Customised care is coming soon, and existing inflammatory biomarkers will play an important role.
At asthma meetings these days you will hear from some speakers that the current stepwise approach to asthma management is soon to be superseded by precise, targeted therapy. This is not so much a revolution as an evolution of our understanding of asthma.
Our asthma guidelines still recommend a stepwise approach, but the recommendations are changing as we grasp the importance of treating inflammation in asthma right from the start, and as treatment options expand for people with more difficult asthma. Inflammatory biomarkers have a growing role in managing severe asthma but are still not part of everyday asthma management in primary care. So far, only a few inflammatory biomarkers have been validated for clinical application.
The stepwise approach still works in primary care
We now know that nearly all patients with asthma aged six years and over benefit from low-dose inhaled corticosteroid (ICS) treatment.
For adolescents and adults, the traditional stepwise approach now involves ‘self-titration’ of doses in the form of as-needed-only budesonide-formoterol (anti-inflammatory reliever therapy) as an option right from step 1, or as ICS-formoterol in a maintenance-and-reliever therapy regimen. Using as-needed salbutamol alone doesn’t treat airway inflammation and will not control asthma.
For most people with asthma, airway inflammation can be controlled with a low-to-medium dose of ICS, with good adherence and inhaler technique – but what to do when this isn’t working? This is where the paradigm changes to a targeted, biomarker-guided approach.
The biologics story
Airway inflammation in asthma involves eosinophils and mast cells infiltrating the airways, and activation of type 2 lymphocytes that produce IgE and cytokines such as, interleukin (IL)13, IL4 and IL5.
Our understanding of these inflammatory pathways has led to the development of monoclonal antibody (biologic) therapies that are highly specific in targeting aspects of this inflammation: anti-IgE (omalizumab), anti-IL5 (mepolizumab and benralizumab) and anti-IL4 receptor/IL13 (dupilumab).
Unlike prednisone, which blocks all aspects of inflammation (with side effects), these only work in people with persistent type 2 inflammation that can’t be controlled by ICS. They do not work if inflammation is not present.
It wouldn’t be practical to use biologic therapies if we had to measure airway inflammation directly by bronchoscopy or even with induced sputum, but persistent airway inflammation can now be measured in the clinic.
The first step was when we found that omalizumab improved asthma control and reduced exacerbations in people with allergy and severe asthma despite treatment with combination ICS-long-acting beta2 agonist (LABA). A blood test will measure IgE, and allergy can be measured by a skin prick test or in the blood by RAST.
The next important step was when we discovered we could measure non-allergic, type 2 airway inflammation directly by looking at blood eosinophil counts and exhaled nitric oxide (FeNO). These tests are easy to perform.
What is happening with inflammatory biomarkers?
Blood eosinophils: It was already established that measurement of sputum eosinophils enabled accurate step-up/step-down ICS treatment which reduced exacerbation rates.1 We have since found that blood eosinophil levels correlate with airway eosinophils in people with asthma and predict risks of exacerbations and development of persistent airflow limitation. Treatment with mepolizumab or benralizumab is highly effective in people with blood eosinophil levels above 300L/mL and persistent poor asthma symptom control despite medium- or high-dose ICS-LABA.
We don’t know why some patients with severe asthma show persistent eosinophilia despite corticosteroid treatment. This might be a clue that the mechanisms to switch off type 2 immune responses may be impaired in severe asthma.2 We do know it means that ICS alone is not controlling the person’s asthma and a biologic agent might be effective.
Blood eosinophil testing is required for PBS reimbursement for initial treatment with some monoclonal antibody therapies.
Fractional exhaled nitric oxide (FeNO)
FeNO levels directly measure type 2 inflammation (especially the effect of IL-4/13) in the airways and usually correlate with elevated eosinophils. FeNO levels can be influenced by external variables including ambient air quality, smoking, sinus disease, allergic rhinitis, diet and virus infection, so these factors must be considered when interpreting results.
ICS treatment in people with asthma usually reduces FeNO levels in asthma. FeNO testing can help in the diagnosis of asthma and can be used to guide step-up/step-down treatment with ICS to reduce exacerbations in adults and children.1
Persistently elevated FeNO with poor asthma symptom control despite medium- to high-dose ICS could mean poor adherence to treatment, or resistant inflammation that requires treatment with a biologic agent. FeNO is not required to meet PBS criteria for monoclonal antibody therapy, but an elevated FeNO means people with severe asthma are more likely to benefit.
The FeNO test is easy for patients to perform. Portable FeNO analysers are available. Testing is performed by breathing into the analyser device. FeNO is listed as a reimbursable test on the Australian Medical Benefits Schedule (MBS), when performed in a pulmonary function laboratory and is now offered in most labs.
New biomarkers
New biomarkers are under investigation include sputum mRNA analysis (identifies panels of cytokines), exhaled volatile organic compounds, particles in exhaled air, dipeptidyl peptidase-4, urinary leukotriene. New sampling methods including saliva (for genetics and cytokines), nasal swabs (for transcriptomics, epigenetics and microbiomics), and nasal or bronchial sponges (for transcriptomics and microbiomics) are currently being explored and validated.
It’s getting complex
In children and young people, type 2 airway inflammation is strongly associated with allergy, but in adults it can occur without allergy.
Type 2 inflammation is seen in most, though not all, people with asthma.
