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The Proceedings of the American Thoracic Society 1:184-190 (2004)
© 2004 The American Thoracic Society

Effects of Inhaled Corticosteroids on Pathology in Asthma and Chronic Obstructive Pulmonary Disease

Pascal Chanez, Arnaud Bourdin, Isabelle Vachier, Philippe Godard, Jean Bousquet and A. M. Vignola

Clinique des Maladies Respiratoires, INSERM U454-IFR 3, CHU-Montpellier, France

Correspondence and requests for reprints should be addressed to Dr. Pascal Chanez, M.D., Ph.D., Clinique des Maladies Respiratoires, Hôpital Arnaud de Villeneuve, 371 Av. du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France. E-mail: chanez{at}montp.inserm.fr


   ABSTRACT
TOP
 ABSTRACT
METHODOLOGICAL ISSUES
 EFFECTS OF ICS ON...
 EFFECTS OF ICSs ON...
 RELATION OF BIOPSY FINDINGS...
 CONCLUSIONS
 REFERENCES
 
The effects of inhaled corticosteroids (ICSs) have been investigated in asthma and chronic obstructive pulmonary disease (COPD) using endobronchial biopsies. In asthma, most studies have shown reductions in infiltrating eosinophils, mast cells, and T lymphocytes. Cell-associated mediators, such as cytokines derived from type 2 T-helper lymphocytes, are decreased as assessed by immunostaining and molecular biology techniques. More recently, attention has been devoted to the effect of ICSs on structural changes. In asthma, ICSs have been shown in some studies to affect collagen deposition (size of the reticular basement membrane), the number of vessels, or epithelial integrity. The correlations between those findings and various clinical and functional outcomes are far from clear. A long-term study has shown a decrease in the basement membrane size in a group of patients with asthma treated according to their level of airway hyperreactivity. In COPD, ICSs generally do not decrease neutrophils, macrophages, and CD8+ T lymphocytes. The effects of these drugs on structural changes in COPD have not been investigated extensively. Long-term prospective studies are needed to demonstrate the potential for ICSs to affect the natural history of chronic bronchial diseases.

Key Words: endobronchial biopsy • epithelial integrity • reticular basement membrane • vascularity

Since its introduction in the early 1980s, fiberoptic bronchoscopy has been used as a research tool to sample the airways in various respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD). Samples such as bronchoalveolar lavage fluid and endobronchial biopsies have provided important information about the pathophysiology of these chronic bronchial diseases (1). Asthma and COPD are now well recognized as inflammatory diseases that affect the airways and that are associated with airway structural changes (2). At present, noninvasive methods are extensively used to sample these diseases, and they can be particularly useful in longitudinal studies when repeated measurements are important (3, 4). The value of endobronchial biopsy analysis remains crucial, however, because it is the only way to appreciate inflammation and remodeling of the bronchi on the same sample. Recent studies have investigated whether therapeutic interventions, including inhaled corticosteroids (ICSs), can interfere with inflammation and structural changes in situ. Endobronchial biopsy has been promoted as a valuable tool in this research, as its intersubject reproducibility is satisfactory, provided that a sufficient number of patients are studied. In this article, we survey the current knowledge about the ability of ICS treatment to affect the pathology of asthma and COPD, based on the results of endobronchial biopsy analysis.


   METHODOLOGICAL ISSUES
TOP
 ABSTRACT
 METHODOLOGICAL ISSUES
EFFECTS OF ICS ON...
 EFFECTS OF ICSs ON...
 RELATION OF BIOPSY FINDINGS...
 CONCLUSIONS
 REFERENCES
 
Many studies have investigated the efficacy of ICSs in reducing airway inflammation and airway wall structural changes. Following the initial description of the pattern observed in asthma and COPD, a range of studies were performed and published, from open trials to well-powered double-blind, randomized, controlled studies. Some failed to find the expected effects of this therapeutic intervention (5). Whether poor design and/or inadequate patient numbers have contributed to the variability of the reported results is unknown. Many procedural factors, from sampling airways to analyzing slides, including counting inflammatory cells, could have contributed to the wide range of data reported (6). As with all clinical research studies, it is crucial to raise an a priori hypothesis, and procedures should be standardized and mastered by the investigators (1). In a multicenter study, it is paramount to train the investigators before the commencement of the study and to standardize the measurements that are most likely to be highly variable.

