Influence of sex, cigarette smoking and airway inflammation on treatable traits in CBIOPRED severe asthma

Wei Gu : Data curation (Equal), Investigation (Equal), Resources (Equal). Kian Fan Chung : Investigation (Equal), Methodology (Equal), Project administration (Equal), Supervision (Equal), Validation (Equal), Writing – original draft (Equal), Writing – review&editing(Equal). QinglingZhang :Investigation(Equal),Project administration (Equal), Writing – review & editing (Equal). Nanshan Zhong : Project administration (Equal), Supervision (Equal), Writing – review & editing (Equal).


Influence of sex, cigarette smoking and airway inflammation on treatable traits in CBIOPRED severe asthma
To the Editor Asthma presents a major public health challenge in China, where it affects 45.7 million adults with an estimated prevalence of 4.2%; 26.2% of adults with asthma have airflow limitation. 1 Severe asthma is recognised in China with the recent publication of an expert consensus guidelines for the diagnosis and management of severe asthma. 2 Severe asthma has been defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming "uncontrolled" or that remains "uncontrolled" despite this therapy. 3 More recently, the identification of a higher number of treatable traits in severe asthma compared to mild-moderate asthma has facilitated a strategy for the management of airways disease. 4 However, the influence of various factors on the major treatable traits such as airflow obstruction and exacerbations is unclear. Therefore, we examined the role of sex and cigarette smoking on these traits and also their link to airway inflammation measured by inflammatory cell counts in induced sputum samples.

In the Chinese Biomarkers for the Prediction of Respiratory
Disease Outcomes (C-BIOPRED) cohort of severe asthma, we compared the parameters of male to female non-smoking severe asthma (NSA) and male current smoking severe asthma (CSA) and exsmoking (ESA) severe asthma at entry and at 1 year ( Figure 1).
Participants attended severe asthma university clinics where the diagnosis was ascertained and asthma treatment with adherence optimised. Non-smoking severe asthma were non-smokers for the past 12 months, with <5 pack-year smoking. CSA and ESA, exclusively male, had a smoking history of >5 pack-years. Severe asthma was defined according to European Respiratory Society and American Thoracic Society guidelines. 3 There were no differences in clinical parameters and asthma control between NSA male and female but the pre-bronchodilator FEV 1 (% predicted) were lower in male compared to female participants while the bronchodilator response was similar in both groups.   Table S1), with no difference in blood eosinophil counts, but neutrophil counts were highest in ESA. CSA showed a trend towards higher sputum neutrophil (%) and lower eosinophil (%) counts compared to ESA and CSA (p = 0.08 and 0.07, respectively). At 1 year, in the NSA female, there was an improvement in ACQ5 and in total AQLQ reflected in the symptom, activity limitation and emotional domains, accompanied by an improvement in prebronchodilator FEV 1 (% predicted) from 67.8% to 72.23% (p = 0.066) ( Figure 1C). In both male and female groups in NSA, there was a significant reduction in the bronchodilator response from 18.7% to 12.0% (p = 0.002) and from 21.50% to 12.15% (p < 0.001), respectively. There was no change in pre-and post-bronchodilator FEV 1 (% predicted), ACQ and AQLQ and FeNO and blood eosinophil counts in the CSA and ESA male participants ( Figure 1D).
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. eosinophil counts compared to male NSA. This is in contrast to the report of a higher disease burden of asthma in women compared to men. 5 It may be because of the post-menopause (as female NSA were aged 54 years) who were not obese and who have a lower ageadjusted risk of asthma than premenopausal women. 6,7 There is also the consideration that asthma sometimes improves after the menopause. 8  Currently-smoking severe asthma patients subjects had lower eosinophilic inflammation, likely to be a suppressive effect of current smoking, with higher sputum neutrophilia. 9 However, the degree of neutrophilia was related to airflow obstruction in NSA as previously reported. 10 Interestingly, the level of eosinophilic inflammation was correlated with the number of exacerbations in the previous year, supporting its link with Type-2 inflammation. 11 In the C-BIOPRED cohort, we have shown that sex differences and the effect of smoking are important influences on the treatable traits of severe asthma, with a likelihood of improvement in females at 1 year follow-up and lower type-2 inflammatory markers in currently-smoking asthmatics. Importantly, our data indicate that in severe asthma, while neutrophilic inflammation may be linked to airflow obstruction, eosinophilia is associated with exacerbation rates.

KEYWORDS
baseline and longitudinal, gender, severe asthma, smoking

ACKNOWLEDGEMENT
We are grateful to all the members of the C-BIOPRED Study Group who took part in the design and in the recruitment of participants into the study. We also thank all the participants across China who willingly took part in C-BIOPRED study. This study was funded by Astra-Zeneca China.

CONFLICT OF INTEREST
The authors declare no conflict of interest.

CONSENT
All participants gave written and signed informed consent.

FUNDING INFORMATION
Astra-Zeneca China.