Babies With Rash Get Cream To Damp Immune System; Can It Stop the 'Cascade'?
By MARILYN CHASE
Staff Reporter of THE WALL STREET JOURNAL
June 24, 2004; Page A1
SACRAMENTO, Calif. -- The week after he was born, Ryan Ishibashi was a "mass of rash," his mother remembers. As he nestled in her arms, she thought he was cuddling. He was actually itching from a common skin disease called eczema. Sometimes he tore his skin until it bled.
The bigger risk is still to come for Ryan, who is now 21 months old. Half of kids with eczema develop asthma by age 6. Ryan's doctor puts his risk at 70% or 80% because of his family history. Both his mother, LaVerne Ishibashi, and his older sister have allergies and asthma.
In the long search for the cause of asthma -- a fast-growing disease that affects some nine million American children under 18 -- scientists have variously blamed pollution, exposure to irritants in food and even excessive hygiene. But a new theory focuses on the kind of rashes Ryan has had as a baby. It suggests that infant eczema is the trigger of an allergic chain reaction that can lead to a childhood full of wheezing.
Doctors are now testing the theory in a six-year study led by the National Jewish Hospital and Research Center in Denver. Hundreds of babies at 20 sites nationwide are being treated with a cream called Elidel that suppresses the immune system. Block the eczema, the thinking goes, and you block the march to asthma.
The study is unusual because the patients are so young -- 3 months to 18 months. "Parents aren't sitting around thinking, 'Do I want to do a study with my little infant?' " says Mark Boguniewicz, the National Jewish Hospital researcher leading the study. "It's the most challenging study most of us have ever been involved in."
Some specialists doubt the treatment will work. Not everyone who develops asthma started out with eczema as a baby. John Warner, a professor of child health at the University of Southampton in England, says the cream might quell the itching of rashes but probably isn't powerful enough to put a halt to the entire immune-system process that causes asthma. Dr. Warner was involved in a European study that tested the popular antihistamine Zyrtec in 1- and 2-year-olds as a way of preventing asthma. It failed to show superiority over a placebo overall, although a subset of patients with grass pollen and dust mite allergies did seem to benefit.
Novartis AG, the big Swiss drug company and maker of the Elidel cream, is sponsoring the new study. Elidel is currently approved by the Food and Drug Administration to treat eczema in adults and children 2 years and older. It recorded sales of $80 million in the first quarter of 2004.
If Elidel wins FDA approval someday as a preventive measure against asthma, the potential market is big. The proportion of infants with eczema ranges from 17% in the U.S. to as high as 24% in Japan. The drug costs at least $165 retail for a 100-gram tube and is usually covered by insurance. However, it isn't known what side effects Elidel might cause in babies. As an immune suppressant, doctors say it might interfere with the body's development of a strong defense against infections.
More than 20 million Americans have asthma, a chronic inflammation of the lungs that causes airways to constrict. Prevalence has nearly doubled in the last two decades for reasons that remain mysterious but may include urbanization and air pollution. Allergens such as grasses, pollen and vehicle exhaust as well as infections, exercise and cold air can set off asthma attacks.
The symptoms can range from mild to catastrophic. During an asthma attack, the tubules in the lungs clamp down and oxygen can't reach the bloodstream. In extreme cases it becomes impossible to breathe: About 5,000 Americans die of asthma each year.
For parents, the distress of watching a child fight for air and the constant vigilance required to manage asthma take a heavy toll. Long-term treatment with steroids taken orally carries many risks, including immune suppression and osteoporosis. Inhaled steroids are less dangerous but can cause temporary slowing of growth. Asthma costs the U.S. about $13 billion a year in health-care costs, according to Datamonitor, a market research firm.
Doctors have found little to stop asthma from developing, although it helps to clean the environment of allergy-causing agents such as household dust, mold and pet fur. Researchers continue to probe the "hygiene hypothesis," which holds that modern homes are too clean, leaving kids with underdeveloped immune systems that overreact later. Breastfeeding, new baby formulas, and small doses of allergens are under study as preventatives.
The Elidel study represents another approach to asthma: trying to attack the immune system's overreaction at its origin. Elidel inhibits a molecule called calcineurin, which is a key early activator of the allergic response. Doctors hope this will keep in check the antibody IgE, which is found at high levels in 80% of kids with eczema. IgE is seen as a master switch that turns on inflammation-producing immune cells. According to the new theory, these cells at first cluster around the skin, producing eczema in infants, and later migrate to the lymph nodes and lungs, where they cause asthma. That could explain why asthmatics tend to have high IgE levels.
Evidence to support this theory came from some wheezing mice in the lab of Jonathan Spergel, an assistant professor of pediatrics at the University of Pennsylvania and the Children's Hospital of Philadelphia. Dr. Spergel, who is a consultant to Novartis, induced eczema by smearing egg white protein -- a common cause of allergies -- onto the skin of young lab mice. The mice developed eczema. Next he gave these mice and healthy control animals a whiff of egg-white protein through their airways. Mice without eczema breathed normally. "But mice who had had pre-exposure to the skin would wheeze," he says. "The mouse work really showed things went from the skin to the lungs." Through skin irritation, he says, "we were inducing asthma."
