Difficult Asthma - ATS Journals

Difficult Asthma Mary E. Strek Section of Pulmonary and Critical Care Medicine, Department of Medicine, and Committee on Clinical Pharmacology and Pharmacogenetics, University of Chicago, Chicago, Illinois

The correct diagnosis of asthma is usually easily made and most patients with asthma respond to therapy. Approximately 5% of patients with asthma, however, have disease that is difficult to control despite taking maximal doses of inhaled medications. Patients with therapy-resistant or difficult-to-control asthma require a rigorous and systematic approach to their diagnosis and treatment. The first step is evaluation and testing directed at determining that asthma is the correct diagnosis. Many diseases mimic asthma and these alternate diagnoses should be considered. The second step is to identify and eliminate triggers that worsen asthma. Cigarette smoking, occupational exposures, and allergic rhinitis contribute to worsening disease. Most patients with “difficult asthma” require treatment with high-dose inhaled corticosteroids and long-acting inhaled ␤2-agonists. Despite maximal inhaled therapy, these patients will require either frequent bursts or chronic daily therapy with oral corticosteroids. These patients may have “resistant” inflammation with a persistent inflammatory state. Numerous studies also suggest that compliance with asthma therapy is poor. Combination therapy with inhaled corticosteroids and long-acting ␤2agonist in a single inhaler may improve patient compliance. In selected patients, additional therapy with leukotriene modifiers or anti-IgE antibody can result in improved asthma control and may allow tapering of corticosteroids. Use of methotrexate is not justified based on current data. Emerging evidence suggests that different phenotypes of difficult or therapy-resistant asthma exist. Recognition of these subgroups allows tailored therapy and prevents overmedication in an attempt to normalize lung function in patients with irreversible airflow obstruction. Keywords: asthma; diagnosis; difficult asthma; management

Although most physicians have no trouble recognizing the patient with difficult-to-control asthma, agreeing on a precise definition can be more problematic. Previously, difficult asthma has been defined as a disease that causes severe, life-threatening attacks or frequent hospitalization, or requires chronic corticosteroid use. More recently, the definition has been expanded to include patients with asthma who cannot be controlled on maximal doses of inhaled medications (1–3). Approximately 5% of patients with asthma have disease that is difficult to control despite taking maximally recommended doses of inhaled medications—in particular, inhaled corticosteroids. Most of these patients meet the criteria for severe asthma, but patients with “difficult asthma” may have chronic mild or moderate disease with severe acute exacerbations. Although patients with difficult or therapy-resistant asthma are in the minority, they account for a large share of the indirect and direct costs related to asthma care and consume a disproportionate amount of physician time and resources.

(Received in original form October 24, 2005; accepted in final form October 25, 2005) Correspondence and requests for reprints should be addressed to Mary E. Strek, M.D., Department of Medicine, MC 6076, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637. E-mail: [email protected] Proc Am Thorac Soc Vol 3. pp 116–123, 2006 DOI: 10.1513/pats.200510-115JH Internet address: www.atsjournals.org

