Criteria to predict cytokine storm in COVID-19 patients identified

Like a cold front that moves in, setting the stage for severe weather, coronavirus infection triggers showers of infection-fighting immune molecules—showers that sometimes escalate into a chaotic immune response known as a cytokine storm. About 20 to 30 percent of patients hospitalized with COVID-19 develop severe immune manifestations, in some instances leading to cytokine storm, with life-threatening organ damage and high risk of death.

Predicting which COVID-19 patients will develop cytokine storm is challenging, owing to the many variables that influence immune function. But now, in breakthrough work, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) have developed and validated predictive criteria for early identification of COVID-19 patients who are developing hyperimmune responses, raising the possibility for early therapeutic intervention.

“If we can anticipate cytokine storm, we can apply treatment sooner and possibly decrease mortality,” explained Roberto Caricchio, MD, Chief of the Section of Rheumatology, Director of the Temple Lupus Program, Professor of Medicine and Microbiology and Immunology at LKSOM, and lead author on the new report.

The report, published online in the Annals of the Rheumatic Diseases, is the first to identify criteria that can be readily used in clinical practice to potentially head off the worst of the hyperimmune attack against COVID-19.

The breakthrough is the result of an extensive collaboration between researchers and clinicians across multiple departments in the Lewis Katz School of Medicine and Temple University Hospital, constituting the Temple University COVID-19 Research Group.

According to Dr. Caricchio, large numbers of COVID-19 patients have been treated at Temple since the pandemic emerged in the United States. “We have a significant amount of data in terms of variables to predict cytokine storm,” he said.

Since early March, every patient admitted to Temple University Hospital (TUH) has had data on more than 60 different laboratory variables collected daily until the time of recovery or time of death. Among variables measured every day are factors like white blood cell count, metabolic enzyme activity, and markers of inflammation and respiratory function. Importantly these markers are commonly used in hospitals across the globe and therefore are readily available.

The research group carried out statistical analyses on laboratory data for 513 COVID-19 patients hospitalized at TUH in March and April, 64 of whom developed cytokine storm. A genetic algorithm was used to identify cut-off values for each individual laboratory variable to define the predictive requirements for cytokine storm. Genetic algorithms mimic the processes of natural selection and evolution in analyzing the data, and in this case, over multiple iterations, the algorithm turned up variables indicating which patients are most likely to develop cytokine storm.

Overall, the analyses yielded six predictive criteria comprising three clusters of laboratory results relating to inflammation, cell death and tissue damage, and electrolyte imbalance. In particular, patients in cytokine storm exhibited a proinflammatory status and elevated levels of enzymes indicating significant systemic tissue damage. Moreover, patients who met the criteria had extended hospital stays and were at increased risk of death from COVID-19, with almost half of patients who experienced cytokine storm meeting all criteria within the first day of hospitalization.

The researchers validated the criteria in a subsequent cohort of 258 patients admitted to TUH for COVID-19 infection. “The algorithm correctly predicted cytokine storm in almost 70 percent of patients,” Dr. Caricchio said.

“The ability to reproduce our results in a second cohort of patients means that our group of variables are effective criteria for cytokine storm diagnosis in COVID-19 patients,” he added. The final step now is to have the criteria validated by other centers where COVID-19 patients are admitted for care.

Dr. Caricchio noted that the criteria could be applied to COVID-19 patients at any hospital or level of hospitalization anywhere in the world. “This makes the criteria very valuable for guiding decisions about how to treat COVID-19 patients worldwide,” he said. Applied more broadly, the criteria could greatly facilitate early diagnosis and intervention, helping save many lives.

Source: Read Full Article

Viral ‘molecular scissor’ is next COVID-19 drug target

American and Polish scientists, reporting Oct. 16 in the journal Science Advances, laid out a novel rationale for COVID-19 drug design—blocking a molecular “scissor” that the virus uses for virus production and to disable human proteins crucial to the immune response.

The researchers are from The University of Texas Health Science Center at San Antonio (UT Health San Antonio) and the Wroclaw University of Science and Technology. Information gleaned by the American team helped Polish chemists to develop two molecules that inhibit the cutter, an enzyme called SARS-CoV-2-PLpro.

