Convalescent plasma: the picture is getting clearer

 Slowly, there is evidence accumulating that convalescent plasma is helpful in treating patients with severe Covid, if it is administered early.  There is also evidence that it doesn't help much once the disease has become well established, particularly when the primary symptoms become due to the body's own immune reaction.  These caveats help explain why early reports did not find an effect of convalescent plasma--i.e. it helped only a subset of the patients to whom it was administered. But for those it was sometimes life saving. Here is a recent paper from the New England Journal of Medicine.

Convalescent Plasma for Covid-19–Induced ARDS in Mechanically Ventilated Patients by Benoît Misset, M.D., Michael Piagnerelli, M.D., Ph.D., Eric Hoste, M.D., Ph.D., Nadia Dardenne, M.Sc., David Grimaldi, M.D., Ph.D., Isabelle Michaux, M.D., Ph.D., Elisabeth De Waele, M.D., Ph.D., Alexander Dumoulin, M.D., Philippe G. Jorens, M.D., Ph.D., Emmanuel van der Hauwaert, M.D., Frédéric Vallot, M.D., Stoffel Lamote, M.D., et al., October 26, 2023, N Engl J Med 2023; 389:1590-1600 DOI: 10.1056/NEJMoa2209502

"Abstract

BACKGROUND

Passive immunization with plasma collected from convalescent patients has been regularly used to treat coronavirus disease 2019 (Covid-19). Minimal data are available regarding the use of convalescent plasma in patients with Covid-19–induced acute respiratory distress syndrome (ARDS).

METHODS

In this open-label trial, we randomly assigned adult patients with Covid-19–induced ARDS who had been receiving invasive mechanical ventilation for less than 5 days in a 1:1 ratio to receive either convalescent plasma with a neutralizing antibody titer of at least 1:320 or standard care alone. Randomization was stratified according to the time from tracheal intubation to inclusion. The primary outcome was death by day 28.

RESULTS

A total of 475 patients underwent randomization from September 2020 through March 2022. Overall, 237 patients were assigned to receive convalescent plasma and 238 to receive standard care. Owing to a shortage of convalescent plasma, a neutralizing antibody titer of 1:160 was administered to 17.7% of the patients in the convalescent-plasma group. Glucocorticoids were administered to 466 patients (98.1%). At day 28, mortality was 35.4% in the convalescent-plasma group and 45.0% in the standard-care group (P=0.03). In a prespecified analysis, this effect was observed mainly in patients who underwent randomization 48 hours or less after the initiation of invasive mechanical ventilation. Serious adverse events did not differ substantially between the two groups.

CONCLUSIONS

The administration of plasma collected from convalescent donors with a neutralizing antibody titer of at least 1:160 to patients with Covid-19–induced ARDS within 5 days after the initiation of invasive mechanical ventilation significantly reduced mortality at day 28. This effect was mainly observed in patients who underwent randomization 48 hours or less after ventilation initiation."

#####

Here are my posts on convalescent plasma, and the confusing initial reports about its effects.

Plasma donations at the border

Here's a WSJ story about the confluence of two controversial transactions, immigration and compensation for plasma donors.

Block on Blood-Plasma Donors From Mexico Threatens Supplies. U.S. officials say crossing border to donate for a fee isn’t allowed with a visitor visa  By Mike Cherney,  Renée Onque and Daniela Hernandez

"Pharmaceutical companies and U.S. officials are fighting over whether to allow people to cross the border from Mexico to be paid for giving blood plasma, a critical ingredient in treatments for some neurological and autoimmune diseases.

"Up to 10% of plasma collected in the U.S. usually comes from Mexican nationals who enter on visitor visas and are paid about $50 to donate, according to legal filings from pharmaceutical companies. Last June, U.S. border officials indicated they would stop the roughly 30-year practice because they viewed it as labor for hire, which isn’t allowed under a visitor visa.

"The pharmaceutical companies that collect plasma have asked federal courts in Washington, D.C., to overturn the decision, which came just as U.S. plasma donations were disrupted by the Covid-19 pandemic. Some companies have argued that the payment compensates donors for their time and commitment rather than for the plasma itself, and isn’t in exchange for any actual work.

...

"The U.S., which provides much of the global plasma supply, is one of the few countries that allows payments to plasma donors, and supporters of the policy say that helps to ensure enough plasma is collected. Two big plasma companies, Australia-based CSL Ltd. and Spain-based Grifols SA, have invested millions of dollars in collection centers near the U.S.-Mexican border.

...

"A spokesperson for U.S. Customs and Border Protection declined to discuss the litigation.

...

"The agency said pharmaceutical companies could increase payments to attract more domestic supply and that Mexicans could still donate plasma without getting paid."

Bleeding (and more) for Canada

Peter Jaworski in USA today discusses Canadian repugnance for paying for blood or sperm.

If it weren’t for America's free-market ways, more Canadians would have trouble getting pregnant.

