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Current and Future Pharmacologic Therapy of Exacerbations in Chronic Obstructive Pulmonary Disease and Asthma

Roland Buhl and Stephen G. Farmer


Pulmonary Department, Mainz University Hospital, Mainz, Germany; and AstraZeneca Pharmaceuticals, Wilmington, Delaware

Exacerbations are an important cause of the morbidity and mortality associated with asthma and chronic obstructive pulmonary disease. Newer therapies include long-acting 2-agonists, which are more effective than short-acting bronchodilators. Inhaled corticosteroids and, in asthma, leukotriene receptor antagonists may have roles in the early phase of exacerbation as an alternative to or added to oral prednisolone. In the future, combinations of long-acting 2-agonists and anticholinergic bronchodilators may offer additive clinical benefits. However, although the treatment and prevention of exacerbations of chronic obstructive pulmonary disease and asthma have been improved by using combinations of known therapies, further research addressing the underlying etiology as well as molecular and pathophysiologic mechanisms of exacerbation is needed to better target novel therapies to the appropriate patient populations and to develop new therapeutic strategies. Keywords: chronic obstructive pulmonary disease; asthma; exacerbation; therapy

Exacerbations of chronic obstructive pulmonary disease (COPD) and asthma are important causes of morbidity, mortality, increased healthcare use, and hospital admissions. Furthermore, the global increase in the prevalence of asthma and COPD renders disease exacerbation an increasingly worrisome phenomenon for clinicians, healthcare organizations, society, and patients. Consequently, there is a growing interest not only in optimal treatment strategies but also in the prevention of further exacerbations. These facts underline the pressing need to improve the therapy of COPD and asthma exacerbations and to develop new classes of drugs. In this review, we outline current approaches to the pharmacotherapy of acute exacerbation in both asthma and COPD, as well as discuss drugs that may be available in the future. Therapeutic strategies to prevent asthma and COPD exacerbations are reviewed elsewhere in several articles in this issue.

COPD
Exacerbation of COPD

(2). Exacerbations have considerable impact on patients symptoms, daily activities, and health status. Treatment, therefore, should aim to prevent and control symptoms during exacerbation while improving the patients lung function and health-related quality of life. All new therapeutic approaches must be judged against these endpoints. Unfortunately, to date, there is no widely accepted denition of what constitutes an exacerbation of COPD (1, 3) (see article by Pauwels in this issue). Indeed, several denitions co-exist, and many clinical trials employ substantially different criteria or describe poorly the denition(s) used to diagnose exacerbation. Tracheobronchial infections are believed to be a common cause of exacerbation in COPD, although controversy exists regarding the nature of the infectious agent as well as its exact role (5). In addition, exacerbations of COPD are clearly associated with the levels of respirable particles and environmental air pollutants, and these have been linked to hospital admission rates (6). The outcomes of COPD exacerbation are similarly heterogeneous. Although nearly 50% of exacerbations remain unreported to physicians, those requiring hospitalization are associated with an inpatient mortality of 34%. For COPD patients requiring treatment for exacerbation in an intensive care unit, the mortality rates are substantially higher (in hospital, 1124%; by 1 year, 4346%). After an exacerbation, most patients are expected to experience at least a temporary impairment in functional status and quality of life, and half of those patients who are hospitalized are expected to be readmitted at least once in the ensuing 6 months (7). Indeed, it is possible that exacerbation may contribute to a worsening in the rate of disease progression in COPD (8), as discussed by Rennard and Farmer in this issue (9). Thus, there is an urgent need for better treatment options of COPD exacerbation to relieve symptoms and reduce the onset or severity of further exacerbations, to provide better health-related quality of life for individual patients, and to develop new classes of therapy (10).
Drug Treatment of Exacerbations of COPD

COPD patients have chronic progressive symptoms, airow obstruction, and impaired health status. They are predisposed to exacerbation, that is, an acute worsening of their respiratory symptoms (1). Exacerbations are infrequent in early COPD and are a feature largely of moderate to severe disease, increasing in frequency from on average less than one exacerbation per year in patients with an FEV1 of greater than 1.5 L to more than 2.5 per year in patients with very severe COPD (FEV1 1.25 L)

