Key Points
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Large geographical variations in the prevalence of allergic diseases exist worldwide among children and adults.
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Lower prevalences have been reported from developing countries, eastern European areas, rural areas in Africa and Asia, and farm populations in Europe.
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The prevalence of asthma and allergies has increased over the last few decades. This trend seems to have reached a plateau in affluent countries, but not in low- to mid-income countries.
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Allergic diseases are multifactorial illnesses determined by a complex interplay between genetic and environmental factors.
Introduction
Traditionally, asthma, allergic rhinitis and hay fever as well as atopic dermatitis and food allergy have been categorized as atopic diseases, yet the relation between clinical manifestations of these diseases and the production of IgE antibodies has not been fully clarified. Although in many patients high levels of total and specific IgE antibodies are found, many individuals in the general population will not show any signs of illness despite elevated total and specific IgE levels. In some individuals various atopic illnesses can be co-expressed, whereas in others only one manifestation of an atopic illness is present. The prevalence of these four atopic entities therefore only partially overlaps in the general population ( Figure 1-1 ). Risk factors and determinants of atopy, defined as the presence of IgE antibodies, differ from those associated with asthma, atopic dermatitis and hay fever.
Asthma, atopic dermatitis and hay fever are complex diseases and their incidence is determined by an intricate interplay of genetic and environmental factors. Environmental exposures may affect susceptible individuals during certain time windows in which particular organ systems are vulnerable to extrinsic influences such as early in life. Moreover, most allergic illnesses are likely to represent syndromes with many different phenotypes rather than single disease entities. The search for determinants of allergic illnesses must therefore take phenotypes, genes, environmental exposures and the timing (developmental aspect) of these exposures into account.
Prevalence of Childhood Asthma and Allergies
Asthma is a complex syndrome rather than a single disease entity. Different phenotypes with varying prognosis and determinants have been described, particularly over childhood years, using hypothesis and data-driven approaches. Transient wheezing is characterized by the occurrence of wheezing in infants up to the age of 2 to 3 years which disappears thereafter and does not progress to childhood asthma. There are epidemiological observations suggesting that these children may be at risk of developing chronic obstructive pulmonary disease (COPD) in adulthood. The main predictor of transient wheeze is premorbid reduced lung function, in part determined by passive smoke exposure in utero. Wheeze among school-aged children can be classified into an atopic and nonatopic phenotype. This differentiation has clinical implications as nonatopic children with wheeze outgrow their symptoms and retain normal lung function at school age. In turn, among atopic wheezy children, the time of new onset of atopic sensitization and the severity of airway responsiveness determine the progression of this wheezing phenotype over school and adolescent years.
Data-driven latent class analyses of birth cohort studies have consistently shown a persistent phenotype with symptoms starting very early in life and progressing into school age and beyond. Late onset and intermediate phenotypes have also been described. These phenotypes can only be identified in prospective studies following infants from birth, up to school age and through adolescence, enabling the differential analysis of risk factors and determinants for distinct wheezing phenotypes over time. These limitations must be borne in mind when discussing and interpreting findings from cross-sectional surveys. The relative proportion of different wheezing phenotypes is likely to vary among age groups and therefore the strength of association between different risk factors and wheeze is also likely to vary across age groups.
Similarly, limitations apply with respect to the epidemiology of atopic dermatitis. The definition of atopic eczema varies from study to study and validations of questionnaire-based estimates have been few. Skin examinations by trained field workers, adding an objective parameter to questionnaire-based data, reflect a point prevalence of skin symptoms at the time of examination and can therefore, in only a limited way, corroborate estimates of lifetime prevalence.
Lastly, identified risk factors in all cross-sectional surveys relate to the prevalence of the condition. The prevalence in turn reflects the incidence and the persistence of a disease. It is therefore often difficult to disentangle aggravating from causal factors in such studies. Only prospective surveys can identify environmental exposures prior to the onset of an atopic illness and thus infer a potentially causal relationship to the new onset of disease.
Western versus Developing Countries
In general, reported rates of asthma, hay fever and atopic dermatitis are higher in affluent, western countries than in developing countries. The worldwide prevalence of allergic diseases was assessed in the 1990s by the large scale International Study of Asthma and Allergy in Childhood (ISAAC). A total of 463,801 children in 155 collaborating centers in 56 countries were studied. Between 20-fold and 60-fold differences were found between centers in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis and atopic eczema ( Figure 1-2 ).
