Asthma phenotypes identified, validated
medwireNews: Researchers have defined and validated four asthma phenotypes that they believe will aid patient classification and the development of tailored therapies.
The phenotypes, which are defined by a distinct set of nine clinical and biomarker variables that can be easily acquired and used in routine clinical practice, were created from cluster analysis of data on 156 patients with asthma and 31 healthy individuals from the Airway Disease Endotyping for Personalized Therapeutics (ADEPT) study.
A maximum of four clusters was determined to be optimal, and classification probability showed that more than 75% of participants in each cluster had a more than 80% probability of being in their assigned phenotype, while only one patient per phenotype had a less than 50% probability.
Phenotype A1 comprised 28 individuals, most of whom had mild asthma, with average Asthma Control Questionnaire (ACQ)-7 scores of 0.5 and the vast majority, at 93%, was not currently taking inhaled corticosteroids. This group had the youngest age of asthma onset, at a mean of 15 years, and normal lung function that did not differ from that of healthy participants. They also had a low inflammation burden and low levels of blood and sputum eosinophils and sputum neutrophils.
Phenotype A2 involved 44 patients with mostly moderate or less severe asthma (52% and 32%, respectively). This was characterized by mild, reversible airflow obstruction and the average ACQ-7 score was 1.1. This group had the most hyper-responsive individuals, as measured by methacholine PC20, and the highest degree of type 2 eosinophilic inflammation (mean fraction of exhaled nitric oxide [FeNO]=43.8 ppb, mean blood eosinophils= 0.299 x 1000/uL, mean sputum eosinophils=7.1% of white blood cells). These patients were also the most atopic according to total and specific serum immunoglobulin (Ig)E levels.
The 49 patients showing phenotype A3 characteristics had a mix of mild (27%), moderate (43%), and severe (31%) disease. For most, asthma was reasonably well-controlled, and airflow obstruction and airway hyper-responsiveness were mild and often reversible. Patients tended to be non-eosinophilic and non-atopic, whereas sputum neutrophil counts were high, at an average 63.1 % of white blood cells.
The remaining 35 patients were categorized into phenotype A4. These patients had predominantly (63%) severe asthma, which was often uncontrolled. And they had the greatest airflow obstruction, the highest bronchodilator reversibility, and a high degree of airway hyper-responsiveness. They had prominent mixed eosinophilic and neutrophilic inflammation, and although the group had a similar percentage of patients with high serum IgE levels as phenotype A2, the rate of atopy was lower, similar to that of phenotype A3.
The ADEPT participants largely remained in their assigned phenotype for the duration of the 12-month study, with phenotype A4 found to be the least stable.
The four phenotypes also stood up to independent validation using data from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcome (U-BIOPRED) cohort, both when compared with a cohort of 82 patients with similar clinical characteristics to those assessed in ADEPT and a non-restricted cohort of 397 participants.
Additionally, biopsy gene expression data available for 81 patients suggested that the phenotypes could be differentiated according to the expression of genes associated with immune mechanisms driven by the T2 cytokine interleukin (IL)-13 and may be relevant to therapies that target such mechanisms.
Frédéric Baribaud (Janssen Research & Development LLC, Spring House, Pennsylvania, USA) and colleagues comment in Respiratory Research that “[f]ocusing on the biology of each phenotype and understanding the unmet need will aid in developing tailored therapies.”
For phenotype A1, there is minimal need for treatment other than disease interception, they suggest, while the profile for patients with phenotype A2 suggests steroid insensitivity and therefore potential for treatment with biologics or other drugs targeting T2 inflammation.
Patents with phenotype A3 have fewer options at present, they note, with disease driven more by infection than atopy, but possibly alternative anti-inflammatories could be explored, the team suggests. Patients with the most severe phenotype A4 may respond to therapies targeting IL-13 biology and/or eosinophilic inflammation, they believe.
By Lucy Piper
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