Difficult Asthma Liam G Heaney, Andrew Menzies-Gow
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Definition, Epidemiology, and Phenotypes of Severe AsthmaCHAPTER 1

Sally E Wenzel
Asthma has long been defined by the presence of reversible airflow limitation (or bronchial hyper-responsiveness) in the setting of appropriate symptoms.1,2 In more recent years, inflammation has loosely been connected to the definition of asthma, but in most cases no measurement or characterization of inflammation in a given clinical patient is performed. This current definition of asthma is almost certainly broad enough to encompass numerous diseases, syndromes, or phenotypes. Yet, until recently, only modest effort had been undertaken to differentiate these different patients and their “conditions.” Further, in milder forms of asthma, most patients are reasonably well treated with nonspecific anti-inflammatory and bronchodilating medications and the ability to distinguish subgroups is less important. However, patients with a diagnosis of severe asthma present with a broad range of characteristics, usually in conjunction with poor response to corticosteroids (CSs) and other traditional therapies and, therefore, distinguishing one subgroup from another is likely to be clinically and scientifically important.
Interestingly, similar to the definition of asthma, most definitions of severe asthma are also general. In addition to ruling out “difficult-to-treat asthma,” most currently utilized definitions require that a patient meets the general diagnosis of asthma and then rely primarily on dependency for high-dose CS treatment in light of ongoing symptoms, frequent or severe exacerbations, and/or poor lung function. Numerous specific definitions have been proposed for severe asthma over the last 20 years, including those proposed by the European Respiratory Society (ERS) and American Thoracic Society (ATS).3,4 Both of these earlier definitions contrasted with various guidelines-based definitions by inclusion of the need for background therapy with high-dose inhaled or systemic CS, and in the case of ERS definition, evaluation and treatment by an asthma specialist. The ATS definition went so far as to propose two major criteria and seven minor criteria encompassing aspects of treatment and control.2
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Figure 1-1: Difficult asthma, defined by poorly controlled symptoms despite treatment or controlled symptoms only on high-dose treatment can be initially subgrouped into those who are difficult to control because of potentially treatment responsive issues, persistent comorbidities, or who have truly treatment resistant (refractory) disease. Adapted from Taylor DR, Bateman ED, Boulet LP, et al. A new perspective on concepts of asthma severity and control. Eur Respir J. 2008;32:545-54.
More recently, the World Health Organization (WHO) defined severe asthma by first identifying three “global” subgroups: (i) untreated severe asthma, an enormous problem in areas of the world where current therapies for asthma are not widely available, (ii) treatment-resistant severe asthma, and (iii) difficult-to-treat (but potentially responsive) asthma.5 Treatment-resistant asthma was further differentiated into those who achieve control on current medications and those who are never able to achieve control despite current medications (Figure 1-1).
Very recently, the Innovative Medicine Initiative (IMI) proposed the term “problematic asthma” as an umbrella term for poorly controlled asthma.6 The consensus statement then categorized problematic asthma into two groups: “difficult asthma,” a group in which the disease itself may not be severe but issues with adherence and poor treatment of confounders make it difficult to control and “severe refractory asthma,” a term reserved for those who have persistent poor control, frequent exacerbations despite acceptable adherence to high-intensity treatment, and treatment of comorbidities (Table 1-1). This IMI definition of asthma will likely form the basis of future joint ATS-ERS definitions.
These definitions from WHO and IMI are based on data from recent large scale studies of severe asthma, which have greatly expanded on our understanding of the range of characteristics accompanying patients with this syndrome.7-9 As part of these studies, the presence of frequent and/or severe exacerbations, low baseline 3lung function and near daily symptoms, all in the face of treatment with high doses of inhaled and/or oral CS have been identified as present in the majority of severe asthma patients.