The European Community Respiratory Health Survey (ECRHS) studied young adults aged 20 to 44 years. A highly standardized and comprehensive study instrument including questionnaires, lung function and allergy testing was used by 35 to 48 centers in 22 countries, predominantly in Western Europe, but also in Australia, New Zealand and the USA. The ECRHS has shown large geographical differences in the prevalence of respiratory symptoms, asthma, bronchial responsiveness and atopic sensitization with high prevalence in English speaking countries and low prevalence rates in the Mediterranean region and Eastern Europe. The geographical pattern emerging from questionnaire findings was consistent with the distribution of atopy and bronchial hyperresponsiveness, supporting the conclusion that the geographical variation in asthma is true and not attributable to methodological factors such as the questionnaire phrasing, the skin testing technique or the type of assay for the measurement of specific IgE.
A strong correlation was found between the findings from children as assessed by the ISAAC Study and the rates in adults as reported by the ECRHS questionnaire. Although there were differences in the absolute prevalences observed in the two surveys, there was good overall agreement, adding support to the validity of both studies.
Dissociations between the prevalence of asthma and atopy have, however, been documented in developing countries. The ISAAC Phase II Study has demonstrated that the fractions and prevalence rates of wheeze attributable to skin test reactivity correlated strongly with the gross national income of the respective country. These findings suggest that the strength of association between atopy and asthma across the world is determined by affluence and factors relating to affluence.
The East-West Gradient across Europe
A number of reports have been published demonstrating large differences in the prevalence of asthma, airway hyperresponsiveness, hay fever and atopy in children and adults between east and west European areas. The prevalence of asthma was significantly lower in all study areas in eastern Europe compared to western Europe. Among the older age group of 13- to 14-year-old children, the prevalence of wheezing was 11.2% to 19.7% in Finland and Sweden, 7.6% to 8.5% in Estonia, Latvia and Poland, and 2.6% to 5.9% in Albania, Romania, Russia, Georgia and Uzbekistan (except Samarkand).
The rates of allergic illnesses have been rising rapidly. After reunification of Germany in 1989 a significantly lower prevalence of allergic diseases was found in East Germany. Only a few years later (2003–2006) differences in the prevalence rates between East and West Germany were no longer observed. The causes underlying the increase in prevalence in East Germany are not fully understood. The drastic decrease in family size after reunification, changes in dietary habits or indoor exposures may have contributed to this trend. Likewise, Poland’s accession to the European Union was followed by a rapid and striking increase in the prevalence of atopy in rural areas. This increase may in part be attributable to loss of traditional farming exposures.
Differences between Rural and Urban Populations
The prevalence of asthma and allergies is not only increasing with westernization and affluence, but also with urbanization. The rates of asthma and atopy among children living in Hong Kong are similar to European figures. In rural China, asthma is almost nonexistent with a prevalence of less than 1%. In Mongolia, a country in transition from rural, farming lifestyles to an industrial society, marked differences in the prevalence of asthma, allergic rhinoconjunctivitis and atopy exist. Inhabitants of small rural villages are least affected, whereas residents of the capital city, Ulaanbaatar, have high rates of allergic diseases comparable to affluent western countries.
Across Europe, differences between urban and rural areas are less clear. However, strong contrasts exist on a lower spatial scale, i.e. among children raised on a farm in comparison to their neighbours living in the same rural area but not on a farm. Since 1999, more than 30 studies have corroborated these findings. Children raised on farms retain their protection from allergy at least into adulthood.
The timing and duration of exposure seem to play a critical role. The largest reduction in risk of developing respiratory allergies is seen among those who are exposed prenatally and continue to be exposed throughout their life. The protective factors in these farming environments have not been completely unraveled. Contact with farm animals, particularly cattle, confers protection. Also the consumption of unprocessed cow’s milk has been shown to be beneficial with respect to childhood asthma and allergies. Increased levels and diversity of microbial exposures also contribute to the protective effects.
