Childhood Asthma Lesley Lowe, BSc, Adnan Custovic, MSc, DM, MD, PhD, and Ashley Woodcock, BSc, MB, ChB, MD, FRCP

Address North West Lung Centre, Wythenshawe Hospital, Southmoor Road, Wythenshawe, Manchester M23 9LT, UK. E-mail: [email protected] Current Allergy and Asthma Reports 2004, 4:159–165 Current Science Inc. ISSN 1529-7322 Copyright © 2004 by Current Science Inc.

The prevalence of asthma and wheezing illness in children has increased substantially over recent decades and places a large burden on health care resources. Despite increasing evidence that both genetic and environmental factors have significant effects on airway development and function in early life, our understanding of the natural history of the disease is limited. Several phenotypes of wheeze have been described and many risk factors identified for the development of asthma. A thorough knowledge of early life lung physiology will enable us to identify children at risk for developing persistent disease. The development of objective outcome measures that can be applied in early life will aid in distinguishing between children with transient early wheeze and those who will progress to persistent disease, enabling effective, targeted therapy.

Introduction There is little doubt that the prevalence of asthma and wheezing illness has increased substantially over the last three decades, although there might be signs that the increase might have reached a plateau [1]. Asthma now affects more than 5 million people in the UK, including 1.4 million children [2]. In primary care, doctor-diagnosed asthma accounts for 1 in 20 of all consultations with children, with the rate of consultations being particularly high in the pre-school age group [3]. Respiratory disease accounts for 14% of all hospital admissions in childhood with 15% of these being related to asthma. Among children hospitalized with asthma, pre-school children are admitted more often than older children [4]. Asthma is at least partially defined by abnormalities of lung function, including variable airway obstruction and increased bronchial hyperresponsiveness (BHR). As more than 80% of all cases of persistent asthma begin before the age of 6 years, there is a growing interest in developing objective measures of lung function that can be applied in very young children to elucidate the critical factors in the development of the disease and quantify responses to

treatment. However, it is estimated that one in four of all children being treated for asthma (including one in five children being treated with inhaled corticosteroids) have never had their lung function assessed, even with a simple peak flow meter.

Identification of Wheeze Phenotypes In recent years our understanding of the nature of childhood wheezing illness has been augmented by the characterization of distinct wheeze phenotypes in early life. The Tucson study assigned children to four categories according to their history of wheezing [5]. • Never wheezing: Children who had no recorded lower respiratory tract illness with wheezing during the first 3 years of life and had no wheezing at 6 years of age. • Transient early wheezing: Children with at least one lower respiratory tract illness with wheezing during the first 3 years of life, but no wheezing at 6 years of age. These children tend to have reduced lung function at birth, and lung function remains low at age 6, compared with children with no history of wheeze. • Late-onset wheezing: Children who had no lower respiratory tract illness with wheezing during the first 3 years of life, but who had wheezing at 6 years of age. In common with persistent wheezers, these children had reduced maximal expiratory flow at functional residual capacity (VmaxFRC) values in infancy that were not significantly different from children who had never wheezed. • Persistent wheezing: Children who had at least one lower respiratory tract illness with wheezing in the first 3 years of life and had wheezing at 6 years of age. These children had significantly reduced lung function at the age of 6 years; however, their lung function in infancy was similar to children who had never wheezed.

However, it should be emphasized that these categories predominantly reflect the temporal distribution of symptoms, rather than symptom severity. Within the groups of children with late-onset and persistent wheezing, there is a whole spectrum of phenotypes, ranging from individuals with mild intermittent symptoms to those with severe and

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troublesome asthma. Longitudinal data provide evidence for the relationship between deficits in lung function and the clinical expression of asthma, suggesting that most asthma originates in childhood in association with disordered lung function that tracks to subsequent persistent disease. The Melbourne Asthma Study assessed lung function from the age of 7 to 42 years [6]. Subjects with asthma and severe asthma were found to have persistent airflow obstruction throughout childhood and into adult life. The magnitude of the difference in lung function did not increase over time, suggesting that the deficits had occurred in early childhood and did not progress. Further evidence of the relationship between childhood events and respiratory health in adult life comes from a study of 1037 children in New Zealand who were followed from the age of 9 to 26 years [7]. Postbronchodilator forced expiratory volume in 1 second–vital capacity (FEV 1/VC) ratio was used as a marker of airway remodeling. Subjects with a low ratio at 26 years of age already had diminished lung function at the age of 9 years, with a slow progressive loss of reversibility, confirming that airway remodeling had begun in early childhood.

