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Treatment of severe asthma in adolescents and adults

Last literature review version 17.3: September 2009  |  This topic last updated: May 12, 2009   (More)

INTRODUCTION — The classification of "severe asthma" refers to patients who require high dose inhaled glucocorticoid (GC), or continuous or near continuous oral GC treatment to maintain asthma control. In addition to at least one of these two major criteria, the working definition of severe asthma proposed by the American Thoracic Society requires the presence of at least two of seven minor criteria (table 1) [1].

The NAEPP and GINA guidelines have a slightly different category of "severe persistent asthma" that describes patients who have frequent and severe asthma symptoms and evidence of airflow limitation, but are not on asthma controller medication (table 2) [2,3]. Patients with severe asthma (by ATS criteria) generally require high doses of controller medications to achieve control; without these medications their asthma is either "not well controlled" or "very poorly controlled" by NAEPP/GINA criteria (table 3).

Achieving the usual goals of asthma treatment (prevent chronic and troublesome symptoms, normalize pulmonary function, maintain normal activity levels, prevent exacerbations, improve health-related quality of life, and provide optimal pharmacotherapy with minimal or no adverse effects) may not be fully possible in patients with severe asthma. It may be necessary to accept some degree of reduced activity and persistent airflow limitation, and to focus instead on reducing the frequency and severity of exacerbations and hospitalizations, avoiding further loss of pulmonary function, and limiting toxicity from medications.

The evaluation of patients with severe asthma symptoms, a general overview of asthma management, and a review of nonpharmacologic management are presented separately. (See "Evaluation of severe asthma in adolescents and adults" and "An overview of asthma management" and "Trigger control to enhance asthma management".)

Treatment issues that pertain to patients with severe asthma are reviewed here. Treatment approaches to mild and moderate persistent asthma are reviewed separately. (See "Treatment of intermittent and chronic mild asthma in adolescents and adults" and "Treatment of moderate persistent asthma in adolescents and adults".)

GENERAL TREATMENT PRINCIPLES — Treatment of severe asthma frequently requires a multidisciplinary approach to address patient education needs, remediate irritant and allergic triggers, treat comorbidities, and design an optimal medication regimen.

Patient education — A written asthma action plan is recommended for all patients with severe asthma [2]. Either a symptom or peak flow based plan may be used; although evidence shows similar benefits, patients who are poor perceivers of dyspnea may benefit from a plan based on objective measure of airflow limitation. We frequently provide a prescription for a short course of prednisone (eg, 40 mg daily for 5 days) for patients to keep on hand and to start based on specific criteria in their action plan. (See "What do patients need to know about their asthma?".)

Patients may still not know how to use their inhalers correctly despite a long history of asthma; each patient's technique should be observed and correct technique carefully demonstrated. (See "Metered dose inhaler techniques in adults" and "Delivery of inhaled medication in adults".)

Compliance/adherence — Compliance/adherence to medications should be addressed at each visit, in partnership with the patient [4]. There are many reasons for non-adherence. Strategies to maintain adherence can be discussed while developing the action plan. If a medication is not subjectively or objectively improving the patient's symptoms or respiratory function after a three month trial, it should be stopped. (See "Enhancing patient adherence to asthma therapy".)

Controlling asthma triggers — Ongoing exposure to asthma triggers is an important cause of poor asthma control in some patients. For patients with severe asthma who have no allergic component to their disease, allergen control measures will have little effect. Potential triggers that are identified during evaluation (eg, pets, dust mites, workplace exposures, tobacco smoke) need renewed strategies for control (table 4). (See "Trigger control to enhance asthma management" and 'Treatment of comorbidities' below.)

Monitoring — Once a regimen has been developed, we usually request that patients with severe asthma return for follow up visits at four to eight week intervals. We evaluate control using standardized questions, either the Asthma Control Questionnaire (ACQ) or Asthma Control Test (ACT) [5-7]. Objective measures of airflow limitation (eg, peak expiratory flow, spirometry) are important; spirometry may need to be performed more frequently than in patients with milder asthma. In particular, we perform spirometry when there is a significant change in clinical status and to confirm that a step-down in medication has not caused a clinically-silent decline in lung function. Spirometry may also have utility in comparing the efficacy of various add-on controller agents.

SHORT-ACTING BETA AGONISTS — Inhaled short-acting beta agonists (SABAs) should be prescribed for the relief of acute symptoms. Albuterol, at a dose of 2 to 4 puffs, is commonly prescribed, although other equivalent agents are available (table 5). This dose may be repeated twice within an hour if needed for an acute exacerbation. SABAs should only be used on an as needed basis. (See "Beta agonists in asthma: Acute administration and prophylactic use".)