SARS-CoV-2-PLpro promotes infection by sensing and processing both viral and human proteins, said senior author Shaun K. Olsen, Ph.D., associate professor of biochemistry and structural biology in the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio.

“This enzyme executes a double-whammy,” Dr. Olsen said. “It stimulates the release of proteins that are essential for the virus to replicate, and it also inhibits molecules called cytokines and chemokines that signal the immune system to attack the infection,” Dr. Olsen said.

SARS-CoV-2-PLpro cuts human proteins ubiquitin and ISG15, which help maintain protein integrity. “The enzyme acts like a molecular scissor,” Dr. Olsen said. “It cleaves ubiquitin and ISG15 away from other proteins, which reverses their normal effects.”

Dr. Olsen’s team, which recently moved to the Long School of Medicine at UT Health San Antonio from the Medical University of South Carolina, solved the three-dimensional structures of SARS-CoV-2-PLpro and the two inhibitor molecules, which are called VIR250 and VIR251. X-ray crystallography was performed at the Argonne National Laboratory near Chicago.

“Our collaborator, Dr. Marcin Drag, and his team developed the inhibitors, which are very efficient at blocking the activity of SARS-CoV-2-PLpro, yet do not recognize other similar enzymes in human cells,” Dr. Olsen said. “This is a critical point: The inhibitor is specific for this one viral enzyme and doesn’t cross-react with human enzymes with a similar function.”

Specificity will be a key determinant of therapeutic value down the road, he said.

The American team also compared SARS-CoV-2-PLpro against similar enzymes from coronaviruses of recent decades, SARS-CoV-1 and MERS. They learned that SARS-CoV-2-PLpro processes ubiquitin and ISG15 much differently than its SARS-1 counterpart.

“One of the key questions is whether that accounts for some of the differences we see in how those viruses affect humans, if at all,” Dr. Olsen said.

Source: Read Full Article

US hoping for two Covid-19 vaccines by end of November

Two American companies expect to apply for emergency approval for their COVID-19 vaccines by late November, welcome news as the US hits a third surge of its coronavirus epidemic and approaches its eight millionth case.

Pfizer said Friday it hopes to move ahead with its vaccine after safety data is available in the third week of November, a couple of weeks after the November 3 presidential election.

The announcement means the United States could have two vaccines ready by the end of the year, with Massachusetts biotech firm Moderna aiming for November 25 to seek authorization.

“So let me be clear, assuming positive data, Pfizer will apply for Emergency Authorization Use in the US soon after the safety milestone is achieved in the third week of November,” the company’s chairman and CEO Albert Bourla said in an open letter. The news lifted the company’s shares two percent in the US.

But experts warn that even when vaccines are approved, it will take many months until they are widely available.

In any case, they are unlikely to be a good substitute for mask wearing, social distancing and other recommended behavior to curb transmission because we don’t know how effective they will be.

Indoor gatherings in colder weather

After falling numbers throughout the summer, the country hit an inflection point in its coronavirus outbreak around the second week of September—with a new daily case average of more than 50,000 according to the latest figures, and the trajectory is upward.

With a shade under eight million confirmed infections and more than 217,000 deaths, America is the hardest-hit country in the world.

The US never came close to returning to its baseline after its first wave in spring, meaning the current spike can be more accurately termed a third surge.

Geographically, the major hotspots are in the Upper Midwest and parts of the Rocky Mountains in the west, while parts of the Northeast that were hit hard in spring are seeing their outbreaks starting to rekindle.

Harvard surgeon and health policy researcher Thomas Tsai told AFP there were multiple factors behind the rising cases—from under testing in the Midwest to authorities failing to monitor the reopening of bars and restaurants and dialing back when necessary.

What’s more, “from the contact tracing reports from various municipalities and states, the worry is that the spread is driven now, by indoor social gatherings in people’s homes,” he added, as the focus of social life shifts from public to private spaces in the colder weather.

