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Complexity of severe asthma

Inflammation in asthma is complex and heterogeneous, which makes it challenging to manage1–4

Home EpiFundamentals Complexity of severe asthma

Inflammation in asthma is complex and heterogeneous, which makes it challenging to manage1–4

  • Activation of the airway epithelium, following exposure to environmental triggers, results in epithelial cytokine release1,5​,6
  • Upstream activation of epithelial cytokines can lead to initiation of multiple downstream inflammatory pathways, including T2 inflammation (allergic and/or eosinophilic) and beyond T2 inflammation (structural changes to the airway)1,6–9​
  • Patients may display overlapping, dynamic inflammatory pathways, which can change over time owing to different circumstances1–4,9; many patients are thought to have multiple drivers of disease2​
  • Dynamic, objective, and diagnostic clinical biomarkers can help to identify phenotypes and endotypes of severe asthma and serve as valuable tools to support in the selection of an appropriate treatment and improving patient outcomes10

Improved understanding of the key inflammatory pathways and mechanisms that underpin epithelial diseases will continue to drive research and development of new treatment solutions, with the goal of achieving greater disease stability and ultimately remission, improving patient outcomes6,11,12

T2, type 2​.

References
1. Busse WW. Allergol Int. 2019;68:158–166. 2. Tran TN, et al. Ann Allergy Asthma Immunol. 2016;116:37–42. 3. Price D, Canonica GW. World Allergy Organ J. 2020;13:100380. ​4. Kupczyk M, et al. Allergy. 2014;69:1198–1204. 5. Lambrecht BN, Hammad H. Nat Med. 2012;18:684–692. ​6. Gauvreau GM, et al. Expert Opin Ther Targets. 2020;24:777–792. 7. Cao L, et al. Exp Lung Res. 2018;44:288–301. 8. Wu J, et al. Cell Biochem Funct. 2013;31:496–503. 9. Kuruvilla ME, et al. Clin Rev Allergy Immunol. 2019;56:219–233. 10. Carr TF, Kraft M. Ann Allergy Asthma Immunol. 2018;121:414–420. ​11. Kaur R, Chupp G. J Allergy Clin Immunol. 2019;144:1–12. 12. Agache I, et al. Allergy. 2012;67:835–846.

Inflammation in severe asthma

Inflammation in asthma leads to increased symptoms.1,5 Asthma-associated inflammation is complex and heterogeneous,1–4 and numerous cell types, mediators, and downstream immune pathways are involved.1–6 Multiple inflammatory endotypes have been characterized – allergic and eosinophilic inflammation, to name a few.6

Video: Watch Professor Christopher Brightling introduce the complexity of severe asthma ​ (04:09)

Inflammatory pathways infographic

Multiple inflammatory pathways underpin the complexity and heterogeneity of inflammation in severe asthma

For a deep dive on the inflammatory pathways that underpin the complexity of inflammation in severe asthma, please listen to Dr. Jonathan Corren here from 06:45 min.

Overlapping and changing inflammatory pathways in severe asthma

Activation of the airway epithelium by exposure to a pollutant or allergen results in the production of epithelial cytokines and leads to a cascade of events that result in airway inflammation and the clinical manifestations of asthma.1,7 This airway inflammation drives changes in asthma pathophysiology and leads to airway hyperresponsiveness and airflow obstruction.1

The production of epithelial cytokines leads to multiple downstream immune pathways in patients with severe asthma, including: 

  • Type 2 (T2) inflammation, typically marked by allergic and/or eosinophilic inflammation1
  • Mechanisms beyond T2 inflammation, characterized by neutrophilic or paucigranulocytic inflammation and airway hyperresponsiveness, airway remodeling, or microbial dysbiosis, which may exist together with T2 inflammation1,8,9

While many patients have T2 disease,1 a sizable group has mechanisms that are beyond T2 disease.2  

Video: Watch Professor Ian Pavord discuss the asthma heterogeneity and the dynamic nature of airway inflammation in asthma (01:05)

Some patients have concurrent overlapping inflammatory pathways.1–4 Often, the extent of overlap is unknown; however, it is likely that many patients have a mixture of pathways that drive their disease.1,2 The dominant pathway may change over time owing to different circumstances, such as changes in medications, treatment adherence, exacerbations, or exposure to allergens.1–4 In a biomarker study conducted in patients with severe asthma, the phenotype changed in ~50% of patients based on their sputum biomarker clustering after 1 year of follow-up.4

