Physiologic Consequences of Long-term Inflammation

LEONARDO M. FABBRI, GAETANO CARAMORI, BIANCO BEGHÉ, ALBERTO PAPI, and ADALBERTO CIACCIA

Department of Clinical and Experimental Medicine, Section of Respiratory Diseases, University of Ferrara, Ferrara, Italy

	ARTICLE

TOP Article REFERENCES

The most recent guidelines for asthma (1) emphasize the need for future research into several unexplored or poorly explored areas of asthma. One of these areas is the natural history of asthma, particularly the natural history and the physiologic consequences of asthmatic bronchopulmonary inflammation. This review will consider the evidence that asthma is a disease associated with both an exaggerated decline in lung function and an increase in mortality, the relationship of airway inflammation as we understand it to such events, and the potential for early therapeutic intervention to modify the disease process.

Natural History of Asthma

The onset of asthma is often difficult to define in the individual patient. Most studies have investigated newly diagnosed asthma. Newly diagnosed asthma and early asthma should not be considered synonymous, as asthma symptoms may be present for several years before the diagnosis of asthma. The concept of early asthma should be restricted to recently developed symptoms, and possibly to patients who have developed symptoms within the 12-mo period before diagnosis (5, 6). Early asthma usually manifests with mild symptoms, but in some cases it may manifest with severe life-threatening asthma exacerbations (5, 6).

Almost independent of the severity at first diagnosis, early asthma is associated with airway epithelial damage, subepithelial fibrosis, and an increased number of eosinophils, metachromatic cells, and activated lymphocytes in the airway mucosa (7). This characteristic asthmatic airway inflammation is likely to be present even before asthma is diagnosed.

The physiologic consequences of this very early asthmatic airway inflammation are still unknown. However, asthmatic airway inflammation can be significantly, although transiently and not completely, reduced by treatment with inhaled glucocorticoids. This reduction is associated with clinical improvements (12). In addition, pharmacologic studies have shown that a delayed onset of treatment with inhaled glucocorticoids is associated with a reduced improvement of lung function (22), suggesting that untreated, ongoing airway inflammation might produce irreversible remodeling of the airways and possibly of the lung itself.

One of the most important and intriguing questions in asthma is whether asthma is associated with the development of chronic airflow limitation. Indeed, most epidemiologic studies suggest that asthma is associated with a marked decrease in FEV₁ (26) and even with excessive mortality (35, 36, 38- 43). However, some studies have not confirmed these results (44, 45), and their findings may relate to the timing of observation in relation to the natural history of the disease.

Burrows and colleagues (44) followed three groups of subjects for 10 yr. One group of 27 subjects had the characteristic features of asthma; one group of 45 subjects had the characteristic features of chronic obstructive pulmonary disease; and the third group of 45 subjects had some features of each disease. Interestingly, in contrast to the chronic obstructive pulmonary disease subjects, asthmatic subjects had no marked decrease in FEV₁ nor excessive mortality over the 10 yr of follow-up (44). However, most subjects were between ages 50 and 60 yr and had already developed a severe airflow limitation (FEV₁ around 50%) when follow-up began. In separate studies, Burrows and colleagues showed that asthmatic subjects may indeed have a marked decrease in FEV₁, but only from the time symptoms were noticed to the time that asthma was diagnosed by a physician, suggesting that once treatment is started FEV₁ returns to normal limits (46, 47). Also, the life expectancy of asthmatic subjects may not differ from the average population, possibly depending upon the socioeconomic conditions of the population and the kind of health services available (45).

Thus, asthmatic subjects appear to develop chronic airflow limitation and/or have a decreased life expectancy. Whether these risks are limited to untreated asthmatic subjects and can be prevented by appropriate treatment needs further evaluation, but evidence is accruing concerning the benefit of early intervention.

