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The development of respiratory inflammation in children
PAEDIATRIC RESPIRATORY REVIEWS (2006) 7, 89–96
MINI-SYMPOSIUM: LUNG PHYSIOLOGY
The development of respiratory inflammation in children Susan L. Prescott* School of Paediatrics and Child Health, University of Western Australia, PO Box D184, Princess Margaret Hospital, Perth WA 6001, Australia KEYWORDS Asthma; Childhood; Allergy; Airway remodelling; Airway inflammation; Mucosal immune system; Type 2 T-helper cell cytokines
Summary With the rising world burden of asthma, it is crucial to define the early events that lead to chronic inflammation and airway remodelling. Chronic airway inflammation appears to be the culmination of both local epithelial dysfunction and a more generalised immune dysregulation that results in allergic predisposition. A number of antenatal and early postnatal events may contribute to this. However, although a systemic propensity for allergic responses (typically food allergy) frequently pre-exists in children who go on to develop asthma, there is still uncertainty over whether epithelial changes occur as a primary event or whether these are consequent to this evolving systemic propensity for type 2 T-helper cell allergic responses. Many children with asthma already show many of the features of chronic airway inflammation, with epithelial desquamation, inflammatory cell infiltrates, subepithelial basement membrane thickening and fibrosis, goblet cell hyperplasia and smooth muscle hypertrophy. These changes can be evident before asthma is diagnosed, and there is also evidence that airway inflammation and early remodelling can progress in a subclinical state. New studies suggest that early airway damage is irreversible and that subsequent lung function is ‘set’ in the first years of life. These observations highlight the need to identify affected or at-risk children early and to develop interventions that can abort or prevent ongoing airway inflammation and remodelling. ß 2006 Elsevier Ltd. All rights reserved.
INTRODUCTION
propensity for immunoglobulin (Ig) E-mediated immune responses (atopy). However, although there is a strong association between allergen sensitisation and asthma, these processes appear to develop through independent processes,1 leading to much debate about the primary events that lead to airways disease. Events in early life, when systems are developing, have a critical influence on both structural development and functional responses. Furthermore, the consequences of these still poorly defined events are also set early. Manifestations of allergic predisposition are apparent within the first few months of life, typically as atopic dermatitis and food allergy. Presymptomatic airways inflammation can also be detected in this early period.2 Although most infants
Asthma is the most common cause of chronic airway inflammation in children living in developed countries and the same concerning trends are now occurring in developing countries. The increasing prevalence over the last 30–40 years indicates that environmental changes are responsible. Although the specific causes are not clear, this has been associated with parallel increases in allergic rhinitis, food allergy and atopic dermatitis, suggesting that all of these conditions result from an underlying increase in the * Tel.: +61 8 9340 8171; Fax: +61 8 9388 2097. E-mail address: [email protected]. 1526-0542/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2006.03.001
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with early virus-associated ‘recurrent wheeze’ do not develop asthma, as many as 80% of those with early evidence of allergic disease (atopic dermatitis and food allergy) will go on to develop allergic airway disease (asthma or allergic rhinitis).3 Early sensitisation is also major risk factor for persistent wheezing and airway hyperreactivity.4 Around 70–90% of individuals with established asthma have allergen sensitisation, and the proportion of asthmatics with sensitisation is highest in children. By school age, around 40% of children living in developed countries have sensitisation to inhalant allergens but not all of these children will develop symptomatic airway disease. The factors that determine tissue specific manifestation of allergic inflammation are also unclear. Thus, asthma appears to be the result of a two-stage process initiated in early life which involves: 1. the development of a systemic propensity for IgE allergen sensitisation; 2. the development of local propensity for airway inflammation, with subsequent damage to growing lung tissues and altered respiratory function. The sequence and relationship of these events are, however, unclear. Compounding this further, asthma also appears to be a heterogeneous condition with different contributing events in different individuals.
EVIDENCE OF EARLY AIRWAY INFLAMMATION AND REMODELLING IN CHILDREN Mucosal events arguably play the most pivotal role in both systemic immune development and local inflammation. These events are, however, still poorly understood in humans because of logistic and ethical limitations of studies in this area, particularly in young children. Inflammation is a normal host response to noxious agents, which is usually inhibited by local regulatory systems once repair processes have been initiated and the threat has been eliminated. In children, persistent inflammation will develop with more chronic or repeated exposure to noxious agents, most commonly due to repeated viral infection or exposure to passive smoking. Because these exposures are common, many children develop symptoms of airway inflammation, but most will not go on to develop asthma (‘transient wheezers’). Abnormalities in host responses appear to be an important secondary determining factor. These include both inappropriate systemic responses to otherwise innocuous agents (allergen sensitisation) and poorly regulated local responses that contribute to abnormal tissue repair (airway remodelling). It has been extremely difficult to determine the relative contribution of these pathways in initiating events.
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Chronic inflammation in the lower airway is associated with chronic inflammatory cell infiltrates, epithelial damage (desquamation), subepithelial basement membrane thickening and fibrosis, goblet cell hyperplasia and smooth muscle hypertrophy.5 All of these changes are seen in children with asthma.2,5,6 More significantly, changes have also been seen in preschool children before a diagnosis of asthma has been made.2 This worrying observation suggests that airway inflammation and early remodelling may occur in a subclinical disease state.6 There is also accumulating evidence that subsequent lung function is ‘set’ in the first years of life.7,8 This highlights the need to identify affected or at-risk children early and to develop interventions that can abort or prevent ongoing airway inflammation and remodelling. There is preliminary evidence that early intervention with inhaled corticosteroids can reduce the progression of airway remodelling in children9,10 but the long-term effects are still not clear. Epithelial damage is associated with increased expression of pro-inflammatory cytokines (interleukin-1b (IL-1b), granulocyte-macrophage colony-stimulating factor) and growth factors including platelet-derived growth factor, fibroblast growth factor, transforming growth factor-b (TGFb) and endothelin-1. This can ultimately lead to airway remodelling with subepithelial fibrosis, and abnormal vascularisation with significant effects on lung function. This is believed to be the result of dysregulated attempts to repair repeated mucosal injury by allergens, viruses and pollutants. Although there has been accumulating evidence that airway remodelling probably occurs secondary to chronic inflammation, there has also been speculation that this could occur independently as a result of primary dysfunction in endothelial-mesenchymal repair processes (for a review, see Ref. 11). At this stage, the relative contributions role of host and environmental factors in the initiation of chronic airway inflammation are still not clear. There is still uncertainty as to whether epithelial changes occur as a primary event or consequent to an evolving systemic propensity for type 2 Thelper (Th2) allergic responses.
RELATIONSHIP BETWEEN ALLERGEN SENSITISATION AND AIRWAY INFLAMMATION IN CHILDREN Identifying future asthmatics from the heterogeneous group of early infant wheezers remains a significant and important challenge, and requires a better understanding of the underlying causal pathways. The role of allergic propensity in the early development of airway inflammation is not clear. Although over 80% of older school-aged children have evidence of aeroallergen sensitisation, the corresponding figure in preschool children
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is substantially lower. In these younger children, airway inflammation is commonly present before evidence of inhalant sensitisation. Although this suggests that inhalant sensitisation does not play a primary role in the initiation of airway inflammation, the presence of other allergic disease (atopic dermatitis) and prior sensitisation to other allergens (i.e. foods) is frequently a defining feature in the subgroup of ‘early infant wheezers’ who go on to develop asthma (for a review, see Ref. 12). This indicates that a systemic propensity for Th2 allergic responses frequently pre-exists in these children. This allergic propensity appears to be determined by both genetic or environmental events in utero and could foreseeably also influence local patterns of response in airways, although this remains to be determined.
