ROME—Two new studies further bolster the hygiene hypothesis, which says that reduced microbial exposure because of increased sanitation and cleaner lifestyles has facilitated the rise in asthma and allergic disease in the Western world. One of the studies, conducted by Paolo M. Matricardi, MD, and colleagues, is the first to lend credence to the hygiene hypothesis in a US general population sample.

The study linked seropositivity for hepatitis A virus, Toxoplasma gondii, and herpes simplex virus type 1 to a decreased risk of hay fever, asthma, and atopic sensitization.[1] “Until now, these relationships were only observed in European populations,” said Dr. Matricardi, one of the study’s coauthors and a research consultant for the National Research Council in Rome when the study was published. He pointed out, however, that seropositivity for hepatitis A, T gondii, or herpes simplex-1 is merely a marker of microbial exposure, not proof that these specific infections are responsible for the reduced allergic disease risk that he and his colleagues observed. Dr. Matricardi is now a technical officer at the Chronic Respiratory Diseases and Arthritis Unit at the World Health Organization Headquarters in Geneva.

In the second study, another such marker—the level of endotoxin found in dust samples from bedding—was inversely related to the occurrence of hay fever, atopic asthma, and atopic sensitization among children in rural areas of Germany, Austria, and Switzerland.[2] “We saw the same association whether or not a child came from a farming family,” related lead investigator Charlotte Braun-Fahrländer, MD.

Thus, it appears that endotoxin exposure may protect against childhood atopic disease even when levels are not as high as those found on farms, said Dr. Braun-Fahrländer, Professor at the University of Basel’s Institute of Social and Preventive Medicine in Switzerland.

A PUBLIC REGISTRY

“Anybody can verify the findings of our study,” stated Dr. Matricardi, “because the data we used came from a public registry.” That registry is a result of the Third National Health and Nutrition Examination Survey (NHANES III) conducted from 1988 through 1994 by the Centers for Disease Control and Prevention. The survey included 33,994 US residents ages 1 year to older than 90.

After adjustment for sociodemographic variables, simultaneous seropositivity for hepatitis A, T gondii, and herpes simplex-1 was associated with odds ratios (ORs) of 0.27 (95% confidence interval [CI], 0.18 to 0.41) for hay fever and 0.45 (95% CI, 0.31 to 0.66) for asthma. Among hepatitis A–seronegative individuals, the likelihood of being diagnosed with hay fever or asthma by age 18 increased progressively over time (from 2.7% in people born before 1920 up to 8.5% in those born in the 1960s); however, this likelihood remained constant in all cohorts of individuals who were hepatitis A–seropositive at examination.

Also, hepatitis A–seropositive individuals younger than 40 at the time of the NHANES III had a lower risk of allergy to peanuts and to eight of the nine airborne allergens studied than did those who were hepatitis A seronegative. However, the hepatitis A–seropositive group did not have a lower prevalence of skin test sensitivity to cockroach at any age.

ENDOTOXIN AND ALLERGIC DISEASE

In Dr. Braun-Fahrländer’s study, complete data on hay fever and asthma were available for 812 children ages 6 to 13. Dust samples from the mattresses of those living in farming households contained an average of 37.8 U/mg of endotoxin versus 22.8 U/mg for samples from the mattresses of children from nonfarming households. Endotoxin exposure was also much greater among children living on farms when the exposure was expressed as units per square millimeter of mattress surface area.

However, it was the level of endotoxin, and not residence on a farm per se, that appeared to be protective. When the analysis was confined to the 493 children who did not live on farms, a negative correlation between endotoxin exposure and atopic conditions was still seen.

Endotoxin exposure appeared to protect against atopic immune responses only. Although endotoxin did not appear to decrease the prevalence of nonatopic asthma or nonatopic wheeze, it was associated with a significant decrease in all of the atopic conditions studied (hay fever, sneezing and itchy eyes during the previous year, atopic wheeze, atopic asthma, and atopic sensitization). Children from farming and nonfarming households often had similar ORs for these conditions, although there was a tendency toward larger risk reductions in the former group.

An inverse relationship was observed between the level of endotoxin in the mattresses used by the children and the ability of the children’s peripheral blood leukocytes to produce cytokines after innate immune system activation, indicating a marked down-regulation of immune responses in the endotoxin-exposed children. “The mechanism behind this protective effect is unclear, but we must better understand it before we can develop a preventive medication,” Dr. Braun-Fahrländer said.

HOW TO LOWER THE RISK?

“Eating dirt or moving to a farm are at best theoretical rather than practical clinical recommendations for the prevention of asthma,” remarked Scott T. Weiss, MD, in an editorial that accompanied Dr. Braun-Fahrländer’s study.[3] “However, a number of environmental factors are known to be associated with a lower incidence of allergic disease early in life,” added Dr. Weiss, Professor of Medicine at Harvard Medical School in Boston.

Those factors include oral supplementation with Lactobacillus ruminus, the presence of a dog or other pet in the home since before birth, and attending day care during the first year of life. “The challenge will be … to determine the extent of exposure that will ensure safety and have the desired outcome—the development of a healthy child with a very low risk of autoimmune disease,” Dr. Weiss said.

Clean food and water and the treatment of infection are the most common reasons for the reduced microbial exposure associated with allergic disease in the modern world, Jean-François Bach, MD, suggested in an interview. “However, such advances are essential because they keep us from losing children the way less developed countries do,” stressed Dr. Bach, Professor of Immunology at the Necker Research Institute in Paris and author of a new paper on the role of infection in autoimmune and allergic disease.[4]

Rather than eliminate progress, it will be necessary to develop a treatment that substitutes for the infections that formerly protected against autoimmune and allergic disease. People should also not worry too much about cleanliness and maintaining bacteria-free environments, Dr. Bach said. “That is not to say that dirt is good, but too much cleanliness is not really necessary,” he concluded.

—Timothy Begany