Increasing prevalence of asthma and allergic rhinitis and the role of environmental factors

INTRODUCTION — Allergic rhinitis and asthma are both common chronic diseases that affect the quality of life of patients and have a significant economic impact. The prevalence of allergic rhinitis increased in Westernized countries from the 1870s through the 1950s. The rate of asthma subsequently increased in these countries beginning in the 1960s. Asthma and allergic rhinitis prevalence began increasing in many developing countries in the late 1980s to early 1990s.

Changes in genetic factors are unlikely to be the underlying cause of the rise in allergic diseases since the increases in allergic rhinitis and asthma occurred relatively rapidly. Instead, multiple environmental factors may have played a role. These include improvements in hygiene, eradication of most parasitic worm infections, changes in home heating and ventilation, and a decline in physical activity and alterations in diet due to lifestyle changes. Although we lack a complete understanding of the possible role of epigenetic changes in the rise of allergic diseases, there is increasing literature on potential mechanisms by which environmental exposures associated with specific epigenetic changes could lead to allergic phenotypes [1].

This topic discusses the increase in rates of allergic rhinitis and asthma and the environmental changes that may have led to their alterations in prevalence. Risk factors for the development of asthma, including atopy and allergen sensitization, and the relationship between allergic rhinitis and asthma are discussed separately. (See "Risk factors for asthma" and "Relationships between rhinosinusitis and asthma".)

The rising prevalence of food allergy and the factors that may play a role in this increase are also reviewed in detail separately. (See "Food allergy in children: Prevalence, natural history, and monitoring for resolution", section on 'Prevalence of childhood food allergy' and "Pathogenesis of food allergy", section on 'Prevalence'.)

EPIDEMIOLOGIC HISTORY — Seasonal allergic rhinitis was first described in the United States in 1872 (autumnal catarrh or ragweed hay fever) [2] and in England in 1873 (catarrhus aestivus) [3]. The disease was well recognized in England and Germany by 1900 and in the United States by 1920. The island of Heligoland in the North Sea was established as a summer refuge for hay fever patients by 1910, and, during the early part of the 20^th century, it became common for sufferers in New England to retreat to resorts in the mountains to escape the pollen. The first paper on immunotherapy against pollen "toxin" was published in 1911 [4]. At that time, hay fever was considered to be a disease of the affluent and was rarely reported among working-class people, especially farmers.

By the 1930s, allergic rhinitis became sufficiently common to allow the development of the subspecialty of allergy. In 1935, the University of Virginia appointed a professor of Allergy and Rheumatology. In 1946, the city of New York initiated a ragweed eradication campaign that was designed to help control hay fever [5]. However, by the early 1950s, 10 percent of New Yorkers were reported to suffer from allergic rhinitis [6], and, in 1952, the campaign was abandoned because it was not possible to control pollen levels [7]. Similar high rates of hay fever were documented in Tecumseh, Michigan in the 1960s [8].

The general view is that both allergic rhinitis and asthma increased between 1960 and 1990 in Westernized countries. However, evidence suggests that the prevalence of allergic rhinitis was relatively stable, at approximately 15 percent, over that time period [9]. The prevalence has continued to remain relatively stable since then and may even be falling in some countries [10].

The International Study of Asthma and Allergies in Childhood (ISAAC) compared time trends in symptom prevalence of rhinoconjunctivitis between approximately 1994 to 1995 for phase I and 2002 to 2003 for phase III [10]. They found similar prevalence rates of approximately 15 to 20 percent in most Westernized countries during this time period. The symptom prevalence of allergic rhinoconjunctivitis generally decreased between the two study phases in countries with the highest prevalence in the first phase, including most English-speaking countries. In contrast, some of the countries that had low prevalence in the mid-1990s had increased rates in the early 2000s.

An increase in asthma was first reported in 1970, among school children in Birmingham, England between 1958 and 1968 [11]. A higher prevalence of asthma was seen among the children of West Indian immigrants, and there was a strong association with sensitization to dust mites. A rise in asthma prevalence was reported in New Zealand, Australia, and Japan over the next 10 years. In each of these countries, dust mite allergens were the most common sensitization associated with asthma [12-14]. By the late 1970s, there was a widespread view that the increase in asthma in the United Kingdom had occurred at least in part because of the increase in dust mites in homes between 1955 and 1975 [15-17].

