Aspects of Asthma: Severe Asthma

Globally, 5-10% of the total asthma population suffers from severe asthma.^1,2

Approximately 2 million people suffer from severe asthma in the United States and yet it remains poorly understood.³

The average cost per patient with severe asthma is reportedly six times that of mild asthma.⁴

Approximately 10% of patients with severe asthma have reported a history of intubation for asthma.⁵

Medication usage is high in patients with severe asthma, with almost 26% using three or more controllers.⁵

The mortality rate amongst individuals with severe asthma is estimated to be 6.7 per 100 person - years.¹⁹

Definition of Severe Asthma

The term, severe asthma, has undergone several changes in definition since the first attempt by the Global Initiative for Asthma Management (GINA) guidelines in 1995.⁸ Various societies and organisations such as the European Respiratory Society (ERS), American Thoracic Society (ATS), World Health Organisation (WHO) and Innovative  Medicines  Initiative (IMI) have tried to define severe asthma using various terminologies such as ‘difficult asthma’, ‘severe refractory asthma’, ‘poorly controlled asthma’, and ‘uncontrolled asthma’.⁷

Recently, a joint ERS/ATS taskforce has defined severe asthma as ‘‘Asthma that requires treatment with guidelines-suggested medications for GINA guidelines steps 4-5 (high-dose inhaled corticosteroids (ICS) and long-acting beta - agonist (LABA) or leukotriene modifier/theophylline) for the previous year or systemic corticosteroids (CS) for >50% of the previous year to prevent it from becoming ‘‘Uncontrolled’’  or which remains ‘uncontrolled despite this therapy’.¹  Further, the WHO recommends that severe asthma because of no treatment or undertreatment should be considered as untreated severe asthma, especially in the developing parts of the world.⁸

Risk Factors and Contributory Factors

In 2001, the National Institutes of Health (NIH) and the National Heart, Lung and Blood Institute (NHLBI) in the United States established one of the most comprehensive networks of researchers on severe asthma called the Severe Asthma Research Program or SARP.9 SARP is an ongoing research initiative to understand the mechanisms, phenotypes and characteristics of severe asthma to develop better management strategies for this condition.¹⁰

The following are some of the risk factors that have been identified from the various SARP studies so far:

• Female gender¹¹
• Adult-onset¹¹
• Obesity¹¹
• Tobacco smoke exposure¹¹
• Comorbid diseases such as gastro-oesophageal reflux disease (GERD)¹²
• History of sino pulmonary infections/sinusitis/pneumonia¹²
• Aspirin-sensitivity¹²

Severe asthma is also associated with several comorbidities and contributory factors as listed below:

1.  Rhinosinusitis/ (adults) nasal polyps¹

2.  Psychological factors such as depression, anxiety, personality traits¹

3.  Vocal cord dysfunction¹

4.  Obesity¹

5.  Smoking/smoking-related diseases¹

6.  Obstructive sleep apnoea¹

7.  Hyperventilation syndrome¹

8.  Hormonal influences¹

9.  Symptomatic GERD¹

10. Drugs¹

11. Non-adherence¹

Identifying Severe Asthma in Clinical Practice

Recognising severe asthma can be quite tricky in real-life practice. Severe asthma has been described as asthma that requires step 4 or step 5 treatment as described in the GINA guidelines–that is, high-dose ICS/LABA to prevent it from becoming uncontrolled or if it remains uncontrolled despite this treatment.¹⁴

The word ‘severe’ is also used by the patients’ to describe the intensity or frequency of  their symptoms, which may not  necessarily indicate a severe disease as it may be possible to control the symptoms using the right doses of ICS.14 Hence, it is quite important to explain the term ‘severe’ to the patient when diagnosing severe asthma.¹⁴

The first step  towards  diagnosing severe asthma is  its  differentiation from uncontrolled asthma.14  Uncontrolled asthma is a very common reason for persistent symptoms and frequent exacerbations of asthma and may be easily improved.14 The following problems, which contribute to ‘difficult’ asthma,15 need to be excluded before considering the diagnosis of severe asthma:¹⁴

• Ability to use inhalers correctly
• Adherence issues
• Confirmed diagnosis of asthma
• Ruling out the alternate diagnosis of asthma
• Comorbidities and contributory conditions
• Exposure to irritants and allergens

The common differential diagnoses of severe asthma in adults and children are as follows:

One of the key  differences between  difficult asthma  and  treatment-resistant/refractory severe asthma is that difficult asthma can be managed by modification of the common problems mentioned above.15 Treatment-resistant / refractory severe asthma probably needs more than the traditional treatment options and, hence, is now the focus of research in the development of targeted therapies in the form of monoclonal antibodies.

Treatment Options for Severe Asthma

The various international guidelines recommend treating severe asthma with established treatments such as high-dose ICS with or without LABAs and/or oral corticosteroids and/or other additional controllers such as leukotriene receptor antagonists (LTRAs), or theophylline.^7,14

The high doses of ICS for the treatment of severe asthma have been defined by the ATS/ERS guidelines on the treatment of severe asthma and are described in Table 1 below.

