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
–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
-Coronavirus in the U.S.: Where cases are growing and declining
-Modes of transmission of the Covid-19 virus
-Transmission by Function and Activities
-Precautions to take to prevent transmission
-How is it detected
-Symptoms of Covid-19
-Comorbidities that increase the lethality of the disease
-COVID-19 in people with diabetes: understanding the reasons for worse outcomes
-How the coronavirus affects your body
-Therapeutics and Treatment Modalities
-The Heart and the QT interval
-Medications that can prolong the QT interval
-At Home Coronavirus Treatment
-Therapeutics and treatment modalities revisited
-Post-acute Covid-19 Syndrome
-New Developments in Covid Research
-video showing three therapeutics in action
-ventilator associated meds
medications being currently tested
-More information on the vaccines
-How ‘killer’ T cells could boost COVID immunity in face of new variants
-Should you get the Covid-19 vaccine while pregnant?
-The vaccine alternatives for people with compromised immune systems
-Why your arm might be sore after getting a vaccine
– What we know so far about the effort to vaccinate children
-Why kids need their own COVID-19 vaccine trials
-Where can you travel safely once you’ve been vaccinated?
-top 10 reasons to believe the Wuhan Virology Lab caused 2019-nCoV
-covid-19 and healthcare links
–Information from The Next Revolution w/Steve Hilton on the Origins of the Coronavirus
-We still don’t know the origins of the coronavirus. Here are 4 scenarios.
-Covid-19 Testing Fiasco Timetable
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.
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
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
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 email@example.com@ 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.
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.
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.
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.
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.
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
Source: medical professionalsGraphic: Merrill Sherman and Josh Ulick
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.
SHARE YOUR THOUGHTS
Have you suffered long-term Covid-19 effects? What are your symptoms? Join the discussion below.
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.
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.
visiblebody.com, “DNA and RNA Basics: Replication, Transcription, and Translation,” By Laura Snider; ncbi.nlm.nih.gog, “Features, Evaluation, and Treatment of Coronavirus (COVID-19),” By, Marco Cascella; Michael Rajnik; Arturo Cuomo; Scott C. Dulebohn; Raffaela Di Napoli; healthline.com, “Here’s What Happens to the Body After Contracting the New Coronavirus,” en.wikipedia.org, “the heart,” By, wikipedia editors; webmd.com, “Coronavirus (COVID-19) Treatment,” By WebMD editors; mayoclinic.org, “Coronavirus disease 2019 (Covid-19); theatlantic.com, “The Coronavirus Is Never Going Away, No matter what happens now, the virus will continue to circulate around the world,” By Sarah Zhang; theatlantic.com, “A Vaccine Reality Check, So much hope is riding on a breakthrough, but a vaccine is only the beginning of the end,” By Sarah Zhang; theatlantic.com, “A New Understanding of Herd Immunity:The portion of the population that needs to get sick is not fixed. We can change it,” By James Hamblin;
wsj.com,”Doctors Begin to Crack Covid’s Mysterious Long-Term Effects,” By Sarah Toy, Sumathi Reddy and Daniela Hernadez; apnews, “3rd major COVID-19 vaccine shown to be effective and cheaper,” By Danica Kirka; pfizer.com, “PFIZER AND BIONTECH ACHIEVE FIRST AUTHORIZATION IN THE WORLD FOR A VACCINE TO COMBAT COVID-19;” apnews.com, “2nd virus vaccine shows striking success in US tests,” By Lauren Neergaard; Nature.com, “The biggest mystery: what it will take to trace the coronavirus source,” By David Cyranoski; thesun.ie, “SMOKING GUN:Wuhan lab leak is the ‘most credible’ origin of coronavirus pandemic, top US official says amid ‘whistleblower’ claims,” By Joseph Gamp;
listverse.com, “Top 10 Reasons To Believe the Wuhan Virology Lab Caused 2019-nCoV,” By Mark Oliver; The Dailywire.com, “How Bureaucracy Killed Hundreds of Thousands of Americans,” By Ben Shapiro; nypost.com, “Dr. Fauci backed funding for controversial Wuhan lab studying origin of coronavirus,” By Joe Tacopino; afa.net, “Did Dr. Fauci Fund the Research That Led to Coronavirus Outbreak?” newsweek.com, “Dr. Fauci Backed Controversial Wuhan Lab with U.S. Dollars for Risky Coronavirus Research,” By Fred Guterl; sciencemag.org, “NIH lifts 3-year ban on funding risky virus studies,” By Jocelyn Kaiser; nature.com, “Post-acute COVID-19 syndrome,: By Ani Nalbandian, et al;
nationalgeographic.com, “The coronavirus is mutating—but what determines how quickly?” By Maya Wei-Haas; nationalgeographic.com, “Should you get the COVID-19 vaccine while pregnant? Here’s what experts say,” By Amy McKeever; nature.com, “How ‘killer’ T cells could boost COVID immunity in face of new variants,” By Heidi Ledford; nationalgeographic.com, “The vaccine alternatives for people with compromised immune systems,” By David Cox;thelancet.com, “COVID-19 in people with diabetes: understanding the reasons for worse outcomes,” By Matteo Apicella, Maria Cristina Campopiano, Michele Mantuano, Laura Mazoni, Alberto Coppelli, Stefano Del Prato; nationalgeographic.com, ” Coronavirus in the US: Where cases are growing and declining;”
hsph.harvard.edu, “Ban on deadly pathogen research lifts, but controversy remains,” By Marc Lipsitch; nationalgeographic.com, “Why your arm might be sore after getting a vaccine,” By Emily Sohn; nationalgeographic.com, “Where can you travel safely once you’ve had the COVID-19 vaccine?” By Johanna Read; nationalgeographuic.com, “We still don’t know the origins of the coronavirus. Here are 4 scenarios. Experts say that understanding how the virus first leapt from animals to humans is essential to preventing future pandemics,” By Amy McKeever; nationalgeographic.com, “Why kids need their own COVID-19 vaccine trials: Adolescents are being tested now. Younger children will be next. Why did vaccine manufacturers wait to study them?” By Sarah Elizabeth Richards; nationalgeographic.com, “What we know so far about the effort to vaccinate children: To achieve herd immunity, experts say kids need to get vaccinated, reducing the virus’s ability to spread,” By Tara Haelle;
Video showing three therapeutics in action:
This treatment modality could revolutionize the treatment for covid-19. President Trump is the first person to receive it.
*Ventilator use commonly associated medications:
+Sedation: Versed, Fentanyl, Precedex ( notable Heart rate suppression with higher doses), Propofol(should be as a last alternative, blood pressure suppression)
+Proton Pump inhibitors; Pepcid, Protonix
+Blood Pressure Support: phenylephrine, vasopressin, dopamine, levophed, dobutamine and epinephrine. All have side effects. Including shunting of blood supply to the extremities, and gastrointestinal tract. Some are hard on the blood vessels and require special large bore IV’s like PICC lines and central Lines.
+paralytics: are sometimes required to slow down the respiratory rate.
I am not a doctor, I am a nurse with a License that I have to protect. So I have to be very careful what I say, and I can’t make any recommendations, because that would be practicing medicine without a license, something I would never do. But If I had a family member in the hospital with covid I would really want an aggressive doctor. I would ask about hydroxychloroquine, zinc, zithromycin, lovenox, Remdesevir, IVF and decadron as an early treatment. And if your loved one is intubated , ask about dialysis, fentanyl and versed for sedation, no lasix unless patient is a CHF patient, heparin drip for blood clots, more decadron, and convalescent plasma, what can it hurt. Monoclonal Antibodies are coming out. Remember I am not recommending these things, just suggesting that you open up a dialog with your doctor. It pays to be a little educated on the disease and treatments when you talk to them.
Medications that are being currently tested:
Developed a decade ago, this drug failed in clinical trials against Ebola in 2014. But it was found to be generally safe in people. Research with MERS, a disease caused by a different coronavirus, showed that the drug blocked the virus from replicating. The drug is being tested in many COVID-19 clinical trials around the world. This includes studies in which remdesivir is being administered alongside other drugs, such as the anti-inflammatory drug baricitinibTrusted Source. The drug is also being tested in children with moderate to severe COVID-19.
In late April, the drug’s manufacturer, Gilead Sciences, announced one of its trials had been “terminated” due to low enrollment. Gilead officials said the results of that trial had been “inconclusive” when it was ended. A few days later, the company announced that preliminary data from another trial of remdesivir overseen by the National Institute of Allergy and Infectious Diseases (NIAID) had “met its primary endpoint.”
Dr. Anthony FauciTrusted Source, the institute’s director, told reporters the trial produced a “clear cut positive effect in diminishing time to recover.” He said people taking the drug recovered from COVID-19 in 11 days compared with 15 days for people who didn’t take remdesivir. More details will be released after the trial is peer reviewed and published. Gary Schwitzer, founder of HealthNewsReview.org, though, said the researchers changed the primary endpoint 2 weeks before Fauci’s announcement.
At the same time, another studyTrusted Source published in The Lancet reported that participants in a clinical trial who took remdesivir showed no benefits compared to people who took a placebo. Despite the conflicting results, the FDA issued an orderTrusted Source on May 1 for the emergency use of remdesivir. In early June, federal officials announced their supply of remdesivir will run out by the end of June. Gilead is ramping up production, but it’s unclear how much of the drug will be available this summer.
In mid-July, Gilead officials announced results from an ongoing phase III trial of remdesivir. They said the drug was “associated with an improvement in clinical recovery and a 62 percent reduction in the risk of mortality compared with standard of care.” They called it an an “important finding that requires confirmation in prospective clinical trials.” In mid-September, officials at Eli Lilly announced that in early stage trials their drug Olumiant when added to remdesivir can shorten hospital stays by one day for people with COVID-19. Olumiant is already used to treat rheumatoid arthritis and other conditions that involved overactive immune systems.
This antiviral was tested along with the drug lopinavir/ritonavir as a treatment for COVID-19. Researchers reported in mid-April that the two drugs didn’t improve the clinical outcomes for people hospitalized with mild to moderate cases of COVID-19.
This drug was created by scientists at a nonprofit biotech company owned by Emory University. Research in mice has shown that it can reduce replication of multiple coronaviruses, including SARS-CoV-2. Pharmaceutical company Merck and Ridgeback Biotherapeutics LP signed an agreement in May to develop this drug. It’s already being tested in a clinical trial in the United Kingdom. Unlike remdesivir, EIDD-2801 can be taken orally, which would make it available to a larger number of people.
This drug is approved in some countries outside the United States to treat influenza. Some reports from China suggest it may work as a treatment for COVID-19. These results, though, haven’t been published yet. Japan, where the medication is made, is sending the drug to 43 countries for clinical trial testing in people with mild or moderate COVID-19. Canadian researchers are testing to see whether the drug can help fight outbreaks in long-term care homes.
This is a combination of two drugs — lopinavir and ritonavir — that work against HIV. Clinical trials are being done to see whether it also works against SARS-CoV-2. One small study published May 4 in the journal Med by Cell Press found that lopinavir/ritonavir didn’t improve outcomes in people with mild or moderate COVID-19 compared to those receiving standard care. Another study, published May 7 in the New England Journal of Medicine, found that the drug combination wasn’t effective for people with severe COVID-19. But another studyTrusted Source found that people who were given lopinavir/ritonavir along with two other drugs — ribavirin and interferon beta-1b — took less time to clear the virus from their body. This study was published May 8 in The Lancet.
This drug developed by ViralClear Pharmaceuticals Inc. has been shown previously to have antiviral and immune-suppressing effects. It was tested against hepatitis C but had only modest effects. The company is running a phase II trial of this drug. People with advanced COVID-19 will be randomized to receive either merimepodib with remdesivir, or remdesivir plus a placebo. The company hopes to have results by late summer of this year.
REGN-COV2 is a combination of two monoclonal antibodies (REGN10933 and REGN10987) and was designed specifically to block infectivity of SARS-CoV-2, the virus that causes COVID-19. It appeared to help the seronegative patients, powerfully reducing the amount of virus found in nasopharyngeal swabs and alleviating symptoms more quickly. Both Lilly and Regeneron say they are discussing their data with regulators to see whether their monoclonal antibodies might warrant moving to widespread use more quickly through mechanisms like the U.S. Food and Drug Administration’s emergency use authorization process. Additional studies of their monoclonal treatments are underway in hospitalized COVID-19 patients and, separately, as preventives in uninfected people.
