Differing immune responses discovered in asymptomatic cases versus those with severe COVID-19

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The largest study of its type in the UK has identified differences in the immune response to COVID-19 between people with no symptoms and those suffering a more serious reaction to the virus.

Researchers from the Wellcome Sanger Institute, Newcastle University, University College London, University of Cambridge, EMBL’s European Bioinformatics Institute (EMBL-EBI) and their collaborators within the Human Cell Atlas initiative, found raised levels of specific immune cells in asymptomatic people. They also showed people with more serious symptoms had lost these protective cell types, but gained inflammatory cells. These differences in the immune response could help explain serious lung inflammation and blood clotting symptoms, and could be used to identify potential targets for developing therapies.

The research, published today (20th April 2021) in Nature Medicine, is one of the only studies to include people who were asymptomatic. This large-scale collaborative study is part of the Human Cell Atlas initiative to map every cell type in the human body, to transform our understanding of health, infection and disease.

So far, the COVID-19 global pandemic has caused millions of deaths and many more infections worldwide. Symptoms vary widely in severity and can range from a mild cough to severe respiratory distress, blood clots and organ failure. Several previous studies have highlighted a complex immune response in the blood, but until now the full coordinated immune response and how this differs between symptomatic and asymptotic patients had not been investigated in detail.

In a new study to understand how different immune cells responded to the infection, a large team of researchers came together to analyze blood from 130 people with COVID-19. These patients came from three different UK centers (Newcastle, Cambridge and London) and ranged from asymptomatic to critically severe.

The team performed single-cell sequencing from ~800,000 individual immune cells, along with detailed analysis of cell surface proteins and antigen receptors found on immune cells in the blood. They revealed differences in multiple types of immune cells that are involved in the body’s response to COVID-19.

In those with no symptoms, the team found increased levels of B cells that produce antibodies that are found in mucus passages, such as the nose. These antibodies may be one of our first line of defense in COVID-19. However, these protective B cells were missing in people with serious symptoms, indicating the importance of an effective antibody-associated immune response at the nose and other mucus passages.

The team discovered that whereas patients with mild to moderate symptoms, had high levels of B cells and helper T-cells, which help fight infection, those with serious symptoms had lost many of these immune cells, suggesting that this part of the immune system had failed in people with severe disease.

In contrast, people with more serious symptoms leading to hospitalization had an uncontrolled increase in monocytes and killer T-cells, high levels of which can lead to lung inflammation. Those with severe disease also had raised levels of platelet-producing cells, which help blood to clot.

Professor Muzlifah Haniffa, senior author from Newcastle University and Senior Clinical Fellow at the Wellcome Sanger Institute, said: “This is one of the only studies of its kind that looks at samples collected from asymptomatic people, which helps us start to understand why some people react differently to COVID-19 infection. It could also explain symptoms such as lung inflammation and blood clots. The immune system is made up of lots of different groups of cells, similar to the way an orchestra is made up of different groups of instruments, and in order to understand the coordinated immune response, you have to look at these immune cells together.”

While it is not yet understood how the infection stimulates these immune responses, the study gives a molecular explanation for how COVID-19 could cause an increased risk of blood clotting and inflammation in the lungs, which can lead to the patient needing a ventilator. This also uncovers potential new therapeutic targets to help protect patients against inflammation and severe disease. For example, it may be possible to develop treatments that decrease platelet production or reduce the number of killer T-cells produced, however more research is required.

Professor Menna Clatworthy, senior author and Professor of Translational Immunology at the University of Cambridge and Wellcome Sanger Institute Associate Faculty, said: “This is one of the most detailed studies of immune responses in COVID-19 to date, and begins to help us understand why some people get really sick while others fight off the virus without even knowing they have it. This new knowledge will help identify specific targets for therapy for patients that get sick with COVID-19.”

In the future, research may identify those who are more likely to experience moderate to severe disease by looking at levels of these immune cells in their blood.

This study used samples from three centers in the UK, and found that some antibody responses were similar in individuals in one geographic area compared with those at a different center, hinting that this part of the immune response may be tailored to different variants of the virus.

Dr. John Marioni, senior author and head of research at EMBL’s European Bioinformatics Institute (EMBL-EBI) and Senior Group Leader at the Cancer Research UK Cambridge Institute, said: “Using data from three different centers has allowed us to look at how people react to COVID-19 throughout the UK. The amount of data collected in this study has given us crucial insight into the immune reaction in various different severities of COVID-19 infection.”

