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• Response to correspondence (Jackson et al. Thorax 2021)
  Liam G Heaney, David J Jackson
  Published on: 7 April 2021
• Letter to the editors
  Varun Sharma, Douglas C Cowan
  Published on: 7 April 2021

• Published on: 7 April 2021

  Response to correspondence (Jackson et al. Thorax 2021)

  • Liam G Heaney, Professor of Respiratory Medicine Queens University Belfast
  • Other Contributors:
    • David J Jackson, Consultant Respiratory Physician

  The influence of obesity on both asthma and T2 biomarkers remains poorly understood and we fully agree this requires further investigation, as does the relationship between obesity, depression and persistent symptoms of breathlessness. However, the data correlating obesity and FeNO is conflicting and the reported weak positive associations have often not been adjusted for corticosteroid dose and may simply reflect higher doses of corticosteroid therapy in more breathless obese patients than by those of normal weight, rather than a specific mechanistic relationship.
  Moreover, the UKSAR population appears very different from the cohorts described in some of these reports. For example, the average FeNO was only 25ppb in the Komakula study, whilst in the study by Lugogo subjects were predominantly T2-low across all BMI categories: the upper quartile value of blood eosinophils in both lean and obese groups was <300 cells/µL, whilst the upper quartile of FeNO in both lean and obese groups was <30ppb. In contrast, even in the UKSAR T2 high cohort, the mean BMI was in the obese range.
  The nature and veracity of the ‘T2-low’ phenotype remains unclear, particularly in severe asthma. What is increasingly apparent is that patients are frequently prescribed high dose inhaled and systemic corticosteroids for respiratory symptoms, which suppresses T2 inflammation in the process. In the context of obesity and other co-morbidities known to be associated with increased re...

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  The influence of obesity on both asthma and T2 biomarkers remains poorly understood and we fully agree this requires further investigation, as does the relationship between obesity, depression and persistent symptoms of breathlessness. However, the data correlating obesity and FeNO is conflicting and the reported weak positive associations have often not been adjusted for corticosteroid dose and may simply reflect higher doses of corticosteroid therapy in more breathless obese patients than by those of normal weight, rather than a specific mechanistic relationship.
  Moreover, the UKSAR population appears very different from the cohorts described in some of these reports. For example, the average FeNO was only 25ppb in the Komakula study, whilst in the study by Lugogo subjects were predominantly T2-low across all BMI categories: the upper quartile value of blood eosinophils in both lean and obese groups was <300 cells/µL, whilst the upper quartile of FeNO in both lean and obese groups was <30ppb. In contrast, even in the UKSAR T2 high cohort, the mean BMI was in the obese range.
  The nature and veracity of the ‘T2-low’ phenotype remains unclear, particularly in severe asthma. What is increasingly apparent is that patients are frequently prescribed high dose inhaled and systemic corticosteroids for respiratory symptoms, which suppresses T2 inflammation in the process. In the context of obesity and other co-morbidities known to be associated with increased respiratory symptoms, such as breathing pattern disorders and laryngeal dysfunction, this leads to high levels of avoidable corticosteroid-induced toxicity. The recent study by Heaney and colleagues in the RASP-UK programme, demonstrated that when corticosteroids were reduced based on T2-biomarkers, the maximal prevalence of T2-Low severe asthma was ~5%. Importantly in the sub-group analysis of patients with “uncontrolled asthma” defined as ACQ-7≥1.5, biomarker directed care resulted in significant reduction of corticosteroid treatment with no loss of control and patients in this uncontrolled group were predominantly female, obese with restrictive lung function, more likely to be on oral corticosteroids and with higher levels of reflux, depression and osteoporosis, all consistent with corticosteroid overtreatment.
  Until such time as corticosteroid doses are more effectively optimized in a T2 biomarker directed fashion, the influence of steroids themselves on many inflammatory pathways will continue to hamper our understanding of what mechanistically constitutes ‘T2-low’ asthma.
  References
  Komakula S, Khatri S, Mermis J, et al. Body mass index is associated with reduced exhaled nitric oxide and higher exhaled 8-isoprostanes in asthmatics. Respir Res. 2007Apr 16;8(1):32.
  Lugogo N, Green CL, Agada N, et al. Obesity's effect on asthma extends to diagnostic criteria. J Allergy Clin Immunol. 2018;141(3):1096-1104.
  Heaney LG, Busby J, Hanratty CE, et al. Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial. Lancet Respir Med. 2021 Jan;9(1):57-68.

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  Conflict of Interest:
  None declared.

