The importance of airway remodelling in the natural course of asthma

Authors


  • Conflicts of interest
    This article forms part of a supplement sponsored by GlaxoSmithKline. The author states explicitly that there are no conflicts of interest in connection with this article

Christer Janson, MD, PhD, Department of Medical Sciences: Respiratory Medicine & Allergology, Uppsala Universitet, Akademiska Sjukhuset
SE-75652 Uppsala, Sweden.
Tel: +46 186114115
Fax: +46 186110228
email: christer.janson@medsci.uu.se

Abstract

Introduction:  Asthma is associated with airflow limitation and increased decline in lung function. The underlying mechanism for this was probably that persisting inflammation leads to remodelling of the airways.

Objectives:  To review the importance of different factors which are related to airflow limitation and lung function decline in asthma.

Methods:  Case report and literature review.

Results:  Asthma severity, smoking, bronchial hyperresponsiveness and eosinophil inflammation were the variables that were most convincingly related to decline in forced expiratory volume in 1 s (FEV1) in asthma. Treatment with inhaled corticosteroids probably decreased the rate of FEV1 decline, although this was more uncertain because of the lack of randomised double blind studies that show such an effect. Progress in the field of the genetics of asthma may, in the near future, elucidate the role of gene–environment interaction in lung function decline in asthma.

Conclusion:  Regular treatment with inhaled corticosteroids may partly have a beneficial effect on airway remodelling in asthma. Improved understanding of the processes leading to airway remodelling is, however, important in order to prevent a large number of asthmatics from developing irreversible airflow obstruction.

Please cite this paper as: Janson C. The importance of airway remodelling in the natural course of asthma. Clin Respir J 2010; 4 (Suppl. 1): 28–34.

Introduction

Asthma is associated with airflow limitation and increased decline in lung function. The underlying mechanism for this impairment and decline is probably that persisting inflammation leads to remodelling of the airways. The purpose of this review is to investigate the importance of different factors that are related to airflow limitation and lung function decline in asthma.

Asthma is defined as a disease characterised by airway inflammation, variable airflow obstruction, bronchial hyperresponsiveness (BHR) and airway symptoms such as wheeze and attacks of breathlessness (1). It has been showed in several investigations that asthma is associated with increased decline in lung function (2–9). As an example, Peat et al. found that the average rate of decline in forced expiratory volume in 1 s (FEV1) was 50 mL/year in non-smoking male asthmatics compared with 35 mL/year in non-smoking non-asthmatic men (2).

The underlying mechanism for the progressive lung function decline in asthma is probably that persisting inflammation leads to remodelling of airways with subepithelial fibrosis, smooth muscle hypertrophy and increased vascularisation (10–12). The fact that most asthmatics have persistently increased bronchial responsiveness despite long-term anti-inflammatory treatment is also probably related to airway remodelling (13). A model for the relationship between symptoms, airflow obstructions, bronchial hyperresponsiveness and remodelling and asthma is presented in Fig. 1.

Figure 1.

Relationship between symptoms, airflow obstruction, inflammation, bronchial hyperresponsiveness and remodelling in asthma.

The purpose of this review is to present data on the importance of different factors that are related to airflow limitation and lung function decline in asthma.

Patient cases with air flow limitation

The review begins with a case report of two patients as a way of demonstrating different aspects of airflow limitation in asthma. The two patients were found to have airflow limitation (FEV1/forced vital capacity < 0.7) at a first visit to an outpatient asthma department (Table 1).

Table 1.  Two asthma patients with airflow limitation at first visit
 Patient 1Patient 2
  1. FEV1, forced expiratory volume in 1 s; FVC, forced volume vital capacity.

