Severe asthma: current challenges and progress

Asthma is not a modern disease. Descriptions of the disease and its treatment can be found in ancient Egyptian and Chinese literature. It was not until relatively late in the 20th century, however, that asthma was recognised as an inflammatory disease, allowing treatment of the disorder to extend beyond mere symptom relief. 

Moreover, only in the past 20-30 years has it been established that, far from constituting a single disease entity, asthma rather should be considered a syndrome, a final symptomatic pathway with a myriad of underlying pathobiologies.

With this understanding of the cellular and molecular mechanisms of asthma has come huge strides in the treatment of the disorder. Nonetheless, asthma remains a potentially serious condition – in 2010 asthma accounted for over 5,000 hospital admissions, 101 ICU admissions and at least 44 deaths in Ireland. Consequently, identifying and appropriately treating patients with severe asthma remains a clear priority. 

Patient phenotyping

Asthma is characterised by airway inflammation, airflow obstruction and bronchial hyper-responsiveness. However, the nature of this inflammation can vary greatly from one asthmatic individual to the next, and may often predict responses to medical therapy. Selecting the right treatment for the right patient should be a hallmark of modern asthma management, an approach that should help to avoid the futile prescription of ineffective medications. Data from the US Severe Asthma Research Project and from the UK have allowed the identification of clinically relevant, phenotypically distinct groups of patients with severe asthma.^1,2 Broadly speaking, these can be classified according to the degree and nature of airway inflammation, airflow obstruction and bronchial hyper-responsiveness, along with obesity and age of disease onset. 

An important clinical upshot of this work has been the identification of a group of obese, often female, asthma patients who are less likely to respond to front-line asthma drug therapy. Meanwhile, the importance of characterising the nature of asthmatic airway inflammation has been demonstrated by trials of novel therapies, which are only efficacious in certain sub-populations of asthma patients,^3,4 and will be discussed in further detail below. It should be emphasised that these advances in phenotyping are not a substitute for established methods. Specifically, all poorly controlled/severe asthma patients should undergo careful evaluation for atopy by, at a minimum, skin testing for aeroallergens and measurement of serum IgE.

Confounding factors

Despite thorough phenotyping and initiation of appropriate therapy, a substantial proportion of severe asthma patients may not achieve adequate control of their disease. Before escalation of treatment using emerging, sophisticated and expensive modalities is considered, a number of potential confounding factors should be addressed. Probably the most important of these is compliance with prescribed treatment. 

Suboptimal adherence to medication leads to increased asthma-related morbidity and mortality, and appears to be strikingly prevalent in cohorts with poorly controlled asthma, with over a third of such patients filling 50% or less of their prescriptions.⁵ An astonishing 45% of patients prescribed long-term, maintenance oral corticosteroids are non-adherent to their medication regimen. While changes in measurements of plasma prednisolone levels or of exhaled biomarkers, such as fractional exhaled nitric oxide (FeNO), can be used to provide objective evidence of compliance,⁶ at the very least an evaluation of the patient’s prescription uptake should be considered mandatory. A number of medical comorbidities may also lead to significant difficulty in successfully treating severe asthma. In particular, concomitant rhino-sinusitis, bronchiectasis and allergic broncho-pulmonary aspergillosis (ABPA) should all be considered, with appropriate treatment initiated if history, examination or clinical investigations suggest their presence. Similarly, gastro-oesophageal reflux disease (GORD) appears to occur in approximately 40% of severe asthmatics, is frequently occult, and may worsen asthma symptoms via micro-aspiration or via vagal nerve stimulation.⁷ However, while high-dose acid suppression therapy appears to be beneficial in a subset of asthma patients with significant nocturnal asthma symptoms and symptomatic GORD,⁸ its utility in subjects with occult GORD remains controversial.⁷

An under-appreciated driver of severe asthma is aspirin sensitivity. Typically manifested by the gradual development of refractory rhinitis, nasal polyposis, and subsequent lower airway inflammation, aspirin-sensitivity may be present in 20% of adults with asthma.⁹ While a formal aspirin challenge is required to definitively establish the diagnosis, a dramatic response to leukotriene receptor blockers may be highly suggestive of its presence. In a subset of patients, aspirin desensitisation followed by daily aspirin therapy may be required to achieve satisfactory symptom control.

