Why Does Airway Inflammation Persist? Is It Failure to Treat Early?

SØREN PEDERSEN

Kolding Hospital, Kolding, Denmark

	INTRODUCTION

TOP INTRODUCTION WHAT IS KNOWN? WHAT IS PARTLY KNOWN... DISCUSSION IMPORTANT QUESTIONS REFERENCES

At present there is no direct evidence to demonstrate that early use of antiinflammatory therapy will reduce the persistence of airway inflammation. However, there is evidence that early treatment with inhaled corticosteroids is associated with better clinical effects, including a modification of the course of asthma so that it becomes easier to treat. Exactly how or if this relates to differences in control of airway inflammation is not known.

	WHAT IS KNOWN?

TOP INTRODUCTION WHAT IS KNOWN? WHAT IS PARTLY KNOWN... DISCUSSION IMPORTANT QUESTIONS REFERENCES

Marked Airway Inflammation Is Present in Early Asthma, and Also in Patients with Mild Disease

Bronchial biopsy specimens, sputum, and fluid obtained by bronchoalveolar lavage have shown that significant inflammation is present in early asthma, and also in patients with only a short duration of symptoms, or with mild disease (1). It is assumed that chronic inflammation can lead to airway remodeling, including an increase in airway smooth muscle (hyperplasia and hypertrophy), vascular proliferation, an increase in bronchial glands, edema formation, and collagen deposition (8). The direct relation of airway inflammation to airway remodeling and disturbances of lung function, development of irreversible changes in lung function, and increased bronchial responsiveness is complex and difficult to assess (9).

The Longer the Duration of Asthma the Lower the Lung Function and the Worse the Bronchial Hyperresponsiveness and Symptoms

A negative correlation between percent predicted lung function and duration of asthma before treatment is initiated has been reported in several studiesboth of children (10, 11) and of adults (12). Moreover, children with persistent asthma during childhood continued to have lower levels of lung function (17) and increased bronchial reactivity to specific and nonspecific agents (25) into adult life, regardless of whether they had lost their asthmatic symptoms or not. Furthermore, some children with chronic childhood asthma may develop chronic irreversible airway obstruction to a clinically important extent (12, 14, 17, 19, 21, 28, 29). Finally, a number of studies have found that growth of lung function was compromised in children with persistent asthma compared with healthy nonasthmatic children (10, 12, 17, 30, 31).

Some studies also found that the reduction in lung function with time parallels increases in bronchial hyperresponsiveness, use of rescue ₂-agonists, and increases in symptoms, suggesting that the disease worsens/progresses with time (11, 14).

These findings indirectly suggest that asthma itself (or chronic inflammation?) can adversely influence the growth/ decline of lung function. None of the studies has tried to relate the lung function measurements to airway inflammation. Furthermore, the studies have mainly used rather crude measures such as FEV₁ or FVC, which may be normal even in the presence of marked airway inflammation or damage in the smaller airways.

Inhaled Corticosteroids Suppress Airway Inflammation in a Dose-dependent Manner

Several studies have demonstrated that inhaled corticosteroids suppress airway inflammation (assessed by inflammatory markers in induced sputum or bronchial biopsies) in a dose-dependent fashion. Daily doses of about 400 µg of fluticasone propionate seem to have a moderate effect, whereas doses of  500 or 800 µg produce marked suppression (1, 6, 32). None of these studies has addressed the question of timing of treatment in relation to the effect.

One study assessed the importance of including a measure of airway inflammation (bronchial hyperresponsiveness, BHR) in the management plan of adult patients with asthma. It was found that this strategy resulted in a higher mean daily dose of inhaled corticosteroids, greater improvements in FEV₁, fewer exacerbations, and a greater reduction in bronchial responsiveness. In bronchial biopsies this was accompanied by a greater reduction in thickness of the subepithelial reticular layer in the BHR strategy group than in the reference strategy group. The changes in BHR in both strategy groups were correlated with eosinophil counts in the biopsies (42). This study also found a greater effect in patients with a short duration of asthma at the time the treatment was initiated (46).

Discontinuation of Antiinflammatory Therapy Results in a Deterioration in Asthma Control and Bronchial Hyperreactivity within Months in the Majority of Trials

At present, only a limited number of studies have assessed how long treatment with inhaled corticosteroids should be continued after clinical remission (47). In most of the studies the patients have been treated only for a few months before an attempt has been made to stop the therapy. The findings of these studies can be summarized as follows: When inhaled steroid treatment is discontinued, there is usually a deterioration in asthma control and bronchial hyperreactivity to pretreatment level within weeks to months, although in some patients the beneficial effect is maintained much longer (47, 48, 50). The studies with the highest and longest remission rates seem to be those that have treated patients with rather mild disease for a period of 1 yr or more (47, 48, 54, 55). In these studies the decline in lung function was gradual and not significant for several months and about 25% of the patients did not deteriorate at all (47, 48).

