From the Allergic Living Archives. First published in the magazine in 2008.
If you have a child with peanut allergies, other parents will say to you: “Nobody was allergic to peanut butter when I was a kid.” If a cat swishing through a room starts you wheezing, you’ll get asked: “How come so many people have asthma?” Both are reasonable questions, variants on the broader million-dollar one: “Why do so many people have allergies today?”
If you want an easy answer, allergy experts will simply say they don’t know. But what they mean is – they don’t know entirely. The fact is that scientists understand a lot more about allergic disease than they did a decade ago. There are still gaping holes in their knowledge, but as they continue to fill in the pieces to the puzzle, what they are finding is fascinating and often surprising. In the following investigation, Allergic Living examines what science knows so far about why allergies occur.
In the Beginning
When a baby is born, its immune system is a work in progress. “You’re born with a naïve, allergic-skewed immune system,” explains Dr. Michael Cyr, an allergist and immunologist at McMaster University in Hamilton, Ontario. This is what scientists call the Th2 mode.
During the first days, weeks and months of life, as the baby comes into contact with various germs, bacteria, viruses and infection, the system is supposed to start learning to distinguish between what is harmful and what is benign.
Some allergists liken the emerging immune system to a toggle switch or a reset button: we’re all born in that Th2 mode and then that first bout of sniffles at eight weeks or the ear infection at four months begins to “switch” the immune system over from Th2 to Th1 mode or fighting bacterial infection mode.
But in the person with a genetic inclination to allergy, something misfires and the switchover doesn’t happen properly. Cyr, who’s a researcher with AllerGen  (the Allergy, Genes and Environment Network), says that why this process happens easily for some people but not for others remains unclear, and may depend on a confluence of factors.
The young child who doesn’t get switched over is now atopic – predisposed to developing an allergic response to a trigger such as cat dander or ragweed pollen or peanuts. After breathing in or consuming one of those, the child’s immune system creates allergy antibodies – specifically Immunoglobulin E or IgE antibodies – to guard against the offending trigger. The next time the immune system encounters it, the IgE will go on the defensive, setting off a cascade of allergic symptoms.
Though genetics are a large contributing factor to whether a person becomes allergic, scientists haven’t found one specific allergy gene. “It’s becoming clear that it’s not a gene, it’s a whole series of genes,” says Cyr. Something has changed to increase the number of us who are developing allergies, says Dr. Dennis Ownby, a professor of pediatrics and the head of allergy and immunology at the Medical College of Georgia in Augusta.
“What seems to have happened over the last three decades, at least in developed countries, is that genetic ability [to be allergic] has become more prominent,” he says.
Just how much have allergies and asthma grown? Figures from the World Allergy Organization reveal the global prevalence of asthma has increased by an astounding 50 per cent every decade for the past 40 years. In North America today, leading allergy organizations estimate that about 24 million Americans and three million Canadians have asthma.
In the past decade alone, the prevalence of food allergy, once an uncommon condition, has skyrocketed. The Food Allergy & Anaphylaxis Network*, the U.S. education group, estimates that about 12 million Americans – 4 per cent of the population – now contend with the disease. The Canadian rate of food allergy is estimated to be comparable. Peanut allergy alone has doubled in young American kids.
In our modern world, allergy has spread like wildfire. Scientists are certain that genes alone can’t be the whole reason why. “The genetic pool does not dramatically change over decades,” notes Cyr. “So it’s obvious there’s something else going on.” And that something appears to be our environment.
Getting to the Dirt
While references to asthma date back to ancient Chinese medical texts, the real story of our modern understanding of allergy begins in earnest in 1989. It was a heady year, with the fall of Berlin Wall and the beginning of the opening up of the former East bloc. A team of German scientists decided this presented a great opportunity to compare the prevalence of asthma in Leipzig (former East Germany) and Munich (former West Germany).
Here were two highly similar gene pools of people who had been living in very different societies and conditions. “At that stage, everyone, including us, believed that air pollution was causing asthma  and allergies,” says Dr. Erika von Mutius, who was then a young pediatrician and team leader, and who today is a professor and head of the asthma and allergy department of Munich University’s Children’s Hospital.
When the findings began coming back showing that there was considerably more asthma in modern, Western, hygienic Munich than among the study group living in Leipzig with its billowing factory smokestacks, the researchers were incredulous.
“It was so opposite what we’d anticipated,” recalls von Mutius on the phone from Munich. “We didn’t believe it, so we thought it was a mistake in data entry and re-entered all the data.” But the data were right, and the results were published in 1992.
*Update: The organization FAAN has been renamed FARE.
