Version July 2025
INTRODUCTION —
Asthma is defined and diagnosed through a combination of clinical symptoms and physiologic abnormalities, generally without reliance upon pathologic or biologic markers. However, the physiologic definition of asthma is relatively nonspecific, consisting of airway hyperreactivity and airflow limitation during expiration, which is variable and/or reversible with bronchodilators. In most asthma patients, bronchial hyperreactivity is never objectively confirmed.
The data suggesting that multiple phenotypes exist within the classification of "severe asthma" are reviewed here. Details regarding the classification, evaluation, diagnosis, and treatment of severe asthma are provided separately. (See "An overview of asthma management in children and adults" and "Evaluation of severe asthma in adolescents and adults" and "Asthma in adolescents and adults: Evaluation and diagnosis" and "Treatment of severe asthma in adolescents and adults" and "Glucocorticoid resistance in asthma".)
DEFINITION OF SEVERE ASTHMA —
The diagnosis of asthma is based upon the presence or history of symptoms consistent with asthma (most commonly episodic cough, wheezing, or dyspnea) provoked by typical triggers, combined with the demonstration of variable expiratory airflow obstruction. After confirming a diagnosis of asthma and addressing comorbidities, severe asthma is that which requires treatment with high-dose inhaled glucocorticoids (GC) (table 1) plus a second controller (eg, long-acting beta-agonist, leukotriene modifier, theophylline) and/or systemic GC for 50 percent or more of the year to prevent asthma from becoming "uncontrolled" or that which remains "uncontrolled" despite this therapy (table 2) [1,2]. In addition to ensuring appropriate inhaler technique and asthma maintenance therapy use, other conditions must have been evaluated and excluded, and potential exacerbating factors must be remediated.
Based on these definitions of severe and uncontrolled asthma, patients with severe asthma often have the following clinical features regardless of phenotype:
●Glucocorticoid resistance – By definition, severe asthmatics do not have a robust response to low- or medium-dose inhaled GC. Most severe asthmatics receive oral or high doses of inhaled GC at some point in their clinical course, and the response to therapy is often variable [3]. In some patients with severe asthma, the response appears to be shifted so that although a response occurs, it requires extremely high doses. These patients are often described as "glucocorticoid dependent." In a minority of these patients, even high doses of GC may lead to little or no response, or even worsening. These patients may be genuinely GC-resistant. (See "Glucocorticoid resistance in asthma".)
Many, if not most, studies of GC resistance have been done in moderate rather than severe asthmatics, and extrapolation from those results is often difficult [4,5]. Some severe asthmatics may not demonstrate an improvement with GC on a chronic basis but may demonstrate improvement with GC during a period of exacerbation. This difference in the acute versus chronic response has not been studied to date. In addition, patients with persistent sputum eosinophilia appear to respond better to high-dose GC therapy than those with no evidence of eosinophilia [6]. Thus, GC resistance is a rather vague term. Generally, this term has been replaced with more specific phenotypes below.
●Frequent exacerbations – Approximately 30 percent of patients with severe asthma are uncontrolled due to frequent episodes of extreme airflow limitation (aka, brittle asthma) [7,8]. No consistent definition of "frequent exacerbation" has been proposed, but the definition of more than two or three exacerbations per year is commonly used [1]. Patients with frequent exacerbations tend to have greater peripheral airflow obstruction on pulmonary function tests, persistent eosinophilia in blood and bronchoalveolar lavage, and more comorbidities (eg, chronic rhinosinusitis, recurrent respiratory infections, obesity, obstructive sleep apnea, and psychosocial issues) [9-11].
Among patients enrolled in the Severe Asthma Research Program (SARP), frequent exacerbations were associated with persistent eosinophilic inflammation in peripheral blood despite high doses of systemic GC as well as high plasma interleukin (IL)-6 levels [9,12]. However, similar to GC-resistant asthma, the clinical characteristics of frequent exacerbations may be due to multiple different contributors, like smoking, obesity, and psychologic factors. Therefore, this clinical phenotype has generally been replaced with the phenotypes described below.