An interesting point has been underlined by Faul and colleagues (7), who reported important variability in repeated measures of inflammatory cells in patients with mild asthma who initially received placebo for 8 weeks. Endobronchial biopsies were performed at 0, 2, and 8 weeks. The EG2+ cell count was found to be relatively reproducible, whereas CD68+, tryptase+, and CD4+ cell counts varied in an "unacceptable" range. The authors concluded that the antiinflammatory effects of any treatment for mild asthma can be appreciated only in large groups of patients. This statement was confirmed by Sont and coworkers (6), who reported considerable within-section, within-biopsy, and between-biopsy variability in patients with atopic asthma. They recommended enrolling 8 to 25 patients per group and examining multiple biopsies representing a large surface area of tissue. This group recently reported a tremendous reduction in bias and variability when a computer system was used to assess cellular counts and cytokine expression in endobronchial biopsies (8). Hence, endobronchial biopsy should still be considered a useful tool to elucidate the antiinflammatory effects of ICSs in asthma and COPD, as long as the methods used are well standardized from the fiberoptic bronchoscopy theater to the pathology laboratory (9). Richmond and colleagues clearly demonstrated in a well designed trial that intrasubject variability was high enough to require 15 patients per group in double-blind studies and 58 patients per group in crossover studies (10).

The relationships between pathology and clinical and functional indices are controversial and warrant further investigation. There are apparently only weak relationships between a decrease in the number of inflammatory cells and clinical and functional improvement (11).

The data obtained using endobronchial biopsies should be compared with those obtained from less invasive techniques (12), and comparisons between endobronchial airway biopsy samples and samples obtained at surgery or at autopsy are also warranted. Some authors have shown that the reticular basement membrane thickness in central airways, which may be assessed by endobronchial biopsy, is correlated with airway remodeling in cartilaginous airways but not with airway wall dimensions of membranous airways (13).

The place of transbronchial biopsies in therapeutic trials should at least be discussed (14). In severe asthma, it is difficult to discriminate the contribution of the natural history of the disease and its severity from the effects of current treatments, and this probably explains many of the discrepancies among the clinical trials conducted so far (15).


   EFFECTS OF ICS ON INFLAMMATORY CELL INFILTRATION
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 ABSTRACT
 METHODOLOGICAL ISSUES
 EFFECTS OF ICS ON...
EFFECTS OF ICSs ON...
 RELATION OF BIOPSY FINDINGS...
 CONCLUSIONS
 REFERENCES
 
Asthma
Endobronchial biopsies have been widely used to investigate the pathophysiologic mechanisms underlying asthma chronicity. Observation of the increased number of infiltrating inflammatory cells and their related mediators helped establish the role of inflammation in the disease. Corticosteroids have many effects that may alter the pathobiology of asthma, and researchers have therefore attempted to confirm the putative antiinflammatory effect of ICSs in patients with asthma. More than 40 different studies, controlled or not, some involving healthy individuals, have investigated changes in inflammatory cell counts before and after treatment with ICSs, using a bronchoscopic procedure. They have used various designs and methodologic approaches and have raised different research questions. Most of the studies have investigated mild asthma in relative suboptimally controlled patients (16). The number of patients has been highly variable, as have the drugs, dosages, and durations of exposure. There has been no long-term placebo-controlled study (Table 1).


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  		TABLE 1. Effects of inhaled corticosteroids on mucosal and submucosal inflammatory cells in asthma

 
A number of the studies have demonstrated that treatment with ICSs reduces the number of inflammatory cells in the bronchi, such as mast cells, eosinophils, and lymphocytes (17). Short-term treatment with ICSs reduces the numbers of mononuclear cells such as CD68+ cells (macrophages, including CD1a+ cells), in the submucosa or within the epithelium (18). ICSs have also been shown to decrease the number of CD4+ type 2 T-helper cells and their related cytokines interleukin (IL)-4 and IL-5 in asthmatic airways, at least in patients sensitive to treatment (19). Some authors have demonstrated that in most cases these effects were present 2 weeks after the beginning of treatment, without additional effects 6 weeks later. No dose–response relationship could be found (20). Sont and coworkers demonstrated that despite treatment with an ICS, there was persistent eosinophilic inflammation of the airways in asthma (6). The various effects of ICSs on bronchial inflammation are believed to improve lung function, reduce bronchial hyperresponsiveness, and improve asthma control. However, the precise contribution of each antiinflammatory action to clinical and functional outcomes is still largely unknown (17).

