‘Breakthrough finding’ reveals why certain Covid-19 patients die

https://www.yahoo.com/news/why-covid-19-kills-certain-100211975.html

Dr. Megan Ranney has learned a lot about Covid-19 since she began treating patients with the disease in the emergency department in February.

But there’s one question she still can’t answer: What makes some patients so much sicker than others?

Advancing age and underlying medical problems explain only part of the phenomenon, said Ranney, who has seen patients of similar age, background and health status follow wildly different trajectories.

“Why does one 40-year-old get really sick and another one not even need to be admitted?” asked Ranney, an associate professor of emergency medicine at Brown University.

In some cases, provocative new research shows, some people — men in particular — succumb because their immune systems are hit by friendly fire. Researchers hope the finding will help them develop targeted therapies for those patients.

In an international study in Science, 10 percent of nearly 1,000 Covid-19 patients who developed life-threatening pneumonia had antibodies that disable key immune system proteins called interferons. These antibodies — known as autoantibodies, because they attack the body itself — weren’t found at all in 663 people with mild or asymptomatic Covid-19 infections. Only four of 1,227 healthy patients had the autoantibodies. The study was led by the Covid Human Genetic Effort, which includes 200 research centers in 40 countries.

“This is one of the most important things we’ve learned about the immune system since the start of the pandemic,” said Dr. Eric Topol, executive vice president for research at Scripps Research in San Diego, who wasn’t involved in the new study. “This is a breakthrough finding.”

In a second Science study by the same team, the authors found that an additional 3.5 percent of critically ill patients had mutations in genes that control the interferons involved in fighting viruses. Given that the body has 500 to 600 of those genes, it’s possible that researchers will find more mutations, said Qian Zhang, lead author of the second study.

Interferons serve as the body’s first line of defense against infection, sounding the alarm and activating an army of virus-fighting genes, said virologist Angela Rasmussen, an associate research scientist at the Center for Infection and Immunity at Columbia University’s Mailman School of Public Health.

“Interferons are like a fire alarm and a sprinkler system all in one,” said Rasmussen, who wasn’t involved in the new studies.

Lab studies show that interferons are suppressed in some people with Covid-19, perhaps by the virus itself.

Interferons are particularly important for protecting the body against new viruses, such as the coronavirus, which the body has never encountered, said Zhang, a researcher at Rockefeller University’s St. Giles Laboratory of Human Genetics of Infectious Diseases.

When infected with the novel coronavirus, “your body should have alarms ringing everywhere,” Zhang said. “If you don’t get the alarm out, you could have viruses everywhere in large numbers.”

Significantly, patients didn’t make autoantibodies in response to the virus. Instead, they appeared to have had them before the pandemic even began, said Paul Bastard, the antibody study’s lead author, who is also a researcher at Rockefeller University.

For reasons that researchers don’t understand, the autoantibodies never caused a problem until patients were infected with Covid-19, Bastard said. Somehow, the coronavirus, or the immune response it triggered, appears to have set them in motion.

“Before Covid, their condition was silent,” Bastard said. “Most of them hadn’t gotten sick before.”

Bastard said he now wonders whether autoantibodies against interferon also increase the risk from other viruses, such as influenza. Among patients in his study, “some of them had gotten flu in the past, and we’re looking to see if the autoantibodies could have had an effect on flu.”

Scientists have long known that viruses and the immune system compete in a sort of arms race, with viruses evolving ways to evade the immune system and even suppress its response, said Sabra Klein, a professor of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health.

Antibodies are usually the heroes of the immune system, defending the body against viruses and other threats. But sometimes, in a phenomenon known as autoimmune disease, the immune system appears confused and creates autoantibodies. This occurs in diseases such as rheumatoid arthritis, when antibodies attack the joints, and Type 1 diabetes, in which the immune system attacks insulin-producing cells in the pancreas.

Although doctors don’t know the exact causes of autoimmune disease, they’ve observed that the conditions often occur after viral infections. Autoimmune diseases are more common as people age.

In yet another unexpected finding, 94 percent of patients in the study with the autoantibodies were men. About 12.5 percent of men with life-threatening Covid-19 pneumonia had autoantibodies against interferon, compared with 2.6 percent of women.

That was unexpected, given that autoimmune disease is far more common in women, Klein said.

“I’ve been studying sex differences in viral infections for 22 years, and I don’t think anybody who studies autoantibodies thought this would be a risk factor for Covid-19,” Klein said.

The study might help explain why men are more likely than women to become critically ill with Covid-19 and die, Klein said.

“You see significantly more men dying in their 30s, not just in their 80s,” she said.

Akiko Iwasaki, a professor of immunobiology at the Yale School of Medicine, noted that several genes involved in the immune system’s response to viruses are on the X chromosome.

Women have two copies of this chromosome — along with two copies of each gene. That gives women a backup in case one copy of a gene becomes defective, Iwasaki said.

Men, however, have only one copy of the X chromosome. So if there is a defect or a harmful gene on the X chromosome, they have no other copy of the gene to correct the problem, Iwasaki said.

Bastard noted that one woman in the study who developed autoantibodies has a rare genetic condition in which she has only one X chromosome.

Women more likely to be ‘long-haulers’

Scientists have struggled to explain why men have a higher risk of hospitalization and death from Covid-19. When the disease first appeared in China, experts speculated that men suffered more from the virus because they are much more likely to smoke than Chinese women.

Researchers quickly noticed that men in Spain were also more likely to die of Covid-19, however, even though men and women there smoke at about the same rate, Klein said.

Experts have hypothesized that men might be put at higher risk by being less likely to wear masks in public than women and more likely to delay seeking medical care, Klein said.

But behavioral differences between men and women provide only part of the answer. Scientists say it’s possible that the hormone estrogen may somehow protect women, while testosterone may put men at greater risk. Interestingly, recent studies have found that obesity poses a much greater risk to men with Covid-19 than to women, Klein said.

Yet women have their own form of suffering from Covid-19.

Studies show that women are four times more likely to experience long-term Covid-19 symptoms, lasting weeks or months, including fatigue, weakness and a kind of mental confusion known as “brain fog,” Klein said.

As women, “maybe we survive it and are less likely to die, but then we have all these long-term complications,” she said.

After reading the studies, Klein said she would like to learn whether patients who become severely ill from other viruses, such as influenza, also harbor genes or antibodies that disable interferon.

“There’s no evidence for this in flu,” Klein said. “But we haven’t looked. Through Covid-19, we may have uncovered a very novel mechanism of disease, which we could find is present in a number of diseases.”

To be sure, scientists say the new study solves only part of the mystery of why patient outcomes can vary so greatly.

Researchers say it’s possible that some patients are protected by previous exposure to other coronaviruses. Patients who get very sick also may have inhaled higher doses of the virus, such as from repeated exposure to infected co-workers.

Although doctors have looked for links between disease outcomes and blood type, studies have produced conflicting results.

Screening patients for autoantibodies against interferons could help predict which patients are more likely to become very sick, said Bastard, who is also affiliated with the Necker Hospital for Sick Children in Paris. Testing takes about two days. Hospitals in Paris can now screen patients on request from a doctor, he said.

Although only 10 percent of patients with life-threatening Covid-19 have autoantibodies, “I think we should give the test to everyone who is admitted,” Bastard said. Otherwise, “we wouldn’t know who is at risk for a severe form of the disease.”

Bastard said he hopes his findings will lead to new therapies that save lives. He noted that the body manufactures many types of interferons. Giving patients a different type of interferon — one not disabled by their genes or autoantibodies — might help them fight off the virus.

In fact, a pilot study of 98 patients published Thursday in the Lancet Respiratory Medicine journal found benefits from an inhaled form of interferon. In the industry-funded British study, hospitalized Covid-19 patients randomly assigned to receive interferon beta-1a were more than twice as likely as others to recover enough to resume their regular activities.

Researchers need to confirm the findings in a much larger study, said Dr. Nathan Peiffer-Smadja, a researcher at Imperial College London who wasn’t involved in the study but wrote an accompanying editorial. Future studies should test patients’ blood for genetic mutations and autoantibodies against interferon to see whether they respond differently from others.

Peiffer-Smadja said inhaled interferon may work better than an injected form of the drug because it’s delivered directly to the lungs. While injected versions of interferon have been used for years to treat other diseases, the inhaled version is still experimental and not commercially available.

And doctors should be cautious about interferon for now, because a study led by the World Health Organization found no benefit to an injected form of the drug in Covid-19 patients, Peiffer-Smadja said. In fact, there was a trend toward higher mortality rates in patients given interferon, although the finding could have been due to chance. Giving interferon later in the course of disease could encourage a destructive immune overreaction called a cytokine storm, in which the immune system does more damage than the virus.

