ROME-- A lack of exposure to microbes may be contributing to the asthma and allergy epidemic in developed nations, a new Italian study suggests.[1] "Indeed, we found that infections transmitted by contaminated food and the orofecal route were inversely related--in a dose-dependent manner--to atopy and respiratory allergies," lead study author Paolo M. Matricardi, MD, recently told RESPIRATORY REVIEWS.

The results might help to explain why asthma and allergy rates have sharply increased in developed nations, where inhabitants typically practice good personal hygiene and have a semisterile diet. Ironically, some studies suggest that such cleanliness may prevent adequate exposure to pathogens that infect the gut and stimulate lymphoid tissue to produce the right (not allergic) immune response against airborne allergens.

BUILDING UPON EARLIER WORK

The notion that some infections, particularly those acquired in early childhood, may prevent atopy is highly controversial. Evidence in support of this concept--known as the hygiene hypothesis--comes also from a previous retrospective study of Italian male military cadets.[2] Matricardi et al found that atopy was inversely related to seropositivity for hepatitis A virus, which is a marker of high exposure to orofecal microbes.

The researchers recently extended that retrospective analysis of Italian male military cadets. This time they examined the link between allergies and exposure not only to hepatitis A virus, but also to eight other microbes, including two (Toxoplasma gondii and Helicobacter pylori) that are mainly food-borne and orofecal organisms. The remaining six microbes are primarily airborne viruses: measles, mumps, rubella, chickenpox, cytomegalovirus, and herpes simplex type 1.

A total of 1,659 cadets (age 17 to 24 years) underwent serologic testing for hepatitis A virus, T gondii, and H pylori; serum assays for total immunoglobulin (Ig) E concentration; skin tests for sensitivity to seven common airborne allergens (Dermatophagoides pteronyssinus, cat, Alternaria alternata, mixed grass, Parietaria judaica, Olea europaea, and Artemisia vulgaris); and assessment for allergic asthma or rhinitis. In addition, a subset of 240 atopic cadets and 240 nonatopic cadets underwent serologic examination for all nine of the microbes being studied.

ATOPY DECLINES WITH EXPOSURE

Among the 480 cadets who were directly compared, the nonatopic group had a higher prevalence of serum markers for orofecal or food-borne microbes than did the atopic group; the difference reached statistical significance for T gondii and hepatitis A virus, but not for H pylori. For all of the six viruses transmitted through the air and by other routes, serum markers had no relationship to atopy. The likelihood of atopy declined linearly--and significantly--with cumulative exposure to T gondii, hepatitis A, and H pylori, the study also found.

When all of the cadets were examined, Matricardi et al observed that those who lacked antibodies to hepatitis A virus, T gondii, and H pylori were 2.7 times more likely to be highly atopic than were those with antibodies to two or three of these microbes (20.1% vs 7.8%, respectively).

Furthermore, the researchers detected asthma in just 0.4% and allergic rhinitis in only 7% of the cadets exposed to at least two of these three microbes (Figure 1). In contrast, the prevalence of asthma and allergic rhinitis was 5% and 16%, respectively, in the group with no exposure to these microbes.

Cumulative exposure to these microbes was also inversely related to sensitization on skin testing to all of the airborne allergens studied, except Parietaria judaica. Interestingly, exposure to hepatitis A virus, T gondii, and H pylori did not appear to affect total IgE concentrations, but only specific IgE antibodies.

A GUT REACTION?

This study provides indirect, but strong evidence that lymphoid tissue in the gut is a vital site of microbial infection leading to the right kind of allergen immunity. "We do not, however, necessarily attribute a direct causal role to H pylori, hepatitis A virus, or T gondii in the observed lower risk of atopy," the researchers noted. More likely, seropositivity to these organisms is a reliable indicator of having grown up in an environment that provided higher exposure to many orofecal or food-borne microbes.

"So, our study supports the hygiene hypothesis," concluded Dr. Matricardi, who is the research director at the Medical Department of the Italian Air Force in Pzatica di Mare AFB Rome. "Future research may identify molecules (mainly from bacteria) that stimulate the immune system in the right way and thus may be used both to prevent and cure atopy and asthma."

In fact, in two clinical studies that are already under way (one in the United States and the other in England), investigators are attempting to combine bacterial components and allergens into a new immunotherapeutic allergy vaccine. Preliminary data from these studies suggest that the vaccine may be very effective for reducing the risk of asthma symptoms due to allergy, Dr. Matricardi told RESPIRATORY REVIEWS.

--Timothy Begany

References
1. Matricardi PM, Rosmini F, Riondino S, et al. Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic rhinitis: epidemiological study. BMJ. 2000;320:412-417.
2. Matricardi PM, Rosmini F, Ferrigno L, et al. Cross-sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus. BMJ. 1997;314:999-1003.