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National Asthma Education and Prevention Program, Third Expert Panel on the Diagnosis and Management of Asthma. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda (MD): National Heart, Lung, and Blood Institute (US); 2007 Aug.

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Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma.

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Section 4, Stepwise Approach for Managing Asthma in Youths ≥12 Years of Age and Adults

Treatment: Principles of Stepwise Therapy in Youths ≥12 Years of Age and Adults

The Expert Panel recommends that the goal of asthma therapy is to maintain control of asthma with the least amount of medication and hence minimal risk for adverse effects (Evidence A). Control of asthma is viewed in the context of two domains, impairment and risk, and is defined as:

  • ▪ Reducing impairment
    • — Prevent chronic and troublesome symptoms (e.g., coughing or breathlessness in the daytime, in the night, or after exertion)
    • — Require infrequent use (≤2 days a week) of SABA for quick relief of symptoms
    • — Maintain (near) normal pulmonary function
    • — Maintain normal activity levels (including exercise and other physical activity and attendance at work or school)
    • — Meet patients' and families' expectations of and satisfaction with asthma care
  • ▪ Reducing risk
    • — Prevent recurrent exacerbations of asthma, and minimize the need for ED visits or hospitalizations
    • — Prevent progressive loss of lung function; for youths, prevent reduced lung growth
    • — Provide optimal pharmacotherapy with minimal or no adverse effects

The stepwise approach to therapy, in which the dose and number of medications and frequency of administration are increased as necessary and decreased when possible, is used to achieve and maintain this control. This approach is illustrated in figure 4-5. Because asthma is a chronic inflammatory disorder of the airways with recurrent exacerbations, therapy for persistent asthma must emphasize efforts to suppress inflammation over the long term and to prevent exacerbations. Recommendations in the stepwise approach to therapy are based on the Expert Panel's review of the literature (See "Component 4: Medications.") and the Expert Panel's experience.

Figure 4-5

Figure 4-5

STEPWISE APPROACH FOR MANAGING ASTHMA IN YOUTHS ≥12 YEARS OF AGE AND ADULTS Notes:

The steps of care for managing asthma are presented in figure 4-5. Deciding which step of care is appropriate for a patient depends on whether long-term control therapy is being initiated for the first time or whether therapy is being adjusted. Care is stepped up to regain control, and it is stepped down for patients who have maintained control for a sufficient length of time to determine the minimal amount of medication required to maintain control and/or reduce the risk of side effects. The classification of asthma severity (figure 4-6), which considers the severity of both impairment and risk domains, provides a guide for initiating therapy for patients who are not currently taking long-term control medications. Once therapy is selected, or if the patient is already taking long-term control medication, the patient's response to therapy will guide decisions about adjusting therapy based on the level of control achieved in both the impairment and risk domains (See figure 4-7.).

Figure 4-6

Figure 4-6

CLASSIFYING ASTHMA SEVERITY AND INITIATING TREATMENT IN YOUTHS ≥12 YEARS OF AGE AND ADULTS Notes:

Figure 4-7

Figure 4-7

ASSESSING ASTHMA CONTROL AND ADJUSTING THERAPY INYOUTHS ≥12YEARSOFAGEANDADULTS Notes:

ACHIEVING CONTROL OF ASTHMA

Selecting Initial Therapy for Patients Not Currently Taking Long-Term Control Medications

The Expert Panel recommends the following actions to achieve asthma control in patients who are not currently taking long-term control medications.

  • ▪ Assess asthma severity (EPR—2 1997). Asthma severity is based on measurements of impairment and risk; see figure 4-6 and the discussion in "Component 1: Measures of Asthma Assessment and Monitoring."
  • ▪ Select treatment that corresponds to the patient's level of asthma severity (EPR—2 1997). See figure 4-6 for the recommended step of care at different levels of severity, and see figure 4-5 for treatment options at each step of care. See figures 4-8a, b, and c for usual dosages of medications. However, the clinician must also judge the individual patient's needs and circumstances to determine at what step to initiate therapy. For example, patients who have moderate or severe asthma that frequently interferes with sleep or normal activity often benefit from a course of oral corticosteroids to gain control of asthma more rapidly. Each patient's response to treatment must also be assessed.
  • ▪ If at a followup visit in 2–6 weeks after starting treatment, depending on severity, asthma is not well controlled (see below), then treatment should be advanced to the next step. If uncontrolled asthma persists, then the diagnosis should be reevaluated, and, if confirmed, treatment should be advanced another step (Evidence D).

