Definitions of the levels of the evidence (A, B, C, D) and strength of recommendations ("is recommended" and "should or may, be considered") are presented at the end of the "Major Recommendations" field.
Note from the National Asthma Education and Prevention Program (NAEPP): Panel members only included ranking of evidence for recommendations they made based on the scientific literature in the current evidence review. They did not assign evidence rankings to recommendations pulled through from the Expert Panel Report (EPR)—2 1997 on topics that are still important to the diagnosis and management of asthma but for which there was little new published literature. These "pull through" recommendations are designated by EPR—2 1997 in parentheses following the first mention of the recommendation.
Note from the NAEPP and the National Guideline Clearinghouse (NGC): The Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma have been divided into individual summaries covering assessment, education, medications, and management. In addition to the current summary, the following are available:
Key Points: Medications
Medications for asthma are categorized into two general classes: long-term control medications used to achieve and maintain control of persistent asthma and quick-relief medications used to treat acute symptoms and exacerbations.
Long-Term Control Medications (Listed in Alphabetical Order)
- Corticosteroids: Block late-phase reaction to allergen, reduce airway hyperresponsiveness, and inhibit inflammatory cell migration and activation. They are the most potent and effective anti-inflammatory medication currently available (Evidence A). Inhaled corticosteroids (ICSs) are used in the long-term control of asthma. Short courses of oral systemic corticosteroids are often used to gain prompt control of the disease when initiating long-term therapy; long-term oral systemic corticosteroid is used for severe persistent asthma.
- Cromolyn sodium and nedocromil: Stabilize mast cells and interfere with chloride channel function. They are used as alternative, but not preferred, medication for the treatment of mild persistent asthma (Evidence A). They can also be used as preventive treatment prior to exercise or unavoidable exposure to known allergens.
- Immunomodulators: Omalizumab (anti-immunoglobulin E [IgE]) is a monoclonal antibody that prevents binding of IgE to the high-affinity receptors on basophils and mast cells. Omalizumab is used as adjunctive therapy for patients >12 years of age who have allergies and severe persistent asthma (Evidence B). Clinicians who administer omalizumab should be prepared and equipped to identify and treat anaphylaxis that may occur (see discussion in the text of the original guideline document).
- Leukotriene modifiers: Include leukotriene receptor antagonists (LTRAs) and a 5-lipoxygenase inhibitor. Two LTRAs are available—montelukast (for patients >1 year of age) and zafirlukast (for patients >7 years of age). The 5-lipoxygenase pathway inhibitor zileuton is available for patients >12 years of age; liver function monitoring is essential. LTRAs are alternative, but not preferred, therapy for the treatment of mild persistent asthma (Step 2 care) (Evidence A). LTRAs can also be used as adjunctive therapy with ICSs, but for youths >12 years of age and adults they are not the preferred adjunctive therapy compared to the addition of long-acting beta2-agonist(s) (LABAs) (Evidence A). Zileuton can be used as alternative but not preferred adjunctive therapy in adults (Evidence D).
- LABAs: Salmeterol and formoterol are bronchodilators that have a duration of bronchodilation of at least 12 hours after a single dose.
- LABAs are not to be used as monotherapy for long-term control of asthma (Evidence A).
- LABAs are used in combination with ICSs for long-term control and prevention of symptoms in moderate or severe persistent asthma (step 3 care or higher in children >5 years of age and adults) (Evidence A for ≥12 years of age, Evidence B for 5 to 11 years of age)
- Of the adjunctive therapies available, LABA is the preferred therapy to combine with ICS in youths ≥12 years of age and adults (Evidence A).
- In the opinion of the Expert Panel, the beneficial effects of LABA in combination therapy for the great majority of patients who require more therapy than low-dose ICS alone to control asthma (i.e., require step 3 care or higher) should be weighed against the increased risk of severe exacerbations, although uncommon, associated with the daily use of LABAs (see discussion in the text of the original guideline document).
