Key Points
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The atopic disorders – atopic dermatitis, food and inhalant allergies, allergic rhinoconjunctivitis and asthma – tend to cluster in individuals, families and locales
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A developmental ‘allergic march’ of childhood begins with atopic dermatitis, food allergies and bronchiolitis episodes in the first few years of life, and progresses to inhalant allergic sensitization, allergic rhinoconjunctivitis and atopic asthma.
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Although persistent asthma commonly begins in the first few years of life, most infants and toddlers who have recurrent bronchiolitis episodes do not go on to have persistent asthma in later childhood and adulthood. Early life predictive factors for disease persistence include allergic march manifestations (atopic dermatitis, food allergy, allergic sensitization to inhalant allergens), recurrent bronchiolitis episodes triggered by common rhinoviruses, and parental asthma.
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Epidemiologic evidence suggests that atopic disorders are caused by environmental and lifestyle factors in the susceptible host.
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While atopy is a common feature of childhood asthma, additional factors appear to contribute to severe, persistent disease expression, including early onset, chronic exposure to sensitized allergen in the home and a dysregulated ‘Th2-high’ immunopathology.
Natural history studies of allergic diseases and asthma are fundamental for predicting disease onset and prognosis. Such studies reveal a developmental ‘allergic march’ in childhood, from the early onset of atopic dermatitis (AD) and food allergies in infancy, to asthma, allergic rhinitis (AR) and inhalant allergen sensitization in later childhood. Allergy and asthma of earlier onset and greater severity are generally associated with disease persistence. Therefore, allergy and asthma commonly develop during the early childhood years, the period of greatest immune maturation and lung growth. This highlights the importance of growth and development in a conceptual framework for allergy and asthma pathogenesis.
This chapter reviews the allergic march of childhood and its different clinical manifestations: food allergies, AD, inhalant allergies, AR and asthma. The natural history of anaphylaxis, an allergic condition not currently implicated in the allergic march, is also covered. Interventions that reduce the prevalence of allergy and asthma are reviewed toward the end of the chapter. The findings and conclusions presented in this chapter are largely based on long-term prospective (i.e. ‘natural history’) studies. Complementary reviews of the epidemiology of allergic diseases in childhood can be found in Chapter 1 , and the prevention and natural history of food allergy in Chapter 43 .
Allergic March of Childhood
Three prospective, longitudinal, birth cohort studies exemplify optimized natural history studies that are rich resources for our current understanding of the development and outcome of allergy and asthma in childhood: (1) the Tucson Children’s Respiratory Study (CRS) in Tucson, Arizona (begun in 1980); (2) a Kaiser-based study in San Diego, California (begun in 1981); and the German Multicentre Allergy Study (MAS) in Germany (begun in 1990). The major findings of these studies have been consistent and reveal a common pattern of allergy and asthma development that begins in infancy.
- 1.
The highest incidence of AD and food allergies is in the first 2 years of life ( Figure 2-1 ). It is generally believed that infants rarely manifest allergic symptoms in the first month of life. By 3 months of age, however, AD, food allergies and wheezing problems are common.
Figure 2-1
Allergic march of early childhood. Period prevalence of atopic dermatitis, food allergy, allergic rhinitis and asthma from birth to 7 years in prophylactic-treated (allergenic food avoidance) and untreated (control) groups (Kaiser Permanente; San Diego). * P ≤ .05; ** P < .01.
(Data from Zeiger RS, Heller S, J Allergy Clin Immunol 1995;95:1179–90; and Zeiger RS, Heller S, Mellon MH, et al. J Allergy Clin Immunol 1989;84:72–89.)
- 2.
This is paralleled by a high prevalence of food allergen sensitization in the first 2 years of life. Early food allergen sensitization is an important risk factor for food allergies, AD and asthma.
- 3.
Allergic airways diseases generally begin slightly later in childhood (see Figure 2-1 ). Childhood asthma often initially manifests with a lower respiratory tract infection or bronchiolitis episodes in the first few years of life.
