Evaluation of severe asthma in adolescents and adults

INTRODUCTION — 

Severe asthma afflicts 5 to 10 percent of the asthma population, but drives the majority of the morbidity and costs of the disease [1]. The clinician must first determine that a patient with severe and/or frequent respiratory symptoms suggestive of severe asthma has been given the correct diagnosis. Alternative possibilities include the following:

●Asthma that is exacerbated by uncontrolled triggers

●Asthma that is poorly controlled because of nonadherence

●An alternative disorder/disease that mimics asthma

●Asthma that is exacerbated by a comorbid condition

This topic review will address the approach to a patient with symptoms suggestive of severe asthma. The general approach to asthma diagnosis and treatment, a discussion of asthma phenotypes and their influence on treatment, and more detailed guidance on trigger control, inhaler technique, and medication adherence are provided separately.

●(See "Asthma in adolescents and adults: Evaluation and diagnosis".)

●(See "An overview of asthma management in children and adults".)

●(See "Characterizing severe asthma phenotypes".)

●(See "Trigger control to enhance asthma management".)

●(See "The use of inhaler devices in adults".)

●(See "Enhancing patient adherence to asthma therapy".)

DEFINITION — 

Severe asthma is defined by international societies as asthma that is uncontrolled despite prolonged treatment using moderate- to high-dose inhaled glucocorticoids (table 1) with additional controller agents (ie, step 4 or 5 therapy (table 2)) or that worsens whenever these treatments are decreased (table 3) [2,3]. Patients receiving systemic glucocorticoids for more than 50 percent of the year to achieve asthma control also qualify. Other conditions must have been evaluated and excluded, potential exacerbating factors remediated, and lack of adherence determined not to be a significant contributor to poor asthma control.

Notably, severe asthma is not determined based on the severity of untreated symptoms or exacerbations. Even patients with highly symptomatic or life-threatening asthma when untreated can usually achieve good asthma control with standard controller therapies. (See "An overview of asthma management in children and adults" and "Initiating asthma therapy and monitoring in adolescents and adults".)

EPIDEMIOLOGY — 

Little is known about the epidemiology of severe asthma [4]. It may progress from milder childhood asthma, have been severe throughout life, or develop de novo in adulthood [5-7]. Approximately 5 to 10 percent of patients with asthma have severe asthma in large cohorts [8]. Native Americans may have a particularly high risk of having severe asthma; one large prospective cohort study found that among the 6 percent of patients who had clinician-diagnosed asthma, 52 percent had severe asthma (with a mean forced expiratory volume in one second [FEV₁] of 61 percent of predicted) [9].

As a group, patients with severe asthma are at significant risk for work disability. The prevalence of full work disability was 14 percent in a prospective cohort study of 865 American patients with severe asthma, while partial work disability was present in 38 percent [10]. However, the risk factors for the development of severe asthma (either adult- or childhood-onset) remain poorly understood.

Severe asthma may also be more common in adult females [11]. However, female patients with severe asthma generally have more favorable objective findings than males, such as a better FEV₁ and FEV₁/forced vital capacity (FVC), lower total and specific immunoglobulin (Ig)-E, and decreased fraction of exhaled nitric oxide (FE_NO). Obesity is a risk factor for severe asthma. (See "Obesity and asthma".)

EVALUATION — 

When evaluating a patient with symptoms suggestive of severe asthma, the key factors to identify are those that differentiate asthma from its mimics and those that increase the risk of exacerbations. As with less severe asthma, information about uncontrolled triggers, barriers to adherence, and contributing comorbidities should be sought [12].

History and physical — Important elements of the history in patients with severe asthma are reviewed here. The history and physical examination findings that are typical of asthma are discussed separately. (See "Asthma in adolescents and adults: Evaluation and diagnosis".)

Symptom and exacerbation pattern — We suggest the following approach to help identify the patient’s asthma phenotype and important comorbidities:

●Characterize the specific symptoms (eg, dyspnea, cough, wheeze, chest tightness, sputum), including their frequency and severity. Symptoms that may suggest a nonasthma diagnosis include hoarseness, prominent sputum production, constitutional symptoms, and lack of improvement with appropriate asthma medication.

●Clarify when symptoms began. Childhood onset of symptoms favors a diagnosis of atopic asthma. Asthma is diagnosed in childhood in approximately 75 percent of all asthma patients; however, adult-onset asthma tends to be more severe and less likely allergic [13]. When type-2 inflammation is also present, time of disease onset may predict response to biologic therapies [14].

●Identify temporal patterns of symptoms. Nocturnal symptoms suggest greater asthma severity, although gastroesophageal reflux disease (GERD) and obstructive sleep apnea (OSA) may also cause nocturnal choking and dyspnea.

●Determine the severity of exacerbations. Previous emergency department visits, hospitalizations, intensive care unit admissions, and/or invasive mechanical ventilation imply a greater risk of future severe asthma exacerbations. (See "Identifying patients at risk for fatal asthma".)