Risk Factors for Poor Lung Function in Asthma The duration of asthma can adversely affect lung function. Zeiger et al. [8] investigated the relationship between asthma duration and lung function in a cohort of children enrolled in the Childhood Asthma Management Program. Spirometric parameters and methacholine responsiveness correlated significantly and inversely with asthma duration. However, an alternative explanation might be that children with earlier onset of symptoms (and thus longer asthma duration) could have acquired poorer lung function earlier in life (possibly prior to the expression of symptoms), and that the observed differences were a part of the cause, rather than the consequence of asthma. Identification of children likely to be at risk for persistent disease, along with an increased understanding of the underlying physiology will enable us to target those children who are most likely to benefit from treatment interventions and monitoring. Numerous factors have been shown to increase the risk of asthma development in early life. The contribution of the various risk factors might differ depending on which stage of lung growth and development they are applied.

Gender The prevalence of atopy, wheeze, and doctor-diagnosed asthma are more common in boys than in girls. The rate of hospitalization for diagnosed asthma, which is a marker of severity, is also higher in boys [4,9–13]. These findings might be related to differences in lung growth and development during the prenatal and postnatal periods. Studies of fetal mouth movements are thought to reflect fetal breathing, which, in turn, might be an

important determinant of lung development. In a study of fetal mouth movements in 16- to 26-week-old fetuses, Hepper et al. [14] found evidence of more advanced maturation in females than in males. Studies of surfactant production in 26- to 36-week-old fetuses have also demonstrated a female advantage in terms of lung maturation [15,16]. Hibbert et al. [17] found that girls tend to have higher size-corrected flow rates than boys, which suggests that the ratio of their large to small airways is higher. There is also evidence that the airway epithelium is less well developed in males, which might mean that the male lung is at a greater risk for respiratory insults from which remodeling might occur as the lung attempts to heal itself [18]. Later in life, the picture changes, and women tend to have an increased risk of asthma. This might relate to hormonal changes, because female sex hormones are known to be proinflammatory. A review by Haggerty et al. [19] recently concluded that both estrogen and progesterone can modify airway responsiveness and alter lung function. Decreases in pulmonary function and increases in asthma exacerbations were more common during the premenstrual and menstrual phases in pre-menstrual women, and the use of hormone replacement therapy and oral contraceptives were associated with improved lung function and a reduction in exacerbations. Progesterone has also recently been shown to increase bronchial hyperresponsiveness and aggravate the phenotype of eosinophilic airway inflammation in a murine model of allergic asthma [20••].

Family History Several investigators have reported the importance of a familial component in asthma. Harris et al. [21] have estimated the genetic contribution to childhood asthma to be as high as 75%. A family history of asthma has been shown to be independently associated with significantly earlier onset of wheezing in infants, and diminished lung function in infants has been shown to be associated with wheezing in the first year and with impaired lung function at 6 years of age [5]. In a study evaluating the response to treatment with inhaled corticosteroids, children with a parental history of increased bronchial hyperresponsiveness (BHR) had a much smaller improvement in their own reactivity after 6 months of treatment than children of parents with no family history of BHR [22]. Young et al. [23] have also reported that a family history of asthma contributes to elevated levels of BHR even in infants as young as 4 weeks of age. This is confirmed by Dezateux et al. [24] who measured specific conductance (sGaw) in healthy term infants younger than 13 weeks of age. Infants with a family history of asthma had a significantly reduced sGaw and were more susceptible to wheezing by the age of 1 year. Celedon et al. [25••] investigated the impact of day care attendance on asthma in children. Children who had experienced day care in the first year of life had a reduced risk of asthma at the age of 6 years unless they had

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a maternal history of asthma, in which case day care in early life had no protective effect on either asthma or wheezing in the first 6 years of life. Prospective birth cohort studies are particularly important in elucidating the factors associated with asthma in early life. Kurukulaaratchy et al. [26••] recently sought to identify factors influencing symptom expression in a large, prospective birth cohort. They reported that maternal asthma was significantly and independently associated with increased bronchial hyperresponsiveness assessed at age 10 years. Murray et al. [27] measured VmaxFRC before the age of 8 weeks to assess airway function in a group of infants enrolled in the Manchester Asthma and Allergy Study. The children were designated as high-risk by virtue of having two atopic parents. Children who subsequently went on to have recurrent wheezy episodes or became prone to excessive coughing were found to have decreased lung function early in life.

