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Allergies, infections and the hygiene hypothesis – The epidemiological evidence
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Immunobiology 212 (2007) 433–439 www.elsevier.de/imbio
Allergies, infections and the hygiene hypothesis – The epidemiological evidence Erika von Mutius University Children’s Hospital, Lindwurmstr. 4, D 80337 Munich, Germany Received 1 March 2007; accepted 1 March 2007
Abstract The ‘hygiene hypothesis’ was first proposed by Strachan in 1989 suggesting that infections and unhygienic contact with older siblings or through other exposures may confer protection from the development of allergic illnesses. This hypothesis has evolved in various ways exploring the role of overt viral and bacterial infections, the significance of environmental exposure to microbial compounds, and their effect on underlying responses of innate and adaptive immunity. So far a truly unifying concept is still lacking, but various pieces of a complex interplay between a host’s immune response, characteristics of the invading microorganism, the level and variety of the environmental exposure, and the interactions between a genetic background and a range of exposures become apparent. All these pieces eventually assemble to the clinical presentation of a complex syndrome namely of asthma and allergic illnesses. Even if today practical implications cannot directly be deduced from these findings, there is great potential for the development of novel preventive and therapeutic strategies in the future based on the concepts of the ‘hygiene hypothesis’. r 2007 Elsevier GmbH. All rights reserved. Keywords: Hygiene hypothesis; Epidemiology; Allergy; Infection
Introduction In 1989, David Strachan was the first to suggest that infections and unhygienic contact may confer protection from the development of allergic illnesses. Dr. Strachan had observed that the prevalence of hay fever was inversely related to the number of siblings of the study subject (Strachan, 1989). The effect was stronger for every older sibling than for every younger sibling. In his landmark paper he proposed that ‘‘infection in early childhood, transmitted by unhygienic contact with older siblings or acquired prenatal from a mother infected by contact with her older children’’ might prevent the development of Tel.: +49 89 5160 2709; fax: +49 89 5160 4452.
E-mail address: [email protected]. 0171-2985/$ - see front matter r 2007 Elsevier GmbH. All rights reserved. doi:10.1016/j.imbio.2007.03.002
allergic illnesses. A large number of population-based studies have since confirmed the inverse association between the number of siblings and the development of allergic outcomes. Widespread attention has since been given to the hygiene hypothesis and a large scientific and lay audience has been confronted with these ideas over the last few years. The original epidemiological observations have subsequently been applied to other disciplines such as immunology and the assessment of microbial exposures in the environment. Over the course of numerous discussions, new angles and aspects of the hygiene hypothesis have thus been proposed. One may identify three distinct claims on the proper nature of the hygiene hypothesis: 1. Potentially, overt and unapparent infections of human subjects with viruses and bacteria may decrease the risk of developing allergic illnesses.
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2. Non-invasive microbial exposures in the environment may decrease the risk of allergies. 3. Both of these exposures, be it infections or noninvasive microbial exposures, may influence a subject’s innate and adaptive immune response. Progress in epidemiological studies over the last decades has clearly shown that the hygiene hypothesis is not one single straightforward idea, but rather a complex interaction of many factors. There are at least four dimensions of the pieces for this jigsaw, which must be assembled. These pieces comprise the various allergic illnesses including the different phenotypes; the timing of the exposure; the various environmental exposures; and a subject’s genetic susceptibility to react to these exposures. Numerous prospective cohort studies have clearly shown that particularly for asthma, different phenotypes exist. In infant years, wheezing may be attributable to inborn impairment in lung function, which becomes clinically manifest as wheezing episodes in the context of viral infections. Maternal smoking during pregnancy is clearly a risk factor for this phenotype, but allergic phenomena such as the presence of atopic eczema, elevated total or specific IgE antibodies, or a family history of allergic diseases are not associated with this so called ‘‘transient infant wheezing’’ which remits around the second to third birthday. Other forms of wheeze, however, continue into school age. Recent evidence again suggests that there are distinct phenotypes. One wheezing phenotype is associated with the detection of specific IgE antibodies to various food and inhalant allergens, whereas the other wheezing phenotype is not related to atopy. The non-atopic wheezing phenotype has a much better prognosis as these children show remission of their symptoms during school age years and retain normal lung function. It is the allergic wheezing phenotype, which goes on to develop a chronic course of the illness with impairment of lung function and the development of airway hyper-responsiveness. Thus clinical signs of wheeze do not sufficiently distinguish underlying phenotypes and mechanisms involved in the development of these various conditions. The second dimension of the complexity of the associations between various exposures potentially related to the hygiene hypothesis and asthma as well as other allergic illnesses relates to the timing of the exposure. A number of studies have clearly shown that the effect of a given exposure depends on the age at which a subject or an individual is exposed. At least in childhood and adolescence the human organism is in a constant stage of development and maturation. It is therefore conceivable that it is in these vulnerable periods that certain exposures have the most profound effect on the maturing immune system and thereby the development of allergic illnesses. A number of studies