THE DEVELOPMENT OF AIRWAY IMMUNE NETWORKS IN EARLY LIFE Antigen-presenting cells in the local airways play a critical role in initiating and regulating early inflammatory events, particularly related to airway dendritic cells and alveolar macrophages. In the first year of life, infants do not typically exhibit airway dendritic cells in the absence of inflammation.13 Animal studies also confirm that local airway dendritic cells networks are less developed in the early postnatal period, with markedly attenuated responses to inflammatory triggers.14,15 Severe respiratory infection is associated with the appearance of mature dendritic cells in infant airways,13 suggesting that local tissue events in infancy can influence the local maturation of dendritic cells in humans. This has renewed interest in the role of respiratory infection in early life in the aetiology of atopic asthma (discussed below). As well as providing an important ‘first line’ of innate immune defence, local antigen-presenting cells (particularly dendritic cells) play a critical role in programming T cell responses. These cells also appear to have a major role in the late-phase response.16,17 After encountering local antigens, dendritic cells undergo migration-induced maturation to regional nodes,16 where they present antigen and typically produce Th1-trophic signals, such as IL-12. These signals may occur under conditions of infection or other local stress18,19 that evoke protective Th1 effector T cell responses. In the absence of these obligatory Th1-trophic signals, resting dendritic cells are more likely to stimulate Th2 development, at least in animals.20 Thus, age-related immaturity in dendritic cell function21 may lead to a reduced capacity for these cells to produce Th1 trophic signals, increasing the risk of Th2 responses in early life. Factors that influence activation of the maturation of airway dendritic cells could have a key role in determining the subsequent pattern of local T cell responses. This could include genetically programmed functional variations as well as local environmental exposures in early life, such as infection and pollutants (below).
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ROLE OF THE ‘COMMON MUCOSAL IMMUNE SYSTEM’ IN THE DEVELOPMENT OF RESPIRATORY TOLERANCE The ‘common mucosal immune system’ has been recognised as a functional entity for many years.22 The developing gut is a reservoir for T and B cell precursors, which mature and eventually migrate to the respiratory tract. In addition, it is likely that the gut precursor populations also include subpopulations of maturing regulatory cells (including CD4+CD25+ T cells), which play a key role in controlling peripheral immune responses. Thus, although anatomically separate, components of the mucosal system immune system are functionally integrated, and this may explain how changes in gut flora can influence immune function (IgA production) in the respiratory tract.23 These observations are an important consideration in defining events that lead to the development (or failure) of ‘respiratory tolerance’. Immune tolerance is driven by environmental exposures and is first evident as ‘oral tolerance’ to ingested allergens. Although still poorly understood, failure of oral tolerance (food allergy) is frequently a preceding event in children who subsequently develop respiratory allergy. Again, it is not clear how these events are linked – whether this is a causal relationship or whether these children are predisposed to failed tolerance for independent reasons. These observations highlight the importance of looking beyond the respiratory mucosa for new pathways in pathogenesis, treatment and prevention. The concept of an integrated mucosal immune system may also explain the remote effects of both ‘natural’ tolerance and tolerance ‘induced’ by mucosal immunotherapy. In the respiratory tract, the bulk of ambient aeroallergen exposure occurs in the ‘upper’ airway. Under normal conditions, this appears to result in the generation of CD4+CD25+ regulatory T cells and a low level Th1 response on subsequent exposure. Because this process appears to be dependent on dose (the intensity of antigenic stimulation), mucosal allergen administration has been used therapeutically in the upper airway to induce systemic tolerance. This has been most successful using a sublingual route (sublingual immunotherapy (SLIT)), with a growing number of reports of clinical benefits. In children with mild-to-moderate persistent asthma and dust mite sensitisation, recent studies suggest a low-tomoderate clinical benefit of SLIT when used in addition to measures to reduce environmental exposure.24 There is also preliminary evidence that SLIT may reduce the risk of asthma developing in children with allergic rhinitis.25 New studies are now planned to examine the effects of SLIT in the primary prevention of aeroallergen sensitisation. In this proposed randomised controlled trial, 200 children (aged 18 months to 3 years and at high risk of developing allergic respiratory disease) will receive inhalant allergen SLIT (house dust mite, cat and timothy grass) or a placebo
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for 12 months. These children will already have evidence of allergic disease (food allergy or atopic dermatitis) but no sensitisation to inhalants. The children will be monitored for 3 years, aiming to detect a 50% reduction in IgE and allergic Th2 responses to allergens, as well as a 50% reduction in asthma (www.immunetolerance.org/research/allergy/trials/ holt.html). The results are awaited with great interest. Finally, it is also clinically relevant to consider the interactions between the ‘upper’ and ‘lower’ airway. Discussion of respiratory inflammation often focuses predominantly on the lower respiratory tract, despite the fact that upper airway disease (allergic rhinitis) is also a major cause of morbidity. There is currently a growing awareness of the clinical relevance of this functional relationship, now discussed in terms of ‘one airway’ (for a review, see Ref. 26). Patients with allergic rhinitis frequently have associated bronchial hyperreactivity,27 and an estimated 60–78% of asthma patients have coexisting allergic rhinitis.28 Moreover, the treatment of allergic rhinitis improves asthma control.29 Although most of these observations have been made in adults, this is also likely to be relevant in children.
ROLE OF ‘TH2’ CYTOKINES IN AIRWAY INFLAMMATION In rodents, Th2 cytokines (namely IL-13) are especially critical for the development of reactive airways disease (see Ref. 30 and others), but in humans it is still not clear what role the systemic predisposition for Th2 responses plays in initiating chronic airway inflammation. Once inflammation is established, T lymphocytes are principal effector cells, and there is substantial evidence implicating Th2 (IL-4, IL-5, IL-9, IL-13) in airways inflammation. Th2 cytokines (IL-4, IL-5, IL-13) are also produced by mast cells (IL-4, IL-5, IL-13) and eosinophils (IL-4, IL-13), which are abundant in the asthmatic airway. IL-13 and IL-4 also appear to contribute to airway remodelling through effects on the epithelial-mesenchymal trophic unit. These cytokines stimulate the release of TGFb2 from bronchial epithelial cells31 which plays a key role in promoting the proliferation and transformation of fibroblasts. Eosinophils (under the influence of Th2 cytokines) also produce TGFb and make a significant contribution to this process. Despite the clear role of Th2 pathways in chronic airway inflammation, asthma and other allergic diseases are not due to simple Th2 polarisation as previously thought. Th1 cells also play a role in allergic inflammation,32 and the level of Th1 interferon-g (IFNg) is elevated in the serum of asthmatics during acute exacerbations,33 and in bronchoalveolar lavage fluid after allergen challenge.34 These observations suggest that allergic inflammation may be secondary to a more fundamental failure of underlying immune regulation. It has recently been proposed that allergic disease is the result of an inappropriate balance between regulatory cells (including CD4+CD25+ T regulatory cells) and Th2 effector cells. In the airways, a number
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of other cells, including epithelial cells and airway dendritic cells, also have important regulatory effects on local immune responses. Although the development of normal tolerance to inhalant allergens is still poorly understood, all of these cells are likely to play an important role.
