‘Uncontrolled’ asthma | Lesson

1. How is “severe asthma” defined and what is the approach in evaluating it?

European Respiratory Society and American Thoracic Society have recently published an updated guideline on severe asthma.¹ According to this severe asthma is being defined as:

Asthma which requires treatment with guidelines suggested medications for GINA (Global Initiative for Asthma) steps 4–5 asthma (high dose ICS and LABA or leukotriene modifier/theophylline) for the previous year or systemic corticosteroids for ≥ 50% of the previous year to prevent it from becoming ‘‘uncontrolled’’ or which remains ‘‘uncontrolled‘‘ despite this therapy.

Uncontrolled asthma is defined as at least one of the following:

1) Poor symptom control: ACQ consistently >1.5, ACT < 20 (or ‘‘not well controlled’’ by NAEPP (National Asthma Education and Prevention Program) / GINA guidelines)

2) Frequent severe exacerbations: two or more bursts of systemic CS (>3 days each) in the previous year

3) Serious exacerbations: at least one hospitalisation, ICU stay or mechanical ventilation in the previous year

4) Airflow limitation: after appropriate bronchodilator withhold FEV1 <80% predicted (in the face of reduced FEV1/FVC defined as less than the lower limit of normal)

Controlled asthma that worsens on tapering of these high doses of ICS or systemic CS (or additional biologics).

The guidelines suggest, that a patient with suspected severe asthma or “difficult to treat asthma” firstly be re-evaluted by an asthma specialist to confirm a definite asthma diagnosis. A substantial proportion will turn out to have an alternative diagnosis that mimics severe asthma and many patients will have relevant suboptimal controlled co-morbidities.

The single most common cause for poor asthma control remains non-compliance with treatment. Poor inhaler technique can also play a role.

Conditions that can masquerade as severe asthma are vocal cord dysfunction, hyperventilation attacks, bronchiectasis, endobronchial lesions /foreign bodies, ABPA or COPD to name just a few.

Common co-morbidities or contributing factors that need to be addressed are:

• rhinosinusitis/nasal polyps
• obesity
• obstructive sleep apnoea
• smoking
• psychological factors (personality trait, anxiety, depression, etc)
• hyperventilation syndrome and vocal cord dysfunction can both mimic asthma and co-exist with asthma
• GORD
• medication ( e.g. β-blocker, aspirin/NSAIDs, ACE-inhibitors)

2. Where is omalizumab indicated and how does it work?

Omalizumab is a monoclonal antibody that specifically binds to free human immunoglobulin E (IgE) in the blood and interstitial fluid and to membrane-bound form of IgE (mIgE) on the surface of mIgE-expressing B lymphocytes.²

It is indicated in children over the age of 6 and adults with severe persistent allergic asthma despite optimized standard therapy, with a positive skin test or in vitro reactivity to a perennial aeroallergen and a raised total IgE level.

It should only be considered for patients with convincing IgE-mediated asthma, who have

• an FEV₁ less than 80%
• frequent daytime symptoms or night-time awakenings or
• multiple documented severe exacerbations despite daily high-dose inhaled corticosteroids plus a long-acting inhaled beta₂ agonist.³

Omalizumab is given subcutaneously every 2 or 4 weeks, the dosage is determined by the concentration of serum IgE before the start of treatment and body weight. It is safe and usually well tolerated and side effects are rare, however there is a low risk of anaphylaxis. It is therefore required that it is being administered in a hospital outpatient clinic setting. Unfortunately, access in most centres is limited by the high cost of the drug, which is currently not covered under the high-tech drug scheme.

The effect of the therapy needs to be assessed after about 16 weeks and only responders should be continued on omalizumab.

3. What is the current evidence of using inhaled long acting muscarinic antagonists (LAMA) in asthma?

Inhaled corticosteroids (ICS), remain the mainstay of controller therapy in persistent asthma. Where a medium dose of ICS alone fails to achieve asthma control the combination with long-acting β-agonists (LABA) is the preferred treatment option.

Short–acting anticholinergics such as ipratropium bromide are established as relievers, where short-acting β-agonists (SABA) are not tolerated due to side effects (such as tachycardia, arrhythmia or tremor), even though they are less effective.

LAMA, which are a mainstay of treatment for COPD are not an approved therapy in asthma yet, but showed promising results in a small number of studies.^4,5

In a recent larger trial,⁶ which enrolled 912 patients with poorly controlled asthma despite ICS/LABA therapy, tiotropium 5μg daily delivered via the c device when added to combination therapy treatment, substantially improved the FEV₁ from baseline in both studies when compared with placebo, and substantially reduced the risk of severe asthma exacerbations by 21%. Thus, tiotropium may be a useful third-line drug to add to the combination of inhaled corticosteroids and long-acting β2-agonists in patients that remain uncontrolled on ICS/LABA alone.