Biologically, a vaccine against the COVID-19 virus is unlikely to offer complete protection. Logistically, manufacturers will have to make hundreds of millions of doses while relying, perhaps, on technology never before used in vaccines and competing for basic supplies such as glass vials. Then the federal government will have to allocate doses, perhaps through a patchwork of state and local health departments with no existing infrastructure for vaccinating adults at scale. The Centers for Disease Control and Prevention, which has led vaccine distribution efforts in the past, has been strikingly absent in discussions so far—a worrying sign that the leadership failures that have characterized the American pandemic could also hamper this process. To complicate it all, 20 percent of Americans already say they will refuse to get a COVID-19 vaccine, and with another 31 percent unsure, reaching herd immunity could be that much more difficult.
The good news, because it is worth saying, is that experts think there will be a COVID-19 vaccine. The virus that causes COVID-19 does not seem to be an outlier like HIV. Scientists have gone from discovery of the virus to more than 165 candidate vaccines in record time, with 27 vaccines already in human trials. Human trials consist of at least three phases: Phase 1 for safety, Phase 2 for efficacy and dosing, and Phase 3 for efficacy in a huge group of tens of thousands of people. At least six COVID-19 vaccines are in or about to enter Phase 3 trials, which will take several more months.
We are almost five months into the pandemic and probably another five from a safe and effective vaccine—assuming the clinical trials work out perfectly. “Even when a vaccine is introduced,” says Jesse Goodman, the former chief scientist at the Food and Drug Administration, “I think we will have several months of significant infection or at least risk of infection to look forward to.”
All of this means that we may have to endure more months under the threat of the coronavirus than we have already survived. Without the measures that have beat back the virus in much of Europe and Asia, there will continue to be more outbreaks, more school closings, more loneliness, more deaths ahead. A vaccine, when it is available, will mark only the beginning of a long, slow ramp down. And how long that ramp down takes will depend on the efficacy of a vaccine, the success in delivering hundreds of millions of doses, and the willingness of people to get it at all. It is awful to contemplate the suffering still ahead. It is easier to think about the promise of a vaccine.
Vaccines are, in essence, a way to activate the immune system without disease. They can be made with weakened viruses, inactivated viruses, the proteins from a virus, a viral protein grafted onto an innocuous virus, or even just the mRNA that encodes a viral protein. Getting exposed to a vaccine is a bit like having survived the disease once, without the drawbacks. A lot remains unknown about the long-term immune response to COVID-19, but, as my colleague Derek Thompson has explained, there are good reasons to believe getting COVID-19 will protect against future infections in some way. Vaccine-induced immunity, though, tends to be weaker than immunity that arises after an infection. Vaccines are typically given as a shot straight into a muscle. Once your body recognizes the foreign invader, it mounts an immune response by, for example, producing long-lasting antibodies that circulate in the blood.
Even if all of this goes well—the earliest candidates are effective, the trials conclude quickly, the technology works—another huge task lies ahead: When vaccines are approved, 300 million doses will not be available all at once, and a system is needed to distribute limited supplies to the public. This is exactly the sort of challenge that the U.S. government has proved unprepared for in this pandemic.
I have an update on Vaccinations There are currently three vaccines that have either have finished stage three or are almost finished this level of testing. Pfizer is the first to its vaccine get it approved by England. It is currently being evaluated by our rather sluggish FDA. It has proven to be safe in all ages and is rated at 95% effective, though it likely will take two injections. Moderna has come out with a vaccine, that will soon be evaluated by the FDA as well, it is also 94 to 95% effective, though it requires less stringent storage facilities, which should help its administration in more rural, areas. The third company, AstraZeneca is still in its last stage of trials, it has had a little road block with dosing, but it is being touted as be just as effective and cheaper and even easier to store than Moderna’s vaccine. While the first two should be rolled out this year, it may take a few months longer for the third one. In 2021, we should see even more vaccines rolling out, which will help increase the inoculation rate world wide. In the U.S. first responders and the elderly and higher risk individuals will get the vaccination first, the general population will start receiving the vaccinations around May or June of 2021. (update 12/5/2020)
More Information on the Vaccines
How Bureaucracy Killed Hundreds of Thousands of Americans
Over the course of the COVID-19 pandemic, the media have spilled barrels of ink over mistakes by the federal government. We’ve heard endlessly about the failure to quickly ramp up testing, the confusion over mask-wearing and the debates over proper lockdown policy. But when the history of this time is written, the fundamental mistake made by the United States government won’t be rhetorical excesses by the president or conflicting public health advice. It will be the same mistake the government always makes: trusting the bureaucracy.
We now know that the miraculous Moderna vaccine for COVID-19 had been designed by Jan. 13, 2020 . That was just two days after the sequencing of the virus had been made public. As David Wallace-Wells writes for New York magazine, “the Moderna vaccine design took all of one weekend. … By the time the first American death was announced a month later, the vaccine had already been manufactured and shipped to the National Institutes of Health for the beginning of its Phase I clinical trial.” Meanwhile, for six weeks, Dr. Anthony Fauci assured Americans that there was little to worry about with COVID-19.
Fast-forward to the end of 2020. Hundreds of thousands of Americans have died. Tens of thousands of Americans continue to die every week. The Food and Drug Administration has still not cleared the Oxford-AstraZeneca vaccine, which costs a fraction of the other vaccines (about $4 per dose, as opposed to $15 to $25 per dose for Moderna’s vaccine or $20 per dose for the Pfizer-BioNTech vaccine). The FDA approval process cost us critical months, with thousands of Americans dying each day. As Dr. Marty Makary of Johns Hopkins University told me this week, “Safety is their eternal excuse. They are entirely a broken federal bureaucracy … Why did we not have a combined Phase I-Phase II clinical trial for these vaccines?”This is an excellent question, of course. Phase I trials involve small numbers of participants, who are then monitored. Phase II trials involve larger numbers. Huge numbers of Americans would have volunteered for a combined Phase I-Phase II trial. And even after we knew the vaccines were effective, the FDA delayed. Data was collected by late October that suggested Phase II/III trials had been successful. The FDA quickly requested more results, which it did not receive until November. It then took until Dec. 11 for the FDA to issue emergency use authorization for the Pfizer vaccine. The Moderna vaccine wasn’t cleared until Dec. 18, nearly a year after it had first been produced.
The disgrace continues. The government continues to hold back secondary doses of the vaccine, despite the fact that the first doses provide a significant effect. As Makary says, “We’re in a war. The first dose gives immunity that may be as high as 80 to 90 percent protection, and we can probably give half the dose, as Dr. Moncef Slaoui suggested … We can quadruple our supply overnight.”
Meanwhile, states continue to be confused by the Centers for Disease Control and Prevention guidance on how to tranche out the vaccines. It took until nine days after the FDA authorized the Pfizer vaccine for the CDC to release its recommendations. Those recommendations were still complex and confusing and often rife with self-defeating standards — even though it was perfectly obvious from the start that the solution ought to be based on age.
Americans have relied on the government — a government supposedly comprised of well-meaning experts — to get us through a pandemic. The government not only failed with conflicting information and incoherent lockdown policy but also actively obstructed the chief mechanism for ending the pandemic thanks to bureaucratic bloat. If Americans’ takeaway from the COVID-19 pandemic is that centralized government is the all-purpose solution, they’re taking precisely the lesson most likely to end in mass death in the future. (Updated 1/12/2021)
Supersites for getting the Vaccination in the US. (Updated 2/28/2021)
The website listed below is a good starting place to gain information on where to find locations for getting the vaccination.
How ‘killer’ T cells could boost COVID immunity in face of new variants
In the race against emerging coronavirus variants, researchers are looking beyond antibodies for clues to lasting protection from COVID-19.
Concerns about coronavirus variants that might be partially resistant to antibody defences have spurred renewed interest in other immune responses that protect against viruses. In particular, scientists are hopeful that T cells — a group of immune cells that can target and destroy virus-infected cells — could provide some immunity to COVID-19, even if antibodies become less effective at fighting the disease.
Researchers are now picking apart the available data, looking for signs that T cells could help to maintain lasting immunity.
“We know the antibodies are likely less effective, but maybe the T cells can save us,” says Daina Graybosch, a biotechnology analyst at investment bank SVB Leerink in New York City. “It makes sense biologically. We don’t have the data, but we can hope.”
Coronavirus vaccine development has largely focused on antibodies, and for good reason, says immunologist Alessandro Sette at the La Jolla Institute for Immunology in California. Antibodies — particularly those that bind to crucial viral proteins and block infection — can hold the key to ‘sterilizing immunity’, which not only reduces the severity of an illness, but prevents infection altogether.
That level of protection is considered the gold standard, but typically it requires large numbers of antibodies, says Sette. “That is great if that can be achieved, but it’s not necessarily always the case,” he says.
Alongside antibodies, the immune system produces a battalion of T cells that can target viruses. Some of these, known as killer T cells (or CD8+ T cells), seek out and destroy cells that are infected with the virus. Others, called helper T cells (or CD4+ T cells) are important for various immune functions, including stimulating the production of antibodies and killer T cells.
T cells do not prevent infection, because they kick into action only after a virus has infiltrated the body. But they are important for clearing an infection that has already started. In the case of COVID-19, killer T cells could mean the difference between a mild infection and a severe one that requires hospital treatment, says Annika Karlsson, an immunologist at the Karolinska Institute in Stockholm. “If they are able to kill the virus-infected cells before they spread from the upper respiratory tract, it will influence how sick you feel,” she says. They could also reduce transmission by restricting the amount of virus circulating in an infected person, meaning that the person sheds fewer virus particles into the community.
T cells could also be more resistant than antibodies to threats posed by emerging variants. Studies by Sette and his colleagues have shown that people who have been infected with SARS-CoV-2 typically generate T cells that target at least 15–20 different fragments of coronavirus proteins1. But which protein snippets are used as targets can vary widely from person to person, meaning that a population will generate a large variety of T cells that could snare a virus. “That makes it very hard for the virus to mutate to escape cell recognition,” says Sette, “unlike the situation for antibodies.”
So when laboratory tests showed that the 501Y.V2 variant identified in South Africa (also called B.1.351) is partially resistant to antibodies raised against previous coronavirus variants, researchers wondered whether T cells could be less vulnerable to its mutations.
Early results suggest that this might be the case. In a preprint published on 9 February, researchers found that most T-cell responses to coronavirus vaccination or previous infection do not target regions that were mutated in two recently discovered variants, including 501Y.V22. Sette says that his group also has preliminary evidence that the vast majority of T-cell responses are unlikely to be affected by the mutations.
If T cells remain active against the 501Y.V2 variant, they might protect against severe disease, says immunologist John Wherry at the University of Pennsylvania in Philadelphia. But it is hard to know from the data available thus far, he cautions. “We’re trying to infer a lot of scientific and mechanistic information from data that doesn’t really have it to give,” he says. “We’re kind of putting things together and building a bridge across these big gaps.”
Researchers have been analysing clinical-trial data for several coronavirus vaccines, to look for clues as to whether their effectiveness fades in the face of the 501Y.V2 variant. So far, at least three vaccines — a protein vaccine made by Novavax of Gaithersburg, Maryland, a single-shot vaccine made by Johnson & Johnson of New Brunswick, New Jersey, and a vaccine made by AstraZeneca of Cambridge, UK, and the University of Oxford, UK — were less effective at protecting against mild COVID-19 in South Africa, where the 501Y.V2 variant dominates, than in countries where that variant is less common.
In the case of AstraZeneca’s vaccine, the results were particularly striking: the vaccine was only 22% effective against mild COVID-19 in a sample of 2,000 people in South Africa. However, that trial was too small and its participants too young for researchers to draw any conclusions about severe disease, says Shane Crotty, an immunologist at the La Jolla Institute for Immunology.