ANTENATAL EVENTS THAT CONTRIBUTE TO AIRWAY INFLAMMATION Antenatal events have the capacity to contribute to airway inflammation on two broad levels: first, through effects on the development airway structure and function, and second, by immune effects that may alter the risk of subsequent allergic sensitisation. The growth and development of the airways in utero appears to be an important determining factor in subsequent lung function. Children with ‘smaller’ airways are more likely to have milder respiratory tract symptoms with viral infections (typically the early transient wheezers described by Martinez and colleagues35). Maternal smoking is the best described antenatal exposure to be associated with subsequent reduced lung function, airways inflammation and increased susceptibility to wheezy respiratory infection (see Ref. 36 and others). These effects on lung function persist into later childhood and are independent of subsequent postnatal smoke exposure.37 Although fetal immune responses are typically skewed towards Th2 in pregnancy,38 a number of subtle differences have been found in neonates who go on to develop allergic disease (for a review, see Ref. 39). Although this was originally thought to be genetically programmed, there is now evidence that in utero exposures can influence fetal immune function. These are of interest as either risk factors or potential prevention strategies, and include dietary factors with anti-inflammatory properties,40,41 maternal smoking,40,42 microbial exposure43 and direct effects of maternal allergy (independent of genetic influence).44 Although there is now good evidence that the fetus is exposed to allergens (particularly food allergens from the maternal diet),45 the effects of this are not clear. Allergen exposure (at any age) does not usually lead to sensitisation. Instead, repeated allergen exposure is essential for the development of normal tolerance processes. It could be argued that early exposure to innocuous proteins from the future environment may be physiological rather than pathological, particularly as this phenomenon is observed in a significant proportion of babies regardless of atopic risk. As in the early postnatal period, this could, in the absence of ‘danger’ signals, be important for initiating tolerance. This might explain the lack of correlation between the level of exposure and neonatal responses and the failure of allergen avoidance in pregnancy to prevent allergy. At this stage, further studies are needed before specific interventions can be recommended in early life for the prevention of asthma and allergic diseases (with the clear exception of smoking).
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POSTNATAL EVENTS THAT MAY INFLUENCE THE DEVELOPMENT OF AIRWAY INFLAMMATION Local events in the airways are critical for programming all systemic and local defence systems, culminating in a highly adaptive surveillance network. In the early postnatal period, environmental exposure plays a key role in driving global immune maturation, which appears to depend on exogenous factors (namely microbial exposure) to develop normally. The pattern of environmental antigen exposure determines the specificity of responses required for host defence, and local conditions during antigen-processing in local tissues appear to influence the patterns of immune maturation and resulting immune responses. Local encounters with noxious environmental factors, including irritants (such as cigarette smoke) and respiratory pathogens, are likely to influence the development of immune networks in the airways and the propensity for chronic inflammation. Similarly, other exposures could have potential modulating influences, for example exposure to dietary (and endogenous) antioxidants and omega-3 polyunsaturated fatty acids, as discussed further below.
Role of allergens For many years, early allergen exposure was regarded as the major factor in the development of asthma and allergic disease. Although evidence was limited, this was the basis for allergen avoidance as the first main strategy for primary allergy prevention in those who were genetically predisposed. The results of such measures have been fairly disappointing or even paradoxical,46 shifting interest to other potential aetiological factors. Thus, although sensitisation is a strong risk factor for asthma, wheeze and bronchial hyperactivity,47 the relationship between early allergen exposure and these clinical symptoms has been much harder to confirm. On balance, the existing evidence indicates that postnatal allergen exposure has a significant role as a triggering factor in older children with established disease, but the role and importance of aeroallergen exposure in initiating airway inflammation is still not clear. At this stage, it appears more likely that other factors are likely to influence the development of sensitisation rather than just allergen encounter per se. Many host and environmental factors have the capacity to influence local and systemic immune responses at the time of first allergen encounter, as well as in the subsequent period when memory immune responses are being determined. Moreover, new allergy-prevention studies are focusing on the potential role of controlled allergen administration (immunotherapy) rather than allergen avoidance (as above).
Role of respiratory tract infections Respiratory infections are the most common cause of acute airway inflammation in childhood. Despite this, the relation-
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ship between early respiratory tract infections and chronic airway inflammation (and allergic airway disease) has been confusing. These infectious agents have been clearly identified as asthma triggers in children with established disease. Respiratory syncytial virus infection in infancy has also been long regarded as a risk factor for subsequent asthma, at least in the first 6 years of life.48 This may be in part because of the Th2-trophic properties of this and other respiratory viruses, but it may also be an indirect consequence of the delayed capacity to mount Th1 IFNg responses in the early postnatal period. A predisposition to wheezing lower respiratory infection in the first year of life is a strong risk factor for asthma at 6 years of age in both non-atopic (odds ratio 4.1, P < 0.0005) and atopic (odds ratio 9.0, P < 0.0005) children.49 This strongly suggests that significant infectioninduced airway inflammation during the early period of postnatal lung growth and development can have profound long-term effects that appear to be more marked than with inflammation occurring at later ages. In contrast, the notion that infection can serve only as a priming factor for subsequent allergic inflammation is at odds with other observations that, in some circumstances, infections appear to protect from allergic disease (for a review, see Ref. 50). This suggests the alternate possibility that early encounter with infectious agents has the potential to accelerate the maturation of local immune networks (including dendritic cells and regulatory T cells as discussed above), producing Th1 defence responses that may override the Th2 default response in immunologically immature infants. There is growing evidence that key regulatory cells (particularly antigen-presenting cells and T regulatory cells) depend on Toll-like receptor (TLR) mediated signalling for activation and maturation, and there is growing speculation that both genetic polymorphisms (affecting TLR function) and environmental factors (such reduced microbial exposure) predispose to allergic disease through effects on these innate immune pathways. A number of animal studies collectively suggest that early microbially driven TLR activation may modify immune development and the risk of sensitisation, although the effects appear to be more significant before responses have been established.51,52 There is only indirect evidence that early bacterial exposure may be protective in humans. This includes the many epidemiological studies (for a review, see Ref. 50) that formed the basis of the ‘hygiene hypothesis’. Intervention studies also suggest that the administration of bacterial products to children may have clinical (see Refs. 53 and 54 and others) and immune effects.55 Although it has been inferred that these variations in microbial exposure may be responsible for differences in innate (and subsequent cognate) immune function, this has not been documented directly. Genetic studies currently provide better supportive evidence that functional variations in aspects of TLR microbial signalling are associated with clinical phenotypes. Specifically, polymorphisms in the gene coding for CD14
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(involved in lipopolysaccharide signalling through TLR4) have been linked to total serum IgE levels.56 More recently, a TLR2 genetic polymorphism was shown to have a protective effect against asthma.57 Notably, the ‘protective’ effect was only seen when children were raised in environments with a ‘high’ microbial burden, illustrating the interactive effects of genetic and environmental factors on these pathways. Taken together, these findings suggest that alterations in TLR function, either as a result of differences in early environmental exposures or function genetic polymorphisms, have an effect on the subsequent development of adaptive immune function. Thus, the complexity of the relationships between infection and allergic inflammation needs to be further dissected. In particular, variations in the consequences of infection on allergic propensity may involve differences in the timing of exposure, the nature of the infectious agent and the location of the infection (upper or lower airway), in addition to genetic factors.
Role of irritants and pollutants The effects of pollutant exposure in childhood are best described for passive exposure to parental smoking. In animals, there is considerable evidence that tobacco smoke can cause inflammation in the lower respiratory tract. Few studies have explored this in humans, although associations have been documented between parental exhaled tobacco smoke and higher numbers of IgE+ cells and eosinophils in the nasal mucosa of children, as well as increased neutrophil counts. We may speculate that local inflammation (such as that induced by exhaled tobacco smoke) during allergen encounter may predispose to allergic responses. Evidence of this is indirect and inconclusive. Some have noted associations between parental smoking and systemic markers of atopy in children, including serum IgE levels, eosinophilia and positive skin-prick tests,58–60 although this has not been confirmed in other studies. These observations suggest immunological effects in addition to airway irritation and early effects on lung mechanics, but further studies are needed.
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There is also preliminary evidence that fish oil supplementation in early life has an effect on early immune responses41 and reduces symptoms of airway inflammation (wheeze and cough) in preschool children.63 These effects were subtle but could indicate both systemic and local airway influences. There are still insufficient data to make specific recommendations for disease prevention. Taken together, these observations suggest that early environmental exposures have the potential to influence the maturation of both local and systemic local immune function, thereby altering the susceptibility to airway inflammation. With the mounting burden of disease, further studies are urgently needed in this area to help to determine potential modifiable exposures that may be of benefit in disease prevention.
