Researchers at George Washington University tested the blood of 299 COVID-19 patients hospitalized at the school’s facility
Of those, 200 had all five biomarkers linked to inflammation and blood vessel problems
Higher levels of any or all of the biomarkers were linked to greater risks of ICU admission or needing to be put on a mechanical ventilator
Patients with levels the highest levels of two of the five biomarkers were at greatest risk of death, suggesting blood tests could indicate who gets sickest
PUBLISHED: 19:22 EST, 11 August 2020 | UPDATED: 10:41 EST, 12 August 2020
Researchers at George Washington University (GWU) believe that a simple blood test could predict which coronavirus patients could become deathly ill.
The scientists have identified five biomarkers that indicate risks of complications like inflammation and bleeding disorders that make someone more likely to die if they contract coronavirus.
High levels of two of these blood indicators, in particular, are linked to far greater odds of dying from the infection.
The GWU team believes a blood test for these biomarkers could give doctors a clearer picture of who might need ventilator support or early aggressive treatment with a more finely tuned tool than general risk factors like age and underlying conditions.
A blood test for five biomarkers of inflammation and blood vessel malfunctions could help doctors predict which coronavirus patients are at greatest risk of death, a new study suggests
People over the age of 65 and those with underlying conditions are typically less able to fight off any infection, not just COVID-19.
But coronavirus has proven deadly to scores of otherwise healthy, relatively young people too – and scientists are still not sure exactly why some COVID-19 patients quickly spiral downward and others have no symptoms at all.
And knowing who might need the most aggressive care is critical for hospitals when the threat of drug and supply shortages looms.
New York City narrowly avoided a shortage of ventilators when it became the global epicenter of the pandemic in March and April.
Several hospitals in hard-hit parts of Texas completely ran out of beds for coronavirus patients (or others) as cases spiked there in June and July.
Even though Texas and other sunbelt states are seeing fewer new cases per day, hospitalization rates remain high. Florida reported a new record high number of coronavirus deaths in a single day on Tuesday and cases continue to climb in states like Georgia, Alabama, Illinois and Illinois.
And nationwide, there are still shortages of drugs needed for patients on mechanical ventilators and of the only FDA-authorized treatment, remdesivir.
Treating any and all patients sick enough to need to be hospitalized as early as possible is the best course of action – but it’s also a luxury doctors may not have the needed supplies are so precious.
Grim though it may sound, health care providers may have to choose for one patient to get treatment over another – and a blood test could make these decisions both easier and more likely to be the correct ones.
‘When we first started treating COVID-19 patients, we watched them get better or get worse, but we didn’t know why,’ said Dr Juan Reyes, study co-author and assistant professor at GW School of Medicine.
‘Some initial studies had come out of China showing certain biomarkers were associated with bad outcomes. There was a desire to see if that was true for our patients here in the US.’
The data that Dr Reyes and his colleagues saw out of China inspired them to assess the blood levels of five biomarkers in COVID-19 patients at GW Hospital.
The biomarkers they looked at were:
IL-6, which is short for interleukin 6, one of several cytokine immune cells that raises the alarm to other parts of the immune cell and can indicate out of control inflammation.
D-dimers, which are bits of degraded protein detectable in the blood after a clot disintegrates, and signal that the virus may be attacking blood vessels.
CRP, or C-reactive protein, which is released by the liver in response to inflammation.
LDH, or Lactate Dehydrogenase, an enzyme in lactic acid that the body sends to heal damaged tissues.
Ferritin, a protein that helps the body’s cells store iron. Iron in turn, is crucial for healthy red blood cells that carry oxygen throughout the body. Too much or too little ferritin can signal anemia or an infection that’s impairing blood cell function.
Of the 299 COVID-19 patients whose blood they tested, the researchers found all five biomarkers in 200.
Patients with higher levels any or all of these biomarkers were more likely to need to be treated in the ICU or put on ventilators.
High LDH levels (greater than 1200 units/l) or high D-dimer levels (greater than 3 μg/ml) predicted the greatest risks that patients would die of coronavirus.
‘We hope these biomarkers help physicians determine how aggressively they need to treat patients, whether a patient should be discharged, and how to monitor patients who are going home, among other clinical decisions,’ said Dr Shant Ayanian, an assistant professor and the study’s first author.
While the latest research suggests that antibodies against Covid-19 could be lost in just three months, a new hope has appeared on the horizon: the enigmatic T cell.
