By Ronald Kotulak
Why don't children who live on farms develop many allergies while those who live in cities have a 40 to 50 percent risk of becoming allergic to something?
Why do children who start day care before 6 months of age have little risk of developing asthma an allergy while the disease is epidemic among rich, middle-class and poor children who enter child care later?
Why can children growing up in Jamaica eat all the peanuts they want while Jamaican children growing up in London develop peanut allergies?
Why are more and more adults, who never had allergies or asthma as children, suddenly becoming allergic or asthmatic, like the 12 pediatricians who recently developed asthma after going to work in the Bronx, a high asthma-risk area?
Hot on the trail of a worldwide allergy "epidemic," scientists asking these questions are homing in on a theory for why allergies have doubled in the last 10 to 15 years, threatening now to become the biggest health problem in the U.S. and other industrialized countries.
The theory not only holds promise for finding the cause but already has scientists testing vaccines against allergies, with limited success.
The answer to all of the above questions, scientists believe, may simply be that we've become too clean. We don't grow up in dirt and dung anymore and our bodies are failing to develop a balanced immune system early on.
This theory of what causes allergies and asthma is called the "hygiene hypothesis." It says that our war against germs from detergents and chlorine to antibiotics and vaccines to antibacterial soaps and, now, antiseptic diapers has been too successful.
We get fewer infections from the bad germs that used to kill a lot of children, but we don't encounter as many "good" bugs that are supposed to teach our immune system how to grow up.
It used to be said that a child ate a bushel of dirt by the age of 5, a thought that makes most parents today cringe.
Our affluent modern lifestyle, which commits us to spend 93 percent of our time indoors, usually in tightly sealed buildings, is failing to educate our immune system. Instead of ignoring the multitude of harmless things we breathe in or touch, it overreacts to them.
At the turn of the century, hay fever was a rare disorder restricted to the privileged class, whose children were already living a cleaner lifestyle.
Today all socioeconomic groups are affected and allergic respiratory diseases are doubling every 10 years.
Forty years ago asthma was still rare, but today it is the most common reason why preschoolers and children are admitted to Children's Memorial Hospital, said Dr. Richard Evans, a child asthma expert.
"At first we thought it was the diagnosis we were using that was accounting for the increase," he said. "But, no, it wasn't. It's true asthma and it's increasing at a pretty astounding rate."
Hypersensitive in Denmark
One of the most thorough studies to document the rapid increase in the allergy epidemic found that in Denmark 33.9 percent of the population has become hypersensitive to something in their environment, an increase of 25 percent in just eight years.
In the U.S. and many European countries it is estimated that 40 to 50 percent of the population have become hypersensitive meaning that a person has become allergic to something but may not yet have developed symptoms. When doctors prick their skin with an allergen, such as ragweed pollen or dust mite particles, a red splotch will appear.
The Denmark study showed that symptoms might develop quickly among hypersensitive people between the ages of 20 and 40. Fifty percent of the people who were sensitized at the beginning of the study but who did not have symptoms developed allergic symptoms within eight years.
"More people are sensitized and they are sensitized to more than one allergen," said Dr. Allan Linneberg of Glostrup University Hospital, Glostrup, Denmark. "Not only has the prevalence increased but the severity of the disease has increased. So we could experience in years to come more people with severe allergies.
"From a public health point of view, this is pretty alarming."
At the same time that the allergy epidemic is growing worse, diagnosis and treatment are declining, warned Dr. Roy Patterson, chief of Northwestern University Medical School's Allergy Division.
"There is less early treatment of asthma because there is less education about allergies in medical schools, there is less treatment, especially with effective drugs such as corticosteriods, and there are fewer allergists available for diagnosis," he said.
Unwittingly, we seem to have taken away the environmental triggers that turn on a vital arm of the immune system, thereby allowing the allergic response to go haywire, according to the new theory.
The body has two major immune responses.
One, called the Th1 response, gets rid of germs and other foreign invaders by building individual antibodies against each one. Then the invaders are attacked, engulfed and destroyed. It's the John Wayne way of doing things, killing only the bad guys.
The other, the Th2 response, is more like a Mafia vendetta. It says: "I will remember who you are and what you did, and I will go after you, your children and your children's children."
Th2 does this by establishing an early warning system for parasites and other invaders, even harmless ones that it has seen before. When one is spotted, immune cells are commanded to fire histamine and other chemical weapons. But these weapons also hit normal cells, causing them to leak, swell and sometimes die, producing the symptoms of allergic rhinitis also know as hay fever, it is the most common chronic condition of childhood dermatitis and asthma.
