Abstract
Asthma occurs as a result of the interplay of genetic susceptibility and environmental influences on the developing lungs and immune system. Asthma in children is predominantly associated with the development of allergic sensitization and the pathological features of eosinophilic airway inflammation and structural airway wall changes, collectively termed airway remodeling. The clinical manifestation of disease is heterogeneous but includes symptoms of breathlessness and wheeze, which result from bronchoconstriction. Acute attacks in children commonly result from respiratory infection, with repeated episodes of infection with rhinovirus and respiratory syncytial virus in early life being especially associated with the risk of recurrent wheezing and asthma in children who also develop early allergic sensitization and have a genetic susceptibility. The focus of this chapter is to discuss the basic immunological mechanisms that drive the pathophysiology of asthma, with specific focus on the close interactions between innate and adaptive immune responses in driving disease. The immunopathology of specific clinical manifestations of disease, including exacerbations and preschool wheezing disorders, will also be discussed, and mechanisms that are unique to the developing pediatric airway and that cannot be extrapolated from adult disease will be highlighted.
Keywords
asthma, preschool wheeze, innate immunity, mechanisms, inflammation, remodeling
The fundamental pathophysiological features of asthma include airway hyperresponsiveness (which can also manifest as reversible airflow obstruction), inflammation, and structural changes in the airway wall, collectively termed airway remodeling. The development of allergic sensitization is also key to the immunopathology of pediatric disease. The combined clinical effects of these abnormalities result in the manifestation of symptoms which include shortness of breath and wheezing, with or without cough.
A key factor that needs to be considered in the immunopathogenesis of pediatric asthma is the age of the child. Wheezing disorders are common in children aged 5 and under, but not all preschool wheezers will develop asthma and the mechanisms mediating preschool wheeze are likely to be distinct from those that result in progression to asthma and drive asthma in school-aged children. A complex interplay between host susceptibility, the developing airway microbiome, environmental insults such as exposure to allergens and pollution, and respiratory infections results in pulmonary immune responses and the pathophysiological features of asthma ( Fig. 43.1 ). The aim of this chapter is to summarize what is known about the immunology and pathology of allergic asthma in children and to highlight specific situations, such as preschool wheeze, asthma exacerbations, and severe therapy resistant asthma, in which this common immunopathology may not apply. The need to focus on approaches to achieve disease modification and asthma prevention in the future will also be discussed.
Altered Pulmonary Immunity in Asthma Inception
Development of allergic sensitization is a key component of asthma pathogenesis in children. Sensitization may develop to food or aero-allergens and is initiated at mucosal or barrier surfaces where there is an epithelial layer. Respiratory mucosal surfaces (airways) are continuously exposed to inhaled, nonpathogenic foreign particles (antigens, microbes, and pollutants). A key challenge for the healthy respiratory system is therefore to distinguish innocuous antigens from pathological microbes. However, in disease, and with a host underlying susceptibility to allergic disease, an exaggerated immune response is mounted to inhaled allergens. The pulmonary epithelium is the first point of contact and both barrier and immune function of this airway structure is altered in children with asthma. The altered bronchial epithelial function results in a “leaky” airway wall and permits entry of antigen (allergen) through the epithelium ( Fig. 43.2 ) with recognition and uptake by the pulmonary antigen presenting cells—dendritic cells (DCs)—that are continuously undertaking surveillance close to the mucosal surface. DC dendrites may protrude through to the airway lumen to undertake antigen recognition via cell surface receptors (see Fig. 43.2 ). DCs take up the antigen, then migrate to the pulmonary draining (mediastinal) lymph nodes where they present the antigen to naive T cells. The naive T helper (Th0) cells subsequently differentiate to type 2 T helper cells under the influence of inflammatory cytokines such as interleukin (IL)-4. The Th2 cells are then released and migrate back to the pulmonary tissue where, with further allergen exposure, they initiate an allergic reaction characterized by the release of additional allergic inflammatory cytokines including IL-5 and IL-13. In parallel, antigen is presented to B cells in the draining lymph nodes where the antigen (allergen) is processed, and immunoglobulin (Ig)E antibody to the antigen is secreted by B cells and released into the circulation and pulmonary tissue in preparation for a response to future allergen exposure (see Fig. 43.2 ). IL-4 is necessary to allow the isotype switch of antibody production from IgG molecules to Ig-E molecules in an allergic environment. Allergen sensitization results from the initial allergen exposure, and subsequent allergen exposure results in an allergic reaction. This is characterized by recognition of the allergen (antigen) by Ig-E (antibody), which binds to mast cells and results in mast cell degranulation with release of histamine and leukotrienes and a resulting type 1 immediate reaction (see Fig. 43.2 ). This is associated with a more chronic allergic reaction that results from induction of Th2 cells and downstream inflammatory mediators including IL-4, IL-5, and IL-13, which are the hallmark of and drive for allergic reactions.