Female patients frequently describe greater allergic (and general) symptoms, have lower asthma-specific quality of life, are more likely to be obese, and have more frequent and severe exacerbations [11]. Those with premenstrual asthma appear to be at a particularly high risk of severe asthma exacerbations [15]. While the reasons for more symptomatic disease in females as compared with males remain unknown, it is important to consider severe asthma in females despite lesser (but not absent) objective findings [15].

Additional helpful questions include whether symptoms began after an upper respiratory infection (which may suggest bronchiolitis) and if the patient has had pneumonia or recurrent bronchitis (which may suggest bronchiectasis).

Trigger identification — Ongoing exposures to triggers in any setting may contribute to poor asthma control, so the patient's home, school, and work environments should be carefully reviewed. Triggers may be inhaled (eg, allergens, irritants) or ingested (eg, nonsteroidal anti-inflammatory drug [NSAID] and beta-blocker medications). A series of potential questions is given in the table (table 4). (See "Trigger control to enhance asthma management".)

Occupational asthma may not be immediately apparent; patients should be asked about workplace exposures to inhaled allergens, such as laboratory animals, latex, and flour, as well as sensitizers such as glutaraldehyde, toluene diisocyanate, and trimellitic anhydride (table 5). Some of the antigens may cause both asthma and hypersensitivity pneumonitis (HP). (See 'Assessing conditions that mimic asthma' below and "Occupational asthma: Definitions, epidemiology, causes, and risk factors".)

Inhaler adherence and technique — Incomplete adherence to prescribed medications is present in many, if not all, chronic diseases and generally to the same degree (approximately 50 percent) [16]. Asthma is no exception, so adherence to medications must always be addressed [17-19]. In addition to adherence to scheduled doses, proper inhaler management requires appropriate inhaler technique (which varies by inhaler device) to optimize delivery of the medication to the lungs. (See "The use of inhaler devices in adults".)

Patients should bring their inhalers to each appointment and explain how they are using them (both technique and dosing). Inhaler technique should be demonstrated for the patient and reviewed at every visit. If available, pharmacy records can supplement patient self-report of adherence.

Adherence should be encouraged in a nonjudgmental manner (especially if a medication is known to be helpful to that patient), and reasons behind nonadherence explored (eg, fear of side effects or dependence, forgetfulness, cost of medication) (table 6).An overall understanding of the patient's social situation regarding access to medical care and to medications, as well as their associated costs, is often critical. (See "Enhancing patient adherence to asthma therapy".)

Physical examination — The physical examination in patients with suspected severe asthma should assess lower airway disease while also looking for evidence of comorbidities or alternative diagnoses. Wheezing is the most likely finding, although it may be absent between exacerbations; air-trapping, accessory muscle use, and poor air movement are more common in poorly controlled disease. (See "Asthma in adolescents and adults: Evaluation and diagnosis", section on 'Physical findings'.)

A complete physical examination should include:

●A thorough nasal/sinus evaluation looking for stigmata of nasal obstruction, nasal polyposis, sinusitis, and allergic rhinitis

●Examination of the neck for masses and tracheal deviation

●A complete cardiopulmonary examination, looking for focal versus diffuse wheeze, stridor, situs inversus, and evidence of alternative diagnoses (eg, crackles suggestive of HP, cryptogenic organizing pneumonitis, interstitial lung disease, or heart failure)

●A skin examination looking for stigmata of atopic dermatitis, sarcoidosis, and vasculitis.

Pulmonary function testing — In patients with severe asthma, additional pulmonary function testing beyond spirometry is warranted to confirm the diagnosis of asthma and to rule out comorbid diseases or mimickers. The most helpful testing includes pre- and postbronchodilator spirometry with inspiratory and expiratory flow loops as well as lung volumes and diffusing capacity. Evidence of expiratory airflow limitation with a bronchodilator response is consistent with an asthma diagnosis. Persistent airflow limitation is seen in approximately 50 percent of patients with severe asthma [20]. (See "Pulmonary function testing in asthma" and "Flow-volume loops".)

Air-trapping, as manifest by a reduced forced vital capacity (FVC) and increased residual volume and total lung capacity (on plethysmographic pulmonary function testing), is characteristic of severe asthma where there is significant small airways disease (SAD) [21].

In cases where there is a minimal expiratory airflow limitation, often in the face of a high degree of symptoms, a methacholine challenge can determine the presence of hyperreactive airways, helping to confirm an asthma diagnosis. Those with symptoms consistent with severe asthma but demonstrating a negative methacholine challenge should pursue alternative diagnoses. (See "Bronchoprovocation testing".)

The diffusing capacity for carbon monoxide (DLCO) is typically normal or increased in asthma. However, some variants of severe asthma, including asthmatic granulomatosis, may have mild or moderate reductions in diffusing capacity. (See "Diffusing capacity for carbon monoxide", section on 'Interpretation'.)