(Received in original form August 4, 2003; accepted in final form December 18, 2003) Correspondence and requests for reprints should be addressed to Roland Buhl, Pulmonary Department, Mainz University Hospital, Langenbeckstrasse 1, D-55131 Mainz, Germany. E-mail: r.buhl@3-med.klinik.uni-mainz.de Proc Am Thorac Soc Vol 1. pp 136142, 2004 DOI: 10.1513/pats.2306035 Internet address: www.atsjournals.org

Bronchodilators. Currently, short-acting 2-agonists, anticholinergic agents, theophylline, and a combination of these drugs are standard, rst-line bronchodilators in the symptomatic management of COPD exacerbations (11, 12). The choice between these drugs depends on the availability and individual response in terms of symptoms relief and side effects. Inhaled short-acting 2-agonists are usually the preferred bronchodilators (1315), although some studies suggest that anticholinergic bronchodilator drugs have comparable effects on lung function as measured by spirometry (16, 17) and a greater effect than bronchodilators administered parenterally (18). If a prompt, benecial response to these drugs does not occur, the addition of a second bronchodilator is recommended (1215, 19, 20). Although the evidence concerning the effectiveness of combinations of bronchodilators is controversial, such an approach may improve efcacy and decrease the risk of side effects compared with increasing the dose of a single agent (21, 22). Despite their widespread clinical use, the role of methylxanthines in

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the treatment of COPD exacerbation is also contentious. Most studies of theophylline have demonstrated only minor improvements in lung volume, but also a worsening of gas exchange and hypoxemia (23, 24). In more severe exacerbations, the addition of oral or intravenous methylxanthines to the treatment regime can be considered (12). The toxicity prole of the methylxanthines such as theophylline makes them potentially harmful. Adverse effects associated with this class of drugs include nausea, vomiting, headache, cardiac arrhythmia, and seizure. The effects are more signicant among those patients with higher blood levels of theophylline (see [12] and references therein for review). New bronchodilator options in COPD exacerbation include the long-acting 2-agonists (LABAs) salmeterol and formoterol, although this class of drugs is currently not approved for use in COPD exacerbation. This assumption is supported by results demonstrating that doses of both formoterol and salmeterol induce an effective increase in lung function parameters in patients with a COPD exacerbation and by small studies suggesting a potential use of LABAs during acute exacerbations (2530). This is particularly true for formoterol because of its rapid onset and long duration of action. There are, however, some concerns about the use of LABAs in this setting (31), and larger, randomized trials are needed before rm recommendations can be made. New developments in this eld may include combinations of LABA with anticholinergics (3234), 2-agonists with a duration of action of up to 24 hours, and R,R-formoterol, the active enantiomer of formoterol. To our knowledge, none of these compounds or combinations has as yet been examined in COPD exacerbations. Apart from these improvements to existing drugs, there are currently no new classes of bronchodilators in clinical testing for COPD. Corticosteroids. There is no doubt that a short course of systemic corticosteroid therapy given to patients having exacerbation of COPD improves lung function and decreases the relapse rate. Furthermore, there is good evidence indicating that a 2-week period of oral steroid therapy is sufcient to improve lung function parameters rapidly and to reduce the risk of treatment failure (35, 36). However, the optimal dose and duration of such treatment remains uncertain. Few data exist documenting the efcacy of oral corticosteroids in outpatient settings (37), and therapy with systemic corticosteroids is associated with potentially serious side effects, the most common one being hyperglycemia, particularly in patients predisposed to diabetes mellitus. A newer therapeutic approach is nebulized corticosteroids in the treatment of exacerbation of COPD. This treatment regimen was tested in a pilot trial comparing nebulized budesonide (Pulmicort Respules, 2 mg every 6 hours) with oral prednisolone (30 mg every 12 hours) and placebo (38). In addition, all patients received standard therapy, including nebulized 2-agonists, ipratropium bromide, oral antibiotics, and supplemental oxygen. In this study, the mean change in post bronchodilator FEV1 over the rst 3 days was signicantly greater with both active treatments than with placebo. The improvement in FEV1 in the budesonide group tended to be smaller than in the prednisolone group; however, this difference was not signicant. With the exception of a greater improvement in PaO2 in the prednisolone arm and a greater decline in PaCO2 in the two active treatment groups, the clinical outcome in all three arms of the study was similar. This was also true for the occurrence of serious adverse events in the 10-day period after study entry. Budesonide exhibited less systemic activity than prednisolone, as indicated by a higher incidence of hyperglycemia observed with the latter. The authors concluded that nebulized glucocorticosteroids, notably budesonide, may be an attractive alternative to oral prednisolone in the treatment of milder, nonacidotic exacerbations of COPD