That year, von Mutius took her research with her to Tuscon, Arizona, where she worked on a fellowship at the University of Arizona under her mentor, Dr. Fernando Martinez, the well-known asthma researcher who today is the director of the Arizona Respiratory Center. One day he read a medical paper out of Britain about something called “the hygiene hypothesis”.
The author of that paper, an epidemiologist named David Strachan, had conducted a study of over 17,000 British children and found that youngsters who had older siblings and were exposed to more infections and bacteria early in life were less likely to develop hay fever or eczema. Writing in that same pivotal year of 1989, Strachan had theorized that smaller family sizes and higher levels of hygiene in modern Western homes may have been contributing directly to the increased prevalence of allergy.
Martinez was intrigued. What, he asked, would happen if von Mutius took into account the sizes of her East German and West German families? The data were incomplete, but it was the less allergic East Germans who clearly had more children per family. She and Martinez followed up with a study comparing family sizes and allergy in Munich and Leipzig (and a neighboring city).
A pattern emerged: the most allergic were the Munich kids with one or no siblings; the least allergic were the East Germans with two or more brothers and sisters. Children in the larger families were being exposed to more germs. It fit with this rudimentary hygiene hypothesis. “It took off from there,” says von Mutius.
Back to the Land
Where the hygiene theory took off to was a place caught in a time warp: the traditional European farm, where father, mother and children still do all the manual labor, from milking to sweeping out the stables. The idea to look at the family-run farm actually came from a school doctor in a Swiss village. He noticed that farm children under his care, unlike other kids, never seemed to get hay fever.
Struck by this observation, he began writing to allergy experts in Basel, research colleagues of von Mutius. At first they were skeptical of the rural doctor’s notion, but then a few Swiss professors ran a small study. The findings were compelling: there was markedly less allergy and asthma on the farms in question. This merited further examination.
And so in 1998, von Mutius began her long-running involvement in a series of European farm studies that have become the underpinning of current allergy research. The first was ALEX (the Allergy and Endotoxin Study), involving scientists from Germany, Austria and Switzerland. The team began gathering and publishing data, and the central findings were consistent: children who lived on these farms were significantly less inclined to have allergies and asthma than children in the neighboring village.
Then came other major studies of the family farms: the multi-center PARSIFAL study of children enrolled in Steiner schools (akin to Waldorf education), which involved 6,600 pupils in five countries; and the PASTURE study, which examined children’s exposure to microbes on farms across Europe. With each study, with each new set of samples of stable and mattress dust, with each new set of blood-test results for environmental and food allergies, a little more was known. “We are getting somewhere,” says von Mutius, taking stock for a moment. “There are now 17 papers [since 1999] that all show the same things.”
They reveal what’s termed “the farming effect,” a phenomenon that protects against allergic disease. Von Mutius and her colleagues have narrowed the effect down to three key factors: livestock (specifically cows, pigs or poultry); type of fodder (for instance, whether it’s fresh grass or hay); and drinking of raw farm milk.
The findings have been generally consistent – about 1 to 2 per cent of the farm children in the studies had asthma compared to 12 per cent of local, non-farm children in control groups. “I’m completely convinced that this is real,” says von Mutius. “The question is – are we going to be able to solve the puzzle.” She chuckles: “For that we need a lot of luck.”
To that end, today von Mutius is co-leader of a massive European Commission project called GABRIEL, which involves 14 countries and 40,000 test subjects. Among its goals is to identify what in those three key elements of livestock, fodder and unpasteurized milk confers protection against allergy, whether it acts alone or in combination with other farm factors as well as the genetic background, and how this all takes place.
For a while, some thought a key was endotoxin in the barns – that’s the membrane of certain bacteria that stimulates the immune system and can cause illness. But fungal spores are also proving important. At this stage, von Mutius finds endotoxin a minor player. “It’s not just endotoxin, of that I’m pretty sure. We think it is microbial factors on the farms – it’s probably anything that’s bacterial, or molds, maybe yeasts. We’re trying to develop new tools to measure those exposures.”
While her researchers are dealing in microscopic levels and minute interactions, von Mutius remains keenly aware of the bigger picture, of the “why” of allergies.
“Mankind has evolved with farm animals for thousands of years, and so probably there is an evolutionary system here that tells the immune system – ‘this is normal,’” she says. “Maybe that’s something the immune system needs in order to know that – this [protein] is harmless, this is nothing that needs to be recognized. In the absence of these factors, all of a sudden these proteins are being recognized as foreign where the immune system starts to mount an IgE response.”