Some coronavirus vaccine developers are already looking at ways to develop next-generation vaccines that stimulate T cells more effectively. Antibodies detect only proteins outside cells, and many coronavirus vaccines target a protein called spike that decorates the surface of the virus. But the spike protein is “quite variable”, suggesting that it might be prone to mutating, says Karlsson, and raising the risk that emerging variants will be able to evade antibody detection.
T cells, by contrast, can target viral proteins expressed inside infected cells, and some of those proteins are very stable, she says. This raises the possibility of designing vaccines against proteins that mutate less frequently than spike, and incorporating targets from multiple proteins into one vaccine.
Biotechnology firm Gritstone Oncology of Emeryville, California, is designing an experimental vaccine that incorporates the genetic code for fragments of several coronavirus proteins known to elicit T-cell responses, as well as for the full spike protein, to ensure that antibody responses are robust. Clinical trials are due to start in the first quarter of this year.
But Gritstone president Andrew Allen hopes that current vaccines will be effective against new variants, and that his company’s vaccine will never be needed. “We developed this absolutely to prepare for bad scenarios,” he says. “We’re half hoping that everything we did was a waste of time. But it’s good to be ready.”
Should you get the Covid-19 vaccine while pregnant?
Pregnant people might hesitate to get vaccinated because there’s no data on how it works for them. Medical experts lay out what is known and how each person can weigh their own risks and benefits.
For people who are pregnant, the rollout of COVID-19 vaccines is prompting agonizing questions about whether it’s safer to get the vaccine or risk infection. Despite emerging evidence that the vaccines are generally safe and effective, there is virtually no data as to whether that’s true for those who are expecting, even though they are at higher risk of complications from the disease.
The world’s regulatory bodies have at times issued contradictory advice about pregnancy and COVID-19 vaccines. The Centers for Disease Control and Prevention (CDC) has said that the vaccines should be available to pregnant people but ultimately leaves the decision up to expectant parents and their doctors. The World Health Organization (WHO) recommends against it unless the pregnant person is at high risk.
So how does someone make an evidence-based decision about whether it’s safe to get the vaccine in the absence of any safety data? “It all turns on the features of your life,” says Ruth Faden, founder of the Johns Hopkins Berman Institute of Bioethics in Maryland. Each person must balance what is known about the vaccine with what is known about their own risk of getting infected.
Although experts suggest talking throughthese decisions with a medical provider, here’s a look at the facts available, what’s still being sorted out, and why there’s reason to be optimistic.
What we know about past vaccines
Scientists generally know quite a lot about vaccines and pregnancy—although historically it has taken longer to get that evidence than general safety data. Because of the ethical complexities of pregnancy—in which parents and their fetuses face interconnected risks—and fears of legal liability, pregnant people are typically excluded from the randomized clinical trials that are required to obtain approval for a drug or vaccine.
In the past, it has taken years after vaccines are approved for general use to gather enough data to show how they work during pregnancy. Many of these follow-on studies are observational and involve fewer participants. As a result, women who are pregnant may be hesitant to get a vaccine, and doctors may hold off on recommending them.
“What has resulted from this has been decades of essentially unfairness to pregnant women,” says Faden, who also leads the Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) project. Although at times it might make sense to not include expectant parents in early trials, she says, “we’ve been protecting pregnant women to death.”
But scientists have accumulated incontrovertible evidence that certain vaccines are safe, effective and, in some cases, direly needed. Today, the CDC highly encourages pregnant people to get vaccinations against influenza, which is known to cause severe complications in pregnant women. Medical experts also advise getting the vaccine for pertussis (or whooping cough), which can be fatal to newborns. Expectant people can also receive immunizations for a handful of other diseases, including hepatitis and meningitis.
Lessons from those vaccines have shown that there’s no reason to worry about the types of shots that use an inactivated virus to elicit an immune response, since they cannot infect either the parent or the baby, says Geeta Swamy, associate professor of obstetrics and gynecology at the Duke University School of Medicine in North Carolina and a leading maternal immunization researcher.
On the other hand, vaccines using a small amount of live virus—such as the one for measles, mumps, and rubella and the one for chickenpox—can cause low-grade infections that some scientists worry could harm a fetus. But, Swamy says, “even that is based on theoretical risk concerns,” not on evidence that it occurs.
What’s different about the COVID-19 vaccines
The Moderna and Pfizer-BioNTech vaccines for COVID-19 pose a new challenge. Until now, the messenger RNA platform they use had not been licensed for human use. As such, the only pregnancy-related data available are from preclinical studies in laboratory animals and a handful of clinical trial participants who later discovered they were pregnant.
But we do know a fair amount about how the mRNA technology works. Instead of using inactivated or live virus, these vaccines contain snippets of genetic code encased in lipids, or fat globules, that protect the code from degrading. Once injected, the mRNA instructs cells to produce the SARS-CoV-2 spike protein, which triggers the body’s immune response.
Theoretically, all of this is promising because, like past vaccines, it does not involve a live virus. “Everything that is understood to be biologically the case about mRNA vaccines is incredibly reassuring,” Faden says. “It shouldn’t have any impact on pregnancy or pregnancy outcomes.”
Anthony Fauci, White House chief medical adviser, has also said that the data “so far has no red flags” for pregnant people.
Still, scientists have raised questions about how the mRNA vaccines will work in reality. The biggest concern is whether mRNA can cross the placenta and generate the spike protein in the fetus. It wouldn’t necessarily be harmful if it did—and would not cause birth defects—but the worry is that the fetus could experience side effects including pain, swelling, and fever. Swamy says the animal studies showed no signs of physical side effects, but that is yet to be tested in humans.
Side effects in the mother may also be an issue. Christina Chambers, a perinatal epidemiologist at the University of California, San Diego, is conducting a study of COVID-19 vaccinated pregnant women. She notes that it can be harmful to the baby when a pregnant woman runs a high fever. “If that is a side effect, you’d want to pay attention to that and talk to your provider about taking something to reduce the fever,” she says.
There are clinical trials in the pipeline to investigate the effects of the vaccines in pregnant women. Faden wishes these trials had started as soon as the vaccines received FDA approval, but she points out that the process is still moving more rapidly than it has in the past.
“We used to feel like one or two lonely drums out there, beating our drums in this vast silence,” she says. “Now we’ve got like a whole percussion section calling for more data and the inclusion of pregnant women in the rollout of the vaccine. And that’s a really good thing.”
The risks of infection
On the flip side, we do know plenty about the risks getting COVID-19 poses to expectant parents. “There’s no question at all that pregnant women fare worse than not-pregnant people,” Swamy says.
Studies have shown that pregnant people with COVID-19 are at an increased risk for hospitalization, ICU admission, and mechanical ventilation. In January, a study published in the journal JAMA Internal Medicine found that COVID-19 was associated with higher odds of blood pressure problems and premature birth, though there weren’t greater chances of stillbirth. And a study in October found that one in four pregnant people may be COVID-19 “long-haulers,” whose symptoms can linger for weeks or even months.
But the risk of severe illness is lower for the expecting than for other high-risk groups, such as the elderly or those with heart disease. So it’s critical to look at individual factors that increase a person’s individual risks—including numbers of daily contacts, access to testing and high-quality PPE, and comorbidities such as asthma or obesity—and whether there’s anything that can be done to reduce them.
Timing has to be taken into consideration, too. Swamy says there’s no evidence that a vaccine can cause developmental problems or miscarriage in the first trimester. But women at lower risk of infection may choose not to get vaccinated during that period, which is vital for fetal organ development and is when miscarriages typically occur. (The influenza vaccine is safe at any point during pregnancy.)
For pregnant women who are at high risk of exposure and who don’t have the option of reducing that risk, it may make sense to consider getting the vaccine as soon as they’re eligible. But to find out for sure, Chambers says, “the urgency is to get the data on people who are getting vaccinated.”
What we’re still trying to find out
There’s reason to hope that scientists will soon have a better understanding of how the COVID-19 vaccines work during pregnancy. In the near term, scientists are looking forward to the data from pregnant health-care workers who began taking the vaccines in December. Faden says that data should be robust, since more than 15,000 pregnancies among the vaccinated were reported to the CDC as of January 20.
Beyond the mRNA vaccines, there are some new options on the horizon. Johnson & Johnson submitted its vaccine for FDA approval on February 4, while AstraZeneca and Novavax have recently released critical phase three trial data. All three vaccines rely on technologies that have been studied in pregnant women in the past, which Swamy says could provide further reassurance.
Recent studies have also suggested that there could be extra benefits to vaccination while pregnant. One study published in the journal JAMA Pediatrics showed that women who have been infected with COVID-19 efficiently transfer protective antibodies to their babies—particularly if infected earlier in the pregnancy. The study does not suggest this transfer will happen after vaccination, notes co-author Karen Puopolo, attending neonatologist at Pennsylvania Hospital. But Swamy says it’s good news that antibodies are regularly crossing the placenta in natural infection, and that she expects vaccination would have a similar response.
“It tells us that vaccinating women could have that kind of two-for-the-price of-one,” she says, “that by vaccinating women we’re also providing some benefit during early childhood.”
The vaccine alternatives for people with compromised immune systems
Drug makers are increasingly turning to monoclonal antibodies to protect the millions of people who may not be able to use vaccines. But questions swirl about their cost and long-term viability.
As the COVID-19 vaccine rollout gathers pace, a population is at risk of being left behind: the millions of people around the globe who lack fully functional immune systems.
While the exact number of the immunocompromised worldwide is unknown, estimates suggest that about 10 million live in the U.S. alone, or around 3 percent of the national population. The number encompasses a diverse range of vulnerabilities, including rare genetic immune deficiencies, chronic illnesses that impair the immune system such as rheumatoid arthritis, and cancer and organ-transplant patients who must take immune-suppressing medications.
For them, vaccines may not be as effective, because they are less capable of making their own antibodies to neutralize the SARS-CoV-2 virus. Instead, pharmaceutical companies around the world are racing to develop alternative treatments that bypass the immune system altogether.
The most common option is called monoclonal antibody treatments. These artificially generated antibodies mimic the body’s natural immune response by binding to key sites on the virus’ spike protein, preventing it entering cells and reproducing. Companies including AstraZeneca, Regeneron, and Eli Lilly are currently testing whether monoclonal antibodies can protect immunocompromised people from SARS-CoV-2.
“You often find that patients who have had bone marrow transplants end up getting terrible flu and other infections, which they can’t clear without additional help,” says Nicky Longley, an infectious diseases consultant at University College London Hospitals. “It was these heavily immune-suppressed populations who did very badly during the first wave of COVID-19.”
In addition, preventing immunocompromised people from getting infected will be a key part of keeping the disease in check in the long run, says Andrew Ustianowski, an infectious disease specialist at the U.K.’s National Institute for Health Research.
“If we want to control this virus and get back into normal life, then being able to protect everybody, so we don’t have ongoing transmission in subgroups of the population, is important,” he says.
But while many scientists are excited about the potential of monoclonal antibodies to address gaps in the world’s vaccination programs, questions remain. The coming months will tell us whether these treatments are sufficiently cost-effective to be used on a large scale, if they can really provide adequate protection for months at a time, and whether using monoclonal antibodies may inadvertently do more harm than good.
A potential ‘game changer’
In the past, the only alternative means of protecting immunocompromised people during viral outbreaks was a product called intravenous immunoglobulin, or IVIG. Taken from the blood plasma of healthy donors, infusions of IVIG are one way of supplying patients with natural antibodies against a broad range of infections most people are commonly exposed to.
But supplies are limited, and IVIG is expensive, with a single patient’s cost sometimes reaching up to $30,000 a year. It also provides protection for only three weeks at a time, as the antibody concentrations in the product slowly wane, and it isn’t guaranteed to work against any specific virus.
“If you could get them a more targeted form of passive immunization which is made synthetically, it could be a real game changer,” says Longley.
However, creating monoclonal antibodies is also a painstaking process. It involves first extracting a broad range of antibodies from the blood of recovering patients, testing them in animals to identify which are best at neutralizing the virus, cloning the chosen ones in the lab, and then growing them in sufficient quantities in gigantic steel bioreactors.
