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Bubble girl - Better screening, treatments offer hope for kids with immune disorder


Bubble girl

Better screening, treatments offer hope for kids with immune disorder

A little walk is a big deal for Isabella Messina and her parents.

For most of Isabella Messina’s first year of life, people who wanted to see her had to squirt their hands with sanitizing gel, pull open the heavy door of the Bass Center for Childhood Cancer and Blood Diseases at Lucile Packard Children’s Hospital, and walk across a strip of sticky flooring that took dirt off their shoes. Isabella’s visitors stopped at the unit’s scrub sinks for a vigorous two-minute hand washing, then progressed down a much-mopped floor through fluorescent-lit hallways equipped with negative-pressure ventilation to keep out germs. At the door of her room, they donned gloves, shoe booties, face masks and full-length, long-sleeved disposable gowns. When they finally entered the small room that was Isabella’s entire world, her doctors, nurses and family members looked oddly similar, distinguishable only by the small rectangles of face visible around their eyes.

The person who looked back at them — a baby with light brown hair and a keen smile — was too young to ask why she was confined to a hospital room, too little to understand that she had been born with almost no immune system. But she was quick to locate her favorite eyes, the large, liquid-crystal-blue pair that belonged to her mom, Kim, and the dancing brown eyes of her dad, Giovanni.

For their only child, Kim McFall and Giovanni Messina had eyes full of smiles. But when they left Isabella’s room, worry overtook their expressions. Isabella had been diagnosed at three weeks of age with a rare variant of severe combined immunodeficiency, the disorder known colloquially as “bubble boy disease” after a SCID patient whose confinement to a sterile environment was dramatized in the 1976 film The Boy in the Plastic Bubble. For her parents, Isabella’s diagnosis felt both lucky and painful. Because the disease was caught so quickly, Isabella was cocooned in the hospital, protected from run-of-the-mill infections that kill many SCID patients before their first birthdays. Early diagnosis also provided her with a much better shot at a successful treatment. However, to go home, she needed her immune system repaired via a stem cell transplant, a procedure with no guarantee of success.

Hard as it is to fathom given the uncertainty of Isabella’s situation, blood disease experts anticipate a hopeful new era of research and treatment breakthroughs for all forms of SCID, including Omenn syndrome, Isabella’s diagnosis. One reason is a newborn-screening test for SCID that was rolled out across California in August 2010 and is gradually being introduced in other states around the country. Another is improvement in the stem cell transplants used to treat SCID. Originally developed for patients with blood cancers, the procedures, which were previously called bone marrow transplants, replace all or part of a patient’s malfunctioning immune system with that of a healthy donor. But the cancer-oriented protocols carry the risk of severe side effects, including fatal complications. Scientists want to tailor the transplant procedures so they are less harsh and more specific to non-malignant diseases, including genetic anemias such as sickle cell disease, several hereditary metabolic diseases and the various forms of SCID.

“I’ve taken care of five kids total in my career with Omenn syndrome, and only one of the previous four is still alive,” says Kenneth Weinberg, MD, one of Isabella’s stem cell transplant doctors at Packard Children’s, who has worked in the field for three decades. “I’m hoping Isabella will make it two out of five.”

Before Isabella’s birth in December 2010, Messina and McFall lived a pleasantly ordinary life in a small town on the California coast. Messina worked days at a preschool and nights at a restaurant; McFall ran the local yarn store with her grandmother. They could see the ocean from their kitchen window.

“They said the only cure was a bone marrow transplant. I remember thinking, ‘What are you talking about?’ It’s shocking — you don’t absorb it right away.”

In the first weeks of Isabella’s life, they were plunged into a medical world where “ordinary” vanished. As a newborn, Isabella failed to gain weight and developed a severe rash. Fortunately, her pediatrician immediately referred the family to Packard Children’s, where an immunologist diagnosed Omenn syndrome, a disease so rare that most doctors wouldn’t recognize it. (All forms of SCID together affect perhaps one person in 100,000; Omenn syndrome cases are a small fraction of these.)