IS IT ASTHMA? Patients with therapy-resistant or difficult-to-control asthma require a rigorous and systematic approach to their diagnosis and treatment. The first step in the care of these patients is evaluation and testing directed at determining that asthma is the correct diagnosis. When approaching these patients, it is helpful to remember the definition of asthma as outlined by the National Asthma Education and Prevention Program Expert Panel Report (4), which includes episodic respiratory symptoms, reversible airflow obstruction, increased airway hyperreactivity, and airway inflammation (Table 1). Asthma is suggested by the characteristic history of recurrent episodes of wheezing, breathlessness, chest tightness, and/or cough, especially at night or in the early morning. When possible, documentation of reversible airflow obstruction is extremely helpful. In patients with a history of asthma but normal lung function, methacholine challenge testing can help confirm or rule out the diagnosis of asthma. Although not routinely evaluated, sputum and peripheral blood eosinophilia lend support to the diagnosis of asthma. A therapeutic response to asthma therapy with improved symptoms and lung function confirms the diagnosis. Findings in the medical history that increase the likelihood that asthma is the correct diagnosis include the following: patient symptoms worsen after exposure to allergens, irritants, or exercise; the patient has allergic rhinitis or atopic dermatitis; or the patient has a family history of asthma, allergy, or sinus disease. The likelihood that nonspecific respiratory symptoms are due to asthma is increased if they occur in the early morning or awaken the patient at night. A large-population study of nearly 8,000 patients with asthma in the United Kingdom demonstrated that 74% awakened at night at least once per week and 64% reported awakening at least three times per week with symptoms of asthma (5). This was despite the fact that nearly half (48%) of these patients were on inhaled corticosteroids. The certainty that asthma is the correct diagnosis is increased when either clinic spirometry or pulmonary function tests demonstrate airflow obstruction that improves significantly, defined as both a 12% and 200-ml improvement in either FEV1 or FVC in response to inhaled bronchodilator. The greater the improvement and closer to normal the lung function becomes, the more likely the diagnosis is asthma and not chronic obstructive pulmonary disease (COPD) or other cause of obstructive lung disease. In patients with difficult asthma of some duration, airflow obstruction may be persistent and reversibility may not occur acutely in response to inhaled short-acting ␤-agonist therapy. Serial spirometry over time may demonstrate improvement in airflow obstruction corresponding to augmented asthma therapy. In some cases, peak expiratory flow (PEF) monitoring may demonstrate decreased flows in response to real-life triggers, with increased flows after treatment. A minority of patients with difficult asthma have normal lung function yet have typical asthma symptoms that fail to respond to escalating asthma therapy, or have apparent life-threatening asthma attacks prompting maximal medical therapy. In these patients, a methacholine challenge test is especially useful (6). The PC20 (provocative concentration causing a 20% fall in FEV1)

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TABLE 1. CHARACTERISTICS OF ASTHMA AND THEIR CLINICAL CORRELATES Characteristics Episodic respiratory symptoms Reversible airflow obstruction Increased airway hyperreactivity Airway inflammation

Clinical Correlate Recurrent wheezing, breathlessness, chest tightness, and/or cough, especially at night Decreased FEV1 or PEF with improvement acutely after bronchodilator or over time with treatment Positive bronchial provocation study to methacholine, histamine, or exercise Sputum or blood eosinophilia Bronchoscopy with endobronchial biopsy showing typical changes of asthma (in research settings)

Definition of abbreviation: PEF ⫽ peak expiratory flow.

value is determined. American Thoracic Society guidelines suggest the following categorization of test results. Normal bronchial responsiveness is indicated by a PC20 of greater than 16 mg/ml; borderline bronchial hyperresponsiveness is present when the PC20 is between 4.0 and 16 mg/ml, with a positive test defined as a PC20 of less than 4.0 mg/ml. A negative study excludes asthma with a high degree of certainty. A positive study confirms that abnormal airway reactivity is present but does not definitively diagnose asthma because atopy, upper respiratory infection, COPD, bronchiectasis, sarcoid, and congestive heart failure have all been reported to cause bronchial hyperresponsiveness. The pretest probability of asthma can improve the positive predictive value of the methacholine challenge test (Figure 1). If the pretest probability is very low (no symptoms, thus similar to the 5–7% prevalence of asthma in the general population), even with a positive methacholine challenge test (PC20 ⬍ 1.0 mg/ml) asthma is not likely. However, if a patient has symptoms suggestive of asthma, the pretest probability is higher (i.e., pretest probability of ⵑ 30–70%) and a methacholine challenge test is very helpful to rule in or out asthma. In this group of patients, a PC20 of 1 mg/ml means the posttest likelihood of asthma is approximately 90 to 98%, whereas the negative predictive power is more than 90%.