- 4.
AR commonly begins in childhood, although there is also good evidence that it often develops in early adulthood.
- 5.
The development of AR and persistent asthma is paralleled by a rise in inhalant allergen sensitization. Perennial inhalant allergen sensitization (i.e. cat dander, dust mites) emerges between 2 and 5 years of age, and seasonal inhalant allergen sensitization becomes apparent slightly later in life (ages 3 to 5 years).
Early Immune Development Underlying Allergies
A paradigm of immune development underlies allergy development and progression in early childhood (see Chapter 6 ). Briefly, the immune system of the fetus is maintained in a tolerogenic state, preventing adverse immune responses and rejection between the mother and fetus. Placental interleukin-10 (IL-10) suppresses the production of immune-potentiating interferon gamma (IFN-γ) by fetal immune cells. IFN-γ down-regulates the production of pro-allergic cytokines, such as IL-4 and IL-13. The reciprocal relationship between these cytokines and the immune cells that produce them defines ‘T-helper 2’ (Th2), pro-allergic immune responses (i.e. IL-4, IL-13), and antiallergic ‘T-helper 1’ (Th1) immune development (i.e. IFN-γ). Thus the conditions that favor immune tolerance in utero may also foster allergic immune responses, such that newborn immune responses to ubiquitous ingested and inhaled proteins are Th2 biased. Postnatally, encounters with these common allergenic proteins lead to the development of mature immune responses to them. The underlying immune characteristics of allergic diseases – allergen-specific memory Th2 cells and immunoglobulin E (IgE) – can be viewed as aberrant manifestations of immune maturation that typically develop during these early years, and might have their roots in the inadequate or delayed development of regulatory T lymphocytes that can inhibit them.
Total Serum IgE Levels
At birth, cord blood IgE levels are almost undetectable; these levels increase during the first 6 years of life. Elevated serum IgE levels in infancy have been associated with persistent asthma in later childhood. High serum IgE levels in later childhood (i.e. after 11 years of age) have also been well correlated with bronchial hyperresponsiveness (BHR) and asthma.
Allergen-Specific IgE
In two birth cohort (up to 5 years old) studies of IgG and IgE antibody development to common food and inhalant allergens, IgG antibodies to milk and egg proteins were detectable in nearly all subjects in the first 12 months of life, implying that the infant immune system sees and responds to commonly ingested proteins. In comparison, food allergen-specific IgE (especially to egg) was measurable in approximately 30% of subjects at 1 year of age. Low-level IgE responses to food allergens in infancy were common and transient, and sometimes occurred before introduction of the foods into the diet. In children who developed clinical allergic conditions, higher levels and persistence of food allergen-specific IgE were typical.
Of seasonal inhalant allergens, ragweed and grass allergen-specific IgGs were detectable in approximately 25% of subjects at 3 to 6 months of age, and steadily increased to 40% to 50% by 5 years of age. In comparison, allergen-specific IgE was detected in < 5% of subjects from 3 to 12 months of age, and increased in prevalence to approximately 20% by 5 years of age. Therefore, allergen-specific IgE production emerges in the preschool years and persists in those who develop clinical allergies.
