Shauna Davison: "I would have maybe had a little longer"

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British teenager Shauna Davison received an experimental transplant in 2012 in the hope of extending her life. Her mother says that she had been informed in advance of two patients who had survived a similar operation – but not those who had died. Deborah Cohen of the BBC asks if Shauna, who died after two weeks, had been a victim of the rush to develop stem cell technology.

Shauna Davison was born with a lung, a cleft palate and an important cardiac malformation. Despite staying at the hospital, she remained a happy child.

"Her illness has never come down and she always has a smile on her face," says Shauna's mother Karen Davison. "Everyone was so nice to her, they looked beyond her problems."

At the age of 12 weeks, doctors found tracheal or tracheal problems. It was very narrow and when it became clogged, she could not breathe anymore. She had 48 hours to live.

Legend

Karen Davison: "It was a cheeky but beloved child of all"

A surgeon in Leeds came to the rescue. David Crabbe warned that it might not work, but he managed to rebuild Shauna's trachea from his ribs.

Shauna had to stay in the hospital for six months and had ring-shaped stents installed in her trachea to keep her open.

Mr. Crabbe was very caring, says Karen Davison. "The hospital was exceptional."

Over the years, Shauna's stents needed to be dilated as she grew up. She had a tracheostomy – an opening at the front of the neck – to help her breathe.

"There were times when we did not think she would get there because she was still falling apart," says Karen Davison.

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You can also watch Deborah Cohen's report for Newsnight on the BBC iPlayer

At home in Middlesbrough, she learned how to change Shauna's tracheostomy tube, use a ventilator, do physiotherapy to help clear her airways, aspirate her airways, perform CPR and give him antibiotics intravenously.

"I did everything for her," she says. "Shauna is wonderfully well behaved in. But she did not know anything else."

Passionate about Middlesbrough football club, Shauna loved to wear a football kit. She went to a regular school, with the support of a caregiver, where she could attend other children.

"He was a brazen child, but loved by all," said his mother. "She lit up everybody's day."

Shauna had a lot of operations but she had always passed. Sometimes she has not been to a hospital for years, Karen says.

However, a moment has come, David Crabbe told him that his Shauna treatment technique would no longer be sufficient. Her airways were too small and they should look for other options.

"Mr. Crabbe showed me images of a normal respiratory tract and his airways – it was tiny," Karen Davison said.

Shauna started going to Great Ormond Street Hospital (GOSH) in London for testing and replacing her stent. In 2011, doctors told him that the airways would not last much longer.

At age 15, Shauna suffered a respiratory arrest – a serious incident in which she became unable to breathe -. Professor Martin Elliott, a cardiothoracic surgeon and former medical director of Great Ormond Street Hospital, told the family that the surgeon had been operated on.

"They said that there had been research on tracheal transplants and that there had been two other cases where this had been done, but they could not talk to me about it because of the confidentiality patients, "explains Karen Davison. One of them was a 10 year old boy, she adds.

"That would be the only chance she would have."

Shauna's transplant was not conventional.

She would receive a donor trachea, but this one would be assembled with her own stem cells, which makes her almost like hers. She would not need any medicine to prevent her body from rejecting it. He was at the forefront of new stem cell technology – and remains very experimental.

Physicians can use experimental treatments if a person is terminally ill and there is no alternative treatment. This is what is called "compassionate use".

Karen says that she was told that Shauna would not need a tracheotomy or a ventilator and that she would lead a normal life. But she was also informed of the risks, adds Shauna. Shauna could still refuse the transplant and undergo a general anesthetic is never without risk.

Martin Elliott had previously worked closely with Martin Birchall, professor of otolaryngology at the internationally renowned University College London (UCL), on the implantation of a trachea donor containing stem cells in another child. They would work together again in Shauna's case.

Shauna was neat at Great Ormond Street during a BBC documentary about the hospital in 2012. She was evaluated by various specialists and asked what her hopes were for the future. Shauna told Dr. Pneumology consultant Dr. Martin Wallis that she wanted to be able to go swimming.

It was not an easy decision to have the operation. According to Martin Wallis, it was not a situation where there was nothing to lose.

"They have a lot to lose and that will make the decision difficult," he said. "She has a reasonable quality of life, she has her good friend, she clearly has sense of humor and fun, it makes things more difficult."

"I wanted her to do it while she was fine rather than wait until she was not well and that may not happen," said Karen Davison. .

But because it was an experimental procedure, his medical team discussed it with the ethics committee of Great Ormond Street Hospital.

