The clinical features and inflammatory mediators of adult-onset asthma were associated with distinct endotype groups defined by eosinophil and neutrophil levels, based on data from a real-life long term study of 203 patients.
Asthma is a chronic condition from lower respiratory tract inflammation composed of complex, heterogeneous endotypes with T2 helper cells being one way to distinguish between them. Endotypes have previously been suggested to have differing risks for asthma exacerbations and severity. However, clinical and biomarker information used for recognizing and targeting treatment is largely lacking in those subgroups other than eosinophilic asthma, according to Ella Flinkman, faculty of medicine and health technology, of Tampere University (Finland), and colleagues.
In a study published in The Journal of Allergy and Clinical Immunology: In Practice the researchers reported on their single-center 12-year follow-up phase II Seinäjoki Adult Asthma Study (SAAS). The included cohort of 203 patients had a median age of 58 years and 58% were women; all participants were originally diagnosed by a respiratory specialist physician as having new adult-onset asthma during the years 1999-2000 using asthma symptoms and objective lung function measurements.
To evaluate the association between clinical features and inflammation mediators to venous blood granulocytes this cohort was divided into paucigranulocytic (n = 108), neutrophilic (n = 60), eosinophilic (n = 21), and mixed granulocytic (n = 14) endotype subgroups based on eosinophil and neutrophil levels. Objective comparisons between groups were made using measurements from forced expiratory volume in 1 second (FEV1), fraction of exhaled nitric oxide (FeNO), immunoglobin E (IgE), high-sensitivity C-reactive protein (hsCRP), IL-6, resistin, MMP-9, plasma soluble urokinase plasminogen activator receptor (suPAR), leptin, HMW adiponectin, and periostin tests. Asthma-related medications and disease exacerbation data were collected from medical records accumulated over the 12-year study period.
The neutrophilic group was defined by high (≥ 4.4×109/L) neutrophil but low (< 0.30×109/L) eosinophil counts and conversely the eosinophilic group had low (< 4.4×109/L) neutrophil but high (≥ 0.30×109/L) eosinophil counts. The paucigranulocytic was low and the mixed granulocytic group was high for both eosinophil and neutrophil levels, respectively. Each group was associated with a unique profile of features related to asthma prognosis and treatment. The paucigranulocytic endotype was used as the base comparison group in regression analysis as it was the least likely to meet the definition of severe asthma. This was indicated by the lowest use of inhaled corticosteroid (ICS), antibiotics, and occurrence of unplanned respiratory visits. The other three groups were more likely to fulfill a severe asthma classification.
Negative binomial regression analysis showed significant association of increased incidence rate ratio (IRR) of unplanned respiratory visits, highest body mass index (BMI), and highest dispensed doses of ICS with neutrophilic asthma. Additional significantly associated factors included smoking history and gender. Adjustment for dispensed ICS 2 years prior to the 12-year follow-up visit resulted in a change from borderline to significant association of increased IRR for the eosinophilic group. Both the eosinophilic and neutrophilic groups were associated with the most antibiotic use over the 12-year follow-up period. The authors suggested their data may indicate that antibiotics are overprescribed for asthma and further investigation is required.
Multiple linear regression analysis showed a decline in lung function associated with the eosinophilic but not the neutrophilic group. Connections between specific blood endotypes and molecular features were also identified. Highest periostin and FeNO levels found in the eosinophilic group were consistent with other studies on patients specifically diagnosed with eosinophilic asthma.
The neutrophilic group was distinguished by the highest hsCRP, MMP-9, IL-6, leptin, and suPAR levels. Highest resistin levels were found in both the mixed granulocyte and neutrophilic groups.
This study was strengthened by its real life long-term nature and method for cohort selection, according to the authors, though the value of a larger population to raise numbers particularly in the smaller sized groups was noted.
The authors concluded: “Our study indicates that assays of blood eosinophil and neutrophil counts provide useful information for assessing and treating patients with adult-onset asthma. These granulocyte counts reflect the underlying inflammatory pattern and reveal important differences in asthma clinical features and outcomes.” Additional research “regarding biomarkers used to identify different endotypes of asthma” is needed.
The study was sponsored by a number of research foundations in Finland as well as hospital research center funds. Several of the authors disclosed associations with pharmaceutical companies, including Astra Zeneca, Boehringer-Ingelheim, GSK, Novartis, and Sanofi.