists are conducting clinical trials and are exploring alternative strategies to boost the immune response for the immunocompromised.
Segev, for instance, is leading a randomized clinical trial involving kidney and liver transplant recipients who have failed to produce antibodies after two, three, or four mRNA vaccine doses and giving them an additional dose. In some participants he’s also reducing their immunosuppressive medication one week before and two weeks after giving them the additional COVID-19 shot to see if such an adjustment improves the immune response, similar to what researchers have observed in people with autoimmune diseases.
At the University of California, Davis, Transplant Center, Aileen Wang is leading a similar clinical trial specifically with kidney transplant recipients for whom the second or third mRNA vaccine doses weren’t adequate. Before and after giving an additional shot, she and her colleagues plan to halve the dose of one immunosuppressive drug called mycophenolate, which prevents the recipient’s body from rejecting a transplant organ.
Grupper, who isn’t involved in these studies, feels the research will be informative. But she emphasizes the delicate balance between increasing a transplant recipient’s immune response to the vaccine while still preventing organ rejection. Monitoring clinical trial participants’ health closely is key, she says.
As this work continues and researchers recruit more participants, transplant recipients may have to wait at least another three months, if not more, to find out if Segev, Wang, and their colleague’s approach is successful.
In the meantime, as COVID-19 continues to be a serious risk for many immunocompromised individuals, they’re also struggling to access Evusheld—the only monoclonal antibody authorized for prevention of COVID-19 in people who can’t take the vaccine due to a severe allergy or an immunocompromised condition. The intramuscular injection must be given once every six months while the virus circulates, and supplies are extremely limited. Last week the FDA revised its initial dosing regimen in light of Omicron to a higher dose.
“People have driven hours, sometimes eight to 10 hours, to get the injection,” Handal says. Alongside finding ways to access additional vaccine doses, “we’re also strategizing about how to get Evusheld.”
With several states rolling back masking mandates and pushing for a return to normalcy, Handal and others remain frustrated. “We know we’re not safe,” she says, “and there isn’t adequate treatment if you get sick.” She’s planning on getting her fifth dose very soon.
Did Dr. Fauci Fund research in the Wuhan Institute of Virology Lab in China?
Dr. Fauci’s National Institute of Allergy and Infectious Diseases has shelled out a total of $7.4 million to the Wuhan Institute of Virology lab — which has become the focus of theories about the origin of COVID-19. It has been reported that Fauci chaffed at the restrictions by the National Institutes of Health (NIH) and a ban by President Obama while he was in office on Gain-of-Function Research on viruses. It is hypothesized that he funded this research in Wuhan, where China does not fall under the restrictions. Dr. Fauci was also aware off the less than stellar safety record at the lab. There had been outbreaks associated with the lab in the past. However, he thought that the benefits out weighted the risks. We now know that he was wrong about this too. Apparently three scientists became infected with the virus, and spread it to the surrounding communities. When the local government found out of the outbreak, they closed down travel from Wuhan to the rest of China, but allowed travel to the rest of the world. In fact they encouraged travel to the rest of the world and they bristled at restrictions placed on travel to Europe and the U.S.. China had the opportunity to stop the pandemic in its tracks, but they chose to use it as a biological weapon. So with Dr Fauci failing to follow restrictions from the governing board on viral research, he was indirectly responsible for the pandemic. Instead of him being investigated and charged with malfeasence, he has been given the lead position in the Covid task force under the last two presidents, with a very nice salary.
I now have proof thanks to work done by investigators from the Fox News Show The Next Revolution w/ Steve Hilton. I am going to show in the addendum section at the end of this article, a series of screen grabs from the show depicting records and factoids. (Updated 1/29/2021)
Additional information has come to light, apparently the original work done in the Wuhan Provence in 2014, was not originally gain of function research, which was restricted under the Obama administration. These restrictions were removed in 2017. Even though the ban on research was lifted the controversy on these types of studies wages on. Those who support such research think that it is necessary to develop strategies to fight rapidly evolving pathogens that pose a threat to public health, such as the flu virus, the viruses causing Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS), or Ebola. Many experts worry that human error could lead to the accidental release of a virus that has been enhanced in the lab so that it is more deadly or more contagious than it already is. There have already been accidents involving pathogens. We don’t have an exact timeline as to when the studies became gain of function in nature. From 2014 through 2020 research in Wuhan has been funded by Dr Fauci’s group. Even though, we now know that Fauci did not violate President Obama’s mandates, he is still culpable. He was aware of the controversy surrounding gain of function viral studies and the risks inherent in these studies. In this case the benefits did not outweigh the risks. (Updated 2/28/2021)
In April, lab director Yuan Zhiming said the virus did not come from the lab. He told Chinese state broadcaster CGTN: “We know what virus research is being carried out, we know how viruses are managed, we know how samples are managed. The virus is definitely not coming from here.” No one at the Wuhan Institute of Virology responded to Nature’s multiple requests for comment on the suggestions that the lab might have involved in the outbreak.
In 2017, Nature visited the Wuhan BSL-4 lab and Yuan showed off its gleaming new equipment, high-security testing rooms and a ventilation system carefully designed to ensure that the pathogens were securely contained. He said that his team had worked with French biosafety scientists to build the most advanced biosafety research lab in the world, and that the group was taking every measure to prevent accidents. Yuan said he “wanted to let the world understand why we want to construct this lab, and to describe its role in safeguarding the world”.
There is also no record of accidents at the institute, but viruses, including SARS, have previously accidentally escaped from labs, including in China — although none has led to a significant outbreak. An accidental release of SARS was traced back to a lab in Beijing in 2004 when researchers there got sick. But there have been no reports of researchers at WIV becoming ill.
Determining whether the lab had anything to do with the virus will require a forensic investigation, say several scientists. Investigators would be looking for viruses that matched the genetic sequence of SARS-CoV-2 and, if they found one, any evidence that it could have escaped. To do that, authorities would need to take samples from the lab, interview staff, review lab books and records of safety incidents, and see what types of experiment researchers had been doing, says Richard Ebright, a structural biologist at Rutgers University in Piscataway, New Jersey.
In an interview with Chinese publication Caixin in February, Shi said she hoped there would be an investigation, because she was confident that no connection would be found between her institute and the new coronavirus. Chinese state media have also said an investigation is likely, although no details have been released.
But such an investigation might not yield anything conclusive either way, says Frank Hamill, who previously managed a BSL-4 lab in the United States. Hamill, who currently works for MRIGlobal, which advises laboratories on biosafety, in Gaithersburg, Maryland, says that it would be in the best interests of the lab to be more open about what research its staff are doing. But he adds that US biosecurity laboratories are far from fully transparent about their own research. “We are in a tough spot when we ask the Wuhan institute to open up its files and let people starting poking around. It’s a bit hypocritical,” says Hamill.
A product of nature
Some scientists outside China have studied the virus’s genome in detail and conclude that it emerged naturally rather than from a lab.
An analysis published in Nature Medicine on 17 March discusses several unusual features of the virus, and suggests how they likely arose from natural processes. For starters, when performing experiments that seek to genetically modify a virus, researchers have to use the RNA of an existing coronavirus as a backbone. If scientists had worked on the new coronavirus, it’s likely that they would have used a known backbone. But the study’s authors report that no known viruses recorded in the scientific literature could have served as a backbone to create SARS-CoV-2.
To enter cells, coronaviruses use a ‘receptor binding domain’ (RDB) to latch onto a receptor on the cell’s surface. SARS-CoV-2’s RBD has sections that are unlike those in any other coronavirus. Although experimental evidence — and the sheer size of the pandemic — shows that the virus binds very successfully to human cells, the authors note that computer analyses of its unique RBD parts predict that it shouldn’t bind well. The authors suggest that as a result, no one trying to engineer a virus would design the RBD in this way — which makes it more likely that the feature emerged as a result of natural selection.
The authors also point to another unusual feature of SARS-CoV-2, which is also part of the mechanism that helps the virus to work its way into human cells, known as the furin cleavage site. The authors argue that natural processes can explain how this feature emerged. Indeed, a similar site has been identified in a closely-related coronavirus, supporting the authors claim that the components of SARS-CoV-2 could all have emerged from natural processes.
The analyses show that it is highly unlikely that SARS-CoV-2 was made or manipulated in a lab, says Kristian Andersen, a virologist at Scripps Research in La Jolla, California, and the lead author of the paper. “We have a lot of data showing this is natural, but no data, or evidence, to show that there’s any connection to a lab,” he says.
But several scientists say that although they do not believe that the virus escaped from the lab, analyses are limited in what they can reveal about its origin.
There is unlikely to be a characteristic sign that a genome has been manipulated, says Jack Nunberg, a virologist at the University of Montana in Missoula, who does not believe the virus came from a lab. If, for instance, scientists had added instructions for a furin cleavage site into the virus’s genome, “there is no way to know whether humans or nature inserted the site”, he says.
In the end, it will be very difficult, or even impossible, to prove or disprove the theory that the virus escaped from a lab, says Milad Miladi, who studies RNA evolution at the University of Freiburg in Breisgau, Germany. And despite scientists such as Shi warning the world that a new infectious respiratory disease would emerge at some point, “unfortunately, little was done to prepare for that,” he says. Hopefully governments will learn and be better prepared for the next pandemic, he says.
Classification and structure:
Human Coronavirus Types
Coronaviruses are named for the crown-like spikes on their surface. There are four main sub-groupings of coronaviruses, known as alpha, beta, gamma, and delta.
Human coronaviruses were first identified in the mid-1960s. The seven coronaviruses that can infect people are:
Common human coronaviruses
- 229E (alpha coronavirus)
- NL63 (alpha coronavirus)
- OC43 (beta coronavirus)
- HKU1 (beta coronavirus)
Other human coronaviruses
- MERS-CoV (the beta coronavirus that causes Middle East Respiratory Syndrome, or MERS)
- SARS-CoV (the beta coronavirus that causes severe acute respiratory syndrome, or SARS)
- SARS-CoV-2 (the novel coronavirus that causes coronavirus disease 2019, or COVID-19)
People around the world commonly get infected with human coronaviruses 229E, NL63, OC43, and HKU1.
Sometimes coronaviruses that infect animals can evolve and make people sick and become a new human coronavirus. Three recent examples of this are 2019-nCoV, SARS-CoV, and MERS-CoV.
Covid-19 and Coronavirus is A RNA virus. This is a complicated subject and I will do my best to explain it in a meaningful manner. I have taken graduate level classes in organic chemistry, biochemistry, cell biology, immunology, microbiology, virology, genetics and molecular genetics and I still find the subject intimidating. So don’t feel bad if you have a difficult time with this subject. In order to understand viruses you need to have a basic understanding on their composition and how they reproduce. Viruses are host dependent, they cannot reproduce on their own. Reproduction is one of the requirements for true life, so in the strictest interpretation a virus is not alive. They basically are inert outside the host or in the case of Covid-19, mammals (bats, humans, dogs and even big cats, so far).
Viruses use the replication apparatus of the host cells, and have additionally developed a number of special characteristics. Scientists differentiate viruses according to the genome type – there are DNA and RNA viruses: viruses may have single-stranded or double-stranded linear RNA, single-stranded or double-stranded linear DNA, single-stranded or double-stranded circular DNA and other variations. Some viruses contain some of the enzymes required for their replication, for example the influenza virus, whose envelope not only contains an RNA genome but also an RNA polymerase. When the virus enters the host cell, the enzyme RNA polymerase starts to replicate the viral genome. The synthesis of the genome of DNA viruses usually begins at a replication origin that binds specific initiator proteins, which recruit replication enzymes of the host cell which then replicate the viral genome. RNA synthesis, like nearly all biological polymerization reactions, takes place in three stages: initiation, elongation, and termination. RNA polymerase performs multiple functions in this process: 1. It searches DNA for initiation sites, also called promoter sites or simply promoters.
In order to understand how all this works it is necessary to understand the structure of DNA and RNA.
Replication of a cell’s DNA occurs before a cell prepares to undergo division—either mitosis or meiosis I.
It takes place in three(ish) steps.
- DNA unwinds from the histones.
- An enzyme called DNA helicase opens up the helix structure on a segment of DNA, breaking the bonds between the nitrogenous bases. It does this in a zipper-like fashion, leaving a replication fork behind it.
- Here’s where things get funky.
- On the 5’–3’ strand of the DNA, an enzyme called DNA polymerase slides towards the replication fork and uses the sequence of nitrogenous bases on that strand to make a new strand of DNA complementary to it (this means that its bases pair with the ones on the old strand).
- On the 3’–5’ strand, multiple DNA polymerases match up base pairs in partial segments, moving away from the replication fork. Later, DNA ligase connects these partial strands into a new continuous segment of DNA.
Want to know something neat? When a DNA molecule replicates, each of the resulting new DNA molecules contains a strand of the original, so neither is completely “new.” Also, new histones are made at the same time the DNA replicates so that the new strands of DNA can coil around them.
Interlude: RNA vs DNA
Before we discuss transcription and translation, the two processes key to protein synthesis, we need to talk about another kind of molecule: RNA.
RNA is a lot like DNA—it’s got a sugar-phosphate backbone and contains sequences of nitrogenous bases. However, there are a couple of vital differences between RNA and DNA:
- RNA has only one nucleotide chain. It looks like only one side of the DNA ladder.
- RNA has ribose as the sugar in its backbone.
- RNA has Uracil (U) instead of thymine.
- RNA is smaller than DNA. RNA caps out at around 10,000 bases long, while DNA averages about 100 million.
- RNA can leave the nucleus. In fact, it does most of its work in the cytoplasm.
There are several different types of RNA, each with different functions, but for the purposes of this article, we’re going to focus on messenger RNA (mRNA) and transfer RNA (tRNA).
Making a Protein, Part 1: Transcription
Transcription is the first phase of the protein-making process, even though the actual protein synthesis doesn’t happen until the second phase. Essentially, what happens during transcription is that an mRNA “copies down” the instructions for making a protein from DNA.
Image from A&P 6.
First, an enzyme called RNA polymerase opens up a section of DNA and assembles a strand of mRNA by “reading” the sequence of bases on one of the strands of DNA. If there’s a C on the DNA, there will be a G on the RNA (and vice versa). If there’s a T on the DNA, there will be an A on the RNA, but if there’s an A on the DNA, there will be a U (instead of a T) on the RNA. As the RNA polymerase travels down the string of DNA, it closes the helical structure back up after it.
Before the new mRNA can go out to deliver its protein fabrication instructions, it gets “cleaned up” by enzymes. They remove segments called introns and then splice the remaining segments, called exons, together. Exons are the sequences that actually code for proteins, so they’re the ones the mRNA needs to keep. You can think of introns like padding between the exons.
Also, remember how I mentioned that a single sequence of DNA can code for multiple proteins? Alternative splicing is the reason why: before the mRNA leaves the nucleus, its exons can be spliced together in different ways.
Making a Protein, Part 2: Translation
After it’s all cleaned up and ready to go, the mRNA leaves the nucleus and goes out to fulfill its destiny: taking part in translation, the second half of protein construction.
In the cytoplasm, the mRNA must interface with tRNA with the help of a ribosome. tRNA is a type of RNA that has a place to bind to free amino acids and a special sequence of three nitrogenous bases (an anticodon) that binds to the ribosome.
Ribosomes are organelles that facilitate the meeting of tRNA and mRNA. During translation, ribosomes and tRNA follow the instructions on the mRNA and assemble amino acids into proteins.
Image from A&P 6.
Each ribosome is made up of two subunits (large and small). These come together at the start of translation. Ribosomal subunits can usually be found floating around in the cytoplasm, but a ribosome will dock on the rough endoplasmic reticulum if the protein it’s making needs to be put into a transport vesicle. Ribosomes also have three binding sites where tRNA can dock: the A site (aminoacyl, first position), the P site (peptidyl, second position) and the E site (the exit position).
Ultimately, translation has three steps: initiation, elongation, and termination.
During initiation, the strand of mRNA forms a loop, and a small ribosomal subunit (the bottom of the ribosome) hooks onto it and finds a sequence of bases that signals it to begin transcription. This is called the start codon (AUG).
Then, a tRNA with UAC anticodon pairs with this start codon and takes up the second position (P) site of the ribosome. This tRNA carries the amino acid Methionine (Met). At this point, the large ribosomal subunit gets in position as well (it’s above the mRNA and the small subunit is below).
In the elongation phase, the fully-assembled ribosome starts to slide along the mRNA. Let’s say the next sequence of bases it encounters after the start codon is GCU. A tRNA molecule with the anticodon CGA will bind to the first position (A) site of the ribosome. The amino acid it’s carrying (alanine) forms a peptide bond with Met. Afterward, the CGA tRNA (carrying the Met-Ala chain) moves to the second position and the UAC tRNA enters the E binding site. The first position site is then ready to accept a new tRNA. This process keeps going until the ribosome gets to a “stop” codon.
Termination is pretty much what it sounds like. Upon reaching the “stop” codon, the tRNA that binds to the first position carries a protein called a release factor. The amino acid chain then breaks off from the ribosome, either going off into the cytosol or into the cisterna of the rough ER, and the ribosome disassembles. However, it might very well reassemble and go around the mRNA loop again. Also, multiple ribosomes can work on the same mRNA at once!
And those are the basics of DNA!
Here’s a handy chart you can look at if you need to remember the differences between transcription, translation, and replication:
|Replication||Nucleus||Duplicate a full strand of DNA||DNA|
|2 identical strands of DNA|
|Transcription||Nucleus||Use a strand of DNA to build a molecule of mRNA||DNA|
|Translation||Cytoplasm||Use mRNA to build an amino acid chain||mRNA|
RibosometRNA (and amino acids)
|Amino acid chain (protein)|
So now yo have a better understanding of how viruses reproduce we can go to the next step, how are they are spread. So we now know that a virus is not truly a living organism and is inert until it comes in contact with a supporting host.
WITHOUT GENETIC MUTATIONS, there would be no humans. There wouldn’t be any living beings at all—no mammals, insects, or plants, not even bacteria.
These tiny errors, which can happen at random each time a cell or virus copies itself, provide the raw materials for evolution to take place. Mutations create variation in a population, which allows natural selection to amplify the traits that help creatures thrive—stretching a giraffe’s long neck to reach high leaves, or camouflagingcaterpillars like poop to evade birds’ notice.
Amid a pandemic, however, the word “mutation” strikes a more ominous note. Viruses, though not technically alive, also mutate and evolve as they infect a hosts’ cells and replicate. The resulting tweaks to the virus’s genetic code could help it more readily hop between humans or evade the defenses of the immune system. Three such mutants of the virus SARS-CoV-2 have prompted experts to advocate for redoubled efforts to curb the coronavirus’s spread.
But these three versions of the virus are just a few among thousands of SARS-CoV-2 variants that have sprung up since the pandemic began. “We are creating variants like gangbusters right now because we have so many humans infected with SARS CoV-2,” says Siobain Duffy, a vial evolutionary biologist at Rutgers School of Environmental and Biological Sciences.
Many of these variants have since vanished. So why do some versions disappear, and why does the virus change in the first place? What mechanisms play puppet master for evolving viruses?
“The virus will change because that’s the underlying biology,” says Simon Anthony, a virologist working in infectious diseases at the University of California, Davis. “The question then becomes, are those changes significant to us?”
A successful virus is one that makes more of itself. But these tiny entities can’t do much on their own. Viruses are essentially coils of genetic material stuffed into a protein shell that’s sometimes blanketed in an outer envelope. In order to replicate, they must find a host. The virus binds to its target’s cells, injecting genetic material that hijacks the host’s cellular machinery to make a new generation of viral progeny.
But each time a new copy is made, there’s a chance that an error, or mutation, will occur. Mutations are like typos in the string of “letters” that make up a strand of DNA or RNA code. The majority of mutations are harmful to a virus or cell, limiting the spread of an error through a population. For example, mutations can tweak the building blocks of proteins encoded in the DNA or RNA, which alters a protein’s final shape and prevents it from doing its intended job, Duffy explains.
Many other mutations are neutral, having no effect on how efficiently a virus or cell reproduces. Such mutations sometimes spread at random, when a virus carrying the mutation spreads to a population that hasn’t been exposed to any variants of the virus yet. “It’s the only kid on the block,” Anthony says.
However, a select few mutations prove useful to a virus or cell. For example, some changes could make a virus better at jumping from one host to the next, helping it outcompete other variants in the area. This was what happened with the SARS-CoV-2 variant B.1.1.7 that was first identified in the United Kingdom but has now spread to dozens of countries around the world. Scientists estimate the variant is roughly 50 percent more transmissible than past forms of the virus, giving it an evolutionary edge.
Mutations may happen randomly, but the rate at which they occur depends on the virus. The enzymes that copy DNA viruses, called DNA polymerases, can proofread and fix errors in the resulting strings of genetic letters, leaving few mutations in each generation of copies.
But RNA viruses, like SARS-CoV-2, are the evolutionary gamblers of the microscopic world. The RNA polymerase that copies the virus’s genes generally lacks proofreading skills, which makes RNA viruses prone to high mutation rates—up to a million times greater than the DNA-containing cells of their hosts.
Coronaviruses have a slightly lower mutation rate than many other RNA viruses because they can do some light genetic proofreading. “But it’s not enough that it prevents these mutations from accumulating,” says virologist Louis Mansky, the director for the Institute for Molecular Virology at the University of Minnesota. So as the novel coronavirus ran amok around the world, it was inevitable that a range of variants would arise.
The true mutation rate of a virus is difficult to measure though. “Most of those mutations are going to be lethal to the virus, and you’ll never see them in the actively growing, evolving virus population,” Mansky says.
Instead, genetic surveys of sick people can help determine what’s known as the fixation rate, which is a measure of how often accumulated mutations become “fixed” within a viral population. Unlike mutation rate, this is measured over a period of time. So the more a virus spreads, the more opportunities it has to replicate, the higher its fixation rate will be, and the more the virus will evolve, Duffy says.
For SARS-CoV-2, scientists estimate that one mutation becomes established in the population every 11 days or so. But this process may not always happen at a steady pace.
In December 2020, the variant B.1.1.7 caught scientists’ attention when its 23 mutations seemed to suddenly crop up as the virus rampaged through Kent, England. Some scientists speculate that a chronically ill patient provided more opportunities for replication and mutation, and the use of therapies such as convalescent plasma may have pressured the virus to evolve. Not every change was necessarily useful to the virus, Duffy notes, yet some mutations that emerged allowed the variant to spread rapidly.
Mutations drive evolution, but they are not the only way that a virus can change over time. Some viruses, like influenza, have other ways to increase their diversity.
Influenza is made up of eight genetic segments, which can be rearranged—a process called reassortment—if multiple viruses infect a single cell to replicate at the same time. As the viral progeny are packaged into their protein capsules, the RNA segments from the parent viruses can be mixed and matched like viral Legos. This process can cause rapid shifts in the viral function. For example, reassortments of flu strains circulating in pigs, birds, and humans led to the 2009 H1N1 flu pandemic.
Unlike influenza, however, coronaviruses possess no physical segmentation to undergo reassortment. Coronaviruses can experience some shifts in function through a process known as recombination, when segments of one viral genome are spliced onto another by the enzyme making the viral copy. But researchers are still working to determine how important this process is for SARS-CoV-2’s evolution.
Understanding these evolutionary dynamics of SARS-CoV-2 is vital to ensure that treatments and vaccines keep pace with the virus. For now, the available vaccines are effective in preventing severe disease from all the viral variants.
And the study of SARS-CoV-2’s evolution could help answer another looming question: Where did the virus come from? While the disease likely originated from bats, there are still missing chapters in the tale of SARS-CoV-2’s leap to human hosts. Filling in these blanks could help us learn how to protect ourselves in the future.
Coronavirus in the U.S.: Where cases are growing and declining
As cases continue to rise, the path of the pandemic will be defined by the variants that are popping up around the world.
The variant first identified in the U.K. and known as B.1.1.7 has become the leading strain in the United States. It is deadlier and more contagious than the original SARS-CoV-2 virus that began the pandemic more than a year ago. Cases of this variant are rising particularly fast in California, Colorado, Florida, Georgia, Massachusetts, Michigan, Minnesota, Pennsylvania, and Tennessee. In addition, a so-called double mutant—which carries two mutations that have not been seen together before in the same variant—has now been reported in California. It was first identified in India, where it is responsible for between 15 and 20 percent of cases in the megacity of Mumbai. More studies are underway to determine how the double mutant behaves, and whether it is more contagious or harmful.
Overall, cases in the U.S. are rising in more than 24 states and Puerto Rico. The average number of cases was 5 percent higher in the last two-week period compared to the two weeks prior. But the variants are not all to blame for the growing number of cases. More people are traveling, and more states and counties are relaxing public health measures prematurely.
With this perfect storm of variants, travel, and more social gatherings, experts say it is more important than ever to get vaccinated. The vaccines work well against the B.1.1.7 variant and one that arose in California, known as B.1.429, which has now spread to 25 other countries. The good news is that the Biden administration says “all adult Americans will be eligible to be vaccinated by April 19”—two weeks ahead of the May 1 date previously announced.
Modes of transmission of the COVID-19 virus
Respiratory infections can be transmitted through droplets of different sizes: when the droplet particles are >5-10 μm in diameter they are referred to as respiratory droplets, and when then are <5μm in diameter, they are referred to as droplet nuclei.1 According to current evidence, COVID-19 virus is primarily transmitted between people through respiratory droplets and contact routes. In an analysis of 75,465 COVID-19 cases in China, airborne transmission was not reported.
Droplet transmission occurs when a person is in in close contact (within 1 m) with someone who has respiratory symptoms (e.g., coughing or sneezing) and is therefore at risk of having his/her mucosae (mouth and nose) or conjunctiva (eyes) exposed to potentially infective respiratory droplets. Transmission may also occur through fomites in the immediate environment around the infected person. Therefore, transmission of the COVID-19 virus can occur by direct contact with infected people and indirect contact with surfaces in the immediate environment or with objects used on the infected person (e.g., stethoscope or thermometer).
Airborne transmission is different from droplet transmission as it refers to the presence of microbes within droplet nuclei, which are generally considered to be particles <5μm in diameter, can remain in the air for long periods of time and be transmitted to others over distances greater than 1 m.
In the context of COVID-19, airborne transmission may be possible in specific circumstances and settings in which procedures or support treatments that generate aerosols are performed; i.e., endotracheal intubation, bronchoscopy, open suctioning, administration of nebulized treatment, manual ventilation before intubation, turning the patient to the prone position, disconnecting the patient from the ventilator, non-invasive positive-pressure ventilation, tracheostomy, and cardiopulmonary resuscitation.
Based on the available evidence, including the recent publications mentioned above, WHO continues to recommend droplet and contact precautions for those people caring for COVID-19 patients. WHO continues to recommend airborne precautions for circumstances and settings in which aerosol generating procedures and support treatment are performed, according to risk assessment. These recommendations are consistent with other national and international guidelines, including those developed by the European Society of Intensive Care Medicine and Society of Critical Care Medicine and those currently used in Australia, Canada, and United Kingdom.
Transmission by Function and Activities
How the coronavirus infects cells — and why Delta is so dangerous
Scientists are unpicking the life cycle of SARS-CoV-2 and how the virus uses tricks to evade detection.
The coronavirus sports a luxurious sugar coat. “It’s striking,” thought Rommie Amaro, staring at her computer simulation of one of the trademark spike proteins of SARS-CoV-2, which stick out from the virus’s surface. It was swathed in sugar molecules, known as glycans.
“When you see it with all the glycans, it’s almost unrecognizable,” says Amaro, a computational biophysical chemist at the University of California, San Diego.
Many viruses have glycans covering their outer proteins, camouflaging them from the human immune system like a wolf in sheep’s clothing. But last year, Amaro’s laboratory group and collaborators created the most detailed visualization yet of this coat, based on structural and genetic data and rendered atom-by-atom by a supercomputer. On 22 March 2020, she posted the simulation to Twitter. Within an hour, one researcher asked in a comment: what was the naked, uncoated loop sticking out of the top of the protein?
Amaro had no idea. But ten minutes later, structural biologist Jason McLellan at the University of Texas at Austin chimed in: the uncoated loop was a receptor binding domain (RBD), one of three sections of the spike that bind to receptors on human cells (see ‘A hidden spike’).
In Amaro’s simulation, when the RBD lifted up above the glycan cloud, two glycans swooped in to lock it into place, like a kickstand on a bicycle. When Amaro mutated the glycans in the computer model, the RBD collapsed. McLellan’s team built a way to try the same experiment in the lab, and by June 2020, the collaborators had reported that mutating the two glycans reduced the ability of the spike protein to bind to a human cell receptor — a role that no one has previously recognized in coronaviruses, McLellan says. It’s possible that snipping out those two sugars could reduce the virus’s infectivity, says Amaro, although researchers don’t yet have a way to do this.
Since the start of the COVID-19 pandemic, scientists have been developing a detailed understanding of how SARS-CoV-2 infects cells. By picking apart the infection process, they hope to find better ways to interrupt it through improved treatments and vaccines, and learn why the latest strains, such as the Delta variant, are more transmissible.
What has emerged from 19 months of work, backed by decades of coronavirus research, is a blow-by-blow account of how SARS-CoV-2 invades human cells (see ‘Life cycle of the pandemic coronavirus’). Scientists have discovered key adaptations that help the virus to grab on to human cells with surprising strength and then hide itself once inside. Later, as it leaves cells, SARS-CoV-2 executes a crucial processing step to prepare its particles for infecting even more human cells. These are some of the tools that have enabled the virus to spread so quickly and claim millions of lives. “That’s why it’s so difficult to control,” says Wendy Barclay, a virologist at Imperial College London.
Barbed and ready
It starts with the spikes. Each SARS-CoV-2 virion (virus particle) has an outer surface peppered with 24–40 haphazardly arranged spike proteins that are its key to fusing with human cells. For other types of virus, such as influenza, external fusion proteins are relatively rigid. SARS-CoV-2 spikes, however, are wildly flexible and hinge at three points, according to work published in August 2020 by biochemist Martin Beck at the Max Planck Institute of Biophysics in Frankfurt, Germany, and his colleagues.
That allows the spikes to flop around, sway and rotate, which could make it easier for them to scan the cell surface and for multiple spikes to bind to a human cell. There are no similar experimental data for other coronaviruses, but because spike-protein sequences are highly evolutionarily conserved, it is fair to assume the trait is shared, says Beck.
Early in the pandemic, researchers confirmed that the RBDs of SARS-CoV-2 spike proteins attach to a familiar protein called the ACE2 receptor, which adorns the outside of most human throat and lung cells. This receptor is also the docking point for SARS-CoV, the virus that causes severe acute respiratory syndrome (SARS). But compared with SARS-CoV, SARS-CoV-2 binds to ACE2 an estimated 2–4 times more strongly, because several changes in the RBD stabilize its virus-binding hotspots.
Worrying variants of SARS-CoV-2 tend to have mutations in the S1 subunit of the spike protein, which hosts the RBDs and is responsible for binding to the ACE2 receptor. (A second spike subunit, S2, prompts viral fusion with the host cell’s membrane.)
The Alpha variant, for example, includes ten changes in the spike-protein sequence, which result in RBDs being more likely to stay in the ‘up’ position. “It is helping the virus along by making it easier to enter into cells,” says Priyamvada Acharya, a structural biologist at the Duke Human Vaccine Institute in Durham, North Carolina, who is studying the spike mutations.
The Delta variant, which is now spreading around the world, hosts multiple mutations in the S1 subunit, including three in the RBD that seem to improve the RBD’s ability to bind to ACE2 and evade the immune system.
Once the viral spikes bind to ACE2, other proteins on the host cell’s surface initiate a process that leads to the merging of viral and cell membranes (see ‘Viral entry up close’).
The virus that causes SARS, SARS-CoV, uses either of two host protease enzymes to break in: TMPRSS2 (pronounced ‘tempress two’) or cathepsin L. TMPRSS2 is the faster route in, but SARS-CoV often enters instead through an endosome — a lipid-surrounded bubble — which relies on cathepsin L. When virions enter cells by this route, however, antiviral proteins can trap them.
SARS-CoV-2 differs from SARS-CoV because it efficiently uses TMPRSS2, an enzyme found in high amounts on the outside of respiratory cells. First, TMPRSS2 cuts a site on the spike’s S2 subunit. That cut exposes a run of hydrophobic amino acids that rapidly buries itself in the closest membrane — that of the host cell. Next, the extended spike folds back onto itself, like a zipper, forcing the viral and cell membranes to fuse.
The virus then ejects its genome directly into the cell. By invading in this spring-loaded manner, SARS-CoV-2 infects faster than SARS-CoV and avoids being trapped in endosomes, according to work published in April by Barclay and her colleagues at Imperial College London.
The virus’s speedy entry using TMPRSS2 explains why the malaria drug chloroquine didn’t work in clinical trials as a COVID-19 treatment, despite early promising studies in the lab. Those turned out to have used cells that rely exclusively on cathepsins for endosomal entry. “When the virus transmits and replicates in the human airway, it doesn’t use endosomes, so chloroquine, which is an endosomal disrupting drug, is not effective in real life,” says Barclay.
The discovery also points to protease inhibitors as a promising therapeutic option to prevent a virus from using TMPRSS2, cathepsin L or other proteases to enter host cells. One TMPRSS2 inhibitor, camostat mesylate, which is approved in Japan to treat pancreatitis, blocked viral entry into lung cells, but the drug did not improve patients’ outcomes in an initial clinical trial.
“From my perspective, we should have such protease inhibitors as broad antivirals available to fight new disease outbreaks and prevent future pandemics at the very beginning,” says Stefan Pöhlmann, director of the Infection Biology Unit at the German Primate Center in Göttingen, who has led research on ACE2 binding and the TMPRSS2 pathway.
The next steps of infection are murkier. “There are a lot more black boxes once you are inside the cell,” says chemist Janet Iwasa at the University of Utah in Salt Lake City, who is developing an annotated animation of the viral life cycle. “There’s more uncertainty, and competing hypotheses.”
After the virus shoots its RNA genome into the cell, ribosomes in the cytoplasm translate two sections of viral RNA into long strings of amino acids, which are then snipped into 16 proteins, including many involved in RNA synthesis. Later, more RNAs are generated that code for a total of 26 known viral proteins, including structural ones used to make new virus particles, such as the spike, and other accessory proteins. In this way, the virus begins churning out copies of its own messenger RNA. But it needs the cell’s machinery to translate those mRNAs into proteins.
Coronaviruses take over that machinery in many ways. Virologist Noam Stern-Ginossar and her team at the Weizmann Institute of Science in Rehovot, Israel, zoomed in on three mechanisms by which SARS-CoV-2 suppresses the translation of host mRNA in favour of its own. None are exclusive to this virus, but the combination, speed and magnitude of the effects seem unique, says Stern-Ginossar.
First, the virus eliminates the competition: viral protein Nsp1, one of the first proteins translated when the virus arrives, recruits host proteins to systematically chop up all cellular mRNAs that don’t have a viral tag. When Stern-Ginossar’s team put that same tag on the end of a host mRNA, the mRNA was not chopped up.
Second, infection reduces overall protein translation in the cell by 70%. Nsp1 is again the main culprit, this time physically blocking the entry channel of ribosomes so mRNA can’t get inside, according to work from two research teams. The little translation capacity that remains is dedicated to viral RNAs, says Stern-Ginossar.
Finally, the virus shuts down the cell’s alarm system. This happens in numerous ways, but Stern-Ginossar’s team identified one clear mechanism for SARS-CoV-2: the virus prevents cellular mRNA from getting out of the nucleus, including instructions for proteins meant to alert the immune system to infection. A second team confirmed this finding, and again pointed to Nsp1: the protein seems to jam up exit channels in the nucleus so nothing can escape.
Because gene transcripts can’t get out of the nucleus, the infected cells don’t release many interferons — these are signalling proteins that alert the immune system to the presence of a virus. SARS-Cov-2 is particularly efficient at shutting down this alarm system: compared with other respiratory viruses, including SARS-CoV and respiratory syncytial virus, SARS-CoV-2 infection induces significantly lower levels of interferons. And this June, researchers reported mutations in the Alpha variant that seem to enable it to subdue interferon production even more efficiently.
“It’s clear that SARS-CoV-2 is a very fast virus that has a unique ability to prevent our immune system from recognizing and combating infection in the first stages,” says Stern-Ginossar. By the time the immune system does realize there is a virus, there is so much of it that immune-response proteins sometimes flood the bloodstream at a faster rate than normal — which can cause damage. Doctors saw early in the pandemic that some people with COVID-19 who become very ill are harmed by an overactive immune response to SARS-CoV-2, as well as by the virus itself. Some proven treatments work by dampening down this immune response.
Once the virus has taken over host translation, it starts a home makeover, extensively remodelling the interior and exterior of the cell to its needs.
First, some of the newly made viral spike proteins travel to the surface of the cell and poke out of the host-cell membrane. There, they activate a host calcium-ion channel, which expels a fatty coating onto the outside of the cell — the same coating found on cells that naturally fuse together, such as muscle cells. At this point, the infected cell fuses to neighbouring cells expressing ACE2, developing into massive individual respiratory cells filled with up to 20 nuclei.
These fused structures, called syncytia, are induced by viral infections such as HIV and herpes simplex virus, but not by the SARS virus, says molecular biologist Mauro Giacca at King’s College London, who led the team that published the finding in April. He hypothesizes that forming syncytia allows infected cells to thrive for long periods of time, churning out more and more virions. “This is not a hit-and-run virus,” he says. “It persists.” A second team, led by researcher Qiang Sun at the Chinese Academy of Medical Sciences in Beijing, found that some COVID-19-infected cells even form syncytia with lymphocytes — one of the body’s own immune cells. This is a known mechanism of immune evasion by tumor cells, but not by viruses. It suggests that infected cells avoid immune detection by simply grabbing on to and merging with nearby immune scouts.
On the inside of the cell, even more change is occurring. Like other coronaviruses, SARS-CoV-2 transforms the long, thin endoplasmic reticulum (ER), a network of flat membranes involved in protein synthesis and transport, into double-membrane spheres, as if the ER were blowing bubbles. These double-membrane vesicles (DMVs) might provide a safe place for viral RNA to be replicated and translated, shielding it from innate immune sensors in the cell, but that hypothesis is still being investigated.
Proteins involved in making DMVs could be good drug targets, because they seem to be necessary for viral replication. For instance, a host protein, TMEM41B, is needed to mobilize cholesterol and other lipids to expand the ER membranes so that all the virus parts will fit inside. “When you take TMEM41B out, it has a major impact on infection,” says Vineet Menachery, a coronavirus researcher at the University of Texas Medical Branch in Galveston, who was involved in the research. The coronavirus transmembrane protein Nsp3 could also be a target: it creates a crown-like pore in the walls of the DMVs to shuttle out newly made viral RNA.
Most viruses that have an outer wrapping, known as an envelope, form this feature by assembly directly at the edge of the cell, co-opting some of the cell’s own plasma membrane on their way out. But newly made coronavirus proteins take a different path.
For years, evidence has suggested that coronaviruses are transported out of the cell through the Golgi complex, an organelle that works like a post office, packaging molecules in membranes and sending them off to other parts of the cell. There, the virus forms a lipid envelope from the Golgi complex’s membrane; newly formed virions are then carried inside Golgi vesicles to the cell surface, where they are spat out of the cell, says virologist and cell biologist Carolyn Machamer at Johns Hopkins University in Baltimore, Maryland, who has studied coronaviruses for 30 years.
But in December, cell biologist Nihal Altan-Bonnet at the US National Heart, Lung, and Blood Institute in Bethesda, Maryland, and her colleagues reported that they had detected coronaviruses leaving the cell through lysosomes — cellular rubbish bins full of enzymes that break down cell parts. Blocking the Golgi-based secretory pathway didn’t seem to affect the amount of infectious virus being released, says Altan-Bonnet. Her team’s evidence suggests that viral proteins form an envelope by budding into the ER, then take over lysosomes to get out of the cell. The researchers are currently testing inhibitors that block the lysosomal exit process as potential antiviral candidates.
Leaving a cell through either the Golgi or lysosomes is slow and inefficient compared with budding out of a plasma membrane, so scientists don’t know why SARS-CoV-2 does it. Machamer suspects that the lipid composition of a Golgi- or lysosome-derived envelope is somehow more beneficial to the virus than one from the plasma membrane. “If we understood this part a little bit better, there would be great opportunities for novel antiviral therapeutics,” she says.
On the way out of the cell, one more event makes this virus into an infectious juggernaut: a quick snip at a site of five amino acids prepares the virus to strike its next target.
Where other coronaviruses have a single arginine amino acid at the junction of the S1 and S2 subunits of the spike, SARS-CoV-2 has a line of five amino acids: proline, arginine, arginine, alanine and arginine. “Because the site was unusual, we focused on it, and it turned out that, yes, the site is essential for invasion of lung cells,” says Pöhlmann. In May 2020, he and his colleagues reported that a host-cell protein called furin recognizes and clips that string of amino acids — and the cut is “essential” for the virus to enter human lung cells efficiently.
It’s not the first time that researchers have identified a furin cleavage site on a virus; highly pathogenic avian influenza viruses also have it, says Barclay. When a colleague sent Barclay a strain of SARS-CoV-2 in culture that had spontaneously lost the furin cleavage site, her team found that ferrets infected with this strain shed viral particles in lower amounts than did those infected with the pandemic strain, and did not transmit the infection to nearby animals9. At the same time as Barclay’s team reported its results in a September 2020 preprint, a study in the Netherlands also found that coronavirus with an intact furin cleavage site enters human airway cells faster than do those without it.
Furin is suspected to cut the site at some point during virion assembly, or just before release. The timing might explain why the virus exits through the Golgi or lysosomes, says Tom Gallagher, a virologist at Loyola University Chicago in Illinois. “The virus, once assembled, moves into an organelle where it can be bathed in the presence of the furin protease.”
By snipping the bond between the S1 and S2 subunits, the furin cut loosens up virion spike proteins so that during cell entry they respond to a second cut by TMPRSS2, which exposes the hydrophobic area that rapidly buries itself in a host-cell membrane, says Gallagher. If spikes are not pre-clipped by furin —and they aren’t always — they bypass TMPRSS2, and enter through the slower endosomal pathway, if at all.
Two coronavirus variants, Alpha and Delta, have altered furin cleavage sites. In the Alpha variant, the initial proline amino acid is changed to a histidine (P681H) ; in the Delta variant, it is changed to an arginine (P681R). Both changes make the sequence less acidic, and the more basic the string of amino acids, the more effectively furin recognizes and cuts it, says Barclay. “We would hypothesize that this is the virus getting even better at transmitting.”
More furin cuts mean more spike proteins primed to enter human cells. In SARS-CoV, less than 10% of spike proteins are primed, says Menachery, whose lab group has been quantifying the primed spike proteins but is yet to publish this work. In SARS-CoV-2, that percentage rises to 50%. In the Alpha variant, it’s more than 50%. In the highly transmissible Delta variant, the group has found, greater than 75% of spikes are primed to infect a human cell.
The scientific community is still scratching the surface of its understanding of SARS-CoV-2. Key unknowns include the number of ACE2 receptors needed to bind to each spike protein; when exactly the S2 site is cleaved by TMPRSS2; and the number of spikes needed for virus–cell membrane fusion, says McLellan — and that’s just for entry. In April 2020, a team at the University of California, San Francisco, identified at least 332 interactions between SARS-CoV-2 and human proteins.
It is not easy to keep pace with the quickly mutating virus. Most mutations so far are associated with how effectively the virus spreads, not with how much the virus damages the host, experts agree. This month, a study reported that the Delta variant grew more rapidly and at higher levels inside people’s lungs and throats than did earlier versions of the virus.
But it is not yet certain how Delta’s mutations have supercharged the variant in this way, says Stern-Ginossar. “This is something many labs are trying to figure out.”
Precautions to take to prevent transmission:
So we know that it can be spread by droplet, suspected airborne and contact.
Lets discuss the contact part first. A recent study found that the COVID-19 coronavirus can survive up to four hours on copper, up to 24 hours on cardboard, and up to two to three days on plastic and stainless steel. Cleaning surfaces is simple and does not require expensive industrial cleaning agents. Diluted household bleach solutions can be used if appropriate for the surface. Unexpired household bleach will be effective against coronaviruses when properly diluted: Use bleach containing 5.25%–8.25% sodium hypochlorite. Do not use a bleach product if the percentage is not in this range or is not specified. Clean your hands often, either with soap and water for 20 seconds or a hand sanitizer that contains at least 60% alcohol. If you are going to continuously be in contact with contaminated surfaces wear disposable gloves. You may ask if it is airborne, why do we have to worry about surfaces? The problem is that people constantly touch there faces. If the virus is on your hands and you (don’t get grossed out, everybody does it) you pick your nose, you have now been infected.
Wearing masks: Surgical masks protect the individual from drop transmission. Since viruses are very small, you need a N95 mask to stop that form of transmission, which is called airborne. The distances vary for these transmissions, typically droplet is 3 to 6 feet, airborne particles can travel much further, so social distancing is truly problematic and anecdotal at best. All you can truly do is to lessen the risk. With both individuals wearing basic masks the risks of transmission are lessened but not eliminated. You also have to factor in length of contact. If you just have incidental contact, like say in a grocery store, the chances of having transmission are negligible. I work in the ICU. I routinely come in contact with Covid-19 positive patients for prolonged periods of time, thereby greatly increasing the risks of transmission. So I have to take care to stay healthy. If I am going to come in direct contact I wear disposable gowns. I also wear a N95 Mask and full faceshield and of course gloves. Some people wear full head gear with filtered air flow. The problem there is that multiple people wear this gear. Staff have become infected because of poor sanitizing of gear. I use my own face shield.
So if you want to guarantee total safety you can wear this mask and this shield and don’t forget gloves. But let me ask you a question, do you want to live this way?
This is an anecdotal update on the prevention of the spread of covid. In the last month there has been an uptick in cases, and yes even deaths. Many hospitals are becoming over run by new cases. I have a feeling it is the climate. It appears that covid like its flu virus brother is happier in the colder climate. This theory was proposed last spring. So all we can do is to continue being safe. Though I have a few ideas of my own on how to do this. I have been taking care of covid patients since march of this year, I have watched many of my colleagues become infected with the virus. These individuals have all been wearing N95 masks and other other PPE, included gowns and shoe covers. I have been lucky. While I do my best to protect myself, I don’t go to the extremes that many of them do. Though In the last few months I have started wearing a face shield, but I have stopped wearing an N95 mask and I am wearing a three layer cloth mask instead. I find it much more comfortable to wear for 12 hours. I was getting skin breakdown on my nose and ears from the more restrictive masks. You may ask me why I feel comfortable doing this? I believe I have the answer. The reason Why I believe that I haven’t been infected is that I wear glasses. I believe that people are getting infected via the vascular tissue surrounding the eyes. Stop and think about it, people have been wearing masks for the better part of 5 months in this country, yet the numbers keep on jumping all over. But how many people wear glasses all the time, like I do? We now have 50 employees in our hospital infected with covid, they all wear masks while at work. However, I am still covid free. I am 57, have HTN, and close to being pre-diabetic and I am over weight. And I take care of 2 and sometimes 3 covid positive patients a night for 12 hours. I am in close contact with these patients for hours at a time. I do wear gloves religiously and wash the hell out of my hands. When I get home I immediately place all my clothes in the washer, so my wife doesn’t have to touch them, and my shoes have a designated spot in the entrance of the house. My wife is covid free as well. So you do the math. Maybe people should wear protective goggles. I am sure somebody could come up with some stylish models that would be popular. I think the alternative is certainly better than more lockdowns. (update 12/5/2020)
To help prevent the spread of COVID-19, everyone should:
+Clean your hands often, either with soap and water for 20 seconds or a hand sanitizer that contains at least 60% alcohol.