RATIONALE FOR CHARACTERIZING ASTHMA PHENOTYPES —
Patients with severe asthma present with a variety of clinical histories, physiologic changes (beyond changes in forced expiratory volume in one second [FEV1]), and airway inflammation, suggesting that severe asthma is not a single disease or is a single process that produces widely varying host responses [1,13-15]. Patients with severe asthma may have manifested severe disease all their life, developed progressively more severe disease over time, or may never have had asthma (to the best of their recollection) until some point in their adult life, after which the disease progressed at a rapid pace [13]. Some patients with severe asthma have a clearly defined atopic history, while others give little indication of an allergic component.
In addition to the variability in clinical features, patients with asthma do not respond in a uniform fashion to asthma medications, including glucocorticoids (GC), biologics, and other nonspecific anti-inflammatory/cytotoxic medications. Furthermore, it is increasingly clear that molecular pathways can have different, clinically recognizable phenotypes [16-18]. It is hoped that exploration of asthma phenotypes will translate into an improved understanding of asthma pathophysiology and optimized medication selection [1,19].
SEVERE ASTHMA PHENOTYPES —
Disease characteristics (phenotypes) that are most commonly used to differentiate patients with severe asthma are described in this section. However, substantial overlap among groups exists; as an example, adult-onset asthma does not exclude atopy, although it makes it less likely.
The largest division of severe asthma phenotypes is between those characterized by increased type 2 inflammation (T2-high) and those that are not (T2-low). Type 2 inflammation is defined by elevated airway and blood eosinophils and increased expression of the cytokines IL-4, IL-5, and IL-13. The following sections describe characteristics that have been identified (with greater or lesser frequency) among patients with severe asthma divided into these two groups.
In an attempt to assess phenotypes objectively, two statistical cluster analyses were performed on patients participating in the Severe Asthma Research Program (SARP), including those with mild, moderate, and severe asthma [13]. The first cluster analysis only utilized clinical and physiologic data [13], while the second analysis also included bronchoscopic and inflammatory variables [9]. While similar, some differences were noted. Both cluster analyses identified childhood-onset allergic asthma and very severe asthma with a mixed inflammatory process. The inflammatory clusters also identified a distinct group with adult-onset disease and nasal polyposis (see 'Hypereosinophilic adult-onset asthma with extrapulmonary disease' below). Many of these distinctions may be helpful in directing therapy.
Type 2 asthma phenotypes — Approximately 70 percent of patients with severe asthma have evidence of high levels of T2 inflammation (T2-high); the remainder have little or no evidence for T2 inflammation (T2-low). In general, the eosinophilic/T2-high phenotype appears more common among late-onset severe asthma than childhood-onset, which is more typically associated with atopy.
This division of asthma phenotypes based on biomarkers is increasingly important, at least in the case of T2 biomarkers, as specific T2-targeted therapies with considerable efficacy have been approved for use in T2-high patients (eg, dupilumab, mepolizumab, reslizumab, benralizumab). However, patients with different clinical characteristics or biomarker patterns seem to respond differently to individual biologics and other therapies, as described separately and below. (See "Treatment of severe asthma in adolescents and adults", section on 'Selecting among biologic agents'.)
T2 inflammation is mediated by eosinophils, mast cells, basophils, T helper-2 lymphocytes (which secrete IL-4, IL-5, and IL-13), group 2 innate lymphoid cells (ILC2s), and immunoglobulin E (IgE)-producing B cells [20]. Type 2 inflammation is typically identified using biomarkers, including sputum or blood eosinophilia and fraction of exhaled nitric oxide (FeNO). The European Respiratory Society/American Thoracic Society and the Global Initiative for Asthma (GINA) guidelines suggest that treatment of severe asthma be guided by clinical criteria and biomarkers such as blood eosinophil levels or FeNO rather than by clinical criteria alone [2,21]. Data in support of these measures of T2 inflammation arise from the Severe Asthma Research Program (SARP) and other clinical networks, as well as efficacy clinical trials of antibodies directed towards T2 cytokines [22-26].
Based on response to type 2-directed therapies, blood eosinophil levels between 200 and 300/microL or FeNO levels above 24 ppb support an underlying active type 2 immune process [23,27,28]. Higher levels of these type 2 biomarkers are also associated with higher rates of lung function decline [29]. Nevertheless, individual patient responses to T2 biologics are heterogeneous, and the ideal method for assessing type 2 inflammation is not known [30].