McFall was at Isabella’s bedside with Messina’s mother, who was visiting from Italy, when the doctors delivered the diagnosis. “I remember the looks on their faces when they said, ‘We think she has severe combined immunodeficiency, Omenn syndrome specifically,’” McFall says, pressing her fingers under her eyes to slow the tears produced by the memory. “I said, ‘What does that mean?’ They said the only cure was a bone marrow transplant. I remember thinking, ‘What are you talking about?’ It’s shocking — you don’t absorb it right away.”

McFall and Messina were further surprised to learn that Omenn syndrome is an autosomal recessive genetic disease, meaning affected children inherit a mutated copy of the relevant gene from each parent. The chance that McFall, who grew up in the United States, and her husband, who emigrated from Italy as an adult, could both be carriers was so miniscule that it has left them searching for meaning behind the disease.

“There has to be a reason,” McFall says. She treasures a photo of Isabella holding a stethoscope — one of many from Isabella’s long hospitalization, when taking photos of their baby was one of the only normal-feeling activities her parents had available to them — and says half-seriously that she hopes her daughter will grow up to be a physician who makes groundbreaking scientific discoveries that help other children. “It’s hard to accept that there’s no reason, that it’s just the way it is.”

“As long as she’s OK in the end,” Messina adds. “We look for the outcome.”

But the outcome is uncertain. And although they express their feelings about the diagnosis differently — McFall is more talkative and anxious, Messina quietly optimistic — it wears on both of them that their daughter is now 2 years old and, still, no one can reassure them that she’ll ever be cured.

In classic SCID, the body fails to make T cells, white blood cells that perform many important immune functions. Normally, T cells destroy virus-infected and tumor cells; remember and eradicate pathogens the body has previously fought off; assist other types of immune cells; and shut down the immune response at the end of an immune reaction. Without any T cells, most SCID patients succumb to pneumonia or viral infections in infancy.

Omenn syndrome patients make a small number of T cells but they are abnormal and malfunction. Instead of protecting the body, they attack healthy tissue, causing the rashes and digestive problems Isabella experienced as a newborn.

The only treatment is a stem cell transplant to supply healthy bone marrow that can form normal white blood cells. The transplants, originally developed to treat blood cancers such as leukemia and lymphoma, are now offered to individuals with a variety of hereditary metabolic diseases and blood disorders, such as sickle cell anemia. Unlike adults who usually receive transplants for cancer, about one-half of children who could benefit from a transplant have non-malignant, usually genetic, diseases. But in the past, few Omenn syndrome or SCID patients were diagnosed in time for a transplant to help.

“I’ve gotten plenty of phone calls about sick or dying 6-month-olds for whom, too late, someone figured out they have SCID,” says Weinberg, who is the Anne T. and Robert M. Bass Professor in Pediatric Cancer and Blood Diseases at the School of Medicine in addition to his position at Packard Children’s. Late-diagnosed patients often have such severe viral infections that they cannot tolerate the chemotherapy needed to prepare for a stem cell transplant. Weinberg hopes newborn screening will eliminate late diagnoses. As of January 2013, nine states including California screen all new babies for SCID and an additional nine states either screen for SCID in select populations or are working to implement universal SCID screening. “The goal in the past was always approached as, ‘Let’s educate pediatricians to recognize SCID so they refer kids earlier,’” Weinberg says. “But the disease is so rare that you could educate a pediatrician and they might never see it in their entire career. Universal newborn screening will save lives by allowing earlier treatment before these babies become ill.”

Although early diagnosis was an important factor in saving Isabella’s life, it was only the first step in a protracted medical journey. McFall and Messina began spending large chunks of each day at Packard Children’s, and after Isabella started chemotherapy, one of them stayed with her every night. Messina also quit his preschool job; he couldn’t risk catching germs from his charges that he might pass on to Isabella.

“They told us, ‘This will be a long haul; you have to pace yourself,’” McFall recalls. Isabella’s stem cell transplant would require several months’ hospitalization to give time for the donor’s stem cells to take root and grow.