"Canada used to have a sufficient supply of domestic sperm donors. But in 2004, we passed the Assisted Human Reproduction Act, which made it illegal to compensate donors for their sperm. Shortly thereafter, the number of willing donors plummeted, and sperm donor clinics were shuttered. Now, there is basically just one sperm donor clinic in Canada, and 30-70 Canadian men who donate sperm. Since demand far outstrips supply, we turn to you. We import sperm from for-profit companies in the U.S., where compensating sperm donors is both legal and normal.
...
"Canada has never had enough domestic blood plasma for plasma-protein products, such as immune globulin. Our demand for those products, however, is increasing. Last year, we collected only enough blood plasma from unremunerated donors to manufacture 17% of the immune globulin demanded. The rest we imported from you, in exchange for $623 million, or $512 million U.S.

Reliance on your blood plasma looked like it might change a little bit when, in 2012, a company called Canadian Plasma Resources announced plans to open clinics in Ontario dedicated to collecting blood plasma. The trouble is that its business model included compensating donors. Almost immediately, groups such as the Canadian Union of Public Employees and the Canadian Health Coalition began to lobby the Ontario government to pass a law to stop CPR from opening clinics. Ontario obliged in 2014, passing the Safeguarding Health Care Integrity Act, which among other things made compensation illegal.

When CPR shifted attention to Alberta, so did the groups opposing them. Just this year, the Alberta government introduced the Voluntary Blood Donation Act, which would prohibit compensation.

British Columbia’s government is just now looking at options to ban it as well.

What persuaded these governments? The anti-compensation groups argued that blood plasma from compensated donors was less safe, that people should donate blood plasma for free rather than for money, and that there is something wrong with having a for-profit business model in health care.

The latter two concerns are strangely specific. They don’t seem to apply to you Americans. If they did, the groups would have lobbied to make importation of anything other than products made from unremunerated donors also illegal. But they didn’t.

Instead, they object to a Canadian for-profit company compensating Canadian blood plasma donors in Canada, but American for-profit companies compensating American donors in America does not appear to register on their moral radar. Like the importation of sperm from for-profit U.S. companies that compensate donors, it has all the appearance of moral NIMBYism. It’s fine if it happens in your backyard, and we’ll happily buy the products, but we object to it happening in our backyard."

************

And here, in Canada's National Post:

Peter Jaworski: Canada needs blood plasma. We should pay donors to get it

Canada buys the vast majority of its plasma-protein products from American companies that attract plasma donors by paying them. Yet we ban the same practice here

Compensation for plasma donors--calls for a ban in Canada

At the same time as there are calls for decriminalizing drug use in Canada (see yesterday's post), there are calls for bans on compensating plasma donors. (Repugnance is a big topic..)

This post collects some thoughts on compensation for plasma donors, following my participation in the recent Plasma Protein Forum.

Much discussed there is the rash of recent legislation and proposed legislation in Canada to ban compensation for donors (a sort of repugnance event...).

E.g.
B.C. joins 3 other provinces in banning payment for blood and plasma
Alberta, Ontario and Quebec already have laws prohibiting profit from blood donations

Senator introducing bill to ban payments for blood donation
"“The point of this bill is better safe than sorry,” Wallin said.

“Canadian blood donors are not meant to be a revenue stream.”

Time to end for-profit plasma donations

Canada must never allow another tainted blood crisis and must put an end to cash-for-blood clinics. by (Senator) PAMELA WALLIN

***************

One perplexing feature of this debate is that Canada already buys lots of plasma from the U.S., where it is supplied by paid donors. No one seems to be suggesting that should be changed.

(Here are my posts to date on plasma in Canada.)

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In related notes, China seems to be ramping up it's "source" plasma collection (obtained at the source via plasmapheresis, as distinct from "recovered" plasma obtained from whole blood donations), with collection of about 7 million liters in 2017.  My understanding is that Chinese law forbids the importation of blood products except for albumin.

See this Lancet editorial from 2017:

The big business of blood plasma

"China,  a  country  that  holds  the  questionable  honour  of  being a world leader in liver disease, is now also the highest consumer  of  serum  albumin,  using  300  tonnes  annually,  roughly  half  of  the  worldwide  total  use,  according  to  an  article  in  the  Financial  Times. 

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In Brazil, compensation of plasma donors is forbidden (along with compensation of organ donors) in the Constitution, article 199

"(4) The law establishes the conditions and requirements to allow the removal of human organs, tissues, and substances intended for transplantation, research, and treatment, as well as the collection, processing, and transfusion of blood and its by products, all kinds of sale being forbidden."