Professor Berthold Göttgens, senior author and professor of molecular hematology at the University of Cambridge, said: “Along with the findings, the way this study was conducted is noteworthy, as it was a new way of doing biomedical science. By bringing different experts together, we were able to employ a divide and conquer approach, which allowed us to complete the work in extra quick time. This study required a large teamwork effort, in the middle of the pandemic when labs were being shut down. This was an incredibly rewarding study to work on, with everyone understanding the importance of the work and willing to go the extra mile.”

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Feeling rundown? It could raise your odds for severe COVID

Feeling rundown?  it could raise your odds for severe COVID

Groggy during the day? Feeling burned out at work? That could put you at increased risk for COVID-19 and more severe illness, a new study suggests.

“We found that lack of sleep at night, severe sleep problems and high level of burnout may be risk factors for COVID-19” for frontline health care workers, according to a team led by Dr. Sara Seidelmann, an assistant professor of clinical medicine at Columbia College of Physicians and Surgeons, Stamford Hospital, Conn.

One expert who wasn’t connected to the research said the findings made sense.

“This study reconfirms several items that have been suspected about the relationship of sleep, stress and infectious diseases,” said Dr. Thomas Kilkenny, who directs sleep medicine at Staten Island University Hospital in New York City. “The researchers demonstrate, in a very comprehensive way, that both sleep deprivation through lack of sleep increases both the risk of developing COVID 19 but also the duration of the illness.”

Prior research has found that poor sleep and job burnout are linked with a greater risk for a variety of viral and bacterial infections, so the authors of this new study wanted to find out if they’re also risk factors for COVID-19.

In this latest study, published March 22 in the journal BMJ Nutrition Prevention & Health, they analyzed the responses of nearly 2,900 health care workers in the United States, France, Germany, Italy, Spain and Britain. All had participated in an online survey from July 17 to Sept. 25, 2020. Of those health care workers, 568 reported having gotten infected with the new coronavirus.

The health care workers averaged between 6 and 7 hours of sleep a night.

The study couldn’t prove cause-and-effect, but after the researchers accounted for other factors, they concluded that every extra hour of sleep at night was associated with a 12% lower risk of the worker getting COVID-19.

However, when that extra hour of shuteye took place was crucial. An extra hour of sleep via daytime napping was associated with a 6% higher risk of getting COVID-19, the team noted in a journal news release.

According to Kilkenny, that shows that “staffers that needed to take naps during the day—a surrogate for lack of sleep—were also at an increased risk for the disease.”

About 1 in 4 (24%) of the people who went on to contract COVID-19 had already reported long-term difficulties sleeping at night, compared with about 1 in every 5 (21%) of those who hadn’t gotten the illness.

Seidelmann’s group also found that 5% of those with COVID-19 had three or more sleep problems—including difficulties falling asleep, staying asleep, or needing to use sleeping pills on three or more nights of the week—compared with 3% of those without COVID-19.

People with those three sleep problems were 88% more likely to develop COVID-19 than those with no sleep problems, the study found.

Another finding was that 5.5% of those with COVID-19 reported daily work burnout, compared with 3% of those without COVID-19. Compared to those with no burnout, those with daily burnout had twice the risk of getting COVID-19, and they were about 3 times more likely to have severe COVID-19 and to take longer to recover.

Dr. Harly Greenberg is chief of pulmonary, critical care and sleep Medicine at Northwell Health, in Great Neck, N.Y. He wasn’t involved in the research, but said it “adds to the mounting literature that sleep is much more than simply withdrawing from the environment; rather it is an essential and active biological process that restores brain function including memory, mood, cognition and resiliency to stress.”

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New trial finds arthritis drug tocilizumab no better than standard care for severe COVID-19

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Adding the arthritis drug tocilizumab to standard care for patients in hospital with severe or critical COVID-19 is no better than standard care alone in improving clinical outcomes at 15 days, finds a new trial published by The BMJ today.

There was an increased number of deaths at 15 days in patients receiving tocilizumab, resulting in the trial being stopped early.

Today’s results contradict earlier observational studies suggesting a benefit of tocilizumab. However, observational effects are limited by a high risk that they may be due to other unknown (confounding) factors—and some studies have not yet been peer reviewed or published in a medical journal.

A randomised trial assessing tocilizumab in critically ill patients with COVID-19 (REMAP-CAP) published as a preprint earlier this month, found a beneficial effect of the drug on days free from organ support within 21 days and mortality. Reasons for these apparently contradictory effects, for example differences between patients’ characteristics, need to be assessed in future analysis, say the researchers.