Allergen-Specific Th2 Lymphocytes, and Their Regulation by Th1 and TREG Lymphocytes
The development of allergen-specific antibody production is indicative of allergen-specific T lymphocytes that are guiding the development and differentiation of B lymphocytes to produce IgE through secreted Th2-type cytokines (i.e. IL-4, IL-13) and cell surface molecular interactions (i.e. CD40/CD40 ligand). T cell-derived IL-4, IL-5 and GM-CSF also support eosinophil and mast cell development and differentiation in allergic inflammation. A current paradigm for allergic disease suggests that pro-allergic Th2 cells are (1) differentiated to produce cytokines that direct allergic responses and inflammation, (2) opposed by Th1 cells that produce counter-regulatory cytokines (e.g. IFN-γ) that inhibit Th2 differentiation, and (3) suppressed by regulatory T lymphocytes. As an example of this Th2/Th1/T reg paradigm, peripheral blood mononuclear cells from infants who have milk allergy or peanut sensitization, or ultimately manifest allergic disease at 2 years of age, produce more pro-allergic Th2 cytokines (i.e. IL-4) to allergen-specific stimulation in vitro. In comparison, infants who continue to be nonallergic (i.e. no allergic disease and/or no allergen sensitization in later childhood) produce more counter-regulatory IFN-γ to nonspecific and allergen-specific stimuli. Infants with reduced allergic sensitization also have increased IL-10-producing T lymphocyte numbers and suppressive function.
Infants with diminished Th1 responses may be more susceptible to developing asthma for additional reasons. Bronchiolitic infants who continue to have persistent wheezing and airflow obstruction also produce less IFN-γ. This suggests that infants who produce less IFN-γ to ubiquitous allergens and to airway viral infections are susceptible to chronic allergic diseases and asthma because (1) they are less able to impede the development of allergen-specific T cells and IgE, and (2) they are more likely to manifest persistent airways abnormalities following respiratory viral infections.
Childhood Asthma
Approximately 80% of asthmatic patients report disease onset before 6 years of age. However, of all young children who experience recurrent wheezing, only a minority will go on to have persistent asthma in later life. The most common form of recurrent wheezing in preschool children occurs primarily with viral infections ( Box 2-1 ). These ‘transient wheezers’ or ‘wheezy bronchitics’ are not at an increased risk of having asthma in later life. Transient wheezing is associated with airways viral infections, smaller airways and lung size, male gender, low birth weight, and prenatal environmental tobacco smoke (ETS) exposure.
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Transient early wheezing or wheezy bronchitis: most common in infancy and preschool years
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Persistent allergy-associated asthma: most common phenotype in school-age children, adults and elderly
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Nonallergic wheezing: associated with bronchial hyperresponsiveness at birth; continues into childhood
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Asthma associated with obesity, female gender and early-onset puberty: emerges between 6 and 11 years of age
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Asthma mediated by occupational-type exposures: a probable type of childhood asthma in children living in particular locales, although not yet demonstrated
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Triad asthma: asthma associated with chronic sinusitis, nasal polyposis and/or hypersensitivity to nonsteroidal antiinflammatory medications (e.g. aspirin, ibuprofen); rarely begins in childhood
Persistent asthma commonly begins and co-exists with the large population of transient wheezers (see Box 2-1 ). Persistent asthma is strongly associated with allergy, which is evident in the early childhood years as clinical conditions (i.e. AD, AR, food allergies) or by testing for allergen sensitization to inhalant and food allergens (e.g. IgE, allergy skin testing). Severity of childhood asthma, determined clinically or by lung function impairment, also predicts asthma persistence into adulthood.
Early Childhood: Transient vs Persistent Asthma
In the Tucson CRS study, approximately 50% of young children experienced a period of recurrent wheezing and/or coughing in the first 6 years of life. These early-childhood wheezers were further subdivided into: (1) ‘transient early wheezers,’ with wheezing only < 3 years; (2) ‘persistent wheezers,’ with manifestations through the first 6 years; and (3) ‘late-onset wheezers,’ with manifestations only after 3 years. Transient wheezers comprised the largest proportion of the group, at 20%; persistent and late-onset wheezers made up slightly smaller proportions (14% and 15%, respectively). Of the three groups, persistent wheezers had the greatest likelihood of persistent asthma in later childhood ( Figure 2-2 ). By age 16 years, approximately 50% of those with persistent or late-onset wheezing in early life continued to have recurrent wheezing/coughing episodes. In contrast, the prevalence of persistent asthma in the transient wheezer group was approximately 20% and not different from nonwheezers.
