Insight into the pathogenesis of asthma has been key in the development of drug treatments.

As many as 15 million US residents (more than 5% of the population) have asthma.^1,2 Collectively, people with asthma have more than 100 million days of restricted activity and 470,000 hospitalizations annually.³ More than 5,000 people die of asthma each year.⁴ Asthma hospitalization rates have been greatest among black patients and children, while death rates for asthma are consistently highest among black patients aged 15 to 24 years.⁵ These rates have generally increased over the past decade.

The total annual estimated US cost of asthma is approximately $6 billion.⁶ Direct costs, which include payments for ambulatory care visits, hospital outpatient services, hospital inpatient stays, emergency-department visits, physician and facility payments, and prescribed medicines, account for approximately $5 billion.⁷ Indirect costs, which include costs resulting from missed work or school and days of restricted activity at work, account for nearly $1 billion.^4,6

New treatment approaches have been developed in recent years with the goals of reducing the morbidity, mortality, and overall costs associated with this illness and improving the quality of life of patients and their families. The cornerstones of asthma care remain early diagnosis, education about the disease and its treatment, appropriate pharmacologic balance, and adherence to a recommended self-care regimen.

Pathogenesis of Asthma
Asthma is a chronic inflammatory disease of the airways characterized by episodic symptoms (wheezing, chest tightness, cough, and dyspnea); variable airflow obstruction; and increased bronchial hyperresponsiveness. Over the past few years, however, significantly more insight into the pathogenesis of asthma has been gained, particularly with regard to the components of the inflammatory cascade.

Studies^8,9 examining the relationship between the pathologic changes and the clinical features of asthma have shown that the key inflammatory cells involved in the pathogenesis of asthma are mast cells, eosinophils, lymphocytes, and epithelial cells. Upon exposure to an initiating stimulus (an asthma inducer), these inflammatory cells release inflammatory mediators such as histamine, leukotrienes, prostaglandins, cytokines, chemokines, and platelet-activating factor. These compounds have direct and indirect effects on airway smooth muscle and capillary permeability. Inflammatory mediators contribute to epithelial injury, mucosal edema, abnormalities in smooth-muscle responsiveness, and airflow obstruction. The airflow obstruction produces the signs and symptoms of asthma.

The airway response to antigen has provided a laboratory model for the study of the events that take place during allergic inflammation. At the cellular level, the inflammatory response in asthma is similar to that in other allergic diseases. Upon exposure to the initiating stimulus, an intense local reaction (the early-phase response) results, causing epithelial damage, damage to nerve endings within muscles lining the airways, and subsequent activation of an axonal reflex. These cellular responses correlate with the clinical manifestations of the early-phase response. For example, if sufficient antigen is inhaled by an asthma patient, there is invariably an immediate fall in forced expiratory volume in 1 second. This bronchospastic response to antigen is related to the release of inflammatory mediators from the pulmonary mast cell. The late-phase response is characterized by more persistent airflow obstruction, an increase in airway responsiveness, and infiltration with inflammatory cells.

An understanding of the inflammatory cells involved in the asthmatic response forms the pharmacologic basis for anti-inflammatory drugs used in the treatment of asthma. The key inflammatory cells of the asthmatic response—mast cells, eosinophils, lymphocytes, and epithelial cells—are found in increased numbers in the airways of patients with asthma.^7,10

Eosinophils contribute to inflammation by causing the release of leukotrienes, prostaglandins, granular proteins, and proinflammatory cytokines. Granular proteins may damage airway tissue and promote airway hyperresponsiveness. Lymphocytes, particularly subpopulations of T-helper (TH) lymphocytes, are believed to contribute to inflammation in asthma through the release of various cytokines.¹¹ Epithelial cells are another source of proinflammatory mediators in asthma, including leukotrienes and other eicosanoids, cytokines, chemokines, and nitric oxide.

The airways of patients with asthma are infiltrated by eosinophils and mononuclear cells, and there is vasodilation and evidence of microvascular leakage and epithelial disruption. The airway smooth muscle is often hypertrophied; this is characterized by new vessel formation, increased numbers of epithelial goblet cells, and deposition of interstitial collagens beneath the epithelium. These features of airway-wall remodeling in asthma patients further underscore the importance of chronic, recurrent inflammation in asthma and its effects on the airway.

Leukotriene Modifiers
The first of the new advances has been the introduction of cysteinyl leukotriene antagonists montelukast and zafirlukast and the 5-lipoxygenase inhibitor zileuton. Leukotrienes, a family of lipid mediators derived from arachidonic acid, are produced by leukocytes and many other cells, including those found in the lung. Several leukotrienes have been implicated in the inflammatory cascade leading to asthma.¹² Leukotriene modifiers, therefore, represent an important therapeutic advance in the management of chronic asthma.