- For patients >5 years of age who have moderate persistent asthma or asthma inadequately controlled on low-dose ICS, the option to increase the ICS dose should be given equal weight to the option of adding LABA.
- For patients >5 years of age who have severe persistent asthma or asthma inadequately controlled on step 3 care, the combination of LABA and ICS is the preferred therapy.
- LABA may be used before exercise to prevent exercise-induced bronchospasm (EIB) (Evidence A), but duration of action does not exceed 5 hours with chronic regular use. Frequent and chronic use of LABA for EIB is discouraged, because this use may disguise poorly controlled persistent asthma (Evidence D).
- In the opinion of the Expert Panel, the use of LABA for the treatment of acute symptoms or exacerbations is not currently recommended (Evidence D).
- Methylxanthines: Sustained-release theophylline is a mild to moderate bronchodilator used as alternative, not preferred, adjunctive therapy with ICS (Evidence A). Theophylline may have mild anti-inflammatory effects. Monitoring of serum theophylline concentration is essential.
Quick-Relief Medications (Listed in Alphabetical Order)
- Anticholinergics: Inhibit muscarinic cholinergic receptors and reduce intrinsic vagal tone of the airway. Ipratropium bromide provides additive benefit to short-acting beta2-agonist(s) (SABA) in moderate-to-severe asthma exacerbations. May be used as an alternative bronchodilator for patients who do not tolerate SABA (Evidence D).
- SABAs: Albuterol, levalbuterol, and pirbuterol are bronchodilators that relax smooth muscle. Therapy of choice for relief of acute symptoms and prevention of EIB (Evidence A).
- Systemic corticosteroids: Although not short acting, oral systemic corticosteroids are used for moderate and severe exacerbations as adjunct to SABAs to speed recovery and prevent recurrence of exacerbations (Evidence A).
Key Differences from the 1997 and 2002 Expert Panel Reports
- Information about asthma medications has been updated based on review of evidence published since 1997. This updated report (EPR—3: Full Report 2007) continues to emphasize that the most effective medications for long-term therapy are those shown to have anti-inflammatory effects.
- New medications—immunomodulators—are available for long-term control of asthma.
- New data on the safety of LABAs are discussed, and the position of LABA in therapy has been revised (see text in the original guideline document). The most significant difference is that for youths >12 years of age and adults who have moderate persistent asthma or asthma inadequately controlled on low-dose ICS, the option of increasing the dose of medium-dose ICS should be given equal weight to the option of adding LABA to low-dose ICS.
- The estimated clinical comparability of different ICS preparations has been updated. (See the NGC summaries of the NAEPP guidelines Managing Asthma Long Term in Children 0-4 Years of Age and 5-11 Years of Age and Managing Asthma Long Term in Youths >12 Years of Age and Adults). The significant role of ICSs in asthma therapy continues to be supported.
Overview of the Medications
Long Term Control Medications
The Expert Panel recommends that long-term control medications be taken daily on a long-term basis to achieve and maintain control of persistent asthma. The most effective long-term-control medications are those that attenuate the underlying inflammation characteristic of asthma (Evidence A).
Inhaled Corticosteroids
Mechanism
The Expert Panel concludes that ICSs are the most potent and consistently effective long-term control medication for asthma (Evidence A).
Inhaled Corticosteroid Insensitivity
The Expert Panel concludes that sensitivity and consequently clinical response to ICS can vary among patients (Evidence B).
Efficacy of Inhaled Corticosteroids as Compared to Other Long-Term Control Medications as Monotherapy
The Expert Panel concludes that studies demonstrate that ICSs improve asthma control more effectively in both children and adults than LTRAs or any other single long-term control medication (Evidence A).