+Avoid close contact with people who are sick. Put distance between yourself and other people (at least 6 feet).
+ Avoid large events and mass gatherings.
+Stay home as much as possible and keep distance between yourself and others (within about 6 feet, or 2 meters), especially if you have a higher risk of serious illness. Keep in mind some people may have COVID-19 and spread it to others, even if they don’t have symptoms or don’t know they have COVID-19.
+Stay home from work, school and public areas if you’re sick, unless you’re going to get medical care. Avoid public transportation, taxis and ride-sharing if you’re sick.
+Cover your mouth and nose with a mask when around others.
+Avoid touching your eyes, nose and mouth.
+Avoid sharing dishes, glasses, towels, bedding and other household items if you’re sick.
+Avoid sharing dishes, glasses, towels, bedding and other household items if you’re sick.
+Cover your cough or sneeze with a tissue, then throw the tissue in the trash.
+Wash your hands often with soap and water for at least 20 seconds, or use an alcohol-based hand sanitizer that contains at least 60% alcohol.
+Clean and disinfect frequently touched objects and surfaces daily.
+CDC recommends that people wear masks in public settings and when around people outside of their household, especially when other social distancing measures are difficult to maintain.
+Masks may help prevent people who have COVID-19 from spreading the virus to others. Learn more on cdc.gov
If you’re planning to travel, first check the CDC and WHO websites for updates and advice. Also look for any health advisories that may be in place where you plan to travel. You may also want to talk with your doctor if you have health conditions that make you more susceptible to respiratory infections and complications.
It has been determined that covid-19 is temperature sensitive. Temperatures of over 130 degrees kills the virus. if you believe you have been infected by covid-19, it typically resides in the sinuses for a time before it eventually gets into the blood stream. So it might be possible to eliminate the virus before you are infected by using a vics vaporizer with medicated steam. This might actually kill it, since the temperature of the steam is greater than 130 degrees and the vics might be effective as well. There are no studies being done on this as far as I know. This is me, just thinking outside the box. But what do you have to lose, right?
How It is detected?
A simple swab test of your nares and a 15 minute if you are lucky enough to have access to the rapid test.
Symptoms of covid-19:
Every virus affects the body in different ways.
Symptoms may appear 2-14 days after exposure to the virus. People with these symptoms may have COVID-19:
+Fever or chills
+CoughShortness of breath or difficulty breathing
+Fatigue Muscle or body aches
+New loss of taste or smell
+Congestion or runny nose
+Nausea or vomiting
Look for emergency warning signs for COVID-19. If someone is showing any of these signs, seek emergency medical care immediately:
+Trouble breathing or Shortness of Breath
+Persistent pain or pressure in the chest
+ Pink eye (conjunctivitis)
+Inability to wake or stay awake
+Bluish lips or face
Comorbidities that increase the lethality of the Disease:
- Serious heart diseases, such as heart failure, coronary artery disease or cardiomyopathy
- Chronic obstructive pulmonary disease (COPD)
- Type 2 diabetes
- Severe obesity
- Chronic kidney disease
- Sickle cell disease
- Weakened immune system from solid organ transplants
Other conditions may increase the risk of serious illness, such as:
- Liver disease
- Chronic lung diseases such as cystic fibrosis
- Brain and nervous system conditions
- Weakened immune system from bone marrow transplant, HIV or some medications
- Type 1 diabetes
- High blood pressure
Can COVID-19 alter your personality? Here’s what brain research shows.
Alzheimer’s, Parkinson’s, and traumatic brain injury can cause changes in behavior by altering brain anatomy. Now it seems the coronavirus can too.
At the height of the COVID-19 tsunami that engulfed New York City in early 2020, a highly respected emergency room doctor, Lorna Breen, died by suicide. She had been serving as medical director at Manhattan’s NewYork Presbyterian Allen Hospital, and she was regarded as brilliant, energetic, and organized. She had no history of mental illness. But that changed after Breen contracted the virus.
The 49-year-old doctor first showed symptoms on March 18. After a 10-day illness, she returned to work. Her family was alarmed: She was confused, hesitant, nearly catatonic, exhausted. Something was wrong. They brought her home to Charlottesville, and Breen checked into a psychiatric ward at University of Virginia Medical Center. Soon after she was released on April 26, she took her own life.
“She had COVID, and I believe that it altered her brain,” her sister Jennifer Feist said on NBC’s Today show.
At the time, doctors were just learning that this new coronavirus doesn’t target only the lungs and heart. It also impacts other organs, including the brain. “People arrived at the hospital with severe depression, hallucinations, or paranoia—and then we diagnosed them with COVID,” says Maura Boldrini, a neuroscientist and psychiatrist at Manhattan’s Columbia University Irving Medical Center.
Now, almost two years into the pandemic, it’s become clear that neurological problems from COVID-19 can linger or intensify. After recovering from the virus, an alarming number of patients remain shrouded in brain fog, suffering from anxiety or depression, unable to think straight or hold on to memories, and fumbling for words. Not all had been hospitalized; some had only mild infections.
Today these neurological problems are an established element of a larger syndrome known as long COVID that includes at least 203 symptoms in 10 organ systems.
Boldrini notes that some long COVID symptoms mirror those caused by various chronic brain- and personality-altering conditions, including other viral infections, traumatic brain injuries, and neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s. These conditions can radically change how people experience, interpret, and understand the world; destabilize emotions; and influence how people think about themselves or interact with others.
While little is known about the mechanisms behind many of these symptoms, researchers increasingly believe that inflammation may play a key role. With COVID-19, a storm of inflammatory cytokine proteins can trigger an out-of-control immune response that might permanently damage or destroy brain cells.
And with damage to the brain, Boldrini says, “we may not be the same person anymore.”
Personality, behavior, and the brain
Human personality is the set of deeply ingrained characteristics and habits that influence how people think, feel, and behave. It’s created by a complex interaction of nature and nurture: Inherited traits encoded in our DNA are influenced by our social environment and modified during early developmental experiences.
“The brain is obviously so important in defining who we are. It’s our ego; it’s everything about our identity,” says Ann McKee, who studies repetitive head trauma as a neurologist, neuropathologist, and head of Boston University’s Chronic Traumatic Encephalopathy (CTE) Center. “It’s a highly specialized organ, with each part doing fantastically specific things.”
While basic personality tends to remain constant throughout adult life, conditions that disrupt brain function can induce extreme shifts in personality—and evidence is mounting that this happens for some people who contract COVID-19.
Some patients have developed impulsive or irrational behavior, like Ivan Agerton. The 50-year-old former Marine and documentary photographer experienced psychosis in early 2021 after he recovered from a COVID-19 infection. He grew paranoid, terrified that people were following him and convinced that a SWAT officer was encamped outside his Seattle home. He was ultimately hospitalized in a psychiatric ward, twice.
For some patients, this so-called COVID psychosis resolves with time. By June, Agerton said he’d fully recovered. But no one knows how long such COVID-induced symptoms might persist. A study of 395 people who were hospitalized with COVID-19 found that 91 percent had cognitive issues, fatigue, depression, anxiety, sleep problems, or struggled with routine activities six months after they returned home.
Healthcare workers and researchers are on the hunt for ways to treat these long-lasting symptoms, and that starts with figuring out why they happen in the first place.
Recognizing changes in the brain
In 1906 psychiatrist and neuroanatomist Alois Alzheimer detailed the results of a brain autopsy on a 55-year-old woman named Auguste D. In the years before her death, she’d progressively lost her connection to reality, becoming an aggressive insomniac beset by increasing paranoia and suspicions about her family. She’d also suffered profound loss of memory.
Upon examination, Alzheimer observed that her brain had shrunk dramatically. It was riddled with sticky clumps of plaque, abnormal deposits that nearly 80 years later would become the hallmark of Alzheimer’s disease. These jumbles of beta-amyloid protein had accumulated between neurons in the brain. We now know that they block electrical signals from reaching other parts of the brain, muscles, and organs. Alzheimer also found tangles of another protein, tau, that also disrupted communication between neurons.
As neurons stop functioning and die, the brain shrinks and a person’s behavior becomes more erratic. With fewer neurons in the brain’s learning and memory regions, these functions begin to suffer, Boldrini says. People with Alzheimer’s disease forget where they put things and become disoriented. They become easily upset, confused, angered, belligerent, or lash out at loved ones or caregivers, whom they may not recognize.
Damage to the cerebral cortex then impacts language, reasoning, and social behavior; it ultimately spreads and destroys much of the brain. The dementia becomes debilitating, and the disease eventually proves fatal, says Antonio Terracciano, a professor in the department of geriatrics at Florida State University.
Alois Alzheimer’s discovery was a milestone in neurological research, linking changes in behavior to changes in the brain. Since Alzheimer’s seminal observations, researchers have recognized that many diseases can spark shifts in personality or mood disorders.
Huntington’s, an inherited disease that breaks down neurons in a brain region called the basal ganglia, can cause people to lose their inhibitions or become more impulsive. It’s part of the reason why suicide rates among people with Huntington’s are up to 10 times the national average.
In Parkinson’s disease, which is likely caused by a combination of genetics and environmental factors, neurons that produce the neurotransmitter dopamine break down or die. Without enough dopamine, the disease’s hallmark tremors appear, and movements become slow.
Parkinson’s also lowers levels of a neurotransmitter called serotonin, which regulates mood, appetite, and sleep. These changes in brain chemistry can cause neurological symptoms that frequently manifest years before the tremors begin, says Jeff Bronstein, who directs the Movement Disorders Program at the David Geffen School of Medicine at University of California, Los Angeles.
Patients may grow anxious, struggle to concentrate or shift between tasks. About half of patients grow depressed, Bronstein says. He has also seen patients slump into apathy, pulling into themselves. As their speech suffers or they grow forgetful, they avoid conversations with family and friends, becoming more withdrawn as depression deepens.
Uncharacteristic irritability or mood swings can also signal Lyme disease. This bacterial infection from a tick bite causes inflammation that can set off swelling of the brain or its lining, inducing short-term memory loss, difficulty focusing, and symptoms such as anxiety and depression.
Many viruses are already known to wreak havoc in the brain. Boldrini recounted what happened in the early days of the HIV epidemic, before antiviral medications were available that blocked replication of the pathogen and reduced viral load.
“We used to see people who had HIV-AIDS with paranoia, hallucinations, but also cognitive symptoms, memory problems, concentration problems,” Boldrini says. As the viral infection spread through the brain, the membranes of the brain and spinal column swelled, and this AIDS dementia complex worsened.
Many of the changes in behavior seen in COVID long-haulers also mirror those from traumatic brain injuries incurred in a car crash, a concussion from a contact sport like football or rugby, or from wartime military service. Damage to the frontal lobes, which sit behind the forehead, can impair executive functioning: organizing, planning, and multitasking. Memory and self-awareness may slip, and patients may not be aware of what they’ve lost.
Some head injury survivors lose emotional control, says Boston University’s McKee, including young, previously easy-going people. She’s seen cognitive changes in athletes as young as 17 who play contact sports, and playing football before the age of 12 increases the odds.
The COVID connection
One common theme among these conditions is a sustained inflammatory process. It’s been implicated in head injuries and in neurological diseases such as Alzheimer’s, where it causes additional loss of brain cells and exacerbates the formation of plaques.
When the immune system launches an attack against a virus or another invader, waves of inflammatory cells circulate through the bloodstream like foot soldiers. With COVID-19 and other conditions, those immune cells may permeate the normally protective blood-brain barrier. If inflammation gets out of hand, the process may kill neurons, Bronstein says.
Kriegstein notes that “most of the neurological manifestations of SARS-CoV-2 infection appear to be the result of indirect effects likely mediated through inflammation or immune responses.”
Inflammation also seems to interfere with brain metabolism. Researchers suspect that the process interrupts the flow of serotonin and prompts the body to instead produce a cascade of substances that are toxic to neurons.
Boldrini was among the first to examine the brains of humans and research animals who’d died of COVID-19 to see what was happening on a cellular level. Under a microscope, Boldrini and her team examined brain samples stained with brightly colored dyes to characterize different types of cells. They observed changes to the hippocampus, a brain region that is embedded deep in the temporal lobe and plays a major role in learning and memory. She and her team counted about a tenth as many new neurons as are normally present in the hippocampus.
“The brain fog made a lot of sense to me when I saw that there is loss of these neurons from COVID,” Boldrini says. The team also found damage to the medulla, which controls respiration and movement. Boldrini notes that they will continue to examine other brain regions for possible damage.
Other researchers using brain imaging data from the U.K. recently discovered evidence of tissue damage, a thinner cortex, and loss of gray matter in people who had tested positive for the virus. The authors noted that there was “significantly greater cognitive decline” in patients who had been hospitalized.
In addition to causing inflammation, the virus may be able to directly infect brain cells. “We discovered evidence that certain cells within the brain are capable of being infected with SARS-CoV-2, where the virus can replicate and infect other cell types,” says Joseph G. Gleeson, a neurologist at the University of California, San Diego.
Other researchers have found that key support cells in the brain called astrocytes were the main cell types vulnerable to infection, says Madeline Andrews, a postdoctoral neuroscience scholar at the University of California, San Francisco. These star-shaped cells, abundant in the brain and spinal cord, regulate how neurons communicate, ensure that the barrier between the brain and the rest of the body is intact, and more.
“Infected astrocytes may function differently and might not be able to maintain their typical roles in healthy brain homeostasis,” says Andrews.
The virus that causes COVID-19 may also reduce blood flow to neurons by constricting capillaries—tiny blood vessels—or by interfering with their function. This may explain why the virus induces strokes: by starving the brain of oxygen. “The brain is very delicate, and alterations to blood flow or cellular health can lead to permanent changes to brain function,” Gleeson says.
Many questions remain, though, including how to prevent the virus from causing significant cognitive damage. The key, Boldrini says, is to not let the immune system fight too long or too aggressively.
Various treatments are being used to prevent the immune system from overreacting. Remdesivir, an intravenous antiviral treatment is approved for hospitalized patients; two new oral antivirals, Merck’s molnupiravir andPfizer’s Paxlovid, have been shown to reduce hospitalizations and death in patients at risk of serious illness. These drugs prevent the virus from reproducing, which may prevent an overactive immune response.
Other drugs are used specifically to modulate the response: corticosteroids, Interleukin-6 inhibitors, and Janus kinase inhibitors.
Understanding how COVID-19 affects the brain may have far broader implications. Boldrini has preserved a few dozen brains from patients who died of the virus. By comparing tissues from patients who had experienced neurological symptoms with those who hadn’t, she hopes to shed light on the role of inflammation in a wide swath of neurodegenerative diseases.
“As devastating as this disease is,” she says, “maybe it will help us better understand how the brain works.”
COVID-19 in people with diabetes: understanding the reasons for worse outcomes
Since the initial COVID-19 outbreak in China, much attention has focused on people with diabetes because of poor prognosis in those with the infection. Initial reports were mainly on people with type 2 diabetes, although recent surveys have shown that individuals with type 1 diabetes are also at risk of severe COVID-19. The reason for worse prognosis in people with diabetes is likely to be multifactorial, thus reflecting the syndromic nature of diabetes. Age, sex, ethnicity, comorbidities such as hypertension and cardiovascular disease, obesity, and a pro-inflammatory and pro-coagulative state all probably contribute to the risk of worse outcomes. Glucose-lowering agents and anti-viral treatments can modulate the risk, but limitations to their use and potential interactions with COVID-19 treatments should be carefully assessed. Finally, severe acute respiratory syndrome coronavirus 2 infection itself might represent a worsening factor for people with diabetes, as it can precipitate acute metabolic complications through direct negative effects on β-cell function. These effects on β-cell function might also cause diabetic ketoacidosis in individuals with diabetes, hyperglycemia at hospital admission in individuals with unknown history of diabetes, and potentially new onset diabetes.
In December, 2019, a cluster of cases of atypical interstitial pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in Wuhan, China. Following the rapid spread of COVID-19, WHO on March 11, 2020, declared COVID-19 a global pandemic. As a result, social containment measures have been adopted worldwide and health-care systems reorganized to cope with a growing number of acutely ill patients. At the time this Review was written, more than 12 million cases and more than 550000 deaths have been reported worldwide. Among those with severe COVID-19 and those who died, there is a high prevalence of concomitant conditions including diabetes, cardiovascular disease, hypertension, obesity, and chronic obstructive pulmonary disease. The fatality rate is particularly high in older patients, in whom comorbidities are common.
Most of the available information refers to patients with type 2 diabetes, and in this Review we mainly refer to patients with type 2 diabetes, unless otherwise stated. In previous disease epidemics, a greater risk of viral infection was observed in people with diabetes. This does not seem to be the case for COVID-19, though diabetes is more common among those with severe COVID-19. Data from two hospitals in Wuhan including 1561 patients with COVID-19 showed that those with diabetes (9·8%) were more likely to require admission to an intensive care unit (ICU) or to die. Similarly, in a British cohort of 5693 patients with COVID-19 in hospital, the risk of death was more common in those with uncontrolled diabetes (hazard ratio [HR] 2·36, 95% CI 2·18–2·56). Whether such worse prognosis is due to diabetes per se or to concomitant morbidities and risk factors remains to be fully elucidated. This Review is, therefore, intended to provide a systematic assessment of potential prognostic factors in patients with diabetes with COVID-19.
Diabetes is known to confer increased risk for infections. Previous studies have shown a J-curve relationship between HbA1c and risk of being admitted to hospital for infections in general, and infections of the respiratory tract in particular. An increased risk of infection was reported during previous outbreaks of severe acute respiratory syndrome, Middle East respiratory syndrome, and H1N1 influenza virus;9 however, this doesn’t seem to be the case for COVID-19. In an analysis, the prevalence of diabetes in 1590 Chinese patients with COVID-19 was 8·2%, similar to the prevalence of diabetes in China. However, the prevalence of diabetes rose to 34·6% in patients with severe COVID-19. In a meta-analysis of six Chinese studies, the prevalence of diabetes was 9·7% in the whole COVID-19 cohort (n=1527), similar to the estimated diabetes prevalence in China (10·9%). In 146 patients with a mean age of 65·3 years admitted to hospital for COVID-19 in northern Italy, a prevalence of diabetes of 8·9% was reported, slightly lower than the diabetes prevalence in the same region for the same age stratum (11%).
Diabetes does not seem to increase the risk of COVID-19 occurring, although diabetes is more frequent in patients with severe COVID-19 (table 1). In a Chinese retrospective study, patients with diabetes had more severe pneumonia, higher concentrations of lactate dehydrogenase, α-hydroxybutyrate dehydrogenase, alanine aminotransferase, and γ-glutamyl transferase, and fewer lymphocytes with a higher neutrophil count. In the same study, a subgroup of 24 patients with diabetes had greater mortality compared to 26 patients without diabetes (16·5% vs 0%). In a prospective cohort study of patients with COVID-19 from New York City (NY, USA), the prevalence of diabetes and obesity was higher in individuals admitted to hospital than those not admitted to hospital (34·7% vs 9·7% for diabetes and 39·5% vs 30·8% for obesity, respectively). In a meta-analysis of Lancet Diabetes Endocrinol 2020: 8; 782–92 Published Online July 17, 2020 https://doi.org/10.1016/ S2213-8587(20)30238-2 This online publication has been corrected. The corrected version first appeared at thelancet.com/ diabetes endocrinology on September 15, 2020 and further corrections on October 13. *Contributed equally Department of Clinical & Experimental Medicine, University of Pisa, Pisa, Italy (M Apicella MD, M C Campopiano MD, M Mantuano MD, L Mazoni MD, Prof S Del Prato MD); and Azienda Ospedaliero Universitaria Pisana, Pisa, Italy (A Coppelli MD) Correspondence to: Prof Stefano Del Prato, Department of Clinical and Experimental Medicine, University of Pisa, Nuovo Ospedale Santa Chiara, 56124 Pisa, Italy firstname.lastname@example.org@ SDelprato http://www.thelancet.com/diabetes-endocrinology Vol 8 September 2020 783 Review eight studies,14 patients with COVID-19 with diabetes had an increased risk of ICU admission. In a retrospective study13 of 191 patients with COVID-19 admitted to hospital, compared with survivors (n=137) those who died (n=54) had a higher prevalence of hypertension (23% vs 48%), diabetes (14% vs 31%), and coronary heart disease (1% vs 24%). In Italy, an analysis22 of 27 955 patients who died from COVID-19 showed a prevalence of diabetes of 31·1%.
A survey done in England (UK)20 showed that of 23 804 patients with COVID-19 dying in hospital, 32% had type 2 diabetes and 1·5% had type 1 diabetes, with 2·03 and 3·5 times the odds of dying compared with patients without diabetes, respectively. In the French population of the CORONADO study,23 3% had type 1 diabetes, 88·5% had type 2 diabetes, 5·4% had other type diabetes, and 3·1% were diagnosed at admission. A further study showed adjusted HRs with HbA1c greater than 86 mmol/mol (10%) compared with HbA1c 48–53 mmol/mol (6·5%–7·0%) of 2·19 (95% CI 1·46–3·29) for type 1 diabetes and 1·62 (95% CI 1·48–1·79) for type 2 diabetes.
In summary, patients with COVID-19 with diabetes have a worse prognosis, most probably because of the concurring effect of multiple factors. In an American survey, 33 individuals with type 1 diabetes with COVID-19 were identified; they were young (mean age 24·8 years [SD 17·49]), with high glucose concentrations at presentation and diabetic ketoacidosis reported in 45·5% of the cases. Similar to those with type 2 diabetes, obesity, hypertension, and cardiovascular disease were the most common comorbidities.
Potential prognostic factors
Age, sex, and ethnicity
Older age and male sex are epidemiological features related to a higher prevalence of COVID-19 and a more severe clinical course. In the early phase of the outbreak, the highest prevalence of COVID-19 occurred in older people in most of the regions of the world, with the exception of South Korea where the highest rate of confirmed SARS-CoV-2 infection occurred in those aged 20–29 years. However, an increased prevalence in those below the age of 30 years has been recently observed in Florida (USA), most probably due to social reasons. In all other countries the highest prevalence of COVID-19 has been in older people. In a large case series of the Chinese pandemic (72 314 cases, updated to Feb 11, 2020), the peak of morbidity was in people aged 50–59 years. The overall case-fatality rate was 2·3% but this increased up to 14·8% in individuals aged 80 years and older. The prevalence of diabetes increases with age in both the general population and in patients with COVID-19. Accordingly, the average age of patients with COVID-19 with diabetes is older than those without diabetes. In one survey, patients with diabetes were at least 10 years older than patients without diabetes. Moreover, age was associated with a greater odds ratio (OR) of in-hospital death that was similar in individuals without diabetes (multivariate OR 1·09, 95% CI 1·07–1·12) and those with diabetes (1·09, 1·04–1·15). A separate study of a matched population of patients with COVID-19 with and without diabetes reported that survivors were younger than non survivors, with age 70 years and older being an independent predictor of in-hospital death (no diabetes HR 5·87, 95% CI 1·88–18·33; diabetes HR 2·39, 1·03–5·56).
Despite overall similar sex distribution of people infected with SARS-CoV-2, (male 51%, female 49%), the case-fatality rate has been higher in males (2·8%) than in females (1·7%).19 A study7 confirmed age and male sex as risk factors for worse outcomes in COVID-19, with those aged 80 years and older having a 12-times higher risk compared with those aged 50–59 years and males having twice the risk as females (HR 1·99, 95% CI 1·88–2·10).
Non-white ethnic groups seem to be at greater risk as indicated by HRs adjusted for age and sex ranging between 1·83 and 2·17 for black, Asian or Asian British, and mixed ethnicities compared with white people.7 This finding confirms a US report on a link between racial minorities and worse outcomes from COVID-19. An analysis of a database representative of 10% of the US population showed that 33% of people admitted to hospital with COVID-19 were African Americans, even though they represent 18% of the sample population. The Johns Hopkins University and American Community Survey reported that in 131 predominantly black counties in the USA, infection and death rates were more than three times and six times higher, respectively, than in predominantly white counties. In New York City, Hispanic or Latin people account for 28% of the population, but 34% of COVID-19 deaths. In New Mexico, Native Americans represent 11% of the population, but 37% of COVID-19 cases.
The higher incidence and worse outcomes of COVID-19 reported in ethnic minority groups are unlikely to reflect biological factors, and are predominantly due to lifestyle and socioeconomic factors. Although data fully adjusted for comorbidities are not yet available, a higher prevalence of cardiovascular risk factors such as hypertension, diabetes, and obesity in ethnic minorities compared with the white population might partly account for the increased risk of poor outcome in these minority populations. These populations are also more likely to be socioeconomically disadvantaged as they more often live in poor and overcrowded houses and are employed in jobs requiring human interaction with resulting increased exposure to the risk of virus transmission. However, in India, Pakistan, and Bangladesh, despite a high prevalence of diabetes and deprivation, a relatively low COVID-19 mortality has been reported so far. This finding has suggested a potential geographical or climatic effect on the spreading of the infection. However, a careful geopolitical analysis considering latitude, temperature, and humidity could only find a weak negative association with relative humidity.
In summary, available data suggest that age is associated with worse outcomes in COVID-19, and it can be hypothesized that this relationship is stronger in people with diabetes for at least three reasons. First, the prevalence of diabetes increases with age to reach a peak in people older than 65 years. Second, people older than 65 years are more likely to have a longer duration of diabetes and a greater prevalence of diabetic complications. Third, diabetes and older age often correlate with comorbidities such as cardiovascular disease, hypertension, and obesity.
In a retrospective analysis of patients with COVID-19,6 those with diabetes had a greater prevalence of hypertension (56·9%), cardiovascular disease (20·9%), and cerebrovascular disease (7·8%) than those without diabetes (28·8%, 11·1%, and 1·3%, respectively). Moreover, in the patients with diabetes, non-survivors had a greater prevalence of comorbidities than survivors (hypertension 83·9% vs 50·0%; cardiovascular disease 45·2% vs 14·8%; cerebrovascular disease 16·1% vs 5·7%; chronic pulmonary disease 12·9% vs 3·3%; and chronic kidney disease 6·5% vs 3·3%). In a Cox multi-regression analysis, in patients with diabetes but not in those without diabetes, hypertension (HR 3·10, 95% CI 1·14–8·44), cardiovascular disease (1·87, 0·88–4·00), and chronic pulmonary disease (2·77, 0·90–8·54) were independent risk factors for in-hospital death. These findings were also noted in 136 patients with diabetes of 904 patients with COVID-19. In the patients with COVID-19, those with diabetes more commonly had hypertension, cardiovascular disease, nervous system disease, and chronic kidney disease; cardiovascular disease, nervous system disease, and chronic kidney disease were all associated with risk for in-hospital death and poor prognosis. In the CORONADO study, an estimated glomerular filtration rate on admission to hospital of 60 mL/min per 1·73 m² or less was an independent predictor of early death in patients with diabetes. SARS-CoV-2 might directly target the kidney through an angiotensin-converting enzyme (ACE) 2-dependent pathway, causing acute renal impairment and increased lethality.
+Chronic Kidney Disease–20.11%
+Congestive Heart Failure–10.36%
According to the Louisiana Department of Health percentages of comorbidities in Covid-19 Deaths. (Updated 5/8/2021)
According to numbers by the CDC, the breakdown of hospitalized patients infected with covid had the following percentages of the following comorbidities:
+Serious Heart Conditions. 27.8%
+Chronic lung disease. 34.6%
Arterial hypertension is by far the most frequent comorbidity seen in patients with COVID-19.34 It has been speculated that the high prevalence of the infection could be due to use of ACE inhibitors since SARS-CoV-2 binds to ACE2 to enter target cells. ACE2 is expressed in the lung, heart, liver, kidney, ileum, and brain and is physiologically involved in anti-inflammatory responses. Experimental evidence suggests that ACE inhibitors and angiotensin receptor blockers increase the expression of ACE2, and it was proposed that these drugs could facilitate target organ infection and promote progression of the disease. However, this evidence was obtained in in vitro and animal studies. Given its structural differences with ACE, ACE2 does not represent a target of these drugs. Moreover, the interaction between ACE inhibitors and the renin–angiotensin system is complex and not completely understood in humans. SARS-CoV-2 has been claimed to increase the expression of angiotensin II with subsequent downregulation of ACE2 and loss of anti-inflammatory effect in the respiratory tract, resulting in alveolar wall thickening, oedema, inflammatory infiltration, and bleeding. Moreover, a favourable effect of ACE inhibitors and angiotensin receptor blockers on the risk of community acquired pneumonia, especially in Asian populations, has been suggested. Initial reports on 8910 patients with COVID-19 from 11 countries could not detect an association between ACE inhibitors or angiotensin receptor blockers and the risk of in-hospital death. A population-based case-control study from Lombardy, an Italian region particularly affected by the pandemic, led to similar conclusions. A Chinese study has even shown a lower rate of severe diseases and a trend toward a lower inflammatory response in 17 patients with COVID-19 treated with ACE inhibitors or angiotensin receptor blockers versus 25 patients given other anti-hypertensive drugs. In summary, ACE inhibitors are unlikely to account for the association between COVID-19 and hypertension.
Patients with COVID-19 have a high prevalence of cardiovascular disease. Cases of acute myocarditis associated with COVID-19 have been reported and a direct myocardial injury has been postulated. The evidence for myocardial injury is largely indirect, with no evidence of viral genomes from myocardial biopsy samples.45 In an autopsy report for 23 patients with COVID-19, 13 showed cardiac manifestations, along with pulmonary involvement. Three patients had obesity and had multifocal acute cardiomyocyte injury without inflammatory cellular infiltrates, lymphocytic myocarditis, or lymphocytic pericarditis associated with signs of chronic cardiac disease. In a metaanalysis of 4189 patients from 28 observational studies, patients with more severe COVID-19 had higher troponin concentrations, which was associated with an increased risk of death.
A manifestation of secondary cardiac involvement in COVID-19 is stress-induced (Takotsubo) cardiomyopathy. Cardiovascular complications might also develop because of reduced systemic oxygenation due to pneumonia and concomitant increased cardiac demand, by immune dysregulation, electrolyte imbalance, or because of adverse effects of drugs such as hydroxychloroquine and azithromycin.
Many reports have linked obesity to more severe COVID-19 illness and death. Several mechanisms can account for this association. The first concerns the detrimental restrictive ventilatory effect of abdominal fat. In a French study, the risk for invasive mechanical ventilation in patients with COVID-19 admitted to an ICU was more than seven times higher in those with a BMI of more than 35 kg/m² than those with a BMI of less than 25 kg/m². Second, in addition to the ventilatory defect, the respiratory dysfunction in patients with severe COVID-19 might depend on impaired lung perfusion due to intravascular disseminated coagulation. In line with this hypothesis, low-molecular-weight heparin was found to reduce mortality. Obesity and diabetes are prothrombotic conditions that might contribute to worse prognosis in patients with COVID-19. In an autopsy study from Germany, deep venous thrombosis was found in seven of 12 patients (58%) and pulmonary embolism was the direct cause of death in four. Of these patients, the BMI of those who died from pulmonary embolism was 36·8 kg/m². Finally, obesity is associated with immune dysregulation and chronic inflammation that could mediate progression toward organ failure in severe COVID-19 patients.
Myocarditis and cardiomyocyte dysfunction could be worsened by local biological effects of epicardial adipose tissue, a source of adipokines and pro-inflammatory mediators, and the volume of epicardial adipose tissue is directly associated with BMI. Moreover, ACE2 is highly expressed in the epicardial adipose tissue of patients with obesity. This could promote virus internalization into the adipocytes and enhance tumor necrosis factor (TNF) α and IL-6 release. Liver steatosis might also play a role. A Chinese study reported a six-times increased risk of severe COVID-19 in patients with a BMI of more than 25 kg/m² and metabolic associated fatty liver disease compared with patients without obesity. Nonalcoholic fatty liver disease and non-alcoholic steatohepatitis are common in people with abdominal obesity and diabetes.58 Elevated aspartate aminotransferase concentrations have been associated with poorer prognosis in patients with COVID-19. The extent to which SARS-CoV-2 could directly affect liver function remains to be established as ACE2 is mainly expressed in cholangiocytes.
Obesity and diabetes are characterized by chronic low grade inflammation with increased concentrations of pro-inflammatory leptin and reduced anti-inflammatory adiponectin. Additionally, people with obesity are often physically inactive, more insulin resistant, and with gut dysbiosis, which might increase the inflammatory response to infection with SARS-CoV-2. Moreover, individuals with obesity have lower vitamin D concentrations, which could also reduce the immune response. The role of vitamin D supplementation is currently being investigated in ongoing clinical trials.
SARS-CoV-2 infects not only cells of the upper respiratory system and alveolar epithelial cells in the lung but also, among others, circulating immune cells (CD3, CD4, and CD8 T cells) inducing apoptosis of lymphocytes to an extent that reflects the severity of SARS-CoV-2 infection. As T cells of the adaptive immune system inhibit overactivation of innate immunity, the resulting lymphocytopenia might suppress the innate immune system and enhance secretion of cytokines. The overproduction of pro-inflammatory cytokines (TNFα, IL-6, IL-1β, and CXC-chemokine ligand 10) results in a so-called cytokine storm, which leads to high risk of vascular hyperpermeability, multiorgan failure, and death. High blood concentrations of inflammatory markers (ie, C-reactive protein, procalcitonin, and ferritin), a high neutrophil-to-lymphocyte ratio, and increased blood concentrations of inflammatory cytokines and chemokines have been associated with both COVID-19 severity and death. Post-mortem analyses of patients with COVID-1967–69 have revealed inflammatory infiltration of the lungs, heart, spleen, lymph nodes, and kidneys. In those with severe COVID-19, a study found higher concentrations of leukocytes (5·3 vs 4·5×10⁹ L, p=0·014), C-reactive protein (47·6 vs 28·7 mg/L, p<0·001), and procalcitonin (0·1 vs 0·05 ng/mL, p<0·001), and lower lymphocyte percentages (median 0·7% [IQR 0·5–1·0] vs 0·8% [0·6–1·2], p=0·048) compared with patients with non-severe COVID-19. Moreover, C-reactive protein concentrations of more than 200 mg/L and ferritin concentrations of more than 2500 ng/mL at hospital admission are risk factors for critical COVID-19. Several reports confirmed these results and a meta-analysis66 including more than 3000 patients with COVID-19 identified high concentrations of IL-6, IL-10, and serum ferritin as strong indicators for severe disease. A dysregulated inflammatory innate and adaptive impaired immune response might occur in patients with diabetes, accounting for the systemic tissue damage and respiratory and multiorgan failure. The cytokine storm is more likely to develop in patients with diabetes, as diabetes is already characterized by low-grade chronic inflammation. Moreover, in the case of high viral load, the capacity to raise an acute immune response might be compromised in patients with diabetes, exposing them to more severe adverse effects. One study reported that patients with COVID-19 with diabetes had higher concentrations of inflammation-related biomarkers, such as C-reactive protein, serum ferritin, and IL-6, and a higher erythrocyte sedimentation rate, compared with patients with COVID-19 without diabetes. These results were supported by findings from a multicenter study in a Chinese population of patients with COVID-19 (952 with diabetes and 6385 without diabetes), showing that those with diabetes had a higher incidence of lymphopenia (44·5% vs 32·6%), and elevated inflammatory biomarkers (C-reactive protein 57·0% vs 42·4% and procalcitonin 33·3% vs 20·3%]. For patients with COVID-19, those with diabetes are more susceptible to the destructive effect of the cytokine storm than those without diabetes.
COVID-19 has been found to be associated with increased coagulation activity. The endothelial dysfunction associated with hypoxia can favor intra-vessel coagulation during COVID-19 infection. Post-mortem studies have found changes in lung vessels, massive pulmonary interstitial fibrosis, variable degrees of hemorrhagic pulmonary infarction, severe endothelial injury, widespread vascular thrombosis with nearly total occlusion of alveolar capillaries, structurally deformed capillaries, and growth of new vessels through a mechanism of intussusceptive angiogenesis. Moreover, intravascular disseminated coagulation can be the terminal event in severe COVID-19, and anticoagulant therapy seems to improve prognosis.
Diabetes is associated with a prothrombotic state, with an imbalance between clotting factors and fibrinolysis and an increased risk of thromboembolic events. In a retrospective Chinese study in patients with diabetes admitted to hospital for COVID-19, non-survivors had longer prothrombin times and higher concentrations of D-dimer. Patients with COVID-19 with diabetes often present other risk factors such as obesity, older age, and being admitted to hospital that could increase the pro-coagulative state and the risk of thrombotic complications.
Despite its syndromic nature, diabetes is still identified as a disturbance of glucose homoeostasis and progressive worsening of hyperglycemia. In previous infectious disease epidemics, a high glucose concentration was shown to be an independent predictor of death and morbidity. This is likely to also be the case for COVID-19.11, The role of hyperglycemia, however, requires a systematic analysis, as suggested by Scheen and colleagues, as the role of glycemic control before hospital admission, at the time of hospital admission, and during treatment in hospital needs to be considered.
Glycemic control before hospital admission
A cohort analysis5 of more than 5500 patients with COVID-19 in the UK found that poor glycemic control before hospital admission, as indicated by HbA1c concentrations, was associated with a high risk of in-hospital death. In a model adjusted for sociodemographic variables and comorbidities, the HR for in-hospital death was greater in patients with HbA1c of 58 mmol/mol (7·5%) or more (3·36, 95% CI 2·18–2·56) than in those with lower HbA1c (1·50, 1·40–1·60) or those without recent HbA1c measurement (1·87, 1·63–2·16). Findings from a separate study also suggested a higher risk of mortality from COVID-19 in patients with either type 1 or type 2 diabetes with HbA1c of more than 86 mmol/mol (10%) compared with those with HbA1c of less than 48 mmol/mol (6·5%). Surprisingly, in the CORONADO study no association was noted between HbA1c concentrations and the primary composite outcome (death and tracheal intubation for mechanical ventilation within the first 7 days after hospital admission) in patients with diabetes admitted to hospital with COVID-19. However, the mean HbA1c value (65 mmol/mol [8·1%]) at admission in this study was higher than the average HbA1c values (54 mmol/mol [7·1%]) in the age-matched French population in a separate study.
Plasma glucose at admission
Despite no association being found between HbA1c and outcomes in the CORONADO study, an association was noted between plasma glucose concentration at admission and the primary outcome. In a retrospective study of 85 patients with COVID-19, hyperglycemia at hospital admission was the best predictor of worst chest radiographic imaging results. Another study found a higher risk of a composite outcome (ICU admission, mechanical ventilation, and death) in patients with hyperglycemia at admission (fasting blood glucose >7 mmol/L) and without history of diabetes compared with patients without diabetes and normoglycemia (OR 5·47, 95% CI 1·56–19·82). This finding is supported by results from a retrospective analysis82 that showed death occurred in 40 of 96 uncontrolled patients with hyperglycemia (41·7%) compared with deaths in 13 of 88 patients with diabetes (14·8%, p<0·001). Altogether, these results highlight the need for improving glycemic control in all patients presenting with hyperglycemia, irrespective of a known diagnosis of diabetes.
In-hospital glycemic control
Random hyperglycemia during treatment in hospital was noted to contribute to worse prognosis for patients with COVID-19 in Wuhan. In 1122 patients with COVID-19 admitted to hospital in the USA, the mortality rate was four times higher in those with diabetes or hyperglycemia during the hospital stay (28·8%) than those with normoglycemia (6·2%). Moreover, mortality was higher in those with hyperglycemia and without known diabetes than in patients with known diabetes. Another study showed that hyperglycemia during treatment in hospital was a risk factor for death in patients with severe COVID-19 (adjusted HR 1·8, 95% CI 1·1–2·8). Patients with COVID-19 with diabetes with an in hospital median blood glucose concentration of less than 6·4 mmol/L (IQR 5·2–7·5) had lower incidences of lymphopenia (30·5% vs 49·6%), neutrophilia (10·7% vs 19·4%), increases in C-reactive protein (47·5% vs 59⋅5%), and procalcitonin (24·2% vs 35·0%) than patients with a median blood glucose concentration of 7·5 mmol/L or higher. Good glycemic control was also associated with a lower rate of complications and all cause mortality.16 These results were confirmed in a propensity-matched score analysis, matching diabetes related comorbidities.
An unusually high number of COVID-19 patients developing diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome have been noted and negative outcomes during COVID-19 have been reported in two clinical cases of diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. In one analysis, ketosis occurred in 6·4% of patients with COVID-19 and its prevalence rose to 11·6% in patients with COVID-19 with diabetes, resulting in a high mortality rate (33·3%). In the CORONADO study,23 11·1% of the participants had diabetes-related disorders at admission including 132 patients with severe hyperglycemia and 40 with ketosis, of whom 19 had diabetic ketoacidosis. Although ketosis might have resulted from discontinuation of glucose-lowering drugs because of anorexia before hospital admission, a direct effect of SARS-CoV-2 should be considered. The virus binds to ACE2 receptors, which, among other locations, are expressed in pancreatic tissue and β-cells in particular.36 Therefore, an acute loss of insulin secretory capacity along with a stress condition and the cytokine storm could lead to a rapid metabolic deterioration with development of diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome. Additionally, hyperglycemic hyperosmolar syndrome is likely to increase the risk of thrombosis that already characterizes severe COVID-19. Because of the severity of diabetic ketoacidosis in patients with COVID-19, ad hoc recommendations for its treatment have been released in the UK.
The SARS-Cov-2 tropism for the β-cell could cause acute impairment of insulin secretion or destruction of β-cells resulting in de novo development of diabetes. This hypothesis is supported by a previous observation88 that infection with human herpesvirus 8 in a sub-Saharan African population induced ketosis-prone type 2 diabetes. In line with this view, new-onset diabetes has been reported in patients with COVID-19 being treated in hospital. In a population of 453 patients with COVID-19, 94 were identified with new-onset diabetes (defined as first recognition of fasting plasma glucose ≥7 mmol/L and HbA1c ≥48 mmol/mol (6·5%) at hospital admission); additionally, these individuals had a greater risk of mortality (HR 9·42, 95% CI 2·18 0–40·7) than those with hyperglycemia (3·29, 0·65–16·6) or diabetes (4·63, 1·02–21·0).
In summary, poor glycemic control at hospital admission and during the hospital stay worsens outcomes for patients with COVID-19. Moreover, consideration should be given for a direct effect of SARS-CoV-2 on β-cell function and survival, causing worsening rapid and severe deterioration of metabolic control in people with pre-existing diabetes or leading to the development of new-onset diabetes (figure). In people with hyperglycemia, glycemic control should be ensured to reduce the risk of threatening metabolic complications (table 2), which should integrate all therapeutic maneuvers put in place to reduce the risk of severe outcomes and mortality. Finally, achievement and maintenance of glycemic control should take into consideration the implications of the use of different glucose-lowering agents in the setting of COVID-19.
Use of glucose-lowering agents might raise specific considerations in patients with COVID-19 (table 3). In the presence of mild COVID-19 in an out-patient setting, usual glucose-lowering therapies for patients with diabetes could be continued if the patient eats and drinks adequately and a more frequent blood glucose-monitoring regimen is implemented. Patients admitted to hospital for severe COVID-19 might need modifications to their diabetes therapy, including withdrawing ongoing treatments and initiating insulin therapy. Such a decision should be based on the severity of COVID-19, nutritional status, actual glycemic control, risk of hypoglycemia, renal function, and drug interactions. Although insulin treatment has been recommended in patients with diabetes with severe COVID-19, one study showed worse clinical outcomes and a worse laboratory results profile in patients on insulin compared with those on metformin. Nonetheless, these results should be viewed with caution because of potential confounding by indication, as insulin treatment could have been used simply because the diabetes was more severe. In keeping with this hypothesis, another study found that insulin infusion allowed achievement of glycaemic targets and improved outcomes in patients with hyperglycaemia with COVID-19.
Despite better outcomes reported in patients with COVID-19 with diabetes treated with metformin,28 the drug should be stopped in patients with respiratory distress, renal impairment, or heart failure90 because of a risk of lactic acidosis. A favorable effect of metformin in patients with COVID-19 has been hypothesized as the drug might prevent virus entry into target cells via adenosine monophosphate-activated protein kinase activation and the phosphatidylinositol-3-kinase–protein kinase B–mammalian target of rapamycin signaling pathway.
A hypothetical anti-viral effect of SGLT2-inhibitors has also been suggested as these agents can decrease intracellular pH and increase lactate concentrations that could reduce the viral load. Nonetheless, SGLT2 inhibitors require optimal hydration to avoid hypovolemia and electrolyte imbalance, and proper adjustment of insulin doses because of the risk of diabetic ketoacidosis. GLP-1 receptor agonists might aggravate anorexia and should be discontinued in severely ill patients with COVID-19 because of a potential risk of aspiration pneumonia. Nonetheless, their associated anti-inflammatory actions and lung protection should be evaluated since preclinical studies have suggested that GLP-1 receptor agonists might attenuate pulmonary inflammation and preserve lung function in rats with experimental lung injury and respiratory syncytial virus infection.
DPP-4 inhibitors are associated with a low risk of hypoglycemia and can be used for a wide renal function range. DPP-4 inhibitors are generally well tolerated and, in experimental studies, they were shown to mitigate inflammatory response. Because soluble DPP-4 might act as a co-receptor for a subset of coronaviruses, DPP-4 inhibitors might interfere with and modify such binding and hypothetically reduce virulence. However, there is no clinical evidence of such an advantage and in two studies no association was found between individual glucose lowering drugs and outcomes. Because of the risk of hypoglycemia, sulfonylureas should be stopped in patients with diabetes with COVID-19, particularly if oral intake is poor or chloroquine is simultaneously used.
Pioglitazone has anti-inflammatory properties, and in experimental animal models it reduced lung inflammation and fibrosis.100,101 Nonetheless, the use of pioglitazone in patients with diabetes with COVID-19 is controversial because of the risk of fluid retention and edema in hemodynamically unstable patients.