(38). Further trials are needed to conrm these results and to evaluate the long-term impact of this new therapeutic strategy on clinical outcomes. Combinations of inhaled corticosteroids and long-acting 2agonists. The xed combination of both drugs may have a role in the therapy and prevention of exacerbations of COPD. This topic is discussed in greater length in the article by Calverley in this issue (39). Antibiotic therapy. The proportion of exacerbations of COPD with a bacterial etiology is unknown, as sputum cultures from stable COPD grow pathogenic bacteria in a signicant proportion of cases. Viruses undoubtedly also play a signicant role. Recent evidence suggests that bacterial colonization and/ or infection are a chief cause responsible for COPD exacerbations. In general, therefore, antibiotics are benecial in the treatment of patients with exacerbation of their COPD, in particular in subjects experiencing clinical signs of airway infection (e.g., increased volume and/or change of color of sputum and/or fever). COPD patients with more frequent exacerbations and/or greater severity require appropriate antimicrobial therapy. Typical administration periods range from 3 to 14 days, although there is little evidence regarding the appropriate duration of administration of antibiotics (4046). The potential causative roles of bacterial and viral agents in acute exacerbations of COPD and the use of antibiotic therapy for the management of COPD patients are discussed by Sethi (47) and Wedzicha (48) in this issue. Mucus clearing strategies. Expectorants, mucolytics, and mucokinetic drugs have not been demonstrated to shorten the course of treatment for patients with exacerbations of COPD, although there is a possibility that these agents may improve symptoms (49). This is further discussed later in this article.
Future Therapeutic Targets and Strategies in Exacerbation of COPD

Inammatory chemokines and cytokines. Novel drugs aimed at ameliorating inammatory processes that are likely pivotal in the exacerbation cycle may represent exciting new approaches in the therapy and/or prevention of COPD exacerbation. Tumor necrosis factor-, interleukin (IL)-8, and monocyte chemoattractant protein-1 are important chemotactic mediators for macrophages and neutrophils, the predominant inammatory cells associated with COPD, and the pharmacologic actions and/or generation of such mediators represent attractive targets for novel drug discovery (50, 51). Indeed, clinical trials with at least one antitumor necrosis factor and one antiIL-8 biopharmaceutical product in COPD are currently ongoing, and some companies are exploring the potential of small molecule inhibitors of p38 mitogen-activated kinase, a key signaling component in the intracellular production of tumor necrosis factor, as novel therapies for COPD (52). Lung concentrations of most if not all of these substances are higher in COPD compared with subjects who do not have airow obstruction, suggesting that such inammatory mediators are potential targets for the development of specic antagonists and/or inhibitors to treat or prevent exacerbations (49). Proteases. Neutrophil elastase has long been a target for drug discovery for novel therapies for several inammatory disorders, including COPD (10, 53). This serine protease has been implicated not only in the proteolytic destruction of lung matrix proteins and development of pulmonary emphysema but also as a potent mediator of airways goblet cell hyperplasia and mucus hypersecretion (54). Lung levels of neutrophils and neutrophil elastase are elevated in exacerbation of COPD (55), and the pharmacologic inhibition of this destructive enzyme may in the future represent a potentially exciting and efcacious therapeutic strategy in the prevention and/or treatment of exacerbations. In