Although not universally available, oscillometry has been shown to be abnormal in most patients with asthma due to the presence of detectable SAD. For example, the ATLANTIS study demonstrated the presence of SAD in up to 91 percent of patients with asthma depending upon the physiologic test employed [22]. In the longitudinal portion of ATLANTIS, abnormal oscillometry (R5-R20, AX, and X5) correlated with exacerbations and asthma control. Combined oscillometry measures were better at predicting exacerbations than forced expiratory volume in one second (FEV₁) alone [23].

Chest imaging — Even though not indicated in the routine evaluation of asthma, a chest radiograph is often appropriate in patients with symptoms suggestive of severe asthma, especially if the symptoms are somewhat atypical or do not respond to short-acting bronchodilator therapies [2]. If interstitial opacities are noted on the chest radiograph, if the DLCO is reduced, or if there has been a rapid decline in lung function, a high-resolution computed tomography (HRCT) scan of the thorax should be performed to assess for interstitial lung disease and bronchiolitis; this should include expiratory images. When trying to discriminate between severe asthma and bronchiolitis, the presence of a mosaic attenuation pattern (more prominent on expiratory views) makes bronchiolitis more likely [24]. (See "Overview of bronchiolar disorders in adults".)

HRCT can also be helpful in identifying bronchiectasis, tracheal strictures and masses, and vascular anomalies that mimic asthma (eg, right-sided aortic arch and aberrant left subclavian artery) [25-27]. Patients with large amounts of mucus production should receive computed tomography (CT) evaluation for bronchiectasis. (See "Clinical manifestations and diagnosis of bronchiectasis in adults", section on 'Diagnostic evaluation' and "Vascular rings and slings".)

Laboratory/immunologic testing — There are no laboratory tests that confirm or exclude asthma. However, testing can help to evaluate associated conditions as well as asthma triggers and may be useful to guide treatment.

●Routine testing – For virtually all patients with severe persistent asthma, a complete blood count (CBC) with differential (to evaluate the presence/absence of eosinophils and exclude anemia as a cause of dyspnea) and a total serum IgE level (to assess for allergic bronchopulmonary aspergillosis [ABPA] or identify of candidates for anti-IgE therapy) should be obtained.

●Patients with elevated blood eosinophil counts – Specific IgE testing for aspergillus sensitization (skin test or immunoassay) and an antineutrophil cytoplasmic antibody (ANCA) should be performed in those with high blood eosinophils to evaluate for ABPA and eosinophilic granulomatosis with polyangiitis (EGPA), respectively. (See "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis" and "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis" and "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis".)

In patients from endemic areas, eosinophilia may be a manifestation of Strongyloides or filarial infection and can be further evaluated with specific antibody testing. In patients born in developed countries, eosinophilia is more likely to be due to adult-onset (or aspirin-sensitive) asthma, BPA, asthmatic granulomatosis, or rarely, EGPA. However, peripheral eosinophilia can be seen across all subphenotypes of type-2 asthma. (See 'Assessing conditions that mimic asthma' below and "Overview of pulmonary eosinophilia" and "Characterizing severe asthma phenotypes", section on 'Type 2 asthma phenotypes'.)

●Patients with irreversible obstruction – For those with persistent and irreversible airflow obstruction, a one-time measurement of the serum alpha-1 antitrypsin level is recommended. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency".)

●Patients with suspected environmental allergens – If the patient has not had specific allergy testing, either allergy skin tests or immunoassays for allergen-specific IgE should be done if environmental factors are suspected triggers (eg, a cat or dog in the household). (See "Asthma in adolescents and adults: Evaluation and diagnosis", section on 'Tests for allergy'.)

●Patients with personal or family history of autoimmune disease – For those with a personal or strong family history of autoimmune disease, we frequently assess for common autoantibodies and systemic inflammation (erythrocyte sedimentation rate, c-reactive protein, rheumatoid factor, anticitrullinated cyclic peptide, ANCA, and antineutrophil antibody level). Rheumatoid arthritis, and EGPA in particular, may cause airway manifestations and worsen asthma, and treatment of other underlying autoimmune disorders, when present, can sometimes positively impact asthma symptoms. However, low titers of autoantibodies are frequently false positives and should not be presumed to suggest active disease, especially in older females, where they can be particularly common.

●Patients with recurrent infectious triggers – Difficult-to-control or severe asthma can occasionally arise from immunodeficiency to respiratory pathogens. In those with a well-documented history of recurrent infections, we check immunoglobulin levels, IgG subclasses, and pneumococcal titers (with postimmunization recheck in those with low levels).

In one large Korean cohort, the prevalence of an immunoglobulin deficiency (immunoglobulin G/A/M or IgG subclass) was 5.5 percent in asthmatic patients, with severe asthma more common in that group (32 versus 13 percent) [28]. Low IgG concentrations may also associate with risk of viral exacerbation [29]. Treatment of immunodeficiency (with immunoglobulin) may be helpful in asthma control for select patients [30,31].

