Professor David Price recently spoke about the management of asthma in different phenotypes at the Asian Pacific Society of Respirology’s Asthma Symposium 2019.
While asthma hospitalization and mortality rates have been declining in past years, a recent spike has been noticed. A 2014 report by The National Review of Asthma Deaths (NRAD) on asthma-related deaths in the UK discovered that a shocking 46% of these deaths could have been avoided* if guidelines were appropriately followed. Furthermore, personalised asthma plans were only held by 23% of studied patients, and 43% of patients had no review in the year prior to the study’s commencement. These gaps in asthma management must be addressed to improve the level of care that patients currently receive. It should also be noted that exacerbations occur at all levels of asthma severity* (as classified by the British Thoracic Society’s guidelines), therefore, it is not just severe asthma patients who are at risk.
In the UK, systemic corticosteroids (SCS) are most commonly prescribed for asthma when compared to other diseases. While long-term oral corticosteroid (OCS) or SCS use is primarily observed in patients with severe/uncontrolled asthma, short-term use has been observed across all severities. However, OCS/SCS use can cause several acute and chronic adverse side effects*, including pneumonia, ulcers, osteoporosis, diabetes, anxiety/depression and cardiovascular complications. The onset of these side-effects can occur with as little as 1g of OCS/SCS dose – this is equivalent to 4 short courses of OCS at the usual doses. Furthermore, cumulative exposure increases the risk of these side-effects in a dose-response manner. There therefore exists a need to identify other treatment options with fewer adverse effects.
To properly address and treat asthma, the different endotypes and phenotypes must be considered to better target effective therapies to patients. Here, endotype refers to “a subtype of a disease defined functionally and pathologically by a molecular mechanism or by treatment response” whereas phenotype is defined as “a single or combination of disease attribute(s) that describe differences between individuals as they relate to clinically meaningful outcomes”. Essentially, an endotype is the underlying disease whereas phenotype is categorized according to observable characteristics in the patient.
There are two main endotypes in asthma – Type 2 and Non-Type 2. In Type 2 asthma, inflammation is more severe and is typically characterized by cytokines such as interleukin (IL)-4, IL-5 and IL-13* and is often accompanied by eosinophilia, increased FeNO and possibly atopy. In Non-Type 2 asthma, inflammation is less severe and is characterized by airway neutrophilia and a poor response to corticosteroids.
Type 2 asthma can then be subdivided into the following phenotypes*: allergic asthma, exercise-induced asthma, late-onset eosinophilic asthma and aspirin-exacerbated respiratory disease. Non-Type 2 asthma can be subdivided into obesity-associated asthma, smoking-associated neutrophilic asthma and smooth-muscle mediated paucigranulocytic asthma. Very-late onset asthma, which mostly occurs in women, can be observed in both Type 2 and Non-Type 2 asthma.
To identify the phenotypes of asthma, biomarkers can be used. Biomarkers are defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or biological responses to a therapeutic intervention”. They can (1) be part of the pathophysiology of a disease, (2) help inform disease risk and control prediction, (3) predict risk to an intervention, and (4) show biological response to a treatment.
- Biomarkers are part of the pathophysiology of a disease
Eosinophil count, FeNO and total/specific IgE are biomarkers of asthma pathophysiology by identifying Type 2 inflammation driven by IL-4, IL-13 and IL-5. This enables the identification of the asthma endotype.
- Biomarkers help inform disease risk and control prediction
Blood eosinophilia and high FeNO levels are associated with a greater rate of exacerbations in asthma. In fact, the two biomarkers are complementary to one another – when both are high, exacerbation rates are also high.
- Biomarkers predict response to an intervention
A low eosinophil count is associated with a poorer response to ICS treatment. Furthermore, eosinophil and FeNO levels can be used to predict response to and guide ICS doses. Response to biologics can also be predicted using biomarkers – high FeNO and eosinophil levels are indicative of a good response to omalizumab and dupilumab, and high eosinophil levels are indicative of a good response to mepolizumab and benralizumab.
Apart from biomarkers, clinical features such as chronic rhinosinusitis and nasal polyps can also predict response to an intervention – exacerbations were reduced in patients displaying these comorbidities alongside asthma.
The GINA 2019 guidelines for severe asthma also highlight the usefulness of biomarkers and clinical features in guiding therapy.
- Biomarkers show biological response to a treatment
The reduction of FeNO and IgE levels are a predictor of response to dupilumab in asthma patients, whereas reduced eosinophil levels predict response to mepolizumab and benralizumab. Response to tezepelumab can be identified via a reduction of FeNO levels.
Biomarkers are therefore incredibly useful in effectively diagnosing and treating asthma. However, they are mainly useful in the management of Type 2 asthma as the associated categories of biomarkers (eosinophilia, increased FeNO levels, etc) are mostly seen in this endotype. As per the GINA 2019 recommendations for the diagnosis and management of severe asthma, non-biologic therapies should be considered when Type 2 inflammation is not observed.
There are currently four main treatment options for patients with Non-Type 2 asthma. They are macrolides, triple therapy, bronchial-thermoplasty and tezepelumab*. Macrolides, tezepelumab and bronchial-thermoplasty have been observed to reduce exacerbations across asthma endotypes. Triple therapy, which refers to the addition of tiotropium, a long-acting muscarinic antagonist (LAMA), to the medication regimen when a combination of ICS and long-acting beta-agonists (LABA) were not sufficiently controlling symptoms, has also been noted to improve lung function and reduce severe exacerbations.
The International Severe Asthma Registry (ISAR) is a valuable resource when it comes to identifying and understanding the prevalence of severe asthma across the globe. This database holds information regarding the prevalence of severe asthma as well as the distribution of the aforementioned biomarkers* in various country populations. You can learn more about ISAR here.
Another useful database is the Australasian Severe Asthma Web-Based Database (SAWD)*, which holds information regarding the prevalence of pulmonary, extra-pulmonary and behavioural traits in patients with severe asthma. This information can be used to predict future exacerbations and provide better care for patients.
In conclusion, Asthma is a heterogeneous disease – different asthma phenotypes respond differentially to different treatments. Biomarkers such as total and specific IgE, blood eosinophils and FeNO can be used to assess these phenotypes and provide targeted treatment across all severities. Clinical features such as nasal polyps and chronic rhinosinusitis can also be used to guide therapy.
Finally, most of the data discussed here is focused on severe asthma. This begs the question – should biomarkers just be reserved for severe asthma, or could they be valuable in guiding treatment for mild/moderate asthma too?