PRACTICE POINTS Antenatal events may have an important role in determining allergic predisposition and airway function. Ultimate lung function is determined in the preschool years. Infants with early evidence of allergic predisposition are at risk of asthma, and this diagnosis should be considered if these children present with recurrent chest symptoms. Some children may have subclinical airway inflammation and early remodelling. There are important functional relationships between the upper and the lower respiratory tract: patients with asthma should be assessed for associated allergic rhinitis and treated appropriately.26 The early use of anti-inflammatory medication may reduce the risk of airway remodelling even in mild asthma.
Role of other environmental factors
RESEARCH DIRECTIONS
A number of dietary factors have the potential to modulate inflammatory responses, including omega-3 polyunsaturated fatty acids and other known immunomodulatory factors such as antioxidants. Although the therapeutic effects in established disease are at best weak, these factors could have a more significant role earlier in life when immune responses are being initiated and patterns of subsequent reactivity are being set. Population studies suggest that diets rich in antioxidants (fresh fruits)61 and oily fish (omega-3 polyunsaturated fatty acids)62 reduce the risk of recurrent wheeze in childhood, suggesting protective effects against airway inflammation.
To understand the role of respiratory infections, allergens and pollutants in the development of chronic airway inflammation and remodelling. To identify the role of allergic predisposition in the evolution of airway inflammation. To be able to identify future asthmatics from the heterogeneous group of early infant ‘wheezers’. To develop methods to identify children with subclinical airway inflammation and early remodelling. To develop early interventions that can prevent chronic airway inflammation and remodelling.
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REFERENCES 1. Lau S, Illi S, Sommerfeld C, Niggemann B et al. Early exposure to house-dust mite and cat allergens and development of childhood asthma: a cohort study. Multicentre Allergy Study Group. Lancet 2000; 356: 1392–1397. 2. Pohunek P, Warner JO, Turzikova J, Kudrmann J, Roche WR. Markers of eosinophilic inflammation and tissue re-modelling in children before clinically diagnosed bronchial asthma. Pediatr Allergy Immunol 2005; 16: 43–51. 3. Eichenfield LF, Hanifin JM, Beck LA et al. Atopic dermatitis and asthma: parallels in the evolution of treatment. Pediatrics 2003; 111: 608–616. 4. Guilbert TW, Morgan WJ, Zeiger RS et al. Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma. J Allergy Clin Immunol 2004; 114: 1282–1287. 5. Cutz E, Levison H, Cooper DM. Ultrastructure of airways in children with asthma. Histopathology 1978; 2: 407–421. 6. van den Toorn LM, Overbeek SE, de Jongste JC, Leman K, Hoogsteden HC, Prins JB. Airway inflammation is present during clinical remission of atopic asthma. Am J Respir Crit Care Med 2001; 164: 2107–2113. 7. Morgan WJ, Stern DA, Sherrill DL et al. Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence. Am J Respir Crit Care Med 2005; 172: 1253–1258. 8. Rasmussen F, Taylor DR, Flannery EM et al. Risk factors for airway remodeling in asthma manifested by a low postbronchodilator FEV1/ vital capacity ratio: a longitudinal population study from childhood to adulthood. Am J Respir Crit Care Med 2002; 165: 1480–1488. 9. Bibi HS, Feigenbaum D, Hessen M, Shoseyov D. Do current treatment protocols adequately prevent airway remodeling in children with mild intermittent asthma? Respir Med 2006; 100: 458–462. 10. Merkus PJ, van Pelt W, van Houwelingen JC et al. Inhaled corticosteroids and growth of airway function in asthmatic children. Eur Respir J 2004; 23: 861–868. 11. Holgate ST. Epithelial damage and response. Clin Exp Allergy 2000; 30(suppl 1): 37–41. 12. Martinez FD, Helms PJ. Types of asthma and wheezing. Eur Respir J Suppl 1998; 27: 3s–8s. 13. Tschernig T, Debertin AS, Paulsen F, Kleemann WJ, Pabst R. Dendritic cells in the mucosa of the human trachea are not regularly found in the first year of life. Thorax 2001; 56: 427–431. 14. Nelson D, McMenamin C, McWilliam A, Brenan M, Holt P. Development of the airway intraepithelial dendritic cell network in the rat from class II MHC (Ia) negative precursors: differential regulation of Ia expression at different levels of the respiratory tract. J Exp Med 1994; 179: 203–212. 15. Nelson D, Holt P. Defective regional immunity in the respiratory tract of neonates is attributable to hyporesponsiveness of local dendritic cells to activation signals. J Immunol 1995; 155: 3517–3524. 16. Huh JC, Strickland DH, Jahnsen FL et al. Bidirectional interactions between antigen-bearing respiratory tract dendritic cells (DCs) and T cells precede the late phase reaction in experimental asthma: DC activation occurs in the airway mucosa but not in the lung parenchyma. J Exp Med 2003; 198: 19–30. 17. Jahnsen FL, Moloney ED, Hogan T, Upham JW, Burke CM, Holt PG. Rapid dendritic cell recruitment to the bronchial mucosa of patients with atopic asthma in response to local allergen challenge. Thorax 2001; 56: 823–826. 18. Stampfli MR, Wiley RE, Neigh GS et al. GM-CSF transgene expression in the airway allows aerosolized ovalbumin to induce allergic sensitization in mice. J Clin Invest 1998; 102: 1704–1714. 19. Yamamoto N, Suzuki S, Shirai A et al. Dendritic cells are associated with augmentation of antigen sensitization by influenza A virus infection in mice. Eur J Immunol 2000; 30: 316–326. 20. Stumbles PA, Thomas JA, Pimm CL et al. Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (Th2) responses and require obligatory cytokine signals for induction of Th1 immunity. J Exp Med 1998; 188: 2019–2031.