Tocilizumab blocks a specific part of the immune system (interleukin 6) that can go into overdrive in some patients with COVID-19. Doctors think this might help lessen the body’s inflammatory response to the virus and avert some of the more dire consequences of the disease, but its effects are not well defined.

To test this theory, researchers based in Brazil conducted a randomised controlled trial comparing tocilizumab plus standard care with standard care alone in patients admitted to hospital with severe or critical COVID-19.

Their findings are based on 129 relatively young adults (average age 57 years) with confirmed COVID-19 at nine hospitals in Brazil between 8 May and 17 July 2020.

Patients were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two chemicals linked to inflammation in their blood.

Patients were randomly divided into two groups: 65 received tocilizumab plus standard care and 64 received standard care alone.

Other potentially important factors, such as underlying conditions and use of other medication, were taken into account and all patients were monitored for 15 days.

By day 15, 18 (28%) patients in the tocilizumab group and 13 (20%) in the standard care group were receiving mechanical ventilation or died.

Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group.

The increased number of deaths in the tocilizumab group raised safety concerns and the trial was stopped early. In both groups, deaths were attributed to COVID-19 related acute respiratory failure or multiple organ dysfunction.

The researchers point to some limitations including the small sample size, which affects the chances of detecting a true effect. However, results were consistent after adjusting for levels of respiratory support needed by patients at the start of the trial, suggesting that the findings withstand scrutiny.

As such, the researchers conclude that in patients with severe or critical COVID-19, “tocilizumab plus standard care was not superior to standard care alone in improving clinical status at 15 days and might increase mortality.”

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Immune cell activation in severe COVID-19 resembles lupus

In severe cases of COVID-19, Emory researchers have been observing an exuberant activation of immune cells, resembling acute flares of systemic lupus erythematosus (SLE), an autoimmune disease.

Their findings point towards tests that could separate some COVID-19 patients who need immune-calming therapies from others who may not. They also may begin to explain why some people infected with SARS-CoV-2 produce abundant antibodies against the virus, yet experience poor outcomes.

The results were published online on Oct. 7 in Nature Immunology.

The Emory team’s results converge with recent findings by other investigators, who found that high inflammation in COVID-19 may disrupt the formation of germinal centers, structures in lymph nodes where antibody-producing cells are trained. The Emory group observed that B cell activation is moving ahead along an “extrafollicular” pathway outside germinal centers—looking similar to they had observed in SLE.

B cells represent a library of blueprints for antibodies, which the immune system can tap to fight infection. In severe COVID-19, the immune system is, in effect, pulling library books off the shelves and throwing them into a disorganized heap.

Before the COVID-19 pandemic, co-senior author Ignacio (Iñaki) Sanz, MD and his lab were focused on studying SLE and how the disease perturbs the development of B cells.

Sanz is head of the division of rheumatology in the Department of Medicine, director of the Lowance Center for Human Immunology, and a Georgia Research Alliance Eminent Scholar. Co-senior author Frances Eun-Hyung Lee, MD is associate professor of medicine and director of Emory’s Asthma/Allergy Immunology program.

“We came in pretty unbiased,” Sanz says. “It wasn’t until the third or fourth ICU patient whose cells we analyzed, that we realized that we were seeing patterns highly reminiscent of acute flares in SLE.”

In people with SLE, B cells are abnormally activated and avoid the checks and balances that usually constrain them. That often leads to production of “autoantibodies” that react against cells in the body, causing symptoms such as fatigue, joint pain, skin rashes and kidney problems. Flares are times when the symptoms are worse.

Whether severe COVID-19 leads to autoantibody production with clinical consequences is currently under investigation by the Emory team. Sanz notes that other investigators have observed autoantibodies in the acute phase of the disease, and it will be important to understand whether long-term autoimmune responses may be related to the fatigue, joint pain and other symptoms experienced by some survivors.

“It’s an important question that we need to address through careful long-term follow-up,” he says. “Not all severe infections do this. Sepsis doesn’t look like this.”

In lupus, extrafollicular B cell responses are characteristic of African-American patients with severe disease, he adds. In the new study, the majority of patients with severe infection were African-American. It will be important to understand how underlying conditions and health-related disparities drive the intensity and quality of B cell responses in both autoimmune diseases and COVID-19, Sanz says.

The study compared 10 critically ill COVID-19 patients (4 of whom died) admitted to intensive care units at Emory hospitals to 7 people with COVID-19 who were treated as outpatients and 37 healthy controls.