	WHAT IS PARTLY KNOWN OR CONFLICTING?

TOP INTRODUCTION WHAT IS KNOWN? WHAT IS PARTLY KNOWN... DISCUSSION IMPORTANT QUESTIONS REFERENCES

Early Use of Inhaled Corticosteroids Produces a Better Clinical Result than Delayed Use

Several studies have found that antiinflammatory treatment started early in the course of asthma is associated with a better effect than treatment started after a delay of some years (10, 24, 46, 48, 54, 56).

In one study (54) patients with asthmatic symptoms for less than 1 yr and no previous antiinflammatory therapy were randomized to treatment with either inhaled budesonide or terbutaline. Two years of treatment with inhaled budesonide resulted in almost complete clinical recovery and normalization of lung function. The study was continued for a third year to investigate the effects of discontinuation of steroid treatment and a delayed introduction of inhaled steroid. The patients who received terbutaline for 2 yr before treatment with budesonide was initiated did not reach the same level of lung function or improvement in bronchial hyperresponsiveness as those who were treated with budesonide as first-line therapy (48).

Overbeek and coworkers reported similar results in a more heterogeneous group of patients who had had symptoms for several years at study start. The patients were randomized to 2.5 yr of intervention with bronchodilators alone or with ₂-agonists and steroid (beclomethasone) (56). The study then continued after the first 2.5 yr to investigate the effects of adding beclomethasone (800 µg daily) to the treatment of patient groups that had not previously received it (56). Airway hyperresponsiveness showed no significant change after 6 mo of receiving the new (2.5 yr-delayed) intervention, whereas it had shown a significant improvement already after 3 mo in the patients who started beclomethasone. Furthermore, the increase in lung function was lower when inhaled corticosteroids were started with a 2.5-yr delay as compared with "early" use of inhaled corticosteroids.

Selroos and coworkers (57) reported a negative correlation between improvement in lung function during inhaled corticosteroid therapy and duration of asthma; early treatment of asthma with inhaled steroid resulted in a better clinical result than late treatment.

In a long-term study (10) budesonide treatment was compared with treatment with combinations of other antiasthma drugs (₂-agonists, theophylline, and disodium cromoglycate) in 278 children. The effect on lung function was significantly greater when budesonide was started early after asthma was diagnosed (within 2 yr). Children who started treatment early had a more rapid response and obtained significantly better lung function than did children who did not start treatment with budesonide until some years after the onset of asthma symptoms (10). In addition, the accumulated dose of budesonide taken after 4.5 yr of continuous treatment was significantly lower in the children who started treatment early than in the children who did not initiate budesonide treatment until after more than 5 yr of continuous symptoms.

In agreement with this, early use of inhaled corticosteroids produced a significantly better effect on bronchial hyperresponsiveness in Japanese children than late treatment (60).

One study of 181 patients, aged 13 to 44 yr, assessed the chance of improving or even becoming symptom free over a period of more than 25 yr (58). It was found that the longer the patients went without treatment after symptom debut the less likely they were to show a decline in or normalization of bronchial hyperresponsiveness. The data also indicated that patients who improved or became symptom free tended to be those who were diagnosed and treated at a younger age or had less severe disease at the time of diagnosis.

In a 13-yr retrospective review of patient files, König and Shaffer reported higher lung function in children with mild asthma who were treated with sodium cromoglycate early after diagnosis than in children who received this treatment late in the course of disease (24). It was concluded that treatment with either cromoglycate or inhaled corticosteroids improved the long-term prognosis of asthma.

Finally, a prospective study designed to assess the benefits of early use of inhaled corticosteroids found that patients in whom treatment with inhaled corticosteroids was initiated within the first 2 yr after asthma diagnosis achieved optimal clinical control at a daily budesonide dose of 200 µg whereas patients who started the treatment after 5 yr required 800 µg/d to be optimally controlled (59).

Treatment May Prevent the Decline/Normalize the Growth of Lung Function that Occurs over Time

In a long-term study budesonide significantly increased the growth rate of lung function with age in comparison with children not receiving inhaled steroids (10). FEV₁ in the control group not receiving inhaled steroids showed an annual decline of 1.3% against the predicted value.

