The Covid-19 plasma boom is over. What did we learn from it?

Scott Cohen was on a ventilator struggling for his life with Covid-19 last April when his brothers asked Plainview Hospital on Long Island to infuse him with blood plasma from a recovered patient.

Experimental treatment was difficult to come by, but it gained attention at a time when doctors had little else. After an online petition drew 18,000 signatures, the hospital gave Mr. Cohen, a retired paramedic from Nassau County, an infusion of the pale yellow material some referred to as "liquid gold."

In those dire first months of the pandemic, the idea that antibody-rich plasma could save lives took on a life of its own before there was evidence that it worked. The Trump administration, backed by advocates of elite medical facilities, used plasma as good news at a time when there weren't many others. It awarded more than $ 800 million to companies involved in its collection and management, and brought Dr. Anthony S. Fauci's face on billboards promoting the treatment.

A coalition of corporations and nonprofits, including the Mayo Clinic, the Red Cross, and Microsoft, mobilized to solicit donations from people who had recovered from Covid-19, and hired celebrities like Samuel L. Jackson and Dwayne Johnson, the actor known as rock. Volunteers, some in superhero capes, showed up in droves at blood banks.

Mr. Cohen, who later recovered, was one of them. He donated his own plasma eleven times.

However, there was no good evidence of convalescent plasma by the end of the year, leading many reputable medical centers to quietly abandon it. By February, when cases and hospital stays declined, demand sank below blood bank stocks. In March, the New York Blood Center called Mr. Cohen to cancel his 12th appointment. It no longer needed plasma.

A year ago, when Americans were dying from Covid at an alarming rate, the federal government made a big bet on plasma. Nobody knew if the treatment would work, but it seemed biologically plausible and safe, and there wasn't much else to try. In total, more than 722,000 units of plasma have been distributed to hospitals thanks to the federal program that ends this month.

The government's bet resulted in neither blockbuster treatment for Covid-19 nor a decent one. But it gave the country real-time training in the pitfalls of testing medical treatment in the middle of an emergency. Medical science is messy and slow. And when treatment fails, which it often does, it can be difficult for the strongest proponents to let go of.

With the government giving plasma to so many patients outside of a controlled clinical trial, it took a long time to measure effectiveness. Finally, studies surfaced suggesting that plasma could be helpful in the right conditions. However, there is now ample evidence that the country's massive, costly plasma campaign has had little impact, especially on people whose disease was so advanced that they could end up in hospital.

In interviews three federal health officials – Dr. Stephen M. Hahn, former Commissioner for the Food and Drug Administration; Dr. Peter Marks, a top F.D.A. Regulator; and Dr. H. Clifford Lane, a clinical director at the National Institutes of Health, acknowledged that the evidence for plasma was limited.

"The data is just not that strong and it makes it difficult, in my opinion, to be excited that it continues to be used," said Dr. Lane. The N.I.H. Recently, an outpatient study with plasma was canceled due to lack of benefit.

Plasma Actions

Doctors have used antibodies from recovered patients to treat diseases such as diphtheria, 1918 flu, and Ebola for more than a century.

When patients contracted the new coronavirus last year, doctors around the world turned to the old standby mode.

In the United States, two hospitals – Mount Sinai in New York City and Houston Methodist in Texas – administered the first units of plasma to Covid-19 patients within a few hours on March 28.

Dr. Nicole M. Bouvier, an infectious disease doctor who helped set up Mount Sinai's plasma program, said the hospital tried the experimental treatment because blood transfusions have a relatively low risk of harm. With a new virus spreading rapidly and with no approved treatments, "nature is a much better maker than we are," she said.

As Mount Sinai prepared to infuse patients with plasma, Diana Berrent, a photographer, was recovering from Covid-19 at her home in Port Washington, New York. Friends began to send the call of their Mount Sinai for donors.

"I had no idea what plasma was – I haven't taken a science class since high school," Ms. Berrent recalled. But as she looked into history of previous disease outbreaks, she was fixated on how to help.

She started a Facebook group of Covid-19 survivors that grew to more than 160,000 members and eventually became a health promotion organization, Survivor Corps. She livestreamed her own fundraising sessions to the Facebook group, which in turn led to more donations.

"People flew places to donate plasma to each other," she said. "It was really a nice thing to see."