Plasma shortage alert from the IDF--the Immune Deficiency Foundation

Patients with primary immunodeficiencies don't produce antibodies, and depend on immunoglobulin, one of the primary plasma products produced by donated plasma (the other is albumin, and there are other life-saving and life-improving pharmaceuticals as well).  The IDF is a foundation dedicated to this complex of diseases:

Immune Deficiency Foundation
Dedicated to improving the diagnosis, treatment and quality of life of persons with primary immunodeficiencies

In recent years immunoglobulin has been used around the world to treat other immune deficiency diseases also, as well as to modulate the immune systems of people with auto-immune diseases.

But shortages occur, because the U.S. remains the primary supplier of donated plasma (since it is legal to compensate plasma donors in the U.S., but not everywhere...)

Here's a blog post from John Boyle, the IDF president

Immunoglobulin Product Availability Issues: The Sky Is Not Falling but the World Needs More Plasma
"IDF is working with those who are seeking to increase yields of Ig from plasma, introduce new fractionation technologies, grow plasma donations at collection centers, and more, but those are long term solutions.

"Ultimately, the issue is that the world needs more plasma, and the only good way to make that happen is to collect more plasma. The one thing that we can all do right now is to encourage people to become regular plasma donors if there’s a collection center anywhere near them."
***********

"Biologic" medicines are regulated by the Food and Drug Administration's
Center for Biologics Evaluation and Research (CBER)

"CBER is the Center within FDA that regulates biological products for human use under applicable federal laws, including the Public Health Service Act and the Federal Food, Drug and Cosmetic Act. CBER protects and advances the public health by ensuring that biological products are safe and effective and available to those who need them. CBER also provides the public with information to promote the safe and appropriate use of biological products."

Here is their list of CBER-Regulated Products: Current Shortages
"GAMMAGARD LIQUID® Immune Globulin Infusion (Human) is currently available, though patient shipping schedules may be impacted as continued high demand exceeds production plans and available inventory."
which they attribute to: "Demand increase in the drug or biological product."

The rise and fall of convalescent plasma as a treatment for Covid

 The NY Times follows the story:

The Covid-19 Plasma Boom Is Over. What Did We Learn From It?  The U.S. government invested $800 million in plasma when the country was desperate for Covid-19 treatments. A year later, the program has fizzled.  By Katie Thomas and Noah Weiland

"In those terrifying early 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, buoyed by proponents at elite medical institutions, seized on plasma as a good-news story at a time when there weren’t many others. It awarded more than $800 million to entities involved in its collection and administration, and put Dr. Anthony S. Fauci’s face on billboards promoting the treatment.

"A coalition of companies and nonprofit groups, including the Mayo Clinic, Red Cross and Microsoft, mobilized to urge donations from people who had recovered from Covid-19, enlisting celebrities like Samuel L. Jackson and Dwayne Johnson, the actor known as the Rock. Volunteers, some dressed in superhero capes, showed up to blood banks in droves.

...

"But by the end of the year, good evidence for convalescent plasma had not materialized, prompting many prestigious medical centers to quietly abandon it. By February, with cases and hospitalizations dropping, demand dipped below what blood banks had stockpiled.

...

"All told, more than 722,000 units of plasma were distributed to hospitals thanks to the federal program, which ends this month."

***********

There were also parallel private efforts that mobilized convalescent plasma donation through social media, and via faith based organizations.  I followed some of the science in a series of posts on plasma and plasma donation more generally.  I should note that, although convalescent plasma hasn't emerged as a treatment for Covid-19, it continues to have many very well documented life-saving uses.

Plasma donation in the EU: compensated and uncompensated

 Here's a commentary on the EU Parliament's current efforts to ban compensation to plasma donors in the EU, published today.

 Julio J Elias, Nicola Lacetera, Mario Macis, Axel Ockenfels, Alvin E Roth, "Quality and safety for substances of human origins: scientific evidence and the new EU regulations," BMJ Global Health, Volume 9, Issue 4 (21 April, 2024) https://doi.org/10.1136/bmjgh-2024-015122

"Summary box

The new European Union (EU) ‘Regulation on standards of quality and safety for substances of human origin (SoHOs) intended for human application’ is based on a long-standing diffidence towards offering compensation to donors of SoHOs.

We point to recent, growing empirical evidence indicating that carefully designed compensation can increase the supply of SoHOs without negatively affecting quality and safety. We also elaborate arguments that address some of the moral concerns that motivate the aversion to payments.

As member states proceed to adopt the new EU regulation, our article may provide insights on how to achieve both self-sufficiency and safety"

...