During the 1960s through the 1980s, there were still elements of doubt about the increasing prevalence of asthma in Westernized countries [18]. It did not become clear until approximately 1990 that increases in asthma prevalence had occurred in Westernized countries worldwide (figure 1). Looking back, it appears that the rise in the number of children and young adults reporting wheezing began between 1955 and 1965 in these countries [19,20]. Increases were also seen in asthma-related hospitalization and mortality [19-22]. The growth in asthma prevalence was seen even in countries where dust mites were not important allergens, such as Finland [23]. Over the period from 1960 to 2000, there was at least a 10-fold increase in asthma [24,25]. However, there was wide variability in this increase in absolute terms. In some countries, numbers rose from 2 to 20 percent, while in others the rate increased from 0.5 to 5 percent. The rates appear to have peaked, and may even be declining, in many of these countries [26-35]. This leveling-off is seen even in countries in which rates of sensitization to aeroallergens continue to increase [36].

Asthma prevalence began increasing in developing countries in the late 1980s to early 1990s, mainly in more affluent, urban populations [37-39]. Gains in the prevalence of self-reported wheeze in the past year in children occurred between the mid-1990s to early 2000s, mainly in non-English-speaking countries [26]. These increases were seen both in regions that had high to intermediate symptom prevalence rates in the 1990s, such as Latin America and Eastern Europe, and in countries that had low rates in the initial survey, such as Asian-Pacific (particularly Indonesia and China) and African countries. A concomitant increase in symptom prevalence of rhinoconjunctivitis was also seen in many of these countries [10]. In contrast, there are still rural villages in developing or undeveloped countries, such as Ethiopia, Papua New Guinea, Kenya, and Nepal, where asthma remains rare [37,38,40-42]. In addition, an association between allergen sensitization and respiratory symptoms or abnormal lung function is not always seen in these populations [37,38].

ENVIRONMENTAL CHANGES — The epidemiologic findings raise the question: What changes occurred in Westernized countries during the 20^th century, when the rise in prevalence of allergic rhinitis and then asthma were seen, that are now occurring in developing countries?

The changes in prevalence are too sudden to be attributed to genetic factors. The gene-environment interactions that lead to the development of atopic diseases such as allergic rhinitis and asthma are complex [43-45]. More than 100 genes have been associated with the development of asthma, and we assume that each gene product interacts with multiple environmental factors. Environmental factors such as tobacco smoke and pollution alter expression of DNA methyltransferases, which could potentially impact the immune response to allergen(s) [46-48]. The emerging field of epigenetics adds another level to the gene-environment interaction and may well have a significant impact on inheritance and epidemiology related to allergic diseases. (See "Genetics of asthma".)

The contrasts between children living in the villages of Papua New Guinea or Kenya, on the one hand, and children raised in central New York or the suburbs of Auckland, on the other, are so great that it is unlikely that a single environmental difference is responsible for the major differences in the burden of asthma. It is also unlikely that identical environmental factors influenced the development of both allergic rhinitis and asthma.

Multiple environmental changes occurred gradually from the mid-1800s onward in Westernized countries, and these changes are now occurring, often more rapidly and simultaneously, in developing countries. Many of these changes may have influenced the development of allergic rhinitis and/or asthma.

Mid to late 1800s — Two major events occurred during the latter half of the 19^th century that may be relevant to the increase in allergic rhinitis during this time period [49]:

●There was complete separation of drinking water from sewage in the major North American and European cities by 1900 and a consequent progressive decline in enteric diseases.

●Reform of the Corn Laws in England in 1846 led to a dramatic decline in growing of wheat, which was gradually replaced by Italian rye grass that was used to feed the expanding herds of cattle. Italian rye grass pollinated much more heavily than the traditional field grasses [49]. Similar changes occurred in grass growing in Northern Germany, and it is thought that the extension of agriculture in the United States after 1865 led to major increases in both ragweed and grass pollen.

Early to mid-1900s — After 1900, there were further improvements in hygiene in Europe and the United States, including:

●A final decline both in the number of farm animals living in towns and in the use of horses for transportation

●Universal wearing of shoes

●Chlorination of water

●Eradication of helminths and malaria

These changes were paralleled in the United States by an almost 90 percent decline in deaths from infectious disease, mainly enteric disease and tuberculosis, over the period from 1900 to 1940 [50].