Cells, Molecules, and Cytokines Involved in Pediatric Allergic Asthma
Eosinophils and Interleukin-5
Eosinophils are the hallmark feature of the asthmatic immune response in most patients, children in particular. The role of eosinophils in allergic inflammation is summarized in Box 43.1 .
- 1.
Initiation of events that lead to Th2 inflammation
- 2.
Suppression of Th1 mediated immunity
- 3.
Recruitment of Th2 cells to the lung
- 4.
Release of growth factors that contribute to the development of airway remodeling
Th, T helper.
Eosinophils contain multiple granule proteins that exhibit an array of toxic and immune-modulatory activities. The granule proteins can be released by different mechanisms, including during an acute allergic insult, and they cascade the proinflammatory, Th2 responses associated with allergic asthma. The cytokines and chemokines released following eosinophil degranulation promote longevity of eosinophils in tissues, which leads to the cyclical nature of signaling, activation, and survival. Additionally, these proteins target any foreign antigen, promote inflammation in the area, and may cause considerable damage to surrounding structures.
IL-5 is released by Th2 cells in asthma ( Fig. 43.3 ) and results in the induction and recruitment of eosinophils from the peripheral circulation to the airways. IL-5 also promotes eosinophil differentiation, growth, and survival. The airway eosinophilia that is characteristic of pediatric allergic asthma in children is therefore thought to be mediated by IL-5. However, this is an assumption based on extrapolation from animal and adult studies. Firm evidence for the presence of IL-5 in the airways of children with stable asthma is difficult to find. As airway samples are not easily obtained from children, most studies investigating the mediators of allergic asthma include assessments of peripheral blood, but this is not always a reliable surrogate for the airways. Another issue that affects the detection of Th2 cytokines in asthma is that they are steroid sensitive, so it can be difficult to find elevated levels in patients who are not “steroid naïve” and who have been prescribed maintenance inhaled steroids (which is the case for most children long before referral to hospital). However, it remains certain that the predominant airway inflammatory phenotype of pediatric asthma is eosinophilic, and this is independent of disease severity or duration. Therefore modulating eosinophil function or reducing their numbers has been one of the most important therapeutic goals in asthma for many years. The mainstay of treatment for asthma is inhaled glucocorticoid steroids. Glucocorticoids increase eosinophil apoptosis and block the survival effect of interleukin-5, resulting in a reduction in airway eosinophilia with steroid therapy. Assessment of the receptor for IL-5 on peripheral blood eosinophils from healthy, steroid naïve, and steroid treated asthmatic children has shown reduced IL-5 receptor expression in patients treated with inhaled steroids, and this was concomitant with reduced in vitro responsiveness to IL-5. This is therefore a potential mechanism by which steroids inhibit IL-5 in children on maintenance therapy for asthma. Interestingly, children with severe asthma, who are on high-dose maintenance inhaled steroids, have a persistent airway eosinophilia in the absence of detectable IL-5, suggesting that alternative mechanisms contribute to the development of eosinophilia as disease becomes more severe. This has obvious implications for the use of anti-TH2 monoclonal therapy.
