Posted: December 2008
Phillip L. Lieberman, MD, FAAACI
Clinical Professor of Medicine & Pediatrics
Division of Allergy & Immunology
University of Tennessee College of Medicine
The idea that asthma can result in permanent lung damage and an irreversible decline in forced expiratory volume in one second (FEV1) is not new, but has received prominence recently. Before 1980, a search of the literature revealed no references to what is now called asthma remodeling. Between 1980 and 1990, two references were found. From 1990 to the present, more than 160 references were found. Perhaps it is no coincidence that this increase in recognition of the remodeling process has been simultaneously accompanied by an increase in articles referring to the inflammatory process in asthma. Before 1980, only 54 such examples were found; between 1980 and 1990, 519 were found; and, at present, more than 3,500 articles address this topic in the literature. This increase in articles on inflammation and remodeling in asthma perhaps reflects our increased understanding of one of the mechanisms of eosinophilic inflammation that leads to the remodeling process.
There is no true, single definition of the term remodeling as it refers to the airway and asthma. To define the concept, one must look at three distinct features of remodeling:
- Pathologic changes
- Physiologic changes
- Functional changes
The classic structural pathologic changes of the remodeling process, defined by biopsy, are as follows:
- Epithelial damage
- Smooth muscle hyperplasia and hypertrophy
- Thickening of the lamina lucida
- Increased deposition of ground substance and collagen in the parenchyma
- Destruction of elastic tissue
- Mucous gland hypertrophy
These histologic changes result in easily detectable physiologic abnormalities that are expressed in the following ways:
- Decreased airway distensibility
- Diminished elastic recoil
- Progressive decline not only in FEV1, but also in forced vital capacity (FVC)
The functional and, therefore, clinical features include the following:
- Progressive loss in airway function that is not reversible with bronchodilators and/or antiinflammatory therapies, including corticosteroids
- Increase in dyspnea and an impaired ability to exercise
Although no studies have assessed the effect of these changes on quality of life, it is presumed that they can exert a profound effect and, therefore, certainly merit our attention.
Thus, perhaps the definition of remodeling in asthma might be as follows: "A gradual but progressive and irreversible decline in airway function due to an inflammatory process that results in structural changes in the airway walls."
The Clinical Detection of Remodeling via Serial Measurements of Airway Function
Classically, remodeling changes have been detected via serial measurements of FEV1. It has been known for many years that some asthmatics experience a decline in FEV1 that exceeds normal, and, for the most part, when populations of asthmatics are compared with non-asthmatics, this decline is accentuated in the asthmatic population as a whole.
Perhaps the first notation in the literature referring to this process occurred as early as 1961 when Orie stated, "There is an accelerated decline in lung function that is related to bronchial responsiveness and atopy." Perhaps the first study to address this issue appeared in 1976, when Fletcher et al showed an accelerated decrease in FEV1 in 17 asthmatics compared with control subjects who were followed from 1961 to 1969. Subsequent to these seminal reports, many investigations have confirmed this accelerated decline. These investigations, for the most part, looked at pre-bronchodilator FEV1 measurements. However, in some instances both pre- and post-bronchodilator measurements were assessed, and, overall, there is little doubt that this remodeling process does occur and is detectable in asthmatic populations as a whole. But the decline in lung function is not significant in all asthmatics. However, an irreversible decline in lung function does occur in a significant number of asthmatics. Studies have shown that from 16% to 25% of asthmatics will experience an irreversible decline in lung function that is clinically significant and that is accelerated compared with that in healthy controls. The magnitude of this decline, of course, varies from patient to patient. However, over a lifetime, it can exceed 1 L.
The features gleaned from these many serial studies of the decline in FEV1, which predispose to a more rapid decline, are as follows:
- Bronchial hyperresponsiveness (this is perhaps the most consistently found abnormality, i.e., the more hyperresponsive the airways, the greater the decline and the greater the chance of a more rapid decline)
- The duration of asthma
- The severity of asthma, defined by the minimum dose of corticosteroid required to maintain control?
