Management of Asthma: Beyond the Cost
Unmet Needs in Asthma
Southampton General Hospital
Although the management of asthma according to standardised guidelines leads to the effective control of the disease in the majority of patients, it is realised that a proportion of asthmatics have disease that is more recalcitrant to therapy and as a consequence have both poorer quality of life scores and higher health care costs than is standard for asthma (1-4). It has been suggested that this group represents between 5% and 10% of the asthma population, dependent upon the criteria for selection, and accounts for upward of 40% of the total costs of asthma care (5). For example differences in annual costs for treating adult asthmatics with respectively mild and severe disease have been calculated as 1,336 US$ versus 6,393 US$ (5), 3,339 Deutsche Marks (DM) versus 12,016 DM (6) and 549.8 Euros versus 1,451.3 Euros (7). These costs do not take into account the indirect costs of disease and in those who require hospital admission for their asthma the costs are considerably greater, with hospital costs accounting in excess of 80% of their total annual medical resource utilisation costs (7). In this study involving 1,038 asthmatic subjects, although the average cost of severe asthma was 1,451.3 Euros, there was a long distribution tail of costs with 97 subjects (9.4%) having costs in excess of 2,000 Euros, with the greatest individual cost being 51,674 Euros (7). There is thus a need to identify novel therapies that would be applicable to this more severe group of patients, as effective intervention in such patients would have a significant impact on health care costs in addition to improving the quality of life in such asthmatics. As such, it is reasonable to consider in this asthmatic population with more severe disease, therapies that have a higher utilisation cost than would be tolerated in those with mild disease.
Targeting airway inflammation
The concept that bronchial asthma is an inflammatory disorder is now deeply embedded in the assessment of this disease and its subsequent management. Detailed immunologic, pharmacologic and histopathologic studies on bronchial biopsies and lavage from patients with mild-moderate asthma with or without an allergic component have reinforced the view that polarisation of T cells towards a Th-2 phenotype involving the upregulation of the IL-4 cytokine gene cluster on chromosome 5q (31-33) is intimately involved in the expression of the inflammatory response. The majority of asthma, especially that form that begins in childhood, is associated with atopy as an integral component of the Th2 response with both systemic and local production of allergen-specific IgE. The interaction between Th2 type T cells, IgE and the recruitment and activation of effector cells of allergy into the airways is depicted in figure 1.
The importance of these inflammatory pathways in asthma pathophysiology has been reinforced by the potent effects that inhaled and oral corticosteroids have on the various cellular and mediator elements. It is only relatively recently, however, that it is has been possible to explore the hierarchy within these components that translates into disordered airway function, disease expression and its natural history. Animal models of allergic airways disease, as well as descriptive studies in human asthma, identify the eosinophil leukocyte as a key infiltrating cell with the capacity to secrete an array of preformed and newly generated mediators and cytokines. The primacy of this cell in asthma has, however, recently been challenged by studies using humanised monoclonal antibodies against one of the principal pro-eosinophilic cytokines - interleukin 5 (IL-5). These failed to show any effect of the intervention on the allergen-induced early or late phase bronchoconstrictor response or hyperresponsiveness before or after allergen challenge (8) or any clinically significantly changes in indices of chronic asthma (symptoms, lung function or exacerbations) (Compton C. Presented at AAAAI 2001 - manuscript in preparation) despite reducing the circulating eosinophil level by >80% and paralleled by a major reduction (~ 80%) in sputum eosinophilia. This questions the importance of the eosinophil in clinical disease expression in asthma. Countering this, however, is a recent bronchial biopsy study has shown that, despite producing a considerable eosinopenia with 3 monthly injections of anti-IL-5 Mab, eosinophils in the airway submucosa and bone marrow were only reduced by ~50% (9) and that eosinophils within the tissue could thus be still contributing to clinical disease. Although it has been stated that this finding provides evidence for continuing eosinophil participation in asthma, it is not clear whether the cells identified immunohistochemically were alive, and if so, whether they were actively secreting mediators. It remains somewhat surprising even so, if such a conclusion is to be considered, that despite this reduction in tissue eosinophils and a clear marked reduction in tenascin C immunoreactivity in the subepithelial basement membrane (10), that trials involving over 200 patients who received anti-IL-5 at two doses, using the same treatment regimen, failed to identify any clinical benefit over 3-4 months. This raises the important questions as to whether a subset of eosinophils is involved in asthma pathogenesis which is not amenable to anti-IL5 therapy (eg the IL-5R is down-regulated as shown in vitro) or that further or prolonged therapy (beyond 3 months) is needed before a clinical effect is observed. When interpreting the structural effects of anti-IL5 therapy and indirectly assessing the potential involvement of eosinophils in airway remodelling, the specificity for any effects needs to be taken into account, since the airway epithelium is both a source of IL-5 and expresses IL-5 receptors. It is probable that in this study anti-IL-5 therapy may have modified tenascin C production by a direct effect on epithelial cells rather than an effect on eosinophils.