●Sputum and blood eosinophilia – Sputum eosinophilia and measurement of T2 cytokine messenger ribonucleic acid (mRNA) in sputum predict airway eosinophilia, but they are time-consuming and observer-dependent [31]. Statistical associations have been noted between sputum eosinophilia and peripheral blood eosinophil counts and FeNO, but the accuracy of these biomarkers for predicting sputum eosinophilia is imperfect [32,33].
Peripheral blood eosinophils appear to be good predictors of response to type 2-targeted therapy, as shown in studies of the monoclonal antibodies to IL-5 (ie, mepolizumab, benralizumab and reslizumab) and also anti-IL-4RA [27,34-36]. (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)'.)
●Fraction of exhaled nitric oxide – Measurement of FeNO has been used as a biomarker for type 2 inflammation. Increased FeNO levels (eg, greater than 50 ppb in adults or greater than 35 ppb in children) correlate with eosinophilic airway inflammation and responsiveness to inhaled glucocorticoids. (See "Exhaled nitric oxide analysis and applications", section on 'Clinical use of FENO in asthma'.)
In a study of bronchial brushings and sputum obtained from participants with severe asthma, mild/moderate asthma (on or off inhaled glucocorticoids [GC]), and healthy controls, FeNO correlated with sputum eosinophils, while expression of inducible nitric oxide synthetase (iNOS), the enzyme that generates exhaled nitric oxide, differentiated severe asthma from the other groups better than FeNO, arginase 2 mRNA/protein, or nitrotyrosine (NT) protein [37]. In a separate study from SARP, FeNO was a better predictor of systemic GC use among patients with severe asthma than forced expiratory volume in one second (FEV1) [38]. FeNO also consistently decreases in response to IL-4/IL-13-targeted therapies suggesting that at least a portion of the FeNO is driven by these cytokines. In patients with moderate to severe asthma, the addition of FeNO levels to blood eosinophil counts improved prediction of future exacerbations as well as response to dupilumab therapy [28,39].
However, a number of other factors have been identified that affect FeNO values, such as age, sex, atopy, and cigarette smoking, making it an imperfect biomarker for guiding therapeutic decisions. Thus, the European Respiratory Society/American Thoracic Society guidelines [2], the National Asthma Education and Prevention Program (NAEPP) guidelines [40], and the GINA guidelines [21] all suggest that additional research is needed to clarify when and how FeNO should be used (eg, in addition to blood eosinophils) to guide diagnosis and treatment decisions in severe asthma.
Future identification of additional type 2 biomarkers will likely allow better targeting of type 2-directed therapies than currently achievable using clinical factors, blood eosinophils, and FeNO.
Childhood-onset type 2 asthma — Data from case series of patients with severe asthma [41] suggest that childhood-onset (before the age of 12) versus later onset (after age 12) distinguishes two distinct subgroups [13,42-44]. Adults suffering from childhood-onset asthma represents a relatively homogeneous group of patients, often with a strong allergic history and family history of asthma. In contrast, adult-onset asthmatics are a very mixed group of patients. Practically, patients with childhood-onset asthma appear to respond better to anti-IL-4R and anti-TSLP (thymic stromal lymphopoietin) therapies than anti-IL-5/5R therapies. (See "Treatment of severe asthma in adolescents and adults", section on 'Selecting among biologic agents'.)
Adult-onset type 2 asthma — Among patients with adult-onset asthma, those with severe disease are less likely to be atopic (34 percent) than those with mild to moderate persistent asthma (52 percent) [41,45]. While only applicable to a minority of severe asthma patients, atopic/allergic asthma can arise in adulthood, often in patients with a history of allergic rhinitis in childhood. Identifying the presence of atopy has implications for selection of therapy and potentially for environmental modifications (eg, dust mite mitigation). (See "Trigger control to enhance asthma management".)
Many patients with adult-onset type 2 asthma describe the onset of asthma symptoms following a viral illness, occupational exposure, or the ingestion of aspirin, while such histories are less frequent among those with childhood-onset asthma. In adult-onset asthma, an allergic component may be more difficult to confirm, as significantly fewer asthmatics with onset of disease after the age of 12 demonstrate positive allergy skin tests or specific allergic symptoms compared with patients having early-onset disease [46,47]. This phenotype of asthma is also characterized by significant peripheral eosinophilia [41].