One bright sign is that COVID-19 treatments have improved markedly, and since the cases are more spread out than before, hospitals aren’t being overwhelmed.

Widespread mask use might also mean that when people do get infected, they have less virus in their body which makes them less sick.

‘No magic bullet’

While vaccines are a crucial tool against the virus, experts have warned they can’t be a substitute for behavioral measures like masks and distancing.

“It’s welcome news that there will be one more thing that can help prevent COVID transmission,” said Priya Sampathkumar, an infectious disease doctor and professor at Mayo Clinic.

“But I think we need to be cautious and understand that a vaccine isn’t a magic bullet,” she added.

Pfizer and Moderna, both funded by the US government, launched Phase 3 of their clinical trials at the end of July, and both were producing their doses at the same time.

They aim to deliver tens of millions of doses in the US by the end of the year.

Both are “mRNA vaccines,” an experimental new platform that has never before been fully approved.

They both inject people with the genetic material necessary to grow the “spike protein” of SARS-CoV-2 inside their own cells, thus eliciting an immune response the body will remember when it encounters the real virus.

This effectively turns a person’s own body into a vaccine factory, avoiding the costly and difficult processes that more traditional vaccine production requires.

Source: Read Full Article

Preliminary results find COVID-19 vaccine candidate based on inactivated SARS-CoV-2 virus is safe

A Chinese COVID-19 vaccine candidate based on the inactivated whole SARS-CoV-2 virus (BBIBP-CorV) is safe and elicits an antibody response, findings from a small early-phase randomised clinical trial published today in The Lancet Infectious Diseases journal have found.

A previous clinical trial reported similar results for a different vaccine that is also based on inactivated whole SARS-CoV-2 virus, but in that study the vaccine was only tested in people aged under 60 years.

The latest study included participants aged between 18 and 80 years, and found that antibody responses were induced in all recipients. Participants aged 60 and over were slower to respond, taking 42 days before antibodies were detected in all recipients compared with 28 days for participants aged 18-59. Antibody levels were also lower in those aged 60-80 years compared with those aged 18-59 (Mean neutralising antibody titre 42 days after receiving a 8μg vaccine dose was 228.7 for people aged 18-59, and 170.9 for those aged 60-80).

The trial was not designed to assess efficacy of the vaccine, so it is not possible to say whether the antibody responses induced by the vaccine, called BBIBP-CorV, are sufficient to protect from SARS-CoV-2 infection.

Professor Xiaoming Yang, one of the authors of the study, from the Beijing Institute of Biological Products Company Limited, Beijing, China, said: “Protecting older people is a key aim of a successful COVID-19 vaccine as this age group is at greater risk of severe illness from the disease. However, vaccines are sometimes less effective in this group because the immune system weakens with age. It is therefore encouraging to see that BBIBP-CorV induces antibody responses in people aged 60 and older, and we believe this justifies further investigation.”

There are currently 42 vaccines for COVID-19 in clinical trials. These vary in type and include DNA plasmid vaccines, inactivated virus vaccines, adenovirus-vectored vaccines, RNA vaccines, protein subunit vaccines and virus-like particle vaccines. Some of these have already been shown to be safe and to elicit immune responses in early phase clinical trials.

The BBIBP-CorV vaccine used in the study reported here is based on a sample of the virus that was isolated from a patient in China. Stocks of the virus were grown in the lab using cell lines and then inactivated using a chemical called beta-proprionolactone. BBIBP-CorV includes the killed virus mixed with another component, aluminium hydroxide, which is called an adjuvant because it is known to boost immune responses.

The first phase of the study was designed to find the optimal safe dose for BBIBP-CorV. It involved 96 healthy volunteers aged between 18 and 59 years and a second group of 96 participants aged between 60 years and 80 years. Within each group, the vaccine was tested at three different dose levels (2μg, 4μg and 8μg, 24 participants per group), with two vaccinations administered on day 0 and 28. A fourth group within each age group (24 participants in each age group) were given two doses of a placebo vaccine. In total, in phase 1 of the study, 144 participants received the vaccine and 48 received the placebo.