Around the world, scientists have launched more than 100 clinical trials of interferons, according to clinicaltrials.gov, a database of research studies from the National Institutes of Health.

Until larger studies are completed, doctors say, Bastard’s findings are unlikely to change how they treat Covid-19.

Dr. Lewis Kaplan, president of the Society of Critical Care Medicine, said he treats patients according to their symptoms, not their risk factors.

“If you are a little sick, you get treated with a little bit of care,” Kaplan said. “You are really sick, you get a lot of care. But if a Covid patient comes in with hypertension, diabetes and obesity, we don’t say: ‘They have risk factors. Let’s put them in the ICU.'”

What You Need To Know About Pfizer’s Covid-19 Vaccine

Pfizer's Covid-19 Vaccine Is 90% Effective, But Has Storage & Shipping  Issues | Boomers Daily

On Monday, Pfizer announced preliminary results from the phase 3 trial of the vaccine that it has developed with German company BioNTech, suggesting that it may be up to 90% effective at preventing Covid-19 with no serious safety concerns. The vaccine, which represents a new way to make a vaccine, might be ready for an Emergency Use Authorization from the FDA by the end of the year. 

BioNTech’s vaccine is an mRNA (as in “messenger RNA,” which might ring a faint bell from high school biology class) vaccine, similar to one being developed by Boston-based Moderna as well as Translate Bio, which is partnered with pharmaceutical giant Sanofi. This type of vaccine has been in the works for other diseases, including the flu, but none have been approved for use by any regulatory body yet. Success with this platform has the potential to accelerate the development of vaccines for new diseases, a process which can typically take close to a decade. 

Here’s what you need to know.  

Pfizer’s vaccine is based on a new kind of technology

Traditional vaccines are made from dead or weakened versions of an infectious virus. This new type of vaccine is different. To develop it, the genes of the SARS-CoV-2 virus, which causes Covid-19, were first analyzed to locate the part that codes its “spike” protein, which is what enables the virus to infect people. The codes for that protein are then isolated and copied as mRNA fragments, which is what cells use as instructions for making proteins. Those fragments are packaged up into special molecules, then injected into the patient’s cells.

Within the cells, the mRNA comes into the body’s protein factories, called ribosomes. The ribosomes “read” the mRNA, and follow its instructions to make copies of the spike protein. Those copies of the spike protein can’t, by themselves, cause harm. But they’ll trigger the body to make antibodies against the virus. Those antibodies, in turn, will protect patients from a Covid-19 infection. At least, that’s the idea. 

The vaccine still needs to be approved by the Food and Drug Administration

Before the vaccine can be distributed, it has to first be approved by appropriate regulatory bodies. In the United States, that’s the FDA. Pfizer has said that it intends to seek an Emergency Use Authorization from the FDA to enable distribution and administration of the vaccine in late November, at which point the company will have an average of two months’ worth of safety data for each patient. That’s because most bad reactions to vaccines happen shortly after infection. Additionally, Pfizer will continue to monitor the patients in its study for two years after the vaccine administration. 

Distributing this vaccine is more complicated than for a typical vaccine

Although one advantage of mRNA vaccines is that they’re potentially faster to develop than traditional vaccines, their administration and distribution is scads more complicated. For example, the Pfizer vaccine is currently being tested on a two-dose schedule, 21 days apart, unlike the single dose of a typical vaccine for diseases like the flu. The 21-day separation has raised some concerns about the patient compliance needed for vaccines to work.

For long-term storage, the vaccine has to be kept at very cold temperatures—around –70° Celsius (–94° Fahrenheit), which requires a specialized freezer. (Flu vaccines, by contrast, can usually be stored in a refrigerator.) The company has developed a specialty thermal shipping container, which can be kept cold with dry ice and be used to store the vaccine doses for up to 15 days. If long-term storage isn’t required, Pfizer’s vaccine can be stored in a refrigerator, but only for up to five days. 

Pfizer footed the bill for its own part of vaccine development

Several companies, such as Moderna, have received federal funding and support for the development of their vaccines and treatments through the research and development process. Pfizer opted out of that, choosing instead to spend $1 billion of its own money to move the vaccine forward. “A billion dollars is not going to break us,” CEO Albert Bourla told Forbes earlier this year. 

That said, BioNTech did receive a $442 million grant from the German government to help develop the vaccine. And in July, the two companies signed an agreement to sell at least 100 million doses to the U.S. Department of Health and Human Services (HHS) for $1.95 billion. The country of Spain has initially secured 20 million doses of the vaccine as well. 

Nevada man’s COVID-19 reinfection, the first in the US, is ‘yellow caution light’ about risk of coronavirus

https://www.yahoo.com/news/nevada-mans-covid-19-reinfection-223155707.html

COVID-19 reinfection: Nevada man is first confirmed American case

An otherwise healthy 25-year-old Nevada man is the first American confirmed to have caught COVID-19 twice, with the second infection worse than the first.

He has recovered, but his case raises questions about how long people are protected after being infected with the coronavirus that causes the disease, and potentially how protective a vaccine might be.

“It’s a yellow caution light,” said Dr. William Schaffner, an infectious disease expert at the Vanderbilt University School of Medicine in Nashville, Tennessee, who was not involved in the research.

Respiratory infections like COVID-19 don’t provide lifelong immunity like a measles infection. So, Dr. Paul Offit, an infectious disease expert at Children’s Hospital of Philadelphia, said he’s not at all surprised people could get infected twice with the coronavirus, SARS-CoV-2. 

It’s too soon to know whether the man from Washoe County, Nevada, who had no known health problems other than his double infection, was highly unusual or if many people could easily get infected more than once with SARS-CoV-2, Schaffner said.

“There’s hardly an infectious disease doctor in the country who hasn’t encountered a patient who thinks they’ve had a second infection,” he said. “Whether that’s true or not, we don’t know. There are lots of respiratory infections out there.”

How rare is he?

There have been at least 22 documented cases of reinfection worldwide since the start of the pandemic, but it’s unclear how many cases there have actually been, and how common it may be among people who don’t even know they’re infected.

“It could be a one in a million event, we don’t know,” said Akiko Iwasaki, an immunologist at Yale University and an investigator with the Howard Hughes Medical Institute, who wrote a commentary with the study.

With millions of people infected, it’s hard to know if case studies like the new one represent very rare events or the tip of an iceberg, she said. “It’s possible that the vast majority of people are completely protected from reinfection, but we’re not measuring them, because they’re not coming to the hospital.” 

Also, many people don’t know they are infected the first time, so it’s hard to say whether they’re getting re-infected.

In one of the recent cases, a Hong Kong man only knew he was reinfected because it was caught during a routine screening when he returned from outside the country, months after he had cleared an infection and tested negative. 

One reason there may not be more documented cases of reinfection: It’s tough to prove, said Mark Pandori, a pathologist at the University of Nevada, Reno School of Medicine, and senior author on the new study

His team coordinated early in the pandemic with members of the Washoe County Health District to look for repeat infections. They had the benefit of sequencing equipment on campus, as well as microbiologists, he said. And they got lucky finding someone who had been tested both times he was infected and cleared in between. 

Why his infection was worse the second time remains unclear, said Pandori, director of the Nevada State Public Health Laboratory. “I can’t tell you if it tells us anything in particular about the biology of this virus.”

The man caught a slightly different version of the virus the second time, according a genetic analysis of the man’s infections. It’s possible the second version was more dangerous, though there is no evidence of that, or that it was just different enough that his body didn’t recognize it, the paper said.

Implications for vaccination

Iwasaki said the study raises questions about how long immunity lasts after a natural infection. Protection with a vaccine is likely to be quite different, she said.

“Vaccines can be designed to induce much higher levels of antibody and much longer lasting immunity,” she said. Just because the natural infection doesn’t give you protection doesn’t mean the vaccines cannot. It’s a separate issue.”

Offit, also a vaccine expert at the Perelman School of Medicine at the University of Pennsylvania, said he expects protection from vaccines will likely last at least a year or two.

The protection provided by infection or vaccination isn’t 100% perfect until the day it disappears completely, he said. Instead, protection fades gradually, so someone exposed to a huge dose of the virus might get re-infected within months, while others could be protected for years, Offit said.

It’s also possible the Nevada man has an undiagnosed problem with his immune system. “He probably should be seen by an immunologist,” Offit said. 

The length of time an infection will be protective remains one of the key open questions about the virus.

