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. 2022 Aug;27(8):573-577.
doi: 10.1111/resp.14294. Epub 2022 May 19.

Sub-stratification of type-2 high airway disease for therapeutic decision-making: A 'bomb' (blood eosinophils) meets 'magnet' (FeNO) framework

Affiliations

Sub-stratification of type-2 high airway disease for therapeutic decision-making: A 'bomb' (blood eosinophils) meets 'magnet' (FeNO) framework

Simon Couillard et al. Respirology. 2022 Aug.
No abstract available

Keywords: airway markers; asthma; eosinophils; inflammation; nitric oxide.

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Conflict of interest statement

Simon Couillard received non‐restricted research grants from Sanofi‐Genzyme, the Quebec Respiratory Health Research Network and the Association Pulmonaire du Québec, outside the submitted work; received speaker honoraria from GlaxoSmithKline, Sanofi‐Regeneron and AstraZeneca, outside the submitted work; and is on the advisory board of Biometry Inc, outside the submitted work. In the last 5 years, Ian D. Pavord has received speaker's honoraria for speaking at sponsored meetings from AstraZeneca, Boehringer Ingelheim, Aerocrine AB, Almirall, Novartis, Teva, Chiesi, Sanofi/Regeneron, Menarini and GSK, and payments for organizing educational events from AstraZeneca, GSK, Sanofi/Regeneron and Teva. He has received honoraria for attending advisory panels with Genentech, Sanofi/Regeneron, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Circassia, Chiesi and Knopp, and payments to support FDA approval meetings from GSK. He has received sponsorship to attend international scientific meetings from Boehringer Ingelheim, GSK, AstraZeneca, Teva and Chiesi. He has received grants from Chiesi and Sanofi Genzyme. He is co‐patent holder of the rights to the Leicester Cough Questionnaire and has received payments for its use in clinical trials from Merck, Bayer and Insmed. During 2014–2015, he was an expert witness for a patent dispute involving AstraZeneca and Teva. Liam G. Heaney has received grant funding, participated in advisory boards and given lectures at meetings supported by Amgen, AstraZeneca, Boehringer Ingelheim, Circassia, Hoffmann la Roche, GlaxoSmithKline, Novartis, Theravance, Evelo Biosciences, Sanofi and Teva. He has received grants from MedImmune, Novartis UK, Roche/Genentech Inc, Glaxo Smith Kline, Amgen, Genentech/Hoffman la Roche, Astra Zeneca, MedImmune, Glaxo Smith Kline, Aerocrine and Vitalograph. He has received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK and Napp Pharmaceuticals. He has also taken part in asthma clinical trials sponsored by AstraZeneca, Boehringer Ingelheim, Hoffmann la Roche and GlaxoSmithKline for which his institution received remuneration. He is the Academic Lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma which involves industrial partnerships with a number of pharmaceutical companies including Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann la Roche and Janssen. Nayia Petousi is supported from the NIHR Oxford BRC. She has received grants from the University of Oxford and NIHR research capability funding from Oxford University Hospitals outside the submitted work. She has received personal fees from Astra Zeneca, outside the submitted work. Timothy S. C. Hinks has received grants from the Wellcome Trust, The Guardians of the Beit Fellowship, Pfizer Inc., Kymab Ltd, Sensyne Health, University of Oxford and from the NIHR Oxford BRC, outside the submitted work. He has received personal fees from Astra Zeneca, TEVA, Omniprex and Peer Voice, outside the submitted work.

Figures

FIGURE 1
FIGURE 1
Type‐2 airway inflammation is driven by an adaptive and innate immune response driven by epithelial alarmins (particularly IL‐33 and thymic stromal lymphopoietin). Type‐2 airway inflammation is detected in clinical practice by assessing fractional exhaled nitric oxide (reflecting airway IL‐13 activity) and blood eosinophils (reflecting systemic IL‐5 activity). The main functional consequence of type‐2 inflammation is airflow limitation as a result of airway mucus plugging, airway wall oedema and thickening, airway smooth muscle hyperplasia and the induction of airway hyperresponsiveness. Key cellular players, cytokines, chemokines, effector mediators and their receptors, are shown. Coloured crosses indicate the pathways inhibited by the relevant biologic (shown in same colour); corticosteroids inhibit most pathways at the cost of associated toxicity.
FIGURE 2
FIGURE 2
In severe asthma with documented treatment adherence to high‐dose inhaled corticosteroids (as demonstrated following a fractional exhaled nitric oxide [FeNO] suppression test), FeNO is correlated with increased induced sputum levels of airway type‐2 cytokines, chemokines and alarmins. In contrast, blood eosinophils correlate with serum IL‐5 and not with any assessed measure in sputum. These results imply that FeNO and blood eosinophils relate to different components and compartments of type‐2 inflammation, with FeNO reflecting the chemotactic pull (magnet) to the airways and blood eosinophils reflecting the systemic pool of available eosinophils (bomb). When both occur together, the risk of asthma attacks (bomb detonating) is particularly high. The biomarker profile of magnet‐driven disease is shown in the blue outlined area and bomb‐driven disease in the black outlined area overlaying a grid showing the relative risk of asthma attacks according to data from placebo arms of randomized controlled trials. Colour codes reflect the relative risk of asthma attacks: green (low risk) to red (high risk). Based on data from Couillard et al, ; figure reproduced from Couillard et al with permission from Elsevier.
FIGURE 3
FIGURE 3
A prototype nomogram to interpret the strength of the fractional exhaled nitric oxide (FeNO) (‘magnet’) versus eosinophil (‘bomb’) signals: The line linking two biomarker values identifies bomb‐ versus magnet‐predominant asthma. Dashed grey line (—): Example of the nomogram result for a patient with an FeNO of 60 ppb and a blood eosinophil count (Eos) of 0.3 × 109/L, suggesting a magnet‐driven asthma; see Table 1 for other phenotypic characteristics that may influence case interpretations. The cut‐off points and their positions on the nomogram are based on the fact that (a) clinical cut‐off points are 0.15–0.3 × 109/L for blood eosinophils and 20–40 ppb for FeNO, (b) the predictive value of these biomarkers are approximately linear up 0.6 × 109/L and 60 ppb, respectively, in the placebo arms of severe asthma trials and (c) upper values are logarithmically distributed.

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