GenderMaleFemale
Age3556
Asthma onsetAt childhoodAt childhood
Allergen sensitisationPetsPollen, pets, mite
Allergen exposureNoneLiving on a horse farm
Smoking historyNever smokerNever smoker
Medication at first visitLow dose inhaled corticosteroidsModerate doses of inhaled corticosteroids + long acting β2-agonists
FEV1 first visit2.49 L (56% of predicted)1.79 L (59% of predicted)
FEV1/FVC first visit0.610.54
InterventionIncreased inhaled corticosteroid doseUnchanged medication and exposure
FEV1 second visit4.01 L (91% of predicted)Unchanged
FEV1/FVC second visit0.75Unchanged

Both patients had a fairly similar spirometric result at the first visit. In the younger male patient, the airflow limitation was reversed after increasing the dose of inhaled corticosteroids (ICS). The second patient was already treated with a fairly high dose of ICS – budesonide 400 µg b i d – in combination with a long acting β2-agonist (salmeterol 50 µg b i d). A likely cause of the airflow limitation in the second patient was remodelling related to long-term exposure to an allergen that she was sensitised to – horse. In the case of the second patient, avoidance of allergen exposure was not possible for social reasons. Continuous treatment with ICS is probably important. No obvious further deterioration in lung function has occurred during latter follow ups of the patient.

Factors influencing lung function decline

The rate of decline in lung function in asthma is highly variable, from a normal 20–30 mL/year to a rapid decline of >50 mL/year, which in some few patients eventually lead to severe non-irreversible airflow obstruction (14).

Bai et al. showed that asthmatics with frequent exacerbations have a quicker decline in FEV1 than asthmatics with less frequent exacerbations (15). In that study, an exacerbation rate of one severe exacerbation/year was associated with an excess FEV1 decline of 30 mL/year. There are also a number of other studies showing that the degree of lung function decline is related to asthma severity (16–18) and asthma duration (6, 19).

ten Brinke and co-workers studied 132 severe asthmatics. Of these, a little less than half had persistent airflow limitation defined as post-bronchodilator FEV1 or FEV1/vital capacity < 75% predicted (20). The patients underwent a structured clinical evaluation including histamine challenge, induced sputum, exhaled nitric oxide (eNO), assessment of allergic sensitisation and a structured interview. Sputum eosinophils, bronchial hyperresponsiveness and adult onset were independently related to airflow limitation, while no significant association was found with eNO or allergic sensitisation. However, in a follow-up of the same patient population, a high eNO level was the most important predictor for FEV1 decline (21). An association between the level of bronchial responsiveness and lung function decline in asthma has also been found in several other studies (22–26). The association between FEV1 decline and BHR has so far only been studied using provocation with direct agents: methacholine and histamine. The association between the level of inflammation and airflow limitation also fits in with three investigations of Danish asthmatics where lung function was negatively related to higher levels of eosinophils in blood (27–29). In one study, non-atopic asthma was related to a faster decline in FEV1 than atopic asthma (27).

Smoking asthmatics display a faster lung function decline (27), and in a study on asthmatics by Grol et al., stopping smoking reduced the decline rate in FEV1(26). Occupational exposure has also been related to lung function decline, and Anees et al. showed that removal from such exposure leads to a slower FEV1 decline in patients with occupational asthma (30). Moreover, obesity has been identified as an important risk factor for asthma (31). A faster decline in FEV1 was found in asthmatics that gained weight during a 9-year follow-up (32). This effect was stronger in men than in women (20 mL/year/kg vs 6 mL/year/kg).

It is plausible that gene-environmental interactions play an important role in lung function decline in asthma. Knowledge regarding the genetics of asthma is rapidly expanding (32), but at present, little is known on the genetic aspect of lung function decline in asthma.

Therapy

ICS

ICS are considered as the first-line treatment in asthma (1). ICS reduce the number of inflammatory cells in the air way mucosa (33, 34). Some, but not all studies, indicate that inhaled steroids may at least, to some extent, prevent remodelling (35–38). Systematic reviews of randomised controlled trials have shown that ICS improve lung function and reduce symptoms and the risk of asthmatic exacerbations (39, 40). A few studies have indicated that inhaled steroids reduce asthma-related mortality (41, 42).

Treatment with inhaled steroids decreases bronchial responsiveness. The effect is moderate, usually equivalent to 1–3 doubling doses of methacholine or histamine in challenge tests (43–47). Most of the improvement occurs within the first 3 months of regular treatment but some patients may continue to improve after that (45). The effect of inhaled steroids on BHR may be larger in patients where inhaled steroids are introduced early than in patients with a longer-standing disease (48, 49). If the treatment is discontinued, then the level of BHR usually returns to the level seen before treatment (49, 50).