"At least where plasma for fractionation is concerned, the unpaid-donor system has failed to meet demand. Table 1 indicates that in Europe, countries allowing monetary compensation for donors are the only ones achieving self-sufficiency in plasma collection for the production of immunoglobulin. The plasma sector in countries that compensate plasma donors, notably the USA, serves as supplier to many countries experiencing chronic shortages. The USA alone collects about 70% of the world’s plasma supply.10 A combination of a favourable regulatory environment, an extensive collection network and advanced technological infrastructure contributed to establishing the US position.11

Table 1

Plasma self-reliance and models of plasma collection15–19

Country	Reliance on domestic supply (% of total national need)	Monetary payments allowed	Current payment amount	Other incentives
Austria (2020)	100	Yes	€30–40	–
Czech Republic (2020)	100	Yes	€30–35	–
Germany (2020)	100	Yes	€25	–
Hungary (2020)	100	Yes	€30	–
Latvia (2018)	100	Yes	€17	–
Italy (2018)	76	No	–	Paid leave of absence from work
Slovenia (2017)	54	No	–	Paid leave of absence from work
Belgium (2019)	50	No	–	Paid leave of absence from work
France (2020)	50	No	–	–
Netherlands (2020)	45	No	–	–
Slovakia (2018)	41	No	–	–
Denmark (2018)	34	No	–	–
Spain (2020)	34	No	–	–
Portugal (2018)	22	No	–	Exemption from National Health Service user fees

• The table shows, for each country, the percentage of plasma needed for immunoglobulin (Ig) production that is collected domestically. The year in parenthesis is the one to which the data on self-reliance refer. The table then reports whether monetary payments are allowed, the current range of payments per donation and any other incentives in use in each country. In countries that allow payments, plasma collectors offer, in addition to monetary compensation for each donation, additional monetary or in-kind rewards, for example, when a donor reaches a certain number of donations (eg, 5, 10,…), or to first-time donors. The figures reported above do not include these additional rewards.

Canadian Blood Services to start paying Canadian plasma donors

 CBC news has the story, which seems to mark a turning point in a long struggle with repugnance for paying donors.

Canadian Blood Services signs agreement with private company to boost national plasma supply.  Some advocates calling for the resignation of Canadian Blood Services leaders over agreement. by Stephanie Dubois 

"Canadian Blood Services (CBS) is partnering with a private healthcare company to boost Canada's national blood plasma supply, the organization announced Wednesday.

...

"CBS has signed an agreement with Grifols, a company headquartered in Spain, which specializes in producing plasma medicines, the national blood collection organization said in a news release.

...

"Grifols will help CBS meet national targets for plasma supply by both collecting paid-for plasma and by turning Canadian plasma into immunoglobulins —a form of specialized medications called plasma protein products– for Canadian patients. 

...

"Health Canada says on its website there's currently "not enough plasma collected in Canada to meet the demand," and most of the plasma products distributed by CBS and Héma-Quebec are purchased from U.S. manufacturers and made from U.S. paid-donor plasma. "

Blood money: plasma and ambivalence

 The Guardian has a long review of the book Blood Money, by Kathleen McLaughlin, who is dependent on blood plasma, but suggests reasons to be ambivalent about the American market for paid plasma.

‘It’s gamified’: inside America’s blood plasma donation industry. In her new book Blood Money, Kathleen McLaughlin uses a personal lens to examine an industry that rewards mass plasma donation  by David Smith

"So who is the typical blood seller and why do they do it? McLaughlin had expected to find the poorest of the poor but, it transpires, most of them are screened out because a plasma donor must have a permanent address.

“What I found instead was a lot of people who, say, 25 years ago would have been middle class, and they just don’t make enough money for that lifestyle any more. I get the sense that one of the biggest demographics is college students. We’re talking about like big public universities where there are a lot of students who don’t come from wealthy backgrounds; I’ve talked to people who use this money to buy books, to pay to go out for a night, for ‘beer money’.

“You will also find people in communities like Flint, Michigan, where I spent a lot of time, who used to be able to expect to have this very normal American middle-class lifestyle and wages and benefits no longer keep pace with that. There are people doing it to buy groceries and to pay for housing. There are also people who are selling plasma to take a vacation."

...

"And whereas donating blood for free is lauded, donating it for money is stigmatised. “If you think about blood donation, it’s something that we consider quite heroic. If you go to the Red Cross and donate blood, you’re saving a life, you’re not getting paid for it.

“But somehow this practice of donating plasma for pay comes with a pretty heavy stigma. A lot of the people I interviewed who do sell plasma had not told their families that they do it because they were afraid of what their families would think: there would be some kind of judgment or their families would be worried about their health or concerned that they don’t have enough money.

‘The stigma is entirely linked to the fact that we stigmatise poverty in the United States. We look down on it. We don’t respect people who aren’t wealthy in the same way that we respect wealthy people. It’s been interesting for me to see the way that people view selling plasma as being somehow problematic and that’s definitely contributed to the fact that this industry is kind of hidden.”

"Still, should we make a moral judgment about the blood industry? It is not, after all, pushing an addictive substance like opioids, but rather is helping the health of people in America and around the world, McLaughlin included. She replies: “We need to ask ourselves that. From my perspective as someone who depends on this substance, what people are doing is incredibly altruistic.