Many diseases present with respiratory symptoms that mimic asthma and may be associated with airflow obstruction (Table 2). These include the following: COPD; bronchiectasis and cystic fibrosis; constrictive bronchiolitis; sarcoid; congestive heart failure, including diastolic dysfunction; upper airway obstruction; aspiration or inhaled foreign body; neuromuscular weakness; or a mitochondrial disorder (7–9). Vocal cord dysfunction and hyperventilation/panic disorder can both mimic asthma and occur in conjunction with asthma (10, 11). Primary bronchiolar disorders, including constrictive bronchiolitis, also known as bronchiolitis obliterans, may be an underrecognized cause of minimally reversible obstructive lung disease (7). It may follow a respiratory infection, inhalational injury, or medication use, be associated with a systemic inflammatory disorder such as connective tissue or inflammatory bowel diseases, or be seen in allograft recipients after heart-lung, lung, or bone marrow transplants. Patients report cough and worsening dyspnea. Constrictive bronchiolitis is suggested by progressive airflow obstruction with minimal response to bronchodilators. The diffusing capacity is often reduced. High-resolution chest computed tomography (CT) scan shows mosaic or multilobar areas of decreased attenuation and vascularity and air trapping that is accentuated on expiratory views and may show peripheral cylindric bronchiectasis. Heterogeneity of lung density (mosaic attenuation) may be seen due to decreased perfusion of areas with bronchiolar obstruction and blood flow redistribution to normal areas. These findings are not specific for constrictive bronchiolitis, and some of them may be seen in asthma, but they suggest the diagnosis in the appropriate clinical setting. Constrictive bronchiolitis tends to be progressive and poorly responsive to corticosteroids. Immunosuppressive therapy can be of benefit in selected cases. Both sarcoidosis and asthma are more prevalent in AfricanAmerican patients. Cough, chest tightness, dyspnea, and even wheezing may be reported in patients with sarcoid. Although some patients with sarcoid may also have asthma, there is evidence to suggest that sarcoid is associated with airflow limitation and in some cases may be mistaken for asthma. An obstructive component is present in at least one-third of patients with pulmonary parenchymal involvement from sarcoid (8). A study of over 100 patients with newly diagnosed sarcoidosis found that airflow obstruction manifest by a decreased FEV1/FVC ratio was the most common physiologic abnormality. As noted above,

TABLE 2. DISEASES THAT MIMIC ASTHMA Figure 1. Curves illustrating pretest and posttest probability of asthma after a methacholine challenge test with four PC20 values. The curves represent a compilation of information, are approximations to illustrate principles of decision analysis, and are not intended to calculate precise posttest probabilities in patients. Reprinted by permission from Reference 6.

• Chronic obstructive pulmonary disease • Bronchiectasis and cystic fibrosis • Primary bronchiolar disorders • Congestive heart failure, including diastolic dysfunction

• • • • • •

Upper airway obstruction Aspiration or inhaled foreign body Neuromuscular weakness Mitochondrial disorder Vocal cord dysfunction Hyperventilation/panic disorder

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increased bronchial responsiveness with a positive methacholine challenge test has been noted in some patients with sarcoid. These patients may benefit from treatment of the airflow limitation with bronchodilators and corticosteroids by inhalation. Airflow obstruction may be associated with increased pulmonary vascular pressures without obvious pulmonary edema (9). Decreased expiratory flow rates and FEV1 and FVC that improve with diuresis have been noted in acute heart failure (9, 12). As noted above, increased bronchial responsiveness is also seen in heart failure. Some asthma therapy may worsen diastolic dysfunction by increasing heart rate, thus decreasing filling time. Elevated plasma brain natriuretic peptide, produced in response to ventricular strain or stretch, may aid in the diagnosis of congestive heart failure and is also elevated in diastolic dysfunction. Vocal cord dysfunction or “pseudo-asthma” is characterized by the paradoxical inspiratory closure of the vocal cords, resulting in a functional upper airway obstruction. This inspiratory flow limitation causes wheezing, stridor, shortness of breath, and exertional dyspnea. These patients are frequently misdiagnosed with asthma that is difficult to control with the need for frequent acute care and emergency room visits. The acute presentation can even lead to intubation for perceived status asthmaticus or acute upper airway obstruction. Considerable morbidity occurs from these patients receiving large doses of asthma medications, including oral corticosteroids. Symptoms may be absent at rest and only induced by exercise (11). Spirometry can show decreased flows depending on patient effort and vocal cord function, but expiratory flow limitation is often absent. Careful inspection of the flow-volume loop often shows suboptimal effort on forced expiratory curves with reduced inspiratory flows and flattening or truncation of the inspiratory limb suggestive of this diagnosis (1). In a recent study, 60% of patients with vocal cord dysfunction had changes in the flow-volume loop after methacholine (11). Direct laryngoscopic visualization confirms the paradoxical vocal cord movement but this may only be present after challenge with exercise or methacholine. Up to onethird of these patients may also have asthma, which can make recognition of vocal cord dysfunction problematic (1). Management of these patients is difficult, with some patients responding to reassurance, speech therapy, and as-needed ␤-agonist use. Anxiety disorders and panic attacks may be mistaken for asthma. In this setting, both pulmonary function tests and methacholine challenge tests will be normal (10). Asthma is often associated with anxiety and panic. From 6 to 30% of patients with asthma meet the criteria for panic disorder. Among patients with asthma, increased panic and anxiety are associated with the use of more intensive corticosteroid regimens, overuse of bronchodilators, and more frequent hospitalizations regardless of the objective lung function. Sometimes patients have asthma that is difficult to control because it is associated with another undiagnosed or untreated illness that worsens asthma, such as allergic bronchopulmonary aspergillosis, eosinophilic pneumonia, Churg-Strauss syndrome, ␣1-antitrypsin deficiency, carcinoid syndrome, thyrotoxicosis, or obstructive sleep apnea that requires additional or specific therapy (Table 3). Obesity is associated with asthma, especially in women (13).

