The Devastating Allure of Medical Miracles
Sheila Advento was not feeling well. It was July 6, 2003, and her mother’s house in northern New Jersey was filled with people. Sheila and her mom were there, along with Sheila’s boyfriend, sister, and brother-in-law—a slice of a huge extended family, many of whom, like Sheila and her parents, had immigrated to the US from the Philippines. They ate cheeseburgers and adobo and raised Pabst Blue Ribbon and San Miguel to toast one another, independence, good health, and freedom—almost all of which Sheila, who was 26, was about to lose.
For days she’d been having headaches. Her stomach wasn’t right. She was starting to think she had the flu. She trudged to a basement bedroom to lie down. Family members took turns checking on her. When her mother, Peachie, looked in around dinner time, she found Sheila lying on the bathroom floor. Peachie, who was a nurse manager at New York University’s Langone Medical Center, took one look at her daughter and knew she was in trouble. Sheila, she said, I have to take you to the hospital. Your lips are blue. In the car, Sheila had trouble breathing. Her last memory before blacking out was someone lifting her hand to put one of those white clips on her dusky blue finger.
Sheila was in acute septic shock. An infection in her bloodstream had unleashed an inflammatory storm. Her body was shutting down, starting with the limbs. The ER team blasted her with antibiotics and fluids and eased her into an induced coma. They wanted her body, undistracted by mind or maintenance, to focus on the fight ahead.
After about eight days on a ventilator, Sheila’s doctors unhooked the machine, stopped the sedatives, and waited. Later that day, she awoke and looked at her hands. They were nearly black, dull, dead as coal. She couldn’t move or feel them. They seemed no part of her. She nodded at her hands and said, “We have to take these off.” She was right. The hands had to go. So did her feet and legs, almost up to the knees.
Over the next three months or so, Sheila had five operations. After one, she remembers the surgeon saying something about wanting the muscles in her arm to work “if you get a transplant someday.” Sheila had never heard of hand transplants. At the time, just 20 had been done worldwide.
Over the years, Sheila gained mastery of prosthetic legs and the split hooks she used as hands. She lived for a while with her mother, then on her own. After a time, she returned to her job at a call center for a medical diagnostics company. She had work, family, a love life, friends. But like most hand amputees, she missed the fluid dexterity and perceptive power of her fingers, the ability to wipe her nose or scoop up a set of keys, to shuffle cards or remove an eyelash from the corner of her eye. She wanted hands.
In 2009, six years after losing her limbs, Sheila heard that the University of Pittsburgh was looking for patients for an experimental hand transplant program. She wrote to them immediately, and a few weeks later drove with Peachie to Pittsburgh. She spent a week there, taking physical and psychiatric tests and giving blood for lab work. The doctor heading the program, W. P. Andrew Lee, was charming and accomplished: He had done physics at Harvard, medical school and training at Johns Hopkins, and more training at Harvard and Massachusetts General. Like Sheila, Lee was an immigrant. He had come to the US as a teenager—in his case, from Taiwan. She liked his warm smile and gentle manner. “I thought he was fantastic,” she says.
Lee’s team called a few weeks later to tell Sheila that she had been accepted into the trial. They told her it might be months or years before they found a donor well-matched in size, skin color, and immune profile. Or it could be tomorrow, so pack a duffel. When things moved, they would move fast. She packed as soon as she got home. When the call came about eight months later, in September 2010, she was watching TV in her apartment. She hung up and called Peachie. Mom, she said, come get me.
When Sheila Advento arrived at the Thomas E. Starzl Transplantation Institute at the University of Pittsburgh, the man for whom it was named was 84 years old and still a presence there. Starzl, who had done the first human liver transplant in the early 1960s, was acclaimed as “the father of transplantation.” Starzl himself insisted that the rightful owner of that title was a zoologist named Peter Medawar, who at midcentury had helped solve transplantation’s central puzzle—one not surgical but immunological.
The body has a fierce need to protect itself. It does so by turning its immune system against any foreign body—an obvious obstacle to accepting another person’s organ. In experiments on animals in the 1940s and ’50s, however, Medawar and his colleagues discovered a mechanism for preventing immune rejection of transplanted organs. In studies on mice, they found that if they introduced an eventual organ donor’s cells to the recipient in utero or just after birth, the mouse would develop an acquired tolerance—a diplomatic ploy to have the foreign flesh accepted as kin.
Alas, as a practical matter, introducing a future human donor’s cells in utero or infancy so one could later get a timely transplant from them would require superhuman prescience. But by demonstrating that immunological tolerance could be acquired, Medawar had given the field hope.
In the 1960s, researchers began developing immunosuppressant drugs and launching transplant programs. Unfortunately, the side effects of early anti-rejection drugs were severe, and mortality rates were high. Organ transplants did not become viable as routine treatment until around 1980, when an anti-rejection drug called cyclosporine was introduced. A similar drug, tacrolimus, followed a decade later. With those drugs, five-year survival rates for organ transplant patients jumped. Most transplant patients are now treated with a three-drug cocktail that includes cyclosporine or tacrolimus along with steroids and a second, gentler anti-rejection drug. Such transplants, now routine, have saved or extended more than 750,000 lives in the US.
