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Column 1: old school treatment for a 21st century pandemic

A few weeks after the arrival of the new coronavirus on the coasts of the United States, dr. Arturo Casadevall has come up with a plan to suppress the epidemic with medical progress so powerful that he has won a Nobel prize.

In 1901.

It was then that Dr. Emil Adolf von Behring was honored for pioneering the use of so-called convalescent serum as a treatment for diphtheria. In 1892, the Prussian bacteriologist infected horses with the pathogen causing the fatal disease. If the beasts recovered, Von Behring collected their blood, removed its red blood cells and coagulation proteins, and introduced the resulting antibody-rich fluid into the blood flows of patients with human diphtheria.

Until a diphtheria vaccine became widely used in the 1

930s, Von Behring’s bold experiments saved countless lives. In the late 19th century, diphtheria, known as the “strangled angel”, was the 10th most common cause of death in the United States and a ruthless killer of children.

The convalescent serum would become a pillar in the treatment of measles, mumps, tetanus, smallpox and poliomyelitis before “the vaccine era” began in the late 1940s.

“It’s a beautiful story,” said Casadevall, a microbiologist and doctor from Johns Hopkins University, with fervent enthusiasm. “It was the birth of immunology”.

A bag of convalescent plasma donated by a COVID-19 survivor.

A bag of convalescent plasma donated by a COVID-19 survivor.

(Mayo Clinic)

Between a pandemic response that promises wonders of genetic engineering, vaccines developed at “warp speed” and artificial intelligence at the bedside, it takes courage for a scientist to brush up on a remedy from history books and propose it as modern medicine.

The yellowish elixir now taken from the blood of recovered COVID-19 patients is plasma, which retains some clotting factors. It has been tried against the Ebola virus and new flu strains, which should only be shelved when vaccines are available.

Reviving the 19th century invention to fight a 21st century pandemic is not a job for the faint hearted. It will not generate profits or scientific glory. However, to navigate a glove of clinical trials and logistical challenges, it requires a powerful intellect, a heap of energy, the ability to muster an army of qualified recruits and a talent for fundraising.

Column One

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And so, almost every night for five months, Casadevall and two longtime colleagues – Dr. Michael Joyner of the Mayo Clinic and Dr. Liise-anne Pirofski of the Albert Einstein College of Medicine – met online to track the potential. return of the convalescent plasma. They hope it will become both a treatment for COVID-19 and a way to protect people at high risk of coronavirus infection.

All in their sixties and well on their way to major medical careers, this trio could have spent the pandemic engaged in quieter activities. Instead, the three are subjecting immune system proteins from healed patients to modern scientific studies, hoping to buy time for other medical advancements.

They created the National COVID-19 Convalescent Plasma Project, a consortium of 260 doctors and scientists from 57 institutions across the country. Their coalition members launched more than 50 laboratory studies and clinical trials, and by Thursday 79,059 patients had been treated under the project’s “compassionate use” experimental program. Preliminary results are expected shortly.

Dr. Michael Joyner in his Mayo Clinic laboratory

Dr. Michael Joyner in his laboratory at the Mayo Clinic in Rochester, Minn.

(Mayo Clinic)

Their passion makes them live in “COVID time”, practicing science at all hours of the night and day as children and spouses approach their improvised home offices. The pace of the search has been compressed beyond recognition.

Joyner, who manages the daily management of the project, wakes up at 4 in the morning and works for 16 hours, crushing a series of 50 push-ups between meetings and falling asleep at his desk. Casadevall and Pirofski oversee the evidence, recruit scientific talent and build support for the national effort.

If their work also shows a modest benefit, convalescent plasma could help bring children back to school safely and allow the reopening of a larger part of the economy. Positive results could also speed up vaccine development by making it possible to deliberately infect testers, thereby speeding up the evaluation process.

The initiative has reached far beyond the major academic medical centers where most clinical trials are performed. Dozens of doctors and patients in small and medium-sized community hospitals had the opportunity to participate.

Dr Shmuel Shoham, a Johns Hopkins participant who normally treats transplant patients and cancer patients with compromised immunity, said: “We are taking care of the crowdsourcing of a cure.”

“A light bulb moment”

By mid-February, the coronavirus novel had devastated Wuhan in China and spread to Egypt, Iran, South Korea and much of Europe. Cases of community spread in the United States have been reported, prompting Casadevall to assess the readiness of his profession to treat respiratory plague.

It was bleak. But using the power of convalescent plasma, he thought, it could be less.

He exposed his case in an essay in the Wall Street Journal that told the story of Dr. J. Roswell Gallagher, who in 1934 hurled himself from an outbreak of measles giving people plasma shots from recovered patients. The approach was worth another try, he argued.

Pirofski also read the piece. “It was a lightbulb moment” for the medical institution, he said. He turned to Casadevall and they both wrote an article to convince their medical colleagues that it was worth trying the convalescent plasma. It was published on March 13 in the Journal of Clinical Investigation.

Dr. Liise-anne Pirofski

Dr. Liise-anne Pirofski of the Albert Einstein College of Medicine joined the convalescent plasma project after reading Dr. Arturo Casadevall’s essay in the Wall Street Journal.

(Albert Einstein College of Medicine)

Joyner also came across the essay in the Wall Street Journal and was galvanized by the simplicity of the idea. Also anamnesis reader, he discovered articles on the use of convalescent plasma during the flu pandemic of 1918, where it seems to have reduced the risk of patient death from 25% to 50%. “This could work!” he said to himself.

The next day, he called Casadevall and offered his services.

The three form a powerful, though unlikely, team.