Inner City Areas of the USA
Living conditions in inner city areas in the USA are associated with a markedly increased risk of asthma. Several potential risk factors are being investigated, such as race and poverty, adherence to asthma treatment and factors related to the disproportionate exposures associated with socioeconomic disadvantage such as indoor and outdoor exposure to pollution and cockroach infestation. Cockroach exposure, at least in early life, has been associated with the development of sensitization to cockroach allergen and wheeze in infants living in inner city areas of the USA. Problems relating to inner city asthma will be discussed in more detail in Chapter 33 .
Time Trends in the Prevalence of Allergic Diseases
Data collected over the last 40 years in industrialized countries indicate a significant increase in the prevalence of asthma, hay fever and atopic dermatitis in repeated cross-sectional surveys using identical questionnaires. Most studies from industrialized countries suggest an overall increase in the prevalence of asthma and wheezing between 1960 and 1990. Many studies have been performed among children and little is known about time trends in adults. Twenty-year trends of the prevalence of treated asthma among pediatric and adult members of a large US health maintenance organization were reported. During the period 1967–1987, the treated prevalence of asthma increased significantly in all age-sex categories except males aged 65 and older. In the USA, the greatest increase was detected among children and young adults living in inner cities.
Recent studies suggest that in some areas this trend may have reached a plateau. Studies from Italy showed that among school children surveyed in 1974, 1992 and 1998 the prevalence of asthma had increased significantly during the 1974–1992 period, whereas it remained stable from 1992 to 1998. Similar findings have been reported from Germany and Switzerland, where prevalence rates have been on a plateau since the 1990s. On a global scale, time trends in the prevalence of asthma and allergic rhinoconjunctivitis have been assessed in ISAAC Phase III. The findings indicate that international differences in symptom prevalence have reduced with decreases in prevalence in English-speaking countries and Western Europe and increases in prevalence in regions where prevalence was previously low, i.e. in low- to mid-income countries.
Environmental Risk Factors for Allergic Diseases
Air Pollution
There is considerable evidence showing that increased exposure to air pollutants is a risk factor for increased morbidity of asthma with worsening of symptoms and lung function. Air pollution is a complex mixture of particulate matter of variable size and various gases. As particulates and polluting gases often co-occur, their individual contribution to worsening of asthma is hard to disentangle. In panel and time-series studies, air pollutants such as fine particles and ozone reduce lung function in children already affected by asthma and increase symptoms and medication use. Likewise, emergency room visits, general practitioner activities and hospital admissions for asthma and wheeze are positively associated with ambient air pollution levels.
Mixes of particulate matter, especially those seen with traffic related exposures, seem to have the most adverse effects. Traffic related air pollution is a complex mix of particulate matter and primary gaseous emissions including nitrogen oxides, which lead to the generation of secondary pollutants such as ozone, nitrates and organic aerosol. Traffic related pollution decreases quickly with distance from roadways. For adverse effects, distance within 300–500 m of roadways seems to be most significant. In large North American cities, 30–45% of people live within this distance and so the impact of traffic related air pollution is significant. The closeness to major roadways may be even greater in cities in Europe and the developing world. Given that disadvantaged families live close to major roadways, other risk factors such as poverty, stress and cigarette smoking may aggravate the effects.
The role of air pollution in the new onset of asthma and allergic sensitization is less well understood. There is however a growing body of prospective studies suggesting a causal role for the incidence of asthma among children and adults. In particular, long-term exposure to traffic related air pollution may again play a significant role.
Environmental Tobacco Smoke
Numerous surveys have consistently reported an association between environmental tobacco smoke (ETS) exposure and respiratory diseases. Strong evidence exists that passive smoking increases the risk of lower respiratory tract illnesses such as bronchitis, wheezy bronchitis and pneumonia in infants and young children. Maternal smoking during pregnancy and early childhood has been shown to be strongly associated with impaired lung growth and diminished lung function, which in turn may predispose infants to develop transient early wheezing. In children with asthma, parental smoking increases symptoms and the frequency of asthma attacks. Banning tobacco smoke in public places has been shown in a number of countries to result in a significant reduction in hospital admissions for asthma.
A series of epidemiological studies has also been performed to determine the effect of ETS exposure on the new onset of asthma. In most cross-sectional and longitudinal studies, passive and more importantly active smoking appears to be an important risk factor for the development of childhood, adolescent and adult asthma. In turn, no unequivocal association between ETS exposure, atopic sensitization and atopic dermatitis was found.
