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
-COVID and the brain: researchers zero in on how damage occurs
-Can COVID-19 lead to diabetes? Here’s what you need to know
-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
-The world may need to learn to live with the virus.
-Will we ever know the real death toll of the pandemic?
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 firstname.lastname@example.org@ SDelprato http://www.thelancet.com/diabetes-endocrinology Vol 8 September 2020 783 Review eight studies,14 patients with COVID-19 with diabetes had an increased risk of ICU admission. In a retrospective study13 of 191 patients with COVID-19 admitted to hospital, compared with survivors (n=137) those who died (n=54) had a higher prevalence of hypertension (23% vs 48%), diabetes (14% vs 31%), and coronary heart disease (1% vs 24%). In Italy, an analysis22 of 27 955 patients who died from COVID-19 showed a prevalence of diabetes of 31·1%.
A survey done in England (UK)20 showed that of 23 804 patients with COVID-19 dying in hospital, 32% had type 2 diabetes and 1·5% had type 1 diabetes, with 2·03 and 3·5 times the odds of dying compared with patients without diabetes, respectively. In the French population of the CORONADO study,23 3% had type 1 diabetes, 88·5% had type 2 diabetes, 5·4% had other type diabetes, and 3·1% were diagnosed at admission. A further study showed adjusted HRs with HbA1c greater than 86 mmol/mol (10%) compared with HbA1c 48–53 mmol/mol (6·5%–7·0%) of 2·19 (95% CI 1·46–3·29) for type 1 diabetes and 1·62 (95% CI 1·48–1·79) for type 2 diabetes.
In summary, patients with COVID-19 with diabetes have a worse prognosis, most probably because of the concurring effect of multiple factors. In an American survey, 33 individuals with type 1 diabetes with COVID-19 were identified; they were young (mean age 24·8 years [SD 17·49]), with high glucose concentrations at presentation and diabetic ketoacidosis reported in 45·5% of the cases. Similar to those with type 2 diabetes, obesity, hypertension, and cardiovascular disease were the most common comorbidities.
Potential prognostic factors
Age, sex, and ethnicity
Older age and male sex are epidemiological features related to a higher prevalence of COVID-19 and a more severe clinical course. In the early phase of the outbreak, the highest prevalence of COVID-19 occurred in older people in most of the regions of the world, with the exception of South Korea where the highest rate of confirmed SARS-CoV-2 infection occurred in those aged 20–29 years. However, an increased prevalence in those below the age of 30 years has been recently observed in Florida (USA), most probably due to social reasons. In all other countries the highest prevalence of COVID-19 has been in older people. In a large case series of the Chinese pandemic (72 314 cases, updated to Feb 11, 2020), the peak of morbidity was in people aged 50–59 years. The overall case-fatality rate was 2·3% but this increased up to 14·8% in individuals aged 80 years and older. The prevalence of diabetes increases with age in both the general population and in patients with COVID-19. Accordingly, the average age of patients with COVID-19 with diabetes is older than those without diabetes. In one survey, patients with diabetes were at least 10 years older than patients without diabetes. Moreover, age was associated with a greater odds ratio (OR) of in-hospital death that was similar in individuals without diabetes (multivariate OR 1·09, 95% CI 1·07–1·12) and those with diabetes (1·09, 1·04–1·15). A separate study of a matched population of patients with COVID-19 with and without diabetes reported that survivors were younger than non survivors, with age 70 years and older being an independent predictor of in-hospital death (no diabetes HR 5·87, 95% CI 1·88–18·33; diabetes HR 2·39, 1·03–5·56).
Despite overall similar sex distribution of people infected with SARS-CoV-2, (male 51%, female 49%), the case-fatality rate has been higher in males (2·8%) than in females (1·7%).19 A study7 confirmed age and male sex as risk factors for worse outcomes in COVID-19, with those aged 80 years and older having a 12-times higher risk compared with those aged 50–59 years and males having twice the risk as females (HR 1·99, 95% CI 1·88–2·10).
Non-white ethnic groups seem to be at greater risk as indicated by HRs adjusted for age and sex ranging between 1·83 and 2·17 for black, Asian or Asian British, and mixed ethnicities compared with white people.7 This finding confirms a US report on a link between racial minorities and worse outcomes from COVID-19. An analysis of a database representative of 10% of the US population showed that 33% of people admitted to hospital with COVID-19 were African Americans, even though they represent 18% of the sample population. The Johns Hopkins University and American Community Survey reported that in 131 predominantly black counties in the USA, infection and death rates were more than three times and six times higher, respectively, than in predominantly white counties. In New York City, Hispanic or Latin people account for 28% of the population, but 34% of COVID-19 deaths. In New Mexico, Native Americans represent 11% of the population, but 37% of COVID-19 cases.
The higher incidence and worse outcomes of COVID-19 reported in ethnic minority groups are unlikely to reflect biological factors, and are predominantly due to lifestyle and socioeconomic factors. Although data fully adjusted for comorbidities are not yet available, a higher prevalence of cardiovascular risk factors such as hypertension, diabetes, and obesity in ethnic minorities compared with the white population might partly account for the increased risk of poor outcome in these minority populations. These populations are also more likely to be socioeconomically disadvantaged as they more often live in poor and overcrowded houses and are employed in jobs requiring human interaction with resulting increased exposure to the risk of virus transmission. However, in India, Pakistan, and Bangladesh, despite a high prevalence of diabetes and deprivation, a relatively low COVID-19 mortality has been reported so far. This finding has suggested a potential geographical or climatic effect on the spreading of the infection. However, a careful geopolitical analysis considering latitude, temperature, and humidity could only find a weak negative association with relative humidity.
In summary, available data suggest that age is associated with worse outcomes in COVID-19, and it can be hypothesized that this relationship is stronger in people with diabetes for at least three reasons. First, the prevalence of diabetes increases with age to reach a peak in people older than 65 years. Second, people older than 65 years are more likely to have a longer duration of diabetes and a greater prevalence of diabetic complications. Third, diabetes and older age often correlate with comorbidities such as cardiovascular disease, hypertension, and obesity.
In a retrospective analysis of patients with COVID-19,6 those with diabetes had a greater prevalence of hypertension (56·9%), cardiovascular disease (20·9%), and cerebrovascular disease (7·8%) than those without diabetes (28·8%, 11·1%, and 1·3%, respectively). Moreover, in the patients with diabetes, non-survivors had a greater prevalence of comorbidities than survivors (hypertension 83·9% vs 50·0%; cardiovascular disease 45·2% vs 14·8%; cerebrovascular disease 16·1% vs 5·7%; chronic pulmonary disease 12·9% vs 3·3%; and chronic kidney disease 6·5% vs 3·3%). In a Cox multi-regression analysis, in patients with diabetes but not in those without diabetes, hypertension (HR 3·10, 95% CI 1·14–8·44), cardiovascular disease (1·87, 0·88–4·00), and chronic pulmonary disease (2·77, 0·90–8·54) were independent risk factors for in-hospital death. These findings were also noted in 136 patients with diabetes of 904 patients with COVID-19. In the patients with COVID-19, those with diabetes more commonly had hypertension, cardiovascular disease, nervous system disease, and chronic kidney disease; cardiovascular disease, nervous system disease, and chronic kidney disease were all associated with risk for in-hospital death and poor prognosis. In the CORONADO study, an estimated glomerular filtration rate on admission to hospital of 60 mL/min per 1·73 m² or less was an independent predictor of early death in patients with diabetes. SARS-CoV-2 might directly target the kidney through an angiotensin-converting enzyme (ACE) 2-dependent pathway, causing acute renal impairment and increased lethality.