Patients with adult-onset type 2 asthma respond better than T2-low patients to anti-IgE, anti-IL-4R, anti-IL-5R, and anti-TSLP biologics. (See "Treatment of severe asthma in adolescents and adults", section on 'Selecting among biologic agents' and "Anti-IgE therapy", section on 'Predictors of response'.)
Hypereosinophilic adult-onset asthma with extrapulmonary disease — A subset of patients with adult-onset eosinophilic asthma require systemic GC to maintain control of their asthma and often need aggressive therapies early in the course of disease [9,42,43,45]. They are less likely to be atopic/allergic but have high levels of blood and tissue eosinophils, as well as high levels of exhaled nitric oxide. These findings are often seen in association with severe sinus disease, nasal polyposis, and, in a minority, aspirin-exacerbated respiratory disease (AERD).
●Chronic rhinosinusitis with nasal polyposis – Patients with eosinophilic inflammation frequently develop symptoms of chronic sinusitis (anterior and posterior nasal drainage, nasal congestion, facial pain/pressure, and reduction of the sense of smell) as well as the development of nasal polyps in the bilateral middle meatus (picture 1 and picture 2). Chronic rhinosinusitis with nasal polyposis and asthma share eosinophilic histopathologic features, a susceptibility to environmental exposures and allergens, and increased levels of type 2 cytokines within the affected tissues. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis", section on 'CRS with nasal polyposis'.)
Agents targeting type 2 inflammation may also have a role in treating nasal polyposis and AERD, particularly in those with concomitant severe asthma. Dupilumab, mepolizumab, and omalizumab are all approved by the United States Food and Drug Administration (FDA) for the treatment of nasal polyps. A post-hoc analysis of tezepelumab also showed benefit for sinonasal symptoms and asthma outcomes in patients with severe asthma and AERD [48]. The higher dosing of dupilumab is typically used in those with nasal polyposis. (See "Chronic rhinosinusitis with nasal polyposis: Management and prognosis", section on 'Biologic therapies'.)
●AERD – AERD refers to the combination of asthma, chronic rhinosinusitis (CRS) with nasal polyposis, and acute upper and lower respiratory tract reactions to ingestion of aspirin (acetylsalicylic acid [ASA]) and other cyclooxygenase-1 (COX-1)-inhibiting nonsteroidal antiinflammatory drugs (NSAIDs). (See "Aspirin-exacerbated respiratory disease".)
AERD is a good example of the complex overlap between the various phenotypes of severe asthma, as illustrated by the following observations. Peripheral blood eosinophilia occurs in approximately 50 percent of patients with AERD, although not all patients with eosinophilic asthma have AERD. Depending on the case series, between 30 and 70 percent of patients with AERD are atopic.
Aspirin desensitization and daily aspirin therapy can be helpful in patients with AERD (with primary benefits in the upper airway). However, it is not used in all patients, often for safety concerns. Leukotriene modifiers may also be helpful. Dupilumab is the best-studied biologic agent in this setting, although omalizumab and mepolizumab have also shown efficacy. (See "Aspirin-exacerbated respiratory disease", section on 'Management'.)
●Eosinophilic granulomatosis with polyangiitis (EGPA) – Asthma is a cardinal feature of EGPA, a multisystem disorder characterized by difficult-to-control asthma, rhinitis, nasal polyps, and prominent peripheral blood and tissue eosinophilia. Patients with EGPA frequently require anti-inflammatory medications for disease control, but they also often benefit from anti-IL-5/5R-directed therapies for disease maintenance. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA)" and "Eosinophilic granulomatosis with polyangiitis: Treatment and prognosis".)
Asthmatic granulomatosis — Some patients with severe asthma have granulomatous inflammation on lung biopsy that is not related to eosinophilic granulomatosis with polyangiitis. It is unknown whether this inflammation is an intercurrent disease process, a consequence of therapy, or a different asthma phenotype. In a case series that included 19 patients with severe asthma who underwent video-assisted lung biopsy, 10 were found to have interstitial nonnecrotizing granulomas with asthma-like submucosal inflammation and mucus plugging in the small airways without evidence of hypersensitivity pneumonitis [49]. Peripheral blood eosinophilia was present in most, and the FeNO was elevated. Atopy was present in 6 of 10. Computed tomography (CT) was abnormal in some patients, and a large majority had a family history of autoimmune disease. (See "Evaluation of severe asthma in adolescents and adults", section on 'Assessing conditions that mimic asthma'.)
