Airway type 2 inflammation refractory to corticosteroids in many severe asthma patients
medwireNews: Airway type 2 inflammation is not fully suppressed in around half of asthma patients despite receipt of inhaled corticosteroid treatment (ICS), study findings show.
These patients tend to be older and have more severe asthma than their counterparts with low type 2 inflammation and could be good candidates for adjunctive treatment with specific inhibitors of type 2 inflammation, say John Fahy (University of California, San Francisco, USA) and co-authors.
They add: “This is consistent with the idea that type-2 airway inflammation is refractory to treatment with corticosteroids in a subgroup of asthmatics, and that incompletely suppressed type 2 inflammation is a mechanism of severe asthma.”
The team generated a composite metric of type 2 inflammation – type 2 gene mean (T2GM) – based on the average expression of genes for three type 2 cytokines (interleukin [IL]-4, IL-5, and IL-13) in induced sputum cells.
The mean sputum expression levels of the type 2 cytokines and T2GM were significantly increased in the 259 patients with asthma receiving ICS treatment, compared with 30 healthy controls. T2GM remained significantly increased even after treatment with intramuscular triamcinolone, which the researchers say refutes the idea that persistent type 2 inflammation is simply the result of patients not adhering to treatment or being given too low a corticosteroid dose.
When the researchers looked at T2GM expression levels in the asthma group alone using the 50th centile as a cutoff point, they found that 130 of the asthma patients – 50.2% – could be classified as having high T2GM despite ICS treatment.
This group of steroid-treated type 2-high (srT2-high) patients were significantly older than srT2-low patients, at an average of 50.3 versus 46.2 years (p=0.02), and in support of this T2GM was found to be significantly higher in older than younger age quintiles (p=0.003).
Asthma patients in the srT2-high group also had more severe asthma, as evidenced by lower forced expiratory volume in 1 second (FEV1; 17.9 vs 19.2% predicted; p=0.005), a higher frequency of asthma exacerbations in the prior year, and a higher frequency of a severe asthma diagnosis.
Indeed, the rate of srT2-high asthma was significantly greater among patients with severe asthma than among those with non-severe disease, at 55% versus 40% (p=0.02). And the researchers believe that these srT2-high patients “stand to benefit from adjunctive treatment with specific inhibitors of type 2 inflammation, including inhibitors of type 2 cytokine[s] or inhibitors of the prostaglandin D2 receptor 2.”
By comparison, the 45% of severe asthmatics who did not have increased type 2 inflammation are less likely to benefit from such adjunctive treatment, say Fahy and team.
The authors report in The Journal of Allergy and Clinical Immunology that sputum eosinophils and blood eosinophils were the best non-invasive biomarkers for identifying patients with refractory airway type 2 inflammation, with accuracies of 79% and 76%, respectively.
But they caution that age and body mass index (BMI) could modify the performance of these biomarkers. Notably, blood eosinophils performed badly in patients over the age of 35 years, compared with in younger patients.
“These data are highly relevant to decisions for when to treat patients with severe asthma with protein therapeutics,” says the team.
Also, blood eosinophil number was a strong indicator of srT2-high asthma in patients with a BMI below 40 kg/m2, but a poor indicator in morbidly obese patients, and so a low count in these individuals should not necessarily rule out the use of adjunctive treatment with type 2 inflammation inhibitors, the researchers advise.
By Lucy Piper
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