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Awareness of the complete differential diagnosis of asthma allows a consideration of other diagnostic possibilities based on the appropriate clinical setting. The minimum evaluation of the patient with difficult-to-control asthma includes the following: complete blood count with eosinophil count, serum total IgE level, chest radiograph, a full set of pulmonary function tests with both careful inspection of the inspiratory and expiratory flow–volume loop and reversibility testing, and home PEF monitoring. If clinically indicated, a methacholine challenge test, chest CT scan, fiberoptic bronchoscopy, echocardiogram, sleep study, sweat test, plasma brain natriuretic peptide, sputum for eosinophil count and culture, serum IgE for aspergillus, ␣1-antitrypsin levels, sedimentation rate, antineutrophil cytoplasmic antibodies and thyroid function tests should be performed.

TRIGGERS The second step is to identify and eliminate triggers that worsen asthma (Table 4). These include cigarette smoking and crack cocaine use, allergens such as dust mites, cats or cockroaches, and medications such as aspirin, nonsteroidal antiinflammatory drugs, ␤-blockers, and perhaps, in a small minority of patients, angiotensin-converting enzyme inhibitors. Occupational asthma, premenstrual worsening of asthma in women, and stress may be underrecognized contributors to difficult-to-control asthma. There is strong evidence for uncontrolled allergic rhinitis and sinus disease as a cause of asthma worsening, less so for gastroesophageal reflux disease (GERD). Cigarette smoking is both a trigger to acute asthma attacks and a cause of refractoriness to current asthma medications. In adults presenting to emergency departments with acute asthma, 35% were cigarette smokers whereas 13% had urine cocaine tests that were positive (14, 15). The response to 40 mg/d prednisolone for 2 wk was significant in never-smokers with asthma, whereas active smokers with asthma did not have an improvement in FEV1, daily PEF, or symptom score (16). Environmental triggers may play an important role in some patients. In a study of patients with severe asthma, all 28 had skin tests positive to at least one of the following antigens: dust mite, dog, or cat; in addition, 20 of 28 patients were positive to all three compared with a much lower rate of allergen positivity in patients with mild asthma (17). Exposure to these allergens was greater in both living and bedroom dust analysis, except for bedroom cat antigen, in those with severe asthma compared with mild asthma. Occupational asthma should be considered, especially in patients with adult-onset asthma where it accounts for 9 to 15% of all cases of adult asthma (18, 19). In addition, preexisting asthma may be worsened by irritants inhaled at work. More than 300 agents have been reported to cause occupational asthma. The diagnosis should be confirmed by objective testing for asthma and by establishing the relation between asthma and work. This includes a compatible history and the presence of variable airflow obstruction, or if lung volumes are normal, demonstration

TABLE 4. ASTHMA TRIGGERS TABLE 3. DISEASES ASSOCIATED WITH ASTHMA • • • • •

Allergic bronchopulmonary aspergillosis Eosinophilic pneumonia Churg-Strauss syndrome ␣1-Antitrypsin deficiency Vocal cord dysfunction

• • • • •

Hyperventilation/panic disorder Carcinoid syndrome Thyrotoxicosis Obstructive sleep apnea Obesity

• • • • • • • •

Cigarette smoking and cocaine use Medications (aspirin, nonsteroidal antiinflammatory medications, ␤-blockers) Dust mites, cats, cockroaches Occupational agents Premenstrual worsening Stress Upper airway disease Gastroesophageal reflux disease