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addition to neutrophil elastase, other proteolytic enzymes such as matrix metalloproteases-9 and -12 are now being explored as potential therapeutic targets for intervention in COPD (5658). Such agents may in the future occupy an important place in our armamentarium of therapies for exacerbations in COPD. Other future approaches to the therapy of COPD exacerbation. Mucus hypersecretion is a characteristic feature of COPD, and as discussed previously, increased sputum volume and/or purulence are used frequently as diagnostic markers of exacerbation. The cellular and molecular components involved in mucus formation, content, release, and transport are, consequently, potentially attractive targets for therapeutic intervention. Such strategies include drugs that inhibit mucus production as well as ion channel-activating agents that increase the hydration of mucus, thereby enhancing mucociliary clearance (59, 60). Therapeutic strategies aimed at preventing infectious exacerbations, perhaps through reducing bacterial adherence or limiting cellular damage in the presence of microorganisms, should be pursued. Finally, the determination of biological markers of infection and inammation (e.g., endogenous protease inhibitors, antioxidants, and cytokines) in the blood and/or sputum may in the future provide valuable diagnostic tools with which to identify an approaching exacerbation, as well as in determining the efcacy of novel therapies in clinical trials (50, 53).

ASTHMA
Exacerbation of Asthma

Asthma is characterized clinically by variable airow obstruction and bronchial hyperreactivity. A common disease that can cause much morbidity and mortality (61, 62), asthma is a chronic disorder of the airways that are inamed and hyperreactive to bronchoconstrictor stimuli (reviewed by Grootendorst and Rabe in this issue [63]). In an acute asthma attack (or exacerbation), when patients are exposed to various inhaled stimuli or other triggers, the airways become obstructed, and the airow is limited by bronchial smooth muscle contraction (bronchoconstriction), mucus plugging, edema, and increased inammation. Initiators of such exacerbations in asthma include viral infections, allergens (such as those derived from animals, cockroaches, domestic dust mites, pollens, and molds), air pollution, tobacco smoke, exercise, and chemicals. Although asthma attacks occur in what are known as episodes, the inammation of the airways is present chronically. Asthma requires long-term management, and for many patients, this necessitates taking their medication every day in order to prevent symptoms.
Current Therapy for Asthma Exacerbation

Although bronchodilators and moderate doses of regular inhaled corticosteroids (ICSs) provide good control for most patients with asthma, some of these individuals develop severe exacerbations that are difcult to prevent and can lead to time off from work, admission to hospital, and life-threatening attacks. The current rst-line medical treatment of asthma exacerbation consists of inhaled short-acting 2-agonists, anticholinergics, theophylline, and systemic corticosteroids (61, 64). Although the prevention and treatment of asthma exacerbations are not as dissatisfying as therapy available presently for COPD exacerbations, the development of new drugs to better prevent and more effectively treat attacks is a priority for asthma research.
Bronchodilators

2-Agonists. Salbutamol, the standard short-acting 2-agonist, is a 50:50 racemic mixture of R-salbutamol, the active enantiomer, and S-albuterol, which appears to be inactive as a bronchodilator in humans but which may have proinammatory effects. The