Therapies for COVID-19 in people with diabetes
Medical teams should ensure adequate glycemic control in patients with diabetes with COVID-19. This requires considering all potential implications that therapies for COVID-19 might generate when used in patients with diabetes.
Treatment with chloroquine or hydroxychloroquine can cause hypoglycemia, particularly in patients on insulin or sulfonylureas, because of their effects on insulin secretion, degradation, and action. Conversely, antiviral drugs such as lopinavir and ritonavir could lead to hyperglycemia and worsen glycemic control. These agents can cause hepatic and muscle toxicity so caution is recommended when they are used in combination with statins and in patients with fatty liver disease. Pharmacokinetic interactions with antidiabetic drugs are also common, causing over-exposure or under-exposure to either antivirals or anti-diabetic drugs.
Glucocorticoids have been used in patients with COVID-19 with severe acute respiratory distress syndrome as symptomatic and anti-inflammatory treatment. Their use, however, can worsen insulin resistance, sustain gluconeogenesis, worsen glycemic control, and cause marked hyperglycemia. As known, glucocorticoids exert their hyperglycemic effects by reducing insulin sensitivity and insulin secretion, and also by interfering with GLP-1 effects, and enhancing production of glucagon.
People with diabetes with COVID-19 are at a greater risk of worse prognosis and mortality. Given the high worldwide prevalence of diabetes, these individuals represent a large vulnerable segment of the COVID-19 population. The poorer prognosis of people with diabetes is the likely consequence of the syndromic nature of the disease (figure): hyperglycemia, older age, comorbidities, and in particular hypertension, obesity, and cardiovascular disease all contribute to increase the risk in these individuals. The picture, however, is more complicated as it requires factoring in societal factors such as deprivation and ethnicity as well as factors that become relevant at the time that a patient with severe COVID-19 needs to be managed. Here, a physician has to account for not only the health status of the person with diabetes but also to balance carefully glucose-lowering treatments with specific treatments for the viral infection.
Once again, diabetes management in patients with COVID-19 poses a great clinical challenge, one that requires a much-integrated team approach, as this is an indispensable strategy to reduce the risk of medical complications and death as much as possible. Careful assessment of the many components that contribute to poor prognosis with COVID-19 in patients with diabetes might represent the best, if not the only way to overcome the current situation and enable our health systems to be ready to face any future challenges in a prompt and effective manner.
How The Coronavirus Affects Your Body:
Complications can include:
- Pneumonia and trouble breathing
- Organ failure in several organs
- Heart problems
- A severe lung condition that causes a low amount of oxygen to go through your bloodstream to your organs (acute respiratory distress syndrome)
- Blood clots
- Acute kidney injury
- Additional viral and bacterial infections
I have included each organ or system that is affected more indepth below.
As with other coronavirusTrusted Source illnesses — including SARS, MERS, and the common cold — COVID-19 is a respiratory disease, so the lungs are usually affected first. Early symptomsTrusted Source include fever, cough, and shortness of breath. These appear as soon as 2 days, or as long as 14 days, after exposure to the virus.
While fever is at the top of the Centers for Disease Control and Prevention’s list of symptoms, not everyone who gets sick has a fever. In one study in the Journal of the American Medical Association, researchers found that around 70 percentTrusted Source of patients hospitalized with COVID-19 didn’t have a fever.
Cough is more common, but treatment guidelines developed by Boston’s Brigham and Women’s Hospital found that cough occurs in 68 to 83 percent of people who show up at the hospital with COVID-19. Only 11 to 40 percent had shortness of breath. Other less common symptoms included confusion, headache, nausea, and diarrhea.
The severity of COVID-19 varies from mild or no symptoms to severe or sometimes fatal illness. Data on more than 17,000 reported cases in China found that almost 81 percent of cases were mild. The rest were severe or critical. Older people and those with chronic medical conditions appear to have a higher riskTrusted Source for developing severe illness. This variability also shows up in how COVID-19 affects the lungs.
Some people may only have minor respiratory symptomsTrusted Source, while others develop non-life-threatening pneumonia. But there’s a subset of people who develop severe lung damage. “What we’re frequently seeing in patients who are severely ill with [COVID-19] is a condition that we call acute respiratory distress syndrome, or ARDS,” said Dr. Laura E. Evans, a member of the Society of Critical Care Medicine Leadership Council and an associate professor of pulmonary, critical care, and sleep medicine at the University of Washington Medical Center in Seattle.
ARDS doesn’t happen just with COVID-19. A number of events can trigger it, including infection, trauma, and sepsis. These cause damage to the lungs, which leads to fluid leaking from small blood vessels in the lungs. The fluid collects in the lungs’ air sacs, or alveoli. This makes it difficult for the lungs to transfer oxygen from the air to the blood.
While there’s a shortage of information on the type of damage that occurs in the lungs during COVID-19, a recent report suggests it’s similarTrusted Source to the damage caused by SARS and MERS. One recent studyTrusted Source of 138 people hospitalized for COVID-19 found that on average, people started having difficulty breathing 5 days after showing symptoms. ARDS developed on average 8 days after symptoms. Treatment for ARDS involves supplemental oxygen and mechanical ventilation, with the goal of getting more oxygen into the blood. “There isn’t a specific treatment for ARDS,” Evans said. “We just support the person through this process as best we can, allowing their bodies to heal and their immune system to address the underlying events.”
One curious thing about COVID-19 is that many patients have potentially deadly low blood oxygen levels, but they don’t seem starved of oxygen. This has led some doctors to rethink putting patients on a ventilator simply because of low oxygen levels in the blood.
The lungs are the main organs affected by COVID-19. But in serious cases, the rest of the body can also be affected. In serious cases, the rest of the body can also be affected. “In patients who become severely ill, a good proportion of those patients also develop dysfunction in other organ systems,” Evans said. However, she says this can happen with any severe infection. This damage to the organs isn’t always directly caused by the infection, but can result from the body’s response to infection.
Some people with COVID-19 have reported gastrointestinal symptomsTrusted Source, such as nausea or diarrhea, although these symptoms are much less common than problems with the lungs. While coronaviruses seem to have an easier time entering the body through the lungs, the intestines aren’t out of reach for these viruses. Earlier reports identified the viruses that cause SARS and MERS in intestinal tissue biopsies and stool samples. Two recent studies — one in the New England Journal of Medicine and a preprint on medRxiv — report that stool samples of some people with COVID-19 tested positive for the virus. However, researchers don’t know yet whether fecal transmission of this virus can occur.ADVERTISING
Evans says COVID-19 can also affect the heart and blood vessels. This may show up as irregular heart rhythms, not enough blood getting to the tissues, or blood pressure low enough that it requires medications. So far, though, it’s not clearTrusted Source that the virus directly damages the heart. In one study of hospitalized patients in Wuhan, 20 percentTrusted Source had some form of heart damage. In another, 44 percentTrusted Source of those in an intensive care unit (ICU) had an irregular heart rhythm. There are also signs that COVID-19 may cause the blood to clot more easily. It’s not clear how much this plays in the severity of the illness, but clots could increase the risk of a stroke or heart attack.CORONAVIRUS UPDATESStay on top of the COVID-19 pandemic. We’ll email you the latest developments about the novel coronavirus and Healthline’s top health news stories, daily.
When liver cells are inflamed or damaged, they can leak higher than normal amounts of enzymes into the bloodstream. Elevated liver enzymes aren’t always a sign of a serious problem, but this laboratory finding was seen in people with SARS or MERSTrusted Source. In one study of hospitalized COVID-19 patients in Wuhan, 27 percent had kidney failure. One recent reportTrusted Source found signs of liver damage in a person with COVID-19. Doctors says it’s not clear, though, if the virus or the drugs being used to treat the person caused the damage. Some people hospitalized with COVID-19 have also had acute kidney damageTrusted Source, sometimes requiring a kidney transplant. This also occurred with SARS and MERSTrusted Source. During the SARS outbreak, scientists even found the virus that causes this illness in the tubules of the kidneys.
There’s “little evidence,” though, to show that the virus directly caused the kidney injury, according to a World Health Organization report. Dr. James Cherry, a research professor of pediatrics in the David Geffen School of Medicine at UCLA, says the kidney damage may be due to other changes that happen during coronavirus infection. “When you have pneumonia, you have less oxygen circulating,” he said, “and that can damage the kidneys.”
With any infection, the body’s immune system responds by attacking the foreign virus or bacteria. While this immune response can rid the body of the infection, it can also sometimes cause collateral damage in the body. This can come in the form of an intense inflammatory response, sometimes called a “cytokine storm.” The immune cells produce cytokines to fight infection, but if too many are released, it can cause problems in the body. “A lot of [the damage in the body during COVID-19] is due to what we would call a sepsis syndrome, which is due to complex immune reactions,” Evans said. “The infection itself can generate an intense inflammatory response in the body that can affect the function of multiple organ systems.”
Another thing about the immune system is that, so far, there are almost no cases of COVID-19 in children under 9 years old. Scientists aren’t sure whether young children aren’t getting infected or their symptoms are so mild that no one notices it. Cherry says children also have a less severe illness than adults during other kinds of infections, including measles and pneumococcal infections. He says this may be because children have a “straightforward immune response,” whereas older people can sometimes have an “over-response.” It’s this excess immune response that causes some of the damage during infections. “There was evidence of this happening during SARS,” Cherry said, “and I suspect it could also be playing out here [with COVID-19].”
What has been discovered is that there are micro blood clots being formed in the body. The reason for this is not fully understood. But is suspected that this is a major causative agent for organ damage, especially the heavily vascular organs, like the kidneys and liver.
Here’s what coronavirus does to the body
From blood storms to honeycomb lungs, here’s an organ-by-organ look at how COVID-19 harms humans.
Much remains unknown about the novel coronavirus ripping through China, but one thing is certain. The disease can cast a storm over the whole human body.
Such has been the nature of past zoonotic coronaviruses, ones that hopped from animals to humans like SARS and MERS. Unlike their common-cold-causing cousins, these emergent coronaviruses can spark a viral-induced fire throughout many of a person’s organs, and the new disease—dubbed “COVID-19” by the World Health Organization—is no exception when it is severe.
That helps explain why the COVID-19 epidemic has killed more than 1,800 people, surpassing the SARS death toll in a matter of weeks. While the death rate for COVID-19 appears to be a fifth of SARS, the novel coronavirus has spread faster.
Confirmed cases rose to more than 60,000 last Thursday, nearly a 50 percent jump relative to the prior day, and the tally has since increased by another 13,000. This leap reflects a change in the way Chinese authorities are diagnosing infections instead of a massive shift in the scope of the outbreak. Rather than wait for patients to test positive for the virus, diagnoses now include anyone whose chest scan reveals COVID-19’s distinctive pattern of pneumonia. This method will hopefully allow authorities to isolate and treat patients more quickly.
If this outbreak continues to spread, there’s no telling how harmful it could become. A leading epidemiologist at the University of Hong Kong warned this week that COVID-19 could infect 60 percent of the globe if left unchecked.
On Monday, the Chinese Center for Disease Control and Prevention released clinical details on the first 72,314 patients diagnosed through February 11. The report shows that COVID-19 killed 2.3 percent of patients, meaning it is currently 23 times more fatal than the seasonal flu. Severe disease and deaths were reported in every age group, except kids under nine years old.
Meanwhile, countries have been scrambling to evacuate their citizens from a cruise ship that’s been quarantined off the coast of Japan. The Japanese health ministry announced Tuesday that an additional 88 passengers on the ship were diagnosed with COVID-19—bringing the total to 542. Of the more than 300 Americans who have been repatriated from the ship, 14 have tested positive for the coronavirus.
But what actually happens to your body when it is infected by the coronavirus? The new strain is so genetically similar to SARS that it has inherited the title SARS-CoV-2. So combining early research on the new outbreak with past lessons from SARS and MERS can provide an answer.
The Lungs: Ground zero
For most patients, COVID-19 begins and ends in their lungs, because like the flu, coronaviruses are respiratory diseases.
They spread typically when an infected person coughs or sneezes, spraying droplets that can transmit the virus to anyone in close contact. Coronaviruses also cause flu-like symptoms: Patients might start out with a fever and cough that progresses to pneumonia or worse.
After the SARS outbreak, the World Health Organization reported that the disease typically attacked the lungs in three phases: viral replication, immune hyper-reactivity, and pulmonary destruction.
Not all patients went through all three phases—in fact only 25 percent of SARS patients suffered respiratory failure, the defining signature of severe cases. Likewise, COVID-19, according to early data, causes milder symptoms in about 82 percent of cases, while the remainder are severe or critical.
Look deeper, and the novel coronavirus appears to follow other patterns of SARS, says University of Maryland School of Medicine associate professor Matthew B. Frieman, who studies highly pathogenic coronaviruses.
In the early days of an infection, the novel coronavirus rapidly invades human lung cells. Those lung cells come in two classes: ones that make mucus and ones with hair-like batons called cilia.
Mucus, though gross when outside the body, helps protect lung tissue from pathogens and make sure your breathing organ doesn’t dry out. The cilia cells beat around the mucus, clearing out debris like pollen or viruses.
Frieman explains that SARS loved to infect and kill cilia cells, which then sloughed off and filled patients’ airways with debris and fluids, and he hypothesizes that the same is happening with the novel coronavirus. That’s because the earliest studies on COVID-19 have shown that many patients develop pneumonia in both lungs, accompanied by symptoms like shortness of breath.
That’s when phase two and the immune system kicks in. Aroused by the presence of a viral invader, our bodies step up to fight the disease by flooding the lungs with immune cells to clear away the damage and repair the lung tissue.
When working properly, this inflammatory process is tightly regulated and confined only to infected areas. But sometimes your immune system goes haywire and those cells kill anything in their way, including your healthy tissue.
“So you get more damage instead of less from the immune response,” Frieman says. Even more debris clogs up the lungs, and pneumonia worsens.
During the third phase, lung damage continues to build—which can result in respiratory failure. Even if death doesn’t occur, some patients survive with permanent lung damage. According to the WHO, SARS punched holes in the lungs, giving them “a honeycomb-like appearance”—and these lesions are present in those afflicted by novel coronavirus, too.
These holes are likely created by the immune system’s hyperactive response, which creates scars that both protect and stiffen the lungs.When that occurs, patients often have to be put on ventilators to assist their breathing. Meanwhile, inflammation also makes the membranes between the air sacs and blood vessels more permeable, which can fill the lungs with fluid and affect their ability to oxygenate blood.
“In severe cases, you basically flood your lungs and you can’t breathe,” Frieman says. “That’s how people are dying.”
The Stomach: A shared gateway
During the SARS and MERS outbreaks, nearly a quarter of patients had diarrhea—a much more significant feature of those zoonotic coronaviruses. But Frieman says it’s still not clear whether gastrointestinal symptoms play a major part in the latest outbreak, given cases diarrhea and abdominal pain have been rare. But why does a respiratory virus bother the gut at all?
When any virus enters your body, it looks for human cells with its favorite doorways—proteins on the outside of the cells called receptors. If the virus finds a compatible receptor on a cell, it can invade.
Some viruses are picky about which door they choose, but others are a little more promiscuous. “They can very easily penetrate into all types of cells,” says Anna Suk-Fong Lok, assistant dean for clinical research at the University of Michigan Medical School and former president of the American Association for the Study of Liver Diseases.
Both SARS and MERS viruses can access the cells that line your intestines and large and small colon, and those infections appear to flourish in the gut, potentially causing the damage or the leakage of fluid that becomes diarrhea.
But Frieman says we don’t know yet if the novel coronavirus does the same. Researchers believe COVID-19 uses the same receptor as SARS, and this doorway can be found in your lungs and small intestines.
Two studies—one in the New England Journal of Medicine and one preprint in medRxiv involving 1,099 cases—have also detected the virus in stool samples, which might indicate the virus could spread via feces. But this is far from conclusive.
“Whether that kind of fecal transmission is occuring for this Wuhan virus, we don’t know at all,” Frieman says. “But it definitely looks like it’s there in the stool and it looks like people do have GI symptoms associated with this.”
Coronaviruses can also cause problems in other systems of the body, due to the hyperactive immune response we mentioned earlier.
A 2014 study showed that 92 percent of patients with MERS had at least one manifestation of the coronavirus outside of the lungs. In fact, signs of a full body blitz have been witnessed with all three of the zoonotic coronaviruses: elevated liver enzymes, lower white blood cell and platelet count, and low blood pressure. In rare cases, patients have suffered from acute kidney injury and cardiac arrest.
But this isn’t necessarily a sign that the virus itself is spreading throughout the body, says Angela Rasmussen, a virologist and associate research scientist at Columbia University Mailman School of Public Health. It might be a cytokine storm.
Cytokines are proteins used by the immune system as alarm beacons—they recruit immune cells to the site of infection. The immune cells then kill off the infected tissue in a bid to save the rest of the body.Basically you’re bleeding out of your blood vessels.
Humans rely on our immune systems to keep their cool when facing a threat. But during a runaway coronavirus infection, when the immune system dumps cytokines into the lungs without any regulation, this culling becomes a free-for-all, Rasmussen says “Instead of shooting at a target with a gun, you’re using a missile launcher,” she says. That’s where the problem arises: Your body is not just targeting the infected cells. It is attacking healthy tissue too.
The implications extend outside the lungs. Cytokine storms create inflammation that weakens blood vessels in the lungs and causes fluid to seep through to the air sacs. “Basically you’re bleeding out of your blood vessels,” Rasmussen says. The storm spills into your circulatory system and creates systemic issues across multiple organs.
From there, things can take a sharp turn for the worse. In some of the most severe COVID-19 cases, the cytokine response—combined with a diminished capacity to pump oxygen to the rest of the body—can result in multi-organ failure. Scientists don’t know exactly why some patients experience complications outside of the lung, but it might be linked to underlying conditions like heart disease or diabetes.
“Even if the virus doesn’t get to kidneys and liver and spleen and other things, it can have clear downstream effects on all of those processes,” Frieman says. And that’s when things can get serious.
Liver: Collateral damage
When a zoonotic coronavirus spreads from the respiratory system, your liver is often one downstream organ that suffers. Doctors have seen indications of liver injury with SARS, MERS, and COVID-19—often mild, though more severe cases have led to severe liver damage and even liver failure. So what’s happening?
“Once a virus gets into your bloodstream, they can swim to any part of your body,” Lok says. “The liver is a very vascular organ so [a coronavirus] can very easily get into your liver.”
Your liver works pretty hard to make sure your body can function properly. Its main job is to process your blood after it leaves the stomach, filtering out the toxins and creating nutrients your body can use. It also makes the bile that helps your small intestine break down fats. Your liver also contains enzymes, which speed up chemical reactions in the body.
In a normal body, Lok explains, liver cells are constantly dying off and releasing enzymes into your bloodstream. This resourceful organ then quickly regenerates new cells and carries on with its day. Because of that regeneration process, the liver can withstand a lot of injury.
When you have abnormally high levels of enzymes in your blood, though—as has been a common characteristic of patients suffering from SARS and MERS—it’s a warning sign. It might be a mild injury that the liver will quickly bounce back from or it could be something more severe—even liver failure.
Lok says scientists don’t completely understand how these respiratory viruses behave in the liver. The virus might be directly infecting the liver, replicating and killing off the cells itself. Or those cells might be collateral damage as your body’s immune response to the virus sets off a severe inflammatory reaction in the liver.
Either way, she notes that liver failure was never the sole cause of death for SARS patients. “By the time the liver fails,” she says, “oftentimes you’ll find that the patient not only has lung problems and liver problems but they may also have kidney problems. By then it becomes a systemic infection.”
Kidney: It’s all connected
Yes, your kidneys are caught up in this mess, too. Six percent of SARS patients—and a full quarter of MERS patients—suffered acute renal injury. Studies have shown the novel coronavirus can do the same. It may be a relatively uncommon feature of the disease, but it is a fatal one. Ultimately 91.7 percent of SARS patients with acute renal impairment died, according to a 2005 study in Kidney International.
Like the liver, your kidneys act as a filter your blood. Each kidney is filled with about 800,000 of microscopic distilling units called nephrons. These nephrons have two main components: a filter to clean the blood and a little tubes that return the good stuff back to your body or send the waste down to your bladder as urine.
It’s the kidney tubules that seem to be most affected by these zoonotic coronaviruses. After the SARS outbreak, the WHO reported that the virus was found in kidney tubules, which can become inflamed.
It’s not uncommon to detect a virus in the tubules if it’s in your bloodstream, says Kar Neng Lai, a professor emeritus at the University of Hong Kong and consultant nephrologist at Hong Kong Sanatorium and Hospital. As your kidneys are continuously filtering blood, sometimes the tubular cells can trap the virus and cause a transient, or milder, injury.
That injury could become lethal if the virus penetrates the cells and begins to replicate. But Lai—who was also a member of the first group of researchers reporting on SARS and contributed to the Kidney International study—says there was no evidence that the SARS virus was replicating in the kidney.
That finding, Lai says, suggests acute kidney injury in SARS patients might be due to a diverse set of causes, including low blood pressure, sepsis, drugs, or a metabolic disturbance. Meanwhile, the more severe cases that led to acute renal failure showed signs of—you guessed it—a cytokine storm.
Acute renal failure can also sometimes be brought on by antibiotics, multi-organ failure, or being connected to a ventilator for too long. Everything is connected.
Pregnancy and coronavirus?
It’s the great irony of the Twitter age that we know too little about the novel coronavirus as we drown in information updates about it. Medical journals have published several studies about this outbreak—some more vetted than others as researchers rush to feed the maw. Meanwhile, news outlets are reporting every development. All this information whirls around the internet where discerning fact from fiction is a notorious challenge.
“This is really unprecedented in terms of the up-to-the-minute reporting on what’s going on in these studies,” Rasmussen says. “It’s really tricky trying to sort through all of the information and figure out what’s really supported, what’s speculative, and what’s plain wrong.”
For example last week, doctors at a hospital in Wuhan reported that two infants tested positive for the novel coronavirus, one just 30 hours after birth. Naturally, this troubling headline spread across news organizations, given it raised questions of whether pregnant women can infect their unborn children in utero or whether the disease can be transmitted during birth or through breast milk.
But let’s pump the brakes. Mother-to-infant transmission wasn’t observed with SARS nor MERS despite numerous cases involving pregnant women. Plus, there are other ways a newborn could catch the coronavirus, Rasmussen says, such as by being born at hospital overrun with infected patients during a hectic emergency.
In fact, a new study published Thursday in The Lancet offers preliminary evidence that the coronavirus cannot be passed from mother to child.
In the report, researchers observed nine women in Wuhan who had COVID-19 pneumonia. Some of the women had pregnancy complications, but all cases resulted in live births without evidence of transmitting the infection. While this study doesn’t completely rule out the possibility of transmission during pregnancy, it underscores the need to exercise caution in speculating about this disease.
“There needs to be a high standard of evidence before you can say that’s happening definitively—and certainly before you start making changes to how cases are managed clinically or in terms of public policy,” Rasmussen says.
Frieman agrees. He hopes this epidemic will prompt more funding for coronavirus research like the recent pledges from the European Union and the Bill & Melinda Gates Foundation. Last Thursday, China’s National Health Commission said more than 1,700 health care workers are ill with the new virus, and the announcement came just a day after the WHO wrapped a summit on the best protocols for hospital care and the development of therapeutics, like vaccines.
Frieman wants the support and interest to last even if this outbreak eventually fizzles out, unlike what happened with SARS research.
“Right after the SARS outbreak, there was a big bunch of money and then it went away,” Frieman says. “Why don’t we have these answers? Nobody funded these things.”
COVID and the brain: researchers zero in on how damage occurs
Growing evidence suggests that the coronavirus causes ‘brain fog’ and other neurological symptoms through multiple mechanisms.
How COVID-19 damages the brain is becoming clearer. New evidence suggests that the coronavirus’s assault on the brain could be multipronged: it might attack certain brain cells directly, reduce blood flow to brain tissue or trigger production of immune molecules that can harm brain cells.
Infection with the coronavirus SARS-CoV-2 can cause memory loss, strokes and other effects on the brain. The question, says Serena Spudich, a neurologist at Yale University in New Haven, Connecticut, is: “Can we intervene early to address these abnormalities so that people don’t have long-term problems?”
With so many people affected — neurological symptoms appeared in 80% of the people hospitalized with COVID-19 who were surveyed in one study1 — researchers hope that the growing evidence base will point the way to better treatments.
Breaking into the brain
SARS-CoV-2 can have severe effects: a preprint posted last month2 compared images of people’s brains from before and after they had COVID-19, and found loss of grey matter in several areas of the cerebral cortex. (Preprints are published without peer review.)
Early in the pandemic, researchers speculated that the virus might cause damage by somehow entering the brain and infecting neurons, the cells responsible for transmitting and processing information. But studies have since indicated3 that the virus has difficulty getting past the brain’s defence system — the blood–brain barrier — and that it doesn’t necessarily attack neurons in any significant way.COVID’s toll on smell and taste: what scientists do and don’t know
One way in which SARS-CoV-2 might be accessing the brain, experts say, is by passing through the olfactory mucosa, the lining of the nasal cavity, which borders the brain. The virus is often found in the nasal cavity — one reason that health-care workers test for COVID-19 by swabbing the nose.
Even so, “there’s not a tonne of virus in the brain”, says Spudich, who co-authored a review of autopsies and other evidence that was published online in April4.
But that doesn’t mean it is not infecting any brain cells at all.
Studies now suggest that SARS-CoV-2 can infect astrocytes, a type of cell that’s abundant in the brain and has many functions. “Astrocytes do quite a lot that supports normal brain function,” including providing nutrients to neurons to keep them working, says Arnold Kriegstein, a neurologist at the University of California, San Francisco.
In a preprint posted in January, Kriegstein and his colleagues reported5 that SARS-CoV-2 preferentially infects astrocytes over other brain cells. The researchers exposed brain organoids — miniature brain-like structures grown from stem cells in the lab — to the virus. SARS-CoV-2 almost exclusively infected astrocytes over all other cells present.
Bolstering these lab studies, a group including Daniel Martins-de-Souza, head of proteomics at the University of Campinas in Brazil, reported6 in a February preprint that it had analysed brain samples from 26 people who died with COVID-19. In the five whose brain cells showed evidence of SARS-CoV-2 infection, 66% of the affected cells were astrocytes.
Infected astrocytes could explain some of the neurological symptoms associated with COVID-19, especially fatigue, depression and ‘brain fog’, which includes confusion and forgetfulness, argues Kriegstein. “Those kinds of symptoms may not be reflective of neuronal damage, but could be reflective of dysfunctions of some sort. That could be consistent with astrocyte vulnerability.”The mini lungs and other organoids helping to beat COVID
Astrocytes might be vulnerable even if they are not infected by the virus. A study published on 21 June7 compared the brains of 8 deceased people who had COVID-19 with the brains of 14 controls. The researchers found no trace of SARS-CoV-2 in the brains of the infected people, but they did find that gene expression had been affected in some astrocytes, which were not working properly.
Given all these findings, researchers want to know how many brain cells need to be either infected or damaged to cause neurological symptoms, says Ricardo Costa, a physiologist at Louisiana State University Health in Shreveport whose team is studying SARS-CoV-2’s effects on brain cells.
Unfortunately, there probably isn’t a simple answer, says Kriegstein, pointing out that cells, including neurons, in some regions of the brain will cause more dysfunction than others, if damaged.
Blocking blood flow
Evidence has also accumulated that SARS-CoV-2 can affect the brain by reducing blood flow to it — impairing neurons’ function and ultimately killing them.
Pericytes are cells found on small blood vessels called capillaries throughout the body — including in the brain. A February preprint reported that SARS-CoV-2 could infect pericyte-like cells in brain organoids8.How COVID-19 can damage the brain
In April, David Attwell, a neuroscientist at University College London, and his colleagues published a preprint showing evidence that SARS-CoV-2 can affect pericytes’ behaviour9. The researchers observed that, in slices of hamster brain, SARS-CoV-2 blocks the functioning of receptors on pericytes, causing capillaries in the tissue to constrict. “It turns out this is a big effect,” says Attwell.
It’s a “really cool” study, says Spudich. “It could be something that is determining some of the permanent injury we see — some of these small-vessel strokes.”
Attwell suggests that drugs used to treat high blood pressure, which involves blood-vessel restriction, might be useful in some cases of COVID-19. Two clinical trials are currently investigating the effect of the blood-pressure drug losartan to treat the disease.
There is also growing evidence that some neurological symptoms and damage are the result of the body’s own immune system overreacting and even misfiring after encountering the coronavirus.
In the past 15 years, it has become clear that in response to infection, some people’s immune systems inadvertently make ‘autoantibodies’ that attack their own tissue, says Harald Prüss, a neuroimmunologist at the German Center for Neurodegenerative Diseases in Berlin. This can cause long-term conditions such as neuromyelitis optica, in which people experience symptoms such as loss of vision, and weakness in their limbs. In a review published in May10, Prüss summarized evidence that these autoantibodies can pass through the blood–brain barrier, and contribute to neurological disorders ranging from memory impairment to psychosis.Autopsy slowdown hinders quest to determine how coronavirus kills
This pathway might also operate in COVID-19. In a study published last year11, Prüss and his colleagues isolated antibodies against SARS-CoV-2 from people, and found one that was able to protect hamsters from infection and lung damage. The aim was to create new treatments. But the researchers also found that some of the antibodies could bind to brain tissue, suggesting that they might damage it. “We’re currently trying to prove that clinically and experimentally,” says Prüss.
In a second paper, published online last December, a team including Prüss studied the blood and cerebrospinal fluid of 11 people critically ill with COVID-19, all of whom had neurological symptoms12. All produced autoantibodies capable of binding neurons. And there is evidence that giving patients intravenous immunoglobulin, another type of antibody, to suppress the harmful autoantibodies’ action is “quite successful”, says Prüss.
These pathways — astrocytes, pericytes and autoantibodies — are not mutually exclusive, and are probably not the only ones: it is likely that people with COVID-19 experience neurological symptoms for a range of reasons. Prüss says a key question is what proportion of cases is caused by each of the pathways. “That will determine treatment,” he says.
How does COVID-19 affect the brain? A troubling picture emerges.
Researchers find that people who only suffered mild infections can be plagued with life-altering and sometimes debilitating cognitive deficits
Hannah Davis contracted COVID-19 in March 2020, the early days of the pandemic. At the time, the New Yorker was a healthy, 32-year-old freelance data scientist and artist. But unlike many people who come down with the disease, Davis’s first sign of infection wasn’t a dry cough or fever. Her first symptom was that she couldn’t read a text message from a friend. She thought she was just tired, but the fuzziness she felt didn’t go away after a full night’s sleep.
More neurological issues followed. She developed sudden and severe headaches. Her attention span suffered. She couldn’t watch TV or play video games. She had trouble concentrating on everyday tasks like cooking. She’d leave a pot on the stove and forget about it until she smelled food burning. She failed to look both ways while crossing the street, narrowly missing traffic. She’d never had any of these issues before COVID-19.
Davis is among a large portion of COVID-19 patients—possibly as high as 30 percent, according an estimate from the National Institutes of Health—who suffer some type of neurological or psychiatric symptoms. Even more troubling is that for many of these individuals, like Davis, these cognitive issues can linger for weeks or months after the initial infection.
Last year, dozens of hospitals and healthcare systems across the country opened post-COVID clinics to help patients who had been admitted to intensive care units with severe COVID-19. But as the pandemic has dragged on, those clinics have filled with people who were never hospitalized but suffer lingering symptoms, including brain fog and other cognitive issues.
“The expectation was that all these people in the ICU were going to have really long protracted recovery periods,” says Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health. “The big surprise was the people who never required hospitalization that are having persistent trouble.” Koroshetz is co-leading a study at NIH to understand why some COVID-19 patients recover faster than others and to learn the biological reasons why others don’t get well even months later.
A picture is starting to emerge of how COVID-19 causes these cognitive issues. What’s less clear is how many people will eventually recover and how many will be left with devastating long-term effects.
A year and a half later, Davis can only work a few hours a day because of lingering brain fog, short-term memory loss, and other cognitive issues. She’s seen a dozen or so medical specialists and has been diagnosed with post-viral dysautonomia, a nervous system disorder that causes dizziness, rapid heartbeat, and fast breathing when rising from sitting or lying down. It’s sometimes treated with fludrocortisone, a corticosteroid, or midodrine, a blood pressure drug.
“I’ve never experienced anything like this in my life,” Davis says. “Your body just it feels like it’s breaking down. You lose your sense of self.”
The Great British Intelligence Test
Before the pandemic began, cognitive neuroscientist Adam Hampshire and his colleagues at Imperial College London were planning a large, nationwide survey called the Great British Intelligence Test. Their goal: to understand how cognitive ability varies among the population and how factors like age, alcohol consumption, or occupation might affect cognition. The test, which is anonymous and takes about a half hour to complete, involves a questionnaire and exercises to measure planning and reasoning skills, working memory, and attention span.
With the help of the BBC, the team launched the survey in January 2020. As the pandemic began to unfold in the U.K., Hampshire and his colleagues realized they had a unique opportunity to capture cognitive data on both coronavirus patients and healthy people. In May 2020, they updated the test to include questions about experiences with COVID-19.
Out of more than 81,000 participants who took the questionnaire and test between January and December 2020, nearly 13,000 people reported COVID-19 infections varying from mild to severe. Among those, results revealed that they had cognitive issues compared with a group that not suffered from COVID-19.
“On the worst extreme of the spectrum, people who had gone to hospital and been put onto a ventilator showed the largest underperformance cognitively speaking,” Hampshire says.
These individuals had more trouble with reasoning, problem solving, and spatial planning on the test compared to people of their same age group and educational backgrounds who hadn’t been hospitalized with COVID-19. The difference was similar to the average cognitive decline seen over 10 years of aging. The findings were published in The Lancet on July 22.
The ICU brain
Though Hampshire’s findings sound startling, it’s fairly common for patients admitted to the ICU to suffer lasting cognitive issues. Megan Hosey, a rehabilitation psychologist at Johns Hopkins Medicine, says about a third of ICU patients who have acute respiratory failure have symptoms that are similar to those of traumatic brain injury.
One reason is because patients are often sedated in the ICU to reduce anxiety and discomfort, such as that caused by mechanical ventilators. Sedatives slow down brain activity and in doing so can cause delirium, a sudden change in mental status that leads to confusion and disorientation. Patients have trouble focusing or they may not know where they are; it’s a condition that can last hours, days, or even weeks.
“What we know is that the longer somebody is delirious, the worse their cognitive picture will look in the long-term,” Hosey says.
But sedation doesn’t explain all cases of neurological and cognitive issues in long-COVID patients, she says. Many COVID-19 patients don’t need ventilators, and others, like Davis, are never hospitalized.
Some previously hospitalized COVID-19 patients have such severe neurological and cognitive problems that they can’t participate in follow-up phone screenings about how they feel, says Jennifer Frontera, a neuro-critical care specialist at NYU Langone Health.
In a study published July 15, Frontera and her colleagues screened for neurological problems in patients admitted to the hospital with severe COVID-19. Of 382 patients, 50 percent reported that they had impaired cognition and a diminished capacity to carry out daily activities, walk, or take care of themselves six months after being discharged. Of those who worked prior to being hospitalized, 47 percent could not return to their jobs six months later.
The researchers also found that a subset of the 382 COVID-19 patients who had no previous neurological syndromes experienced strokes and seizures while in the hospital. At the same time, individuals with a history of neurological problems were at higher risk for developing new ones while hospitalized with COVID-19, Frontera says. The findings underscore just how much damage COVID-19 can do to the nervous system, especially those who develop severe disease.
In the U.K. cognition survey, a portion of those who had a confirmed case of COVID-19 but were not hospitalized had cognitive deficits as well, though not as severe as the hospitalized group. Other studies confirm that people who experienced “mild” or “moderate” COVID-19 can have lingering cognitive issues that have a profound impact on daily life.
Davis and others like her have formed the Patient-Led Research Collaborative, a self-organized group of long COVID-19 patients who are collecting data on neurological and other lasting symptoms. In a peer-reviewed paper published on July 15, Davis’s group found that out of nearly 3,800 people surveyed who suffered from long COVID, 85 percent reported “brain fog” — which the authors define as poor attention, problem-solving, executive-functioning, and decision-making. Only a small portion of those—317 people—were previously hospitalized with severe COVID-19.
In one post-COVID-19 clinic at Northwestern Memorial Hospital in Chicago, researchers found that many individuals with long COVID were never hospitalized yet had neurologic symptoms lasting longer than six weeks. Out of 100 patients, the most common neurologic manifestations were brain fog, and numbness and tingling, which affected 81 percent and 60 percent of patients respectively, according to a study published in March. These individuals also performed worse in attention and working-memory cognitive tasks compared to people their age who hadn’t gotten sick with COVID-19.
Probing the brain
Other viruses like West Nile, Zika, herpes simplex, and the virus that causes chickenpox and shingles are known to directly infect the brain. When COVID-19 patients first started reporting cognitive and neurological side effects last year, scientists wondered if SARS-CoV-2 might do the same thing.
Researchers started probing the brains of people who died of COVID-19 looking for traces of the virus. But brain tissue is hard to come by. Few people donate their brains to research, and strict protocols for handling potentially infectious brain tissue make studying it even more difficult. As a result, these studies are small, often involving just a handful to a few dozen patients.
While a few studies have detected the presence of the virus in neurons and their supportive glia cells, which hold neurons together like glue, scientists now think it’s unlikely that SARS-CoV-2 infects brain cells, at least in large enough quantities to cause neurological damage. If the virus is present there at all, it’s likely in very small amounts or is contained within the brain’s blood vessels.
A Columbia University study of 40 people who died of COVID-19 found no evidence of viral RNA or proteins in samples of patient brain cells. The results were published in April in the journal Brain. The authors suggest that previous reports of virus detected in brain cells may be due to contamination during the autopsy.
“The fact that SARS-CoV-2 is potentially causing these cognitive effects at a distance makes it a bit unusual,” says Christopher Bartley, a postdoctoral fellow in immunopsychiatry at the University of California, San Francisco, who wasn’t involved in the Columbia study.
If SARS-CoV-2 doesn’t infect brain cells, how is so destructive to cognition? There are two leading hypotheses.
The first is that the infection somehow triggers inflammation in the brain. Some COVID-19 patients have suffered encephalitis, or swelling of the brain, which can cause confusion and double vision, and in serious cases, speech, hearing, or vision problems. If left untreated, patients can develop cognitive problems. Viruses like West Nile and Zika can cause encephalitis by directly infecting the brain cells, but how COVID-19 may lead to brain inflammation is less clear.
An immune response run amok, known as autoimmunity, might be to blame for some instances of inflammation throughout the body, including the brain. When the immune system is fighting a disease like COVID-19, it unleashes antibodies to do battle against the infection. But sometimes a person’s immune system becomes hyperactive and instead starts making self-attacking antibodies, known as autoantibodies, which can contribute to inflammation and blood clots. These autoantibodies have been found in the cerebrospinal fluid of COVID-19 patients with neurological symptoms.
In the Columbia study, researchers found clusters of microglia—special immune cells in the brain whose job is to clear out damaged neurons—that appeared to be attacking healthy neurons. The phenomenon is called neuronophagia. Most of these rogue microglia were in the brain stem, which regulates heartbeat, breathing, and sleeping. The researchers think these microglia may get activated by signaling molecules called inflammatory cytokines found in patients with severe COVID-19. These molecules are supposed to help regulate the immune system, but some people’s bodies release too many inflammatory cytokines in response to a viral infection.
When researchers at Stanford looked at brain tissue from eight patients who died of COVID-19, they also observed signs of inflammation compared to 14 control brains. Using a technique called single-cell RNA sequencing, they found that hundreds of genes associated with inflammation were activated in brain cells from COVID-19 patients compared to controls.
They also noted molecular changes in the cerebral cortex, the part of the brain involved in decision-making and memory that suggested signaling imbalances in neurons. Similar imbalances have been seen in patients with Alzheimer’s disease. The results were published in Nature in June.
A second explanation for cognitive issues is that COVID-19 may restrict blood flow to the brain and deprive it of oxygen. In patients who have died of COVID-19, researchers have found evidence of brain tissue damage caused by hypoxia, or the lack of oxygen.
“The brain is an organ that requires a lot of oxygen to do its job,” says Billie Schultz, a physiatrist at the Mayo Clinic in Rochester, Minnesota, who specialized in rehabilitating stroke and traumatic brain injury patients before COVID-19 hit.
Other symptoms that accompany post-COVID-19 syndrome—pain, fatigue, and shortness of breath—can negatively affect cognition too, Schultz says. “It’s not just a brain issue; it’s a multi-system body issue that needs to be addressed.”
The next health crisis
Schultz is hopeful that many people experiencing persistent cognitive issues from COVID-19 will eventually improve. Many stroke and traumatic brain injury patients experience spontaneous recovery, in which the brain heals itself within three to six months.
But others worry that cognitive issues caused by COVID-19 may lead to dementia. At the Alzheimer’s Association International Conference in July, scientists presented research showing that hospitalized COVID-19 patients had similar blood biomarkers, neurodegeneration, and inflammation to those with Alzheimer’s disease. The research has not yet been peer-reviewed.
Heather Snyder, vice president of medical and scientific relations at the Alzheimer’s Association, cautions that the findings don’t necessarily mean someone who gets COVID-19 is more likely to develop Alzheimer’s or another type of dementia. “We’re still trying to understand those associations,” she says.
For now, there are no specific treatments for COVID-related brain fog, memory loss, and other cognitive effects. Instead, doctors are using cognitive therapy, occupational therapy, or speech-language pathology to treat symptoms. Many studies, like the NIH one, are trying to understand the underlying mechanisms of cognitive dysfunction in long COVID patients in hopes of identifying potential treatments.
“We and others are collecting anecdotal data from patients on what has helped them, but we are far from definitive therapeutics,” Frontera says.
In the U.S. alone, millions of people have developed lasting cognitive and neurological problems long after an initial COVID-19 infection. Some of these patients may be permanently disabled and need long-term care. “My concern is that we’re going to have huge numbers of the population who aren’t able to function at their cognitive baseline. They can’t go back to work, or at least not to what they did before,” Frontera says. “We haven’t even thought of the long-term implications. It could be an incredible blow to the economy.”
Davis says the scariest part about COVID-19’s cognitive effects is that people of all ages and health status are affected. “This is something everyone is at risk for, and it’s completely debilitating.”
How COVID-19 harms the heart
Many patients are experiencing heart palpitations, chest pain, and shortness of breath even after recovering from COVID-19. But new studies offer reason for hope.
Danielle Huff was on her treadmill when she first noticed the pain in her chest. She had just recovered from a terrible case of COVID-19 about two or three weeks earlier, during which she’d had just about every symptom imaginable: sore throat, headache, congestion, coughing, loss of smell, body aches, a mild case of pinkeye, and a constant heaviness in her chest like there was a bowling ball weighing it down.
But this feeling in her chest was different—it was a sharper pain that came on suddenly. Huff, an Illinois school administrator in her 30s, has a family history of heart issues, and she worried that it might signal something serious. Although she’d always tried to live a healthy lifestyle—doing yoga or walking every day—she soon found herself too frightened to exercise.
“It got to the point where I just couldn’t,” she says. “I was scared of the chest pain because I didn’t know what it was.” Ultimately, her doctor referred her to a cardiologist who specializes in treating patients who have recovered from COVID-19 but still experience cardiac symptoms.
From the earliest months of the pandemic, scientists have suspected that COVID-19 is not just a disease of the lungs, but also a disease of the heart and blood vessels. “We realized very, very early that clotting was playing a major role,” says Jeffrey Berger, director of New York University Langone’s Center for the Prevention of Cardiovascular Disease. Even in March 2020, physicians were seeing unexpectedly high rates of blood clots in their patients, leading to a rise in heart attacks and strokes. Autopsies also revealed masses of tiny blood clots in places where doctors don’t normally see them, such as the liver and the kidneys.
Now it has become clear that COVID-19’s cardiovascular damage doesn’t resolve as soon as a patient recovers from the initial infection. For some patients, MRI scans show signs of inflammation months after clearing the virus. Others continue to have elevated levels of troponin, a chemical that’s released into the blood whenever there’s damage to the heart muscle.
Oddly, Huff took a battery of heart-related tests and the results came back normal. Still, she found herself so short of breath she had to step out of a yoga class and couldn’t walk across her school building without needing to sit down. And about a month after she recovered from COVID-19, she began feeling random heart palpitations.
Adding to the mystery, some people who had only mild or even asymptomatic cases of COVID-19 also report long-lasting symptoms such as heart palpitations, chest pain, shortness of breath, and extreme fatigue. Scientists are still baffled about what’s causing them.
“To me there’s no question these individuals are suffering real symptoms,” says James de Lemos, a cardiologist at the University of Texas Southwestern Medical Center and a co-chair of the American Heart Association’s COVID-19 CVD registry steering committee. “The question is, is there some injury to the heart that’s leading to symptoms that we’re not seeing?”
There is reason for hope. Researchers have made strides toward understanding how to prevent COVID-19 from attacking the heart and blood vessels. Meanwhile, physicians are learning more every day about how to treat long COVID symptoms—and rigorous investigations are underway to help shed light on why they occur.
How COVID-19 attacks the cardiovascular system
Physicians quickly learned in early 2020 that the use of blood thinners, which help keep blood from clotting, improved the chances of survival for moderately ill COVID-19 patients. But Berger says it also became clear that there was more to the deadly blood clotting than what they could treat with these anticoagulant therapies alone.
“One in four patients were still dying or requiring organ support,” he says.
In the last five to 10 years, scientists have begun to understand that platelets play a role in promoting unwanted clotting and inflammation in other diseases such as HIV, psoriasis, lupus, and rheumatoid arthritis. These tiny round blood cells serve one major purpose: to stop bleeding by binding to a damaged blood vessel and forming a clot. With that in mind, Berger and a team of researchers set out to investigate what role the platelets might play in COVID-19.
“We found it was nothing like we would have expected,” Berger says. “It was like somebody changed the genetic architecture of these platelets.”
In a study published in Science Advances, the researchers showed that the virus can enter megakaryocytes, the bone marrow cells that make platelets. The infected cell then alters the genetic material in the platelets so that they become more active and give off protein signals that make the lining of the blood vessels sticky and inflamed. This makes the vessels prone to developing clots that can spread throughout the body.
Scientists also learned that the virus weakens connections in the tissue that lines blood vessels, making them leaky instead of sealing them up, as you might expect when clots are present.
“It’s like a double-edged sword,” says Ben Maoz, a biomedical engineer at Tel Aviv University and lead author of a recent study that identified the SARS-CoV-2 proteins that cause the most damage to the blood vessel lining. Somehow, he says, COVID-19 affects the blood vessels “in a dual and opposite way.”