COPD
The inflammatory pattern in COPD as observed on endobronchial biopsies is clearly distinct from that in asthma (Table 2) (21). In COPD there are increases in CD8+ lymphocytes, neutrophils, and macrophages. Changes in eosinophils and mast cells are more questionable (22), but during COPD exacerbations there is a massive increase of eosinophils within the bronchial submucosa, and there are data describing subgroups of patients with COPD with more pronounced eosinophilic inflammation of the airways. These patients have been shown to benefit more from a short course of systemic steroids, in functional outcomes (mainly FEV1), than patients without elevated levels of eosinophils (23–25). It may be that ICS treatment decreases the number of COPD exacerbations or the duration and severity of the exacerbations that do occur. On the other hand, the long-term benefit of ICSs may be associated with the presence or absence of eosinophilic inflammation at baseline.


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  		TABLE 2. Effects of inhaled corticosteroids on mucosal and submucosal inflammatory cells in chronic obstructive pulmonary disease

 
Few studies have investigated the effects of ICS on airway inflammation in COPD, especially based upon endobronchial biopsies. Then, most of the following data are issued from induced sputum. When sputum analysis was used as a surrogate parameter, no acute antiinflammatory effect was detected (26). Recently, a double-blind study was conducted in which 30 patients with COPD received placebo or 1,000 µg of fluticasone for 3 months (27). The fluticasone-treated patients had no reductions of CD8+ lymphocytes, CD68+ macrophages, or neutrophils as assessed by endobronchial biospies. However, treated patients showed a decrease in mast cell infiltration in the submucosa and a decrease of the CD8:CD4 ratio in the epithelial layer. They were less symptomatic and reported fewer exacerbations than the patients on placebo. From this study, we can conclude that at least during a short period, the ICS did not affect the most prominent aspect of airway inflammation commonly seen in COPD. There was no real relationship with any clinical parameter. Clearly, however, the finding of mast cell reduction deserves further investigation. The same group has showed a 65% decrease in the number of mucosal mast cells, using an electron microscopic analysis (28). ICSs may affect "asthma-like airway inflammation" in COPD, which might be more important in relation to exacerbations than to other aspects of COPD. Investigation of the so-called reversible component of airway inflammation might lead to better long-term treatment of patients with COPD. Small airways and lung parenchyma might play a predominant role in COPD (29); the absence of any data regarding the potential of ICS on those aspects of lung inflammation deserves further investigations.


   EFFECTS OF ICSs ON STRUCTURAL CHANGES
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 ABSTRACT
 METHODOLOGICAL ISSUES
 EFFECTS OF ICS ON...
 EFFECTS OF ICSs ON...
RELATION OF BIOPSY FINDINGS...
 CONCLUSIONS
 REFERENCES
 
Epithelial Findings
In asthma, the bronchial epithelium is modified and appears fragile and activated. Abnormalities include loss of the most superficial layer of the epithelium, destruction of ciliated cells, upregulation of growth factor release, and overexpression of receptors such as epidermal growth factor receptors. The gross morphology of the epithelium observed on endobronchial biopsies has been controversial. The shedding of the epithelium reported early by investigators looking at endobronchial biopsies is now thought to be due at least in part to the sampling procedure (30). Despite this potential confounding factor, the fragility of the epithelium remains a reality.

No single study has demonstrated the ability of ICSs to restore a complete normal epithelial layer (31). Short-term double-blind controlled studies have investigated the effect of ICSs on various components of epithelium in asthma. Laitinen and coworkers were the first to report, based on a well-designed study using electron microscopy, improvement in the epithelium in biopsies obtained from budesonide-treated patients (32). In another study, there was a tendency for regeneration of ciliated cells (33). A long-term open study showed restoration of ciliated cells when no change was observed in the epithelium integrity on electron microscopy. Of note, there was no relationship between cell restoration and the degree of bronchial hyperresponsiveness (31). Immunostaining for growth factors such as granulocyte macrophage colony-stimulating factor (GM-CSF) was significantly decreased on epithelial cells after a 3-month treatment with 1,000 µg of beclomethasone sulfate, compared with the initial expression (34). Conversely, Booth and colleagues were unable to describe any consistent change in the epithelium in a fluticasone-treated group compared with a placebo group (35).