Around the same time, Chaim Lebovits, a shoe wholesaler from Monsey, New York, in hard-hit Rockland County, was spreading the topic of plasma in his Orthodox Jewish community. Mr Lebovits called several rabbis he knew and soon thousands of Orthodox Jews were tested for coronavirus antibodies and came to donate. It was exhausting to coordinate everything.

"April," recalled Mr Lebovits with a laugh, "was like 20 decades."

Two developments this month have further accelerated the use of plasma. With the help of federal funds of $ 66 million, the F.D.A. tapped Mayo Clinic to run an expanded access program for hospitals across the country. And the government agreed to pay the administrative costs of collecting plasma and sign contracts with the American Red Cross and blood centers.

The press releases announcing these deals did not catch the noticeable media attention that the billion dollar Covid-19 vaccine deals had when they arrived later that summer. And the government didn't say how much it would invest.

This investment turned out to be significant. According to contract documents, the US government has paid $ 647 million to the American Red Cross and American blood centers since last April.

"The convalescence plasma program should meet the urgent need for a possible therapy at the beginning of the pandemic," a spokeswoman for the Ministry of Health said in a statement. "When these contracts began, there were no treatments available for Covid-19 patients in the hospital."

Updated

April 17, 2021, 11:41 a.m. ET

As spring turned to summer, the Trump administration – like the unproven drug hydroxychloroquine – used plasma as a promising solution. In July, the government announced an $ 8 million advertising campaign "urging Americans to donate their plasma and save lives". The Blitz included radio commercials and billboards featuring Dr. Fauci and Dr. Hahn, the F.D.A. Commissioner.

A coalition to organize the plasma collection took shape, bringing together researchers, federal officials, activists like Ms. Berrent and Mr. Lebovits, and large corporations like Microsoft and Anthem on regular calls that continue to this day. Nonprofit blood banks and nonprofit plasma collection companies also joined the partnership called Fight Is In Us.

The group also included Miter Corporation, a little-known nonprofit that had received a $ 37 million government grant to promote plasma donation across the country.

The participants sometimes had conflicting interests. While the blood banks were collecting plasma to infuse immediately into hospital patients, the nonprofits needed plasma donations to develop their own blood-based treatment for Covid-19. Donations at the centers of these companies had also declined after national lockdowns.

"They don't all get along," said Peter Lee, corporate vice president of research and incubations at Microsoft, at a virtual science forum organized by Scripps Research in March.

Microsoft was enlisted to develop a locator tool for potential donors embedded on the group's website. But the company took on a broader role "as a neutral broker," said Dr. Lee.

The company also granted access to its advertising agency that created the look and feel of the Fight Is In Us campaign, which featured video testimonials from celebrities.

Lack of evidence

In August the F.D.A. authorized emergency plasma under pressure from President Donald J. Trump to punish federal scientists for moving too slowly.

At a press conference, Dr. Hahn, the agency's commissioner, greatly exaggerated the data, although he later corrected his remarks following criticism from the scientific community.

In a recent interview, he said that Mr Trump's involvement in the plasma permit polarized the issue.

"There was no discussion of the science and medicine behind it, as it became a political issue, not a medical and scientific issue," said Dr. Rooster.

The approval abolished the Mayo Clinic system and opened up access to even more hospitals. As Covid-19 cases, hospitalizations, and deaths skyrocketed in the fall and winter, plasma use soared, according to Blood Centers of America's national use data. As of January of this year, when the United States was performing an average of more than 130,000 hospitalizations per day, hospitals were administering 25,000 units of plasma per week.

Many community hospitals, which serve lower-income patients with few other options and plasma, advocated the treatment. In the Integris Health system in Oklahoma, it became standard practice between November and January to give patients two units of plasma.

Dr. Infection Prevention System's medical director David Chansolme admitted that studies with plasma showed it was "missing more than it was hit," but said his hospitals lacked the resources of larger facilities, including access to, over the past year antiviral drug remdesivir. Doctors with a deluge of patients – many of them Hispanic and rural communities – were desperate to treat them with whatever they could that was safe, said Dr. Chansolme.