The next big leap came in 1998, when the world’s first initially successful hand transplant, in Lyon, France, accelerated the practice of vascularized composite-tissue allotransplantation, or VCA. (For complex reasons, the patient had it removed in 2001.) These transplants, mainly of hands but also of faces and genitals, differ in two important ways from solid-organ transplants: They involve multiple tissue types intricately tied together, and they don’t extend life—they enhance it.
That they improved lives rather than saving them posed a serious new ethical problem. Even today’s transplant drugs cause side effects ranging from passing nausea, dizziness, and weight loss to life-threatening conditions such as diabetes, infection, cancer, and kidney failure. In a 2003 study, up to 21 percent of transplant recipients experienced total renal failure within five years, forcing patients to have dialysis or a kidney transplant.
Most people readily accept such risks to get a new heart, lung, or liver: When the benefit is life itself, most find almost any cost bearable. But a hand transplant sharply changes this calculus. Is taking dangerous drugs for the rest of one’s life worth the satisfaction of tying a shoelace or moving a strand of hair from a child’s face? Such deeply personal questions test the boundaries of medical ethics.
Solid-organ transplants had been common for almost 20 years by the time doctors and hospitals started performing VCA. It had taken two decades to find the right levels of immunosuppressants. Once this breakthrough arrived and the Lyon team gave their patient a new hand, doctors and major hospitals worldwide began to add VCA units. The hand transplant’s day had arrived. In 1999, Warren Breidenbach became the first US surgeon to perform a VCA transplant when he gave a new left hand to Matt Scott, a 37-year-old who’d lost his to a firecracker. Hand transplant teams started in Innsbruck, Paris, Pittsburgh, Los Angeles, Boston, and other cities. In less than two decades, there were dozens.
The University of Pittsburgh joined the field in 2002, with the hiring of Andrew Lee to lead its new program. A rising star in hand-reconstruction research, Lee came to Pittsburgh partly to work with Starzl, the legendary surgeon. According to Lee, Starzl may have seen in hand transplants a chance to revisit Medawar’s proposal to trick the body into accepting a donated organ as its own. Starzl began working with Lee to develop a new regimen that might open the way to such a safer, drug-free immune tolerance. (Starzl died in 2017, at age 90.)
This new treatment regimen was dubbed the Pittsburgh protocol. Its most distinctive feature was to infuse the recipient with bone-marrow cells from the donor’s body two weeks after surgery. The idea was that those cells, leaving the marrow and spreading through the recipient’s bloodstream, would make the entire immune system receptive to the donated limb. Then, instead of taking three drugs, the patient would take a low dose of just one, tacrolimus. Lee’s hope—the hypothesis his protocol would test—was that the bone-marrow treatment would allow the patient to take only a minimal dose of tacrolimus or even give up the drug entirely.
The possibilities raised by Lee’s research and similar efforts elsewhere stirred keen interest at the US Department of Defense. Approximately 1,600 troops returned from Iraq and Afghanistan with amputations. If a safe way to transplant these multitissue limbs could be developed, it would bring life-changing treatment to these veterans. So in 2008, the Defense Department gave millions of dollars in grants to fund clinical trials, including one to test the Pittsburgh protocol.
In March 2009, Lee performed his first hand transplant in that DOD-funded trial. The patient was Josh Maloney, a likable, somewhat rambunctious 24-year-old who had lost his right hand to a stick of TNT during a Marine training exercise. A couple of weeks after the surgery, Lee held a press conference with Maloney at his side. According to the Pittsburgh Post-Gazette, Lee told the gathered reporters about the Pittsburgh protocol and said, “I think there’s clearly a chance of weaning Joshua off immunosuppressants altogether.”
Wayne Arrigo and his granddaughter, Cody.
Eighteen months later, Sheila Advento, having become the fifth patient in Lee’s trial on September 18, 2010, woke groggily in the University of Pittsburgh Medical Center recovery area to find her new hands. “People had said they might not seem like mine right away,” she told me. “But mine did. Right away they were mine.”
When she had recovered enough to get out of bed, she put on her leg prostheses to walk around the transplant program’s dedicated wing. One of the first people she met was Jessica Arrigo, a slender, friendly, and deceptively tough 27-year-old who had received a transplant of her right hand a week before Sheila’s operation.
Like Sheila, Jessica had almost died of septic shock. That was in 2004, when she was barely 21. She had been living with her father, Wayne, in West Virginia when the sepsis hit. It took both feet, her right fingers, and on her left hand, all but the stubs of her middle, ring, and index fingers. Alongside those, the surgeons fashioned a sort of thumb so she’d have a pinch-grip. It worked pretty well. She worked, drove, shot pool, even went skydiving with Wayne. Jessica met a man with whom she had a daughter, Cody, in 2009. Jessica and Cody moved in with Wayne, who by then was living in Millville, New Jersey. “She was living a pretty full life,” Wayne says. But like Sheila, Jessica wanted a hand.
The two women took to each other. Over the next four or five months, they would spend most of their time together, up to five hours a day in occupational therapy, walking the halls, talking, comparing notes on family, love, life, fate, and hands.
“I just loved her,” Sheila says. “We had so much fun. We had our own section, our own therapist. We were always laughing.”