Figure 4-8a

Figure 4-8a

USUAL DOSAGES FOR LONG-TERM CONTROL MEDICATIONS FOR YOUTHS ≥12 YEARS OF AGE AND ADULTS

Figure 4-8b

Figure 4-8b

ESTIMATED COMPARATIVE DAILY DOSAGES FOR INHALED CORTICOSTEROIDS FOR YOUTHS ≥12 YEARS OF AGE AND ADULTS Notes:

Figure 4-8c

Figure 4-8c

USUAL DOSAGES FOR QUICK-RELIEF MEDICATIONS FOR YOUTHS ≥12 YEARS OF AGE AND ADULTS

Adjusting Therapy

The Expert Panel recommends that, once therapy is selected, or if the clinician sees a patient for the first time who is already taking a long-term control medication, treatment decisions are based on the level of the patient's asthma control (See figure 4-7.) (Evidence A).

  • ▪ Assess asthma control. As in assessment of asthma severity, asthma control can be considered in terms of impairment and risk domains (Evidence C). Both domains should be addressed to select appropriate therapy; the level of control is generally judged on the most severe indicator of impairment or risk (Evidence D).
Impairment Domain

This domain is multifactorial because the different manifestations of asthma do not necessarily correlate with each other, and each factor should be assessed if possible (Evidence C).

Symptoms

Three types of symptom assessments each appear to provide unique information regarding asthma control: symptom frequency, nighttime awakening, and activity limitation (Fuhlbrigge et al. 2002; Nathan et al. 2004; Vollmer et al. 1999). Frequency of shortness of breath appears to be particularly related to asthma control (Nathan et al. 2004) and quality of life (Moy et al. 2001).

SABA use

Frequency of SABA use is a good measure of short-term (past month) (Nathan et al. 2004; Vollmer et al. 1999) and long-term (past year) asthma control (Schatz et al. 2006). Frequent use of SABA before exercise may confound these measures unless quick relief and prophylactic use can be separated.

Pulmonary function

Office spirometry (prebronchodilator) or home peak flow measures reflect control in treated patients (Bateman et al. 2004; Juniper et al. 1999, 2001). Pulmonary function measures may be poorly correlated with asthma symptoms (Shingo et al. 2001; Stahl 2000).

Validated questionnaires

Several validated tools have been developed to measure asthma control (Juniper et al. 1999; Nathan et al. 2004; Vollmer et al. 1999) and can be used to classify asthma control. (See "Component 1: Measures of Asthma Assessment and Monitoring," figure 3-8.)

Risk Domain

The risk domain includes frequency and severity of exacerbations and the occurrence of treatment-related adverse effects. Patients at any level of control of impairment may experience severe exacerbations. A history of previous exacerbations, especially exacerbations leading to ED visits or hospitalizations in the previous year, significantly increases the risk of subsequent exacerbations (Adams et al. 2000; Cowie et al. 2001; Eisner et al. 2001; Lieu et al. 1998; Schatz et al. 2004; Yurk et al. 2004). This highlights the need to obtain a history of previous exacerbations requiring hospitalization (including need for intensive care unit (ICU) admission or intubation), ED visits, and other unscheduled physician visits. In addition, increasing exacerbation rates are noted with decreasing FEV1 categories >80 percent, 60–79 percent, and <60 percent predicted (Fuhlbrigge et al. 2001, 2006; Kitch et al. 2004).

It is generally hoped that control of impairment will reduce the risk of exacerbations (Schatz et al. 2005; Vollmer et al. 1999), but there may be a disassociation between the two. It has been demonstrated that control based on bronchial hyperreactivity (Sont et al. 1999), sputum eosinophilia (Green et al. 2002), or possibly fractional exhaled nitric oxide (FeNO) (Smith et al. 2005) is more effective in reducing exacerbations than control based on clinical markers alone, but more studies are needed, and only FeNO monitoring may become practical enough to be used clinically for this purpose.

  • ▪ Adjust therapy based on level of asthma control (Evidence A). The following considerations will guide selection of therapy based on level of asthma control. Classify current level of asthma control, generally, by the most severe indicator of impairment or risk (figure 4-7) (Evidence D).
    • — If the patient's asthma is not well controlled:
      • ♦ Identify the patient's current treatment step (figure 4-5), based on what he or she is actually taking. In general, step up one step for patients whose asthma is not well controlled. For patients who have very poorly controlled asthma, consider increasing by two steps, a course of oral corticosteroids, or both. Before increasing pharmacologic therapy, consider poor inhaler technique, adverse environmental exposures, poor adherence, or comorbidities as targets for intervention.
      • ♦ If the office spirometry suggests worse control than does the assessment of impairment based on other measures, (1) consider fixed airway obstruction as the explanation (Aburuz et al. 2005) (See "Component 1: Measures of Asthma Assessment and Monitoring".), and use changes from percent personal best rather than percent predicted to guide therapy; (2) reassess the other measures of impairment; and (3) if fixed airway obstruction does not appear to be the explanation, consider a step up in therapy, especially if the patient has a history of frequent moderate or severe exacerbations.
      • ♦ If the history of exacerbations suggests poorer control than does the assessment of impairment, (1) reassess impairment; (2) review control of factors capable of making asthma worse (e.g., lack of adherence, adverse environmental exposure, or comorbidities); (3) review the written action plan, and be sure it includes oral prednisone for patients who have histories of severe exacerbations; and (4) consider a step up in therapy, especially if the patient has reduced FEV1.
      • ♦ For troublesome or debilitating side effects, explore a change in therapy. In addition, confirm maximal efforts to control factors capable of making asthma worse (See "Component 3: Control of Environmental Factors and Comorbid Conditions That Affect Asthma.").
      • ♦ After treatment is adjusted, reevaluate in 2–6 weeks, depending on the level of control.
    • — If the patient's asthma is well controlled, see the following section on "Maintaining Control of Asthma."