Since 1960 — Many discussions of the rise in asthma prevalence assume that this increase is a direct consequence of the general increase in allergic disease. As a result, the various theories focus on causes of the supposed increase in T helper cell type 2 (Th2) response with associated increase in immunoglobulin E (IgE) (the allergic isotype). However, as we have discussed, there is a substantial body of evidence that allergic rhinitis was already common before 1960 and rates had leveled off by then.

Thus, our approach is to also consider the reasons why asthma increased among the allergic population [51]. The list of incriminated factors is long and includes the introduction and widespread use of broad-spectrum antibiotics, a further decline in hepatitis A virus (HAV) infection, increased immunization of children for multiple diseases, and the major changes in lifestyle (eg, diet, exercise, time spent outdoors), linked to the introduction of new forms of sedentary entertainment. We have chosen to group these possible contributing factors into three general categories (table 1), while recognizing that the effects of many of these changes overlap and other changes have occurred that may not fit neatly into one of these groups [52,53].

We believe that epidemic asthma with the highest prevalence and severity (Model A) (figure 1) requires the following:

●Improved hygiene to allow allergic disease to develop

●High concentrations of one of the major nonmammalian indoor allergens

●Decline in physical activity, which removes a protective effect of repeated expansion of the lungs

Improved hygiene — Early life exposure to infectious pathogens as well as normal gut microbiota may influence the development of the immune system. The hygiene hypothesis postulates that better hygiene, resulting in decreased microbial exposure, leads to an increase in allergic disease (table 1) [54,55]. The hygiene hypothesis is like the Hydra from Greek mythology. As soon as one explanation of the effect is disputed, it rapidly reappears in a different form.

When the hypothesis was first proposed in 1989, it was based upon the observation that rates of allergic disease were lower among British children with one or more older siblings [56]. This prompted clinical researchers to focus on the effects of repeated viral infections since this was one of the primary consequences of having older siblings [57]. This approach was supported by evidence that American children who attended daycare during the first six months of life had a decreased risk of asthma at age six years despite increased episodes of infection early in life [58]. However, the number of children in daycare increased over the period when asthma was rising most rapidly. Furthermore, a report from Denmark documented early bacterial colonization of children as a risk factor for development of asthma, and they found a higher prevalence of asthma among children with older siblings [59]. In addition, another study found that the risk of persistent or late-onset asthma varied in a quadratic fashion, with toddlers exposed to few or no other children at highest risk, followed by those exposed to 10 or more children [60]. This effect was independent of the number of respiratory tract infections reported, suggesting that other protective mechanisms were involved.

The next version of the hygiene hypothesis was based upon the findings of an inverse association between skin sensitivity to Mycobacterium tuberculosis and asthma in Japanese schoolchildren [61]. The authors of this article suggested that Bacillus Calmette-Guérin (BCG) vaccination could reduce the risk of allergic disease. Their observation sparked a series of studies with different strains of mycobacteria, including Mycobacterium vaccae [62,63]. However, the primary observations were not confirmed in other studies, and rates of asthma are not lower in countries with routine use of BCG [64]. In addition, tuberculosis was still a major scourge even in upper levels of society during the period when hay fever first became a common disease among affluent families in Northern Europe. Furthermore, the major decline in tuberculosis mortality occurred between 1900 and 1940, before effective antibiotic therapy was available (ie, streptomycin in 1948) and before the rise in asthma began.

The hygiene hypothesis also reappeared in relation to HAV serology. The initial evidence about a negative association between allergic disease and positive HAV serology among army recruits in Italy [65] was followed by similar evidence from the National Health and Nutrition Examination survey (NHANES) data in the United States [66]. In addition, susceptibility to allergic disease was associated with genetic variants of the receptor for HAV. It is well accepted that the prevalence of positive HAV serology declined over the period with which we are concerned (ie, 1960 to 1990). However, it had already begun to decline before that [50], and the idea that one enteric virus could dominate the immune response seems simplistic. Furthermore, HAV infection remains common in African cities where asthma is increasing.