It was good to have cheerful company, because the physical work the new hands demanded was grueling. The operations Lee had performed were enormously complex, lasting 10 to 15 hours and requiring microsurgery to connect dozens of tendons, muscles, bones, nerves, and vessels sometimes no bigger than vermicelli. These blood vessels promptly pinked the women’s new fingertips. But newly connected nerve fibers do not instantly carry current. The fibers in the recipient’s arm must grow from the transplant’s attachment points clear down into the new hand, at a rate of about an inch a month, to give the donated hands anything but the crudest sensations and movement control. Making her new fingers and hands pinch, flex, and grip was some of the hardest work Sheila had ever done.
Sheila and Jessica, for hours at a time, picked up peas, pennies, marbles, and weights, stacked cups, slid blocks into boxes like nursery school children, assembled things and disassembled them. They struggled to remaster buttons and laces. They came up with their own tasks. “You remember friendship bracelets?” Sheila says. “We started making them. Good for the fingers.” They took tests: Close your eyes and tell me which of your fingers I’m touching, then tell me what part of your finger I’m touching. “We found ways to make it interesting,” Sheila says. “But it was exhausting.”
Sometimes they were joined by Josh Maloney, who lived with his parents 40 minutes south of Pittsburgh. Eighteen months after his surgery, Maloney was Lee’s star patient. Sheila remembers seeing videos of Maloney lifting weights, Maloney screwing in a light bulb. He was taking a training course to become a car mechanic. He traveled with Lee to press events and medical meetings to promote the protocol. He even shook hands and chatted with Prince Harry on the USS Intrepid at an event honoring British and American veterans. CBS Evening News ran a spot about him. “I don’t feel broken anymore,” he told the reporter.
At times, two other trial patients would also return to the hospital for checkups. Jeff Kepner, Patient 2, had lost both hands to sepsis; Chris Pollock, Patient 3, destroyed his hands while reaching for an ear of corn in a corn picker. Pollock already dressed himself, drove, opened windows and doors. Kepner was struggling. He had trouble holding things or opening doors.
Sheila and Jessica made steady progress. But in December, while still in Pittsburgh recovering from the surgery, Jessica confessed to the transplant team that she had struggled with drug addiction since she was a teenager. This history would have barred her from participating in the trial had it come out during the screening process, interviews, or drug testing. (It “surprised us,” Lee told me. “I think this shows that even a detailed weeklong process is not perfect.” ) Jessica began getting addiction treatment, which would work better at some times than others.
In early 2011, after several months of intense work, Sheila and Jessica had progressed enough to go home. The team reviewed with them what would come next: The women would need to keep up the rehab work at home; return to the hospital monthly or quarterly for a while, and then less as time passed; and for the rest of their lives, or as long as they had the transplant, get regular blood tests that would be sent to the transplant team to monitor for complications and drug side effects. On this everyone agrees. The details of those discussions, particularly about specific dangers from the drugs, would later become a matter of dispute. Sheila packed up and moved into her mother’s house. Jessica returned to Cody and Wayne in Millville.
In the fall of 2010, about two months after he performed Jessica’s and Sheila’s transplants, Andrew Lee took a position running the new Department of Plastic and Reconstructive Surgery at Johns Hopkins University School of Medicine, in Baltimore. Some of his Pittsburgh team later joined him, others stayed behind. His transplant trial patients could be treated in either location. In Baltimore, Lee would eventually perform three more transplants, in 2012, 2015, and 2017, bringing the trial’s total to eight.
A year after her operation, a CNN report about Sheila showed her putting on eye makeup, driving, and talking about what it meant to be able to feel the fabric of her jeans under her fingers. Other patients found life with the transplanted hands full of complications, some quite challenging. Nearly 16 months after Jeff Kepner’s surgery, he also appeared on a CNN broadcast, but he showed far less progress: He had trouble writing with a marker, picking up small balls, and doing tasks that Lee’s other transplant patients had accomplished just weeks out. Progress in transplant patients is variable, depending on how quickly the nerves regenerate and the patient’s commitment to rehab.
Maloney, the ex-Marine, was still in auto-mechanic school. He was also driving two hours round-trip to Pittsburgh, two times a week, for lengthy evening rehab sessions. Sometimes he didn’t protect his hand well enough while working on cars, he said, and the injuries or rejection episodes forced him to rest it, stalling both schooling and rehab. “You’re supposed to keep from getting infections, getting a cold, getting sick, getting cuts and dirt in it,” Maloney told me. “I wasn’t the best at that. I was trying to go back to my old life.” He grew discouraged and at times too disheartened to go to rehab; sometimes he lacked the money to make the trip.
He also grew less vigilant about his twice-daily drug regimen. In that, he had company: Some 20 to 25 percent of all transplant patients miss doses. It can be difficult to remember to take the drugs, and side effects ranging from hair loss and heartburn to headaches, confusion, and mood changes can be hard to tolerate. One hope for the Pittsburgh protocol was that by reducing the number of immunosuppressants from three to one, it would be easier for patients to comply.
Maloney’s body increasingly tried to reject the transplanted hand. “When it finally started to go downhill,” Maloney told me, “it went fast.” A particularly nasty rejection put Maloney in the hospital for about a week. His hand turned red, rashy, and blistery. Afterward it didn’t work as well. The realization that set in took him weeks to say out loud: I no longer want this hand. On March 14, 2013, four years to the day after he got his transplant, he had the surgeons take it off.