- Initial FEV1 at the time the measurements are initiated (the lower the measurement at the beginning, the more likely an accelerated decline)
- The presence of aspirin-sensitive asthma
- Hypereosinophilia (there are no studies at this time regarding the potential effect of other cellular phenotypes, eg neutrophilic asthma, on the remodeling process)
- Elevated immunoglobulin E (IgE)
The Role of IgE and Atopy
The purpose of this article is to assess the role of IgE and atopy in the remodeling process.
Three lines of evidence incriminate elevated IgE levels as a risk factor for remodeling:
- Comparisons of serial FEV1 measurements between asthmatics with and those without elevated IgE and/or atopy
- Allergen-challenge models in animals and humans
- Biopsies of allergic and non-allergic (intrinsic) asthmatic airways
Serial Measurements of Lung Function Supporting a Role for IgE and/or Atopy
The first study to look at the effect of IgE on the decline in lung function was part of the Tucson Epidemiologic Asthma Program, which at that time was under the direction of Dr. Ben Burrows. In this study, the presence of an elevated IgE was associated with a more rapid decline in lung function and lower lung function overall, regardless of the presence or absence of atopy. Several studies since then have shown an inverse relationship between IgE levels and FEV1/forced vital capacity (FVC), independent of smoking status and asthma. Some studies have shown an exaggerated decline in lung function in atopic asthmatics compared with non-atopics. In addition, atopy and IgE levels are associated with a faster decline in FEV1 in smokers.
An individual does not have to have asthma for the process of atopy to result in a more rapid decline in FEV1. For example, the Normative Aging Study followed 2,280 subjects without obstructive lung disease. One-thousand eighty-five of these subjects underwent skin testing and had lung function evaluated. Skin test reactivity was clearly correlated with a more rapid decline in FEV1 and in FEV1/FVC. The Tucson Epidemiologic Asthma Program began in 1971 and is ongoing; repeated reports from this program continue to reflect the early findings of Burrows. In 1995, a study conducted in 1,533 subjects, who had been followed for 24 years, showed that IgE levels were inversely correlated with FEV1, independent of the presence of asthma or smoking.
More recently, the Tenor Study confirmed these results. The Tenor Study involves a multicenter evaluation of the natural history of asthma in severe cases. Two-thousand seventy-four patients in Tenor had IgE levels below 100 IU, and 2,451 had levels above 100 IU. The FEV1 was significantly lower in patients with high IgE levels across all ages.
Thus, serial measurements of airway function generally show that function is inversely related to IgE levels. Perhaps the most surprising aspect of this observation is that this relationship was true not only for asthmatics, but also for persons without obstructive lung disease.
Allergen-Inhalation-Challenge Studies in Animal Models and Humans Supporting a Role for IgE and Atopy
In addition to serial lung function testing, challenge studies in both animals and humans have shown that allergen exposure results in histologic changes in remodeling. For example, repeated allergen inhalation in mice and guinea pigs results in characteristic hypertrophy of the bronchial wall. In addition, allergen challenge in mild asthmatics followed by biopsies noted the following changes:
- Increase in subepithelial basement membrane thickness
- Increase in the deposition of tenascin
- Activation of fibroblasts
- Increased production of transforming growth factor-β
These changes occur early and can persist for several days after challenge. For example, airway aeroallergen challenge in humans has been shown to cause increased deposition of procollagen III and tenascin that persists for 7 days (in association with the persistence of airway hyperreactivity), long after cellular inflammation has resolved.
Bronchial Biopsies of Asthmatics Support a Role for IgE and Atopy
Studies, even without challenge, that compared biopsy results of atopic asthmatics with those of non-atopic asthmatics of equal severity have shown that atopic asthmatics have a greater deposition of tenascin and laminin in their airways compared to both controls and their non-allergic asthmatic counterparts.
On the basis of a review of the above studies, it is clear that IgE itself, i.e., elevated levels of IgE, and the presence of atopy are risk factors for the remodeling process in asthmatics. A more provocative and less easily understood observation is that IgE alone, in the absence of detectable atopy and in both asthmatic and non-asthmatic populations, represents a risk factor for this process.