Timing is Everything
What also appears to be important is when a child is first exposed to an environment that affords protection against allergies. It seems the earlier, the better. In 2001, the journal The Lancet published ALEX research in which children who were exposed to farm life from birth to age 5 were tested for allergies. Those children’s results were compared to levels from children who first came to live on a farm between the ages of 1 and 5. The most protected by far were the children who had lived on farms all of their lives until the age of 5, with fewer than 1 per cent developing either asthma or hay fever.
Von Mutius and her colleagues have deduced that the protective “farming effect” begins even before the baby is born. On the traditional farms, women continue to do chores through pregnancy, spending much time in the barn and around cattle. The exposure to the protective stimuli “already starts in utero, and we think the first two years in life are the most important ones,” says von Mutius.
Evidence of immunity before birth could be clearly seen in the umbilical cord blood of 922 babies in the five-country PASTURE study. The blood belonging to the farm babies was much less likely to contain allergy-causing antibodies to airborne triggers such as grass.
A consensus is forming around the importance of cord blood to allergy research. Back across the Atlantic, Cyr has been focusing on this at the McMaster University Medical Centre. His findings indicate that “the more allergic that mothers are, the less mature the cord blood’s stem cells appear to be in terms of the receptors that are important to the Th2-Th1 switch.” This could be a clue to future allergic status.
“It may well be that cord-blood stem cells are a marker,” Cyr says. They could indicate that “even from the day allergic kids are born, their immune systems are already less mature than kids from non-allergic parents.”
Umbilical cord blood will be examined in as many as 5,000 Canadian babies as part of the CHILD (Canadian Healthy Infant Longitudinal Development) study that recently received $12 million in funding from the Canadian government and AllerGen. The four-city study is designed to follow this group of children from pregnancy to the age of 5, and the first-phase of the project is well underway in Vancouver.
Dr. Stuart Turvey leads that pilot project, nicknamed Mini-CHILD, and he speaks excitedly about the prospect of having access to the cord blood of so many children and seeing “the quality of the immune response on the day the babies are born.” A pediatric allergist-immunologist at the University of British Columbia and B.C. Children’s Hospital, he, too, views the period from fetal development in the womb to 2 years of age as crucial, even in those individuals who don’t develop allergies until later.
What is in an Environment?
The primary interest of the big Canadian study is to identify environmental factors in urban living that put children at greater risk for allergies and asthma. In conversation, people tend to use the word “environment” as a catchall for the great outdoors and pollution or perhaps to mean one’s living space. But to epidemiologists and immunologists it’s much more. The womb, for instance, is one environment.
When Turvey speaks of the “environment” that the families enrolling in CHILD are exposed to, he breaks it down into several sub-categories. First, he sees the physical environments – the home, the daycare, the level of pollution outside them; the levels of dust, mold, tobacco smoke and chemical exposures inside; and whether pets are owned.
“And I think the infectious environment is important – factors such as cold viruses and bacteria in a baby’s body,” he says. He even views diet as another environment of stimuli that may influence immune responses: “environment is everything we’re exposed to.”
Turvey also describes a psycho-social environment, and here, he’s largely talking about the amount of stress on the mother in pregnancy or in the home after birth. Is there, for instance, a financial burden or might her support network be lacking?
“There’s evidence that stress can make asthma worse and may even set the scene for asthma predisposition in infants,” he says. He thinks these aspects, even in utero, “should not be underestimated.”
CHILD’s researchers are examining all the environments of the babies. They collect dust, mold, air and blood samples, and will retest at specified intervals for comparison. The researchers ask for the very first bowel movement of newborns in the study. This is no joke: they want to know what bacteria the brand new baby has in his gut, and then compare those bacteria to what’s found in the intestines over time, up until the age of 5. They are trying to understand, Turvey says: “Are there protective bacteria or bad bacteria?”
Bacterial exposures are fascinating if complicated. Dr. Malcolm Sears, the epidemiologist who is director of the CHILD project, explains that how a person’s immune system will respond to a given bacteria will vary, and may depend on which bacteria and the quantity involved. “Certain genetic structures may make a substance like endotoxin, for instance, protective in some people and increase allergies in others. It’s not neutral, it can go either way depending on the genetic background. It’s not always protective,” says Sears, who is a professor of medicine at McMaster University and research director of the Firestone Institute for Respiratory Health at St. Joseph’s Healthcare in Hamilton.
When we speak of “good” bacteria, probiotics leap to mind, those so-called “friendly” micro-organisms that are beneficial to the gastrointestinal system. Could introducing them to a diet contribute to allergy prevention? Von Mutius sees indications that probiotics “might work,” but says the definitive study has yet to be produced.
