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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 . 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.

The steps of care for managing asthma are presented in . 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 (), 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 .).

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 ( Asthma severity is based on measurements of impairment and risk; see and the discussion in "Component 1: Measures of Asthma Assessment and Monitoring." ▪ Select treatment that corresponds to the patient's level of asthma severity ( See for the recommended step of care at different levels of severity, and see for treatment options at each step of care. See , , and 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).

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 .) (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).

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).

Three types of symptom assessments each appear to provide unique information regarding asthma control: symptom frequency, nighttime awakening, and activity limitation (; ; ). Frequency of shortness of breath appears to be particularly related to asthma control () and quality of life ().

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

Office spirometry (prebronchodilator) or home peak flow measures reflect control in treated patients (; , ). Pulmonary function measures may be poorly correlated with asthma symptoms (; ).

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

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 (; ; ; ; ; ). 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 FEV 1 categories >80 percent, 60–79 percent, and <60 percent predicted (, ; ). It is generally hoped that control of impairment will reduce the risk of exacerbations (; ), but there may be a disassociation between the two. It has been demonstrated that control based on bronchial hyperreactivity (), sputum eosinophilia (), or possibly fractional exhaled nitric oxide (FeNO) () 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 () (Evidence D). — If the patient's asthma is not well controlled: ♦ Identify the patient's current treatment step (), 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 () (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 FEV 1 . ♦ 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."

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 (; ). Patients may relapse when the ICS is completely discontinued (; ). The Expert Panel recommends that, if asthma control is not achieved and maintained at any step of care (See .), 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 .) 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).

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 (). 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." 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.

▪ SABA taken as needed to treat symptoms is usually sufficient therapy for intermittent asthma ( 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 () (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 ().

▪ The following actions for managing exacerbations due to viral respiratory infections are recommended ( 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.

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 (). 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 (; ).

▪ 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).

▪ 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 (). 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 (). 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 (). However, other outcomes in this study were significantly better in patients taking regular versus intermittent ICS therapy (symptom-free days, prebronchodilator FEV 1 , 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.

▪ 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 Beta 2 -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 (; ; ; ). 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 () 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 (). 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 () 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 (). 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 (). 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 (). 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 (). ▪ 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 (), but adding LABA has the potential risk of rare life-threatening or fatal exacerbations.