MAINTAINING CONTROL OF ASTHMA

The Expert Panel recommends that regular followup contact is essential (Evidence B). Contact at 1- to 6-month intervals is recommended, depending on the level of control; consider 3-month intervals if a step down in therapy is anticipated (Evidence D). Clinicians need to assess whether control of asthma has been maintained and whether a step up or down in therapy is appropriate. Clinicians also need to monitor and review the patient's written asthma action plan, the medications, and the patient's self-management behaviors (e.g., inhaler and peak flow monitoring techniques, actions to control factors that aggravate their asthma) (See "Component 2: Education for a Partnership in Asthma Care," figures 3-11 and 3-15.).

The Expert Panel recommends that, once asthma is well controlled and the control is achieved and maintained for at least 3 months, a reduction in pharmacologic therapy—a step down—can be considered. This will be helpful to identify the minimum therapy for maintaining good control of asthma (Evidence D). Reduction in therapy should be gradual and closely monitored, because asthma can deteriorate at a highly variable rate and intensity. The patient should be instructed to contact the clinician if and when asthma worsens. Guidelines for the rate of reduction and intervals for evaluation have not been validated, and clinical judgment of the individual patient's response to therapy is important. The opinion of the Expert Panel is that the dose of ICS may be reduced about 25–50 percent every 3 months to the lowest dose possible that is required to maintain control (Hawkins et al. 2003; Lemanske et al. 2001). Patients may relapse when the ICS is completely discontinued (Lemanske et al. 2001; Waalkens et al. 1993).

The Expert Panel recommends that, if asthma control is not achieved and maintained at any step of care (See figure 4-7.), several actions may be considered:

  • ▪ Patient adherence and technique in using medications correctly should be assessed (Evidence B). See "Component 2: Education for a Partnership in Asthma Care" for discussion on assessing adherence. Key questions to consider asking patients include:
    • — Which medicines are you currently taking? How often?
    • — Please show me how you take the medicine.
    • — How many times a week do you miss taking the medication?
    • — What problems have you had taking the medicine (cost, time, lack of perceived need)?
    • — What concerns do you have about your asthma medicines?
  • ▪ A temporary increase in anti-inflammatory therapy may be indicated to reestablish asthma control (Evidence D). A deterioration of asthma may be characterized by gradual reduction in PEF (approximately 20 percent), by failure of SABA bronchodilators to produce a sustained response, by a reduced tolerance to activities or exercise, and by the development of increasing symptoms or nocturnal awakenings from asthma. To regain control of asthma, a short course of oral prednisone (See figure 4-8a.) is often effective. If asthma symptoms do not recur and pulmonary functions remain normal, no additional therapy is necessary. However, if the prednisone burst does not control symptoms, is effective only for a short period of time (e.g., less than 1–2 weeks), or is repeated frequently, the patient should be managed according to the next higher step of care.
  • ▪ Other factors that diminish control may have to be identified and addressed (Evidence C). These factors include the presence of a coexisting condition (e.g., rhinitis/sinusitis, gastroesophageal reflux, obesity), a new or increased exposure to allergens or irritants, patient or family barriers to adequate self-management behaviors, or psychosocial problems. In some cases, alternative diagnoses, such as VCD, should be considered.
  • ▪ A step up to the next higher step of care may be necessary (Evidence A).
  • ▪ Consultation with an asthma specialist may be indicated (See "Component 1: Measures of Asthma Assessment and Monitoring.") (Evidence D). The Expert Panel recommends referral to an asthma specialist for consultation or comanagement if: there are difficulties achieving or maintaining control of asthma; immunotherapy or omalizumab is being considered; the patient requires step 4 care or higher; or the patient has had an exacerbation requiring a hospitalization. (See "Component 1: Measures of Asthma Assessment and Monitoring."). Referral may be considered if a patient requires step 3 care (Evidence D).

Treatment: Pharmacologic Steps

The Expert Panel recommends that specific therapy should be tailored to the needs and circumstances of individual patients. Pharmacologic therapy must be accompanied at every step by patient education and measures to control those environmental factors or comorbid conditions that can make asthma worse (EPR—2 1997). See "Component 3: Control of Environmental Factors and Comorbid Conditions That Affect Asthma" which includes discussion of the role of allergen immunotherapy, and "Component 2: Education for a Partnership in Asthma Care." Figure 4-5 presents treatment options for the stepwise approach for managing asthma youths ≥12 years of age and adults. The recommendations for steps of pharmacologic therapy are intended to be general guidelines for assisting, not replacing, clinical decisionmaking. The recommendations are not intended to be prescriptions for individual treatment.