Efficacy of Inhaled Corticosteroid and Adjunctive Therapy (Combination Therapy)
The Expert Panel recommends that when patients >12 years of age require more than low-dose ICS alone to control asthma (i.e., step 3 care or higher), a therapeutic option is to add LABA to ICS (Evidence A). Alternative, but not preferred adjunctive therapies include LTRA (Evidence B), theophylline (Evidence B), or, in adults, zileuton (Evidence D). For children 0–11 years of age, LABA, LTRA, and, in children 5–11 years of age, theophylline may be considered as adjunctive therapies in combination with ICS (Evidence B, based on extrapolation from studies in older children and adults; see also the NGC summaries of the NAEPP guidelines Managing Asthma Long Term in Children 0-4 Years of Age and 5-11 Years of Age and Managing Asthma Long Term in Youths >12 Years of Age and Adults for recommendations on adjunctive therapies at different steps of care for different age groups in children).
Dose-Response and Delivery Device
The Expert Panel concludes that dosages for ICSs vary, depending upon the specific product and delivery devices. (See figure 3–24 in the original guideline document for issues on delivery devices; see the NGC summaries of the NAEPP guidelines Managing Asthma Long Term in Children 0-4 Years of Age and 5-11 Years of Age and Managing Asthma Long Term in Youths >12 Years of Age and Adults for comparative ICS dosages.) For all ICS preparations, the dose-response relationship appears to flatten in patients who have mild or moderate asthma for most clinical parameters and lung function in the low- to medium-dose range (Evidence C).
Variability in Response and Adjustable Dose Therapy
The Expert Panel recommends that, given the variations over time in the severity of the pathophysiologic processes underlying asthma, it may be useful to adjust anti-inflammatory therapy accordingly (Evidence B).
Safety of Inhaled Corticosteroids
Key Points: Safety of Inhaled Corticosteroids
- ICSs are the most effective long-term therapy available for mild, moderate, or severe persistent asthma; in general, ICSs are well tolerated and safe at the recommended dosages (Evidence A).
- The potential but small risk of adverse events from the use of ICS treatment is well balanced by their efficacy (Evidence A).
- The dose-response curve for ICS treatment begins to flatten for many measures of efficacy at low to medium doses, although some data suggest that higher doses may reduce the risk of exacerbations. Most benefit is achieved with relatively low doses, whereas the risk of adverse effects increases with dose (Evidence B).
- To reduce the potential for adverse effects, the following measures are recommended:
- Spacers or valved holding chambers (VHCs) used with non-breath-activated metered dose inhalers (MDIs) reduce local side effects (Evidence A), but there are no data on use of spacers with ultra fine particle hydrofluoroalkane (HFA) MDIs.
- Advise patients to rinse their mouths (rinse and spit) after inhalation (Evidence B).
- Use the lowest dose of ICS that maintains asthma control. Evaluate patient adherence and inhaler technique as well as environmental factors that may contribute to asthma severity before increasing the dose of ICS (Evidence B).
- To achieve or maintain control of asthma, consider adding a LABA to a low or medium dose of ICS rather than using a higher dose of ICS (Evidence A).
- For children, monitor growth (Evidence A). (See "Key Points: Inhaled Corticosteroids and Linear Growth in Children" below).
- In adult patients, consider supplements of calcium (1,000–1,500 mg per day) and vitamin D (400–800 units a day), particularly in perimenopausal women (Evidence D). Bone-sparing therapy (e.g., bisphosphonate), where appropriate, may be considered for patients on medium or high doses of ICS, particularly for those who are at risk of osteoporosis or who have low bone mineral density (BMD) scores by dual energy x ray absorptiometry (or DEXA) scan (Evidence C). In children, age-appropriate dietary intake of calcium and exercise should be reviewed with the child's caregivers (Evidence D).
The Expert Panel concludes that ICSs are the most effective long-term therapy available for patients who have persistent asthma and, in general, ICSs are well tolerated and safe at the recommended dosages (Evidence A).
The Expert Panel recommends the following actions to minimize potential adverse effects of ICS.
