Difficult-to-Treat Severe Asthma (out of print)

Difficult-to-treat severe asthma patients should be systematically approached in the clinic to confirm the diagnosis of asthma, exclude alternative diagnosis, identify comorbidities, assess treatment compliance and evaluate for treatment-induced side-effects. During the initial evaluation process the following procedures are recommended: 1) the recording of a subjects detailed clinical history focusing on asthma, determining triggers and comorbidities that may contribute to poor asthma control; 2) a physical examination; 3) lung function tests, including spirometry with bronchodilator responses, lung volumes and diffusion capacity; and 4) laboratory tests, including serum immunoglobulin E levels and peripheral eosinophil count. Compliance with the treatment plan and inhaler technique should also be reviewed. Additional tests, including allergy skin testing, sputum eosinophil detection, multidetector row computed tomography scanning, laryngoscopy, polysomnograph and bronchoscopy may also be used as indicators for the evaluation of comorbidities and the confirmation of an asthma diagnosis. Evaluation of difficult-to-treat asthma should be performed by clinicians with special expertise in asthma or in specialised asthma centres.

Severe asthma is characterised by frequent and severe exacerbations, ongoing symptoms and often low lung function. In countries where asthma medications are easily available these factors often persist despite high doses of medication. This group of characteristics in association with severe asthma suggests that definitions require a background need for high doses of “gold standard” asthma medications to prevent the asthma from becoming poorly controlled, or which remains uncontrolled despite this therapy. In addition, it is recognised that the umbrella term “severe asthma” encompasses multiple different phenotypes. Various biased and unbiased studies have led to the general appreciation that early onset allergic asthma probably contributes to the largest number of severe asthmatics. However, other phenotypes, including a late onset, eosinophilic phenotype, as well as a symptom-prone very late onset disease common in females, are also becoming better recognised. Ongoing studies linking phenotypes to genetic/epigenetic background and ongoing gene expression will strengthen the mechanistic understanding of these phenotypes and improve the search for biological therapeutic targets.

Asthma is a multifactorial disease caused by the interaction of genes and the environment. This interaction can influence the development of asthma and the progression and severity of this disease. Early genetic studies focused on known candidate genes and pathways associated with asthma susceptibility, although positive associations were not always replicated. Recent genome-wide association studies (GWAS) identified five genomic regions consistently associated with asthma: ORMDL3-GSDMB, interleukin (IL)-33, IL-1RL1, RAD50-IL-13 and HLA-DR/DQ.

Current studies are using comprehensive phenotyping methods to investigate the role of gene variation in disease progression. A GWAS in a cohort of subjects with difficult-to-treat allergic asthma also identified RAD50/IL-13 on chromosome 5, suggesting that this region may contribute to more severe disease. Asthma severity is also influenced by specific genes that modulate pulmonary function or a pharmacogenetic response to asthma therapy. Future genetic studies will integrate genetic information from the comprehensively phenotyped cohorts and environmental exposures to predict disease risk and to develop targeted therapies for all asthma patients.

Severe asthma phenotypes have been associated with a number of allergic and nonallergic factors. Specific allergens, such as cockroach and Alternaria, as well as mould sensitivity, are associated with severe exacerbations and more severe disease, although evidence from severe asthma cohort studies, such as the European Network For Understanding Mechanisms Of Severe Asthma (ENFUMOSA) and The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) studies, show that allergens may play a less important role in severe compared to mild asthma. Occupational sensitisers and environmental factors (such as outdoor air pollutants and active or passive smoking) have been implicated in the increase in asthma morbidity since the early 1960s, and can be considered as inducers of the disease or triggers of exacerbations. Infections, mainly with respiratory viruses, but also with bacteria, such as Chlamydophila pneumoniae, contribute to severe asthma exacerbations, but their role in the development of severe persistent asthma remains unknown. Moreover, in individuals with severe asthma, a number of comorbid conditions are common, including psychopathology, hormonal dysfunction, obesity, rhinosinusitis, gastro-oesophageal reflux and sleep apnoea syndrome. All of these can lead to worsening of the asthma symptoms and a more severe phenotype of the disease. In order to improve the treatment of patients with severe asthma and to control the disease, all of these factors must be taken into consideration, and it is important to manage these conditions concurrently.

Deaths due to asthma are considered uncommon, but still account for approximately 287,000 deaths annually worldwide.

Near-fatal asthma (NFA) is usually associated with hypercapnia, respiratory acidosis and respiratory arrest requiring intubation and mechanical ventilation, and may result in death if not properly treated.

Epidemics in asthma mortality were observed in the 1960s and 1970s in many countries, but asthma deaths have decreased since the late 1980s with better disease management.

Factors frequently associated with NFA and fatal asthma (FA) include a previous near-fatal exacerbation of asthma, previous intubation and mechanical ventilation, and intensive care unit or hospital admission for asthma.