Some patients with severe asthma derive better symptom relief from nebulized albuterol, compared with the metered dose preparation. Patients should be advised to seek emergency department evaluation, if they are unimproved after two home nebulizer treatments within an hour.

INITIATING CONTROLLER THERAPY — Some patients presenting with symptoms and objective measures consistent with NAEPP and GINA definitions of "severe persistent asthma" are not on controller therapy (table 2) (see 'Introduction' above [2,3]. With addition of controller medication, many will improve enough that they do not meet ATS criteria for severe asthma (table 1). This section will describe our approach to patients who meet NAEPP/GINA criteria for "severe persistent asthma" at their initial visit.

Initial controller agents for severe persistent asthma include oral and inhaled GCs, and long acting beta agonists. Generally, combination therapy with two or more controller agents will be needed to achieve improved control in patients with severe persistent asthma.

Oral glucocorticoids — Most patients who are not on any controller medication and meet NAEPP criteria for "severe persistent asthma" will need an initial, brief course of oral GC therapy to bring their asthma under control (graph 1) [2]. In deciding when to prescribe oral GC, we consider the severity of symptoms, degree of airflow limitation, and whether symptoms have been stable or worsening. In general, we prescribe a brief course of an oral GC to patients with frequent daytime or nocturnal symptoms, recent deterioration (eg, increased need for SABA), or a forced expiratory volume in one second (FEV1) less than 60 percent of predicted. The treatment of acute asthma exacerbations is discussed separately. (See "Treatment of acute exacerbations of asthma in adults".)

A reevaluation in two weeks will assess the response to therapy and determine the need for longer term, low dose oral GC versus transition to inhaled GC alone.

A two to three week course of oral GC may also be considered in patients who have baseline stable airflow obstruction that does not reverse with inhaled bronchodilator. In this way, the degree of reversibility to GCs can be determined. The forced expiratory volume in one second (FEV1) at the end of the trial may be used as a goal for ongoing controller therapy, instead of the usual target of 80 percent of the predicted value.

Inhaled glucocorticoids — Inhaled GCs (called inhaled corticosteroids (ICS) in the NHLBI guidelines) that are high potency and used at a high dose are the foundation of long term controller therapy in severe asthma (table 6 and table 7) [2,5,8,9]. Several formulations are available; we usually choose one from the "high potency" group that allows for the least number of puffs per day. (See "Delivery of inhaled medication in adults".)

The dose of inhaled GC is adjusted at subsequent visits based on asthma control. (See 'Adjusting controller therapy' below.)

Long acting beta agonists (LABA) — Most patients with severe asthma are treated with a combination of inhaled GC and a LABA (either salmeterol or formoterol) (table 7) [2,3,8]. (See 'Combination inhaled GC/LABA' below.)

ADJUSTING CONTROLLER THERAPY — Once a patient who presents with severe asthma is receiving controller therapy with inhaled GCs and a LABA, subsequent visits are usually scheduled at four to six week intervals. At these visits, therapy is adjusted based upon an assessment of asthma control and any adverse effects of medication, remembering that the degree of asthma control is determined by the most severe indicator of impairment (table 3).

Patients who fail to achieve asthma control on inhaled GC doses around the equivalent of fluticasone 800 to 1000 mcg per day, or who have difficulty tapering oral GCs, should be reassessed for accuracy of the diagnosis, lack of adherence, ongoing exposure to asthma triggers, and comorbid conditions.

If severe asthma is confirmed, based on ATS criteria (table 1), explanations for persistent symptoms despite high dose combination therapy include: residual inflammation is relatively GC resistant, remodeling (not inflammation) is causing airflow limitation, and inflammation in the distal airways is not reached by the inhaled GCs. At this point, we consider several choices, which are discussed in more detail in the sections that follow:

Referral to an asthma specialist is suggested for all patients with this degree of asthma severity.

Systemic glucocorticoids — Oral GCs are the most potent and effective controller agent for asthma, but have substantial side effects when used for months to years [2,3]. We always try to use the lowest dose of oral GC for the shortest duration possible, because of the side effects of systemic GCs. We use high dose inhaled GC, LABA, and other controller medications to maintain asthma control and allow tapering of oral GC, because these other controller medications have fewer systemic effects.