Mast Cells in Asthma
The immediate response during an allergic reaction in a patient with asthma results from binding of allergen-specific Ig-E antibodies to mast cells, and following cross-linking of the allergen across two antibody molecules, the resulting degranulation of mast cells results in a release of mediators that cause the symptoms of bronchoconstriction, airway edema, and inflammation (see Fig. 43.2 ). The predominant mast cell mediators that are released include histamine and cysteine leukotrienes. Despite the obvious role of mast cells in allergic reactions, their importance in asthma pathogenesis remains uncertain, since treatments that have aimed to prevent or reduce mast cell degranulation, such as sodium cromoglycate and other mast cell stabilizers, have been relatively ineffective in children, and there is little evidence of an increase in tissue mast cells in children with severe asthma. Therapies that have targeted mast cell mediators, such as leukotriene receptor antagonists that minimize the downstream proinflammatory effects of leukotrienes, have also been trialed in children with asthma, but again, their efficacy has been disappointing. It may be that the location of mast cells within specific structures in the airway wall is important in determining their pathological effect. Increased numbers of mast cells have been shown to be present specifically within airway smooth muscle in patients with asthma but not those with eosinophilic bronchitis. Moreover, mast cells have been shown to modulate the function of airway smooth muscle and, via release of Th2 mediators such as IL-13, can result in increased airway hyperresponsiveness. It is therefore likely that only therapies targeting tissue-specific mast cells will prove to be beneficial.
Lymphoid Cells
T-Lymphocytes
The key inflammatory cell that is central to driving asthma pathogenesis, and is induced following the development of an adaptive immune response to allergen exposure, is the T-helper 2 (Th2) lymphocyte (see Fig. 43.2 ). These CD4 + cells express the T-cell receptor and have the capacity to secrete various cytokines depending on their local environment. Th2 lymphocytes are induced following allergen exposure and release hallmark Th2 cytokines including IL-4, IL-5, and IL-13 (see Fig. 43.3 ), which are considered important in the initiation and development of the pathophysiology of asthma. IL-4 is essential for the development of Ig-E and allergic sensitization; IL-5 is an eosinophil growth factor, chemoattractant, and promoter of eosinophil survival; while IL-13 is most closely associated with the development of airway hyperresponsiveness (AHR) and airway remodeling. Although Th2 cells are important in driving allergic airway responses, these are not the only lymphocyte subset involved in asthma pathogenesis. Numerous other T-cell subsets have been implicated in asthma, including Th9 cells and Th17 cells. Effector CD4 + T cells are defined by expression of specific transcription factors, which determine their secreted cytokines. Th2 cells express the transcription factor GATA3 and secrete IL4, 5, 13; while Th17 cells express receptor-related orphan receptor gamma t (ROR-γT) and secrete IL-17 (see Fig. 43.3 ). However, it is also becoming increasingly apparent that the inflammatory environment is central to determining cellular function. A change in milieu can result in a change in cytokine secretory pattern, which is termed T-cell plasticity. In addition, not all T lymphocytes are proinflammatory and pathogenic. There is a critical balance between regulatory and proinflammatory T-lymphocytes that needs to be maintained to prevent disease, and it is proposed that in asthma an imbalance in favor of Th2 cells with a concomitant reduction in T regulatory (Tregs) cells results in disease manifestation. There are two main types of Tregs in the lung: CD4 + cells that secrete the antiinflammatory cytokine IL-10, and CD4 + CD25 + cells that have the transcription factor FoxP3. At present, data relating to the presence of these cells in the airways of children with asthma is scant, but assessment of peripheral blood and bronchoalveolar lavage has shown reduced numbers of CD4 + CD25 + FoxP3 + cells in asthmatics compared to healthy children ; however, these results were from steroid naïve patients. It is interesting to note that treatment with inhaled steroids results in higher levels of circulating and airway Tregs, but the cells remain functionally impaired. Children with severe asthma, whose symptoms are not controlled despite high-dose steroid therapy, have significantly lower levels of airway IL-10 and have a significantly reduced capacity for secreting IL-10 from circulating peripheral blood CD4 + T cells, suggesting relatively steroid resistant disease is characterized by a poor induction of IL-10 secretion from CD4 + cells after steroid therapy.