Leaky vessels allow blood and other chemicals in the body to spill into places they’re not supposed to go—including the air sacs of the lungs and the tissues of other organs. That can have a cascade of downstream effects, from the flooded lungs seen in many severe COVID-19 cases to complications of the liver, kidneys, and, of course, the heart.
“Things we’re supposed to be protected from are suddenly coming in,” Maoz says. He likens the harm this causes to a garbage bag with holes in it: Those holes will allow some waste to seep back into your home. Some of the subsequent damage, like the smell and the foul liquid, will be noticeable right away. But others—like, say, a resulting rat infestation—may not be evident for months. The extent of that harm will depend on how bad the leak was and how long it lasted.
But it’s not clear exactly how this blood vessel damage is connected to the lingering cardiovascular symptoms in patients who have recovered from COVID-19. Maoz points out that the virus causes harm in many complex ways that are difficult to disentangle. Yet physicians have continued to see signs of damaged heart tissue such as myocarditis, inflammation of the heart muscle, or high levels of troponin months after hospitalization from COVID-19.
Berger says it’s not unusual for a virus that causes such severe inflammation to have residual consequences post-recovery—particularly among patients who had moderate or severe disease and needed to be hospitalized. Worryingly, some patients who had asymptomatic, mild, or moderate disease—including children—also have similar evidence of heart damage.
Yet mounting evidence suggests that myocarditis due to COVID-19 is more rare than initially believed, de Lemos says. In September a Centers for Disease Control and Prevention study showed that the risk of myocarditis is nearly 16 times higher in patients with COVID-19 than those without. However, the study concluded that the condition is uncommon for both populations—and the risk of myocarditis from COVID-19 is just 0.146 percent. De Lemos says the condition also does heal within months.
“Most of those hearts look fairly normal when reevaluated during follow-up,” he says.
Then there are patients like Huff. Amanda Verma, a cardiologist who treated Huff at the Washington University School of Medicine’s post-COVID clinic in St. Louis, says that some patients come in with chest pain but their stress tests are normal. Others complain of palpitations, yet when equipped with heart rate monitors, their heart rhythms appear normal. Still, Verma says those tests aren’t telling the whole story.
“If you dig a little deeper, you’ll notice that the heart rate pattern isn’t quite normal,” she says. Although it’s expected for a person’s heart rate to rise while walking, it’s not normal for the heart rates of younger and athletic patients to jump from 60 to 120 just from walking across a room or while they’re asleep—which is what was happening to Huff.
This abnormal increase suggests COVID-19 triggered dysfunction in the autonomic nervous system, the pathways of nerve cells that automatically control vital functions such as breathing and the heartbeat, Verma says. It’s part of the evolutionary “fight or flight” response that allows your body to function without having to be consciously instructed. For COVID-19 long-haulers, that system appears to be out of whack.
“People often tell me they’re exhausted by the end of the day—and, yeah, who wouldn’t be if your heart rate was up that high all day?” Verma says. “It’s like you’ve been running all day.”
Scientists have yet to understand how COVID-19 might be causing this type of dysfunction. Some hypotheses suggest it could be a result of the body’s excessive inflammatory response to the virus, or perhaps it could even be related to sex hormones, since women are more likely than men to become COVID-19 long-haulers. Either way, the inability to name the syndrome makes it challenging to get insurance companies to cover treatments—and is maddening for patients who feel their symptoms are not being taken seriously.
“It’s unbelievably frustrating for patients who suffer from this because they don’t get answers,” de Lemos says. “To some extent validating that this is real is the first step. This is real illness, and we just don’t understand it yet.”
Reasons for hope
Researchers are making progress on finding treatments that could reduce the severity of COVID-19—and ultimately improve cardiovascular outcomes. Berger and his team are studying drugs that target the platelets to prevent them from activating and causing clotting.
Meanwhile, Maoz and his team have identified the five virus proteins that cause the most harm to the blood vessel lining. They are testing a model that will allow researchers to identity the proteins that inflict damage on other parts of the body. This molecular understanding will help to develop drugs that can block the specific proteins from attacking the blood vessels and causing critical illness.
“It’s amazing to see how fast we’ve been able to adapt and answer fundamental questions,” Berger says. “The speed of science has dramatically improved.”
However, he acknowledges that none of these potential drugs that would prevent the platelets from clotting or block the virus proteins from attacking the blood vessels will help people who are already suffering from long COVID. To do that, scientists ultimately need to figure out what’s behind their strange constellation of symptoms.
Earlier this year, the National Institutes of Health launched a collaborative research initiative that will support large-scale studies of long COVID-19 in children and adults. And Verma says that physicians who specialize in long COVID-19 are starting to find ways to treat it, from prescribing anti-inflammatories for chest pain to beta blockers for reducing a patient’s blood pressure when their heart rate is out of control. Even exercise—when carefully monitored and structured so that it doesn’t exacerbate fatigue—can help.
There’s also anecdotal evidence that long COVID can resolve over time—even if that may take a year to 18 months. Verma says she’s been able to take some of her patients off their medication, and many of those who haven’t recovered completely do eventually feel better after treatment
“The big question though is, is this going to impact their health in 10 or 15 years down the road?” she says. “Did it do something we just can’t see?”
For Huff, things have gotten better. After taking medications for her high blood pressure and elevated heart rate, the palpitations and shortness of breath have dissipated. Intriguingly enough, so did the frequent migraines that she’s had since she was 13. She’s still too afraid of the chest pain to go back to exercising, but she’s hopeful for the answers that ongoing research and open communication between doctors and their patients may yield as they learn together about the long-term implications of COVID-19.
“There’s a lot to learn, and I can understand the frustration with not knowing what’s going on,” she says. “But I’m at a point of acceptance that I’m just not going to have all the answers right now.”
The real risk of heart inflammation to kids is from COVID-19—not the vaccine
Pediatric experts agree that an infection causes more severe heart issues—and carries higher risk for long-term or permanent damage.
Elizabeth Brown, a mother of two who lives outside Denver, Colorado, had a tough decision to make when childhood COVID-19 vaccines became available. Her five-year-old was born with a congenital heart defect that required a risky surgery when he was two years old to avoid a lifelong risk of heart inflammation from infection. But Brown also knew that after getting some COVID-19 vaccines, adolescent boys are at risk of developing myocarditis, a different kind of inflammation of the heart.
”To read about children with no cardiac history having myocarditis as a pediatric vaccine complication was scary,” Brown says. “There were a lot of inflammatory headlines from the media that preyed on a parent’s fear in terms of the vaccination and very little information readily available regarding the damage COVID can do.”
Brown spoke with her son’s cardiologist and mulled it over for weeks. As more information came out, she says, “I became more confident in vaccination.” Her son received his first vaccine dose two weeks ago.
Many pediatricians and pediatric cardiologists lament that myocarditis—a rare side effect from the mRNA COVID-19 vaccines in adolescents—has been hyped, receiving arguably more attention than the life-saving benefits of the vaccine. Likewise, they say, some physicians who treat adults have minimized the threat that COVID-19 poses to children. Meanwhile, two members of the advisory board that recommended the Food and Drug Administration authorize the vaccine for children between ages 5 and 11 have questioned whether all younger children should be vaccinated before there is more information on the risk of myocarditis.
The mixed messages have left parents feeling confused and uncertain. Although more than one million children ages five through 11 in the U.S. have now been vaccinated, a substantial proportion of parents remain uneasy about it, according to a recent nationwide survey. Shortly before the FDA authorized the Pfizer vaccine for younger children, one in three parents planned to “wait and see” before vaccinating their kids, according to a Kaiser Family Foundation poll. Another 27 percent planned to vaccinate their kids immediately, while 30 percent said they would not vaccinate their kids at all.
Yet review of more than two dozen articles in peer-reviewed medical journals, government documents, and interviews with 10 pediatric cardiologists and pediatricians offer a reassuring picture of the safety of pediatric COVID-19 vaccination. Myocarditis after the vaccine is rarer and usually milder than the cardiac complications from COVID-19, including those from multisystem inflammatory syndrome (MIS-C), says Matthew Elias, a pediatric cardiologist at Children’s Hospital of Philadelphia. MIS-C is a serious condition that can occur two to six weeks after an acute SARS-CoV-2 infection in about one out of 3,200 infected children, even if the infection was mild or asymptomatic. MIS-C can involve inflammation of many organs, including the heart, lungs, kidneys, brain, skin, eyes, and digestive organs. The Centers for Disease Control and Prevention reports that more than 5,500 U.S. children have had MIS-C since the pandemic began, though experts believe that’s an underestimate.
“The pediatric hospital experience shows that the risk of patients at any age having cardiac involvement from COVID is uniformly worse than vaccination myocarditis risk,” says Frank Han, a pediatric cardiologist at OSF Healthcare in central Illinois. Like Elias, Han says most vaccine-associated myocarditis cases are mild, without “significant disturbance to the heart function or inability to maintain blood pressure.”
Different types of myocarditis
Broadly speaking, myocarditis refers to inflammation of the heart and can involve a wide range of symptoms and severity, from very mild pain to heart failure, explains Elias. But different types of myocarditis exist, including three types related to COVID-19: myocarditis from the SARS-CoV-2 infection itself, from COVID-19-triggered MIS-C, and from the vaccine.
Myocarditis during a COVID-19 infection is similar to the classic myocarditis that pediatric cardiologists use to describe what they see with some non-COVID viral infections. But this classic type is more frequent in adults with COVID-19 and rarely occurs in children sick with COVID-19.
What’s far more common in children is either myocarditis from MIS-C, or cardiac symptoms associated with MIS-C that resemble myocarditis. Part of the confusion over pediatric rates of myocarditis related to COVID-19 stem from trying to characterize the cardiac symptoms of MIS-C—whether to call them myocarditis or not—since MIS-C is such a new phenomenom.
What most pediatric cardiologists agree on is that cardiac complications seen with MIS-C are more serious than the myocarditis seen from the vaccine.
Though nearly all children who suffered cardiac problems connected to MIS-C have since recovered, the long-term effects remain unclear. Some children with MIS-C get coronary artery aneurysms, in which a coronary artery widens well beyond what’s considered normal, says Jacqueline Szmuszkovicz, a pediatric cardiologist who specializes in MIS-C at the Heart Institute at Children’s Hospital Los Angeles. Though rare, these aneurysms can sometimes be fatal. They also require long-term follow-up, possibly until adulthood, since they may affect a child’s future risk of coronary artery disease, Han says. Importantly, these aneurysms have been seen with MIS-C but not with the vaccine.
By contrast, one of the first case reports of post-vaccine myocarditis, published in early June, revealed relatively mild characteristics that subsequent research confirmed: Chest pain and shortness of breath are the most common symptoms, sometimes accompanied by a fever. Treatment includes ibuprofen for pain and sometimes steroids or a drug called IVIG that boosts the immune system. Hospital stays typically last a few days, primarily for monitoring. Su says most teens who develop post-vaccine myocarditis probably don’t need hospitalization, but since the phenomenon is new, most clinicians err on the side of caution.
Elias adds that vaccine-related myocarditis is still very stressful for parents. Indeed, two families who spoke with National Geographic described how terrifying it was to see their teen sons hospitalized with chest pain and then restricted from physical activity for several months after they went home. “When we say mild,” Elias adds, “we don’t want to minimize the stress that parents feel when their child is in the hospital.”
Comparing risks of the vaccine and the disease
Many parents want to be able to compare the risk of myocarditis from contracting COVID-19 with the risk of getting it from the vaccine. But experts say that’s difficult to judge.
For starters, one to three cases of myocarditis per 100,000 children and teens typically occur each year unrelated to COVID-19, explains Jennifer Su, director of heart failure and cardiomyopathies at the Heart Institute of Children’s Hospital Los Angeles. Still, researchers estimate that risk is 36 times higher in children under 16 who have had COVID-19, she says. Elias says that about 50 percent of the children he treated with MIS-C have decreased heart function resembling myocarditis, and one study found that 75 percent of 255 patients with MIS-C had myocarditis.
Rates of myocarditis after the vaccine vary by age and sex, with adolescent boys more likely than other groups to experience myocarditis after vaccination. In a study of more than four million mRNA vaccine doses given to adolescents ages 12 though 17, the risk of post-vaccine myocarditis was about one in 16,000 boys and one in 115,000 girls.
No reports of myocarditis after the vaccine have been reported so far in children under 12—the age group at highest risk for MIS-C. The largest and most rigorous peer-reviewed study to investigate myocarditis after vaccination, by a group of Israeli university and government scientists, identifies boys ages 16 to 19 as the highest risk group: one out of 6,637 vaccine recipients of these ages develop myocarditis after the second dose.
Many questions remain about myocarditis from the vaccine, and the CDC has continued tracking and investigating cases. The only known risk factor is being an adolescent male, but it’s not clear why, nor do researchers know if there’s a genetic risk, if a lower vaccine dose reduces the risk, or why the vaccine can cause myocarditis, though several hypotheses exist. It’s also unclear if some small percentage of cases will have long-term effects.
Published research so far shows that nearly all adolescents fully recover, but Michael Portman, director of pediatric cardiovascular research at Seattle Children’s Hospital, is concerned about heart inflammation seen on cardiac MRIs three months later in a few teens who had vaccine-related myocarditis. It may resolve in another three months, but “the jury’s still out,” he says, and “we need to find out what happens long term.” Elias likewise says it’s too soon to say if some late inflammation he’s seen in a couple cases will fully resolve, but those cases make up a small fraction of vaccine-related myocarditis.
“I make it really clear that we encounter many more heart issues and more severe heart issues from COVID-19 itself compared to the vaccine,” Elias says.
Regardless, fixating only on myocarditis and ignoring other impacts of the virus doesn’t tell the full story, says Daniel Freeman, a pediatric neurologist in Austin, Texas. He pointed out that one in four children who have died from COVID-19 had no underlying conditions. Then there’s the potential long-term impact of the disease to consider, including neurological effects he has seen.
Further, the risk of MIS-C is that it can involve organs in nearly every major body system. About 60 to 70 percent of children with MIS-C are admitted to the ICU, and one to two percent die. By contrast, vaccine-related myocarditis rarely requires ICU admission and has not resulted in any documented deaths in adolescents.
Aside from MIS-C, COVID-19 is also more serious for children than the flu, with higher rates of ICU admission and intubation and longer hospital stays. Since the pandemic began, COVID-19 has been responsible for 1.7 percent of all deaths in children ages five to 11.
The likelihood that vaccine-caused myocarditis will significantly affect kids’ lives long-term is “just infinitesimally small compared to your risk of getting really sick from COVID,” Su says. “Unfortunately, in this phase of the pandemic, I think the choice is not really to get vaccinated or not, the choice is would you rather get COVID or get the vaccine.”
Brown, the Colorado mother who vaccinated her five-year-old son with a congenital heart defect, accepts that “everything has risks.” She and her husband had already opted for the short-term, rare risks of the procedure to correct his heart condition instead of the lifetime risk of infection-caused endocarditis, a life-threatening inflammation of the heart’s inner lining.
“I saw the vaccine as the same,” Brown says. “We would take the incredibly small risk of a potential short-term vaccine complication over the lifelong, unpredictable and possibly life-ending or life-altering risks of contracting COVID.”
Can COVID-19 lead to diabetes? Here’s what you need to know
New studies show that the COVID-19 virus can attack the pancreas, destroy cells that make insulin, and cause some cases of diabetes.
During the spring of 2020, physicians in New York City, the U.S. epicenter of the pandemic at the time, noticed a considerable number of people hospitalized with COVID-19 had too much sugar in their blood, a condition called hyperglycemia that is a signature feature of diabetes.
“[My colleagues and I] found it very challenging to control the blood glucose level of some COVID-19 patients, even those without a history of diabetes,” says stem cell biologist Shuibing Chen at Weill Cornell Medicine. More surprising, says Chen, was that some patients who did not have diabetes prior to the infection, developed new-onset diabetes after recovering from COVID-19.
The COVID-19 virus, SARS-CoV-2, is best known for wreaking havoc in the lungs and causing acute respiratory distress. But how and why a COVID-19 patient would suddenly develop a chronic disease like diabetes is a mystery, as is the number of people who must then deal with this complication.
A global 2020 analysis led by population health researcher Thirunavukkarasu Sathish at McMaster University in Canada found that nearly 15 percent of severe COVID-19 patients also developed diabetes. But, he admits, “this figure is likely to be higher among high-risk individuals, prediabetes for example.”Research led by endocrinologist Paolo Fiorina at Harvard Medical School and published in 2021 reported that of 551 patients hospitalized for COVID-19 in Italy, nearly half became hyperglycemic.
Peter Jackson, a biochemist at the Stanford University School of Medicine, estimates “as many as 30 percent of patients with severe COVID-19 may develop diabetes.”
Intrigued by the startling connection between COVID-19 and diabetes, Chen and Jackson both launched independent investigations to uncover how SARS-CoV-2 might trigger hyperglycemia. Both groups published their results in the May issue of Cell Metabolism.
“Their findings provide critical insights into the underlying mechanisms by which COVID-19 can lead to the development of new-onset diabetes in infected patients,” says Rita Kalyani, an associate professor of medicine at Johns Hopkins Division of Endocrinology, Diabetes, and Metabolism, who was not involved with either study.
The pancreas is another target of the COVID-19 virus
SARS-CoV-2 affects people in very different ways. Many people experience only minor symptoms, but others develop severe, life-threatening disease. As the pandemic unfolded it became apparent that this virus could spread beyond the lungs and damage other critical organs, including the liver, heart, and kidneys. It also became clear that diabetes and obesity were common risk factors for severe COVID-19.
In an earlier study, Chen’s group grew various types of tissues in the lab and tested which ones were vulnerable to the COVID-19 virus. “Very surprisingly, we found that beta cells of the pancreas are highly permissive to SARS-CoV-2 infection,” says Chen. The pancreas, which lies behind the stomach, is a complex organ composed of numerous types of cells that assist with digestion. It also contains beta cells that make insulin, the hormone that escorts sugar molecules from the blood into the body’s cells where it is used for energy.
But just because a virus can infect cells grown in a dish in the lab doesn’t mean it attacks the body in the same way. To ensure the laboratory observations were a true reflection of what happens in living humans, both the Chen and Jackson teams acquired autopsy samples from patients who succumbed to COVID-19. Both groups detected SARS-CoV-2 in pancreatic beta cells from these deceased patients.
But how, exactly, does a respiratory virus move from the lungs to the pancreas? After patients experience pneumonia, the infection of the lower lung may cause tissue damage that allows the virus to leak from lung alveoli and into the blood vessels, explains Jackson. “Once in circulation, the virus can enter other highly vascularized tissues like the pancreas, brain, and kidney.” Others have speculated that the virus could get into the bloodstream by leaking out of the gut, which may occur in patients lacking healthy intestinal bacteria. (Microbes in your gut may be new recruits in the fight against viruses)
How the virus shuts down insulin production
Both research teams noted that beta cells infected with SARS-CoV-2 stop making insulin. In Jackson’s study, the infected beta cells died via apoptosis, a genetically-programmed autodestruct sequence initiated by injured cells.
Chen’s group found that infected beta cells underwent a process called transdifferentiation, which means they converted into another type of cell; one that no longer manufactures insulin. It is possible that some infected beta cells undergo transdifferentiation while others self-destruct.
In both cases, the end result is the same: when the COVID-19 virus attacks the pancreatic beta cells, insulin production decreases.
This can lead to type 1 diabetes, which is usually caused by genetic risk factors that spur an autoimmune reaction that attacks and destroys beta cells. Type 1 diabetes is more commonly seen early in life and requires patients to inject insulin every day since their body no longer makes the hormone. Type 1 diabetes also involves an environmental trigger, such as an infection, to initiate the autoimmune reaction.
In contrast, the far more common type 2 diabetes occurs when the body becomes resistant to the insulin it makes. Type 2 diabetes can be managed with changes in diet and exercise, although sometimes medications that enhance insulin sensitivity are needed. Collectively, 34.2 million Americans have diabetes according to a 2020 report issued by the Centers for Disease Control.
The fate of the infected beta cells is important to study further as there may be a way to prevent their destruction in patients with severe COVID-19. Chen’s team surveyed a large panel of chemicals in hopes of finding one that could prevent the transdifferentiation process.
The survey identified a compound called trans-ISRIB that helped beta cells maintain their identity and their ability to produce insulin when infected with SARS-CoV-2. Trans-ISRIB, which stands for Integrated Stress Response InhiBitor, is a compound discovered in 2013 that is able to prevent a cell’s normal response to stress. Such compounds are being explored as potential therapeutics to prevent widespread apoptosis and damage.
Chen cautions, “Trans-ISRIB is not an FDA-approved drug, so it cannot be used in patients yet. But our studies support the idea that a new drug could be developed to prevent COVID-19 from causing diabetes.” Jackson’s group found that a cellular protein receptor called neuropilin-1 was critical for SARS-CoV-2 to invade beta cells; blocking this receptor keeps them from being infected.
There is also great interest among the broader research community to develop drugs that stop cells from destroying themselves by apoptosis. Experimental compounds called caspase inhibitors, which prevent cell suicide, are being studied by others as potential therapies to ameliorate or prevent severe COVID-19. Unfortunately, caspase inhibitors have not proved a complete success in the clinic despite great promise and interest. Nonetheless, “they might work for short term exposure to limit viral damage,” Jackson says.
Chen adds that SARS-CoV-2 is not the only virus that threatens the pancreas. “Coxsackievirus B, rotavirus, mumps virus, and cytomegalovirus have been shown to infect and damage beta cells. Whether they are a direct cause of type 1 diabetes has been controversial.” More research is needed to determine if it is possible to neutralize the viral attacks on the pancreas, either by blocking infection or preventing the virus from reaching the organ in the first place.
Kalyani stresses that these studies “further underscore the importance of getting vaccinated for COVID-19. Individuals who contract COVID-19, particularly those with prediabetes or other risk factors for diabetes, should let their health care providers know if they develop symptoms of hyperglycemia such as frequent urination, excessive thirst, blurry vision, or unexplained weight loss.”
These new findings emphasize that there is much to learn about COVID-19 and its aftereffects. It seems clear that for some unlucky people, defeating the virus is only the beginning. Additional complications may arise depending on which systems in the body have been damaged in the wake of the viral infection.
Why some COVID-19 infections may be free of symptoms but not free of harm
Scientists are studying the potential consequences of asymptomatic COVID-19 and how many people may suffer long term health problems.
Eric Topol was worried when he first saw images of the lungs of people who had been infected with COVID-19 aboard the Diamond Princess, a cruise ship that was quarantined off the coast of Japan in the earliest weeks of the pandemic.
A study of 104 passengers found that 76 of them had COVID but were asymptomatic. Of that group, CT scans showed that 54 percent had lung abnormalities—patchy gray spots known as ground glass opacities that signal fluid build-up in the lungs.
These CT scans were “disturbing,” wrote Topol, founder and director of the Scripps Research Translational Institute, with co-author Daniel Oran in a narrative review of asymptomatic disease published in the Annals of Internal Medicine. “If confirmed, this finding suggests that the absence of symptoms might not necessarily mean the absence of harm.”
The United States has recorded nearly 40 million COVID-19 infections since the beginning of the pandemic. One recent study estimated that a staggering 35 percent of all COVID-19 infections are asymptomatic. “That’s why it’s important to know if this is a vulnerability,” Topol says.
But Topol says he hasn’t seen any further studies investigating lung abnormalities in asymptomatic people in the more than a year and a half since the Diamond Princess cases were first documented. “It’s like we just gave up on it.”
He argues that asymptomatic disease hasn’t gotten the attention it should amid the race to treat severe disease and develop vaccines to prevent it. As a result, scientists are still largely in the dark about the potential consequences of asymptomatic infections—or how many people are suffering those consequences.
One stumbling block that scientists worry could keep them from truly understanding the scope of the problem is that it’s incredibly challenging to pinpoint how many people had asymptomatic infections. “There’s probably a pool of people out there who had asymptomatic disease but were never tested so they don’t know they had COVID at that time,” says Ann Parker, assistant professor of medicine at Johns Hopkins and a specialist in post-acute COVID-19 care.
Still, there is some evidence that asymptomatic disease can cause serious harm among some people—including blood clots, heart damage, a mysterious inflammatory disorder, and long COVID, the syndrome marked by a range of symptoms from breathing difficulties to brain fog that linger after an infection. Here’s a look at what scientists know so far about the effects of asymptomatic COVID-19 and what they’re still trying to figure out.
Heart inflammation and blood clots
Just as imaging scans have revealed damage to the lungs of asymptomatic individuals, chest scans have also shown abnormalities in the hearts and blood of people with asymptomatic infections—including blood clots and inflammation.
Thrombosis Journal and other publications have described several cases of blood clots in the kidneys, lungs, and brains of people who hadn’t had any symptoms. When these gel-like clumps get stuck in a vein, they prevent an organ from getting the blood it needs to function—which can lead to seizures, strokes, heart attacks, and death.
There have been relatively few of these case reports—and it’s unclear whether some patients might have had other underlying issues that could have caused a clot. But the Washington State researchers who reported on one case of renal blood clot write that it “suggests that unexplained thrombus in otherwise asymptomatic patients can be a direct result of COVID-19 infection, and serves as a call to action for emergency department clinicians to treat unexplained thrombotic events as evidence of COVID-19.”
Meanwhile, studies also suggest that asymptomatic infections could be causing harm to the heart. In May, cardiac MRI scans of 1,600 college athletes who had tested positive for COVID-19 revealed evidence of myocarditis, or inflammation of the heart muscle, in 37 people—28 of whom hadn’t had any symptoms, says Saurabh Rajpal, a cardiovascular disease specialist at the Ohio State University and lead author on the study.
Myocarditis can cause symptoms such as chest pain, palpitations, and fainting—but sometimes it doesn’t produce any symptoms at all. Rajpal says that while the athletes in the study were asymptomatic, “the changes on the MRI were similar to or almost the same as those who had clinical or symptomatic myocarditis.”
Although these chest scans are worrisome, Rajpal says that scientists don’t know yet what they ultimately mean for the health of asymptomatic patients. It’s possible that myocarditis might resolve over time—perhaps even before patients know they had it—or it could develop into a more serious long-term health issue. Long-term studies are necessary to suss that out.
The athletes’ heart inflammation might also be completely unrelated to their COVID-19 infection. Scientists would need to compare the scans with a set taken just before an individual was infected with COVID-19. So that, Rajpal says, will still need to be teased out.
Additionally, people with asymptomatic infections are at risk of becoming so-called COVID-19 long-haulers, a syndrome whose definition has been hard to pin down as it can include any combination of diverse and often overlapping symptoms such as pain, breathing difficulties, fatigue, brain fog, dizziness, sleep disturbance, and hypertension.
“There’s a myth out there that it only occurs with severe COVID, and obviously it occurs far more frequently in mild COVID,” Topol says.
Linda Geng, co-director of Stanford Health Care’s Post-Acute COVID-19 Syndrome Clinic, agrees. “There is actually not a great predictive factor about the severity of your illness in the acute phase and whether you will get long COVID,” she says. “And long COVID can be quite debilitating, and we don’t know the endpoint for those who are suffering from it.”
Studies attempting to assess how many asymptomatic infections account for long COVID symptoms have varied. FAIR Health, a national healthcare nonprofit, found from an analysis of healthcare claims that about a fifth of asymptomatic patients went on to become long-haulers. Another study, which is under peer review, used data from the University of California’s electronic health records and estimated that number could be as high as 32 percent.
Melissa Pinto, a co-author of the latter study and associate professor in the Sue & Bill Gross School of Nursing at University of California Irvine, says the researchers examined healthcare records of people who tested positive for COVID-19 but hadn’t reported symptoms at the time of infection—only to come in later with symptoms associated with long COVID-19. To ensure they were identifying long-haulers, the researchers screened out anyone with a preexisting illness that could explain their later symptoms.
“This is not from another chronic disease,” she says. “These are new symptoms.”
But it’s unclear how accurate any of these estimates might be. Pinto says that some long-haulers are wary of seeking care after having their symptoms dismissed by physicians who weren’t familiar with long COVID-19 syndrome. That’s why she believes that the rates of asymptomatic infections among long-haulers are an underestimate.
Anecdotally, Geng and Parker both say that while they’ve seen plenty of patients with mild symptoms that initially went unrecognized, they’ve had little experience treating patients who were truly asymptomatic.
“We saw many patients who didn’t think they had symptoms except in retrospect because they found out that they had tested positive,” Geng says. “Because they’ve had these long unexplained symptoms of what’s presumed to be long COVID, they think, well, maybe that wasn’t allergies.”
But she thinks that most people who were truly asymptomatic are unlikely to have gotten tested and therefore wouldn’t think to consult a specialist in post-COVID-19 care if they started experiencing unexplained symptoms like brain fog and dizziness.
Parker says that ultimately physicians are still trying to understand the broad symptoms seen in long-haulers. “When a patient comes to see us, we do a very thorough evaluation because we still don’t know exactly what to attribute to COVID and what might be a pre-existing underlying syndrome,” she says. “The last thing I want to have happen is to say to a patient, yes, this is because you had COVID and miss something else that we could have addressed.”
Mysterious inflammation in children
Physicians have also seen troubling clinical manifestations of asymptomatic COVID-19 in children. Early in the pandemic, reports emerged of a rare and mysterious inflammatory syndrome similar to Kawasaki disease that typically sets in weeks after an initial infection.
“Six weeks down the line these people, especially children, will develop inflammation throughout their body,” Rajpal says.
The condition—now called multisystem inflammatory syndrome in children, or MIS-C—typically causes fever, rash, abdominal pain, vomiting, and diarrhea. It can have harmful effects on multiple organs, from hearts that have trouble pumping blood to lungs that are scarred. It is typically seen among children under 14, although adults have also been diagnosed with this syndrome.
MIS-C is incredibly rare. Kanwal Farooqi, assistant professor of pediatrics at Columbia University Vagelos College of Physicians and Surgeons, says that less than one percent of pediatric COVID-19 patients present with some type of critical disease—and MIS-C is just one of them. However, asymptomatic infections do play a role in the syndrome: A recent study of 1,075 children who had been diagnosed with MIS-C showed that three-quarters had originally been asymptomatic.
But there’s reason to hope that this syndrome might not cause long-term effects in patients, symptomatic or otherwise. Farooqi was the lead author on a recent study of 45 pediatric patients showing that their heart problems—which ranged from leaky valves to enlarged coronary arteries—mostly resolved within six months.
“That is reassuring,” Farooqi says. Still, she recommends administering follow-up MRI scans even to patients whose heart troubles seem to have resolved to make sure there’s no longer-term damage, such as scarring. She also says that it’s “really reasonable” to be cautious about asymptomatic infections and encourages parents to have their child evaluated if they have any persistent symptoms even if the original infection was mild or asymptomatic.
“What’s important is that we can’t right now say that there are no consequences,” she says.
Calls for more studies
Scientists caution that there’s still so much we don’t know about the potential harm of asymptomatic infections. Many have called for more rigorous studies to get to the bottom of the long-term effects of asymptomatic disease, why those effects occur, and how to treat them.
Rajpal points out that his study was only possible because the Big 10 athletic conference requires athletes to get tested every few days. Regular testing is key for uncovering asymptomatic cases, he says, which means that most data on asymptomatic disease is likely to come from healthcare workers, athletes, and other workplaces with strict testing protocols.
It’s also unclear what could be causing these lingering side effects. Scientists hypothesize that it could be an inflammatory response of the body’s immune system that persists long after an infection has been cleared. Others suggest there could be remnants of the virus lingering in the body that continue to trigger an immune reaction months after the COVID-19 infection peaked.
“This is all unchartered, unproven, just a lot of theories,” Topol says.
Yet even if asymptomatic infections aren’t linked in high rates to death and hospitalization, Pinto and others say it’s important to keep in mind that long COVID-19 symptoms can be debilitating to a patient’s quality of life.
“Even if people survive, we don’t want them to be having a lifelong chronic disease,” Pinto says. “We don’t know what this does to the body, so it’s not something that I would want to take my chances with.”
The bottom line
With so much we don’t know about the long-term effects of asymptomatic COVID-19, scientists insist it’s better to err on the side of caution.
“The full impact can take years to show,” Rajpal says. Although the chances are slim that an individual with asymptomatic infection will have a really bad outcome, he points out that the continuing high rate of infections means that more people are going to suffer.
“Even rare things can affect a lot of people,” he says. “From a public health perspective if you can reduce the number of people that get this infection, you will reduce the number of people who get severe outcomes.”
Parker agrees, adding that it’s particularly important to prevent infection now as the more transmissible Delta variant drives surges in cases and hospitalizations across the country.
“We have had an amazing breakthrough in terms of the rapid development of effective and safe vaccines,” she says. Although Parker and other scientists remain uncertain of the health effects of asymptomatic COVID-19, “we do know that vaccinations are safe and effective and available.”
How COVID-19 can damage all five senses
The virus that causes the disease disrupts not just smell and taste, but all the ways humans perceive the world. For some, the loss may be permanent.
Considering how sick he was, Michael Goldsmith seemed like one of the lucky ones, because he survived. After becoming severely ill with COVID-19 in March 2020, he spent 22 days on a ventilator in the ICU. Fortunately, Goldsmith’s condition improved, and he was moved to an intermediate level of care in the hospital as he recovered. That’s when he began to realize he had lost most of his hearing in his left ear.
“Anything I did hear had to be loud, and then it sounded like Charlie Brown’s teacher,” says Goldsmith, now 35, referencing the nonsensical noises the teacher made in the popular cartoon show.
He also had a static sound in that ear that turned out to be tinnitus. After he fully recovered from the infection and went back to his home in Bergenfield, New Jersey, the IT security analyst and father of two saw one doctor after another, seeking relief for his hearing problems. He tried several different prescription medicines, and still he was no better off.
It’s easy to take our senses for granted—until there’s a problem with one of them. This is something many people who suffered from COVID-19 discovered when they unexpectedly lost their senses of smell and taste. More recently, though, it has become apparent that a COVID-19 infection can also affect sight, hearing, and touch.
In the short term and the long run, this virus can affect all the ways we perceive and interact with the world.
Though not life-threatening, “it’s disarming to lose any of these senses, especially as suddenly as happens in the context of this infection,” says Jennifer Frontera, a professor of neurology at the NYU Grossman School of Medicine.
Like Goldsmith, many people who recovered from COVID-19 continued to experience some auditory loss. In the March issue of the International Journal of Audiology,researchersreviewed published case studies and other reports of COVID-19 symptoms, and they estimate that hearing loss has occurred in about 8 percent of patients who had COVID, while about 15 percent developed tinnitus.
The mechanisms aren’t completely understood, but experts suspect the disease may affect the eustachian tube, which connects the middle ear with the throat. “With any viral infection, you can have eustachian tube dysfunction, which can lead to fluid build-up in the middle ear—this acts as a mechanical dampener on the ear drum,” explains Elias Michaelides, an associate professor of otolaryngology at Rush University Medical Center in Chicago.
Once someone recovers from the illness, the eustachian tube drains and hearing returns to normal in most cases, though it can take a couple of weeks, he says. In the meantime, taking an oral decongestant and using a nasal steroid spray may help hasten drainage, says Michaelides.
But if the virus damages the sensory neurons in the inner ear or cochlea, sudden hearing loss may occur, and it may be permanent. Exactly how this nerve damage happens isn’t clear, though it may have to do with COVID-19’s ability to trigger a cascade of inflammatory effects and small blood vessel damage.
Because Goldsmith’s hearing didn’t improve in his left ear after he fully recovered and tried various prescription medications, he went to see J. Thomas Roland, Jr., chair of the department of otolaryngology-head and neck surgery at NYU Langone Health. Roland told him he was a good candidate for a cochlear implant, a small electronic device that can directly stimulate the auditory nerve and generate signals that the brain registers as sound.
“The inner ear is a very delicate organ and very susceptible to microvascular problems and inflammation, so I’m not surprised people have experienced hearing loss or tinnitus related to COVID,” says Roland.
In September 2020, Goldsmith had a cochlear implant surgically placed in his left ear. It has made a world of difference, he says. “I now have 80 percent recognition of single words, and it’s even higher with full sentences in my left ear.” And when the device is on, his tinnitus disappears completely. “I wish I didn’t need this,” Goldsmith says, “but I’m glad I had it.”
Other people who’ve had COVID-19 have reported problems with their vision. A study published last year in BMJ Open Ophthalmologyfound that light sensitivity, sore eyes, and blurred vision are among the more common eye disorders experienced by patients. And in a study involving 400 COVID-19 patients who were hospitalized, researchers found that 10 percent had eye disorders, including conjunctivitis, vision changes, and eye irritation.
“There is definitely a viral load in the eye that causes symptoms, but that doesn’t mean it necessarily causes long-term diseases in the eye,” says study co-author Shahzad I. Mian, a professor of ophthalmology and visual sciences at the University of Michigan Medical School.
Still, some doctors are finding that the SARS-CoV-2 virus can increase the risk of blood clots throughout the body, including in blood vessels in the retina, which can cause blurry vision or some degree of vision loss, explains Julia A. Haller, ophthalmologist-in-chief at the Wills Eye Hospital in Philadelphia.
If someone experiences any vision changes possibly related to COVID-19, it’s important for them to see an ophthalmologist as soon as possible, the experts say. “Some forms of vision loss are treatable with medications, depending on how much damage has occurred,” Haller says.
Tingling and numbness
A person’s sense of touch also can be affected by a COVID-19 infection, since the disease has been shown to cause persistent neurologic symptoms.
In a study published in May 2021, researchers evaluated 100 people who weren’t hospitalized for COVID-19 but had ongoing symptoms. They found that 60 percent had numbness and tingling six to nine months after the onset of their illness. Sometimes these symptoms were widespread throughout the body; in other instances, they were localized to the hands and feet.
The exact mechanisms behind these stubborn symptoms aren’t well understood, but they most likely relate to local inflammation and local infection with COVID-19 virus in the nerves, explains Igor Koralnik, a professor of neurology at the Northwestern Feinberg School of Medicine and chief of the division of neuroinfectious diseases and global neurology at Northwestern Memorial Hospital in Chicago.
“In most cases, [the numbness and tingling] improves over time,” he says. “Everybody goes at their own pace.” And in some cases, tingling and other symptoms of neuropathy can be treated with medications like gabapentin, a drug that is used to prevent seizures and relieve nerve pain.
Loss of smell and taste
Perhaps the most recognizable effect COVID-19 has on the senses is the one-two punch of lost smell and taste. Elizabeth DeFranco, a medical sales rep in Cleveland, Ohio, experienced both sensory changes shortly after developing a mild COVID-19 infection in June 2020.
“I was eating salt and vinegar potato chips, and I couldn’t taste anything,” recalls DeFranco, 58. Then she realized she couldn’t smell anything, either. These losses remain with her to this day, though once in a while she gets a brief whiff of an odor like freshly cut grass.
Viral-induced smell loss existed before anyone had ever heard of COVID-19, but the percentage of people who experience smell dysfunction or loss is much higher with this virus than with other types of infections, experts say. A review of studies published in 2020 found that of 8,000 subjects with confirmed COVID-19, 41 percent experienced problems with smell and 38 percent reported problems with taste. When people who contract COVID-19 lose their sense of smell, a condition called anosmia, they lose it across the board, not just with one type of scent.
Generally speaking, there are two major types of smell loss. Conductive smell loss can occur when nasal congestion or obstruction prevents odor molecules from passing into the nasal cavity. Sensorineural smell loss involves damage or dysfunction to the olfactory neurons, which seems to be what’s happening with COVID-19.
“With COVID-19, most people don’t have a lot of nasal symptoms, and yet smell loss can be fairly severe,” says Justin Turner, an associate professor of otolaryngology-head and neck surgery at Vanderbilt University Medical Center and director of the Vanderbilt Smell and Taste Center. “We believe this stems from damage to sustentacular cells that live way up in the nose and are particularly susceptible to infection by the virus.”
As people recover from COVID-19, regenerating cells can spring into action and make new functional neurons, Turner explains. This allows most people to regain their sense of smell six to eight weeks after infection—but not everyone does. At that point, doctors may prescribe systemic or topical steroids and sometimes smell conditioning, which involves repeated exposure to essential oils that have different scents. It’s like the olfactory equivalent of physical therapy.
“What you’re doing is exposing the olfactory system to these odorants and helping the brain form new connections,” Turner explains. “Once the damage [to neurons] has been done, we’re relying on regenerative capacity in the olfactory system to help people regain their sense of smell.”
Losing the sense of taste usually goes hand in hand with the loss of smell, says Michael Benninger, professor and chair of the department of otolaryngology-head and neck surgery at the Cleveland Clinic Lerner College of Medicine.
“We are not seeing people who have truly lost their sense of taste [with COVID-19 infection]. When people lose their sense of smell, their taste is diminished”—meaning, their ability to discriminate between different flavors is lost. “If the sense of smell comes back, taste comes back, too,” Benninger says.
Since she recovered from COVID-19, DeFranco has tried numerous interventions—including steroid medications, antibiotics, cryotherapy, craniosacral therapy, supplements, homeopathic remedies, and smell retraining. Nothing has helped. So she has found ways to work around these limitations to protect her safety. She installed additional smoke detectors in her home because she wouldn’t be able to smell smoke. She throws all her food out by the “best by” date and often has a neighbor smell food from her fridge to make sure it hasn’t spoiled.
The worst part: “It is very depressing to think that this anosmia could be forever. I have no enjoyment of food,” she says. “I may never be able to appreciate the taste of wine or chocolate or the smell of a barbecue or cookies baking in the oven or the salt in the air when I go to the ocean. No one can really empathize unless it happens to them.”
Therapeutics and treatment modalities(more will follow):
We know by now that the virus is a serious and lethal agent of infection. The more therapeutics we have on board the better. I also believe that politics and the thirst for profit should in no way be a determining factor in the selection of medications. When it comes to the lives of tens of thousands of people, the insurance companies willingness to pay should also not be a factor. I know in the past they have had a very big impact in the choice of therapeutics. We also have be willing to listen to experts from other countries when it involves the efficacy of treatments and their studies. I am sure you can see where I am going with this discussion. In order to discuss one medication in particular I have to discuss a few terms. Get your Nodoz, or caffeine this section is long.
Three Treatment Principles
-Use medicatrions to slow down the virus
-Use medications to attenuate or reduce inflammation
-Address blood clotting
-azithromycin or doxycycline
-Nasal Rinses and dilute virucidal agents
-full dose aspirin
-antithrombotics (heparin, lovenox, and Apixaban)
The heart and the QT interval:
The heart is a muscular organ in most animals, which pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to the lungs. In humans, the heart is approximately the size of a closed fist and is located between the lungs, in the middle compartment of the chest.
In humans, other mammals, and birds, the heart is divided into four chambers: upper left and right atria and lower left and right ventricles. Commonly the right atrium and ventricle are referred together as the right heart and their left counterparts as the left heart.
The heart pumps blood with a rhythm determined by a group of pacemaking cells in the sinoatrial node. These generate a current that causes contraction of the heart, traveling through the atrioventricular node and along the conduction system of the heart. The heart receives blood low in oxygen from the systemic circulation, which enters the right atrium from the superior and inferiorvenae cavae and passes to the right ventricle. From here it is pumped into the pulmonary circulation, through the lungs where it receives oxygen and gives off carbon dioxide. Oxygenated blood then returns to the left atrium, passes through the left ventricle and is pumped out through the aorta to the systemic circulation−where the oxygen is used and metabolized to carbon dioxide. The heart beats at a resting rate close to 72 beats per minute.
The normal rhythmical heart beat, called sinus rhythm, is established by the heart’s own pacemaker, the sinoatrial node (also known as the sinus node or the SA node). Here an electrical signal is created that travels through the heart, causing the heart muscle to contract. The sinoatrial node is found in the upper part of the right atrium near to the junction with the superior vena cava. The electrical signal generated by the sinoatrial node travels through the right atrium in a radial way that is not completely understood. It travels to the left atrium via Bachmann’s bundle, such that the muscles of the left and right atria contract together. The signal then travels to the atrioventricular node. This is found at the bottom of the right atrium in the atrioventricular septum—the boundary between the right atrium and the left ventricle. The septum is part of the cardiac skeleton, tissue within the heart that the electrical signal cannot pass through, which forces the signal to pass through the atrioventricular node only. The signal then travels along the bundle of His to left and right bundle branches through to the ventricles of the heart. In the ventricles the signal is carried by specialized tissue called the Purkinje fibers which then transmit the electric charge to the heart muscle.
The normal sinus rhythm of the heart, giving the resting heart rate, is influenced by a number of factors. The cardiovascular centres in the brainstem that control the sympathetic and parasympathetic influences to the heart through the vagus nerve and sympathetic trunk. These cardiovascular centres receive input from a series of receptors including baroreceptors, sensing stretch the stretching of blood vessels and chemoreceptors, sensing the amount of oxygen and carbon dioxide in the blood and its pH. Through a series of reflexes these help regulate and sustain blood flow.
Baroreceptors are stretch receptors located in the aortic sinus, carotid bodies, the venae cavae, and other locations, including pulmonary vessels and the right side of the heart itself. Baroreceptors fire at a rate determined by how much they are stretched, which is influenced by blood pressure, level of physical activity, and the relative distribution of blood. With increased pressure and stretch, the rate of baroreceptor firing increases, and the cardiac centers decrease sympathetic stimulation and increase parasympathetic stimulation. As pressure and stretch decrease, the rate of baroreceptor firing decreases, and the cardiac centers increase sympathetic stimulation and decrease parasympathetic stimulation. There is a similar reflex, called the atrial reflex or Bainbridge reflex, associated with varying rates of blood flow to the atria. Increased venous return stretches the walls of the atria where specialized baroreceptors are located. However, as the atrial baroreceptors increase their rate of firing and as they stretch due to the increased blood pressure, the cardiac center responds by increasing sympathetic stimulation and inhibiting parasympathetic stimulation to increase heart rate. The opposite is also true. Chemoreceptors present in the carotid body or adjacent to the aorta in an aortic body respond to the blood’s oxygen, carbon dioxide levels. Low oxygen or high carbon dioxide will stimulate firing of the receptors.
Exercise and fitness levels, age, body temperature, basal metabolic rate, and even a person’s emotional state can all affect the heart rate. High levels of the hormones epinephrine, norepinephrine, and thyroid hormones can increase the heart rate. The levels of electrolytes including calcium, potassium, and sodium can also influence the speed and regularity of the heart rate; low blood oxygen, low blood pressure and dehydration may increase it.