Because of the time it takes to make a finished product, monoclonal antibodies were long considered impractical against viruses. Over the past decade, they have been most commonly used as treatments for cancer and autoimmune diseases.
“Viruses mutate rapidly, so scientists might well find the perfect site, begin production of the perfect monoclonal antibody, and then all of a sudden the virus mutates so the antibody doesn’t bind as well, or worse, doesn’t bind at all,” says Rodney Rohde, professor of clinical laboratory science at Texas State University.
But various research programs have driven a number of technological advances in recent years. Antibodies can now be isolated from convalescent patients in less than a month, while virologists have got progressively better both at identifying sites in the viral genome that are less likely to mutate. Five years ago, the quickest time frame for creating monoclonal antibodies was 18 months. Today, it’s about 10 months.
Even more crucial, scientists have tweaked the underlying structure of monoclonal antibodies, making it harder for the body to remove them from the bloodstream—meaning they can potentially last for months at a time rather than weeks.
These developments had initiated renewed interest in monoclonal antibodies as virus fighters even before the COVID-19 pandemic. A study published in December 2019 found that such treatments reduced mortality during an Ebola outbreak in the Democratic Republic of the Congo by 15 percent. And that autumn, the National Institute of Allergy and Infectious Diseases (NIAD) funded a research program to assess the viability of identifying monoclonal antibodies for use against seasonal influenza.
Now, Ustianowski is leading a global clinical trial called PROVENT, in conjunction with AstraZeneca, that’s attempting to find monoclonal antibodies that will work against SARS-CoV-2. In the PROVENT trial, 5,000 people around the world with various immune deficiencies will receive a dose of either a monoclonal antibody-based cocktail or a placebo. They’ll be followed over the course of a year to see whether the treatment prevents them getting COVID-19, and how long protection lasts.
If PROVENT is successful, Longley suggests that the treatment could also be used to protect people who produced too few natural antibodies in response to the vaccine, such as elderly individuals whose immune systems are not as active. This would mean that even though they have had the vaccine, they are not protected. “Vaccines take a bit of time to build immunity in the body, but injecting monoclonal antibodies should work immediately, so it could work as a preventative measure,” she says.
Both Eli Lilly and Regeneron are already looking at whether these antibodies can offer protection to nursing home residents in areas where the vaccine rollout has been delayed. Last week, Eli Lilly released data from a phase three trial which showed that its monoclonal antibody treatment bamlanivimab reduced the risk of contracting COVID-19 by up to 80 percent in care facilities.
In the longer term, with COVID-19 widely expected to develop into an endemic disease, Ustianowski predicts that monoclonal antibodies could be used as periodic boosters every six months to a year to protect vulnerable immunocompromised people even after herd immunity has been achieved in the general population.
“Coronavirus is not going to disappear from the Earth over the next few years,” he says. “For those at ongoing risk, I could imagine them receiving these periodic injections.”
Fears of an access gap
One of the major hurdles for monoclonal antibodies has always been the staggering costs. While seven of the top 10 best-selling drugs of 2019 were monoclonal antibodies for cancer and autoimmune diseases, one study found the average annual price per patient worked out to be $96,731. Access has therefore been restricted to only the wealthiest nations. Currently, 80 percent of global sales of licensed therapeutic antibodies are in the U.S., Europe, and Canada.
Pharmaceutical companies making monoclonal antibodies for COVID-19 insist that the price tag per dose will not be in the tens of thousands.
“We’re not ever going to be talking about a price for these drugs that’s of the order of $100,000,” says Alexandra Bowie, a spokesperson for Regeneron. “If you look at what we’ve done so far, the price per dose for the contracts we’ve signed with the U.S. government is more on the order of $2,000.”
However, $2,000 is still significantly more expensive than vaccinations, and the price may prove unaffordable in many parts of the world. By comparison, the Pfizer-BioNTech jab costs $20 per dose, and the AstraZeneca vaccine comes in at just $4 per dose. On balance, though, Ustianowski argues that it’s better to have the drugs available for the smaller portion of the population that really needs them.
“This isn’t for everybody; it’s just for those that can’t have the cheaper and more cost-effective vaccines,” Ustianowski says. “If you’re talking about a subset of individuals, then it’s easier to encompass that cost.”
Steps are already being taken to address the potential access gap. Bowie says that the U.S. government has so far committed to making 1.5 million doses ordered from Regeneron free for patients, regardless of whether they have health insurance. Currently this batch is being used as treatments for non-hospitalized patients with mild to moderate cases of COVID-19, though future supplies could be used as passive immunizations pending regulatory approval. In addition, she says a donation strategy will be put in place specifically for lower- and middle-income countries, in conjunction with their manufacturing partner, Roche.
Jens Lundgren, an infectious disease physician at the University of Copenhagen, also expects pharmaceutical companies will strike deals with generic drug manufacturers in lower-income nations.
“The actual production price once you have the antibody clones developed is very minimal,” he says. “This is why you can already see generic manufacturers in Asia producing monoclonal antibodies for some autoimmune diseases and selling them at a very low price per dose.”
But cost is only one of the concerns surrounding monoclonal antibodies. There are safety issues to consider, which will be monitored closely in both the PROVENT trial and other clinical trials.
One of these is a troubling phenomenon called antibody-dependent enhancement, which was observed by scientists trying to create vaccines against dengue fever. Receptors on the tail region of antibodies normally bind to immune cells, allowing antibodies to activate the immune system. In some cases, though, it seems these receptors can accidentally attach to viruses too, allowing the pathogens to access cells rather than stopping them. Monoclonal antibody manufacturers are now taking steps to minimize that likelihood, such as engineering receptors with mutations that limit the risk of virus binding.
Another major issue is whether monoclonal antibodies could quickly become obsolete as new variants of SARS-CoV-2 emerge, something which is already proving to be a challenge. Recent studies conducted in the U.S., South Africa, and China suggest that Eli Lilly and GSK’s products, which each consist of a single monoclonal antibody, may not work against one or more of the three major variants of SARS-CoV-2. These papers were released on the bioRxiv preprint server and are not yet peer reviewed.
Regeneron’s product consists of a cocktail of two monoclonal antibodies, and the data suggest it is still effective against the variants. Eli Lilly and GSK are testing whether combining their products into an antibody cocktail can improve efficacy. There is no data yet for how AstraZeneca’s monoclonal antibody product fares against the variants.
Another theory suggests that using these products as emergency treatments for hospitalized patients could encourage viral evolution. A recent lab study found that the virus is indeed capable of deliberately mutating to evade multiple antibodies found in convalescent plasma. If monoclonal antibodies derived from this plasma do not immediately inactivate the virus, they may encourage it to mutate further, creating new variants.
At the same time, many scientists involved in monoclonal antibody research believe that greater use of them as passive immunizations in vulnerable populations could actually help stop new variants from appearing.
“For most of 2020, the majority of the population was immunologically naïve to this virus, and thus the virus was freely circulating among vulnerable individuals, including the immunocompromised individuals,” says Ali Ellebedy, assistant professor of pathology and immunology at Washington University School of Medicine. In the immunocompromised, the virus can keep replicating—and thus mutating—in the same person for weeks, providing what Ellebedy calls the “perfect platform” for new variants to emerge. In theory, protecting more of these vulnerable people can thus limit the virus’s chances of spawning new variants.
For the scientists leading the PROVENT trial, much depends on the coming months and whether monoclonal antibodies can be shown to provide long-lasting protection in vulnerable populations. If so, they feel this will open doors for monoclonal antibodies protecting more immunocompromised patients as part of standard medical care.
“If effective, I could see these immunizations being used in some cancer patients, for example those who are being treated for acute leukeumias,” says Longley. “They can’t have vaccines, and you’re worried about them being exposed during a flu or a measles outbreak. This could keep them safe until they have their curative treatment.”
Why your arm might be sore after getting a vaccine
For most COVID-19 vaccine recipients, the poke of the needle is no big deal. In the hours afterwards, however, many go on to develop sore arms, according to anecdotal reports and published data.
That common side effect is not unique to COVID-19 vaccines. But as the United States undergoes its first mass vaccination campaign in recent memory, the widespread prevalence of arm pain is sparking questions about why certain shots hurt so much, why some people feel more pain than others, and why some don’t feel any pain at all.
The good news, experts say, is that arm pain and even rashes are normal responses to the injection of foreign substances into our bodies. “Getting that reaction at the site is exactly what we would expect a vaccine to do that is trying to mimic a pathogen without causing the disease,” says Deborah Fuller, a vaccinologist at the University of Washington School of Medicine, in Seattle.
Given the many intricacies of the immune system and individual quirks, not feeling pain is normal, too, says William Moss, an epidemiologist and executive director of the International Vaccine Access Center at the Johns Hopkins School of Public Health in Baltimore. “People can develop protective immune responses and not have any of that kind of local reaction,” he says.
A variety of vaccines are notorious for the soreness they cause around the injection site, and the explanation for why begins with so-called antigen-presenting cells. These cells are constantly on the prowl in our muscles, skin, and other tissues. When they detect a foreign invader, they set off a chain reaction that eventually produces antibodies and long-lasting protection against specific pathogens. That process, known as the adaptive immune response, can take a week or two to ramp up.
Meanwhile, within minutes or even seconds of getting vaccinated or detecting a virus, antigen-presenting cells also send out “danger” signals that, Moss says, essentially say, “‘Hey, there’s something here that doesn’t belong. You guys should come here. We should get rid of it.’”
This rapid reaction, known as the innate immune response, involves a slew of immune cells that arrive on the scene and produce proteins known as cytokines, chemokines, and prostaglandins, which recruit yet more immune cells and have all sorts of physical effects, Fuller says. Cytokines dilate blood vessels to increase blood flow, causing swelling and redness. They can also irritate nerves, causing pain. Cytokines and chemokines induce inflammation, which is also painful. Prostaglandins interact directly with local pain receptors.
The innate immune response doesn’t stop at the arm. For some people, the same inflammatory process also can cause fevers, body aches, joint pain, rashes or headaches.
The reason some vaccines cause more symptoms than others—a tendency called reactogenicity—is because of the strategies and ingredients they employ. The vaccine for measles, mumps, and rubella (MMR), for example, is made from live, weakened forms of the viruses that intentionally cause a mild form of infection and stimulate the body’s innate immune response, leading to a variety of symptoms, including sore arms. Other vaccines, including some flu shots, introduce inactivated viruses. The hepatitis B vaccine presents parts of the virus along with chemicals called adjuvants that are designed to get antigen-presenting cells riled up and boost the adaptive immune response.
Those substances, Fuller says, “are the first trigger your body gets to say, ‘Something is going on here, and I need to respond to it.’”
All three FDA-approved COVID-19 vaccines are delivered via a needle into the arm, and all cause the same kind of poking pain that comes with a quick stab. After that, their post-vaccination arm-soreness profiles vary, according to company data compiled by the Centers for Disease Control and Prevention.
After the first dose of the two-shot Moderna regimen, 87 percent of people under 65 years old and 74 percent of those 65 and up in clinical trials reported localized pain, echoing research that shows a decline in immune reactivity with age. After the second shot, those numbers rose to 90 percent of the younger age group and 83 percent of older people.
The first Pfizer shot, likewise, caused a lot of sore arms in trials: 83 percent of people up to age 55, and 71 percent in older people. Shot-two soreness occurred in 78 percent of the younger group and 66 percent of the older one.
The one-dose Johnson & Johnson vaccine caused less arm pain—59 percent of people under 60 and 33 percent of older people.
The elevated rates of arm pain with the Pfizer and Moderna vaccines might have something to do with technology they use, Fuller says. Unlike J&J, which uses a modified virus to deliver a gene that directs our cells to make the SARS-CoV-2’s spike protein, Pfizer in Madera deliver instructions for making the protein via mRNA. Researchers have long known that RNA, which some viruses use to carry their genetic material, is a potent trigger of the innate immune system.
In fact, she says, when scientists started considering mRNA as a vaccine strategy some 30 years ago, they rejected the idea, in part because of concerns that it would overstimulate inflammatory pathways. They were also too unstable to work. More recent breakthroughs in the ability to modify mRNA and encapsulate it in lipid nanoparticle coatings made the new generation of vaccines possible, but common adverse reactions remain relatively high. The nanoparticle coating itself acts as an adjuvant that likely contributes to local reactions, Fuller adds.