Casadevall is a courteous doctor of Cuban origin, a pioneer in the study of fungi that cause disease and a student with a passion for history.

Pirofski is a Californian who came late to science and medicine from the humanities. As an intern at Casadevall during the height of the AIDS crisis, she honed a doctor’s compassion and a reputation for fiercely intelligent immunologist.

Joyner is an anesthesiologist, a sports madman and a leading authority in athletic performance. On a scale of 1 to 10 in extroversion, she volunteers happily to score a 15.

By the first week of March, the three were recruiting inactive co-workers from pandemic residence orders, prompting them to jump where they could.

A Johns Hopkins pathologist holds a donated COVID-19 convalescent plasma bag.

Dr. Aaron Tobian, pathologist and director of transfusion medicine at Johns Hopkins, removes a bag of COVID-19 convalescent plasma donated after it has thawed.

(Will Kirk / Johns Hopkins University)

There was so much to learn about the mysterious new coronavirus: which antibodies mattered most and which existing tests could detect them? Did all infected patients develop the types of antibodies that conferred immunity? How long could this immunity last?

Other issues would require the instincts of frontline doctors. Which dose of convalescent plasma would have the best help dose and how should it be administered? What risks would a transfusion present? Which patients will benefit most and what results would you measure?

Testing experimental therapy would require scientists with statistical ribs and a robust data collection system. They would need people with logistical skills to launch blood in the middle of a pandemic and distribute the plasma, which lasts for three days, from where it is collected to where it is most needed.

In the meantime, someone would need to navigate the federal government’s regulatory machinery – a task that requires the hustle and bustle, contacts and zeal of an accountant for bureaucratic details and budgets.

Some obstacles would be particularly difficult. Antibody tests should be inexpensive, accurate and easy to implement. Blood banks and national collection agencies should be involved. If therapy had proven to help, a small supply chain would have to become very large – quickly.

A man cured of COVID-19 donates plasma.

A man who has recovered from COVID-19 donates plasma that will be tested as a treatment.

(Dartmouth-Hitchcock Health)

Doctors in a number of specialties signed, as did biostatists, public health researchers, microbiologists, blood bankers and computer specialists.

“They were so collaborative,” said Pirofski. “There is nothing of that selfishness in science, where there is a race that must be the first.”

With big profits at stake, pharmaceutical giants regularly gather resources to get such complex initiatives on the finish line. But convalescent plasma promises no exclusive marketing rights, no intellectual property and no big paydays.

In the first two months of the initiative, two crucial ingredients were scarce. The first was the plasma itself. Patients in the first hotspots were just emerging from their tests and few knew that their blood could have value for others.

This began to change when collaborators from the New York Bloody Center approached the hard-hit Orthodox Jewish community in the area. The survivors responded by rolling up their sleeves. It was the beginning of a basic recruiting effort.

Chaim Lebovits, a patient recovered from COVID-19, donates his blood plasma for antibodies.

In addition, the lifeblood of modern medical research – federal funding – was nowhere to be seen. Officials have been encouraging in the phone calls and online meetings, Joyner said, “but no one has brought their checkbook.”

Volunteers through a range of skills had worked for free for more than a month – an unheard of situation. However, Joyner and the others knew that without federal funding, they would hit a wall when the time came to conduct clinical trials.

In early April, the initiative had managed to secure approximately $ 5 million in seed financing, including $ 3 million from Bloomberg’s philanthropies and $ 1 million from the state of Maryland. So, in early May, the federal tap started flowing. The advanced biomedical research and development authority, known as BARDA, in the Department of Health and Human Services, committed $ 50 million to testing convalescent plasma – a sum greater than that of many drug manufacturers and vaccine designers. .

“This is helping people”

So far, the Herculean effort seems to be showing signs of promise. Data from approximately 5,000 patients with severe cases of COVID-19 suggest that treatment is safe. The results of an unfinished study in China suggest that critically ill elderly people and patients of all ages with moderate disease could benefit most from the treatment.

A “study study” published online by project leaders on Friday offers a tempting, albeit preliminary, hint at the lives that could be saved from convalescent plasma. Led by Joyner, the team aggregated the results of the Chinese study and 10 other studies that documented the use of convalescent plasma in a total of 525 COVID-19 hospitalized patients. Patients who received the experimental treatment were 57% less likely to die from COVID-19 than patients with comparable diseases who did not, the researchers concluded.

Results that are expected to be released in the coming weeks will begin to show whether this promise has been confirmed in American hospitalized patients for COVID-19, Joyner said. By late summer, team members will analyze the effects of therapy on patients who have not needed hospitalization and those who have been exposed but show no signs of illness.

“All the indicators indicate that this is helping people,” Casadevall told his troops in a weekly phone call on July 24th. If this is confirmed, “we will probably be able to save many lives in the summer and fall” before better vaccines or treatments emerge, he said.

A convalescent bag of COVID-19 plasma.

A thawed bag of COVID-19 convalescent plasma donated to the Johns Hopkins Medicine blood bank.

(Will Kirk / Johns Hopkins University)

It is certainly possible that the convalescent plasma will fail. It could be overtaken by more effective medicines or a vaccine. Some fluke of the coronavirus, or twist in the pandemic, may make it impractical as a treatment or prevention.

Casadevall, Joyner and Pirofski are ready to accept these results.

“If I’m wrong, too bad,” said Casadevall.

Regardless, he and his army will have taught young doctors how research was done when resources were scarce. Scientists will learn about the body’s response to coronavirus infection and see what progress can be made when they gather in a national crisis.

“This will not bring anyone a ticket to Stockholm” for another Nobel laureate, Joyner said. But towards the end of a long career, “I was very happy to get into the breach”.

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