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of bronchial hyperreactivity to methacholine or histamine. Improved outcome is noted with removal of the patient from the exposure and treatment with inhaled corticosteroids (18). A recent study in France demonstrated that significant associations were observed between severe adult-onset asthma and exposure to any occupational asthmogen (19). Thus, a careful and detailed occupational history is important in the patient with difficult asthma. Recent studies suggest that hormonal factors may play a role in the development and severity of asthma in women (20–22). In a cohort study of hormone replacement therapy, postmenopausal women who were never-users of replacement hormones had a decreased risk of asthma, whereas both past and current hormone use increased the risk of asthma significantly (average, 1.50), with risk increasing with greater length (⬎ 10 yr) and dose of therapy (20). Asthma severity is associated with increased body mass index in women, with the association between body mass index and severity stronger in women with early menarche (21). In one study, 50% of emergency room visits occurred during the perimenstrual phase (22). Perimenstrual asthma is defined by increased symptoms and fall in PEF 2 to 5 d before the onset of the menstrual cycle. The reasons this might occur are poorly understood but may relate to hormonally mediated changes in airway function or inflammation. In some patients, this asthma is mild, and responds to increased doses of inhaled corticosteroids, but in some patients, it is severe and corticosteroid resistant. Progesterone given in large doses parenterally has been reported to be effective (1). Stress and emotional factors may contribute to worsening asthma (23). As noted above, asthma and panic disorder frequently coexist, with a recent study suggesting that asthma was strongly associated with panic disorder (odds ratio, 4.0) and active asthma predicts subsequent panic disorder (odds ratio, 4.5) (24). A recent study of college students with mild asthma demonstrated increased eosinophilic airway inflammation in response to antigen challenge during final examination week (25). Benefit from psychotherapeutic interventions in these patients has been suggested by some, but not all, studies and breathing exercises may benefit those with an abnormal breathing pattern (26). Epidemiologic studies suggest that asthma and rhinitis coexist in the same patient, with rhinitis noted in 75 to 80% of patients with asthma (27). The upper and lower airway may be considered as one entity influenced by a common inflammatory pathway. Allergic rhinitis is a risk factor for both the development and severity of asthma. Treatment of rhinitis may improve asthma control. Oral antihistamines are first-line therapy for allergic rhinitis and may modestly improve asthma symptoms but have no effect on pulmonary function tests. Intranasal corticosteroids are more effective than antihistamines in improving asthma control in the setting of upper airway disease, with both asthma symptoms and lung function improved in some studies (27). Oral corticosteroids are highly effective in the treatment of both upper and lower airway disease. Leukotriene modifiers when given with oral antihistamines have been shown to improve PEF in patients with asthma and seasonal allergic rhinitis (28). GERD is associated with asthma but its contribution to difficult or therapy-resistant asthma is less clear. A greater prevalence of gastroesophageal reflux symptoms and reflux-associated respiratory symptoms were noted in patients with asthma as compared with control subjects (29). A more recent study of patients with difficult-to-control asthma showed that, although GERD is common, treatment did not relate to improvement in asthma control (30). Some authors have suggested that higher doses of proton pump inhibitors for prolonged periods may be

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required, while noting that response to this intense therapy is often disappointing (1). The minimum evaluation of triggers in the patient with difficultto-control asthma includes a thorough medication, drug and cigarette smoking, occupational, environmental, and, in women, menstrual history. Asking the patient to keep an asthma diary tracking asthma symptoms, ␤-agonist use, and PEF monitoring in relation to work and menstrual cycle may be useful in selected patients. In many patients, allergy testing, a sinus CT scan, and ears-nose-throat evaluation may help identify and treat allergic triggers of rhinitis and asthma. Once identified, removal and treatment of triggers, as discussed above, is in order.