●Patients with cardiac comorbidities or uncertain diagnosis – For patients with persistent dyspnea that is not well-explained by the degree of airflow limitation noted on pulmonary function tests, measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) with evaluation of cardiac function (eg, echocardiogram, stress testing, cardiopulmonary exercise testing) may help to exclude cardiac disease.

Assessing airway inflammation — We agree with the European Respiratory Society/American Thoracic Society guidelines that treatment of severe asthma should be guided by clinical criteria and biomarkers of airway inflammation rather than by clinical criteria alone [3]. (See "Exhaled nitric oxide analysis and applications" and "Characterizing severe asthma phenotypes", section on 'Type 2 asthma phenotypes'.)

The following markers of airway inflammation are helpful in characterizing severe asthma:

●Blood eosinophil count – A peripheral blood eosinophil count is an indirect way to estimate airway inflammation. A blood eosinophil count ≥300 cells/microL may help to predict those who are at increased risk for exacerbations in the next year [32-35]. In addition, the blood eosinophil count is used to identify patients with severe eosinophilic asthma who may benefit from anti-interleukin (IL)-5 or anti-IL-4 receptor alpha antibody therapy, although the precise cut-points for response to these therapies is less clear (table 7). (See "Treatment of severe asthma in adolescents and adults", section on 'Anti-IL-5/5R antibodies' and "Treatment of severe asthma in adolescents and adults", section on 'Anti-IL-4 receptor alpha subunit antibody (dupilumab)'.)

●Sputum eosinophils and neutrophils – Sputum analyses are frequently not available even in tertiary institutions because they must be done by a trained technician to standardize both collection and cell counting. Generally, an induced sputum eosinophil count ≥3 percent is considered elevated [36]. For those receiving systemic or high-dose inhaled glucocorticoids, the appropriate sputum eosinophil threshold is less certain but likely much lower. (See "Exhaled nitric oxide analysis and applications" and "Characterizing severe asthma phenotypes", section on 'Type 2 asthma phenotypes'.)

The presence of sputum eosinophils despite high-dose inhaled or oral glucocorticoids has been associated with more symptomatic disease and worse outcomes [36]. Several studies have evaluated eosinophil counts in induced sputum and on endobronchial biopsies to determine whether persistent eosinophilic or neutrophilic inflammation might be contributing to poor asthma control [13,20,36-39]. In a systematic review of six studies (374 participants with moderate to severe asthma), evaluation and treatment based on sputum eosinophils led to fewer exacerbations than management based on symptoms and/or lung function (odds ratio [OR] 0.57, 95% CI 0.38-0.86) [39]. However, no difference was noted in symptoms, quality of life, or lung function.

Some patients with severe asthma have elevated sputum neutrophil counts alone or in combination with sputum eosinophilia, raising the possibility that they have an alternate asthma pathogenesis or particularly severe disease [11,13,37,40-43]. (See "Characterizing severe asthma phenotypes", section on 'Neutrophilic asthma'.)

●Fraction of exhaled nitric oxide – The fraction of exhaled nitric oxide (FE_NO) is another method to assess ongoing airway inflammation [44,45]. Sustained high levels of FE_NO appear to be strongly associated with both regular requirement of systemic glucocorticoids and increased exacerbation risk in patients with severe asthma [46,47]. High levels of FE_NO in a patient with uncontrolled asthma may indicate an opportunity to achieve better disease control through increased doses of inhaled corticosteroids, and we suggest a trial of increased inhaled corticosteroid dose in these patients, usually for three to six months. However, management of patients by monitoring and treatment of FE_NO has not been shown to be of clear clinical benefit [44]. FE_NO also predicts improvement in FEV₁ in patients treated with some biologics, particularly anti-IL-4Ra antibodies [48,49]. (See "Exhaled nitric oxide analysis and applications" and "Treatment of severe asthma in adolescents and adults", section on 'Selecting among biologic agents'.)

A focused guideline update by the National Asthma Education and Prevention Program in 2020 advised that FE_NO can be used as part of a diagnostic approach for asthma but not alone for diagnosis in patients >4 years of age; it should also be used as part of an ongoing monitoring and management strategy to predict future exacerbations and assess exacerbation severity [50].

Bronchoscopic evaluation is generally not needed for patients with severe asthma; endobronchial brushings or biopsies can demonstrate characteristic asthma features but are usually performed only in research settings. Occasionally, bronchoscopy with or without endobronchial or transbronchial biopsy can be helpful to evaluate for alternative diagnoses such as chronic eosinophilic pneumonia, sarcoidosis, or HP. (See "Approach to the adult with interstitial lung disease: Diagnostic testing".)

Phenotyping asthma — Patients with severe asthma have diverse clinical and pathophysiologic features that can be characterized into phenotypes; these phenotypes are taking on increasing importance in therapeutic selection in the era of biologics and personalized medicine [11,13,37,40,51]. Clinically, clusters of patients with severe asthma include those who are atopic and presented in childhood, those with a course characterized by frequent and often severe exacerbations, and those with chronic, sometimes severe, airflow limitation that is only partially reversible. (See "Characterizing severe asthma phenotypes".)