have shown that not only the maturing immune system of an infant or toddler is susceptible to environmental exposure, but that also prenatal exposures may play a significant role either through mechanisms acting in utero or as epigenetic modulation of subsequent developmental trajectories. The third dimension, which is becoming increasingly obvious to many researchers, is the genetic background of an exposed individual. The Human Genome Project has opened a new and fascinating field of research, which is still at the very beginning of its explosion. However, it becomes increasingly evident that not one gene accounts for hereditability of allergic illnesses but rather a number of alterations in many genes which interact with environmental influences at various time points of development, are expected to contribute to the mechanisms underlying the various allergic conditions. There is an ongoing debate about the potential underlying immunological mechanisms resulting in a decrease in risk of allergies and asthma by living in a less hygienic environment. Various authors in this special issue of Immunobiology will address some of these issues in the following papers (e.g. Garn and Renz, 2007).
The role of infections for the development of asthma and allergies Viral infections and asthma As discussed above, there are distinct wheezing phenotypes, which pertain to the asthma syndrome. Different risk factors have been related to these various wheezing phenotypes in epidemiological studies. Therefore, it is of importance to attempt to dissect the relation between viral exposures and the various wheezing phenotypes. For transient wheezing in infancy which is not really an asthma phenotype, viral infections of the upper respiratory tract are the most prevalent and potent triggers (Rusconi et al., 1999). Yet, as discussed above these viral infections are unlikely to be causal determinants of this condition. Conflicting results have emerged from epidemiological studies attempting to associate viral infections with a risk or protection from asthma and persistent wheeze. While infections of the lower respiratory tract early in life have been identified as risk factors for persisting wheeze and asthma, nasal symptoms and day care attendance early in life have consistently been inversely related to the same outcomes at school age. This inconsistency may in part be attributable to the neglect of an important discriminating factor, namely atopy. In two birth cohorts, one in the UK and the other in Germany, non-atopic wheeze was as prevalent as atopic wheeze at school age and each phenotype affected around 5–10% of enrolled children (Kurukulaaratchy
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et al., 2005). However, the risk factor profile differed significantly between both conditions. Non-atopic wheeze was mainly associated with recurrent chest infections at age 2 years or infections of the lower respiratory tract, whereas atopic wheeze was related to allergic illnesses of the child and the family. Moreover, the allergic wheezing phenotype was aggravated by exposure to environmental allergens, potentially contributing to the allergic airway inflammation in these sensitised subjects, which contributes to the chronicity of the condition. In contrast the viral associated wheeze has a milder course and better prognosis than the allergic asthma. Therefore, the inverse association between frequent wheeze at school age and day care or nasal symptoms early in life might be attributable to the strong link of viral infection with a milder form of nonatopic wheeze. However, it is also conceivable that a child’s increased exposure to viral infections through day care or contact with other children can influence the phenotypic expression. Recurrent respiratory tract infections during the first three years of life have been shown to be negatively associated with atopy among asthmatic children at school age in cross sectional surveys (von Mutius et al., 1999; Calvani et al., 2002). By suppressing the atopic component of the wheezing phenotype the increased exposure to various viruses may foster a milder form of the disease. Such a notion might be supported by the findings that day care and rhinitis exposure early in life show a protection from atopy in exposed children (Ball et al., 2000; Illi et al., 2001; Celedon et al., 2002a). The assessment of viral infections was rather crude in these epidemiological studies. Most of the information was based on self-administered parental questionnaires and on parental reported diagnoses. We know, however, that the virulence and severity of the infection and the viral load differ markedly between different types of viruses. From studies either using serological, virus culture or PCR methods it has become increasingly clear that mostly two respiratory viruses play a role in wheezing illnesses, namely rhinovirus and respiratory syncitial virus (RSV). In school-aged asthmatic children rhinovirus has been detected in 80% of nasal aspirates within four days of the parents reported episodes of wheezing (Johnston et al., 1995). In lower age groups, namely in infants and toddlers up to the age of 3 years, rhinovirus has also been found the main isolate from nasal lavages taken during symptomatic periods (Lemanske et al., 2005). These rhinovirus illnesses were the ones most significantly associated with the prevalence of wheezing in the third year of life. Interestingly, in the COAST study infants with wheezing illnesses attributable to rhinovirus infections where two to three times more likely to wheeze in the third year of life compared with infants who wheezed with RSV infections (Hoffjan et al., 2005).