+Chronic Kidney Disease–20.11%
+Congestive Heart Failure–10.36%
According to the Louisiana Department of Health percentages of comorbidities in Covid-19 Deaths. (Updated 5/8/2021)
According to numbers by the CDC, the breakdown of hospitalized patients infected with covid had the following percentages of the following comorbidities:
+Serious Heart Conditions. 27.8%
+Chronic lung disease. 34.6%
Arterial hypertension is by far the most frequent comorbidity seen in patients with COVID-19.34 It has been speculated that the high prevalence of the infection could be due to use of ACE inhibitors since SARS-CoV-2 binds to ACE2 to enter target cells. ACE2 is expressed in the lung, heart, liver, kidney, ileum, and brain and is physiologically involved in anti-inflammatory responses. Experimental evidence suggests that ACE inhibitors and angiotensin receptor blockers increase the expression of ACE2, and it was proposed that these drugs could facilitate target organ infection and promote progression of the disease. However, this evidence was obtained in in vitro and animal studies. Given its structural differences with ACE, ACE2 does not represent a target of these drugs. Moreover, the interaction between ACE inhibitors and the renin–angiotensin system is complex and not completely understood in humans. SARS-CoV-2 has been claimed to increase the expression of angiotensin II with subsequent downregulation of ACE2 and loss of anti-inflammatory effect in the respiratory tract, resulting in alveolar wall thickening, oedema, inflammatory infiltration, and bleeding. Moreover, a favourable effect of ACE inhibitors and angiotensin receptor blockers on the risk of community acquired pneumonia, especially in Asian populations, has been suggested. Initial reports on 8910 patients with COVID-19 from 11 countries could not detect an association between ACE inhibitors or angiotensin receptor blockers and the risk of in-hospital death. A population-based case-control study from Lombardy, an Italian region particularly affected by the pandemic, led to similar conclusions. A Chinese study has even shown a lower rate of severe diseases and a trend toward a lower inflammatory response in 17 patients with COVID-19 treated with ACE inhibitors or angiotensin receptor blockers versus 25 patients given other anti-hypertensive drugs. In summary, ACE inhibitors are unlikely to account for the association between COVID-19 and hypertension.
Patients with COVID-19 have a high prevalence of cardiovascular disease. Cases of acute myocarditis associated with COVID-19 have been reported and a direct myocardial injury has been postulated. The evidence for myocardial injury is largely indirect, with no evidence of viral genomes from myocardial biopsy samples.45 In an autopsy report for 23 patients with COVID-19, 13 showed cardiac manifestations, along with pulmonary involvement. Three patients had obesity and had multifocal acute cardiomyocyte injury without inflammatory cellular infiltrates, lymphocytic myocarditis, or lymphocytic pericarditis associated with signs of chronic cardiac disease. In a metaanalysis of 4189 patients from 28 observational studies, patients with more severe COVID-19 had higher troponin concentrations, which was associated with an increased risk of death.
A manifestation of secondary cardiac involvement in COVID-19 is stress-induced (Takotsubo) cardiomyopathy. Cardiovascular complications might also develop because of reduced systemic oxygenation due to pneumonia and concomitant increased cardiac demand, by immune dysregulation, electrolyte imbalance, or because of adverse effects of drugs such as hydroxychloroquine and azithromycin.
Many reports have linked obesity to more severe COVID-19 illness and death. Several mechanisms can account for this association. The first concerns the detrimental restrictive ventilatory effect of abdominal fat. In a French study, the risk for invasive mechanical ventilation in patients with COVID-19 admitted to an ICU was more than seven times higher in those with a BMI of more than 35 kg/m² than those with a BMI of less than 25 kg/m². Second, in addition to the ventilatory defect, the respiratory dysfunction in patients with severe COVID-19 might depend on impaired lung perfusion due to intravascular disseminated coagulation. In line with this hypothesis, low-molecular-weight heparin was found to reduce mortality. Obesity and diabetes are prothrombotic conditions that might contribute to worse prognosis in patients with COVID-19. In an autopsy study from Germany, deep venous thrombosis was found in seven of 12 patients (58%) and pulmonary embolism was the direct cause of death in four. Of these patients, the BMI of those who died from pulmonary embolism was 36·8 kg/m². Finally, obesity is associated with immune dysregulation and chronic inflammation that could mediate progression toward organ failure in severe COVID-19 patients.
Myocarditis and cardiomyocyte dysfunction could be worsened by local biological effects of epicardial adipose tissue, a source of adipokines and pro-inflammatory mediators, and the volume of epicardial adipose tissue is directly associated with BMI. Moreover, ACE2 is highly expressed in the epicardial adipose tissue of patients with obesity. This could promote virus internalization into the adipocytes and enhance tumor necrosis factor (TNF) α and IL-6 release. Liver steatosis might also play a role. A Chinese study reported a six-times increased risk of severe COVID-19 in patients with a BMI of more than 25 kg/m² and metabolic associated fatty liver disease compared with patients without obesity. Nonalcoholic fatty liver disease and non-alcoholic steatohepatitis are common in people with abdominal obesity and diabetes.58 Elevated aspartate aminotransferase concentrations have been associated with poorer prognosis in patients with COVID-19. The extent to which SARS-CoV-2 could directly affect liver function remains to be established as ACE2 is mainly expressed in cholangiocytes.
Obesity and diabetes are characterized by chronic low grade inflammation with increased concentrations of pro-inflammatory leptin and reduced anti-inflammatory adiponectin. Additionally, people with obesity are often physically inactive, more insulin resistant, and with gut dysbiosis, which might increase the inflammatory response to infection with SARS-CoV-2. Moreover, individuals with obesity have lower vitamin D concentrations, which could also reduce the immune response. The role of vitamin D supplementation is currently being investigated in ongoing clinical trials.
SARS-CoV-2 infects not only cells of the upper respiratory system and alveolar epithelial cells in the lung but also, among others, circulating immune cells (CD3, CD4, and CD8 T cells) inducing apoptosis of lymphocytes to an extent that reflects the severity of SARS-CoV-2 infection. As T cells of the adaptive immune system inhibit overactivation of innate immunity, the resulting lymphocytopenia might suppress the innate immune system and enhance secretion of cytokines. The overproduction of pro-inflammatory cytokines (TNFα, IL-6, IL-1β, and CXC-chemokine ligand 10) results in a so-called cytokine storm, which leads to high risk of vascular hyperpermeability, multiorgan failure, and death. High blood concentrations of inflammatory markers (ie, C-reactive protein, procalcitonin, and ferritin), a high neutrophil-to-lymphocyte ratio, and increased blood concentrations of inflammatory cytokines and chemokines have been associated with both COVID-19 severity and death. Post-mortem analyses of patients with COVID-1967–69 have revealed inflammatory infiltration of the lungs, heart, spleen, lymph nodes, and kidneys. In those with severe COVID-19, a study found higher concentrations of leukocytes (5·3 vs 4·5×10⁹ L, p=0·014), C-reactive protein (47·6 vs 28·7 mg/L, p<0·001), and procalcitonin (0·1 vs 0·05 ng/mL, p<0·001), and lower lymphocyte percentages (median 0·7% [IQR 0·5–1·0] vs 0·8% [0·6–1·2], p=0·048) compared with patients with non-severe COVID-19. Moreover, C-reactive protein concentrations of more than 200 mg/L and ferritin concentrations of more than 2500 ng/mL at hospital admission are risk factors for critical COVID-19. Several reports confirmed these results and a meta-analysis66 including more than 3000 patients with COVID-19 identified high concentrations of IL-6, IL-10, and serum ferritin as strong indicators for severe disease. A dysregulated inflammatory innate and adaptive impaired immune response might occur in patients with diabetes, accounting for the systemic tissue damage and respiratory and multiorgan failure. The cytokine storm is more likely to develop in patients with diabetes, as diabetes is already characterized by low-grade chronic inflammation. Moreover, in the case of high viral load, the capacity to raise an acute immune response might be compromised in patients with diabetes, exposing them to more severe adverse effects. One study reported that patients with COVID-19 with diabetes had higher concentrations of inflammation-related biomarkers, such as C-reactive protein, serum ferritin, and IL-6, and a higher erythrocyte sedimentation rate, compared with patients with COVID-19 without diabetes. These results were supported by findings from a multicenter study in a Chinese population of patients with COVID-19 (952 with diabetes and 6385 without diabetes), showing that those with diabetes had a higher incidence of lymphopenia (44·5% vs 32·6%), and elevated inflammatory biomarkers (C-reactive protein 57·0% vs 42·4% and procalcitonin 33·3% vs 20·3%]. For patients with COVID-19, those with diabetes are more susceptible to the destructive effect of the cytokine storm than those without diabetes.
COVID-19 has been found to be associated with increased coagulation activity. The endothelial dysfunction associated with hypoxia can favor intra-vessel coagulation during COVID-19 infection. Post-mortem studies have found changes in lung vessels, massive pulmonary interstitial fibrosis, variable degrees of hemorrhagic pulmonary infarction, severe endothelial injury, widespread vascular thrombosis with nearly total occlusion of alveolar capillaries, structurally deformed capillaries, and growth of new vessels through a mechanism of intussusceptive angiogenesis. Moreover, intravascular disseminated coagulation can be the terminal event in severe COVID-19, and anticoagulant therapy seems to improve prognosis.
