Are we too clean? The hygiene hypothesis and asthma

Cleanliness is next to wheeziness?
An article in The New Yorker last week says that physicians have it all wrong when it comes to childhood allergies (also called atopy).  The recommendation of the American Pediatric Association since 2000 has been that, to prevent food allergies, infants should be breastfed exclusively for 6 months, with solid foods introduced one by one for the next 6 months, to monitor effects of each food, but avoiding eggs and peanuts, because they are the foods to which kids are most likely to develop allergies.

But peanut, egg and dairy allergies are now skyrocketing!  So, some people are starting to think that prevention by avoidance may actually be causing the disease and suggesting that perhaps infants should be exposed to these foods in small quantities much earlier than current recommendations.  And some studies are beginning to show that such exposure might in fact eliminate even an existing allergy.  Perhaps, according to the article, medicine has erred on the side of excessive cleanliness once again. Cleanliness reduces serious infectious disease exposures, perhaps, but one shouldn't overdo it because we've evolved to be commensal with microorganisms, both viruses and bacteria--we've coevolved with them, are absolutely covered inside and out with them, and in many ways our lives literally depend on them.

By the way, it's worth pointing out that while there is undoubtedly some genetic variation, overall genes have little if anything to do with the spike in allergy incidence--genomes haven't changed in the last 50 years! 

An inverse relationship between allergy and helminth infection has been recognized since the 1960s, despite the fact that both induce a similar immunological response, but the reasoning that allergy may be a side effect of excessive cleanliness starts with a hypothesis first proposed in 1989 in a paper published in the British Medical Journal in 1989.  This paper was the first to propose that the 'post industrial revolution epidemic' of hay fever and eczema in Britain could be due to what has come to be called the 'hygiene hypothesis'.  The author looked at a handful of factors that could be associated with risk of hay fever, in a study sample of 18,000 children. "Of the 16 perinatal, social, and environmental factors studied the most striking associations with hay fever were those for family size and position in the household in childhood."

The author concludes,

These observations do not support suggestions that viral infections, particularly of the respiratory tract, are important precipitants of the expression of atopy. They could, however, be explained if allergic diseases were prevented by infection in early childhood, transmitted by unhygienic contact with older siblings, or acquired prenatally from a mother infected by contact with her older children. Later infection or reinfection by younger siblings might confer additional protection against hay fever.  

Over the past century declining family size, improvements in household amenities, and higher standards of personal cleanliness have reduced the opportunity for cross infection in young families. This may have resulted in more widespread clinical expression of atopic disease, emerging earlier in wealthier people, as seems to have occurred for hay fever. 

The idea was soon fleshed out to suggest that reduced exposure to pathogens, such as hepatitis A, Toxoplasma gondii or helicobacter pylori, changes the balance between two types of immune response, type 1 (T_H1, triggered by bacterial and viral infections and autoimmune diseases), and type 2 (T_H2, associated with helminth infections and allergic diseases).  An extension of the hygiene hypothesis to include autoimmune diseases was proposed in 2002 (cited here), and has subsequently been demonstrated in animals.  E.g., in lab mice, the incidence of type 1 diabetes rises with cage cleanliness.  (Type 1 diabetes is another disease whose incidence has risen in the industrialized world, along with asthma.)


 A much-cited paper in Science in 2002 is worth quoting at length.

There has been a significant increase in the prevalence of allergic diseases over the past 2 to 3 decades. Currently, more than 130 million people suffer from asthma, and the numbers are increasing ; nevertheless, there is a considerably lower prevalence of allergic diseases in developing countries. There are also clear differences in the prevalence of allergies between rural and urban areas within one country. For example, in Ethiopia, asthma is more prevalent in urban areas than in rural villages, and asthma is more common in residents of urban Germany than in farmers living in rural Bavaria. To explain these observations, environmental factors associated with more industrialized and urban living have been studied intensively, but there is little consistent evidence to suggest that obvious risk factors, such as increased exposure to indoor allergens, pollution, or changes in diet and breastfeeding, could account for the rise in atopic diseases. However, another category of environmental factors, childhood infections, shows an overwhelming and consistent negative association with atopy and allergic diseases. Allergic sensitization is overrepresented among first-born but is less frequent in children from large families and those attending day care, suggesting that a frequent exchange of infections may have a protective effect. 

