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 and a discussion of asthma phenotypes and their influence on treatment are provided separately. (See "Asthma in adolescents and adults: Evaluation and diagnosis" and "An overview of asthma management" and "Severe asthma phenotypes" and "Treatment of severe asthma in adolescents and adults".)

DEFINITION — We reserve the classification of "severe asthma" for patients who require high-dose inhaled or near continuous oral glucocorticoid treatment to maintain asthma control or who never achieve control despite that treatment. The European Respiratory Society and the American Thoracic Society definition of severe asthma requires that patients have needed therapy with high-dose inhaled glucocorticoid (table 1) and a second controller such as a long-acting beta-agonist (LABA) or leukotriene modifier/theophylline for the previous year and/or have needed systemic glucocorticoids for 50 percent or more of the year to prevent asthma from becoming uncontrolled, or which doesn’t achieve control despite this therapy (table 2) [2], despite having seen a specialist for three months or more. 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.

The 2007 NAEPP guidelines include a category of "severe asthma" among patients who are not initially on controller medication (table 3) [3]. Some patients who are in this category before therapy are able to achieve asthma control with moderate doses of inhaled glucocorticoids and thus do not meet criteria for severe persistent asthma. In patients with severe persistent asthma, attempts at lowering the glucocorticoid dose lead to deterioration in asthma control (table 4) [3].

EPIDEMIOLOGY — Little is known about the epidemiology of severe asthma [4]. It may progress from childhood asthma, have been severe throughout life, or develop de novo in adulthood [5-7]. It is estimated that 5 to 10 percent of patients with asthma have severe asthma [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 and 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 be more common in adult women [11]. However, women with severe asthma generally have more favorable objective findings than men, such as a better FEV₁ and FEV₁/FVC, and lower total and specific IgE and fraction of exhaled nitric oxide (FE_NO). Obesity is a risk factor for 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".)

●Characterize the specific symptoms (eg, dyspnea, cough, wheeze, chest tightness, sputum), 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, it may predict response to anti-interleukin (IL)-5 pathway therapies [14].

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

●Determine the severity of exacerbations: previous emergency department visits, hospitalizations, and/or invasive mechanical ventilation imply a greater risk of future severe asthma exacerbations.

Women 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]. Women with premenstrual asthma appear to be at a particularly high risk of severe asthma exacerbations [15]. While the reasons for more symptomatic disease in women as compared with men remain unknown, it is important to consider severe asthma in women despite lesser (but not absent) objective findings [15].

Additional helpful questions include whether asthma symptoms vary with the menstrual cycle [16]; whether symptoms began after an upper respiratory infection (may suggest bronchiolitis); and if the patient has had pneumonia or recurrent bronchitis (may suggest bronchiectasis).

The 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 exam, looking for focal versus diffuse wheeze, stridor, situs inversus and evidence of alternative diagnoses (eg, crackles suggestive of hypersensitivity pneumonitis, cryptogenic organizing pneumonitis, interstitial lung disease, or heart failure); and skin examination looking for stigmata of atopic dermatitis, sarcoidosis, and vasculitis.

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, NSAID and beta blocker medications). A series of potential questions is given in the table (table 5). (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 6). Some of the antigens may cause both asthma and hypersensitivity pneumonitis. (See 'Assessing conditions that mimic asthma' below and "Occupational asthma: Definitions, epidemiology, causes, and risk factors".)

Pulmonary function tests — In patients with severe asthma, additional pulmonary function testing beyond spirometry is warranted. The most helpful testing includes pre- and post-bronchodilator spirometry with inspiratory and expiratory flow loops, lung volumes, and diffusing capacity. Confirmation of the asthma diagnosis requires evidence of expiratory airflow limitation with a bronchodilator response. (See "Pulmonary function testing in asthma" and "Flow-volume loops".)

Persistent airflow limitation is seen in approximately 50 percent of patients with severe asthma [17]. In addition, 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 [18]. 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. 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 moderate reductions in diffusing capacity. (See "Bronchoprovocation testing" and "Diffusing capacity for carbon monoxide".)