“I also think a lot of people are being financially coerced to do it and, the way the system is set up, you get paid more per donation for each donation you make. It’s gamified in such a way that people are encouraged to donate quite often and because it is a hidden industry, most Americans haven’t really considered if this is who we want to be.

“If you know that there are potentially millions of Americans who have sold their plasma to pay for things like groceries and vacations, are you OK with that? For me, it’s more a matter of getting people to think about it, that our economic situation is such that this is part of our fabric now and are we comfortable with being that way or do we want to think more deeply about how we can make this more feel more of a choice for people?”

"She adds: “The industry itself isn’t necessarily the problem. The problem is that we have let this industry become a part of people’s incomes. I don’t know that that’s the kind of society we want to be.”

“It’s these places where people are economically fragile, not necessarily desperately poor. The kind of fragility that we didn’t have 25 or 30 years ago when there were more social-safety protections.”

Blood and plasma: a brief history, from 1628

With all my discussion of convalescent plasma for Covid-19 this week*, here's a historical perspective on the technology and changes in medical practice since the discovery of blood circulation in 1628 that allows blood and plasma to be used in medicine.


A history of blood transfusion: a confluence of science—in peace, in war, and in the laboratory
by Kevin R. Loughlin
Hektoen International, Volume 12, Issue 2 – Spring 2020.

"Since 1628 when William Harvey discovered the circulation of blood, there had been hope that blood transfusion would be possible.
...
"After Harvey’s discovery, transfusion attempts began. In 1665 Richard Lower kept dogs alive by transfusing blood from other dogs.2 In 1667 French physician Jean Denys transfused nine ounces of blood from the carotid artery of a lamb into the vein of a young man. He continued the practice until the third patient so treated, died.3 Denys was sued by the wife of the deceased patient, who presumably died from a hemolytic reaction, but was exonerated. However, the French Parliament, the Royal Society, and the Catholic Church subsequently issued a general prohibition against transfusions.4

"It would not be until 1818 when transfusions were seriously considered again. A British obstetrician, James Blundell, performed a human blood transfusion in the setting of a postpartum hemorrhage.5 However, the debate over transfusions continued over the remainder of the nineteenth century. In 1849 C.H.F. Routh reviewed all the published transfusions to date and remarked in the Medical Times that of the 48 recorded cases, 18 had a fatal outcome and concluded that the mortality rate was unacceptably high.5 The next major advance in transfusion therapy would wait until the turn of the century.

"Karl Landsteiner was an Austrian physician and immunologist. While working at the University of Vienna, he became interested in blood serum work, specifically the factors that led to hemagglutination of red blood cells. This resulted in two landmark publications in 1900 and 1901 that described the evidence of blood groups that he named A, B, and C.6,7 These would later be modified to A, B, and O. Two years later, two of his colleagues, Alfred Von Decastelo and Adriano Sturli, would add a fourth blood type, AB.8,9 Landsteiner would be awarded the Nobel Prize in 1930 for his elucidation of the blood groups.

... in 1912, Doctor Roger Lee demonstrated that O blood could be given to a person of any blood type (universal donor) and that a person with AB blood could receive blood from any blood group (universal recipient).
...
"As blood transfusions became more widespread in medical practice, the concept of establishing blood banks became attractive. In the 1930s Bernard Fantus at Cook County Hospital20 and Carl W. Walter at Peter Bent Brigham Hospital started blood banks. In Boston, Walter’s efforts were viewed with such skepticism and disdain that his facility was relegated to a basement room at Harvard because some trustees thought the storage and use of blood was “immoral and unethical.”21 Fifteen years later he invented the plastic blood bag, which greatly facilitated transfusion therapy.21
...
"In 1940 Edwin Cohn developed ethanol fractionation, the process of breaking down plasma into component products. Albumin, gamma globulin, and fibrinogen were isolated to become available for clinical use.

"In 1944 dried plasma became available for the treatment of combat injuries. Component transfusion therapy became more widely used as the war progressed. The Red Cross concluded its World War II blood program in 1945 after 13 million pints had been collected.11

"In 1961 platelet concentrates became recognized for reducing mortality from hemorrhage in cancer patients. In 1964 plasmapheresis was introduced as a means of collecting plasma for fractionation. In 1971 Hepatitis B surface antigen (HbsAg) testing of donated blood began and in 1992 testing of donor blood for HIV-1 and HIV-2 antibodies commenced.
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*here's a recap of my earlier coronavirus posts relating to plasma this week:

Sunday, May 17, 2020

Cascades of convalescent plasma for Covid-19, and chains of exchanges, by Kominers, Pathak, Sönmez, and Ünver

Monday, May 18, 2020

Plasma and plasma products (such as antibodies) are a big business (and the U.S. dominates the international market)

Wednesday, May 20, 2020

Convalescent plasma collection and distribution

Canadian Blood Services in talks around paid donations of plasma

Canadian Blood Services in talks around paid donations of plasma as supply dwindles. by Christopher Reynolds

"Canadian Blood Services is in talks with companies that pay donors for plasma as it faces a decrease in collections.

