A parent’s worst nightmare can happen as easily as this. Your toddler is cranky after having surgery to remove his tonsils and adenoids. You measure out and give him a dose of the codeine syrup prescribed by his doctor — repeating it every four to six hours, exactly as you were told to do. On the second night following the surgery, your son develops a fever and wheezing, then sleeps. When you walk into his bedroom the next morning, his face looks pale and he isn’t breathing. You call 911. The paramedics can’t revive him.
That is how a two-year-old Ontario boy died, suffering a fatal reaction to codeine after his tonsils and adenoids were removed to treat sleep apnea. An autopsy showed the child had toxic levels of morphine in his blood. His mother had given him only the prescribed dose of codeine and acetaminophen syrup following a routine operation.
Why did it happen? In a 2009 report in The New England Journal of Medicine, Canadian drug surveillance researchers revealed that the toddler had extra copies of a gene that converts codeine into morphine, which can slow or stop breathing. He was an ultra-rapid metabolizer, who converted codeine into morphine much faster than most children.
Unfortunately, it’s not just the drugs prescribed to children that can harm them. Like almost half of the new mothers in Canada, Rani Jamieson, a Toronto accountant, was prescribed Tylenol No. 3 (with codeine) after giving birth to her son, Tariq. Twelve days later, he died of a morphine overdose. An investigation found that the mother’s breastmilk had a concentration of morphine 10 to 20 times greater than expected and the baby’s blood had lethal levels. In a 2006 report, the drug surveillance researchers discovered that the mom was an ultra-rapid metabolizer, whose genes turned her breastmilk into a toxic brew.
These two deaths, triggered by unexpected adverse drug reactions (ADRs) to a popular pain reliever, are not isolated examples. They represent a more widespread problem that should concern all parents. More than 2,500 Canadian kids die from toxic reactions to drugs each year and many more develop permanent disabilities, such as heart damage and loss of hearing. One of seven children treated in hospital suffers an ADR. “Young kids are particularly vulnerable because they can’t evaluate or express their response to a medication,” says Bruce Carleton, a clinical pharmacologist at BC Children’s Hospital in Vancouver and co-leader of a Canada-wide paediatric ADR surveillance network.
Also, says Carleton, “over 75 percent of drugs used to treat children have never been tested for safety in kids.” He set up the network with University of British Columbia geneticist Michael Hayden to track and investigate ADRs in kids. They saw a unique opportunity to save lives and prevent disabling side effects by identifying genetic differences that predispose kids to ADRs.
The network, known as the Canadian Pharma-cogenomic Network for Drug Safety (CPNDS), operates in 13 children’s hospitals from coast to coast. Carleton estimates that half of ADRs in children result from differences in genetic makeup that cause some children to break down certain drugs differently. Some other examples are: life-threatening skin reactions to ibuprofen; anaphylactic reactions to antibiotics; and destruction of bone tissue from corticosteroids.
“If we know in advance that some children have specific genetic variations that lead to harmful reactions, we can make better decisions about using a particular drug,” says Carleton, a senior clinician at Vancouver’s Child & Family Research Institute.
Saving lives — at a cost
Dana Tent wishes there had been a genetic test available to predict her son Stefan’s reaction to cisplatin, a life-saving anti-cancer drug. Stefan was diagnosed with a malignant brain tumour at 15 months of age. In a 4½-hour operation at BC Children’s Hospital, the neurosurgeon removed a baseball-sized mass from his brain. This was followed by six rounds of aggressive chemotherapy that included cisplatin, which is used to treat more than one million patients a year.
Stefan’s parents knew the chemo would make him very sick, but were told most of the side effects would be temporary. With one exception. “The doctors warned us his hearing could be affected and hearing loss was the only thing they couldn’t do anything about,” Tent recalls. Audio tests were done after each round. Stefan seemed fine until his hearing was tested after the sixth and final treatment, just before his second birthday. “It’s not good. We’re seeing hearing loss in high-frequency sounds,” the audiologist said.
His mom refused to believe the results until he was retested a month later. The resilient toddler had survived brain surgery, endured six months of chemo and beaten cancer. But his hearing was permanently damaged. Stefan has trouble hearing high-frequency consonants, like s, t and f, and if there’s background noise, it’s hard for him to understand a conversation. He has to wear a hearing aid, which he kept removing for the first year, and he needed speech therapy. This active boy, now six, is healthy and cancer-free and for this, Tent is truly grateful. “Looking at the whole picture, we’re a really happy story. But why do we need to have this hearing problem?”
Hayden and Carleton asked each other the same question.