INTERMITTENT ASTHMA

The Expert Panel recommends the following therapy for intermittent asthma:

Step 1 Care

  • ▪ SABA taken as needed to treat symptoms is usually sufficient therapy for intermittent asthma (EPR—2 1997). If effective in relieving infrequent symptoms and normalizing pulmonary function, intermittent use of SABA can continue on an as-needed basis. If significant symptoms recur or SABA is required for quick-relief treatment more than 2 days a week (with the exception of using SABA for exacerbations caused by viral infections and for EIB), the patient should be treated for persistent asthma (See below.).
  • ▪ Patients who have intermittent asthma and experience EIB benefit from taking SABA, cromolyn, or nedocromil shortly before exercise (EPR—2 1997) (See in "Exercise-Induced Bronchospasm" in "Managing Special Situations in Asthma."). Cromolyn or nedocromil may be beneficial if taken before unavoidable exposure to an aeroallergen known to exacerbate the patient's asthma (Cockcroft and Murdock 1987).
  • ▪ The following actions for managing exacerbations due to viral respiratory infections are recommended (EPR—2 1997). If the symptoms are mild, SABA (every 4–6 hours for 24 hours, longer with a physician consult) may be sufficient to control symptoms and improve lung function. If this therapy must be repeated more frequently than every 6 weeks, a step up in long-term care is recommended. If the viral respiratory infection provokes a moderate-to-severe exacerbation, a short course of systemic corticosteroids should be considered. For those patients who have a history of severe exacerbations with viral respiratory infections, systemic corticosteroids should be considered at the first sign of the infection.
  • ▪ A detailed written asthma action plan is recommended for those patients who have intermittent asthma and particularly those who have a history of severe exacerbations (Evidence B) (See "Component 2: Education for a Partnership in Asthma Care."). Intermittent asthma—infrequent exacerbations separated by periods of no symptoms and normal pulmonary function—is often mild. Some patients who have intermittent asthma experience sudden, severe, and life-threatening exacerbations. It is essential to treat these exacerbations accordingly. The patient's written asthma action plan should include indicators of worsening asthma (specific symptoms and PEF measurements), as well as specific recommendations for using SABA, early administering a course of oral systemic corticosteroids, and seeking medical care. Furthermore, periodic monitoring (See "Component 1: Measures of Asthma Assessment and Monitoring.") of the patient is appropriate to evaluate whether the patient's asthma is indeed intermittent or whether a stepup in long-term therapy is warranted.

PERSISTENT ASTHMA

The Expert Panel recommends the following therapy for persistent asthma:

  • ▪ Daily long-term control medication is recommended for patients who have persistent asthma. The long-term control medication should be one with anti-inflammatory effects. Of the available medications, ICSs are the most effective single agents (Evidence A) (see component 4—Medications).
  • ▪ Quick-relief medication must be available to all patients who have persistent asthma. SABA should be taken as needed to relieve symptoms (EPR—2 1997). The intensity of treatment will depend on the severity of the exacerbation (See section 5, "Managing Exacerbations of Asthma."). Increasing use of SABA or use more than 2 days a week for symptom control (not for preventing EIB) indicates the need to step up therapy.
  • ▪ Consider treating patients who may have seasonal asthma (asthma symptoms only in relation to certain seasonal molds or pollens with few symptoms the rest of the year) as having persistent asthma during the season and as having intermittent asthma the rest of the year. Confirm characteristics of intermittent asthma out of season (Evidence D). Some patients experience asthma symptoms only in relationship to certain pollens and molds. Asthma exacerbations in children are common in the fall and seem to correlate with increased exposure to viral respiratory infections in the school environment (Hammerman et al. 2002; Johnston et al. 2005).
  • ▪ Consider treating patients who had two or more exacerbations requiring oral corticosteroids in the past year the same as patients who have persistent asthma, even in the absence of an impairment level consistent with persistent asthma (Evidence D).

