A keen eye for observation
Canadian universities attract world-class medical researchers who make significant national and global contributions. One epidemiological researcher who has made a far-reaching impact on our understanding of asthma and allergy is Dr. Malcolm Sears, a New Zealand native who came to McMaster University, Hamilton, in 1990.
Early in his career, Sears linked up with an ongoing longitudinal birth cohort study in Dunedin, New Zealand that has expanded our understanding of the natural history of asthma from early childhood to adulthood. The study group or cohort is now being seen at 45 years of age, and over 90% are still involved.
An innate curiosity, rugged determination, keen power to intuit observations, and capacity to think and act outside the box have driven Sears along controversial roads to discovery throughout his career.
Sears was instrumental in establishing and directs the Canadian Healthy Infant Longitudinal Development (CHILD) study, which is leading to pivotal insights into how genetics and environment affect asthma development in early childhood.
He was the first to undertake a long-term clinical trial that demonstrated that routine use of short-acting beta-agonists worsens rather than benefits severe asthma – a paradigm-shifting finding with major implications on asthma treatment. A well-researched longitudinal study established that breastfeeding is not as universally beneficial in preventing allergy as once thought, although much remains to be learned.
Early impact on asthma research
Sears studied medicine at the University of Otago, New Zealand. He planned to go into family practice, but “I haven’t got there yet,” he jokes.
His mentor, Dr. Tom O’Donnell, recruited Sears to develop the intensive care unit for patients with respiratory disease and later arranged for a fellowship in research methodology in Seattle at the University of Washington. When Sears returned, O’Donnell invited him to take over a large asthma clinic in Dunedin.
“I launched into managing asthma, and started asking a lot of questions about why asthma was so troublesome.”
Then, two of his young patients with severe asthma died suddenly.
“It was really quite upsetting,” he recalls. “Then I discovered, talking to colleagues and family physicians, that others were also seeing an occasional death from severe asthma. This was something new, clearly an epidemic of deaths in young people.”
Sears participated in a New Zealand Medical Research Council task force to investigate. Very little research had been done on the prevalence of asthma in New Zealand. “One of my colleagues asked me, why don’t you look at your birth cohort in Dunedin and see how much asthma is developing in these children?”
Sears was not aware of the birth cohort, which he jokingly describes as a “well-kept pediatric secret.” In 1972, a psychologist working with a neonatologist had documented the prenatal and postnatal history of every birth at a Dunedin maternity hospital. Local children were recalled at ages 3 and 5 years for an early childhood development study. When Sears learned of it, the children were 6 years old.
He knocked on the director’s door but was turned away. He persisted and eventually gained permission to include two asthma-related questions in study questionnaires when the cohort returned for assessment at 7 years of age. Now 45-years old, the cohort is still followed in one of the world’s most successful longitudinal multidisciplinary studies, which includes studying the natural history of asthma.
No stranger to controversy
During that time, Sears participated in a New Zealand study that examined 271 asthma-related deaths over a 2-year period studying disease severity, treatment or lack of treatment, and many other details. The numerous reports which he authored led to new recommendations for asthma management.
In the late 1980s, his powers of observation again led him into controversial waters. While undertaking a small pharmaceutical study, he noticed a marked improvement in several of the 30 patients with chronic asthma. However, when the code was broken, results showed no difference between placebo and drug treatment.
“The penny dropped”, he says, when he recalled that the protocol required patients to stop regular beta-agonist therapy before entering the study. Could that be the reason why some patients had improved?
On a sabbatical at McMaster University in 1986, Sears studied epidemiology and study design. There, he established the protocol for a groundbreaking study of regular short-acting beta-agonist use.
“Many thought I was on the wrong track, because we all knew that these drugs were beneficial,” he says.
In the double-blind, randomised study, patients took a potent beta-agonist, fenoterol, 4 times daily for 6 months then received a placebo, 4 times daily, for the next 6 months or vice versa. Throughout the study, they continued to take their regular asthma medications.
“By the time we finished, I thought it was a crazy idea,” Sears admits. “I thought it wasn’t going to tell us anything. I was astonished when it very clearly did. During the 6 months on regular fenoterol, asthma worsened in almost all respects.”
Published in The Lancet in 1990, the study is a hallmark of Sears’ career. It kicked off a major controversy that eventually shifted treatment away from the regular use of short-acting beta-agonists. Today, they are used primarily only as intermittent rescue medication.
Canadian Healthy Infant Longitudinal Development (CHILD) Study
Dr. Paul O’Byrne, now Dean of Medicine, invited Sears to relocate to Canada as a professor at McMaster University’s Division of Respirology shortly after his sabbatical there. They discussed findings from the New Zealand cohort at 26 years of age. Among those with persistent or relapsing asthma, Sears and his team had found that lung function was significantly reduced.
“My question was when did this abnormality occur? When did lung function fall off the curve? We discovered that, even at age 9, children with persistent asthma were never on the normal curve.” The abnormalities had occurred in early childhood, before Sears began to measure lung function in the New Zealand cohort.
O’Byrne introduced Sears to Dr. Padmaja Subbarao, a SickKids-based expert who could measure lung function in infants. And, Sears was invited to help form a new Network of Centres of Excellence in Allergy, Genes and Environment (AllerGen), a cross-Canada network of allergy-interested investigators.
These collaborations led to development of the CHILD study, which began 8 years ago with CIHR and AllerGen funding. CHILD’s purpose was to look at how genes and environment interact in early life to cause asthma, allergy and other respiratory diseases.
CHILD, one of the world’s largest hands-on birth cohort studies, has recruited 3,495 healthy babies, born from 2008 to 2012, along with their mothers and more than 80% of fathers. A team of investigators across Canada has assessed this birth cohort regularly to age 5, with major assessments at 3 months (during a home visit) and at 1, 3 and 5 years.
In addition to standard asthma questions, investigators have examined each child’s nutritional environment – maternal diet during pregnancy, breastfeeding habits, timing of food introduction in infants’ diet, and more. Researchers have collected genetic samples, cord blood, nasal, urine, and stool samples and assessed each child’s physical and psychological environments.
“We are very interested in the child’s first few months of life and exposures in the home,” explains Sears. “Some of the most important facts that we’ve learned from CHILD relates to things that we really didn’t know much about when we started.”
For example, analyses of stool samples collected at 3 months and 1 year of age have revealed that gut bacteria – the microbiotic environment of our digestive system – impacts early immune-system development in children with asthma and allergy. Looking at differences in gut microbes may eventually lead to new treatments, he believes.
CHILD data are being used to re-evaluate Sears’ previous findings that breastfeeding is not universally protective. Benefits likely vary, depending on a variety of factors, such as maternal genetics and ethnicity, duration of breastfeeding, complementary feeding, and more.
Other findings support the conclusion of a British study (LEAP) that introducing complementary foods, such as peanut, egg, and cow’s milk before 6 months of age confers a lower risk of food allergy in later life.
“Epidemiology very rarely proves cause and effect,” says Sears. “It suggests associations and, in those, a need for further investigation.”
CHILD investigators are now seeking funding to continue to follow the birth cohort up to 14 years of age. Sears, who has led the study since its inception, plans to hand over the leadership reigns later this year.
“You shouldn’t start a longitudinal study when you’re in your 60s,” he jokes. “That was an error of judgment, but it was a good error. I’ve enjoyed it thoroughly.”