First results from the Phase III GraziaTinA-asthma study were recently announced at the American Academy of Allergy, Asthma and Immunology (AAAAI) 2014 annual meeting in San Diego and are only published in abstract form yet7

This trial enrolled 464 mild asthmatics who remained symptomatic on a low dose ICS. Tiotropium, both in the studied 2.5 and 5μg daily dose, improved FEV₁ significantly versus placebo, without improvement in the ACQ-7 score.

No data exist yet comparing this approach to the step-up therapy of adding a LABA to the ICS established in the current guidelines.

4. What new drug treatments are on the horizon and for which asthma phenotypes will they work?

Asthma, and particularly severe chronic asthma, is a mixture of many different underlying mechanisms and identifying specific phenotypes has the potential to lead to personalised therapeutic approaches.

Biological approaches targeting specific inflammatory pathways have reported positive results.

In patients with severe eosinophilic asthma (persistent sputum or blood eosinophilia) the anti-IL5 antibody mepolizumab has been shown to decrease the frequency of exacerbations, reduce the oral corticosteroid use and in some studies also improve QoL and FEV₁.⁸ The largest multicentre trial so far published in 2012 included 621 patients with refractory eosinophilic asthma randomized to either placebo or 3 different doses of mepolizumab. It showed 52% reduction in exacerbation rate on the higher dose compared to placebo and therapy appeared to be well tolerated without significantly higher rates of severe adverse event rates compared to placebo. The improvements in FEV₁ and QoL scores were not statistically significant.⁹

Trials with other anti IL-5 antibodies including reslizumab had comparable results.^10,11

The anti IL-13 antibody lebrikizumab was associated with a significant improvement in FEV₁ in asthma patients who remained uncontrolled despite moderate to high doses of ICS with or without LABA (n = 219).

There was no reduction of exacerbations or QoL seen.

Interleukin-13 induces bronchial epithelial cells to secrete periostin, a matricellular protein. Serum perostin could be a suitable surrogate marker of Th2 activity. Patients with high pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab than did patients with low periostin levels.¹²

Despite the success of a focused treatment approach for patients with persisting airway eosinophilia, investigators have identified that about half of patients with mild-to-moderate asthma have persistent non-eosinophilic airway inflammation, which is often neutrophilic and this remains a huge therapeutic challenge. Neutrophil migration is mediated partly by activation of the chemokine receptor CXCR2. One antagonist (SCH527123) was studied in a small, randomised, double-blind, 4-week study of 32 patients with severe refractory asthma and airway neutrophilia.¹³ Treatment with SCH527123 substantially reduced the amount of both blood and sputum neutrophils, with a notable decrease in mild exacerbations but only a trend towards improvement in asthma control questionnaire score. These results suggest that airway neutrophils might have a role in the persistence of severe refractory asthma in some patients, but larger studies of longer duration are needed to assess their effect on other asthma outcomes, including severe exacerbations and additional phenotyping may improve outcomes as the definition of sputum neutrophilia remains unsatisfactory.

5. What is the role of bronchial thermoplasty in severe asthma?

Bronchial thermoplasty is a relatively new interventional technique which aims to reduce airway smooth muscle mass, thereby reducing the ability of the airway to constrict.

A specially designed catheter is introduced through a bronchoscope and radiofrequency energy is applied circumferentially to sequential portions of the airway wall, moving from distal to proximal (main bronchi) at 5mm intervals. Treatment is usually delivered in 3 sessions with an interval of at least 3 weeks between each session.

Previous non-randomized or uncontrolled trials^14,15,16 were promising. A subsequent larger randomized, controlled clinical trial 17 showed an increase in quality of life, a reduction in severe exacerbations by 0.22 per year (0.48 vs 0.7 in sham arm), and decreases in ED visits as well as days lost from school or work. The trials did not show a reduction in hyper-responsiveness or improvement in FEV₁. Short-term adverse effects include an increase in exacerbation rate, an increase in respiratory infections and an increase in hospitalizations.

Interesting is the substantial improvement in asthma control in the patients in the control arm that underwent only a sham procedure: 64% of the these patients had an improvement in the AQLQ of > 0.5 compared to 79% of the patients treated with real BT and the average AQLQ in the BT arm was only 0.18 higher than sham (5.66 vs. 5.48) (Intention to treat analysis).

In the 5-year follow up of the studies available there was evidence of clinical and functional stability of the treated patients.^18,19 Further studies are necessary to identify an asthma phenotype that responds well to this treatment.

It is therefore currently recommended that bronchial thermoplasty is only performed in specialized centres and in the context of a systematic registry or a clinical study.