Step 2 Care, Long-Term Control Medication

  • ▪ Preferred treatment for step 2 care is daily ICS at a low dose (Evidence A).
  • ▪ Alternative, but not preferred, treatments include (listed alphabetically) cromolyn, LTRA, nedocromil (Evidence A), and sustained release theophylline (Evidence B). There is insufficient evidence to recommend LABA in combination with ICS for step 2 therapy.
    • — Cromolyn and nedocromil have some, but limited, effectiveness and a strong safety profile.
    • — LTRAs (montelukast and zafirlukast) provide long-term control, prevent symptoms, and are alternative, but not preferred, therapies for patients who have mild persistent asthma, because studies comparing overall efficacy of ICS and LTRA favor ICS on most asthma outcome measures (Evidence A). (See section 3, "Component 4: Medications.") Zileuton, a leukotriene inhibitor, is not recommended in step 2 care, because no studies of zileuton specifically in patients who have mild persistent asthma have been reported, and zileuton requires liver function test monitoring (Evidence D).
    • — Sustained-release theophylline is an alternative, but not preferred, long-term control medication. It is not preferred because the modest clinical effectiveness (theophylline is primarily a bronchodilator and its anti-inflammatory activity demonstrated thus far is modest) must be balanced against concerns about potential toxicity (See "Component 4: Medications."). Theophylline remains a therapeutic option for certain patients due to expense or need for tablet-form medication. Sustained-release theophylline is given to achieve a serum concentration of between 5 and 15 mcg/mL. Periodic theophylline monitoring is necessary to maintain a therapeutic—but not toxic—level.
    • — Insufficient evidence is available to recommend LABA in combination with ICS in step 2 care (O'Byrne et al. 2001). In steroid naïve patients who have mild persistent asthma, the initiation of an ICS in combination with a LABA does not significantly reduce the rate of exacerbations or the use of SABA for quick relief over that achieved with ICS alone, although the combination therapy can improve lung function and symptom days compared to ICS alone (Ni et al. 2005). Thus, there is insufficient efficacy evidence to recommend this combination therapy in step 2 care. In addition, the possibility of rare but potentially life-threatening outcomes with LABAs (See "Component 4: Medications.") supports this recommendation.
    • — A recent study has suggested that some patients who have mild persistent asthma may be successfully managed with intermittent use of low-dose ICS, because study participants taking daily budesonide, daily zafirlukast, or intermittent treatment with ICS and SABA (according to a symptom-based action plan) had similar improvement in morning PEF and a similarly low number of exacerbations (Boushey et al. 2005). However, other outcomes in this study were significantly better in patients taking regular versus intermittent ICS therapy (symptom-free days, prebronchodilator FEV1, airway hyperresponsiveness, and inflammatory markers). Currently, data are insufficient to recommend intermittent use of ICS for most patients who have mild persistent asthma, although it may be considered as a step-down therapy strategy for patients who are well controlled on step 2 therapy. Further studies are needed to evaluate the use of intermittent therapy with either ICSs or leukotriene modifiers.

Step 3 Care, Long-Term Control Medications

  • ▪ Consultation with an asthma specialist may be considered because the therapeutic options at this juncture pose a number of challenging risk/benefit considerations (Evidence D). Before increasing therapy, however, the clinician should review the patient's inhaler technique and adherence to therapy (Evidence B), as well as determine whether environmental factors, particularly allergens (Evidence A), or comorbid conditions are contributing to the patient's worsening asthma (Evidence C).
  • ▪ Preferred step 3 care options: Two equally acceptable options are available, given the consideration of both benefits and risks for each.
    • — Add a LABA to a low dose of ICS (Evidence A). Studies on LABAs as adjunctive therapy have revealed both benefit and some risk. See "Component 4: Medications," section on "Safety of Long-Acting Beta2-Agonists," for a complete discussion. In summary:
      • ♦ Studies demonstrate the addition of a LABA (salmeterol or formoterol) to medications for patients whose asthma is not well controlled on a low to medium dose of ICSs improves lung function, decreases symptoms, and reduces exacerbations and use of quick-relief medication in most patients who have asthma (Bateman et al. 2004; EPR—2 1997; Greenstone et al. 2005; Masoli et al. 2005). See also Evidence Table 11: Inhaled Corticosteroids—Combination Therapy.
      • ♦ A large clinical trial comparing daily treatment with salmeterol or placebo added to usual asthma therapy (Nelson et al. 2006) demonstrated an increased risk of asthma-related deaths in patients treated with salmeterol (13 deaths out of 13,176 patients treated for 28 weeks with salmeterol versus 3 deaths out of 13,179 patients treated with placebo). In addition, an increased number of severe asthma exacerbations were noted in the pivotal trials submitted to the FDA for formoterol approval, particularly in the higher dose formoterol arms of the trials (Mann et al. 2003). Thus the FDA determined that a Black Box warning was warranted on all preparations containing a LABA.
      • ♦ The Expert Panel recommends that the established, beneficial effects of LABAs for the great majority of patients who have asthma not sufficiently controlled with ICS therapy alone be weighed carefully against the increased risk for potentially deleterious, although uncommon, side effects associated with the daily use of LABAs.
      • ♦ Therefore, the Expert Panel has modified its previous recommendation (EPR—Update 2002) and has now concluded that, for patients who have asthma not sufficiently controlled with a low-dose ICS alone, the step-up option to increase the ICS dose should be given equal weight to that of the addition of a LABA to ICS.
    OR
    • — Continue the ICS as monotherapy by increasing the dose to the medium-dose range (Evidence A). Studies of adults in whom the dose of ICS was at least doubled demonstrate some improvements in lung function and other outcomes in those patients who have asthma not completely controlled on a low-to-medium dose of ICS, although these results are generally less effective than adding a LABA (Ind et al. 2003). In the GOAL study of 3,421 patients who had uncontrolled asthma, a substantial proportion of the patients who received a dose escalation of ICS achieved well-controlled (59 percent) or totally controlled (28 percent) asthma (Bateman et al. 2004). Furthermore, a study of 2,670 patients showed similar rates of exacerbations and nighttime awakenings among the daily medium-dose ICS and daily combination low-dose (ICS/formoterol) study treatment groups (O'Byrne et al. 2005). Both studies confirm the benefits of increasing the dose of ICS (see below for further discussion on weighing the benefits and risks of different step 3 care options).