Local Adverse Effects
- Oral Candidiasis (Thrush). Use a spacer or VHC with a non-breath-activated MDI to reduce the incidence of colonization and clinical thrush; rinse mouth with water after inhalation (Selroos and Halme, 1991). No data are available on the use of spacers or VHCs with ultrafine-particle-generated HFA MDIs. Administer ICS less frequently (twice a day [bid] versus four times a day [qid]). Topical or oral antifungal agents should be used to treat active infections (EPR—2 1997).
- Dysphonia. Use a spacer or VHC with a non-breath-activated MDI, temporarily reduce dosage, or rest for vocal stress (EPR—2 1997).
- Reflex Cough And Bronchospasm. These effects can be reduced by slower rates of inspiration and/or use of a spacer or valved holding chamber or by pretreatment with SABA. There is no convincing evidence that the routine use of a SABA before each dose of ICS increases intrapulmonary delivery of the ICS or reduces dosage requirement (EPR—2 1997).
Systemic Adverse Effects
Oral Systemic Corticosteroids
The Expert Panel recommends that chronic administration of oral systemic corticosteroids as a long-term-control medication be used only for the most severe, difficult-to-control asthma because of well-documented risk for side effects (EPR—2 1997).
The Expert Panel recommends that, because the magnitude of adverse effects is often related to the dose, frequency of administration, and the duration of corticosteroid use (Evidence A), every consideration should be given to minimize systemic corticosteroid doses and maximize other modes of therapy (Evidence D). It is necessary, therefore, to monitor for the development and progression of adverse effects and to take appropriate steps to minimize the risk and impact of adverse corticosteroid effects (Evidence D).
Cromolyn Sodium and Nedocromil
Cromolyn and nedocromil are alternative, not preferred, medications for the treatment of mild persistent asthma (Evidence A). They can also be used as preventive treatment before exercise or unavoidable exposure to known allergens (EPR—2 1997).
Immunomodulators
Omalizumab
The Expert Panel recommends that omalizumab may be considered as adjunctive therapy in step 5 or 6 care for patients who have allergies and severe persistent asthma that is inadequately controlled with the combination of high-dose ICS and LABA (Evidence B).
Antibiotics
In the opinion of the Expert Panel, the data at present are insufficient to support a recommendation about the use of macrolide in chronic asthma.
Others
The Expert Panel concludes that current evidence does not support the use of methotrexate, soluble interleukin-4 (IL-4) receptor, humanized monoclonal antibody against IL-5 or IL-12, cyclosporin A, intravenous immunoglobulin ( IVIG), gold, troleandomycin (TAO), or colchicine for asthma treatment (Evidence B).
Leukotriene Modifiers
The Expert Panel recommends that LTRAs are an alternative, not preferred, treatment option for mild persistent asthma (Step 2 care) (Evidence A). LTRAs can also be used as adjunct therapy with ICS, but for youths >12 years of age and adults they are not the preferred, adjunct therapy compared to the addition of LABAs (Evidence A). A 5-lipoxygenase inhibitor (zileuton) is an alternative treatment option that is less desirable than LTRAs due to more limited efficacy data and the need for liver function monitoring (Evidence D).
Inhaled Long-Acting Beta2-Agonists
The Expert Panel concludes the following regarding the use of LABAs:
- LABAs are used as an adjunct to ICS therapy for providing long-term control of symptoms (Evidence A). Of the adjunctive therapies available, LABA is the preferred treatment to combine with ICS in youths >12 years of age and adults (Evidence A).
- LABAs are not recommended for use as monotherapy for long-term control of persistent asthma (Evidence A).
- Use of LABA is not currently recommended to treat acute symptoms or exacerbations of asthma (Evidence D). Studies are underway examining the potential use of formoterol in acute exacerbations and in adjustable-dose therapy in combination with ICS; see the discussion below in the section on "Quick-Relief Medications" and on "Inhaled Short-Acting Beta2-Agonists."