The clues have been mounting for a while. First, scientists discovered patients who had recovered from infection with Covid-19, but mysteriously didn’t have any antibodies against it. Next it emerged that this might be the case for a significant number of people. Then came the finding that many of those who do develop antibodies seem to lose them again after just a few months.
In short, though antibodies have proved invaluable for tracking the spread of the pandemic, they might not have the leading role in immunity that we once thought. If we are going to acquire long-term protection, it looks increasingly like it might have to come from somewhere else.
But while the world has been preoccupied with antibodies, researchers have started to realise that there might be another form of immunity – one which, in some cases, has been lurking undetected in the body for years. An enigmatic type of white blood cell is gaining prominence. And though it hasn’t previously featured heavily in the public consciousness, it may well prove to be crucial in our fight against Covid-19. This could be the T cell’s big moment.
When researchers tested blood samples taken years before the pandemic started, they found T cells which were specifically tailored to detect proteins on the surface of Covid-19
T cells are a kind of immune cell, whose main purpose is to identify and kill invading pathogens or infected cells. It does this using proteins on its surface, which can bind to proteins on the surface of these imposters. Each T cell is highly specific – there are trillions of possible versions of these surface proteins, which can each recognise a different target. Because T cells can hang around in the blood for years after an infection, they also contribute to the immune system’s “long-term memory” and allow it to mount a faster and more effective response when it’s exposed to an old foe.
Several studies have shown that people infected with Covid-19 tend to have T cells that can target the virus, regardless of whether they have experienced symptoms. So far, so normal. But scientists have also recently discovered that some people can test negative for antibodies against Covid-19 and positive for T cells that can identify the virus. This has led to suspicions that some level of immunity against the disease might be twice as common as was previously thought.
Most bizarrely of all, when researchers tested blood samples taken years before the pandemic started, they found T cells which were specifically tailored to detect proteins on the surface of Covid-19. This suggests that some people already had a pre-existing degree of resistance against the virus before it ever infected a human. And it appears to be surprisingly prevalent: 40-60% of unexposed individuals had these cells.
Aids is primarily a disease of T cells, which are systematically eliminated by HIV in patients who are infected by the virus (Credit: Martin Keene/PA)
It looks increasingly like T cells might be a secret source of immunity to Covid-19.
The central role of T cells could also help to explain some of the quirks that have so far eluded understanding – from the dramatic escalation in risk that people face from the virus as they get older, to the mysterious discovery that it can destroy the spleen.
Deciphering the importance of T cells isn’t just a matter of academic curiosity. If scientists know which aspects of the immune system are the most important, they can direct their efforts to make vaccines and treatments that work.
How immunity unfolds
Most people probably haven’t thought about T cells, or T lymphocytes as they are also known, since school, but to see just how crucial they are for immunity, we can look to late-stage Aids. The persistent fevers. The sores. The fatigue. The weight loss. The rare cancers. The normally harmless microbes, such as the fungus Candida albicans – usually found on the skin – which start to take over the body.
Over the course of months or years, HIV enacts a kind of T cell genocide, in which it hunts them down, gets inside them and systematically makes them commit suicide. “It wipes out a large fraction of them,” says Adrian Hayday, an immunology professor at King’s College London and group leader at the Francis Crick Institute. “And so that really emphasises how incredibly important these cells are – and that antibodies alone are not going to get you through.”
During a normal immune response – to, let’s say, a flu virus – the first line of defence is the innate immune system, which involves white blood cells and chemical signals that raise the alarm. This initiates the production of antibodies, which kick in a few weeks later.
“And in parallel with that, starting out about four or five days after infection, you begin to see T cells getting activated, and indications they are specifically recognising cells infected with the virus,” says Hayday. These unlucky cells are then dispatched quickly and brutally – either directly by the T cells themselves, or by other parts of the immune system they recruit to do the unpleasant task for them – before the virus has a chance to turn them into factories that churn out more copies of itself.
There’s growing evidence that some people might have a hidden reservoir of protection from Covid-19 (Credit: Getty Images)
The good and bad news
So, what do we know about T cells and Covid-19?
“Looking at Covid-19 patients – but also I’m happy to say, looking at individuals who have been infected but did not need hospitalisation – it’s absolutely clear that there are T cell responses,” says Hayday. “And almost certainly this is very good news for those who are interested in vaccines, because clearly we’re capable of making antibodies and making T cells that see the virus. That’s all good.”