Innate Lymphoid Cells
Until recently, the predominant immune response that was thought to drive allergic asthma was an adaptive response mediated by Ig-E and T lymphocytes. However, it is now apparent that innate immunity plays a significant role in asthma pathogenesis. Murine experimental models have demonstrated the release of innate cytokines from the airway epithelium in response to allergen. These cytokines include IL-33, IL-25, and thymic stromal lymphopoeitin (TSLP). Of these, IL-33 has more specifically been associated with the onset of allergic immune responses by the induction of a group of cells called innate lymphoid cells (ILCs) ( Fig. 43.4 ). ILCs are of comparable size and morphology to T lymphocytes, but lack the T-cell receptor and surface markers, such as CD3/CD4/CD8 that are the hallmark features of T cells ( Table 43.1 ). The importance of the innate cytokines and ILCs in initiating pediatric asthma remains uncertain, but IL-33 is likely to be important in mediating severe therapy resistant asthma since it promotes airway remodeling and is relatively steroid resistant. Subpopulations of ILCs are induced depending on the stimulus and environment in a similar manner to T cell subtypes. Group 2 ILCs (ILC2s) that secrete the Th2 cytokines IL-4, IL-5, and IL-13 are therefore induced by IL-33 upon allergen exposure. There is evidence for increased numbers of ILC2s in the airways of children with severe asthma compared to controls, but their functional role in mediating disease and relative importance compared to T lymphocytes in pediatric disease remains unknown. Importantly, it is becoming increasingly apparent that an equal interplay between both ILCs and T cells is essential in initiation and persistence of disease, and it is unlikely that only one cell type is predominant.
| Th2 | ILC2 |
|---|---|
| Lineage surface markers | Lineage negative |
| T cell receptor, CD4 + , CD3 + | No T cell receptor |
| Lymphoid morphology | Lymphoid morphology |
| Intranuclear transcription factor GATA3 | Intranuclear transcription factor GATA3 |
| Induced via adaptive immune responses: Ig-E, dendritic cells, lymph nodes | Induced via innate epithelial cytokines: IL-33, IL-25, TSLP |
| Type 2 cytokine production: IL-4, IL-5, IL-13, IL-9 | Type 2 cytokine production: IL-4, IL-5, IL-13 |
Neutrophils
Neutrophils are thought to be important in mediating severe asthma in adults and it is proposed that dampening down neutrophilic inflammation may be beneficial. However, their role in pediatric disease is far less clear. There is no convincing evidence of increased airway mucosal neutrophils in children with asthma during stable disease. However, neutrophils are increased during exacerbations that are precipitated by infection, suggesting they may not be pathogenic, but an important response in clearing infection. There is recent evidence showing a subgroup of children with severe asthma have increased neutrophils specifically within the airway epithelium, and contrary to expectation, those with intraepithelial neutrophils had better lung function, symptom control, and were on lower doses of maintenance inhaled steroids. Therefore at present, blocking or reducing neutrophils cannot be recommended as an important therapeutic strategy for children with asthma, as they may indeed be beneficial. The role of neutrophils in the specific case of wheezing in preschool disorders is discussed below.
School-Age Allergic Asthma: Pathology and Mechanisms
Asthma is a chronic inflammatory airway disease, which in children is characterized by a predominance of eosinophils in the airway wall and lumen. Evidence of eosinophilia has been confirmed in endobronchial biopsies and broncho-alveolar lavage from school-aged children regardless of disease severity. The inflammation is accompanied by the presence of structural airway wall changes, or airway remodeling ( Fig. 43.5 ). These changes are thought to be inappropriate to maintain normal lung function. However, there is some evidence that certain structural changes, increased thickness of the reticular basement membrane in particular, may be protective as they provide reduced airway collapsibility. The specific structural airway changes present in children with asthma include increased thickness of the sub-epithelial reticular basement membrane (RBM), increase in both size and quantity of airway smooth muscle ( Fig. 43.6 ), and increased number of vessels (angiogenesis). All of these changes are present by school age regardless of disease severity. Certain features, such as thickness of the RBM, are present to the same extent in children as they are in adults with asthma and are therefore also independent of disease duration.
