Recent Advances in Asthma Treatment Dr Timothy SC Hinks (1998 Wadham College), Wellcome Trust Career Development Fellow and Honorary Consultant, Nuffield Department of Medicine, University of Oxford The last decade witnessed a revolution in how we understand and treat asthma. The world’s most common lung condition was perhaps described in Chinese medical literature c 2600BC1, and Homer used the term ‘asthma’ – ἅσθμα – in his Iliad2, a term adopted in English since around 16003. Treatments were limited but in the ninteenth century, the Dorset born physician, Henry Hyde Salter, eloquently described the condition from which he suffered and his self-medication with coffee, no doubt benefitting from bronchodilation from methylxanthines4,5. He could also have smoked Datura stramonium6, an the r o anticholinergic: both forerunners of treatments d f oks ne o twentieth century bronchodilators. Last century sti ry B e D sto saw only two major new classes of treatments: Hi ephedrine in 1928, leading to a whole family of increasingly selective and longlasting beta-adrenoreceptor agonists, and steroids given systemically in 1949 and by inhalation from 1972. For those with severe asthma life was miserable, and often limited. Older patients remember being in special schools for asthmatics and witnessing friends dying from attacks. Steroids and beta-agonists certainly made a vast difference to most patients, though as a registrar I had little to offer those with severe disease, beyond ever escalating doses of inhaled corticosteroids. The clinic had a reputation for patients with either poor adherence or insoluble clinical problems. Just 10 years later, the outlook now is very different, for four reasons.
poor adherence. Now our Sherlock Holmes pharmacist has scrutinised prescription records before I first meet the patient. Adherence is addressed non-confrontationally with the aid of a home FeNO suppression test. Fractional exhaled nitric oxide directly measures interleukin-13-mediated airway inflammation in exhaled breath, which takes 10 seconds to measure by a simple hand-held device. Patients with high FeNO take home a micro-chipped inhaler and FeNO monitor for a week. In two thirds with poor adherence, FeNO falls, symptoms improve, and we offer smart phone synchronised inhalers: problem solved. The other third, whose FeNO remains stubbornly elevated, have steroidunresponsive disease and need biologics, short-cutting months of ineffective medication changes. Another key MDT member is our speech and language therapist, identifying and treating laryngeal wheeze. Such vocal cord dysfunction is terrifying, leading to inappropriate treatment, recurrent admissions, and on occasion intubation. Likewise, many symptoms are due to breathing pattern disorders, which are debilitating – think Emma Raducanu exiting Wimbledon – but are effectively treated by our physiotherapists. Thirdly, macrolides. I’m always looking for another ‘treatable trait’: persistent bacterial bronchitis. Those with a chronic mucopurulent cough and ‘type-2 low’ asthma invariably have lower airway colonisation with non-typeable Haemophilus influenzae, with a striking response to long-term, low dose macrolides. The mechanisms underlying this drug’s unique antibacterial, antiviral and anti-inflammatory effects are a major current focus for my research group, using infection of air-liquid interphase cultures, bacterial metagenomics and single cell sequencing of bronchoscopy samples.
First, clinical phenotyping and biologics. Not all asthma is the same. My colleague, Ian Pavord, described the severe eosinophilic phenotype: people with adult onset, severe disease, which responds dramatically to systemic steroids, characterised by excess eosinophils in sputum and blood. This observation rescued a whole class of drugs-the anitinterleukin (IL)-5 monoclonal ‘biologics’ from failure in trials. Targeted to the right patient, based simply on a full blood count eosinophilia, these produce dramatic improvements, reducing exacerbations by three-quarters, and obviate the need for maintenance steroids. We treat over 300 patients on these monthly or bimonthly subcutaneous injections: patients who typically describe them as ‘transformative’. Five biologics are now licensed targeting the three pathways: immunoglobulin E, the IL-5 pathway and the IL-4/13 pathways. Benralizumab acts so fast our team – in a trial led by Mona Bafadhel – are testing its use first line for acute exacerbations, in asthma and chronic obstructive pulmonary disease. If successful, these drugs will consign systemic steroids to the history books. Secondly, the multi-disciplinary team. For too long for those with ‘difficult asthma’, the elephant in the room was ‘A patient’s experience of living with asthma. Marije Kootstra, 2011 reproduced with permission from herself and U-BIOPRED’
14 Oxford Medicine | Autumn/Winter 2021