During fetal development the Th1 response is turned off. The reason is that this powerful response is also responsible for the rejection of transplanted organs. If it were activated, the fetus' immune system would reject the mother's body, resulting in a spontaneous abortion.
In a sense, then, most of us are born with a tendency toward allergies.
Scientists now believe that what turns the Th1 response on is exposure to certain types of germs after birth, typically harmless bacteria found in dirt and animal droppings. This has not been a problem during the millions of years of human evolution because babies were born into a sea of germs.
But today, most babies are born into sterile environments. Their bodies do not see many germs, except for airborne viruses like those that cause colds, and their Th1 system does not get activated as quickly as it should. A working Th1 system is important for another reason it subdues the hyperactive allergic Th2 response.
"We're programmed to adapt to what we need in the outside environment," said Dr. Fernando D. Martinez, director of the University of Arizona's Respiratory Sciences Center. "If we live in an environment that is full of bugs, and that's how we have lived from the very beginning of life, it is clear that the first signal we need is precisely those bugs, because inside the womb we're completely germ free."
With Th1 quiescent, the Th2 system, which has been operating during fetal life, stays dominant. Then when a baby develops a cold or some other upper respiratory infection, Th1 is not there to fight it, but Th2 is.
As a result, because Th2 is not as proficient at fighting these invaders, it becomes a lot easier for common colds that settle deep in the lungs to cause severe inflammation.
The respiratory syncytial virus (RSV) causes deep lung infections and its symptoms mimic those of asthma wheezing, coughing and shortness of breath. By age 1, 60 percent of all babies are infected with this bug; by age 2, 100 percent.
Because the Th1 system is not on guard to destroy the germs causing the infection, the inflammation rages on. Lung tissue becomes damaged from this prolonged attack, creating the domino effect that leads to allergies and asthma.
Animal studies conducted by Dr. Stephen T. Holgate, professor of medicine at the University of Southampton, England, show that inflammation causes repair genes in lung cells to be turned on. Furiously trying to fix the injury, the repair genes cause the immature lungs to develop abnormally stiffening the architecture, narrowing airway tubes and making cells more fragile.
"The airway tissue in asthma changes," he said. "It thickens, there's more smooth muscle, more mucus glands, more blood vessels the whole thing becomes like a chronic wound really. You've got this sort of exuberant response which interacts with the inflammation and creates the chronicity of the disease."
Other things, like smog, may also cause lung injury and induce asthma. Dr. Charles Plopper of the University of California at Davis produces asthma in young monkeys by exposing them to ozone, a potentially harmful ingredient in polluted air, and dust mites.
"The pattern of exposure we gave the monkeys would suggest someone who grew up and spent the first 6 months in Los Angeles," he said. In the most polluted areas of L.A., 30 percent of children have asthma.
During the inflammatory process, which usually occurs within the first 6 to 12 months of life, Th2 goes on high alert and makes antibodies to anything it sees in the lungs, from viruses to inhaled particles coming from such things as dust mites, cockroaches, molds, ragweed, cigarette smoke, pollen, fungi and cat dander.
Dust mites are linked to 50 to 80 percent of U.S. asthma cases, while cockroach particles are a major instigator of asthma among urban African-American children.
These allergens are ubiquitous. Dust mites, only 1/100th of an inch in length, can't be seen with the naked eye. The average mattress is home to 100,000 to 10 million mites, munching away on human skin cells, which we shed at the rate of 7 million cells per minute. Mites are also in carpeting and furniture. Ragweed pollen, another common allergen, is produced at the rate of one billion pollen grains per plant.
Rates of allergy generally remain the same in different geographical regions even though the types of allergens change.
The trouble starts when Th2 memorizes these antigens and sets up recognition receptors on immune cells. So when these antigens are again encountered, Th2 fires all of its weapons, producing allergic reactions ranging from a runny nose, itchy eyes, sneezing, itching and sometimes swelling of the lungs' airways to such an extent that breathing becomes labored and may endanger life.
The Th2 system was designed to get rid of parasites, which no longer are common. But unchecked by the Th1 system, Th2 sees enzymes in dust mite particles, pollen, molds and other allergens as parasites and builds allergic responses to get rid of them. It does so by constructing chemical lookouts, called IgE antibodies, which recognize specific allergens, thereby sensitizing a person to that allergen.
IgE antibodies bind to something called "mast cells," part of the Th2 system that exists throughout the body lung tissue, skin, intestine, brain waiting to find allergens. When they do, they tell the mast cell to spew out histamine, leukotrienes, cytokines and other chemicals.