clinical signicance of this, however, is debatable (65, 66). Regardless, levalbuterol, the pure R-isomer of racemic salbutamol, is a new therapeutic option in asthma. Studies conducted in patients with stable asthma, however, indicate that this agent is neither safer nor more effective than an equimolar dose of racemic salbutamol (levalbuterol 1.25 mg salbutamol 2.5 mg) (67). This may not be the case, however, in patients with an acute asthma exacerbation who often require higher doses of 2-agonists. Nevertheless, at present, there are insufcient data to assess the prospects of levalbuterol in acute asthma exacerbation, in particular any potential (small) advantages over salbutamol justifying the extra cost (68). This is also true for R,R-formoterol, currently in phase III clinical development as a therapy in asthma and COPD. Despite concerns that the use of LABA could be associated with risk of worsening asthma, to date, these drugs have proven safe and highly effective (69, 70). LABAs are recommended as maintenance therapy in patients with moderate and severe asthma. Salmeterol, because of its slow onset of action, may have a role as an adjunct to conventional therapy for the inhospital management of asthma exacerbations (71, 72). In contrast, formoterol, combining rapid onset of action with prolonged bronchodilatation and safety even at high doses (7375), similar to that of short-acting 2-agonists, is recommended for on-demand treatment in asthma (61, 64). A recent real-life study demonstrated that formoterol as needed has a similar safety prole to salbutamol, and its use as a reliever therapy is associated with fewer asthma symptoms and exacerbations (76). These qualities also make formoterol a potential new therapeutic option for acute bronchoconstriction. This has been demonstrated clearly in a study comparing the safety of formoterol with terbutaline, both drugs being delivered via Turbuhaler, in patients with acute airway obstruction (26). In this study, 48 patients were randomized for treatment, including 33 patients with a diagnosis of asthma, 8 with chronic obstructive asthma, and 7 with COPD. Patients received a total of 90 g of formoterol (delivered dose) or 10 mg of terbutaline (metered dose) on six occasions during 3 hours (20 inhalations of each drug). In the 12 hours after the rst dose, the mean values of serum potassium decreased from 4.02 to 3.89 mM for formoterol and from 4.22 to 3.76 mM for terbutaline. The mean 12-hour pulse rate was signicantly (p 0.01) higher in the terbutaline group (101.7 beats per minute) than in the formoterol group (93.5 beats per minute). No individual patient value, however, was considered clinically important or alarming. FEV1 improved in both groups but with no statistically signicant difference between either drug treatment. Four patients discontinued the trial, one on formoterol and three on terbutaline. These data are in agreement with data from other studies (75, 76) and indicate that the pattern of systemic side effects of formoterol is similar to or less pronounced than that of the traditional short-acting 2-agonists. Furthermore, these data also indicate that even in patients with acute bronchoconstriction due to asthma and COPD formoterol is at least as safe and well tolerated as terbutaline. Regardless, formoterol is not yet approved in this setting, and a logical next step would be to investigate the efcacy of formoterol in the treatment of acute asthma attacks (77). Anticholinergic drugs. The administration of anticholinergic agents (and ICS) to patients with an asthma exacerbation already treated with 2-agonists improves pulmonary function and reduces the hospitalization rate. In a recently published clinical trial, asthma patients who presented to an emergency department were assigned to receive salbutamol (400 g), ipratropium bromide (84 g), and unisolide (1,000 g) in triple combination, or salbutamol and ipratropium, or salbutamol and unisolide inhaled at 10-minute intervals for 3 hours. Patients who received