A more surprising reaction
Soon after the Moderna vaccine was approved in December, allergist and researcher Kimberly Blumenthal began receiving photographs of arms from colleagues at Massachusetts General Hospital in Boston. The photos showed large red splotches around patients’ injection sites. Some people had a second rash below the first. Some had red marks shaped like ringed targets. Some rashes appeared on elbows and hands.
After accumulating a dozen images, Blumenthal wrote a letter for the New England Journal of Medicine with the goal of alerting physicians—and reassuring them—about the potential for delayed reactions to the vaccine. Some doctors were prescribing antibiotics for suspected infections, but the pattern she saw suggested that antibiotics were not necessary.
Unlike the rare and dangerous anaphylactic reaction that can happen immediately after injection, delayed rashes don’t usually require treatment, Blumenthal says. In a biopsy of one patient, she and colleagues found a variety of T cells, suggesting a type of hypersensitivity. Delayed rashes are known to show up occasionally after other vaccines too, she adds, and they can be a sign of hypersensitivity or a normal part of the immune response. Researchers don’t yet know which is happening with the Moderna vaccine. In this case, they may appear especially common because so many people are getting vaccinated at once.
Still, late-onset rashes might be more common than official data suggest. In clinical trials, Moderna reported them in 0.8 percent of vaccine recipients four or more days after the first shot, and in 0.2 percent of people after the second dose. But delayed rashes tend to appear an average of seven or eight days after injection, and initial trials weren’t designed to pick up on all symptoms that showed up that late, Blumenthal says, likely because they weren’t expecting them.
She has created a registry for physicians to report delayed rashes and is working on one for patients, in order to understand the range of what they can look like and detect any patterns about which rashes might be more worrisome. “Since we published this,” she says, “my in-box has been flooded with photos.”
Who feels the pain?
Among the people I know who have been vaccinated so far, some have felt little to no soreness. Others couldn’t sleep for days because of the pain. One friend who got the Pfizer shot said it felt like he had been punched by a professional boxer.
For symptoms like arm pain, individual variation is the norm, and studies suggest multiple explanations. Age can diminish immune reactions, for example. So can higher BMIs, found a recent preprint study.
Genetics likely plays a role in varied and complex ways, experts say. And gender matters, too. In addition to a vast literature on sex differences and immunity, women appear to experience more side effects then men in response to a COVID-19 vaccine, according to emerging evidence, even though men seem to suffer a larger impact from the virus itself.
Pain perception is another X-factor. Everyone processes pain signals differently. And fear and anxiety can exacerbate the feelings of pain, says Anna Taddio, a pharmacy professor who studies pain related to medical procedures in children at the University of Toronto.
Studies show that fear of needles is an important barrier to vaccination for a significant number of people. A quarter of adults reported being afraid of needles in a 2012 study by Taddio and colleagues. According to one new analysis of 119 published studies, 16 percent of adults and 27 percent of hospital employees avoided flu shots because of needle fears.
Amidst efforts to get people vaccinated as quickly as possible, public health officials often overlook opportunities to make the experience more positive, says Taddio, who has developed an approach for reducing fear and promoting coping skills to improve the vaccination experience.
And there are plenty of simple ways to make people feel less anxious about needles. Helpful strategies, according to Taddio’s approach, can include reminding people to wear a short-sleeve shirt to the clinic to make it easy to access their arms; allowing them to bring someone for support; encouraging the use of distractions; deep breathing and topical anesthetics; and inviting people to ask questions so that they feel informed and prepared.
She also recommends that providers and public health officials talk about vaccines in neutral terms—emphasizing the ability to get protection from the coronavirus instead of scaring people with phrases like “shots in arms.”
“You can talk all you want about the COVID vaccines and how safe they are, but we’re not addressing the underlying issue for a whole chunk of people,” she says. “Where do you hear about how we’re going to make this comfortable for you?”
What we know so far about the effort to vaccinate children
To achieve herd immunity, experts say kids need to get vaccinated, reducing the virus’s ability to spread.
Millions of parents breathed a collective sigh of relief this week as the preliminary results of the Pfizer/BioNTech COVID-19 vaccine trial in 12 to 15 year-olds revealed what so many had been hoping for: The vaccine works in teens too.
“Jubilation—that was my response,” says Nia Heard-Garris, an attending pediatrician at Lurie Children’s in Chicago and assistant professor of pediatrics at Northwestern University Feinberg School of Medicine—and a parent herself. She wasn’t the only one feeling that way.
With nearly a third of the country having already received at least one dose of a COVID-19 vaccine and more than 2 million vaccinations occurring every day, the cloud of anxiety that has plagued the nation for the past year is finally beginning to lift. The end of the pandemic is in sight. Attaining herd immunity—the point at which transmission stops because the virus doesn’t have enough susceptible hosts to infect—now feels like a real possibility. But there’s a catch: The children must be vaccinated.
“We’ll never get to that population level of herd immunity until we vaccinate kids,” says Jennifer Nayak, division chief of pediatric infectious diseases at the University of Rochester Medical Center in New York. She was also “incredibly excited” by the Pfizer/BioNTech results.
“The fact that children are mounting a robust response to the vaccine is very positive and really bodes well that hopefully we’ll see the same thing as we move into the lower age groups in testing vaccines,” Nayak says.
With kids making up about 22 percent of the population in the United States, their immunity is crucial to reaching a national threshold of immunity, which experts estimate to range from 70 up to 90 percent, explains Tara C. Smith, an epidemiologist at Kent State University in Ohio.
Even if the U.S. reached that range without children, the disease would continue spreading because it’s herd immunity at the local, not national, level that matters, says Dominique Heinke, a postdoctoral researcher and epidemiologist in North Carolina. Even in a highly vaccinated population, unvaccinated people clustering together and interacting allows the virus to continue circulating, especially if they congregate indoors without masks and social distancing.
“That’s exactly what we see with kids’ social structures,” Heinke says. “Even if you’re at ‘herd immunity’ levels for adults, if the kids aren’t immune, either through natural immunity or through vaccination, then those chains of transmission aren’t getting broken and you’ve got a whole group of susceptible individuals where the virus can continue to transmit.”
The more transmission continues, the more the virus replicates and evolves, and the more opportunities it has to accrue mutations. “My biggest concern is the emergence of new variants,” Smith says. “We already have several here, and I’m concerned we’ll have more that could potentially escape immunity. I suspect we will see kids becoming a more prominent reservoir of this virus as more adults are protected by vaccination.”
Variants could keep the virus circulating
The variants that originated in South Africa (B.1.351) and Brazil (P.1), can infect people with immunity from previous infections, says Vaughn Cooper, a microbiologist and molecular geneticist at the University of Pittsburgh.
“That basically creates more chances for more infections in adults and more opportunities for transmission and subsequent evolution,” Cooper says. “To handle an evolutionary problem, you have to handle the number of evolutionary events. We’re not going to be able to stop that until we stop transmission among kids.”
Cooper also worries that the U.K. B.1.1.7 variant, which may be anywhere from 43 to 90 percent more contagious, and others like it will become the predominant viruses in the U.S. because they spread more easily. Since herd immunity is based on the reproduction number—the average number of infections that result from one infected person—a more contagious variant can also boost the level of herd immunity required to stop transmission, Smith says.
Unvaccinated and immune-compromised adults would therefore continue to be at risk for severe disease and death. And the risk is not zero for children either.
Kids left behind in vaccine trials
An estimated 3.4 million infections have occurred in children, according to the American Academy of Pediatrics, accounting for more than 13 percent of all U.S. cases. Children’s risk of death from COVID-19 is extraordinarily low—under 0.03 percent—and the most common complication, Multisystem Inflammatory Syndrome in Children is also rare, with just over 2,600 cases and 33 deaths through the end of February. But those numbers will increase as children make up an increasing proportion of infections.
Hence the frustration among some experts that it has taken so long to get pediatric vaccine trials running.
“What’s been hard from a pediatrician and a parent perspective is that we’ve been so excited about the COVID-19 vaccine and what this means for our lives, but really, we have left children out of that celebration and excitement,” Heard-Garris says, the attending pediatrician at Lurie Children’s in Chicago and assistant professor of pediatrics at Northwestern University Feinberg School of Medicine. “We’re a little late to the party. We should have thought about including kids from day one.”
In addition to their trial in adolescents, Pfizer is also testing their vaccine in 4,500 children ages 6 months to 11 years old. Moderna has an adolescent trial in progress and began recruiting 6,750 participants ages 6 months to 11 years old for another. AstraZeneca began a trial last month for those aged 6 to 17 years old, and Johnson & Johnson is planning a pediatric trial.
While there’s a good chance the FDA will authorize the Pfizer/BioNTech vaccine for that age group before school starts, results from the other trials aren’t likely until at least fall of 2021.
“What I’m worried about is that we are not going to roll these vaccines out fast enough to kids,” says Sallie Permar, chair of pediatrics at Weill Cornell Medicine and New York-Presbyterian Komansky Children’s Hospital. “We’re going to try to get them in their schools and their normal lives, which they need because we have a crisis on our hands in terms of mental health and obesity and all the things that came with social isolation and the shutdown. They may not be showing up with severe COVID disease, but they’re showing up with the symptoms of the social isolation in our health system.”
Weighing risks of social isolation against risk of disease
Returning to school before vaccines are available for all children means tough decisions for communities and families. Pediatric experts agree that returning to in-person school next fall must be a priority.
Joelle Simpson, interim division chief of emergency medicine at Children’s National in Washington, DC, says children need to be in classrooms next year whether or not they can get vaccines before school starts. She acknowledges how much researchers still don’t know about COVID-19 infections in children, including whether long-term effects are possible. But the evidence is clear regarding the negative impact on kids’ mental health, socialization, and development when they’re not in a school environment.
“We are certainly seeing an uptick in pretty severe mental health presentations as well as kids who have injuries from abuse, whether that be mental health or physical,” Simpsons says. “We have a school system that allows us to have trained eyes on kids to identify things like learning disorders, abuse and chronic conditions, which frankly cannot happen when they’re at home.”
Research has shown that wearing masks and maintaining three-feet distancing works well to prevent infections, Permar said. But questions remain regarding how well all schools can implement those measures and how officials will respond when infections occur.
“It would be amazing if every school had the resources they needed to be there five days a week and also offer virtual options for parents or caregivers that did not feel comfortable sending their kids back,” Heard-Garris says. “I don’t think that’ going to be a reality. If we see upticks in infection rates, then schools are going to go back the other way and kids will go back home, and that isolation and loneliness will get worse. If our children aren’t extended the vaccine or we don’t reach herd immunity, I worry those impacts are going to get bigger and bigger.”
Communities will need to strike a balance between the substantial benefits of in-person school and activities, and the risk of infection in that region and of individual populations, says Christopher Golden, an associate professor of pediatrics at Johns Hopkins University School of Medicine.
“We have not seen a spike in the number of kids that have had severe infections, but there are populations that may be at risk,” Golden says. “We’ve done a very important job of keeping people isolated and quarantined, but we still have seen that African American and Latino children and children with chronic medical conditions are at higher risk, so if we do open things back up again, there is the possibility that infections could increase and be more severe in at-risk populations.”
Inequities in vaccine distribution could worsen disparities
Even when pediatric vaccines do become available, disparities in some of these vulnerable populations may increase.
“It’s troubling,” Heard-Garris says, because many cities already are not equitably distributing vaccines to the racial and ethnic minority populations at highest risk. “One of the things we worry about when we talk about equity is that you can widen disparities inadvertently by offering certain interventions, such as offering a vaccine that a large population either can’t get or has concerns about.”
Experts also worry about vaccine hesitancy among parents, especially since no previous vaccine approved for kids older than toddlers has achieved coverage rates of more than 50 percent, Permar says. The longer it takes for vaccines to become available for children, the longer it will take to address that hesitancy and ultimately vaccinate enough children to make headway toward herd immunity.