The second phase of the study was designed to identify the optimal timing schedule for vaccination. 448 participants aged between 18 and 59 years were randomly assigned to receive either one 8?g shot of vaccine or placebo, or two shots of 4μg vaccine or placebo (at 0 and 14 days, 0 and 21 days or 0 and 28 days). In this second phase, there were 112 participants per group, with 336 receiving the vaccine, and 112 receiving the placebo.

Participants were asked to report any adverse events for the first seven days after each vaccination and these were verified by the research team. Thereafter, participants recorded any adverse events using paper cards for the following 4 weeks. During phase 1, laboratory tests were carried out after the first and second vaccinations to assess kidney function, liver function and other organ functions. Blood samples were taken to test antibody levels for SARS-CoV-2 before and after vaccination.

No serious adverse events were reported within 28 days of the final vaccination. The most common side effect was pain at the injection site (phase 1 results: 24% [34/144] of vaccine recipients, vs 6% [3/48] of placebo recipients). A small number of participants reported experiencing a fever (phase 1 results: 4% [5/144] of vaccine recipients, vs 6% [3/48] of placebo recipients). There were no instances of clinically significant changes in organ functions detected in laboratory tests in any of the groups.

The greatest antibody responses were elicited by two 4μg doses of the vaccine at either days 0 and 21 or 0 and 28 (Mean neutralising antibody titres 28 days after second vaccination were 282.7 for two 4μg injections at day 0 and 21, and 218.0 for two 4μg injections at day 0 and 28).

Professor Xiaoming Yang said: “Our findings indicate that a booster shot is necessary to achieve the greatest antibody responses against SARS-CoV-2 and could be important for protection. This provides useful information for a phase 3 trial.”

The authors noted some limitations with the study, including the short duration of follow up at just 42 days. They also highlighted that the study did not include children and adolescents aged under 18. Trials with these groups will be carried out when the full analysis of data from adult groups is completed, the researchers say.

Source: Read Full Article

Superspreading events could help make COVID-19 endemic

The COVID-19 coronavirus is not your average virus. During the pandemic, it has become increasingly clear that averages do not apply in understanding the paths the virus takes or when or where it attacks. What some scientists and specialists in infectious diseases may say in the morning will be ridiculed before sunset. Consequently, we must be scientifically humble in predicting what is likely to happen over the next year or two.

But from the limited data that we have have, it appears that clusters of transmission from one person to a potentially large group are particularly important to maintaining the virus’s spread. In fact, these so-called superspreading events could be so significant that—without highly effective testing and contact tracing—they could cause COVID-19 to become a constant feature of our lives, even if case numbers are brought to manageable lows.

Scientists and politicians have so far relied heavily on the calculated average contagiousness of the virus to track progress in dealing with the pandemic. This is represented by the “R number”, which basically indicates how many people an infected individual will pass the virus on to. If they infect more than one, then the number of cases will grow and we have a problem. If they infect less than one, we are safer because the number of cases will decrease as people recover.

But being an average measure, R tends to obscure the real picture of a virus that typically spreads in clusters rather than from one person to one or two others. Indeed, sometimes an infected person will cause virtually no spread of the virus while another will infect almost everyone in a crowded room. When so many factors are involved outbreaks are not always predictable and this provides the basis for a future with endemic COVID-19 spread.

For example, a preprint (not yet peer reviewed) study has shown that some outbreaks in nursing homes only occurred after several new introductions of infection. This indicates that what can look like a single outbreak actually is a situation with multiple concurrent but independent introductions of COVID-19.

Another preprint study carried out in New Zealand used genetic sequencing to track how individual strains of the virus were being transmitted. It found that only one in five infections entering the country led to additional cases and most cases were linked to a single transmission cluster. Meanwhile, a single person in South Korea is thought to have infected more than 5,000 people in a large church cluster.

Such clusters of transmission appear to take place under certain conditions that enable the virus to disperse rapidly through a crowd. Crowded indoor places that are badly ventilated and where people are physically or vocally active for a relatively long period seem to create a particular risk. This may be because virus can accumulate in the air in rooms without proper ventilation and allow transmission even when social distancing is taking place.