With the availability of T2-targeted biologic therapies, the most important categorization of severe asthma is the presence or absence of a T2-high phenotype, which is characterized by activation of IL-4, IL-5, and IL-13 from a range of cells including Th2 and innate lymphoid T2 (ILC2) cells and the consequent downstream eosinophilic inflammation [52-54]. This eosinophil-predominant inflammation is currently identified through biomarkers of airway inflammation and allergy testing. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Th2' and 'Laboratory/immunologic testing' above and 'Assessing airway inflammation' above.)

Identification of T2-high severe asthma allows more targeted interventions, such as increased doses of inhaled glucocorticoids, omalizumab, or specific T2-targeted therapies (ie, antibodies to IL-4 and IL-13 [dupilumab], IL-5 [mepolizumab and reslizumab], or the IL-5 receptor [benralizumab]), which are more effective in patients with biomarker-based evidence of T2 inflammation than in those without evidence of T2 inflammation. Tezepelumab, an antithymic stromal lymphopoietin monoclonal antibody, while not specifically targeting T2 inflammation, is also effective in patients with T2-high severe asthma. Specific additional phenotypic features among T2-high patients can help further guide therapy. These phenotypic features and biologic therapies are reviewed in more detail separately [55]. (See "Treatment of severe asthma in adolescents and adults", section on 'Persistently uncontrolled severe asthma' and "Characterizing severe asthma phenotypes", section on 'Type 2 asthma phenotypes'.)

Severe asthma phenotypes in the absence of evidence for T2 inflammation are less well understood, although neutrophilic inflammation, obesity, and metabolic factors may play an important role [56]. Tezepelumab is a biologic therapy that decreases exacerbations in patients without T2 inflammation. Additionally, effective weight loss interventions can be helpful in those with obesity. Other therapies are under active investigation for this patient group. (See "Characterizing severe asthma phenotypes", section on 'Non-type 2 asthma phenotypes' and "Treatment of severe asthma in adolescents and adults", section on 'Anti-thymic stromal lymphopoietin (tezepelumab)' and "Obesity and asthma", section on 'Weight loss interventions'.)

ASSESSING CONDITIONS THAT MIMIC ASTHMA — 

Several conditions share a symptom complex and can be confused with severe asthma; the most common of these are reviewed here (table 8). In addition, some conditions may accompany asthma and cause it to appear more severe or less responsive to therapy. These include: paradoxical vocal fold motion, allergic bronchopulmonary aspergillosis (ABPA), chronic obstructive pulmonary disease (COPD), chronic eosinophilic pneumonia, and eosinophilic granulomatosis with polyangiitis (EGPA). Additional details are provided below and separately.

●Inducible laryngeal obstruction (paradoxical vocal fold motion) – The most common masquerader of severe asthma is inducible laryngeal obstruction (ILO; also called paradoxical vocal fold motion or vocal cord dysfunction) [57,58]. This syndrome involves involuntary closure of the vocal folds, commonly during inspiration, and can be seen in both males and females. Symptoms include episodic and severe shortness of breath, wheezing, and intractable cough, often in response to irritant exposures (perfumes) or exercise. Patients may have concomitant dysphonia, variable or inconsistent symptom relief from bronchodilators, and frequently report an "inability to get enough air (in)." This diagnosis can be made using a combination of inspiratory flow volume loops and laryngoscopy during symptoms, possibly performed at the time of methacholine or exercise challenge. Small airways dysfunction, as assessed by oscillometry, may also help to distinguish asthma from ILO [59]. (See 'Pulmonary function testing' above and "Inducible laryngeal obstruction (paradoxical vocal fold motion)", section on 'Evaluation'.)

It is important to note that ILO can also occur in the presence of severe asthma. It is often triggered by exercise and worsened by factors that also worsen asthma, including postnasal drip, gastroesophageal reflux disease (GERD), and anxiety [60]. (See "Inducible laryngeal obstruction (paradoxical vocal fold motion)" and "Exercise-induced laryngeal obstruction".)

Vocal fold paralysis and vocal fold lesions are associated with exertional dyspnea and, frequently, dysphonia. A history of intubation, trauma, or surgery with potential injury to the laryngeal nerve would be a clue to evaluate these diagnoses further. (See "Hoarseness in adults".)

●Central airway obstruction – Central airway obstruction includes tracheal strictures (eg, from prior intubation), tracheal compression by goiter, tracheal and proximal bronchial tumors, and vascular rings [25]. Patients may present with exertional dyspnea and, sometimes, monophonic wheeze or stridor.

A flow volume loop including the inspiratory phase is the first step in evaluation (see 'Pulmonary function testing' above). Chest CT may detect airway compromise, but the test as routinely performed is not sensitive. If an airway lesion is suspected, a high-resolution CT (HRCT) with three-dimensional airway reconstruction can prove helpful, but direct visualization is usually needed for a definitive diagnosis. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults".)