It had been proposed that repeated cycles of inflammation resulting from allergen exposure resulted in the development of structural airway changes, however, experiments using a neonatal mouse model and findings from cross-sectional studies that have investigated asthma pathology in children have shown that the key pathophysiological changes of allergic asthma (airway hyperresponsiveness, eosinophilic inflammation, and airway remodeling) develop in parallel (see Fig. 43.5 ). Importantly, this implies that therapies that only target eosinophilic inflammation may be insufficient to achieve optimal disease control and improved lung function in all patients. Targeting eosinophilic inflammation alone, using inhaled steroids, has resulted in improved symptom control and lung function in the majority of children; however, it is apparent that this approach in isolation does not achieve disease modification, specifically when used in early onset preschool disease. It is now accepted that the airway structural cells are not just altered in quantity in asthma, but they are immunologically active and have a fundamentally altered functional phenotype which contributes to asthma pathogenesis as well.
The Clinical Relevance of Eosinophilic Inflammation in School-Age Asthma
Stability of Eosinophilic Inflammation in Pediatric Asthma and Impact on Therapy
Although pediatric asthma is predominantly an eosinophilic condition, the inflammatory profile is heterogeneous between patients. The predominant pattern of airway inflammation has been used to define and subdivide patients with asthma according to inflammatory phenotypes. These include eosinophilic, neutrophilic, pauci-granulocytic (no inflammation), or mixed. However, it is recognized that the inflammatory phenotype may not remain stable over time in the same patient. One reason for a “switch” in inflammatory phenotype is the development of an acute respiratory infection, which may change the profile from predominantly eosinophilic to neutrophilic or mixed. However, intriguingly, in children with asthma, change in airway inflammatory phenotype can be documented over time independently of exacerbations, symptoms, disease manifestation, or alteration in therapy. Therefore a possible explanation for eosinophil directed therapy being unsuccessful in children may be the impact of phenotype switching, or indeed, a less important functional role of eosinophils in causing disease pathogenesis in children compared to adults. The differences between eosinophil targeted therapy in adults and children highlights the importance of investigating disease mechanisms in age appropriate experimental models and not undertaking direct extrapolation of data from studies in adults to children. In addition, these findings question whether novel therapies that are targeted to a reduction in levels of IL-5 (monoclonal antibody to IL-5 or its receptor) and thus a specific reduction in eosinophils will be beneficial in children. Mepolizumab (monoclonal antibody to IL-5) has proven to be effective in reducing exacerbations in adult eosinophilic asthma, but efficacy data in children are awaited, and are mandatory before these therapies are offered to children.
Noninvasive Biomarkers of Eosinophilic Inflammation
Much effort has been undertaken to find a noninvasive objective biomarker to assess the efficacy of inhaled steroids in reducing airway eosinophilia as a guide to monitor disease and tailor treatment. Several biomarkers have been investigated in pediatric allergic asthma. One of the first was serum eosinophilic cationic protein (ECP), a mediator that is released by eosinophils when they are activated. It has been shown that ECP is steroid sensitive and therefore is reduced following treatment, and levels are closely related to peripheral blood eosinophils, but there is little evidence to show ECP levels relate to airway eosinophil numbers or activation status, meaning serum ECP adds little as a biomarker over peripheral blood eosinophil counts, and it is therefore not used to monitor disease. Another issue that complicates the use of eosinophil biomarkers measured in the peripheral circulation and not in the airways in asthma is that other allergic conditions may also be associated with elevated levels. For example, children with atopic dermatitis, whether or not they have asthma, may have elevated ECP, and blood eosinophils. It is therefore important to interpret results, specifically of peripheral blood biomarkers, with some caution.