The picture is more complicated in severe asthma. Some have non-type 2 inflammation which does not respond well to ICS or current biologics. Severe asthma is more likely to be associated with fixed airflow obstruction (identified on spirometry), leading to more breathlessness and exacerbations. Comorbidities (e.g. rhinosinusitis, obesity, anxiety and depression) can also contribute.
If a patient has poor asthma control, but no evidence of active type 2 inflammation, neither high-dose ICS, oral corticosteroids nor biologic therapy will help. But be aware that long-term oral corticosteroids can mask type 2 inflammatory markers.
For a patient with poor control of asthma symptoms despite ICS-LABA treatment, how do you decide between increasing their ICS or adding a long-acting muscarinic antagonist (LAMA)? And when should GPs refer the patient to a specialist for biologic therapies?
Case study: Jeanette, 52 years
Consider Jeanette, who developed asthma in her 40s, possibly after a chest infection.
She has no history of childhood asthma, smoking, atopy or occupational exposures to respiratory sensitisers/irritants. Despite budesonide 400g-formoterol 12g, two puffs daily, she continues to be troubled by frequent symptoms with exercise, uses salbutamol most days, experiences occasional night waking, and during the past 12 months has had two asthma exacerbations that required treatment with prednisone 50mg/day for seven days.
Her FEV1 is 72% predicted (FEV1/FVC 0.65), and FeNO is 35ppB. You note that her recent blood eosinophil count was 400L/mL, but has been as high as 800L/mL within the last 12 months. You are confident that Jeanette is using her inhaler correctly and as prescribed.
What should you do?
Jeanette has persistent type 2 inflammation, despite high-dose ICS (high blood eosinophils and high FeNO), and there is only mild persistent airflow obstruction. This puts her at a high risk of future exacerbations, poor asthma symptom control and ongoing exposure to prednisone. She would benefit from referral for specialist assessment for biologic therapy.
Case study: Michael, 61 years
Michael, a lifetime non-smoker with a BMI of 35, wants to do more exercise to help him lose weight, but is experiencing breathlessness and needs a new script for salbutamol, which he uses most days but rarely overnight. He wants to know if there is something more you could do for his asthma and has heard about injections. Michael “grew out of” childhood asthma, but it returned in his 30s. He is allergic to house dust mite. He uses fluticasone furoate 100g–vilanterol 25g, one inhalation daily. In the past 24 months he has had one exacerbation triggered by “flu” that required a five-day course of prednisone.
His FEV1 is 62% predicted (FEV1/FVC 0.58), with FeNO 17ppB. Total IgE is 100IU/ml, his RAST shows response to house dust mite, and his blood eosinophil count is 150L/mL (highest in the last 12 months was 200L/mL).
Michael is allergic and has persistent symptoms. He does not appear to have persistently elevated type 2 inflammation and his exacerbations are infrequent. The FeNO <25ppB and low blood eosinophils suggest he is likely to benefit from increasing his ICS dose, and a biologic therapy is unlikely to address his concerns, especially in regard breathlessness. His spirometry does show persistent moderate airflow limitation, despite ICS-LABA.
What should you do?
After ruling out other causes of breathlessness such as cardiac disease, I would keep his ICS dose the same but add a LAMA. This should improve his symptoms and lung function and will also reduce his risk of future exacerbations. To keep his treatment simple and allow him to keep using the inhaler device he is familiar with, I would prescribe fluticasone 100g–vilanterol 25g–umeclidium 62.g as a single inhaler. Michael might also benefit from an exercise program and dietary advice.
FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity
What’s new?
The “treatable traits” concept for respiratory disease is gaining popularity. It acknowledges that traditional diagnostic entities (asthma and COPD) are probably crude generalisations for what is actually a wide range of aetiologies and phenotypes that overlap in many people.
The Australian Centre of Excellence in Severe Asthma is developing approaches to management of severe asthma. Our recent trial of a biomarker-driven treatment-decision algorithm, to identify inflammatory phenotypes in people with severe asthma and target these directly, found that this approach improved participants’ quality of life and asthma control.3
Conclusion
We don’t need to measure biomarkers for all patients with asthma. Most have mild to moderately severe asthma and will do well with stepwise ICS-based treatment, following the recommendations in the Australian asthma management handbook (asthmahandbook.org.au).
When a patient has poor asthma control despite medium-dose ICS-LABA, blood eosinophils and FeNO may assist in management – in the context of a careful history, measurement of lung function, and after optimising adherence and correct inhaler technique.
Meanwhile, expectations for personalised medicine are rising. Are we there yet? The answer depends on who you ask: for specialists, it’s “getting closer”.
For primary care, let’s start thinking more about asthma: Is there good control of symptoms? Have we reduced the risk of exacerbations and the need to use prednisone, with a medium dose of ICS-LABA? If the answer is no, blood eosinophils (and, if available, FeNO) will help with deciding what to do next.
Professor Peter Wark, National Asthma Council Australia Director, senior staff specialist in Respiratory and Sleep Medicine at John Hunter Hospital, Newcastle and conjoint Professor at The University of Newcastle.
References
1. Petsky HL, Cates CJ, Kew KM, et al. Tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils): a systematic review and meta-analysis. Thorax 2018; 73: 1110-1119.
2. King GG, James A, Harkness L, et al. Pathophysiology of severe asthma: We’ve only just started. Respirology 2018; 23: 262-271.
3. McDonald VM, Clark VL, Cordova-Rivera L, et al. Targeting treatable traits in severe asthma: a randomised controlled trial. Eur Respir J 2020; 55.