Infected twice, two months apart

The Nevada man, considered an essential worker, started feeling ill in late March, with a sore throat, cough, headache, nausea and diarrhea. His workplace had been hit with an outbreak early in the pandemic, before safety measures like masks could be put in place, said Heather Kerwin, senior epidemiologist at the Washoe County Health District and a co-author on the paper. 

He went for testing on April 18 and his infection with the coronavirus was confirmed.

On April 27, he reported his symptoms had all resolved and he felt fine, but at the time, employees were required to test negative for COVID-19 twice before they would be allowed back to work, Kerwin said. So he remained isolated at home.

A month later, he began feeling poorly again. At the same time, there was an outbreak where one of his parent’s, also an essential worker, was employed, Kerwin said.

On May 31, he went to an urgent care center, reporting fever, headache, dizziness, cough, nausea and diarrhea. On June 5, he went to see a doctor who found his oxygen levels dangerously low and had him hospitalized. Again, the man tested positive for the virus, even though he still had antibodies to the virus in his bloodstream, Kerwin said.

Genetic differences between the viruses responsible for each of his infections suggested he was infected two separate times. The virus doesn’t mutate quickly enough within a single person to explain the differences between the two infections, the researchers found. 

A parent living with the man also caught COVID-19 and was diagnosed on June 5.

Mark Pandori, pathologist
Mark Pandori, pathologist

The paper reports it’s possible the man was reinfected because he was exposed to a higher dose of the virus the second time, perhaps from the family member.

His cough lingered and he suffered from shortness of breath and mental fog, and was on oxygen for six weeks after the second infection, Kerwin said. He has now fully recovered.

Reinfections imply so-called herd immunity cannot be obtained just through natural infection. If natural infection protects for only a few months, then it will be impossible for enough people to be protected simultaneously to reach herd immunity.

The moral of the case study, said co-author Pandori, is even people who already have been sick with COVID-19 need to protect themselves by wearing a mask, avoiding large gatherings, washing hands frequently and maintaining social distance.

“You’re not invulnerable to this,” Pandori said. “In fact, you could get it worse the second time.”

A high-profile reminder of the importance of therapeutics

https://mailchi.mp/45f15de483b9/the-weekly-gist-october-9-2020?e=d1e747d2d8

Stemline Therapeutics Inc (NASDAQ:STML): What's The Other Side Of The  Story? - Market Exclusive

Along with the many political and public health questions raised by President Trump’s recent and very public bout with COVID-19 is the issue of when the public might have access to the same monoclonal antibody therapy that he received from doctors last week.

Having seen the President tout the benefits of Regeneron’s experimental antibody cocktail, COVID patients have reportedly been asking physicians about participating in clinical trials of the therapy, which is only available on a “compassionate use” basis outside of ongoing studies.

On Wednesday, Regeneron announced it had submitted a request to the US Food and Drug Administration (FDA) for an Emergency Use Authorization (EUA) for the treatment, claiming that early data from ongoing trials showed promise in moderating coronavirus symptoms.

Eli Lilly, which is developing a similar antibody therapy, also announced plans to apply for an EUA, saying its drug has shown the ability to reduce hospitalizations among those infected with the virus.

The US government has already paid Regeneron $450M to access up to 300,000 doses of the therapy, and on Friday a spokesman for the Department of Health and Human Services (HHS) said the government would acquire up to a million doses from Regeneron and Eli Lilly by the end of the year, which it will allocate to hospitals in a similar approach to the way it has distributed Gilead Science’s antiviral drug remdesivir, which the President was also given last week.
 
News on the availability of potentially effective therapies to mitigate the impact of COVID-19 is welcome, particularly as the timeline for COVID vaccines appears to be lengthening.

In guidance released this week, the FDA said it would require pharmaceutical companies to submit two months’ worth of data on vaccine safety and efficacy after patients received their final dose, as part of the EUA application process. The data requirement effectively means that, despite repeated promises from the White House, none of the vaccine candidates being developed will be available before the November 3rd Presidential election.

The head of the government’s vaccine program said separately this week that he expects data on vaccines being developed by Pfizer and Moderna to be available by December. As many have predictedit will take months beyond that for a safe and effective vaccine to be distributed and administered to a majority of Americans.

Challenges will abound: ensuring sufficient manufacturing capacity, managing a complex supply chain, setting up specialized distribution and vaccination centers, and tracking those vaccinated (especially if two shots will be required). A massive public education campaign will also be needed to overcome vaccine hesitancy and ensure widespread immunization. And all of that will take time, and money. 

President Trump’s recent and unfortunate illness underscores the importance of paying equal attention to the development of therapies and treatments—which are essentially a holding maneuver to get us through the coming winter and spring, and eventually to the promise of immunity that lies beyond.

A Doctor Went to His Own Employer for a COVID-19 Antibody Test. It Cost $10,984.

https://www.propublica.org/article/a-doctor-went-to-his-own-employer-for-a-covid-19-antibody-test-it-cost-10-984

An Austin Doctor Went To His Own Employer For A COVID-19 Antibody Test. It Cost  $10,984. – Corridor News

Physicians Premier ER charged Dr. Zachary Sussman’s insurance $10,984 for his COVID-19 antibody test even though Sussman worked for the chain and knows the testing materials only cost about $8. Even more surprising: The insurer paid in full.

When Dr. Zachary Sussman went to Physicians Premier ER in Austin for a COVID-19 antibody test, he assumed he would get a freebie because he was a doctor for the chain. Instead, the free-standing emergency room charged his insurance company an astonishing $10,984 for the visit — and got paid every penny, with no pushback.

The bill left him so dismayed he quit his job. And now, after ProPublica’s questions, the parent company of his insurer said the case is being investigated and could lead to repayment or a referral to law enforcement.

The case is the latest to show how providers have sometimes charged exorbitant prices for visits for simple and inexpensive COVID-19 tests. ProPublica recently reported how a $175 COVID-19 test resulted in charges of $2,479 at a different free-standing ER in Texas. In that situation, the health plan said the payment for the visit would be reduced and the facility said the family would not receive a bill. In Sussman’s case, the insurer paid it all. But those dollars come from people who pay insurance premiums, and health experts say high prices are a major reason why Americans pay so much for health care.

Sussman, a 44-year-old pathologist, was working under contract as a part-time medical director at four of Physicians Premier’s other locations. He said he made $4,000 a month to oversee the antibody tests, which can detect signs of a previous COVID-19 infection. It was a temporary position holding him over between hospital gigs in Austin and New Mexico, where he now lives and works.

In May, before visiting his family in Scottsdale, Arizona, Sussman wanted the test because he had recently had a headache, which can be a symptom of COVID-19. He decided to go to one of his own company’s locations because he was curious to see how the process played out from a patient’s point of view. He knew the materials for each antibody test only amounted to about $8, and it gets read on the spot — similar to an at-home pregnancy test.

He could even do the reading himself. So he assumed Physicians Premier would comp him and administer it on the house. But the staff went ahead and took down his insurance details, while promising him he would not be responsible for any portion of the bill. He had a short-term plan through Golden Rule Insurance Company, which is owned by UnitedHealthcare, the largest insurer in the country. (The insurance was not provided through his work.)

During the brief visit, Sussman said he chatted with the emergency room doctor, whom he didn’t know. He said there was no physical examination. “Never laid a hand on me,” he said. His vitals were checked and his blood was drawn. He tested negative. He said the whole encounter took about 30 minutes.

About a month later, Golden Rule sent Sussman his explanation of benefits for the physician portion of the bill. The charges came to $2,100. Sussman was surprised by the expense but he said he was familiar with the Physicians Premier high-dollar business model, in which the convenience of a free-standing ER with no wait comes at a cost.

“It may as well say Gucci on the outside,” he said of the facility. Physicians Premier says on its website that it bills private insurance plans, but that it is out-of-network with them, meaning it does not have agreed-upon prices. That often leads to higher charges, which then get negotiated down by the insurers, or result in medical bills getting passed on to patients.

Sussman felt more puzzled to see the insurance document say, “Payable at: 100%.” So apparently Golden Rule hadn’t fought for a better deal and had paid more than two grand for a quick, walk-in visit for a test. He was happy not to get hit with a bill, but it also didn’t feel right.

He said he let the issue slide until a few weeks later when a second explanation of benefits arrived from Golden Rule, for the Physicians Premier facility charges. This time, an entity listed as USA Emergency sought $8,884.16. Again, the insurer said, “Payable at: 100%.”

USA Emergency Centers says on its website that it licenses the Physicians Premier ER name for some of its locations.