When a patient has frequent exacerbations despite high doses of inhaled GCs, it is helpful to determine whether the patient's asthma is actually responsive to GCs. This can be accomplished with injection of a long acting GC, such as triamcinolone [10]. With this approach, adherence/compliance is no longer an issue. In a randomized trial, patients with a high level of lung eosinophils, despite high dose inhaled (and even oral) GCs, responded to 3 mL (40 mg/mL) of intramuscular triamcinolone acetonide with improved FEV1, reduced rescue medication, and decreased lung eosinophils when assessed two weeks later [11]. Patients who respond to triamcinolone are not steroid resistant, but rather poorly adherent or poorly steroid responsive, requiring very high doses of GC that may be associated with substantial side effects. After intramuscular triamcinolone, the anti-inflammatory effect and hypothalamic-pituitary-adrenal suppression last for about two to six weeks. It is reasonable to reassess symptom control and spirometry in three to four weeks.

Patients who fail to respond to systemic GCs may rarely have GC resistant asthma. For clinical purposes, this is defined by a forced vital capacity in one second (FEV1) that is less than 75 percent of predicted and fails to improve by 15 percent after a two week trial of oral GC (eg, prednisone 40 mg per day). (See "Glucocorticoid-resistant asthma".)

Consideration should be given to daily low dose oral GCs (5 to 10 mg/day) when bursts of oral GCs are required every two to three months despite high dose inhaled GC, long acting inhaled beta agonist, and trials of other controller agents described below. The lowest possible daily should be used.

Patients on chronic oral GC need to be monitored for GC side effects. (See "Major side effects of systemic glucocorticoids" and "Major side effects of inhaled glucocorticoids".)

Inhaled glucocorticoids — Inhaled GCs have broad anti-inflammatory effects in asthma and are effective in many patients with severe asthma [2,3,12,13]. They have been shown to reduce asthma symptoms; improve peak expiratory flow rate (PEFR), spirometry, and quality of life; diminish airway hyperresponsiveness; and prevent or reduce the frequency of exacerbations. We usually use a high potency GC that allows for the least number of puffs per day. (See "Delivery of inhaled medication in adults".)

When asthma is not well controlled on high dose inhaled GC (eg, about 1000 mcg per day), but appears to be GC responsive, we consider a further increase in dose or use of an inhaled GC with a smaller particle size. The evidence for increasing the dose of inhaled GC above 1000 mcg per day is limited and not all patients will improve with higher inhaled GC doses. As an example, a double blind, parallel group study of 671 patients with severe asthma found slightly greater efficacy with fluticasone 2 mg per day compared to fluticasone 1 mg per day or to budesonide 1.6 mg per day [14]. Outcome measures were morning peak flow, rescue medication, daily symptom scores and diurnal peak flow variation. However, systemic GC side effects are likely to occur in this dose range.

Most of the currently available inhaled GCs are delivered in aerosols of a particle size that do not reach the distal airways. Hydrofluoroalkane (HFA)-beclomethasone has a particle size of approximately one micron, which enhances its delivery to the distal airways [15,16]. Although evidence is lacking, adding an HFA or other small particle size formulation (eg, budesonide DPI) of inhaled GCs to a traditional GC/LABA combination preparation (eg, 160 to 320 mcg of inhaled GC at midday in addition to the twice daily dosing of a combination product) may improve measures of small airway disease, and perhaps clinical outcomes [17].

Monitoring for GC related side effects is appropriate for patients on chronic high dose inhaled GC. (See "Major side effects of inhaled glucocorticoids".)

Combination inhaled GC/LABA — Most patients with severe asthma should receive a trial of combination therapy with inhaled GC and a long acting beta agonist (LABA) [2,3,8]. These can be prescribed as separate inhalers or as a combination inhaler (table 5 and table 6 and table 7).

The evidence in favor of combined GC/LABA therapy comes largely from extrapolation from trials in patients with moderately severe asthma and a few trials that studied addition of a LABA in patients with severe asthma [8,18,19]. In contrast, one randomized, placebo-controlled trial found only minimal improvement with addition of salmeterol or formoterol to high dose inhaled or oral GC treatment [20].

Concerns have been raised about the safety of LABA because of reports in a small subgroup of patients of severe exacerbations and increased mortality [21-23]. Patients should be monitored for any deterioration in asthma control after initiation of LABA therapy. LABAs are never used as monotherapy in severe asthma. (See "Beta agonists in asthma: Controversy regarding chronic use".)

If asthma symptoms, SABA use, and objective measures are unimproved after a trial of LABA therapy, consideration should be given to stopping the LABA.

