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Anna C Murphy, MSc, MRPharmS
Consultant Respiratory Pharmacist,
University Hospitals of Leicester NHS Trust,
Asthma is one of the most common chronic conditions worldwide, affecting about 300 million people of all ages and is estimated to account for about one of every 250 deaths.1
GINA (Global Initiative for Asthma) defines asthma as a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation causes an associated increase in airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night or in the early morning.
These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment.1
Definition of difficult asthma
The correct diagnosis of asthma is usually easily made and most patients have mild disease that is readily controlled on low-to-moderate doses of inhaled corticosteroids (ICS) together with a combination of short- and long-acting beta-2 agonists (SABA/LABA).
However, between 5 and 10% of asthmatics have disease which is more difficult to control, experiencing persistent symptoms and frequent exacerbations.2 Morbidity and health costs are disproportionately high in these patients and they are at greater risk of fatal and near-fatal exacerbations. In addition, the regular prescribing of both oral and high-dose inhaled corticosteroids to control the asthma increases the risk of corticosteroidrelated adverse effects.
There is no universally accepted definition of difficult asthma. Different international task forces, workshops, guideline committees and authors have used a number of terms, including severe, refractory and difficult asthma to describe this population. The most recent consensus3 is to distinguish patients with ‘severe refractory asthma’ from those with ‘difficult asthma’.
The term ‘difficult asthma’ should be reserved for patients who present with uncontrolled asthma despite the prescription of high-intensity asthma treatment – defined in adults as >1,000 microgram/day fluticasone equivalent and/or daily corticosteroids combined with LABA or any other controller medication.
It is likely to be due to other factors than asthma itself, such as poor adherence to therapy, incorrect inhaler technique, environmental factors, psychological problems and untreated or undertreated co-existing conditions.
In contrast, patients with ‘severe refractory asthma’ are those patients with ‘difficult asthma’ that remain uncontrolled despite attention to and resolution of all these factors (see Figure 1).3
Within the group of patients with difficult asthma, a proportion of these will have severe refractory disease. This group can only be identified after detailed clinical evaluation.
In most cases, multiple factors are responsible for uncontrolled disease in patients with difficult asthma. Such factors should be addressed in the clinical assessment of the patient.
Patients require a rigorous and systematic approach to their diagnosis and treatment. Ideally, the assessment should be facilitated through a dedicated multidisciplinary ‘difficult asthma’ service by a team experienced in the assessment and management of difficult asthma.4
The assessment should include the following headings:
The first step in the care of these patients is evaluation and testing directed at determining that asthma is the correct diagnosis. An in-depth assessment and documentation of the following is extremely helpful:
In patients with a history of asthma but normal lung function, methacholine challenge testing can help confirm or rule out the diagnosis of asthma.
In confirming the diagnosis, it is important to consider and exclude other diseases in the differential diagnosis of asthma. Specifically, patients should be evaluated for diseases that mimic asthma symptoms (wheeze, dyspnoea, cough), such as chronic obstructive pulmonary disease, congestive cardiac failure, allergic bronchopulmonary aspergillosis, bronchiectasis, cystic fibrosis and vocal cord dysfunction.
The second step is to identify and eliminate triggers that worsen asthma. These triggers include cigarette smoke, allergens such as house dust mites (HDM), dog or cat dander, medications, occupational agents, stress, female hormonal changes and other co-existing conditions.
A number of different environmental factors have the potential to exacerbate asthma. Increased sensitisation to aero-allergens has been associated with greater airway hyperresponsiveness. In a study of patients with severe asthma, all 28 patients had skin prick tests positive to at least one aero-allergen (HDM, dog or cat).5 Sensitisation to fungal allergens has been linked to life-threatening asthma.
Cigarette smoking can both trigger asthma and cause refractoriness to current asthma medications. Exposure to cigarette smoke is associated with persistent wheezing, decreased lung function and higher mortality. It also reduces the airway sensitivity to the effects of ICS compared to non-smokers.3 Higher doses of ICS are usually required in patients with asthma who actively smoke.