Now Sussman said he felt spooked. He knew Physicians Premier provided top-notch care and testing on the medical side of things. But somehow his employer had charged his health plan $10,984.16 for a quick visit for a COVID-19 test. And even more troubling to Sussman: Golden Rule paid the whole thing.

Sussman was so shaken he resigned. “I have decided I can no longer ethically provide Medical directorship services to the company,” he wrote in his July 13 resignation email. “If not outright fraudulent, these charges are at least exorbitant and seek to take advantage of payers in the midst of the COVID19 pandemic.”

Sussman agreed to waive his patient privacy so officials from the company could speak to ProPublica. USA Emergency Centers declined interview requests and provided a statement, saying “the allegations are false,” though it did not say which ones.

The statement also said the company “takes all complaints seriously and will continue to work directly with patients to resolve issues pertaining to their emergency room care or bill. …The allegations received pertain to a former contracted employee, and we cannot provide details or further comment at this time.”

Physicians Premier advertises itself as a COVID-19 testing facility on its website, with “results in an hour.” According to the claims submitted by Physicians Premier to Golden Rule, obtained by Sussman, the physician fee and facility fees were coded as emergency room visits of moderate complexity. That would mean his visit included an expanded, problem-focused history and examination. But Sussman said the staff only took down a cursory medical history that took a few minutes related to his possible exposure to COVID-19. And he said no one examined him.

The claims also included codes for a nasal swab coronavirus test. But that test was not performed, Sussman said. The physician’s orders documented in the facility’s medical record also do not mention the nasal swab test. Those charges came to $4,989.

The claims show two charges totaling $1,600 for the antibody test Sussman received. In a spreadsheet available on its website on Friday, Physicians Premier lists a price of $75 for the antibody test.

For comparison, Medicare lists its payment at $42.13 for COVID-19 antibody tests. That’s because Medicare, the government’s insurance plan for the disabled and people over 65, sets prices.

Complicating matters, Texas is the nation’s epicenter for free-standing emergency rooms that are not connected to hospitals. Vivian Ho, an economist at Rice University who studies the facilities, said their business model is based on “trying to mislead the consumer.” They set up in locations where a high proportion of people have health insurance, but they don’t have contracted rates with the insurers, Ho said. They are designed to look like lower-priced urgent care centers or walk-in clinics, Ho said, but charge much higher emergency room rates. (The centers have defended their practices, saying that they clearly identify as emergency rooms and are equipped to handle serious emergencies, and that patients value the convenience.)

The day after he resigned, Sussman texted an acquaintance who works as a doctor at Physicians Premier. The acquaintance said the facility typically only collects a small percentage of what gets billed. “I just don’t want to be part of the game,” Sussman texted to him.

Shelley Safian, a Florida health care coding expert who has written four books on medical coding, reviewed Sussman’s medical records and claims at ProPublica’s request. The records do not document a case of a complex patient that would justify the bills used to code the patient visit, she said. For example, the chief complaint is listed as: “A generic problem (COVID TESTING).” Under “final acuity,” the medical record says, “less urgent.” Under the medical history it says, “NO SYMPTOMS.”

Safian described the charges as “obscene” and said she was shocked the insurer paid them in full. “This is the exact opposite of an employee discount,” she said. “Obviously nobody is minding the store.”

Congress opened the door to profiteering during the pandemic when it passed the CARES Act. The legislation, signed into law in March, says health insurers must pay for out-of-network testing at the cash price a facility posts on its website, or less. But there may be other charges associated with the tests, and insurers generally have tried to avoid making patients pay any portion of costs related to COVID-19 testing or treatment.

The charges for Sussman’s COVID-19 test visit are “ridiculous,” said Niall Brennan, president and CEO of the Health Care Cost Institute, a nonprofit organization that studies health care prices. Brennan wondered whether the CARES Act has made insurers feel legally obligated to cover COVID-19 costs. He called it “well intentioned” public policy that allows for “unscrupulous behavior” by some providers. “Insurance companies and patients are reliant on the good will and honesty of providers,” Brennan said. “But this whole pandemic, combined with the CARES Act provision, seems designed for unscrupulous medical providers to exploit.”

It’s illegal for medical providers to charge for services they did not provide. But ProPublica has previously reported how little insurers, including UnitedHealthcare, do to prevent fraud in their commercial health plans, even though experts estimate it consumes about 10% of all health care costs. For-profit insurance companies don’t want to spend the time and money it takes to hold fraudulent medical providers accountable, former fraud investigators have told ProPublica. Also, the insurance companies want to keep providers in their networks, so they easily cave.

In mid-July, Sussman used the messenger system on Golden Rule’s website to report his concerns about the case. Short-term health plans are typically less expensive because they offer less comprehensive coverage. Sussman said he appreciated that his plan covered the charges, and felt compelled to tell the company what had happened.

That led to a phone conversation with a fraud investigator. They went line by line through the charges and Sussman told him many of the services had not been provided. “His attitude was kind of passive,” Sussman said of the fraud investigator. “There was no indignation. He took in stride, like, ‘Yep, that’s what happens.’” The investigator said he would escalate the case and see if the facility had submitted any other suspect claims. But Sussman never heard back.

Maria Gordon-Shydlo, a spokeswoman for UnitedHealthcare, which owns Golden Rule, would not provide anyone to be interviewed. She said in an emailed statement that the company’s first priority during the pandemic “has been to ensure our members get the care they need and are not billed for COVID testing and treatment. Unfortunately, there are some providers who are trying to take advantage of this and are inappropriately or even fraudulently billing.”

“Golden Rule has put processes in place to address excessive COVID-related billing,” the statement said. “We are currently investigating this matter and, if appropriate, will seek to recoup any overpayment and potentially refer this case to law enforcement.”

Golden Rule’s 100% payment of the charges may simply come down to “incompetence,” said Dr. Eric Bricker, a Texas internist who spent years running a company that advised employers who self-fund their insurance. Insurance companies auto-adjudicate millions of claims on software that may be decades old, said Bricker, who produces videos to help consumers and employers understand health care. If bills are under a certain threshold, like $15,000, they may sail through and get paid without a second look, he said.

UnitedHealth Group reported net earnings of $6.6 billion in the second quarter of 2020. Bricker said the company may be paying bills without questioning them because it doesn’t “want to create any noise” by saying no at a time its own earnings are so high, Bricker said.

Texas has a consumer protection law that’s designed to prevent businesses from exploiting the public during a disaster. The attorney general’s office has received and processed 52 complaints about health care businesses and billing or price gouging related to the pandemic, a spokeswoman from the office said in an email. The agency does not comment on the existence of any investigations, but has not filed any cases related to overpriced COVID-19 tests.

Sussman said he got one voicemail from a billing person at Physicians Premier, saying she wanted to explain the charges, but he did not call back. He said he spoke out about it to ProPublica because he opposes Medicare-for-all health care reform proposals. Bad actors in the profession could cause doctors to lose their privilege to bill and be reimbursed independently, he said. Most physicians are fair with their billing, or even conservative, he said. “If instances like these go unchecked it will provide more ammo for advocates of a single-payer system.”

 

 

 

Declining antibodies and immunity to COVID-19 – why the worry?

https://theconversation.com/declining-antibodies-and-immunity-to-covid-19-why-the-worry-143323?utm_medium=email&utm_campaign=Latest%20from%20The%20Conversation%20for%20August%2026%202020%20-%201713516549&utm_content=Latest%20from%20The%20Conversation%20for%20August%2026%202020%20-%201713516549+Version+A+CID_ca860340297de2ef2c2c85020b74576b&utm_source=campaign_monitor_us&utm_term=Declining%20antibodies%20and%20immunity%20to%20COVID-19%20%20why%20the%20worry

Most people are aware that testing for antibodies in a person’s blood can show if someone has had a specific disease, such as COVID-19. Those antibodies provide protection from getting the disease again.

But in a paper published in the New England Journal of Medicine, researchers found that antibody levels decline in individuals who have recovered from COVID-19, dropping by half every 36 days. Does that mean people who have recovered from COVID-19 have lost their immunity?

I am a geneticist interested in innate immune response – the part of the immune system that we have at birth – and how the innate immune cells “educate” antibody-producing cells about a pathogen and how to identify and destroy it. As I’ll explain, antibodies are important for immunity, but they aren’t the only factor that counts.

Two arms of the immune system

The immune system is made up of two parts: innate immunity and adaptive – or acquired – immunity.