Research from China has confirmed that ventilation is particularly important. Buses that recirculated air were found to be linked with more cases than those not using recirculation. And, in one case of a transmission cluster in a restaurant, those who sat closest to the ventilation outlet all contracted COVID-19 while none of the customers near the ventilation inlet were infected.

However, what’s puzzling is that this doesn’t explain why some potential superspreading events don’t cause an outbreak, and why there are outbreaks that do not have the known characteristics of a superspreading event. This suggests there are other unknown factors. It looks as if some clusters provide valuable information while others don’t.

Our analysis is skewed by the fact that we only have data for relatively well-defined outbreaks where everybody involved were easily identified, such as tourists on cruise ships, choirs, Zumba dance groups or church congregations. But in real life most outbreaks occur without a clear social setting or in groups where some members are difficult to track down. Further genetic surveillance of outbreaks will probably help us develop our understanding.

It’s also harder to obtain the necessary information to track clusters of infections that come from certain social or cultural groups. For example, stigma or fear of the authorities could discourage some people from reporting their illness. Those taking part in secret or illicit parties might underestimate the risk and consequences of their catching the virus.

Bad luck

Some of the worst initial outbreaks in Italy, China, Ecuador and other places may have been due to sheer bad luck: too many of the known factors occurring in the same place at the same time. It’s not a very clever or scientifically satisfying explanation, but that’s probably a feature of COVID-19 that we must live with for now.

But as Italy and Ecuador have shown, COVID-19 has the potential to turn bad luck into a disaster. This means that even if control measures such as social distancing help us to bring R below 1 and reduce ongoing community spread to relatively low levels, superspreading events can can turn comfort into chaos in a few days.

Those countries that have successfully contained epidemic for significant periods of time, such as New Zealand, have done so through very rigorous contact tracing of the person that starts a cluster of transmission combined with strategic testing. But even in these cases, new outbreaks have occurred.

Source: Read Full Article

New study shows which medical procedures pose COVID-19 risk to health-care providers

Autopsy, airway suctioning and cardiopulmonary resuscitation are among the list of medical procedures that pose a risk of spreading COVID-19 from a patient to their health-care provider by creating aerosols, according to new research published in the journal BMJ Open Respiratory Research by an international team of experts including occupational health, preventive medicine and infectious disease specialists.

The team, led by University of Alberta medicine professor Sebastian Straube, carried out a systematic review of public health guidelines, research papers and policy documents from around the globe to determine which procedures are classified as aerosol-generating.

“What we sought to do was to understand which procedures generate aerosols and therefore require a higher grade of personal protective equipment,” said Straube, who also heads the preventive medicine division of the Faculty of Medicine & Dentistry.

“Where there is 80 percent agreement from a number of different source documents, we are reasonably confident that, yes, the classification of these procedures as aerosol-generating is accurate.”

Straube recommended that further research be done on the short list of procedures for which they found no consensus, such as taking throat swabs.

The team of 19 Canadian, British, American and other researchers includes renowned Oxford University primary care expert Trisha Greenhalgh and first author Tanya Jackson, Straube’s research associate. They came together to share their expertise at the outset of the COVID-19 pandemic and have published rapid reviews on the efficacy of respirator masks versus standard surgical masks, eye protection and shoe covers.

“We are providing a summary of the evidence to inform policy-making decisions and guideline development,” Straube said.

An aerosol is a suspension of fine solid or liquid particles in air, Straube said. “Larger particles settle in a reasonably short distance, and are referred to as ‘droplets’ in the infection control context,” the paper states. “Smaller particles can travel as aerosols on air currents, remaining in the air for longer and distributing over a wide area.”

Straube said the goal is to prevent health-care workers from becoming infected with COVID-19, both to protect them from severe disease as individuals and to maintain staffing levels in health-care systems during the pandemic.

Health-care workers who perform aerosol-generating procedures should wear filtering facepiece respirators, known as N-95 masks in North America, Straube said, along with other personal protective equipment (PPE) such as gloves, gowns and eye protection.