Like Stefan, about 60 percent of kids treated with cisplatin experience some degree of hearing loss; 40 percent require hearing aids or cochlear implants. Why does the drug harm one child and not another? The two scientists suspected that genetic differences between kids were important, but had no idea which genes were involved. They collected DNA samples from 162 kids across Canada who were treated with cisplatin and analyzed their genetic makeup.
Each of us has about 25,000 genes on 23 pairs of chromosomes. Hayden and Carleton narrowed their three-year search by targeting 300 genes involved in drug metabolism, hoping to find some key ones that were different only in the kids with hearing problems. They discovered two genetic culprits, known as TPMT and COMT. “If a child treated with cisplatin has these gene variants, that child will go partially or completely deaf,” says Hayden.
Hayden and Carleton are developing an inexpensive DNA saliva test that would allow doctors to predict who is genetically susceptible. In future, high-risk kids could be offered other treatment options: an alternative chemo drug, lower doses of cisplatin, or a protective drug. Paediatric oncologist Rod Rassekh, who helped identify the gene variants, is now doing a study to see whether a drug called sodium thiosulphate can prevent hearing loss in kids with high-risk genes when administered with cisplatin. The Vancouver researchers are also investigating whether the two genes cause hearing loss in adult patients.
The team is also focusing hard on anthracyclines, a class of drugs given to almost three-quarters of childhood cancer patients. They’ve helped boost survival rates for kids to over 80 percent, but at a price: possible heart damage. “We’ve seen kids die because of this,” Rassekh says. “One study estimated that the risk of death from cardiac causes was 8.2 times that of the normal population, even 25 years after therapy.” Hayden and Carleton have collected DNA from more than 1,400 kids treated with anthracyclines and identified genetic differences in those who developed heart problems. These include certain genes, called drug transporters, involved in pumping the drug out of heart cells. “We’ve found some preliminary markers that are promising,” says Carleton.
Their goal is to develop a genetic test that can predict who is at high risk for heart failure. “I can see a day when the dose, or the type of drug, will be based on your genes rather than your body surface area,” says Rassekh.
The network has collected DNA samples from more than 3,000 kids affected by ADRs and more than 25,000 who took the same drugs safely. Using this large and growing DNA bank, Hayden and Carleton hope to develop tests that can predict the safety of many different drugs for children, and help prevent the most common and severe ADRs.
The future: Customized care?
The network’s research is already saving lives. In the case of codeine, network investigator Gideon Koren discovered that some nursing moms metabolize the drug in such a way that it can be life-threatening to their babies. The impact was immediate: The FDA in the United States and Health Canada issued warnings that breastfeeding moms taking codeine should watch their infants for shallow breathing, limpness, unusual sleepiness (sleeping more than four hours at a time), and other signs of morphine overdose. Regulators also required drug manufacturers to change the labelling of medicines containing codeine to highlight the potential risk.
Koren, director of the Motherisk program at Toronto’s Hospital for Sick Children, found in a 2009 follow-up study that nearly 25 percent of breastfed babies became less alert or had abnormal breathing after their mothers took codeine. So, an ADR that was thought to be rare happens more frequently.
The network is now doing a study to test the benefits of a predictive genetic test for mothers that might help prevent codeine ADRs in breastfed infants. Three hundred women giving birth by Caesarean section at hospitals in Toronto and London, Ont., will take a simple DNA saliva test to see if they metabolize codeine very rapidly. Those identified as ultra-rapid metabolizers will be given another pain reliever, such as ibuprofen.
Another control group of 300 women will receive a standard dose of codeine medicine for pain relief, and both the moms and their babies will be closely monitored for ADR symptoms. If the study shows that personalizing pain relief treatment to match a woman’s genetic makeup is safer for her and her baby, this could mean that the test would be offered to women giving birth in hospitals across the country.
Making drugs safer for kids matters to all families. More than 50 percent of kids take prescription drugs annually, many of them receiving multiple prescriptions a year. And we now know that some kids face much greater risks based on their genes. The CPNDS is working to lower that risk. “These are not just unfortunate side effects,” says Carleton. “We need to treat disease without creating additional disability.”
For Tent, a genetic test that could have predicted her son’s risk of permanent hearing loss would have made a huge difference. “I would love to have had that choice. If I’d had the option of giving him another drug or a lower dose of cisplatin, I’d have gone for it,” she says. Knowing that Stefan’s case helped researchers at BC Children’s Hospital find a way to prevent similar reactions in other children means a lot to her. “It’s amazing. So many kids will benefit from this test, and their parents will have a choice.”