Diabetes is associated with a prothrombotic state, with an imbalance between clotting factors and fibrinolysis and an increased risk of thromboembolic events. In a retrospective Chinese study in patients with diabetes admitted to hospital for COVID-19, non-survivors had longer prothrombin times and higher concentrations of D-dimer. Patients with COVID-19 with diabetes often present other risk factors such as obesity, older age, and being admitted to hospital that could increase the pro-coagulative state and the risk of thrombotic complications.
Despite its syndromic nature, diabetes is still identified as a disturbance of glucose homoeostasis and progressive worsening of hyperglycemia. In previous infectious disease epidemics, a high glucose concentration was shown to be an independent predictor of death and morbidity. This is likely to also be the case for COVID-19.11, The role of hyperglycemia, however, requires a systematic analysis, as suggested by Scheen and colleagues, as the role of glycemic control before hospital admission, at the time of hospital admission, and during treatment in hospital needs to be considered.
Glycemic control before hospital admission
A cohort analysis5 of more than 5500 patients with COVID-19 in the UK found that poor glycemic control before hospital admission, as indicated by HbA1c concentrations, was associated with a high risk of in-hospital death. In a model adjusted for sociodemographic variables and comorbidities, the HR for in-hospital death was greater in patients with HbA1c of 58 mmol/mol (7·5%) or more (3·36, 95% CI 2·18–2·56) than in those with lower HbA1c (1·50, 1·40–1·60) or those without recent HbA1c measurement (1·87, 1·63–2·16). Findings from a separate study also suggested a higher risk of mortality from COVID-19 in patients with either type 1 or type 2 diabetes with HbA1c of more than 86 mmol/mol (10%) compared with those with HbA1c of less than 48 mmol/mol (6·5%). Surprisingly, in the CORONADO study no association was noted between HbA1c concentrations and the primary composite outcome (death and tracheal intubation for mechanical ventilation within the first 7 days after hospital admission) in patients with diabetes admitted to hospital with COVID-19. However, the mean HbA1c value (65 mmol/mol [8·1%]) at admission in this study was higher than the average HbA1c values (54 mmol/mol [7·1%]) in the age-matched French population in a separate study.
Plasma glucose at admission
Despite no association being found between HbA1c and outcomes in the CORONADO study, an association was noted between plasma glucose concentration at admission and the primary outcome. In a retrospective study of 85 patients with COVID-19, hyperglycemia at hospital admission was the best predictor of worst chest radiographic imaging results. Another study found a higher risk of a composite outcome (ICU admission, mechanical ventilation, and death) in patients with hyperglycemia at admission (fasting blood glucose >7 mmol/L) and without history of diabetes compared with patients without diabetes and normoglycemia (OR 5·47, 95% CI 1·56–19·82). This finding is supported by results from a retrospective analysis82 that showed death occurred in 40 of 96 uncontrolled patients with hyperglycemia (41·7%) compared with deaths in 13 of 88 patients with diabetes (14·8%, p<0·001). Altogether, these results highlight the need for improving glycemic control in all patients presenting with hyperglycemia, irrespective of a known diagnosis of diabetes.
In-hospital glycemic control
Random hyperglycemia during treatment in hospital was noted to contribute to worse prognosis for patients with COVID-19 in Wuhan. In 1122 patients with COVID-19 admitted to hospital in the USA, the mortality rate was four times higher in those with diabetes or hyperglycemia during the hospital stay (28·8%) than those with normoglycemia (6·2%). Moreover, mortality was higher in those with hyperglycemia and without known diabetes than in patients with known diabetes. Another study showed that hyperglycemia during treatment in hospital was a risk factor for death in patients with severe COVID-19 (adjusted HR 1·8, 95% CI 1·1–2·8). Patients with COVID-19 with diabetes with an in hospital median blood glucose concentration of less than 6·4 mmol/L (IQR 5·2–7·5) had lower incidences of lymphopenia (30·5% vs 49·6%), neutrophilia (10·7% vs 19·4%), increases in C-reactive protein (47·5% vs 59⋅5%), and procalcitonin (24·2% vs 35·0%) than patients with a median blood glucose concentration of 7·5 mmol/L or higher. Good glycemic control was also associated with a lower rate of complications and all cause mortality.16 These results were confirmed in a propensity-matched score analysis, matching diabetes related comorbidities.
An unusually high number of COVID-19 patients developing diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome have been noted and negative outcomes during COVID-19 have been reported in two clinical cases of diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. In one analysis, ketosis occurred in 6·4% of patients with COVID-19 and its prevalence rose to 11·6% in patients with COVID-19 with diabetes, resulting in a high mortality rate (33·3%). In the CORONADO study,23 11·1% of the participants had diabetes-related disorders at admission including 132 patients with severe hyperglycemia and 40 with ketosis, of whom 19 had diabetic ketoacidosis. Although ketosis might have resulted from discontinuation of glucose-lowering drugs because of anorexia before hospital admission, a direct effect of SARS-CoV-2 should be considered. The virus binds to ACE2 receptors, which, among other locations, are expressed in pancreatic tissue and β-cells in particular.36 Therefore, an acute loss of insulin secretory capacity along with a stress condition and the cytokine storm could lead to a rapid metabolic deterioration with development of diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome. Additionally, hyperglycemic hyperosmolar syndrome is likely to increase the risk of thrombosis that already characterizes severe COVID-19. Because of the severity of diabetic ketoacidosis in patients with COVID-19, ad hoc recommendations for its treatment have been released in the UK.
The SARS-Cov-2 tropism for the β-cell could cause acute impairment of insulin secretion or destruction of β-cells resulting in de novo development of diabetes. This hypothesis is supported by a previous observation88 that infection with human herpesvirus 8 in a sub-Saharan African population induced ketosis-prone type 2 diabetes. In line with this view, new-onset diabetes has been reported in patients with COVID-19 being treated in hospital. In a population of 453 patients with COVID-19, 94 were identified with new-onset diabetes (defined as first recognition of fasting plasma glucose ≥7 mmol/L and HbA1c ≥48 mmol/mol (6·5%) at hospital admission); additionally, these individuals had a greater risk of mortality (HR 9·42, 95% CI 2·18 0–40·7) than those with hyperglycemia (3·29, 0·65–16·6) or diabetes (4·63, 1·02–21·0).
In summary, poor glycemic control at hospital admission and during the hospital stay worsens outcomes for patients with COVID-19. Moreover, consideration should be given for a direct effect of SARS-CoV-2 on β-cell function and survival, causing worsening rapid and severe deterioration of metabolic control in people with pre-existing diabetes or leading to the development of new-onset diabetes (figure). In people with hyperglycemia, glycemic control should be ensured to reduce the risk of threatening metabolic complications (table 2), which should integrate all therapeutic maneuvers put in place to reduce the risk of severe outcomes and mortality. Finally, achievement and maintenance of glycemic control should take into consideration the implications of the use of different glucose-lowering agents in the setting of COVID-19.
Use of glucose-lowering agents might raise specific considerations in patients with COVID-19 (table 3). In the presence of mild COVID-19 in an out-patient setting, usual glucose-lowering therapies for patients with diabetes could be continued if the patient eats and drinks adequately and a more frequent blood glucose-monitoring regimen is implemented. Patients admitted to hospital for severe COVID-19 might need modifications to their diabetes therapy, including withdrawing ongoing treatments and initiating insulin therapy. Such a decision should be based on the severity of COVID-19, nutritional status, actual glycemic control, risk of hypoglycemia, renal function, and drug interactions. Although insulin treatment has been recommended in patients with diabetes with severe COVID-19, one study showed worse clinical outcomes and a worse laboratory results profile in patients on insulin compared with those on metformin. Nonetheless, these results should be viewed with caution because of potential confounding by indication, as insulin treatment could have been used simply because the diabetes was more severe. In keeping with this hypothesis, another study found that insulin infusion allowed achievement of glycaemic targets and improved outcomes in patients with hyperglycaemia with COVID-19.
Despite better outcomes reported in patients with COVID-19 with diabetes treated with metformin,28 the drug should be stopped in patients with respiratory distress, renal impairment, or heart failure90 because of a risk of lactic acidosis. A favorable effect of metformin in patients with COVID-19 has been hypothesized as the drug might prevent virus entry into target cells via adenosine monophosphate-activated protein kinase activation and the phosphatidylinositol-3-kinase–protein kinase B–mammalian target of rapamycin signaling pathway.