Certain lifestyle factors and household practices can also influence early microbial exposure and are associated with atopic disease prevalence. In one study, for example, asthma, eczema, and allergen sensitization were less common in toddlers whose parents "cleaned" the pacifiers used during infancy by sucking them compared with other methods such as rinsing the pacifier [67]. The salivary microbiota also differed between these two groups. In another study, hand dishwashing was associated with a lower risk of development of atopic disease (asthma, eczema, and rhinoconjunctivitis) at seven to eight years of age compared with machine dishwashing [68]. Serving fermented food and purchasing food directly from a farm were also associated with a decreased risk of allergic disease.

In a Canadian birth cohort study, decreased abundance of certain bacteria at three months of age was seen in the children with atopy and wheezing at one year of age and an increased risk of asthma at three years of age [69]. In a US birth cohort study, decreased abundance of particular bacteria, increased abundance of certain fungi, and enhanced proinflammatory metabolites in the fecal metabolome were seen associated with sensitization to multiple allergens at two years of age and doctor-diagnosed asthma at four years of age [70]. In keeping with an effect from the gut microbiome, early-life exposures that can affect the microbiome composition, such as antibiotics and Cesarean section birth, are also associated with increased risk for childhood atopy [71]. (See "Pathogenesis of food allergy", section on 'Gut and skin microbiota'.)

Exposure to farm animals and endotoxin is discussed below. (See 'Farms, villages, worms, and other parasites' below.)

Overall, there are several major problems with the hygiene hypothesis. First, the major changes in hygiene in Northern European cities occurred long before any evidence for the increase in asthma in children, although those changes were associated with the earlier appearance of hay fever. Second, the increase in asthma in Africa is observed in cities where the standards of hygiene are less advanced than those in New York, London, or Berlin in 1920. Thus, improvements in hygiene do not relate temporally to the increase in asthma.

Increased indoor allergen exposure — Changes in homes and lifestyles that led to increased indoor allergen exposure include increased insulation, increased indoor temperature, the nearly universal adoption of fitted or wall-to-wall carpeting (which began in the 1930s, although there has been some reversal of this trend), and increased time spent indoors (table 1) [72].

Conditions favoring dust mite growth in homes in London were enhanced between 1955 and 1975 [17]. These changes were mirrored in Australia and New Zealand. Prior to 1950, homes in England were heated mainly with open coal fires and coal gas. Both of these presented a significant risk of carbon monoxide poisoning. For this reason, there were strict regulations about ventilation that virtually assured that homes were both "drafty" and cold.

Coal fires were largely eliminated after the United Kingdom's worst air pollution event, the Great Smog of 1952, when an estimated 12,000 Londoners died as a result of this pollution episode. Coal gas was replaced by natural gas in the 1960s, and it was safer to make homes more airtight after these changes took place. The primary effect was an increase in the temperature of homes during the cooler seasons.

Dust mites thrive in a warmer, more humid environment. By the early 1980s, when it became possible to measure the dust mite allergen levels in environmental samples from homes, the allergen was found not only in beds, but also in carpets, sofas, drapes, and clothing [73]. In turn, it became clear that the level of dust mite exposure was an important predictor of dust mite allergen sensitization and development of asthma [74].

The increase in indoor allergen exposure was followed by a decrease in pollen exposure as air filtration and air conditioning became available during the 1950s and 1960s. Pollen exposure was greater prior to this, both because people generally spent more time outdoors and because there was greater exposure to pollen indoors due to open windows with or without window fans. This may explain, at least in part, the leveling-off of allergic rhinitis seen since the mid-1960s.

Several developments during the 1980s made it clear that increases in dust mite alone were not sufficient to explain the increase in asthma:

●First, the upsurge in asthma had occurred in countries where mites were not a significant indoor allergen [23]. In these settings, asthma was often associated with the dominant indoor allergens in that region. The rise in asthma prevalence was particularly severe among minority populations in the United States where cockroach was the dominant indoor allergen [75,76]. Asthma was related to cat and dog sensitivity in New Mexico, where there were no mites or cockroaches in homes [77]. Decreased ventilation in homes leads to increased airborne quantities of cat and dog allergens. Small particles, which remain airborne, are generally removed by ventilation so that low ventilation rates will tend to increase the quantities of cat allergen remaining airborne [52,53,78-80].