Airway Inflammation in Asthma

Several studies have consistently shown that asthmatic subjects, compared with control subjects and patients with chronic bronchitis, have an increased number of mononuclear cells, eosinophils, and mast cells in the mucosa of their large airways (48). Also, the thickness of the reticular layer of the basement membrane is characteristically increased in asthma, an abnormality named subepithelial fibrosis. Recent studies conducted in postmortem lung specimens from asthmatic subjects who died of causes other than asthma have shown that similar abnormalities are present in both the large and small airways (49- 52), and that even the alveolar wall may be infiltrated by inflammatory cells (53). Indeed, one aspect of the bronchopulmonary pathology of asthma that remains unclear is whether asthmatic inflammation is confined to the airways or whether it also extends to the adventitia of the small airways and to the alveolar walls. Saetta and colleagues (54) showed that in subjects who died of asthma, inflammation extends well beyond the airway smooth muscle and is still significant around the pulmonary arterioles. Most recently Kraft and colleagues (53) elegantly showed in transbronchial biopsies that nocturnal asthma is associated with infiltration of the alveolar walls by neutrophils and eosinophils. These data, taken together, suggest that inflammation affects all bronchopulmonary structures but the airways are the most affected.

In conclusion, the intensity and distribution of inflammation in the airways and lungs of asthmatic subjects is still largely limited to knowledge about large airway events in vivo. Thus, it is difficult to predict the potential influence of inflammation on lung function, especially small airway function, as standard measures of lung function are a poor reflection of disease in this region. Further information concerning small airway physiology in asthma is thus required.

Correlation between Severity of Airway Inflammation and Severity of Asthma

Correlations between indices of airway inflammation, as assessed by inflammatory cell counts and/or activation status, and indices of severity of asthma have been reported in several studies (8, 55). There are also recent studies that report a significant, albeit weak, correlation between the thickness of the reticular layer of the airway mucosa basement membrane and the severity of asthma (21, 58), suggesting the potential importance of at least one feature of airway remodeling (e.g., subepithelial fibrosis) as a contributor to disease. These findings support the previous reports relating subepithelial fibrosis, airway inflammation, and disease severity that have arisen from studies examining the effect of stopping exposure in occupational asthma (59). These studies have shown that occupational asthma induced by isocyanatessmall-molecular-weight chemicals widely used in industryimproved significantly after exposure ceased. This improvement was associated not only with a decrease in inflammatory cells in the airway mucosa but also, and more consistently, with a decrease in the thickness of the basement membrane reticular layer (59, 60).

Interestingly, the decrease in thickness of the basement membrane reticular layer was also associated with a decrease in the number of fibroblasts in the submucosa. Similar results have, more recently, also been obtained by other groups with steroid therapy in allergic asthma. In separate studies, three groups consistently showed that adequate doses of inhaled steroids not only decreased the number of inflammatory cells in the airway mucosa, but also reversed the subepithelial fibrosis associated with asthma (20, 21, 61). The message of these studies is that at least one feature of the airway wall remodeling associated with asthma, i.e., subepithelial fibrosis, is reversible and thus by acting early enough, either with preventive measures or with anti-inflammatory treatment, it is possible to prevent its development.

Is Early Treatment of Asthma Useful?

In the last few years some prominent researchers interested in adult (22, 25) and childhood (62) asthma have suggested that early intervention with inhaled glucocorticosteroids in asthmatics leads to a better long-term outcome. The first study suggesting the importance of early intervention compared the effect of long-term treatment with an inhaled ₂ agonist (terbutaline) with an inhaled glucocorticoid (budesonide) in patients with newly diagnosed asthma (63). Two years of treatment with budesonide were more effective than treatment with terbutaline in patients with newly diagnosed, generally mild asthma (63). In another study by the same group, patients who had received terbutaline for 2 yr were treated with budesonide for a third year (22). The airway function of patients who were switched from terbutaline therapy to treatment with budesonide improved. However, the degree of improvement in these patients appeared to be less than in those who had been treated with budesonide from the beginning of the 3-yr study, suggesting that delayed initiation of anti-inflammatory therapy could be associated with an irreversible loss of lung function, possibly due to irreversible remodeling (22).