A hypothetical anti-viral effect of SGLT2-inhibitors has also been suggested as these agents can decrease intracellular pH and increase lactate concentrations that could reduce the viral load. Nonetheless, SGLT2 inhibitors require optimal hydration to avoid hypovolemia and electrolyte imbalance, and proper adjustment of insulin doses because of the risk of diabetic ketoacidosis. GLP-1 receptor agonists might aggravate anorexia and should be discontinued in severely ill patients with COVID-19 because of a potential risk of aspiration pneumonia. Nonetheless, their associated anti-inflammatory actions and lung protection should be evaluated since preclinical studies have suggested that GLP-1 receptor agonists might attenuate pulmonary inflammation and preserve lung function in rats with experimental lung injury and respiratory syncytial virus infection.
DPP-4 inhibitors are associated with a low risk of hypoglycemia and can be used for a wide renal function range. DPP-4 inhibitors are generally well tolerated and, in experimental studies, they were shown to mitigate inflammatory response. Because soluble DPP-4 might act as a co-receptor for a subset of coronaviruses, DPP-4 inhibitors might interfere with and modify such binding and hypothetically reduce virulence. However, there is no clinical evidence of such an advantage and in two studies no association was found between individual glucose lowering drugs and outcomes. Because of the risk of hypoglycemia, sulfonylureas should be stopped in patients with diabetes with COVID-19, particularly if oral intake is poor or chloroquine is simultaneously used.
Pioglitazone has anti-inflammatory properties, and in experimental animal models it reduced lung inflammation and fibrosis.100,101 Nonetheless, the use of pioglitazone in patients with diabetes with COVID-19 is controversial because of the risk of fluid retention and edema in hemodynamically unstable patients.
Therapies for COVID-19 in people with diabetes
Medical teams should ensure adequate glycemic control in patients with diabetes with COVID-19. This requires considering all potential implications that therapies for COVID-19 might generate when used in patients with diabetes.
Treatment with chloroquine or hydroxychloroquine can cause hypoglycemia, particularly in patients on insulin or sulfonylureas, because of their effects on insulin secretion, degradation, and action. Conversely, antiviral drugs such as lopinavir and ritonavir could lead to hyperglycemia and worsen glycemic control. These agents can cause hepatic and muscle toxicity so caution is recommended when they are used in combination with statins and in patients with fatty liver disease. Pharmacokinetic interactions with antidiabetic drugs are also common, causing over-exposure or under-exposure to either antivirals or anti-diabetic drugs.
Glucocorticoids have been used in patients with COVID-19 with severe acute respiratory distress syndrome as symptomatic and anti-inflammatory treatment. Their use, however, can worsen insulin resistance, sustain gluconeogenesis, worsen glycemic control, and cause marked hyperglycemia. As known, glucocorticoids exert their hyperglycemic effects by reducing insulin sensitivity and insulin secretion, and also by interfering with GLP-1 effects, and enhancing production of glucagon.
People with diabetes with COVID-19 are at a greater risk of worse prognosis and mortality. Given the high worldwide prevalence of diabetes, these individuals represent a large vulnerable segment of the COVID-19 population. The poorer prognosis of people with diabetes is the likely consequence of the syndromic nature of the disease (figure): hyperglycemia, older age, comorbidities, and in particular hypertension, obesity, and cardiovascular disease all contribute to increase the risk in these individuals. The picture, however, is more complicated as it requires factoring in societal factors such as deprivation and ethnicity as well as factors that become relevant at the time that a patient with severe COVID-19 needs to be managed. Here, a physician has to account for not only the health status of the person with diabetes but also to balance carefully glucose-lowering treatments with specific treatments for the viral infection.
Once again, diabetes management in patients with COVID-19 poses a great clinical challenge, one that requires a much-integrated team approach, as this is an indispensable strategy to reduce the risk of medical complications and death as much as possible. Careful assessment of the many components that contribute to poor prognosis with COVID-19 in patients with diabetes might represent the best, if not the only way to overcome the current situation and enable our health systems to be ready to face any future challenges in a prompt and effective manner.
How The Coronavirus Affects Your Body:
Complications can include:
- Pneumonia and trouble breathing
- Organ failure in several organs
- Heart problems
- A severe lung condition that causes a low amount of oxygen to go through your bloodstream to your organs (acute respiratory distress syndrome)
- Blood clots
- Acute kidney injury
- Additional viral and bacterial infections
I have included each organ or system that is affected more indepth below.
As with other coronavirusTrusted Source illnesses — including SARS, MERS, and the common cold — COVID-19 is a respiratory disease, so the lungs are usually affected first. Early symptomsTrusted Source include fever, cough, and shortness of breath. These appear as soon as 2 days, or as long as 14 days, after exposure to the virus.
While fever is at the top of the Centers for Disease Control and Prevention’s list of symptoms, not everyone who gets sick has a fever. In one study in the Journal of the American Medical Association, researchers found that around 70 percentTrusted Source of patients hospitalized with COVID-19 didn’t have a fever.
Cough is more common, but treatment guidelines developed by Boston’s Brigham and Women’s Hospital found that cough occurs in 68 to 83 percent of people who show up at the hospital with COVID-19. Only 11 to 40 percent had shortness of breath. Other less common symptoms included confusion, headache, nausea, and diarrhea.
The severity of COVID-19 varies from mild or no symptoms to severe or sometimes fatal illness. Data on more than 17,000 reported cases in China found that almost 81 percent of cases were mild. The rest were severe or critical. Older people and those with chronic medical conditions appear to have a higher riskTrusted Source for developing severe illness. This variability also shows up in how COVID-19 affects the lungs.
Some people may only have minor respiratory symptomsTrusted Source, while others develop non-life-threatening pneumonia. But there’s a subset of people who develop severe lung damage. “What we’re frequently seeing in patients who are severely ill with [COVID-19] is a condition that we call acute respiratory distress syndrome, or ARDS,” said Dr. Laura E. Evans, a member of the Society of Critical Care Medicine Leadership Council and an associate professor of pulmonary, critical care, and sleep medicine at the University of Washington Medical Center in Seattle.
ARDS doesn’t happen just with COVID-19. A number of events can trigger it, including infection, trauma, and sepsis. These cause damage to the lungs, which leads to fluid leaking from small blood vessels in the lungs. The fluid collects in the lungs’ air sacs, or alveoli. This makes it difficult for the lungs to transfer oxygen from the air to the blood.
While there’s a shortage of information on the type of damage that occurs in the lungs during COVID-19, a recent report suggests it’s similarTrusted Source to the damage caused by SARS and MERS. One recent studyTrusted Source of 138 people hospitalized for COVID-19 found that on average, people started having difficulty breathing 5 days after showing symptoms. ARDS developed on average 8 days after symptoms. Treatment for ARDS involves supplemental oxygen and mechanical ventilation, with the goal of getting more oxygen into the blood. “There isn’t a specific treatment for ARDS,” Evans said. “We just support the person through this process as best we can, allowing their bodies to heal and their immune system to address the underlying events.”
One curious thing about COVID-19 is that many patients have potentially deadly low blood oxygen levels, but they don’t seem starved of oxygen. This has led some doctors to rethink putting patients on a ventilator simply because of low oxygen levels in the blood.
The lungs are the main organs affected by COVID-19. But in serious cases, the rest of the body can also be affected. In serious cases, the rest of the body can also be affected. “In patients who become severely ill, a good proportion of those patients also develop dysfunction in other organ systems,” Evans said. However, she says this can happen with any severe infection. This damage to the organs isn’t always directly caused by the infection, but can result from the body’s response to infection.
Some people with COVID-19 have reported gastrointestinal symptomsTrusted Source, such as nausea or diarrhea, although these symptoms are much less common than problems with the lungs. While coronaviruses seem to have an easier time entering the body through the lungs, the intestines aren’t out of reach for these viruses. Earlier reports identified the viruses that cause SARS and MERS in intestinal tissue biopsies and stool samples. Two recent studies — one in the New England Journal of Medicine and a preprint on medRxiv — report that stool samples of some people with COVID-19 tested positive for the virus. However, researchers don’t know yet whether fecal transmission of this virus can occur.ADVERTISING
Evans says COVID-19 can also affect the heart and blood vessels. This may show up as irregular heart rhythms, not enough blood getting to the tissues, or blood pressure low enough that it requires medications. So far, though, it’s not clearTrusted Source that the virus directly damages the heart. In one study of hospitalized patients in Wuhan, 20 percentTrusted Source had some form of heart damage. In another, 44 percentTrusted Source of those in an intensive care unit (ICU) had an irregular heart rhythm. There are also signs that COVID-19 may cause the blood to clot more easily. It’s not clear how much this plays in the severity of the illness, but clots could increase the risk of a stroke or heart attack.CORONAVIRUS UPDATESStay on top of the COVID-19 pandemic. We’ll email you the latest developments about the novel coronavirus and Healthline’s top health news stories, daily.