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triple therapy had an overall 64% greater improvement in FEV1 (2.1 0.6 L) than those who received salbutamol/unisolide (1.7 0.6 l, p 0.002) and a 41% greater improvement than those who received salbutamol/ipratropium (1.8 0.6 L, p 0.04). There was even a trend toward a reduction in hospital admission rates (11%, 20%, 25%), suggesting a therapeutic benet from the high-dose administration of all three drugs, particularly in those patients in whom the FEV1 was below 30% of the predicted value (78). Glucagon. The hormone glucagon is a rapidly acting smooth muscle relaxant with a short half-life. However, although some trials have suggested that glucagon may have bronchodilator effects, in a well controlled study in emergency department patients with asthma exacerbation, intravenous glucagon (0.03 mg/kg body weight) provided no clinically relevant immediate bronchodilation (79). ICSs. Systemic corticosteroids are generally accepted as treatment for all but the mildest exacerbations of asthma (61, 64), although there is no consensus on dose, timing, and route of administration. Recent guidelines recommend doses of systemic glucocorticosteroids equivalent to 60 to 80 mg methylprednisolone per day for at least 2 days for hospitalized patients and a 10- to 14-day course of a lower oral dose as follow-up. There is no evidence that it is benecial to taper the dose either in the short term or over several weeks. Systemic glucocorticosteroids administered by ingestion are usually as effective as those administered intravenously and are preferred because this route of delivery is less invasive and less expensive (see [80] for review). In contrast, ICSs have been used principally for the longterm management of asthma but are not widely accepted for the treatment of exacerbations. However, although traditionally considered to have delayed effects in acute asthma, studies now suggest that ICSs may have an effect even in the early phase of asthma exacerbations (see reviews in [8083], as well as article by OByrne in this issue [84]). The onset of action of ICS in acute asthma normally begins in approximately 1 hour. In patients who presented to an emergency room for treatment of an exacerbation of asthma, an ICS, unisolide (1 mg), administered together with salbutamol (400 g) at 10-minute intervals for 3 hours improved FEV1 and peak ow rates signicantly more than salbutamol alone at 90, 120, 150, and 180 minutes. No clinically relevant side effects were observed. A subgroup analysis revealed that the FEV1 was particularly low at 23 hours in patients with a long duration of symptoms ( 24 hours) before presenting at the emergency room. These ndings suggest a role for high and cumulative doses of ICS in patients with an asthma exacerbation and a prolonged duration of symptoms before treatment (85). In terms of mechanisms, the rapid response is most likely caused by a direct topical antiinammatory effect of ICSs, leading to transient pulmonary vasoconstriction, prevention of plasma leakage, and reduction of airway mucosal edema (86, 87). Indeed, cutaneous blanching has been used to measure such topical corticosteroid activity for over 10 years (88). In contrast, in a trial in children with severe acute asthma, the degree of improvement in pulmonary function in the initial 4 hours in patients given oral prednisone (2 mg per kg of body weight) was about twice that in those given a single high ICS dose (2 mg of uticasone). The rate of hospitalization in the uticasone group was about three times that in the prednisone group (89). This is in line with a study showing that just doubling the dose of ICS in case of an asthma exacerbation does not improve the outcome, at least in children (90). ICSs are effective in treating acute episodes after discharge from the emergency department. Inhaled budesonide (1,600 g/ day for 21 days) in addition to an oral corticosteroid (prednisone, 50 mg/day for 7 days) prevents asthma relapse after discharge

from the emergency department. After 21 days, 12 of 94 patients in the budesonide group compared with 23 of 94 patients in the placebo group (p 0.049) experienced a relapse. In addition, quality-of-life and improvement-of-symptom scores were better, and the use of 2-agonists was lower in the budesonide group. Using this approach, as few as nine patients would require budesonide to prevent one relapse (91). These ndings are conrmed by a trial showing that after 48 hours of intravenous treatment with corticosteroids, the use of high-dose inhaled unisolide (250 g per activation, eight puffs per day) is as effective as systemic corticosteroids (40 mg of prednisone) in adults hospitalized for a severe asthma exacerbation. From Day 1 to Day 7, peak ow rates (unisolide, 190 to 379 L/minute; prednisone, 207 to 347 L/minute), FEV1 (unisolide, 1.6 to 2.3 L; prednisone, 1.4 to 2.1 L), and symptom scores improved similarly in both groups (92). Thus, although ICSs are not recommended as standard therapy for patients with an asthma exacerbation, repeated administration of high-dose ICSs may decrease the need for hospital admission, improve pulmonary function, and reduce the number of days with increased symptoms as well as future relapses. This is primarily true for patients with mild-to-moderate exacerbation, most likely irrespective of the patients age (80, 89). Leukotriene D4 receptor antagonists. Leukotriene D4 receptor antagonists such as montelukast or zarlukast are generally recommended for the treatment of mild asthma, in particular in patients who are reluctant to take ICSs, or as add-on therapy for patients who remain symptomatic despite ICSs (61). A recent pilot study in patients with acute asthma attacks postulates an extra benet from the addition of intravenous montelukast compared with standard treatment alone (93). In this study, nearly 200 patients were treated with nebulized albuterol. If their initial response to the 2-agonist was less than adequate, as evidenced by a failure to demonstrate either a strong improvement in FEV1 or an FEV1 that was above a commonly accepted threshold, patients were then randomized to either intravenous montelukast (7 mg or 14 mg) or placebo. Further treatment was at the discretion of the investigators. Interestingly, montelukast signicantly improved FEV1 over the rst 20 minutes after administration compared with placebo (mean change 14.8% vs. 3.6% for the pooled montelukast and placebo treatment groups). This benet was also observed at 10 minutes and over 2 hours after therapy. In addition, patients treated with montelukast tended to receive less 2-agonists and have fewer treatment failures than patients receiving placebo. The tolerability prole for montelukast was similar to placebo, and no unexpected adverse events were seen. These preliminary results suggest that montelukast may confer added immediate benet to current treatment options in patients with acute asthma who do not demonstrate an adequate initial response to 2-agonists. Potential limitations of this study include the unavailability of anticholinergics, methylxanthines, and magnesium as part of standard treatment. This is especially relevant given the rapid onset of action, and the primary mechanism of action of montelukast in this setting is likely one of bronchodilation. Furthermore, patients on regular treatment with leukotriene D4 antagonists were excluded from participation in this study. It is conceivable, therefore, that this effect might not be observed in patients with an asthma exacerbation despite prior treatment with a leukotriene D4 antagonist. Clearly, the potential of montelukast in the therapy of acute asthma needs to be conrmed in larger trials in which patients are prescribed a currently recommended initial bronchodilator in addition to adjunct therapy (83, 94). Magnesium sulfate. Until recently, studies of intravenous magnesium sulfate as a treatment for acute asthma have yielded

