How many types of asthma are there... and does it matter?
Asthma is a complex, heterogeneous syndrome and there is increasing interest in whether reclassifying it will help in terms of understanding its mechanisms and directing treatments
Far from being a well-understood, pathological problem causing a uniform set of familiar symptoms that responds to treatment in a predictable fashion, asthma is now acknowledged to be a complex, heterogeneous syndrome. The recognition of the heterogeneity of asthma has led to a current and increasing interest in whether reclassifying the condition will be helpful, both in terms of understanding its underlying mechanisms and in enabling more specific directing of treatments. This article reviews the current state of play in this endeavour and will familiarise you with the up-to-date terminologies surrounding the classification of asthma.
THE TERMINOLOGY
There are a variety of current national and international definitions of asthma,1-3 all based on a similar premise. They focus on a constellation of commonly accepted and recognised respiratory symptoms, such as chest tightness, wheeze, cough and breathlessness, associated with evidence of variable airway calibre and underpinned by airway inflammation.
Intrinsic and extrinsic asthma
While there has always been recognition of the importance of a genetic component to asthma, historically asthma was considered to be divided into allergic ('extrinsic') asthma, associated with hypersensitivity to environmental allergens, and non-allergic ('intrinsic') asthma, where no such associations were immediately apparent.
The concept of non-allergic, 'intrinsic' asthma is not new. It was initially described in the 1940s4 and was based on the observation that a clinical syndrome similar to asthma occurred later in life, often following an episode of infection, and was not characterised by the presence of IgE (immunoglobulin E) or a raised eosinophil count - the hallmarks of allergy and allergic asthma. The subsequent five decades saw a quest to describe the immunological processes and pathology behind the hypothesis of the two different types of asthma, extrinsic and intrinsic, leading to the development of the concept of allergic 'extrinsic' asthma being associated with a T-helper 2 (TH-2) cell mediated inflammatory process - the TH-2 inflammation hypothesis.5
Essentially the TH-2 inflammation hypothesis proposes that allergens are processed in the airways, leading to TH-2 cells facilitating the production of IgE and eosinophilic inflammation. The concept is that patients become sensitised to various allergens and that subsequent exposure to those allergens drives the inflammatory changes seen on close examination of the airways, which are responsible for the symptoms seen.
Many studies in animal models lend support to this hypothesis6,7 and have helped identify the mechanisms involved in TH-2 mediated airway inflammation. However, although laboratory and animal studies appeared to point the way to an effective treatment for extrinisic asthma fueled by TH-2 inflammation, the clinical observation was that, while many patients with asthma demonstrated these clinical and pathological characteristics, the results with treatments that had anti-TH2 activity, such as methotrexate and cyclosporin, were disappointing.8,9 As is often the case in medical research, results from the laboratory are not always mirrored by clinical reality! In addition, evolving techniques in airway physiology and pathology identified that bronchial hyper-responsiveness and airway remodeling, well recognised features of asthma, could be present in the absence of TH-2 airway inflammation.10,11
ASTHMA PHENOTYPING
As a result of the obvious clinical heterogeneity seen in patients with asthma, both in childhood and adult life, work began to focus on identifying clinically similar groups of patients. This process became known as asthma phenotyping. A phenotype is defined as:
'The observable characteristics of an individual that are the result of an interaction between the genes and the environment.'12
Recently a number of clinical asthma phenotypes have been described13-15 and this has prompted an attempt to target specific treatments at specific groups of patients. A current example of this type of targeted therapy would be the use of monoclonal anti-IgE antibody (omalizumab) therapy in patients with severe allergic asthma who suffer from recurrent exacerbations.16
Much of the interest in adult asthma phenotypes has focused on patients with 'difficult asthma' that is resistant to standard inhaled therapy, such as inhaled corticosteroids or long-acting beta-agonists. However, phenotypic evaluation in paediatric asthma has centred mainly on the observation of the natural history of wheezing from early years into adulthood. Four distinct clinical patterns have emerged:
- Transient wheeze of infancy
- Non-atopic wheezing in toddlers
- IgE-mediated wheeze -'?asthma'
- Late-onset childhood asthma.17
In both adults and children studies of the mechanisms underlying these clinical phenotypes have helped inform our understanding of airway biology, but have also provided confusing results. For example, it would be reasonable to assume that early intervention in IgE-mediated wheezing in children would help preserve lung function in later life. However, this has not always proved to be the case.18 Indeed, the study of the mechanisms of disease in various clinical asthma phenotypes has only served to reinforce the heterogeneity of asthma in terms of underlying mechanisms. As a consequence there is now a move to define and characterise people with asthma by the mechanisms involved in their disease (endotype) as well as their phenotype.
ASTHMA ENDOTYPING
The rationale for endotyping in asthma is that by defining it on the basis of a functional or pathophysiological mechanism it may be possible to develop markers of disease activity for the various mechanisms and also to develop distinct therapies against the process, or processes, involved in a particular individual. This is not to say that clinical phenotypes of asthma will be rendered obsolete - far from it. It will remain important to appreciate that a patient with asthma may have more than one endotype and that any targeted management strategy will therefore have to address all the processes involved if it is to be fully effective.