The innate immune system, which includes white blood cells called dendritic cells, monocytes and neutrophils, is present at birth and responds instantly to invaders. This group of white blood cells bombard pathogens with destructive chemicals and swallow and destroy viruses and bacteria. The innate immune system provides an instantaneous reaction to a pathogen. The problem is that it’s a blunt instrument – it responds the same way to all perceived threats.

The adaptive immune system, which is made up of B cells and T cells, must learn about a pathogen and its characteristics from the innate immune cells. This system takes longer to kick in, but the up side is that it is very specific and in many cases lasts a lifetime.

The immune system’s memory

The history of pathogen exposure is carried in so-called memory T cells and memory B cells. When an infection is defeated and gone, these cells reside in the peripheral tissues of the body such as lymph nodes or spleen and serve as a memory of the disease-causing virus. This immunological memory is responsible for the host defense and kicks into action in case of the second wave or attack of the pathogen.

It is normal for antibody levels to decline after a person has recovered from a disease. But the New England Journal of Medicine paper raised concerns because it suggests that we are losing our immunological memory – which is as bad as losing a real memory.

What role do T cells play in immunity?

B cells and antibodies are only part of the immune response. T cells help B cells produce antibodies – which are proteins that can bind to a specific pathogen and destroy it.

The way this happens is that first the B cells swallow the virus and start producing antibodies.

T cells cannot swallow the virus. But a type of white blood cell called an antigen-presenting cell can. After it does, it “shows” different parts of the virus to the T cells. The T cells then learn about the virus which they can now seek and destroy.

T cells also stick to the B cells and send them the activation signals that help B cells ramp up antibody production.

If antibodies decline, what does this mean for COVID-19 immunity?

It suggests that when there are fewer antibodies in the blood, there is a greater chance that a number of individual virus particles, called virions, will survive and escape destruction. Therefore, the remaining virions will continue to proliferate and cause disease.

What do declining antibody levels mean for establishing herd immunity?

Herd immunity refers to a population and occurs when a sufficiently high number of people within a community are immune to the virus and incapable of transmitting it. That provides protection for those who are still vulnerable. For example, if 60% of people are protected against COVID – because they have survived the infection and carry antibodies – it might protect (via less frequent interactions) the remaining 40% from getting sick.

But the results in the New England Journal of Medicine suggest that people with lower levels of antibody may still have the virus and may not have symptoms of the disease.

That means that if these people with low antibody levels hang around healthy, uninfected people, they present a danger to them because they can transmit the virus.

When antibody levels fall, does immunity disappear?

In general, the answer is no. If the virus attempts to cause a second infection, the memory B and T cells are able to recognize it, multiply million of times and defend the body against the virus, preventing it from triggering another full-blown infection.

The protection provided by memory T and B cells is the reason that vaccine-based protection works.

However, there are exceptions. A lifelong vaccine against the flu does not work because flu’s genetic code changes rapidly, altering the appearance of the flu, and therefore requires a new vaccine every season.

But with SARS-CoV-2, the problem as I see it, seems to be that those memory T cells and B cells seem to be wiped out.

Antibodies are proteins and last for only between three and four weeks in the blood circulation. To keep antibody levels high, B cells need to replenish them with a fresh supply. But in COVID-19, the declining antibody levels suggest that the cells that produce these antibodies are not present in sufficient numbers, which would explain the drop in antibody levels. Studies of how long immunity from COVID-19 last may shed more light, but for now we do not know the reason why.

 

 

 

 

Long-Haulers Are Redefining COVID-19

https://www.theatlantic.com/health/archive/2020/08/long-haulers-covid-19-recognition-support-groups-symptoms/615382/

Long-Haulers Deal With Symptoms Weeks After Coronavirus Infection ...

Without understanding the lingering illness that some patients experience, we can’t understand the pandemic.

Lauren nichols has been sick with COVID-19 since March 10, shortly before Tom Hanks announced his diagnosis and the NBA temporarily canceled its season. She has lived through one month of hand tremors, three of fever, and four of night sweats. When we spoke on day 150, she was on her fifth month of gastrointestinal problems and severe morning nausea. She still has extreme fatigue, bulging veins, excessive bruising, an erratic heartbeat, short-term memory loss, gynecological problems, sensitivity to light and sounds, and brain fog. Even writing an email can be hard, she told me, “because the words I think I’m writing are not the words coming out.” She wakes up gasping for air twice a month. It still hurts to inhale.

Tens of thousands of people, collectively known as “long-haulers,” have similar stories. I first wrote about them in early June. Since then, I’ve received hundreds of messages from people who have been suffering for months—alone, unheard, and pummeled by unrelenting and unpredictable symptoms. “It’s like every day, you reach your hand into a bucket of symptoms, throw some on the table, and say, ‘This is you for today,’” says David Putrino, a neuroscientist and a rehabilitation specialist at Mount Sinai Hospital who has cared for many long-haulers.

Of the long-haulers Putrino has surveyed, most are women. Their average age is 44. Most were formerly fit and healthy. They look very different from the typical portrait of a COVID-19 patient—an elderly person with preexisting health problems. “It’s scary because in the states that are surging, we have all these young people going out thinking they’re invincible, and this could easily knock them out for months,” Putrino told me. And for some, months of illness could turn into years of disability.

Our understanding of COVID-19 has accreted around the idea that it kills a few and is “mild” for the rest. That caricature was sketched before the new coronavirus even had a name; instead of shifting in the light of fresh data, it calcified. It affected the questions scientists sought to ask, the stories journalists sought to tell, and the patients doctors sought to treat. It excluded long-haulers from help and answers. Nichols’s initial symptoms were so unlike the official description of COVID-19 that her first doctor told her she had acid reflux and refused to get her tested. “Even if you did have COVID-19, you’re 32, you’re healthy, and you’re not going to die,” she remembers him saying. (She has since tested positive.)

Long-haulers had to set up their own support groups. They had to start running their own research projects. They formed alliances with people who have similar illnesses, such as dysautonomia and myalgic encephalomyelitis, also known as chronic fatigue syndrome. A British group—LongCovidSOS—launched a campaign to push the government for recognition, research, and support.

All of this effort started to have an effect. More journalists wrote stories about them. Some doctors began taking their illness seriously. Some researchers are developing treatment and rehabilitation programs. Representative Jamie Raskin of Maryland introduced a bill that would allow the National Institutes of Health to fund and coordinate more research into chronic illnesses that follow viral infections.

It’s not enough, argues Nisreen Alwan, a public-health professor at the University of Southampton who has had COVID-19 since March 20. She says that experts and officials should stop referring to all nonhospitalized cases as “mild.” They should agree on a definition of recovery that goes beyond being discharged from the hospital or testing negative for the virus, and accounts for a patient’s quality of life. “We cannot fight what we do not measure,” Alwan says. “Death is not the only thing that counts. We must also count lives changed.”

Only then will we truly know the full stakes of the pandemic. As many people still fantasize about returning to their previous lives, some are already staring at a future where that is no longer possible.

A few formal studies have hinted at the lingering damage that COVID-19 can inflict. In an Italian study, 87 percent of hospitalized patients still had symptoms after two months; a British study found similar trends. A German study that included many patients who recovered at home found that 78 percent had heart abnormalities after two or three months. A team from the Centers for Disease Control and Prevention found that a third of 270 nonhospitalized patients hadn’t returned to their usual state of health after two weeks. (For comparison, roughly 90 percent of people who get the flu recover within that time frame.)

These findings, though limited, are galling. They suggest that in the United States alone, which has more than 5 million confirmed COVID-19 cases, there are probably hundreds of thousands of long-haulers.

These people are still paying the price for early pandemic failures. Many long-haulers couldn’t get tested when they first fell sick, because such tests were scarce. Others were denied tests because their symptoms didn’t conform to a list we now know was incomplete. False negatives are more common as time wears on; when many long-haulers finally got tested weeks or months into their illness, the results were negative. On average, long-haulers who tested negative experienced the same set of symptoms as those who tested positive, which suggests that they truly do have COVID-19. But their negative result still hangs over them, shutting them out of research and treatments.

Several studies have found that most COVID-19 patients produce antibodies that recognize the new coronavirus, and that these molecules endure for months. Their presence should confirm whether a long-hauler was indeed infected. But there’s a catch: Most existing antibody studies focused on either hospitalized patients or those with mild symptoms and swift recoveries. By contrast, Putrino told me that in his survey of 1,400 long-haulers, two-thirds of those who have had antibody tests got negative results, even though their symptoms were consistent with COVID-19. Nichols, for example, tested negative for antibodies after twice testing positive for the coronavirus itself. “Just because you’re negative for antibodies doesn’t mean you didn’t have COVID-19,” Putrino said.