If these chemicals are released from mast cells in the nose, the symptoms of hay fever are stirred up. In the lungs, mast cells cause wheezing, coughing and asthma. Chemicals released in the skin cause hives and eczema, in the intestine food allergy or diarrhea, and in the brain migraines.
With a multimillion-dollar grant from the National Institutes of Health, Dr. Robert Lemanske of the University of Wisconsin is attempting to pin down the hygiene hypothesis.
He is enrolling 300 infants and measuring their Th1 and Th2 balance from cord blood at birth, and then following them for three years to determine which ones become infected with RSV and when, and if they go on to develop asthma.
"In some way the RSV infection is turning on this inflammation in the airway," he said. "Then some other factor, perhaps dust mite or cockroach exposure, continues to fuel the fire over time, keeping the process going and setting the stage for allergies or asthma."
While there is growing evidence suggesting that the hygiene hypothesis is on target, the operation of the immune system is likely to turn out to be more complicated.
Yet the new information is opening the door to the development of anti-allergy vaccines and therapies.
An anti-IgE compound developed by Genentech and Novartis has been tested in more than 2,000 people. The drug is designed to block IgE receptors on mast cells, preventing allergens that trigger asthma from being recognized. Blinded to an allergen, such as dust mites, mast cells do not fire their histamine cannons and an asthma attack is avoided. The drug, given by injection, enabled asthmatic children to stop using their steroid inhalers, and about half of the adult asthmatics were also able to do so.
Holgate and his colleagues are developing a compound that could be a prototype of an anti-allergy vaccine. Called SRL 172, it is made from a harmless germ, a mycobacterium that lives in the soil in South Africa but causes no human infection. The active ingredient appears to be endotoxin, a compound that is found in many bugs and is thought to be a major chemical that stimulates the maturation of the Th1 immune response.
Given to asthmatics who were then challenged with an allergen, SRL 172 reduced their risk of an asthma attack by 30 percent.
First big boost
The first big boost to the hygiene hypothesis came several years after the reunification of East and West Germany in 1990. Everyone thought that East German children would have asthma rates off the charts because of heavy air pollution in the former Communist country.
Researchers were surprised to find that East German children had far lower rates of asthma and allergies than West German youngsters did. The only viable explanation they could come up with is that infants in East Germany were placed in large day-care centers before 6 months of age. They were exposed to infections from other children, which may have stimulated the development of their Th1 systems, protecting the Th2 system from developing allergies.
West German children, on the other hand, didn't enter child care until much later, and they lived in an environment that was much more germ free. Presumably their Th1 system was underdeveloped, making them more prone to allergies.
But the most surprising thing is that the rate of allergies and asthma among East German children caught up to that of children in the West after their parents adopted westernized lifestyles.
Early exposure to typical farm animal germs also appears to protect children from asthma.
"They measured the level of bacterial products in the beds of these children and found huge levels of animal fecal bacterial products," Holgate said. "They were breathing this stuff all the time, and presumably it was driving a protective response."
Although allergens are all around, they can be reduced and the rate of allergies decreased, as Holgate found in a study of 800 children on the Isle of Wight, off the English coast, who were studied since infancy.
Mites, molds, pollen and other allergens were eliminated as best they could be. In addition, pregnant women were asked to eat nutritiously and not to smoke, both of which can adversely affect the development of fetal lungs and increase the risk of allergy and asthma. One of 13 U.S. childhood asthma cases is blamed on maternal smoking during pregnancy.
By the time the Isle of Wight children reached their 10th birthday, their allergy rate was 50 percent lower than a comparable group of children.
But the complex nature of the immune system raised its head. While allergies were drastically reduced, the asthma rate remained the same, suggesting that asthma can be caused by still unknown mechanisms.
An opposite phenomenon is occurring in Western African countries, which are adopting westernized lifestyles. There the allergy rates are skyrocketing, but asthma remains nearly nonexistent. That compares with London and Australia, where 1 of 4 children has asthma.
The explosion of allergies and asthma is not only one of the biggest mysteries in medicine, but it is one of the most fascinating. It is telling us something very important about the way we got here as a species.
"Essentially we're very adaptable to the environment that surrounds us," said Arizona's Martinez. "Maybe most of the diseases that we're seeing right now that are so strange and appear to be so different than those in the past, are diseases of maladaptation to the environment.
"That may be what allergy and asthma is teaching us: The adaptation process has become unbalanced and we are being overexposed and underexposed to certain things."
26 dec 2000