Antileukotriene agents — Evidence for the efficacy of leukotriene receptor antagonists (LTRAs) as add-on therapy in severe asthma is limited [24-27]. One study evaluated LTRAs as additive therapy in patients whose asthma was not controlled with inhaled GC and LABA and did not find a benefit, but the study duration was only two weeks [25]. On the other hand, we believe that leukotriene modifiers and receptor antagonists are often helpful in patients with late onset disease, particularly those with a history of aspirin sensitivity [28,29]. If a LTRA does not improve asthma control within 3 months, we frequently try the 5-lipoxygenase inhibitor zileuton as an alternative [30,31].

The NAEPP guidelines also suggest a trial of an antileukotriene agent in patients with severe asthma who are not controlled on high dose inhaled GC and LABA [2]. Currently available agents include the 5-lipoxygenase inhibitor zileuton (Zyflo) and the cysLT receptor antagonists (LTRAs) montelukast (Singulair) and zafirlukast (Accolate) (table 8). (See "Agents affecting the 5-lipoxygenase pathway in the treatment of asthma".)

Theophylline — Oral theophylline has been used as an additional controller agent, although data are lacking regarding its efficacy when added to inhaled GC and a LABA. It is usually not as efficacious as LABAs when compared head-to-head [32-34]. Studies of withdrawal of theophylline from patients with severe asthma have demonstrated a high rate of asthma flares, suggesting that theophylline may play a role beyond its weak bronchodilator capacity [35]. (See "Theophylline use in asthma".)

Chromones — Cromolyn sodium and nedocromil, two mast cell stabilizing medications from the chromone class (also called cromoglycates), are useful in the management of some patients with mild-to-moderate asthma. In general, these medications are not effective enough to be of benefit in severe asthma [2,3]. (See "The use of chromones (cromoglycates) in the treatment of asthma".)

ANTI-IGE THERAPY — A trial of subcutaneously injected omalizumab may be considered in patients with moderate and severe allergic asthma, an IgE level of 30 to 700 IU/mL, and positive allergen skin or specific IgE tests to a perennial allergen [36-38]. Omalizumab is dosed by IgE level and body weight such that many obese patients with IgE levels of 700 IU/mL or less may not be appropriate candidates. The response to therapy is variable and difficult to predict, with response rates averaging 30 to 50 percent [39]. A pooled analysis of 4308 patients (93 percent severe asthma) found a 38 percent reduction in the frequency of asthma exacerbations [40]. However, cost benefit analyses of omalizumab in patients with severe asthma have yielded conflicting results [38,41,42]. (See "Anti-IgE therapy".)

TAPERING THERAPY — When asthma control is achieved, oral GCs are tapered, as tolerated, and discontinued. Reducing the dose of other controller medications is based on perceived efficacy, presence of adverse effects, patient preference, and cost considerations.

Reducing the dose of inhaled GCs may be considered in patients who achieve complete asthma control, once oral GCs have been discontinued. Guidelines for tapering of inhaled GCs have not been validated, but we usually decrease by 20 to 25 percent increments at one to three month intervals to a medium or low dose [43]. We usually do not discontinue inhaled GCs in patients with a history of severe asthma [44].

EXPERIMENTAL APPROACHES — Various pharmacologic and nonpharmacologic agents have been used in an attempt to improve asthma control and ameliorate the many adverse effects of chronic oral GC therapy in patients with severe asthma. These therapies are reviewed in more detail separately. (See "Alternative and experimental agents for the treatment of asthma".)

Immunomodulatory therapy — Numerous agents with antiinflammatory properties have been studied in an effort to eliminate or decrease the inflammation that underlies chronic asthma. Methotrexate and cyclosporine have shown glucocorticoid sparing effects in some small trials, but side effects, especially with cyclosporine, are substantial and likely outweigh any potential benefit. Other immunomodulatory drugs, such as azathioprine, cyclophosphamide, and mycophenolic acid have not undergone treatment trials in severe asthma.

Anti-IL-5 antibodies — Monoclonal antibodies to anti-interleukin 5 (IL-5) have been studied for use in asthma because of the potent effect of IL-5 on eosinophil recruitment to the airways. Treatment with the anti-IL-5 monoclonal antibody, mepolizumab, reduced the number of asthma exacerbations in a randomized trial of patients with eosinophilic asthma, but had no effect on symptoms or lung function. This class of medication is not FDA approved or readily available. (See "Alternative and experimental agents for the treatment of asthma", section on 'Anti-IL-5 antibodies'.)

Tumor necrosis factor-alpha inhibitors — Inhibitors of tumor necrosis factor (TNF)-alpha have been studied in the treatment of asthma. The largest trial did not achieve the primary endpoints (reduction in exacerbations and improvement in FEV1), and substantial side effects were noted [45]. (See "Alternative and experimental agents for the treatment of asthma", section on 'Anti-TNFa agents'.)