“PPE is typically displayed at the bottom rung of the hierarchy of hazard controls,” Straube said.

Source: Read Full Article

NIH launches trial of antibody drugs against COVID-19

(HealthDay)—A study to assess whether certain approved or experimental drugs are effective against COVID-19 and warrant testing in large clinical trials has been launched by the U.S. National Institutes of Health (NIH).

The research will largely focus on monoclonal antibody medications. These types of drugs garnered headlines last week as President Donald Trump credited one such drug cocktail, made by Regeneron, with helping him recover from his coronavirus infection.

However, the therapy is not yet approved against COVID-19 and is still considered experimental.

“The goal here is to identify as quickly as possible the experimental therapeutics that demonstrate the most clinical promise as COVID-19 treatments and move them into larger-scale testing,” said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID).

According to the NIH, the new phase 2 study will enroll adults hospitalized with COVID-19 at as many as 40 U.S sites and is being conducted by NIAID.

The study will assess the approved monoclonal antibody risankizumab in conjunction with the antiviral drug remdesivir, compared to a placebo plus remdesivir. It will also test the experimental monoclonal antibody lenzilumab with remdesivir, compared to placebo and remdesivir.

Remdesivir has shown benefits for patients with severe COVID-19—so severe they needed supplemental oxygen—and is now considered standard of care for hospitalized COVID-19 patients, the NIH said.

Monoclonal antibodies are laboratory versions of proteins naturally produced by the immune system in response to invading viruses or other pathogens. Some are already approved for non-COVID uses: Risankizumab received U.S. Food and Drug Administration approval in 2019 for the treatment of severe plaque psoriasis.

Lenzilumab is currently being tested separately in a phase 3 COVID-19 study, and in a phase 1b/2 study as sequenced therapy along with CAR-T treatments.

About 100 volunteers will be assigned to each study arm, with each of the study sites testing no more than three treatments at once.

The new study “aims to streamline the pathway to finding urgently needed COVID-19 treatments,” NIH Director Dr. Francis Collins explained in an NIH news release. That might be accomplished “by repurposing either licensed or late-stage-development medicines and testing them in a way that identifies the most promising agents for larger clinical studies in the most expedient way possible,” he said.

Source: Read Full Article

COVID-19 Taking Huge Toll in Excess U.S. Deaths

TUESDAY, Oct. 13, 2020 — A pair of new studies assert that the U.S. response to the COVID-19 pandemic has been a disaster, causing more deaths than thought and prolonging Americans’ suffering more than any other country.

The United States experienced a 20% increase over expected deaths between March and August 2020, with more than 225,500 people needlessly dying, said the lead researcher on the first study, Dr. Steven Woolf. He’s director of the Virginia Commonwealth University Center on Society and Health, in Richmond.

All of those excess deaths can be laid at the feet of the COVID-19 pandemic and the inadequate U.S. response to it, Woolf said.

According to Dr. Amesh Adalja, a senior scholar with the Johns Hopkins Center for Health Security in Baltimore, “The research on excess mortality from COVID-19 really underscores what many of us have seen on a day-to-day basis. This pandemic was earth-shattering for this country, and the reverberations of the pandemic were felt everywhere and extended even to those who were never infected with the virus.”

As a result, the United States is first among developed nations in the number of citizens per capita who have died due to COVID-19.

Worse, the U.S. pandemic continued on through the summer even as other countries managed to gain control over the new coronavirus, the second study reports.

Between May and September, the United States experienced more than 31 excess deaths per 100,000 people, Dr. Ezekiel Emanuel, of the University of Pennsylvania in Philadelphia, and his colleague found.

By comparison, other countries who have lost many people to COVID-19 — Spain, the United Kingdom, Belgium, France, Sweden — had much lower excess death rates due to the pandemic over the summer, as they adopted tactics to halt transmission of the virus.

For example, Sweden had about 15 excess deaths per 100,000, half as many as the United States, and the United Kingdom had about 14 excess deaths per 100,000.