“This virus isn’t going away, ever, but I think the pandemic, the mess that we’re in right now, it will have a very long and painful tail—many years—if we don’t vaccinate kids,” Cooper says.
o until widespread vaccination in kids returns them to normal classrooms, the rest of the country won’t be returning to true normal either.
“We’ll still have to have a lot of mitigation measures in place,” Heinke says. “It’s still going to be a matter of wearing masks, remaining distanced, probably limitations on the number of people in buildings and ventilation still being very important. To some extent, individuals will be able to live in a more normal existence if they’re vaccinated, but the whole society won’t be able to go back without vaccinating children.”
Why kids need their own COVID-19 vaccine trials
Adolescents are being tested now. Younger children will be next. Why did vaccine manufacturers wait to study them?
In January, Megan Egbert saw a post on her Facebook feed that COVID-19 vaccine manufacturer Moderna was recruiting volunteers for a clinical trial in adolescents. She quickly thought about her two daughters, ages 14 and 12.
Like most teenagers, the girls had been through a tough year of remote learning and missed activities. Egbert, a librarian from Boise, Idaho, hoped that participating in the clinical trial was a way for her daughters to get access to the vaccine, which so far has been authorized for use only in adults. (The Moderna vaccine is cleared for ages 18 and older; the age cutoff for the other vaccine authorized in the U.S., from Pfizer-BioNTech, is 16.)
Her daughters were taller than most adults, so she didn’t think they would be at risk to take the regular-size dose that was being tested. The girls quickly agreed to the idea; a few weeks later, they received their first shot, with a two-in-three chance that it was the real vaccine instead of a placebo.
A local television station interviewed the sisters, who had become “mini celebrities” at school for participating in the trial, says Egbert. The next day, she checked the link to the news report on Facebook and found hundreds of comments. While some hailed the sisters as “brave young ladies,” others questioned their parents’ judgment.
“People were saying we were using our kids as guinea pigs,” says Egbert. “They were saying it’s not for teens until it’s been tested.” But that raises a long-standing quandary of pediatric medicine: How can scientists know the vaccines are safe for children unless they test them on actual children? And if children can benefit from the vaccine and play an important role is establishing herd immunity, why have pharmaceutical companies waited to study them?
Different immune systems
The U.S. Food and Drug Administration requires that new vaccines be independently studied in children. Children’s immune systems are still maturing and are unpredictable, so they might react to the coronavirus differently or have side effects that don’t occur in adults.
“They might respond better or worse,” says James Campbell, professor of pediatrics at the University of Maryland School of Medicine’s Center for Vaccine Development and Global Health. “Until you do the study with the vaccine, you don’t know what will happen.”
Despite early perceptions that the pandemic has largely spared U.S. children, the cumulative data reveal a different story. As of February 11, up to 2.3 percent of the more than three million children who have tested positive for COVID-19 were hospitalized, and at least 241 children have died.
While vaccination can protect children from becoming infected with—and spreading—COVID-19, pediatricians also hope that it will prevent a dangerous and rare disorder known as Multisystem Inflammatory Syndrome in Children, which has been documented in coronavirus patients. The disorder can involve inflammation in several vital body parts, including the heart, lungs, and brain.
“I’m seeing these inflammatory conditions constantly in the hospital and am worried,” says Joseph Domachowske, professor of pediatrics at State University of New York Upstate University in Syracuse. “If we can prevent the onset of the infection itself, we can prevent the post-infection consequences.”
Last fall, the influential American Academy of Pediatricians called for children to be included in COVID-19 vaccine trials, and many parents are eagerly waiting to see if vaccinations will be available before the start of the school year.
Several trials of COVID-19 vaccines involving adolescents are already underway. Pfizer-BioNTech is testing its coronavirus vaccine on 2,259 children between 12 and 15. Moderna is enrolling 3,000 participants ages 12 to 17, and Johnson & Johnson has said it will launch a similar trial if its vaccine candidate receives emergency authorization from the FDA.
The initial vaccine data for the adolescent groups could come as early as the summer. Data for younger children could be available the following year. Once that data is in, the companies will conduct additional trials with children as young as six months.
Building on adult results
Despite the urgency, Campbell says the staggered approach is a prudent one for COVID-19 vaccines, because children aren’t in the highest risk group. One recent Icelandic study of 40,000 people found that children under 15 were half as likely to get the coronavirus as adults and half as likely to spread it.
So-called “age de-escalation” is a common strategy in drug development, especially when a disease is more severe in adults, according to Campbell. For example, he’s studying a universal influenza vaccine that was tested in adults first and yielded promising results. Now he’s starting trials with children in three staggered age groups so he can compare the side effects, dosage levels, and immune responses.
One advantage of studying adolescents immediately after adults is that researchers can build on the track record of adult volunteers. During the FDA review process of the Pfizer-BioNTech vaccine in December, the agency looked at data from 21,720 people who’d taken the vaccine as part of the phase three study. That data clearly showed that the vaccine is 94-percent effective at preventing COVID-19.
“We don’t need more efficacy data,” says Robert Frenck, director of the Vaccine Research Center at Cincinnati Children’s Hospital, who’s also the principal investigator for the Pfizer-BioNTech vaccine trial there. “We know it’s 94 percent. We think the immune response will translate.”
That’s why investigators are studying a far smaller number of adolescents to evaluate vaccine safety and validate the adult results. The concept is known as an immunological bridge: Since they know the vaccine’s efficacy from adult trials, they simply need to evaluate whether adolescents who received the vaccine also successfully produce antibodies to ward off future COVID-19 infections.
It also makes sense to target adolescents first, since they’re more likely to get infected than their younger peers. In one review of pediatric COVID-19 cases, children ages 12 to 17 made up 63 percent of cases, while children five to 11 accounted for just 37 percent.
Because children’s immune systems develop over time, evaluating COVID-19 vaccines in younger children will require a new strategy altogether to see if they need a different formulation or dosage, says Domachowske, who’s supervising pediatric trials for Pfizer-BioNTech at SUNY Upstate University.
“Children are most certainly not just small adults,” he says. Although children reach adult-like levels of immunity by age six, that pace differs from child to child based on genetics and environment.
In the Pfizer-BioNTech trial of children ages five to 11, which could begin as early as March, those participants will start off with a lower dose than the amount currently given to adults and adolescents. “It’s just to see side effects and demonstrate that they have a protective immune response,” Domachowske says. “Then, if needed, we try the next higher dose to see if that’s acceptable and to determine if the vaccine has a safety and efficacy profile that’s similar to adults.”
Next phases will include children as young as two years, and then for babies down to six months. Depending on the results, the vaccine makers could end up producing a different dose for younger children.
Domachowske said pediatricians often gave half the amount of a typical flu vaccine shot to children from six months to three years out of an abundance of caution, but recently started giving the full dosage after new data showed the full amount was tolerated just as well and even produced an equal—or better—antibody response.
This careful approach to pediatric research is a welcome contrast to the period from the 1900s until the 1970s, when some children were subjected to abuse in the name of medical progress, says Douglas Diekema, director of education for the Treuman Katz Center for Pediatric Bioethics at Seattle Children’s Hospital.
“Few people know about the kids in institutions that were involved in egregious research,” he says.
Take these shocking examples: In 1949, dozens of boys at the now-closed Fernald State School in Massachusetts were fed oatmeal laced with radioactive tracers as part of an experiment to see how nutrients traveled throughout the body. Another 14-year study started in 1956 at Willowbrook State School, a home for children with cognitive disabilities in Staten Island, New York. There, healthy children were purposely fed live hepatitis virus from stool samples of sick children to see if they would become ill.
Following widespread reforms in the 1970s, all research with human subjects must go through a hospital’s institutional review board. Children are also now specifically protected under legislation created in 1983, adds Liza-Marie Johnson, chair of the Hospital Ethics Committee at St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Some people have wondered why kids weren’t enrolled in COVID-19 trials earlier, but the purpose of these regulations is to protect kids from unnecessary risk,” says Johnson. For instance, children were enrolled only when there was enough data about the vaccines’ safety in adults. “Research is opened to minors when a trial is low risk and offers potential for benefit.”
However, researchers routinely struggle with convincing parents to enroll their children in pediatric trials. Not surprisingly, successful recruitment is directly related to how sick a child is. “Parents are extremely motivated to participate if their child has a rare disease,” says Erica Denhoff, education program manager of Institutional Centers for Clinical and Translational Research at Boston Children’s Hospital. “Oftentimes this drug might be their only hope whether their child survives or has a chance of having a normal life.”
Getting kids into trials becomes much more challenging if they’re not in immediate danger, and participation requires frequent appointments or monitoring. Parents are more likely to opt out if a study has rigid hours, or they’re juggling child-care or transportation issues, she says.
Even joining COVID-19 vaccine trials requires a significant commitment. Egbert says that for the Moderna study, her daughters had to agree to keep symptom diaries for a week following both injections, attend regular telemedicine visits, and submit to four coronavirus tests and four blood draws over 13 months. “I tell them this is like a job,” she says, adding that they will each be compensated $1600 by Moderna, paid in increments, as long as they stay in the trial.
A sense of purpose
The most effective way to enroll and retain study participants is to help them form an emotional connection to the trial’s purpose, says Tricia Barrett, senior vice president and managing director at Praxis Communications, a clinical trial recruitment firm.
“There’s a big sense of altruism. Parents think, I’m not only helping my child, but others as well,” she says. “For the kids, we help make them feel like part of something cool.”
Bob McDonnell is one of the nearly two million legendary “polio pioneers,” whose participation in the Salk trials helped stop the spread of the paralyzing disease. At age nine, he didn’t have much say in participating. But as a 76-year-old retiree in Loveland, Colorado, he’s grown more grateful of his role over time. “Now I’m glad I was part of something for the good of mankind,” he says.
Charles and Lara Mashek of Oklahoma City also considered the practical and magnanimous implications when they signed up their daughters, ages 14 and 12, in the Moderna trial at the Lynn Health Science Institute. Both physicians, they’d already been immunized against COVID-19 and were eager for their kids to have a chance at getting the shot. “We believe strongly in vaccines, and we see the value of testing and trials,” says Charles Mashek.
Where can you travel safely once you’ve had the COVID-19 vaccine?
After more than a year of COVID-19 pandemic restrictions, the U.S. Centers for Disease Control and Prevention (CDC) released an official statement many of us have been longing to hear: vaccinated people can safely engage in many activities.
At press time, 11 percent of the United States population had been fully vaccinated against COVID-19, and 21 percent had received at least one dose. For the inoculated, the news is good—but the temptation to take a trip is greater.
Last Friday, some 1.357 million people passed through U.S. airports, according to the Transportation Security Administration. It was the highest single-day tally since the World Health Organization declared the coronavirus outbreak a pandemic in March 2020. Such activity is possibly at odds with the latest CDC guidelines, which stipulate that even fully vaccinated people should avoid travel unless necessary.
As travel rules start lifting, here’s what vaccinated visitors need to know before planning an international trip.
Vaccines protect you more than others
Travel will become safer for those who have been inoculated and have built up COVID-19 antibodies. “As a vaccinated traveler, you are almost 100 percent protected from severe disease if exposed to SARS-CoV-2,” says Monica Gandhi, an infectious disease doctor and professor of medicine at the University of California San Francisco.
Early studies show that vaccines are preventing viral transmission too, meaning vaccinated people are unlikely to spread COVID-19. But until that’s confirmed—results of several clinical trials are expected by fall—you’ll need to maintain the usual virus-transmitting precautions.
Other unknowns—how long immunity lasts after vaccination, what will happen with those dangerous variants—will continue to vex scientists and challenge populations.
Once vaccinated, the main worry for a traveler is giving COVID-19 to other people while in transit to or at a destination. “It is still important to practice precautions known to mitigate risk to you and to others: wear a mask, keep your distance, wash your hands, [choose] outdoors over indoors, and avoid crowded spaces,” says Joyce Sanchez, infectious disease doctor and medical director of the Travel Health Clinic at Froedtert and the Medical College of Wisconsin.
Where can you go?
Government travel advisories and border rules will continue to dictate choices. Research your options via the U.S. Department of State’s country pages, the CDC’s recommendations by destination, or CovidControls.co, which tracks countries by vaccination rate, entry rules, and lockdown status.