Based on review of the evidence and in consideration of the potential benefits for improvements in the asthma control domains of impairment and risk, as well as consideration of the potential for adverse effects that exist for each therapeutic option, the Expert Panel recommends that either increasing the dose of the ICS to medium dose or adding LABA to low-dose ICS is an equally acceptable step-up option for patients whose asthma is not adequately controlled on a low dose of ICS.

Overall, the results of the Expert Panel's review of the evidence indicate that the choice one makes at this juncture of stepping up therapy should be based on which therapeutic outcome should be the focus for each individual patient: that is, the desired degree of asthma control in the domains of either impairment or risk, or both, weighed against the relative risks of side effects for the therapeutic options.

  • ▪ For the impairment domain, adding LABA, rather than increasing the dose of ICS, more consistently results in improvements in the impairment domain (EPR—Update 2002).
  • ▪ If the risk domain is of particular concern, then a balance of potential risks needs to be considered (See also "Component 4: Medications.").
    • — Adding LABA to low-dose ICS reduces the frequency of exacerbations to a greater extent than doubling the dose of ICS (Masoli et al. 2005), but adding LABA has the potential risk of rare life-threatening or fatal exacerbations.
    • — Increasing the dose of ICS can significantly reduce the risk of exacerbations, but this benefit may require up to a fourfold increase in the ICS dose (Pauwels et al. 1997). This may increase the potential risk of systemic effects, although within the medium-dose range the risk is small.
  • ▪ Alternative, but not preferred, step 3 therapy is to add (listed alphabetically) an LTRA (Evidence A), theophylline (Evidence B), or zileuton (Evidence D) to low-dose ICS.
    Considerations favoring one of these alternative combinations would be the patient's lack of response to or intolerance of the side effects of the LABA if that option was tried; marked preference for oral therapy; previous demonstration of superior responsiveness to the alternative class of drug; and/or financial considerations (theophylline is the least expensive).
    The addition of either LTRA, theophylline, or zileuton has produced modest improvement in lung function and some other outcomes in patients who have asthma that is not completely controlled by an ICS. The addition of theophylline, however, has not been shown to be more effective than doubling the dose of the ICS (Evans et al. 1997; Ukena et al. 1997). LTRAs have produced improvements in lung function and in some but not all measures of asthma control in both adults (Laviolette et al. 1999) and children (Simons et al. 2001) whose asthma is not well controlled by ICSs. When the addition of the LTRA to an ICS has been compared with doubling the dose of the ICS, similar results were observed for a number of outcome measures (Price et al. 2003). Direct comparisons of the addition of an LTRA or a LABA to therapy for patients whose asthma is not well controlled by ICS show significantly greater improvement in lung function and other measures of asthma control for patients receiving the LABA and ICS combination (Ram et al. 2005). Because efficacy data are limited for zileuton as add-on therapy (Dahlen et al. 1998; Lazarus et al. 1998), and zileuton requires monitoring of liver function tests, the Expert Panel considers zileuton a less desirable alternative than LTRA or theophylline for step 3 add-on therapy.
  • ▪ If an alternative, but not preferred, treatment is initially administered and does not lead to improvement in asthma control, discontinue it and use a preferred step 3 option before stepping up to step 4 (Evidence D).

Step 4 Care, Long-Term Control Medications

  • ▪ The preferred option is to increase the dose of ICS to the medium-dose range AND add a LABA (Evidence B). This step is recommended for patients who have asthma not controlled by step 3 therapy. This approach is also recommended for those patients who experience recurring severe exacerbations requiring oral prednisone, ED visits, or hospitalizations. In a 1-year trial of combination therapy, the addition of a LABA to either low-dose or high-dose ICS significantly reduced both mild and severe exacerbation (Pauwels et al. 1997). In addition, fewer exacerbations occurred in the group receiving high-dose ICS compared with the group receiving the lower dose, although statistical analysis was not done. See also the discussion on LABA and combination therapy in "Component 4: Medications."
  • ▪ Alternative, but not preferred, step 4 therapy includes medium-dose ICS AND either LTRA or theophylline (Evidence B), or zileuton (Evidence D).
  • ▪ If the add-on therapy initially administered does not lead to improvement in asthma control, discontinue it and consider a trial of a different add-on therapy before stepping up (Evidence D).

