Our search included a detailed appraisal of the published peer-reviewed research using the NCBI PubMed website as well as source literature that the authors have accumulated because of a major ongoing interest in severe asthma. Keywords used in the search were “severe asthma”, “classification”, “pathophysiology”, “remodelling”, “treatment”, “diagnosis”, and “natural history”. We only reviewed articles published within the past 10 years in English.
ReviewThe mechanisms, diagnosis, and management of severe asthma in adults
Section snippets
Subphenotypes
Most mild-moderate asthma is associated with atopy, but in the most severe and chronic phenotype other characteristics emerge. Refractory asthma is a heterogeneous disorder that can be subdivided on the basis of different clinical aetiological, physiological, or pathophysiological characteristics.9 Although most cases of severe asthma begin in early childhood as persistent wheezing associated with atopy,10 adult-onset asthma is commonly non-allergic and often misdiagnosed because it possesses
Contributing factors to asthma severity
In most cases, multiple factors are responsible for difficult-to-treat asthma. Many of the risk factors that contribute to disease chronicity are also triggers of worsening asthma and exacerbations, indicating complex interactions with the environment.
Mechanisms of severe asthma
Until relatively recently, all asthma cases were regarded as being similar, differing only in severity and therefore requiring treatment that differed only in the dose, route, or frequency of corticosteroid and β2-adrenoceptor agonist required to control the disease. However, with the identification of asthma subphenotypes this view is being challenged.50 Research over the past two decades has identified allergic pathways as being fundamental to asthma with a prominent part played by a subset
Corticosteroid responsiveness
If dependency on glucocorticoids is essential for maintaining asthma control, then any defects in this pathway will be problematic. Corticosteroid treatment is effective in only about 70% of the general population with asthma.64 In severe asthma the proportion of patients with reduced responsiveness to inhaled and oral corticosteroids is higher than in mild-moderate disease. A wide range of mechanisms have been proposed for corticosteroid refractoriness,65, 66 including proinflammatory cytokine
Airway remodelling
All studies of chronic severe asthma have identified a degree of fixed airflow obstruction as a distinctive characteristic.18, 19, 26 However, there is a subgroup of severe asthma with highly unstable airways and marked bronchial hyper-responsiveness detected even after inhalation of isotonic saline, which has been described as brittle asthma.69 These patients are at great risk of unexpected severe bronchoconstriction, which may be catastrophic. Patients are often young, female, and highly
Asthma exacerbations
Asthma exacerbations are acute worsening of the disease with durations of 3 days or more and a need for unscheduled health-care intervention with an increase in treatment and a suspension of normal activities. Severe asthma is characterised by two or more exacerbations per year. Until recently, there has been little attempt to understand the underlying causes of these events, other than attributing them to allergen exposure or under-treatment. With the availability of gene-based detection
Chronic airway inflammation
Although chronic asthma is associated with airway eosinophilia, when the disease adopts a severe phenotype the inflammatory profile commonly changes to the presence of neutrophils alone or in combination with eosinophils. Initially this process was thought to be a response to increasing inhaled corticosteroids because, by contrast with their proapoptotic effect on eosinophils, these drugs enhance neutrophil survival.99 However, in severe asthma the neutrophils also seem to be in an activated
Role of small airways
Pathology studies in patients who have died from asthma reveal extensive involvement of the peripheral airways with inflammatory, smooth muscle, and remodelling responses (figure 1).111 Transbronchial biopsies have confirmed peripheral airway involvement in severe asthma including the alveoli.112 Additionally, the distribution of inflammatory cells also changes with greater infiltration of the adventitial region with a range of inflammatory cells including chymase-positive (connective
Diagnosis and assessment of severe asthma
Although new algorithm-based approaches are being tested for diagnosis and subphenotyping of severe asthma,115 none has yet been validated in a clinic setting. However, a series of key steps might include establishing asthma as the diagnosis, assessing underlying factors (including under-treatment and poor adherence), and providing an asthma phenotype. Although the diagnosis of asthma according to established guidelines should be relatively straightforward, the presence of phenotypes where
Management of severe asthma
Figure 4 shows an algorithm for the treatment of severe asthma. In accordance with global guidelines, tertiary prevention aims to reduce exposure to known inducers and triggers to improve asthma control. However, there is little evidence that treating such factors has much effect on asthma control; for example, although inhaled allergens are known to be important in driving asthmatic inflammation, allergen-avoidance strategies have generally been disappointing.121 Standard treatment for severe
New approaches to treatment
The introduction of the humanised monoclonal immunoglobulin G1 blocking antibody directed to immunoglobulin E (omalizumab) represents an advance in the treatment of severe allergic asthma when symptoms remain despite use of optimum combination treatment (figure 5).152 In the GOAL (Gaining Optimal Asthma Control) study153 of 3421 patients with uncontrolled asthma in whom combination treatment was increased until total control had been achieved or 1000 μg fluticasone reached, 38% remained
Conclusions
The recognition that there is a substantial number of patients whose asthma is not adequately controlled with conventional treatments reveals an important unmet clinical need in this disease. With the recent increasing trends in childhood asthma, the burden of severe asthma in adults is likely to increase. A combination of early diagnosis and subphenotyping of asthma taking disease severity into account will provide the basis for more accurate diagnosis and targeting of preventative and
Search strategy and selection criteria
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