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These findings go along with previous observations regarding RSV infections and their relation to asthma development. Overall, not all children who are infected with RSV develop wheezing symptoms suggesting that it is host factors, which are likely to play a significant role for the development of the asthma-like illness. The underlying disposition is unmasked by the virus rather than the virus being the cause of the illness. After RSV infection the prevalence of recurrent wheezing is increased until school age and early adolescent age (Stein et al., 1999; Henderson et al., 2005). It is of interest that most studies did not find an association between RSV infections and atopy (Stein et al., 1999), suggesting that RSV is just one of many respiratory viruses which are associated with a non-atopic wheezing phenotype. Other viral infections and allergic illnesses There are a number of studies relating results of serological studies on Hepatitis A to the prevalence of hay fever and atopic sensitisation in population based studies (Matricardi et al., 1997, 2002; Linneberg et al., 2003). These studies have, however, brought up conflicting evidence. A number of surveys have shown protection of allergy whereas others could not confirm these results (Jarvis et al., 2004; Bodner et al., 2000; Cullinan et al., 2003). Hepatitis A might just be a marker of unhygienic environmental exposures rather than being a true culprit of the association. Little is known about other viruses in the context of epidemiological studies on asthma and allergies. Two reports have suggested a protective role for herpes infections but confirmation in other populations is still awaited (Illi et al., 2001; Matricardi et al., 2002). Bacterial infections There is scarce data regarding the potential role of bacterial infections for the development of asthma and allergies in childhood. Otitis media in infancy was negatively associated with allergic sensitisation at school age in children of atopic parents in Norway (Nja et al., 2003). This finding is in contrast to a German prospective birth cohort where no relation between a number of bacterial infections, including otitis media, and the development of asthma and allergies was seen (Illi et al., 2001). There is limited evidence to suggest that children being hospitalised for salmonellosis may be protected from developing allergic rhinoconjunctivitis and asthma as compared to children hospitalised for various other reasons. But infections of the gastrointestinal tract may play a role as a number of studies have shown that infections with Helicobacter pylori and Toxoplasma gondii may be inversely related to atopy, allergic rhinitis and asthma (Matricardi et al., 2000; Kosunen et al., 2002; Linneberg et al., 2003; Jarvis et al., 2004). The potential role of mycobacteria in turn has
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been heavily debated. There is no clear evidence emanating from various population-based studies. While first findings suggesting a strong inverse association between BCG vaccination and the prevalence of allergic illnesses in Japan strongly promoted this hypothesis (Shirakawa et al., 1997), subsequent studies failed to confirm the findings (Alm et al., 1997; Gruber et al., 2002; Krause et al., 2003; Annus et al., 2004). It remains to be seen whether observations in murine models of allergic asthma suggesting a beneficiary role of mycobacteria can be generalised to human populations. Likewise the role of parasites remains somewhat unclear. A high load of parasitic endemic infections in areas such as in Africa or Latin America may provide protection from the development of atopy. A further contribution within this special issue of Immunobiology by Dr. Yazdanbakhsh will discuss the various aspects of these findings in more detail (van Riet et al., 2007).