Jessica Arrigo had gone home in decent health in early 2011. Her hand was working well, allowing her to take care of Cody and work at a series of jobs at Toys “R” Us and Kmart. In 2012, she met a man named Robert Doak, whom she would marry two years later. Jaimie Shores, the Lee team’s clinical director, was impressed with her rapid progress. “She really surprised us in some ways with how well she did early on,” he says. “She started taking private pilot lessons. She sent us a video of her flying a plane. I was just like, ‘Oh my goodness. That’s incredible.’ ”
Complicating Jessica’s case, however, were two foreboding factors. The first was the history of illicit drug use she’d confessed to the team three months after the transplant: cocaine in her teens, she said, and more recently, struggles with an on-and-off addiction to opioids—a class of drugs that sometimes cause symptoms easily confused with possible immunosuppressant side effects and which she was prescribed periodically for hand pain. (Joseph Losee, a surgeon who helped oversee Jessica’s care at Pittsburgh, declined to comment on her case.)
The other factor was that Jessica’s kidneys began to quickly decline. Just seven months after her transplant, a Pittsburgh nephrologist diagnosed her with early chronic kidney disease. The next year, another nephrologist at Pittsburgh gave Jessica her second diagnosis of chronic kidney disease and told her that her kidney function would most likely worsen as long as she continued to take tacrolimus. Managing immunosuppressive drugs, says Yale transplant nephrologist Richard Formica, is a delicate art. You want to give enough medication to restrain the immune system from attacking the transplanted organ, but not so much that it harms the kidneys or other organs. In some patients, you find this sweet spot easily; in others, you find it elusive.
Jessica was one of the latter. Physiologically, Shores says, “she was a little bit more challenging in terms of dosing.” All the transplant patients took weekly blood tests to monitor for signs of infection, diabetes, organ damage, or other treatment side effects. Of particular interest was creatinine, a waste product that is cleared by the kidney and whose presence in the blood can be used to derive an estimated glomerular filtration rate, or eGFR, the standard lab measure of kidney health. A healthy GFR is around 90 to 100. Scores below 60 signal mild to increasingly severe kidney damage, with the likelihood of permanent damage or total kidney failure rising greatly with sustained scores below 30. A sustained score under 15 usually means you need dialysis or a new kidney.
Jessica’s medical records, which her father shared with me, show her scores first dipping below 60 for weeks at a time in 2011, less than a year after her transplant. In 2012 they dropped steadily through the 50s and 40s, plunging to 17 one day that December—which led to a weeklong hospital stay in Pittsburgh to get her kidney function on track. The following year Jessica moved her treatment to Johns Hopkins, which was closer to her home and because Lee was there. After that point the Pittsburgh team no longer received regular updates about her kidney health, says Vijay Gorantla, a surgeon who was at Pittsburgh at the time.
Apart from her kidney issues, Jessica had also been suffering bouts of abdominal pain that were sometimes so severe, Wayne says, that she curled up on her bed. She’d have spells of vomiting or diarrhea; other times she’d be constipated for days. Jessica had suffered similar episodes before the transplant, Wayne says, but her GI issues now came more frequently and with more fury. Most dispiriting of all, her hand was having more painful rejections, requiring more trips to the hospital.
In March of 2015, a livid rejection sent Jessica to Hopkins. Her hand was in terrible shape. The biopsy revealed areas of deep necrosis in her skin, the tissue below riven with blisters and signs of infection. Everyone agreed it was time. Shores and a surgical team removed the graft later that day.
Shores, who helped oversee Jessica’s post-transplant care at Hopkins, says he viewed her particular mix of problems—the stubbornly recurring rejections; the rising creatinine levels; the gastric torments—as arising both from her distinct physiology and from what appeared to be an inconsistent adherence to diet and drug regimens. To the team, it seemed that Jessica often failed to drink enough water, courting dehydration that strained her kidneys, and took her tacrolimus doses erratically. Both Shores and Lee acknowledge her kidney issues but said that when they adjusted her medication and care, the episodes would pass. Shores noted that patients like Jessica and Sheila who have had episodes of sepsis are more predisposed to kidney problems.
Once her arm healed, Jessica resumed using her short thumb and finger stubs on her left hand and made do with her right. She cared for Cody and looked for work. She was free of the tacrolimus, and, according to Shores, her creatinine levels improved immediately after the reamputation. But her GI issues persisted. According to Robert Doak, meals would often put her in excruciating pain. She usually tried to tough it out at home, but every few weeks, it seems, the pain was so bad that Wayne or Doak took her to a nearby emergency room.
On November 21, 2017, just before Thanksgiving, Jessica had another painful episode. That evening, Doak took Jessica to the ER while Wayne stayed home with Cody. At the hospital, the ER team worked furiously as Jessica grew weaker. By this time, Doak told me, “She was in absolute agony.” Doak says that as a former EMT and combat veteran, “I’ve seen men shot on the battlefield. I’ve seen all kinds of things. I’ve never seen somebody in quite that much pain.” Doak called Wayne and told him to come. By the time Wayne got there, his daughter was still. “I was there when she died,” he says. “But I don’t think she knew.”
The attending doctors, consulting with the medical examiner, ruled the cause of death to be mesenteric ischemia, although there was no autopsy. Mesenteric ischemia is a rare, painful condition in which the blood supply to the small intestine slows or closes off. It sometimes creates a toxic sludge that fills the gut and spreads sepsis through the body. The disease, which generally arises from multiple factors, is notoriously difficult to diagnose. Much of Jessica’s long, complicated medical and drug history likely put her at risk.