A different approach to treating allergic asthma has been investigated by reducing circulating and tissue IgE levels using the monoclonal anti-IgE antibody, omalizumab (Xolair®). When administered at 2-4 weekly intervals anti-IgE has a powerful effect in inhibiting both early and late phase allergen induced responses as well as the acquired increase in bronchial hyperresponsiveness (BHR) and ~70% reduction in sputum eosinophils. In both adults and children with atopic asthma, clinical trials of omalizumab have revealed efficacy even in patients with chronic severe disease requiring regular inhaled/oral corticosteroids and long acting ß2-adrenoceptor agonists (reviewed in 11). However, patients in the trials were selected on the basis of their total serum IgE falling between 200 and 600 IU/l and the confirmed evidence of atopy. In the more severe asthmatic patients, good therapeutic responses were observed with anti-IgE on symptoms and quality of life, but changes in lung function were not particularly impressive (12). One interpretation of these data is that in chronic severe asthma there is a level of irreversibility to the airflow obstruction and diminished opportunity to gain further improvements, at least in the short-medium term. It maybe that this systemic therapy also has effects on the inflammatory response in the small airways that are poorly reflected by conventional lung function tests. In a recent bronchial biopsy study involving patients with relatively mild asthma, it has been clearly shown that anti-IgE therapy markedly reduces not only eosinophils, but also mast cells and T cells and FceR1+ cells, in the submucosa and reduces sputum eosinophilia (13). This latter response on eosinophils is similar to that observed with anti-IL5 therapy (9), but in the case of anti-IgE, the loss of inflammatory cells is also accompanied by clear evidence of clinical efficacy.
That airway inflammation involving T cells and eosinophils is
not always accompanied by disordered airway function is exemplified
by the condition referred to as eosinophilic bronchitis, a form
of cough variant asthma (14). In this airways disorder the proportion
of eosinophils in induced sputum and in the submucosa of biopsies
is similar to that observed in more classical asthma and yet bronchial
hyperresponsiveness and variability of airway obstruction are
not observed (15). In a recent biopsy study in patients with eosinophilic
bronchitis and classical asthma, the inflammatory response involving
T cells, eosinophils and mast cells is similar in the epithelium
and submucosa, but the content of mast cells (but notably not
eosinophils) was much greater in the airway smooth muscle of the
asthmatic patients when compared to those with eosinophilic bronchitis
(15). Moreover, the increased smooth muscle mast cell population
did not consist of the mucosal (MCT) subtype, but exhibited the
neutral protease profile of connective tissue type mast cells
(MCTC). Differentiation of mast cells to the MCTC phenotype occurs
in the presence of TGF-ß, a growth factor associated with
differentiation of fibroblasts to myofibroblasts and smooth muscle
(16). Thus it is possible that some of the clinical efficacy observed
with omalizumab in interfering with IgE function may relate to
its effect on mast cells in airway muscle as well as in the submucosa
and epithelium. As an addendum to these observations, when patients
are treated with moderate-high dose inhaled corticosteroids, the
mast cell and eosinophil content of the epithelium and mucosa
decreases markedly, but in the case of mast cells in airway smooth
muscle, there occurs only a partial response (Howarth P, personal
A new paradigm for the pathophysiology of chronic asthma