“We knew it was bad. It’s actually even worse,” said Dr. Harvey Fineberg, president of the Gordon and Betty Moore Foundation in Palo Alto, Calif.

The two new studies and an editorial by Fineberg were published online Oct. 12 in the Journal of the American Medical Association.

The 20% increase in U.S. deaths were all related to the pandemic, but not all were caused by the virus, Woolf said. COVID-19 was a documented cause in only 67% of those cases.

“The calculation of excess deaths shows that for every two Americans that we know are dying from COVID-19, an additional American is dying from causes other than COVID-19,” Woolf said.

The other pandemic-related deaths are due to:

  • People not getting care in emergency situations — for example, “the patient with chest pain who’s scared to call 911 because they don’t want to get the virus, and dies of a heart attack,” Woolf said.
  • Patients dying from chronic conditions like diabetes, cancer and heart problems, because they didn’t have access to the medical care that had helped them control their health problems.
  • People suffering from pandemic-related anxiety, depression or stress who either die by suicide or die from an accidental overdose.

“The opioid epidemic hasn’t gone away,” Woolf said. “People under stress trying to cope with the strains of this pandemic may have taken a drug overdose and died. We suspect some of those excess deaths are from these other causes.”

It’s also likely that at least some of these unexplained excess deaths really are due to undetected COVID-19 infections, Woolf added.

Woolf and his team also found that the U.S. struggle with COVID-19 was compounded by decisions in some states to emerge from lockdown prematurely, without any good plan to control virus transmission.

“States like Florida, Texas, Arizona and others that made the choice to reopen early, like in late April or early May, their curves look very different,” Woolf said. “You see a pattern of initially slowly rising and then surging excess deaths in the summer. That dragged out the length of their epidemic.”

By comparison, U.S. states hit hardest early on — such as New York and New Jersey — had an early spike in mid-April that then fell rapidly “because they did a very good job of controlling community spread,” Woolf said.

Combined with the second study’s global comparison, the studies “together say something very important,” Woolf said.

Other countries have taken effective steps to control the pandemic — comprehensive travel bans, production of personal protective equipment (PPE), access to testing, and public health work like contact tracing.

“You find that the U.S. faltered in each of those steps in a rather dramatic way,” Woolf said.

He pointed to the early travel ban that President Donald Trump often cites as proof that his administration effectively responded to the pandemic.

The ban only applied to Chinese nationals, while other countries “really locked down arrivals into their country in a way that the U.S. did not do,” Woolf said.

“U.S. citizens were still flying in from China, but more importantly the virus was coming from Europe and there was no ban imposed there until March,” Woolf said. “Those kinds of shortcomings in our response have led the U.S. to end up with a mortality rate that is exceeding those of other countries.”

Adalja agreed.

“It is also important to remember that we did not have to have this trajectory with the pandemic,” Adalja said. “There were clear actions that could’ve been taken in January, February and March but were not and are still not.”

The United States failed to swing its industrial might behind an effort to develop a testing strategy, Adalja noted.

The United States “also failed to fortify our public health infrastructure despite the fact we knew that this virus is going to come here and it would be a huge burden on case investigators and contact tracers,” he added. “There was also no effort to augment [personal protective equipment] until it became too late. Imagine if we would’ve started thinking about PPE in January and making strategic buys at that point in order to increase supply.”

All of this has added up to a staggering loss of life that, not coincidentally, has ravaged the U.S. economy, Fineberg said.

“The economic consequences of this pandemic are stunning,” he said. “They estimate it has essentially stripped away almost a full year of the whole nation’s productivity, in their estimate a cost of $16 trillion. That’s made up of both direct health costs and other costs to the economy.”

Source: Read Full Article

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.

Source: Read Full Article

Turning hotels into emergency shelters as part of COVID-19 response limited spread of coronavirus

A King County initiative that moved people out of homeless shelters and into hotel rooms earlier this year helped slow the transmission of coronavirus, according to early findings from a study of the intervention.

The intervention also produced other benefits to the people who were relocated, say authors of the joint study from King County Department of Community and Human Services (DCHS) and the University of Washington. Individuals who moved to area hotels—an arrangement managed by the County and social service providers—reported improved physical and mental health, and the ability to focus on long-term goals such as obtaining housing, employment and education, rather than simply focusing on day-to-day survival.