While Jessica Arrigo’s health was declining, Sheila Advento was doing well. Her new hands let her work, cook, drive. She got her annual checkups (like Jessica, she’d moved her care to Johns Hopkins, for the shorter trip and because Lee was there), and she says she faithfully took her drugs each day. She gave talks and did press events. “Everyone loved her,” says Vijay Gorantla, who was a former member of the Pittsburgh team and is now director of the VCA program at Wake Forest School of Medicine, “because she was the perfect patient. She did everything asked of her.” She got more headaches than before, and they were worse—a common side effect of tacrolimus that she accepted as the price of her wondrous hands. She passed the five-year mark, in September 2015, in good health.
But in the two years after that, Sheila’s blood tests began to show a decline in kidney health. Around October 2017, Thomas Salazer, a New Jersey nephrologist who often had been Sheila’s primary care provider since her original 2003 sepsis episode, was concerned enough about her blood tests that he recommended a kidney biopsy. He suggested that she schedule one as soon as possible.
As it happened, Sheila didn’t have that biopsy until five months later. The Hopkins team says they told Sheila her kidneys were declining and tried to schedule the biopsy starting in November. Sheila, they said, was unable to make any appointments before March. According to Sheila, Salazer’s biopsy recommendation was her first notice that her kidneys were declining, and if she delayed or canceled appointments, it was because she had trouble taking time off work.
In any event, Peachie dropped Sheila off in Baltimore on March 13, 2018, for the biopsy. That same day, Sheila says, she remembers learning about Jessica’s death. She hadn’t talked to Jessica in two or three years. “It came to me as a complete shock,” she says.
A few weeks later, Sheila received the biopsy results: It seemed her kidneys had lost about three-quarters of their function. Stunned, Sheila called Gorantla, who had counseled her through tough patches before. He urged her to call the Hopkins team immediately and ask for an appointment with their nephrologist to discuss a treatment plan—the sooner, the better. Text messages between Sheila and a patient coordinator show that Hopkins offered to set up an appointment or a conference call. Sheila said she was too tired to make the trip and preferred to speak alone to a nephrologist over the phone. Scheduling efforts continued into June. Meanwhile, the pain in her lower back surged. She was always tired and often nauseous. Her legs swelled, her head hurt. It had been more than six months since Salazer first told her to get a biopsy. She wanted a plan.
“Six months. There were things I could have been doing,” she said, to try to slow what was now her kidney’s inevitable decline. It was July 2018, and we were eating dinner in a Mexican restaurant near her house, an hour from New York City. Sheila, who walked with only a slight limp and looked sharp in a simple black top and slacks, was animated, funny, smart, and personable. She was also clearly still shocked by the diagnosis she had received only weeks before. She said she felt certain she had never been told the drugs could destroy her kidneys. “I had no idea this could happen,” she told me.
Jaimie Shores, who was involved in Sheila’s care from the beginning, says he tried to convey the threats to kidney health vividly and regularly to all patients, including Sheila, starting at the screening process and continuing through all pre- and post-transplant care. According to Hopkins, other team members did too. “She may not have received the message that I thought I was communicating,” Shores says. When I asked the Hopkins team to send me any written records documenting such conversations with Sheila, they said they couldn’t provide any, and added in a statement, “We do not document every conversation with patients.”
Sheila and the other patients did sign a 27-page consent form that included a warning about the drug’s possible “toxicity to the nervous system (brain, nerves), kidneys, or liver.” An appendix further warned of side effects like nausea, vomiting, diarrhea, headache, abdominal pain, and “kidney injury.” The patients themselves report varying experiences: Jeff Kepner says he doesn’t recall being warned that his immunosuppressants could lead to kidney failure, nor does Wayne Arrigo feel that Jessica was adequately informed. However, Chris Pollock and two others, Jeff Swedarsky and Eric Lund, say they were fully told of the consequences. “The main thing I recall is the fact that there’s a possibility of kidney failure,” Pollock says. “I will remember that until I die.” Gorantla says he’s dismayed that the risks were not unambiguously clear to Sheila. “Informed consent is not just a form you sign,” he says. “It’s an ongoing process in which you keep the patient informed and involve them in every significant decision.”
On May 15, 2018, nine weeks after the biopsy, Hopkins sent Sheila a letter. It said she had stage 3b chronic kidney disease, which the letter attributed in part to the tacrolimus she’d been taking for more than seven years, along with her sepsis episodes 15 years before, her hypertension, and other issues. The letter recommended switching from a twice-daily dose of tacrolimus to an extended-release form taken once a day. Then it said, “Even with these changes and continuous monitoring, it is possible that at some point, you may require a kidney transplant” and suggested she check in at least yearly with the Hopkins hand transplant team and a transplant nephrologist. “As you know from the last seven plus years,” the letter concluded, “our most important priority is your overall health.” It was signed, “The Johns Hopkins Hand Transplant Team.”
A few weeks later, Gorantla referred Sheila to a kidney transplant team at the University of Maryland. Around the same time, she says, a transplant physician told her there was a possibility, small but real, that the challenge posed by a new kidney to her immune system might spark a rejection episode that could affect her hands. “I don’t know what to do,” she told me. “I don’t want to lose my hands.”