"The blood-collection agency issued a statement on Friday saying it is in “ongoing discussion with governments and the commercial plasma industry” on how to more than double domestic plasma collection to 50 per cent of supply.

"Canadian Blood Services has previously cautioned that letting companies trade cash for plasma - a practice banned in British Columbia, Ontario and Quebec - could funnel donors away from voluntary giving.

"The bulk of the non-profit agency's supply currently comes from abroad, including via organizations that pay donors."

HT: Frank McCormack

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The Globe and Mail adds some detail:

Canadian Blood Services eyes getting plasma from paid donors amid supply challenges by Chris Hannay

"Industry observers say the most likely commercial partner for CBS is Grifols, an international pharmaceutical company headquartered in Spain. The company purchased a large-scale plasma processing facility in Montreal in 2020, and in January bought an existing for-profit plasma donation centre in Winnipeg.”

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See my full set of posts on plasma in Canada

Is convalescent plasma useful for treating covid-19?

The reported results on convalescent plasma are so far still quite incomplete, and mixed.  If I had to summarize, I'd say that a growing body of evidence suggests that treating early stage (e.g. just hospitalized) covid-19 patients increases and speeds the chance of recovery, while there is little convincing evidence that convalescent plasma helps more severely ill patients who have begun to have serious complications.

Here is a recent WSJ article:

Convalescent Plasma Reduced Death Rate Among Covid-19 Patients, Study Data Signals

Hospitalized patients who got earlier transfusions of blood plasma rich in antibodies to the coronavirus show a lower mortality rate

By Amy Dockser Marcus

"Hospitalized Covid-19 patients who received transfusions of blood plasma rich with antibodies from recovered patients reduced their mortality rate by about 50%, according to researchers running a large national study.

...

"The researchers said they saw signs that the treatment might be working in patients who received high levels of antibodies in plasma early in the course of their illness. They based their conclusions on an analysis of about 3,000 patients."

************

Here's a recent paper in JAMA on a very small randomized trial in China that doesn't find statistically significant effects on patients who 

August 4, 2020

Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial

Ling Li, MD, PhD; Wei Zhang, MD; Yu Hu, MD, PhD; Xunliang Tong, MD, PhD; Shangen Zheng, MD; Juntao Yang, PhD; Yujie Kong, MD; Lili Ren, PhD; Qing Wei, MD; Heng Mei, MD, PhD; Caiying Hu, MD; Cuihua Tao, MD; Ru Yang, MD; Jue Wang, MD; Yongpei Yu, PhD; Yong Guo, PhD; Xiaoxiong Wu, MD; Zhihua Xu, MD; Li Zeng, MD; Nian Xiong, MD, PhD; Lifeng Chen, MD; Juan Wang, MD; Ning Man, MD; Yu Liu, PhD; Haixia Xu, MD; E. Deng, MS; Xuejun Zhang, MS; Chenyue Li, MD; Conghui Wang, PhD; Shisheng Su, PhD; Linqi Zhang, PhD; Jianwei Wang, PhD; Yanyun Wu, MD, PhD; Zhong Liu, MD, PhD

  JAMA. 2020; 324(5):460-470. doi: 10.1001/jama.2020.10044

Abstract: This randomized trial compares the effects of convalescent plasma therapy with standard care vs standard care alone on time to clinical improvement among patients with severe or life-threatening COVID-19 disease in China.

"Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment did not significantly improve the time to clinical improvement within 28 days, although the trial was terminated early and may have been underpowered to detect a clinically important difference."

**********

My last donation had high enough antibodies to qualify me for another: I hope these are going to patients for whom they will be useful.

More on convalescent plasma for treating Covid-19

Early results concerning the effectiveness of convalescent plasma have been mixed.  Here's a new study, in the NEJM, and reported in the NY Times. (see my earlier posts here.)

Here's the Times story:

Blood Plasma Reduces Risk of Severe Covid-19 if Given Early  By Katherine J. Wu

"A small but rigorous clinical trial in Argentina has found that blood plasma from recovered Covid-19 patients can keep older adults from getting seriously sick with the coronavirus — if they get the therapy within days of the onset of the illness.

"The results, published Wednesday in the New England Journal of Medicine, are some of the first to conclusively point toward the oft-discussed treatment’s beneficial effects."

And here's the NEJM article:

Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults

List of authors.

Romina Libster, M.D., Gonzalo Pérez Marc, M.D., Diego Wappner, M.D., Silvina Coviello, M.S., Alejandra Bianchi, Virginia Braem, Ignacio Esteban, M.D., Mauricio T. Caballero, M.D., Cristian Wood, M.D., Mabel Berrueta, M.D., Aníbal Rondan, M.D., Gabriela Lescano, M.D., et al., for the Fundación INFANT–COVID-19 Group*

"BACKGROUND: Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness.