Testing is essential. Not only is proof of a negative COVID-19 test required by many international destinations, it is also required for U.S. citizens flying home from abroad. As of January 12, Americans must be tested no more than three days before flying back from outside of the country and show a negative result to the airline before boarding (or present documentation of recovery from COVID-19). You can research testing rules for other countries via CovidControls.co.
Dozens of countries are open to U.S. travelers, with an ever-shifting patchwork of requirements and regulations to visit. Some (United Kingdom, Peru) require both negative COVID tests and quarantines; others, such as Mexico and Costa Rica, have few restrictions beyond temperature screenings.
Many Caribbean destinations—including Jamaica, St. Kitts and Nevis, and Dominica—will permit U.S. travelers with a negative result from a lab-issued COVID-19 PCR test that’s no more than 72 hours old upon arrival. The Dominican Republic no longer requires U.S. visitors to show a negative COVID-19 PCR test result on arrival.
In what may be the new normal for “vaccination vacations” to come, Seychelles is now open only to travelers—Americans included—who have been fully inoculated and can show proof.
Vaccine passports are in the works for citizens of countries including Iceland, Poland, and Portugal, as are electronic travel passes from organizations like the World Economic Forum and the International Air Transport Assocition. The CDC hasn’t yet implemented such a program, which could be riddled with practical and ethical issues. Certification indicating you are vaccinated would be easy to forge, and creating a group of vaccinated people who can travel while others can’t seems elitist.
Another good choice is Rwanda, where one of the world’s swiftest COVID responses successfully protected both its citizens and its endangered mountain gorillas. This allowed the east African nation to reopen to tourism in August 2020.
Countries that managed the pandemic well are likely to continue doing so, making tourism in these places safer for everyone as borders open up. Finland, for example, has fewer than 70,000 COVID cases, the Koronavilkku contact-tracing app, and its FINENTRY program provides free testing for travelers upon arrival.
Still, there’s a catch: Places with strict COVID-19 protocols and low caseloads (New Zealand, Taiwan) may be slow to let Americans back in—and quick to reimpose rigorous preventative measures, meaning, says Sanchez, “you may run the risk of being stuck in a new lockdown if cases rise during your stay.”
Because mass vaccination efforts are currently underway, the destinations and activities you choose as a traveler can play an important role in shielding yet-to-be-vaccinated locals.
Once border rules allow Americans to visit, inadvertent virus spread will cause less damage in countries with the highest vaccination rates (these include Israel, Seychelles, and the Maldives) than in countries with weaker vaccination programs and less robust healthcare infrastructures.
In Singapore, almost all frontline transportation workers have their first dose. In Bali, Indonesia, tourism workers have vaccination priority. In Thailand, which managed the pandemic well, efforts to accelerate vaccinating residents of popular resort island Phuket aim to allow vaccinated travelers to visit quarantine-free by October.
As rules start to relax, vacations that minimize public transportation and crowds are your best choices. Save festivals and nightclubs for later; now’s the time for exploring outdoors, planning a road trip to Canada’s British Columbia, or exploring Malta’s walkable cities.
All-inclusive resorts have always aimed for worry-free vacations, so many of them have been quick to implement robust COVID protocols that benefit guests andemployees. Even better are naturally isolated destinations and experiences, including parklands, private islands, and safari conservations.
How can you help protect locals?
Most travelers want to know they’re helping, not hurting, a destination’s population. Until everyone has access to vaccines, travelers need to balance how to support tourism-reliant economies while not putting their residents and healthcare systems at risk.
The pandemic increased the already-wide gap between marginalized people and those who have the privilege to travel. But, according to some experts, it’s important not to avoid destinations with COVID-jeopardized economies until their populations are vaccinated.
“The ethical economic considerations are about not isolating areas because of their inability to get the vaccine on time,” says Judy Kepher Gona, founder of Sustainable Travel & Tourism Agenda which works to catalyze sustainable tourism in Africa.
“For some developing countries, the risk of disease infection is more acceptable than the risk of industry failure and significant economic decline,” says Greg Klassen, partner at Twenty31 Consulting, which helps tourism destinations prepare for the future. He says it’s not up to citizens in developed countries to decide for those in developing countries.
In short, embrace companies that prioritize the health and safety of staff and their communities. And choose destinations that have made strong efforts to protect locals and sustain robust healthcare systems. Responsible research and planning will do far more good for everyone than free hand sanitizer.
Top 10 Reasons To Believe the Wuhan Virology Lab Caused 2019-nCoV
+10. The Outbreak Started Across The Street From A Virology Lab
The official story is that 2019-nCoV started in a seafood market in Wuhan. Unclean animals sold there were carrying the virus, Chinese scientists have suggested, and, as a result, some unlucky shoppers ended up becoming patient zeros for a global crisis.
You’ve probably already heard that explanation before, and there’s a good chance you’ve accepted it as a fact — but there are some glaring problems with it.
For one thing, the first patients with 2019-nCoV have no connection to the market whatsoever. They lived nearby, and they appear to have spread the disease to people who went there — but the real patient zeros never actually stepped foot inside of it.
Also, 2019-nCoV is believed to have originated in bats — and this was a seafood market. Nobody was selling bats inside of this market. Bats just aren’t something people in Wuhan normally eat.
Even China’s scientists have started backing away from this theory. To quote one directly:
“It seems clear that [the] seafood market is not the only origin of the virus… But to be honest, we still do not know where the virus came from.”
A lot of people have pointed to the Wuhan Institute of Virology, which is just a 30 minutes drive for the seafood market. But if that’s not close enough for you, there’s another lab that researches bat coronaviruses that’s even closer: The Wuhan Center for Disease Control & Prevention.
It’s not just on the other side of town. It’s on the other side of the street.
+9. The Wuhan Virology Lab Was Studying Bat Coronaviruses
The Wuhan Center for Disease Control & Prevention isn’t just an administrative office. Scientists were inside that building actively conducting research — including studies on coronaviruses in bats.
A lot of researchers in Wuhan were. It had been a major project for the city, and the Wuhan Institute of Virology took great pride in. They were at the forefront in researching the causes of SARS, and it was their researchers who had proven that the last SARS outbreak originated in bats.
They had to look at an awful lot of sick bats to do it, though. Researchers had been gathering bats infected with the coronavirus since at least 2012, and they were focusing on ones that could spread their illness to human beings.
There were hundreds of bats in Wuhan’s labs when the 2019-nCoV outbreak started, and the researchers there were studying at least 11 new strains of SARS-related viruses in them. And, yes — they were doing it across the street from the place where the outbreak started.
+8. 2019-nCoV Is a 96% Match For A Bat Virus In The Wuhan Virology Lab
The coronavirus that’s spreading around the world at this very moment has been called “novel” because it’s unique. It’s different from past diseases, like SARS. About 30% different, to be exact.
That’s not just a number we pulled out of our heads. Scientists have compared the genetic sequence of SARS to 2019-nCoV, and they’ve found that they’re about 70% similar.
That’s a rough number — the real one might be a bit higher. But the real number probably isn’t 96% — which is the percentage match scientists have found between 2019-nCov and a form of the coronavirus carried by bats inside of the Wuhan Institute of Virology.
“But wait a minute,” you say. “If those bats had the virus, there were probably bats all around Wuhan that had it — right?”
Afraid not. 2019-nCoV isn’t just similar to bat coronaviruses in general — it’s similar to a very specific strain of bat coronavirus carried by bats in the Wuhan Institute of Virology. Not every bat coronavirus has that 96% match — in fact, when another lab compared 2019-nCoV to their own bats, the closest match they could find was 88%.
And those bats weren’t local. If you were living in Wuhan and you really wanted to find one of those bats, you’d either have to go to the virology lab or to the place those bats had come from: Yunnan and Zhejiang.
That’s a little over 900km away.
+7. An Infected Bat Bled On A Researcher Shortly Before The Outbreak
Ok, so a disease lab was researching diseases. So what? That doesn’t prove that it ever got out — right?
While it’s highly unlikely that the Wuhan Institute of Virology deliberately plagued its own people, it really wouldn’t have been that hard for somebody to catch it by accident.
Imagine if a bat attacked a researcher and, in the chaos, spilled its blood onto his bare skin. Or imagine if he got a bit too close and got bat urine on his body. Or imagine both of those things happened to the same person not long before the 2019-nCoV outbreak began.
That’s exactly what happened. According to a report by Chinese researchers Botao and Lei Xiao, a researcher named Junhua Tian described these exact experiences in an interview with the Changjiang Times.
Junhua Tian claims he quarantined himself to keep from spreading these disease — but even if he and his colleagues used every possible precaution, it’s possible that the virus still could have leaked out.
One thing we’ve learned since the outbreak is that people can show no symptoms at all and still be infected. And, according to a recent study out of Japan, people who have recovered can still carry the virus.
+6. SARS Escaped From A Beijing Lab Twice
Of course, it’s also possible that the staff at the Wuhan Institute of Virology just didn’t use every possible precaution.
It wouldn’t be the first time someone’s walked out of a Chinese virology lab carrying a deadly sickness. It’s happened before — in fact, it once happened twice in a single month.
On April 4, 2004, a postgraduate student working at a virology lab in Beijing was diagnosed with SARS. She had gotten infected while researching the virus, and, unaware that she was sick, walked out into the public and very nearly caused a second outbreak.
That’s pretty bad — but what makes it downright terrifying is that, two weeks later, another postgraduate student working at the exact same lab did the exact same thing.
That’s not just negligent. According to scientist Antoine Danchin, it should technically be impossible.
“Normally, it’s not possible to contaminate people even under level two confinement if the security rules are obeyed,” he said after the incident. “It suggests there has been some mishandling of something.
“The lab might have all the right rules, but the people may not comply.”
+5. The Wuhan Virology Lab Was Testing A Virus That Matches 2019-nCoV
In case there was any doubt, the Wuhan Institute of Virology definitely had postgraduate students on staff.
We can confirm that because, on Nov. 18, 2019, shortly before the breakout, the institute put up a job posting asking for postgraduate students to help study the coronavirus in humans and bats.
That’s not exactly out of the ordinary — but the description in the job posting is a little disturbing. It says that they were particularly interested in molecular mechanisms that let coronavirus lie dormant for a long time without symptoms.
Sound familiar? That’s one of the distinguishing traits of 2019-nCoV — the fact that people can go around without any apparent symptoms and still spread it.
322 of the people on the Diamond Princess cruise ship tested positive without symptoms, and there’s proof that those asymptomatic people can spread the disease. In fact, one woman is confirmed to have spread it at least five people without showing any symptoms of her own.
+4. Researchers At The Lab Had Recently Created A New Coronavirus
The staff at Wuhan Institute of Virology didn’t just work on cures. They also spent some developing new, super viruses of their own.
In 2015, two researchers at the Institute participated in an international experiment led by American scientist Ralph Baric. The goal? Create a new coronavirus with the ability to infect human beings.
If that sounds like a weird goal to you, you’re not alone. A significant part of the scientific community was outraged by this experiment.
“The only impact of this work is the creation, in a lab, of a new, non-natural risk,” biologist Richard Ebright protested when the work came out.
French virologist Simon Wain-Hobson agreed. “If the virus escaped,” he warned, “nobody could predict the trajectory.”
+3. 2019-nCoV Has Eerie Similarities to HIV
According to a controversial study out of India, some aspects of 2019-nCoV have “uncanny similarities” to HIV.
Full disclosure — this study’s gotten a fair degree of scrutiny. Some scientists have questioned whether it used enough data to be statistically significant, and they’ve put it through the wringer enough that, at this point, the study’s authors have withdrawn their work.
But while their work might be unproven, that doesn’t necessarily make it wrong — and there’s a little bit of evidence to back it up. HIV drugs are proving to be remarkably effective in treating the drug, and most patients are showing low white blood cell counts — something that doesn’t happen with any other form of coronavirus.
That’s creepy — because researchers in the Wuhan Institute of Virology have worked on or conducted studies combining SARS-CoV and an HIV pseudovirus in bats and humans.
There’s no hard proof that the 2019-nCoV is a man-made virus — but if scientists ever find proof that it is, there’s a lot of reason to be worried.