“Moving people from large shelters to individual hotel rooms not only succeeded in slowing the spread of COVID-19, but also provided security, privacy and dignity to hundreds of people in our region experiencing homelessness,” said King County Executive Dow Constantine. “This study conclusively demonstrates the positive impacts of providing our most vulnerable neighbors a place to call their own and 24/7 support, and it underscores the urgency in expanding these efforts in the coming months.”

The research is being presented Wednesday to the Washington Low-Income Housing Alliance Conference on Ending Homelessness.

“Everything we know about homelessness reinforces that we need to remove the crisis of homelessness to allow people to move forward,” said Rachel Fyall, an associate professor of public policy at the UW and one of the study’s authors. “We know that from housing interventions, and what we know of mental health and getting to a place of stability, this intervention—while not perfect and not a substitute for housing—is closer to what we think might create conditions for someone to move on.”

When the first cases of coronavirus, and information about the infectious nature of the disease, emerged in late winter, Seattle and King County sought alternatives for people staying in homeless shelters, both by relocating individuals and reconfiguring existing shelter spaces to allow for social distancing.

Beginning in April, the county leased hotel rooms in Seattle, Bellevue, Renton and SeaTac, with management by four local housing service providers. The rooms have since served as temporary shelter for more than 800 people, and the hotels are not open to other guests.

Initial findings from the study of the hotel intervention showed that it achieved its primary goal: to slow the spread of COVID-19 among people experiencing homelessness. Researchers found fewer clusters and outbreaks of COVID-19 among individuals who stayed in hotels than among those who remained in traditional, large-group shelter settings.

“This emergency intervention is an example of an effective public response under very challenging circumstances that kept large numbers of highly vulnerable people safe during a pandemic,” said Gregg Colburn, an assistant professor of real estate at the UW who specializes in housing affordability issues.

King County is evaluating how to continue and expand the program during and beyond the pandemic, incorporating information from people who have stayed at the hotels, social service providers and neighboring businesses. The county has extended the hotel leases through January 2021. The King County Council is also currently reviewing a proposal from the County Executive as part of the 2021-2022 biennial budget to purchase single-room properties such as hotels and nursing homes to create emergency housing and move as many as 2,000 people out of homelessness.

“Our service providers met the moment. They shifted from congregate shelters to hotels on a week’s notice, and they kept their residents safe, slowed our entire community’s spread of COVID, and tested a better approach that we are now trying to bring to scale in partnership with cities across the County,” said Leo Flor, director of King County’s Department of Community and Human Services. “This report provides strong evidence that we can slow the spread of disease and turn the tide on chronic homelessness. Housing is a foundation for health at the individual and community levels.”

Shortly after the program launched in the spring, evaluators with DCHS partnered with UW researchers Colburn and Fyall to study the effectiveness of the hotel intervention in protecting people from COVID-19.

With support from the social services agencies managing the intervention, researchers interviewed nearly two dozen people, as well as several staff members, at four hotels over the summer. The study also relied on data from the King County Homeless Management Information System, the Washington Disease Reporting System and Seattle Fire 911 dispatches to local agencies.

In addition to the findings related to disease transmission, researchers found that staff and individuals staying in the hotels reported other benefits:

  • Increased feelings of stability associated with consistent access to a private room;
  • Improved health and well-being, including sleep, hygiene and mental health;
  • Reduced conflict, as evidenced by declines in 911 call volume from shelters;
  • More time to think about and take steps toward future goals;
  • Higher rates of exits to permanent housing.
  • Researchers found that basic hotel features contributed to the program’s success. Individuals had secure, private rooms; consistent access to meals; and the ability to store belongings and the freedom to come and go.

“What we learned from our interviews was how incredibly grateful the people were who moved to hotels. It was a total life-changer for them,” said Colburn. “A little privacy, good sleep, and consistent meals can have a very significant impact on individual well-being.”

Source: Read Full Article