Upstream activation of epithelial cytokines can lead to initiation of multiple downstream inflammatory pathways.10 The wide spectrum and overlap of downstream pathways in severe asthma mean that diagnosis and treatment can be challenging.2 For example, in one study, ~60% of adults with severe asthma have ≥2 elevated biomarkers characterized by elevated immunoglobulin E (IgE), fractional exhaled nitric oxide (FeNO), and blood eosinophils of ≥300 cells/µL.11 It would be advantageous to further understand any overlap and common drivers (such as epithelial cytokines) of the downstream endotypes of severe asthma.12,13 

Biomarkers in severe asthma 

Dynamic, objective, and diagnostic biomarkers can help to identify phenotypes and endotypes of severe asthma and help in the selection of an appropriate treatment.14 As such, it is important that clinicians are able to interpret biomarkers effectively to improve patient outcomes.14 

Various biomarkers of T2-mediated inflammation, including specific blood IgE, blood or sputum eosinophils, and FeNO, are available to clinicians,1,14,15 and these, among others, can be used in clinical practice for phenotyping of severe asthma.14

  • Allergen-specific blood IgE levels, measured via blood or skin prick testing, are higher in patients with allergic asthma compared with healthy individuals and can be used as a surrogate measure for atopy14,16
  • Blood eosinophils and sputum eosinophils are surrogate markers of T2 inflammation and the T2-inflammatory cytokine, interleukin (IL)-5, which is required for eosinophil activation and survival.15 These are useful biomarkers as patients with higher eosinophil counts are prone to experiencing severe disease and poorer asthma outcomes than patients with lower eosinophil counts17
  • FeNO is a biomarker of airway epithelial cell exposure to IL-13 and IL-4.10,15 These cytokines upregulate inducible nitric oxide synthase (iNOS) in the airway epithelium and result in increased nitric oxide production.15 A high FeNO measurement correlates with airway eosinophilia in asthma and indicates increased airway T2 inflammation15

Biomarkers assessment in a 49-year-old man infographic

Biomarker assessment in a 49-year-old man with severe asthma

Phenotyping a patient with sever asthma infographic

Phenotyping a patient with severe asthma

It is important to note that biomarker levels may be affected by treatments.16 Biomarkers of T2 inflammation are often suppressed by inhaled corticosteroids and oral corticosteroids (OCS); therefore, eosinophils and FeNO assessments are encouraged before commencing a short course or maintenance OCS, or on the lowest possible OCS dose.16

Some gaps exist in the clinical predictive value of existing biomarkers owing to the challenge of identifying a single predominant endotype of severe asthma.6 Furthermore, there are currently no readily available biomarkers in clinical practice that identify T2-independent asthma.10,18,19 For now, biomarker data need to be interpreted alongside symptoms and lung function and need to focus on identifying tractable features of asthma, such as airway hyperresponsiveness.20

Video: Watch Professor Christopher Brightling ​explain the use of biomarkers in airway inflammation and their predictive value (07:11)

Find out more about the EpiCreator – Professor Christopher Brightling.

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Role of the epithelium in asthma

Professor Celeste Porsbjerg, MD, PhD

To learn more about how the epithelium mediates airway inflammation, visit the 'Role of the epithelium in asthma' page.

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References

1. Busse WW. Allergol Int. 2019;68:158–166. 2. Tran TN, et al. Ann Allergy Asthma Immunol. 2016;116:37–42. 3. Price D, Canonica GW. World Allergy Organ J. 2020;13:100380. 4. Kupczyk M, et al. Allergy. 2014;69:1198–1204. 5. Barnes PJ. Pathophysiology of asthma. In: Eur Respir Mon. 2003;23:84–113. 6. Gauvreau GM, et al. Expert Opin Ther Targets. 2020;24:777–792. 7. Lambrecht BN, Hammad H. Nat Med. 2012;18:684–692. 8. Cao L, et al. Exp Lung Res. 2018;44:288–301. 9. Wu J, et al. Cell Biochem Funct. 2013;31:496–503. 10. Kuruvilla ME, et al. Clin Rev Allergy Immunol. 2019;56:219–233. 11. Denton E, et al. J Allergy Clin Immunol Pract. 2021;9:2680–2688. 12. Kaur R, Chupp G. J Allergy Clin Immunol. 2019;144:1–12. 13. Agache I, et al. Allergy. 2012;67:835–846. 14. Carr TF, Kraft M. Ann Allergy Asthma Immunol. 2018;121:414–420. 15. Peters MC, et al. Curr Allergy Asthma Rep. 2016;16:71. 16. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. 2021. https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf. Accessed January 2024. 17. Kostikas K, et al. Curr Drug Targets. 2018;19:1882–1896. 18. Schleich F, et al. Curr Top Med Chem. 2016;16:1561–1573. 19. Quoc QL, et al. Exp Mol Med. 2021;53:1170–1179. 20. James A, Hedlin G. Curr Treat Options Allergy. 2016;3:439–452.