Non-steroidal anti-inflammatory drugs (NSAIDs), beta blockers (including eye drops) and aspirin can exacerbate asthma and should be avoided. It is reported that aspirin-sensitive asthma may be present in up to 20% of people with asthma.6 Chronic cough caused by angiotensin-converting enzyme inhibitors may also mimic less well controlled asthma.
Occupational asthma, premenstrual worsening of asthma in women, and stress may be under-recognised contributors to difficult asthma. Occupational asthma may account for as much as 10-15% of late-onset disease.4 Patients should be questioned about occupational exposure to airway irritants. Those whose symptoms improve on holiday or on days away from work should be investigated for occupational asthma.
Other conditions may exist alongside the asthma and exacerbate the disease. Such exacerbating factors include sinus disease, bronchiectasis, psychological disorders, obesity and gastrooesophageal reflux disease.
Epidemiologic studies suggest that asthma and rhinitis coexist in the same patient, with rhinitis noted in 75 to 80% of patients with asthma.7 There is strong evidence for uncontrolled allergic rhinitis and sinus disease as a cause of asthma worsening.
Asthma and obesity are frequently associated, but the contribution of obesity to difficult asthma is not known. However, weight loss should be encouraged. If co-existing conditions are correctly identified and managed, it may be possible to improve symptom control without escalating asthma treatments.
Check adherence to medication
Adherence is defined by the World Health Organization as the extent to which a person’s behaviour corresponds with agreed-on recommendations by the health care provider.8 The failure of patients to adhere to prescribed regimens is well documented in many chronic diseases. A significant number of patients with difficult asthma are non-adherent with their asthma medication, which is correlated with several poor clinical outcomes.9
The identification of non-adherence is critical for effective disease management. Adherence rates can be measured by a variety of methods, but none can be considered the ‘gold standard’. Direct or objective measures such as theophylline and prednisolone bloods levels or measuring sputum eosinophil counts provide a reliable guide.
Surrogate measures – for example, pharmacy prescription refill or repeat prescribing records – have been found to be a useful method of identifying nonadherence.
Consultations should give patients an opportunity to talk about their concerns, beliefs, needs and expectations in relation to their asthma and its treatment. Action can then be taken to address any problems identified.
Education regarding correct inhaler technique is essential. Studies have shown that many patients are unable to use their hand-held inhalers appropriately, reducing the efficacy of the medication. Inhalers should be prescribed only after patients have received training in the use of the device and have demonstrated satisfactory technique.
Phenotypes of severe asthma
There is increasing awareness of heterogeneity in the manifestations of asthma and in its response to treatment. Several different clinical phenotypes are recognised on the basis of cluster analysis of clinical and other features of asthma. The detailed characterisation (phenotyping) of patients with severe asthma in order to confirm a diagnosis and to identify which treatments are likely to be of most benefit is now recommended.
The majority of research has been undertaken on inflammatory phenotypes, identified using sputum induction. Patients with eosinophilic phenotype have a marked clinical response to corticosteroids and should be prescribed adequate doses, compared to those with non-eosinophilic asthma, who require lower doses of corticosteroids.3,10
Treatment of severe refractory asthma
Treatment of severe refractory asthma usually consists of a combination of various preventers (corticosteroids, leukotriene receptor antagonists) and reliever medications (SABA, LABA, theophyllines).
Patients usually require an oral corticosteroid to maintain asthma control, especially if their phenotype shows an eosinophilic picture. If needed, the lowest effective dose should be prescribed. To reduce the dose or eliminate the oral corticosteroid, patients should be prescribed high dose ICS (fluticasone 1,000 micrograms/day or equivalent).
There is also strong evidence that adequate ICS treatment substantially reduces asthma mortality and hospital admissions for severe asthma. In patients with severe refractory asthma who remain symptomatic despite optimal prescribing of conventional therapy and management of other factors, some studies have demonstrated efficacy of alternative medicines, such as omalizumab, triamcinolone intramuscular injection, mepolizumab, methotrexate, gold, ciclosporin, intravenous gamma globulin and macrolide antibiotics.