In COPD, there is an increase in goblet cells, and the epithelium undergoes squamous metaplasia and loss of cilia (36, 37). These changes are thought to be associated with reduced mucociliary clearance and a predisposition to carcinogenesis. The epithelial cells obtained by brushing during fiberoptic bronchoscopy in patients with COPD are activated and release proinflammatory cytokines such as IL-8 and GM-CSF, as well as overexpressing intercellular cell adhesion molecule-1 (38). All these events are linked to the activation of the transcription factor nuclear factor-{kappa}B, which comprises several subunits, including p65. The total number of p65-immunoreactive cells in the bronchial epithelium of smoking patients with or without COPD is significantly increased compared with the epithelium of normal nonsmokers (39). At present, there is no published study reporting the effects of ICSs on the epithelial changes observed in COPD airways.

Collagen Deposition and Basement Membrane Changes
The basement membrane of surface epithelium consists of the basal lamina (true basement membrane) and the lamina reticularis. The basal lamina does not appear on TEM studies to be affected in airway diseases. The thickening observed on microscopy is linked to the lamina reticularis and has been described as an early and characteristic feature of asthma. It consists of proteiform deposition of immunoglobulins, collagen I and III, fibronectin, and tenascin, but not laminin. These proteins are likely to be produced by activated fibroblasts such as myofibroblasts, leading to the concept of early structural changes in the bronchi of individuals with asthma. These changes potentially increase the stiffness of the airways and affect the folding of the epithelium layer when the muscle shortens to reduce the airway caliber. The superficial layer beneath the true basement membrane extends deeper into the airway, and this fact should be considered when reporting measurements of the "basement membrane." Allergic patients with chronic rhinitis exhibited deposition of collagen I and III and fibronectin, which was associated with bronchial hyperresponsiveness and symptomatic asthma (40). Most of the data reported are highly variable and controversial, moreover, when considering technical aspects of the measures (Table 3). The situation in COPD is less clear; thickening of the basement membrane appears not to exist in the milder form of the disease. No difference in this regard was recently observed by one of us when comparing 50 subjects with mild asthma with 50 patients with COPD (Figures 1 and 2), whereas these conditions were different in healthy control subjects (n = 20) and subjects with severe asthma (n = 30). In one study, a thicker basement membrane correlated with response to a short course of oral steroids (23). There have been contradictory findings about the effects of ICSs on the size of the basement membrane in asthma, depending on the methodology used, including the type of measurement and the number of patients enrolled (Table 3). Jeffery and associates did not find any positive effect (5), whereas Trigg and colleagues reported a substantial decrease (41). More recently, a study showed a positive effect of short-term ICS treatment on the thickness of the lamina reticularis (42). Hoshino and coworkers reported a significant decrease of the lamina reticularis associated with a decrease in inflammatory cell infiltration and a reduction of insulin-like growth factor (43, 44). After 12 months of treatment with fluticasone (1,500 µg/day), the thickness of the basement membrane decreased significantly compared with the baseline value and the value in the placebo group (17). The authors did not find any change at 3 months. Another study has demonstrated that collagen and tenascin deposition are likely to decrease in patients being treated with an ICS (45).


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  		TABLE 3. Rbm thickness changes observed after ics treatment

 


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  		Figure 1. Measurement of RBM thickness according to Wilson and Li (55) in computer-assisted method establishing the area by length ratio on endobronchial biopsy samples stained with hematoxylin and eosin.

 


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  		Figure 2. RBM thickness measured on endobronchial biopsies obtained from 50 patients with mild asthma, 50 patients with COPD, 30 patients with severe asthma, and 20 healthy control subjects. Mild asthma and COPD did not exhibit any difference (5.72 µm ± 1.14 vs. 5.21 ± 1.1 µm). Control subjects and patients with severe asthma had significantly different results than all other groups (personal data).

 
A long-term study (24 months) has shown a greater decrease in basement membrane size in a group of patients with asthma treated according to a strategy aimed at reducing bronchial hyperreactivity, compared with a group treated solely according to existing guidelines. In the patients being treated on the basis of their methacholine PC20 response, the rate of exacerbations improved with only a slight increase in the ICS requirement (46). The relationships between bronchial hyperresponsiveness and subepithelial changes clearly deserve further investigation, as they may suggest targets for therapeutic interventions.