The role of non-invasive environmental exposures There is accumulating evidence to suggest that not only overt infections of the human body but also environmental exposures to non-viable microbial products may pertain to the hygiene hypothesis. A number of studies showing that children growing up on a farm are protected from the development of asthma, hay fever and allergic sensitisation may be seen as a natural experiment. These children are in fact exposed to a large number of diverse microbial environments in animal sheds, haylofts, harvesting activities and other farm activities. Children from a neighbourhood in the same village but much less exposed to farm activities serve as natural controls. There is rather consistent evidence showing that farm children have a significantly lower prevalence of hay fever and atopic sensitisation in childhood which is persisting into adulthood (Ernst and Cormier, 2000; Klintberg et al., 2001; Leynaert et al., 2001; Riedler et al., 2001; Portengen et al., 2002; Rennie et al., 2002; Remes et al., 2003; Eduard et al., 2004; Elliott et al., 2004; Radon et al., 2004a). It is still unclear which specific farm exposures explain the protective effect, but animal sheds, hay lofts and the consumption of unpasteurised cow’s milk have so far all been identified as protective exposures (Riedler et al., 2001). Again, the timing of the exposure plays an important role as early life exposure has a much stronger effect as compared to exposure occurring after the first year of life (Riedler et al., 2001; Radon et al., 2004b). Moreover, a maternal effect was seen as the maternal exposure to animal sheds during pregnancy resulted in protection from allergy in the offspring until school age (Riedler et al., 2001). Up to date there is limited technology to assess microbial exposure in these environments. Higher level
of bacterial products such as endotoxin from gram negative bacteria and muramic acid for all bacteria were found in mattresses of farm children as compared to non-farm children (Braun-Fahrlander et al., 2002; van Strien et al., 2004). Likewise, high concentrations of fungal exposure were found in these environments (Schram-Bijkerk et al., 2005). These microbial exposures; however, do not explain the farming effect. Not all exposures are furthermore beneficial for all phenotypes. While endotoxin was inversely related to atopic sensitisation and hay fever, it was found to be a risk factor for non-atopic wheeze, asthma, airway hyperresponsiveness and low lung function (Braun-Fahrlander et al., 2002; Portengen et al., 2005). In turn, levels of muramic acid were inversely associated with the nonatopic wheezing phenotype (van Strien et al., 2004), and levels of fungal exposure had a weak association with the atopic wheeze (Schram-Bijkerk et al., 2005). Overall these findings support the notion that also non-viable products in the environment can stimulate immune responses in ways to protect from allergies. A number of studies have also shown that the genetic susceptibility of an exposed subject modifies the effect of the exposure. Polymorphisms in the genes for TLR-2 and TLR-4 clearly interact with the environmental exposures (Eder et al., 2004). Only subjects with genes conferring sensitivity to the exposure are associated with a protective effect from the environment, whereas other polymorphisms are not associated with protection even in highly protective environments. Potential mechanisms underlying these gene-by-environment interactions will be later discussed in this issue of Immunobiology relating to TOLL-like receptors (Bauer et al., 2007).
Practical implications Unfortunately, to date there are no practical implications from the hygiene hypothesis for the prevention of asthma and allergies. Mostly in the lay press a generalisation from the hygiene hypothesis to medical practice such as in the prescription of antibiotics and vaccinations has been brought forward. These discussions are, however, not founded on scientific evidence. A number of studies have in fact shown that all types of vaccination strategies do not result in either increased or decreased risk of asthma and allergies up to school age (Celedon et al., 2002b). The prescription of antibiotics has been related as a risk factor to the development of asthma and wheeze in children in a number of studies (Celedon et al., 2002b). However, these associations are likely to be attributable to reverse causation. Because in many countries asthma, particularly at young age, is still treated with antibiotics an association between the use of these drugs and asthma must become positive. Only surveys taking the
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indication of the antibiotic prescription or the antedating of drug usage before the beginning of asthma into account will therefore be able to adequately address this question. Such studies do, however, not show a convincing effect of antibiotic usage on the development of asthma and allergic illnesses (Celedon et al., 2002b). Therefore, antibiotics should be prescribed as needed and are unlikely to significantly increase the risk of asthma and allergies. The first attempt to introduce the hygiene hypothesis into clinical application was by the administration of probiotics as a means of preventing allergies in young children. Although the first results of the Finnish studies are encouraging (Kalliomaki et al., 2003), confirmation in other populations is needed before a wide use of these products can be recommended. Again, therapeutic strategies with TLR ligands will be discussed further in this issue of Immunobiology (Bauer et al., 2007). The hygiene hypothesis has seen many modifications through research performed in epidemiology, clinical science and immunology. Today it seems likely that overt infections but also exposure to non-viable microbial compounds in the environment and the interaction of both with underlying innate and adaptive immune responses may play a role. A truly unifying concept is, however, missing and practical implications cannot directly be deduced from these findings. However, a great potential for novel preventive and therapeutic strategies in the future may be gained from these studies.
Acknowledgement I am indebted to Giovanna Menhard for outstanding assistance with the preparation of the manuscript.