●Chronic obstructive pulmonary disease – COPD should be considered in patients with a history of smoking (eg, greater than 15 to 20 pack-years), fume or dust exposure, or a family history of emphysema or alpha-1 antitrypsin deficiency [61]. Some patients may have features of both asthma and COPD, as described separately. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency" and "Concomitant asthma and COPD" and "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Risk factors, including smoking and inhalational exposures'.)

In addition to the history of smoking, clues to the presence of COPD include irreversible airflow obstruction and the combination of airflow obstruction and a low diffusing capacity for carbon monoxide (DLCO). (See "Chronic obstructive pulmonary disease: Diagnosis and staging".)

●Bronchiectasis – Patients with bronchiectasis typically have a chief complaint of productive cough, and the amount of sputum production is usually more than what would be expected in pure asthma. An end-inspiratory squeak may be heard on physical examination that can mimic a wheeze. The cough is typically refractory to bronchodilator therapy. HRCT of the thorax will help determine whether bronchiectasis is present. (See 'Chest imaging' above and "Clinical manifestations and diagnosis of bronchiectasis in adults".)

●Allergic bronchopulmonary aspergillosis – ABPA may develop in patients with asthma due to colonization of the airways with aspergillus and typically presents with recurrent mucoid impaction and atelectasis. The resulting immunologic reaction leads to proximal bronchiectasis. ABPA should be suspected in patients with severe asthma and elevated IgE levels and evaluated with skin test positivity to aspergillus and HRCT imaging. (See "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis".)

●Bronchiolitis – Several bronchiolar diseases share features of asthma such as cough and dyspnea that worsens with exertion. Bronchiolitis is typically a consequence of a respiratory infection, inhalational injury, organ transplantation, or autoimmune and/or connective tissue disease. Physical examination may reveal crackles and inspiratory squeaks; pulmonary function tests show progressive airflow obstruction not responsive to bronchodilators; DLCO and oxygen saturation are reduced; chest CT scan will show interstitial opacities in a mosaic pattern [24]. Inspiratory and expiratory views on HRCT may reveal patchy areas of air trapping. (See "Overview of bronchiolar disorders in adults".)

●Hypereosinophilic obliterative bronchiolitis – A small number of patients with clinical features of severe asthma have been found to have hypereosinophilic obliterative bronchiolitis [62-64]. Differentiating characteristics of this condition include a peripheral blood eosinophil count ≥1000 cells/microL (1 x 10⁹/L) and/or bronchoalveolar lavage eosinophils >25 percent; persistent airflow obstruction with a postbronchodilator forced expiratory volume in one second (FEV₁) <80 percent predicted and an FEV₁/forced vital capacity (FVC) <70 percent not improved after four to six weeks of high-dose inhaled glucocorticoids; and a lung biopsy showing prominent bronchiolar wall infiltration by eosinophils and/or HRCT features of bronchiolitis. Hypereosinophilic obliterative bronchiolitis appears to respond to oral prednisone with initial doses of 0.5 to 1 mg/kg per day tapering to maintenance doses of approximately 10 mg per day [62].

●Cryptogenic organizing pneumonia – Cryptogenic organizing pneumonia (also known as bronchiolitis obliterans organizing pneumonia [BOOP]) is usually manifest by a nonproductive cough, sometimes dyspnea, systemic symptoms of malaise, and sometimes fever. Crackles are usually noted on chest examination, and an HRCT reveals interstitial opacities and/or patchy areas of consolidation. Pulmonary function tests typically show a restrictive pattern; airflow limitation is seen uncommonly and generally only in cigarette smokers. (See "Cryptogenic organizing pneumonia".)

●Hypersensitivity pneumonitis – Patients with hypersensitivity pneumonitis (HP) may report intermittent dyspnea that can be confused with asthma. Exposure to allergens that typically cause HP (eg, birds, barns, humidifiers) should alert the clinician to this possibility. Pulmonary function tests may show a mixed obstructive and restrictive pattern and a reduced DLCO. Fleeting infiltrates are another clue. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis".)

●Eosinophilic pulmonary diseases – Filarial and Strongyloides infections, EGPA, and chronic eosinophilic pneumonia may present with asthma that cannot be controlled until the underlying disease is treated. Filarial and Strongyloides infection should be suspected in patients who have blood eosinophilia and elevated IgE if they are from an endemic area (typically tropical and subtropical regions, but strongyloidiasis may also be found in the southeastern United States). Specific IgG antibodies to filarial and Strongyloides antigens will be positive. Improvement with specific treatment confirms the diagnosis. (See "Overview of pulmonary eosinophilia" and "Tropical pulmonary eosinophilia" and "Strongyloidiasis".)

Patients with EGPA and chronic eosinophilic pneumonia may have asthma but also have other findings (eg, blood eosinophilia, pulmonary infiltrates). Paranasal sinus disease, skin lesions, a peripheral neuropathy, and eosinophilia >10 percent are common in EGPA, although blood eosinophilia may be masked by systemic glucocorticoids.