“The day of transplant is sort of like conception day for the new immune system,” Weinberg explains, adding that normal immune-system development in utero takes approximately six months.

To begin treatment, Isabella’s physicians used immune-suppressing drugs to bring her rogue T cells under control. Then, they waited for her to grow old enough to receive the chemotherapy drugs that “condition” the patient’s bone marrow before a stem cell transplant. The chemotherapy conditioning has two goals: It creates physical space in the bone marrow for donor stem cells, and it suppresses the patient’s immune function to prevent rejection of the new cells.

“Babies handle the drugs differently than older children or adults, so the doses have to be monitored very carefully,” Weinberg says, noting that the drugs, which were designed for cancer treatment, carry some risk of organ damage in infants. To reduce the risk, Isabella’s chemotherapy was delayed until she was 16 weeks old, and the drug regimen was modified to take her vulnerable age into account.

The conditioning drugs are unnecessarily harsh for infants with SCID, Weinberg notes, but doctors lack other treatment options. Weinberg and his research colleagues are conducting two clinical trials to test gentler alternatives.

One trial for genetic diseases, begun several months after Isabella received her conditioning, uses non-cancer drugs to reduce the doses of cancer drugs. A second trial, funded by a $20 million grant from the California Institute for Regenerative Medicine to Judith Shizuru, MD, PhD, an associate professor of medicine, will substitute antibodies for conditioning drugs. The antibodies recognize a molecular marker on the surface of blood-forming stem cells and tag the cells for destruction. After a waiting period to allow all the antibodies to be cleared from the body, patients will receive infusions of highly purified donor stem cells, rather than the unpurified infusions of both blood and bone marrow now used. Shizuru has found that the method works in a mouse model of SCID and has few side effects. Her team plans to begin enrolling children in the human study in the winter of 2014.

A third study that will launch at Stanford and Packard Children’s later this year is intended to speed the stem-cell transplant process after conditioning is complete. “We’re supplementing stem cells with cells that are like teenage lymphocytes — not fully grown but not newborns, either,” Weinberg says. He and Janice Brown, MD, associate professor of medicine, have found that giving these cells, called common lymphoid progenitor cells, to mice undergoing transplant quickly restores their immune systems and protects them from early infections. The new study will test the cells in children with leukemia. If the cells safely speed transplants in that context, they may later be added to the treatment regimens of infants with SCID.

Another approach being developed at Stanford will use stem cells from patients’ own bone marrow. Matthew Porteus, MD, associate professor of pediatrics and another of Isabella’s stem cell transplant doctors, wants to correct the SCID-causing genetic mutations in the stem cells. These “corrected” cells could be transplanted without concern for rejection. Porteus recently received a National Institutes of Health grant to develop this approach for SCID’s two most common forms.

Most of the nascent science, promising as it is, came too late to help Isabella. Nevertheless, she received her first infusion of stem cells — supplied by an anonymous donor — on April 18, 2011.

Then came the most difficult and uncertain part of Isabella’s treatment: waiting. Throughout much of 2011, Isabella’s physicians monitored her T cell counts while McFall and Messina waited for good news. The hospital routine no longer seemed foreign — they were used to the gloves, gowns, booties and masks; used to washing their hands over and over; used to spending a little time each day with their face masks off so that Isabella could see their mouths moving as they spoke, an important sensory input for language development; used to the regular parade of doctors and nurses through Isabella’s room; used to the fact that, for now, pictures and videos of the outside world had to be substituted for Isabella’s ability to experience it directly.

And they were heartened by their baby’s cheerfulness — she grinned and gurgled at them like any other infant, and her development progressed on close to a typical schedule. They dressed her up in adorable outfits for holidays and showed her off to her caregivers. When he visited the family, Weinberg took joy in seeing how both parents doted on Isabella, commenting especially on Messina’s close bond with the baby. “When he looks at her, if it was a cartoon, there would be a big balloon saying ‘Love!’ overhead,” Weinberg says. “It’s how every child dreams of being seen by their parent.”