Lung function in the Tucson CRS was measured in the first year of life (before the occurrence of lower respiratory tract infections) and at 6 years of age. Interestingly, transient wheezers had the lowest airflow measures in infancy, suggesting that they had the narrowest airways and/or the smallest lungs at birth. Their reduced lung function improved significantly by age 6 years, but continued to be lower than normal at age 16 years. In comparison, persistent wheezers demonstrated normal lung function in the first few months of life but a significant decline in airflow measures by 6 years of age that persisted as lower than normal at age 16 years. Therefore, lung function in transient early and persistent wheezers remained lower than normal nonwheezers through age 16 years, indicating two different clinical patterns of recurrent wheezing in early childhood that are associated with persistently low lung function established early in life.
Some children with BHR in early life are also more likely to have persistent asthma. Investigators of a birth cohort in Perth, Australia, found that BHR at 1 month of age was associated with lower lung function (i.e. FEV 1 and FVC) and a higher likelihood of asthma at 6 years of age. Interestingly, congenital BHR was not associated with total serum IgE, eosinophilia, allergen sensitization or BHR at 6 years of age and was independent of gender, family history of asthma and maternal smoking. In the Tucson CRS study, BHR measured at age 6 years predicted chronic and newly diagnosed asthma at age 22 years.
Asthma from Childhood to Adulthood
A cohort of 7-year-old children with asthma living in Melbourne, Australia, was restudied for persistence and severity of asthma at 10, 14, 21, 28, 35 and 42 years of age. At 42 years of age, 71% of the asthmatics and 89% of the severe asthmatics continued to have asthma symptoms; 76% of the severe asthmatics reported frequent or persistent asthma. In comparison, 15% of ‘mild wheezy bronchitics’ (i.e. wheezing only with colds at 7 years of age) and 28% of ‘wheezy bronchitics’ (i.e. at least five episodes of wheezing with colds) reported frequent or persistent asthma. These observations – that many children with asthma experience disease remission or improvement in early adulthood but that severe asthma persists with age – are remarkably similar to those of several other natural history studies of childhood asthma into adulthood.
Spirometric measures of lung function of the Melbourne study children initially revealed that asthmatics (especially severe asthmatics) had lung function impairment, whereas wheezy bronchitics (i.e. ‘transient’ wheezers) had lung function that was not different from that of nonasthmatics. Over the ensuing years these differences in lung function impairment between groups persisted in parallel, without a greater rate of decline in lung function in any group ( Figure 2-3 ). Beginning from birth, in the Tucson CRS, low lung function in infancy also persisted through ages 11, 16 and 22 years. However, some children with persistent asthma demonstrated progressive decline in lung function. In the longitudinal CAMP study, approximately 25% of elementary school-age children with persistent asthma manifested progressive decline in lung function annually for 4 years. Risk factors for progressive decline in lung function included male gender, younger age and hyperinflation. These findings support the importance of the early childhood years in lung and asthma development. The establishment of chronic disease and lung function impairment in early life appears to predict persistent asthma and lung dysfunction well into adulthood; however, progressive decline in lung function can occur in some children during school-age years.
Risk Factors for Persistent Asthma
Natural history studies of asthma have identified biologic, genetic and environmental risk factors for persistent asthma ( Box 2-2 ). From the Tucson CRS, a statistical optimization of the major risk factors for persistent childhood asthma provided 97% specificity and 77% positive predictive value for persistent asthma in later childhood ( Figure 2-4 ).