Lab/immunologic testing — There are no laboratory tests that confirm or exclude asthma, but testing can help to evaluate associated conditions and asthma triggers.

For virtually all patients with severe persistent asthma, a complete blood count (CBC), peripheral blood eosinophil count (to evaluate the presence/absence of eosinophils and exclude anemia as a cause of dyspnea), and a total serum immunoglobulin E (IgE) level (eg, for allergic bronchopulmonary aspergillosis [ABPA] or identification of candidates for anti-IgE therapy) are obtained.

Specific 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 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 (Churg-Strauss)".)

For the lifelong non-smoker 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".)

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'.)

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, allergic bronchopulmonary aspergillosis, 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 "Severe asthma phenotypes", section on 'Phenotyping based on biomarkers of inflammation'.)

For patients with persistent dyspnea that is not well-explained by the degree of airflow limitation noted on pulmonary function tests, measurement of B-type natriuretic peptide (BNP) with evaluation of cardiac function (eg, echocardiogram) may help to exclude cardiac disease.

Airway inflammation — The European Respiratory Society/American Thoracic Society guidelines suggest that treatment of severe asthma be guided by clinical criteria and biomarkers such as blood, sputum eosinophil counts, or fraction of exhaled nitric oxide (FE_NO), rather than by clinical criteria alone [19]. (See "Severe asthma phenotypes", section on 'Phenotyping based on biomarkers of inflammation' and "Exhaled nitric oxide analysis and applications".)

●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 asthmatics who are at increased risk for exacerbations in the next year [20-22]. 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 therapy' and "Treatment of severe asthma in adolescents and adults", section on 'Anti-lL-4 receptor alpha subunit antibody (dupilumab)'.)

●Sputum eosinophils and neutrophils – Sputum analyses must be done by a trained technician to standardize both collection and cell counting and have limited availability. Generally, an induced sputum eosinophil count ≥3 percent is considered elevated [23]. (See "Severe asthma phenotypes", section on 'Phenotyping based on biomarkers of inflammation' and "Exhaled nitric oxide analysis and applications".)

The presence of sputum eosinophils despite high dose inhaled or oral glucocorticoids has been associated with more symptomatic disease and worse outcomes [23]. 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 [13,17,23-26]. 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 (OR 0.57, 95% CI 0.38-0.86) [26]. 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 [11,13,24,27-30]. (See "Severe asthma phenotypes", section on 'Neutrophilic asthma'.)

●Fraction of exhaled nitric oxide (FE_NO) – The FE_NO is another method to assess ongoing airway inflammation [31,32]. Sustained high levels of FE_NO appear to be strongly associated with both regular use of systemic glucocorticoids and increased exacerbation risk in patients with severe asthma [33,34]. Management of patients by monitoring and treatment of FE_NO, though much easier to collect than sputum, has not been shown to be of clear clinical benefit [31]. However, FE_NO predicts improvement in FEV₁ in patients treated with some biologics, particularly anti-IL-4Ra antibodies [35,36]. Thus, its utility in severe asthma is evolving. (See "Exhaled nitric oxide analysis and applications".)

●Endobronchial biopsies – Obtaining endobronchial biopsies to assess eosinophilic inflammation carries greater risk than induced sputum and should only be performed at institutions where quantitative measurements are commonly obtained. Bronchoscopy may be helpful to evaluate interstitial findings on CT scanning, for example when chronic eosinophilic pneumonia, sarcoidosis, or hypersensitivity pneumonitis are suspected. (See "Approach to the adult with interstitial lung disease: Diagnostic testing".)

Phenotyping asthma — Some experts have suggested that patients with severe asthma can be characterized into phenotypes [11,13,24,27,37]. Briefly, among patients with severe asthma some are atopic and "early onset," some have a course characterized by frequent and often severe exacerbations, and others have chronic, sometimes severe, airflow limitation that is only partially reversible. (See "Severe asthma phenotypes".)