Non-type 2 asthma phenotypes — Patients with asthma who lack peripheral and sputum eosinophilia and have a low FeNO are considered to have non-type 2 (T2-low) asthma, which is often characterized by the presence of other mediators such as IL-6, IL-17, IL-1, and IL-18. Clinical characteristics of non-type 2 asthma include obesity, metabolic dysfunction/insulin resistance, history of cigarette smoking or exposure, and neutrophilic inflammation. It is typically later in onset with fewer exacerbations and less obstruction [43,50-52]. There is also less responsiveness to corticosteroids [53], which sometimes leads to treatment with higher doses of inhaled or oral corticosteroids, exacerbating obesity. Treatment for each of these characteristics, often termed "treatable traits," may improve asthma outcomes. Proposed interventions include the use of long-acting muscarinic antagonists, which can benefit asthma irrespective of T2 status [54], chronic azithromycin [55], weight loss, and the anti-TSLP biologic tezepelumab [48,56].
The exact promoters of severe asthma in patients with T2-low inflammation are less well-characterized than the T2-high phenotype but likely involve neutrophilic, smooth muscle, or metabolic-related processes [57]. Mediators shown to be present in (but not exclusive to) non-type 2 asthma include IL-1 beta, IL-6, IL-17, IL-18, interferon gamma, and tumor necrosis factor alpha [57-62]. Despite recognition of some of the biologic mechanisms underlying T2-low asthma, the utility of these cytokines as reliable and consistent biomarkers remains to be determined. The mediator TSLP, which is associated with both non-type 2 and type 2 asthma, holds promise but is not reported in peripheral blood samples. Inhibition of this airway epithelial cell product, also called an "alarmin," reduces exacerbations in non-type 2 asthma, but greater benefits are seen in patients with type 2 markers [63-65]. (See "Treatment of severe asthma in adolescents and adults", section on 'Anti-thymic stromal lymphopoietin (tezepelumab)'.)
Neutrophilic asthma — The existence of a neutrophilic asthma phenotype (eg, 40 to 60 percent neutrophils in induced sputum) is controversial [50,66,67]. The specificity of neutrophilic inflammation for a particular subtype of asthma is complicated by the many confounding factors that can contribute to neutrophilia in sputum, including the use of inhaled GC, air pollution, respiratory infection, sensitization to aspergillus, and gastroesophageal disease.
Analysis of patients in SARP identified two subgroups with moderate to severe asthma and frequent health care use despite treatment with high doses of inhaled or oral GC; one of these subgroups also had reduced lung function [9,13,68]. The majority (>83 percent) of those with reduced lung function had sputum neutrophilia alone or in combination with sputum eosinophilia. The combination of neutrophilia and eosinophilia in sputum appears to identify a more severe phenotype [68]. (See 'Rationale for characterizing asthma phenotypes' above.)
Sputum and blood neutrophilia have shown associations with asthma morbidity in some [69-72], but not all [73,74], cohorts. In one cohort study, sputum neutrophilia was associated with pre- and postbronchodilator FEV1, suggesting that neutrophilic airway inflammation may have a role in persistent airflow limitation in asthma [69]. Several separate long-term cohort studies have demonstrated that elevated blood neutrophilia is also associated with an increased risk of asthma exacerbations [70-72]. For example, in one cohort, asthma patients with blood neutrophil counts >4400 cells/microL demonstrated higher inhaled corticosteroid and antibiotic use, increased BMI (body mass index), elevated C-reactive protein, and lack of lung function decline compared with patients without neutrophilia [72].
Clinical trials of agents targeting neutrophilic information have not demonstrated benefit. One clinical trial of a CXCR2 (IL-8 receptor) antagonist in severe uncontrolled asthma did not show efficacy in reducing exacerbation rates [75]. A separate study confirmed reduction of lung neutrophil recruitment in participants with asthma treated with this inhibitor [76], suggesting that improving lung neutrophilia does not significantly reduce exacerbations.