Water Hardness and Dampness
The domestic water supply may be relevant for the inception of atopic dermatitis. An ecological study of the relation between domestic water hardness and the prevalence of atopic eczema among British school children was performed. Geographical information systems were used to link the geographical distribution of eczema in the study area to four categories of domestic water-hardness data. Among school children aged 4 to 16 years, a significant relation was found between the prevalence of atopic eczema and water hardness, both before and after adjustment for potential confounding factors. The effect on recent eczema symptoms was stronger than on lifetime prevalence, which may indicate that water hardness acts more on existing dermatitis by exacerbating the disorder or prolonging its duration rather than as a cause of new cases. These observations await replication by other studies.
In 2004 a report by the Institutes of Medicine Committee on Damp Indoor Spaces and Health in the USA concluded that there is sufficient evidence of an association between exposure to a damp indoor environment and worsening of asthma symptoms, and that there is suggestive evidence of an association between exposure to a damp indoor environment and the development of asthma in children and adults. Dampness can elicit a number of different exposures such as fungi, bacteria or their constituents and emissions, or other agents related to damp indoor environments such as house dust mites and cockroaches. The responsible factors are not known but may vary among individuals or be potentiated in complex mixtures.
Nutrition
Breastfeeding has long been recommended for the prevention of allergic diseases. The epidemiological evidence is, however, highly controversial. Some studies even suggest that breastfeeding may result in risk of asthma and atopy, but these studies may reflect adherence to recommendations. Likewise, the age at introduction of solid foods has been fiercely debated and no conclusive evidence has been reached that would allow general recommendations. Recently, the diversity of solid foods introduced in the first year of life has been linked to less atopic dermatitis and asthma later in life.
There is increasing evidence relating body mass index to the prevalence and incidence of asthma in children and adults, males, and, more consistently, in adolescent females. It is unlikely that the association is attributable to reverse causation, i.e. that asthma precedes obesity because of exercise-induced symptoms. Rather, weight gain can antedate the development of asthma. Weight reduction among asthmatic patients can result in improvements in lung function. Obesity has been associated with inflammatory processes, which may contribute to asthma development. Other potential explanations are that mechanical factors promote asthma symptoms in obese individuals, or that gastroesophageal reflux as a result of obesity induces asthma. Furthermore, physical inactivity may promote both obesity and asthma.
Fruit, vegetable, cereal and starch consumption and intake of various fatty acids, vitamins A, C, D, E, minerals and antioxidants have all been studied. However, diet is complex and difficult to measure, and standardized tools are still lacking. All methods pertaining to food frequency, individual food items, food patterns and serum nutrients can introduce substantial misclassification, and the close correlation of many nutrients presents problems when trying to identify independent effects. The evidence from prospective studies and randomized clinical trials for individual food items has been disappointing. Thus, measures such as Mediterranean diet may better reflect real world exposures. A Mediterranean diet has in turn been linked to protection from asthma.
Allergen Exposure
Although in some studies a clear, almost linear dose-response relation between allergen exposure and sensitization has been found, others describe a bell-shaped association with higher levels of exposures relating to lower rates of atopic sensitization. Part of the discrepancy may relate to the type of allergen, since mostly cat but not house dust mite allergen exposure has been shown, in some studies, to exert protective effects at higher levels of exposure. Furthermore, there is some evidence that the presence of a dog or a cat, or both, protects from the development of allergic sensitization, indicating that the presence of an animal is more important than just exposure to its allergens.
The relationship between allergens, particularly house dust mite exposure, and asthma has been studied for many years. Overall, there is little evidence to suggest a positive association between house dust mite exposure and the new onset of childhood asthma. Intervention studies have failed to show convincing evidence of a reduction in asthma risk after the implementation of avoidance strategies. Other co-factors of exposure should, however, also be taken into account, such as exposure to microbial compounds. For example, levels of endotoxin and other microbial exposures have been shown to modify the effect of allergen exposure
Family Size, Infections and Hygiene
Strachan first reported that sibship size, the number of children produced by a pair of parents, is inversely related to the prevalence of childhood atopic diseases and thereby proposed the ‘hygiene hypothesis’. This observation has since been confirmed by numerous studies, all showing that atopy, hay fever and atopic eczema were inversely related to increasing numbers of siblings. In contrast, the relation between family size and childhood asthma and airway hyperresponsiveness is less clear. However, the underlying causes of this consistent protective effect remain unknown.