Vascular Changes
Marked vascular changes have been observed and reported in asthma (Table 4). The number of vessels is increased, especially in severe disease (47). The vascular contribution to the increase in the size of the airway wall is difficult to measure, but various overexpressed growth factors may contribute to angiogenesis, including transforming growth factor-ß, tumor necrosis factor-{alpha}, and the more specific vascular endothelial growth factor. Factor VIII immunostaining or type IV collagen is frequently used to assess nonlymphatic vessels in endobronchial biopsies (48). Using these respective approaches, it has been shown that 1,000 µg of fluticasone for 6 weeks (49) or 800 µg of budesonide for 6 months (50, 51) significantly decreased the number of vessels in subjects with mild asthma compared with baseline values. This effect is dose-dependent, because no effect was observed using 200 µg of fluticasone (49).


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  		TABLE 4. Studies focused on vascular changes observed in asthma under ics treatment

 
In COPD, vascular changes at baseline and after antiinflammatory treatment have not been yet characterized.


   RELATION OF BIOPSY FINDINGS TO CLINICAL OUTCOMES
TOP
 ABSTRACT
 METHODOLOGICAL ISSUES
 EFFECTS OF ICS ON...
 EFFECTS OF ICSs ON...
 RELATION OF BIOPSY FINDINGS...
CONCLUSIONS
 REFERENCES
 
The links between the airway inflammation and remodeling observed on endobronchial biopsy and the outcome measures used to assess disease control are not at all well understood. In most of the studies that have shown a decrease in airway inflammation on endobronchial biopsy, asthma control improved. In general, though, these studies were done in patients with mild disease in whom improvement on other parameters, such as lung function or bronchial hyperresponsiveness, was difficult to demonstrate in a short period (52). In fact, few studies other than that of Djukanovic and colleagues (53) (CD4+ number decreased on oral steroids) have clearly related a decrease of inflammation or remodeling with improvement in airway reactivity. However, as mentioned previously, Sont and associates found a long-term effect of ICSs on inflammation and remodeling in their evaluation of treatment based on airway reactivity (46). Treatment based on methacholine PC20 response was more likely than conventional treatment to decrease exacerbation rates and decrease basement membrane thickness. Although the exact link is far from established, this study suggests a new way to manage asthma and perhaps other chronic airway diseases by considering structural changes. Ward and colleagues reported a time-dependent relationship between ICS treatment and maximal benefit on remodeling (reticular basement membrane [RBM] thickness; cf. Table 3) and PD20, when symptoms and lung function alone were insufficient to determine the appropriate dose of ICS (17).

In patients with COPD, there were a decrease in symptom scores and a decrease in the rate of exacerbations in the fluticasone arm in the unique study that used endobronchial biopsies (27). Nevertheless, no relationships were found between biopsy results and clinical outcomes. These findings call into question the relevance of the bronchial inflammatory infiltrate to the clinical and functional pattern in COPD.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODOLOGICAL ISSUES
 EFFECTS OF ICS ON...
 EFFECTS OF ICSs ON...
 RELATION OF BIOPSY FINDINGS...
 CONCLUSIONS
REFERENCES
 
The effects of ICS on the pathology of asthma have now been largely documented and, as expected, clearly support their supposed mechanism of action by reducing the number of inflammatory cells. These data are less clear in COPD, because few studies focused on this aim. Remodeling still represents a wide range of structural changes, clearly insufficiently characterized, according to the differences in the methods used. The pathologic changes attributed to ICS are still controversial in this disease and need more advanced and well powered double-blind controlled studies. The value of endobronchial biopsies in this aim should remain associated with clinical researches (54).


   ACKNOWLEDGMENTS
 
P.C. has been reimbursed by Merck Sharp & Dohme (MSD), GlaxoSmithKline (GSK), and Altana for attending several conferences and has participated as a speaker for GSK and MSD and has served as a consultant for Wyeth and was part of Centocor's Advisory Board from 2001 to 2003; A.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; I.V. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; P.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.M.V. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form February 17, 2004; accepted in final form September 17, 2004)


   REFERENCES
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 ABSTRACT
 METHODOLOGICAL ISSUES
 EFFECTS OF ICS ON...
 EFFECTS OF ICSs ON...
 RELATION OF BIOPSY FINDINGS...
 CONCLUSIONS
 REFERENCES
 

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