- LABA may be used before exercise to prevent EIB (Evidence B), but frequent and chronic use of LABA for EIB may indicate poorly controlled asthma which should be managed with daily anti-inflammatory therapy.
- Safety issues have been raised regarding LABAs. The Expert Panel reviewed the safety data provided to the U.S. Food and Drug Administration (FDA) Pulmonary and Allergy Drugs Advisory Committee as well as the extensive accumulation of clinical trials and meta-analyses on the use of LABA, both as monotherapy and in conjunction with ICS. The Expert Panel concluded that LABAs should not be used as monotherapy as long-term control medication in persistent asthma but that LABAs should continue to be considered for adjunctive therapy in patients >5 years of age who have asthma that requires more than low-dose ICS. For patients inadequately controlled on low-dose ICS, the option to increase the ICS dose should be given equal weight to the addition of a LABA. For patients who have more severe persistent asthma (i.e., those who require step 4 care or higher), the Expert Panel continues to endorse the use of a combination of LABA and ICS as the most effective therapy. The basis of this opinion is discussed in the original guideline document.
Key Points: Safety of Inhaled Long-Acting Beta2-Agonists
- The addition of LABA (salmeterol or formoterol) to the treatment of patients whose asthma is not well controlled on low- or medium-dose ICS improves lung function, decreases symptoms, and reduces exacerbations and use of SABA for quick relief in most patients (EPR-Update 2002; Greenstone et al., 2005; Masoli et al., 2005).
- A large clinical trial comparing daily treatment with salmeterol or placebo added to usual asthma therapy (Nelson et al., 2006) resulted in 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 with placebo). In addition, increased numbers 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 LABA for the great majority of patients whose asthma is not well controlled with ICS alone should be weighed against the increased risk for severe exacerbations, although uncommon, 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 ICS alone, the option to increase the ICS dose should be given equal weight to the option of the addition of a LABA to ICS.
- Daily use of LABA generally should not exceed 100 micrograms salmeterol or 24 micrograms formoterol.
- It is not currently recommended that LABA be used for treatment of acute symptoms or exacerbations.
- LABAs are not to be used as monotherapy for long-term control. Patients should be instructed not to stop ICS therapy while taking salmeterol or formoterol even though their symptoms may significantly improve.
Methylxanthines
The Expert Panel recommends that sustained-release theophylline is an alternative but not preferred treatment for mild persistent asthma (Step 2 care) (Evidence A); it may also be used as alternative but not preferred adjunctive therapy with ICS (Evidence B).
Quick Relief Medications
Anticholinergics
The Expert Panel concludes that ipratropium bromide, administered in multiple doses along with SABA in moderate or severe asthma exacerbations in the ED, provides additive benefit (Evidence B).
Inhaled Short-Acting Beta2-Agonists
The Expert Panel recommends that SABAs are the drug of choice for treating acute asthma symptoms and exacerbations and for preventing EIB (Evidence A).
Safety of Inhaled Short-Acting Beta2-Agonists
Key Points: Safety of Inhaled Short-Acting Beta2-Agonists
- SABAs are the most effective medication for relieving acute bronchospasm (Evidence A).
- Increasing use of SABA treatment or using SABA >2 days a week for symptom relief (not prevention of EIB) generally indicates inadequate control of asthma and the need for initiating or intensifying anti-inflammatory therapy (Evidence C).
- Regularly scheduled, daily, chronic use of SABA is not recommended (Evidence A).
The Expert Panel recommends the use of SABA as the most effective medication for relieving acute bronchoconstriction; SABAs have few negative cardiovascular effects (Evidence A).
The Expert Panel does not recommend regularly scheduled, daily, long-term use of SABA (Evidence A).
Systemic Corticosteroids
The Expert Panel recommends the use of oral systemic corticosteroids in moderate or severe exacerbations (Evidence A).