Allergy
Atopic dermatitis
Allergic rhinitis
Elevated total serum IgE levels (first year of life)
Peripheral blood eosinophilia > 4% (2 to 3 years of age)
Inhalant and food allergen sensitization
Gender
Males
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Transient wheezing
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Persistent allergy-associated asthma
Females
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Asthma associated with obesity and early-onset puberty
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‘Triad’ asthma (adulthood)
Parental Asthma
LOWER RESPIRATORY TRACT INFECTIONS
Rhinovirus, respiratory syncytial virus
Severe bronchiolitis (i.e. requiring hospitalization)
Pneumonia
ENVIRONMENTAL TOBACCO SMOKE EXPOSURE (INCLUDING PRENATAL)
Allergy
Essentially all of the current natural history studies have found that allergic disease and evidence of pro-allergic immune development are significant risk factors for persistent asthma. For example, in the Tucson CRS, early AD, AR, elevated serum IgE levels in the first year of life and peripheral blood eosinophilia were all significant risk factors for persistent asthma. In the Berlin MAS study, additional risk factors for asthma and BHR at age 7 years included persistent sensitization to foods (i.e. hen’s egg, cow’s milk, wheat and/or soy) and perennial inhalant allergens (i.e. dust mite, cat dander), especially in early life. The combination of allergic sensitization to major indoor allergens (dog, cat and/or mite) by age 3 years with higher levels of allergen exposure in the home was associated with persistent wheezing and lower lung function into adolescence. In the Kaiser San Diego study, milk or peanut allergen sensitization was a risk factor for asthma. Natural history studies of asthma that have extended into adulthood continue to find allergy to be a risk factor for persistent asthma. Since the eight-center Childhood Asthma Management Program (CAMP) study of 1,041 asthmatic children ages 5 to 12 years found that 88% were sensitized to at least one inhalant allergen at study enrollment, allergy-associated asthma appears to be the most common form of asthma in elementary school-age children in the USA. Furthermore, in the International Study of Asthma and Allergies in Childhood (ISAAC), strong correlations between high asthma prevalence and both high allergic rhinoconjunctivitis and high AD prevalence in different sites throughout the world suggest that allergy-associated asthma is also the most common form of childhood asthma worldwide. In children with recurrent cough or wheeze in early life, early manifestations of atopy are well-regarded predictive risk factors for persistent lung dysfunction and clinical disease ( Figure 2-4 ).
Gender
Male gender is a risk factor for both transient wheezing and persistent asthma in childhood. This is generally believed to be caused by the smaller airways of young boys when compared with girls. Later in childhood, BHR and inhalant allergen sensitization are more prevalent in boys than in girls. For asthma persistence from childhood to adulthood, female gender is a risk factor for greater asthma severity and BHR. Female children who become overweight and have early-onset puberty are also more likely to develop asthma in adolescence, an association not appreciated in males (see Figure 2-2 ). These observations are consistent with the gender ‘flip’ in asthma prevalence – higher in males in childhood, and in females by adulthood.
Parental History of Asthma
Infants whose parents report a history of childhood asthma have lower lung function and are more likely to wheeze in early life, in later childhood and in adulthood. However, in a two-generation, longitudinal study in Aberdeen, Scotland, the children of well-characterized subjects without atopy or asthma were found to have a surprisingly high prevalence of allergen sensitization (56%) and wheezing (33%). Similarly, in the MAS study, the majority of children with AD and/or asthma in early childhood were born to nonallergic parents. For example, of the study’s asthmatic children at 5 years of age, 57% were born to parents without an atopic history. Therefore allergen sensitization and asthma seem to be occurring at high rates, even in persons considered to be at low genetic risk for allergy and asthma.
Lower Respiratory Tract Infections
Certain respiratory viruses have been associated with persistent wheezing problems in children. It is not known if persistent airways abnormalities are primarily the result of virus-induced damage, vulnerable individuals revealing their airway susceptibility to virus-induced airflow obstruction, or airways injury with aberrant repair. In long-term studies, infants hospitalized with respiratory syncytial virus (RSV) bronchiolitis (most occurred by 4 months of age) were significantly more likely to have asthma and lung dysfunction through age 13 years. In the Tucson CRS birth cohort, 91% of lower respiratory tract infections (LRTIs) in the first 3 years of life were cultured for common pathogens: 44% were RSV-positive, 14% were parainfluenza-positive, 14% were culture-positive for other respiratory pathogens, and 27% were culture-negative. Followed prospectively, infants with RSV LRTI were more likely to have wheezing symptoms at 6 years of age but not at later ages (i.e. 11 and 13 years old). However, young children who had radiographic evidence of pneumonia or croup symptoms accompanying wheezing were more likely to have persistent asthma symptoms and lung function impairment at 6 and 11 years of age.