Cardiac arrhythmias: While in the healthy heart, waves of electrical impulses originate in the sinus node before spreading to the rest of the atria, the atrioventricular node, and finally the ventricles (referred to as a normal sinus rhythm), this normal rhythm can be disrupted. Abnormal heart rhythms or arrhythmias may be asymptomatic or may cause palpitations, blackouts, or breathlessness. Some types of arrhythmia such as atrial fibrillation increase the long term risk of stroke. Some arrhythmias cause the heart to beat abnormally slowly, referred to as a bradycardia or bradyarrhythmia. This may be caused by an abnormally slow sinus node or damage within the cardiac conduction system (heart block). In other arrhythmias the heart may beat abnormally rapidly, referred to as a tachycardia or tachyarrhythmia. These arrhythmias can take many forms and can originate from different structures within the heart—some arise from the atria (e.g. atrial flutter), some from the atrioventricular node (e.g. AV nodal re-entrant tachycardia) whilst others arise from the ventricles (e.g. ventricular tachycardia). Some tachyarrhythmias are caused by scarring within the heart (e.g. some forms of ventricular tachycardia), others by an irritable focus (e.g. focal atrial tachycardia), while others are caused by additional abnormal conduction tissue that has been present since birth (e.g. Wolff-Parkinson-White syndrome). The most dangerous form of heart racing is ventricular fibrillation, in which the ventricles quiver rather than contract, and which if untreated is rapidly fatal.
Electrocardiography is the process of producing an electrocardiogram (ECG or EKG). It is a graph of voltage versus time of the electrical activity of the heart using electrodes placed on the skin. These electrodes detect the small electrical changes that are a consequence of cardiac muscle depolarization followed by repolarization during each cardiac cycle (heartbeat). Changes in the normal ECG pattern occur in numerous cardiac abnormalities, including cardiac rhythm disturbances (such as atrial fibrillation and ventricular tachycardia), inadequate coronary artery blood flow (such as myocardial ischemia and myocardial infarction), and electrolyte disturbances (such as hypokalemia and hyperkalemia).
Interpretation of the ECG is ultimately that of pattern recognition. In order to understand the patterns found, it is helpful to understand the theory of what ECGs represent. The theory is rooted in electromagnetics and boils down to the four following points:
- depolarization of the heart towards the positive electrode produces a positive deflection
- depolarization of the heart away from the positive electrode produces a negative deflection
- repolarization of the heart towards the positive electrode produces a negative deflection
- repolarization of the heart away from the positive electrode produces a positive deflection
Normal rhythm produces four entities – a P wave, a QRS complex, a T wave, and a U wave – that each have a fairly unique pattern.
- The P wave represents atrial depolarization.
- The QRS complex represents ventricular depolarization.
- The T wave represents ventricular repolarization.
- The U wave represents papillary muscle repolarization.
Changes in the structure of the heart and its surroundings (including blood composition) change the patterns of these four entities.
|P wave||The P wave represents depolarization of the atria. Atrial depolarization spreads from the SA node towards the AV node, and from the right atrium to the left atrium.||The P wave is typically upright in most leads except for aVR; an unusual P wave axis (inverted in other leads) can indicate an ectopic atrial pacemaker. If the P wave is of unusually long duration, it may represent atrial enlargement. Typically a large right atrium gives a tall, peaked P wave while a large left atrium gives a two-humped bifid P wave.||<80 ms|
|PR interval||The PR interval is measured from the beginning of the P wave to the beginning of the QRS complex. This interval reflects the time the electrical impulse takes to travel from the sinus node through the AV node.||A PR interval shorter than 120 ms suggests that the electrical impulse is bypassing the AV node, as in Wolf-Parkinson-White syndrome. A PR interval consistently longer than 200 ms diagnoses first degree atrioventricular block. The PR segment (the portion of the tracing after the P wave and before the QRS complex) is typically completely flat, but may be depressed in pericarditis.||120 to 200 ms|
|QRS complex||The QRS complex represents the rapid depolarization of the right and left ventricles. The ventricles have a large muscle mass compared to the atria, so the QRS complex usually has a much larger amplitude than the P wave.||If the QRS complex is wide (longer than 120 ms) it suggests disruption of the heart’s conduction system, such as in LBBB, RBBB, or ventricular rhythms such as ventricular tachycardia. Metabolic issues such as severe hyperkalemia, or tricyclic antidepressant overdose can also widen the QRS complex. An unusually tall QRS complex may represent left ventricular hypertrophy while a very low-amplitude QRS complex may represent a pericardial effusion or infiltrative myocardial disease.||80 to 100 ms|
|J-point||The J-point is the point at which the QRS complex finishes and the ST segment begins.||The J-point may be elevated as a normal variant. The appearance of a separate J wave or Osborn wave at the J-point is pathognomonic of hypothermia or hypercalcemia.|
|ST segment||The ST segment connects the QRS complex and the T wave; it represents the period when the ventricles are depolarized.||It is usually isoelectric, but may be depressed or elevated with myocardial infarction or ischemia. ST depression can also be caused by LVH or digoxin. ST elevation can also be caused by pericarditis, Brugada syndrome, or can be a normal variant (J-point elevation).|
|T wave||The T wave represents the repolarization of the ventricles. It is generally upright in all leads except aVR and lead V1.||Inverted T waves can be a sign of myocardial ischemia, left ventricular hypertrophy, high intracranial pressure, or metabolic abnormalities. Peaked T waves can be a sign of hyperkalemia or very early myocardial infarction.||160 ms|
|Corrected QT interval (QTc)||The QT interval is measured from the beginning of the QRS complex to the end of the T wave. Acceptable ranges vary with heart rate, so it must be corrected to the QTc by dividing by the square root of the RR interval.||A prolonged QTc interval is a risk factor for ventricular tachyarrhythmias and sudden death. Long QT can arise as a genetic syndrome, or as a side effect of certain medications. An unusually short QTc can be seen in severe hypercalcemia.||<440 ms|
|U wave||The U wave is hypothesized to be caused by the repolarization of the interventricular septum. It normally has a low amplitude, and even more often is completely absent.||A very prominent U wave can be a sign of hypokalemia, hypercalcemia or hyperthyroidism.|
ST elevation myocardial infarctions (STEMIs) have different characteristic ECG findings based on the amount of time elapsed since the MI first occurred. The earliest sign is hyperacute T waves, peaked T waves due to local hyperkalemia in ischemic myocardium. This then progresses over a period of minutes to elevations of the ST segment by at least 1 mm. Over a period of hours, a pathologic Q wave may appear and the T wave will invert. Over a period of days the ST elevation will resolve. Pathologic Q waves generally will remain permanently.
Rhythm disturbances or arrhythmias:
- Atrial fibrillation and atrial flutter without rapid ventricular response
- Premature atrial contraction (PACs) and premature ventricular contraction (PVCs)
- Sinus arrhythmia
- Sinus bradycardia and sinus tachycardia
- Sinus pause and sinoatrial arrest
- Sick sinus syndrome: bradycardia-tachycardia syndrome
- Supraventricular tachycardia
- Atrial fibrillation with rapid ventricular response
- Atrial flutter with rapid ventricular response
- AV nodal reentrant tachycardia
- Atrioventricular reentrant tachycardia
- Junctional ectopic tachycardia
- Atrial tachycardia
- Sinoatrial nodal reentrant tachycardia
- Torsades de pointes (polymorphic ventricular tachycardia)
- Wide complex tachycardia
- Pre-excitation syndrome
- J wave (Osborn wave)
Heart block and conduction problems:
- Sinoatrial block: first, second, and third-degree
- AV node
- Right bundle
- Left bundle
- QT syndromes
- Right and left atrial abnormality
Electrolytes disturbances and intoxication:
- Digitalis intoxication
- Calcium: hypocalcemia and hypercalcemia
- Potassium: hypokalemia and hyperkalemia
Ischemia and infarction:
- Wellens’ syndrome (LAD occlusion)
- de Winter T waves (LAD occlusion) 
- ST elevation and ST depression
- High Frequency QRS changes
- Myocardial infarction (heart attack)
Now we are getting somewhere. Medications can cause a lot heart rhythm changes. The one that I want to key in on is the prolonged Q-T interval. Long QT syndrome (LQTS) is a condition in which repolarization of the heart after a heartbeat is affected. It results in an increased risk of an irregular heartbeat which can result in fainting, drowning, seizures, or sudden death. These episodes can be triggered by exercise or stress. Some rare forms of LQTS are associated with other symptoms and signs including deafness and periods of muscle weakness. Management may include avoiding strenuous exercise, getting sufficient potassium in the diet, the use of beta blockers, or an implantable cardiac defibrillator. For people with LQTS who survive cardiac arrest and remain untreated, the risk of death within 15 years is greater than 50%. With proper treatment this decreases to less than 1% over 20 years.
Many people with long QT syndrome have no signs or symptoms. When symptoms occur, they are generally caused by abnormal heart rhythms (arrhythmias), most commonly a form of ventricular tachycardia called Torsades de pointes (TdP). If the arrhythmia reverts to a normal rhythm spontaneously the affected person may experience lightheadedness (known as presyncope) or faint which may be preceded by a fluttering sensation in the chest. If the arrhythmia continues, the affected person may experience a cardiac arrest, which if untreated may lead to sudden death. Those with LQTS may also experience seizure-like activity (non-epileptic seizure) as a result of reduced blood flow to the brain during an arrhythmia. Epilepsy is also associated with certain types of long QT syndrome.
Medications that can prolong the Q-T interval:
Ok, so now that you are afraid to take any medicine, I know it is quite a list. That is why it is so important to have a doctor over see your medications and to get regular checkups, including EKG’s, especially if your medicine has cardiac side effects. But we also know is that Pharmaceutical companies like to cover the asses. So even if there is a one in the million chance that you are going to grow a third arm, they have to put it in the list of side effects. The good thing if you are told that your QT interval is lengthening, simply have the doctor change your medication or even better D/C it, and your heart will gradually return to normal. This widening effect usually occurs with prolonged use or if you are on large doses of the medication.
Did I forget to tell you that this article was going to be almost as long as War and Peace? Sorry, but we are getting close to the end, I promise. This subject is really complicated. In order to understand all the stuff these professionals are saying on TV about Covid-19, you have to have a basic understanding of a lot of stuff. Now we are ready for the therapeutic section. As I promised it will be more indepth.
I am going to start with Home treatments then move on to the hospital stuff.
At-Home Coronavirus Treatment
If your symptoms are mild enough that you can recover at home, you should:
- Rest. It can make you feel better and may speed your recovery.
- Stay home. Don’t go to work, school, or public places.
- Drink fluids. You lose more water when you’re sick. Dehydration can make symptoms worse and cause other health problems.
- Monitor. If your symptoms get worse, call your doctor right away. Don’t go to their office without calling first. They might tell you to stay home, or they may need to take extra steps to protect staff and other patients.
- Ask your doctor about over-the-counter medicines that may help, like acetaminophen to lower your fever.
- New drugs listed and recommended by Dr. William Grace: N-acetylcysteine 600mg, Vitamin-D 1000IU, Reduced glutathione 500mg, Zinc 50mg. (updated 10/21/2020 10:41PM)
The most important thing to do is to avoid infecting other people, especially those who are over 65 or who have other health problems.
- Try to stay in one place in your home. Use a separate bedroom and bathroom if you can.
- Tell others you’re sick so they keep their distance.
- Cover your coughs and sneezes with a tissue or your elbow.
- Wear a mask over your nose and mouth if you can.
- Wash regularly, especially your hands.
- Don’t share dishes, cups, eating utensils, towels, or bedding with anyone else.
- Clean and disinfect common surfaces like doorknobs, counters, and tabletops.
What to expect
Symptoms begin 2 to 14 days after you come into contact with the virus. Early studies show that many people who have mild infections recover within 2 weeks. More severe cases tend to last 3 to 6 weeks.
COVID-19 is linked to new diabetes cases—but long-term problems could be more severe
In addition to driving new cases of diabetes, the virus may be directly damaging the pancreas in ways that could lead to chronic inflammation and even cancer.
Almost daily microbiologist Peter Jackson receives emails from people who recovered from COVID-19 only to discover that their health troubles have just begun.
Recently, a mother of two in her 30s wrote to the Stanford University professor to say that she now takes a slew of diabetes medications every day—even though she hadn’t been at risk for the disease before her coronavirus infection.
Experts have known since the beginning of the pandemic that having diabetes—a condition when the body doesn’t make enough insulin or use it well enough to counteract a rise in blood sugar—is a risk factor for more severe COVID-19 infections. But they have also long suspected that the inverse might be true as well. In May, Jackson published a study in the journal Cell Metabolism showing that SARS-CoV-2 infects cells in the pancreas that produce insulin and may even target and destroy them—suggesting that the virus may also cause diabetes. (Why scientists began investigating the link between COVID-19 and diabetes.)
“This is a real thing,” Jackson says of the complaints from newly diabetic people that have flooded his inbox. Although some experts argue that the condition is rare, Jackson says the data suggests that in 2020 as many as 100,000 people were diagnosed with an unexpected case of diabetes.
He is one of many scientists who worry there could be a new wave of diabetes patients who will have to monitor their blood sugar levels for the rest of their lives. But he and his colleagues are also concerned that the virus may be harming the pancreas in ways that may not be visible now but could one day have troubling implications for the organ itself and for the rest of the digestive system.
“This could be a pandemic in a pandemic,” says Paolo Fiorina, a professor of endocrinology at the University of Milan and lecturer at Harvard Medical School, who has also spearheaded investigations into the connection between COVID-19 and diabetes.
Scientists are still hashing out how serious a threat COVID-19 poses to the pancreas in the long term—and whether those who do develop diabetes are really stuck with it forever. Although it will take large studies and potentially many years to answer those questions, researchers are already on the case.
How COVID damages the pancreas
First, a refresher on the pancreas—an organ that plays a key role in the digestive system. Located behind the stomach, the widest part of the pancreas is connected to the small intestine, close to where the stomach empties partially digested food. There, the pancreas secretes a variety of juices to the mix to further break it down.
Most of that food is broken down into sugar that is released into the bloodstream. The pancreas is responsible for regulating those blood sugar levels by producing hormones: insulin, which lowers blood sugar, and glucagon, which raises it. But if this glucose balance isn’t carefully regulated, prolonged high blood glucose can cause organs to malfunction and permanently damage the retina, kidneys, nerves, heart, and blood vessels.
In Italy, a COVID-19 epicenter in the earliest days of the pandemic, it became clear that the blood sugar levels of people who were hospitalized with COVID-19 were out of whack. Fiorina became interested in investigating these effects in April 2020. At the time, he was the chief of endocrinology at a hospital in Milan, which saw upwards of 20,000 new cases of COVID-19 on a daily basis—and held one funeral every hour.
One day, a pathologist remarked to Fiorina how strange it was that so many of the patients who had died were hyperglycemic, meaning that their blood sugar was too high—a sign that the pancreas wasn’t doing its job. “I know that people with diabetes are more prone to dying,” Fiorina recalls telling the pathologist at the time. “But there might be something else.”
Fiorina decided to investigate. In May 2021, he published a study of 551 patients with no prior history of diabetes showing that 46 percent were newly hyperglycemic. COVID-19 had completely disrupted the hormone profile of these patients—although their levels had been normal before their infection, now their glucose was dangerously high as their body had become less efficient at using insulin.
Around the same time, autopsies of people who died from COVID-19 also showed that the virus had infected the pancreas—which researchers confirmed in a set of studies published in the journal Cell Metabolism. Jackson, who was among those researchers, found that SARS-CoV-2 infects and kill the beta cells that produce insulin. It’s thought that these cells are not easily replenished—and losing them makes you more susceptible to diabetes.
One thing that still wasn’t clear at that point, though, is how the virus gets to the pancreas to kill the cells. Fiorina says his latest research, which has not yet been published, attempts to answer that question. His data shows that SARS-CoV-2 can be detected in the pancreatic lymph node, suggesting that it could reach that location by traveling directly through the lymphatic system or through the bloodstream.
If confirmed, Fiorina says these findings would indicate that the virus infects the pancreas directly. In the meantime, however, he adds that SARS-CoV-2 also harms the pancreas in more indirect ways.
When the immune system mounts a defense against COVID-19, it can sometimes overreact and attack indiscriminately, causing inflammation throughout the body. This can stress the pancreas and raise blood sugar levels. Meanwhile, the steroids that hospitals use to treat that inflammatory response can also make matters worse. Kathleen Wyne, an endocrinologist at the Ohio State University’s Wexner Medical Center, says that people with normal hormonal profiles and no risk factors for diabetes receive these steroids without any problems. But for those who are already susceptible to diabetes, steroids can tell the body to create so much insulin that the cells stop responding to it—which also drives up blood sugar levels.
The implications for long-term health
It hasn’t been long enough yet for scientists to fully understand the fate of the pancreas in the months after patients recover from a COVID-19 infection. But in May, Fiorina’s study showed that a third of the people who were newly hyperglycemic remained that way for at least six months after their recovery.
Jackson points out that this still amounts to a lot more diabetes diagnoses than would be expected in a year—and “that’s just the tip of the iceberg.”
“I don’t want to be alarmist at all, but we may see more long-term effects on the pancreas than you think,” Jackson says. “People don’t know what the state of their pancreas is until they have real problems.” He adds that even those who don’t have diabetes now in the months after their COVID-19 infection may still develop it in the future.
It’s bad enough to develop a chronic disease like diabetes, which requires vigilant blood sugar level monitoring and regular insulin injections. But COVID-19 might also be silently harming the pancreas in ways that could have downstream repercussions for health.
Jackson likens it to a house catching on fire, where you’re so focused on the flames that are consuming your furniture you might not notice all the damage the smoke is causing to the structure of your home. Jackson says the virus can scar the tissues of the pancreas, which could possibly make it more susceptible to complications such as pancreatitis—chronic inflammation of the pancreas—or even pancreatic cancer.
“It’s not like having a clean wall that you can put new fresh plaster on,” he says. “You’ve got inherent problems in the architecture of the organ now that it’s damaged. So then repairing things is harder because you’re starting with a bumpy wall.”
Jackson says that damage to the pancreas could also harm nearby structures like the bile duct or the kidneys—which are typical targets for long-term complications from diabetes. According to the Mayo Clinic, about a quarter of people with diabetes eventually develop kidney disease because of damage to the blood vessels that filter waste from the blood.
But how much does the general population need to worry about these complications? That’s still up for debate.
Who is at risk?
That’s because many people do recover after the acute phase of the infection. Many of her patients at OSU’s Wexner Medical Center have been able to stop taking insulin soon after being discharged. Wyne also says that new diagnoses of type 1 diabetes have not increased at her clinic during the pandemic nor has she observed any evidence of a massive die-off of beta cells.
“I think the real question becomes—what happens when the inflammatory response subsides, what happens when the steroids go away?” Wyne says. “If the diabetes stays there, is that the person who was about to tip over the edge into diabetes anyway?”
She explains that people who develop diabetes post-infection may have been at risk for the disease anyway and that the stress COVID-19 put on their bodies merely sped it up. They might develop chronic diabetes or it might only be temporary, similar to the way that some people develop gestational diabetes during pregnancy only for their blood sugar levels to eventually return to normal.
“That’s been my approach with these COVID patients,” she says. “If they’re not going on diabetes medicines or only go on low doses, I’m going to tell them this is a warning sign that you’re going to have diabetes—I just don’t know when.”
Wyne points out that it will be decades before scientists can look at the population data to determine whether the pandemic had any effect on the rate of diabetes diagnoses.
In the meantime, researchers in the opposing camp admit that it’s possible some of the newly diagnoses diabetes cases may include people who were predisposed to it—and they too expect hyperglycemia to resolve among some people over time. But they point out that there’s no data suggesting otherwise either. To them, the pandemic presents an opportunity to answer a question that has plagued researchers for years: Can a virus trigger diabetes?
Solving an age-old mystery
Scientists have long hypothesized that type 1 diabetes is caused by an infection in the same way that other autoimmune diseases such as Hashimoto’s disease, a condition where the immune system attacks the thyroid, and lupus, a condition where the immune system attacks healthy tissue throughout the body, are suspected to be triggered by viruses.
But there’s never been enough evidence to prove this hypothesis. Although some people were diagnosed with diabetes in the wake of previous outbreaks of SARS and MERS, it was too rare an outcome to draw any conclusions. By infecting vastly more people, COVID-19 has made collecting this data a real possibility, says Francesco Rubino, chair of metabolic and bariatric surgery at King’s College London.
Last August, he and other leading diabetes researchers launched a global registry of patients with COVID-19-related diabetes to finally collect that information. He says not only will it have clinical implications for understanding the relationship between SARS-CoV-2 and the pancreas, but he expects it will also have broader ramifications.
“If you prove with some degree of confidence that COVID can actually cause diabetes then you have a proof of concept for a viral mechanism behind diabetes,” Rubino says.
Rubino says that registry has finally reached more than 620 cases, which his team of researchers has decided is a large enough sample size to begin an analysis of the data. He expects that for some patients on the global registry, their hyperglycemia will resolve over time. But among those with true diabetes, they’ll look to see if there are any patterns—which Rubino says could ultimately even reveal a new form of diabetes.
“The reason why so many of us are investigating this is because it could inform us not just about COVID-19—it could inform us about diabetes more broadly,” he says. “We might actually have to rethink much about what we know about diabetes if we were to find that this virus actually can alone trigger diabetes from scratch. That would be a very consequential discovery.”
Whatever the mechanism post-COVID-19 diabetes, however, Rubino says it’s important for those who have been infected with COVID-19 to remember that diabetes often strikes silently—and can have serious complications. He recommends anyone who has recovered from a coronavirus infection to be aware of the early warning signs such as fatigue, frequent urination, and inexplicable thirst and seek treatment right away.
“I think it’s not likely to be a problem for the vast majority of people who had COVID,” he says. “But if you can know earlier rather than later it’s much better for you.”
Therapeutics and treatment modalities Revisited:
President Trump made the mistake of mentioning a therapeutic that showed promise when the Coronavirus first burst on the scene. Hydroxychloroquine, has now become a political hot potato. It has received a lot of bad press, mainly because of biased test results. So it along with zithromax and Zinc is rarely used in the US. However it is used in the rest of the world with good results. First of all these three drugs all together cost approximately $21.00 for 5 days of treatment. That is part of the problem. Also the drug has to be given early enough to be effective, once organ damage has set in and the patient is intubated, no drug is really going to be effective. These drugs have been prescribed for decades and when taken under the guidance of a doctor have been extremely safe. But like any medicine they have to be monitored. I gave you a very scary list of medications, have these medications been banned in the US, the answer is no. They are given under strict monitoring techniques. So why has hydroxychloroquine not been given? Are we so much better than the rest of the world that we can simply ignore everybody else?
Remdesivir is another new drug on the market. While hydroxychloroquine, zithromax and zinc are recognized around the world and prescribed everywhere, Remdesevir is only licensed in the US, and is not currently authorized to be used anywhere else. Also did I forget to mention 5 days of treatment cost over $3000.00. It is so expensive that it’s use is delayed until the later stages of the disease, when the chances of it working are greatly reduced. The same holds true with convalescent Plasma, I have no idea how expensive this treatment is, but I do know that it has to be recommended by and infectious disease doctor and ordered by an intensivist. Which probably means it is also being administered too late. The only drugs cheap enough to be given immediately are being blocked in the US.
DMARDS (disease-modifying antirheumatic drugs). Clinical trials are underway to test the effect of drugs currently prescribed to suppress the immune system, in the hopes of tamping down widespread inflammation that occurs in severely ill patients. One is the biologic sarilumab (Kevzara), for patients hospitalized with COVID-19. The other biologic is tocilizumab (Actemra), for patients hospitalized with COVID-19 pneumonia. Both biologics are human monoclonal antibodies that target the immune system to decrease inflammation. (Tocilizumab is approved for treatment of cytokine storm syndrome in patients who have undergone CAR T-cell therapy for cancer.) The oral DMARD, baricitinib is in clinical trial as well.
There are other treatments and drugs on the market, but they are mainly for the treatment of the symptoms of the disease. Decadron is a steroid. It helps with the inflamation process, Lovenox and heparin are administered to reduce the occurrence of blood clots. Intravenous fluids are administered (provided they are not contraindicated) to help the patient stay hydrated and keep the kidneys flushed out.
Medical specialist have found out that patients have better outcomes if they can stay of the ventilator. Alternatively, Bilevel positive airway pressure (BiPAP) therapy, Continuous positive airway pressure (CPAP) therapy, HiFlo nasal cannulas and Non rebreather and venti masks are used. The use of ventilators is prolonged as much as possible because of the whole set of therapeutics that are usually associated with them. *
Hemodialysis and CRRT (Continuous Renal Replacement Therapy) help maintain appropriate fluid levels, and electrolytes in the blood stream, I also (and this is me thinking outside the box only) that it might be effective in reducing the blood clots in the body. I know it is an issue money. But Australia and New Zealand put over 95% of their ICU patients on CRRT, with average ICU times being around three days (pre covid numbers), thereby being cost effective in the long run.
If liver damage occurs, the use of albumin might be beneficial to shift the fluid from the tissues back into the blood stream. Advanced liver patients often have a shifting of fluid from the blood stream into the tissues. And albumin can sometimes help to reverse some of that fluid movement.
Initially patients with covid-19 were flooded with IVFs, now the trend seems to be to dry the patients out with diuretics, like lasix. Just maybe a middle of the road treatment modality might be something that should be investigated.
The shaky science behind ivermectin as a COVID-19 cure
Studies are inconclusive and misinformation is rampant. But many Americans now see a deworming medicine as a go-to drug to prevent and fight the Delta variant.
Over the last month, Frank Wallmeyer and several other farm supply store owners in some parts of the United States noticed an antiparasitic medication called ivermectin flying off the shelves. At his own store in Jacksonville, Florida, ivermectin sales have nearly tripled, and the phone rings at least a dozen times each day with inquiries about the drug, Wallmeyer says.
But many of those inquiring weren’t looking to get rid of worms in cattle and horse intestines. Rather, they wanted to use the drug for themselves or their loved ones to prevent and treat COVID-19. Touted as a miracle COVID-19 cure by some doctors and campaigners, despite lacking scientific support, ivermectin seems to be in high demand among unvaccinated Americans. As the fast-spreading Delta variant ravages the country, the search for alternative medication has led vaccine sceptics to ivermectin. Although the Food and Drug Administration has approved ivermectin to treat certain parasites in humans and animals, its use against COVID-19 isn’t authorized.
Poison control centers in several states including Florida, Mississippi, and Texas reported a recent surge in calls and cases associated with ivermectin misuse and overdose. Also, the Centers for Disease Control and Prevention reported that in the week ending August 13, 2021, more than 88,000 prescriptions were written for ivermectin, representing a 24-fold increase from the pre-pandemic baseline of 3,600 prescriptions per week. That meant some physicians were prescribing the drug for COVID-19, despite the FDA’s stand.
“It vastly complicates the management of [COVID-19] patients because there are so many and there is so much misinformation,” says John Sinnott, an epidemiologist at University of South Florida’s Morsani College of Medicine who is also affiliated with Tampa General Hospital.
Also, the drug preparations and doses vary for animals and humans, and the FDA warned people of potential harm from consuming the concentrated animal version, which contains inactive ingredients not tested for use in humans.
In an August 21 tweet, the FDA issued a warning:“You are not a horse. You are not a cow. Seriously, y’all. Stop it.”
But even human-grade ivermectin, considered generally safe for approved purposes—worms, head lice, and skin conditions such as rosacea—can cause side effects including headaches, nausea, diarrhea, skin rashes, and spikes in blood pressure. And seizures can result from high doses, leading to hospitalization.
What science tells us
While some studies suggest reduced risk of death, and others hint at fewer COVID-19 patients progressing to severe disease after taking ivermectin at an early stage of infection, the evidence is shaky. “We don’t know whether ivermectin is helpful or not in the fight against COVID-19,” says Stephanie Weibel, a biologist at the University of Wuerzburg in Germany. “Trustworthiness of the pool of available studies is limited.”
In a recent review of 14 ivermectin studies, Weibel and her colleagues found that often the trials enrolled few patients or weren’t designed well, sometimes leading researchers to overestimate ivermectin’s impacts. She encourages more robust clinical trials, like the one underway at the University of Oxford in the United Kingdom.
Even Merck, an ivermectin manufacturer, in a February 2021 statement said that its own analysis of the scientific literature didn’t support the drug’s use against COVID-19. However, the argument that supporters sometimes make is that even if ivermectin use may not provide obvious benefits, it can’t hurt.
“If there isn’t evidence that the product works, then any risk the product might convey is unacceptable,” says Peter Lurie, president of the Center for Science in the Public Interest and former associate commissioner at the FDA. “We have people who have gotten ill from ivermectin, who’ve wasted a bunch of money for no proven benefit, and the concern is that ivermectin is diverting people from things that actually work: vaccines, masks, and social distancing.”
Also, ivermectin supporters, who possibly weren’t able to acquire prescriptions for the drug from their physicians, may resort to the animal-version stocked in farm supply stores, not knowing the difference. The recommended dose for animals is much higher, and if people ingest ivermectin at that high dose, they’re likely to be poisoned, says Michael Teng, a health virologist at the University of South Florida.
Some vaccine sceptics are also resorting to ivermectin to prevent getting COVID-19, even though there is no strong scientific evidence to support such behavior and physicians warn against using ivermectin for extended periods. As of now, the FDA states that ivermectin should only be used or prescribed for COVID-19 in a clinical trial setting, which often involves follow-ups and health monitoring for the enrolled participants.
What triggered the ivermectin frenzy
Ivermectin was discovered and developed in the 1970s. In a hunt to find antiparasitic compounds, scientists identified a new species of bacteria—Streptomyces avermitilis—from soil near a golf course in Japan that eradicated worms in mice. The microbes produced therapeutic molecules called avermectins, which were responsible for deworming and which later led to the creation of a commercialized veterinary drug called ivermectin. In 1987, after human clinical trials showed its effectiveness against river blindness caused by the parasitic worm Onchocerca volvulus, the FDA approved the drug for humans in 1996 under the brand name Stromectol.
Since then, ivermectin has come to be recognized as a safe treatment for several tropical diseases caused by parasites ranging from mites to roundworms.
So, when scientists were looking to test safe generic drugs that could be repurposed for COVID-19 treatment, ivermectin made the list.
Among the earliest research included a study published online in April last year that showed how high ivermectin doses prevented the replication of SARS-COV-2, the virus responsible for COVID-19, in test tubes. While the researchers didn’t test the drug for treating or preventing COVID-19 in humans or animals, the study made headlines and piqued the general public’s interest in ivermectin. The FDA quickly issued a warning against its use to cure COVID-19. Two letters sent to the journal’s editor expressed concerns about the high ivermectin dose used in the experiments.
Around the same time, a controversial paper which had not yet been peer reviewed and was later retracted entirely, claimed large reduction in mortality among COVID-19 patients given ivermectin. Although the study didn’t make the cut for publication in a scientific journal, it helped popularize ivermectin in Latin America.
As the efficacy and safety of ivermectin continued to be tested in clinical trials across the world, the results of a November 2020 publication led by Egyptian researcher Ahmed Elgazzar renewed interest in the drug’s potential. The preprint study claimed substantial recovery among COVID-19 patients given ivermectin in the early stages of infection and a reduction in mortality exceeding 90 percent. But ethical concerns led to the paper’s withdrawal in July this year.
“It’s troubling that people are putting their faith in a drug not proven to be effective against COVID,” Teng says. “I wish people would just take the vaccine.”
In mid-February, the Harvard epidemiologist Marc Lipsitch stated that this virus could infect most people in the United States if the country’s leaders did not take action. At the time, the U.S. had only a handful of confirmed cases. Few people were imagining the future Lipsitch saw—in which millions, even hundreds of millions, of Americans could fall ill. This was, at least in part, because we weren’t testing for the virus.
Lipsitch even received some criticism from scientists who felt uncomfortable with his estimate, since there were so little data to go on. Indeed, at that point, many futures were still possible. But when a virus spreads as quickly and effectively as this one was spreading in February—killing many while leaving others who had few or no symptoms to spread the disease—that virus can be expected to run its course through a population that does not take dramatic measures.
Now, based on the U.S. response since February, Lipsitch believes that we’re still likely to see the virus spread to the point of becoming endemic. That would mean it is with us indefinitely, and the current pandemic would end when we reach levels of “herd immunity,” traditionally defined as the threshold at which enough people in a group have immune protection so the virus can no longer cause huge spikes in disease.
The concept of herd immunity comes from vaccination policy, in which it’s used to calculate the number of people who need to be vaccinated in order to ensure the safety of the population. But a coronavirus vaccine is still far off, and last month, Anthony Fauci, the head of the National Institute of Allergy and Infectious Diseases, said that, because of a “general anti-science, anti-authority, anti-vaccine feeling,” the U.S. is “unlikely” to achieve herd immunity even after a vaccine is available.
In February, Lipsitch gave a very rough estimate that, absent intervention, herd immunity might happen after 40 to 70 percent of the population had been infected. The idea of hitting this level of infection implied grim forecasts about disease and death. The case-fatality rate for COVID-19 is now very roughly 1 percent overall. In the absolute simplest, linear model, if 70 percent of the world were to get infected, that would mean more than 54 million deaths.
But the effects of the coronavirus are not linear. The virus affects individuals and populations in very different ways. The case-fatality rate varies drastically between adults under 40 and the elderly. This same characteristic variability of the virus—what makes it so dangerous in early stages of outbreaks—also gives a clue as to why those outbreaks could burn out earlier than initially expected. In countries with uncontained spread of the virus, such as the U.S., exactly what the herd-immunity threshold turns out to be could make a dramatic difference in how many people fall ill and die. Without a better plan, this threshold—the percentage of people who have been infected that would constitute herd immunity—seems to have become central to our fates.
“If there is a large variability of susceptibility among humans, then herd immunity could be as low as 20 percent,” Britton told me. But there’s reason to suspect that people do not have such dramatically disparate susceptibility to the coronavirus. High degrees of variability are more common in things such as sexually transmitted infections, where a person with 100 partners a year is far more susceptible than someone celibate. Respiratory viruses tend to be more equal-opportunity invaders. “I don’t think it will happen at 20 percent,” Britton said. “Between 35 and 45 percent—I think that would be a level where spreading drops drastically.”
“This virus is proving there can be orders-of-magnitude differences in attack rates, depending on political and societal decisions, which I don’t know how to forecast.” In the context of vaccination, herd-immunity thresholds are relatively fixed and predictable. In the context of an ongoing pandemic, thinking of this threshold as some static concept can be dangerously misleading.
“COVID-19 is the first disease in modern times where the whole world has changed their behavior and disease spread has been reduced,” Britton noted. That made old models and numbers obsolete. Social distancing and other reactive measures changed the R0 value, and they will continue to do so. The virus has certain immutable properties, but there is nothing immutable about how many infections it causes in the real world.
What we seem to need is a better understanding of herd immunity in this novel context. The threshold can change based on how a virus spreads. The spread keeps on changing based on how we react to it at every stage, and the effects compound. Small preventive measures have big downstream effects. In other words, the herd in question determines its immunity. There is no mystery in how to drop the R0 to below 1 and reach an effective herd immunity: masks, social distancing, hand-washing, and everything everyone is tired of hearing about. It is already being done.
Essentially, at present, New York City might be said to be at a version of herd immunity, or at least safe equilibrium. Our case counts are very low. They have been low for weeks. Our antibody counts mean that a not-insignificant number of people are effectively removed from the chain of transmission. Many more can be effectively excluded because they’re staying isolated and distanced, wearing masks, and being hygienically vigilant. If we keep living just as we are, another big wave of disease seems unlikely.
Lipsitch stands by the February projection that Americans are likely to get the coronavirus, but not because that’s the only possible future. In other countries, it isn’t the case. “I think it no longer seems impossible that Switzerland or Germany could remain near where they are in terms of cases, meaning not very much larger outbreaks, until there’s a vaccine,” he said. They seem to have the will and systems in place to keep their economies closed enough to maintain their current equilibrium.
Other wealthy countries could hypothetically create societies that are effectively immune to further surges, where the effective herd-immunity threshold is low. Even in the U.S., it’s not too late to create a world in which you are not likely to get the coronavirus. We can wear masks and enable people to stay housed and fed without taking up dangerous work. But, judging by the decisions U.S. leaders have made so far, it seems that few places in the country will choose to live this way. Many cities and states will push backwards into an old way of life, where the herd-immunity threshold is high. Dangerous decisions will be amplified by the dynamic systems of society. People will travel and seed outbreaks in places that have worked tirelessly to contain the virus. In some cases, a single infected person will indirectly lead to hundreds or thousands of deaths.
We have the wealth in this country to care for people, and to set the herd-immunity threshold where we choose. Parts of the world are illuminating a third way forward, something in between total lock down and simply resuming the old ways of life. It happens through individual choices and collective actions, reimagining new ways of living, and having the state support and leadership to make those ways possible. For as much attention as we give to the virus, and to drugs and our immune systems, the variable in the system is us. There will only be as much chaos as we allow.
Post-acute Covid-19 Syndrome
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for coronavirus disease 2019 (COVID-19), has caused morbidity and mortality at an unprecedented scale globally. Scientific and clinical evidence is evolving on the subacute and long-term effects of COVID-19, which can affect multiple organ systems. Early reports suggest residual effects of SARS-CoV-2 infection, such as fatigue, dyspnea, chest pain, cognitive disturbances, arthralgia and decline in quality of life. Cellular damage, a robust innate immune response with inflammatory cytokine production, and a pro-coagulant state induced by SARS-CoV-2 infection may contribute to these sequelae. Survivors of previous coronavirus infections, including the SARS epidemic of 2003 and the Middle East respiratory syndrome (MERS) outbreak of 2012, have demonstrated a similar constellation of persistent symptoms, reinforcing concern for clinically significant sequelae of COVID-19.
Systematic study of sequelae after recovery from acute COVID-19 is needed to develop an evidence-based multidisciplinary team approach for caring for these patients, and to inform research priorities. A comprehensive understanding of patient care needs beyond the acute phase will help in the development of infrastructure for COVID-19 clinics that will be equipped to provide integrated multispecialty care in the outpatient setting. While the definition of the post-acute COVID-19 timeline is evolving, it has been suggested to include persistence of symptoms or development of sequelae beyond 3 or 4 weeks from the onset of acute symptoms of COVID-19, as replication-competent SARS-CoV-2 has not been isolated after 3 weeks. For the purpose of this review, we defined post-acute COVID-19 as persistent symptoms and/or delayed or long-term complications of SARS-CoV-2 infection beyond 4 weeks from the onset of symptoms (Fig. 1). Based on recent literature, it is further divided into two categories: (1) subacute or ongoing symptomatic COVID-19, which includes symptoms and abnormalities present from 4–12 weeks beyond acute COVID-19; and (2) chronic or post-COVID-19 syndrome, which includes symptoms and abnormalities persisting or present beyond 12 weeks of the onset of acute COVID-19 and not attributable to alternative diagnoses. Herein, we summarize the epidemiology and organ-specific sequelae of post-acute COVID-19 and address management considerations for the interdisciplinary comprehensive care of these patients in COVID-19 clinics (Box 1 and Fig. 2).
Box 1 Summary of post-acute COVID-19 by organ system
- Dyspnea, decreased exercise capacity and hypoxia are commonly persistent symptoms and signs
- Reduced diffusion capacity, restrictive pulmonary physiology, and ground-glass opacities and fibrotic changes on imaging have been noted at follow-up of COVID-19 survivors
- Assessment of progression or recovery of pulmonary disease and function may include home pulse oximetry, 6MWTs, PFTs, high-resolution computed tomography of the chest and computed tomography pulmonary angiogram as clinically appropriate
- Thromboembolic events have been noted to be <5% in post-acute COVID-19 in retrospective studies
- The duration of the hyperinflammatory state induced by infection with SARS-CoV-2 is unknown
- Direct oral anticoagulants and low-molecular-weight heparin may be considered for extended thromboprophylaxis after risk–benefit discussion in patients with predisposing risk factors for immobility, persistently elevated D-dimer levels (greater than twice the upper limit of normal) and other high-risk comorbidities such as cancer
- Persistent symptoms may include palpitations, dyspnea and chest pain
- Long-term sequelae may include increased cardiometabolic demand, myocardial fibrosis or scarring (detectable via cardiac MRI), arrhythmias, tachycardia and autonomic dysfunction
- Patients with cardiovascular complications during acute infection or those experiencing persistent cardiac symptoms may be monitored with serial clinical, echocardiogram and electrocardiogram follow-up
- Persistent abnormalities may include fatigue, myalgia, headache, dysautonomia and cognitive impairment (brain fog)
- Anxiety, depression, sleep disturbances and PTSD have been reported in 30–40% of COVID-19 survivors, similar to survivors of other pathogenic coronaviruses
- The pathophysiology of neuropsychiatric complications is mechanistically diverse and entails immune dysregulation, inflammation, microvascular thrombosis, iatrogenic effects of medications and psychosocial impacts of infection
- Resolution of AKI during acute COVID-19 occurs in the majority of patients; however, reduced eGFR has been reported at 6 months follow-up
- COVAN may be the predominant pattern of renal injury in individuals of African descent
- COVID-19 survivors with persistent impaired renal function may benefit from early and close follow-up in AKI survivor clinics
- Endocrine sequelae may include new or worsening control of existing diabetes mellitus, subacute thyroiditis and bone demineralization
- Patients with newly diagnosed diabetes in the absence of traditional risk factors for type 2 diabetes, suspected hypothalamic–pituitary–adrenal axis suppression or hyperthyroidism should undergo the appropriate laboratory testing and should be referred to endocrinology
Gastrointestinal and hepatobiliary
- Prolonged viral fecal shedding can occur in COVID-19 even after negative nasopharyngeal swab testing
- COVID-19 has the potential to alter the gut microbiome, including enrichment of opportunistic organisms and depletion of beneficial commensals
- Hair loss is the predominant symptom and has been reported in approximately 20% of COVID-19 survivors
- Diagnostic criteria: <21 years old with fever, elevated inflammatory markers, multiple organ dysfunction, current or recent SARS-CoV-2 infection and exclusion of other plausible diagnoses
- Typically affects children >7 years and disproportionately of African, Afro-Caribbean or Hispanic origin
- Cardiovascular (coronary artery aneurysm) and neurologic (headache, encephalopathy, stroke and seizure) complications can occur
Early reports have now emerged on post-acute infectious consequences of COVID-19, with studies from the United States, Europe and China reporting outcomes for those who survived hospitalization for acute COVID-19. The findings from studies reporting outcomes in subacute/ongoing symptomatic COVID-19 and chronic/post-COVID-19 syndrome are summarized in Table 1.
An observational cohort study from 38 hospitals in Michigan, United States evaluated the outcomes of 1,250 patients discharged alive at 60 d by utilizing medical record abstraction and telephone surveys (hereby referred to as the post-acute COVID-19 US study). During the study period, 6.7% of patients died, while 15.1% of patients required re-admission. Of 488 patients who completed the telephone survey in this study, 32.6% of patients reported persistent symptoms, including 18.9% with new or worsened symptoms. Dyspnea while walking up the stairs (22.9%) was most commonly reported, while other symptoms included cough (15.4%) and persistent loss of taste and/or smell (13.1%).
Similar findings were reported from studies in Europe. A post-acute outpatient service established in Italy (hereby referred to as the post-acute COVID-19 Italian study) reported persistence of symptoms in 87.4% of 143 patients discharged from hospital who recovered from acute COVID-19 at a mean follow-up of 60 d from the onset of the first symptom. Fatigue (53.1%), dyspnea (43.4%), joint pain (27.3%) and chest pain (21.7%) were the most commonly reported symptoms, with 55% of patients continuing to experience three or more symptoms. A decline in quality of life, as measured by the EuroQol visual analog scale, was noted in 44.1% of patients in this study. A study focused on 150 survivors of non-critical COVID-19 from France similarly reported persistence of symptoms in two-thirds of individuals at 60 d follow-up, with one-third reporting feeling worse than at the onset of acute COVID-19. Other studies, including in-person prospective follow-up studies of 110 survivors in the United Kingdom at 8–12 weeks after hospital admission and 277 survivors in Spain at 10–14 weeks after disease onset, as well as survey studies of 100 COVID-19 survivors in the United Kingdom at 4–8 weeks post-discharge, 183 individuals in the United States at 35 d post-discharge and 120 patients discharged from hospital in France, at 100 d following admission, reported similar findings. Fatigue, dyspnea and psychological distress, such as post-traumatic stress disorder (PTSD), anxiety, depression and concentration and sleep abnormalities, were noted in approximately 30% or more study participants at the time of follow-up.
In a prospective cohort study from Wuhan, China, long-term consequences of acute COVID-19 were evaluated by comprehensive in-person evaluation of 1,733 patients at 6 months from symptom onset (hereby referred to as the post-acute COVID-19 Chinese study). The study utilized survey questionnaires, physical examination, 6-min walk tests (6MWT) and blood tests and, in selected cases, pulmonary function tests (PFTs), high-resolution computed tomography of the chest and ultrasonography to evaluate post-acute COVID-19 end organ injury. A majority of the patients (76%) reported at least one symptom. Similar to other studies, fatigue/muscular weakness was the most commonly reported symptom (63%), followed by sleep difficulties (26%) and anxiety/depression (23%).
These studies provide early evidence to aid the identification of people at high risk for post-acute COVID-19. The severity of illness during acute COVID-19 (measured, for example, by admission to an intensive care unit (ICU) and/or requirement for non-invasive and/or invasive mechanical ventilation) has been significantly associated with the presence or persistence of symptoms (such as dyspnea, fatigue/muscular weakness and PTSD), reduction in health-related quality of life scores, pulmonary function abnormalities and radiographic abnormalities in the post-acute COVID-19 setting. Furthermore, Halpin reported additional associations between pre-existing respiratory disease, higher body mass index, older age and Black, Asian and minority ethnic (BAME) and dyspnea at 4–8 weeks follow-up. The post-acute COVID-19 Chinese study also suggested sex differences, with women more likely to experience fatigue and anxiety/depression at 6 months follow-up, similar to SARS survivors. While other comorbidities, such as diabetes, obesity, chronic cardiovascular or kidney disease, cancer and organ transplantation, are well-recognized determinants of increased severity and mortality related to acute COVID-19, their association with post-acute COVID-19 outcomes in those who have recovered remains to be determined.
The predominant pathophysiologic mechanisms of acute COVID-19 include the following: direct viral toxicity; endothelial damage and microvascular injury; immune system dysregulation and stimulation of a hyperinflammatory state; hypercoagulability with resultant in situ thrombosis and macrothrombosis; and maladaptation of the angiotensin-converting enzyme 2 (ACE2) pathway. The overlap of sequelae of post-acute COVID-19 with those of SARS and MERS may be explained by phylogenetic similarities between the responsible pathogenic coronaviruses. The overlap of genomic sequence identity of SARS-CoV-2 is 79% with SARS-CoV-1 and 50% with MERS-CoV. Moreover, SARS-CoV-1 and SARS-CoV-2 share the same host cell receptor: ACE2. However, there are notable differences, such as the higher affinity of SARS-CoV-2 for ACE2 compared with SARS-CoV-1, which is probably due to differences in the receptor-binding domain of the spike protein that mediates contact with ACE2. In contrast with the other structural genes, the spike gene has diverged in SARS-CoV-2, with only 73% amino acid similarity with SARS-CoV-1 in the receptor-binding domain of the spike protein. Moreover, an additional S1–S2 cleavage site in SARS-CoV-2 enables more effective cleavage by host proteases and facilitates more effective binding. These mechanisms have probably contributed to the more effective and widespread transmission of SARS-CoV-2.