Atopy Asthma is often associated with atopy, particularly in children. Children of atopic parents are at risk for developing atopic disease themselves with the risk for atopy being approximately 70% in the children of two atopic parents. Atopy appears to be an important risk factor for persistent but not transient wheeze. Sensitization to indoor allergens is a major risk factor for the development of asthma in both children and adults. In a longitudinal study in New Zealand, Sears et al. [28] found that in children followed from birth to 13 years of age, sensitization to dust mite or cat allergen was a highly significant independent risk factor for the development of asthma symptoms and BHR. A recent important report from this group noted that sensitization to house dust mite predicted the persistence of wheezing and relapse in children from the age of 9 to 26 years of age [29••]. Concurring with these results, Carter et al. [30] found that sensitization to house dust mites was significantly associated with doctor-diagnosed asthma. Kurukulaaratchy et al. [26••] found that symptomatic BHR measured at 10 years of age was independently associated with sensitization at age 4 and at age 10 years. In the Denver Childhood Asthma Prevention Study, impulse oscillometry (IOS) and spirometry were used to assess bronchodilator response in children at the age of 4 ye ar s. Os cil lome t ry i nvolves t he im pos it ion of very low amplitude acoustic oscillations on the airways, causing slight disruptions in airflow. The pressure in the airway changes in response to these disruptions, and those pressure changes are measured with a pressure screen pneumotachograph. The technique allows calculation of the respiratory resistance and reactance from the resulting pressure/flow relationship. Responses in atopic children with a history of wheezing were found to be abnormal when measured by IOS, whereas no significant findings were established using conventional spirometry [31••].

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We have recently reported that in young children, at age 3 years, lung function is poorer amongst sensitized individuals, even in the absence of wheeze, suggesting a detrimental effect of atopy on lung function that is independent of asthma [32]. The measurement of nitric oxide (NO) levels in exhaled air is a novel lung function test that might serve as a marker for airway inflammation, and relatively high values have been reported in asthmatic subjects [33–35]. Van Amsterdam et al. [36••] recently reported the results of a study in the Netherlands investigating the relationship between epithelial NO (eNO) levels and allergic sensitization in 450 children aged 7 to 12 years of age. Mean levels of eNO were 1.5 times higher in children who were sensitized to common indoor allergens. Levels were less elevated in those sensitized to outdoor allergens. The results also showed that eNO levels increased with the number of positive skin prick tests. Similar results were reported by Strunk et al. [37], who investigated the relationship between eNO and clinical and inflammatory markers of persistent asthma in children. As in the previous study [36••], levels of eNO were found to be correlated with the number of positive skin tests.

Environmental Tobacco Smoke Maternal smoking during pregnancy and in early life has been shown to be strongly associated with impaired lung growth and diminished lung function [38,39]. The Tucson Cohort Study found maternal smoking to be associated with both transient early and persistent wheezing [5]. Strachan and Cook [40], in a meta-analysis of 51 studies, estimated that parental smoking increased the risk of the development of asthma by 37% up to the age of 6 years and by 13% after that age. Children with documented asthma have been shown to suffer more frequent symptoms and an increased frequency of attacks [41••]. There is little available information on the immunologic effects of maternal smoking in pregnancy on the fetus; however, Noakes et al. [42] recently compared cord blood mononuclear cell cytokine responses to house dust mite in mothers who had smoked throughout pregnancy and those who had never smoked. Maternal smoking during pregnancy was found to be associated with significantly higher neonatal T helper type responses to house dust mite even after allowing for confounders, such as maternal atopy. The Isle of White study [26••] reported maternal smoking at age 4 years to be associated with symptomatic BHR at age 10 years. An important report from the German Multicentre Allergy Study (MAS90) found that maternal smoking in pregnancy was associated with impaired lung function in transient early wheezers at 7 years of age [43••]. Results from the Children’s Health Study in Los Angeles assessed the effect of in utero exposure on lung function. Children without asthma were found to have reduced forced expriatory flow at 25% to 75% of forced

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vital capacity (FEF 25–75 ) and reduced FEV 1 /FVC and FEF25–75/FVC ratios; however, the deficits were larger in children with an asthma diagnosis [41••].

later in life. Viral infections might damage the immature lung in early life and lead to airway remodeling or promote an immune response that will promote airway inflammation. Alternatively, children who have an underlying predisposition might be at risk for more severe disease.

Family Size Strachan [44] was the first to report an inverse relationship between sibling numbers and the prevalence of atopic diseases in childhood. Various studies since have reported a lower prevalence of hay fever, atopic eczema, positive skin prick tests, and allergen-specific IgE [45–47]. The evidence for a relationship between asthma, BHR, and family size is less clear. Although some studies have reported a protective effect of older siblings [48,49], others have failed to find such an effect [50,51]. In a study of children genetically at high risk for atopy, Koppelman et al. [52] found that the presence of older siblings was inversely related to atopy defined by skin prick test result, with the effect being more pronounced with an increasing number of positive skin tests. No sibling effect was found, however, for serum total IgE or for bronchial hyperresponsiveness. There are few studies that have directly investigated the relationship between lung function and sibling numbers; however, Mattes et al. [53] performed spirometry measurements in 677 children and showed that both FVC and FEV1 expressed as a percentage of the predicted value increased significantly in line with the number of siblings in a family when compared with children with no siblings. Values for FVC% ranged from +1.3% with one sibling to +4.0% with four or more siblings, and FEV 1 % ranged from +1.6% with one sibling to +6.5% with four or more siblings. The association between pulmonary function and number of siblings could not be explained by the child’s atopic status, prevalence of asthma, or history of pneumonia, nor by former or current cigarette smoke exposure [53].