Improved PCR-based detection methods have affirmed a strong association between rhinovirus infection and asthma exacerbations, such that approximately 40% to 70% of wheezing illnesses and asthma exacerbations in children can be attributed to rhinovirus. People with asthma do not appear to be more susceptible to rhinovirus infection, but they are more likely to develop an LRTI with symptoms that are more severe and longer lasting. In the Childhood Origins of Asthma (COAST) birth cohort study, 90% of children with rhinovirus-associated wheezing episodes at age 3 years had asthma at age 6 years, such that a rhinovirus-associated wheezing episode at age 3 years was a stronger predictor of subsequent asthma than aeroallergen sensitization (odds ratios 25.6 vs 3.4). This supports the premise that individuals with lower airway vulnerability to common respiratory viruses are at risk for wheezing episodes and persistent asthma.
Environmental Tobacco Smoke Exposure
ETS exposure is a risk factor for wheezing problems at all ages. Prenatal ETS exposure is associated, in a dose-dependent manner, with wheezing manifestations and decreased lung function in infancy and early childhood. Postnatal ETS exposure is associated with a greater likelihood of wheezing in infancy, transient wheezing, and persistent asthma in childhood. Cigarette smoking has also been strongly associated with persistent asthma and asthma relapses in adulthood.
ETS exposure is also associated with food allergen sensitization, AR, hospitalization for LRTIs, BHR and elevated serum IgE levels. In a 7-year prospective study, ETS exposure was associated with greater inhalant allergen sensitization and reduced lung function.
Asthma- and Allergy-Protective Influences
Some lifestyle differences may impart asthma- and/or allergy-protective effects. Natural history studies have started to contribute some epidemiologic evidence in support of these hypotheses.
Breastfeeding
Numerous studies have investigated the potential of early breastfeeding as a protective influence against the development of allergy and asthma. Meta-analyses of prospective studies of exclusive breastfeeding for 4 or more months from birth have been associated with less AD and asthma (summary odds ratios of 0.68 and 0.70, respectively).
Microbial Exposures
Numerous epidemiologic studies have found that a variety of microbial exposures are associated with a lower likelihood of allergen sensitization, allergic disease and asthma. This has led to a ‘hygiene’ hypothesis, which proposes that the reduction of microbial exposures in childhood in modernized locales has led to the rise in allergy and asthma. Microbes and their molecular components are believed to influence early childhood development by inducing Th1-type and regulatory immune development and immune memory, thereby preventing the development of allergen sensitization and diseases, while strengthening the immune response and controlling inflammation to common respiratory viral infections.
To address this hypothesis, natural history studies have begun to explore the relationships between microbes and their components (e.g. home environmental bacterial endotoxin) to the development of allergies and asthma:
- 1.
In the Tucson CRS, children raised in larger families or in daycare from an early age (believed to be surrogate measures for more respiratory infections and microbial exposures) were less likely to have asthma symptoms in later childhood. In the German MAS study, more runny nose colds in the first 3 years of life were associated with a lower likelihood of allergen sensitization, asthma and BHR at 7 years of age. A dose-dependent effect was observed, such that children who experienced at least eight colds by age 3 years had an adjusted odds ratio of 0.16 for asthma at age 7 years.
- 2.
In infants and children, higher house dust endotoxin levels were associated with less AD, inhalant allergen sensitization, AR and asthma. Complementary immunologic studies reveal that higher house dust endotoxin levels were associated with increased proportions of Th1-type cells, higher levels of IFN-γ from stimulated peripheral blood samples and immune down-regulation of endotoxin-stimulated blood samples. In contrast to these atopy-protective influences, higher endotoxin levels were associated with more wheezing, even when a protective effect on atopy in early life was concurrently observed.