In children with asthma, it has also been found that the degree of improvement in airway function is greatest in children in whom inhaled budesonide treatment is initiated within 2 yr of the clinical diagnosis of asthma, as compared with the response in children who had symptoms longer before therapy was commenced (62). Similar results have been reported in adults by Selroos and colleagues (25), who retrospectively analyzed the effect of initiating treatment with inhaled glucocorticoids. A total of 105 consecutive patients with mild or moderate asthma who had not received treatment with inhaled glucocorticoids and who needed inhaled bronchodilators three or more times a week and/or had a peak expiratory flow (PEF) of FEV₁ < 75% of predicted values were prescribed the inhaled glucocorticoid budesonide, with most patients starting treatment at 400 µg twice daily. These patients were divided into six groups according to their duration of symptoms. Symptom duration ranged from < 6 mo to > 10 yr. Both PEF and FEV₁ were measured before and after treatment at 3 mo, 1 yr, and 2 yr. In the groups of patients with a duration of symptoms < 2 yr, mean improvement in PEF and FEV₁ were significantly higher at all times than measures from patients with longer asthma symptoms. The maximum effect was usually seen after 1 yr of treatment, with control maintained during the second year. A significant negative correlation was found between duration of symptoms and maximum increase in PEF and FEV₁; this correlation remained after correcting for baseline airway function. No correlation was found between the age of patients or earlier regular use of ₂ agonists and improvements in airway function. The results provide indirect support for the concept that early treatment of asthma with an inhaled glucocorticoid may prevent patients from developing chronic airflow limitation (25).

At variance with these studies, Overbeek and colleagues (24) recently reported that a sufficient dose of inhaled glucocorticoids started up to 2.5 yr after treatment with inhaled bronchodilators alone still provides an improvement of FEV₁ similar to that obtained with early treatment. However, the delay of 2.5 yr was associated with a lesser therapeutic effect on airway hyperresponsiveness than when treatment was initiated earlier in the disease.

The reduced effect of delayed treatment may be overcome by increasing the dose and duration of treatment. Consistent with this, Sont and colleagues (61) have clearly demonstrated that the dose of inhaled steroid necessary to decrease and maintain airway responsiveness not only provides a greater improvement in expiratory flows (PEF or FEV₁) but also produces a greater reversal of airway inflammation (including reversal of the subepithelial fibrosis) than a lower dose of inhaled steroid titrated to produce clinical improvement using standard methods of monitoring disease.

The importance of early intervention is also supported by epidemiologic studies conducted in the general population (31, 44, 46) and studies of occupational asthma (64, 65), which suggest that the prognosis of asthma is better when asthma is milder at the time of diagnosis, when treatment starts, or when occupational exposure ends.

The concept of early intervention has been considered for future therapies. It appears that allergen sensitization and immunologic reaction in the allergic immunoglobulin E-mediated direction may occur as early as in the last few weeks of intrauterine life (66). Preventive measures and/or treatment at this very early stage might indeed be considered to stop the development of asthma. One approach is suggested by recent studies showing that subjects with previous viral (measles or hepatitis A virus) or bacterial (e.g., tuberculosis) infections have a lower incidence of atopy (67). A possible explanation of these interesting epidemiologic observations is that early exposure to infectious agents may direct the immune response toward a more cell-mediated responsiveness and reduce the tendency to develop allergic diseases. Although this hypothesis is highly speculative, it nonetheless stimulates several new strategies for early interventions on the immune system (66), either with vaccines or with cytokines (70).

Conclusions

We suggest that asthma, if not properly treated with preventive measures or anti-inflammatory agents, may indeed be associated with the development of a chronic irreversible airflow limitation and with reduced life expectancy, and that airway and possibly pulmonary inflammation may be responsible for the development of the associated airway wall remodeling. These conclusions, taken together with preliminary evidence that early preventive and pharmacologic interventions are associated with a better prognosis for asthma, suggest new strategies for future research in the area of early interventions to prevent the development and maintenance of the allergic inflammation that seems to be the cause of asthma.

	Footnotes

Correspondence and requests for reprints should be addressed to Professor Leonardo M. Fabbri, Centro di Ricerca su Asma e BPCO, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Ferrara, Via Savonarola 9, 44100 Ferrara, Italy.

Acknowledgments: This work was supported by MURST (Grants 60% and 40%), Consorzio Ferrararicerche, Azienda Ospedaliera Sant'Anna, Ferrara; and European Community Biomed 2 Research Project "ENFUMOSA," Contract BMH4-CT96-1471.

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