●Second, the prevalence and severity of asthma continued to increase well beyond when the environmental changes in homes conducive to dust mite growth had occurred. Major changes in houses had finished by approximately 1975, but increases in asthma in the United Kingdom continued for another 20 years. In a prospective study, there was no significant increase in dust mite allergens in the United Kingdom between 1979 and 1989 [74]. In addition, with increasing awareness of dust mites, families started to change their homes in such a way that dust mite numbers decreased. These changes have been most obvious in the Netherlands, where some estimates suggest that mite allergen levels have decreased as much as 10-fold between 1980 and 2000 [81,82].

●Third, the increase in asthma has occurred in poor, urban populations in which no major change in housing or indoor allergen load has occurred during the same time period [21,76].

●Fourth, whether increased time indoors represents an important cause of increased allergen exposure is not clear. A shift to increased hours spent indoors began in the 1950s, although the timing has been variable. It was previously typical to spend 18 to 20 hours per day indoors, and this has increased to 23 or more hours per day (ie, by 25 percent) [83,84]. By contrast, the time spent "playing" outdoors has decreased 80 percent or more.

●Finally, the argument that increased allergen exposure was an important cause of the increase in allergic disease assumed that there was a linear relationship between exposure and disease. While this may be true for allergens derived from dust mites, cockroach, Alternaria, and pollens, there is considerable evidence that high exposure to cat or dog allergens can induce a form of tolerance [52,53,79,80]. However, asthma has increased in countries where the major allergens were those derived from cats or dogs. This raises major questions about increasing exposure causing the rise in asthma prevalence.

Two papers address the impact of different environments in relation to sensitization and the risk of asthma [85,86]. Results from an inner-city cohort found an inverse relationship between exposure to cockroach, mouse, and cat allergens and asthma [85]. However, this cohort was selected to be high risk for asthma, and the relationship between allergen sensitization and asthma was weak. In contrast, results from a population-based cohort in northern Sweden confirmed the negative association between cat ownership and sensitization but found a strong relationship between high-titer IgE antibodies to cat and persistent asthma [86]. In those studies, exposure to dust mite allergen was low [85] or very low [86].

Initially, it was proposed that the protective effect of an animal in the home was an example of the cleanliness or hygiene hypothesis, in which the animal was a source of endotoxin. However, the presence of a cat in the home does not increase airborne endotoxin. It seems more probable that cat allergens induce a tolerant response, including immunoglobulin G (IgG) and IgG4 antibodies, at high doses because they are mammalian in origin (ie, evolutionarily less foreign than other major allergens). (See "Pets in the home: Impact on allergic disease".)

Air pollution — Changes in air pollution may well be relevant to increasing asthma prevalence in some areas. There is extensive evidence about the effects of vehicular pollution, including both the products of gasoline engines and diesel particulates, on allergic respiratory disease in areas such as Los Angeles [87]. Another study estimated that up to 24 percent of annual cases of childhood asthma were directly attributable to traffic-related air pollution [88]. However, a significant negative correlation between pollution and asthma mortality was documented in Philadelphia [89]. In addition, there are areas of the world with very high asthma prevalence and severity where air pollution is negligible (eg, New Zealand). Furthermore, the original increase in asthma occurred at the time when traditional coal and sulfur pollution was declining in both England and the United States.

Although the mechanism of lung injury by air pollution is not well established, data that are available focus on particulate matter (a major source is diesel exhaust) and nitric oxide [90,91]. Studies suggest that airway cells recognize pollutants and induce an inflammatory response via pattern recognition receptors (PRRs) [92]. Activation of PRRs results in the release of cytokines and chemokines that attract leukocytes and antigen-presenting cells to the lung and trigger their maturation [93]. In addition to PRRs, an increasing number of studies have demonstrated the role of Toll-like receptor (TLR) signaling in pollutant-induced inflammation [94,95]. NOD-like receptors (NLRs) and the subset that assemble and oligomerize to form the inflammasome are also implicated as an innate immune mechanism that may be involved in the inflammatory response to ambient pollutants [96,97].

Lifestyle changes — Changes have occurred in a number of lifestyle factors, including the amount of time spent outside, the amount of time spent on physical play versus sedentary activities, dietary composition, and exposure to farm animals.