When scientists tried other parts of the body instead of the skin, they couldn't induce asthma. "So the hypothesis is there's something special about the skin," says Thomas Hultsch, who heads dermatology research at Novartis. "The skin is the portal."
Dr. Spergel's experiment excited Dr. Boguniewicz, who specializes in pediatric allergies at National Jewish Hospital. He decided to do a study to see if people respond as mice do. Treating from infancy until age 5 or 6, the average age for asthma diagnosis, meant a long and expensive study. Dr. Boguniewicz says he sought National Institutes of Health funding but was advised that because of the cost he should seek corporate sponsorship. Novartis stepped up.
In the trial, 1,100 infants who have eczema have been randomly assigned to take either Elidel or a placebo, which contains the base cream without active ingredient. Neither doctors nor patients know who is receiving which. Parents are instructed to apply the study drug on the child at the first sign of eczema. If the rash lasts longer than three days, they can then turn to steroid creams, which are a proven remedy for eczema.
After three years, researchers will "unblind" the study to see which volunteers got Elidel and which got the placebo. After that, all participants will receive Elidel until the six years are up.
The main goal of the study is to show whether children taking Elidel end up developing fewer cases of asthma. Even if that turns out to be a disappointment, researchers are hoping the results will demonstrate that Elidel, a nonsteroidal drug, is a safe alternative to steroid creams for the youngest infants. Atrophy or thinning of the skin is a major steroid side effect. Elidel generally causes few major side effects in older children and adults, although a small number of people may get herpes skin infections, warts or swollen lymph glands.
Elidel's safety in infants under age 2 has yet to be fully demonstrated. In theory, since the drug suppresses protective immunity it could leave infants vulnerable to infections such as chicken pox. "Any time you change the immune response of the skin, you have to be concerned," says Alfred Lane, chairman of dermatology and professor of pediatrics at Stanford University School of Medicine. He is one of the researchers in the study. Novartis says past tests on 900 infants showed only minor side effects.
For Shannon Beaupre of San Diego, three months in the study has produced no miracles for her 9-month-old son Gavin. The study drug -- she doesn't know if it's Elidel or placebo -- hasn't worked to end his eczema episodes, which always require steroids. Still, she plans to stick with the study. "Asthma scares me," she says.
After her baby developed eczema, Tracy Sherry of Bailey, Colo., saw an ad in the Denver Post and drove an hour to National Jewish Medical and Research Center. A former pediatric nurse, Mrs. Sherry had cared for children with asthma, cancer and AIDS, and she believed in clinical trials. Her faith in research grew during her own bout with a brain tumor. An experimental immune therapy has held cancer at bay for eight years. The study seemed a good option for her son Brian, now 14 months old.
"You get six years of excellent care and follow-up. You can't go wrong. If we can avoid getting asthma, that would be very exciting," says Mrs. Sherry.
LaVerne Ishibashi, Ryan's mother, was more cautious at first, fearing her son would get a placebo. A dermatologist had let Ryan sample Elidel and the improvement to his skin was noticeable. (Although the FDA hasn't approved Elidel for infants under 2, doctors can prescribe any FDA-approved drug for nonapproved uses -- a practice known as "off-label" prescribing.) Mrs. Ishibashi, a social worker, didn't want Ryan to "go backwards" but she wanted to help other children at risk for asthma, so she entered Ryan in the study in March of this year when he was 18 months old.
Now her daily drill is to examine Ryan's skin and follow the study protocol. If he looks normal, she applies a moisturizer. If a rash breaks out, she squeezes a dab of the study drug from an unmarked yellow tube. If his rash persists for more than three days, she applies a steroid cream. She records all of this on a Palm handheld device supplied by Novartis.
One recent Friday, Mrs. Ishibashi was sitting in the office of Ryan's doctor. While she was waiting, she took the Palm from her purse and did her daily diary entry. On the screen, the outline of a child's body appeared. With a stylus she touched the torso, identifying it as a place where Ryan had a rash. She graded it as mild and reported that she applied the study cream. The diary entry took about 45 seconds, even with Ryan poking a curious finger at the screen. Later at home, she placed the Palm in a device that sends the data through phone lines to Novartis.
Mrs. Ishibashi hopes Ryan won't have to endure the experiences of his 12-year-old sister, Megan, who also had eczema as a baby and has suffered from asthma since the age of 3. Megan has had to cut short slumber parties and visits to friends' homes with pets or mold. Mrs. Ishibashi cleans constantly and charts the seasons by Megan's respiratory distress. "Who needs the weather channel?" she asks. "I know when molds are here."
Earlier this year, Ryan developed a "gurgly" cough that frightened his mother. If he was diagnosed with asthma, he'd be out of the prevention study. But a doctor decided the cough wasn't the result of asthma.
Although Mrs. Ishibashi doesn't know what drug Ryan is getting, she has a hunch. "I like whatever medicine we're getting. He's comfortable," she says.
Write to Marilyn Chase at email@example.com