By fall, accumulating evidence showed that plasma wasn't the miracle some early boosters believed. In September, the Infectious Diseases Society of America recommended that plasma not be used in hospital patients outside of a clinical trial. (On Wednesday the Society further limited its advice, saying that plasma should not be used at all in hospital patients.) In January, a highly anticipated study in the UK was prematurely canceled because there was no clear evidence of benefit in hospital patients.

In February the F.D.A. The approval for plasma was restricted in such a way that it only applies to people who were in the early stages at the onset of their illness or who were unable to produce their own antibodies.

Dr. Marks, the F.D.A. The regulator said the scientists were retrospectively too slow to adapt to these recommendations. They had known from previous disease outbreaks that plasma treatment likely works best when given early and when it contains high levels of antibodies, he said.

"Somehow we didn't take this as seriously as we maybe should have," he said. "If this was a lesson, history can actually teach you something."

Nowadays, several medical centers have largely stopped delivering plasma to patients. Researchers at Chicago's Rush University Medical Center found that many hospital patients were already making their own antibodies, eliminating the need for plasma treatments. According to Dr. Simon Mucha, an intensive care doctor, is no longer routinely administering plasma at the Cleveland Clinic because "there is no convincing evidence of its effectiveness".

And earlier this year, Mount Sinai stopped giving plasma to patients outside of a clinical trial. Dr. Bouvier said that she was following the scientific literature and that there was some sort of "pile up" of studies that showed no benefit.

"This is science – it's a process of giving up your old hypotheses in favor of a better one," she said. Many initially promising drugs fail in clinical trials. "This is how the biscuit crumbles."

The future of plasma

Some scientists are calling for the F.D.A. to revoke the emergency approval of plasma. Dr. Luciana Borio, the agency's acting chief scientist under President Barack Obama, said disregarding normal scientific standards in an emergency – what she described as a "pandemic state of emergency" – cost valuable time and attention to discovering other treatments.

"Pandemic state of emergency is something we have learned from previous emergencies that has serious unintended consequences," she said, referring to the way countries relied on insufficient studies during the Ebola outbreak. Using Plasma, she said, "The agency has forgotten lessons from previous emergencies."

While little evidence shows that plasma will help contain the pandemic, a dedicated group of researchers at prominent medical institutions continues to focus on the tight circumstances under which it could work.

Dr. Arturo Casadevall, an immunologist at Johns Hopkins University, said many of the studies were unsuccessful because they tested plasma on very sick patients. "If treated early, the results of the studies are all consistent," he said.

A clinical study in Argentina found that giving plasma to the elderly early reduced the progression of Covid-19. An analysis by the Mayo Clinic program found that patients who were given plasma containing high levels of antibodies did better than those who did not receive the treatment. In March, the N.I.H. Testing of plasma in people not yet seriously ill with Covid-19 has been halted as the agency said it was unlikely to help.

With most medical professionals acknowledging the limited usefulness of plasma, even Fight Is In Us has started to shift its focus. For months, a "clinical research" page on convalescent plasma was dominated by favorable studies and press releases, leaving out key articles that concluded that plasma had little benefit.

Now the website has been redesigned to more broadly promote not only plasma, but tests, vaccines, and other treatments such as monoclonal antibodies, which are synthesized in a laboratory and are believed to be a more effective version of plasma. The clinical research page also has more negative studies on plasma.

Even so, Fight Is In Us is still running Facebook ads that are paid by the federal government and tell Covid-19 survivors that "there is a hero in you" and "keep it up". The ads urge them to donate their plasma even though most blood banks have stopped collecting it.

Two of the early boosters of the plasma, Mr. Lebovits and Ms. Berrent, also turned their attention to monoclonal antibodies. As he did last spring with Plasma, Mr. Lebovits contributed to increasing the acceptance of monoclonals in the Orthodox Jewish community, setting up an information hotline, placing advertisements in Orthodox newspapers and creating rapid test centers that also functioned as infusion centers. In coordination with federal officials, Mr. Lebovits has since shared his strategies with leaders in the Hispanic community in El Paso and San Diego.

And Ms. Berrent worked with a division at UnitedHealth to find the right patients – people with underlying health conditions or those over 65 – about this treatment.

"I believe in plasma for many very important reasons, but if the news came back tomorrow that gummy bears are working better, we'd be promoting gummy bears," she said. "We're here to save lives."