The Expert Panel recommends that multiple courses of oral systemic corticosteroids, especially more than three courses per year, should prompt a reevaluation of the asthma management plan for a patient (Evidence C).
Complementary and Alternative Medicine
Key Points: Complementary and Alternative Medicine
- It is recommended that the clinician ask patients about all medications and treatments they are using for asthma and advise the patients that complementary and alternative medicines and treatments are not a substitute for the clinician's recommendations for asthma treatment (Evidence D).
- Evidence is insufficient to recommend or not recommend most complementary and alternative medicines or treatments.
- Acupuncture is not recommended for the treatment of asthma (Evidence B).
- Patients who use herbal treatments for asthma should be cautioned that there is the potential for harmful ingredients in herbal treatments and for interactions with recommended asthma medications (Evidence D)
Acupuncture
The Expert Panel does not recommend the use of acupuncture for the treatment of asthma (Evidence B).
Chiropractic Therapy
The Expert Panel concludes that there is insufficient evidence to recommend the use of chiropractic or related techniques in the treatment of asthma.
Homeopathy and Herbal Medicine
The Expert Panel concludes that there is insufficient evidence to support effectiveness of homeopathy and that more clinical trial and observational data are necessary.
The Expert Panel concludes that there is insufficient evidence to recommend herbal products for treating asthma. Furthermore, because herbal products are not standardized, one must be aware that some may have harmful ingredients and that some may interact with other pharmaceutical products that the patient may be taking (Evidence D).
Breathing Techniques
The Expert Panel concludes there is insufficient evidence to suggest that breathing techniques provide clinical benefit to patients who have asthma.
Relaxation Techniques
The Expert Panel concludes that, despite some encouraging data from small studies, further positive data from randomized, controlled studies will be necessary before relaxation techniques can be recommended in the treatment of asthma.
Yoga
There is a paucity of well-controlled studies on the effects of yoga on asthma outcomes.
Definitions:
Levels of Evidence
The system* used to describe the level of evidence is as follows:
Evidence Category A: Randomized controlled trials (RCTs), rich body of data.
Evidence is from end points of well-designed RCTs that provide a consistent pattern of findings in the population for which the recommendation is made. Category A requires substantial numbers of studies involving substantial numbers of participants.
Evidence Category B: RCTs, limited body of data.
Evidence is from end points of intervention studies that include only a limited number of patients, post hoc or subgroup analysis of RCTs, or meta-analysis of RCTs. In general, category B pertains when few randomized trials exist; they are small in size, they were undertaken in a population that differs from the target population of the recommendation, or the results are somewhat inconsistent.
Evidence Category C: Nonrandomized trials and observational studies.
Evidence is from outcomes of uncontrolled or nonrandomized trials or from observational studies.
Evidence Category D: Panel consensus judgment.
This category is used only in cases where the provision of some guidance was deemed valuable, but the clinical literature addressing the subject was insufficient to justify placement in one of the other categories. The Panel consensus is based on clinical experience or knowledge that does not meet the criteria for categories A through C.
*Source: Jadad AR, Moher M, Browman GP, Booker L, Sigouin C, Fuentes M, Stevens R. Systematic reviews and meta-analyses on treatment of asthma: critical evaluation. BMJ 2000;320(7234):537-40.
Strength of Recommendations
In addition to specifying the level of evidence supporting a recommendation, the Expert Panel agreed to indicate the strength of the recommendation. When a certain clinical practice "is recommended," this indicates a strong recommendation by the panel. When a certain clinical practice "should, or may, be considered," this indicates that the recommendation is less strong.
This distinction is an effort to address nuances of using evidence ranking systems. For example, a recommendation for which clinical RCT data are not available (e.g., conducting a medical history for symptoms suggestive of asthma) may still be strongly supported by the Panel. Furthermore, the range of evidence that qualifies a definition of "B" or "C" is wide, and the Expert Panel considered this range and the potential implications of a recommendation as they decided how strongly the recommendation should be presented.