As the rate of decline in FEV1 is associated with BHR (23–26), it seems likely that long-term treatment with inhaled steroids slows this process and there are a number of studies supporting this (51–54). In a prospective, open, non-randomised trial, Agertoft and Pedersen followed 278 children during a follow-up period of 4–8 years (52). In children not treated with inhaled steroids, an annual decrease in FEV1 1%–3% of the predicted was observed. In contrast, FEV1 improved significantly with time during budesonide treatment. A significant inverse relationship was found between the duration of asthma at the start of treatment with budesonide and the annual increase in FEV1 during budesonide therapy. Selroos et al. followed FEV1 in 105 consecutive patients who were treated with budesonide during 2 years (53). FEV1 improved during the first year and remained stable during the second. A significant negative correlation was found between duration of symptoms and maximum increases in FEV1. The results of both studies indicate that early intervention with ICS may prevent the development of non-reversible airway obstruction. In contrast to these open non-randomised trials, no significant effect on lung function growth was found in children treated with budesonide compared with those given placebo over a 4-year period in a double blinded randomised controlled study (55).

Several epidemiological observation studies have indicated that ICS have a beneficial effect on lung function decline. De Marco et al. studied 667 asthmatics from the European Community Respiratory Health Survey II (56). Patients that had used ICS for at least 2 years during the follow-up period had a significantly lower rate of FEV1 decline. The effect was, however, restricted to patients that had a total immunoglobulin E (IgE) above 100 kU/L. Other factors that were related to FEV1 decline was: gender – less FEV1 decline in women, and age – a higher rate of decline in older asthmatics. A positive effect of regular ICS treatment have also been found in two other observation studies (57, 58).

Other anti-inflammatory drugs

Anti-leukotriens reduce the rate of asthmatic exacerbations and have certain anti-inflammatory properties (59–61). At present, there is, however, no published information on the long-term effects of anti-leukotriens on lung function development in asthma.

Sodium cromoglycate has been used for several decades in asthma. The drug has anti-inflammatory effects (62) and some, but not all studies, have indicated that the drug decreases unspecific bronchial responsiveness (63, 64). In a retrospective review of 175 children followed from 3 to 17 years, König and Shaffer found that FEV1 increased both in children treated with cromoglycate and ICS; whereas, it decreased in children only treated with bronchodilators (54). No difference was found between the effect of cromoglycate and steroids. The authors conclude that treatment with both types of anti-inflammatory drugs improves the long-term prognosis of asthma.

Summary

Decline in lung function is currently the aspect of airway remodelling in asthma that is most feasible to follow in a clinical or epidemiological setting. A summary of variables that have been related to increased decline of FEV1 in asthma is presented in Table 2. The rate of decline in lung function in asthma is highly variable from normal to rapid, which in some few patients eventually lead to severe non-irreversible airflow obstruction.

Table 2.  Factors related to increased forced expiratory volume in 1 s decline in asthma. Evaluation of evidence level
 Level of evidence
Smoking+++
Bronchial hyperresponsiveness+++
Eosinophil inflammation/ exhaled nitric oxide+++
Asthma severity+++
Age++
Asthma duration++
Not using inhaled corticosteroids++
Occupation exposure+
Male gender+
Allergen exposure+
Non-allergic asthma+
Weight gain+

Treatment with ICS probably decreases the rate of FEV1 decline in asthma although there are no randomised double blinded studies that really prove such an effect. The current progress in the field of asthma genetics will probably, in the near future, elucidate the role of gene-environmental interaction in lung function impairment and decline in asthma.

Asthma severity, smoking, BHR and eosinophil inflammation are the variables that are most convincingly related to decline in FEV1 in asthma. ICS probably decrease the rate of FEV1 decline, although this is more uncertain because of the lack of randomised double blind studies that show such an effect. As it is unlikely that more of such studies will be conducted because of ethical reasons, information from observational studies will probably remain the main source of information on this issue. Progress in the field of the genetics of asthma may, in the near future, elucidate the role of gene-environmental interaction in lung function decline in asthma.

Conclusion

Persistent airflow limitation and an increased decline in FEV1 are common in asthma. These two clinical characteristics are probably related to airway remodelling. Treatment with ICS may partly have a beneficial effect on this process. Improved understanding of the processes leading to airway remodelling is, however, important in order to prevent a large number of asthmatics from developing irreversible airflow obstruction.

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