When liver cells are inflamed or damaged, they can leak higher than normal amounts of enzymes into the bloodstream. Elevated liver enzymes aren’t always a sign of a serious problem, but this laboratory finding was seen in people with SARS or MERSTrusted Source. In one study of hospitalized COVID-19 patients in Wuhan, 27 percent had kidney failure. One recent reportTrusted Source found signs of liver damage in a person with COVID-19. Doctors says it’s not clear, though, if the virus or the drugs being used to treat the person caused the damage. Some people hospitalized with COVID-19 have also had acute kidney damageTrusted Source, sometimes requiring a kidney transplant. This also occurred with SARS and MERSTrusted Source. During the SARS outbreak, scientists even found the virus that causes this illness in the tubules of the kidneys.
There’s “little evidence,” though, to show that the virus directly caused the kidney injury, according to a World Health Organization report. Dr. James Cherry, a research professor of pediatrics in the David Geffen School of Medicine at UCLA, says the kidney damage may be due to other changes that happen during coronavirus infection. “When you have pneumonia, you have less oxygen circulating,” he said, “and that can damage the kidneys.”
With any infection, the body’s immune system responds by attacking the foreign virus or bacteria. While this immune response can rid the body of the infection, it can also sometimes cause collateral damage in the body. This can come in the form of an intense inflammatory response, sometimes called a “cytokine storm.” The immune cells produce cytokines to fight infection, but if too many are released, it can cause problems in the body. “A lot of [the damage in the body during COVID-19] is due to what we would call a sepsis syndrome, which is due to complex immune reactions,” Evans said. “The infection itself can generate an intense inflammatory response in the body that can affect the function of multiple organ systems.”
Another thing about the immune system is that, so far, there are almost no cases of COVID-19 in children under 9 years old. Scientists aren’t sure whether young children aren’t getting infected or their symptoms are so mild that no one notices it. Cherry says children also have a less severe illness than adults during other kinds of infections, including measles and pneumococcal infections. He says this may be because children have a “straightforward immune response,” whereas older people can sometimes have an “over-response.” It’s this excess immune response that causes some of the damage during infections. “There was evidence of this happening during SARS,” Cherry said, “and I suspect it could also be playing out here [with COVID-19].”
What has been discovered is that there are micro blood clots being formed in the body. The reason for this is not fully understood. But is suspected that this is a major causative agent for organ damage, especially the heavily vascular organs, like the kidneys and liver.
COVID and the brain: researchers zero in on how damage occurs
Growing evidence suggests that the coronavirus causes ‘brain fog’ and other neurological symptoms through multiple mechanisms.
How COVID-19 damages the brain is becoming clearer. New evidence suggests that the coronavirus’s assault on the brain could be multipronged: it might attack certain brain cells directly, reduce blood flow to brain tissue or trigger production of immune molecules that can harm brain cells.
Infection with the coronavirus SARS-CoV-2 can cause memory loss, strokes and other effects on the brain. The question, says Serena Spudich, a neurologist at Yale University in New Haven, Connecticut, is: “Can we intervene early to address these abnormalities so that people don’t have long-term problems?”
With so many people affected — neurological symptoms appeared in 80% of the people hospitalized with COVID-19 who were surveyed in one study1 — researchers hope that the growing evidence base will point the way to better treatments.
Breaking into the brain
SARS-CoV-2 can have severe effects: a preprint posted last month2 compared images of people’s brains from before and after they had COVID-19, and found loss of grey matter in several areas of the cerebral cortex. (Preprints are published without peer review.)
Early in the pandemic, researchers speculated that the virus might cause damage by somehow entering the brain and infecting neurons, the cells responsible for transmitting and processing information. But studies have since indicated3 that the virus has difficulty getting past the brain’s defence system — the blood–brain barrier — and that it doesn’t necessarily attack neurons in any significant way.COVID’s toll on smell and taste: what scientists do and don’t know
One way in which SARS-CoV-2 might be accessing the brain, experts say, is by passing through the olfactory mucosa, the lining of the nasal cavity, which borders the brain. The virus is often found in the nasal cavity — one reason that health-care workers test for COVID-19 by swabbing the nose.
Even so, “there’s not a tonne of virus in the brain”, says Spudich, who co-authored a review of autopsies and other evidence that was published online in April4.
But that doesn’t mean it is not infecting any brain cells at all.
Studies now suggest that SARS-CoV-2 can infect astrocytes, a type of cell that’s abundant in the brain and has many functions. “Astrocytes do quite a lot that supports normal brain function,” including providing nutrients to neurons to keep them working, says Arnold Kriegstein, a neurologist at the University of California, San Francisco.
In a preprint posted in January, Kriegstein and his colleagues reported5 that SARS-CoV-2 preferentially infects astrocytes over other brain cells. The researchers exposed brain organoids — miniature brain-like structures grown from stem cells in the lab — to the virus. SARS-CoV-2 almost exclusively infected astrocytes over all other cells present.
Bolstering these lab studies, a group including Daniel Martins-de-Souza, head of proteomics at the University of Campinas in Brazil, reported6 in a February preprint that it had analysed brain samples from 26 people who died with COVID-19. In the five whose brain cells showed evidence of SARS-CoV-2 infection, 66% of the affected cells were astrocytes.
Infected astrocytes could explain some of the neurological symptoms associated with COVID-19, especially fatigue, depression and ‘brain fog’, which includes confusion and forgetfulness, argues Kriegstein. “Those kinds of symptoms may not be reflective of neuronal damage, but could be reflective of dysfunctions of some sort. That could be consistent with astrocyte vulnerability.”The mini lungs and other organoids helping to beat COVID
Astrocytes might be vulnerable even if they are not infected by the virus. A study published on 21 June7 compared the brains of 8 deceased people who had COVID-19 with the brains of 14 controls. The researchers found no trace of SARS-CoV-2 in the brains of the infected people, but they did find that gene expression had been affected in some astrocytes, which were not working properly.
Given all these findings, researchers want to know how many brain cells need to be either infected or damaged to cause neurological symptoms, says Ricardo Costa, a physiologist at Louisiana State University Health in Shreveport whose team is studying SARS-CoV-2’s effects on brain cells.
Unfortunately, there probably isn’t a simple answer, says Kriegstein, pointing out that cells, including neurons, in some regions of the brain will cause more dysfunction than others, if damaged.
Blocking blood flow
Evidence has also accumulated that SARS-CoV-2 can affect the brain by reducing blood flow to it — impairing neurons’ function and ultimately killing them.
Pericytes are cells found on small blood vessels called capillaries throughout the body — including in the brain. A February preprint reported that SARS-CoV-2 could infect pericyte-like cells in brain organoids8.How COVID-19 can damage the brain
In April, David Attwell, a neuroscientist at University College London, and his colleagues published a preprint showing evidence that SARS-CoV-2 can affect pericytes’ behaviour9. The researchers observed that, in slices of hamster brain, SARS-CoV-2 blocks the functioning of receptors on pericytes, causing capillaries in the tissue to constrict. “It turns out this is a big effect,” says Attwell.
It’s a “really cool” study, says Spudich. “It could be something that is determining some of the permanent injury we see — some of these small-vessel strokes.”
Attwell suggests that drugs used to treat high blood pressure, which involves blood-vessel restriction, might be useful in some cases of COVID-19. Two clinical trials are currently investigating the effect of the blood-pressure drug losartan to treat the disease.
There is also growing evidence that some neurological symptoms and damage are the result of the body’s own immune system overreacting and even misfiring after encountering the coronavirus.
In the past 15 years, it has become clear that in response to infection, some people’s immune systems inadvertently make ‘autoantibodies’ that attack their own tissue, says Harald Prüss, a neuroimmunologist at the German Center for Neurodegenerative Diseases in Berlin. This can cause long-term conditions such as neuromyelitis optica, in which people experience symptoms such as loss of vision, and weakness in their limbs. In a review published in May10, Prüss summarized evidence that these autoantibodies can pass through the blood–brain barrier, and contribute to neurological disorders ranging from memory impairment to psychosis.Autopsy slowdown hinders quest to determine how coronavirus kills
This pathway might also operate in COVID-19. In a study published last year11, Prüss and his colleagues isolated antibodies against SARS-CoV-2 from people, and found one that was able to protect hamsters from infection and lung damage. The aim was to create new treatments. But the researchers also found that some of the antibodies could bind to brain tissue, suggesting that they might damage it. “We’re currently trying to prove that clinically and experimentally,” says Prüss.