Soon after the first stem cell infusion, Isabella’s T cell counts climbed, but after a few months, they leveled out and then began to fall. As the summer wore on and Isabella’s T cell counts did not get better, everyone grew more concerned.

In August 2011, Isabella’s medical team realized her own malfunctioning T cells were re-taking her immune system and decided to give a second dose of stem cells from the same donor. She received a targeted form of conditioning to attempt to wipe out her T cells while allowing her donor’s stem cells to remain intact. Weinberg crossed his fingers and hoped this would work. His only other surviving Omenn syndrome patient had undergone two failed stem cell transplants before a third transplant finally succeeded; that child spent more than two years in the hospital. He wanted a better outcome for Isabella.

After the second infusion of donor cells, the medical team periodically measured how much of Isabella’s immune system came from her donor compared with her own cells. Unlike a blood cancer patient, Isabella did not need to have her native immune system eradicated, but she needed a reasonable supply of healthy T-cell-producing stem cells from her donor. The hard part was that no one was sure how many donor stem cells would be enough to allow her to live safely in the outside world.

At first, the test results were so discouraging that Isabella was scheduled for a third transplant procedure in October 2011, and McFall and Messina were told to expect her hospital stay to extend into the spring of 2012. But shortly before the third transplant was to occur, Isabella’s test results jumped.

Suddenly, she was hitting milestones that allowed her to start emerging from her germ-free cocoon. In one of the happiest moments, her doctors told McFall and Messina that they could stop wearing gowns, gloves, booties and masks in her room. “We were able to feel her baby skin with our bare hands and give her kisses for the first time in nine months,” McFall says. “That was a good day.”

Then, in mid-October, Isabella was declared healthy enough to transfer to the Ronald McDonald House near the hospital as the first phase of her transition home. McFall and Messina couldn’t quite believe it.

“We didn’t pack a single thing in advance,” McFall says of the family’s Oct. 23 move out of the hospital. “We left the hospital room at 9 o’clock that night.”

By Thanksgiving 2011, Isabella was well enough to go with McFall and Messina to a small family party at McFall’s mom’s house in San Jose, Calif. In December 2011, after a two-month stay, the family left the Ronald McDonald House and headed home.

Today, about 90 percent of the stem cells in Isabella’s bone marrow are still her own; just 10 percent come from the donor. For a leukemia or lymphoma patient, a stem cell transplant with this outcome would be a failure; in blood cancer, cure requires total replacement of the patient’s blood-forming system. But with her diagnosis, Isabella’s situation may be a resounding success. She’s making a steady supply of functional T cells.

The question is whether that will continue indefinitely. In the past, some children with classic SCID received transplants that left them with many of their donor’s healthy T cells but almost no donor stem cells; these children often ran out of T cells after a few decades and required second transplants.

“I’m optimistic that won’t happen with Isabella; she has stem cells from the donor and is continuing to make T cells, so she’s conceivably stable,” Weinberg says. “I fully expect she’ll attend preschool and kindergarten like everyone else, and I expect her to come home with colds like everyone else.”

At home, though she has slight speech and motor delays, Isabella is thriving — running, climbing, chattering in both English and Italian, and enjoying a typical toddler’s assortment of books, toys, trips to the park and strolls through the neighborhood with her parents. One day in the fall of 2012, as a visitor sat at her kitchen table, she jabbered happily to everyone present, then settled on the floor to entertain herself by threading a shoelace between her toes.

McFall and Messina still worry about taking Isabella to crowded public places, but they have cautiously tried a few expeditions to restaurants and the grocery store. They were encouraged recently when Isabella didn’t catch a cold they both had. And they are gradually expanding Isabella’s contact with other kids — she’ll soon take a parent-child gymnastics class for toddlers, an activity that would have been unthinkable a few short months ago.

In an email, reflecting on her family’s medical journey, McFall says:

“A woman made a comment in a store the other day about how it would be nice to keep them babies forever, and I had a funny reaction to that statement. I think it’s because I want to get as far away from that period, which was her infancy, as possible. I look more forward to the future, and ‘getting on with it.’”



E-mail Erin Digitale






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