Step 5 Care, Long-Term Control Medications

  • ▪ High-dose ICS and LABA is the preferred treatment (Evidence B).
  • ▪ Omalizumab may be considered at this step for patients who have sensitivity to relevant perennial allergens (e.g., dust mites, cockroach, cat, or dog) (Evidence B) (Bousquet et al. 2004; Humbert et al. 2005).
  • ▪ Clinicians who administer omalizumab are advised to be prepared and equipped for the identification and treatment of anaphylaxis that may occur, to observe patients for an appropriate period of time following each omalizumab injection (the optimal length of the observation is not established), and to educate patients about the risks of anaphylaxis and how to recognize and treat it if it occurs (e.g., using prescription auto injectors for emergency self-treatment, and seeking immediate medical care) (FDA 2007).
  • ▪ Consultation with an asthma specialist is recommended for patients who require this step of therapy (Evidence D).

Step 6 Care, Long-Term Control Medications

  • ▪ Add oral corticosteroids to step 5 therapy. Patients who are not controlled on step 5 therapy may require regular oral corticosteroids to achieve well-controlled asthma (EPR—2 1997).
    • — Two studies have examined the benefit of LTRA as adjunctive therapy in patients who have asthma that is not controlled by ICS and LABA. One 2-week study found no benefit for the addition of an LTRA to high-dose ICS and, for most patients in the study, another medication (either theophylline, a LABA, oral corticosteroid, or a combination) (Robinson et al. 2001). Nathan et al. (2005) reported that adding montelukast for patients who had mild or moderate persistent asthma treated with combined fluticasone (100 mcg)–salmeterol did not improve asthma outcome compared to adding placebo. Studies are not available of other long-term control medications added to the combination of medium- to high-dose ICS and LABA in severe persistent asthma. These data are not definitive; therefore, due to the side effects associated with chronic oral corticosteroid therapy, before maintenance prednisone therapy is initiated, the following may be considered: a 2-week course of oral corticosteroids to confirm reversibility; or a combination of high-dose ICS + LABA + trial of either LTRA, low-dose theophylline, or zileuton (Evidence D).
    • — For patients who require long-term systemic corticosteroids:
      • ♦ Use the lowest possible dose (single dose daily or on alternate days).
      • ♦ Monitor patients closely for corticosteroid adverse side effects (See "Component 4: Medications.").
      • ♦ When well-controlled asthma is achieved, make persistent attempts to reduce systemic corticosteroids. High-dose ICS therapy is preferable to oral systemic corticosteroids because ICSs have fewer systemic effects.
      • ♦ Consultation with an asthma specialist is recommended.

SPECIAL ISSUES FOR ADOLESCENTS

The Expert Panel recommends that the pharmacologic management of asthma in school-age children and adolescents follows the same basic principles as those for adults, but the special circumstances of school and social development require special consideration (EPR—2 1997).

Assessment Issues

The Expert Panel recommends that pulmonary function testing should be performed by using comparison data from an appropriate reference population (ATS 1995; EPR—2 1997). Adolescents generally compare better to childhood norms than to adult predicted norms. Testing in a laboratory or clinic that specializes in children can result in higher pulmonary function values and more consistent data. Technicians who conduct pulmonary function testing for children should have special training in achieving the best possible effort from young patients.

Treatment Issues

The Expert Panel recommends that adolescents (and younger children as appropriate) be directly involved in developing their written asthma action plans (See "Component 2: Education for a Partnership in Asthma Care."). Adolescents may experience more difficulties than younger children in adhering to a medication plan because they may fail to recognize the danger of poorly controlled asthma (Strunk et al. 1985), they may not accept having a chronic illness, or they may view the plan as infringing on their emerging independence and adulthood. In teaching adolescents the same asthma self-management techniques expected of adults, the clinician should address adolescent developmental issues, such as building a positive self-image and confidence, increasing personal responsibility, and gaining problem-solving skills. To accomplish this approach, it is often helpful to see the adolescent initially without parents present and to involve the adolescent directly in setting goals for therapy, developing an appropriate asthma action plan, and reviewing the effectiveness of the plan at repeated visits. The parents can be brought in at the end of the visit to review the plan together and to emphasize the parents' important role in supporting the adolescent's efforts.

School Issues

The Expert Panel recommends that the clinician prepare a written asthma action plan for the student's school. Either encourage the youth or the parents to take a copy of the plan to the youth's school or obtain parental permission and send a copy to the school nurse or designee (Evidence C). The written asthma action plan should include the following information: instructions for handling exacerbations (including the clinician's recommendation regarding self-administration of medication); recommendations for long-term control medications and prevention of EIB, if appropriate; and identification of those factors that make the student's asthma worse, so the school may help the student avoid exposure. For a sample plan, See "Asthma Care," figure 3-21.