Severe refractory asthma could be corticosteroid-dependent or corticosteroid insensitive.¹ Although it has been observed in various severe asthma clinical trials that these patients may need regular oral corticosteroids or frequent oral corticosteroid bursts, there is no clarity on the timing of the initiation of oral corticosteroids.1 However, the treatment of patients with corticosteroid insensitivity is not very clear yet and is a subject of intense research.

The ATS/ ERS guidelines also recommend the use of sputum inflammometry by eosinophils count to guide ICS treatment in patients with severe asthma.1 Sputum guided treatment, however, needs specialised centres to carry out the sputum induction techniques and, hence, is not available that easily. With regards to using fractional exhaled nitric oxide (FeNO) to guide ICS treatment in severe asthma, the ATS/ERS guidelines recommend against it because of very low- quality evidence to support its use.¹

Various treatments other than ICS, ICS/LABA, oral corticosteroids, LTRAs and theophylline have been studied in the context of severe asthma, although there are no definite recommendations from the guidelines on their use in routine clinical practice. Some of these have been described below:

• Monoclonal antibodies (mABs): The well-studied, US FDA-approved, commercially available mAB is omalizumab, which is an anti-lgE. Hence, it is mainly recommended in cases of severe allergic asthma that is uncontrolled on Step 4 treatment (high-dose ICS/LABA).14 The new GINA 2016 strategy recommends omalizumab as the preferred Step 5 add-on treatment choice, before initiation of long-term OCS use.6  Subcutaneous omalizumab in moderate-severe asthma has shown a steroid-sparing effect, reduction in exacerbations as well as hospitalisations and an improved quality of life.¹⁶
• Tiotropium: Various recently published studies have shown the beneficial effects of adding tiotropium to ICS+LABA in terms of improvement in lung function and decrease in exacerbations in patients with severe asthma.1 Interestingly, however, the recently updated  GINA guidelines as  well as another published guideline, a collaboration of the Indian Chest Society and the National College of Chest Physicians, recommends adding tiotropium in cases of asthma that stays uncontrolled even after high-dose ICS/LABA treatment.^14,18
• Methotrexate:  The ATS/ERS guidelines recommend against the use of methotrexate in adults and children with severe asthma to avoid the adverse effects associated with the drug.
• Macrolides:  Although there have been some studies that  have shown the positive benefits of  treating severe asthma, especially the neutrophil predominant phenotype with macrolides such as azithromycin,19 the ATS/ ERS guidelines recommend against the use of macrolides for the treatment of severe asthma.¹  This is because of the relatively unclear benefits of the treatment and the risk the developing resistance to macrolides.¹
• Antifungals: The ATS/ ERS guidelines recommend using antifungal treatment in patients with  severe asthma  with  recurrent exacerbations of  allergic bronchopulmonary  aspergillosis (ABPA)¹. However, antifungals are not to be used in patients of severe asthma without ABPA even if they demonstrate fungal sensitisation on the skin prick test or serum lgE.¹

The non-pharmacological treatment that has been studied in the context of severe asthma is bronchial thermoplasty. The ATS/ERS guidelines do not recommend using bronchial thermoplasty outside the clinical trial set-up, because of insufficient evidence in terms of benefit to the patients.¹

The focus of severe asthma research is to now identify the phenotypes or endotypes and develop a phenotype- or endotype-driven treatment. Hence, there has been a lot of stress on identifying the pathophysiological pathways, biomarkers and targeted molecules in the area of severe asthma research.

Phenotypes and Endotypes: A Step Ahead in Personalised Medicine

Severe asthma is not a single uniform entity and its heterogeneity has been recognised with the various research projects characterising phenotyping and, now, endotyping of severe asthma.¹³

Initial studies have recognised that some consistent features of severe asthma include requirement for high doses of ICS with or without oral corticosteroids, low lung function, daily symptoms and frequent and/or severe exacerbations.¹³

However, it was also observed that these characteristics are not universal to severe asthma and, hence, the scientific research is focused on phenotyping severe asthma.¹³

Phenotyping severe asthma involved identifying certain clinical and pathological features.13   For example, various SARP studies identified the following phenotypes of severe asthma.¹³

1. Early-onset

2. Eosinophilic

3. Neutrophilic

4. Obesity-related

However, it was soon realised that none of these phenotypes provide much insight into the pathogenic mechanisms involved in the development of that particular phenotype.13 Hence, the next logical step was to link pathobiology to the clinical phenotypes and, thus, the current focus of research is identifying the endotypes of severe asthma.¹³

The term, endotype means ‘a subtype of a condition that is defined by a distinct functional or pathophysiological mechanism’ and involves identifying biomarkers and genes in addition to the clinical and pathological features.¹³ There have been various studies on severe asthma, which have identified certain endotypes as in Box 1. These endotypes have been identified using a statistical technique called cluster analysis, which, as the name suggests, involves grouping of objects that are similar to each other in some way or the other in the same group, which is known as a cluster.

There is currently a lot of interest in identifying the endotypes of asthma and the work done in this field by SARP is now also being complemented by an European consortium called U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes).¹¹

Endotyping will help develop more targeted treatments, thus taking a step further towards personalised medicines for asthma.