- 3.
Gastrointestinal (GI) microbiota shape early immune development, and some investigators identified differences in stool bacteria from newborns and infants who ultimately go on to develop allergic disease as being less diverse and having more clostridia and Staphylococcus aureus , while nonallergic infants had more enterococci, bifidobacteria, lactobacilli and Bacteroides . Alterations in the gut microbiome of infants from dietary and environmental differences (e.g. breastfeeding, semi-sterile food, infections, antibiotic use, siblings, pets) may influence the developing immune system and allergy outcomes.
- 4.
Diverse environmental microbiomes associated with animal exposures may exert a protective influence on the development of asthma. In Europe, farm versus non-farm children were exposed to a greater diversity of bacteria and fungi in their mattress dust, and diversity of microbial exposure was inversely related to asthma risk. Interestingly, in US inner city locales known for a higher prevalence of severe asthma, cockroach, mouse and cat allergen exposure in the first year of life was inversely associated with recurrent wheeze (odds ratios 0.60–0.75). Cockroach and mouse exposure were associated with bacterial Bacteroidetes and Firmicutes phyla in house dust samples, which were associated with lack of atopy and wheeze.
Conversely, some microbial exposures have been associated with the development of persistent asthma. Nasopharyngeal carriage of common respiratory pathogens ( Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenzae ) in infancy, and in children with asthma in later childhood ( S. pneumoniae, M. catarrhalis ), was associated with asthma exacerbations, implicating these respiratory pathogens as co-exposures in the pathogenesis of asthma persistence and exacerbations.
Pet Ownership
Multiple longitudinal birth cohort studies have observed dog and/or cat ownership to be associated with a lower likelihood of AD, allergen sensitization and asthma. Similarly, in farming and rural locales, a lower likelihood of allergy and asthma has been associated with animal contact or the keeping of domestic animals in the home. Two meta-analyses of numerous studies of domestic animal exposure and allergy and asthma outcomes generally found a protective effect. Although the mechanism(s) for this protective association is unclear, one possibility is that greater bacterial exposure occurs with animal contact and/or animal/petkeeping in the home. Indoor pets are a major factor associated with higher indoor endotoxin levels in metropolitan homes. Bacterial community diversity in house dust samples from households with pet dogs, and some with cats, is increased.
Vitamin D
There is current conjecture that vitamin D supplementation can prevent allergy and asthma. It has been hypothesized that modern lifestyles with greater time spent indoors have fostered more vitamin D deficiency, resulting in more asthma and allergy. The scientific rationale is appealing: vitamin D has been shown to bolster innate antimicrobial and regulatory T lymphocyte responses. Complementing this mechanistic science, three birth cohort studies have observed that high maternal vitamin D intake during pregnancy was associated with a lower risk of recurrent/persistent wheeze or asthma in preschool childhood. Clinical trials to determine the potential preventive benefits of vitamin D supplementation on allergy and asthma are ongoing.
Childhood Asthma Phenotypes
Different severity phenotypes of children with persistent asthma have recently been characterized using cluster analysis. In the Childhood Asthma Management Program (CAMP) study, five main phenotypes were distinguished: (1) ‘mild asthma’ with low atopy, airways obstruction and exacerbation rate; (2) atopic asthma with atopic dermatitis/allergic rhinitis/allergic sensitization, normal lung function and low exacerbation rates; (3) high allergic rhinitis/allergic sensitization, reduced lung function and moderate exacerbation rates; (4) reduced lung function and high bronchodilator responses, BHR and exacerbation/hospitalization rates; and (5) the highest atopy/serum IgE/eosinophilia, reduced lung function, high bronchodilator responses/BHR, and the highest exacerbation and hospitalization rates. Children in these different clusters appeared to be temporally stable over the 5 years of the CAMP study, with mild versus severe diverging over time. These clusters were consistent with those identified in the Severe Asthma Research Program (SARP). The most severe phenotype in children appears consistent with a severe ‘Th2-high’ phenotype in adults, with IL-13-induced epithelial gene expression (e.g. periostin), atopic airways inflammation and exacerbation risk.