"I do not think she will die if we do this, we try to do it so that she does not, at least we will extend her life and quality of life for as long as possible." "said the president. surgeon, Martin Elliott, told the committee on camera.

"They could not give me a moment when she would die but they said that she would eventually die, because her airways were just dropped." So there was this procedure that they said that They were willing to do that, "said Karen Davison. "Like any other parent, if you thought it would help your child live, I accepted it."

Thus, in February 2012, Shauna received the transplant of a donor trachea newly populated with her own stem cells.

Legend

Shauna's transplant was filmed by the BBC

At first, everything seemed to be fine. "The first days she was wonderful," remembers her mother. "I could not believe how much she had recovered afterwards."

Two weeks after her operation, Shauna was transferred from Great Ormond Street by ambulance to a Leeds hospital. But during the transfer, Shauna began to cough a lot and needed suction to clear her throat.

"We thought it was strange, but we thought maybe it was due to the trip," says Davison. "I was just thinking:" Two more weeks and we'll be at home. "

But the next morning, Shauna turned around for the worst.

"His chest was coming in," Karen says. She recalls that Shauna said, "Help me, help me."

"It was the worst day of my life because I could not help it."

Shauna's new trachea had collapsed.

"They said that she had struggled so much to breathe, her heart had given up," says Karen Davison.

"She was a wonderful child, I miss her so much."

When the first transplant using a given trachea-artery, covered with the patient's stem cells, was done in 2008, she made headlines.

It was thought that removing the donor cells from the surface of the trachea and seeding it with the patient's own stem cells created a new organ that would resemble the tissue of the patient. No anti-rejection medication would be needed for the "tissue-engineered" trachea.

The operation was performed by Italian surgeon Paolo Macchiarini with the help of Martin Birchall, then a surgeon at Bristol University. The beneficiary was 30-year-old Claudia Castillo, who had tuberculosis in part of her trachea that was heading for the lungs – the bronchus.

His case was written in the Lancet. Five months after her operation, she would be in perfect health.

Martin Birchall, who had been involved in the preparation of the donor's trachea, said at the time that this would "represent a dramatic change in surgery." Surgeons can now begin to understand and understand the potential of adult stem cells. of tissue engineering to radically improve their abilities to treat patients with serious diseases.

Many people around the world have accepted. It was a "milestone in medicine", "good news without fail" and "a classic example of international collaboration".

"It was considered revolutionary, very innovative … opening the door to a new and exciting technology using a marriage between stem cells and artificial scaffolds that could give birth to this brand new field of regenerative medicine," recalls Professor John Rasko, President of the International Cell Therapy Society.

He had "the smell of a Nobel prize on it," he says.

Indeed, the university that awarded the Nobel Prize for Medicine, the prestigious Karolinska Institute in Stockholm, quickly offered a post to Macchiarini. Birchall, for one, moved to University College London (UCL), where Macchiarini was also named honorary professor.

The operations of Claudia Castillo served as a model and soon other similar procedures were applied. In 2010, Professor Birchall said at a conference "we did five other adults".

In addition to Shauna, Keziah Shorten, 19, and Ciaran Finn-Lynch, 10, receive an artificial trachea. Shauna's surgeon, Martin Elliott, led the transplant team that operated on Ciaran, with the help of Macchiarini and Birchall.

Like Claudia Castillo, her procedure was published in a medical journal and made the headlines. Martin Birchall told reporters: "He still has a healthy organ, made from his own stem cells, which is sort of a miracle."

But soon, questions began to be asked about stem cell tracheae.

For Macchiarini, this meant that his meteoric rise was reflected in a rapid fall in grace. He had abandoned the use of tracheae given in favor of plastic tracheae, also encrusted with stem cells. The results were disastrous – his patients died.

Karolinska repeatedly investigated Macchiarini before sending him away. The charges against him had initially been dismissed, but the institute has since found him guilty of breach of scientific discipline and many of his scientific writings have been retracted. Swedish prosecutors have reopened an investigation for criminal negligence against him last December. He had previously denied any negligence.

Legend

Swedish prosecutor Mikael Bjork announces the reopening of a criminal negligence investigation against Paolo Macchiarini in December 2018

Bo Risberg, professor emeritus of surgery at the University of Gothenberg and former chairman of the Swedish Ethics Council, said that these events were the biggest scandal of research that Sweden had known at the time modern.

"Everything was swept under the rug," he said. Macchiarini's failure to perform preclinical tests on animals using plastic trachea is "the worst crime you can commit," he added.