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mixed results, some trials suggesting a benet in acute severe asthma, but not in mild to moderate asthma. A recent placebocontrolled, double-blind, randomized multicenter study in 248 patients with acute asthma presenting with an FEV1 of 30% or less than predicted (mean FEV1 22.9%) may explain some of these discrepancies (95). In this population, intravenous treatment with magnesium sulfate (2 g), in addition to nebulized salbutamol at regular intervals and intravenous methylprednisolone, improved FEV1 over the rst 4 hours to a greater extent than placebo (48.2% vs. 43.5%, p 0.045). Importantly, the positive effect of magnesium was greater in patients with a lower initial FEV1. If the initial FEV1 was less than 25% predicted, the nal FEV1 in the magnesium-treated group was 45.3% compared with 35.6% predicted in the placebo group. In contrast, magnesium administration was not benecial if the initial FEV1 was 25% or greater than predicted. These results support the use of magnesium sulfate (2 g intravenously), in addition to standard therapy, in the improvement of pulmonary function only in patients with very severe, acute asthma and also help to dene the limitations of this approach. In this regard, the use of magnesium sulfate did not improve hospital admission rates (95). Interestingly, in severe asthma, even use of isotonic magnesium as an adjuvant to nebulized salbutamol results in an enhanced bronchodilator response (96). The mechanisms underlying these benecial effects are unknown, although magnesium is required for a wide variety of cellular activities and, therefore, may exert its effects on a number of biological pathways and mechanisms. It is unclear whether the effect(s) of magnesium is primarily due to replacement of an underlying deciency or through a direct pharmacologic action (97). Antibiotic therapy. Antibiotics are often prescribed to patients with an asthma exacerbation, particularly if it is precipitated by an upper respiratory infection. However, the overwhelming majority of respiratory infections are due to viruses, and strong evidence to support (or to refute) the use of antibiotics in this situation is lacking. Therefore, recommendations regarding the use of antibiotics in asthma exacerbations will remain consensus driven until more research, including larger patient numbers, is conducted (97).

example, despite displaying often remarkable efcacy in preclinical animal experiments, studies in human asthma with antiIL-5 biopharmaceutical agents have been disappointing so far. Little clinical efcacy in asthma has been observed, and the role of IL-5 and the eosinophil in this disorder remains a source of much debate (100102).