People in the critically ill group tended to have higher levels of antibody-secreting cells early on their infection. In addition, the B cells and the antibodies they made displayed characteristics suggesting that the cells were being activated in an extrafollicular pathway. In particular, the cells underwent fewer mutations in their antibody genes than seen in a focused immune response, which is typically honed within germinal centers.

The Nature Immunology paper was the result of a collaboration across Emory. The co-first authors are Matthew Woodruff, Ph.D., an instructor in Sanz’s lab, and Richard Ramonell, MD, a fellow in pulmonary and critical care medicine at Emory University Hospital.

Ramonell notes that the patients studied were treated early during the COVID-19 pandemic. It was before the widespread introduction of the anti-inflammatory corticosteroid dexamethasone, which has been shown to reduce mortality.

The team’s findings could inform the debate about which COVID-19 patients should be given immunomodulatory treatments, such as dexamethasone or anti-IL-6 drugs. Patients with a greater expansion of B cells undergoing extrafollicular activation also had higher levels of inflammatory cytokines, such as IL-6.

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Blood pressure medications decrease death and severe disease in COVID-19 patients

At the start of the pandemic, there was concern that certain drugs for high blood pressure might be linked with worse outcomes for COVID-19 patients.

Because of how the drugs work, it was feared they would make it easier for the coronavirus to get inside the body’s cells. Nevertheless, many national medical societies advised patients to continue taking their medication.

With the potential for a second wave, it was essential to investigate whether patients could safely continue using these drugs. So, our team at the University of East Anglia set out to discover what effect they have on the progress of COVID-19.

Instead of putting patients at risk, we found that these medications actually lower the risk of death and severe disease in COVID-19 patients.

Bad outcomes cut by one-third

We pooled data from 19 relevant COVID-19 studies that included patients taking two particular types of blood pressure medication: angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). This allowed us to look at the outcomes of more than 28,000 COVID-19 patients to assess the effects of these drugs.

ACEIs and ARBs work by acting on the renin-angiotensin-aldosterone system (RAAS), which is essential for regulating blood pressure and the balance of fluids and electrolytes. These drugs were also thought to potentially increase the expression of a protein found on the surface of cells called angiotensin-converting enzyme 2 (ACE2).

Apart from helping regulate blood pressure, the ACE2 protein is also what allows the coronavirus to enter the body’s cells. This is why there were concerns about patients using these drugs. If the medications increased the amount of ACE2 present on cells, it was suspected they would make it easier for the virus to infect them, worsening a patient’s condition.

But when we looked at the outcomes of patients taking ACEIs and ARBs compared with those not on these medications, this wasn’t the case.

We found no evidence that these medications might increase the severity of COVID-19 or the risk of death. On the contrary, among patients taking ACEIs and ARBs that had been prescribed to treat high blood pressure, there was actually a significantly lower risk of death, being admitted to intensive care or being put on ventilation. We observed a reduction of such events by one-third in this group.

It may be that these medications actually have a protective role—particularly in patients with high blood pressure.

What’s behind this effect?

It’s not clear why patients taking ACEIs and ARBs experienced less severe disease, but there are a couple of points to consider.

The first is that while theoretically these drugs were thought to increase ACE2 levels, there’s no convincing evidence that this actually happens. We don’t have any clinical data on the effects of these drugs on ACE2 expression in human tissue.

And even if these drugs do increase ACE2 levels in cells, not all of it is surface-bound. Additional ACE2 that appears elsewhere in the cell might not function as an entry point for SARS-CoV-2.

There’s also a second potentially relevant piece of information. Infection with SARS-CoV-2 may also lead to an overreaction of the RAAS pathway – which is what these blood pressure drugs target—and inflammation. This increased inflammatory process is thought to be the culprit for acute lung injury and can lead to worsening pneumonia and acute respiratory distress syndrome. Hence, it might be that taking medications that inhibit the RAAS system prevents such a sequence of events and improves clinical outcomes in COVID-19.

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Elevated clotting factor V levels linked to worse outcomes in severe COVID-19 infections

Patients hospitalized with severe COVID-19 infections who have high levels of the blood clotting protein factor V are at elevated risk for serious injury from blood clots such as deep vein thrombosis or pulmonary embolism, investigators at Massachusetts General Hospital (MGH) have found.

On the other hand, critically ill patients with COVID-19 and low levels of factor V appear to be at increased risk for death from a coagulopathy that resembles disseminated intravascular coagulation (DIC), a devastating, often fatal abnormality in which blood clots form in small vessels throughout the body, leading to exhaustion of clotting factors and proteins that control coagulation, report Elizabeth M. Van Cott, MD, investigator in the deparment of pathology at MGH and colleagues.