It was early in my reporting for this story, in May 2018, when I first interviewed Andrew Lee. At that point, I planned to write a story about the emotional challenge of making a new hand one’s own. I hadn’t yet met Sheila Advento or Wayne Arrigo. I had learned of Jessica’s death only a few weeks before, when Jessica’s mother, Janet Carpenter, returned my third call to Jessica’s cell number and told me that her daughter had died in November. She sounded so pained that I didn’t ask how it happened. As I was soon to meet Lee, I figured I’d ask him. Lee, wearing an elegant gray suit, showed me into his office on the Johns Hopkins medical campus in Baltimore. We started by discussing where he saw hand transplants in their arc of development. He said that he believed hand transplants were almost mature enough to be routinely covered by insurance. I asked him what surprised him most about doing hand transplants. He said it was the bond one forms with the patient. “You keep a lifelong close relationship with the patient … You get to know one another really well, you stay in close touch, you have their cell phone number, you text one another. It’s a long-term and close relationship.”
He spoke with animation about Brendan Marrocco, his sixth patient, an irrepressible soldier who’d lost both arms and legs to an IED in Iraq. In public appearances, Marrocco seemed delighted with the double hand transplant Lee did for him in 2012; in a 2014 episode with Lee on the Late Show With David Letterman, Marrocco pretty much stole the show. “He’s still driving his car,” Lee told me, smiling, “going all over the country. He does everything a young man does.”
When I asked him about Jessica Arrigo he became far more circumspect. I asked how he’d heard of her death. He said through word of mouth. Then he offered, “We really don’t know the cause of death. We don’t think it’s related to her transplant. But we don’t know the cause of death.”
Perhaps I’d misheard him. I asked, “Is that because you didn’t know of any existing medical issues?”
“Well, after her hand was removed, we did not follow her,” he said. “But the last we heard she was in good health.”
A few months later, I got Jessica’s death certificate. I shared with Lee that the certificate listed mesenteric ischemia as the cause of death; it seemed to be news to him. When asked about Arrigo’s cause of death recently, Lee said that he wasn’t aware of any evidence of association between transplantation or immunosuppressive drugs and mesenteric ischemia.
Of Lee’s eight transplant patients, I have spoken with six of them and the father of a seventh, Jessica. As one would expect, some have fared better than others.
The most recent patient, Patient 8, Eric Lund, 35, lost both arms above the elbows in 2012 to an IED in Afghanistan and had a double transplant in November 2017. When I recently talked to Lund, he said his two-year rehab program to bring his arms and hands to full function was on schedule. He could lift his arms and push things around with his hands, but he couldn’t grab anything with them yet. The hands still provided only faint movement and sensation, as the nerve fibers still had a ways to grow to reach his fingers. He expects better sensation will come. He’s glad he had the operation.
Jeff Swedarsky, Patient 7, received a bicep-level transplant of a left arm in mid 2015 and has regained fair function. At 38, he does weight training daily, has built a busy food-tourism business, and is so thrilled with his transplant that he encourages others to apply for the program. “Best decision I ever made,” he says.
Brendan Marrocco, Patient 6, did not return my calls but appears to be doing well.
Sheila Advento is on the kidney transplant waiting list.
Patient 4, Jessica Arrigo, is survived by her husband, Robert Doak; her father, Wayne Arrigo; and her daughter, Cody, who made third-grade honor roll last fall.
Chris Pollock, Patient 3, is doing great. When I called him at his home in Pennsylvania, he was mowing his lawn. He easily takes care of himself, makes toast and eggs (scrambled or fried), drives, and much more. He feels blessed.
Jeff Kepner, Patient 2, wakes each day to two transplanted hands that he feels are utterly useless. “I could do almost everything with my prosthetics,” he says. “Now I can’t do anything.”
Patient 1, Josh Maloney, the Marine who had his transplant amputated in 2013, started a course in turf management last year—a step toward working in golf course greenkeeping. With his soldier’s acceptance of bad outcomes, he does not question his original decision to get a transplant. Yet when asked if he feels he made the right decision in having it removed, he says, “Absolutely.”
Josh Maloney, who asked to have his transplanted hand removed.
On a cloudy Thursday afternoon last November, about 150 members of the American Society for Reconstructive Transplantation, the main organization that represents the VCA field in the US, gathered at the Drake Hotel in Chicago for the society’s biennial meeting. As a cold wind swirled outside, transplant surgeons, rehab specialists, immunologists, and others gathered in a ballroom with two-story ceilings and ornate columns—the Gold Coast Room—to hear Gerald Brandacher, the scientific director of Lee’s team and the incoming president of the society, give the opening speech.
Brandacher was taking over at a pivotal moment for the VCA field. For one thing, just two weeks earlier, news broke that Andrew Lee, Brandacher’s longtime mentor, a cofounder of the ASRT, and one of the VCA field’s most public faces, was leaving Hopkins to take a job as dean of the huge medical education complex at the University of Texas Southwestern Medical School. Brandacher later told me that this came as a “complete surprise” to his team.
In addition, the VCA field was facing something of an existential crisis: The Department of Defense grants that funded many of the US clinical trials of hand transplants were running out. “The field is running on fumes,” says L. Scott Levin, a prominent surgeon and former ASRT president who runs the VCA program at the University of Pennsylvania.