Table 1-1   Diagnosis of Severe Refractory Asthma—An International Consensus Statement from the Innovative Medicine Initiative
  1. Requires confirmed diagnosis of asthma, compliance/adherence, and comorbidities addressed
  2. All severe asthma patients require treatment with high-intensity treatment by an asthma specialist to prevent patients from becoming uncontrolled or who remain uncontrolled
  1. High-dose therapy: high-dose inhaled CS and LABA (or LT modifier)/or systemic CS. (High-dose inhaled CS-fluticasone >1000 μg/day)
  2. Uncontrolled defined as any one of the following:
    1. Poor symptom control: ACQ consistently >1.5 (or “not well controlled” by published guidelines)
    2. Frequent or severe exacerbations: 2 or systemic CS requiring, including those requiring ER visits or hospitalizations, per year
  3. Controlled or uncontrolled asthma on these high doses of inhaled CSs or systemic CSs (or additional biologics) places a patient at high future risk for side effects from medications
CS, corticosteroid; LABA, long-acting β2-agonist; LT, leukotriene; ACQ, Asthma Control Questionnaire; ER, emergency room.
Source: Bel EH, Sousa A, Fleming L, Bush A, Chung KF, Versnel J, et al. Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative. Thorax. 2011;66:910-17.
Distinguishing Severe Asthma from Difficult-to-treat Asthma
When a patient presents with any or all of these characteristics, a physician should first determine whether a patient has severe asthma or whether the asthma is in reality, not severe, but difficult-to-treat (Figure 1-1).5,10 This often requires evaluation, by an asthma specialist, of comorbid conditions, including those related to compliance/adherence, sinusitis, allergies, gastroesophageal reflux disease (GERD), and psychosocial issues. Studies suggest that adequately addressing these issues will improve the clinical picture in about 50% of patients.11 However, despite the high prevalence of GERD and psychologic disturbances in asthma, particularly depression, treatment of these comorbidities appears to do little to improve asthma outcomes.12,13 Additionally, some comorbidities, including sinusitis and obesity, can be difficult-to-treat and may contribute to the overall refractoriness of severe disease. Significant airflow limitation and air trapping, either by quantitative computed tomography (CT) imaging or physiologic measures, are also often seen in severe refractory asthma and are not easily improved.14-164
As noted, the definition of severe asthma still relies primarily on nonspecific clinical characteristics. Data from both European and North American cohorts, using both biased and unbiased approaches, now strongly support the presence of several subgroups or phenotypes of severe asthma, all of which meet the simple clinical/physiologic definitions for asthma and severe asthma noted earlier. Characterization of these phenotypes should eventually allow identification of genetic, genomic, proteomic, and lipidomic biomarkers, which better define these phenotypes.
Phenotype Definition
The concept of phenotype has been recognized and defined as observable characteristics of an organism, which develop from the interaction of the organism with its environment. In relation to asthma, multiple different terms have been used to identify phenotypes, including phenotypes related to clinical characteristic factors (severity, fixed airflow limitation, and age at onset), which associate or trigger asthma (allergy, aspirin) and finally, pathobiologic characteristics (neutrophils/eosinophils). However, as this field expands and, becomes better defined, a phenotype may better be understood as a “grouping” of several observable or measureable characteristics, often including elements from each of those categories (Table 1-2). As an example, the presence of high numbers of eosinophils in blood/sputum, when evaluated in isolation are in actuality only an observable characteristic. Recent studies are now recognizing that the presence of high numbers of lung eosinophils, especially in someone treated with CS, often has additional associated characteristics, including later age of asthma onset, frequent and severe exacerbations, sinus disease and/or nasal polyps, requirements for high doses of CS to maintain control, and in a subgroup, sensitivity to nonsteroidal anti-inflammatory.17-21 For this chapter, only phenotypes, which satisfy the criteria for multiple consistent and reproducible characteristics from epidemiologic to genetics to biomarkers will be included (Table 1-2).
Table 1-2   Severe Asthma Phenotypes with Numerous Identifiable and Consistent Characteristics
  • Allergic asthma (early or late onset)
  • Adult onset/persistent eosinophilic asthma
  • Aspirin sensitive asthma
  • Late adult onset/female/hormonal and obesity linked
  • Adult onset/infection-related
Approaches to Phenotyping
While the number and type of characteristics required to define a phenotype have not been determined, it is likely that at least 3–4 shared characteristics ranging 5from similarities in epidemiology, genetics, physiology, clinical characteristics, and responses to therapy to the presence of specific biomarkers or pathobiologic mechanisms should be present. These phenotypes can be identified using a biased approach based on observations and analysis of patients as seen clinically, or through un- or lesser-biased statistical approaches. No truly unbiased approaches to phenotyping of asthma or severe asthma have yet been published, as even the statistical cluster analyses were based on initial biased associations of certain characteristics (medication use or eosinophils for instance) and assumptions of what variables to include in the models. Intriguingly, however, both biased and unbiased approaches are pointing towards similar phenotypes and the results are complementary.