Potential mechanisms contributing to the pathophysiology of post-acute COVID-19 include: (1) virus-specific pathophysiologic changes; (2) immunologic aberrations and inflammatory damage in response to the acute infection; and (3) expected sequelae of post-critical illness. While the first two are discussed in more detail in the organ-specific sections below, post-intensive care syndrome is now well recognized and includes new or worsening abnormalities in physical, cognitive and psychiatric domains after critical illness. The pathophysiology of post-intensive care syndrome is multifactorial and has been proposed to involve microvascular ischemia and injury, immobility and metabolic alterations during critical illness. Additionally, similar to previous studies of SARS survivors, 25–30% of whom experienced secondary infections, survivors of acute COVID-19 may be at increased risk of infections with bacterial, fungal (pulmonary aspergillosis) or other pathogens. However, these secondary infections do not explain the persistent and prolonged sequelae of post-acute COVID-19.
Epidemiology and clinical manifestations
A spectrum of pulmonary manifestations, ranging from dyspnea (with or without chronic oxygen dependence) to difficult ventilator weaning and fibrotic lung damage, has been reported among COVID-19 survivors. Similar to survivors of acute respiratory distress syndrome (ARDS) from other etiologies, dyspnea is the most common persistent symptom beyond acute COVID-19, ranging from 42–66% prevalence at 60–100 d follow-up. In the post-acute COVID-19 Chinese study, the median 6-min walking distance was lower than normal reference values in approximately one-quarter of patients at 6 months—a prevalence similar to that in SARS and MERS survivors. The need for supplemental oxygen due to persistent hypoxemia, or new requirement for continuous positive airway pressure or other breathing support while sleeping, was reported in 6.6 and 6.9% of patients, respectively, at 60 d follow-up in the post-acute COVID-19 US study. Among 1,800 patients requiring tracheostomies during acute COVID-19, only 52% were successfully weaned from mechanical ventilation 1 month later in a national cohort study from Spain. A reduction in diffusion capacity is the most commonly reported physiologic impairment in post-acute COVID-19, with significant decrement directly related to the severity of acute illness, which is consistent with studies of SARS and MERS survivors, mild H1N1 influenza survivors and historical ARDS survivors. Although less common, hospitalized COVID-19 survivors have been found to have restrictive pulmonary physiology at 3 and 6 months, which has also been observed in historical ARDS survivor populations.
Approximately 50% of 349 patients who underwent high-resolution computed tomography of the chest at 6 months had at least one abnormal pattern in the post-acute COVID-19 Chinese study. The majority of abnormalities observed by computed tomography were ground-glass opacities. This study did not investigate chronic pulmonary embolism as computed tomography pulmonary angiograms were not obtained. The long-term risks of chronic pulmonary embolism and consequent pulmonary hypertension are unknown at this time. Fibrotic changes on computed tomography scans of the chest, consisting primarily of reticulations or traction bronchiectasis, were observed 3 months after hospital discharge in approximately 25 and 65% of survivors in cohort studies of mild-to-moderate cases and mostly severe cases, respectively, as distinguished by a requirement for supplemental oxygen. However, these prevalence estimates should be considered preliminary given the sample size of each of these cohorts. The prevalence estimates of post-acute COVID-19 sequelae from these studies suggest that patients with greater severity of acute COVID-19 (especially those requiring a high-flow nasal cannula and non-invasive or invasive mechanical ventilation) are at the highest risk for long-term pulmonary complications, including persistent diffusion impairment and radiographic pulmonary abnormalities (such as pulmonary fibrosis).
Pathology and pathophysiology
Viral-dependent mechanisms (including invasion of alveolar epithelial and endothelial cells by SARS-CoV-2) and viral-independent mechanisms (such as immunological damage, including perivascular inflammation) contribute to the breakdown of the endothelial–epithelial barrier with invasion of monocytes and neutrophils and extravasation of a protein-rich exudate into the alveolar space, consistent with other forms of ARDS. All phases of diffuse alveolar damage have been reported in COVID-19 autopsy series, with organizing and focal fibroproliferative diffuse alveolar damage seen later in the disease course, consistent with other etiologies of ARDS. Rare areas of myofibroblast proliferation, mural fibrosis and microcystic honeycombing have also been noted. This fibrotic state may be provoked by cytokines such as interleukin-6 (IL-6) and transforming growth factor-β, which have been implicated in the development of pulmonary fibrosis and may predispose to bacterial colonization and subsequent infection. Analysis of lung tissue from five cases with severe COVID-19-associated pneumonia, including two autopsy specimens and three specimens from explanted lungs of recipients of lung transplantation, showed histopathologic and single-cell RNA expression patterns similar to end-stage pulmonary fibrosis without persistent SARS-CoV-2 infection, suggesting that some individuals develop accelerated lung fibrosis after resolution of the active infection.
Pulmonary vascular microthrombosis and macrothrombosis have been observed in 20–30% of patients with COVID-19, which is higher than in other critically ill patient populations (1–10%). In addition, the severity of endothelial injury and widespread thrombosis with microangiopathy seen on lung autopsy is greater than that seen in ARDS from influenza.
Post-hospital discharge care of COVID-19 survivors has been recognized as a major research priority by professional organizations, and guidance for the management of these patients is still evolving. Home pulse oximetry using Food and Drug Administration-approved devices has been suggested as a useful tool for monitoring patients with persistent symptoms; however, supporting evidence is currently lacking. Some experts have also proposed evaluation with serial PFTs and 6MWTs for those with persistent dyspnea, as well as high-resolution computed tomography of the chest at 6 and 12 months.
In a guidance document adopted by the British Thoracic Society, algorithms for evaluating COVID-19 survivors in the first 3 months after hospital discharge are based on the severity of acute COVID-19 and whether or not the patient received ICU-level care. Algorithms for both severe and mild-to-moderate COVID-19 groups recommend clinical assessment and chest X-ray in all patients at 12 weeks, along with consideration of PFTs, 6MWTs, sputum sampling and echocardiogram according to clinical judgment. Based on this 12-week assessment, patients are further recommended to be evaluated with high-resolution computed tomography of the chest, computed tomography pulmonary angiogram or echocardiogram, or discharged from follow-up. In addition to this 12-week assessment, an earlier clinical assessment for respiratory, psychiatric and thromboembolic sequelae, as well as rehabilitation needs, is also recommended at 4–6 weeks after discharge for those with severe acute COVID-19, defined as those who had severe pneumonia, required ICU care, are elderly or have multiple comorbidities.
Treatment with corticosteroids may be beneficial in a subset of patients with post-COVID inflammatory lung disease, as suggested by a preliminary observation of significant symptomatic and radiological improvement in a small UK cohort of COVID-19 survivors with organizing pneumonia at 6 weeks after hospital discharge. Steroid use during acute COVID-19 was not associated with diffusion impairment and radiographic abnormalities at 6 months follow-up in the post-acute COVID-19 Chinese study. Lung transplantation has previously been performed for fibroproliferative lung disease after ARDS due to influenza A (H1N1) infection and COVID-19. Clinical trials of antifibrotic therapies to prevent pulmonary fibrosis after COVID-19 are underway.
Epidemiology and clinical manifestations
Retrospective data on post-acute thromboembolic events, although limited by small sample size, variability in outcome ascertainment and inadequate systematic follow-up, suggest the rate of venous thromboembolism (VTE) in the post-acute COVID-19 setting to be <5%. A single-center report of 163 patients from the United States without post-discharge thrombo-prophylaxis suggested a 2.5% cumulative incidence of thrombosis at 30 d following discharge, including segmental pulmonary embolism, intracardiac thrombus, thrombosed arteriovenous fistula and ischemic stroke. The median duration to these events was 23 d post-discharge. In this same study, there was a 3.7% cumulative incidence of bleeding at 30 d post-discharge, mostly related to mechanical falls. Similar VTE rates have been reported in retrospective studies from the United Kingdom. A prospective study from Belgium at 6 weeks post-discharge follow-up assessed D-dimer levels and venous ultrasound in 102 patients; 8% received post-discharge thrombo-prophylaxis. Only one asymptomatic VTE event was reported. Similarly, no DVT was seen in 390 participants (selected using a stratified sampling procedure to include those with a higher severity of acute COVID-19) who had ultrasonography of lower extremities in the post-acute COVID-19 Chinese study. Larger ongoing studies, such as CORONA-VTE, CISCO-19 and CORE-19, will help to establish more definitive rates of such complications.
Pathology and pathophysiology
Unlike the consumptive coagulopathy characteristic of disseminated intravascular coagulation, COVID-19-associated coagulopathy is consistent with a hyperinflammatory and hypercoagulable state. This may explain the disproportionately high rates (20–30%) of thrombotic rather than bleeding complications in acute COVID-19. Mechanisms of thrombo-inflammation include endothelial injury, complement activation, platelet activation and platelet–leukocyte interactions, neutrophil extracellular traps, release of pro-inflammatory cytokines, disruption of normal coagulant pathways and hypoxia, similar to the pathophysiology of thrombotic microangiopathy syndromes. The risk of thrombotic complications in the post-acute COVID-19 phase is probably linked to the duration and severity of a hyperinflammatory state, although how long this persists is unknown.
Although conclusive evidence is not yet available, extended post-hospital discharge (up to 6 weeks) and prolonged primary thrombo-prophylaxis (up to 45 d) in those managed as outpatients may have a more favorable risk–benefit ratio in COVID-19 given the noted increase in thrombotic complications during the acute phase, and this is an area of active investigation. Elevated D-dimer levels (greater than twice the upper limit of normal), in addition to comorbidities such as cancer and immobility, may help to risk stratify patients at the highest risk of post-acute thrombosis; however, individual patient-level considerations for risk versus benefit should dictate recommendations at this time.
Direct oral anticoagulants and low-molecular-weight heparin are preferred anticoagulation agents over vitamin K antagonists due to the lack of need to frequently monitor therapeutic levels, as well as the lower risk of drug–drug interactions. Therapeutic anticoagulation for those with imaging-confirmed VTE is recommended for ≥3 months, similar to provoked VTE. The role of antiplatelet agents such as aspirin as an alternative (or in conjunction with anticoagulation agents) for thrombo-prophylaxis in COVID-19 has not yet been defined and is currently being investigated as a prolonged primary thrombo-prophylaxis strategy in those managed as outpatients. Physical activity and ambulation should be recommended to all patients when appropriate.
Epidemiology and clinical manifestations
Chest pain was reported in up to ~20% of COVID-19 survivors at 60 d follow-up, while ongoing palpitations and chest pain were reported in 9 and 5%, respectively, at 6 months follow-up in the post-acute COVID-19 Chinese study. An increased incidence of stress cardiomyopathy has been noted during the COVID-19 pandemic compared with pre-pandemic periods (7.8 versus 1.5–1.8%, respectively), although mortality and re-hospitalization rates in these patients are similar. Preliminary data with cardiac magnetic resonance imaging (MRI) suggest that ongoing myocardial inflammation may be present at rates as high as 60% more than 2 months after a diagnosis of COVID-19 at a COVID-testing center, although the reproducibility and consistency of these data have been debated. In a study of 26 competitive college athletes with mild or asymptomatic SARS-CoV-2 infection, cardiac MRI revealed features diagnostic of myocarditis in 15% of participants, and previous myocardial injury in 30.8% of participants.
Pathology and pathophysiology
Mechanisms perpetuating cardiovascular sequelae in post-acute COVID-19 include direct viral invasion, downregulation of ACE2, inflammation and the immunologic response affecting the structural integrity of the myocardium, pericardium and conduction system. Autopsy studies in 39 cases of COVID-19 detected virus in the heart tissue of 62.5% of patients. The subsequent inflammatory response may lead to cardiomyocyte death and fibro-fatty displacement of desmosomal proteins important for cell-to-cell adherence.
Recovered patients may have persistently increased cardiometabolic demand, as observed in long-term evaluation of SARS survivors. This may be associated with reduced cardiac reserve, corticosteroid use and dysregulation of the renin–angiotensin–aldosterone system (RAAS). Myocardial fibrosis or scarring, and resultant cardiomyopathy from viral infection, can lead to re-entrant arrhythmias. COVID-19 may also perpetuate arrhythmias due to a heightened catecholaminergic state due to cytokines such as IL-6, IL-1 and tumor necrosis factor-α, which can prolong ventricular action potentials by modulating cardiomyocyte ion channel expression. Autonomic dysfunction after viral illness, resulting in postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia, has previously been reported as a result of adrenergic modulation.
Serial clinical and imaging evaluation with electrocardiogram and echocardiogram at 4–12 weeks may be considered in those with cardiovascular complications during acute infection, or persistent cardiac symptoms. Current evidence does not support the routine utilization of advanced cardiac imaging, and this should be considered on a case-by-case basis. Recommendations for competitive athletes with cardiovascular complications related to COVID-19 include abstinence from competitive sports or aerobic activity for 3–6 months until resolution of myocardial inflammation by cardiac MRI or troponin normalization.
Despite initial theoretical concerns regarding increased levels of ACE2 and the risk of acute COVID-19 with the use of RAAS inhibitors, they have been shown to be safe and should be continued in those with stable cardiovascular disease. Instead, abrupt cessation of RAAS inhibitors may be potentially harmful. In patients with ventricular dysfunction, guideline-directed medical therapy should be initiated and optimized as tolerated. Withdrawal of guideline-directed medical therapy was associated with higher mortality in the acute to post-acute phase in a retrospective study of 3,080 patients with COVID-19. Patients with postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia may benefit from a low-dose beta blocker for heart rate management and reducing adrenergic activity. Attention is warranted to the use of drugs such as anti-arrhythmic agents (for example, amiodarone) in patients with fibrotic pulmonary changes after COVID-19.
Epidemiology and clinical manifestations
Similar to chronic post-SARS syndrome, COVID-19 survivors have reported a post-viral syndrome of chronic malaise, diffuse myalgia, depressive symptoms and non-restorative sleep. Other post-acute manifestations of COVID-19 include migraine-like headaches (often refractory to traditional analgesics) and late-onset headaches ascribed to high cytokine levels. In a follow-up study of 100 patients, approximately 38% had ongoing headaches after 6 weeks. Loss of taste and smell may also persist after resolution of other symptoms in approximately one-tenth of patients at up to 6 months follow-up. Cognitive impairment has been noted with or without fluctuations, including brain fog, which may manifest as difficulties with concentration, memory, receptive language and/or executive function.
Individuals with COVID-19 experience a range of psychiatric symptoms persisting or presenting months after initial infection. In a cohort of 402 COVID-19 survivors in Italy 1 month after hospitalization, approximately 56% screened positive in at least one of the domains evaluated for psychiatric sequelae (PTSD, depression, anxiety, insomnia and obsessive compulsive symptomatology). Clinically significant depression and anxiety were reported in approximately 30–40% of patients following COVID-19, similar to patients with previous severe coronavirus infections. Anxiety, depression and sleep difficulties were present in approximately one-quarter of patients at 6 months follow-up in the post-acute COVID-19 Chinese study. Notably, clinically significant PTSD symptoms were reported in approximately 30% of patients with COVID-19 requiring hospitalization, and may present early during acute infection or months later. A real-world, large-scale dataset analysis of 62,354 COVID-19 survivors from 54 healthcare organizations in the United States estimated the incidence of first and recurrent psychiatric illness between 14 and 90 d of diagnosis to be 18.1%. More importantly, it reported the estimated overall probability of diagnosis of a new psychiatric illness within 90 d after COVID-19 diagnosis to be 5.8% (anxiety disorder = 4.7%; mood disorder = 2%; insomnia = 1.9%; dementia (among those ≥65 years old) = 1.6%) among a subset of 44,759 patients with no known previous psychiatric illness. These values were all significantly higher than in matched control cohorts of patients diagnosed with influenza and other respiratory tract infections.
Similar to other critical illnesses, the complications of acute COVID-19, such as ischemic or hemorrhagic stroke, hypoxic–anoxic damage, posterior reversible encephalopathy syndrome and acute disseminated myelitis, may lead to lingering or permanent neurological deficits requiring extensive rehabilitation. Additionally, acute critical illness myopathy and neuropathies resulting during acute COVID-19 or from the effect of neuromuscular blocking agents can leave residual symptoms persisting for weeks to months.
Pathology and pathophysiology
The mechanisms contributing to neuropathology in COVID-19 can be grouped into overlapping categories of direct viral infection, severe systemic inflammation, neuroinflammation, microvascular thrombosis and neurodegeneration. While viral particles in the brain have previously been reported with other coronavirus infections, there is not yet compelling evidence of SARS-CoV-2 infecting neurons. However, autopsy series have shown that SARS-CoV-2 may cause changes in brain parenchyma and vessels, possibly by effects on blood–brain and blood–cerebrospinal fluid barriers, which drive inflammation in neurons, supportive cells and brain vasculature. Furthermore, levels of immune activation directly correlate with cognitive–behavioral changes. Inflammaging (a chronic low-level brain inflammation), along with the reduced ability to respond to new antigens and an accumulation of memory T cells (hallmarks of immuno-senescence in aging and tissue injury), may play a role in persistent effects of COVID-19. Other proposed mechanisms include dysfunctional lymphatic drainage from circumventricular organs, as well as viral invasion in the extracellular spaces of olfactory epithelium and passive diffusion and axonal transport through the olfactory complex. Biomarkers of cerebral injury, such as elevated peripheral blood levels of neurofilament light chain, have been found in patients with COVID-19, with a more sustained increase in severe infections, suggesting the possibility of more chronic neuronal injury.
Post-COVID brain fog in critically ill patients with COVID-19 may evolve from mechanisms such as deconditioning or PTSD. However, reports of COVID-19 brain fog after mild COVID-19 suggest that dysautonomia may contribute as well. Finally, long-term cognitive impairment is well recognized in the post-critical illness setting, occurring in 20–40% of patients discharged from an ICU.
Standard therapies should be implemented for neurologic complications such as headaches, with imaging evaluation and referral to a specialist reserved for refractory headache. Further neuropsychological evaluation should be considered in the post-acute illness setting in patients with cognitive impairment. Standard screening tools should be used to identify patients with anxiety, depression, sleep disturbances, PTSD, dysautonomia and fatigue.
Epidemiology and clinical manifestations
Severe acute kidney injury (AKI) requiring renal replacement therapy (RRT) occurs in 5% of all hospitalized patients and 20–31% of critically ill patients with acute COVID-19, particularly among those with severe infections requiring mechanical ventilation. Early studies with short-term follow-up in patients requiring RRT showed that 27–64% were dialysis independent by 28 d or ICU discharge. Decreased estimated glomerular filtration rate (eGFR; defined as <90 ml min−1 per 1.73 m2) was reported in 35% of patients at 6 months in the post-acute COVID-19 Chinese study, and 13% developed new-onset reduction of eGFR after documented normal renal function during acute COVID-19. With adequate longer-term follow-up data, those patients who require RRT for severe AKI experience high mortality, with a survival probability of 0.46 at 60 d and rates of renal recovery reportedly at 84% among survivors.
Pathology and pathophysiology
SARS-CoV-2 has been isolated from renal tissue, and acute tubular necrosis is the primary finding noted from renal biopsies and autopsies in COVID-19. COVID-19-associated nephropathy (COVAN) is characterized by the collapsing variant of focal segmental glomerulosclerosis, with involution of the glomerular tuft in addition to acute tubular injury, and is thought to develop in response to interferon and chemokine activation. Association with APOL1 risk alleles suggests that SARS-CoV-2 acts as a second hit in susceptible patients, in a manner similar to human immunodeficiency virus and other viruses. Thrombi in the renal microcirculation may also potentially contribute to the development of renal injury.
While the burden of dialysis-dependent AKI at the time of discharge is low, the extent of the recovery of renal function remains to be seen. As a result, COVID-19 survivors with persistent impaired renal function in the post-acute infectious phase may benefit from early and close follow-up with a nephrologist in AKI survivor clinics, supported by its previous association with improved outcomes.
Epidemiology and clinical manifestations
Diabetic ketoacidosis (DKA) has been observed in patients without known diabetes mellitus weeks to months after resolution of COVID-19 symptoms. It is not yet known how long the increased severity of pre-existing diabetes or predisposition to DKA persists after infection, and this will be addressed by the international CoviDiab registry. Similarly, subacute thyroiditis with clinical thyrotoxicosis has been reported weeks after the resolution of respiratory symptoms. COVID-19 may also potentiate latent thyroid autoimmunity manifesting as new-onset Hashimoto’s thyroiditis or Graves’ disease.
Pathology and pathophysiology
Endocrine manifestations in the post-acute COVID-19 setting may be consequences of direct viral injury, immunological and inflammatory damage, as well as iatrogenic complications. Pre-existing diabetes may first become apparent during the acute phase of COVID-19 and can generally be treated long term with agents other than insulin, even if initially associated with DKA. There is no concrete evidence of lasting damage to pancreatic β cells. Although some surveys have shown ACE2 and transmembrane serine protease (TMPRSS2; the protease involved in SARS-CoV-2 cell entry) expression in β cells, the primary deficit in insulin production is probably mediated by factors such as inflammation or the infection stress response, along with peripheral insulin resistance. So far, there is no evidence that COVID-19-associated diabetes can be reversed after the acute phase, nor that its outcomes differ in COVID-19 long haulers. COVID-19 also presents risk factors for bone demineralization related to systemic inflammation, immobilization, exposure to corticosteroids, vitamin D insufficiency and interruption of antiresorptive or anabolic agents for osteoporosis.
Serologic testing for type 1 diabetes-associated autoantibodies and repeat post-prandial C-peptide measurements should be obtained at follow-up in patients with newly diagnosed diabetes mellitus in the absence of traditional risk factors for type 2 diabetes, whereas it is reasonable to treat patients with such risk factors akin to ketosis-prone type 2 diabetes. Incident hyperthyroidism due to SARS-CoV-2-related destructive thyroiditis can be treated with corticosteroids but new-onset Graves’ disease should also be ruled out.
Gastrointestinal and hepatobiliary sequelae
Significant gastrointestinal and hepatobiliary sequelae have not been reported in COVID-19 survivors. Prolonged viral fecal shedding occurs in COVID-19, with viral ribonucleic acid detectable for a mean duration of 28 d after the onset of SARS-CoV-2 infection symptoms and persisting for a mean of 11 d after negative respiratory samples.
COVID-19 has the potential to alter the gut microbiome, including enrichment of opportunistic infectious organisms and depletion of beneficial commensals. The ability of the gut microbiota to alter the course of respiratory infections (gut–lung axis) has been recognized previously in influenza and other respiratory infections. In COVID-19, Faecalibacterium prausnitzii, a butyrate-producing anaerobe typically associated with good health, has been inversely correlated with disease severity. Studies are currently evaluating the long-term consequences of COVID-19 on the gastrointestinal system, including post-infectious irritable bowel syndrome and dyspepsia.
Dermatologic manifestations of COVID-19 occurred after (64%) or concurrent to (15%) other acute COVID-19 symptoms in an international study of 716 patients with COVID-19, with an average latency from the time of upper respiratory symptoms to dermatologic findings of 7.9 d in adults. Only 3% of patients noted a skin rash at 6 months follow-up in the post-acute COVID-19 Chinese study. The predominant dermatologic complaint was hair loss, which was noted in approximately 20% of patients. Hair loss can possibly be attributed to telogen effluvium resulting from viral infection or a resultant stress response. Ongoing investigations may provide insight into potential immune or inflammatory mechanisms of disease.
Multisystem inflammatory syndrome in children (MIS-C)
Epidemiology and clinical manifestations
MIS-C, also referred to as pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), is defined by the presence of the following symptoms in people <21 years old (or ≤19 years old per the World Health Organization definition): fever; elevated inflammatory markers; multiple organ dysfunction; current or recent SARS-CoV-2 infection; and exclusion of other plausible diagnoses. Clinical presentations of MIS-C include fever, abdominal pain, vomiting, diarrhea, skin rash, mucocutaneous lesions, hypotension and cardiovascular and neurologic compromise. Overlapping features have been noted with Kawasaki disease, an acute pediatric medium-vessel vasculitis. However, comparison of Kawasaki disease and MIS-C cohorts demonstrates distinctive epidemiologic and clinical characteristics. While 80% of Kawasaki disease cases occur in children <5 years of age and primarily of Asian descent, patients with MIS-C are typically >7 years, encompass a broader age range and are of African, Afro-Caribbean or Hispanic origin. A comparable incidence of coronary artery aneurysm and dilation has been noted among MIS-C and Kawasaki disease (20 and 25%, respectively). Neurological complications of MIS-C, such as headache, altered mental status, encephalopathy, cranial nerve palsies, stroke, seizure, reduced reflexes, and muscle weakness, appear to be more frequent than in Kawasaki disease. A pooled meta-analysis of MIS-C studies reported recovery in 91.1% and death in 3.5% of patients. Ongoing studies are evaluating long-term sequelae in these children.
Pathology and pathophysiology
The timing of the emergence of MIS-C (which was lagging approximately 1 month behind peak COVID-19 incidence in epicenters in Spring 2020) and the finding that most patients are negative for acute infection but are antibody positive suggest that MIS-C may result from an aberrant acquired immune response rather than acute viral infection. Insights into the pathophysiology of MIS-C may be derived in part from Kawasaki disease and toxic shock syndrome, with possible mechanisms of injury related to immune complexes, complement activation, autoantibody formation through viral host mimicry, and massive cytokine release related to super-antigen stimulation of T cells.
Current recommendations include immunomodulatory therapy with intravenous immunoglobulin, adjunctive glucocorticoids and low-dose aspirin until coronary arteries are confirmed normal at least 4 weeks after diagnosis. Therapeutic anticoagulation with enoxaparin or warfarin and low-dose aspirin is recommended in those with a coronary artery z score ≥ 10, documented thrombosis or an ejection fraction < 35%. Studies such as the Best Available Treatment Study for Inflammatory Conditions Associated with COVID-19 are evaluating the optimal choice of immunomodulatory agents for treatment.
Serial echocardiographic assessment is recommended at intervals of 1–2 and 4–6 weeks after presentation. Cardiac MRI may be indicated 2–6 months after diagnosis in those presenting with significant transient left ventricular dysfunction (ejection fraction < 50%) in the acute phase or persistent dysfunction to assess for fibrosis and inflammation. Serial electrocardiograms and consideration of an ambulatory cardiac monitor are recommended at follow-up visits in patients with conduction abnormalities at diagnosis.
Racial and ethnic considerations
Acute COVID-19 has been recognized to disproportionately affect communities of color. A total of 51.6% of survivors in the post-acute COVID-19 US study were Black, while the BAME group comprised 19–20.9% in the UK studies. Only one study from the United Kingdom evaluated the association of race/ethnicity and reported that individuals belonging to the BAME group were more likely to experience dyspnea than White individuals (42.1 versus 25%, respectively) at 4–8 weeks post-discharge. Rates of PTSD were similar in BAME and White participants in this study. Emerging data also suggest that COVAN may be the predominant pattern of renal injury in individuals of African descent. MIS-C is also known to disproportionately affect children and adolescents of African, Afro-Caribbean or Hispanic ethnicity. Larger studies are required to ascertain the association between sequelae of post-acute COVID-19 and race and ethnicity.
These important differences noted in preliminary studies may be related to multiple factors, including (but not limited to) socioeconomic determinants and racial/ethnic disparities, plausible differences in the expression of factors involved in SARS-CoV-2 pathogenesis, and comorbidities. Higher nasal epithelial expression has been reported in Black individuals compared with other self-reported races/ethnicities. However, caution is warranted that ongoing and future studies integrate and analyze information along multiple axes (for example, clinical and socioeconomic axes, resource deficits and external stressors) to prevent inaccurate contextualization. The National Institute on Minority Health and Health Disparities at the National Institutes of Health has identified investigation of short- and long-term effects of COVID-19 on health, and how differential outcomes can be reduced among racial and ethnic groups, as a research priority.
Nutrition and rehabilitation considerations
Severe COVID-19, similar to other critical illnesses, causes catabolic muscle wasting, feeding difficulties and frailty, each of which is associated with an increased likelihood of poor outcome. Malnutrition has been noted in 26–45% of patients with COVID-19, as evaluated by the Malnutrition Universal Screening Tool in an Italian study. Protocols to provide nutritional support for patients (many of whom suffered from respiratory distress, nausea, diarrhea and anorexia, with resultant reduction in food intake) continue to be refined.
All post-acute COVID-19 follow-up studies that incorporated assessments of health-related quality of life and functional capacity measures have universally reported significant deficits in these domains, including at 6 months in the post-acute COVID-19 Chinese study. Given the severity of the systemic inflammatory response associated with severe COVID-19 and resultant frailty, early rehabilitation programs are being evaluated in ongoing clinical studies. They have previously been validated to be both safe and effective in critically ill patients with ARDS and in preliminary studies in COVID-19. Model COVID-19 rehabilitation units such as those in Italy are already routinely assessing acute COVID-19 survivors for swallowing function, nutritional status and measures of functional independence.
Patient advocacy groups
Unique to this pandemic is the creation and role of patient advocacy groups in identifying persistent symptoms and influencing research and clinical attention. Such groups include COVID Advocacy Exchange , the National Patient Advocate Foundation COVID Care Resource Center , long-haul COVID fighters Facebook groups, the Body Politic COVID-19 Support Group , Survivor Corps and Patient-Led Research for COVID-19. Surveys conducted by these groups have helped to identify persistent symptoms such as brain fog, fatigue and body aches as important components of post-acute COVID-19. Additionally, they have been instrumental in highlighting the persistence of symptoms in patients with mild-to-moderate disease who did not require hospitalization. Active engagement with these patient advocacy groups, many of whom identify themselves as long haulers, is crucial. Dissemination of contact information and resources of these groups can occur at pharmacies, physician offices and in discharge summaries upon hospital discharge.
Conclusions and future directions
The multi-organ sequelae of COVID-19 beyond the acute phase of infection are increasingly being appreciated as data and clinical experience in this timeframe accrue. Necessary active and future research include the identification and characterization of key clinical, serological, imaging and epidemiologic features of COVID-19 in the acute, subacute and chronic phases of disease, which will help us to better understand the natural history and pathophysiology of this new disease entity. Active and future clinical studies, including prospective cohorts and clinical trials, along with frequent review of emerging evidence by working groups and task forces, are paramount to developing a robust knowledge database and informing clinical practice in this area. Currently, healthcare professionals caring for survivors of acute COVID-19 have the key role of recognizing, carefully documenting, investigating and managing ongoing or new symptoms, as well as following up organ-specific complications that developed during acute illness. It is also imperative that clinicians provide information in accessible formats, including clinical studies available for participation and additional resources such as patient advocacy and support groups.
Moreover, it is clear that care for patients with COVID-19 does not conclude at the time of hospital discharge, and interdisciplinary cooperation is needed for comprehensive care of these patients in the outpatient setting. As such, it is crucial for healthcare systems and hospitals to recognize the need to establish dedicated COVID-19 clinics, where specialists from multiple disciplines are able to provide integrated care. Prioritization of follow-up care may be considered for those at high risk for post-acute COVID-19, including those who had severe illness during acute COVID-19 and/or required care in an ICU, those most susceptible to complications (for example, the elderly, those with multiple organ comorbidities, those post-transplant and those with an active cancer history) and those with the highest burden of persistent symptoms.
Given the global scale of this pandemic, it is apparent that the healthcare needs for patients with sequelae of COVID-19 will continue to increase for the foreseeable future. Rising to this challenge will require harnessing of existing outpatient infrastructure, the development of scalable healthcare models and integration across disciplines for improved mental and physical health of survivors of COVID-19 in the long term.
New Developments In Covid Research
By Sarah Toy, Sumathi Reddy and Daniela Hernandez
Nov. 1, 2020 12:49 pm ET
Nearly a year into the global coronavirus pandemic, scientists, doctors and patients are beginning to unlock a puzzling phenomenon: For many patients, including young ones who never required hospitalization, Covid-19 has a devastating second act.
Many are dealing with symptoms weeks or months after they were expected to recover, often with puzzling new complications that can affect the entire body—severe fatigue, cognitive issues and memory lapses, digestive problems, erratic heart rates, headaches, dizziness, fluctuating blood pressure, even hair loss.
What is surprising to doctors is that many such cases involve people whose original cases weren’t the most serious, undermining the assumption that patients with mild Covid-19 recover within two weeks. Doctors call the condition “post-acute Covid” or “chronic Covid,” and sufferers often refer to themselves as “long haulers” or “long-Covid” patients.
“Usually, the patients with bad disease are most likely to have persistent symptoms, but Covid doesn’t work like that,” said Trisha Greenhalgh, professor of primary care at the University of Oxford and the lead author of an August BMJ study that was among the first to define chronic Covid patients as those with symptoms lasting more than 12 weeks and spanning multiple organ systems.
For many such patients, she said, “the disease itself is not that bad,” but symptoms like memory lapses and rapid heart rate sometimes persist for months.
In October, the National Institutes of Health added a description of such cases to its Covid-19 treatment guidelines, saying doctors were reporting Covid-19-related long-term symptoms and disabilities in people with milder illness.
“You don’t realize how lucky you are with your health until you don’t have it,” said Elizabeth Moore, a 43-year-old lawyer and mother of three in Valparaiso, Ind. Pre-Covid-19 she was an avid skier and did boot-camp workouts several times a week. Since falling ill in March, she has been struggling with symptoms including memory problems and gastrointestinal issues. She has lost nearly 30 pounds.
Estimates about the percentage of Covid-19 patients who experience long-haul symptoms range widely. A recent survey of more than 4,000 Covid-19 patients found that about 10% of those age 18 to 49 still struggled with symptoms four weeks after becoming sick, that 4.5% of all ages had symptoms for more than eight weeks, and 2.3% had them for more than 12 weeks. The study, which hasn’t yet been peer reviewed, was performed using an app created by the health-science company Zoe in cooperation with King’s College London and Massachusetts General Hospital.
Another preliminary study looking mostly at nonhospitalized Covid patients found that about 25% still had at least one symptom after 90 days. A European study found about one-third of 1,837 nonhospitalized patients reported being dependent on a caregiver about three months after symptoms started.
With more than 46 million cases world-wide, even the lower estimates would translate into millions living with long-term, sometimes disabling conditions, increasing the urgency to study this patient population, researchers said. What they find could have implications for how clinicians define recovery and what therapies they prescribe, doctors said.
Doctors say anxiety caused by social isolation and uncertainty surrounding the pandemic may exacerbate symptoms, though that isn’t likely the primary cause.
Other viral outbreaks, including the original SARS, MERS, Ebola, H1N1 and the Spanish flu, have been associated with long-term symptoms. Scientists reported that some patients experienced fatigue, sleep problems and joint and muscle pain long after their bodies cleared a virus, according to a recent review chronicling the long-term effects of viral infections.
What differentiates Covid-19 is the far-reaching nature of its effects. While it starts in the lungs, it often affects many other parts of the body, including the heart, kidneys and the digestive and nervous systems, doctors said.
“I haven’t really seen any other illness that affects so many different organ systems in as many different ways as Covid does,” said Zijian Chen, medical director for Mount Sinai Health System’s Center for Post-Covid Care.
He described colleagues who were energetic, but after getting sick, had trouble getting through the day. He said he has seen up close how Covid-19 still affects their ability to do the things they love.
“We thought it was a virus that, once it does what it does, you recover and you go back to normal,” he said. Sometimes that isn’t the case, and that “is really scary,” he said.
A leading explanation for long-Covid symptoms is that immune-system activity and ensuing inflammation continue to affect organs or the nervous system even after the virus is gone, researchers said.
Some of the most compelling evidence for the inflammation theory comes from Covid-19 patients with signs of heart inflammation and injury months after illness. One study looking at 100 Covid-19 patients two months after getting sick found that 78 had abnormal findings on cardiac magnetic resonance imaging, while 60 had cardiac MRIs indicating heart-muscle inflammation. The study included hospitalized, non-hospitalized and asymptomatic patients.
“Even those who had no symptoms and were young and fit…even in those patients we saw abnormalities,” said Eike Nagel, one of the lead authors and director of the Institute for Experimental and Translational Cardiovascular Imaging at the University Hospital Frankfurt in Germany.
Some patients had scarring on their heart imaging, he said, which worried him. The scarring wasn’t too serious, he said, but “we know from other studies that this is related to worse outcomes.”
Doctors also are reporting cases of long-Covid patients with gastrointestinal issues. Recent work has found the new coronavirus, known as SARS-CoV-2, in fecal matter and intestinal lining of some Covid-19 patients, suggesting the virus can infect and damage the cells of the gut. The intestines have a high density of ACE2 receptors, a type of protein on the surface of cells, which SARS-CoV-2 uses to infiltrate cells. Many patients report issues with concentration and memory, sometimes referred to as “brain fog.” Some say they forget what they’re trying to say or do. Neurologists seeing such patients say cognitive problems are among the most common symptoms.
Some neurologists say they are seeing patients with signs of dysautonomia, or dysregulation of the autonomic nervous system. The autonomic nervous system regulates involuntary functions such as breathing, digestion and heart rate.Taste and Smell
Patients say it can take weeks or months to regain their senses of smell and taste. They say the loss of these senses affects not just their diet but their mental health.Lungs
Some patients report persistent shortness of breath. Doctors often prescribe asthma inhalers and breathing exercises to help improve lung function. The exact cause is unknown. It could be related to aberrant nervous system function, lung injury or a compromised cardiovascular system.Cardiovascular System
Many patients experience a racing heartbeat, or tachycardia, as well as extreme blood pressure changes. Some physicians think this could be related to an issue with the nervous system, particularly the autonomic arm, which deals with involuntary functions like heart rate and blood pressure.
Some patients have signs of heart-muscle inflammation weeks or months after infection, doctors and researchers say. In some cases, they don’t report any symptoms, while others say they have shortness of breath and chest pain.Digestive System
Patients report issues with abdominal pain and diarrhea weeks or months after coming down with Covid-19. Some physicians are recommending avoiding certain foods, such as dairy and gluten.Musculoskeletal System
Some patients report mild muscle and joint aches. Others have more severe pain.
Many patients also report persistent fatigue weeks or months after coming down with Covid-19, even when they had a mild or moderate course of illness and didn’t require hospitalization. The fatigue can be debilitating and get in the way of regular daily activities, like work and spending time with family.A Persistent Multifront AttackHow chronic Covid-19 affects the body
The virus also might cause changes in gut bacteria, said Brennan Spiegel, a gastroenterologist and director of health services research at Cedars-Sinai Health System, who has had patients come in with abdominal pain and diarrhea weeks or months after coming down with Covid-19.
Ms. Moore, the Indiana lawyer, got Covid-19 in March and initially felt better by the end of April. “I thought I beat this thing. I was ecstatic,” said Ms. Moore, who tested positive for coronavirus antibodies in May.
That month, her health took a sharp turn for the worse. She struggled with tachycardia, or a racing heartbeat, and blood-pressure fluctuations. Those symptoms improved, but she still has gastrointestinal problems. A recent test found stomach-lining inflammation. Pepcid, antihistamines and avoiding dairy products have provided some relief, but other symptoms such as memory deficits persist.
“I feel like there has to be some sort of next step,” she said, “because I’m not ready to accept this as my new reality.”
She enrolled in a research study at the Neuro Covid-19 Clinic at Northwestern Medicine in Chicago, one of several clinics across the country aiming to find solutions for patients.
Some symptoms could be collateral damage from the body’s immune response during the acute infection, researchers said. Some patients might harbor an undetectable reservoir of infectious virus or have bits of noninfectious virus in some cells that trigger an immune response, they said.
Another possibility is that the virus causes some people’s immune systems to attack and damage their own organs and tissues, researchers said. A June study found roughly half of 29 hospitalized ICU patients with Covid-19 had one or more types of autoantibodies—antibodies that mistakenly target and attack a patient’s own tissues or organs.
Doctors say some patients appear to be developing dysautonomia, or dysregulation of the autonomic nervous system, the part of the nervous system that regulates involuntary functions like breathing, digestion and heart rate, some researchers and doctors said.
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David Putrino, director of rehabilitation innovation at Mount Sinai Health System in New York City, said the majority of the more than 300 long-Covid patients being seen at its Center for Post-Covid Care appear to have developed a dysautonomia-like condition. About 90% of such patients report having symptoms of exercise intolerance, fatigue and elevated heartbeats. About 40% to 50% also report symptoms such as gastrointestinal issues, headaches and shortness of breath.
Dr. Putrino said inflammation from the virus might be disrupting the normal functioning of the vagus nerve—the body’s longest cranial nerve—which relays messages to the lungs, gut and heart.
As a member of the Johns Hopkins University varsity cross-country team, 19-year-old Christopher Wilhelm used to run 10 miles a day. Now, there are days he can’t even walk a quarter mile with his mom around their Maitland, Fla., neighborhood without feeling wiped out.
Mr. Wilhelm, who tested positive for Covid-19 in June, said his heart rate shoots up during those walks, ranging from 130 to 170 beats a minute. He was diagnosed recently with a form of dysautonomia characterized by fluctuations in blood pressure and heart rate when patients sit or stand up, a condition known as postural orthostatic tachycardia syndrome, or POTS. His doctors also are evaluating him for cardiac issues. Medications he has tried haven’t yet helped his heart-rate spikes.
“After I tested positive, I was just expecting it to be two weeks of flulike symptoms, and then I’d pretty much be back to normal,” he said. “It’s been so long already, it’s kind of daunting.”
Six months after getting sick with Covid-19, Jennica Harris, 33, said she has persistent fatigue and problems with memory and concentration. She struggles to find simple words during conversations, often loses her train of thought and has developed a stutter.
“I usually know what I want to say when I want to say it, and I usually don’t hold back,” she said. “When I try to get my point across and I can’t, that hurts my confidence, my sense of self.”
The constellation of such neurological symptoms, along with persistent fatigue, joint pain and headaches, resembles myalgic encephalomyelitis, also known as chronic fatigue syndrome, said Anthony Komaroff, a Harvard Medical School professor of medicine who has studied the syndrome for decades. The condition can follow certain viral and bacterial infections, he said. He thinks the condition likely follows Covid-19, too, at least in a portion of patients. A 2009 study of 233 SARS survivors found 27% met criteria for chronic fatigue syndrome four years after getting sick.
It still isn’t known whether the new coronavirus gets into the brain itself, or if Covid-19’s neurological symptoms stem from a body-wide inflammatory response, scientists say.
In autopsies of some Covid-19 patients, doctors have observed encephalitis, or inflammation of the brain. Small autopsy studies also have found preliminary evidence of coronavirus particles in regions of the brain important for smell. With other infections, viral particles have been found in the brains of patients with encephalitis, though it is rare, said Walter Royal, a neurovirologist and director of Morehouse School of Medicine’s Neuroscience Institute. What is more common is that the virus infects the lining of the blood vessels, causing damage and inflammation that in turn affects the brain.
How long it will take long-Covid patients to recover remains unknown. Dr. Putrino said most of them won’t get better on their own, and will need at least six months of structured rehabilitation.
“What tends to happen to people who don’t get treatment and don’t get the recognition they need is they slump down to a new normal of function,” he said.
The world may need to learn to live with the virus.
Health care workers administered coronavirus tests in Colombo, Sri Lanka, on Tuesday.Credit…Ishara S. Kodikara/Agence France-Presse
Early in the pandemic, there was hope that the world would one day achieve herd immunity, the point when the coronavirus lacks enough hosts to spread easily. But over a year later, the virus is crushing India with a fearsome second wave and surging in countries from Asia to Latin America.
That means if the virus continues to run rampant through much of the world, it is well on its way to becoming endemic, an ever-present threat.
Virus variants are tearing through places where people gather in large numbers with few or no pandemic protocols, like wearing masks and distancing, according to Dr. David Heymann, a professor of infectious disease epidemiology at the London School of Hygiene and Tropical Medicine.
While the outbreak in India is capturing the most attention, Dr. Heymann said the pervasive reach of the virus means that the likelihood is growing that it will persist in most parts of the world.
As more people contract the virus, developing some level of immunity, and the pace of vaccinations accelerates, future outbreaks won’t be on the scale of those devastating India and Brazil, Dr. Heymann said. Smaller outbreaks that are less deadly but a constant threat should be expected, Dr. Heymann said.
“This is the natural progression of many infections we have in humans, whether it is tuberculosis or H.I.V.,” said Dr. Heymann, a former member of the Epidemiology Intelligence Service at the Centers for Disease Control and Prevention and a former senior official at the World Health Organization. “They have become endemic and we have learned to live with them and we learn how to do risk assessments and how to protect those we want to protect.”
Vaccines that are highly effective against Covid were developed rapidly, but global distribution has been plodding and unequal. As rich countries hoard vaccine doses, poorer countries face big logistical challenges to distributing the doses they manage to get and vaccine hesitancy is an issue everywhere. And experts warn the world is getting vaccinated too slowly for there to be much hope of ever eliminating the virus.
Only two countries have fully vaccinated more than half of their populations, according to the Our World in Data project at the University of Oxford. They are Israel and the East African nation of the Seychelles, an archipelago with a population of fewer than 100,000. And just a handful of other countries have at least partially vaccinated nearly 50 percent or more, including Britain, tiny Bhutan, and the United States.
Less than 10 percent of India’s vast population is at least partly vaccinated, offering little check to its onslaught of infections.
In Africa, the figure is slightly more than 1 percent.
Still, public health experts say a relatively small number of countries, mostly island nations, have largely kept the virus under control and could continue keeping it at bay after vaccinating enough people.
New Zealand, through stringent lockdowns and border closures, has all but eliminated the virus. Dr. Michael Baker, an epidemiologist at the University of Otago who helped devise the country’s coronavirus response, said New Zealand would likely achieve herd immunity by immunizing its population, but it has a long way to go with only about 4.4 percent of New Zealanders at least partially vaccinated.
“All of the surveys show there is a degree of vaccine hesitancy in New Zealand, but also a lot of people are very enthusiastic,” Dr. Baker said. “So I think we will probably get there in the end.”
While new daily cases have remained at near-world record levels, the number of deaths has dropped from a peak in February, going against the normal pattern of high cases followed eventually by high deaths. If that trendline continues, it could offer a glimmer of hope for a future scenario that scientists are rooting for: Even as the virus spreads and seems to be hurtling toward becoming endemic, it could become a less lethal threat that can be managed with vaccines that are updated periodically to protect against variants.
“It may be endemic, but not in a life-threatening way,” Dr. Michael Merson, a professor of global health at Duke University and former director of the World Health Organization’s Global Program on AIDS said. “It may be more like what we see with young kids, a common cold like disease.”