In a second paper, published online last December, a team including Prüss studied the blood and cerebrospinal fluid of 11 people critically ill with COVID-19, all of whom had neurological symptoms12. All produced autoantibodies capable of binding neurons. And there is evidence that giving patients intravenous immunoglobulin, another type of antibody, to suppress the harmful autoantibodies’ action is “quite successful”, says Prüss.
These pathways — astrocytes, pericytes and autoantibodies — are not mutually exclusive, and are probably not the only ones: it is likely that people with COVID-19 experience neurological symptoms for a range of reasons. Prüss says a key question is what proportion of cases is caused by each of the pathways. “That will determine treatment,” he says.
Can COVID-19 lead to diabetes? Here’s what you need to know
New studies show that the COVID-19 virus can attack the pancreas, destroy cells that make insulin, and cause some cases of diabetes.
During the spring of 2020, physicians in New York City, the U.S. epicenter of the pandemic at the time, noticed a considerable number of people hospitalized with COVID-19 had too much sugar in their blood, a condition called hyperglycemia that is a signature feature of diabetes.
“[My colleagues and I] found it very challenging to control the blood glucose level of some COVID-19 patients, even those without a history of diabetes,” says stem cell biologist Shuibing Chen at Weill Cornell Medicine. More surprising, says Chen, was that some patients who did not have diabetes prior to the infection, developed new-onset diabetes after recovering from COVID-19.
The COVID-19 virus, SARS-CoV-2, is best known for wreaking havoc in the lungs and causing acute respiratory distress. But how and why a COVID-19 patient would suddenly develop a chronic disease like diabetes is a mystery, as is the number of people who must then deal with this complication.
A global 2020 analysis led by population health researcher Thirunavukkarasu Sathish at McMaster University in Canada found that nearly 15 percent of severe COVID-19 patients also developed diabetes. But, he admits, “this figure is likely to be higher among high-risk individuals, prediabetes for example.”Research led by endocrinologist Paolo Fiorina at Harvard Medical School and published in 2021 reported that of 551 patients hospitalized for COVID-19 in Italy, nearly half became hyperglycemic.
Peter Jackson, a biochemist at the Stanford University School of Medicine, estimates “as many as 30 percent of patients with severe COVID-19 may develop diabetes.”
Intrigued by the startling connection between COVID-19 and diabetes, Chen and Jackson both launched independent investigations to uncover how SARS-CoV-2 might trigger hyperglycemia. Both groups published their results in the May issue of Cell Metabolism.
“Their findings provide critical insights into the underlying mechanisms by which COVID-19 can lead to the development of new-onset diabetes in infected patients,” says Rita Kalyani, an associate professor of medicine at Johns Hopkins Division of Endocrinology, Diabetes, and Metabolism, who was not involved with either study.
The pancreas is another target of the COVID-19 virus
SARS-CoV-2 affects people in very different ways. Many people experience only minor symptoms, but others develop severe, life-threatening disease. As the pandemic unfolded it became apparent that this virus could spread beyond the lungs and damage other critical organs, including the liver, heart, and kidneys. It also became clear that diabetes and obesity were common risk factors for severe COVID-19.
In an earlier study, Chen’s group grew various types of tissues in the lab and tested which ones were vulnerable to the COVID-19 virus. “Very surprisingly, we found that beta cells of the pancreas are highly permissive to SARS-CoV-2 infection,” says Chen. The pancreas, which lies behind the stomach, is a complex organ composed of numerous types of cells that assist with digestion. It also contains beta cells that make insulin, the hormone that escorts sugar molecules from the blood into the body’s cells where it is used for energy.
But just because a virus can infect cells grown in a dish in the lab doesn’t mean it attacks the body in the same way. To ensure the laboratory observations were a true reflection of what happens in living humans, both the Chen and Jackson teams acquired autopsy samples from patients who succumbed to COVID-19. Both groups detected SARS-CoV-2 in pancreatic beta cells from these deceased patients.
But how, exactly, does a respiratory virus move from the lungs to the pancreas? After patients experience pneumonia, the infection of the lower lung may cause tissue damage that allows the virus to leak from lung alveoli and into the blood vessels, explains Jackson. “Once in circulation, the virus can enter other highly vascularized tissues like the pancreas, brain, and kidney.” Others have speculated that the virus could get into the bloodstream by leaking out of the gut, which may occur in patients lacking healthy intestinal bacteria. (Microbes in your gut may be new recruits in the fight against viruses)
How the virus shuts down insulin production
Both research teams noted that beta cells infected with SARS-CoV-2 stop making insulin. In Jackson’s study, the infected beta cells died via apoptosis, a genetically-programmed autodestruct sequence initiated by injured cells.
Chen’s group found that infected beta cells underwent a process called transdifferentiation, which means they converted into another type of cell; one that no longer manufactures insulin. It is possible that some infected beta cells undergo transdifferentiation while others self-destruct.
In both cases, the end result is the same: when the COVID-19 virus attacks the pancreatic beta cells, insulin production decreases.
This can lead to type 1 diabetes, which is usually caused by genetic risk factors that spur an autoimmune reaction that attacks and destroys beta cells. Type 1 diabetes is more commonly seen early in life and requires patients to inject insulin every day since their body no longer makes the hormone. Type 1 diabetes also involves an environmental trigger, such as an infection, to initiate the autoimmune reaction.
In contrast, the far more common type 2 diabetes occurs when the body becomes resistant to the insulin it makes. Type 2 diabetes can be managed with changes in diet and exercise, although sometimes medications that enhance insulin sensitivity are needed. Collectively, 34.2 million Americans have diabetes according to a 2020 report issued by the Centers for Disease Control.
The fate of the infected beta cells is important to study further as there may be a way to prevent their destruction in patients with severe COVID-19. Chen’s team surveyed a large panel of chemicals in hopes of finding one that could prevent the transdifferentiation process.
The survey identified a compound called trans-ISRIB that helped beta cells maintain their identity and their ability to produce insulin when infected with SARS-CoV-2. Trans-ISRIB, which stands for Integrated Stress Response InhiBitor, is a compound discovered in 2013 that is able to prevent a cell’s normal response to stress. Such compounds are being explored as potential therapeutics to prevent widespread apoptosis and damage.
Chen cautions, “Trans-ISRIB is not an FDA-approved drug, so it cannot be used in patients yet. But our studies support the idea that a new drug could be developed to prevent COVID-19 from causing diabetes.” Jackson’s group found that a cellular protein receptor called neuropilin-1 was critical for SARS-CoV-2 to invade beta cells; blocking this receptor keeps them from being infected.
There is also great interest among the broader research community to develop drugs that stop cells from destroying themselves by apoptosis. Experimental compounds called caspase inhibitors, which prevent cell suicide, are being studied by others as potential therapies to ameliorate or prevent severe COVID-19. Unfortunately, caspase inhibitors have not proved a complete success in the clinic despite great promise and interest. Nonetheless, “they might work for short term exposure to limit viral damage,” Jackson says.
Chen adds that SARS-CoV-2 is not the only virus that threatens the pancreas. “Coxsackievirus B, rotavirus, mumps virus, and cytomegalovirus have been shown to infect and damage beta cells. Whether they are a direct cause of type 1 diabetes has been controversial.” More research is needed to determine if it is possible to neutralize the viral attacks on the pancreas, either by blocking infection or preventing the virus from reaching the organ in the first place.
Kalyani stresses that these studies “further underscore the importance of getting vaccinated for COVID-19. Individuals who contract COVID-19, particularly those with prediabetes or other risk factors for diabetes, should let their health care providers know if they develop symptoms of hyperglycemia such as frequent urination, excessive thirst, blurry vision, or unexplained weight loss.”
These new findings emphasize that there is much to learn about COVID-19 and its aftereffects. It seems clear that for some unlucky people, defeating the virus is only the beginning. Additional complications may arise depending on which systems in the body have been damaged in the wake of the viral infection.
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
The virus also might cause changes in gut bacteria, said Brennan Spiegel, a gastroenterologist and director of health services research at Cedars-Sinai Health System, who has had patients come in with abdominal pain and diarrhea weeks or months after coming down with Covid-19.
Ms. Moore, the Indiana lawyer, got Covid-19 in March and initially felt better by the end of April. “I thought I beat this thing. I was ecstatic,” said Ms. Moore, who tested positive for coronavirus antibodies in May.