Two statistical clustering (unbiased) analyses of severe asthma have been published to date. These cluster analyses differed in their input, with the Leicester (UK) cluster not including lung function as an input variable, but including sputum eosinophils, while the Severe Asthma Research Program (SARP)/US cluster analysis included lung function, but did not include lung/sputum eosinophils.20,22 Despite these different approaches, more similarities than differences exist. In both models, age at onset of asthma was one of the strong independent predictors of phenotype group, with younger age at onset asthma tending to associate with an allergy related process, consistent with previous biased studies, which identified early onset or “extrinsic” asthma as a primarily allergic disease with strong hereditary component and onset in early childhood.21,23 The SARP approach identified five separate clusters, primarily differentiated by lung function, β-agonist use, and age at the onset (Figure 1-2). The Leicester approach identified four clusters, including those with early onset, primarily allergic asthma of different severities. Interestingly, both studies suggested that early onset/allergic asthma makes up about 35–40% of all severe asthmatics.
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Figure 1-2: The five clusters identified by Moore et al. SARP, Severe Asthma Research Program; HCU, health care utilization; QOL, quality of life. Adapted from Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010;181:315-23.
6Both cluster analyses identified at least two different clusters of patients with later onset of disease. In each analysis, a group of late onset asthmatics were identified with symptoms out of proportion to their airway obstruction [as measured by forced expiratory volume in 1 second (FEV1)% predicted in the SARP cluster]. These patients tended to be women, with very late onset (median age at onset in the 5th decade) of disease, who were likely to be obese, and in SARP, were likely to be menopausal or have undergone a surgical menopause. However, inflammatory parameters differed in the two analyses, the SARP patient cluster showing evidence for ongoing eosinophilic and neutrophilic inflammation, while the Leicester cluster had rather non-inflammatory by sputum analysis.
The Leicester cohort also identified a group of late onset, highly eosinophilic severe asthmatics who were exacerbation prone. These late onset eosinophilic asthmatics have also been identified in biased clinical studies supporting the existence of this phenotype.21 Whether this cluster is similar to the “6th” SARP cluster, with late onset, less allergic disease is not yet clear given the differences in study design and approach.
Thus, combining biased and unbiased studies of severe asthma available to date, at least three different subgroups of severe asthma have been consistently identified, which include enough different characteristics to be termed a phenotype. These phenotypes include: (i) allergic/early onset severe asthma, (ii) late onset eosinophilic asthma despite CS therapy [with a subset of aspirin intolerant asthma (AIA)], and (iii) a less well-defined very late onset, obese, and highly symptomatic group consisting primarily of women.
However, it is clear that as our molecular understanding of severe asthma improves, our precision in defining phenotypes and associated biomarkers will also improve (Figure 1-3). It is hoped that this investment will lead to a more personalized, effective, and a safe approach to the therapy for greater numbers of severe asthmatics.
Allergic Severe Asthma
From an epidemiologic perspective, this group of severe asthmatic patients primarily develop their disease in childhood well before the age of 10.21,22 Although, allergic asthma with onset in adulthood certainly occurs, there is often a history of allergic reactions of some sort since childhood.24 This phenotype also appears to have a strong genetic component, with a family history of asthma more common in these asthmatics than in later onset disease.21,22 It remains unclear what percentage of these early onset severe asthma patients had severe asthma since childhood and how many progressively developed severe asthma over time. However, the available evidence suggests that more severe asthma in early childhood is more likely to be 7related to more severe asthma in adulthood, with few children with mild asthma progressing to more severe asthma.25,26
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Figure 1-3: Increasing understanding of the molecular basis of severe asthma phenotypes, while initially expensive, should lead to improvements in the ability to personalize care for each phenotype. From Bousquet J, Mantzouranis E, Cruz AA, Aït-Khaled N, Baena-Cagnani CE, Bleecker ER, et al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol. 2010;126:926-38; with permission.