+2. The Communist Chinese Government Ordered Silence
Infectious disease specialist Daniel Lucey got the chance to review the documents and data China had in its possession when 2019-nCoV broke out, and he came out of it baffled. Their official story, he said, just didn’t make any sense.
“China must have realized the epidemic did not originate in that Wuhan Huanan seafood market,” Lucey told the press.
Perhaps he was right. Perhaps somebody in Wuhan knew that the story didn’t add up even when they first announced it. But if they did, they were under strict orders not to say anything about it.
On Jan. 2, 2020 — the day after the Huanan seafood market was blamed for the disease — the Wuhan Institute of Virology sent out a disclosure strictly “prohibiting disclosure of information” on 2019-nCoV.
Some scientists have spoken up anyway. A good part of this article, for example, draws from a study by the National Natural Science Foundation of China called “The possible origins of 2019-nCoV coronavirus”.
It might not surprise you to find out that, shortly after that study was released, the communist government did its best to pull it off the internet with as much vigor as they are using in attempting to stop people referring to the virus as a “Chinese virus” or as the “Wuhan flu”.
+1. The Chinese Government Is Tightening Up Biolab Security
The biggest smoking gun of them all came straight out of the mouth of President Xi Jinping.
On Feb. 14, 2020, President Xi gave a speech on the need to contain 2019-nCoV. Chinese, he said, needs to “learn our lessons… so we can strengthen our areas of weakness and close the loopholes exposed by the epidemic.
While Xi was never completely explicit about how those loopholes were to be closed, he did announce his plan to push through a new law for “biosecurity at laboratories” specifically targeting the use of biological agents that “may harm national security”.
The very next day, the Chinese Ministry of Science and Technology followed up on Xi’s speech with a new directive entitled: “Instructions on strengthening biosecurity management in microbiology labs that handle advanced viruses like the novel coronavirus.”
There’s only one microbiology lab in all of China that handles advanced viruses like the novel coronavirus.
It’s the Wuhan Institute of Virology. (Update 1/5/2021)
Information from The Next Revolution w/Steve Hilton on the Origins of the Coronavirus
We still don’t know the origins of the coronavirus. Here are 4 scenarios.
Experts say that understanding how the virus first leapt from animals to humans is essential to preventing future pandemics.
The search continues for the origins of the virus that causes COVID-19—and the pathway that it took to leap from animals to humans, wreaking havoc across the globe, infecting more than 129 million people, and killing more than 2.8 million.
Earlier this week, the World Health Organization released a report from a team of international researchers that traveled to China to investigate four possible scenarios in which the SARS-CoV-2 virus might have caused the initial outbreak. In the days since, however, world governments have expressed concern that the investigators lacked access to complete data, while scientists say that the report has shed little light on how the virus got jumpstarted.
That’s unsurprising given that it typically takes years to trace a virus back to its roots—if it’s possible at all, says Angela Rasmussen, a virologist at the Center for Global Health Science and Security at Georgetown University Medical Center. But in this case, she says, “I think we do have enough evidence to say that some are more likely than others.”
In the report, the team found that the virus most likely jumped from one animal to another before making its way to humans. They also looked at evidence supporting theories that the virus passed into humans directly from an original host animal, or that it traveled through the supply chain for frozen and refrigerated foods. In addition, the team addressed the possibility that the virus accidentally leaked from a laboratory in Wuhan—a scenario they determined is “extremely unlikely.”
Here’s a look at the evidence the report lays out for each of the four theories—and what experts make of them as possible origin stories for SARS-CoV-2, the virus that causes COVID-19.
1. Direct spillover from animals to humans
WHO ASSESSMENT: possible to likely
The first origin story for SARS-CoV-2 is simple: It suggests that the virus started out in an animal—probably a bat—that came into contact with a human. Boom, infected. At that point, the virus immediately began to spread to other humans.
The WHO report cites strong evidence showing that most coronaviruses that infect humans come from animals, including the virus that caused the SARS epidemic in 2003. Bats are thought to be the most likely culprits, as they host a virus that is genetically related to SARS-CoV-2.
The report acknowledges the possibility that the virus spread to humans from pangolins or minks. But David Robertson, head of viral genomics and bioinformatics at the University of Glasgow, says the WHO joint team sampled many animal species beyond bats for the report. The analyses points to bats as the reservoir species.
“So what you have to worry about then is how did it get from bats to humans?” Robertson says. “Did somebody go into an area, get infected, and then get a train to Wuhan?”
Direct transmission between bats and humans is possible: Studies have shown that people who live near bat caves in southern China’s Yunnan Province have antibodies to bat coronaviruses. But most humans generally don’t spend much time around bats, unless they are bat scientists (who typically wear protective equipment). So it’s unclear why, if the virus jumped from bats directly to humans, the first outbreak would have occurred in Wuhan, a thousand miles away from the bat caves of Yunnan.
Furthermore, the report notes that it would take decades for even the closely related bat coronavirus to evolve into SARS-CoV-2. Since scientists haven’t found a bat virus that would provide the missing link, the WHO team assessed this theory as “possible to likely.”
2. Spillover from animals to humans through an intermediate host
WHO ASSESSMENT: likely to very likely
In the absence of a smoking gun showing that bats passed the virus directly to humans, scientists believe the more likely theory is that the virus first traveled through another animal, such as a mink or a pangolin. Unlike bats, these animals have regular contact with humans—particularly if they’re being raised on a farm or trafficked in the illegal wildlife trade.
If the virus jumped first to another animal, that might also explain how it adapted to be harmful to humans—although Robertson says that the virus likely wouldn’t have had to change much. Genomic analyses suggest that SARS-CoV-2 is a generalist virus rather than one specifically adapted to humans, explaining why it can easily jump among pangolins, mink, cats, and other species.
The WHO report points out that this is the path that previous coronaviruses have taken to infect humans. The SARS virus, for example, is thought to have passed from bats to palm civets before causing a human epidemic in 2002. Meanwhile, the virus that causes MERS has been found in dromedary camels throughout the Middle East.
Daniel Lucey, an adjunct professor of infectious diseases at Georgetown University Medical Center, says that the similarities between SARS-CoV-2 and its relatives SARS and MERS is a compelling argument that it might have started out the same way.
“Now we have three coronaviruses that cause pneumonia and systemic illness and death,” he says. “Past is prologue.”
But, if the theory holds true, it’s not clear what that intermediary animal might have been for SARS-CoV-2. The WHO team analyzed samples from thousands of farmed animals across China, all of which tested negative for the virus. Lucey argues that the WHO team didn’t adequately test China’s farmed mink—one of the suspected intermediaries—but Rasmussen says the report itself acknowledges that it only scratches the surface.
“That’s a fraction of the animals that are farmed or captured or transported for this purpose in China,” she says. “I think we haven’t done anywhere near enough sampling.”
3. Introduction through refrigerated or frozen foods
WHO ASSESSMENT: possible
Another theory holds that the virus may have come to humans through what’s known as the cold chain—the supply line for distributing frozen and refrigerated foods. In this scenario, the virus might have actually originated outside of China but was imported either on the surface of food packaging or in the food itself.
Still, while the cold chain might have played a role in new outbreaks, scientists say there’s little reason to believe that it was the source of the pandemic. There’s no direct evidence that SARS-CoV-2 is responsible for foodborne outbreaks, while Rasmussen notes that COVID-19 rarely spreads through surfaces—which was good news for those weary of wiping down their groceries.
“It’s not impossible,” she says. “You can’t rule it out. But I don’t think the evidence base is particularly strong for that.”
Rasmussen says a more plausible way that the virus might spread through the food chain would be through wildlife that’s farmed for human consumption. But, she points out, that bleeds over into the territory of the theory for an intermediate host.
Some critics claim that this theory is a red herring to push suspicion from China and onto other countries. Lucey considers this pathway the least likely of the four the joint team identified, arguing it’s implausible that the virus would have stayed viable on the packaging for as long as it took to import from Europe or elsewhere. He also questions why these infections would have turned up in Wuhan and nowhere else.
“To me, it’s beyond far-fetched,” he says.
4. Laboratory leak
WHO ASSESSMENT: extremely unlikely
The most controversial hypothesis for the origin of SARS-CoV-2 is also the one that most scientists agree is the least likely: that the virus somehow leaked out of a laboratory in Wuhan where researchers study bat coronaviruses. Originally promulgated by former President Donald Trump and his administration, this theory suggests that perhaps a researcher was infected in the lab—accidentally or otherwise—or manipulated a coronavirus strain to create SARS-CoV-2.
Although there have been laboratory leaks in the past, the WHO report points out that they’re rare. The main evidence it cites to support this theory is the fact that researchers at the Wuhan Institute of Virology have sequenced the bat coronavirus strain—called CoV RaTG13, which is 96.2 percent similar to SARS-CoV-2, and its closest known relative—as part of their effort to prevent zoonotic viruses from spilling over to humans. A laboratory run by the Wuhan Center for Disease Control and Prevention has also worked with bat coronaviruses.
But that’s just about the only evidence that supports this hypothesis. The WHO report says there is no record that any Wuhan laboratory was working with a virus more closely related to SARS-CoV-2 before the first cases of COVID-19 were diagnosed in December 2019, nor did any laboratory staff report any COVID-like symptoms suggesting that they had been infected. But scientists point out that the evidence both for and against the lab leak hypothesis is thin.
Lucey believes the lab leak theory is plausible, though less likely than zoonotic transmission, given the lack of evidence. He points out that there was no forensic investigation of the labs in Wuhan, and he questions why the WHO authorized the team to investigate the lab at all without the mandate to conduct such an investigation or team members with the subject-matter expertise to carry it out.
“There’s not really any way to prove or disprove the lab leak theory based on what’s been presented in this report,” Rasmussen agrees, noting that to put the matter to rest there would need to be a forensic audit of lab records to look for the ancestral virus to SARS-COV-2. “But my opinion is that the lab leak theory, while not impossible, is less likely to be the explanation.”
Rasmussen explains that there’s no evidence that SARS-CoV-2 is the result of genetic manipulation, nor is it likely that it could have been created by accident. It’s incredibly difficult to culture a virus that’s strong enough to cause human infections from a bat sample, she says. Meanwhile, similar viruses commonly occur in nature, making that the far likelier source.
Robertson says that supporters of the lab leak theory argue that SARS-CoV-2 has traveled too quickly and efficiently through the human population to be natural in origin. But if the virus is a generalist, as genomic studies show, he says it’s not surprising that it is so effective at infecting humans.
“I think the evidence is pretty good that it didn’t have to change much to be successful in humans,” he says.
A research roadmap
Although the WHO report may not have shed much light on the origins of SARS-CoV-2, Robertson says this is just the beginning of what can sometimes be a long process. But he says there’s a public health imperative now to launch more rigorous follow-up studies.
“There’s a virus somewhere out there that’s very close to SARS-CoV-2,” he says. “That seems to be the bit that’s terrifying.”
Rasmussen says that the WHO report lays out a roadmap for further studies to discover the origins of the virus. It recommends better surveillance of captive and farmed animals to determine potential reservoir or intermediate hosts, as well as more sampling among bats—both in China and beyond, as there is also evidence of related coronaviruses circulating in regions such as Southeast Asia. The report also recommends in-depth epidemiological studies of the first COVID-19 cases.
Understanding how an outbreak got started helps scientists and governments pinpoint how to strengthen protections—whether that’s more rigorous surveillance for infections in animals and the food chain, or tighter biosafety protocols in laboratories.
“There’s a popular perception that we need some kind of justice or explanation, and somebody needs to answer for this pandemic,” Rasmussen says. “But the real reason why we need to figure out the origin is so that it can inform our efforts to prevent another pandemic like this from happening.”
COVID-19 Testing Fiasco Timetable
+ January 11: China Posts virus genome online
+ Mid-January: Germany develops test
+ Mid-January: WHO adopts Germany’s test
+January 23 Australia announces test
+January 24 CDC announces own test
+February 5: first CDC tests are shipped
+February 12: CDC announces tests are faulty
+February 29: FDA makes it easier for others to develop tests
covid-19 and Healthcare links