One "phenotype" of asthma appears to be predominantly T helper lymphocyte (Th)2-Hi (now termed Type-2 given the broader cell sources for IL-5 and -13 than T-cells alone) with eosinophilic inflammation (eg, innate lymphoid Type 2 cells) [38-40] (see "The adaptive cellular immune response: T cells and cytokines", section on 'Th2'). It is hypothesized that identification of Type-2 Hi severe asthma may allow more targeted therapy with interventions, such as increased doses of glucocorticoids or omalizumab, which may be less effective in patients without Type-2 inflammation [41]. Type-2-targeted therapies (eg, antibodies to interleukin [IL]-4, IL-5, IL-13) may be more effective in patients with Type-2 inflammation. These therapies are reviewed in more detail separately. (See "Investigational agents for asthma", section on 'Biologic agents' and "Treatment of severe asthma in adolescents and adults", section on 'Persistently uncontrolled asthma'.)

Severe asthma in the absence of evidence for Type-2 inflammation remains poorly understood, although co-morbidities, such as obesity and other metabolic factors, may play important roles [42].

Chest imaging — A chest radiograph can be performed in patients with symptoms suggestive of severe asthma, especially if the symptoms are somewhat atypical, even though this would not be indicated in the routine evaluation of asthma [2]. If interstitial opacities are noted on the chest radiograph or if the diffusing capacity (DLCO) is reduced, a high-resolution CT (HRCT) scan of the thorax should be performed to assess for interstitial lung disease and bronchiolitis. When trying to discriminate between severe asthma and bronchiolitis, the presence of a mosaic attenuation pattern makes bronchiolitis more likely [43]. (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) [44-46]. (See "Vascular rings and slings".)

The European Respiratory Society and the American Thoracic Society (ERS/ATS) severe asthma task force suggests an HRCT when the presentation of the patient is somewhat atypical, such as a rapid decline in lung function, reduced DLCO, or excessive mucus production [2].

MEDICATION ADHERENCE — Incomplete compliance/adherence to medication is present in many, if not all, chronic diseases and generally to the same degree (approximately 50 percent) [47]. Asthma is no exception, so compliance/adherence to medications must always be addressed [48-50].

Compliance/adherence should be encouraged in a non-judgmental manner (especially if a medication is known to be helpful to that patient), and reasons behind non-adherence explored (eg, fear of side effects or dependence, forgetfulness, cost of medication). (See "Enhancing patient adherence to asthma therapy".)

An overall understanding of the patient's social situation regarding access to medical care, medications and their costs is also important.

If available, pharmacy records can supplement patient report of adherence. Additionally, in patients on oral glucocorticoids, a fasting morning cortisol of <5 mcg/dL is helpful to measure compliance, as is the presence of steroid side effects.

ASSESSING CONDITIONS THAT MIMIC ASTHMA — Several conditions share a symptom complex and can be confused with severe asthma; the most common ones presenting to an asthma specialty clinic are reviewed here (table 8). In addition, some of the conditions that mimic asthma may also accompany asthma including: paradoxical vocal fold motion, allergic bronchopulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic eosinophilic pneumonia, and eosinophilic granulomatosis with polyangiitis (EGPA). These conditions cause the asthma to appear more severe, and require specific treatment separate from asthma.

●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) [51,52]. This syndrome involves involuntary closure of the vocal folds, commonly during inspiration, and can be seen in both men and women. 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 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. (See 'Pulmonary function tests' 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 post nasal drip, gastroesophageal reflux disease (GERD), and anxiety [53]. (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 [44]. 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 tests' above). Chest computed tomography (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 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 [54]. 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 "Asthma and COPD overlap (ACO)" 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 (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 exam 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 "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 who have skin test positivity to aspergillus and elevated IgE levels (>1000 ng/mL). (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 connective tissue disease. Physical exam may reveal crackles and inspiratory squeaks; pulmonary function tests show progressive airflow obstruction not responsive to bronchodilator; DLCO and oxygen saturation are reduced; and chest CT scan will show interstitial opacities in a mosaic pattern [43]. 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 [55-57]. 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 post bronchodilator FEV₁ <80 percent predicted and an FEV₁/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 [55].