Asthma mediated by occupational-type exposures is often not considered in children, and yet some children are raised in settings where occupational-type exposures can mediate asthma in adults (e.g. on farms or with farm animals in the home). Children with hypersensitivity and exposure to other common airways irritants or air pollutants such as ETS, endotoxin, ozone, sulfur dioxide or cold air may also contribute to the pool of nonatopic children with persistent asthma. ‘Triad’ asthma, characteristically associated with hyperplastic sinusitis/nasal polyposis and/or hypersensitivity to nonsteroidal antiinflammatory medications (e.g. aspirin, ibuprofen), rarely occurs in childhood.
Atopic Dermatitis
AD usually begins during the preschool years and persists throughout childhood. Two prospective birth cohort studies have found the peak incidence of AD to be in the first 2 years of life (see Figure 2-1 ). Although 66% to 90% of patients with AD have clinical manifestations before 7 years of age, eczematous lesions in the first 2 months of life are rare. Natural history studies of AD have reported a wide variation (35% to 82%) in disease persistence throughout childhood. The greatest remission in AD seems to occur between 8 and 11 years of age and, to a lesser extent, between 12 and 16 years. Natural history studies of AD may have underestimated the persistent nature of the disease for reasons that include (1) AD definition – some studies have included other forms of dermatitis that have a better prognosis over time (i.e. seborrheic dermatitis), (2) AD recurrence – a recent 23-year birth cohort study found that many patients who went into disease remission in childhood had an AD recurrence in early adulthood, and (3) AD manifestation – it is generally believed that patients with childhood AD will often evolve to manifest hand and/or foot dermatitis as adults.
Parental history of AD is an important risk factor for childhood AD. This apparent heritability complements studies revealing a high concordance rate of AD among monozygotic versus dizygotic twins (0.72 vs 0.23, respectively). In a risk factor assessment for AD in the first 2 years of life, higher levels of maternal education and living in less crowded homes were risk factors for early-onset AD. The environmental/lifestyle risk factors reported for AR and asthma are similar. A meta-analysis of prospective breastfeeding studies concluded that exclusive breastfeeding of infants with a family history of atopy for at least the first 3 months of life is associated with a lower likelihood of childhood AD (odds ratio 0.58). This protective effect was not observed, however, in children without a family history of atopy.
Initial AD disease severity seems predictive of later disease severity and persistence. Of adolescents with moderate to severe AD, 77% to 91% continued to have persistent disease in adulthood. In comparison, of adolescents with mild AD, 50% had AD in adulthood. Food allergen sensitization and exposure in early childhood also contribute to AD development and disease severity. Food allergen sensitization is associated with greater AD severity. Furthermore, elimination of common allergenic foods in infancy (i.e. soy, milk, egg, peanuts) is associated with a lower prevalence of allergic skin conditions up to age 2 years (see Figure 2-1 ).
Natural history studies have found early childhood AD to be a major risk factor for food allergen sensitization in infancy, inhalant allergen sensitization and persistent asthma in later childhood. In particular, severe AD in early childhood is associated with a high prevalence of allergen sensitization and airways allergic disease in later childhood (i.e. 4 years later; Figure 2-5 ). Indeed, in young patients with severe AD, 100% developed inhalant allergen sensitization and 75% developed an allergic respiratory disease (mostly asthma) over 4 years. In contrast to severe AD, patients with mild to moderate AD were not as likely to develop allergen sensitization (36%) or an allergic respiratory disease (26%). More information on current concepts of barrier and immune dysfunction in AD, and the role of food hypersensitivity, can be found in Chapters 50 and 47 , respectively.