In fact, one vaccine – developed by the University of Oxford – has already been shown to trigger the production of these cells, in addition to antibodies. It’s still too early to know how protective the response will be, but one member of the research group told BBC News that the results were “extremely promising”. (Read more about the Oxford University vaccine and what it’s like to be part of the trial).
There is a catch, however. In many patients who are hospitalised with more serious Covid-19, the T cell response hasn’t quite gone to plan.
“Vast numbers of T cells are being affected,” says Hayday. “And what is happening to them is a bit like a wedding party or a stag night gone wrong – I mean massive amounts of activity and proliferation, but the cells are also just disappearing from the blood.”
One theory is that these T cells are just being redirected to where they’re needed most, such as the lungs. But his team suspects that a lot of them are dying instead.
“Autopsies of Covid-19 patients are beginning to reveal what we call necrosis, which is a sort of rotting,” he says. This is particularly evident in the areas of the spleen and lymph glands where T cells normally live.
Disconcertingly, spleen necrosis is a hallmark of T cell disease, in which the immune cells themselves are attacked. “If you look in post-mortems of Aids patients, you see these same problems,” says Hayday. “But HIV is a virus that directly infects T cells, it knocks on the door and it gets in.” In contrast, there is currently no evidence that the Covid-19 virus is able to do this.
“There are potentially many explanations for this, but to my knowledge, nobody has one yet,” says Hayday. “We have no idea what is happening. There’s every evidence that the T cells can protect you, probably for many years. But when people get ill, the rug seems to be being pulled from under them in their attempts to set up that protective defence mechanism.”
T cells can lurk in the body for years after an infection is cleared, providing the immune system with a long-term memory (Credit: Reuters/Alkis Konstantinidis)
Dwindling T cells might also be to blame for why the elderly are much more severely affected by Covid-19.
The follow-up study produced similar results, but the twist was that this time the mice were allowed to grow old. As they did so, their T cell responses became significantly weaker.
However, in the same experiment, the scientists also exposed mice to a flu virus. And in contrast to those infected with Covid-19, these mice managed to hold onto their T cells that acted against influenza well into their twilight years.
“It’s an attractive observation, in the sense that it could explain why older individuals are more susceptible to Covid-19,” says Hayday. “When you reach your 30s, you begin to really shrink your thymus [a gland located behind your sternum and between your lungs, which plays an important role in the development of immune cells] and your daily production of T cells is massively diminished.”
What does this mean for long-term immunity?
“With the original Sars virus [which emerged in 2002], people went back to patients and definitely found evidence for T cells some years after they these individuals were infected,” says Hayday. “This is again consistent with the idea that these individuals carried protective T cells, long after they had recovered.”
The fact that coronaviruses can lead to lasting T cells is what recently inspired scientists to check old blood samples taken from people between 2015 and 2018, to see if they would contain any that can recognise Covid-19. The fact that this was indeed the case has led to suggestions that their immune systems learnt to recognise it after being encountering cold viruses with the similar surface proteins in the past.
This raises the tantalising possibility that the reason some people experience more severe infections is that they haven’t got these hoards of T cells which can already recognise the virus. “I think it’s fair to say that the jury is still out,” says Hayday.
Unfortunately, no one has ever verified if people make T cells against any of the coronaviruses that give rise to the common cold. “To get funding to study this would have required a pretty Herculean effort,” says Hayday. Research into the common cold fell out of fashion in the 1980s, after the field stagnated and scientists began to move to other projects, such as studying HIV. Making progress since then has proved tricky, because the illness can be caused by any one of hundreds of viral strains – and many of them have the ability to evolve rapidly.
While antibodies are still important for tracking the spread of Covid-19, they might not save us in the end (Credit: Reuters)
Will this lead to a vaccine?
If old exposures to cold viruses really are leading to milder cases of Covid-19, however, this bodes well for the development of a vaccine – since it’s proof that lingering T cells can provide significant protection, even years after they were made.
But even if this isn’t what’s happening, the involvement of T cells could still be beneficial – and the more we understand what’s going on, the better.
Hayday explains that the way vaccines are designed generally depends on the kind of immune response scientists are hoping to elicit. Some might trigger the production of antibodies – free-floating proteins which can bind to invading pathogens, and either neutralise them or tag them for another part of the immune system to deal with. Others might aim to get T cells involved, or perhaps provoke a response from other parts of the immune system.