Will we ever know the real death toll of the pandemic?
The past year has been a stark reminder of global inequalities—including the resources needed to collect timely and accurate data on deaths. These innovators aim to fix that.
On a sweltering April night in Ahmedabad, the largest city in the Indian state of Gujarat, Shayar Rawal rode his motorbike to a COVID-designated government hospital at 11:55 p.m. Over the next 24 hours, he had just one task: to count the number of dead bodies being brought to the mortuary.
Rawal—a reporter at the Gujarati daily newspaper Divya Bhaskar—counted four deaths in the first hour. Grieving relatives collected five more dead bodies in the next hour. When the number reached 100, he says, reality sunk in.
“I knew the government was hiding numbers, but this was way more than what I had expected,” Rawal says.
Officially, the city recorded just 15 COVID-19 deaths that day. But by the end of his vigil, Rawal had counted 112 bodies—and that was just the dead from one city hospital. Over the next few weeks, his colleagues also counted bodies at crematoria and burial grounds and accessed death certificates from districts across the state. Their final analysis revealed that the death toll over nine weeks in the state of Gujarat was 10 times higher than the official figure. In response to the Divya Bhaskar report, the state government gave multiple reasons for the discrepancy, from saying deaths with co-morbidities cannot be counted as COVID-19 deaths to claiming that duplicates of death certificates had been issued. National Geographic’s questions to the state government went unanswered.
“There are fundamental, inherent challenges,” says Samira Asma, assistant director general for data, analytics, and delivery for impact at the World Health Organization. Even in wealthy nations, officials are grappling with incorrect diagnoses, irregularities in the data tracking, and other factors that can obscure the virus’s true impact. “So because of this, we don’t have a complete understanding of the entire scope of the pandemic.”
But the past year has also been a stark reminder of inequalities throughout the world—including the resources needed to collect timely and accurate data on deaths. In an assessment conducted in 2019, the WHO found that about two-thirds of the countries in the world lack strong civil registration and vital statistics systems that keep a count of births and deaths.
This disparity is having dangerous consequences with COVID-19. The World Health Statistics Report released last month stated that there were 3 million deaths directly and indirectly attributed to the SARS-CoV-2 virus—that’s 1.2 million higher than the official figures reported by countries and then tallied by the WHO.
The lack of robust data in low- and middle-income countries such as India means grassroots efforts such as Rawal’s are crucial in determining the true death toll, which in turn affects our understanding of the pandemic’s global trajectory.
“To have an accurate understanding of historic mortality is key in knowing how effective different interventions have been, but also in helping us to more accurately forecast what may happen in the future of the pandemic,” says Oliver Watson, a postdoctoral researcher in infectious disease epidemiology at Imperial College London.
Deaths due to COVID-19
At the beginning of the pandemic, a lack of standardized methods to designate COVID-19 deaths across countries led to underreporting. In a bid to understand the true toll better, demographers, reporters, and economists developed alternate tracking methods, and each approached the problem from different angles.
For Ariel Karlinsky it started with a meme.
Karlinsky is a graduate student at Hebrew University in Jerusalem and an economist at Kohelet Policy Forum, a think tank. When Israel locked down in March 2020, a popular meme doing the rounds was that COVID-19 was claiming as many lives as the flu had in previous years. Curious to find out if that was true, Karlisnky started digging for data, but he didn’t find any. So he started collecting data on his own from individual countries—he emailed national and regional statistics offices, as well as researchers who were working on the issue in various countries.
In January 2021 he started collaborating with Dmitry Kobak, a research scientist at Tübingen University. Their effort has led to the creation of the World Mortality Dataset, which includes information from 95 countries and territories. The Economist has since used the World Mortality Dataset to make its own projections on global deaths due to COVID-19. Recognizing Karlinsky’s work, the WHO invited him to be part of a technical advisory group that aims to map the death toll of the pandemic across the world.
Karlinsky is surprised. “Usually there are organizations like the World Bank and the OECD [Organization for Economic Cooperation and Development] that essentially do what I did. They take data from each individual country and they harmonize it. For some reason, they hadn’t done it, and they still haven’t done it,” he says, speaking over Zoom on a recent Sunday afternoon. “Although they are now taking my data, which is sort of strange because they are official organizations with a much higher budget than me and my laptop.”
Karlinsky is now also working on local mortality figures based on data for smaller regions, such as cities or states across the world. By collecting and standardizing this data in one place, more people can use the information to make informed decisions about their local pandemic response.
“A lot of data exists, but that data is not being used, the data is not being shared—it’s the same as the data not existing at all, right?” he says.
New sources, old problems
One source that made its way into the World Mortality Dataset comes from Indian data journalist Rukmini S, who like Karlinsky believes that the data exists in India’s civil registration system, which records births and deaths across the country. Knowing this, Rukmini scraped together mortality data for all causes in the city of Chennai, in South India.
One way to get a handle on COVID-19 deaths when specific causes are not available is to look at what are known as excess deaths. This figure represents the gap between the number of deaths in an average year, after adjusting for population growth, and that in a year with an extenuating circumstance, like a pandemic.
Excess deaths could be COVID-19 deaths that went unreported, but they might also be due to indirect causes, such as an inability to access healthcare during lockdown, or due to unrelated diseases. While more analysis and data will be needed to link the past year’s excess deaths to COVID-19, researchers are increasingly relying on excess mortality figures to understand the direct and indirect consequences of the virus.
In Chennai, the data show more than 74,000 deaths in 2020, which is 12,000 more than the average of the five preceding years. That’s a 20 percent increase, despite the fact the city’s official number of reported COVID-19 deaths for that time period was just 4,000.
In other places, public health experts have found even more novel data sources. In Damascus, Syria, public pressure led to the mortuary office releasing data on deaths due to all causes for a limited period of eight days between July 25 and August 1, 2020. Watson, of Imperial College London, matched this information with data from a Facebook group that uploads obituaries.
Using these data points, Watson and his colleagues calculated estimates for the entire duration of the pandemic, from February up until September 2020, to arrive at a staggering figure: Their model shows that only 1.25 percent of COVID-19 deaths in Damascus had been reported as of September 2, 2020, and over 4,380 deaths might have been missed through the official reporting system.
For Watson, the analysis was an eye-opener. “It completely changed how we understood the scale of the pandemic,” he said. ”It was just shocking that you could have that amount of death happen, that level of health system collapse, and how it didn’t get much media attention.”
At first, he says, it was just hard to convince people that the officially reported death toll was inaccurate. But he notes that he has found a sense of community in other researchers who are also willing to question the official data and try various methods to arrive at better estimates.
“Coming across other individuals who are coming at it with an understanding of actually no, we all are missing a lot of what’s actually happened and we need to be doing much better—actually going out there and finding that data—it’s definitely quite a bonding experience,” Watson says.
While acknowledging the benefits of these kinds of creative methods, Rukmini, the data journalist from Chennai, emphasizes that the most accurate data need to be made public by governments.
“While I am all for novel sources, and everyone working on this is doing it out of the spirit of scientific inquiry and obviously working very hard for it, I am a bit concerned that enough democratic pressure is not building for official statistics to be released,” she says.
Chinmay Tumbe, an economist who has studied past pandemics, thinks that relying on government figures would mean that the actual toll would only be revealed in a few years, when census data comes in. But that would be too late for governments, businesses, and other policy-makers to use the data to influence the course of the pandemic.
Getting to the true death toll will eventually help in figuring out the true infection fatality rate, the proportion of all infected people who died because of COVID-19. This value was crucial in the early stage of the pandemic to understand how serious the implications might be if the public health restrictions were not put in place and the virus was allowed to spread freely in populations.
“However, it is very difficult to estimate correctly if we don’t know the true number of people who have died,” Watson says.
He explained that the infection fatality rate for COVID-19 has been a topic of debate. Some people argue that it has been inflated, and they have used that position to discourage lockdowns and other interventions. They also point to lower reported mortality in lower-income settings as evidence that the pandemic is not as deadly as initially thought. “Those arguments are blatantly incorrect, given the scale of underreporting that has been observed,” he says.
That is why researchers need to continue to put pressure on governments to prioritize accurate and timely data collection, Tumbe says. “I think it can easily become a poll issue. And it might even become a manifesto issue—saying that, well, if you elect us, we will form a committee with which we will count the deaths.”
Need for accountability
In some countries, the pressure on the government has worked. Recently, Peru revised its official death count, which now stands at 185,380—almost three times the original figure of 69,342. At 5,551 deaths per million people, Peru has the worst official death toll in the world.
Convincing countries to accept a higher death count than what was officially reported is not going to be an easy task. With the help of the advisory task force, the WHO has a plan, says Asma. By November 2021, the WHO aims to standardize methodology for counting excess deaths, decide what parameters should be used, and have revised estimates for all countries, which will be followed by consultations with representatives of governments.
“We are going to do it in a transparent way, so that is going to be very critical,” she says. That way countries can work with the WHO to flag inconsistencies and land on the most accurate estimates. She believes a dialogue will encourage countries to come to a consensus on the true impact of the pandemic and acknowledge and release better data.
“If data is a public good, it should be open,” she says. “And that is the only way to hold each other accountable.”
Here’s why the CDC reversed course on masks indoors—and how it might affect you
The change in guidance comes as the highly transmissible Delta variant sweeps a nation that is still struggling to get enough shots in arms.
U.S. public health officials’ guidance on mask-wearing is evolving because the virus behind COVID-19 is evolving—and flexible tactics are needed to fight a pandemic that is clearly far from over.
Less than three months after the Centers for Disease Control and Prevention had said that vaccinated people need not mask indoors or outdoors, based on the high protection conferred by the three COVID-19 vaccines authorized in this country, the CDC updated its guidance, urging everyone regardless of vaccination status to wear masks in schools and in public indoor spaces, in parts of the country with high or substantial coronavirus transmission.
Behind the stark warning were even starker facts: As SARS-CoV-2 has spread around the world and replicated in hundreds of millions of people, the virus has had more than a year to stumble upon mutations that let it more effectively enter human cells and evade our immune systems. Now, the world is facing the Delta variant first identified in India, which is roughly twice as transmissible as earlier strains of the virus.
The CDC’s latest guidance rests in part on a newly published analysis of a COVID-19 outbreak in Massachusetts, which began in Cape Cod after gatherings over the July 4 weekend. Of the outbreak’s 469 documented cases, 346—about three-fourths—were among people who had been vaccinated. Of these vaccinated cases, about 80 percent showed symptoms. Delta seems to have driven the outbreak: Health officials sequenced the virus in 133 of the patients, and 90 percent of them had the Delta variant.
Crucially, vaccination seems to have staved off severe outcomes: The CDC reports that within the Massachusetts outbreak, only five people had been hospitalized as of July 27, and none had died.
But this outbreak gives early evidence that for Delta infections, viral loads among the vaccinated and unvaccinated may resemble each other. That means it’s now possible vaccinated people who get even mild infections of Delta can transmit the virus to others—which could put people who can’t get the vaccines or don’t get their full efficacy, such as those with compromised immune systems, at even greater risk.
The global rise of Delta “was probably avoidable, but that [would have taken] a more unified and coordinated response—not just here in the United States, but elsewhere,” says University of Pittsburgh microbiologist Vaughn Cooper. “We are connected, and this variant is remarkably contagious, and our vaccination levels are just not uniformly high.”
How does the CDC measure viral load?
Less than half of the U.S. population is fully vaccinated, according to the CDC, and vaccination rates today are less than a fifth of what they were in April—a lag that has fueled new outbreaks in undervaccinated pockets of the country. In addition to the CDC’s new guidance, President Biden announced earlier this week that his administration is considering requiring all federal workers to be vaccinated against COVID-19. Biden’s remarks followed the the U.S. Department of Veterans Affairs mandating vaccines for its 115,000 frontline healthcare workers.
Though most COVID-19 transmission in the U.S. is among people who are unvaccinated, in cases when vaccinated people suffer so-called breakthrough infections from the Delta variant, those people likely can transmit the SARS-CoV-2 virus, experts say.
In a July 27 news conference, CDC Director Rochelle Walensky noted that people with breakthrough infections carry similar numbers of viral particles as those detected in unvaccinated patients. And on July 30, the CDC published some of the preliminary data backing up that conclusion.
The newly released data includes what’s called a cycle threshold (Ct) value. The most sensitive SARS-CoV-2 tests rely on a technique called PCR, which uses multiple replication cycles to amplify a sample’s snippets of viral genetic material to detectable levels. In general, the fewer cycles it takes to get a clear positive signal, the more viral genetic material the sample started with, and the lower the Ct value.
Among 211 people infected in the Cape Cod outbreak, the average Ct values were indistinguishable between 127 vaccinated people and 84 people who were unvaccinated, not fully vaccinated, or with unknown vaccination status. But Ct values can vary based on how samples were collected, stored, and transported, and because of that variation, there’s no universally accepted conversion between a given Ct value and a specific amount of virus present in the sample.
The similarity seen in the Cape Cod data “might mean that the viral load of vaccinated and unvaccinated persons infected with SARS-CoV-2 is also similar,” the CDC report says. “However, microbiological studies are required to confirm these findings.”
Massachusetts state senator Julian Cyr, who represents Cape Cod and is on the local county’s COVID-19 task force, notes that the outbreak is scientifically useful because Provincetown health officials did such a thorough job tracking it from the beginning.
“We’re very much on the cutting edge of science because we have such good data,” Cyr says. “Hopefully, that’s going to really inform public policy going forward, as we’re trying to figure out what to do in the context of Delta.”
The idea that Delta is especially potent fits with a July 9 study that has not yet been peer-reviewed, which shows that people infected with the Delta variant have about a thousand times more viral particles in their respiratory tracts when they test positive for COVID-19 than people with previous strains at the same stage of infection.
“The Delta variant is showing every day its willingness to outsmart us and to be an opportunist in areas where we have not shown a fortified response against it,” Walensky said in the July 27 briefing.
Where masks are most needed in the U.S.
Many public health experts had lamented the May guidance to relax masking in public places, worried that without verifying who is vaccinated, the change in approach would allow unvaccinated Americans to eschew masks—and place others at risk for new, emerging variants.
The Delta variant, which has been identified in 111 countries so far, has made the situation that much worse. Delta makes up more than 80 percent of new cases in 39 of those countries, including the U.S., the United Kingdom, India, Germany, and Denmark, and is continuing to spread.
“I don’t think we have digested that this variant is kind of a quantum leap ahead in transmissibility,” Cooper says.
In a recent study in the New England Journal of Medicine, a team of U.K. researchers found that among people who had received the full two-dose regimens of the Oxford-AstraZeneca or Pfizer-BioNTech vaccines, the shots were slightly less effective against Delta than against previous variants. But they were still 75 to 88 percent effective at preventing symptomatic COVID-19.
It’s hard for us to stay on guard all the time, and so we all are kind of like, It’s over, we can relax. But viruses don’t think that way. They’re a little bit like zombies in a movie. You think you’ve protected yourself, and then they just come ripping through the door. DOMINIQUE HEINKE EPIDEMIOLOGIST
With the Delta variant spreading rapidly, public health experts agree that extra forms of protection—especially “non-pharmaceutical interventions” such as masks—are needed to bring down current outbreaks and buy time for newly vaccinated people to reach full immunity, especially in parts of the country where vaccination rates are low or infections are high. People are considered immune two weeks after their second doses of the Pfizer-BioNTech and Moderna vaccines, and two weeks after the single-dose Johnson & Johnson shot.
The CDC defines places with “substantial” transmission levels as states and counties where there are between 50 and 99.9 new cases per 100,000 people in the past seven days. “High” transmission regions are where there are 100 or more new cases per 100,000 in the same time frame.
Twenty U.S. states, including Arkansas, Florida, and Louisiana, have “high” transmission as of July 29. And more than two out of every three U.S. counties have substantial or higher levels of community transmission, thereby falling under the CDC’s new guidance. More than half of all U.S. counties—mostly concentrated in the South—fall into the high-transmission category, according to the CDC.
The CDC is also suggesting that vaccinated people in any part of the country who live with young children or people with compromised immune systems don masks when in public spaces indoors. The leaked CDC document notes that “universal masking is essential to reduce transmission of the Delta variant.”
The renewed focus on masking is “great news, it’s very welcome,” says epidemiologist Dominique Heinke, a North Carolina-based graduate of Harvard University’s T.H. Chan School of Public Health. Vaccines remain a vital tool for combating the virus, she says, but face masks not only can help stanch its spread—they can also help prevent its continued mutation.
“It’s hard for us to stay on guard all the time, and so we all are kind of like, It’s over, we can relax, but viruses don’t think that way,” Heinke adds. “They’re a little bit like zombies in a movie. You think you’ve protected yourself, and then they just come ripping through the door.”
Will masks become mandatory?
As concerns over Delta and the U.S.’s vaccination slowdown have mounted, scientists and public health experts have increasingly called for communities to reinstate mask requirements.
National Nurses United, the largest national organization of registered nurses, sent a letter to Walensky on July 12 calling for the agency to reconsider their position on dropping the mask mandate. “New variants, such as the Delta Plus and Lambda variants, have and will continue to emerge and pose a threat while the virus continues to spread,” they wrote.
Some U.S. counties heeded the call before the CDC’s reversal, including Los Angeles County, which now requires masks for everyone in indoor spaces. On July 23, St. Louis, Missouri, and the broader St. Louis County also announced a joint mask mandate for indoor public places and public transportation.
In other parts of the country, public health officials have focused their funds and attention on vaccination outreach. To date, seven U.S. states have banned local districts from mandating masks in schools—even among students younger than 12 who cannot yet be vaccinated.
Local mandates are also facing politically charged blowback: On July 26, Missouri’s attorney general sued St. Louis over its new mask mandate, arguing that the move was “continued government overreach,” as well as “unacceptable and unconstitutional.” On July 27, St. Louis County voted to rescind its mask mandate.
“There is a real COVID fatigue, so it’s harder to sell [mask-wearing] today than it was a year ago,” says George Turabelidze, the state epidemiologist for Missouri, in an interview with National Geographic before the St. Louis mask announcements. “We do not anticipate any improvement anytime soon.”
In the CDC’s latest briefing, Walensky stressed how seriously the agency is taking the threat of Delta—and the policy changes the variant is forcing them to make.
“Eighteen months through this pandemic, not only are people tired, they’re frustrated. We have mental health challenges in this country. We have a lot of continued sickness and death in this country. Our health systems are, in some places, completely overrun [by] what is preventable,” she said. “I know that, in the context of all that, it is not a welcome piece of news that masking is going to be part of people’s lives who are already vaccinated.
“This new data weighs on me. This new guidance weighs on me,” she added. “This was not a decision that was taken lightly.”
Struggling to assess pandemic risks? You’re not alone.
Lots of psychological factors influence individual responses to danger, as well as our willingness to make less risky decisions.
For months, scientists have been calling for mask mandates to control the spread of COVID-19, especially with the rise of the more contagious Delta variant. But some members of a pandemic-weary public have been pushing back on this idea.
This week, U.S. health officials met intense outcry when the Centers for Disease Control and Prevention shifted course and changed its recommendations for wearing masks. The CDC is now urging people who live in high-transmission areas to wear masks indoors—even if they are fully vaccinated. Similarly, public ire is rising after an increasing number of companies and local governments unveiled plans for sweeping vaccine mandates.
Some politicians say the decisions to vaccinate and wear masks should be left up to individuals. And the new guidance from the CDC is just that: guidance. States, schools, and private companies must now decide whether to require face coverings in certain circumstances. In the meantime, masking up—or risking infection—remains a choice for many Americans.
People have had to weigh risks throughout the pandemic, and they’ve often come to drastically different conclusions. As the Delta and Lambda variants rage against a backdrop of social activities resuming, borders reopening, and schools offering in-person learning, people will continue to be presented with risks, and they will have to make decisions about what to do and what to avoid.
But in a world riddled with both obvious and subtle threats, danger can easily be misjudged, ignored, or disagreed upon. “It’s not just that different people see risk differently, but that the same person will react very differently to one danger than to another,” says Paul Slovic, a psychologist who studies risk, and founder of the nonprofit Decision Science Research Institute, based in Oregon.
Deciding which actions are risky is a constant cognitive challenge, says Valerie Reyna, co-director of the Center for Behavioral Economics and Decision Research at Cornell University. “It’s uncertain, it hasn’t happened yet, and it’s based on our best estimate, which changes over time as conditions change. That’s really hard,” she says.
Here, experts explain why humans struggle to assess risk, how the brain responds to risk, and how our need to weigh risks has changed during the ongoing pandemic.
Responding with intuition
Some researchers believe people have two ways of assessing risk and making decisions: a knee-jerk, emotional process—often called experiential or intuitive thinking—and a slower, more analytic mode. “Most of the time, we respond [with] our experiential system,” says Slovic. He’s quick to add that people can use both, “but the human brain is lazy. If we think we can respond to complex situations the easy way—with our feelings—then we go that way.”
That’s not always a bad thing. The analytic mode of reasoning is clunkier and more time consuming, often exemplified by “reason, mathematics, and cost-benefit analysis,” says Slovic. That kind of thinking is “important and powerful, but hard to do.” So, people evolved to assess risk quickly: After all, you don’t want to deliberate too long whether to run from a prowling lion or try and fight it off.
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“If you’ve ever tried to compute the square root of 285, then you have an idea of how it feels to deliberate,” explains Ralf Schmälzle, a communication neuroscientist at Michigan State University. Deliberation “consumes a lot of working memory resources,” while intuition lets people arrive at an answer instantaneously.
And it mostly works: By using intuition, “we manage, we survive, we make it to the next year or through the next two decades,” Slovic says. “In a complex world that is dangerous, we do OK.” But, he adds, “there are times when we do terribly.”
In 2013, Schmälzle studied people’s risk perceptions of another viral threat: the H1N1 pandemic, colloquially known as the swine flu. Along with colleagues at the University of Konstanz in Germany, he asked about 130 people a variety of risk-related questions and divided participants into two groups: those who saw H1N1 as a risk, and those who didn’t.
The participants then watched a fact-based documentary about the swine flu as Schmälzle scanned their brain activity, measuring it with magnetic resonance imaging. The team found that the anterior cingulate cortex—the part of the brain often associated with processing threats—fired synchronously in the participants who already believed H1N1 posed a risk.
“People are noticing some kind of intuitive alarm signal” driven by emotion, he says.
When it comes to COVID-19, “if you lack this sort of intuitive aspect to the risk perception, then you will not see a need to wear a mask or get vaccinated,” says Slovic.
Beyond gut instinct
The theory that people use this so-called dual-systems risk analysis is “an excellent theory supported by a lot of data,” says Cornell University’s Reyna. However, it leaves out other major drivers of decision-making, she notes.
One is called optimistic bias, says Dickinson College social psychologist Marie Helweg-Larsen. This type of bias makes an individual feel like they are somehow exempted from the potential consequences. “We recognize that things can happen to people,” she says, but “we think that we are special. We think that we’re less likely to experience the negative consequences.”
For example, smokers know that cigarettes can be harmful to their health, but some may think their risk of lung cancer is less than that of other smokers, Helweg-Larsen says. “They think if they eat more vegetables, if they puff less on the cigarette, if they smoke healthier cigarettes,” that they can avoid the consequences of smoking, says Helweg-Larsen. “But eating more vegetables doesn’t lead you to not get lung cancer.”
If you are a person who has said that we should trust the science, try to hold on to that idea now. MARIE HELWEG-LARSEN DICKINSON COLLEGE
The same optimistic bias may have played into how people gauge their COVID-19 risks: People who refuse to wear masks likely understand there’s a chance they could catch the coronavirus and even die from it—but they also think their personal risk is less than others’, she says.
“It’s easy to think that people are delusional,” Helweg-Larsen says, but it’s more akin to wearing rose-colored glasses. “It’s what we in psychology call ‘motivated cognition,’ meaning that we draw the conclusions that we wish to draw because it brings us outcomes that we would like.”
Optimism can be helpful, because many things humans do carry some risk. If people thought they would die in an accident every time they got into a car, no one would ever drive. “It would be really hard to navigate our daily lives if we were afraid of possible-but-small risks,” she says.
Consequences that excite people—either in terms of hope or fear—can also motivate people to take or avoid risks, Slovic says. A $100 million jackpot might compel someone to risk wasting money on a ticket even though the chance of winning is miniscule. Similarly, news of a deadly plane crash can make people more afraid to fly, even though it’s statically safer than driving.
A sense of control—or lack thereof—affects people’s ability to assess risk as well, Helweg-Larsen says. “We overestimate the extent to which we can control our outcomes,” she says. In the example of being afraid to fly, someone might overestimate the risk of a crash because they’re not flying the plane.
“It’s not that people think they could fly the plane. But it feels uncertain because they are not in control,” she says. “But it’s all an illusion, of course, because lots of accidents are not caused by the driver in your car.”
During the pandemic, “a lot of people are feeling anxious about entering into the world and relying on other people’s willingness to do the right thing, which has been a problem throughout the pandemic and is still the case now,” Helweg-Larsen says. “We want to control outcomes—and that’s why it feels even scarier.”
What’s more, people can be influenced by direct experience with a particular danger—including a COVID-19 infection. A new study from the University of Alabama shows that people who got COVID-19 and recovered may be less likely to support mitigation efforts such as mask wearing and social distancing. By contrast, those with a friend or family member who contracted the disease were more in favor of mitigation measures.
Study co-author Wanyun Shao, an assistant professor of geography at the University of Alabama, suspects “that hearing ‘horror stories’ from others can evoke concern, while directly experiencing COVID can lower the concern as if the suspense is over.”
Freedom of choice
Researchers say there are ways we can better assess risks as the pandemic drags on. The most important, they agreed, is to continue to follow the science from credible sources. “If you are a person who has said that we should trust the science, try to hold on to that idea now,” says Helweg-Larsen.
It’s also important to recognize that judgments based on intuition often happen in a fraction of a second—but not every situation requires an immediate reaction. Instead, “it’s wise not to react instantly, but to pause and to reflect on the information you’re hearing,” Slovic says.
But with the end of the pandemic hanging in the balance, some public health officials are making the case that society as a whole might not be able to rely on people’s ability to assess risk and make the safest, smartest choices.
In recent weeks, local governments and many companies—including Facebook, Google, Netflix, Morgan Stanley, the Washington Post, and some 600 universities—have announced vaccine mandates. In the past, such mandates have proved pivotal in stamping out pandemics. Between 1919 and 1928, 10 U.S. states introduced vaccine mandates for smallpox, while four states prohibited mandates—and a February 2021 study includes data showing that cases of smallpox were 20 times higher in states that banned mandates than in states that enacted them.
“The problem with people attempting to do a cost-benefit analysis for getting vaccinated is that it sounds logical but people get it wrong,” says Helweg-Larson. “It is overwhelmingly better for most people to get vaccinated. The personal [and societal] benefits outweigh the costs.”
But psychologically, Helweg-Larson says, giving people the freedom of choice is best. “We are willing to limit and restrict people’s choices when our behavior harms other people,” she says. “That’s why we encourage quitting smoking and limit and restrict where you can smoke—but we do not outlaw smoking.”
In the case of COVID-19, she says, the choice could be get vaccinated or “put up with the inconvenience of regular testing and masking.”
Why is Delta more infectious and deadly? New research holds answers.
Studies show that Delta replicates more quickly and generates more virus particles than other variants, but vaccines still protect against serious infections.
As the United States battles a fourth surge of COVID-19, scientists are learning much about the Delta variant that wasn’t known when it was first reported in India in March: it is one of the most infectious respiratory viruses known, it causes more severe COVID-19 than other variants, and it is more likely to evade antibodies.
Evidence of all these traits is clear. The Delta variant has caused a sharp rise in COVID-19 cases, hospitalizations, and deaths across the U.S. and the rest of the world. Driven by relaxed social distancing and mask guidelines, poor vaccine uptake in parts of the U.S., and lack of availability elsewhere, Delta has rapidly become the dominant variant in the U.S., causing more than 93 percent of new infections, according to the Centers for Disease Control and Prevention. It has also spread to more than 135 countries, according to the World Health Organization.
The secret to Delta’s success is the ease with which it spreads. The CDC estimates that Delta can be as infectious as chicken pox and is only slightly less contagious than measles, which is considered one of the most transmissible viruses. Now the Delta variant is spreading like wildfire through the South, particularly in Louisiana, which has one of the lowest vaccination rates in the country; only 37 percent of the population is fully vaccinated compared to 50 percent nationally. In the U.S., daily cases are now averaging 100,000, a nine-fold jump from mid-June.
“It’s surprising the extent of how infectious this particular variant is, and how well it can then replicate in the upper respiratory tract. Just the increased infectivity of this Delta variant has sort of increased our concern relative to what was there for the Alpha variant, which was increased relative to the original virus,” says Mehul Suthar, a virologist at Emory University.
Because the Delta variant is so much more contagious than previous variants, CDC issued new guidelines on July 27, 2021, which recommend that even after vaccination, people should “wear a mask indoors in public if you are in an area of substantial or high transmission.”
A vastly more transmissible virus
To track how easily an infectious disease such as COVID-19 spreads, epidemiologists use a metric called the basic reproductive number or R0 (pronounced “R naught”). R0 is the average number of susceptible people that each infected person is expected to infect. It is difficult to be certain about the R0 for ancient pandemics, but for the 1918 influenza pandemic, the average infected person is thought to have passed the disease to between two and three people, giving it an R0 of between 2.0 and 3.0. The first SARS coronavirus epidemic of 2002, has an R0 of three; for the second coronavirus epidemic—Middle East Respiratory Syndrome (MERS) first identified in 2012—R0 was between 0.69 to 1.3.
Now the CDC estimates that people infected with Delta pass the virus to between five and 9.5 people. This is higher than the original virus identified in Wuhan, China, which had an R0 between 2.3 and 2.7, and the Alpha variant which had an R0 between four and five. Delta can be as infectious as chicken pox, which has an R0 between 9 and 10.
If R0 is larger than one, the number of infected people will keep growing exponentially until all susceptible people have either died or recovered and herd immunity is reached. If R0 is less than one the outbreak will likely fizzle out on its own.
For the original SARS-CoV-2, herd immunity could be reached when around 67 percent of the population was immune—either through natural infection or vaccination. “For Delta, those thresholds we estimate being well over 80 percent, maybe approaching 90 percent,” Ricardo Franco, an assistant professor of medicine at the University of Alabama at Birmingham said at a press briefing organized by the Infectious Diseases Society of America.
A higher viral load
Delta is not only more transmissible than previous SARS-CoV-2 variants, it can also cause more severe disease. People infected with the Delta variant harbor about 1,000 times the number of viral particles (which experts call the “viral load”) in their nasal swab compared to those infected with another strain, “which is an enormous increase,” says Eric Topol, the founder and director of the Scripps Research Translational Institute, who was not involved in this study.
One reason for this is that the Delta variant replicates more quickly in the nose. A study, not yet peer reviewed has shown that the Delta variant took an average of four days to reach detectable levels after exposure to a sick person, compared to about six days for the original Wuhan virus.
Even after vaccination, Delta infections produced a 10-fold higher viral load than non-Delta infections. In fact several recent studies, none peer reviewed yet, show that vaccinated people carry the same viral load as the unvaccinated. “We are seeing infections and seeing the large number of people being infected by a single case, which is quite worrying. It means that the virus is highly transmissible and is able to avoid … vaccine-induced immunity,” said Ravindra Gupta, a clinical microbiologist at the University of Cambridge, who led the study that is not yet peer reviewed.
Delta is also better at destroying cells because of a mutation at position 681 of its spike protein, which is fast becoming common in other variants around the globe and is thought to be an evolutionary game changer. This P681R mutation makes it easier for Delta and the related Kappa variants to invade the host cell by fusing infected cells into structures called syncytium, which is a way of accelerating infection. Syncytia are also formed by other viruses such as HIV. “We found in cell culture experiments that Delta variant shows bigger syncytia when compared to SARS-CoV-2,” explained Kei Sato, a virologist at The University of Tokyo, Japan.
The Delta variant has also undergone multiple mutations in its spike protein that seem to improve the virus’s ability to bind to the ACE2 receptor and evade the immune response.
Breakthrough infections and boosters
The good news is that a complete dose of the currently authorized COVID-19 vaccines remains effective. “All the vaccines work pretty well,” said Jeff Kwong, an infectious diseases epidemiologist at the University of Toronto. “And the vaccines were more protective against the severe outcomes compared to symptomatic infection,” Kwong has shown in a study, not yet peer reviewed, the effectiveness of Pfizer, Moderna, and AstraZeneca vaccines against symptomatic infection, hospitalization, or death between December 2020 and May 2021.
Many studies have shown that Moderna and Pfizer vaccines still protect against Delta, though not as well as against previous variants. Unvaccinated people make up more than 90 percent of confirmed new cases among the states that track case data along with vaccination status.
“[Vaccines] do reduce the risk of serious outcome such as hospitalization quite substantively,” says Aziz Sheikh, a primary care specialist at The University of Edinburgh, Scotland, UK who showed that Delta caused twice as many hospitalizations than the Alpha variant, which caused more severe illness than the original SARS-CoV-2. “Overall, they are working.”
The CDC estimates that COVID-19 vaccination reduces the risk of SARS-CoV-2 infection by eight-fold and the risk of getting ill, being hospitalized, or dying by 25-fold.
But inadequate testing nationwide makes it impossible to know the true extent of the spread of Delta and other variants. When there is high transmission of Delta in the community, even fully vaccinated people are vulnerable to so-called “vaccine breakthrough infections,” which the CDC defines as when genetic material or protein from SARS-CoV-2 is detectable in the nasal swab more than 14 days after a person has received the recommended dose of an FDA-authorized COVID-19 vaccine.
Two doses of the AstraZeneca and Pfizer vaccines are estimated to be 60 and 88 percent effective, respectively, against symptomatic disease caused by Delta. The majority of vaccines administered in the U. S. (Moderna and Pfizer) require two shots for maximum protection. These vaccines are much less effective against Delta after just a single jab, says Olivier Schwartz, head of the Virus and Immunity Unit at Institut Pasteur, Paris, who led a study that showed that a single dose of either AstraZeneca and Pfizer vaccines or previous infection barely inhibit Delta variant.
Prompted by the data on the reduced efficacy against new variants such as Delta, Pfizer is seeking authorization of a booster dose of its vaccine. Moderna is also testing an updated mRNA vaccine booster dose. The U.S. Food and Drug Administration (FDA) is expected to finalize a COVID-19 vaccine booster plan soon.
The single shot J&J vaccine has been shown to be effective against the Delta variant. But a study, not yet peer reviewed, has shown that although all vaccines triggered the development of antibodies that were somewhat less effective against Delta, the reduction was much steeper for J&J than for mRNA vaccines. This study is consistent with similar ones in monkeys and people where two doses of the J&J vaccine show greater efficacy compared with one dose.
To compensate for the lower efficacy of the J&J shot against Delta, people in San Francisco who received this vaccine can now request a “supplemental dose” of an mRNA vaccine. Germany will begin offering mRNA vaccine booster shots in September to a range of people considered vulnerable. However, the demand for boosters is magnifying the inequities in COVID-19 vaccine availability between rich and poor countries. “WHO is calling for a moratorium on boosters until at least the end of September to enable at least 10 percent of the population of every country to be vaccinated,” said Tedros Adhanom Ghebreyesus, Director-General of WHO in a press briefing.
Some preliminary data from Israel suggests that efficacy of the Pfizer vaccine might decline within six months. But this is not surprising since vaccine designers knew that making the antibody response long-lasting was going to be a challenge. Antibodies against the first SARS and MERS viruses declined after one to two years. For coronaviruses that cause the common cold, protection ranges from three to six months, and almost always less than a year.
A study in the U.S. has shown that, following the second dose of the Moderna vaccine, neutralizing antibodies remain high in the blood for six months. “Those antibodies that are there, for the most part, neutralize many of these variants [including Delta]. However, these antibody responses do wane over time,” explains Emory’s Suthar, who led the U.S. study.
Vaccines have prevented millions of infections
Vaccination may have saved approximately 279,000 lives in the U.S. and, by the end of June 2021, prevented up to 1.25 million hospitalizations, according to The Commonwealth Fund’s computer models. Similarly in England the vaccines may have prevented about 30,300 deaths, 46,300 hospitalizations, and 8.15 million infections. The aggressive vaccination campaign in Israel is estimated to have caused a 77 percent drop in cases and a 68 percent decline in hospitalizations from the peak of the pandemic in January, 2021.
Although COVID-19 vaccines in the U.S. are free and effective, only 49.9 percent of the population—just over 165 million people—are fully vaccinated as of August 4, 2021. Vaccination rates vary widely nationwide, and many counties in southern states, including Louisiana, Florida, Arkansas, Mississippi, and Alabama, have low vaccination rates that are now fueling raging outbreaks of the Delta variant.
While more than 347 million COVID-19 shots have been administered in the U.S. since distribution began on December 14, 2020, there are still about 93 million Americans age 12 and older who are eligible for a shot but have not yet received one. There are also 48 million children under the age of 12 who are unvaccinated because they are still not eligible. That makes it difficult to predict how long this current surge will last.
No vaccine is 100 percent effective
With more than half the population incompletely vaccinated, the Delta variant can continue to infect and evolve, leading to more vaccine breakthrough infections than expected and possibly yielding new infectious variants.
Evidence is emerging that breakthrough Delta cases may be as transmissible as Delta infection in unvaccinated individuals. “The vaccines are protective, but obviously a lot of vaccinated people are also getting exposed, some from the unvaccinated and [some] from each other. And so, it’s testing the vaccine capabilities,” says Topol.
But most breakthrough cases, which occur in less than one percent of fully vaccinated people, cause mild or no symptoms. Of the more than 164 million people fully vaccinated nationwide there were only 7,525 patients with COVID-19 vaccine breakthrough infections who were either hospitalized or died in the U.S. through August 2, 2021.
Breakthrough infections are more likely among health care workers who are in frequent contact with infected patients, older age vaccinated people, and those with weakened immunity, such as people with cancer and prior organ transplant. Breakthrough infections are also more likely to occur in situations of close contact, such as in large public gatherings, restaurants, cramped working spaces, and outdoor or indoor parties.
While vaccines can effectively slow down the contagious pandemic by increasing the herd immunity, preventive measures such as social distancing and masking are proven strategies along with vaccination in curbing the spread of the virus. “Even if people have been vaccinated, they can still get infected and can still spread the virus in the population. So that means variants have the chance to get more mutations or to evolve. It is important for people to stop giving the virus [that] chance,” says Sato.
How will the pandemic end? The science of past outbreaks offers clues.
The answer depends on many factors, perhaps the most critical being the global nature of the crisis.
After months of encouraging trendlines, July’s dramatic spike in global COVID-19 infections has dimmed the proverbial light at the end of the pandemic tunnel.
In May, coronavirus cases were declining across the U.S., parts of Europe, and the Middle Eastas vaccination rates rose, spurring an easing of social and travel restrictions and a wave of business reopenings. But in the U.S., at least, any celebration was short-lived. By July, vaccination rates flatlined and highly transmissible coronavirus variants swept the nation, forcing health officials to reimpose masking recommendations and call for increased inoculations.
The World Health Organization declared COVID-19 a pandemic on March 11, 2020. After 17 grueling and chaotic months, weary people are wondering: When will the pandemic finally end?
“Even among the scientific community, you would get really different answers,” says Rachael Piltch-Loeb, a researcher and fellow with the Emergency Preparedness Research, Evaluation & Practice Program at the Harvard T.H. Chan School of Public Health. “There is no one definition of what the end of a pandemic means.”
A pandemic is by definition a global crisis. Lifting some U.S. public health measures and interventions “gave people a sense that the panic was waning,” Piltch-Loeb says. That euphoria blinded many to the worldwide reality, which remains bleak.
“Until this [virus] is controlled or more limited globally, it’s not going away,” Piltch-Loeb says. That means declaring the pandemic’s “end” may be a distant goal, requiring different conditions depending on who’s asked.
Where do diseases go?
When the worldwide spread of a disease is brought under control in a localized area, it’s no longer a pandemic but an epidemic, according to the WHO. If COVID-19 persists globally at what the WHO judges to be “expected or normal levels,” the organization will then re-designate the disease “endemic.”
At that stage, SARS-CoV-2 will become a circulating virus that’s “less consequential as we build immunity,” says Saad Omer, an epidemiologist and director of the Yale Institute for Global Health.
Only two diseases in recorded history that affect humans or other animals have ever been eradicated: smallpox, a life-threatening disease for people that covers bodies in painful blisters, and rinderpest, a viral malady that infected and killed cattle. In both instances, intensive global vaccination campaigns brought new infections to a halt. The last confirmed case of rinderpest was detected in Kenya in 2001, while the last known smallpox case occurred in the U.K. in 1978.
Joshua Epstein, professor of epidemiology in the New York University School of Global Public Health and founding director of its Agent-Based Modeling Laboratory, argues that eradication is so rare that the word should be wiped from our disease vocabulary. Diseases “retreat to their animal reservoirs, or they mutate at low levels,” he says. “But they don’t typically literally disappear from the global biome.”
Most causes of past pandemics are still with us today. More than 3,000 people caught the bacteria that cause both bubonic and pneumonic plague between 2010 and 2015, according to the WHO. And the virus behind the 1918 flu pandemic that ravaged the globe, killing at least 50 million people, ultimately morphed into less lethal variants, with its descendants becoming strains of the seasonal flu.
As with the 1918 flu, it’s likely the SARS-CoV-2 virus will continue to mutate, and the human immune system would eventually adapt to fend it off without shots—but not before many people fell ill and died. “Developing immunity the hard way is not a solution that we should be aspiring to,” Omer says.
Finding ways to slow the spread of a disease and manage its effects is by far the safer path, experts say. Today, for instance, pest control and advanced hygiene keep the plague at bay, while any new cases can be treated with antibiotics.
For other diseases, such as the flu, vaccines can also make a difference. The available COVID-19 vaccines are highly safe and effective, which means getting enough people vaccinated can end this pandemic faster and with lower mortality than natural infections alone.
Why we need vaccines for all
WHO Director Tedros Adhanom Ghebreyesus last week reinstated a goal of vaccinating at least 10 percent of every nation’s population by September, with the loftier goal of reaching 40 percent global inoculation by year’s end and 70 percent by mid-2022.
To date, though, just 28 percent of the world’s population has received at least one dose of a COVID-19 vaccine. And vaccine distribution remains wildly lopsided. The European Union has nearly three-fourths of its eligible population at least partially inoculated; the U.S. has vaccinated 68 percent of people 12 and older.
But other nations that have lost many people to COVID-19—including Indonesia, India, and many of the countries in Africa—are working at a much slower pace. That’s in part because Covax, the United-Nations-backed program to vaccinate the world, has struggled to acquire and deliver vaccines for the world’s poorest countries. This week, the WHO issued a plea for wealthy countries to donate vaccine doses to poorer nations before offering booster shots to their own populations.
Even in countries with sufficient supply, the pace of vaccinations is influenced by hesitancy and misinformation. In the U.S., the daily rate of new vaccinations has plateaued, slowing to an average of 615,000 injections a day, or an 82 percent decline from the peak of vaccine uptake on April 13. U.S. hospitals are filling up with patients as caseloads increase in unvaccinated areas.
With more opportunities to spread and mutate, the virus has developed new variants that are not only more contagious, but more evasive. Delta is the most contagious one detected so far. The variant was first detected in India, where it helped drive one of the world’s worst surges in April. More recently, Delta contributed to a dramatic outbreak in Indonesia; antibody data suggest that more than half the population in the capital city of Jakarta have been infected. Initial research also shows the Lambda variant may be resistant to some vaccines.
The complexity of fighting a rapidly mutating virus “means that sometimes we take two steps forward and one step back,” says Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota.
Who gets to say it’s over?
There is another option, scientists and historians say: People will decide the pandemic is over, long before any governing body declares it so.
It’s happened in the past: The 1918 flu hit in the throes of World War I, and as the fighting ended, there was a “feeling of wanting to put that whole decade to bed, and to embrace a new future,” says Naomi Rogers, professor of the history of medicine and of history at Yale University. The public entered the “Roaring Twenties” despite the flu virus still circulating throughout the U.S. population.
If society attempts to declare an end to the pandemic before science does, we’d be accepting its severe outcomes—including death. That’s often been the case with past pandemics. The flu is no longer considered a pandemic and is now an endemic disease; between 12,000 and 61,000 people in the U.S. still die from the flu each year, based on CDC estimates.
“If we can bring the death count down to a certain level and resume our lives normally, one could say the pandemic has ‘ended’,” says Jagpreet Chhatwal, a decision scientist at the Massachusetts General Hospital Institute for Technology Assessment in Boston. Again, vaccines make a difference. COVID-19 deaths in the U.S. have been tamped down in highly-vaccinated areas.
Nationally, the Centers for Disease Control and Prevention will likely provide guidance on when the pandemic has reached endemic status in the U.S., says Piltch-Loeb. That in turn will offer a path back to some version of normal life, regardless of global declarations.
“We want to go back to what it was like before COVID,” says Andrew Azman, an epidemiologist at Johns Hopkins Bloomberg School of Public Health. “It’s not going to take the WHO saying the pandemic is over for people to do that.”
Delta’s rise is fuelled by rampant spread from people who feel fine
People infected with the Delta variant generally do not have COVID-19 symptoms until two days after they start shedding the coronavirus.
People infected with the Delta variant of SARS-CoV-2 are more likely to spread the virus before developing symptoms than are people infected with earlier versions, suggests a detailed analysis of an outbreak in Guangdong, China1.
“It is just tougher to stop,” says Benjamin Cowling, an epidemiologist at the University of Hong Kong and a co-author of the study, which was posted on a preprint server on 13 August.
Cowling and his colleagues analysed exhaustive test data from 101 people in Guangdong who were infected with Delta between May and June this year, and data from those individuals’ close contacts. They found that, on average, people began having symptoms 5.8 days after infection with Delta — 1.8 days after they first tested positive for viral RNA. That left almost two days for individuals to shed viral RNA before they showed any sign of COVID-19.
A dangerous window
An earlier study2 and an unpublished analysis by Cowling and others estimate that before Delta emerged, individuals infected with SARS-CoV-2 took an average of 6.3 days to develop symptoms and 5.5 days to test positive for viral RNA, leaving a narrower window of 0.8 days for oblivious viral shedding.
In the latest work, the researchers also found that those infected with Delta had higher concentrations of viral particles, or viral load, in their bodies than did people infected with the original version of SARS-CoV-2. “Somehow the virus is appearing quicker and in higher amounts,” says Cowling.
