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.^1,3–6 Multiple inflammatory endotypes have been characterised – allergic and eosinophilic inflammation, to name a few.⁵ 

Overlapping 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:¹ 

• Type 2 (T2) inflammation, typically marked by allergic and/or eosinophilic inflammation¹ 

• Mechanisms beyond T2 inflammation, characterised by neutrophilic or paucigranulocytic inflammation, and airway hyperresponsiveness, airway remodelling or microbial dysbiosis, which may exist together with T2 inflammation^1,8,9 

While many patients have T2 disease,^1,2 a sizeable 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 US study, around a third of adults with severe asthma have both an allergic and an eosinophilic (defined as blood eosinophils >300 µL/cells) phenotype.² It would be advantageous to further understand any overlap and common drivers (such as epithelial cytokines) of the downstream endotypes of severe asthma.^11,12 Understanding this could help to identify appropriate treatments to address the overlap of downstream pathways and to improve patient care.^6,11   

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.¹³ As such, it is important that clinicians are able to interpret biomarkers effectively to improve patient outcomes.¹³  

Various biomarkers of T2-mediated inflammation, including specific blood immunoglobulin (Ig) E, blood or sputum eosinophils, and fractional exhaled nitric oxide (FeNO), are available to clinicians^1,13,14 and these, among others, can be used in clinical practice for phenotyping of severe asthma.¹³ 

• Allergen-specific blood IgE levels, measured via a 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^13,15 

• 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.¹⁴ 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 counts¹⁶ 

• FeNO is a biomarker of airway epithelial cell exposure to IL-13 and IL-4.^10,14 These cytokines upregulate inducible nitric oxide synthase (iNOS) in the airway epithelium, and result in increased nitric oxide production.¹⁴ A high FeNO measurement correlates with airway eosinophilia in asthma and indicates increased airway T2 inflammation¹⁴ 

It is important to note that biomarker levels may be affected by treatments.¹⁵ Biomarkers of T2 inflammation are often suppressed by inhaled corticosteroids and oral corticosteroids; therefore, eosinophils and FeNO assessments are encouraged before commencing a short course or maintenance OCS, or on the lowest possible OCS dose.¹⁵  

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.^10,17,18 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.¹⁹