Airflow obstruction is a principal mechanism by which asthma exerts its symptoms. In asthma, airflow obstruction can be caused by four primary mechanisms: bronchoconstriction caused by contraction of smooth muscle lining the airways, mucosal edema caused by vascular leakage, increased secretion of mucus, and the presence of an inflammatory-cell infiltrate that is rich in eosinophils. The cysteinyl leukotrienes have been found to play a role in each of these mechanisms.¹³

The bronchoconstriction mediated by cysteinyl leukotrienes is perhaps the most significant effect of these agents in asthma. Cysteinyl leukotrienes have been shown to induce bronchoconstriction with a potency 100 to 1,000 times that of histamine.¹⁴ They are among the most powerful bronchoconstrictor agents known. In addition, the bronchoconstriction produced by cysteinyl leukotrienes is more prolonged than that produced by histamine.

Leukotriene B4 (LTB4), a noncysteinyl leukotriene, may also play a role in the pathogenesis of asthma. LTB4 is strongly chemoattractive for neutrophils and somewhat chemoattractive for eosinophils.¹⁵ Eosinophils are thought to play a major role in asthma, and have been found in increased numbers in bronchoalveolar lavage (BAL) fluid and bronchial biopsies from patients with asthma. Neutrophils have also been identified in increasing numbers in BAL fluid after allergen challenge, but their role in asthma is less clear.

Asthma also exerts its effects through bronchial hyperresponsiveness, and leukotrienes may play a role in mediating this response. In healthy subjects, LTD4 has been shown to produce an increase in bronchial responsiveness to methacholine that lasts for up to 2 weeks.^16,17 In addition, an enhanced airway response to histamine has been demonstrated in asthma patients after inhalation of LTC4, LTD4, or LTE4.¹⁴

In asthma, there is increased production of leukotrienes.¹⁸ The most important cellular sources of leukotrienes in asthma are probably eosinophils, mast cells, and basophils. Leukotriene modifiers are long-term controller medications that are prescribed for daily use on a long-term basis to achieve and maintain control of asthma symptoms. Therapy with leukotriene modifiers is aimed at either blocking the formation of leukotrienes at some point along the arachidonic acid cascade or blocking the action of cysteinyl leukotrienes at the leukotriene receptor.

When leukotriene antagonists are used as add-on therapy with inhaled corticosteroids, they produce a modest improvement in the control of asthma manifestations, but do not necessarily permit the corticosteroid dosage to be decreased.³ Leukotriene antagonists may also have anti-inflammatory effects in asthma, but the effectiveness of these agents is less than that of corticosteroids. Their effectiveness varies significantly among patients, and they may have little effect in patients older than 50 years.³ In addition to their well-described effects on bronchoconstriction, it appears that leukotriene antagonists also inhibit the airway remodeling process, at least in experimental models of asthma.¹⁹ Limited data on symptom scores suggest that 4 weeks of treatment with antileukotriene drugs may also be beneficial to children with viral bronchiolitis.

Leukotriene modifiers are generally well tolerated by most patients. In clinical trials, the incidence of adverse events in patients treated with leukotriene modifiers has been similar to that in those who received placebo, with the exception of reversible elevations in liver enzymes seen in 2% to 9% of studies with zileuton.^20,21 However, there have been at least three reports of subfulminant hepatic failure after treatment with zafirlukast,²² and rare reports of eosinophilic conditions, including Churg-Strauss syndrome, in patients treated with zafirlukast.^23-25 Churg-Strauss syndrome is a granulomatous, necrotizing vasculitis that is usually associated with corticosteroid tapering in patients with severe asthma.

Omalizumab
The second new asthma treatment is a recombinant humanized anti-IgE antibody, omalizumab. This therapeutic approach is based on the likelihood that the generation of IgE and the binding of IgE to its high-affinity receptor (FceRI) are critical to the development of the allergic response.

Omalizumab was developed to interfere early in the allergic process by targeting the source of allergy symptoms. By binding to circulating IgE in the blood, this antibody blocks the release of inflammatory mediators by keeping the IgE from binding to mast cells.²⁶ These inflammatory mediators, which include histamine, prostaglandins, and leuko-

trienes, play a role in the pathogenesis of allergic diseases such as allergic asthma, allergic rhinitis, and atopic dermatitis. This approach is an important step forward because severe asthma is poorly controlled by existing therapies other than oral corticosteroids, long-term use of which is associated with numerous adverse effects. Omalizumab is administered via subcutaneous injection.