●Cryptogenic organizing pneumonia – Cryptogenic organizing pneumonia (also known as bronchiolitis obliterans organizing pneumonia or BOOP) is usually manifest by a nonproductive cough, sometimes dyspnea, systemic symptoms of malaise, and sometimes fever. Crackles are usually noted on chest exam 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. Usually, a lung biopsy is required for diagnosis. (See "Cryptogenic organizing pneumonia".)

●Hypersensitivity pneumonitis – Patients with hypersensitivity pneumonitis (HP) may report intermittent dyspnea than 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".)

●Eosinophilia and respiratory symptoms – Filarial and strongyloides infections and EGPA may present with asthma that cannot be controlled until the underlying disease is treated. Filarial and strongyloides infection should be suspected in patients from an endemic area, who have blood eosinophilia and an elevated IgE level. 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 (CEP) 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. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)" and "Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Treatment and prognosis".)

Concomitant fever, weight loss, and night sweats are often seen in CEP; 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 hypersensitivity pneumonitis or pathologic evidence of vasculitis [58]. 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 [59]. At least some studies in milder asthma suggest that improved upper airway therapy leads to better asthma outcomes [60,61].

Allergic rhinitis symptoms and signs should be evaluated and the nose examined for nasal polyps. Patients with nasal polyposis and asthma are likely to have aspirin-exacerbated respiratory disease (AERD) and to have sudden and life-threatening flares of asthma after ingestion of aspirin or 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 computed tomography (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. (See "Gastroesophageal reflux and asthma".)

●Smoking – Several studies report that asthmatics who smoke are at increased risk for exacerbations, have impaired lung function, and respond poorly to inhaled glucocorticoids [62,63]. 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 women and with worsened asthma severity [64-66]. 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 [67-69]. Both obesity and nasal congestion (eg, from allergic rhinitis or nasal polyposis) may further contribute to the development of OSA [59,70,71]. Daytime sleepiness in patients with asthma is more likely related to OSA than asthma [70].

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 [72-78]. In one study, anxiety and depression were present to a much greater degree in patients with severe asthma than the normal population and were a risk factor for more severe asthma [73]. 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

●Patients with severe asthma are typically in the "severe persistent asthma" and "very poorly controlled" categories of the NHLBI and Global Initiative for Asthma (GINA) guidelines. A consensus definition of severe asthma requires that patients have needed therapy with high dose inhaled glucocorticoid (table 1) and a long-acting beta-agonist (LABA) or leukotriene modifier/theophylline for the previous year and/or have needed systemic glucocorticoids for 50 percent or more of the year to prevent asthma from becoming uncontrolled; other conditions must have been excluded, and exacerbating factors treated (table 2). (See 'Definition' above.)

●Important elements in the history include: age of onset of symptoms, exact description of symptoms, temporal pattern of symptoms, exacerbating factors (table 5), 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.)

●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 eosinophilic granulomatosis with polyangiitis), constrictive bronchiolitis, and endobronchial sarcoidosis (table 8). (See 'Assessing conditions that mimic asthma' above and "Inducible laryngeal obstruction (paradoxical vocal fold motion)".)

●Suggested pulmonary function tests include spirometry pre- and post-bronchodilator with inspiratory and expiratory flow loops, lung volumes, and diffusing capacity. Confirmation of the asthma diagnosis requires expiratory airflow limitation with a bronchodilator response or a positive methacholine challenge. (See 'Pulmonary function tests' above.)

●Laboratory testing in asthma is rarely diagnostic, but certain tests may be helpful, including CBC and blood eosinophil count, total IgE level, alpha-1 antitrypsin, and ANCA. Specific allergen skin testing or immunoassays for allergen-specific IgE may help identify triggers like dust mites and animal dander. (See 'Lab/immunologic testing' above.)

●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.)

●Medication adherence is an important cause of poorly controlled asthma, especially when more complicated treatment regimens become necessary. (See 'Medication adherence' above.)

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

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