As a result, 74% of infections with Delta took place during the presymptomatic phase — a higher proportion than for previous variants. This high rate “helps explain how this variant has been able to outpace both the wild-type virus and other variants to become the dominant strain worldwide”, says Barnaby Young, an infectious-disease clinician at the National Centre for Infectious Diseases in Singapore.COVID vaccines slash viral spread – but Delta is an unknown
The researchers also calculated Delta’s ‘basic reproduction number’, or R0, which is the average number of people to whom every infected person will spread the virus in a susceptible population. They estimated that Delta has an R0 of 6.4, which is much higher than the R0 of 2–4 estimated for the original version of SARS-CoV-2, says Marm Kilpatrick, an infectious-disease researcher at the University of California, Santa Cruz. “Delta moves a bit faster, but is much more transmissible.”
A small number of study participants experienced ‘breakthrough infections’ with Delta after receiving two doses of an inactivated-virus COVID-19 vaccine. But the vaccine reduced participants’ viral loads at the peak of infection.
Vaccinated individuals were also 65% less likely than unvaccinated individuals to infect someone else, although the estimate was based on a very small sample size. This reduction “is significant and reassuring that COVID-19 vaccines remain effective and a vital part of our response to the pandemic”, says Young.
COVID-19 may impair men’s sexual performance
Men may be six times more likely to develop brief or long-term erectile dysfunction after contracting the virus. The vaccine can prevent this.
South Florida urologist Ranjith Ramasamy observed a disturbing trend among his patients as COVID-19 spread across the U.S. in 2020: More and more men were complaining that they couldn’t perform in the bedroom.
At first Ramasamy and his colleagues at University of Miami Hospital’s urology clinic thought that the growing reports of sexual dysfunction represented a psychological issue, the result of pandemic stress. But many patients said they weren’t feeling anxious or depressed, and for some, the problem lasted six months or longer. Then the team started to suspect another underlying cause: the SARS-CoV-2 virus that causes COVID-19.
While COVID-19 may harm the lungs, it’s a systemic disease that can also affect the heart, kidneys, brain and other organs, and those effects can last long after someone has recovered. Many people now live in a purgatorial netherworld of “long-haul COVID” that experts are calling our next national health disaster. According to an August article in the New England Journal of Medicine, 10 to 30 percent of those infected with the virus—at least 42 million cases in the U.S. and 229 million worldwide—experience ongoing debilitating symptoms that may cause “significant disability.”
Among the list of ailments, mounting evidence suggests that COVID-19 may sabotage men’s sexual health. “We found that men who hadn’t previously had these issues developed pretty severe erectile dysfunction after COVID-19 infection,” Ramasamy says.
Men may be six times more likely to develop brief or long-term erectile dysfunction after contracting the virus, according to research published in March. Other studies have documented a litany of post-infection health issues that impact sex, either independently or in concert: inability to have or maintain an erection, damage to the testes, testicular pain or swelling, inability to achieve orgasm, low testosterone levels, and mental health issues.
The science stands in stark contrast to anti-vaccine misinformation spreading online—including a now infamous tweet from rapper Nicki Minaj—claiming that COVID-19 vaccines cause swollen testicles and impotence. To date, no studies support that claim.
“It’s important for people to understand that COVID vaccination doesn’t affect erectile function,” Ramasamy says. “The virus can have significant adverse long-term effects, and the vaccine is safe.”
Tracking the virus in tissues
Men most at risk for severe COVID-19—older men or those with hypertension, obesity, diabetes, and heart disease—are already at high risk for sexual dysfunction. These conditions affect their hormones, muscles, blood vessels, and more. However, much younger men have also reported sexual health issues. When it comes to figuring out the short-term and chronic aftereffects of this new virus, “we’re still in the tracking and trends phase,” says Ryan Berglund, a urologist at the Cleveland Clinic in Ohio, and that includes understanding its effects on men’s sexual and reproductive health.
To find out if the virus was indeed invading men’s reproductive organs, Ramasamy and his team performed biopsies on six men ages 20 to 87 who had succumbed to COVID-19. When they examined these tissue samples under an electron microscope, they discovered virus particles lurking in one man’s testicles. Half of the men also had poor sperm quality, backing up data from other small postmortem studies and raising questions about the disease’s impact on fertility.
If the virus was in the testes, Ramasamy wondered if was also present in the penis. The team investigated by studying two men who became impotent after having the virus. One of them had experienced mild symptoms; the other had been hospitalized. Convinced they would never have a natural erection again, they each came to the clinic to see if they might be candidates for penile implant surgery.
The virus was indeed present in their penis tissue, which was shocking, Ramasamy says, given the time frame: It had been up to eight months since the men were first infected. The doctors also found damage to the lining of the organ’s tiny blood vessels.
Blood and bone
A known coronavirus impact, damage to the endothelial cells that line the blood vessels, is the most likely culprit for poor sexual performance. While some mammals have a bone in their penises, erections in humans rely on blood flow. Arteries must open and veins must contract, almost like a canal lock system. Impaired, narrowed blood vessels won’t allow spongy tissue to inflate with blood or hold that blood to maintain an erection.
Without enough blood, cells are oxygen-deprived, tissues become inflamed, and vessels lose elasticity, says Emmanuele A. Jannini, professor of endocrinology and medical sexology at Italy’s University of Rome Tor Vergata. “No oxygen, no sex,” he says.
He notes that COVID-19 also seems to lower amounts of an enzyme—endothelial nitric oxide synthase—that helps dilate blood vessels and engorge the penis. For long-haulers, lung or heart damage may compound the problem by altering blood circulation and oxygen levels in the blood and tissues.
Early in the pandemic, Jannini’s team launched an online survey that gathered information on sexually active Italian men who’d had the virus. This was the study that revealed the six-fold higher risk of erectile dysfunction post-COVID-19 infection. How long symptoms will last remains unknown, Jannini says.
“Since the penis is actually one of the most vascular organs in the body, we were not surprised that erectile dysfunction was more common in men with long COVID,” Ramasamy says.
And in July, the Patient-Led Research Collaborative, a group of researchers who themselves have long COVID, published the most comprehensive information to date. They documented 203 symptoms in 10 organ systems, amassed from an online survey of some 6,500 people from countries across the globe. The results included sexual health problems.
About 18 percent of men reported sexual dysfunction; some 13 percent experienced pain in their testicles; 8 percent noted other sex organ issues; and about 4 percent of men had a decrease in the size of their penis or testicles.
A viral hideout
The testicles are a perfect hideout for viruses. Like the eyes and central nervous system, they are immunologically privileged sites. In these places, viruses including Ebola, mumps, and Zika can remain in tissues, evading the immune system even after the invader has been cleared from other parts of the body.
One study speculated that the testicles might therefore serve as a reservoir for the virus that causes COVID-19. This may explain why 11 percent of men hospitalized with COVID-19 suffered testicular pain. Infection of the organ’s Leydig cells, which produce testosterone, may also explain long haulers’ lowered levels of the male sex hormone. That alone can cause lagging libido and desire. Jannini notes another feedback loop: Testosterone production drops when men aren’t having sex.
State of mind also plays a role in intimacy, Berglund says, “which is partially dependent on our psychological state.” The pandemic has heavily impacted overall mental health for long haulers. Many suffer from PTSD, anxiety, or depression. The psychological effects of COVID-19 on sexual health will ultimately be the most challenging to tease out, Berglund says.
He adds that simply being sick can kill desire. “If you’re struggling to breathe or chronically ill, you’re probably less interested in sex,” he says. That may be compounded by fatigue, one of the most common symptoms, and loss of smell, since scent sparks arousal.
Sex and the vaccine
More studies are needed to understand what the virus actually does to men’s reproductive health. Researchers are working to understand the mechanisms of what is still a relatively new disease. Ramasamy’s team is investigating how this virus evades the immune system and lodges in cells, including in the testes and penis. “If it’s going dormant, will it get reactivated again?” he asks “Does it continue to cause damage? Or is it a one-time insult?”
Congress has awarded $1.15 billion to the U.S. National Institutes of Health for its RECOVER program, which will study the constellation of long haul COVID-19 symptoms over the next four years. Many hope that it will provide much-needed answers – and treatments for those who still suffer.
And despite the misinformation spreading on social media, research continues to counter the notion that vaccines impact fertility. A June study, for instance, found no link between mRNA vaccines and reduced sperm count.
“The plausible relationship between COVID-19 and erectile dysfunction is one more reason for the unvaccinated to get their shots,” Jannini notes. “If they want to have sex, better to get the vaccine.”
Heart-disease risk soars after COVID — even with a mild case
Massive study shows a long-term, substantial rise in risk of cardiovascular disease, including heart attack and stroke, after a SARS-CoV-2 infection.
Even a mild case of COVID-19 can increase a person’s risk of cardiovascular problems for at least a year after diagnosis, a new study1 shows. Researchers found that rates of many conditions, such as heart failure and stroke, were substantially higher in people who had recovered from COVID-19 than in similar people who hadn’t had the disease.
What’s more, the risk was elevated even for those who were under 65 years of age and lacked risk factors, such as obesity or diabetes.
“It doesn’t matter if you are young or old, it doesn’t matter if you smoked, or you didn’t,” says study co-author Ziyad Al-Aly at Washington University in St. Louis, Missouri, and the chief of research and development for the Veterans Affairs (VA) St. Louis Health Care System. “The risk was there.”
Al-Aly and his colleagues based their research on an extensive health-record database curated by the United States Department of Veterans Affairs (VA). The researchers compared more than 150,000 veterans who survived for at least 30 days after contracting COVID-19 with two groups of uninfected people: a group of more than five million people who used the VA medical system during the pandemic, and a similarly sized group that used the system in 2017, before SARS-CoV-2 was circulating.
People who had recovered from COVID-19 showed stark increases in 20 cardiovascular problems over the year after infection. For example, they were 52% more likely to have had a stroke than the contemporary control group, meaning that, out of every 1,000 people studied, there were around 4 more people in the COVID-19 group than in the control group who experienced stroke.
The risk of heart failure increased by 72%, or around 12 more people in the COVID-19 group per 1,000 studied. Hospitalization increased the likelihood of future cardiovascular complications, but even people who avoided hospitalization were at higher risk for many conditions.
“I am actually surprised by these findings that cardiovascular complications of COVID can last so long,” Hossein Ardehali, a cardiologist at Northwestern University in Chicago, Illinois, wrote in an e-mail to Nature. Because severe disease increased the risk of complications much more than mild disease, Ardehali wrote, “it is important that those who are not vaccinated get their vaccine immediately”.
Ardehali cautions that the study’s observational nature comes with some limitations. For example, people in the contemporary control group weren’t tested for COVID-19, so it’s possible that some of them actually had mild infections. And because the authors considered only VA patients — a group that’s predominantly white and male — their results may not translate to all populations.
Ardehali and Al-Aly agree that health-care providers around the world should be prepared to address an increase in cardiovascular conditions. But with high COVID-19 case counts still straining medical resources, Al-Aly worries that health authorities will delay preparing for the pandemic’s aftermath for too long. “We collectively dropped the ball on COVID,” he said. “And I feel we’re about to drop the ball on long COVID.”
How Merck’s antiviral pill could change the game for COVID-19
Promising results from clinical trials suggest that the drug may become the first at-home treatment cleared for use by the FDA.
A new drug by Merck significantly reduces the risk of hospitalization and death in people who take it early in the course of their COVID-19 illness, according to the interim results of a major study released today. It is the first oral antiviral found to be effective against this coronavirus.
People who took this drug, called molnupiravir—four pills twice a day for five days—within five days of showing symptoms were about half as likely to be hospitalized as those taking the placebo. They were also less likely to die, with eight deaths in the placebo group reported within a month of treatment and none in those who received the medicine.
“Having a pill that would be easy for people to take at home would be terrific. If this was available through a drug store, more people could get it,” says Albert Shaw, an infectious diseases specialist at Yale Medicine in New Haven, Connecticut, who was not involved with the research. All of the antiviral medicines available today, including remdesivir and the monoclonal antibodies, must be administered through an IV in a medical setting. Monoclonal antibodies are much more effective against COVID-19 and cut the risk of hospitalization and death by up to 85 percent, but this treatment costs almost three times as much as molnupiravir.
How the antiviral works
Antiviral drugs are used against many viruses, including for herpes and the flu. These drugs take advantage of the fact that viruses need to replicate inside a person’s cells in order to sicken them. Antivirals stop the replication process so the illness doesn’t progress.
The Merck drug works by introducing RNA-like building blocksinto the virus’s genome as it multiplies, which creates numerous mutations, disrupts replication, and kills the virus.
Keeping the virus from multiplying is important because the more it replicates, destroying cell after cell, the sicker a person usually becomes, says Waleed Javaid, an epidemiologist and director of infection prevention and control at Mount Sinai Downtown in New York, who was not involved in the study. Additionally, when enough virus is inside the body the immune system may go into overdrive. “At a certain point the body detects a virus it has never seen and will throw everything against it, like a tank coming at a small target.” he says. This helps the body eliminate the virus but can cause sometimes deadly collateral damage throughout the body in its wake.
The research, which was conducted in numerous sites around the world, was stopped early because the results were so promising, Merck says. The drug was even effective against variants like Delta and Mu. Based on this interim analysis in 775 people, the company plans to submit an application for Emergency Use Authorization (EUA) to the U.S. Food and Drug Administration as well as regulatory bodies in other countries in hopes the drug can be made available. When that will happen is not clear, but the U.S. government has already agreed to purchase 1.7 million courses of treatment at $700 each, Merck notes.
Who can get the drug?
It’s also not known who would ultimately be authorized to take the medicine. The study included only people who were sick and unvaccinated and had at least one risk factor for developing a severe case of COVID-19, says Aaron Weinberg, national director of clinical research at Carbon Health, a for-profit provider of primary and urgent care, and a principal investigator of the study. This includes people who are older than 60, obese, immunocompromised from another condition, or have underlying heart or pulmonary disease, among others.
If the FDA does authorize the drug, it could limit who gets it to people like those in the research, Javaid says.
Although this drug looks promising, it’s a treatment but not a prophylactic like the vaccine. The medicine does not negate the need for unvaccinated people to get their shot, Shaw says. Some people taking the pills still got sick enough to be hospitalized. And while side effects in this study were mild—generally gastrointestinal issues, Weinberg says, and at comparable rates in the treatment and placebo groups—safety issues might emerge when the drug is given more broadly, Shaw says. Meanwhile, hundreds of millions of people have already gotten the vaccines with no major consequences.
Still, the results of this study should be celebrated, Javaid says. “Saving eight lives is huge, as is halving hospitalization,” he says. Perhaps another drug being studied will later prove to be more effective, reducing hospitalization by 80 or even 100 percent, he says. “But this is better than any oral antivirals we have right now, which is none,” he says.
Common antidepressant slashes risk of COVID death
Fluvoxamine is both inexpensive and highly effective at preventing mild COVID-19 from turning severe.
A cheap, widely available drug used to treat mental illness cuts both the risk of death from COVID-19 and the need for people with the disease to receive intensive medical care, according to clinical-trial results1.
The drug, called fluvoxamine, is taken for conditions including depression and obsessive–compulsive disorder. But it is also known to dampen immune responses and temper tissue damage, and researchers credit these properties for its success in the recent trial. Among study participants who took the drug as directed and did so in the early stages of the disease, COVID-19-related deaths fell by roughly 90% and the need for intensive COVID-19-related medical care fell by roughly 65%.
“A major victory for drug repurposing!” Vikas Sukhatme at Emory University School of Medicine in Atlanta, Georgia, who studies drug repurposing, wrote in an e-mail to Nature. “Fluvoxamine treatment should be adopted for those at high risk for deterioration who are not vaccinated or cannot receive monoclonal antibodies.”COVID antibody treatments show promise for preventing severe disease
Study co-author Angela Reiersen, a psychiatrist at Washington University School of Medicine in St. Louis, Missouri, has long been interested in using fluvoxamine to treat a rare genetic condition. While monitoring the fluvoxamine literature before the pandemic, she came across a 2019 study showing that fluvoxamine reduced inflammation in mice with sepsis2. When COVID-19 hit, “I immediately thought back to that paper with the mice,” she says.
Reiersen and her colleagues partnered with the organizers of the TOGETHER Trial, which aims to identify approved drugs that can be repurposed to treat COVID-19. The team’s study included 1,497 people in Brazil who had COVID-19 and were at high risk of severe disease. Roughly half received fluvoxamine, and the rest received a placebo.
The trial’s results, published on 27 October, mean that fluvoxamine is one of a handful of therapies that show strong evidence of preventing progression from mild to severe COVID-19. The only early-stage treatments currently recommended by the US National Institutes of Health are monoclonal antibodies, which are costly and difficult to administer in an outpatient setting.
Experts are excited about the results, but stress that there are caveats. “We don’t know how applicable this would be in a setting outside of Brazil,” said infectious-disease specialist Paul Sax at Brigham and Women’s Hospital in Boston, Massachusetts.
And infectious disease specialist Taison Bell at the University of Virginia in Charlottesville questions how the authors define severe COVID-19, which factors into the assessment of fluvoxamine’s efficacy. The team examined whether people needed more than six hours of treatment in an emergency setting, rather than using the more common metric of hospitalization. Reiersen says the six-hour metric reflects Brazil’s approach to managing COVID-19, in which care is delivered not in hospitals but in COVID-19-specific emergency treatment centres that provide both inpatient and outpatient services.
A COVID drug for the people?
Fluvoxamine’s low cost could make it accessible worldwide, says study co-author Edward Mills, a health researcher at McMaster University in Hamilton, Canada. A ten-day course costs only about US$4, and the drug’s patents have expired, meaning that any company can produce it. “I’ve worked a lot in Africa, for example, where four dollars is a manageable cost,” Mills says.
It’s possible that pairing fluvoxamine with a drug that interferes with viral replication, such as Merck’s upcoming antiviral molnupiravir, could be even more effective, Mills says. “It would be fascinating to look at whether or not the antiviral and [anti-inflammatory drugs combined] give you much greater treatment benefits than either alone.”
Fact and fiction – myths and truths about COVID-19
Frequently asked questions
As fears and misconceptions spread online, the World Health Organization (WHO) has been constantly updating its campaign to educate people on coronavirus, or COVID-19.
Here are key things to know about the novel coronavirus.
1.) Will eating lots of garlic help?
Garlic is considered a healthy food with some antimicrobial properties – but there are no indications it’s helping anyone fight off Covid-19.
2.) Will the flu vaccine protect me?
Also, vaccines against pneumonia and flu do not provide protection against the novel coronavirus, says the WHO. It’s simply too new, and work on a vaccine specifically for the new virus is still in process. At the World Economic Forum Annual Meeting in Davos, the Coalition for Epidemic Preparedness Innovations announced a new partnership to develop vaccines for COVID-19 as quickly as possible.
3.) How can I keep myself safe?
The WHO refutes a number of claims that things like ultra-violet lamps and hot-air hand-dryers can kill the virus. Instead, it strongly recommends robust personal hygiene.
One of the best things you can do is wash your hands regularly – especially if you have been sneezing. And if you have been sneezing, make sure to cover and catch that sneeze. You can cup your hands over your face, or sneeze into the crook of your elbow, or into a tissue. But make sure to securely dispose of the tissue straight away.
Other hygiene and self-care myths the WHO has been keen to clear up include:
Can regularly rinsing your nose with saline help prevent infection with the new coronavirus?
No. There is no evidence that regularly rinsing the nose with saline has protected people from infection with the new coronavirus.
Can spraying alcohol or chlorine all over your body kill the new coronavirus?
No. Spraying alcohol or chlorine all over your body will not kill viruses that have already entered your body.
Are antibiotics effective in preventing and treating the new coronavirus?
No. Antibiotics do not work against viruses, only bacteria.
4.) Does climate affect the virus?
From the evidence so far, the COVID-19 is at home in hot and humid weather, as well as the cold. You could try having a very hot bath – but that wouldn’t do much either, according to the WHO. Your body temperature will not be affected greatly by normal changes in outside temperature, which means the coronavirus will always be comfortable.
5.) Can I contract the virus from letters and packages sent from China?
No. According to the WHO, people receiving post from China are not at risk of catching the new coronavirus. The WHO knows from previous analysis that coronaviruses do not survive long on objects, such as letters or packages.
What is the World Economic Forum doing about epidemics?
6.) What about pets? Can I catch it from them?
COVID-19 may have come from animals, but your pets are not likely to be part of the equation. The WHO says, “At present, there is no evidence that companion animals/pets such as dogs or cats can be infected with the new coronavirus.”
There are lots of other reasons for good hygiene around pets, though. Some common bacteria can pass between animals and people, such as E.coli and Salmonella. Washing your hands with soap and water can guard against them.
Two years later, coronavirus evolution still surprises experts. Here’s why.
Scientists and physicians continue to be amazed by how quickly the virus evolves, what it does to the human body, and how it moves through species.
Raul Andino knows his pathogens. For more than 30 years the University of California, San Francisco researcher has studied RNA viruses, a group that includes the virus that causes COVID-19. And yet he never imagined he’d witness a pandemic of this scale in his lifetime.
“The magnitude of it and the implications of it are still hard to comprehend,” Andino says.
Although experts in his field suspected a pandemic would occur, “it’s hard to know when,” he says. “It’s similar to an earthquake—you know the earthquake will happen, but normally you don’t think about it.”
On March 11, 2020—exactly two years ago—the World Health Organization declared COVID-19 to be a pandemic. The disease has since infected nearly 500 million people in almost 200 countries and killed more than six million people worldwide, and it’s not over yet.
Along the way, this coronavirus has presented scientists with a bevy of surprises: Many experts are still amazed by how quickly the virus evolves, what it does to the human body, and how it moves in and out of other species.
The original SARS-CoV-2 virus rapidly evolved into a string of variants that have hindered a return to pre-pandemic normalcy. Even with the virus’s genetic blueprint in hand and the ability to decode the genomes of new variants within hours, virologists and healthcare professionals struggle to predict how its mutations will alter the virus’s transmissibility and severity.
Millions of people are grappling with symptoms that linger for weeks to several months after they’d been diagnosed with an infection. Scientists are racing to understand the biology of this new and perplexing syndrome called long COVID.
Two years in, there’s still a lot we don’t know about SARS-CoV-2, says David Wohl, an infectious disease specialist at the University of North Carolina. Here’s what scientists have uncovered so far—and the mysteries that continue to tantalize and frustrate coronavirus experts.
Experts had been warning of some kind of looming pandemic for decades. As humans expand settlements into wild areas, they raise the odds of a new pathogen jumping from an animal to a person, giving rise to a deadly zoonotic disease. A study published in Nature showed that emerging infectious diseases originating in wildlife had increased significantly between 1940 and 2004.
But most experts were worried about influenza viruses and would not necessarily have expected a coronavirus to cause such havoc.
That changed with the 2002-04 Severe Acute Respiratory Syndrome (SARS) outbreak, which infected more than 8,000 people in 29 countries and left 774 dead. Then the 2012 Middle East Respiratory Syndrome (MERS) outbreak infected more than 2,000 people in 37 countries; that virus has so far killed nearly 900.
Still, people weren’t paying as much attention to coronaviruses compared to the “really bad guys” like influenza, HIV, dengue viruses, Andino says.
Then SARS-CoV-2 arrived with a bang. It was spreading faster than previous coronaviruses, and one reason, scientists suspect, is its ability to move efficiently from one cell to the next. SARS-CoV-2 is also harder to contain because it causes so many asymptomatic cases, people who can then unknowingly spread the virus. “In a way, SARS-CoV-2 has found a way in which it can [rapidly] spread and also cause disease,” Andino says. “It’s the worst-case scenario playing out.”
March of the variants
Adding to the oddities, the SARS-CoV-2 virus acquired genetic mutations much more rapidly than expected.
Coronaviruses usually mutate at lower rates than other RNA viruses, like influenza and HIV. Both SARS-CoV and SARS-CoV-2 accumulate approximately two mutations each month; half to one sixth the rate seen in influenza viruses. That’s because coronaviruses have proofreading proteins that correct errors introduced into the virus’ genetic material as it replicates.
“That’s why we thought [SARS-CoV-2] would not evolve very fast,” says Ravindra Gupta, a clinical microbiologist at the University of Cambridge.
But the virus quickly proved Gupta and his colleagues wrong. The emergence of Alpha—the first variant of concern identified in the United Kingdom in November 2020—stunned scientists. It had 23 mutations that set it apart from the original SARS-CoV-2 strain, eight of which were in the spike protein, which is essential for anchoring to human cells and infecting them.
“It became clear that the virus could make these [surprising] evolutionary leaps,” says Stephen Goldstein, an evolutionary virologist at the University of Utah. With this set of mutations, Alpha was 50 percent more transmissible than the original virus.
The next version, Beta, was first identified in South Africa and was reported as a variant of concern just a month later. It carried eight mutations on the viral spike, some of which helped the virus escape the body’s immune defenses. And when the Gamma variant emerged in January 2021, it had 21 mutations, 10 of which were in the spike protein. Some of these mutations made Gamma highly transmissible and enabled it to reinfect patients who previously had COVID-19.
“It’s surprising to see these variants make pretty significant leaps in transmissibility,” Goldstein says. “I just don’t think we’ve observed a virus do that before, but of course, we have not actually observed any pandemics previously with the amount of genetic sequencing capacity we have now.”
Then came Delta, one of the most dangerous and contagious variants. It was first identified in India and designated a variant of concern in May 2021. By late 2021 this variant dominated in almost every country. Its unique constellation of mutations—13 overall and seven in the spike—made Delta twice as infectious as the original SARS-CoV-2 strain, led to longer lasting infections, and produced 1,000 times more virus in the bodies of infected people.
“It [SARS-CoV-2]’s ability to come up with new solutions and ways to adapt and spread with such ease—it’s incredibly surprising,” Andino says.
However, Omicron, which is two to four times more contagious than Delta, rapidly replaced that variant in many parts of the world. First identified in November 2021, it carries an unusually high number of mutations—more than 50 overall and at least 30 in the spike—some of which help it evade antibodies better than all the earlier virus versions.
“These huge jumps [in mutations] make the pandemic far less predictable,” says Francois Balloux, a computational biologist at the University College London Genetics Institute in the United Kingdom.
One of the most compelling explanations for the huge leaps in the number of mutations is that that the SARS-CoV-2 virus was able to evolve for long periods of time in the bodies of immunocompromised people.
During the past year, scientists have identified cancer patients and people with advanced HIV disease who were unable to get rid of their COVID-19 infection for months to nearly a year. Their suppressed immune systems enabled the virus to persist, replicate, and mutate for months.
Gupta identified one such mutation (also seen in the Alpha variant) in a sample from a cancer patient who remained infected for 101 days. In an advanced HIV patient in South Africa who was infected for six months, scientists recorded a multitude of mutations that helped the virus escape the body’s immune defenses.
“That the virus is changing its biology this quickly in its evolutionary history is a huge find,” Gupta says. Other viruses like influenza and norovirus also undergo mutation in immunocompromised individuals, but “it is very rare,” Gupta says, and they “infect a narrow range of cells.”
By contrast, SARS-CoV-2 has proven capable of infecting many different areas of the body—creating yet more baffling effects for scientists to untangle.
Not just a respiratory virus
Early in the pandemic medical professionals noticed that the virus wasn’t just causing pneumonia-like illness. Some hospitalized patients also presented heart damage, blood clots, neurologic complications, and kidney and liver defects. Mounting studies within the first few months suggested one reason why.
SARS-CoV-2 uses proteins called ACE2 receptors on the surface of human cells to infect them. But because ACE2 is present in many organs and tissues, the virus was infecting more parts of the body than just the respiratory tract. There were also a few reports of the virus, or parts of it, in blood vessel cells, kidney cells, and small quantities in brain cells.
“I’ve studied a lot of pandemics, and in almost all of them, you look at the brain, you’ll find the virus there,” says Avindra Nath, a neuroimmunologist at the National Institutes of Health. For instance, brain autopsy tissues from 41 hospitalized and dead COVID-19 patients revealed low levels of the virus. But there were also clear signs of damage, including dead neurons and mangled blood vessels.
“That’s the biggest surprise,” Nath says.
It’s likely that the virus triggers the body’s immune system to go into a hyperactive mode called a cytokine storm, which causes inflammation and injury to different organs and tissues. An abnormal immune response can persist even after infection, resulting in lingering symptoms including chronic fatigue, heart palpitations, and brain fog.
“But there are virus reservoirs that can cause chronic inflammation,” says Sonia Villapol, a neuroscientist at theHouston Methodist Research Institute. A recent study that’s not yet been peer-reviewed showed that SARS-CoV-2 genetic material could persist for up to 230 days in the body and brains of COVID-19 patients, even in those who harbored only mild or asymptomatic infections.
Susan Levine is an infectious-disease doctor in New York who specializes in the treatment and diagnosis of chronic fatigue syndrome, which has parallels with long COVID. She now sees 200 patients every week, compared to 60 in pre-pandemic times. Unlike CFS, long COVID “hits you like a ton of bricks,” Levine says. “It’s like a tornado inside your body where you’re going from working 60 hours a week down to being in the bed all day within a week of getting the infection. The action is so compressed.”
Animal reservoirs of SARS-CoV-2
Scientists are now concerned about the persistence of SARS-CoV-2 outside human populations and its potential to spread to other animals and jump back into humans, possibly extending the pandemic.
In April 2020 tigers and lions at New York’s Bronx Zoo tested positive for COVID-19, sparking interest in finding other animals that might be susceptible. Soon after a study identified mammals including certain primates, deer, whales, and dolphins to be among the most vulnerable to COVID-19 given the similarity between their ACE2 receptors and the counterpart in human cells.
Another study used a machine learning approach to assess the abilities of 5,400 mammal species to transmit SARS-CoV-2; it found that several animals most at risk of spreading COVID-19 were those living alongside people, such as livestock and even pets.
So far SARS-CoV-2 has infected pet cats, dogs, and ferrets, ravaged mink farms, and spread to tigers, hyenas, and other animals in zoos. What’s more, SARS-COV-2 has successfully jumped from humans to captive minks and back into mink farmers. And a person in Canada was potentially infected with COVID-19 when the virus jumped from a white-tailed deer.
“The concern is if it continues to evolve in deer to a point where deer become more and more immune to it, their preexisting antibodies from their reinfection could also further drive viral evolution,” says Samira Mubareka at Canada’s Sunnybrook Health Sciences Centre. Also, “the virus may be circulating in other animals out there.”
Still, the spread of SARS-CoV-2 among humans continues to be a bigger concern for scientists, as they learn more about the virus and its presence and impact in both humans and animals.
“We still don’t know what the future holds,” Wohl says. “We’ll be two years plus of history and track record, and even then with that knowledge, it’s still hard to predict what will happen.”
Covid-19 is nothing to mess with follow the guidelines listed by the CDC and yes even Fauci. I know he recommended face shields, which are totally impractical, unless you are caring for a loved one at home that has covid, than by all means protect yourself. A shield really does work. I would know. Good Luck and be safe.
Additional information that belongs in the conclusion section. (10/4/2020) The coronavirus that causes COVID-19 has sickened more than 16.5 million people across six continents. It is raging in countries that never contained the virus. It is resurging in many of the ones that did. If there was ever a time when this coronavirus could be contained, it has probably passed. One outcome is now looking almost certain: As much as I hate to admit it, this virus is never going away. The coronavirus is simply too widespread and too transmissible. The most likely scenario, experts say, is that the pandemic ends at some point—because enough people have been either infected or vaccinated—but the virus continues to circulate in lower levels around the globe. Cases will wax and wane over time. Outbreaks will pop up here and there. Even when a much-anticipated vaccine arrives, it is likely to only suppress but never completely eradicate the virus. (For context, consider that vaccines exist for more than a dozen human viruses but only one, smallpox, has ever been eradicated from the planet, and that took 15 years of immense global coordination.) We will probably be living with this virus for the rest of our lives.
If not, then what does the future of COVID-19 look like? That will depend, says Yonatan Grad, on the strength and duration of immunity against the virus. Grad, an infectious-disease researcher at Harvard, and his colleagues have modeled a few possible trajectories. If immunity lasts only a few months, there could be a big pandemic followed by smaller outbreaks every year. If immunity lasts closer to two years, COVID-19 could peak every other year.
At this point, how long immunity to COVID-19 will last is unclear; the virus simply hasn’t been infecting humans long enough for us to know. But related coronaviruses are reasonable points of comparison: In SARS, antibodies—which are one component of immunity—wane after two years. Antibodies to a handful of other coronaviruses that cause common colds fade in just a year.
This has implications for a vaccine, too. Rather than a onetime deal, a COVID-19 vaccine, when it arrives, could require booster shots to maintain immunity over time. You might get it every year or every other year, much like a flu shot. Even if the virus were somehow eliminated from the human population, it could keep circulating in animals—and spread to humans again. In the best-case scenario, a vaccine and better treatments blunt COVID-19’s severity, making it a much less dangerous and less disruptive disease. Over time, SARS-CoV-2 becomes just another seasonal respiratory virus, like the four other coronaviruses that cause a sizable proportion of common colds: 229E, OC43, NL63, and HKU1. These cold coronaviruses are so common that we have likely all had them at some point, maybe even multiple times. They can cause serious outbreaks, especially in the elderly, but are usually mild enough to fly under the radar. One endgame is that SARS-CoV-2 becomes the fifth coronavirus that regularly circulates among humans.
In a additional section I added that relates to Herd immunity, scientist are promulgating continuous lock downs to prevent further spread of the disease. I find this totally untenable and unsustainable. We mind as well live in the dark ages.
This original posting has increased in size to such an extant that I have had to divide it into two sections. The second section, is the addendum section, where i will include updates for the covid virus. I will also insert additional articles into the first section as appropriate. Additional separate articles will be posted and updated as well.
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nationalgeographic.com, “Why annual COVID-19 boosters may become the norm: To keep the coronavirus in check and stay ahead of new variants, people may need yearly shots like they do for the flu,” By Jillian Kramer; nationalgeographic.com, “Coronavirus in the U.S.: Where cases are growing and declining;” nationalgeographic.com, “Will COVID-19 cancel your family reunion?,” By Viky Hallett; nmationalgeographic.com, “Pfizer and Moderna vaccines safe for pregnant people, major study confirms,” By Tara Haelle; thebulletin.org, “The origin of COVID: Did people or nature open Pandora’s box at Wuhan?,” By Nicolas Wade; nytimes.com, “The world may need to learn to live with the virus,” By Andrés R. Martínez; nationalgeographic.com, “A rare black fungus is infecting many of India’s COVID-19 patients—why?,” By Priyanka Runwal; nationalgeographic.com, “Why vaccine side effects really happen, and when you should worry,: By Linda Marsha;
nationalgeographic.com, “Are we there yet? What happens if the U.S. can’t reach herd immunity,” By Amy McKeever; nationalgeographic.com, “What you need to know about the COVID-19 lab-leak hypothesis,” By Jillian Kramer; nationalgeographic.com, “Can COVID-19 lead to diabetes? Here’s what you need to know,” By Bill Sullivan; nationalgeographic.com, “Will we ever know the real death toll of the pandemic?,” BY AMRUTA BYATNAL; nationalgeographic.com, “The complex situation for immunocompromised people and COVID-19 vaccines: Studies suggest the available shots don’t provide enough protection, leaving more than nine million Americans with compromised immune systems stuck in a waiting game.” BY TARA HAELLE; nature.com, “COVID and the brain: researchers zero in on how damage occurs: Growing evidence suggests that the coronavirus causes ‘brain fog’ and other neurological symptoms through multiple mechanisms.” By Michael Marshall; nature.com, “Will COVID become a disease of the young? A growing share of infections among unvaccinated youths in countries with high vaccination rates is putting the spotlight on the role of young people in the pandemic.” By Smriti Mallapaty;
nationalgeographic.com, “The Delta variant is spreading fast, especially where vaccination rates are low: A new report stresses that only a complete dose of the COVID-19 vaccine can protect against this dangerous variant, which is now dominant in the U.S., U.K., and more than a dozen other countries.” BY SANJAY MISHRA; forbes.com, “Long Covid Has Over 200 Symptoms And Leaves 1 In 5 Unable To Work, Study Finds,’ By Robert Hart; nationalgeographic.com, “The unusual Lambda variant is rapidly spreading in South America. Here’s what we know: Its mutations help it dodge the immune system. Researchers are scrambling to figure out if it is more dangerous or transmissible than Delta.” BY SANJAY MISHRA; nationalgeographic.com, “A spritz instead of a jab? Future COVID-19 vaccines may go up your nose: Spurred by the pandemic, scientists are studying the benefits of intranasal vaccines and what makes them more potent than shots in the arm,” BY MONIQUE BROUILLETTE; nationalgeographic.com, “Here’s why the CDC reversed course on masks indoors—and how it might affect you: The change in guidance comes as the highly transmissible Delta variant sweeps a nation that is still struggling to get enough shots in arms.” BY MICHAEL GRESHKO ANDMAYA WEI-HAAS; nationalgepgraphic.com, “Struggling to assess pandemic risks? You’re not alone: Lots of psychological factors influence individual responses to danger, as well as our willingness to make less risky decisions.” BY JILLIAN KRAMER;
fiercepharma.com, “With expanded FDA nod, Regeneron’s COVID-19 antibody drug can help the immunocompromised,” by Kevin Dunleavy; drugs.com, “Can Ivermectin be used to treat COVID-19 (coronavirus)?, By Melisa Puckey; nationalgeographic.com, “How will the pandemic end? The science of past outbreaks offers clues. The answer depends on many factors, perhaps the most critical being the global nature of the crisis.” By Jillian Kramer; nationalgeographic.com, “Why is Delta more infectious and deadly? New research holds answers. Studies show that Delta replicates more quickly and generates more virus particles than other variants, but vaccines still protect against serious infections.” BY SANJAY MISHRA; nationalgeographic.com, “Delta variant prompts venues to rethink how we stand in line: Can new technology, old-fashioned manners, and floor stickers make the waiting game simpler and safer?” By Rachel Ng; factcheck.org, “Hospital Payments and the COVID-19 Death Count,” By Angelo Fichera; nature.com, “Delta’s rise is fuelled by rampant spread from people who feel fine: People infected with the Delta variant generally do not have COVID-19 symptoms until two days after they start shedding the coronavirus.” By Smriti Mallapaty; nationalgeographic.com, “How does COVID-19 affect the brain? A troubling picture emerges. Researchers find that people who only suffered mild infections can be plagued with life-altering and sometimes debilitating cognitive deficits.” BY EMILY MULLIN;
nationalgeographic.com, “CDC, FDA, NIH—what’s the difference? The U.S. agencies all play an important role in addressing the COVID-19 pandemic, but each evolved from a unique moment in public health history.” By Erin Blakemore; nationalgeographic.com, “Why some COVID-19 infections may be free of symptoms but not free of harm: Scientists are studying the potential consequences of asymptomatic COVID-19 and how many people may suffer long term health problems,” BY AMY MCKEEVER; Nationalgeographic.com, “The shaky science behind ivermectin as a COVID-19 cure: Studies are inconclusive and misinformation is rampant. But many Americans now see a deworming medicine as a go-to drug to prevent and fight the Delta variant,” BY PRIYANKA RUNWAL; nationalgeographic.com, “The Mu variant is on the rise. Scientists weigh in on how much to worry. Laboratory studies suggest this variant may be better at avoiding the immune system but lags Delta when it comes to transmission and infecting cells.” BY SANJAY MISHRA; nationalgeographic.com, “COVID-19 may impair men’s sexual performance: Men may be six times more likely to develop brief or long-term erectile dysfunction after contracting the virus. The vaccine can prevent this.” BY SHARON GUYNUP; nationalgeographic.com, “How Merck’s antiviral pill could change the game for COVID-19: Promising results from clinical trials suggest that the drug may become the first at-home treatment cleared for use by the FDA.” BY MERYL DAVIDS LANDAU; nationalgeographic.com, “How COVID-19 can damage all five senses: The virus that causes the disease disrupts not just smell and taste, but all the ways humans perceive the world. For some, the loss may be permanent.” BY STACEY COLINO; nationalgeographic.com, “The epic COVID-19 memorial on the National Mall, in one stunning photo: 4,882 photos taken over 30 hours. More than 670,000 flags representing American lives lost. An incalculable measure of grief.” By Rachel Hartigan;
nationalgeographic.com, “COVID-19 is linked to new diabetes cases—but long-term problems could be more severe: In addition to driving new cases of diabetes, the virus may be directly damaging the pancreas in ways that could lead to chronic inflammation and even cancer.” BY AMY MCKEEVER; nature.com, “How antiviral pill molnupiravir shot ahead in the COVID drug hunt: The Merck pill, which could become the first oral antiviral COVID treatment, forces the SARS-CoV-2 coronavirus to mutate itself to death.” BY Cassandra Willyard; nationalgeographic.com, “Why even fully vaccinated older people are at high risk for severe COVID-19: Many factors weaken the aging immune system. But vaccines—and booster doses—do offer protection from hospitalization and death.” BY AMY MCKEEVER; nationalgeographic.com, “Here’s what coronavirus does to the body: From blood storms to honeycomb lungs, here’s an organ-by-organ look at how COVID-19 harms humans.” BY AMY MCKEEVER; nationalgeographic.com, “How coronavirus compares to flu, Ebola, and other major outbreaks: Weighing diseases against each other is a complicated calculus. These charts explain why.” BY NSIKAN AKPAN ANDKENNEDY ELLIOTT; nature.com, “Common antidepressant slashes risk of COVID death: Fluvoxamine is both inexpensive and highly effective at preventing mild COVID-19 from turning severe.” BY Saima May Sidik: nationalgeographic.com, “How the rise of antivirals may change the course of the pandemic: Making them isn’t easy. But new pills to treat COVID-19 are now showing promise at curbing illness and saving lives.” BY PRIYANKA RUNWAL; nature.com, “Do vaccines protect against long COVID? What the data say: Vaccines reduce the risk of developing COVID-19 — but studies disagree on their protective effect against long COVID.” By Heidi Ledford;
nature.com, “Heavily mutated coronavirus variant puts scientists on alert: Researchers are racing to determine whether a fast-spreading variant in South Africa poses a threat to COVID vaccines’ effectiveness.” By Ewen Callaway; nationalgeographic.com, “How COVID-19 harms the heart: Many patients are experiencing heart palpitations, chest pain, and shortness of breath even after recovering from COVID-19. But new studies offer reason for hope.” BY AMY MCKEEVER; nationalgeographic.com, “The real risk of heart inflammation to kids is from COVID-19—not the vaccine: Pediatric experts agree that an infection causes more severe heart issues—and carries higher risk for long-term or permanent damage.” BY TARA HAELLE; Thedailywire.com, “The Covid Response Has Broken Our Trust in American Institutions.” By Scott W. Atlas, MD; nature.com, “A tale of two antiviral targets — and the COVID-19 drugs that bind them: The FDA is considering authorizations for Pfizer’s paxlovid and Merck & Co.’s molnupiravir, the first two oral COVID-19 antivirals.” By Megan Cully; dailywire.com, “Viral Tyranny: The World’s Most Oppressive COVID-19 Policies.” Ben Johnson; nationalgeographic.com, “Hippos, hyenas, and other animals are contracting COVID-19: More species are found to be susceptible to the coronavirus, with most cases detected in zoos.” BY NATASHA DALY; nature.com, “How the coronavirus infects cells — and why Delta is so dangerous: Scientists are unpicking the life cycle of SARS-CoV-2 and how the virus uses tricks to evade detection.” By Megan Scudellari;
dailywire.com, “The Big Government COVID-19 Lie.” By Ben Shapiro; nationalgeographic.com, “Can COVID-19 alter your personality? Here’s what brain research shows. Alzheimer’s, Parkinson’s, and traumatic brain injury can cause changes in behavior by altering brain anatomy. Now it seems the coronavirus can too.” By Sharon Guynup; nationalgeographic.com, “Could viruses cause Alzheimer’s? COVID-19 brain studies offer new clues. The diseases share some surprising similarities, and experts now think studying COVID-19 patients’ brains could lead to better treatments for both conditions.” By Emma Yasinski; nature.com, “The pandemic’s true death toll: millions more than official counts: Countries have reported some five million COVID-19 deaths in two years, but global excess deaths are estimated at double or even quadruple that figure.” By David Adam; securetherepublic.com, “Is Coronavirus a Biological Weapon?”; securetherepublic.com.” CDC Admits: Some Coronavirus Deaths Have Been Miscategorized As Flu”; securetherepublic.com. “Coronavirus: Follow The Money… and the Players!”; securetherepublic.com. “Coronavirus / COVID-19 – Exposing Dr. Fauci & the Deep State”; securetherepublic.com. “Open America Now! D.C. Medical Cartel Exposed…”; securetherepublic.com. “COVID-19 Cesspool of Corruption… and Some of the Players”; securetherepublic.com. “COVID-19 Pre-Filled Syringes with RFID Tracking”; weforum.org, “Fact and fiction – myths and truths about COVID-19.” By Sean Fleming; thedesertreview.com, “Hospital Death Camps Exposed.” By Justus R. Hope, MD; dailywire.com, “The COVID-19 Impact Of Expressive Individualism.” By Ben Shapiro; nature.com, “Heart-disease risk soars after COVID — even with a mild case: Massive study shows a long-term, substantial rise in risk of cardiovascular disease, including heart attack and stroke, after a SARS-CoV-2 infection.” By Nature Editors; dailywire.com, “Did ‘The Science’ Change?”;
nationalgeographic.com, “How COVID-19 can harm pregnancy and reproductive health Severe outcomes are uncommon, but serious infections—or long COVID afterward—can endanger mothers and their babies.” By Sharon Guynup; nationalgeographic.com, “As long COVID cases grow, clues emerge about who is most at risk: Tens of millions of people now have an array of lingering symptoms. Figuring out their common risk factors could help tailor treatments.” By EMILY SOHN; nature.com, “Hundreds of COVID trials could provide a deluge of new drugs: Two years into the pandemic, the COVID-19 drugs pipeline is primed to pump out novel treatments — and fresh uses for familiar therapies.” BY Heidi Ledford; nationalgeographic.com, “For millions of vulnerable people, COVID-19 is far from over: Immunocompromised patients remain frightened and frustrated that vaccines aren’t offering enough protection as everyone else moves on. Scientists are racing to figure out what will work.” BYPRIYANKA RUNWAL; nationalgeographic.com, “Two years later, coronavirus evolution still surprises experts. Here’s why. Scientists and physicians continue to be amazed by how quickly the virus evolves, what it does to the human body, and how it moves through species.” BY PRIYANKA RUNWAL; nationalgeographic.com, “Why is it so hard to compensate people for serious vaccine side effects? Though very rare, complications from shots can shatter lives and trust. Now the federal programs designed to help them are struggling with COVID-19.” By Tara Haell; nature.com, “Can drugs reduce the risk of long COVID? What scientists know so far: Researchers are trying to establish whether existing COVID-19 vaccines and treatments can prevent lasting symptoms.” By Heidi Ledford; “The Real Anthony Fauci.” By Robert F. Kennedy Jr.;