The absent or incomplete clinical response observed when IL-5 or IgE are targeted with a specific therapeutic MAb raises an important question as to whether in asthma the Th2 mediator inflammation is indeed primary or occurs as a consequence of other events in the airway wall. Clearly it is important to target other cytokines of the Th2 pathway before any clear conclusions can be drawn. Particular interest has been focused around IL-4 and IL-13 despite, the rather disappointing recent negative phase 3 study with the inhaled form of soluble IL-4 receptor (Nuvance®). There is accumulating evidence that both IL-4 and IL-13 are not only involved in the asthmatic inflammatory response of asthma, but also in the mucus metaplasia that occurs in the bronchial epithelium (17,18). Activation of the IL-13 complex in asthmatic epithelium preferentially stimulates the release of TGF? which, through its high affinity binding to epidermal growth factor receptors, (EGFRs) induces epithelial differentiation in favour of goblet cells (19). IL-4 and IL-13 also activate pathways of remodelling by inducing profibrogenic cytokines such as TGF-ß (16,17), as well as the up-regulating of the bronchoconstrictor adenosine receptors A1, A2B and A3, but notably not the bronchial relaxant receptor, A2A (20, Elias personal communication). Blocking MAbs against IL-4 and IL-13 and soluble receptors or MAbs directed against their receptors are in various stages of clinical development. We have recently shown that IL-4R and IL-13a receptors co-operate to induce STAT-6 signalling whereas engagement of the IL-13 Ra2-receptor into the complex, which has a very high affinity for IL-13, is strongly inhibitory (21). The fact that IL-4 and IL-13 have important effects on airway wall structure has further encouraged a re-look at the pathophysiology of asthma but this time placing structure-function changes at the centre of this disease.
Bronchial biopsy studies in children as young as 2 years of age with persistent wheezing have shown that all the pathological features of chronic asthma are already established including thickening of the lamina reticularis beneath the epithelial basement membrane, goblet cell metaplasia and the deposition of new matrix within the submucosa (22,23). These events can be traced back to a persistent activation of the epithelial mesenchymal trophic unit (EMTU) which is involved both in branching morphogenesis of the lung and in airway repair after injury (24,25). An increased susceptibility of the airway epithelium to injury (26-28) with subsequently prolonged repair responses set into train a series of proliferative responses involving the attenuated fibroblast sheath beneath the epithelium. This provides a source of airway smooth muscle cells, fibroblasts and myofibroblasts with secretion of growth factors and cytokines that provide a microenvironment to support ongoing chronic inflammation (24,29). Our recent studies have shown that airway fibroblasts from asthmatic patients have an increased capacity to secrete a variety of different mediators including endothelin, vascular endothelial growth factor, connective tissue growth factor (CTGF) and TGFß itself. Moreover, in being unable to repair itself properly, the damaged bronchial epithelium in asthma, is also a potent source of TGFß which may be the crucial factor in initiating the remodelling airway response (16,30).
Impaired "airway wound repair" in patients with chronic severe disease, leads to enhanced expression of the EGFR which drives goblet cell metaplasia as well as initiating secretion of an array of secondary pro-inflammatory cytokines including the neutrophil attractant, IL-8 (31). Thus, the neutrophilia that characterises the more chronic and severe asthmatic response may well have its origin in defective wound healing rather than primarily linked to the Th2 response or the use of corticosteroids. If asthma becomes more chronic and severe there is a view that Th1-like responses become expressed and in part are responsible for the increased tissue damage and remodelling.
That these events may occur at an early age is reinforced by some of the longitudinal cohort studies demonstrating that the children with persistent wheezing within the first three years of life are those that track through childhood to chronic severe disease in adulthood, whereas those with mild and intermittent wheezing during the early life period are those that lose their asthma over time or have intermittent asthma in adulthood (32,33). An understanding of the gene-environmental interactions that are critical to the early life origins of asthma are crucial to understanding events later in life and how one might best intervene either preventatively or therapeutically.