That month, her health took a sharp turn for the worse. She struggled with tachycardia, or a racing heartbeat, and blood-pressure fluctuations. Those symptoms improved, but she still has gastrointestinal problems. A recent test found stomach-lining inflammation. Pepcid, antihistamines and avoiding dairy products have provided some relief, but other symptoms such as memory deficits persist.
“I feel like there has to be some sort of next step,” she said, “because I’m not ready to accept this as my new reality.”
She enrolled in a research study at the Neuro Covid-19 Clinic at Northwestern Medicine in Chicago, one of several clinics across the country aiming to find solutions for patients.
Some symptoms could be collateral damage from the body’s immune response during the acute infection, researchers said. Some patients might harbor an undetectable reservoir of infectious virus or have bits of noninfectious virus in some cells that trigger an immune response, they said.
Another possibility is that the virus causes some people’s immune systems to attack and damage their own organs and tissues, researchers said. A June study found roughly half of 29 hospitalized ICU patients with Covid-19 had one or more types of autoantibodies—antibodies that mistakenly target and attack a patient’s own tissues or organs.
Doctors say some patients appear to be developing dysautonomia, or dysregulation of the autonomic nervous system, the part of the nervous system that regulates involuntary functions like breathing, digestion and heart rate, some researchers and doctors said.
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David Putrino, director of rehabilitation innovation at Mount Sinai Health System in New York City, said the majority of the more than 300 long-Covid patients being seen at its Center for Post-Covid Care appear to have developed a dysautonomia-like condition. About 90% of such patients report having symptoms of exercise intolerance, fatigue and elevated heartbeats. About 40% to 50% also report symptoms such as gastrointestinal issues, headaches and shortness of breath.
Dr. Putrino said inflammation from the virus might be disrupting the normal functioning of the vagus nerve—the body’s longest cranial nerve—which relays messages to the lungs, gut and heart.
As a member of the Johns Hopkins University varsity cross-country team, 19-year-old Christopher Wilhelm used to run 10 miles a day. Now, there are days he can’t even walk a quarter mile with his mom around their Maitland, Fla., neighborhood without feeling wiped out.
Mr. Wilhelm, who tested positive for Covid-19 in June, said his heart rate shoots up during those walks, ranging from 130 to 170 beats a minute. He was diagnosed recently with a form of dysautonomia characterized by fluctuations in blood pressure and heart rate when patients sit or stand up, a condition known as postural orthostatic tachycardia syndrome, or POTS. His doctors also are evaluating him for cardiac issues. Medications he has tried haven’t yet helped his heart-rate spikes.
“After I tested positive, I was just expecting it to be two weeks of flulike symptoms, and then I’d pretty much be back to normal,” he said. “It’s been so long already, it’s kind of daunting.”
Six months after getting sick with Covid-19, Jennica Harris, 33, said she has persistent fatigue and problems with memory and concentration. She struggles to find simple words during conversations, often loses her train of thought and has developed a stutter.
“I usually know what I want to say when I want to say it, and I usually don’t hold back,” she said. “When I try to get my point across and I can’t, that hurts my confidence, my sense of self.”
The constellation of such neurological symptoms, along with persistent fatigue, joint pain and headaches, resembles myalgic encephalomyelitis, also known as chronic fatigue syndrome, said Anthony Komaroff, a Harvard Medical School professor of medicine who has studied the syndrome for decades. The condition can follow certain viral and bacterial infections, he said. He thinks the condition likely follows Covid-19, too, at least in a portion of patients. A 2009 study of 233 SARS survivors found 27% met criteria for chronic fatigue syndrome four years after getting sick.
It still isn’t known whether the new coronavirus gets into the brain itself, or if Covid-19’s neurological symptoms stem from a body-wide inflammatory response, scientists say.
In autopsies of some Covid-19 patients, doctors have observed encephalitis, or inflammation of the brain. Small autopsy studies also have found preliminary evidence of coronavirus particles in regions of the brain important for smell. With other infections, viral particles have been found in the brains of patients with encephalitis, though it is rare, said Walter Royal, a neurovirologist and director of Morehouse School of Medicine’s Neuroscience Institute. What is more common is that the virus infects the lining of the blood vessels, causing damage and inflammation that in turn affects the brain.
How long it will take long-Covid patients to recover remains unknown. Dr. Putrino said most of them won’t get better on their own, and will need at least six months of structured rehabilitation.
“What tends to happen to people who don’t get treatment and don’t get the recognition they need is they slump down to a new normal of function,” he said.
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.
The world may need to learn to live with the virus.
Health care workers administered coronavirus tests in Colombo, Sri Lanka, on Tuesday.Credit…Ishara S. Kodikara/Agence France-Presse
Early in the pandemic, there was hope that the world would one day achieve herd immunity, the point when the coronavirus lacks enough hosts to spread easily. But over a year later, the virus is crushing India with a fearsome second wave and surging in countries from Asia to Latin America.
That means if the virus continues to run rampant through much of the world, it is well on its way to becoming endemic, an ever-present threat.
Virus variants are tearing through places where people gather in large numbers with few or no pandemic protocols, like wearing masks and distancing, according to Dr. David Heymann, a professor of infectious disease epidemiology at the London School of Hygiene and Tropical Medicine.
While the outbreak in India is capturing the most attention, Dr. Heymann said the pervasive reach of the virus means that the likelihood is growing that it will persist in most parts of the world.
As more people contract the virus, developing some level of immunity, and the pace of vaccinations accelerates, future outbreaks won’t be on the scale of those devastating India and Brazil, Dr. Heymann said. Smaller outbreaks that are less deadly but a constant threat should be expected, Dr. Heymann said.
“This is the natural progression of many infections we have in humans, whether it is tuberculosis or H.I.V.,” said Dr. Heymann, a former member of the Epidemiology Intelligence Service at the Centers for Disease Control and Prevention and a former senior official at the World Health Organization. “They have become endemic and we have learned to live with them and we learn how to do risk assessments and how to protect those we want to protect.”
Vaccines that are highly effective against Covid were developed rapidly, but global distribution has been plodding and unequal. As rich countries hoard vaccine doses, poorer countries face big logistical challenges to distributing the doses they manage to get and vaccine hesitancy is an issue everywhere. And experts warn the world is getting vaccinated too slowly for there to be much hope of ever eliminating the virus.
Only two countries have fully vaccinated more than half of their populations, according to the Our World in Data project at the University of Oxford. They are Israel and the East African nation of the Seychelles, an archipelago with a population of fewer than 100,000. And just a handful of other countries have at least partially vaccinated nearly 50 percent or more, including Britain, tiny Bhutan, and the United States.
Less than 10 percent of India’s vast population is at least partly vaccinated, offering little check to its onslaught of infections.
In Africa, the figure is slightly more than 1 percent.
Still, public health experts say a relatively small number of countries, mostly island nations, have largely kept the virus under control and could continue keeping it at bay after vaccinating enough people.
New Zealand, through stringent lockdowns and border closures, has all but eliminated the virus. Dr. Michael Baker, an epidemiologist at the University of Otago who helped devise the country’s coronavirus response, said New Zealand would likely achieve herd immunity by immunizing its population, but it has a long way to go with only about 4.4 percent of New Zealanders at least partially vaccinated.
“All of the surveys show there is a degree of vaccine hesitancy in New Zealand, but also a lot of people are very enthusiastic,” Dr. Baker said. “So I think we will probably get there in the end.”
While new daily cases have remained at near-world record levels, the number of deaths has dropped from a peak in February, going against the normal pattern of high cases followed eventually by high deaths. If that trendline continues, it could offer a glimmer of hope for a future scenario that scientists are rooting for: Even as the virus spreads and seems to be hurtling toward becoming endemic, it could become a less lethal threat that can be managed with vaccines that are updated periodically to protect against variants.
“It may be endemic, but not in a life-threatening way,” Dr. Michael Merson, a professor of global health at Duke University and former director of the World Health Organization’s Global Program on AIDS said. “It may be more like what we see with young kids, a common cold like disease.”
Will we ever know the real death toll of the pandemic?
The past year has been a stark reminder of global inequalities—including the resources needed to collect timely and accurate data on deaths. These innovators aim to fix that.
On a sweltering April night in Ahmedabad, the largest city in the Indian state of Gujarat, Shayar Rawal rode his motorbike to a COVID-designated government hospital at 11:55 p.m. Over the next 24 hours, he had just one task: to count the number of dead bodies being brought to the mortuary.
Rawal—a reporter at the Gujarati daily newspaper Divya Bhaskar—counted four deaths in the first hour. Grieving relatives collected five more dead bodies in the next hour. When the number reached 100, he says, reality sunk in.