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21. Upham JW, Lee PT, Holt BJ et al. Development of interleukin-12producing capacity throughout childhood. Infect Immun 2002; 70: 6583–6588. 22. Bienenstock J, Befus D. Gut- and bronchus-associated lymphoid tissue. Am J Anat 1984; 170: 437–445. 23. Vancikova Z, Lodinova-Zadnikova R, Radl J, Tlaskalova-Hogenova H. The early postnatal development of salivary antibody and immunoglobulin response in children orally colonized with a nonpathogenic, probiotic strain of E. coli. Folia Microbiol (Praha) 2003; 48: 281–287. 24. Sopo SM, Macchiaiolo M, Zorzi G, Tripodi S. Sublingual immunotherapy in asthma and rhinoconjunctivitis; systematic review of paediatric literature. Arch Dis Child 2004; 89: 620–624. 25. Novembre E, Galli E, Landi F et al. Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol 2004; 114: 851–857. 26. Bachert C, van Cauwenberge P. The WHO ARIA (allergic rhinitis and its impact on asthma) initiative. Chem Immunol Allergy 2003; 82: 119– 126. 27. Ciprandi G, Cirillo I, Tosca MA, Vizzaccaro A. Bronchial hyperreactivity and spirometric impairment in patients with perennial allergic rhinitis. Int Arch Allergy Immunol 2004; 133: 14–18. 28. Nayak AS. The asthma and allergic rhinitis link. Allergy Asthma Proc 2003; 24: 395–402. 29. Crystal-Peters J, Neslusan C, Crown WH, Torres A. Treating allergic rhinitis in patients with comorbid asthma: the risk of asthma-related hospitalizations and emergency department visits. J Allergy Clin Immunol 2002; 109: 57–62. 30. Wills-Karp M, Luyimbazi J, Xu X et al. Interleukin-13: central mediator of allergic asthma. Science 1998; 282: 2258–2261. 31. Richter A, Puddicombe SM, Lordan JL et al. The contribution of interleukin (IL)-4 and IL-13 to the epithelial-mesenchymal trophic unit in asthma. Am J Respir Cell Mol Biol 2001; 25: 385–391. 32. Hansen G, Berry G, DeKruyff RH, Umetsu DT. Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J Clin Invest 1999; 103: 175–183. 33. Corrigan CJ, Kay AB. CD4 T-lymphocyte activation in acute severe asthma. Relationship to disease severity and atopic status. Am Rev Respir Dis 1990; 141: 970–977. 34. Calhoun WJ, Bates ME, Schrader L, Sedgwick JB, Busse WW. Characteristics of peripheral blood eosinophils in patients with nocturnal asthma. Am Rev Respir Dis 1992; 145: 577–581. 35. Martinez F, Wright A, Taussig L et al. Asthma and wheezing in the first six years of life. N Eng J Med 1995; 332: 133–138. 36. Stick SM, Burton PR, Gurrin L, Sly PD, LeSouef PN. Effects of maternal smoking during pregnancy and a family history of asthma on respiratory function in newborn infants. Lancet 1996; 348: 1060–1064. 37. Gilliland FD, Berhane K, Li YF, Rappaport EB, Peters JM. Effects of early onset asthma and in utero exposure to maternal smoking on childhood lung function. Am J Respir Crit Care Med 2003; 167: 917–924. 38. Prescott S, Macaubas C, Holt B et al. Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T-cell responses towards Th-2 cytokine profile. J Immunol 1998; 160: 4730–4737. 39. Prescott SL. Early origins of allergic disease: a review of processes and influences during early immune development. Curr Opin Allergy Clin Immunol 2003; 3: 125–132. 40. Devereux G, Barker RN, Seaton A. Antenatal determinants of neonatal immune responses to allergens. Clin Exp Allergy 2002; 32: 43–50. 41. Dunstan J, Mori TA, Barden A et al. Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomised controlled trial. J Allergy Clin Immunol 2003; 112: 1178–1184. 42. Noakes PS, Holt PG, Prescott SL. Maternal smoking in pregnancy alters neonatal cytokine responses. Allergy 2003; 58: 1053–1058. 43. Matsuoka T, Matsubara T, Katayama K, Takeda K, Koga M, Furukawa S. Increase of cord blood cytokine-producing T cells in intrauterine infection. Pediatr Int 2001; 43: 453–457.
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44. Prescott S, Jenmalm M, Bjorksten B, Holt P. Effects of maternal allergen-specific IgG in cord blood on early postnatal development of allergen-specific T-cell immunity. Allergy 2000; 55: 470–475. 45. Edelbauer M, Loibichler C, Nentwich I, Gerstmayr M, Urbanek R, Szepfalusi Z. Maternally delivered nutritive allergens in cord blood and in placental tissue of term and preterm neonates. Clin Exp Allergy 2004; 34: 189–193. 46. Woodcock A, Lowe LA, Murray CS et al. Early life environmental control: effect on symptoms, sensitization, and lung function at age 3 years. Am J Respir Crit Care Med 2004; 170: 433–439. 47. Lau S, Nickel R, Niggemann B et al. The development of childhood asthma: lessons from the German Multicentre Allergy Study (MAS). Paediatr Respir Rev 2002; 3: 265–272. 48. Stein RT, Sherrill D, Morgan WJ et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 1999; 354: 541–545. 49. Oddy WH, de Klerk NH, Sly PD, Holt PG. The effects of respiratory infections, atopy, and breastfeeding on childhood asthma. Eur Respir J 2002; 19: 899–905. 50. Strachan DP. Family size, infection and atopy: the first decade of the ‘‘hygiene hypothesis’’. Thorax 2000; 55(suppl 1): S2–S10. 51. Blumer N, Herz U, Wegmann M, Renz H. Prenatal lipopolysaccharideexposure prevents allergic sensitisation and airway inflammation, but not airway responsiveness in a murine model of experimental asthma. Clin Exp Allergy 2005; 35: 397–402. 52. Tulic MK, Wale JL, Holt PG, Sly PD. Modification of the inflammatory response to allergen challenge after exposure to bacterial lipopolysaccharide. Am J Respir Cell Mol Biol 2000; 22: 604– 612. 53. Arkwright PD, David TJ. Intradermal administration of a killed Mycobacterium vaccae suspension (SRL 172) is associated with improvement in atopic dermatitis in children with moderate-to-severe disease. J Allergy Clin Immunol 2001; 107: 531–534.
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54. Weston S, Halbert A, Richmond P, Prescott SL. Effects of probiotics on atopic dermatitis: a randomised controlled trial. Arch Dis Child 2005; 90: 892–897. 55. Prescott SL, Dunstan J, Hale J et al. Clinical effects of probiotics are associated with increased interferon-gamma responses in very young children with atopic dermatitis. Clin Exp Allergy 2005; 35: 1557–1564. 56. Baldini M, Lohman IC, Halonen M, Erickson RP, Holt PG, Martinez FD. A Polymorphism in the 5 flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 1999; 20: 976–983. 57. Eder W, Klimecki W, Yu L et al. Toll-like receptor 2 as a major gene for asthma in children of European farmers. J Allergy Clin Immunol 2004; 113: 482–488. 58. Weiss ST, Tager IB, Munoz A, Speizer FE. The relationship of respiratory infections in early childhood to the occurrence of increased levels of bronchial responsiveness and atopy. Am Rev Respir Dis 1985; 131: 573–578. 59. Martinez FD, Antognoni G, Macri F et al. Parental smoking enhances bronchial responsiveness in nine-year-old children. Am Rev Respir Dis 1988; 138: 518–523. 60. Ronchetti R, Macri F, Ciofetta G et al. Increased serum IgE and increased prevalence of eosinophilia in 9-year-old children of smoking parents. J Allergy Clin Immunol 1990; 86: 400–407. 61. Cook DG, Carey IM, Whincup PH et al. Effect of fresh fruit consumption on lung function and wheeze in children. Thorax 1997; 52: 628–633. 62. Peat J, van-den-Berg R, Green W, Mellis C, Leeder S, Woolcock A. Changing prevalence of asthma in Australian school children. Br Med J 1994; 308: 1591–1596. 63. Peat JK, Mihrshahi S, Kemp AS et al. Three-year outcomes of dietary fatty acid modification and house dust mite reduction in the Childhood Asthma Prevention Study. J Allergy Clin Immunol 2004; 114: 807–813.
MINI-SYMPOSIUM: LUNG PHYSIOLOGY
The development of respiratory inflammation in children Susan L. Prescott* School of Paediatrics and Child Health, University of Western Australia, PO Box D184, Princess Margaret Hospital, Perth WA 6001, Australia KEYWORDS Asthma; Childhood; Allergy; Airway remodelling; Airway inflammation; Mucosal immune system; Type 2 T-helper cell cytokines
Summary With the rising world burden of asthma, it is crucial to define the early events that lead to chronic inflammation and airway remodelling. Chronic airway inflammation appears to be the culmination of both local epithelial dysfunction and a more generalised immune dysregulation that results in allergic predisposition. A number of antenatal and early postnatal events may contribute to this. However, although a systemic propensity for allergic responses (typically food allergy) frequently pre-exists in children who go on to develop asthma, there is still uncertainty over whether epithelial changes occur as a primary event or whether these are consequent to this evolving systemic propensity for type 2 T-helper cell allergic responses. Many children with asthma already show many of the features of chronic airway inflammation, with epithelial desquamation, inflammatory cell infiltrates, subepithelial basement membrane thickening and fibrosis, goblet cell hyperplasia and smooth muscle hypertrophy. These changes can be evident before asthma is diagnosed, and there is also evidence that airway inflammation and early remodelling can progress in a subclinical state. New studies suggest that early airway damage is irreversible and that subsequent lung function is ‘set’ in the first years of life. These observations highlight the need to identify affected or at-risk children early and to develop interventions that can abort or prevent ongoing airway inflammation and remodelling. ß 2006 Elsevier Ltd. All rights reserved.