This early onset allergic group appears to constitute around 40% of all severe asthmatics. In both cluster analyses, patients in this group appeared to be at the extreme end of an allergic asthma phenotype. In the SARP cluster, these patients were more likely to be older, with a longer duration of disease, and were more likely to have reported a history of pneumonia than their milder counterparts. Severe asthmatics with this phenotype are likely to have a high number of allergic skin test reactions, a higher systemic immunoglobulin E (IgE) level, and greater environmental triggers.21,22
Allergy-specific therapeutic approaches have long existed. Allergy immunotherapy in this population is not without risk and there are no data to support its ability to prevent development of severe allergic asthma. In contrast, the introduction of anti-IgE (omalizumab) for the treatment of allergic asthma was one of the 1st attempts to phenotypically direct therapy. Unfortunately, allergic asthma was defined in a rather limited way for these studies. In any case, omalizumab has shown modest efficacy in severe asthma patients with evidence for specific and elevated systemic IgE.27 Intriguingly, however, it does not appear to work in more than 30–50% of “appropriate” patients for unclear reasons, and does not appear to have significant benefit in severe asthmatics on oral CSs.28 Whether anti-IgE would be more effective in 8individuals more rigidly defined as allergic or whether understanding the immmunopathology around IgE would improve responder rates awaits further study.
The presence of an IgE-related process in the airways supports a Th2 immune process.29 Proof of the importance of Th2 cytokines to severe allergic asthma is not yet present, although a recent gene expression study of mild asthma suggested that 50% of mild asthmatics manifested a Th2 gene expression profile associated with atopy/allergic disease.30 Supporting this involvement of Th2 in mild allergic asthma are studies with a mutein of interleukin (IL)-4, which blocks the IL-4 receptor α (IL-4Rα, pitrakinra). These studies demonstrated improvement in both the late fall in FEV1 in response to allergen challenge, as well as in levels of exhaled nitric oxide.31,32 In very small numbers, the response to pitrakinra also appeared to have a genetic component with data suggesting that previously described risk alleles at single nucleotide polymorphisms (SNPs) in IL-4Rα were predictive of response to therapy.32,33 In a 12-week study of a global population of patients with more severe asthma (symptomatic despite modest dose ICS), an antibody to IL-4Rα failed to show efficacy, although a modest benefit was seen in the most symptomatic subjects.34 Unfortunately, no further attempts to characterize the “phenotype,” the responders, was reported in relation to this study. Whether identification of an “allergic/Th2” phentoype would improve the response, particularly in severe asthma, will require further study. Interestingly, studies of lung inflammatory processes (sputum and to some degree tissue) have not consistently shown a predominant eosinophilic inflammation in severe early onset asthma.21,22 In fact, the combination of eosinophilic and neutrophilic inflammation has been associated with the most severe (frequent exacerbations, symptoms, and systemic CS use) disease.35 Whether this implies the additional importance of other immune pathways (particularly Th17) in severe allergic asthma remains to be determined.36,37
Late Onset Hypereosinophilic Severe Asthma (Including Aspirin Intolerant Asthma)
As noted previously, later onset asthma includes several potential phenotypes, although the hypereosinophilic phenotype is perhaps the most distinct, making up around 25% of the severe asthma group, with a recent study confirming the persistence of hypereosinophilia over time.20,21,38 Although two later onset groups were identified in the Moore's clusters, this particular phenotype was not identified. However, it may have been a subset of the later onset, very severe cluster five.22 Epidemiologically, these patients are generally healthy until their late 20s or beyond. An upper or lower respiratory tract infection, with or without the development of chronic sinusitis and nasal polyps can precede the onset of asthma. These individuals typically have both blood and lung eosinophils in high numbers, which persist even in the face of high-dose inhaled CSs. Both eosinophils and cysteinyl leukotrienes (cLTs) are typically higher than those seen in severe allergic asthma.219
A subset reports asthma worsening, often severe, in response to aspirin (Samter's triad), but this phenotype can exist without aspirin intolerance. This AIA is well known to develop later in life and is strongly associated with elevations in eosinophils and cyteinyl leukotrienes.39,40 AIA was the first subgroup of asthma to have specific treatment trials. Because of the high cysteinyl leukotriene levels, treatment with a 5-lipoxygenase inhibitor and/or leukotriene receptor antagonist can lead to marked improvements in both lung function and clinical symptoms.21,41,42
Despite the success of leukotriene modifying drugs in AIA, specific treatment trials in the broader category of hypereosinophilic severe asthma have not been undertaken. However, recent studies with an antibody against the proeosionphilic/Th2 cytokine IL-5 (mepolizumab) have successfully targeted severe asthmatics with high eosinophills.43,44 These studies did not specifically target later onset disease; however, evaluation of the age at onset of the subjects included in the two published clinical trials suggest that the majority of subjects in the trials were later/adult onset hypereosinophilic asthma.