TREATMENT Most patients with difficult asthma meet the U.S. National Asthma Education and Prevention Program guidelines criteria for step 4, severe, persistent asthma (Figure 2), and require highdose inhaled corticosteroids and long-acting inhaled ␤2-agonists as therapy (31). Despite this aggressive therapy, these patients will require either frequent bursts or chronic daily therapy with oral corticosteroids. Corticosteroids have numerous beneficial effects in asthma on both inflammatory and structural cells (Figure 3). They address most of the causes of airflow obstruction in asthma, including airway smooth muscle contraction, mucosal edema, airway inflammation, increased mucus secretion, and perhaps airway remodeling. Corticosteroids decrease the number of eosinophils, mast cells, and dendritic cells in the airway. They decrease cytokine production from T lymphocytes and macrophages. They decrease cytokine and mediator production from epithelial cells, decrease vascular leak from endothelial cells, up-regulate ␤2receptors on airway smooth muscle, and decrease mucus gland secretion (32). There is considerable evidence to suggest that many patients with difficult asthma have “resistant” inflammation, with a persistent inflammatory state in the airway as demonstrated by both studies of airway inflammation in asthma after treatment and studies showing improvement in asthma control in response to augmented therapy with systemic corticosteroids (33, 34). This was confirmed in a recent double-blind, placebo-controlled study of the effects of high-dose intramuscular corticosteroids on airway inflammation and lung function in patients with stable severe asthma (34). All patients were using high doses of inhaled corticosteroids and had at least one course of oral corticosteroids during the past year or 5 mg or more of oral prednisone daily. For inclusion in the study, the baseline percentage of eosinophils in induced sputum had to be 2% or more. After treatment with one intramuscular injection of 120-mg long-acting triamcinolone or placebo, the investigators measured sputum eosinophil count, Borg score, post-bronchodilator FEV1, exhaled nitric oxide, and rescue medication use. They noted decreased airway inflammation in the corticosteroid-treated group with no sputum eosinophils in 82% of patients versus no change in the placebo group. The decreased airway inflammation was associated with significantly improved asthma control. Rescue medication use decreased and FEV1 improved from a median of 73.8 to 88.3% predicted. This likely does not apply to all patients with difficult asthma because not all patients have asthma characterized by sputum eosinophilia (see below). Patients with difficult asthma should receive maximal doses of inhaled corticosteroids (Figure 2). There is evidence that regular use of inhaled corticosteroids in general is associated with decreased risk of death from asthma (35). High-potency inhaled corticosteroids, such as budesonide, fluticasone, and mometasone, will require less puffs of medication to achieve high-dose therapy

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Figure 2. Current treatment recommendations for patients with severe asthma based on U.S. National Asthma Education and Prevention Program guidelines. PEF ⫽ peak expiratory flow. Drawing courtesy of Dr. Steven White, University of Chicago, Chicago, IL.

and may improve compliance (31). Education regarding correct inhaler technique and spacer devices with metered-dose inhalers is essential. Administration of calcium and vitamin D and monitoring of bone mineral density should be done in patients requiring high-dose inhaled and systemic corticosteroid therapy. Preventative therapy should be prescribed for patients with osteopenia. Regular long-acting and as-needed short-acting ␤2-agonist use is recommended for patients with severe persistent asthma (31). ␤2-Agonists act mainly to cause bronchodilation but may also decrease mast cell mediator release, plasma exudation, and cholinergic transmission, and improve mucociliary clearance (Figure 4). The effects of corticosteroids and bronchodilators on airflow obstruction may be additive (36). The long-acting ␤2-agonists formoterol and salmeterol both have substantially less intrinsic activity compared with the strong ␤-agonist isoproterenol; nonetheless, they are both very efficacious in the treatment of asthma (37). Numerous studies have documented that the addition of salmeterol or formoterol to inhaled corticosteroid therapy improves asthma control more than increasing or doubling the dose of corticosteroids (38, 39). Clinical studies comparing these agents directly, as well as further elucidation of the pharmacogenetics of the response to ␤-agonist, are needed. Additional therapy is typically needed in patients with difficult asthma to either control their disease or prevent the need for systemic corticosteroid therapy. A number of medications

have been tried, including leukotriene modifiers, anti-IgE therapy, and methotrexate. Numerous studies indicate that compliance with asthma therapy is poor and contributes to difficultto-control asthma. The leukotriene modifier montelukast decreases airway eosinophilic inflammation and improves asthma control in adult patients with persistent asthma (40, 41). Four weeks of therapy with montelukast decreased sputum and blood eosinophil counts, asthma symptoms, and ␤2-agonist use while significantly increasing morning PEF (40). Leukotriene modifiers may be particularly beneficial in patients with aspirin sensitivity where leukotriene production is typically increased. In patients with allergic asthma and an elevated IgE level, administration of the monoclonal antibody against IgE, omalizumab, can result in decreased airway inflammation and improved asthma control and may allow tapering of corticosteroid medications (42, 43). The dose and frequency of injections are determined by serum IgE level and weight. This medication is given subcutaneously every 2 or 4 wk. Treatment for a minimum of 12 wk is recommended before assessing the response. The most serious adverse effects include anaphylaxis (⬍ 0.1%) and malignancies (0.5% in omalizumab-treated patients vs. 0.2% in placebo group) (43). Methotrexate, gold, and cyclosporine have been proposed as steroid-sparing agents in patients with difficult asthma, with methotrexate the best studied of these potentially toxic agents.