To keep money flowing, the field must now persuade the industry and government bodies that set health insurance and reimbursement standards that hand and face transplants are relatively safe, effective, and financially justified. Only then can the procedures be routinely covered by insurance. The bureaucratic bodies the field must convince include the American Medical Association, the private insurance industry, and the US Centers for Medicare and Medicaid Services, known as CMS. The process of getting these approvals is daunting.
But success was the theme of the conference that day, and Brandacher underscored that idea in his opening speech. Just as solid-organ transplants had moved 30 years earlier from doubt to acceptance, he said, so reconstructive transplants were poised to do the same. Challenges remained. Now that many patients had been on immunosuppression for years, Brandacher noted, they were suffering more renal complications and chronic rejection of the grafts. (Later, in his talks at the conference, Jaimie Shores would say what Sheila Advento already knew—that the Hopkins team had a patient in stage 4 renal failure.) Yet reconstructive transplants, Brandacher said, had already shown their power to restore normalcy to people’s lives. Given the progress being made in animal research at Harvard, Hopkins, and elsewhere on convincing the body to tolerate grafts rather than fight them, he said, “I think we are getting closer to this holy grail, and hopefully can see tolerance in VCA in the not too distant future.” VCA was almost ready to join conventional transplants as established practice. But to accomplish this, he said, “we need to have a unified voice to the public and policymakers, as well as third-party payers.”
However, it’s not clear that the VCA field has accumulated the evidence that policymakers and payers normally want to see. Several experts described the tough path the field faces in gathering the evidence to make their case.
A recent Canadian government examination of the hand transplant field suggested there was much research work to be done. In 2016, Health Quality Ontario, a government body that evaluates new therapies, used a widely adopted standard to examine all available hand-transplant outcome data. While the report found that successful transplants improved function, it found the outcome evidence itself of “very low quality” because of the small number of studies and poor study designs. It concluded: “There is considerable uncertainty as to whether the benefits [of hand transplants] outweigh harms.”
Other observers see similar problems. Francis Perry Wilson, a nephrologist at Yale, read the two most complete studies of global hand transplant outcomes, written by Lee, Shores, and Brandacher in 2015 and 2017, as well as a third study from 2013. The papers “read OK,” he says, and raised no red flags. But they lacked several measures he would have wanted to see. The studies, for instance, were sparse on patients’ own assessments of hand function or quality of life, had little about how the VCA centers chose their patients, and sometimes presented outcome data that was several years old. (The Hopkins team says they plan to include this type of data in future papers.)
This past fall, drawing on conversations and data from patients and clinicians, recent papers, and oral histories collected by Emily Herrington, a doctoral student in communications who is also pursuing a masters in bioethics at the University of Pittsburgh, I was able to compile information on 24 of the 31 known US hand transplant patients. Of these, at least 12 have had serious setbacks. These include seven patients with grafts removed and others who have had kidney problems and poor hand function. In addition to Jessica, Louisville patient Rich Edwards died from suicide, and another patient died of metastatic skin cancer.
This tally is hardly a scientific study, of course. But when I ran these numbers by Scott Levin, who is currently compiling a quality-of-life report for all US patients, he did not dispute the breakdown.
Some of the people in the Gold Coast Room in November weren’t as eager to speak with one voice about VCA’s success. One such person was Warren Breidenbach, the surgeon who led the team that performed the very first hand transplant in the US and is one of the field’s most accomplished, complicated, and confounding figures. After the 1999 operation in which he gave Matt Scott the first hand transplant in the US at the Louisville Jewish Hospital, Breidenbach followed with five more hand transplants over six years. He became the king of a revolutionary medical practice.
Then he fell. By his own account, he tried and failed to get 2008 grants from the Defense Department. Despite serving as a founder of both the field and the ASRT, he felt increasingly alienated at Louisville, which he left in 2011. He hasn’t done a transplant since. He now works as a researcher at the US Army Medical Research and Materiel Command in San Antonio.
As the field has developed—and has gone astray, in his view—Breidenbach has grown increasingly vocal about what he describes as its lack of rigor, transparency, and integrity. He feels that practitioners should publish more information about their patients’ experiences and acknowledge how profoundly these experiments disrupt their lives. Herrington agrees. “It is odd,” she says, “that in a discipline whose entire justification and purpose is quality of life, almost no one adequately emphasizes actual patients’ experiences or includes them in their outcome measures.”
Breidenbach wants his colleagues to publish more and be more transparent. “The rules have always been simple,” he says. “When you do experimental medicine, you must publish—and you must publish what actually happens.” Some of Breidenbach’s colleagues see him as out of touch. “I love Warren Breidenbach,” Scott Levin says. “But this idea that people are hiding things—you have to put his criticisms in perspective.”
Levin does agree with Breidenbach and several others I talked to that Lee’s Pittsburgh protocol has not proven to be better than the three-drug model. As Kadiyala Ravindra, a former Louisville VCA team member who’s now a transplant surgeon at Duke, puts it, the protocol “unfortunately has not worked.” Lee counters that the protocol is designed to reduce immunosuppression and spare patients some of the corrosive effects of the steroids used in the more common three-drug therapy.