For example, in one cohort of 596 patients with severe asthma, the prevalence of EGPA was 3.9 percent [65]. Nearly all patients identified with EGPA had a peak blood eosinophil count greater than 1000 cells/microL; the most frequent additional disease manifestations were upper airway disease, neuropathy, and kidney involvement. A significant delay between asthma and EGPA diagnosis is common (10 years in the above study), so a high clinical suspicion is needed to identify this condition. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis" and "Eosinophilic granulomatosis with polyangiitis: Treatment and prognosis".)

Concomitant fever, weight loss, and night sweats are often seen in chronic eosinophilic pneumonia; blood eosinophilia may be absent. (See "Overview of pulmonary eosinophilia", section on 'Chronic eosinophilic pneumonia'.)

●Asthmatic granulomatosis – Among patients with severe asthma, a subset has been described with nonnecrotizing granulomas in the lung interstitium, asthma-like submucosal inflammation, and mucus plugging in the small airways, but without clinical evidence of HP or pathologic evidence of vasculitis [66]. This disease process has been called "asthmatic granulomatosis." Affected patients frequently have eosinophilia and chronic rhinosinusitis (with or without nasal polyposis) and may have a reduced diffusing capacity. Chest CT may be normal or show air trapping, mosaicism, bronchial dilatation, or bronchial wall thickening. There is often a strong family or personal history of autoimmune disease. The optimal evaluation and management of these patients have not been defined.

●Sarcoidosis – Endobronchial sarcoidosis can present with a refractory cough and dyspnea. Chest radiograph and CT will likely show typical findings of hilar adenopathy and reticular or nodular opacities. (See "Clinical manifestations and diagnosis of sarcoidosis".)

●Cardiac disease – Heart failure can mimic asthma in older adults and can be evaluated with B-type natriuretic peptide (BNP), chest radiograph, and echocardiogram. (See "Diagnosis and management of asthma in older adults", section on 'Heart failure versus asthma'.)

ASSESSING COMORBID CONDITIONS — 

A number of comorbid diseases can contribute to the severity of asthma and should be evaluated in patients with severe asthma (table 9). Addressing these issues may reduce asthma symptoms in some patients.

●Chronic rhinosinusitis – Chronic rhinosinusitis is a frequent comorbid condition and is an independent risk factor for exacerbations of asthma [67]. At least some studies in milder asthma suggest that improved upper airway therapy leads to better asthma outcomes [68,69].

Allergic rhinitis symptoms and signs should be evaluated, and the nose examined for nasal polyps. Patients with nasal polyposis and asthma may also have aspirin-exacerbated respiratory disease (AERD) and have sudden and life-threatening flares of asthma after ingestion of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs). Even in the absence of aspirin or NSAID ingestion, they are likely to have severe asthma symptoms. (See "Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis" and "Aspirin-exacerbated respiratory disease".)

In patients with severe asthma, at least one sinus CT scan looking for chronic rhinosinusitis is probably appropriate, although studies to demonstrate the cost efficacy of this test are not available. Multiplanar sinus CT scan is the preferred imaging modality when evaluating for comorbid chronic rhinosinusitis. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis", section on 'Sinus CT'.)

●Gastroesophageal reflux – Gastroesophageal reflux disease (GERD) is commonly seen in association with severe asthma, but whether treatment improves asthma remains controversial. In our experience, treatment of severe GERD, when present, may improve persistent and refractory cough symptoms that do not respond to usual asthma therapies. (See "Gastroesophageal reflux and asthma".)

●Smoking – Several studies report that patients with asthma who smoke are at increased risk for exacerbations, have impaired lung function, and respond poorly to inhaled glucocorticoids [70,71]. Every effort should be made for the patient to quit; patients should also understand that ongoing smoking is a risk factor for fatal asthma. (See "Patient education: Quitting smoking (Beyond the Basics)" and "Identifying patients at risk for fatal asthma".)

●Obesity – Obesity (body mass index ≥30 kg/m²) is common in patients with severe asthma. Obesity has been associated with increased incident asthma in female patients and with worsened asthma severity [72-74]. Unfortunately, weight loss is difficult for patients with severe asthma, particularly when they require systemic glucocorticoids; in addition to the effects of glucocorticoids, activity is often limited by dyspnea. (See "Obesity and asthma".)

●Obstructive sleep apnea – Obstructive sleep apnea (OSA) is a common disorder that may occur together with asthma and shares certain predisposing factors [75-77]. Both obesity and nasal congestion (eg, from allergic rhinitis or nasal polyposis) may further contribute to the development of OSA [67,78,79]. Daytime sleepiness in patients with asthma is more likely related to OSA than asthma [78]. However, OSA that coexists with asthma can cause worsening of nocturnal asthma [80,81].