Twice-weekly injections of omalizumab lead to a rapid, dose-related, and sustained fall in plasma IgE levels in patients with atopic asthma.²⁷ The antibody is designed to bind to the part of the IgE molecule that interacts with FceRI on mast cells and basophils, thereby preventing the attachment of IgE to these cells.²⁸

In a placebo-controlled study¹⁷ of omalizumab in 317 subjects with moderate-to-severe perennial allergic asthma who were taking inhaled or oral corticosteroids, intravenous injections of either a high dose or a low dose of omalizumab every 2 weeks significantly reduced the symptoms of asthma and improved patients’ quality of life, with a moderate increase in airway function and a reduced need for bronchodilators as rescue medication. During the next 8 weeks of the study, the doses of inhaled or oral corticosteroids were tapered. There were greater reductions in the doses of inhaled and oral corticosteroids and higher rates of discontinuation of these drugs in the high-dose and the low-dose groups than in the placebo group. In the group of 35 subjects who required oral corticosteroids at baseline, there was a significant reduction in the requirement for oral corticosteroids, and nearly twice as many subjects in the high-dose group as in the placebo group were able to stop taking oral corticosteroids.

Treatment with omalizumab has been well tolerated in all studies^29,30 to date, with no specific adverse effects, apart from an urticarial rash after the first dose in a small number of subjects. There is no evidence that antibodies develop against omalizumab, presumably because of the humanization of the antibody (more than 95% of the sequences of the protein are of human rather than murine origin). Moreover, the immune complexes formed by the interaction of omalizumab with IgE appear to be removed by the reticuloendothelial system, with no evidence of damage to the kidney or other organs or tissues.³¹ The greatest benefit of omalizumab has been found in patients with severe, corticosteroid-resistant asthma. The anti-IgE approach to asthma treatment may also have the advantage of being able to treat concomitant atopic diseases (allergic rhinitis and conjunctivitis, atopic dermatitis, and food allergy), regardless of the type of atopic disease and the causative allergens.

Combination Therapies
The third, and clearly most popular, new asthma treatment has been the packaging of inhaled corticosteroids with inhaled long-acting b2-agonists. Examples include a combination of fluticasone propionate and salmeterol and a combination of budesonide and formoterol. Clinical trials^32,33 have suggested that the combination of these two classes of drugs may provide synergistic effects that are greater than their additive actions. In clinical trials, the safety of inhaled corticosteroid plus inhaled long-acting b-agonists has been similar to that of either agent alone. It is also possible that the greater efficacy of prepackaged combinations may be due, at least in part, to improved patient convenience and compliance. Unlike short-acting b2-agonists—reliever drugs that work quickly to relieve an asthma attack—long-acting b2-agonists are used as maintenance drugs because they provide longer-term control.

Treatments Under Investigation
Investigations into new targeted treatment approaches for asthma have focused on the role of interleukins (ILs) in the pathogenesis of the disease. Research has been done to identify key inflammatory mediators, particularly at the level of the interaction of the antigen-presenting cell with the Th2 lymphocyte, in an attempt to switch off many of the inflammatory effects mediated by several TH2 cytokines. Allergen challenge induces the release of several TH2 cytokines, including IL-4, IL-5, IL-9, and IL-13.34 These cytokines have received much attention recently as potential therapeutic targets in asthma. IL-9, in particular, may be a key mediator of the inflammatory response in asthma. It has been implicated as an essential factor in determining mucosal immunity and susceptibility to atopic asthma.³⁵

Patient Education
The respiratory therapist is in a unique position to educate asthma patients about their disease and its management, particularly with the development of new treatments that may be poorly understood by patients. Education of asthma patients usually leads to better control of the disease, fewer physician visits, fewer hospital and emergency-department admissions, and fewer days lost from work.^36,38 The use of medication, particularly inhaled corticosteroids, often increases.³⁹ Quality of life improves, and the resulting cost-benefit balance is usually favorable.⁴⁰

Simply handing out brochures is inadequate because a substantial number of people are functionally illiterate and can only comprehend text at or below a seventh-grade level. Numerous pamphlets on asthma are beyond the comprehension of many in their target audience. The most effective teaching is done in small groups using verbal presentations, videos, and electronic multimedia presentations.⁴¹ The last method appeals to all patients, whether they are visual, auditory, or kinesthetic learners. It also results in improved understanding and retention of the information.⁴¹

Specific areas of education should include explanation of the illness and the rationale for the use of medication for its treatment and prevention; proper use of a metered-dose inhaler and spacers; self-assessment of peak flow rates; and the development of plans of action in anticipation of asthma flares. Improved management of asthma will occur only if changes in airflow are recognized early and combined with self-management action plans. Children’s knowledge about asthma can also influence behavior, and education programs designed specifically for children may improve asthma management.⁴²

Conclusion
The first few years of the 21st century have brought significant advances in asthma care. New therapies are more targeted to the mechanisms of airway inflammation, and offer new hope to many patients, particularly those with difficult-to-control asthma.

John D. Zoidis, MD, is a contributing writer for RT.