INTRODUCTION
propensity for immunoglobulin (Ig) E-mediated immune responses (atopy). However, although there is a strong association between allergen sensitisation and asthma, these processes appear to develop through independent processes,1 leading to much debate about the primary events that lead to airways disease. Events in early life, when systems are developing, have a critical influence on both structural development and functional responses. Furthermore, the consequences of these still poorly defined events are also set early. Manifestations of allergic predisposition are apparent within the first few months of life, typically as atopic dermatitis and food allergy. Presymptomatic airways inflammation can also be detected in this early period.2 Although most infants
Asthma is the most common cause of chronic airway inflammation in children living in developed countries and the same concerning trends are now occurring in developing countries. The increasing prevalence over the last 30–40 years indicates that environmental changes are responsible. Although the specific causes are not clear, this has been associated with parallel increases in allergic rhinitis, food allergy and atopic dermatitis, suggesting that all of these conditions result from an underlying increase in the * Tel.: +61 8 9340 8171; Fax: +61 8 9388 2097. E-mail address: [email protected]. 1526-0542/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2006.03.001
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with early virus-associated ‘recurrent wheeze’ do not develop asthma, as many as 80% of those with early evidence of allergic disease (atopic dermatitis and food allergy) will go on to develop allergic airway disease (asthma or allergic rhinitis).3 Early sensitisation is also major risk factor for persistent wheezing and airway hyperreactivity.4 Around 70–90% of individuals with established asthma have allergen sensitisation, and the proportion of asthmatics with sensitisation is highest in children. By school age, around 40% of children living in developed countries have sensitisation to inhalant allergens but not all of these children will develop symptomatic airway disease. The factors that determine tissue specific manifestation of allergic inflammation are also unclear. Thus, asthma appears to be the result of a two-stage process initiated in early life which involves: 1. the development of a systemic propensity for IgE allergen sensitisation; 2. the development of local propensity for airway inflammation, with subsequent damage to growing lung tissues and altered respiratory function. The sequence and relationship of these events are, however, unclear. Compounding this further, asthma also appears to be a heterogeneous condition with different contributing events in different individuals.
EVIDENCE OF EARLY AIRWAY INFLAMMATION AND REMODELLING IN CHILDREN Mucosal events arguably play the most pivotal role in both systemic immune development and local inflammation. These events are, however, still poorly understood in humans because of logistic and ethical limitations of studies in this area, particularly in young children. Inflammation is a normal host response to noxious agents, which is usually inhibited by local regulatory systems once repair processes have been initiated and the threat has been eliminated. In children, persistent inflammation will develop with more chronic or repeated exposure to noxious agents, most commonly due to repeated viral infection or exposure to passive smoking. Because these exposures are common, many children develop symptoms of airway inflammation, but most will not go on to develop asthma (‘transient wheezers’). Abnormalities in host responses appear to be an important secondary determining factor. These include both inappropriate systemic responses to otherwise innocuous agents (allergen sensitisation) and poorly regulated local responses that contribute to abnormal tissue repair (airway remodelling). It has been extremely difficult to determine the relative contribution of these pathways in initiating events.
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Chronic inflammation in the lower airway is associated with chronic inflammatory cell infiltrates, epithelial damage (desquamation), subepithelial basement membrane thickening and fibrosis, goblet cell hyperplasia and smooth muscle hypertrophy.5 All of these changes are seen in children with asthma.2,5,6 More significantly, changes have also been seen in preschool children before a diagnosis of asthma has been made.2 This worrying observation suggests that airway inflammation and early remodelling may occur in a subclinical disease state.6 There is also accumulating evidence that subsequent lung function is ‘set’ in the first years of life.7,8 This highlights the need to identify affected or at-risk children early and to develop interventions that can abort or prevent ongoing airway inflammation and remodelling. There is preliminary evidence that early intervention with inhaled corticosteroids can reduce the progression of airway remodelling in children9,10 but the long-term effects are still not clear. Epithelial damage is associated with increased expression of pro-inflammatory cytokines (interleukin-1b (IL-1b), granulocyte-macrophage colony-stimulating factor) and growth factors including platelet-derived growth factor, fibroblast growth factor, transforming growth factor-b (TGFb) and endothelin-1. This can ultimately lead to airway remodelling with subepithelial fibrosis, and abnormal vascularisation with significant effects on lung function. This is believed to be the result of dysregulated attempts to repair repeated mucosal injury by allergens, viruses and pollutants. Although there has been accumulating evidence that airway remodelling probably occurs secondary to chronic inflammation, there has also been speculation that this could occur independently as a result of primary dysfunction in endothelial-mesenchymal repair processes (for a review, see Ref. 11). At this stage, the relative contributions role of host and environmental factors in the initiation of chronic airway inflammation are still not clear. There is still uncertainty as to whether epithelial changes occur as a primary event or consequent to an evolving systemic propensity for type 2 Thelper (Th2) allergic responses.
RELATIONSHIP BETWEEN ALLERGEN SENSITISATION AND AIRWAY INFLAMMATION IN CHILDREN Identifying future asthmatics from the heterogeneous group of early infant wheezers remains a significant and important challenge, and requires a better understanding of the underlying causal pathways. The role of allergic propensity in the early development of airway inflammation is not clear. Although over 80% of older school-aged children have evidence of aeroallergen sensitisation, the corresponding figure in preschool children
RESPIRATORY INFLAMMATION IN CHILDREN
is substantially lower. In these younger children, airway inflammation is commonly present before evidence of inhalant sensitisation. Although this suggests that inhalant sensitisation does not play a primary role in the initiation of airway inflammation, the presence of other allergic disease (atopic dermatitis) and prior sensitisation to other allergens (i.e. foods) is frequently a defining feature in the subgroup of ‘early infant wheezers’ who go on to develop asthma (for a review, see Ref. 12). This indicates that a systemic propensity for Th2 allergic responses frequently pre-exists in these children. This allergic propensity appears to be determined by both genetic or environmental events in utero and could foreseeably also influence local patterns of response in airways, although this remains to be determined.
THE DEVELOPMENT OF AIRWAY IMMUNE NETWORKS IN EARLY LIFE Antigen-presenting cells in the local airways play a critical role in initiating and regulating early inflammatory events, particularly related to airway dendritic cells and alveolar macrophages. In the first year of life, infants do not typically exhibit airway dendritic cells in the absence of inflammation.13 Animal studies also confirm that local airway dendritic cells networks are less developed in the early postnatal period, with markedly attenuated responses to inflammatory triggers.14,15 Severe respiratory infection is associated with the appearance of mature dendritic cells in infant airways,13 suggesting that local tissue events in infancy can influence the local maturation of dendritic cells in humans. This has renewed interest in the role of respiratory infection in early life in the aetiology of atopic asthma (discussed below). As well as providing an important ‘first line’ of innate immune defence, local antigen-presenting cells (particularly dendritic cells) play a critical role in programming T cell responses. These cells also appear to have a major role in the late-phase response.16,17 After encountering local antigens, dendritic cells undergo migration-induced maturation to regional nodes,16 where they present antigen and typically produce Th1-trophic signals, such as IL-12. These signals may occur under conditions of infection or other local stress18,19 that evoke protective Th1 effector T cell responses. In the absence of these obligatory Th1-trophic signals, resting dendritic cells are more likely to stimulate Th2 development, at least in animals.20 Thus, age-related immaturity in dendritic cell function21 may lead to a reduced capacity for these cells to produce Th1 trophic signals, increasing the risk of Th2 responses in early life. Factors that influence activation of the maturation of airway dendritic cells could have a key role in determining the subsequent pattern of local T cell responses. This could include genetically programmed functional variations as well as local environmental exposures in early life, such as infection and pollutants (below).
