Inflammation and Treatment in Asthma and COPD

By James F. Donohue, MD, FCCP; and Jill A. Ohar, MD, FCCP

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Asthma

Management

Because inflammation is considered an early and persistent component of asthma, current guidelines recommend that therapy be directed toward long-term asthma control with anti-inflammatory medications such as ICSs, cromones, leukotriene-receptor antagonists, and theophylline. The use of these medications reduces markers of airway inflammation and decreases airway hyperresponsiveness. Evidence suggests that possible early intervention with ICSs can improve asthma control, normalize lung function, and possibly prevent irreversible airway remodeling. Even mild persistent asthmatics should take controller medications. Asthma medications are categorized as either quick-relief medications or long-term, preventive or controller medications. Only anti-inflammatory agents will be discussed.

ICSs. These are the most potent and effective anti-inflammatory agents currently available. Studies have demonstrated their efficacy in improving lung function, decreasing airway hyperresponsiveness, reducing symptoms, reducing the frequency and severity of exacerbations, and improving quality of life. ICSs, if used regularly, are associated with a lower death rate due to asthma and reduced rates of hospitalization. Newer ICSs are fluticasone and mometasone; older agents include beclomethasone, budesonide, triamcinolone, and flunisolide.

ICSs are recommended for most patients with asthma; the dose is increased as required to obtain control or a second agent is added (eg, the long-acting b-agonist salmeterol or formoterol, or a leukotriene modifier). Published data are insufficient to determine with confidence the dose-response relation of ICSs. It appears that lower doses of the newer ICSs may be sufficient to control asthma in most patients. Holt et al⁸ recently reviewed data on the dose-response curve for inhaled fluticasone propionate (FP) in both adults and adolescents with moderate to severe asthma. All major clinical outcomes including exacerbations began to plateau at 100 to 200 mg/d and peaked at 500 mg/d.⁸ Furthermore, a study from the Asthma Clinical Research Network found that near-maximal FEV₁, FVC, and provocative concentration of substance causing 20% fall in FEV₁ occurred at low-medium doses of FP (88 mg) and medium doses of beclomethasone dipropionate (BDP) (627 mg). High-dose ICS therapy did not significantly increase the efficacy measures, but did increase the systemic effects such as overnight cortisol suppression.⁹

With evidence that inflammation occurs even in patients with mild asthma, therapy with ICSs is now recommended at a much earlier stage of the disease. The importance of intervention in mild asthma is underscored by the results of an Australian survey of deaths in children due to asthma^.22 A third of the deaths occurred in children who had been judged to have a history of trivial or mild asthma; 32% had no previous hospital admission for asthma. Many patients are misclassified as having intermittent asthma (> 40%), when in reality they have mild or moderate persistent asthma. Many have abnormalities seen in BAL and bronchial biopsy specimens and changes in small-airway mechanical function—which argues for more use of ICS therapy.

Cromolyn and nedocromil. These two compounds have similar anti-inflammatory actions, and their mechanism of action appears to involve the blockade of chloride channels; they also modulate mast-cell mediator release and, consequently, eosinophil recruitment. Cromolyn and nedocromil inhibit both the early and late asthmatic response to allergens and exercise-induced bronchospasm. Both compounds have an exceptionally good safety profile and are predominantly used as treatment for milder pediatric asthma. They are less effective in the setting of poorly controlled asthma, and are not useful in the treatment of acute asthma.

Leukotriene modifiers. The most recent National Asthma Education and Prevention Program guidelines¹ state that the leukotriene modifiers such as zafirlukast and montelukast may be considered as well as low-dose ICSs, cromolyn, and a nedocromil for patients with mild persistent asthma. Further clinical experience and study are needed to document the long-term usefulness of these agents in asthma therapy. Currently available leukotriene modifiers include leukotriene-receptor antagonists (eg, zafirlukast and montelukast) and an inhibitor of leukotriene synthesis (zileuton). Evidence suggests that these agents can improve lung function, lessen the need for short-acting inhaled b₂-agonists, and protect against exercise-induced bronchospasm.

However, leukotriene modifiers are not as effective as ICSs. In a recent study, patients with persistent asthma who were receiving BDP or triamcinolone acetonide were switched to a low dose of inhaled FP or to zafirlukast.²³ Significantly more patients in the zafirlukast group were more likely to be withdrawn from the study because of lack of efficacy. However, other recent reports suggest that leukotriene modifiers may play a role in combination with low-dose ICS regimens, although they appear to be less effective as add-on therapy than salmeterol. These agents can be used to reduce the dose of ICSs.

Uncontrolled asthma. Treatment guidelines recommend that patients with persistent asthma, whether mild or moderate, receive daily, long-term controller medications. The most effective long-term control medications are those with anti-inflammatory effects that reduce chronic airway inflammation and airway hyperresponsiveness. In some patients with moderate or severe persistent asthma, however, a combination of agents with complementary mechanisms of action may be needed to control the disease.

A meta-analysis²⁴ found that salmeterol added to low-to-moderate doses of ICSs improved lung function and increased the number of symptom-free days and nights, with no increase in exacerbations. Salmeterol or formoterol as an adjunct to ICS is more effective than monotherapy with an ICS dose 2 to 4 times higher, regardless of the type of ICS used. The addition of a long-acting inhaled b₂-agonist is particularly useful in patients with nocturnal symptoms.

Recent studies also suggest that adding a long-acting inhaled b₂-agonist, with its minimal effects on airway inflammation, to a therapeutic regimen of ICS does not eliminate the need for the ICS. There are recent conflicting reports as to whether adding a long-acting inhaled b₂-agonist can even safely permit the dosage of the ICS to be reduced without risking clinical deterioration. In a 24-week study,^25,26 patients whose asthma was poorly controlled with triamcinolone were randomized to receive add-on therapy with salmeterol or placebo. A reduction in corticosteroid dose with salmeterol was attainable, but treatment failure occurred in 46% of patients who discontinued corticosteroid therapy while continuing with salmeterol.

Studies have evaluated combining ICSs with leuoktriene modifiers. Montelukast provided additional asthma control in patients whose asthma was incompletely controlled by inhaled BDP, although withdrawing corticosteroids while continuing montelukast led to deterioration. In patients with chronic asthma receiving high doses of ICSs, the addition of montelukast (10 mg once a day at bedtime) allowed a reduction in the ICS dose while still maintaining clinical control of asthma symptoms.^31,27

ICSs also appear to be superior to leukotriene modifiers as monotherapy. Patients receiving ICSs had a significantly larger increase in FEV1 and a larger decline in daytime symptom scores. While montelukast did have a favorable effect on peak expiratory flow rates, quality of life, nocturnal awakenings, and asthma attacks, outcomes for these variables were better in the BDP group. The combination of FP and salmeterol provided more effective asthma control, including significantly lower exacerbation rates, than did FP and montelukast.^28,29

In some cases, patients whose asthma is not controlled by high doses of ICSs or the addition of long-acting bronchodilators also need oral corticosteroids on a regularly scheduled, long-term basis. When control of asthma is achieved, however, persistent attempts should be made to reduce systemic corticosteroids and replace them with ICSs, since these agents have fewer systemic effects.

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