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Immunobiology 212 (2007) 433–439 www.elsevier.de/imbio
Allergies, infections and the hygiene hypothesis – The epidemiological evidence Erika von Mutius University Children’s Hospital, Lindwurmstr. 4, D 80337 Munich, Germany Received 1 March 2007; accepted 1 March 2007
Abstract The ‘hygiene hypothesis’ was first proposed by Strachan in 1989 suggesting that infections and unhygienic contact with older siblings or through other exposures may confer protection from the development of allergic illnesses. This hypothesis has evolved in various ways exploring the role of overt viral and bacterial infections, the significance of environmental exposure to microbial compounds, and their effect on underlying responses of innate and adaptive immunity. So far a truly unifying concept is still lacking, but various pieces of a complex interplay between a host’s immune response, characteristics of the invading microorganism, the level and variety of the environmental exposure, and the interactions between a genetic background and a range of exposures become apparent. All these pieces eventually assemble to the clinical presentation of a complex syndrome namely of asthma and allergic illnesses. Even if today practical implications cannot directly be deduced from these findings, there is great potential for the development of novel preventive and therapeutic strategies in the future based on the concepts of the ‘hygiene hypothesis’. r 2007 Elsevier GmbH. All rights reserved. Keywords: Hygiene hypothesis; Epidemiology; Allergy; Infection
Introduction In 1989, David Strachan was the first to suggest that infections and unhygienic contact may confer protection from the development of allergic illnesses. Dr. Strachan had observed that the prevalence of hay fever was inversely related to the number of siblings of the study subject (Strachan, 1989). The effect was stronger for every older sibling than for every younger sibling. In his landmark paper he proposed that ‘‘infection in early childhood, transmitted by unhygienic contact with older siblings or acquired prenatal from a mother infected by contact with her older children’’ might prevent the development of Tel.: +49 89 5160 2709; fax: +49 89 5160 4452.
E-mail address: [email protected]. 0171-2985/$ - see front matter r 2007 Elsevier GmbH. All rights reserved. doi:10.1016/j.imbio.2007.03.002
allergic illnesses. A large number of population-based studies have since confirmed the inverse association between the number of siblings and the development of allergic outcomes. Widespread attention has since been given to the hygiene hypothesis and a large scientific and lay audience has been confronted with these ideas over the last few years. The original epidemiological observations have subsequently been applied to other disciplines such as immunology and the assessment of microbial exposures in the environment. Over the course of numerous discussions, new angles and aspects of the hygiene hypothesis have thus been proposed. One may identify three distinct claims on the proper nature of the hygiene hypothesis: 1. Potentially, overt and unapparent infections of human subjects with viruses and bacteria may decrease the risk of developing allergic illnesses.
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2. Non-invasive microbial exposures in the environment may decrease the risk of allergies. 3. Both of these exposures, be it infections or noninvasive microbial exposures, may influence a subject’s innate and adaptive immune response. Progress in epidemiological studies over the last decades has clearly shown that the hygiene hypothesis is not one single straightforward idea, but rather a complex interaction of many factors. There are at least four dimensions of the pieces for this jigsaw, which must be assembled. These pieces comprise the various allergic illnesses including the different phenotypes; the timing of the exposure; the various environmental exposures; and a subject’s genetic susceptibility to react to these exposures. Numerous prospective cohort studies have clearly shown that particularly for asthma, different phenotypes exist. In infant years, wheezing may be attributable to inborn impairment in lung function, which becomes clinically manifest as wheezing episodes in the context of viral infections. Maternal smoking during pregnancy is clearly a risk factor for this phenotype, but allergic phenomena such as the presence of atopic eczema, elevated total or specific IgE antibodies, or a family history of allergic diseases are not associated with this so called ‘‘transient infant wheezing’’ which remits around the second to third birthday. Other forms of wheeze, however, continue into school age. Recent evidence again suggests that there are distinct phenotypes. One wheezing phenotype is associated with the detection of specific IgE antibodies to various food and inhalant allergens, whereas the other wheezing phenotype is not related to atopy. The non-atopic wheezing phenotype has a much better prognosis as these children show remission of their symptoms during school age years and retain normal lung function. It is the allergic wheezing phenotype, which goes on to develop a chronic course of the illness with impairment of lung function and the development of airway hyper-responsiveness. Thus clinical signs of wheeze do not sufficiently distinguish underlying phenotypes and mechanisms involved in the development of these various conditions. The second dimension of the complexity of the associations between various exposures potentially related to the hygiene hypothesis and asthma as well as other allergic illnesses relates to the timing of the exposure. A number of studies have clearly shown that the effect of a given exposure depends on the age at which a subject or an individual is exposed. At least in childhood and adolescence the human organism is in a constant stage of development and maturation. It is therefore conceivable that it is in these vulnerable periods that certain exposures have the most profound effect on the maturing immune system and thereby the development of allergic illnesses. A number of studies