There has been interest in IL-17 as a prominent mediator in neutrophilic asthma. In one study involving three cohorts of children and adolescents with asthma (61 percent with Puerto Rican ancestry, 33 percent with African American ancestry), transcriptomic profiling of the nasal epithelium revealed an "IL-17-inducible (T17)-high/type 2-low" profile in approximately 40 percent of participants [77]. This was distinct from "type 2-high/T17-low" and "type 2-low/T17-low" signatures (present in approximately 25 and 35 percent of participants, respectively). Pathways related to neutrophil adhesions and degranulation, as well as other immune responses to viruses, cytokines, and interferon-gamma, were upregulated in this T17-high group, whereas pathways related to eosinophils and IL-13 were upregulated in the "type 2-high" group. Unfortunately, a study targeting IL-17 did not show any meaningful difference in asthma control [78]. Prespecified subgroup analyses did not focus on blood or sputum eosinophils, so their impact on any possible treatment effect is uncertain.
IL-6/obesity-associated asthma — Obesity has a complex association with asthma, in that development of obesity can both worsen existing asthma and predispose to asthma development. Obesity can also be a consequence of asthma and medications used to treat severe asthma. In general, studies of weight loss interventions show improvements in asthma control, asthma-related quality of life, and lung function if a sufficient amount of weight loss (at least 5 percent) is attained [79]. (See "Obesity and asthma".)
The role of other pathways in the pathogenesis and treatment of non-type 2 asthma associated with obesity include:
●Insulin resistance – Metabolic dysregulation in obese asthmatics is becoming increasingly recognized as resulting in more severe disease. In one study of patients with severe asthma, those with insulin resistance demonstrated a more rapid decline in lung function and increased resistance to beta-agonist and oral GC therapies compared with patients having normal insulin sensitivity [80]. These metabolic effects were more strongly associated with asthma outcomes than obesity itself. Clinical trials evaluating asthmatic participants with insulin resistance are needed to determine if improving insulin resistance improves these asthma outcomes.
●Elevated IL-6 levels – A phenotype of severe asthma associated with obesity and high IL-6 plasma levels has been described [57,81]. In particular, IL-6 levels appear to be associated with higher BMI, and those with obesity and high plasma IL-6 demonstrate decreased lung function and more frequent exacerbations than those with lower IL-6 levels. The presence of this phenotype begs the question of whether agents that inhibit IL-6 could help treat asthma for those with this phenotype. This concept is currently being evaluated in the National Institute of Health funded Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) study [82].
●Arginine metabolism – A link between arginine metabolism, obesity, and nitric oxide production may be involved in late-onset low-T2 asthma associated with obesity. Asymmetric dimethyl arginine (ADMA) inhibits all the isoforms of the enzyme that produces nitric oxide, NO synthase (NOS). In one study, the plasma ratios of L-arginine (the precursor to NO) to ADMA were associated with obesity in those with late-onset (compared with early-onset) asthma and could explain a significant portion of the inverse relationship between BMI and FeNO [83]. In addition, the reduced ADMA to L-arginine ratio was associated with clinical characteristics such as reduced lung function and increased symptoms.
Perimenopausal-onset asthma — Onset of asthma within a year of a last menstrual period may define a separate asthma phenotype [46,47]. In a case series, induced sputum from 40 female participants with menopause-onset asthma showed a higher percentage of neutrophils and a slightly lower percentage of eosinophils compared with sputum from 35 female participants with premenopausal-onset asthma [47]. None of those with menopausal onset asthma were atopic, while 76 percent of the premenopausal-onset asthma group were atopic. Whether menopausal-onset asthma is different from adult-onset asthma in males requires additional study. Similarly, how much overlap there is with other low-T2 adult-onset phenotypes remains to be determined. A large percentage of the late-onset low-T2 cluster 3 from the SARP, for example, were both obese and postmenopausal [13].
Paucigranulocytic asthma — This phenotype of asthma, characterized by a lack of sputum eosinophilia or neutrophilia, is poorly understood. Characteristics of this population may include airway hyperresponsiveness and chronically reduced lung function [84]. However, the lack of cellular inflammation may result from type 2 asthma treatment (wherein T2 biomarkers are reduced). It therefore remains unclear whether this patient group represents a separate clinical phenotype.