Organizations and governments have been slow to recognize what long-haulers call “long COVID.” In July, the U.K. allocated $11 million (£8.4 million) for research into the long-term consequences of COVID-19, but “to be eligible, you have to have been admitted into hospital,” says Trisha Greenhalgh, a primary-health-care professor at the University of Oxford. “That makes no sense.” Meanwhile, the CDC’s website still does not mention this phenomenon, and its list of symptoms barely reflects the full range of neurological problems. As late as June 25, the agency’s deputy director for infectious diseases said “we don’t yet know” whether COVID-19 “could persist for more than a few months.” By then, thousands of long-haulers already did know, and had been talking about it.

Without clear information from official sources, many long-haulers have found answers from one another. Support groups on Facebook have thousands of membersOne Slack group, founded within a wellness organization called Body Politic, has almost doubled in size since June to more than 7,000 active participants from 25 countries. There are channels for discussing every organ system in the body. There are lists of sympathetic medical providers, and tips for convincing those who aren’t listening. Eerily, the group’s membership morphs as the pandemic spreads: “When Brazil had a huge spike, we had a massive influx of Brazilian patients,” said Nichols, who is an administrator.

The Body Politic group has its own team of researchers, whose survey of 640 long-haulers remains the most illuminating study of the long COVID experience. More than any formally published study, it cataloged the full range of symptoms, and explored problems with stigma and testing.

Many long-haulers start feeling better in their fourth or fifth month, but recovery is tentative, variable, and not guaranteed. Hannah Davis, an artist in New York City, still has fever, facial numbness, brain fog, and rapid heartbeats whenever she stands up, but she’s sleeping better, at least; at the end of July, she had her first relatively normal day since mid-March. Margot Gage, a social epidemiologist at Lamar University, has only now regained the ability to read without shooting pain, but still has debilitating headaches and fatigue. Hannah Wei, a product designer based in Ottawa who is a Body Politic researcher, has recovered from her neurological symptoms but not the scars the coronavirus left on her lungs. “Will I be living with this lasting damage, or will it eventually go away?” she says. “I don’t have the answers, and no one can tell me.”

The physical toll of long COVID almost always comes with an equally debilitating comorbidity of disbelief. Employers have told long-haulers that they couldn’t possibly be sick for that long. Friends and family members accused them of being lazy. Doctors refused to believe they had COVID-19. “Every specialist I saw—cardiologist, rheumatologist, dermatologist, neurologist—was wedded to this idea that ‘mild’ COVID-19 infections last two weeks,” says Angela Meriquez Vázquez, a children’s activist in Los Angeles. “In one of my first ER visits, I was referred for a psychiatric evaluation, even though my symptoms were of heart attack and stroke.”

This “medical gaslighting,” whereby physiological suffering is downplayed as a psychological problem such as stress or anxiety, is especially bad for women, and even worse for women of color. “Doctors not taking our conditions seriously is a common issue, and now we have COVID-19 on top of it,” says Gage, who is Black. When she sought medical help for her symptoms, doctors in two separate hospitals assumed she was having a drug overdose.

Such gaslighting still occurs, but has been reduced by the recent spate of media attention. Davis was stunned when she met with a cardiologist who used the term long-hauler without needing an explanation. Vázquez burst into tears after her new primary-care provider instantly believed her. “I went into that appointment armed with my notebook, ready to do battle,” she says. “Just having a doctor who believed that my symptoms were directly related to COVID-19 was transformative.”

Putrino, the Mount Sinai doctor, came to recognize long COVID on his own. Back in March, he realized that some patients who were referred to his hospital were in bad shape but weren’t sick enough to be admitted. His team created an app to keep track of these people remotely. By late May, they realized that “around 10 percent just weren’t getting better,” he told me. He has since started a program at Mount Sinai that’s dedicated to caring for long-haulers.

But such programs are still scarce, creating large geographical deserts where long-haulers cannot find help. Putrino cannot see patients who live outside New York State. Igor Koralnik, a neurologist at Northwestern Medicine who runs a similar operation, was booked solid through April 2021; he has since brought extra staff members so he could accept more patients. Canadian long-haulers “have just one clinic, in Toronto, and that’s it,” Wei says.

Putrino thinks that many long-haulers have symptoms that resemble dysautonomia. This is an umbrella term for disorders that disturb the autonomic nervous system, which controls bodily functions such as breathing, heart rate, blood pressure, and digestion. Damage to this system, whether inflicted by the virus itself or by an overly intense immune response, might explain why many long-haulers struggle for breath when their oxygen levels are normal, or have unsteady heartbeats when they aren’t feeling anxious. Things that were once automatic are now erratic.

More than 90 percent of long-haulers whom Putrino has worked with also have “post-exertional malaise,” in which even mild bouts of physical or mental exertion can trigger a severe physiological crash. “We’re talking about walking up a flight of stairs and being out of commission for two days,” Putrino said. This is the defining symptom of myalgic encephalomyelitis, or chronic fatigue syndrome. For decades, people with ME/CFS have endured the same gendered gaslighting that long-haulers are now experiencing. They’re painfully familiar with both medical neglect and a perplexing portfolio of symptoms.

These symptoms defeat intuitions that people have about work and rest, sickness and recovery. “You have to get away from this idea that you can do more each day, or that you can push through,” says Caroline Dalton of Sheffield Hallam University in England, who works for a COVID-19 rehabilitation program. Many long-haulers push themselves because they miss their lives, or need to return to work. But as her colleague Robert Copeland, a sport psychologist, explains, “managing your fatigue is now your full-time job.”

The trick, then, is to slowly recondition a patient’s nervous system through careful exercises, without triggering a debilitating crash. On Putrino’s team, a strength and conditioning coach devises workouts to slowly get patients accustomed to a higher heart rate. A nutritionist fashions personalized meal plans to compensate for any dietary deficiencies. A neuropsychologist—Gudrun Lange, who has long worked with ME/CFS patients and is helping the group pro bono—uses relaxation and somatic-awareness techniques to help long-haulers manage their feelings about their condition.

Putrino insists on seeing and caring for all the long-haulers that he can. His colleagues at Mount Sinai’s newly launched center for post-COVID-19 care have to follow guidelines that permit them to admit only patients with positive tests. Anyone the center can’t admit is referred to Putrino’s team, which also keeps in touch with the Body Politic group to track patients who fall through the cracks.

I asked him why he is so inclined to believe long-haulers when so many other medical professionals dismiss them. First, he said, “these people are telling us the same things over and over again.” But also, his wife has Ehlers-Danlos syndrome—a group of genetic disorders that affect the body’s connective tissues, and that commonly lead to dysautonomia. “I watched her go through the same thing: ‘You must have anxiety, or panic attacks, or every-excuse-under-the-sun,’” he told me. “Finally, after three years of searching, someone said, ‘Oh, you have dysautonomia and EDS.’ They put her on a treatment protocol, and she could live her life again.”

“If you listen to the population you’re trying to help, they’ll tell you what’s wrong,” he said.

Nichols is a few weeks away from meeting the CDC’s criteria for ME/CFS. She has post-exertional malaise. She has brain fog. On September 9, she’ll mark her sixth month of extreme fatigue. “Am I happy about it? No,” she said. “But I have to face reality. If this is what I have, this is what I have.” Lots of long-haulers are in the same boat. Many (but not all) cases of ME/CFS are triggered by viral infections, and new clusters have historically emerged after outbreaks. “When COVID-19 started to happen, I said to my husband, ‘Oh God, there’s going to be an avalanche of ME/CFS,’” Lange told me.

Some long-haulers are skeptical—and even angry—about the ME/CFS connection. They won’t countenance the prospect of being chronically disabled. They don’t want to be labeled with a condition that has long been trivialized. Nichols sympathizes; she used to trivialize it herself. “I falsely thought it was just people being too tired—and I feel terrible about that,” she said. Her plan is to use her imminent diagnosis as fuel for advocacy, “as a way of paying back the ME community for my disbelief.”

But COVID-19 is still a new disease, and ME/CFS is just one of several possible outcomes. Some long-haulers recover before the six-month threshold. Some don’t have post-exertional malaise. Some have lung damage and breathing problems that aren’t traditional ME/CFS symptoms. Some have symptoms that more closely fit with other chronic illnesses, including dysautonomia, fibromyalgia, or mast cell activation syndrome.

