Three new severe asthma phenotypes have been identified in one of the largest registry analyses of patients with the condition.

Researchers involved in the international study say the novel phenotypes, or clusters, all have very similar biomarker expression but strikingly distinct clinical profiles and associated biological pathways. Being able to identify these patients could help clinicians better tailor targeted therapies such as monoclonal biologics.

The findings come from the largest analysis of severe asthma patients drawn from the International Severe Asthma Registry mostly including patients mostly from the UK and the US.

Biomarkers examined were total serum IgE, BEC, and FeNO at the point of enrolment into the registry. Biomarker positivity was pre-defined as total IgE≥75kU/L, BECs ≥300 cells/µL, and FeNO ≥25ppb.

Of the 1750 patients with severe asthma involved in the analysis almost 60% were positive for each individual biomarker – rates that exceed those reported in the general asthma population, respiratory physician at the Alfred and St Vincent’s Hospitals in Melbourne, and lead investigator Dr Eve Denton told the limbic.

Additionally, 59% were positive for either two or three biomarkers – FeNO and blood eosinophil positivity were more likely to occur together than with IgE positivity, despite previous studies having shown that FeNO does not correlate well with blood eosinophils, she added.

While biomarker overlap occurred in the general asthma population, Dr Denton said the implication in severe asthma was that patients positive for multiple biomarkers may be eligible for treatment with multiple biologic therapies.

Investigators also carried out a cluster analysis based on the biomarkers as continuous variables to identify five distinct severe asthma subgroups.

Three novel clusters

While two of the five groups have previously been identified in other cluster analyses, Dr Denton said the large sample size of the current study allowed investigators to identify a further three novel clusters – including one with significant implications for management.

“Of the three novel clusters there was one, Cluster Five, that has a very high eosinophil count,” she said.

“This was a small cluster, patients are younger, predominantly males and have a very high incidence of nasal polyposis and chronic rhino sinusitis. That’s quite an interesting cluster and its got significant implications for management because potentially they’d be eligible for medications such as bemrolizumab or eplizumab but more recently there’s been dupilumab, which has been shown to be very effective with nasal polyposis.”

Dr Denton said that recognising the cluster could help clinicians choose between one biologic over another.

Patients in Cluster Two, described as older, eosinophilic, exacerbating females, accounted for 18% of the group and were also identified as a novel group.

Their biomarker profile showed high mean BEC (911 cells/uL), elevated FeNO (51 bpp), and relatively low IgE (187 kU/L). Clinically, this group had lower BMI with a relatively shorter duration of asthma.

This cluster also had the highest number of exacerbations of any cluster despite preserved lung function and fewer patients with poor symptom control, says Dr Denton adding that the group did not conform to previously reported characteristics of worse lung function and chronic rhinosinusitis.

Meanwhile, Cluster Three patients had a very high FeNO, were older and had a slight female predominance. Patients also had preserved lung function and lower BMI and had a larger proportion with poor symptom control but relatively less frequent exacerbations.

Unmet need

Further sensitivity analyses also identified a patient group whose clinical needs currently remain unmet by available biologics – the triple biomarker-negative group, which Dr Denton said had significantly more females compared to the triple biomarker-positive group.

“There were 12% of patients in this severe asthma group that were triple biomarker negative – at the moment they don’t have great targeted therapies available to them given these patients may not be eligible for any biologics so it’s an important subgroup that we need to potentially target with future studies.”

Dr Denton suggested that for this group – and established clusters characterised by relatively low biomarker expression – clinicians could target other treatable traits such as obesity.

“Identifying these clusters help us fill in the details. We have this umbrella term, asthma, and about 5 to 10% of patients have severe asthma – which takes up most of the healthcare utilisation resources of asthma patients. So understanding which biological pathways are being activated and how can we can target them – or if patient’s aren’t eligible for biologic medications, knowing  which other treatable traits go along with that cluster – will help identify the best therapy for our patients.”

The study is published in the Journal of Allergy and Clinical Immunology: In Practice here.