Macrolide antibiotics — Macrolide antibiotics have both antimicrobial and anti-inflammatory actions. In a randomized, placebo controlled trial in 46 patients with refractory asthma, eight weeks of clarithromycin improved asthma specific quality of life and reduced sputum neutrophils and IL-8, but did not improve physiologic measures [46]. Patients who provide a history of onset of disease after an acute respiratory illness may respond to macrolide antibiotics on the basis of a mycoplasma or chlamydia-related initiating event [47,48]. We usually prescribe clarithromycin for a four to six week trial in patients who report onset of asthma after a respiratory illness suggestive of these organisms.

TREATMENT OF COMORBIDITIES — Once comorbid conditions that may influence a patient's response to asthma treatment have been identified, every effort should be made to control their impact. However, evidence that this will improve the course of a patient's asthma is limited.

  • Vocal cord dysfunction, when present with severe asthma, should be treated by a knowledgeable speech therapist. Underlying causes (eg, post nasal drip, GERD, and anxiety) should be treated. (See "Paradoxical vocal cord motion".)

  • Obese patients may benefit from counseling regarding ways to improve nutrition and increase activity [55]. In certain cases, obesity may be so severe that bariatric surgery is considered, but in patients on chronic oral GCs, there are likely to be increased complications with this approach as well.
  • Anxiety and depression (or other psychiatric issues) should be evaluated and treated [56].

TREATMENT BY PHENOTYPE — Some patients have refractory asthma despite the best efforts to identify and reduce exposure to asthma triggers, develop a combined modality treatment plan, and treat comorbidities. Attempts to characterize these patients have lead to the concept of severe asthma phenotypes and it is hoped that treatments tailored to the particular phenotype of each patient may improve asthma outcomes [29,57-60]. The description of severe asthma phenotypes and associated treatment suggestions are presented separately. (See "Severe asthma: Evidence for heterogeneity of the disease".)

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Asthma treatment in adolescents and adults".) We encourage you to print or e-mail this topic, or to refer patients to our public web site www.uptodate.com/patients, which includes this and other topics.

SUMMARY AND RECOMMENDATIONS

  • The American Thoracic Society (ATS) classification of "severe asthma" refers to patients who require high dose inhaled or near continuous oral glucocorticoid (GC) treatment to maintain asthma control (table 1). (See 'Introduction' above.)

  • The NAEPP and GINA guidelines have a slightly different category of "severe persistent asthma" that describes patients who have frequent and severe asthma symptoms and evidence of airflow limitation, but are not on asthma controller medication (table 2). Some of these patients will achieve asthma control with modest doses of controller medication; others will require high doses of controller medications to achieve control or will continue to have poor asthma control despite medication. These latter patients have "severe asthma" by ATS criteria.
  • A written action plan should be provided to all patients with severe asthma; the plan may be symptom or peak flow based, or both. (See 'Patient education' above.)

  • Inhaler technique should be observed and corrected when necessary. (See 'Patient education' above.)

  • Some patients with severe asthma may need intermittent or chronic oral GC therapy in addition to high dose inhaled GC. For patients with chronic airflow limitation, a two week trial of oral GCs may help determine the potential for reversibility and define a goal for future adjustments in inhaled GC. (See 'Systemic glucocorticoids' above.)

  • In addition to inhaled GCs, we suggest that patients with severe asthma be started on a long acting beta agonist (LABA) (Grade 2B). However, if asthma symptoms, SABA use, and objective measures are unimproved after a trial of LABA therapy, the LABA is probably not helping and can be discontinued. (See 'Long acting beta agonists (LABA)' above.)

  • In patients who do not achieve adequate control with a combination of a high dose inhaled GC and LABA, we suggest adding either an antileukotriene agent or theophylline (Grade 2C). If asthma control does not improve after a reasonable trial the added medication should be discontinued. (See 'Antileukotriene agents' above and 'Theophylline' above.)

  • Independent of other therapies, in patients with atopic severe asthma, who have a serum IgE level of 30 to 700 IU/mL and documented sensitivity to a perennial allergen, we suggest adding omalizumab (Grade 2B). (See 'Anti-IgE therapy' above.)

  • Treatment of comorbid diseases may be helpful. In particular, every effort should be made to achieve smoking cessation, because ongoing smoking is a risk factor for fatal asthma. (See 'Treatment of comorbidities' above.)

  • Potential alternative and experimental therapies include immunomodulatory therapy and macrolide antibiotics. (See 'Experimental approaches' above.)

  • In the future, treatments tailored to asthma phenotypes may improve asthma outcomes. (See 'Treatment by phenotype' above.)

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