There is something more apparently protective about the raw milk in the European farm studies, but von Mutius and her team do not yet know precisely what bacteria are making a difference, or whether the heating and denaturating of proteins is at play. She is not promoting the drinking of untreated farm milk, noting there are good reasons for wanting to kill pathogens in such a dietary staple. However, pasteurization as we know it has had a good run; Louis Pasteur invented it back in the 1860s.
In future, there may be practical applications from the European findings about raw milk. “You don’t want the pathogens, but maybe there are other ways,” she says. “I think we need to be clever and creative and find ways to do it.”
Like the researchers in CHILD, she and her team consider the farms they’ve studied to be a specific environment. This is a cloistered and natural environment – a big Petri dish of microbes and clues from a time that’s largely passed. We can’t all go back to live on the farm, but this unique environment may divulge answers to help bring the allergy epidemic under control.
From Cows to Dogs
In the urban environment, of course, there is one similarity to the traditional farm. We do still live among animals: those we keep as pets. As news spread from the European farm studies that exposure to cows, pigs and poultry was helping to protect against allergic disease, scientists began to wonder – could this protection be elicited from non-working animals, specifically dogs and cats?
Dr. Dennis Ownby is one of the leading researchers in this area. In 2002, he and a team of researchers from Henry Ford Hospital published findings in the Journal of the American Medical Association that were surprisingly contrary to the long-held belief that pets in the home would lead infants to develop allergies.
Ownby’s group conducted a study of 474 healthy Detroit children from birth to age 6, examining how exposures to cats and dogs affected the participants’ rate of sensitization to common allergens, including the animals themselves, mold, ragweed, grass and dust mites. The results showed that when infants in the first year of life lived with two or more dogs (or dogs and cats in combination), their risk of developing allergies at 6 or 7 years old was less than half (15.4 per cent) that of kids who hadn’t had any pet exposure (33.6 per cent).
In an interview, Ownby said: “There is something about being around an animal that changes the immune system so that you’re less likely to be allergic to anything.” (However, what remains the case is that if an individual in a household develops pet allergies, the animal should be found a new home.)
The topic had been contentious, with some studies making the case for, and some against pets as protective against allergies. However lately, research on dog exposure in early life has been uniformly positive. For instance, scientists in Munich in 2008 examined data from 3,150 children in two large population studies. The results, published in the European Respiratory Journal, revealed that in blood tests at the age of 6, children who had dogs in their homes during the first year of birth showed markedly lower rates of sensitization to inhaled allergens, such as dust mites, cats, grass and birch pollen.
The findings with cats have been more inconsistent, though a 2007 study of New York City children saw some latent positive effects. Scientists from Columbia University found that kids who had infant exposure to cats were more likely to develop antibodies to the animals and wheeze by age 3. Yet, those same children showed signs of a protective effect and were less likely to wheeze by the time they had turned 5. The researchers suggest that prolonged exposure to cats may produce a tolerance to the allergen.
What’s clear from the published research is that if there is a protective benefit to pet ownership, as with livestock, it happens early in life.
Ownby and his team have seen it in follow-up tests with the Detroit study subjects, who are now 18 years old, and his team is currently immersed in another population study, also out of Detroit, that includes both infants and the infants’ mothers. His preliminary data are consistent with the European farm findings that a woman’s microbial exposure while pregnant is significant to her child’s ability to switch to the Th1 mode.
“We were kind of surprised to find that pets actually had an effect through the mother on the fetus even before birth,” Ownby says. The mechanism of protection, however, remains unclear. “One of the prevailing theories on pets is that they increase the level of endotoxin in the home,” says Ownby. Like von Mutius, however, he has his doubts that endotoxin will prove to be the key. Pets, he notes, “are not changing the levels of endotoxin [in homes] very much, so the effect of pets seems to be separate from that.”
Allergy and the Big City
Pets, cows and pigs, farm bacteria, good microbes in the gut, big families and day cares, their protective qualities all fit with the hygiene hypothesis. But the theory does have holes. With the growth in allergy, many people are living with immune systems programmed in the Th2 mode, but at the same time, there has also been a surge in Th1 diseases such as diabetes.
What’s also not easy to reconcile with the theory is the link between exposure to traffic pollution, that unhygienic chemical stew, and high rates of asthma. Perhaps no scientific theory can encompass a range of situations as opposite as the European family farm and the giant American city (the latter of which Turvey could sub-divide into hundreds of environments). But this much is certain: a link among asthma, allergies and traffic exhaust has emerged.
