Fractional Exhaled Nitric Oxide Identifies Worse Outcomes in Asthmatics With Mucus Plugging and Bronchial Wall Thickening

Abstract

Fractional exhaled nitric oxide (FeNO) is a point-of-care breathing test that assesses IL13-mediated airway inflammation which is closely linked to severe asthma exacerbations [1]. Mucus plugging (MP) and bronchial wall thickening (BWT) have been identified as important asthma phenotypes [2, 3] and are, in turn, associated with elevated FeNO [4]. It is unknown, however, whether FeNO is a useful test when investigating asthma patients with MP or BWT.

We, therefore, performed a cross-sectional review of 55 consecutive patients with Global Initiative for Asthma (GINA) defined moderate-to-severe asthma who had a high-resolution computed tomography (HRCT) scan demonstrating the presence of MP or BWT between January 2019 and June 2023. Two senior thoracic radiologists interpreted all scans as previously described and were blinded to clinical information except for a diagnosis of persistent asthma. Briefly, MP was deemed present if any bronchopulmonary segments contained a fully obstructing plug, with a maximum score of 20 if all segments were obstructed [2]. BWT was considered evident if the wall area (WA) thickness exceeded 50% of the total airway area [3]. Patients were subsequently divided into tertiles according to FeNO.

FeNO (NIOX VERO, Circassia, UK) was performed according to American Thoracic Society (ATS) guidelines. Spirometry (Micromedical, Chatham, UK) values were obtained in triplicate as per ATS/European Respiratory Society (ERS) guidelines. A prednisolone prescription of 40 mg for at least 5 days in the preceding year constituted one severe asthma exacerbation. The Asthma Control Questionnaire (ACQ) was used to assess symptom control.

Statistical analysis was performed using SPSS v28 where differences in continuous variables were analysed using independent T-tests or Mann–Whitney U-tests. Categorical variables were analysed using chi-squared tests. A two-tailed alpha error of 0.05 was used to denote statistical significance. Caldicott Guardian approval (IGTCAL10360 and IGTCAL10810+) was obtained before any data collection.

N = 38/55 (69%) and n = 34/55 (62%) patients exhibited a mucus plug score (MPS) ≥1 or WA ≥ 50%, respectively, whilst n = 17/55 (31%) patients exhibited both MPS ≥ 1 and WA ≥ 50%. Patient demographics are presented in Table 1.

The presence of elevated FeNO was associated with significantly worse forced expiratory volume in 1 s percentage predicted (FEV₁%) in patients with MP (Table 1). In patients with BWT, more frequent severe exacerbations and worse symptom control was observed in those with higher FeNO (Table 1). Moreover, patients in both groups with raised FeNO exhibited higher blood eosinophils.

Previous studies have demonstrated greater FeNO levels and worse lung function in asthmatics with MP compared with those without [2]. The present study adds to the existing literature in that, in asthma patients who had MP, the presence of raised FeNO was associated with worse FEV₁, with the mean difference between tertiles amounting to 17%. Indeed, those in the highest FeNO tertile exhibited evidence of airway obstruction as a reduced mean FEV₁/FVC ratio of 65%. This may be predictable since FeNO is regulated by IL-13 signalling, and the latter is responsible for both goblet cell hyperplasia and bronchial smooth muscle contraction. However, it is worth emphasising that this was observed in a phenotype of patients with worse lung function than the general asthma population.

An earlier study reported a relationship between BWT and worse asthma symptom control [5]. In the present study, high FeNO was associated with poorer symptom control in asthma patients who had BWT. The mean ACQ difference between groups was 1.0 which is twice the minimal clinical important difference of 0.5 inferring that this is likely to be clinically relevant. Each 1.0 increase in ACQ score is associated with a 50% increased risk of future asthma exacerbation [6], which is consistent with the findings from the present study of more frequent exacerbations in the FeNO-high cohort.

We appreciate that our data should be interpreted in the context of potential limitations including its retrospective nature as well as being obtained from a single specialist centre. FeNO, spirometry and ACQ values were obtained contemporaneously, whereas HRCTs were performed within 6 months due to National Health Service waiting lists. With a larger cohort of patients, the next logical step might be to assign specific values to clinical imaging phenotypes as part of a holistic risk-scoring system for the prediction of future severe asthma exacerbations. Although it is possible that the bronchial wall thickening analysis was underpowered to examine the FEV₁ outcome, it sufficiently detected statistically significant and clinically relevant differences in ACQ (3.4 vs. 2.3); exacerbations (4 vs. 2) and blood eosinophils. Ultimately, our findings support the results of a recent systematic review and meta-analysis showing that a FeNO-guided approach likely reduces asthma exacerbations [7]. It would also be intriguing to see whether this combination phenotype comprising radiological features in conjunction with high FeNO might respond more favourably to biologics targeting IL-13 mediated inflammation such as dupilumab and tezepelumab.

R.C. and B.L. were responsible for idea conception; R.C., C.D., M.J.T. and B.L. were involved in data collection, analysis and drafting all versions of the manuscript for submission.

This retrospective observational study did not involve intervention or change in therapy, and therefore, Caldicott Guardian approval was granted (IGTCAL10360 and IGTCAL10810+).

Dr Chan reports personal fees (talks) and support attending ERS from AstraZeneca, personal fees (consulting) from Vitalograph, and personal fees (talks) from Thorasys. Dr Duraikannu has no relevant conflicts of interest. Dr Thouseef has no relevant conflicts of interest. Dr Lipworth reports non-financial support (equipment) from GSK; grants, personal fees (consulting, talks and advisory board), other support (attending ATS and ERS) and from AstraZeneca; personal fees (talks and consulting) from Sanofi, personal fees (consulting, talks and advisory board) from Circassia in relation to the submitted work; grants, personal fees (consulting, talks, advisory board), other support (attending ERS) from Teva, personal fees (talks and consulting), grants and other support (attending ERS and BTS) from Chiesi, personal fees (consulting) from Lupin, personal fees (consulting) from Glenmark, personal fees (consulting) from Dr Reddy, personal fees (consulting) from Sandoz; grants, personal fees (consulting, talks, advisory board), other support (attending BTS) from Boehringer Ingelheim, grants and personal fees (advisory board and talks) from Mylan outside of the submitted work; and the son of BJL is presently an employee of AstraZeneca.