It is not clear what the preferred ‘next-step’ medication should be, as the research evidence is insufficient. The treatment goal is to obtain the best asthma control with minimal adverse effects as possible. Ideally, the choice should be guided by careful evaluation of the patient’s underlying phenotype.
Omalizumab is a recombinant humanised monoclonal antibody, which selectively binds to IgE forming an omalizumab-IgE complex.
This prevents IgE binding to receptor sites on mast cells and basophils. As a result, the cells do not release their inflammatory mediators, and the allergic reaction and inflammation are prevented.
In patients with allergic asthma and an elevated IgE level, the administration of omalizumab, can result in decreased airway inflammation and improved asthma control and may allow tapering of corticosteroid medications.
Omalizumab is administered subcutaneously every two or four weeks, with the dose and frequency determined by the patient’s weight and total IgE levels. Peak therapeutic response with omalizumab is achieved 12-16 weeks after starting treatment.
Since only about two-thirds of patients respond to omalizumab, an assessment needs to be completed 16 weeks after starting treatment to determine whether the drug should be continued.
Other biological treatments
In the airways of severe refractory asthma patients there has been shown to be an increase expression in tumour necrosis factor alpha (TNFa).11 The TNFa receptor fusion protein, etanercept initially showed promise in patients with severe asthma, with an improvement in quality of life, lung function and a reduction in exacerbations. Further studies have not demonstrated this.
Mepolizumab is a humanised monoclonal antibody that recognises interleukin-5. In patients with refractory eosinophilic asthma it has been shown to reduce exacerbations and improve quality-of-life scores.12
Methotrexate, ciclosporin and gold have been proposed as steroid-sparing agents in patients with severe asthma. In general, these treatments have limited effects and have appreciable risks of adverse effects. There is more data, albeit modest, to support the use of methotrexate.
In patients with mild-to-moderate asthma, allergic pathways involving T-cells are fundamental to asthma. Tcells produce cytokines and chemokines implicated in the regulation of IgE and the maturation, recruitment, priming and activation of mast cells, basophils and eosinophils. However, in more severe asthma the inflammatory profile commonly changes with greater involvement of neutrophils.11
Recent research has highlighted some benefit in the use of macrolides in patients with neutrophilic asthma. An addition of a macrolide may also be effective in those patients with suspected Chlamydia pneumoniae contributing to their uncontrolled asthma.
Although, proportionally, patients with difficult asthma represent a small percentage of the population, they are challenging to treat. They consume a disproportionate amount of time and resources and suffer morbidity and mortality from what is, for the majority of patients, a treatable and controllable disease.
Epidemiological studies and cluster analysis have helped differentiate between clinical phenotypes within these patients but further accurate characterisations of patients is required to facilitate the development of novel targeted therapies.
Systematic and rigorous evaluation helps to ensure that patients are treated appropriately and that differential diagnosis, associated co-existing conditions and other triggers and medication adherence are addressed.
1. I nitiative for asthma. Global strategy for asthma management and prevention. Updated 2006. www.ginasthma.com
2. Strek ME. Proc Am Thorac Soc. 2006;3:116-123
3. Bel EH et al. Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI). 2010; November 23 (online)
4. British Thoracic Society / Scottish Intercollegiate Guidelines Network. British Guideline on the Management of Asthma: A National Clinical Guideline. 2009. www.brit-thoracic.org.uk/ ClinicalInformation/Asthma/AsthmaGuidelines/ tabid/83/Default.aspx
5. Tunnicliffe WS et al. Eur Respir J 1999;13:654-659
6. Jenkins C et al. BMJ 2004;328:434
7. Allergic Rhinitis and Its Impact of Asthma. Workshop report. J Allergy Clin Immunol 2001;108:5198-240
8. World Health Organization. Adherence to long-term therapies: evidence for action. Annex 2003;1:143
9. Gamble J et al. Am J Respir Crit Care Med 2009;180:817-22
10. Gaga M et al. Eur Repir Rev 2009;18(112):58-65
11. Holgate ST et al. Lancet 2006;368:780-93
12. Currie GP et al. BMJ 2009;338:593-97
13. Haldar P et al. NEJM 2009;360:973-84