Complex combined type 1 and type 2 asthma — Emerging epidemiologic data suggest that a form of severe asthma may exhibit both type 2 and type 1 inflammation, with markers such as interferon-gamma, the macrophage transcription factor IRF5, and chemokines CXCL-9 and 10, suggesting autoimmunity coexisting and possibly complicating the type 2 disease [85-87]. There are also data that the autoimmune disease rheumatoid arthritis may be associated with asthma, but an association with disease severity has not yet been established [88,89]. Type 1 responses may also be associated with intermittent or prolonged presence of respiratory viruses (rhinovirus and coronavirus) [53]. The inflammatory type 1 and type 2 phenotype results in a reduced response to glucocorticoids [90] and, in some cases, a need to consider other immunosuppressive agents.
As an example of complex type 1 and 2 inflammation in asthma, one study described patients with asthma whose airway biopsy specimens demonstrated expression of a transcriptional profile identified by IL-6 and soluble IL-6R activation in cultured bronchial epithelial cells [90]. Compared with patients who did not have this transcriptional signature, these patients had more frequent exacerbations, increased peripheral blood eosinophilia, submucosal infiltration of T-cells and macrophages, and evidence of both impaired epithelial barrier function and airway remodeling. Soluble IL-6R signals through airway epithelium independent of T2 inflammation and creates a separate gene signature. However, it also contributes to T2 inflammation by eliciting IL-33 from epithelial cells, resulting in airway eosinophilia [90].
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".)
SUMMARY
●Definition – A consensus definition of severe asthma requires that patients have needed therapy with high-dose inhaled glucocorticoids (GC) (table 1) and a long-acting beta-agonist (or leukotriene modifier) for the previous year and/or have required systemic GC 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 of severe asthma' above.)
●Rationale for phenotyping severe asthma – Severe asthma represents a heterogeneous population. This heterogeneity is obvious to clinicians who treat asthma routinely and notice that responses to therapy vary among patients. Identification of asthma phenotypes may provide an improved understanding of asthma pathophysiology and optimize treatment selection. (See 'Rationale for characterizing asthma phenotypes' above.)
●Differentiating characteristics – The largest division of severe asthma phenotypes is between those characterized by increased type 2 inflammation (T2-high) and those that are not (T2-low). Type 2 inflammation is defined by elevated airway and blood eosinophils and increased expression of the cytokines IL-4, IL-5, and IL-13. Peripheral blood eosinophil count and the fraction of exhaled nitric oxide (FeNO) are the typical markers used clinically to identify patients with elevated type 2 inflammation.
Other characteristics that appear to differentiate subgroups or "phenotypes" of severe asthma include age, sex, age of asthma onset, atopic status, obesity, extrapulmonary eosinophilic disease, and possibly sputum neutrophilia, although substantial overlap exists among these. Research efforts are focusing on the identification of accurate and reproducible biomarkers that can target therapies efficiently to patients who could most benefit from them. (See 'Severe asthma phenotypes' above.)
●Current uses of phenotyping in severe type 2 asthma – A better understanding of asthma phenotypes has guided current approaches to biologic therapy in those with severe type 2 asthma. As an example, those with adult-onset type 2 asthma appear to benefit more from anti-IL5/5R therapies than those with childhood-onset atopic disease. Those with aspirin-exacerbated respiratory disease (AERD) may benefit from treatment with anti-IL-5/IL-5R antibodies or IL-4RA antibodies. (See 'Type 2 asthma phenotypes' above and "Treatment of severe asthma in adolescents and adults", section on 'Selecting among biologic agents'.)
●Non-type 2 asthma – Non-type 2 asthma is characterized by the absence of eosinophilic inflammation and the presence of other mediators such as IL-6, IL-17, IL-1, and IL-18. Clinical characteristics of these patients include obesity, metabolic dysfunction/insulin resistance, history of cigarette smoking or exposure, and neutrophilic inflammation. (See 'Non-type 2 asthma phenotypes' above.)
At present, asthma lacking type 2 inflammation may be addressed by treatment of associated traits, including weight loss, tobacco cessation, and insulin management. Ongoing clinical research in this area may identify novel therapeutics or mechanisms for this severe asthma subtype.
●Complex combined type 1 and type 2 asthma – Emerging epidemiologic data have demonstrated a form of severe asthma that exhibits both type 2 and type 1 inflammation, suggesting autoimmunity concomitant with type 2 inflammation. As many biologics alter the balance of T2 and T1 immune processes, identifying optimal treatment regimens for these patients may be challenging. (See 'Complex combined type 1 and type 2 asthma' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Sally Wenzel, MD, who contributed to earlier versions of this topic review.