have shown that not only the maturing immune system of an infant or toddler is susceptible to environmental exposure, but that also prenatal exposures may play a significant role either through mechanisms acting in utero or as epigenetic modulation of subsequent developmental trajectories. The third dimension, which is becoming increasingly obvious to many researchers, is the genetic background of an exposed individual. The Human Genome Project has opened a new and fascinating field of research, which is still at the very beginning of its explosion. However, it becomes increasingly evident that not one gene accounts for hereditability of allergic illnesses but rather a number of alterations in many genes which interact with environmental influences at various time points of development, are expected to contribute to the mechanisms underlying the various allergic conditions. There is an ongoing debate about the potential underlying immunological mechanisms resulting in a decrease in risk of allergies and asthma by living in a less hygienic environment. Various authors in this special issue of Immunobiology will address some of these issues in the following papers (e.g. Garn and Renz, 2007).
The role of infections for the development of asthma and allergies Viral infections and asthma As discussed above, there are distinct wheezing phenotypes, which pertain to the asthma syndrome. Different risk factors have been related to these various wheezing phenotypes in epidemiological studies. Therefore, it is of importance to attempt to dissect the relation between viral exposures and the various wheezing phenotypes. For transient wheezing in infancy which is not really an asthma phenotype, viral infections of the upper respiratory tract are the most prevalent and potent triggers (Rusconi et al., 1999). Yet, as discussed above these viral infections are unlikely to be causal determinants of this condition. Conflicting results have emerged from epidemiological studies attempting to associate viral infections with a risk or protection from asthma and persistent wheeze. While infections of the lower respiratory tract early in life have been identified as risk factors for persisting wheeze and asthma, nasal symptoms and day care attendance early in life have consistently been inversely related to the same outcomes at school age. This inconsistency may in part be attributable to the neglect of an important discriminating factor, namely atopy. In two birth cohorts, one in the UK and the other in Germany, non-atopic wheeze was as prevalent as atopic wheeze at school age and each phenotype affected around 5–10% of enrolled children (Kurukulaaratchy
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et al., 2005). However, the risk factor profile differed significantly between both conditions. Non-atopic wheeze was mainly associated with recurrent chest infections at age 2 years or infections of the lower respiratory tract, whereas atopic wheeze was related to allergic illnesses of the child and the family. Moreover, the allergic wheezing phenotype was aggravated by exposure to environmental allergens, potentially contributing to the allergic airway inflammation in these sensitised subjects, which contributes to the chronicity of the condition. In contrast the viral associated wheeze has a milder course and better prognosis than the allergic asthma. Therefore, the inverse association between frequent wheeze at school age and day care or nasal symptoms early in life might be attributable to the strong link of viral infection with a milder form of nonatopic wheeze. However, it is also conceivable that a child’s increased exposure to viral infections through day care or contact with other children can influence the phenotypic expression. Recurrent respiratory tract infections during the first three years of life have been shown to be negatively associated with atopy among asthmatic children at school age in cross sectional surveys (von Mutius et al., 1999; Calvani et al., 2002). By suppressing the atopic component of the wheezing phenotype the increased exposure to various viruses may foster a milder form of the disease. Such a notion might be supported by the findings that day care and rhinitis exposure early in life show a protection from atopy in exposed children (Ball et al., 2000; Illi et al., 2001; Celedon et al., 2002a). The assessment of viral infections was rather crude in these epidemiological studies. Most of the information was based on self-administered parental questionnaires and on parental reported diagnoses. We know, however, that the virulence and severity of the infection and the viral load differ markedly between different types of viruses. From studies either using serological, virus culture or PCR methods it has become increasingly clear that mostly two respiratory viruses play a role in wheezing illnesses, namely rhinovirus and respiratory syncitial virus (RSV). In school-aged asthmatic children rhinovirus has been detected in 80% of nasal aspirates within four days of the parents reported episodes of wheezing (Johnston et al., 1995). In lower age groups, namely in infants and toddlers up to the age of 3 years, rhinovirus has also been found the main isolate from nasal lavages taken during symptomatic periods (Lemanske et al., 2005). These rhinovirus illnesses were the ones most significantly associated with the prevalence of wheezing in the third year of life. Interestingly, in the COAST study infants with wheezing illnesses attributable to rhinovirus infections where two to three times more likely to wheeze in the third year of life compared with infants who wheezed with RSV infections (Hoffjan et al., 2005).
