DENVER—Recent research has drastically altered our understanding of the effects of animal contact on a child’s chances of developing atopy and asthma. Many of these new findings appear quite paradoxical, though. “If you’ve read the literature carefully, and you’re profoundly confused, you’ve read the literature correctly,” admitted Thomas A. E. Platts-Mills, MD, PhD, at the annual meeting of the American Academy of Allergy, Asthma and Immunology. In a symposium at that meeting, Dr. Platts-Mills and other leaders in the field attempted to reconcile some of the seemingly contradictory aspects of this puzzling body of literature.[1]

PETS REDUCE SENSITIZATION

For most allergens, the accepted rule has been that greater exposure yields greater sensitization. However, “recent data on dogs and cats suggests that increasing exposure may not correlate with increasing allergic sensitization,” emphasized Donald Milton, MD, DPH, a Lecturer on Occupational and Environmental Health at the Harvard School of Public Health. Rather, he said, “early exposure to pets and farm animals is protective against becoming sensitized to animals and maybe to other allergens.”

Evidence may be strongest for cat ownership; many studies show that it reduces the risk of sensitization. Although each of these studies has limitations, “overall, there’s no doubt that having a cat in the house is associated with decreased sensitization,” said Dr. Platts-Mills, Head of Allergy and Clinical Immunology at the University of Virginia Medical Center in Charlottesville.

All children may not benefit equally, however. Bo Lundbäck, MD, a docent in the National Institute of Environmental Medicine at the Karolinska Institute in Stockholm, explained that the protective effect of living in a home with a cat was markedly higher in children with a family history of asthma or allergy than in children without such a family history. A weaker but similar protective effect is seen in children who lived in homes with dogs. This finding may present a dilemma for many families: Should they keep a pet or not? “I think you have to remind the parents … that [the pet] is going to affect them, too, if they already have asthma or if they are at risk for developing asthma,” cautioned Dr. Milton. “It may increase their risk while reducing their child’s risk.”

HOW DOES IT WORK?

The mechanisms behind such effects remain far from clear. Some researchers argue that nonspecific stimulation of children’s immune systems by endotoxin and other bacterial products associated with household pets mediates the protective influence of early cat and dog exposure; such an effect would be expected to be nonspecific, suppressing sensitization to a variety of antigens. On the other hand, exposure to particular pet antigens could yield specific tolerance. “If the effect of a cat suppressing responses to cat specifically can occur at later times and is a reversible phenomenon, it’s more likely to be a biological effect related to cat,” said Dr. Platts-Mills. “My real prejudice at the moment is that both effects occur.”

THE CASE FOR ENDOTOXIN

Andrew H. Liu, MD, outlined the evidence for nonspecific stimulation through exposure to endotoxin and other pathogen-associated molecular patterns (PAMPs). How might endotoxin affect allergic asthma? On one hand, “a little bit of endotoxin is necessary for airway exposure to allergens to mediate a TH2 memory response that leads to allergen sensitization and eosinophilic inflammation,” explained Dr. Liu, Associate Professor of Pediatrics at National Jewish Medical and Research Center in Denver. “Higher levels drive TH1 memory, a regulatory response, and tolerance.” Because it is found in higher quantities in homes with animals, he noted, endotoxin is considered a strong candidate for linking animals with atopy and asthma.

Sampling dust from suburban and rural homes in the United States, Dr. Liu and colleagues found that endotoxin levels in farm homes were significantly higher than in urban Denver homes; barn levels were higher still. The presence of cats or dogs was also strongly associated with high endotoxin levels. Another study of children from European farming and nonfarming households identified inverse relationships between household endotoxin levels and incidences of hay fever, atopic asthma, and atopic sensitization, as well as leukocyte cytokine production. Thus, benefits of animal exposure frequently correlate with endotoxin levels.

But in other studies, noted Dr. Liu, differences in endotoxin levels seemed inadequate to explain the large disparities in atopy seen with differing degrees of animal exposure. He hypothesized, “Endotoxin might be serving as a marker for a collection of molecules that are endotoxin-like—the PAMPs,” which include heat-shock proteins and bacterial DNA. Like endotoxin, bacterial DNA is present in higher levels in farm homes than in urban Denver homes, and in even higher quantities in barns. Dr. Liu and colleagues found that this DNA could boost endotoxin-induced cytokine production by monocytes in vitro.

CAT AND MITE ALLERGY

Pet exposure does not protect equally against sensitization to all allergens; protection can be antigen-specific. Thus, the benefits of pet ownership may depend on the presence or absence of other environmental allergens. For instance, in northern Sweden, said Dr. Lundbäck, “there are no mites or cockroaches, because it’s a cold climate, and it’s very dry there. Cats and dogs are the main sensitizers … associated with asthma.” Here, cat ownership is protective against asthma.

In New Zealand, however, very high levels of house dust mite are found in homes, creating a different scenario. Cat ownership did reduce the risk for cat allergy in New Zealand children, but it also increased the risk of dust mite sensitization.

Further complicating our understanding of the effects of pet exposure, said Dr. Platts-Mills, is that the biological response to cat is different than the response to dust mite. He postulated two classes of allergens. Class 1 includes mite and cockroach allergens, which comprise large (5- to 40-mm) fecal particles airborne only during disturbances. These allergens actually have potent enzymatic activity, and, he pointed out, “even in New Zealand, we don’t see any evidence for tolerance.” Cat and dog allergens are class 2 allergens, consisting of smaller (2- to 15-mm) dander particles that remain airborne and are readily inhaled. These are typically present at much higher levels than class 1 allergens and lack enzymatic activity.

QUANTITY OF EXPOSURE

Looking at data from northern Sweden, remarked Dr. Lundbäck, “It’s striking that 83% of the people sensitized to cat had never lived in a house with a cat.” He offered a possible explanation: “We know that cat and dog allergens are passively transferred, while moderate and even high concentrations are common in public buildings.” Based on dust sample surveys in classrooms, said Dr. Lundbäck, “we can conclude that children in schools are all exposed to cat and dog allergens at levels which are sufficient to cause sensitization.”

Levels in homes with cats are much higher. He suggested, “Due to the great natural exposure to cat and dog allergens, the immune system may respond as it does to immunotherapy.” Dr. Platts-Mills concurred, “Exposure to cat allergen in a house with a cat is fully comparable to levels you would use in nasal desensitization.” Cat allergen exposure may be 0.3 to 0.5 µg per day; in contrast, annual exposures to pollens may be 0.5 to 1 µg per year, and dust mite exposures may be similar. “Furthermore, the levels found in houses without a cat in a community with plenty of cats are much higher than anything that has been recorded for dust mite,” said Dr. Platts-Mills. “So, it is perfectly possible that children exposed indirectly to cat allergen have enough to induce suppressor cells [and] regulator cells,” thereby controlling sensitization.

—Mimi Zucker, PhD