Several people I talked to lamented that the discipline has no established protocol for following patients like Josh Maloney and Jessica Arrigo who have had their transplanted hands removed. There are now six people in the US who no longer have their hand transplants but who took immunosuppressive drugs for various periods. But because the DOD grants that funded much of this work didn’t require following patients after a graft was removed, their care and monitoring fell to the discretion of the institutions and research teams.
Francis Perry Wilson, the Yale nephrologist, says VCA teams should follow their patients for the full length of the trial to provide proper care and to track the experiments’ long-term effects. “The patients who are going to do worse in general are going to be more likely to have the graft removed,” he says. “So all the more reason to keep track of them.” Or, as Levin puts it, “If somebody says, ‘Three months after my hands were amputated, I got liver cancer and died,’ we’d want to know that.” Which is why Levin plans to follow any of his patients who lose their grafts.
The Hopkins team’s research protocol does not include a way to do this. The team says they always intended to follow up with patients who had their grafts removed. Shores says he tried to reach both Jessica and Maloney to do a follow-up study around 2016. He couldn’t get ahold of Maloney; he says he talked to Jessica on the phone but couldn’t get her to come in for a follow-up. As a result, the trial has very little data on either of those subjects’ health after the grafts were removed.
In some senses, the field is still struggling with two linked problems that have dogged it at least since that operation in Lyon in 1998: the cost-benefit ratio of VCA transplants and the failure to develop gentler anti-rejection treatments that have been proven to resolve the issue by reducing the risks.
Back in 1999, Andrew Lee and a colleague, writing of this quandary in the wake of the Lyon surgery, concluded that the “deficiency of experimental evidence” then available, along with the known dangers of immunosuppression, “renders precarious the risk-benefit balance of hand transplantation at present.” Still, they believed the VCA field represented “the next frontier” in reconstructive surgery. By 2010, having done three transplants and witnessed 37 worldwide, Lee and others in his team wrote that while much work remained to reduce immunosuppression’s costs, they had faith that the experimental protocols being tested—including their own Pittsburgh protocol—“will surely undergo further evolution during the next decade.”
Yet the burden borne by today’s hand transplant patients seems to be essentially no lighter than that assumed in 1999. Levin believes that the operation’s proven capacity to “give people back their dignity” makes hand transplants justified even now. Of Levin’s three patients, all have functioning hands, although one has begun having renal issues and may need a kidney transplant in the future. “We have enough data that, in my heart of hearts, I can say that we can continue in this field ethically and forcefully … There will be people who have horrible complications, but that’s called medicine.”
Others are less sanguine. Herrington believes the field may need to hit the pause button to gather and weigh more carefully the progress so far. Some surgeons have chosen to wait. Vishal Thanik, a member of the hand transplant team at NYU Langone whose lab is among many trying to develop gentler ways to calm the immune system, does not plan to do any transplants until he has “something really new to bring in terms of immunosuppression.”
To lose a hand—or, God forbid, both—is a catastrophe that inflicts physical, emotional, and psychological consequences that, as one paper on the ethics of hand transplants put it, “are notoriously difficult to overcome.” As that 2012 paper, published in a journal of the Royal Society of Medicine, also notes, the transplant procedure’s experimental nature, along with the temptation for physicians chasing the “thrill of medical advancement” to exaggerate the benefits, “casts doubt on how informed a patient’s decision can truly be.”
Consent in hand transplants is devilishly slippery: Can a person who has lost a hand properly weigh the allure of soon regaining such a vital part of themself against the seemingly distant probabilities of suffering treatment’s possible harms? Levin says this is best addressed by confronting the patient with the grimmest picture possible of the risks and by appointing them an independent patient advocate. James Benedict, a bioethicist at Duquesne University who has studied consent and the US hand transplant community for more than seven years, has a different concern. At this point, he says, “I’m not even sure it’s possible to give informed consent, because the outcome data is so sparse. How can you give consent about accepting risks if you don’t even know what they are?”
In his opening talk at the conference, Brandacher acknowledged that the VCA field had not resolved all its issues. But his main message was one of success and the need to move forward. Most of the day’s talks followed this lead. The last speaker of that afternoon’s long opening session, a bioethicist, in fact, ended by crying, “Let us plow forward with this incredible field!”
Sitting in the room for most of the afternoon was Sheila Advento. She had listened to one speaker after another talk about success and the importance of including patients in its definition. She was sicker than ever. Within a month, she would be put on the waiting list for a kidney. She had flown to Chicago because she wanted to ask a question of Gerald Brandacher, in front of this crowd. She had worked it all out beforehand with Breidenbach, she told me. Breidenbach would station himself near the microphone that was generally in the center aisle at such conferences for audience questions, and when Brandacher finished his introductory talk, Breidenbach would quickly move to the mic and introduce Sheila as she made her way up the aisle. Then she would tell the room that she was in stage 4 kidney failure and ask Brandacher the question that was eating at her: “Why didn’t anyone tell me this was happening to me?”
The plan didn’t work. When Brandacher finished, he left the stage, and a moderator announced that a tight schedule precluded questions, then called the next speaker. Sheila, waiting for her cue in the back of the room, never even stood up. It remained so for the rest of the session. She never got a chance to be heard.
Line art by Claudia de Almeida
David Dobbs (@david_dobbs) writes on science, medicine, and culture.
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