METHODS: We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible.

RESULTS: A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P=0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed.

CONCLUSIONS: Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. "

Convalescent plasma for Covid-19 may not be as effective as hoped

 Here's a recent article from the New England Journal of Medicine: they conclude that treatment of Covid-19 patients with convalescent plasma is no better than a placebo treatment (for a group of seriously ill patients with over a 10% mortality rate).

A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia

by Ventura A. Simonovich, M.D., Leandro D. Burgos Pratx, M.D., Paula Scibona, M.D., María V. Beruto, M.D., Marcelo G. Vallone, M.D., Carolina Vázquez, M.D., Nadia Savoy, M.D., Diego H. Giunta, M.D., M.P.H., Ph.D., Lucía G. Pérez, M.D., Marisa del L. Sánchez, M.D., Andrea Vanesa Gamarnik, Ph.D., Diego S. Ojeda, Ph.D., et al., for the PlasmAr Study Group

RESULTS: A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment. The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to 1:3200]. No patients were lost to follow-up. At day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83 (95% confidence interval [CI], 0.52 to 1.35; P=0.46). Overall mortality was 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of −0.46 percentage points (95% CI, −7.8 to 6.8). Total SARS-CoV-2 antibody titers tended to be higher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse events were similar in the two groups.

CONCLUSIONS: No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo. 

HT: Irene Wapnir

Convalescent plasma collection ramps up

Here's a story from the WSJ:
Blood Banks, Pharma Join Microsoft to Sign Up Covid-19 Survivors for Plasma

"A coalition of research institutions, blood banks, drug companies and recovered Covid-19 patients is working to overcome a major challenge in developing new therapies based on survivors’ blood plasma: a shortage of donors.

"With a campaign launched Tuesday called The Fight Is In Us, the group aims to get tens of thousands of people who have recovered from Covid-19 infections to donate plasma using a self-screening tool developed by Microsoft Corp. MSFT -0.17%

"So far nearly 15,000 seriously ill Covid-19 patients have received plasma transfusions in an emergency, expanded-access program authorized by the Food and Drug Administration
...
"The Red Cross has collected plasma from 4,000 recovered Covid-19 donors to date through its website RedCrossBlood.org/plasma4covid, according to a spokeswoman. She said the organization supports the efforts of the coalition but didn’t join it. “At this time, the Red Cross is fortunate to be able to meet the needs of our hospital partners,” she said. “We also have the capacity to ramp up our supply if necessary.”
...
"Despite the unusual efforts to work together, for-profit companies in the coalition also continue to look for donors on their own through digital advertising and other online outreach, according to industry experts.

"Potential donors who go to the thefightisinus.org website start by using a self-screening tool. It asks if they were diagnosed for Covid-19 infection, have been symptom-free for more than 14 days, meet age and weight requirements for blood donation and have ever been diagnosed with HIV, hepatitis C or hepatitis B, which affects eligibility. The potential donors enter a ZIP Code and get a list of nearby donation centers.

"Peter Lee, corporate vice president at Microsoft, which developed the self-screening tool, said donors are currently directed to centers based on location. Coalition members are still discussing ways to determine how donors are allocated.
...
"Some plasma donors might prefer to give to a for-profit plasma company, where they might be reimbursed. Others might choose a local blood bank, where the plasma would be used right away for sick patients in a hospital and reimbursement isn’t offered
...
"In New York and other places affected early in the outbreak, many recovered patients have encountered long wait times to donate"

Blood Money, by John Dooley and Emily Gallagher

 Are paid plasma donors being exploited? Here's a paper that suggests not, but rather that the payments that plasma donors receive can improve their financial well being not merely by providing additional income, but also by helping them avoid going into expensive debt.

 Dooley, John and  Emily Gallagher, Blood Money (October 11, 2021). Available at SSRN: https://ssrn.com/abstract=3940369 or http://dx.doi.org/10.2139/ssrn.3940369

Abstract: "Little is known about the motivations and outcomes of sellers in remunerated markets for human materials. We exploit dramatic growth in the number of commercial blood plasma centers in the U.S. to study the individuals who sell plasma. We find sellers tend to be young and liquidity constrained with low incomes and credit scores; they also report less access to traditional bank credit. Plasma centers absorb demand for non-traditional credit. The opening of a nearby plasma center reduces payday loan inquires and transactions by 13–18% among young borrowers. Meanwhile, foot traffic increases by over 9% at both essential and non-essential goods establishments when a new plasma center opens nearby. Our findings suggest that, at least in the short-term, constrained households use the discretionary income from plasma centers to smooth consumption without appealing to high-cost debt."

HT: Mario Macis

Update: here's the published version

John M Dooley, Emily A Gallagher, Blood Money: Selling Plasma to Avoid High-Interest Loans, The Review of Financial Studies, 2024;, hhae018, https://doi.org/10.1093/rfs/hhae018

Still bleeding for Canada

Here's a paper on the ongoing debate in Canada about whether it should be legal to pay plasma donors.