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• Published on: 7 April 2021

  Letter to the editors

  • Varun Sharma, Difficult Asthma Clinical Research Fellow, Respiratory Registrar 1. Glasgow Royal Infirmary. 2. Institute of Infection, Immunity and Inflammation, University of Glasgow Inflammation
  • Other Contributors:
    • Douglas C Cowan, Consultant Respiratory Physician

  We read with interest the recent paper from DJ Jackson et al, “Characterisation of patients with severe asthma in the UK Severe Asthma Registry in the biologic era” [1], and share their concerns regarding the risk of excessive corticosteroid exposure in T2-low individuals. We congratulate the authors for gathering such an extensive range of data in this large cohort of people with severe asthma, enabling meaningful comparisons, particularly between biologic and non-biologic populations. We echo the call for further work to identify and validate pragmatic T2-low endotype-specific biomarkers through clearer understanding of this inflammatory cascade. This cohort of patients continues to be under-served, made all the more evident by the paucity of novel therapies in this era of precision medicine.
  We note the authors’ comments on T2-biomarker increase with corticosteroid dose reduction, and the presence of a historic T2-high profile in some individuals from the T2-low group. Whilst the postulated explanation reported by the authors, one of corticosteroid-induced T2-biomarker suppression, is undoubtedly a key factor (and indeed supported by the significant difference in corticosteroids between the groups), we would suggest another important factor that may be relevant to the understanding of the T2-low pathway.
  The authors report a significant difference in BMI between T2-high and T2-low groups (30.2kg/m2 and 32.1kg/m2 respectively, P-value = <0.001). Whilst the...

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  We read with interest the recent paper from DJ Jackson et al, “Characterisation of patients with severe asthma in the UK Severe Asthma Registry in the biologic era” [1], and share their concerns regarding the risk of excessive corticosteroid exposure in T2-low individuals. We congratulate the authors for gathering such an extensive range of data in this large cohort of people with severe asthma, enabling meaningful comparisons, particularly between biologic and non-biologic populations. We echo the call for further work to identify and validate pragmatic T2-low endotype-specific biomarkers through clearer understanding of this inflammatory cascade. This cohort of patients continues to be under-served, made all the more evident by the paucity of novel therapies in this era of precision medicine.
  We note the authors’ comments on T2-biomarker increase with corticosteroid dose reduction, and the presence of a historic T2-high profile in some individuals from the T2-low group. Whilst the postulated explanation reported by the authors, one of corticosteroid-induced T2-biomarker suppression, is undoubtedly a key factor (and indeed supported by the significant difference in corticosteroids between the groups), we would suggest another important factor that may be relevant to the understanding of the T2-low pathway.
  The authors report a significant difference in BMI between T2-high and T2-low groups (30.2kg/m2 and 32.1kg/m2 respectively, P-value = <0.001). Whilst the absolute difference may seem trivial, raised BMI directly affects levels of commonly used T2-biomarkers [2,3,4]. With regards to fractional exhaled nitric oxide (FeNO), there is evidence for an adipose-mediated metabolic imbalance with nitric oxide synthase (NOS) uncoupling that affects NO bioavailability and leads to reduced FeNO [5]. In obesity-associated asthma, whilst total IgE and blood eosinophils correlate to T2-high profiles, this association is relatively weaker and total IgE levels are lower compared to healthy-BMI people with asthma. Furthermore, neither IgE, blood eosinophils nor FeNO predict sputum eosinophilia with current ranges, and evidence suggests lower thresholds are needed for T2-biomarkers in this cohort [4]. This has important implications for asthma phenotyping, monitoring of response to treatment and, as is a focus of the article, determining eligibility for advanced therapies. We would also suggest the difference in depression and anxiety seen within the two groups may be somewhat related to the BMI disparity.
  Obesity-associated asthma remains incompletely understood, however it is becoming clearer that focus is needed on identifying biomarkers and specific treatments for severe T2 low asthma and this may be particularly relevant to the this population.

  References
  [1] – Jackson DJ, Busby J, Pfeffer PE, et al; UK Severe Asthma Registry. Characterisation of patients with severe asthma in the UK Severe Asthma Registry in the biologic era. Thorax. 2021Mar;76(3):220-227.
  [2] – Komakula S, Khatri S, Mermis J, et al. Body mass index is associated with reduced exhaled nitric oxide and higher exhaled 8-isoprostanes in asthmatics. Respir Res. 2007Apr 16;8(1):32.
  [3] – Renata Barros, André Moreira, João Fonseca, et al. Obesity and airway inflammation in asthma. Journal of Allergy and Clinical Immunology. 2006;117:6(1501-1502), ISSN 0091-6749,
  [4] – Lugogo N, Green CL, Agada N, et al. Obesity's effect on asthma extends to diagnostic criteria. J Allergy Clin Immunol. 2018;141(3):1096-1104.
  [5] – Holguin F, Grasemann H, Sharma S, et al. L-Citrulline increases nitric oxide and improves control in obese asthmatics. JCI Insight. 2019 Dec 19;4(24):e131733.

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  Conflict of Interest:
  None declared.

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