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These findings go along with previous observations regarding RSV infections and their relation to asthma development. Overall, not all children who are infected with RSV develop wheezing symptoms suggesting that it is host factors, which are likely to play a significant role for the development of the asthma-like illness. The underlying disposition is unmasked by the virus rather than the virus being the cause of the illness. After RSV infection the prevalence of recurrent wheezing is increased until school age and early adolescent age (Stein et al., 1999; Henderson et al., 2005). It is of interest that most studies did not find an association between RSV infections and atopy (Stein et al., 1999), suggesting that RSV is just one of many respiratory viruses which are associated with a non-atopic wheezing phenotype. Other viral infections and allergic illnesses There are a number of studies relating results of serological studies on Hepatitis A to the prevalence of hay fever and atopic sensitisation in population based studies (Matricardi et al., 1997, 2002; Linneberg et al., 2003). These studies have, however, brought up conflicting evidence. A number of surveys have shown protection of allergy whereas others could not confirm these results (Jarvis et al., 2004; Bodner et al., 2000; Cullinan et al., 2003). Hepatitis A might just be a marker of unhygienic environmental exposures rather than being a true culprit of the association. Little is known about other viruses in the context of epidemiological studies on asthma and allergies. Two reports have suggested a protective role for herpes infections but confirmation in other populations is still awaited (Illi et al., 2001; Matricardi et al., 2002). Bacterial infections There is scarce data regarding the potential role of bacterial infections for the development of asthma and allergies in childhood. Otitis media in infancy was negatively associated with allergic sensitisation at school age in children of atopic parents in Norway (Nja et al., 2003). This finding is in contrast to a German prospective birth cohort where no relation between a number of bacterial infections, including otitis media, and the development of asthma and allergies was seen (Illi et al., 2001). There is limited evidence to suggest that children being hospitalised for salmonellosis may be protected from developing allergic rhinoconjunctivitis and asthma as compared to children hospitalised for various other reasons. But infections of the gastrointestinal tract may play a role as a number of studies have shown that infections with Helicobacter pylori and Toxoplasma gondii may be inversely related to atopy, allergic rhinitis and asthma (Matricardi et al., 2000; Kosunen et al., 2002; Linneberg et al., 2003; Jarvis et al., 2004). The potential role of mycobacteria in turn has
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been heavily debated. There is no clear evidence emanating from various population-based studies. While first findings suggesting a strong inverse association between BCG vaccination and the prevalence of allergic illnesses in Japan strongly promoted this hypothesis (Shirakawa et al., 1997), subsequent studies failed to confirm the findings (Alm et al., 1997; Gruber et al., 2002; Krause et al., 2003; Annus et al., 2004). It remains to be seen whether observations in murine models of allergic asthma suggesting a beneficiary role of mycobacteria can be generalised to human populations. Likewise the role of parasites remains somewhat unclear. A high load of parasitic endemic infections in areas such as in Africa or Latin America may provide protection from the development of atopy. A further contribution within this special issue of Immunobiology by Dr. Yazdanbakhsh will discuss the various aspects of these findings in more detail (van Riet et al., 2007).