Putrino doesn’t want to assign any labels. “Let’s just start helping them,” he said, while simultaneously collecting data that will eventually show how much long COVID overlaps with other known syndromes. (Several other teams are conducting similar studies.) Even when symptoms such as fatigue are shared, their biological roots might differ—and those differences matter. Exercise might be devastating for someone with ME/CFS, but might benefit a patient with something else. Many long-haulers, meanwhile, are treating any diagnosis as more of an anchor than an answer: It’s a starting point for understanding what’s happening to them. Vázquez, for example, was diagnosed with MCAS, and although it’s not a perfect match for her symptoms, “it’s close enough,” she says.

No matter the exact diagnosis, the COVID-19 pandemic will almost certainly create a substantial wave of chronically disabled people. It might be hard to ignore this cohort because of the sheer number of them, the intense attention commanded by the pandemic, and the stories from celebrities such as the actor Alyssa Milano and the journalist Chris Cuomo. Then again, they might face the same neglect that people with ME/CFS have long endured. “We’ve been demanding for decades that people do something,” says Terri Wilder, who has ME/CFS and is an activist with #MEAction. “I’ve met with [NIH Director] Francis Collins. I’ve called Tony Fauci, and state senators. We still have no FDA-approved drugs, no systems of care. We only have 10 to 15 ME/CFS medical experts in the country. We all want our lives back, and we want this broken system fixed.

The uncertainty that long-haulers are experiencing results from that long-standing neglect. But so does the help they’re getting from people with chronic illnesses, who have already walked the same path. When the pandemic began, “it was like watching the roller coaster go up the hill, and only people like us knew that the track was broken,” says Alison Sbrana, who has ME/CFS and dysautonomia. She now spends her few productive weekly hours moderating the Body Politic support group. She has invited ME/CFS and dysautonomia specialists to give seminars, and has directed people to credible resources on aspects of disabled life, including care and benefits.

That frontier, in which long-haulers attempt to access social support, “is about to be a shit show,” Sbrana says. Some want their employers to make accommodations, such as reduced hours or long-term sick leave, so they can keep working at a time when their medical bills are mounting. Others cannot work, but are pressured to do so by bosses who don’t understand what long COVID is. “We keep seeing that people who don’t have a positive test result struggle to get paid time off work,” says Fiona Lowenstein, who founded Body Politic. Yet others “don’t want people to see them as complainers, push themselves, and then get sicker,” says Barbara Comerford, a New Jersey–based attorney who specializes in disability law and has represented many people with ME/CFS.

If they lose their jobs, “they’re in really bad shape,” she adds. Other sources of disability benefits and care, including private insurance and Social Security, are notoriously hard to access. Long-haulers would need to provide a history of being unable to do substantial gainful employment, and ample medical documentation of their disability to prove that it’s expected to last at least a year. Many have neither.

Being a long-hauler in August is very different from being one in February. The first wave, who were infected early in the year, endured months of solitude and confusion. While the national narrative shifted from physical distancing to reopenings, their realities were pinned in place by fever or fatigue. Many had no idea that others were going through the same ordeal. They wondered why they were still sick, or how long they’d be sick for. “We didn’t know what tomorrow would bring,” Nichols said.

Long-hauler support groups act as windows in time. In the Body Politic community, “the earliest person we know got sick in January,” Davis says. “She posts from the future, two months ahead of everyone else.” Conversely, as veteran long-haulers watch new generations pass the same monthly milestones, some are struck by a strange sense of solidarity, validation, and jealousy. The newer long-haulers already know what to call themselves, have bustling communities to learn from, and have better access to tests and medical care. The older ones are battle-worn and weary. “There’s something about having got sick in March and April that’s a unique experience, almost like post-traumatic stress disorder,” Vázquez says.

Throughout the pandemic, systemic failures have been portrayed as personal ones. Many people ignored catastrophic governmental choices that allowed the coronavirus to spread unchecked, and instead castigated individuals for going to beaches or wearing masks incorrectly. So, too, with recovery. The act of getting better is frequently framed as a battle between person and pathogen, ignoring everything else that sways the outcome of that conflict—the disregard from doctors and the sympathy from strangers, the choices of policy makers and the narratives of journalists. Nothing about COVID-19 exists in a social vacuum. If people are to recover, “you have to create the conditions in which they can recover,” Copeland, the sport psychologist from Sheffield Hallam, says.

If those conditions don’t exist, they can be at least partly willed into existence. Here, too, the long-hauler story is a microcosm of the pandemic. In the U.S., citizens chose to physically distance themselves, take precautions, and wear masks long before leaders urged or ordered them to do so. Likewise, the long-haulers have taken matters into their own hands, pushing for respect, research, and support when none were offered.

But such effort comes at a cost. Long-haulers are precariously perched on a physiological precipice—a difficult position from which to fight for their future. “A lot of people who don’t have the energy to educate the world are educating the world,” Nichols said.

 

 

 

Coronavirus Cases may be 10x higher than official count says CDC

https://www.axios.com/newsletters/axios-vitals-59e9ac1a-ab86-4f8a-917a-8c9d52f5835f.html?utm_source=newsletter&utm_medium=email&utm_campaign=newsletter_axiosvitals&stream=top

NC coronavirus update June 25: North Carolina's mask mandate goes ...

The real number of U.S. coronavirus cases could be as high as 23 million — 10 times the 2.3 million currently confirmed cases — the Centers for Disease Control and Prevention told reporters yesterday, Axios’ Marisa Fernandez reports.

Between the lines: The new estimate is based on antibody testing, which indicates whether someone has previously been infected by the virus regardless of whether they had symptoms.

  • “This virus causes so much asymptomatic infection. The traditional approach of looking for symptomatic illness and diagnosing it obviously underestimates the total amount of infections,” CDC director Robert Redfield said.

The agency also expanded its warnings of which demographic groups are at risk, which now include younger people who are obese and who have underlying health problems.

  • The shift reflects what states and hospitals have been seeing since the pandemic began, which is that young people can get seriously ill from COVID-19.

The new guidance also categorizes medical conditions that can affect the severity of illness:

  • Conditions that increase risk: Chronic kidney disease; chronic obstructive pulmonary disease; obesity; weakened immune system from solid organ transplant; serious heart conditions, such as heart failure, coronary artery disease or cardiomyopathies; sickle cell disease; Type 2 diabetes.
  • Conditions that may increase risk: Chronic lung diseases, including moderate to severe asthma and cystic fibrosis; high blood pressure; a weakened immune system; neurologic conditions, such as dementia or history of stroke; liver disease; pregnancy.

 

 

 

 

Blocking the deadly cytokine storm is a vital weapon for treating COVID-19

https://theconversation.com/blocking-the-deadly-cytokine-storm-is-a-vital-weapon-for-treating-covid-19-137690?utm_medium=email&utm_campaign=Latest%20from%20The%20Conversation%20for%20May%2022%202020%20-%201630015658&utm_content=Latest%20from%20The%20Conversation%20for%20May%2022%202020%20-%201630015658+Version+A+CID_f23e0e73a678178a59d0287ef452fe33&utm_source=campaign_monitor_us&utm_term=Blocking%20the%20deadly%20cytokine%20storm%20is%20a%20vital%20weapon%20for%20treating%20COVID-19

Blocking the deadly cytokine storm is a vital weapon for treating ...

The killer is not the virus but the immune response.

The current pandemic is unique not just because it is caused by a new virus that puts everyone at risk, but also because the range of innate immune responses is diverse and unpredictable. In some it is strong enough to kill. In others it is relatively mild.

My research relates to innate immunity. Innate immunity is a person’s inborn defense against pathogens that instruct the body’s adaptive immune system to produce antibodies against viruses. Those antibody responses can be later used for developing vaccination approaches. Working in the lab of Nobel laureate Bruce Beutler, I co-authored the paper that explained how the cells that make up the body’s innate immune system recognize pathogens, and how overreacting to them in general could be detrimental to the host. This is especially true in the COVID-19 patients who are overreacting to the virus.

Cell death – a chess game of sacrifice

I study inflammatory response and cell death, which are two principal components of the innate response. White blood cells called macrophages use a set of sensors to recognize the pathogen and produce proteins called cytokines, which trigger inflammation and recruit other cells of the innate immune system for help. In addition, macrophages instruct the adaptive immune system to learn about the pathogen and ultimately produce antibodies.

To survive within the host, successful pathogens silence the inflammatory response. They do this by blocking the ability of macrophages to release cytokines and alert the rest of the immune system. To counteract the virus’s silencing, infected cells commit suicide, or cell death. Although detrimental at the cellular level, cell death is beneficial at the level of the organism because it stops proliferation of the pathogen.