Their findings, based on studies of patients with COVID-19 in MGH intensive care units (ICUs), point to disturbances in factor V activity as both a potential cause of blood clotting disorders with COVID-19, and to potential methods for identifying at-risk patients with the goal of selecting the proper anticoagulation therapy.

The study results are published online in the American Journal of Hematology.

“Aside from COVID-19, I’ve never seen anything else cause markedly elevated factor V, and I’ve been doing this for 25 years,” Van Cott says.

Patients with severe COVID-19 disease caused by the SARS-CoV-2 virus can develop blood clots in medical lines (intravenous lines, catheters, etc), and in arteries, lungs, and extremities, including the toes. Yet the mechanisms underlying coagulation disorders in patients with COVID-19 are still unknown.

In March 2020, in the early days of the COVID-19 pandemic in Massachusetts, Van Cott and colleagues found that a blood sample from a patient with severe COVID-19 on a ventilator contained factor V levels high above the normal reference range. Four days later, this patient developed a saddle pulmonary embolism, a potentially fatal blood clot occurring at the junction of the left and right pulmonary arteries.

This pointed the investigators to activity of factor V as well as factor VIII and factor X, two other major clotting factors. They studied the levels of these clotting factors and other parameters in a group of 102 consecutive patients with COVID-19, and compared the results with those of current critically ill patients without COVID-19, and with historical controls.

They found that factor V levels were significantly elevated among patients with COVID-19 compared with controls, and that the association between high factor V activity and COVID-19 was the strongest among all clinical parameters studied.

In all, 33 percent of patients with factor V activity well above the reference range had either deep vein thrombosis or a pulmonary embolism, compared with only 13 percent of patients with lower levels. Death rates were significantly higher for patients with lower levels of factor V (30 percent vs. 12 percent), with evidence that this was due to a clinical decline toward a DIC-like state.

Van Cott and colleagues also found that the clinical decline toward DIC was foreshadowed by a measurable change in the shape or “waveform” of a plot charting light absorbance against the time it takes blood to coagulate (waveform of the activated partial thromboplastin time, or aPTT).

“The waveform can actually be a useful tool to help assess patients as to whether their clinical course is declining toward DIC or not,” Van Cott explains. “The lab tests that usually diagnose DIC were not helpful in these cases.”

Importantly, the MGH investigators note that factor V elevation in COVID-19 could cause misdiagnosis of some patients, because under normal circumstances factor V levels are low in the presence of liver dysfunction or DIC. Physicians might therefore mistakenly assume that patients instead have a deficiency in vitamin K.

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Experts make weak recommendation for remdesivir in severe COVID-19

In The BMJ today, a panel of international experts make a weak recommendation for the use of remdesivir in patients with severe covid-19, and strongly support continued enrolment of patients into ongoing clinical trials of remdesivir.

Their advice is part of The BMJ‘s Rapid Recommendations initiative—to produce rapid and trustworthy guidelines for clinical practice based on new evidence to help doctors make better decisions with their patients.

The antiviral medication remdesivir has received worldwide attention as a potentially effective treatment for severe covid-19 and is already being used in clinical practice.

Today’s recommendation is based on a new evidence review comparing the effects of several drug treatments for covid-19 up to 20 July 2020.

It shows that remdesivir may be effective in reducing recovery time in patients with severe covid-19, although the certainty of the evidence is low. But remdesivir probably has no important effect on the need for mechanical ventilation and may have little or no effect on length of hospital stay.

The authors stress that “the effectiveness of most interventions is uncertain because most of the randomised controlled trials so far have been small and have important study limitations.”

After thoroughly reviewing this evidence, the expert panel says that most patients with severe covid-19 would likely choose treatment with remdesivir given the potential reduction in time to clinical improvement.

But given the low certainty evidence, and allowing for different patient perspectives, values, and preferences, they issued a weak recommendation with strong support for continued recruitment in trials.

They suggest that future research should focus on areas such as optimal dose and duration of therapy, and whether there are specific groups of patients most likely to benefit from remdesivir.

The authors also sound a note of caution about the potential opportunity cost of using remdesivir while the evidence base is still uncertain. As a relatively costly drug that is given intravenously, use of remdesivir may divert funds, time, attention, and workforce away from other potentially worthwhile treatments.

The study that today’s recommendation is based on is called a living systematic review.

In a linked editorial, The BMJ editors explain that living systematic reviews are useful in fast moving research areas such as covid-19 because they allow authors to update previously vetted and peer reviewed evidence summaries as new information becomes available.

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