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ROLE OF THE ‘COMMON MUCOSAL IMMUNE SYSTEM’ IN THE DEVELOPMENT OF RESPIRATORY TOLERANCE The ‘common mucosal immune system’ has been recognised as a functional entity for many years.22 The developing gut is a reservoir for T and B cell precursors, which mature and eventually migrate to the respiratory tract. In addition, it is likely that the gut precursor populations also include subpopulations of maturing regulatory cells (including CD4+CD25+ T cells), which play a key role in controlling peripheral immune responses. Thus, although anatomically separate, components of the mucosal system immune system are functionally integrated, and this may explain how changes in gut flora can influence immune function (IgA production) in the respiratory tract.23 These observations are an important consideration in defining events that lead to the development (or failure) of ‘respiratory tolerance’. Immune tolerance is driven by environmental exposures and is first evident as ‘oral tolerance’ to ingested allergens. Although still poorly understood, failure of oral tolerance (food allergy) is frequently a preceding event in children who subsequently develop respiratory allergy. Again, it is not clear how these events are linked – whether this is a causal relationship or whether these children are predisposed to failed tolerance for independent reasons. These observations highlight the importance of looking beyond the respiratory mucosa for new pathways in pathogenesis, treatment and prevention. The concept of an integrated mucosal immune system may also explain the remote effects of both ‘natural’ tolerance and tolerance ‘induced’ by mucosal immunotherapy. In the respiratory tract, the bulk of ambient aeroallergen exposure occurs in the ‘upper’ airway. Under normal conditions, this appears to result in the generation of CD4+CD25+ regulatory T cells and a low level Th1 response on subsequent exposure. Because this process appears to be dependent on dose (the intensity of antigenic stimulation), mucosal allergen administration has been used therapeutically in the upper airway to induce systemic tolerance. This has been most successful using a sublingual route (sublingual immunotherapy (SLIT)), with a growing number of reports of clinical benefits. In children with mild-to-moderate persistent asthma and dust mite sensitisation, recent studies suggest a low-tomoderate clinical benefit of SLIT when used in addition to measures to reduce environmental exposure.24 There is also preliminary evidence that SLIT may reduce the risk of asthma developing in children with allergic rhinitis.25 New studies are now planned to examine the effects of SLIT in the primary prevention of aeroallergen sensitisation. In this proposed randomised controlled trial, 200 children (aged 18 months to 3 years and at high risk of developing allergic respiratory disease) will receive inhalant allergen SLIT (house dust mite, cat and timothy grass) or a placebo
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for 12 months. These children will already have evidence of allergic disease (food allergy or atopic dermatitis) but no sensitisation to inhalants. The children will be monitored for 3 years, aiming to detect a 50% reduction in IgE and allergic Th2 responses to allergens, as well as a 50% reduction in asthma (www.immunetolerance.org/research/allergy/trials/ holt.html). The results are awaited with great interest. Finally, it is also clinically relevant to consider the interactions between the ‘upper’ and ‘lower’ airway. Discussion of respiratory inflammation often focuses predominantly on the lower respiratory tract, despite the fact that upper airway disease (allergic rhinitis) is also a major cause of morbidity. There is currently a growing awareness of the clinical relevance of this functional relationship, now discussed in terms of ‘one airway’ (for a review, see Ref. 26). Patients with allergic rhinitis frequently have associated bronchial hyperreactivity,27 and an estimated 60–78% of asthma patients have coexisting allergic rhinitis.28 Moreover, the treatment of allergic rhinitis improves asthma control.29 Although most of these observations have been made in adults, this is also likely to be relevant in children.
ROLE OF ‘TH2’ CYTOKINES IN AIRWAY INFLAMMATION In rodents, Th2 cytokines (namely IL-13) are especially critical for the development of reactive airways disease (see Ref. 30 and others), but in humans it is still not clear what role the systemic predisposition for Th2 responses plays in initiating chronic airway inflammation. Once inflammation is established, T lymphocytes are principal effector cells, and there is substantial evidence implicating Th2 (IL-4, IL-5, IL-9, IL-13) in airways inflammation. Th2 cytokines (IL-4, IL-5, IL-13) are also produced by mast cells (IL-4, IL-5, IL-13) and eosinophils (IL-4, IL-13), which are abundant in the asthmatic airway. IL-13 and IL-4 also appear to contribute to airway remodelling through effects on the epithelial-mesenchymal trophic unit. These cytokines stimulate the release of TGFb2 from bronchial epithelial cells31 which plays a key role in promoting the proliferation and transformation of fibroblasts. Eosinophils (under the influence of Th2 cytokines) also produce TGFb and make a significant contribution to this process. Despite the clear role of Th2 pathways in chronic airway inflammation, asthma and other allergic diseases are not due to simple Th2 polarisation as previously thought. Th1 cells also play a role in allergic inflammation,32 and the level of Th1 interferon-g (IFNg) is elevated in the serum of asthmatics during acute exacerbations,33 and in bronchoalveolar lavage fluid after allergen challenge.34 These observations suggest that allergic inflammation may be secondary to a more fundamental failure of underlying immune regulation. It has recently been proposed that allergic disease is the result of an inappropriate balance between regulatory cells (including CD4+CD25+ T regulatory cells) and Th2 effector cells. In the airways, a number
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of other cells, including epithelial cells and airway dendritic cells, also have important regulatory effects on local immune responses. Although the development of normal tolerance to inhalant allergens is still poorly understood, all of these cells are likely to play an important role.
ANTENATAL EVENTS THAT CONTRIBUTE TO AIRWAY INFLAMMATION Antenatal events have the capacity to contribute to airway inflammation on two broad levels: first, through effects on the development airway structure and function, and second, by immune effects that may alter the risk of subsequent allergic sensitisation. The growth and development of the airways in utero appears to be an important determining factor in subsequent lung function. Children with ‘smaller’ airways are more likely to have milder respiratory tract symptoms with viral infections (typically the early transient wheezers described by Martinez and colleagues35). Maternal smoking is the best described antenatal exposure to be associated with subsequent reduced lung function, airways inflammation and increased susceptibility to wheezy respiratory infection (see Ref. 36 and others). These effects on lung function persist into later childhood and are independent of subsequent postnatal smoke exposure.37 Although fetal immune responses are typically skewed towards Th2 in pregnancy,38 a number of subtle differences have been found in neonates who go on to develop allergic disease (for a review, see Ref. 39). Although this was originally thought to be genetically programmed, there is now evidence that in utero exposures can influence fetal immune function. These are of interest as either risk factors or potential prevention strategies, and include dietary factors with anti-inflammatory properties,40,41 maternal smoking,40,42 microbial exposure43 and direct effects of maternal allergy (independent of genetic influence).44 Although there is now good evidence that the fetus is exposed to allergens (particularly food allergens from the maternal diet),45 the effects of this are not clear. Allergen exposure (at any age) does not usually lead to sensitisation. Instead, repeated allergen exposure is essential for the development of normal tolerance processes. It could be argued that early exposure to innocuous proteins from the future environment may be physiological rather than pathological, particularly as this phenomenon is observed in a significant proportion of babies regardless of atopic risk. As in the early postnatal period, this could, in the absence of ‘danger’ signals, be important for initiating tolerance. This might explain the lack of correlation between the level of exposure and neonatal responses and the failure of allergen avoidance in pregnancy to prevent allergy. At this stage, further studies are needed before specific interventions can be recommended in early life for the prevention of asthma and allergic diseases (with the clear exception of smoking).
RESPIRATORY INFLAMMATION IN CHILDREN
POSTNATAL EVENTS THAT MAY INFLUENCE THE DEVELOPMENT OF AIRWAY INFLAMMATION Local events in the airways are critical for programming all systemic and local defence systems, culminating in a highly adaptive surveillance network. In the early postnatal period, environmental exposure plays a key role in driving global immune maturation, which appears to depend on exogenous factors (namely microbial exposure) to develop normally. The pattern of environmental antigen exposure determines the specificity of responses required for host defence, and local conditions during antigen-processing in local tissues appear to influence the patterns of immune maturation and resulting immune responses. Local encounters with noxious environmental factors, including irritants (such as cigarette smoke) and respiratory pathogens, are likely to influence the development of immune networks in the airways and the propensity for chronic inflammation. Similarly, other exposures could have potential modulating influences, for example exposure to dietary (and endogenous) antioxidants and omega-3 polyunsaturated fatty acids, as discussed further below.