Viral infections of the respiratory tract are the major precipitants of acute exacerbations of wheezing illness at any age, yet viral respiratory infections are very common during infancy and early childhood and most children do not suffer any aftermath relating to these infections, including infections with respiratory syncytial virus and rhinovirus. Thus, host factors in children susceptible to the development of wheezing illnesses and asthma are likely to play a major role. Deficiencies in innate immune responses have been shown to contribute to a subject’s susceptibility to rhinovirus infections, the most prevalent cause of lower respiratory tract viral infections in infants associated with asthma development. Interactions between viral lower respiratory tract infections and early atopic sensitization may play a role: only among children with early onset of atopy may repeated viral infections become a risk factor for developing asthma.
However, an inverse relation between asthma and the overall burden of respiratory infections may also exist. Several studies investigating children in daycare have rather consistently shown that exposure to a daycare environment in the first months of life is associated with a significantly reduced risk of wheezing, hay fever and atopic sensitization at school age and adolescence. It remains, however, unclear whether the burden of infections or other exposures in daycare early in life account for this protective effect. Several reports have shown that children who are sero-positive for hepatitis A, Toxoplasma gondii or Helicobacter pylori have a significantly lower prevalence of atopic sensitization, allergic rhinitis and allergic asthma as compared to their sero-negative peers.
The use of antibiotics has been proposed as a risk factor for asthma and allergic diseases. In most cross-sectional studies a positive relation between antibiotics and asthma has been found which is, however, most likely to be attributable to reverse causation. Early in life, when it is difficult to diagnose asthma, antibiotics are often prescribed for respiratory symptoms in wheezy children and thus are positively associated with asthma later in life. Most studies using a prospective design have, however, failed to identify antibiotics as a risk factor antedating the new onset of asthma. Similar problems arise when interpreting the positive relation between paracetamol use and asthma seen in cross-sectional studies. Intervention trials are needed to come to firm conclusions.
Active and chronic helminthic infections were reported to be protective from atopy, but findings are less consistent for wheeze and asthma. Part of the discrepancies in the literature reporting associations between helminths and allergic diseases may be the load of parasitic infestation and the type of helminths in a particular area. Microbial stimulation, both from normal commensals and pathogens through the gut, may be another route of exposure which may have altered the normal intestinal colonization pattern in infancy. Thereby, the induction and maintenance of oral tolerance of innocuous antigens such as food proteins and inhaled allergens may be substantially hampered. These hypotheses, though intriguing, have to date not been supported by epidemiological evidence since significant methodological difficulties arise when attempting to measure the microbial pattern of the intestinal flora.
Exposure to microbes does not only occur through invasive infection of human tissues. Viable germs and nonviable parts of microbial organisms are ubiquitous in nature and can be found in varying concentrations in our daily indoor and outdoor environments, and also in urban areas. These microbial products are recognized by the innate immune system and induce an inflammatory response. Therefore, environmental exposure to microbial products may play a crucial role in the maturation of a child’s immune response, enabling tolerance of other components of its natural environment such as pollen and animal dander.
A number of studies have in fact shown that environmental exposure to endotoxin, a component of the cell wall of Gram negative bacteria, is inversely related to the development of atopic sensitization and atopic dermatitis ; yet endotoxin exposure is a risk factor for wheezing and asthma as shown in a number of studies. Muramic acid, a component of the cell wall of all bacteria, but more abundant in Gram positive bacteria, has been inversely related to asthma and wheeze, but not atopy. Compounds related to fungal exposures, such as extracellular polysaccharides derived from Penicillium spp. and Aspergillus spp., have also been inversely associated with asthma. These microbial compounds are found in higher abundance in farming than nonfarming environments. Recent findings using culture based and DNA based analyses suggest that the diversity in environmental microbial (bacterial and fungal) exposures explains at least in part the ‘farm effect’ on childhood asthma.
These environmental microbial exposures may shape a subject’s microbiome at mucosal surfaces. Thus, the true intermediary between the environment and the host may be the microbiota. While there exists intriguing evidence in experimental studies in mice, the precise role of the microbiome for developing allergic diseases on a population level has not been determined.
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