A biomarker that has been extensively investigated more recently is exhaled nitric oxide (FeNO). It is associated with airway eosinophilia in children with difficult asthma and therefore considered a better noninvasive marker than serum ECP or total eosinophils. Reference values for normal levels are also available for children of all ages. FeNO is useful to support a diagnosis of asthma in steroid-naïve patients, although it can be elevated in atopic, nonasthmatics. It is very steroid sensitive, and in children it has been repeatedly shown to be no better than clinical parameters alone to monitor disease control. A recent systematic review of the accuracy of currently available noninvasive biomarkers to detect airway eosinophilia has shown only moderate diagnostic accuracy of exhaled nitric oxide in correctly detecting airway eosinophils, so the use of this alone as a biomarker would lead to a significant number of false positives and false negatives. In addition, longitudinal relationships between FeNO and sputum eosinophils vary over time within the same patient regardless of clinical status. The steroid sensitivity of FeNO can be used as a very reliable surrogate assessment of adherence to inhaled steroids, whereby a significant fall in FeNO was observed in all previously nonadherent patients after a period of directly observed therapy.
Essential Role of Structural Airway Cells in Pulmonary Immunity and Asthma Pathogenesis
Pulmonary Epithelium
Until recently, it was thought that the function of the airway epithelium was simply to act as a passive barrier to prevent the entry of particles such as allergens, pathogens, or pollution into the airway wall. However, it is now known that the pulmonary epithelium is not just a barrier, but is also immunologically active and is central to the development of immune responses involved in the pathogenesis of asthma. Cultured primary bronchial epithelial cells from children with asthma have dysregulated functional capacity to repair wound injury. In addition, responses to rhinovirus infection of epithelial cells from children with asthma are impaired, whereby production of the antiviral cytokine interferon-β is reduced and epithelial repair following infection is delayed. There are significant differences in release of mediators from bronchial epithelial cells following exposure to a range of proinflammatory stimulants including IL-1β, IL-4, and IL-13 between children with and without asthma. The functional importance of the airway epithelium is also reflected in findings from genome wide association studies (GWAS) of asthma susceptibility genes. The majority of genes that are associated with a high risk for asthma, specifically in children, such as interleukin-33, protocadherin, and CDHR3, are expressed in the pulmonary epithelium. This suggests that altered airway epithelial function is central to asthma pathogenesis. Several SNPs in the ORMDL3 gene located on chromosome 17q have been shown repeatedly to be associated with asthma that develops following recurrent infection with rhinovirus in the preschool years. Thus, future studies that manipulate pulmonary epithelial function by altering the expression of these susceptibility genes may uncover novel therapeutic targets that may allow restoration of epithelial function in patients with asthma.
An important immunological function of the airway epithelium in asthma and other chronic inflammatory airway diseases is its ability to secrete cytokines in response to various stimuli. The role of the innate epithelial cytokines in initiating allergic airway responses and in the pathogenesis of asthma is currently being extensively investigated as a pathway that may lead to novel therapies. Exposure of the bronchial epithelium to allergens, infections, and pollutants in patients with asthma is thought to result in the direct release of three key innate cytokines, IL-33, IL-25, or TSLP (see Fig. 43.4 ). The actual cytokine released is determined by the environmental exposure and the host susceptibility. The airway epithelium thus provides an innate mechanism of initiating immune responses, without the need for adaptive immunity via antigen-presenting cells, allergen sensitization, and Ig-E production. The downstream effects of the innate cytokines are to induce ILCs, which have the capacity to function in the same way as T helper 2 cells with secretion of the type 2 cytokines IL-4, IL-5, and IL-13 (above). This key role in disease initiation has put the pulmonary epithelium at the center of asthma pathogenesis and it is a key tissue whose function is being extensively investigated to allow the discovery of novel therapeutic targets.
Airway Smooth Muscle
In an analogous manner to the epithelium, it is known that stimulation of airway smooth muscle does not simply result in contraction, as it is an immunologically active component of the airway wall. There is extensive cross-talk and interaction specifically between mast cells and the airway smooth muscle in asthma (see above section on mast cells). Although the function of airway smooth muscle has been investigated in adult asthma, very little is known about its function in children with asthma. This is an important area for future research since significant evidence suggests that early alterations in smooth muscle function is one of the best predictors of development of asthma from preschool wheeze (see Fig. 43.6 ).
