Dr Liam Heaney is a professor of respiratory medicine at Queen’s University Belfast (UK) and a consultant physician at Belfast City Hospital. He leads the Medical Research Council Refractory Stratification Programme (RASP-UK) to transform clinical management of severe asthma, produce more personalised treatment approaches and investigate novel treatment strategies. Prof. Heaney also founded the British Thoracic Society Difficult Asthma Network and the affiliated National Registry on Difficult Asthma which helps standardise UK specialist clinical services and research into difficult asthma. The award winning work of Prof. Heaney and his research group addresses asthma disease stratification, treatment non-adherence, and clinical management of asthma.
Clinical assessment and phenotyping of difficult to treat and severe asthma
When someone presents clinically with difficult-to-treat or severe asthma, they are often already being prescribed very high dose treatments, yet they are not responding. I think it is important to initially take a step back and ask – what is happening here? Reviewing the diagnosis of asthma and the presence of any co-morbid conditions that may be causing asthma symptoms which are mistaken for asthma is very important before further escalation of treatment. It is possible that these patients have asthma, but there may be other conditions generating their symptoms. I think the Global Initiative for Asthma (GINA) difficult-to-treat and severe asthma guidelines lay out the whole assessment process well whereby, as a physician, one can best define the clinical problem that is in front you 1.
Type 2 inflammation in severe asthma
We have a number of tools to measure levels of type 2 inflammation as part of the analytic process of assessing patients with difficult to treat and severe asthma. Two have come out on top in terms of utility: fractional exhaled nitric oxide (FeNO) and blood eosinophil count 2–5. If either of these biomarkers are present, we can say that there is a type 2 inflammation process which is likely to be contribution to the asthma symptoms, but, it may not be the whole story.
Non-adherence in severe asthma
When a patient has persistent type-2 inflammation despite high dose inhaled corticosteroid treatment (ICS) or even systemic steroid treatment, the first question is – are they actually taking their background treatment efficiently? Many patients with difficult-to-treat asthma are not taking their inhaled treatment either regularly or correctly 6. Quite a lot of work has been done on this in our group and across the UK and the Refractory Asthma Stratification Programme (RASP) 7. When you digitally monitor patients taking ICS, you see profound reductions in FeNO and blood eosinophil count in many of these patients 8. This is important as it may be possible to obtain good disease control in with regular and optimised inhaled treatment. I think this is where a digital inhaler monitor is going to become very useful. We use it a lot in the clinic already, but I think it should be made mandatory for patients before escalation to biologic therapy.
Use of biologic therapy in severe asthma with type 2 inflammation
In some patients it is not possible to suppress an inflammatory process with an inhaled treatment, and therefore may require further treatment such as biologic therapy. Phase 3 clinical trials looking into biologics have highlighted thresholds of both blood eosinophil counts and FeNO readings, below which you are very unlikely to get additional benefits from the use of biologics 9,10. These two biomarkers are very predictive of therapeutic response and, as a result, they have become even more useful in terms of determining the best treatment option for patients. With biologics, if the part of the disease process that is driving most of the patient’s symptoms is being targeted by the biologics, you can see spectacular responses. These patients were pretty much living on rescue systemic steroids and high-dose inhaled steroids dealing with uncontrolled disease. Starting a patient in that situation on biologic therapy can generate a fantastic response where they no longer require systemic steroids or high-dose ICS, so-called ‘super-responders’. We do, however, see differential responses. Besides super-responders, there are people who have an intermediate response without a complete clinical response. There is great interest at the moment in trying to understand precisely why we see these differential responses in patients in whom -to the best of our knowledge- the same biological process is driving disease, which should be suppressed in the same way with biologic therapy. I suspect that this conundrum can be explained by the fact that there are other components of the inflammatory or disease processes that are not being suppressed completely by targeting that pathway.
Future perspectives on severe asthma with type 2 inflammation
The use of health informatics and digital monitoring technology to optimise background therapy and improve treatment choices is an important component going forward. If you have good health informatics, as I have in my clinic, you can see a patient’s blood eosinophil count over the past 10 years, providing a very good idea of what the patient’s underlying biological processes are and where the issue lay before they even come into the clinic. So, aligning health informatics with digital technology to monitor adherence, drug exposure and biological response to treatment I think are all things we could do better with inhaled treatments.