“There really is an enormous spectrum of vaccine design,” says Hayday. He’s particularly encouraged by the fact that the virus is evidently highly visible to the immune system, even in those who are severely affected. “So if we can stop whatever it’s doing to the T cells of the patients we’ve had the privilege to work with, then we will be a lot further along in controlling the disease.”
It seems likely that we are going to be hearing a lot more about T cells in the future.
Determining blood type in the ABO group system. Credit: Getty Images
Since the start of the COVID-19 pandemic several months ago, scientists have been puzzling over the different ways the disease manifests itself. They range from cases with no symptoms at all to severe ones that involve acute respiratory distress syndrome, which can be fatal. What accounts for this variability? Might the answer lie in our genes?
Coronaviruses have raised such questions for more than 15 years. In researching the 2003 outbreak of severe acute respiratory syndrome (SARS), Ralph Baric and his colleagues at the University of North Carolina at Chapel Hill identified a gene that, when silenced by a mutation, makes mice highly susceptible to SARS-CoV, the coronavirus that causes the disease. Called TICAM2, the gene codes for a protein that helps activate a family of receptors, called toll-like receptors (TLRs), that are involved in innate immunity, the first line of defense against pathogens.
Attention has now shifted to SARS-CoV-2, the new coronavirus that causes COVID-19. And TLRs have once again drawn researchers’ interest—this time to help explain the excess number of men who suffer from severe infections.
Men made up 73 percent of severe cases of COVID-19 in intensive care in France, according to a national survey published April 23. Behavioral and hormonal differences may be partially responsible. But genes may also factor into the mix. Unlike men, women have two X chromosomes and so carry double the copies of the gene TLR7, a key detector of viral activity that helps boost immunity.
The genetics of blood groups may offer some insight into whether you are liable to be infected with the virus. In late March Peng George Wang of the Southern University of Science and Technology in China and his colleagues released the results of a preprint study—not yet peer-reviewed—that compared the distribution of blood types among 2,173 COVID-19 patients in three hospitals in the Chinese cities of Wuhan and Shenzhen with that of uninfected people in the same areas. Blood type A appears to be associated with a higher risk of contracting the virus, whereas type O offers the most protection for reasons that have yet to be determined.
The novel coronavirus disease-2019 (COVID-19) has been spreading around the world rapidly and declared as a pandemic by WHO. Here, we compared the ABO blood group distribution in 2,173 patients with COVID-19 confirmed by SARS-CoV-2 test from three hospitals in Wuhan and Shenzhen, China with that in normal people from the corresponding regions. The results showed that blood group A was associated with a higher risk for acquiring COVID-19 compared with non-A blood groups, whereas blood group O was associated with a lower risk for the infection compared with non-O blood groups. This is the first observation of an association between the ABO blood type and COVID-19. It should be emphasized, however, that this is an early study with limitations. It would be premature to use this study to guide clinical practice at this time, but it should encourage further investigation of the relationship between the ABO blood group and the COVID-19 susceptibility.
Infectious diseases have a profound impact on our health and many studies suggest that host genetics play a major role in the pathogenesis of most of them. We perform 23 genome-wide association studies for common infections and infection-associated procedures, including chickenpox, shingles, cold sores, mononucleosis, mumps, hepatitis B, plantar warts, positive tuberculosis test results, strep throat, scarlet fever, pneumonia, bacterial meningitis, yeast infections, urinary tract infections, tonsillectomy, childhood ear infections, myringotomy, measles, hepatitis A, rheumatic fever, common colds, rubella and chronic sinus infection, in over 200,000 individuals of European ancestry. We detect 59 genome-wide significant (P < 5 × 10-8) associations in genes with key roles in immunity and embryonic development. We apply fine-mapping analysis to dissect associations in the human leukocyte antigen region, which suggests important roles of specific amino acid polymorphisms in the antigen-binding clefts. Our findings provide an important step toward dissecting the host genetic architecture of response to common infections. Susceptibility to infectious diseases is, among others, influenced by the genetic landscape of the host. Here, Tian and colleagues perform genome-wide association studies for 23 common infections and find 59 risk loci for 17 of these, both within the HLA region and non-HLA loci.
Recent genome-wide studies have reported novel associations between common polymorphisms and susceptibility to many major infectious diseases in humans. In parallel, an increasing number of rare mutations underlying susceptibility to specific phenotypes of infectious disease have been described. Together, these developments have highlighted a key role for host genetic variation in determining the susceptibility to infectious disease. They have also provided insights into the genetic architecture of infectious disease susceptibility and identified immune molecules and pathways that are directly relevant to the human host defence.