On autopsy, the lungs from FA patients are usually hyperinflated, and there is mucus hypersecretion. Histological findings include epithelial detachment, thickening of the lamina reticularis of the basement membrane, increased submucosal glands and airway smooth muscle, and altered extracellular matrix composition in the large and small airways. Bronchial inflammation is present in the large and small airways, and extends to the peribronchiolar alveoli and perivascular region of the pulmonary artery.

Severe asthma is a complex heterogeneous disease with high mortality and morbidity. Although imaging is an important tool for the assessment of severe asthma, it has limited applications in a clinical setting. Novel qualitative and quantitative imaging techniques have enabled us to study the large airway architecture in detail, allowing for the assessment of the small airway structure and the ability to perform functional or novel physiological evaluations. There is an urgent need for both proof-of-concept studies and large cross-sectional and longitudinal clinical trials in severe asthma to validate and clinically correlate imaging derived measures. This will extend our current understanding of severe asthma pathophysiology and unravel the structure–function relationship. Tools that can integrate various imaging modalities with clinical and physiological data are beginning to emerge and have an unprecedented potential to discover novel severe-asthma phenotypes, and predict mortality, morbidity and the response to existing and novel pharmacological and nonpharmacological therapies.

Although reiterated frequently, the relationship between upper and lower airways is not yet appreciated from a clinical standpoint and not sufficiently understood in terms of pathomechanisms. Here, we summarise the evidence for the impact of acute episodes of rhinitis, allergic, nonallergic or viral, on asthma severity and exacerbations, and differentiate subgroups of chronic rhinosinusitis in terms of their likelihood to interfere with lower airway disease and severity in the long term. We also review recent findings on the effect of staphylococcal enterotoxins, also referred to as superantigens, on mucosal inflammation and how they could serve as a link between nasal polyp disease and late-onset partially severe asthma. Finally, we provide evidence for a possible impact of superantigens on severe refractory asthma independent of sinus disease, via an amplification of the eosinophilic inflammation and polyclonal immunoglobulin E formation. The superantigen concept needs to be taken into consideration in epidemiological approaches to the problem of severe asthma, and if confirmed could eventually lead to new therapeutic targets.

Severe asthma is characterised by heterogeneity at the level of both clinical expression and disease mechanisms.

Airway inflammation is a key component of severe asthma and is heterogeneous in its pattern. This heterogeneity indicates different underlying disease mechanisms and treatment responses in severe asthma.

There are a range of sampling procedures and biomarkers that are available for the noninvasive assessment of airway inflammation in severe asthma. Induced sputum has been extensively studied; however, other markers have undergone only limited evaluation of their clinical utility. Induced sputum markers for the identification of eosinophilic and non-eosinophilic inflammatory patterns are useful in predicting exacerbation risk and identifying potential treatment responses.

Future work aimed at improving sampling methodologies and identifying biomarkers that are suitable for fast-throughput or automated assay platforms would add significantly to the noninvasive assessment of airway inflammation in severe asthma.

Most asthma remains controlled by inhaled corticosteroids (CS) but a significant proportion of patients do not respond to this treatment even when other controllers, such as long-acting β-agonists, are added. Patients with severe asthma continue to have uncontrolled asthma despite being established on high-dose inhaled steroids and often need additional oral CS therapy. In the latter category, there is a need to maximise the benefit/side-effect ratio by using better measures of asthma control and noninvasive biomarkers. CS-sparing agents are generally inefficacious. CS insensitivity is a feature of patients with severe asthma, and probably has similarities to previously described CS-resistant asthma. It is unclear whether those inherently less sensitive to CS develop severe asthma or whether loss of CS insensitivity is acquired. Several conditions have been associated with CS insensitivity in asthma, including obesity, cigarette smoking, vitamin D deficiency and possibly respiratory infections. Molecular mechanisms underlying CS insensitivity include: activation of mitogen-activated protein kinase pathways, particularly p38; overexpression of glucocorticoid receptor β; increased oxidative stress leading to reduction in histone deacetylase activity; or activation of inflammatory transcription factors by interferon-γ. Future treatments for severe asthma may concentrate on targets that will lead to a restoration of CS sensitivity.

There is an urgent need for new treatments particularly with anti-inflammatory properties since not all patients with asthma respond adequately to current anti-asthma treatments, and the response of many patients with severe asthma to corticosteroids and bronchodilators is suboptimal. The optimal use of corticosteroids and bronchodilators should be determined based on evidence. Improved drugs in these categories may be of some benefit. Anti-immunoglobulin E therapy has now been established for the treatment of severe allergic asthma. More specific anti-inflammatory targets are provided by the range of mediators and second messengers that contribute to the chronic inflammatory and remodelling processes in asthma. The targeted inhibition of interleukin (IL)-4/IL-13, IL-5 and IL-17 are currently being investigated. Anti-tumour necrosis factor-α approaches have been ineffective in severe asthma patients and have been associated with infections and malignancies. Other approaches target corticosteroid insensitivity in severe asthma, such as devising small molecule inhibitors of kinases. Bronchial thermoplasty has been reported to provide some benefit to patients with severe asthma. Future specific therapies will be targeted towards specific phenotypes of severe asthma.