A few case series have described improvement in nocturnal and daytime asthma symptoms with treatment of OSA. In one report, for example, all such patients treated with nasal continuous positive airway pressure (CPAP) experienced a marked improvement in nocturnal and daytime asthma symptoms with an associated reduction in the use of bronchodilators and lung function [80]. The exact reason for improved lung function with treatment of OSA is not clear. Proposed mechanisms include elimination of pharyngeal/laryngeal irritation that can cause reflex bronchoconstriction [82], improvement in hypoxia, and/or decreased vagal tone. Nocturnal asthma is not improved with nasal CPAP in the absence of sleep apnea [83].

Polysomnography is suggested in patients with symptoms and clinical features suggestive of OSA, particularly when nocturnal symptoms are persistent. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

●Psychiatric disorders – Psychiatric disorders have long been associated with severe asthma [84-90]. In one study, anxiety and depression were present to a much greater degree in patients with severe asthma than the normal population and were risk factors for more severe asthma [85]. However, it is not clear whether the anxiety and depression are truly risk factors for severe asthma or the result of severe asthma.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Severe asthma in adolescents and adults".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Asthma treatment in adolescents and adults (Beyond the Basics)" and "Patient education: Inhaler techniques in adults (Beyond the Basics)" and "Patient education: Trigger avoidance in asthma (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Severe asthma is defined as asthma that is uncontrolled despite prolonged treatment using moderate- to high-dose inhaled glucocorticoids (table 1) with additional controller agents (ie, step 4 or 5 therapy (table 2)) or that worsens whenever these treatments are decreased (table 3). Patients receiving systemic glucocorticoids for more than 50 percent of the year to achieve asthma control also qualify. Other conditions must have been evaluated and excluded, potential exacerbating factors remediated, and lack of adherence determined not to be a significant contributor to poor asthma control. (See 'Definition' above.)

Severe asthma is not determined based on the severity of untreated symptoms or exacerbations because most patients with asthma can achieve good control with standard therapies.

●History and physical

•Assessing asthma characteristics – Important elements in the history include: age of onset of symptoms, exact description of symptoms, temporal pattern of symptoms, exacerbating factors (table 4), and family history of atopic disease. Assessment of the frequency and severity of asthma exacerbations helps to predict the risk of future exacerbations. (See 'History and physical' above.)

•Assessing medication adherence and inhaler technique – Poor medication adherence or inhaler technique are important causes of poorly controlled asthma, especially when more complicated treatment regimens become necessary. (See 'Inhaler adherence and technique' above.)

●Pulmonary function testing – Suggested pulmonary function tests include spirometry pre- and postbronchodilator with inspiratory and expiratory flow loops, lung volumes, and diffusing capacity to reassess the diagnosis of asthma and evaluate for comorbid diseases or mimickers. An asthma diagnosis is strongly supported by expiratory airflow limitation with a bronchodilator response or a positive methacholine challenge. (See 'Pulmonary function testing' above.)

●Disease phenotyping – Type 2 airway inflammation should be assessed in patients with severe asthma by obtaining a blood eosinophil count, fraction of exhaled nitric oxide (FE_NO), total IgE level, and allergen-specific IgE (by blood or skin testing) if the history is suggestive of atopy. These biomarkers help to phenotype the asthma and may influence treatment decisions.

●Additional laboratory testing – Specific IgE testing for aspergillus sensitization (skin test or immunoassay) and an antineutrophil cytoplasmic antibody (ANCA) are performed in those with high blood eosinophils to evaluate for allergic bronchopulmonary aspergillosis (ABPA) and eosinophilic granulomatosis with polyangiitis (EGPA), respectively. In those from endemic areas, Strongyloides and filarial testing is appropriate. In selected patients, obtaining alpha-1 antitrypsin levels, titers of autoimmune antibodies, or Ig levels may also be helpful. (See 'Laboratory/immunologic testing' above.)

●Chest imaging – Chest radiograph and CT scans may help identify diseases that mimic asthma like central airway obstruction, bronchiectasis, bronchiolitis, and vascular rings. (See 'Chest imaging' above.)

●Differential diagnosis – Typical masqueraders of severe asthma include (in general order of likelihood): inducible laryngeal obstruction (vocal cord dysfunction), chronic obstructive pulmonary disease (COPD), bronchiectasis, hypersensitivity pneumonitis (HP), hypereosinophilic syndromes (including EGPA), constrictive bronchiolitis, and endobronchial sarcoidosis (table 8). (See 'Assessing conditions that mimic asthma' above and "Inducible laryngeal obstruction (paradoxical vocal fold motion)".)

●Assessing comorbid conditions – Comorbid conditions like rhinosinusitis and obesity appear to exacerbate asthma (table 9). It is controversial whether gastroesophageal reflux disease (GERD) exacerbates asthma, but it is common among patients with asthma. Obstructive sleep apnea (OSA) may contribute to nocturnal respiratory symptoms. (See 'Assessing comorbid conditions' above.)

●Treatment – The treatment of severe asthma in adolescents and adults is discussed separately. (See "Treatment of severe asthma in adolescents and adults".)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Sally Wenzel, MD, who contributed to earlier versions of this topic review.