For example, the pathogen that caused the bubonic plague, which killed half of the human population in Europe between 1347 and 1351, was able to disable, or silence, people’s white blood cells and proliferate in them, ultimately causing the death of the individual. However, in rodents the infection played out differently. Just the infected macrophages of rodents died, thus limiting proliferation of the pathogen in the rodents’ bodies which enabled them to survive.

The “silent” response to plague is strikingly different from the violent response to SARS-CoV-2, the virus that causes COVID-19. This suggests that keeping the right balance of innate response is crucial for the survival of COVID-19 patients.

Vintage engraving of a dead cart collecting the bodies of plague victims during the last Great Plague of London, which extended from 1665 to 1666. duncan1890/ Getty Images

Path to a cytokine storm

Here’s how an overreaction from the immune system can endanger a person fighting off an infection.

Some of the proteins that trigger inflammation, named chemokines, alert other immune cells – like neutrophils, which are professional microbe eaters – to convene at the site of infections where they can arrive first and digest the pathogen.

Others cytokines – such as interleukin 1b, interleukin 6 and tumor necrosis factor – guide neutrophils from the blood vessels to the infected tissue. These cytokines can increase heartbeat, elevate body temperature, trigger blood clots that trap the pathogen and stimulate the neurons in the brain to modulate body temperature, fever, weight loss and other physiological responses that have evolved to kill the virus.

When the production of these same cytokines is uncontrolled, immunologists describe the situation as a “cytokine storm.” During a cytokine storm, the blood vessels widen further (vasolidation), leading to low blood pressure and widespread blood vessel injury. The storm triggers a flood of white blood cells to enter the lungs, which in turn summon more immune cells that target and kill virus-infected cells. The result of this battle is a stew of fluid and dead cells, and subsequent organ failure.

The cytokine storm is a centerpiece of the COVID-19 pathology with devastating consequences for the host.

When the cells fail to terminate the inflammatory response, production of the cytokines make macrophages hyperactive. The hyperactivated macrophages destroy the stem cells in the bone marrow, which leads to anemia. Heightened interleukin 1b results in fever and organ failure. The excessive tumor necrosis factor causes massive death of the cells lining the blood vessels, which become clotted. At some point, the storm becomes unstoppable and irreversible.

Drugs that break the cytokine storm

One strategy behind the treatments for COVID is, in part, based in part on breaking the vicious cycle of the “cytokine storm.” This can be done by using antibodies to block the primary mediators of the storm, like IL6, or its receptor, which is present on all cells of the body.

Inhibition of tumor necrosis factor can be achieved with FDA-approved antibody drugs like Remicade or Humira or with a soluble receptor such as Enbrel (originally developed by Bruce Beutler) which binds to tumor necrosis factor and prevents it from triggering inflammation. The global market for tumor necrosis factor inhibitors is US$22 billion.

Drugs that block various cytokines are now in clinical trials to test whether they are effective for stopping the deadly spiral in COVID-19.

 

 

 

 

Vaccine experts say Moderna didn’t produce data critical to assessing Covid-19 vaccine

Vaccine experts say Moderna didn’t produce data critical to assessing Covid-19 vaccine

Moderna taps $1.34B stock offering to bankroll its promising COVID ...

Heavy hearts soared Monday with news that Moderna’s Covid-19 vaccine candidate — the frontrunner in the American market — seemed to be generating an immune response in Phase 1 trial subjects. The company’s stock valuation also surged, hitting $29 billion, an astonishing feat for a company that currently sells zero products.

But was there good reason for so much enthusiasm? Several vaccine experts asked by STAT concluded that, based on the information made available by the Cambridge, Mass.-based company, there’s really no way to know how impressive — or not — the vaccine may be.

While Moderna blitzed the media, it revealed very little information — and most of what it did disclose were words, not data. That’s important: If you ask scientists to read a journal article, they will scour data tables, not corporate statements. With science, numbers speak much louder than words.

Even the figures the company did release don’t mean much on their own, because critical information — effectively the key to interpreting them — was withheld.

Experts suggest we ought to take the early readout with a big grain of salt. Here are a few reasons why.

The silence of the NIAID

The National Institute for Allergy and Infectious Diseases has partnered with Moderna on this vaccine. Scientists at NIAID made the vaccine’s construct, or prototype, and the agency is running the Phase 1 trial. This week’s Moderna readout came from the earliest of data from the NIAID-led Phase 1.

NIAID doesn’t hide its light under a bushel. The institute generally trumpets its findings, often offering director Anthony Fauci — who, fair enough, is pretty busy these days — or other senior personnel for interviews.

But NIAID did not put out a press release Monday and declined to provide comment on Moderna’s announcement.

The n = 8 thing

The company’s statement led with the fact that all 45 subjects (in this analysis) who received doses of 25 micrograms (two doses each), 100 micrograms (two doses each), or a 250 micrograms (one dose) developed binding antibodies.

Later, the statement indicated that eight volunteers — four each from the 25-microgram and 100-microgram arms — developed neutralizing antibodies. Of the two types, these are the ones you’d really want to see.

We don’t know results from the other 37 trial participants. This doesn’t mean that they didn’t develop neutralizing antibodies. Testing for neutralizing antibodies is more time-consuming than other antibody tests and must be done in a biosecurity level 3 laboratory. Moderna disclosed the findings from eight subjects because that’s all it had at that point. Still, it’s a reason for caution.

Separately, while the Phase 1 trial included healthy volunteers ages 18 to 55 years, the exact ages of these eight people are unknown. If, by chance, they mostly clustered around the younger end of the age spectrum, you might expect a better response to the vaccine than if they were mostly from the senior end of it. And given who is at highest risk from the SARS-CoV-2 coronavirus, protecting older adults is what Covid-19 vaccines need to do.

There’s no way to know how durable the response will be

The report of neutralizing antibodies in subjects who were vaccinated comes from blood drawn two weeks after they received their second dose of vaccine.

Two weeks.

“That’s very early. We don’t know if those antibodies are durable,” said Anna Durbin, a vaccine researcher at Johns Hopkins University.

There’s no real way to contextualize the findings

Moderna stated that the antibody levels seen were on a par with — or greater than, in the case of the 100-microgram dose — those seen in people who have recovered from Covid-19 infection.

But studies have shown antibody levels among people who have recovered from the illness vary enormously; the range that may be influenced by the severity of a person’s disease. John “Jack” Rose, a vaccine researcher from Yale University, pointed STAT to a study from China that showed that, among 175 recovered Covid-19 patients studied, 10 had no detectable neutralizing antibodies. Recovered patients at the other end of the spectrum had really high antibody levels.

So though the company said the antibody levels induced by vaccine were as good as those generated by infection, there’s no real way to know what that comparison means.

STAT asked Moderna for information on the antibody levels it used as a comparator. The response: That will be disclosed in an eventual journal article from NIAID, which is part of the National Institutes of Health.

“The convalescent sera levels are not being detailed in our data readout, but would be expected in a downstream full data exposition with NIH and its academic collaborators,” Colleen Hussey, the company’s senior manager for corporate communications, said in an email.

Durbin was struck by the wording of the company’s statement, pointing to this sentence: “The levels of neutralizing antibodies at day 43 were at or above levels generally seen in convalescent sera.”

“I thought: Generally? What does that mean?” Durbin said. Her question, for the time being, can’t be answered.

Rose said the company should disclose the information. “When a company like Moderna with such incredibly vast resources says they have generated SARS-2 neutralizing antibodies in a human trial, I would really like to see numbers from whatever assay they are using,” he said.

Moderna’s approach to disclosure

The company has not yet brought a vaccine to market, but it has a variety of vaccines for infectious diseases in its pipeline. It doesn’t publish on its work in scientific journals. What is known has been disclosed through press releases. That’s not enough to generate confidence within the scientific community.

“My guess is that their numbers are marginal or they would say more,” Rose said about the company’s SARS-2 vaccine, echoing a suspicion that others have about some of the company’s other work.

“I do think it’s a bit of a concern that they haven’t published the results of any of their ongoing trials that they mention in their press release. They have not published any of that,” Durbin noted.

Still, she characterized herself as “cautiously optimistic” based on what the company has said so far.

“I would like to see the data to make my own interpretation of the data. But I think it is at least encouraging that we’ve seen immune responses with this RNA vaccine that we haven’t seen with previous RNA vaccines for other pathogens. Whether it’s going to be enough, we don’t know,” Durbin said.

Moderna has been more forthcoming with data on at least one of its other vaccine candidates. In a statement issued in January about a Phase 1 trial for its cytomegalovirus (CMV) vaccine, it quantified how far over baseline measures antibody levels rose in vaccines.