We also have a number of biological therapies available targeting the interleukin-5 (IL-5) pathway, or dupilumab, which targets the IL-4/IL-13 pathways by acting on the IL-4 receptor 3,10–13. We need to try and be precise about trying to define at the outset which drug would be the best for each patient. We have some clues, for example if a patient has eczema as well, it may be better to give them dupilumab as you will treat both conditions. However, we haven’t really dissected the type 2 inflammatory pathway to the point where we can say exactly which drug might be the best choice for a patient to start. Currently, we are trialing patients on one biologic therapy, and if they get a sub-optimal response, we then tend to switch treatments. This can be an issue as asthma exacerbations can be quite stochastic with good periods and bad spells with many exacerbations. If you put a patient on a new treatment before a good spell, you may say the drug is working really well, therefore, it can be problematic just using clinical observations. We really need blinded controlled trials to compare the available drugs, but my feeling at this stage is that the pharmaceutical industry is not very keen to go down that route as you need an extraordinarily large clinical trial to show the differential response. Therefore, we will likely end up using information for real world clinical registries to try and piece it together.
Future perspectives on severe asthma without type 2 inflammation
We also have patients whose type 2 inflammatory processes are effectively suppressed with uncontrolled symptoms; in those cases, one can conclude that type 2 inflammatory biology is very unlikely to be causing the patient’s symptoms 1,14,15. We need to try and understand what is going on with those patients, whether it is simply that there is another inflammatory process or mechanism underpinning their symptoms, or whether it is due to extra-pulmonary co-morbidities. Obesity, for example, is quite common in this patient population, yet the questions stands as to whether they are simply obese and deconditioned, or whether there is another co-morbid problem that we don’t recognise causing the symptoms. A patient with difficult to treat or severe asthma starting at the same place with the same clinical problem could end up with 4 or 5 diagnoses depending on diagnostic testing results: they could end up not having asthma at all, having mild asthma that is over treated, having type 2 low asthma where their type 2 inflammation has been suppressed 1,15. Research should work towards generating a standardised algorithm to correctly identify the specific endotype in each patient with severe asthma.
1. Diagnosis and Management of Difficult-to-treat and Severe Asthma. Global Initiative for Asthma – GINA. Accessed June 19, 2020. https://ginasthma.org/severeasthma/
2. Smith AD, Cowan JO, Brassett KP, et al. Exhaled Nitric Oxide: A Predictor of Steroid Response. Am J Respir Crit Care Med. 2005;172(4):453-459. doi:10.1164/rccm.200411-1498OC
3. Castro M, Corren J, Pavord ID, et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med. 2018;378(26):2486-2496. doi:10.1056/NEJMoa1804092
4. Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. The Lancet. 2016;388(10039):31-44. doi:10.1016/S0140-6736(16)30307-5
5. Tezepelumab in Adults with Uncontrolled Asthma. N Engl J Med. 2019;380(21):2082-2082. doi:10.1056/NEJMx180026
6. Hekking P-PW, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. The prevalence of severe refractory asthma. Journal of Allergy and Clinical Immunology. 2015;135(4):896-902. doi:10.1016/j.jaci.2014.08.042
7. Gamble J, Stevenson M, McClean E, Heaney LG. The Prevalence of Nonadherence in Difficult Asthma. Am J Respir Crit Care Med. 2009;180(9):817-822. doi:10.1164/rccm.200902-0166OC
8. Murphy AC, Proeschal A, Brightling CE, et al. The relationship between clinical outcomes and medication adherence in difficult-to-control asthma: Table 1. Thorax. 2012;67(8):751-753. doi:10.1136/thoraxjnl-2011-201096
9. Tran N, Coffman JM, Sumino K, Cabana MD. Patient reminder systems and asthma medication adherence: a systematic review. Journal of Asthma. 2014;51(5):536-543. doi:10.3109/02770903.2014.888572
10. Rabe KF, Nair P, Brusselle G, et al. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med. 2018;378(26):2475-2485. doi:10.1056/NEJMoa1804093
11. Farne HA, Wilson A, Powell C, Bax L, Milan SJ. Anti-IL5 therapies for asthma. Cochrane Airways Group, ed. Cochrane Database of Systematic Reviews. Published online September 21, 2017. doi:10.1002/14651858.CD010834.pub3
12. Bel EH, Wenzel SE, Thompson PJ, et al. Oral Glucocorticoid-Sparing Effect of Mepolizumab in Eosinophilic Asthma. N Engl J Med. 2014;371(13):1189-1197. doi:10.1056/NEJMoa1403291
13. Nair P, Wenzel S, Rabe KF, et al. Oral Glucocorticoid–Sparing Effect of Benralizumab in Severe Asthma. N Engl J Med. 2017;376(25):2448-2458. doi:10.1056/NEJMoa1703501
14. on behalf of the RASP-UK (Refractory Asthma Stratification Programme) Consortium, Hanratty CE, Matthews JG, et al. A randomised pragmatic trial of corticosteroid optimization in severe asthma using a composite biomarker algorithm to adjust corticosteroid dose versus standard care: study protocol for a randomised trial. Trials. 2018;19(1):5. doi:10.1186/s13063-017-2384-7
15. McDowell PJ, Heaney LG. Different endotypes and phenotypes drive the heterogeneity in severe asthma. Allergy. 2020;75(2):302-310. doi:10.1111/all.13966
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