Outdoor play/indoor sedentary entertainment — Prior to 1950, there were few reasons for children to play primarily indoors. Normal behavior included two to four hours per day of outdoor play [83]. Starting in the mid-1950s, television programs were targeted at children with increasing success so that, over a period of 15 years, it became normal for children to sit indoors watching a screen for two to four hours [84]. That this change has had negative consequences for the health of children is not in doubt. The most obvious consequence (or parallel change) has been the rise in obesity. The rise in obesity reflects both decreased physical activity and changes in diet, but weight and height are much easier to measure than either activity or diet. Thus, many studies only include reliable data on weight and height. The decrease in physical activity and increased time spent sitting are closely linked, although the possible consequences for lung physiology and asthma are not the same. Putting it simply, is sitting still harmful, or is prolonged activity outside protective?

Evidence that sitting still for long periods of time is harmful has come from several different types of studies [98]:

●First, epidemiologic studies have shown that children who spend longer hours watching television have an increased risk of developing both obesity and asthma [84,99]. Two hours per day at age 3 years doubles the risk of asthma at age 11 [99].

●Second, there is a long series of experiments showing that full expansion of the lungs can decrease lung resistance [100,101]. The normal pattern of breathing includes intermittent deep breaths or sighs, and there is good evidence that sigh rates decline significantly during periods sitting, watching a screen [102].

●Third, in vitro studies on bronchial smooth muscle show that this muscle does not obey Starling's law and will contract from a shorter length if it is not stretched regularly [103]. The authors of those studies argued that normal human sigh rates were only just sufficient to maintain normal tone [102,104]. Further research is needed to determine if prolonged periods of sitting still with low sigh rates allow the lungs to go into bronchospasm.

Assessing the relevance of physical activity is complex. Two to four hours per day playing outside is not the same as aggressive training for sports two to three times per week [105]. The latter type of activity is associated with an increased incidence of new diagnoses of asthma in areas with high ozone. Furthermore, it is well established that exercise can induce acute bronchospasm in patients with asthma. Worse still, there are children whose normal lives include so little activity that any exercise induces breathlessness or "wheezing." Indeed, it may be so difficult to diagnose asthma in obese children that the data on the association between asthma and obesity cannot be evaluated. Overall, we would argue that prolonged exercise is beneficial [106,107], although the data is confusing because so many children are poorly conditioned and develop breathlessness when they exercise vigorously.

The secondary consequences of sedentary entertainment are also complex. More time indoors could increase exposure to indoor allergens. However, it seems unlikely that the amount of increased indoor allergen exposure due to a change from 18 to 23 hours indoors is sufficient to explain the rise in asthma prevalence. Moving indoors has decreased the exposure to sunlight with a consequent decrease in production of vitamin D. However, the relationship between vitamin D deficiency and allergic disease is complex, with both high and low levels of vitamin D associated with development of allergies, and requires further investigation [108,109]. (See "Vitamin D and extraskeletal health", section on 'Autoimmunity'.)

Diet — Dietary changes have included decreased consumption of fresh fruits and vegetables; increased intake of snack foods, convenience foods, and soft drinks; and larger portion sizes. However, proving that specific diet contributes to asthma has been difficult [110]. In one study, a higher intake of beta-carotene was associated with a decreased risk of sensitization to common food and inhalant allergens in school-aged children, but there was no relationship between beta-carotene intake and current wheeze or wheezing phenotypes [111].

Farms, villages, worms, and other parasites — Exposure to farm animals, particularly early in life, is negatively associated with the development of allergic disease [112-116]. In addition, the diversity of environmental microorganism exposure is inversely associated with the risk of asthma [117].

The movement away from an agrarian society started at the time of the industrial revolution and was approximately 90 percent complete by 1940. There were only small further declines in the number of families directly associated with farming between 1960 and 2000. Today, less than 1 percent of children in the United States have contact with farm animals during childhood.