Moral NIMBY-ism? Understanding Societal Support for Monetary Compensation to Plasma Donors in Canada
by
Nicola Lacetera, Mario Macis
NBER Working Paper No. 24572 May 2018

Abstract: "The growing demand for plasma, especially for the manufacture of therapeutic products, prompts discussions on the merits of different procurement systems. We conducted a randomized survey experiment with a representative sample of 826 Canadian residents to assess attitudes toward legalizing payments to plasma donors, a practice that is illegal in several Canadian provinces. We found no evidence of widespread societal opposition to payments to plasma donors. On the contrary, over 70% of respondents reported that they would support compensation. Our Canadian respondents were more in favor of paying plasma donors elsewhere than in Canada, but the differences were small, suggesting a weak role for moral “NIMBY-ism” or relativism. Moral concerns were the respondents’ main reason for opposing payments, together with concerns for the safety of plasma from compensated donors, although most of the plasma in Canada does come from paid U.S. donors. Among those in favor of legalizing payments to donors, the main rationale was to guarantee a higher domestic supply. Finally, roughly half of those who declared to be against payments reported that they would reconsider their position if domestic supply plus imports did not cover domestic demand. Most Canadians, therefore, seem to espouse a consequentialist view on issues related to the procurement of plasma.

Paying for plasma to be legal in Alberta

 Reason magazine has the story:

Canada Inches Closer to Allowing More People To Be Paid for Plasma--For too long, our northern neighbors have depended on plasma imported from the U.S. to meet demand. With the passage of new legislation in Alberta, this may change.  by LIZ WOLFE 

"Albertans will soon be able to receive payment for their blood and plasma donations. Bill 204, the Voluntary Blood Donations Repeal Act, was introduced by Tany Yao, a member of the legislative assembly for Alberta's provincial government, and passed in the legislature this week. It must now get royal assent—a mere formality—for it to become law. The bill overturns a 2017 prohibition on paid plasma, and will allow private companies to pay plasma donors for their efforts. If they so choose, people will still be able to donate blood and plasma without receiving compensation via Canadian Blood Services.

...

"United Nurses of Alberta's president Heather Smith told Global News that "the government is putting its ideology and desire to support profiteers above what is actually safe for Albertans and Canadians." Elsewhere she said that "donating blood should not be viewed as a business venture."

HT: Peter Jaworski

Explaining plasma donation

In recent posts I've commented on the repugnance (in Canada and elsewhere) to paid plasma donation, which is legal in the U.S.. (The U.S. consequently supplies much of the world's plasma needs.)  One question facing the plasma industry is how to defend against compensated plasma donation being seen as a repugnant transaction.

I think they are already very well equipped to communicate the need for plasma proteins, which provide treatments for a host of diseases, and which are used around the world.  But to the extent that (paid or unpaid) donation needs to be defended and encouraged, I would expect to see more stories like this one, from Australia.

This man's blood has saved 2.4 million babies
'I'd keep going if they let me,' says 81-year-old with magical plasma.

"The man with the golden arm

"Harrison's blood is valuable because he naturally produces Rh-negative blood, which contains Rh-positive antibodies. His blood has been used to create anti-D in Australia since 1967.

"Every ampule of Anti-D ever made in Australia has James in it," Robyn Barlow, the Rh program coordinator who recruited Harrison, told the Sydney Morning Herald. "Since the very first mother received her dose at Royal Prince Alfred Hospital in 1967."

Harrison was the program's first donor.

"It's an enormous thing ... He has saved millions of babies. I cry just thinking about it."

Since then, Harrison has donated between 500 and 800 milliliters of blood almost every week. He's made 1,162 donations from his right arm and 10 from his left.

...

Harrison's retirement is a blow to the Rh treatment program in Australia. Only 160 donors support the program, and finding new donors has proven to be difficult. Additionally, attempts to create a synthetic version of anti-D have failed."

Poll: majority of Canadians approve of paying plasma donors

New survey results from Peter Jaworski
Canadians think that pay-for-plasma is “morally appropriate.”

"A significant majority of Canadians (63%) believed that paying Canadians for plasma donations was “morally appropriate.”

By age, 18-34 year-olds were most likely to think that pay-for-plasma was “morally appropriate,” with 75% saying so. 70% of 35-54 year-olds, and 49% of those 55 or older thought pay-for-plasma was morally appropriate.

By region, 64% of Atlantic Canada, 69% in Quebec, 61% in Ontario, 70% in the Prairies, 65% in Alberta, and 56% in British Columbia held that opinion.

The provinces of Ontario (2014), Alberta (2017), and British Columbia (2018) have all recently banned pay-for-plasma citing moral objections as part of the motivation behind the prohibitions"