Asthma rates have been surging around the globe over the past three decades, and for a long time researchers thought they had a good idea of what might be fueling the increase: the world we live in is just a little too clean. According to this notion—known as the hygiene hypothesis—exposure in early childhood to infectious agents programs the immune system to mount differing highly effective defenses against disease-causing viruses, bacteria and parasites. Better sanitary conditions deprive the immune system of this training, so that for reasons that are still unclear, the body pounces on harmless particles—such as dust and ragweed—as if they were deadly threats. The resulting allergic reaction leads to the classic signs of asthma: chronic inflammation or swelling of the airways and acute spasms of those passageways.

Or so the thinking went. Although a lot of data support the hygiene hypothesis for allergies, the same cannot be said for asthma. Contrary to expectations, asthma rates have skyrocketed in urban areas in the U.S. that are not particularly clean. Moreover, the big increase in asthma rates in developed countries did not kick off until the 1980s—well after general sanitary conditions in the richer parts of the world had improved. And some studies are beginning to show that far from protecting children from asthma, respiratory infections in early childhood may actually be a risk factor for it.

The collapse of the hygiene hypothesis as a general explanation for the startling jump in asthma rates has led physicians and scientists to a new realization: asthma is a much more complex condition than anyone had truly appreciated. Indeed, it may not be even be a single disease. Studies now suggest that only half of asthma cases have an allergic component.

The prevention and treatment implications are significant. If, for instance, it is true that allergy is not a fundamental cause of asthma in many people, then an alternative mix of treatments may be more effective for those individuals. To root out asthma’s cause (or causes) and properly treat the burgeoning number of people who are affected—300 million globally at last count—scientists will have to come to grips with the biology of its various forms.

Balancing Act
The hygiene hypothesis was first described in 1989 by David P. Strachan, a British epidemiologist who was studying hay fever. The more children in a family, he noticed, the lower the rates of hay fever and eczema, an allergic skin condition. Children in large families tend to swap colds and other infections more often than children with fewer siblings. Could it be that increased exposure to pathogens from their many siblings was protecting children from large families against allergies?

That same year Erika von Mutius, an epidemiologist at Munich University, was looking into the effect of air pollution on asthma in what was then East and West Germany. Children from dirtier East Germany, she was shocked to find, had dramatically less asthma than their West German counterparts living in cleaner, more modern circumstances. The East German children, unlike their Western counterparts, had spent more time in day care and thus had likely been exposed to many more viruses and bacteria. “That was astonishing,” she recalls, and led to “a major shift” in thinking.

These findings sparked intense debate among scientists. What is it about unhygienic living that might protect against asthma? One of the more popular explanations in the following decades entailed a balance between the immune cells that are involved in the body’s reaction to most viruses and bacteria and those that are involved in the reaction to most parasites and allergens. These two groups of cells produce chemicals that inhibit each other. Early-childhood exposure to bacteria and viruses would cause the infection-related cells to become active, keeping the allergy- and parasite-related cells in check. Without that interplay, the allergy-related cells would later become over­reactive, starting an allergic chain reaction that became chronic and ended in constricted airways, asthmatic spasms and labored breathing.

Inconvenient Facts
There was only one problem. As more data came in, they failed to tell the same story as the hygiene hypothesis. Children in Latin America with high rates of supposedly protective infection have even higher rates of asthma than children in western Europe. Inner-city children in Chicago and New York have quite high rates of asthma, despite unhygienic living. And the rates of asthma varied among countries with very similar histories of cleanliness—indicating that there was more to it than tidiness. For example, by 2004 Sweden’s asthma cases had increased to 10 percent, according to one international study, while the number of cases in the U.K. had soared to 20 percent.

In addition, research showed that the relation between asthma and allergy is not at all straightforward. Some cases of asthma are indeed triggered by allergies, although the consensus among researchers over the past decade is that the connection is probably not as clear-cut as the hygiene hypothesis would suggest. Still other layers of immune regulation must be involved. Maria Yazdanbakhsh, a parasitologist at Leiden University in the Netherlands, has shown that people infected with parasitic worms have very high levels of the allergy-related immune cells but very low rates of asthma, disproving a direct connection between allergy and asthma in these cases at least.

What is more, a landmark review of asthma studies in 1999 by Neil Pearce, now at the London School of Hygiene and Tropical Medicine, demonstrated that at least half of asthma cases in the general population have no connection to allergic reactions at all. These could never be explained by the hygiene hypothesis.

In fact, the same factors that the hygiene hypothesis suggests protect people from developing allergic asthma may cause them to develop nonallergic asthma. “We think that dirt protects against allergic asthma, as foretold by the hygiene hypothesis, but increases the risk of having a nonallergic form,” says Laura Rodrigues of the London School of Hygiene and Tropical Medicine, who studies asthma in Latin America. Pollutants in the air can irritate the airways and cause inflammation that leads to constricted breathing. Childhood colds, which the hygiene hypothesis suggested might help prevent development of asthma, can actually be a risk factor for asthma, especially if severe, says James E. Gern, a pediatrician who studies colds and asthma at the University of Wisconsin–Madison. “Early-life infections are an indicator of asthma risk rather than protective in any way,” he says.

Besides the hygiene hypothesis, what can explain the increase in asthma rates? Other suggested causes include a rise in sedentary lifestyle, which could affect lung strength, and the rise in obesity, which increases inflammation throughout the body. A reworking of the hygiene hypothesis that focuses on changes in the normal nondisease-causing bacteria that live inside and on the body (in the intestines or the airways or on the skin) has promise. Studies by von Mutius and others have shown that children who live on farms where cows or pigs are raised and where they drink raw milk almost never have asthma, allergic or otherwise. Presumably because the children drank unpasteurized milk and handled livestock, they have different strains of normal bacteria in their airways that are somehow more protective than those found in city kids.

But the short answer to the question of why asthma has increased, according to Pearce, von Mutius, Rodrigues and many others, is, “We don’t know.” Pearce, in particular, wonders whether modernization in general or westernization in particular may play a role. “There is something about westernization that means people’s immune systems function in a different way,” he says. “But we don’t know what the mechanism is.”

Getting at the true underlying cause of the climb will require better ways of distinguishing among various possible types of asthma. Major asthma research networks supported by the National Institutes of Health have begun recording the details of thousands of individuals’ symptoms and treatments. As the results are gathered and analyzed, researchers hope to identify clusters of asthma cases that have different causes and respond to different treatments. The hope is that “if you come in with these characteristics in asthma, we can anticipate what the prognosis is going to be and what the most effective treatment for you is going to be,” says William W. Busse of the University of Wisconsin School of Medicine and Public Health, who is part of one such network.
It will take years to understand fully whether microbial exposure, lifestyle changes or the obesity epidemic is more important in explaining the continuing increase in asthma rates. But one thing is clear: the hygiene hypothesis was just the beginning.