One study compared two genetically similar, reproductively isolated farming populations in the US, the Amish and the Hutterites, that are known to have dramatically different rates of asthma (5 and 21 percent, respectively) and allergic sensitization (7 and 33 percent, respectively) in schoolchildren [118]. Thirty children from each group were included in the study, with dust samples taken from 10 homes from each group. The Amish have traditional, single-family farms with exposure to horses and dairy cows, whereas the Hutterites live and work on large, communal farms that are highly industrialized. Thus, not surprisingly, the endotoxin levels were significantly higher in the Amish homes than the Hutterite homes. Dust extracts from the Amish homes, but not the Hutterite homes, significantly blocked airway hyperresponsiveness and eosinophilia in a mouse model of experimental allergic asthma. Differences were also seen in innate immune cells between the two groups, with proportionally increased neutrophils, with a phenotype suggestive of recent emigration from the bone marrow, proportionally decreased eosinophils, monocytes with a suppressive phenotype, and lower levels of cytokine production after innate stimulation in the Amish children compared with the Hutterite children.

Another study examined the differences between house dust microbiota and rates of asthma in farm and non-farm homes of Finnish birth cohorts [119]. As with previous studies, growing up on a farm was associated with a lower asthma prevalence and a rich indoor microbial composition. In contrast to non-farm homes, the microbiota in Finnish farm homes had lower levels of human-associated bacteria such as Streptococcaceae species and higher levels of outdoor microbiota that included cattle-associated bacteria that were typically absent from non-farm homes. The farm microbial profile was associated with decreased secretion of type 1 immunity-associated cytokines including interferon (IFN) gamma, interleukin (IL) 1 beta, IL-6, and IL-12 from leukocytes in cultured whole blood. Asthma risk in children who grew up in non-farm homes was inversely associated with the degree of similarity to bacterial microbiota composition of farm homes. This finding was validated in a rural German cohort of children living in non-farm homes.

A Copenhagen prospective birth cohort study of 700 children compared first year of life airway and gut microbiotas and degree of urbanization with diagnosis of asthma, eczema, allergic rhinitis, and allergen sensitization by six years of age [120]. Similar to other studies, children who lived in more urban areas in infancy were more likely to develop asthma (odds ratio [OR] 2.31, 95% CI 1.47-3.68) and aeroallergen sensitization (OR 1.77, 95% CI 1.05-3.02) after adjusting for lifestyle factors (pet ownership, number of older siblings, parent/caregiver education and income). Few children in the cohort lived on farms. Both the airway and gut microbiota differed between infants living in more versus less urban areas, the most notable difference being the more homogenous airway microbiota in infants living in urban compared with rural areas. Levels of several cytokines and chemokines also differed between the two groups, although the differences were not consistently distributed into T helper cell or regulatory cell patterns.

Some have compared life in rural villages in the developing world with farm life. In both settings, children are exposed to animals from early childhood with the probable protective effects of endotoxin. However, there are major differences as well. Both in rural Africa and Papua New Guinea, where asthma rates are low, the children run in bare feet and are exposed to helminths and ectoparasites. In addition, water quality remains poor in these regions and is frequently contaminated. The children in these villages are physically active, with low average body fat, and generally do not spend much time indoors. In addition, those children tend to have high total serum IgE, in keeping with the high rate of parasitic infections [37,38].

It was assumed for a long time that the IgE induced by parasites was either irrelevant to inhalant allergy or that it acted by blocking binding of allergen-specific IgE [121]. The discovery of tick bite-induced IgE specific for the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) altered this assumption [122]. This IgE antibody binds to any protein that carries the alpha-gal carbohydrate epitope, including proteins from all mammals except primates and humans (eg, it binds to pork thyroglobulin and cat immunoglobulin A [IgA]) [123]. IgE specific for alpha-gal is associated with delayed anaphylactic reactions to red meat [124]. The important finding for the present discussion is that high IgE titers to cat or dog allergens are not associated with respiratory symptoms upon exposure to animals in individuals with alpha-gal-specific IgE [125]. The implication is that IgE antibodies to a hapten (such as alpha-gal) could help to explain how children in African villages can have high total serum IgE without allergic symptoms [38,126]. (See "The biology of IgE" and "Allergy to meats".)

Climate factors — Several studies suggest that changes in climate factors may lead to increased symptoms or disease severity, but not necessarily cause an increase in disease prevalence. There are reported regional differences in allergic rhinitis prevalence associated with climate factors in the United States, but not a national increase in prevalence related to these factors [127]. One study found an association between an increase in outdoor temperatures and an increase in emergency department (ED) visits for asthma [128]. In another study, higher ozone levels were associated with enhanced allergenicity of birch pollen [129]. Further studies are needed to determine what role, if any, climate factors play in the prevalence of asthma and allergic rhinitis.