“I knew the government was hiding numbers, but this was way more than what I had expected,” Rawal says.
Officially, the city recorded just 15 COVID-19 deaths that day. But by the end of his vigil, Rawal had counted 112 bodies—and that was just the dead from one city hospital. Over the next few weeks, his colleagues also counted bodies at crematoria and burial grounds and accessed death certificates from districts across the state. Their final analysis revealed that the death toll over nine weeks in the state of Gujarat was 10 times higher than the official figure. In response to the Divya Bhaskar report, the state government gave multiple reasons for the discrepancy, from saying deaths with co-morbidities cannot be counted as COVID-19 deaths to claiming that duplicates of death certificates had been issued. National Geographic’s questions to the state government went unanswered.
“There are fundamental, inherent challenges,” says Samira Asma, assistant director general for data, analytics, and delivery for impact at the World Health Organization. Even in wealthy nations, officials are grappling with incorrect diagnoses, irregularities in the data tracking, and other factors that can obscure the virus’s true impact. “So because of this, we don’t have a complete understanding of the entire scope of the pandemic.”
But the past year has also been a stark reminder of inequalities throughout the world—including the resources needed to collect timely and accurate data on deaths. In an assessment conducted in 2019, the WHO found that about two-thirds of the countries in the world lack strong civil registration and vital statistics systems that keep a count of births and deaths.
This disparity is having dangerous consequences with COVID-19. The World Health Statistics Report released last month stated that there were 3 million deaths directly and indirectly attributed to the SARS-CoV-2 virus—that’s 1.2 million higher than the official figures reported by countries and then tallied by the WHO.
The lack of robust data in low- and middle-income countries such as India means grassroots efforts such as Rawal’s are crucial in determining the true death toll, which in turn affects our understanding of the pandemic’s global trajectory.
“To have an accurate understanding of historic mortality is key in knowing how effective different interventions have been, but also in helping us to more accurately forecast what may happen in the future of the pandemic,” says Oliver Watson, a postdoctoral researcher in infectious disease epidemiology at Imperial College London.
Deaths due to COVID-19
At the beginning of the pandemic, a lack of standardized methods to designate COVID-19 deaths across countries led to underreporting. In a bid to understand the true toll better, demographers, reporters, and economists developed alternate tracking methods, and each approached the problem from different angles.
For Ariel Karlinsky it started with a meme.
Karlinsky is a graduate student at Hebrew University in Jerusalem and an economist at Kohelet Policy Forum, a think tank. When Israel locked down in March 2020, a popular meme doing the rounds was that COVID-19 was claiming as many lives as the flu had in previous years. Curious to find out if that was true, Karlisnky started digging for data, but he didn’t find any. So he started collecting data on his own from individual countries—he emailed national and regional statistics offices, as well as researchers who were working on the issue in various countries.
In January 2021 he started collaborating with Dmitry Kobak, a research scientist at Tübingen University. Their effort has led to the creation of the World Mortality Dataset, which includes information from 95 countries and territories. The Economist has since used the World Mortality Dataset to make its own projections on global deaths due to COVID-19. Recognizing Karlinsky’s work, the WHO invited him to be part of a technical advisory group that aims to map the death toll of the pandemic across the world.
Karlinsky is surprised. “Usually there are organizations like the World Bank and the OECD [Organization for Economic Cooperation and Development] that essentially do what I did. They take data from each individual country and they harmonize it. For some reason, they hadn’t done it, and they still haven’t done it,” he says, speaking over Zoom on a recent Sunday afternoon. “Although they are now taking my data, which is sort of strange because they are official organizations with a much higher budget than me and my laptop.”
Karlinsky is now also working on local mortality figures based on data for smaller regions, such as cities or states across the world. By collecting and standardizing this data in one place, more people can use the information to make informed decisions about their local pandemic response.
“A lot of data exists, but that data is not being used, the data is not being shared—it’s the same as the data not existing at all, right?” he says.
New sources, old problems
One source that made its way into the World Mortality Dataset comes from Indian data journalist Rukmini S, who like Karlinsky believes that the data exists in India’s civil registration system, which records births and deaths across the country. Knowing this, Rukmini scraped together mortality data for all causes in the city of Chennai, in South India.
One way to get a handle on COVID-19 deaths when specific causes are not available is to look at what are known as excess deaths. This figure represents the gap between the number of deaths in an average year, after adjusting for population growth, and that in a year with an extenuating circumstance, like a pandemic.
Excess deaths could be COVID-19 deaths that went unreported, but they might also be due to indirect causes, such as an inability to access healthcare during lockdown, or due to unrelated diseases. While more analysis and data will be needed to link the past year’s excess deaths to COVID-19, researchers are increasingly relying on excess mortality figures to understand the direct and indirect consequences of the virus.
In Chennai, the data show more than 74,000 deaths in 2020, which is 12,000 more than the average of the five preceding years. That’s a 20 percent increase, despite the fact the city’s official number of reported COVID-19 deaths for that time period was just 4,000.
In other places, public health experts have found even more novel data sources. In Damascus, Syria, public pressure led to the mortuary office releasing data on deaths due to all causes for a limited period of eight days between July 25 and August 1, 2020. Watson, of Imperial College London, matched this information with data from a Facebook group that uploads obituaries.
Using these data points, Watson and his colleagues calculated estimates for the entire duration of the pandemic, from February up until September 2020, to arrive at a staggering figure: Their model shows that only 1.25 percent of COVID-19 deaths in Damascus had been reported as of September 2, 2020, and over 4,380 deaths might have been missed through the official reporting system.
For Watson, the analysis was an eye-opener. “It completely changed how we understood the scale of the pandemic,” he said. ”It was just shocking that you could have that amount of death happen, that level of health system collapse, and how it didn’t get much media attention.”
At first, he says, it was just hard to convince people that the officially reported death toll was inaccurate. But he notes that he has found a sense of community in other researchers who are also willing to question the official data and try various methods to arrive at better estimates.
“Coming across other individuals who are coming at it with an understanding of actually no, we all are missing a lot of what’s actually happened and we need to be doing much better—actually going out there and finding that data—it’s definitely quite a bonding experience,” Watson says.
While acknowledging the benefits of these kinds of creative methods, Rukmini, the data journalist from Chennai, emphasizes that the most accurate data need to be made public by governments.
“While I am all for novel sources, and everyone working on this is doing it out of the spirit of scientific inquiry and obviously working very hard for it, I am a bit concerned that enough democratic pressure is not building for official statistics to be released,” she says.
Chinmay Tumbe, an economist who has studied past pandemics, thinks that relying on government figures would mean that the actual toll would only be revealed in a few years, when census data comes in. But that would be too late for governments, businesses, and other policy-makers to use the data to influence the course of the pandemic.
Getting to the true death toll will eventually help in figuring out the true infection fatality rate, the proportion of all infected people who died because of COVID-19. This value was crucial in the early stage of the pandemic to understand how serious the implications might be if the public health restrictions were not put in place and the virus was allowed to spread freely in populations.
“However, it is very difficult to estimate correctly if we don’t know the true number of people who have died,” Watson says.
He explained that the infection fatality rate for COVID-19 has been a topic of debate. Some people argue that it has been inflated, and they have used that position to discourage lockdowns and other interventions. They also point to lower reported mortality in lower-income settings as evidence that the pandemic is not as deadly as initially thought. “Those arguments are blatantly incorrect, given the scale of underreporting that has been observed,” he says.
That is why researchers need to continue to put pressure on governments to prioritize accurate and timely data collection, Tumbe says. “I think it can easily become a poll issue. And it might even become a manifesto issue—saying that, well, if you elect us, we will form a committee with which we will count the deaths.”
Need for accountability
In some countries, the pressure on the government has worked. Recently, Peru revised its official death count, which now stands at 185,380—almost three times the original figure of 69,342. At 5,551 deaths per million people, Peru has the worst official death toll in the world.
Convincing countries to accept a higher death count than what was officially reported is not going to be an easy task. With the help of the advisory task force, the WHO has a plan, says Asma. By November 2021, the WHO aims to standardize methodology for counting excess deaths, decide what parameters should be used, and have revised estimates for all countries, which will be followed by consultations with representatives of governments.
“We are going to do it in a transparent way, so that is going to be very critical,” she says. That way countries can work with the WHO to flag inconsistencies and land on the most accurate estimates. She believes a dialogue will encourage countries to come to a consensus on the true impact of the pandemic and acknowledge and release better data.
“If data is a public good, it should be open,” she says. “And that is the only way to hold each other accountable.”
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