Management and mechanisms of severe eosinophilic asthma

Thesis

Severe asthma is a complex problem in which eosinophilic asthma is an over-represented phenotype compared to mild and moderate asthma. Asthma attacks, for which persistent eosinophilic inflammation is a major risk factor, are the most clinically concerning aspect of this disease as they result in high healthcare use and spending, treatment related morbidity due to oral corticosteroids, and reduced quality of life for patients.

I studied the response to monitored inhaled corticosteroids (ICS) in patients with severe eosinophilic asthma. Patients who suppressed FeNO, a marker of eosinophilic inflammation, had marked reduction in mediators of eosinophilic inflammation in the airways. This was in contrast to those who did not suppress FeNO, suggesting ICS-resistant pathways. Prostaglandin D2 (PGD2) was particularly non-responsive in this group with ICS-resistant eosinophilic inflammation.

I next studied the effect of timapiprant, an antagonist of the PGD2 receptor CRTH2, in a randomised, placebo-controlled trial in severe eosinophilic asthma. This study found a trend towards a clinically significant lowering of sputum eosinophils compared to placebo, but no changes in lung function or symptom scores. These findings are in keeping with trials of other targeted anti-inflammatory treatments in asthma.

Finally, the effects of mepolizumab, an anti-IL-5 antibody treatment, on exacerbations of severe eosinophilic asthma were investigated for the first time. In novel post hoc analyses I found that exacerbations that occur on mepolizumab are less severe in terms of changes in lung function and symptoms, are associated with less eosinophilic airway inflammation, and may be less steroid-responsive than those on placebo.

In combination, these findings suggest a role for CRTH2 antagonists in the management of severe, treatment-refractory eosinophilic asthma. Further, larger studies required to explore this. The effects of anti-inflammatory treatments on asthma exacerbations needs to be studied in more detail as my analyses have shown them to be different in nature to those on placebo. The underlying drivers of exacerbations occurring on type-2 targeted treatments need to be further understood. These exacerbations may require a different treatment approach tailored towards the underlying pathology.

Authors: Shrimanker, R

• DOI: 10.5287/ora-wr794yxg4
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: severe asthma; eosinophil; crth2; asthma