Environmental toxicants — Accumulating data suggest that there is a relationship between environmental toxicants, such as endocrine disrupting compounds (EDCs) and phthalates, and allergy/asthma. These products have the potential to affect the development of the immune and respiratory systems, although the exact mechanisms are not well defined.

EDCs include antimicrobial agents, such as triclosan, parabens, and bisphenol A (BPA). Triclosan, for example, was registered with the United States Environmental Protection Agency (EPA) as a pesticide in 1969 and began appearing in consumer products in the 1970s. BPA has been used in commercial products since the late 1950s. It is used to make plastics used in common consumer goods, as well as epoxy resins used as coatings in food/beverage containers and for the production of thermal paper. Phthalates are chemicals used to make plastic and vinyl softer and more flexible. These chemicals are found in a wide range of consumer products, although their use in the manufacture of pacifiers and teething products was banned in the United States in 1999.

The following studies are illustrative:

●One study examined the association between urinary levels of BPA or triclosan and the diagnosis of hay fever or allergy using data from the 2003 to 2006 National Health and Nutrition Examination Survey (NHANES) of United States adults and children over six years of age [130]. Higher levels of triclosan, but not BPA, were associated with significantly greater odds of allergy or hay fever diagnosis in those <18 years of age.

●In 860 children aged 6 to 18 years in the 2005 to 2006 NHANES, the odds of aeroallergen sensitization (specific IgE ≥0.35 kU/L) increased significantly with urinary levels of triclosan and propyl and butyl parabens [131]. In addition, the likelihood of food sensitization was positively associated with triclosan level in males but not females.

●In a study of 10-year-old Norwegian children, urinary triclosan levels were positively associated with sensitization to aeroallergens (as measured by skin prick testing or serum specific IgE levels) and allergic rhinitis [132].

●In a mouse model of asthma, triclosan exposure augmented the allergic response to an allergen (ovalbumin) [133].

●Higher concentrations of BPA and high-molecular-weight phthalates in maternal urine during pregnancy were associated with an increased risk of respiratory tract infections and wheezing in early childhood as well as asthma at seven years of age in one study [134].

●However, levels of triclosan and parabens in maternal plasma and urine in three- to four-year-old children at high risk for atopic disease were not associated with parental report of physician-diagnosed asthma or recurrent wheezing or sensitization to food or environmental allergens based upon in vitro testing at three years of age [135]. Several factors may have led to misclassification with regard to diagnosis of asthma (some may be transient wheezers) or level of exposure (more difficult to detect in plasma), which may explain lack of association in this study. Evaluation of these same children when they are a few years older may help clarify these findings.

SUMMARY

●The rise in allergic rhinitis began in the 1870s in Westernized countries and leveled off by the 1950s at a prevalence of approximately 15 to 20 percent. (See 'Epidemiologic history' above.)

●The prevalence of asthma did not begin increasing in Westernized countries until the 1960s. There was at least a 10-fold increase in asthma by 2000, with a wide range in absolute differences. The rates appear to have peaked, and may even be declining, in many of these countries. (See 'Epidemiologic history' above.)

●Asthma and allergic rhinitis prevalence began increasing in many developing countries in the late 1980s to early 1990s. (See 'Epidemiologic history' above.)

●Multiple environmental changes occurred gradually from the mid-1800s onward in Westernized countries, and these changes are now occurring, often more rapidly and simultaneously, in developing countries. These include improvements in hygiene, eradication of most parasitic worm infections, changes in home heating and ventilation, a decline in physical activity and alterations in diet due to lifestyle changes, and increasing use of environmental toxicants. Many of these changes may have influenced the development of allergic rhinitis and/or asthma. (See 'Environmental changes' above.)

●The gene-environment interactions that lead to the development of atopic diseases such as allergic rhinitis and asthma are complex. In any model as complex as this, one would expect to have studies with highly discrepant results. At this point, we have only hypotheses, with evidence to both support and refute them, not definitive conclusions. (See 'Environmental changes' above.)