Mechanisms Underlying the Allergic Remodeling Process
The mechanisms involved in the remodeling process, because it is accentuated in allergic asthmatics, most certainly involve the activation of mast cells and basophils and the subsequent eosinophilic inflammatory cascade. However, because this process may occur in non-allergic asthmatics, other pathways or perhaps shared common mediators can also be responsible.
It is not difficult to make a list of mediators released during the allergic reaction that have demonstrated the ability to activate the remodeling process. Some of these molecules and their actions are as follows:
- Histamine: fibroblast stimulation
- Tryptase: mitogen for smooth muscle
- Leukotrienes: smooth muscle hyperplasia
- Tumor necrosis factor-α: leukocyte activation with the release of elastase and subsequent destruction of elastic tissue
- Vascular endothelial growth factor: angiogenesis
- Transforming growth factor-β: deposition of fibular collagen and ground substance
- Metalloproteinases: degradation of interstitial collagens
These mediators, and potentially many others, which are released and/or activated with mast cell and basophil degranulation could easily be responsible for the histologic features and accelerated decline in lung function characteristic of the remodeling process. It is not difficult to accept the hypothesis that atopy could be associated with an increased predisposition to remodeling.
Can IgE Levels Exert an Effect on the Response to Therapy?
The only agents studied in human asthma with a reasonable number of investigations to ascertain their role in reversing the changes in remodeling are inhaled corticosteroids, which are clinically effective when there is eosinophilic airway inflammation. Many studies of the effect of inhaled corticosteroids on long-term lung function and several on their effect on the histopathologic changes associated with remodeling have been conducted. The results are certainly not definitive, but they highly suggest that inhaled corticosteroids not only exert a beneficial effect on lung function, but they also reverse the histopathologic changes associated with remodeling. No extensive studies have assessed the role of IgE on the beneficial effects of steroids on remodeling; however, at least one study has looked at this issue.
In a large community-based sample of subjects with asthma from the general population who were followed up for up to 9 years, a diminished decline in FEV1 was associated with the prolonged use of inhaled corticosteroids. In this investigation, which was part of the European Community Respiratory Health Survey, the decline in FEV1 was analyzed with respect to sex, age, height, body mass index, duration of inhaled corticosteroid use, smoking status and total IgE levels. When adjusted for all covariates, a clear effect of IgE on the response to inhaled corticosteroids was observed. In subjects with high IgE levels (greater than 100 kU/L), inhaled corticosteroid use for 4 years or more was associated with a diminished decline in FEV1 compared with non-inhaled corticosteroid use. This association was not seen in patients with lower IgE levels. The authors concluded that "subjects with high IgE could maximally benefit from prolonged inhaled corticosteroid treatment."
Thus, although very limited data exist, this study at least suggests that patients with elevated IgE levels will have a more pronounced response to inhaled corticosteroid therapy than will subjects with lower levels.
Finally, it should be noted that not all studies have found a relationship between a decline in FEV1 and IgE levels and atopy. Ulrik et al noted a greater rate of decline in lung function in patients with non-allergic asthma than in patients with allergic asthma. They evaluated 143 patients in a 10-year trial. At the time of enrollment, patients underwent skin testing, had in vitro tests for specific IgE and had total IgE levels measured: 94 of the patients had nonallergic asthma and 49 had IgE-mediated asthma. An inverse relationship between initial FEV1 and the decline in FEV1 was noted for patients with IgE-mediated asthma but not for patients with nonallergic asthma. Patients with nonallergic asthma had an annual decline in FEV1 of 50 ml, whereas those with IgE-mediated asthma had a decline of only 22.5 ml.
Ample evidence indicates an accelerated decline in lung function in a significant proportion of asthmatics. This decline can be permanent and irreversible. Strong support also exists for a role of IgE-mediated disease in the production of this decline, and several studies have shown that IgE and atopy are risk factors for the decline in lung function. This phenomenon has not been shown, however, in all evaluations of serial lung functions in asthmatics. In addition, in at least one study, elevated levels of IgE were associated with a more pronounced response to inhaled corticosteroid therapy in relation to FEV1 measurements.
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