Finally, continued exposure to allergens can drive persistent symptomatology in atopic patients. A number of interventions, ranging from aggressive home cleaning and the use of temperature-controlled laminar airflow devices to remove allergen from the bedroom,¹⁰ to relocation of patients to higher-altitude locations,¹¹ have been shown to be efficacious, but can involve substantial cost and intrusion. 

Emerging therapies

Bariatric surgery

Asthma occurs in about 25% of subjects with morbid obesity, and its prevalence increases in parallel with body mass index. Likely driven by a combination of mechanical factors, metabolic dysfunction and systemic inflammation, asthma in these patients is often refractory to front-line treatments.¹² Performing bariatric surgery appears to improve lung function and reduce bronchial hyper-responsiveness and medication use in obese people with asthma, and may allow for complete cessation of asthma medications in some subjects.^13,14

Bronchial thermoplasty

Airway smooth muscle has been described as a vestigial organ, the pulmonary equivalent of the caecal appendix. In asthma, it is hypertrophied, mediating acute bronchoconstriction and contributing to bronchial hyper-responsiveness. Bronchial thermoplasty (BT) – the ablation of airway smooth muscle by thermal energy with a heat-conducting catheter applied to the bronchial wall through a standard fibreoptic bronchoscope – is predicated on the theory that reducing airway smooth muscle mass will attenuate bronchoconstriction, and improve asthma control. In two multi-centre, randomised, controlled trials in people with severe asthma, BT successfully reduced severe exacerbation frequency and emergency room visits, but at the cost of significantly increased respiratory symptomatology around the treatment period.^15,16 BT is a potentially exciting new development in asthma care, but its exact positioning in the therapeutic armamentarium is yet to be fully established.

Targeted therapies

The translational application of basic scientific research findings has allowed the development of novel targeted biological therapies in asthma. The best established of these is omalizumab, a monoclonal antibody to IgE, which has demonstrated significant efficacy in reducing exacerbation frequency in subjects with severe atopic asthma. Moreover, it also reduces the number of bed days and hospitalisations in such patients, and may lead to substantial overall savings in healthcare costs, despite the relatively high upfront cost of the drug.¹⁷

Interleukin (IL)-5 is a key cytokine-mediating eosinophilic inflammation, and blockade of its effects using another monoclonal antibody, mepolizumab, has been shown to reduce exacerbation frequency and prednisolone requirements in patients on oral corticosteroids with persistent sputum eosinophilia.³ However, the importance of careful patient selection is emphasised by its lack of efficacy in milder asthma populations. Similarly, lebrikizumab blocks IL-13, a driver of airway remodelling and glucocorticoid resistance in the asthmatic airway, and appears to improve lung function and reduce exacerbation rate in asthmatic subjects.⁴ Again, though, this effect appears restricted to subjects with elevated circulating levels of periostin, a matricellular protein secreted by bronchial epithelial cells in response to IL-13, and a putative marker of IL-13 activity.

Not all attempts to translate asthma biology into treatment have been successful, however. Tumour necrosis factor (TNF)-alpha appears to play a role in airway remodelling and eosinophil and neutrophil migration, and initial clinical studies suggest blockade of TNF-alpha with etanercept may reduce bronchial hyper-responsiveness and improve asthma-related quality-of-life scores. However, subsequent larger trials of etanercept and another anti-TNF-alpha agent, golimumab, have proven disappointing, with no substantial treatment benefits observed.^18,19

Conclusion

Key steps in the successful management of patients with severe asthma include careful phenotyping of the patient’s disease, ensuring adherence to treatment with established therapies, and the exclusion of confounding comorbidities. Meanwhile, the burgeoning selection of targeted therapies places the treatment of asthma at the forefront of personalised respiratory medicine.  

References

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