CONCLUDING COMMENTS AND FUTURE DIRECTIONS


In the future, there may be scope for novel therapies that modify the pathogenesis and/or disease course both in asthma and COPD. In the former disorder, it is possible that new treatments aimed at upstream immunologic pathways or at the prevention or reversion of the immunologic abnormalities in atopy may yield drugs that are truly disease-modifying or even cure asthma. The long-term consequences of altering the immune response are of course uncertain, and potentially, somewhat protracted clinical studies may be difcult to perform. In addition to chronic inltration of the airways with inammatory leukocytes, the pathogenesis of asthma is characterized by marked structural and functional changes in resident airways cells and tissues such as smooth muscle, broblasts, and the epithelium and its substructures. This airways remodeling is often evident even very early in the course of asthma and may be important in its progressive course in many patients. Undoubtedly, increased understanding of airways remodeling will lead to new targets and eventually provide novel therapies for asthma (52, 103, 104) (the role of airway remodeling in the pathogenesis of asthma is reviewed by Holgate in this issue [105]). Furthermore, in COPD, the airways and lungs undergo remarkable structural changes, including goblet cell hyperplasia and mucous gland hypertrophy, chronic inammation and plugging of the small airways (bronchiolitis), and overt destruction of the lung parenchyma (emphysema) (60, 106). These, too, represent active areas of research for novel therapies. Novel drugs that help to repair or restore the abnormal structural changes in the respiratory tree in asthma and COPD may slow or even reverse the progressive declines in lung function and impaired health status. This may also encompass decreasing the enhanced susceptibility to infection in many individuals and may indirectly reduce the propensity of asthma and COPD patients to experience exacerbation of their disease. This, in turn, may slow progression and reduce mortality, and arguably symbolizes a Holy Grail in the search for novel therapies for disease chronicity and exacerbation in asthma and COPD. These are indeed signicant challenges to the scientic and medical communities in academia and the pharmaceutical industry (107).
References
1. Rodriguez-Roisin R. Toward a consensus denition for COPD exacerbations. Chest 2000;117:398S401S. 2. Burge S, Wedzicha JA. COPD exacerbations: denitions and classications. Eur Respir J 2003;Suppl 41:46S53S. 3. Voelkel NF, Tuder R. COPD: exacerbation. Chest 2000;117:376S379S. 4. Pauwels RA. Similarities and differences in asthma and chronic obstructive pulmonary disease exacerbations. Proc Am Thorac Soc 2004;1: 7376. 5. Wedzicha JA. Exacerbations: etiology and pathophysiologic mechanisms. Chest 2002;121:136S141S. 6. Schwartz J. Air pollution and hospital admissions for the elderly in Detroit, Michigan. Am J Respir Crit Care Med 1994;150:648655. 7. McCrory DC, Brown C, Gelfand SE, Bach PB. Management of acute exacerbations of chronic obstructive pulmonary disease: a summary and appraisal of published evidence. Chest 2001;119:11901209. 8. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002;57:847852.

FUTURE THERAPEUTIC TARGETS AND STRATEGIES IN EXACERBATION OF ASTHMA


Most asthma patients can be sufciently controlled with existing therapies (61, 64). Approximately 5% of patients, however, have poorly controlled (severe) asthma that requires therapy with high doses of ICS, and approximately 1% of asthma patients require maintenance doses of systemic corticosteroids on a continuous basis (98). New approaches for treating severe asthma are needed, ideally therapeutic strategies with novel, noncorticosteroid mechanisms of action, possibly those that target inammatory cells such as eosinophils, mast cells, and Th2 T lymphocytes believed to be key players in the pathogenesis of asthma. Possible approaches include modulators of the actions or generation of Th2 cytokines (e.g., IL-4 and IL-5 antagonists), chemokine receptor (e.g., CCR3) antagonists, inhibitors of leukocyte adhesion molecules such as very late antigen-4, or signaling pathways (c-Jun N terminal kinase and Syk kinase inhibitors) that are important in regulating key functions of inammatory cells (99). Several pharmaceutical companies have research and development programs aimed at discovering drugs that interfere with some or all of these targets; however, none of these potential new therapeutic agents will offer major advances over existing treatments in the short to medium term (less than 510 years). Furthermore, it can be (and is) argued that inhibition of the actions or biosynthesis of a single mediator, in the complexity of allergic inammation where redundancy of their actions exists, may not be as effective in treating asthma as anticipated. For

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