The role of non-invasive environmental exposures There is accumulating evidence to suggest that not only overt infections of the human body but also environmental exposures to non-viable microbial products may pertain to the hygiene hypothesis. A number of studies showing that children growing up on a farm are protected from the development of asthma, hay fever and allergic sensitisation may be seen as a natural experiment. These children are in fact exposed to a large number of diverse microbial environments in animal sheds, haylofts, harvesting activities and other farm activities. Children from a neighbourhood in the same village but much less exposed to farm activities serve as natural controls. There is rather consistent evidence showing that farm children have a significantly lower prevalence of hay fever and atopic sensitisation in childhood which is persisting into adulthood (Ernst and Cormier, 2000; Klintberg et al., 2001; Leynaert et al., 2001; Riedler et al., 2001; Portengen et al., 2002; Rennie et al., 2002; Remes et al., 2003; Eduard et al., 2004; Elliott et al., 2004; Radon et al., 2004a). It is still unclear which specific farm exposures explain the protective effect, but animal sheds, hay lofts and the consumption of unpasteurised cow’s milk have so far all been identified as protective exposures (Riedler et al., 2001). Again, the timing of the exposure plays an important role as early life exposure has a much stronger effect as compared to exposure occurring after the first year of life (Riedler et al., 2001; Radon et al., 2004b). Moreover, a maternal effect was seen as the maternal exposure to animal sheds during pregnancy resulted in protection from allergy in the offspring until school age (Riedler et al., 2001). Up to date there is limited technology to assess microbial exposure in these environments. Higher level
of bacterial products such as endotoxin from gram negative bacteria and muramic acid for all bacteria were found in mattresses of farm children as compared to non-farm children (Braun-Fahrlander et al., 2002; van Strien et al., 2004). Likewise, high concentrations of fungal exposure were found in these environments (Schram-Bijkerk et al., 2005). These microbial exposures; however, do not explain the farming effect. Not all exposures are furthermore beneficial for all phenotypes. While endotoxin was inversely related to atopic sensitisation and hay fever, it was found to be a risk factor for non-atopic wheeze, asthma, airway hyperresponsiveness and low lung function (Braun-Fahrlander et al., 2002; Portengen et al., 2005). In turn, levels of muramic acid were inversely associated with the nonatopic wheezing phenotype (van Strien et al., 2004), and levels of fungal exposure had a weak association with the atopic wheeze (Schram-Bijkerk et al., 2005). Overall these findings support the notion that also non-viable products in the environment can stimulate immune responses in ways to protect from allergies. A number of studies have also shown that the genetic susceptibility of an exposed subject modifies the effect of the exposure. Polymorphisms in the genes for TLR-2 and TLR-4 clearly interact with the environmental exposures (Eder et al., 2004). Only subjects with genes conferring sensitivity to the exposure are associated with a protective effect from the environment, whereas other polymorphisms are not associated with protection even in highly protective environments. Potential mechanisms underlying these gene-by-environment interactions will be later discussed in this issue of Immunobiology relating to TOLL-like receptors (Bauer et al., 2007).
Practical implications Unfortunately, to date there are no practical implications from the hygiene hypothesis for the prevention of asthma and allergies. Mostly in the lay press a generalisation from the hygiene hypothesis to medical practice such as in the prescription of antibiotics and vaccinations has been brought forward. These discussions are, however, not founded on scientific evidence. A number of studies have in fact shown that all types of vaccination strategies do not result in either increased or decreased risk of asthma and allergies up to school age (Celedon et al., 2002b). The prescription of antibiotics has been related as a risk factor to the development of asthma and wheeze in children in a number of studies (Celedon et al., 2002b). However, these associations are likely to be attributable to reverse causation. Because in many countries asthma, particularly at young age, is still treated with antibiotics an association between the use of these drugs and asthma must become positive. Only surveys taking the
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indication of the antibiotic prescription or the antedating of drug usage before the beginning of asthma into account will therefore be able to adequately address this question. Such studies do, however, not show a convincing effect of antibiotic usage on the development of asthma and allergic illnesses (Celedon et al., 2002b). Therefore, antibiotics should be prescribed as needed and are unlikely to significantly increase the risk of asthma and allergies. The first attempt to introduce the hygiene hypothesis into clinical application was by the administration of probiotics as a means of preventing allergies in young children. Although the first results of the Finnish studies are encouraging (Kalliomaki et al., 2003), confirmation in other populations is needed before a wide use of these products can be recommended. Again, therapeutic strategies with TLR ligands will be discussed further in this issue of Immunobiology (Bauer et al., 2007). The hygiene hypothesis has seen many modifications through research performed in epidemiology, clinical science and immunology. Today it seems likely that overt infections but also exposure to non-viable microbial compounds in the environment and the interaction of both with underlying innate and adaptive immune responses may play a role. A truly unifying concept is, however, missing and practical implications cannot directly be deduced from these findings. However, a great potential for novel preventive and therapeutic strategies in the future may be gained from these studies.
Acknowledgement I am indebted to Giovanna Menhard for outstanding assistance with the preparation of the manuscript.
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