Figure 3. Potential effects of corticosteroids on inflammatory and structural cells in asthma. Reprinted by permission from Reference 32.

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Figure 4. Potential effects of inhaled ␤2-agonists on airways. Their major action is in directly relaxing airway smooth muscle of large and small airways, but they may also act on ␤2-recptors of other airway cells. Infiltrating inflammatory cells also have ␤2-recptors but are rapidly desensitized by ␤2-agonists so that there are no persistent antiinflammatory effects. Reprinted by permission from Reference 32.

Although a meta-analysis of low-dose methotrexate use in corticosteroid-dependent patients with asthma suggested a steroid-sparing effect, careful analysis of two of the most rigorously performed studies does not show a benefit (44–46). A randomized, placebo-controlled, double-blind study of 19 patients with corticosteroid-dependent asthma compared methotrexate with single, high-dose intramuscular triamcinolone versus placebo (46). The group that received triamcinolone had a 40% mean improvement in FEV1, with no change in the groups treated with methotrexate or placebo. Emergency room visits and hospitalizations were greatly reduced in the triamcinolonetreated group, with the methotrexate-treated group having as many emergency room visits as the placebo-treated group. Numerous studies also suggest that compliance with asthma medications is poor. A study of treatment patterns among adult patients with moderate or severe asthma showed that 16% of users of inhaled ␤-agonists reported overuse and 64% of users of inhaled corticosteroids reported underuse (47). A prospective cohort study of patients hospitalized for asthma exacerbations showed that electronically measured adherence to both inhaled and oral corticosteroids dropped to approximately 50% within 7 d of discharge. Poor adherence was correlated with significantly worse symptom control (48). The benefit of therapy for asthma will be greatly improved if compliance with or adherence to a medication regimen is followed. A recent study of adherence to asthma controller medication regimens showed greater compliance when patients were given fluticasone and salmeterol in a single inhaler compared to fluticasone and salmeterol in separate inhalers (49). Suggested strategies for improving adherence include the following: identifying poor adherence; emphasizing the benefits of therapy; providing simple, clear instructions; customizing therapy based on patient’s wishes; and prescribing long-acting medications when possible (50).

PHENOTYPES OF ASTHMA Emerging evidence suggests that there may be different phenotypes of difficult or therapy-resistant asthma (51). These include corticosteroid-dependent asthma, glucocorticoid-resistant asthma, brittle or explosive asthma, and asthma with severe, irreversible airflow obstruction (52–54). Patients with corticosteroid-dependent asthma are the most common. A very small subset of patients are truly corticosteroid resistant and do not benefit from continued administration of systemic corticosteroids. A formal trial of

40 mg/d prednisone for 2 wk (or injection of long-acting intramuscular triamicinalone) is required to assess this. Patients with brittle or explosive asthma require a prescription for and instruction on the use of subcutaneous injection of epinephrine (EpiPen) to prevent acute severe attacks that develop abruptly (53). A very small number of patients with difficult asthma may have irreversible airflow obstruction. Recognition of this subgroup will prevent overmedication in an attempt to normalize lung function. Two cases from my practice illustrate these phenotypes. The first case is a 55-yr-old African-American woman who is a lifelong nonsmoker with asthma since infancy. Her course was notable for frequent hospitalizations and emergency room visits for explosive asthma attacks. Despite this, she has never required intubation. She is unable to taper methylprednisolone below 48 mg/d without having more frequent asthma attacks. She notes typical asthma symptoms of wheezing, cough, and chest tightness in response to typical asthma triggers of cold air, hot weather, fumes, and upper respiratory infections. She does not have allergies or sinus disease. Over the years she has developed significant GERD, weight gain, and cataracts. Her family history is notable for a grandfather, father, brother, and aunt who had all died of asthma. She has more than 100 family members with asthma. Her medications include 48 mg/d methylprednisoline, fluticasone/salmeterol combination inhaler, albuterol, omeprazole, and calcium. On examination, she is mildly cushingoid. She has mild central wheezing anteriorly over her throat in both inspiration and expiration. On lung examination, she has mild expiratory wheezing. Spirometry shows an FEV1 of 1.58 L (65% predicted) and an FVC of 2.31 L (71% predicted) with scooping of the expiratory limb of the flow volume loop. Is it asthma? Over the years, there has been well-documented airflow obstruction with FEV1 of less than 1.0 L during acute asthma attacks, with significant improvement after nebulized albuterol and further improvement after prednisone. There is clinical evidence for vocal chord dysfunction, although direct laryngoscopy has not confirmed this and there is no upper airway obstruction. Breathing exercises have been prescribed and asthma therapy is adjusted upward based on reduced FEV1, not symptoms alone. Associated with the weight gain from corticosteroids, the patient has developed obstructive sleep apnea for which she uses noninvasive mask ventilation. Chest CT scan has not shown bronchiectasis and she does not have Churg-Straus syndrome.