Preschool Wheeze: A Unique Maturing Immune Environment
Phenotypes of Preschool Wheeze and Response to Currently Available Antiinflammatory Therapies
An important clinical phenotype that is very distinct and unique to children is that of wheezing in preschool children. Cohort studies have shown that there are several clinical phenotypes of wheezing in preschool children with different outcomes by school age. However, these phenotypes can only be applied retrospectively after the child is 6 years old. Prospective clinical phenotypes have therefore been defined by the European Respiratory Society. These include viral episodic wheeze, which is characterized by wheezing in discrete episodes with no symptoms in between, and multiple trigger wheeze in which children have symptoms both during and in between acute episodes. Little is known about immunopathogenesis and molecular mechanisms that specifically mediate viral episodic wheeze, but what is known is that usual therapies that are effective in allergic asthma at school age are rarely beneficial in preschool children with viral wheeze. Specifically, during exacerbations, there is no evidence for efficacy of systemic corticosteroids on any clinical outcome measure. In addition, leukotriene receptor antagonists confer little benefit during exacerbations of viral induced preschool wheeze. These data imply the inflammatory process during acute viral wheezing episodes in preschool children is very different to that in allergic asthma. Recently, it has become apparent that similar numbers of wheezing episodes in preschool children are associated with bacterial infections as with viral infection. The term episodic viral wheeze may therefore be better represented as infection associated wheeze. Furthermore, bronchoscopy studies have shown that the airway inflammatory profile of episodic wheezers during stable disease is either similar to nonwheezing controls or it is predominantly neutrophilic, and may be associated with positive bacterial cultures, despite the absence of symptoms. There is therefore increasing data to suggest the pathogens that cause acute episodes of wheezing in preschool children are distinct from those in allergic asthma, and that the underlying immune and inflammatory mechanisms mediating disease are also distinct.
Airway Inflammation in Infection Associated Preschool Wheeze Exacerbations
In view of the evidence for bacterial infections being associated with preschool wheezing episodes, two recent clinical trials have been undertaken to determine the efficacy of the macrolide azithromycin to treat acute exacerbations. Although both have shown a benefit for their primary outcome, the use of azithromycin for acute preschool wheeze cannot be recommended in routine clinical practice, since both trials have significant limitations. Neither showed benefit in the most relevant clinical outcome measure of hospitalizations, or need for oral steroids, and neither investigated the mechanism of action of the azithromycin. The efficacy of the macrolide therapy in both trials seemed more likely due to the antiinflammatory effects of azithromycin than the antibacterial effects. Importantly, and worryingly, the trial by Bacharier et al. showed a significant increase in macrolide resistance over the short trial duration. A much clearer picture of the airway inflammatory profile during both stable disease and exacerbations in preschool wheezers is therefore needed, with an aim to targeting specific inflammatory and infective phenotypes to achieve more effective treatments.
Airway Pathology in Preschool Wheezers With Symptoms During and in Between Exacerbations
Preschool wheezers with persistent symptoms present both during and in between exacerbations (multiple trigger wheeze), and have a distinct airway inflammatory profile compared to those who wheeze only during acute respiratory infections. Preschool confirmed wheezers, with interval wheeze symptoms, have evidence of eosinophilic airway inflammation ( Fig. 43.7 ). Children with this phenotype tend to have a good response to treatments for allergic asthma; in particular they have reduced symptoms and exacerbations if treated with maintenance low-dose inhaled steroids. Although the inflammatory profile is eosinophilic, numbers of mast cells are similar in wheezers and nonwheezers. Little is known about the cytokines driving preschool persistent wheeze, although increased expression of IL-4 in the submucosa has been reported in preschool multiple trigger wheezers. Since leukotriene-receptor antagonists have variable benefit, there are few other therapeutic targets currently available for those with severe preschool wheeze that persists despite high-dose inhaled steroids. It is known that in addition to eosinophilia, features of airway remodeling, specifically increased thickness of the reticular basement membrane, are already present in children with persistent, severe wheeze. However, neither of these features is predictive of asthma development by school age. The only pathological abnormality that predicts future asthma is airway smooth muscle, but at present there are no known biomarkers that represent smooth muscle function in preschoolers, so this feature cannot be used to identify future asthmatics. In any event, we lack interventions to prevent the evolution of preschool wheeze to asthma.