Divergent outcome of T_H2 responses in industrialized (low pathogen exposure) and developing countries (high pathogen exposure). It has been argued that improved hygiene, frequent use of antibiotics, and vaccination has led to reduced bacterial and viral infections in industrialized countries and therefore to insufficient stimulation of T_H1 responses, which in turn allows the expansion of T_H2 cells. T_H2 responses are characterized by increased IgE to allergens, mastocytosis, and eosinophilia. Mast cell degranulation and release of inflammatory mediators leads to mucus production and smooth muscle cell contraction, precipitating allergic diseases of the airways. Helminths are prevalent in developing countries and lead to strong T_H2 responses. Nevertheless, helminth-infected populations show little signs of allergic disorders. This difference may be explained by the differences in exposure to pathogens. A high prevalence of chronic infections in developing countries results in persistent immune challenge, with cycles of infection and inflammation, which is followed by the triggering of anti-inflammatory molecules to restrict immunopathology. This dynamic interaction educates the immune system to establish a robust regulatory network, possibly the key to controlling allergic diseases. Such a network would be weakly developed in industrialized countries with a low pathogen load, allowing inappropriate immunopathological reactions to develop more readily.

As the worm turns!
The helminth connection led to some interesting work in the fine tradition of self-experimentation, with researchers infecting themselves with helminths and monitoring what happened to their own allergies or asthma, with some positive effect.  Some people now propose worm therapy, in fact, but the pathogen load has to be a heavy one.

But, as usual, the story is not so simple.  An article in last week's Scientific American discusses a paper in Pediatric Allergy and Immunology reporting that Ugandan kids of mothers treated for helminth infection when they were pregnant were more likely to have eczema than kids whose mothers weren't treated.  The paper is subscription only, so we don't have access to the full text, but it looks like the story is more complicated than Scientific American would have it.  Mothers were treated with 1 of 2 different anti-helminthic drugs (albendazole or praziquantel) or placebo, and, from what we can tell from the abstract, the effects seem to differ depending on which drug the mother received and which pathogens she was carrying.

Results:  Worms were detected in 68% of women before treatment. Doctor-diagnosed infantile eczema incidence was 10.4/100 infant years. Maternal albendazole treatment was associated with a significantly increased risk of eczema [Cox HR (95% CI), p: 1.82 (1.26–2.64), 0.002]; this effect was slightly stronger among infants whose mothers had no albendazole-susceptible worms than among infants whose mothers had such worms, although this difference was not statistically significant. Praziquantel showed no effect overall but was associated with increased risk among infants of mothers with Schistosoma mansoni [2.65 (1.16–6.08), interaction p = 0.02]. In a sample of infants, skin prick test reactivity and allergen-specific IgE were both associated with doctor-diagnosed eczema, indicating atopic aetiology. Albendazole was also strongly associated with reported recurrent wheeze [1.58 (1.13–2.22), 0.008]; praziquantel showed no effect.

It's impossible to know from the abstract whether the authors considered the alternative explanation, that any atopy and asthma was the result the drug of eliminating the infection, or in fact of the drug--as Holly pointed out here.

And, the same Science paper we've quoted at length suggests that T_H1/ T_H2 balance may not in fact be the explanation for the inverse correlation between helminth infection and allergy, but instead the protective effect of infection may have to do with the anti-inflammatory response it triggers.  Other severe infections such as measles or tuberculosis are also inversely correlated with allergy.  The authors propose an alternative protective pathway to explain the hygiene hypothesis:

Education of the immune system by pathogens. Dendritic cells can develop into distinct subpopulations, depending on the nature of the signals they receive from the microenvironment, and then direct T cell differentiation into polarized subsets. Viruses, bacteria, and helminths carry distinct signature molecules that interact with dendritic cells to stimulate T_H1-type and T_H2-type immune responses. When uncontrolled, strong T_H1 and T_H2 responses lead to autoimmunity and allergy. High pathogen burden may either change the physiology of the microenvironment or result in the accumulation of novel signature molecules that together endow dendritic cells with the ability to induce regulatory T cells. Regulatory T cells produce suppressory cytokines and are part of an anti-inflammatory network that ensures that inflammatory T cells (both T_H1 and T_H2) and their downstream effectors are kept under control.

So, does the 'hygiene hypothesis' explain the significant rise in asthma, allergies and autoimmune diseases in the industrialized world?  The evidence is building, but the relationship is still more of a correlation, based on epidemiological associations, than demonstrated causation and there are still many unanswered questions.  If nothing else, you can be sure that the complexity of the immune response, and how much is still not understood, are limiting factors when it comes to answering those questions.

But it is possible that one day the apparent protective mechanism will be demonstrated and understood, and therapeutic approaches will be designed based on this mechanism so you won't have to infect yourself with helminths to treat your asthma.

And, we'd like to point out that the mechanisms will involve genetic pathways, undoubtedly, and the approaches will involve molecular technology.  But the therapies won't depend on personalized medicine, nor on the sequencing of the human genome -- whose 10th anniversary is being so heavily feted this month in Science.