One of Macchiarini's early critics was Pierre Delaere, professor of otolaryngology at the University Hospital of Leuven in Belgium, who stated that it was "impossible" to have a doctorate. a theoretical point of view "to establish a new blood supply to an artificial trachea, whether it be plastic or fabric. donate.

In 2015, he wrote to UCL to question the idea of "tracheal regeneration", the "biggest lie lie in the history of medicine". By that time, Macchiarini had left UCL.

Legend

Paolo Macchiarini operating

In its subsequent unpublished report on Delaere's allegations, seen by the BBC, UCL questioned the suggestion that stem cells "would play a therapeutic role" in the functioning of Ciaran.

But, he adds, there was no "deliberate fraud" or "misleading intent" on the part of Martin Birchall. Due to the "lack of intention to deceive" the university recommended education and training rather than other formal procedures.

Meanwhile, the university was preparing to conduct clinical trials on stem cell-regenerated trachea and larynx – called Inspire and RegenVox respectively. Martin Birchall was the lead investigator responsible for testing. His team and he would bring millions of dollars of research funds to the university.

This is not the only time that UCL has published a report on Regenerative Medicine at the University. In 2017, he released the results of a special survey, set up after the revelations of Macchiarini. This revealed no fault of Martin Birchall and paved the way for future clinical trials.

Shauna's family was "grateful for the opportunity that her daughter received and had no resentment with the GOSH tracheal team".

UCL told the BBC that "clinicians involved in Shauna Davison's care have informed the commission of investigation".

But Shauna's mother, Karen Davison, said that no one related to the investigation had asked her point of view.

The more I studied the story of Shauna Davison, the more I discovered Karen Davison did not know it.

The two patients Karen and Shauna heard about were Ciaran Finn-Lynch, a 10-year-old boy, and Claudia Castillo, both still alive.

But they were not told that Claudia Castillo's trachea-artery transplant had collapsed a little over three weeks after she had it and that she needed it. stents to stay open. (She has since had a lung removed.)

Karen and Shauna also did not hear about most of the other cases that Martin Birchall had talked about in 2010.

One of these was Keziah Shorten, a teenager from Kent who, in Florence, administered a tissue-engrafted donor trachea about two years ago by Macchiarini in Florence after diagnosing a rare form. of cancer.

But about a year after the operation, his transplant failed. In 2016, Martin Birchall told a Swedish documentary that his genital trachea was out of order. When she was subsequently operated on at University College London Hospital, they replaced her with another plastic one. She died a month before Shauna's operation.

According to John Rasko, there is "a strong obligation to give a full and candid account of all available information.Exceptionalism and exclusion of severe cases are really something unacceptable."

A spokesperson for GOSH said: "As a patient, Keziah's health and transplantation were very different from Shauna's, so it was not clinically relevant to discuss her case. . "

The hospital added that the other patients had not been discussed "because the team was not aware of other relevant cases coming from abroad at this time".

There was more than Karen and Shauna did not know. They heard about Ciaran Finn-Lynch. But there were essential differences between Shauna's operation and his own.

Ciaran had received a stent – but Shauna no. According to the UCL's 2017 survey report, Martin Elliott said he wanted to use a stent, but that he had been advised not to do so.

Ciaran had also received a new donor trachea. Shauna was not cool. It had been frozen and thawed.

It was a treatment that had not been used before – after the thaw of the trachea, the donor cells were removed using a special vacuum technique for members of the medical team. Shauna.

Legend

Martin Birchall reportedly said that Shauna's initial operation had been a success, in a letter to the European Medicines Agency

Trish Murray, professor of stem cell biology and regenerative medicine at the University of Liverpool, makes a number of criticisms.

"In reality, if you do not have a stent, the trachea will collapse, it was the unanimous experience of all patients who had a tracheal transplant," explains she.

"So, although it is notorious that stents cause problems, if you do not have them, the trachea will collapse and the patient will suffocate."

Another problem was the frozen trachea.

For the team, it made perfect sense to freeze a trachea because it could be stored in advance and thawed if necessary. But Trish Murray also criticizes this decision.

"The trachea of Ciaran has not been frozen before, while that of Shauna is frozen-thawed and we know from publications that the group has published itself that it would weaken the trachea … and make it more likely to collapse after its implementation, "she said. said.

However, the UCL questions about the relevance of these studies. He told the BBC that they were not referring to the technique used on Shauna.

Trish Murray says that other disturbing studies should sound the alarm. She cites an unpublished study on the vacuum technique, which shows that a grafted pig died spontaneously and that another developed a "respiratory compromise" and had to be shot down. The study was stopped for humanitarian reasons.