Pathobiologically, although these patients are generally less atopic than those with early onset disease, IgE levels can be elevated and fractional exhaled nitric oxide (FeNO) is often very high, despite inhaled CSs. These findings, combined with the improvement with antibodies against the traditionally Th2-linked cytokine IL-5 suggest that these patients are likely to have a Th2 bias as well, but further confirmation of this relationship is required.
“Later” Onset Symptom-prone Severe Asthma
While this group is included here, as it has, to some degree, been observed in both cluster analyses and is clinically recognized, information on the natural history, pathogenesis, and responses to therapy is limited. In both clusters, these patients were primarily women, with the onset of the disease in the 5th decade or later. Obesity is common and there is an association with natural or surgical menopause.20,22 While systemic CSs in exacerbations are extremely common, more severe exacerbations requiring intensive care or mechanical ventilation rarely occur. Airway obstruction is less than in the other severe asthma phenotypes, but the duration of disease is also less. The pathobiology is unknown with the first cluster analysis suggesting a paucity of inflammation while the 2nd one suggested ongoing eosinophilic and neutrophilic inflammation. Whether targeted weight loss or hormonally based approaches would be helpful awaits further study.
Additional Potential Severe Asthma Phenotypes
While the previous three phenotypes have been consistently described and all present with several linked characteristics, it is likely that additional phenotypes exist. Possible phenotypes include those linked to an initiating upper respiratory 10infection, with associated chronic bronchitic or even bronchiectatic type changes linked to atypical bacteria or viruses, smoking, severe asthma, and others. Some of these later onset asthmatics appear to have a neutrophilic type of inflammation, which has been reported to respond to macrolide antibiotic therapy.45 However, no definitive link to a specific organism has been found, suggesting the response to the macrolide could also be due to anti-inflammatory as opposed to antibiotic effects of the drug. This neutrophilic inflammation also appears to be associated with greater past/current tobacco use, neutrophil elastases, and lower lung function.21,46 A further study of circulating neutrophil gene expression also suggested that the neutrophilic phenotype influenced genes related to cell mobility, apoptosis, and the NF-κB cascade.47 However, targeted therapies beyond macrolide antibiotics have not been attempted.
A final phenotype bears mention as a specific treatment trial suggested efficacy of the antifungal agent itraconazole in asthmatics in the UK with fungal sensitivity.16 Other than rather severe asthma and sensitization to one of several fungal allergens, no additional defining characteristics were observed. Thus, whether this fungal associated severe asthma is merely a subset of allergic asthma or a different phenotype, which will consistently respond better to antifungal therapy, requires further study.
Severe asthma remains a syndrome loosely defined by clinical and physiological changes, without specific biomarkers or pathobiology. Patients with severe asthma, who require current gold standard medications to achieve control, or who never achieve control represent a mix of patient phenotypes, at least three of which have been consistently recognized using both biased and unbiased approaches, and which, to some degree have had successful approaches using targeted therapy. Continued cross-sectional and more importantly, longitudinal and interventional studies are needed to refine our ability to phenotype severe asthma. Future studies, which integrate clinical, pathopysiologic, genetic, and genomic data, including confirmation using targeted biologic therapies should enhance our understanding and treatment of these difficult patients.
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