In population studies from Europe to Southern California, the proximity to busy roadways and increased levels of vehicle exhaust have been related to the onset of asthma in school kids. But whether the inflammation seen in the airways of participating children relates to outdoor allergens as well as the exhaust itself has been a matter for debate.
However, Dr. Joachim Heinrich, head of environmental epidemiology at Munich’s Heimholtz Center, was part of a team of scientists that assessed allergic sensitization among 2,600 children living in high-traffic areas of metropolitan Munich. The resulting study, published in 2008, clearly finds that “living on busy roads is associated with a higher risk for sensitization to pollen.”
It says this might show “interaction between pollen and air pollutants and the effect of this interaction on the human immune response.” Other studies have mentioned the greater likelihood of allergic response to pollen and other airborne allergens when inhaled alongside diesel fuel. All this appears to suggest that components of smog are working alongside pollen triggers, that they are the “facilitators” of allergy.
Yet, University of Southern California scientists at the Keck School of Medicine caution that it’s too soon to say exactly what happens in polluted air to cause children to develop asthma. With at least 13 million cars and trucks on the road every day, and a reputation as a smog capital, Los Angeles has become a natural environment of study. The USC scientists are now drawing findings from a second large population study on the effects of exhaust pollution on children’s lungs.
So far, they’ve shown that the closer a young child lives to a major roadway, and the more sports an older child plays outside in smog, the more likely the onset of asthma. They’ve even been able to make this radical contention: “We have evidence that pollution may actually cause the asthma, not just make it worse,” says Ed Avol, a professor at USC and co-author on this research.
Whether the development of the disease is “an immune response or whether that’s something else that’s going wrong or whether it’s a genetic component – it’s hard to know,” Avol says. His team has recently identified some gene dispositions in children that make them more susceptible to asthma in a polluted environment. As well, smog includes several types of gases and particulates, so sifting through the answers in this area is not a quick process.
Von Mutius doesn’t pretend to be an expert on the inner city; the farm is her lab. But on the pollution question, she advises bearing in mind again what’s meant by the term ‘environment’. “Is the allergen seen [by the immune system] along with chemicals or along with microbes?” she asks. That might either promote or protect against allergy. “My idea is that the context of the allergen exposure matters,” she says.
The context of the exposure. That is something which will change from farm to city and its toxic substances, from one part of the world to another. “I don’t think there’s going to be one factor [to explain allergy] that you can generalize about all the way around the world,” von Mutius says.
“It’s a context of different mixtures, and it’s also in the related background of genetics that will then develop into asthma and allergies.” When it comes to the causes of allergies, she is “pretty sure it’s going to be many things.”
Sears would agree. He notes that the immune system of a child born in rural Africa would probably be different to the immune system of a child born in downtown Manhattan, and explains that “you see enormously high IgE levels without asthma, where the IgE is directed against the parasites in certain parts of the world. So if you don’t have parasites to deal with, then the theory is that the IgE deals with other things – like cats or dust mites.”
Interestingly, in the developing world, a transition in immune system responses can be studied in real time since there has been considerable migration from agrarian life to the big city. Von Mutius points to a recent medical paper about Mongolia. The people in the study “had been living in tents and among camels and there was very little allergy. The more they move toward the larger city, the more the risk of becoming allergic. So there is something in this more affluent lifestyle, this more Westernized lifestyle.” She thinks that previous protection was farm related.
There is no neat bow to put on the complex question of why there are so many allergies today. We have been changing our world, our environments, our contexts and we apply those to our particular sets of genes. Now our immune systems are speaking up – or acting out. The scientists filling in the pieces of the puzzle do hope for answers for the longer term, which won’t just be academic, but will allow them to offer prevention strategies.
Von Mutius is optimistic that if she can identify those protective qualities on the European farms, maybe a vaccine could be produced. The CHILD study is still a work in progress, but Sears and Turvey are also thinking ahead to results.
“We hope there will be recommendations that count in terms of what mothers can do or how houses should be built or how you avoid or encourage exposures such as to animals,” says Sears. By seeing the fundamental differences between kids in Westernized cities who do and do not develop allergies and asthma, this sets the scene for future intervention.
“What ultimately we all care about,” says Turvey, “is being able to prevent or modify these diseases for future generations.” That’s worth all the sampling and analyzing, the late hours in the labs and the intrusions on study participants’ lives. Meantime, Sears gives advice that’s only partly tongue-in-cheek: “On the way home from the maternity hospital,” he suggests, “buy a dog.”
Updated in August 2010 from the Fall 2008 issue of Allergic Living magazine.
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