"We know from information obtained at the request of FOI that the UCL team tried the technique on two pigs and that the two pigs died quite quickly. We also know that they Have tried on rabbits and that there was 100% mortality in rabbits too, "she says.

The BBC asked UCL and Great Ormond Street whether animal studies had been conducted before or after Shauna's operation, but received no response to this question.

And as the Belgian ENT professor Pierre Delaere, Trish Murray questions the role played by stem cells.

"In fact, there is no evidence of the survival of these cells, but in fact a lot of evidence of their non-survival," she says.

But how could doctors and scientists involved in the care of critically ill patients use these tracheas when there was little evidence of their effectiveness?

Usually, researchers must test their innovations in the laboratory and then on animals in preclinical research. Only then, with the formal approval of a research ethics board and regulatory authorities, does it bend.

Martin Birchall, however, wrote in The Lancet that "compassionate studies", the procedure of using new treatments on very sick patients, constituted "a powerful way of documenting well-designed formal tests" and "tests." accelerate the testing of new treatments ".

"The implicated surgeons used this apparent compassionate use loophole to actually experience patients, and then used the data they obtained to contact the regulatory authorities to obtain a report. authorization for testing, "says Trish Murray.

John Rasko agrees with Trish Murray that this is not how the system should work.

"Exercising the option of using for humanitarian purposes involves great responsibilities.This should not be used as a way for doctors to go unnoticed from a properly implemented regulated medical practice" , did he declare.

And Great Ormond Street accepts too. "We do not see compassionate use as a way to test new treatments," said a spokesman.

But Shauna's transplant and that of the other patients were used to obtain funding and approval for clinical trials, as well as to be recorded in medical journals and for an application to the European Atomic Energy Agency. drugs.

The BBC found that at least seven of these documents and publications give a false picture of Shauna's treatment or death.

For example, in an application filed with the European Medicines Agency in 2016, Martin Birchall reportedly stated that Shauna's initial operation had succeeded, but that she had suffered a "fatal cardiovascular event six" weeks after the operation ", whereas she had died after two weeks because of her trachea. it was collapsed.

At the time when the clinical trial to test tissue-engrafted trachea grafts had been approved and funded by government agencies, a procedure had already been modified. Having learned from what happened to Shauna, the team will ensure that patients participating in the trial have a stent.

Even in this case, the approved patient information sheets accompanying one of the tests contained incorrect information about Shauna and even about Claudia Castillo. Ciaran Finn-Lynch and they alone were included in the fact sheet – although the team was informed of at least 10 cases worldwide.

By 2014, Martin Elliott had announced at a conference that 10 patients had received a tissue trachea, all deceased except Claudia and Ciaran.

Last year, clinical trials were suspended. UCL says no one has been recruited to participate.

Much of what the BBC has discovered about what happened in Shauna does not appear in the UCL's special investigation report.

Leonid Schneider is a molecular cell biologist turned journalist who covers regenerative medicine since 2016. He was called to testify at the UCL's investigation and his assessment of the report is unfortunate.

"Why did not Shauna's mother have all the information? And who was the idea not to give her a stent?" he asks.

"Finally, how could UCL researchers recommend the resumption of clinical trials on the donor's trachea, after Professor Delaere and I announced the number of people who died from it?" he adds.

UCL claims that clinical care exceeded "the scope of the investigation".

He adds: "Any research undertaken at UCL must comply with the strictest legal, ethical and regulatory standards, and we will not hesitate to take the necessary measures, if this proves necessary. "

After receiving ethical advice, I explained to Karen what the BBC had discovered about tissue transplants.

She was angry. She said that this could have changed her decision to allow Shauna's operation.

Legend of the media"I hope that no one else will have to go through what I've experienced."

"I really hope that no one else has to go through what I've experienced, they should be stopped, it's such a shock." People ask me: How is Shauna dead? "And I always say, heart attack.I have never accused these surgeons of his death.They have a lot to explain."

GOSH said: "Before Shauna's operation is carried out, a full review of all relevant scientific and medical evidence published."

They also said, "We are sorry that the treatment did not work for Shauna and the family feels that they have not received all the relevant information.We are contacting Shauna's family to offer them to meet them. to discuss their concerns. "

"It took them all that time, but you'd think they'd have phoned me to say something to me," says Karen Davison. "I know I would not always have it, but at least I might have it a little longer."

Photographs by Shauna Davison courtesy of Karen Davison

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