Complexity of severe asthma

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

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 inflammation^1,8,9

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

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 atopy^14,16
• 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

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