In good agreement with this, Verberne and coworkers (31) found that both pre- and postbronchodilator lung function grew significantly better during treatment with beclomethasone dipropionate (BDP) than during treatment with salmeterol. Indeed, there was a trend toward a decrease in lung function over the year of treatment and an increase in bronchial hyperreactivity in the children in the salmeterol group (p = 0.05). These results are similar to the results obtained in a similarly designed study in which inhaled budesonide was compared with short-acting ₂-agonists (61).

The protective effect of inhaled corticosteroids on the possible decline in lung function associated with continuous obstructive lung disease has also been addressed in a study by Dompeling and coworkers (64). During the first 2 yr of study, the subjects were treated with bronchodilator therapy alone. At the end of the first 2 yr, inhaled beclomethasone was instituted at 800 µg/d. There was significant improvement in the prebronchodilator lung function, and an equivalent improvement in FEV₁ values measured after bronchodilator treatment. In addition, the annual decline in lung function noted during the initial 2 yr, i.e., during the bronchodilator treatment alone period, was lessened during treatment with inhaled corticosteroids. When these findings are interpreted it should be noted that the decline in lung function noted during the bronchodilator, run-in period seemed to be greater than that normally found in asthma.

Finally, children treated for several years with inhaled corticosteroids or sodium cromoglycate had significantly higher lung functions than children treated with ₂-agonists as needed (24).

	DISCUSSION

TOP INTRODUCTION WHAT IS KNOWN? WHAT IS PARTLY KNOWN... DISCUSSION IMPORTANT QUESTIONS REFERENCES

It is clear that there are virtually no data to suggest that persistence of airway inflammation in asthma is due to a failure to treat patients early enough. The existing evidence suggests that for the majority of patients inhaled steroids suppress the underlying mechanisms of asthma and cause remission of the condition without "curing" the disease. Discontinuation of inhaled corticosteroids has, however, only been evaluated after less than 2 yr of continuous treatment, and never in a group of patients in whom the treatment was initiated shortly after the onset of the disease. The findings that up to 25% of patients with mild disease do not relapse after 1-2 yr of continuous treatment with inhaled corticosteroids have elicited the hope that perhaps it would be possible to modify the course (cure?) of asthma. It has been hypothesized that there may be a "window of opportunity" in relation to the treatment of asthma, after which inflammation, remodeling, and lung function changes cannot be reversed so that even the introduction of inhaled steroids may not lead to a total normalization of the pathology (65). However, when "early intervention" is early enough has not been clearly defined. Most of the patients included in these studies had experienced symptoms and persistent asthma for a long time before interventions occurred. When increased bronchial responsiveness is detected the opportunity for optimal intervention may have been missed. Inflammation is often present for some time before symptoms appear. Perhaps early detection of inflammation and symptoms could lead to more effective interventions?

On the other hand, infiltration of inflammatory cells in the lamina propria of the airways has been shown to persist in patients with mild to moderate asthma despite regular treatment with inhaled steroids (6). This would indicate a continuous need for regular maintenance antiinflammatory treatment. Asthmatic inflammation is a response that is often provoked by allergic reactions, infections, and other environmental factors. Thus it would be expected that continued or repeated antiinflammatory therapy would be necessary.

The data suggest that the dose can be stepped down with time without loss of asthma control in the majority of patients (10, 54) and that lower doses can be used if treatment is initiated early (10, 59). However, it is not known whether this is due to a more complete suppression of airway inflammation when the treatment is initiated early, so the evidence that earlier use of antiinflammatory therapy will reduce the persistence of airway inflammation is indirect.

	IMPORTANT QUESTIONS

TOP INTRODUCTION WHAT IS KNOWN? WHAT IS PARTLY KNOWN... DISCUSSION IMPORTANT QUESTIONS REFERENCES

• Exactly which components of airway inflammation need to be suppressed to modify the long-term prognosis of asthma?
• Is inflammation early in the disease easier to treat than late in the disease?
• Can early control of inflammation prevent progression of the inflammation to a condition that is more difficult to treat?
• What is the direct relationship of airway inflammation to airway remodeling and disturbances of lung function, development of irreversible changes in lung function, increased bronchial responsiveness, and progression of the disease?
• Which doses of inhaled corticosteroids are needed to achieve this degree of suppression of inflammation? Does this dose depend on the duration of asthma before treatment is initiated?
• Induction, maintenance, and relapse treatments are applied in many chronic immunological/inflammatory diseases. Should these also be applied in the treatment of asthma?
• Asthma often begins in preschool children, and so far no controlled studies of these age groups have been performed; is prompt treatment later in life too late?

	Footnotes

Correspondence and requests for reprints should be addressed to S. Pedersen, M.D., Department of Pediatrics, Kolding Hospital, Kolding 6000, Denmark.

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