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Allergy testing and sinus CT scan are negative. There are no pets at home. She does not smoke, use drugs, or take aspirin. She is a nurse without identified occupational exposures. Aggressive evaluation and treatment of GERD have not made her asthma easier to control. In addition to oral corticosteroids and combination therapy with an inhaled corticosteroid and long-acting ␤2-agonist, she is taking a leukotriene modifier. She has a normal IgE, so antiIgE therapy is not an option. She is seen weekly to monthly with frequent discussions about the need for compliance. For sudden, severe, life-threatening attacks, she has been prescribed an EpiPen. Thus, this patient with difficult asthma has familial asthma that is both corticosteroid-dependent and brittle. The fact that she requires such high doses of oral corticosteroids for control of her asthma suggests that she may have an element of corticosteroid resistance as well. The second case is a 55-yr-old white man who presented with severe, persistent asthma requesting to be in an asthma clinical research study. He is a lifelong nonsmoker with eczema since infancy and asthma since age 3 yr. He has never required hospitalization or intubation but has required oral corticosteroids since childhood to control his asthma. He currently noted wheezing and chest tightness on minimal exertion. His medications included flunisolide metered-dose inhaler, salmeterol metereddose inhaler, oral theophylline, and inhaled albuterol. His examination showed a short man in no distress. Lung examination revealed quiet breath sounds with a prolonged expiratory phase. He was not clubbed. Spirometry showed an FEV1 of 0.60 L (25% predicted) and an FVC of 1.2 L (40% predicted). There was no response to nebulized albuterol. Pulmonary function tests showed severe obstructive lung disease with air trapping and no response to inhaled bronchodilator. The diffusing capacity was normal. To investigate a phenotype of corticosteroid-resistant asthma, a trial of 60 mg/d oral prednisone for 2 wk was begun. The patient returned without any improvement in symptoms or change in lung function, suggesting a phenotype of fixed airflow obstruction due to lifelong asthma. The patient was severely limited by his asthma and eventually had a lung transplantation, which improved his exercise ability. Pathology showed severe diffuse emphysema with focal interstitial fibrosis. This is consistent with a study of CT scans of the lungs in nonsmokers with asthma. There was a significant correlation between asthma severity and emphysema and linear shadows (55).

CONCLUSIONS As these cases illustrate, patients with difficult asthma challenge our current ability to treat this common disease. They consume a disproportionate amount of our time and resources and suffer morbidity and mortality from, what is for the majority of patients, a treatable and controllable disease. There is evidence that a rigorous and systematic approach to the evaluation and treatment of patients with difficult asthma is of benefit (3, 56, 57). In a recent study of patients with difficult asthma, alternate diagnoses were found in 12 of 100 patients; 7 had additional diagnoses. In only 55 patients could asthma definitely be confirmed. In a majority of these patients, asthma triggers could be identified; more than 50% had rhinosinusitis or nasal polyps. In 30%, a psychiatric component was noted. Nonadherence to oral corticosteroids was noted in half the patients taking them. New targeted therapy is especially needed to treat patients with difficult asthma. Conflict of Interest Statement : M.E.S. received the following as research grants for participating in multicenter clinical trials from 2002 to 2005: GlaxoSmithKline, $561,271; AstraZeneca, $33,718; Hoffman LaRoche, $41,980; Intermune,

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VOL 3 2006

$154,919; Genentech, $9,225; Merck, $165,383; SmithKline Beecham, $273,559; and Schering Plough, $115,959.

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