In patients with chronic persistent disease as well as in infants there is increasing evidence of tissue destructive forces being involved incriminating such cytokines as IL-1ß, tumour necrosis factor alpha (TNF?) and IL-6 (34,35). In patients who have died from asthma there is gross over-expression of TNF? messenger RNA as well as product in many different cell types within the airway wall including mast cells, macrophages, eosinophils, T cells and epithelial cells (36). This observation, together with elevated levels of TNF? in BAL fluid and from circulating mononuclear cells from patients with chronic asthma (37,38) has led us to undertake a therapeutic intervention using the soluble receptor TNF? receptor etanercept (Embrel®) (39). The administration of etanercept twice weekly for 3 months to a group of severe asthmatics requiring both inhaled and oral corticosteroids, long acting inhaled ß2-adrenoceptor agonists and nebulised ß2-adrenoceptor agonists has produced dramatic results. Over the three month treatment period, not only did these patients improve symptomatically, but there were marked improvements in spirometric indices of lung function and bronchodilator requirements. Of particular note, however, was a 5-fold improvement in BHR to inhaled methacholine indicating a key role of this cytokine in pathogenesis of BHR (40), at least at the severe end of the disease spectrum. Recently we have shown that TNF? released by human lung mast cells (41) can provide a positive feedback to enhance IgE-dependent mediator secretion by a nuclear factor kappa B (NF?B)-mediated pathway (42). Others have shown similar augmenting effects of TNF? on the function of other inflammatory cells including macrophages, the eosinophils, epithelial cells and smooth muscle (36). Thus by removing the influence of TNF? as a major "stress" cytokine with anti-TNF? therapies, the enhanced functions of pro-asthmatic cells would be reduced and, as a consequence, the disease would become less aggressive. Based on the marked improvement in the quality of life that these chronic severe asthmatic patients experience with anti-TNF? treatment it is clear that randomised studies using both the soluble receptor and blocking MAbs should be undertaken in severe asthma.
New Targets Identified by Genetics
The importance of BHR as a fundamental and important component of chronic asthma has led to a search for its underlying mechanism(s). While there are many theoretical explanations for BHR, from a pathological point of view the increase in airway smooth muscle is likely to be an important determinant of function especially if this occurs early in life following environmental exposures in genetically susceptible individuals, as has recently shown by in non-human primates exposed to inhaled particulates (43) or ozone and housedust mite (44) from early infancy. It remains possible that chronic asthma is initiated by the increase in airway and related matrix and that this in itself becomes the principal driving force behind the ongoing inflammatory reaction. A recent genome wide study of 460 families with two or more children with asthma has identified a novel gene by positional cloning on chromosome 20 p13 - a disintegrin and metalloprotease (ADAM) 33 (38). In the linkage, association and haplotype analyses that were used to identify ADAM 33, the statistical strength of the link was greatly enhanced when the diagnosis of asthma was conditioned by BHR, and weakened when the phenotype was conditioned by either total IgE or specific IgE. This suggested to us (45) and others (46) that ADAM 33 was intimately involved in the pathogenesis of BHR and associated with events of airway wall remodelling. Compatible with these observations, ADAM 33 is preferentially expressed in mesenchymal cells (fibroblast, myofibroblasts and smooth muscle) but not in epithelial cells, T cells, mast cells or eosinophils. In other systems the ADAMs are implicated in the processing of cell-surface growth factors that mediate proliferation or hyperplasia, eg ADAM 12 in cardiac hypertrophy (47) or are fusagenic for individual myocytes to form myotubules which then function as "integrated contractile" units (48,49). By understanding the mechanisms of how ADAM 33 translates its activity into BHR and asthma including the factors that regulate its expression and post-translational modification, new insights may be gained into asthma pathogenesis and as a consequence, novel ways to intervene therapeutically, recognising that the airway smooth muscle contains a heterogeneous population of cells ranging from fibroblasts through myofibroblasts to fully contractile smooth muscle cells. Some populations of mesenchymal cells also have the capacity to generate increased pro-inflammatory adhesion molecules and cytokines and as such, provide a basis for persistent mesenchymal activation and its link to chronic persistent inflammation, as evidenced by the increased residence of mast cells in asthmatic smooth muscle (16).
To conclude, asthma is predominantly a disease of the conducting
airways and involves important structural and functional changes
in addition to inflammation. For the disease to fully manifest,
especially in its chronic and severe form, an interaction between
the epithelial and mesenchymal airway wall components (EMTU) and
inflammatory cells is fundamental to further understanding how
this disease is initiated and persists. While Th2-mediated inflammation
maybe of great importance in causing the exacerbations of asthma
(50), the chronic disease state may have its origin within the
airway wall itself and in particular to the altered functions
of the constitutive units of the epithelium and underlying mesenchyme
and in this way recapitulates events in branching morphogenesis
(51). The identification of novel targets from this revised understanding
of the disease may thus open up new therapeutic avenues to prevent
the development of severe disease or to improve the severity of
pre-existing disease and provide an answer to the current unmet
needs in asthma.
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