Role of allergens For many years, early allergen exposure was regarded as the major factor in the development of asthma and allergic disease. Although evidence was limited, this was the basis for allergen avoidance as the first main strategy for primary allergy prevention in those who were genetically predisposed. The results of such measures have been fairly disappointing or even paradoxical,46 shifting interest to other potential aetiological factors. Thus, although sensitisation is a strong risk factor for asthma, wheeze and bronchial hyperactivity,47 the relationship between early allergen exposure and these clinical symptoms has been much harder to confirm. On balance, the existing evidence indicates that postnatal allergen exposure has a significant role as a triggering factor in older children with established disease, but the role and importance of aeroallergen exposure in initiating airway inflammation is still not clear. At this stage, it appears more likely that other factors are likely to influence the development of sensitisation rather than just allergen encounter per se. Many host and environmental factors have the capacity to influence local and systemic immune responses at the time of first allergen encounter, as well as in the subsequent period when memory immune responses are being determined. Moreover, new allergy-prevention studies are focusing on the potential role of controlled allergen administration (immunotherapy) rather than allergen avoidance (as above).
Role of respiratory tract infections Respiratory infections are the most common cause of acute airway inflammation in childhood. Despite this, the relation-
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ship between early respiratory tract infections and chronic airway inflammation (and allergic airway disease) has been confusing. These infectious agents have been clearly identified as asthma triggers in children with established disease. Respiratory syncytial virus infection in infancy has also been long regarded as a risk factor for subsequent asthma, at least in the first 6 years of life.48 This may be in part because of the Th2-trophic properties of this and other respiratory viruses, but it may also be an indirect consequence of the delayed capacity to mount Th1 IFNg responses in the early postnatal period. A predisposition to wheezing lower respiratory infection in the first year of life is a strong risk factor for asthma at 6 years of age in both non-atopic (odds ratio 4.1, P < 0.0005) and atopic (odds ratio 9.0, P < 0.0005) children.49 This strongly suggests that significant infectioninduced airway inflammation during the early period of postnatal lung growth and development can have profound long-term effects that appear to be more marked than with inflammation occurring at later ages. In contrast, the notion that infection can serve only as a priming factor for subsequent allergic inflammation is at odds with other observations that, in some circumstances, infections appear to protect from allergic disease (for a review, see Ref. 50). This suggests the alternate possibility that early encounter with infectious agents has the potential to accelerate the maturation of local immune networks (including dendritic cells and regulatory T cells as discussed above), producing Th1 defence responses that may override the Th2 default response in immunologically immature infants. There is growing evidence that key regulatory cells (particularly antigen-presenting cells and T regulatory cells) depend on Toll-like receptor (TLR) mediated signalling for activation and maturation, and there is growing speculation that both genetic polymorphisms (affecting TLR function) and environmental factors (such reduced microbial exposure) predispose to allergic disease through effects on these innate immune pathways. A number of animal studies collectively suggest that early microbially driven TLR activation may modify immune development and the risk of sensitisation, although the effects appear to be more significant before responses have been established.51,52 There is only indirect evidence that early bacterial exposure may be protective in humans. This includes the many epidemiological studies (for a review, see Ref. 50) that formed the basis of the ‘hygiene hypothesis’. Intervention studies also suggest that the administration of bacterial products to children may have clinical (see Refs. 53 and 54 and others) and immune effects.55 Although it has been inferred that these variations in microbial exposure may be responsible for differences in innate (and subsequent cognate) immune function, this has not been documented directly. Genetic studies currently provide better supportive evidence that functional variations in aspects of TLR microbial signalling are associated with clinical phenotypes. Specifically, polymorphisms in the gene coding for CD14
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(involved in lipopolysaccharide signalling through TLR4) have been linked to total serum IgE levels.56 More recently, a TLR2 genetic polymorphism was shown to have a protective effect against asthma.57 Notably, the ‘protective’ effect was only seen when children were raised in environments with a ‘high’ microbial burden, illustrating the interactive effects of genetic and environmental factors on these pathways. Taken together, these findings suggest that alterations in TLR function, either as a result of differences in early environmental exposures or function genetic polymorphisms, have an effect on the subsequent development of adaptive immune function. Thus, the complexity of the relationships between infection and allergic inflammation needs to be further dissected. In particular, variations in the consequences of infection on allergic propensity may involve differences in the timing of exposure, the nature of the infectious agent and the location of the infection (upper or lower airway), in addition to genetic factors.
Role of irritants and pollutants The effects of pollutant exposure in childhood are best described for passive exposure to parental smoking. In animals, there is considerable evidence that tobacco smoke can cause inflammation in the lower respiratory tract. Few studies have explored this in humans, although associations have been documented between parental exhaled tobacco smoke and higher numbers of IgE+ cells and eosinophils in the nasal mucosa of children, as well as increased neutrophil counts. We may speculate that local inflammation (such as that induced by exhaled tobacco smoke) during allergen encounter may predispose to allergic responses. Evidence of this is indirect and inconclusive. Some have noted associations between parental smoking and systemic markers of atopy in children, including serum IgE levels, eosinophilia and positive skin-prick tests,58–60 although this has not been confirmed in other studies. These observations suggest immunological effects in addition to airway irritation and early effects on lung mechanics, but further studies are needed.
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There is also preliminary evidence that fish oil supplementation in early life has an effect on early immune responses41 and reduces symptoms of airway inflammation (wheeze and cough) in preschool children.63 These effects were subtle but could indicate both systemic and local airway influences. There are still insufficient data to make specific recommendations for disease prevention. Taken together, these observations suggest that early environmental exposures have the potential to influence the maturation of both local and systemic local immune function, thereby altering the susceptibility to airway inflammation. With the mounting burden of disease, further studies are urgently needed in this area to help to determine potential modifiable exposures that may be of benefit in disease prevention.
PRACTICE POINTS Antenatal events may have an important role in determining allergic predisposition and airway function. Ultimate lung function is determined in the preschool years. Infants with early evidence of allergic predisposition are at risk of asthma, and this diagnosis should be considered if these children present with recurrent chest symptoms. Some children may have subclinical airway inflammation and early remodelling. There are important functional relationships between the upper and the lower respiratory tract: patients with asthma should be assessed for associated allergic rhinitis and treated appropriately.26 The early use of anti-inflammatory medication may reduce the risk of airway remodelling even in mild asthma.
Role of other environmental factors
RESEARCH DIRECTIONS
A number of dietary factors have the potential to modulate inflammatory responses, including omega-3 polyunsaturated fatty acids and other known immunomodulatory factors such as antioxidants. Although the therapeutic effects in established disease are at best weak, these factors could have a more significant role earlier in life when immune responses are being initiated and patterns of subsequent reactivity are being set. Population studies suggest that diets rich in antioxidants (fresh fruits)61 and oily fish (omega-3 polyunsaturated fatty acids)62 reduce the risk of recurrent wheeze in childhood, suggesting protective effects against airway inflammation.
To understand the role of respiratory infections, allergens and pollutants in the development of chronic airway inflammation and remodelling. To identify the role of allergic predisposition in the evolution of airway inflammation. To be able to identify future asthmatics from the heterogeneous group of early infant ‘wheezers’. To develop methods to identify children with subclinical airway inflammation and early remodelling. To develop early interventions that can prevent chronic airway inflammation and remodelling.
RESPIRATORY INFLAMMATION IN CHILDREN
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