It is preferable to schedule daily, long-term medications so that they are not taken at school, even if this results in unequal dosing intervals throughout the day. In school districts that have more comprehensive school nurse coverage, however, youths who would benefit from close supervision to promote adherence may be given medications at school. In this way, daily medication can be administered, and patient education can be supplemented most days of the week.

Students who have asthma often require medication during school to treat acute symptoms or to prevent EIB that may develop during physical education class, school recess, or organized sports. Reliable, prompt access to medication is essential, but it may be difficult because of school rules that preclude the student from carrying medications. The NAEPP and several member organizations have adopted resolutions that endorse allowing students to carry and self-administer medications when the physician and parent consider this appropriate. It may be helpful for some children to have a compressor-driven nebulizer available at the school.

Sports Issues

The Expert Panel recommends that clinicians encourage full participation in physical activities; physical activity at play or in organized sports is an essential part of a child's life (EPR—2 1997). Many children who have asthma experience cough, wheeze, or excessive fatigue when they exercise. Treatment immediately before vigorous activity or exercise usually prevents EIB. If symptoms occur during usual play activities, a step up in long-term therapy is warranted. Poor endurance or EIB can be an indication of poorly controlled persistent asthma; appropriate use of long-term control medication can reduce EIB (See "Exercise-Induced Bronchospasm."). Activity should be limited or curtailed only as a last resort.

SPECIAL ISSUES FOR OLDER ADULTS

Assessment Issues

The Expert Panel recommends that the extent of reversible airflow obstruction be determined because of the high prevalence of other obstructive lung disease (e.g., chronic bronchitis, emphysema) among the elderly (EPR—2 1997). Careful evaluation is required, because the precise cause of severe airflow obstruction can be difficult to identify in older patients who have asthma. A 2- to 3-week trial of therapy with systemic corticosteroids can help detect the presence of significant reversibility of the airway disease. Long-term control asthma medication can then be offered.

Treatment Issues

The Expert Panel recommends that adjustments in therapy may be necessary because asthma medications may have increased adverse effects in the elderly patient (EPR—2 1997).

  • ▪ Airway response to bronchodilators may change with age, although this is not clearly established. Older patients, especially those with preexisting ischemic heart disease, may also be more sensitive to beta2-agonist side effects, including tremor and tachycardia. Concomitant use of an anticholinergic and a SABA may be beneficial to the older patient (Barros and Rees 1990; Gross et al. 1989; Ullah et al. 1981).
  • ▪ Theophylline clearance is reduced in elderly patients (Nielsen-Kudsk et al. 1988), causing increased blood levels of theophylline. In addition, age is an independent risk factor for developing life-threatening events from iatrogenic chronic theophylline overdose (patients 75 years of age or older have a 16-fold greater risk of death from theophylline overdose than do 25-year-old patients) (Shannon and Lovejoy 1990). The potential for drug interaction—especially with antibiotics and H2-histamine antagonists such as cimetidine—is greater because of the increased use of medications in this age group. Theophylline and epinephrine may exacerbate underlying heart conditions.
  • ▪ Systemic corticosteroids can provoke confusion, agitation, and changes in glucose metabolism.
  • ▪ Inhaled corticosteroid. Consider concurrent treatments with calcium supplements and vitamin D, and bone-sparing medications (e.g., bisphosphonates) in patients who have risk factors for osteoporosis or low bone mineral density (Evidence D). ICS use may be associated with a dose-dependent reduction in bone mineral content, although low or medium doses appear to have no major adverse effect. Elderly patients may be more at risk due to preexisting osteoporosis, changes in estrogen levels that affect calcium utilization, and a sedentary lifestyle. The risk of not adequately controlling asthma may limit unnecessarily the patient's mobility and activities (See "Component 4: Medications."). An approach for identifying patients at risk for accelerated bone loss from high-dose ICS therapy is to conduct bone densitometry when treatment begins and again 6 months later (NHLBI 1996), although the benefits of this approach have not yet been evaluated in clinical trials.

The Expert Panel recommends that medications taken for other diseases and conditions be adjusted as necessary, because some medications may exacerbate asthma (EPR—2 1997). Nonsteroidal anti-inflammatory agents for treating arthritis, beta-blockers for treating hypertension (particularly nonselective beta-blockers), or beta-blockers found in some eye drops used to treat glaucoma may exacerbate asthma. See "Component 4: Medications" for more details on drugs that can complicate asthma management.

The Expert Panel recommends that review of the patient's technique in using medications and devices is essential (Evidence B). Observation of technique for use of inhaler devices, peak flow meters, and spirometry is especially important in the elderly because physical (e.g., arthritis, visual) and cognitive impairments (recognized or unrecognized) can make acquisition and retention of proper technique difficult (Allen et al. 2003; Barr et al. 2002; Pezzoli et al. 2003; Wolfenden et al. 2002).

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