HOW ROBUST ARE THE DEFINITIONS?
The main focus of phenotyping in adults has centred on patients with severe asthma since, in the asthma spectrum, they represent an important cause of morbidity. A number of clinical patterns of severe asthma have been recognised and described, including:
- Early or late onset
- Variable or fixed airway obstruction
- Trigger-dependent (such as aspirin sensitivity), and
- Asthma with obesity.19
In addition phenotypes have been identified based on the nature of airway inflammation, such as eosinophil or neutrophil predominant asthma.20 However, whilst these phenotypes may be clinically recognisable, they are inconsistent in terms of mechanisms of asthma. For example, asthma with obesity is associated with mechanical problems with ventilation, low-grade systemic inflammation and airway inflammation, and is not generally associated with eosinophilic airway inflammation... but not all obese asthmatics have no eosinophils in their sputum! Nevertheless, phenotypical classifications of asthma have led to the development of systems designed to identify different processes in individual patients in a systematic fashion, in an attempt to target therapies that are most likely to be successful. As such they may represent a way forward.
One approach to phenotyping of asthma in the UK is the A-E of airways disease.21 (Table 1) As this table illustrates, identifying specific characteristics would enable clinicians to target therapy appropriately to each individual component. The theory is that by maximizing therapies in the A-E range an overall greater improvement in response could be obtained. We await clinical trials to validate this but reports from centres running specialist, difficult asthma clinics are encouraging.22
The main problem in phenotype asthma management at the present time, however, is that there are not many robust markers of phenotypic activity that will enable clinicians and patients to adjust therapy accordingly. With the exception of induced sputum eosinophils and corticosteroid therapy, little is known about what markers of specific pathobiology we should be measuring to determine treatment success. The successful use of sputum eosinophil counts in managing and adjusting corticosteroid dose in eosinophilic asthma, however, should be a real impetus for us to pursue this approach.23 Hence it is likely that, in the future, people with asthma may be 'endotyped'- meaning that the specific pathophysiological mechanism relevant to their disease would be identified - and validated biomarkers of this mechanism utilised to monitor the effects of therapies. Currently six 'partial' asthma endotypes have been proposed (Table 2).
On the surface, the terms 'severe allergic asthma', 'late-onset eosinophilic asthma', 'aspirin-exacerbated airways disease' and 'allergic bronchopulmonary mycoses' are readily recognisable clinically. However, there is still considerable discussion surrounding their underlying pathophysiological mechanisms and where there are possible areas of overlap. The challenge remains to validate these proposed endotypes in patients presenting with symptoms compatible with airways disease, and to develop robust markers of disease presence and response to treatment.
CONCLUSION
Asthma in 2012 remains a heterogeneous condition, which constitutes a syndrome of clinical phenotypes and possible mechanistic endotypes. At present there is considerable overlap in both 'types' and currently we can truly say that we are not sure how many types of asthma there are.
There is much work still to be done, but it is certainly exciting 'work in progress'. In the future, a greater understanding of asthma phenotypes and endotypes may enable us to 'personalise' asthma treatment to produce maximum therapeutic effect and improve outcomes for our patients. Watch this space!
REFERENCES
1. Asthma Definition BTS
2. National Heart, Lung and Blood Institute, National Institutes of Health, US Department of Health and Human Services. Expert Panel Report 3: guidelines for the diagnosis and management of asthma. Section 2 p1. www.nhlbi.gov/guidelines/asthma/asthgdln.htm.
3. Asthma Definition ERS
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8. Vrugt B, Wilson S, Bron A et al. Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma: effect on mucosal inflammation and in vitro sensitivity of mitogen-induced T-cell proliferation.
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http://medical-dictionary.thefreedictionary.com/phenotype 13. Wenzel SE. Phenotypes in Asthma: Useful Guides for therapy, Distinct Biological processes, or Both? Am. J. respire. Crit. Care Med. 2004; 170:579-582
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16. Omalizumab for severe persistent allergic asthma. www.nice.org.uk/TA133.
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18. Den Otter JJ, van Schayck CP, Folgering HT et al. Early intervention with inhaled corticosteroids in subjects with rapid decline in lung function and signs of bronchial hyperresponsiveness: results from the DIMCA programme. Eur. J. Gen. Pract. 2007; 13: 89-91.
19. Lotvall J, Akdis CA, Bacharier LB et al. Asthma Endotypes: A new approach to classification of disease entities within the asthma syndrome. J. Allergy Clin. Immunol. 2011; 127:355-60.
20. Berry M, Morgan A, Shaw DE et al. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax 2007; 62:1043-49
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23. Green RH, Brightling CE, McKenna S et al. Asthma Exacerbations and sputum eosinophil counts: a randomized controlled trial. Lancet 2002; 360:1715-1721.