Infections Upper and lower respiratory tract viral infections are common in early life, and most children suffer no longterm effects relating to these infections. The hygiene hypothesis does not appear to adequately explain the role of viral infections, particularly respiratory syncytial virus (RSV), in the subsequent development of wheezing illness, asthma, and atopy in susceptible children. The Tucson Children’s Respiratory Study looked for evidence of lower respiratory tract illness before the age of 3 years in 472 children. RSV infection was found to increase the risk of both frequent and infrequent wheezing until the age of 6, but was no longer a significant risk factor at 13 years of age. RSV lower respiratory tract illnesses were associated with significantly lower measurements of pre-bronchodilator FEV1 when compared with those of children with no lower respiratory tract illnesses [54]. Various mechanisms have been suggested to explain the association between viruses and respiratory abnormalities

Molds There are more than 80 genera of fungi that have been associated with allergic symptoms of the respiratory tract. Fungi found indoors are generally a mixture of genuine indoor species, and those that have entered from outside and include Penicillium, Aspergillus, Alternaria, Cladosporium, and Candida. Fungal growth favors buildings with high humidity levels or areas where condensation can accumulate, such as bathrooms or damp basements. Allergic reactions associated with fungi normally occur at the site of deposition. Inhaled particles of more than 10 µm are deposited in the nasopharynx and will cause nasal and/or ocular symptoms. In contrast, particles of less than 10 µm, and particularly those less than 5 µm, can penetrate the central and small airways where symptoms tend to manifest as asthma. Two recent studies have confirmed a relationship between fungal levels in homes and respiratory illness. Belanger et al. [55], in a cohort of 849 infants with an asthmatic sibling, reported that persistent mold in the home increased the risk of both wheeze and cough in the infants of mothers with and without asthma. In a study of 499 children with a parental history of asthma and allergy, Stark et al. [56••] examined fungal levels in the household and their contribution to the incidence of lower respiratory illness. A significant increased risk of lower respiratory tract infection was found for Penicillium, Cladosporium, Zygomycetes, and Alternaria. To investigate the relationship between sensitization, exposure, and lung function, children enrolled in the Colorado Childhood Asthma Management Program were assessed using spirometry and methacholine sensitivity. There was a strong direct correlation between increased sensitivity to inhaled methacholine and skin test sensitivity to Alternaria and indoor molds [57].

Pet Ownership Several studies in recent years have suggested that exposure to pet allergens in early life or current pet ownership might be protective against allergen sensitization and the subsequent development of asthma and wheezing illness [58]. A large population-based study in Norway indicated that exposure to pets in early life was associated with a reduced risk for developing atopy-related diseases at 4 years of age [59]. Remes et al. [60], in a longitudinal cohort study of 1246 children, found that children living in households with one or more dogs at birth were less likely to have developed frequent wheeze symptoms than those not having indoor dogs. This inverse association was, however, not evident for children with a history of parental asthma.

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In a large study on 4089 children conducted in Sweden, exposure to cat allergen increased the risk of sensitization to cat but had no effect on the risk of asthma at 4 years of age. Exposure to dog did not appear to increase the risk of sensitization to dog but was associated with a lower risk for asthma [61]. There is a paucity of information on the relationship between exposure to domestic pets and lung function. In the Third National Health and Nutrition Examination Survey (NHANES III), Chapman et al. [62] examined the effects of the household environment on lung function in 8- to 16-year-old children. They found that the presence of a dog or a cat in the home was consistently and significantly associated with an increase in lung function in girls with asthma, but no similar association was seen in asthmatic boys. There is a body of evidence to suggest that endotoxin exposure might protect against the development of atopy and, possibly, asthma. It might be that the timing of exposure and the genetic predisposition of the individual might alter the effects of endotoxin not only on the immune system, but also on the developing lung. However, there is very little information on the relationship between endotoxin exposure and lung function.

Conclusions Clearly, events in early life can determine respiratory health throughout life. Many studies on the development of childhood asthma have inevitably concentrated on symptom histories. Most asthma originates in early life in association with disordered lung function that tracks to subsequent persistent disease. Therefore, increasing our knowledge of the underlying effect on the physiology of the lung early in life can only serve to increase our understanding of the mechanisms of the disease. To do this, we must endeavor to continue to develop new methods for assessing lung physiology that can be applied in young children.

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