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Understanding Type 2 inflammatory pathways

Interest in precision medicine is growing. For asthma, the challenge lies in differentiating between the various types of the disease to allow physicians to select the most appropriate therapy. Type 2 asthma typically responds well to anti-inflammatory treatment, whereas non-Type 2 asthma patients are unlikely to respond to corticosteroids. This article introduces Type 2 inflammation and the biomarkers that can help identify it.

Asthma’s characteristic airway inflammation can be produced by several biological pathways and it may be hard to distinguish between the varying types based on clinical assessment. However, using specific biomarkers, it is possible to identify certain subsets of patients to personalise treatment plans.

Many studies have been published over the last few years looking into the various phenotypes and endotypes of adult asthma to determine whether precision medicine could be made possible.1 They noted that the ability to define asthma endotypes using clinical characteristics and biomarkers should move physicians towards a more personalised approach and precision-based care. In addition, as asserted by the most recent guidelines from the European Respiratory Society, the fact that many asthmatics experience similar symptoms, such as wheezing, coughing and shortness of breath, across asthma subgroups and other diseases, means that clinical history is not enough to diagnose and treat the disease. Identifying the type of inflammation the patient has is therefore critical.

What is Type 2 inflammation?

Type 2 inflammation is thought to result from the activation of molecular pathways of both the adaptive (via CD4+ T-cells) and the innate immune response (mostly natural killer cells and ILC-2). Epithelial cell-derived cytokines, such as IL-25 and IL-33, convert CD4+ T-cells into T-helper type 2 cells (Th2), whilst thymic stromal lymphopoietin (TSLP) plays a key role in inducing a Th2 environment. Th2 cells and ILC-2s produce many Type 2 cytokines, including IL-4, IL-5, IL-9 and IL-13, which induce an inflammatory response.2

An infographic detailing the NO process

An infographic detailing the NO process

IL-4 stimulates B-cells, leading to the production of specific IgE and subsequent airway smooth muscle contraction and mucus hypersecretion. IL-5 and IL-13 increase airway eosinophils and mucus production, as well as airway remodelling. IL-4 and IL-13, via the STAT-6 pathway, drive the transcription of iNOS (inducible Nitric Oxide Synthase), thus increasing nitric oxide (NO) production.2 However, although the adaptive and innate immune responses contribute to overall Type 2 inflammation, the specific inflammatory pathway is not the same between all asthma phenotypes.

What about non-Type 2 inflammation?

We still know very little about the biological basis of non-Type 2 asthma, although we now understand that it is generally characterised by neutrophilic or paucigranulocytic inflammation and unlikely to respond to corticosteroid therapy. It is thought that Th1 and/or Th17 cells may play an important role in this type of asthma. Three main phenotypes are emerging, classified according to clinical characteristics: obesity-associated, smoking-associated, and very late onset.2

Biomarkers of Type 2 inflammation

The most common biomarkers of Type 2 airway inflammation are fractional exhaled nitric oxide (FeNO), sputum and blood eosinophils. Sputum eosinophil count is known as the gold standard test for assessing airway inflammation. Studies have shown that both FeNO and blood eosinophils correlate equally with sputum eosinophils, with high sensitivity and specificity (for sputum eosinophils ≥3%)3 However, it is worth noting that FeNO and blood eosinophils may reflect differing pathways.

How does FeNO work as a biomarker?

Airway epithelial cells in healthy individuals produce NO and low levels of exhaled NO are normal.4 When Type 2 inflammation (the type of inflammation responsible for up to 84% of asthma cases5) is present in the airways, interleukins such as IL-4 and IL-13, upregulate the activity of the iNOS enzyme, which produces NO in the airway.2 Levels of exhaled NO are increased, giving healthcare professionals an objective measure of airway inflammation.4

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Using biomarkers like FeNO can help differentiate between Type 2 and non-Type 2 inflammation to enable more precise treatment. Unlike sputum and blood eosinophil procedures, testing for FeNO is simple, immediate and non-invasive.

FeNO enables Type 2 inflammation to be closely monitored during treatment for a more personalised approach at the point-of-care. Testing can offer prediction and evaluation of the anti-inflammatory treatment response as FeNO levels are reduced by corticosteroids, as well as improve compliance and optimise the steroid dosage.6

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1. Kaur R, Chupp G. Phenotypes and endotypes of adult asthma: Moving toward precision medicine. J Allergy Clin Immunol. 2019;144(1):1-12.
2. Kuruvilla ME et al. Understanding asthma phenotypes, endotypes, and mechanisms of disease. Clin Rev Allergy Immunol. 2019;56(2):219-233.
3. Wagener AH et al. External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma. Thorax. 2015;70(2):115-20.
4. Dweik RA et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FeNO) for clinical applications. Am J Respir Crit Care Med. 2011;184(5):602-15.
5. Heaney LG et al. Eosinophilic and noneosinophilic asthma: an expert consensus framework to characterize phenotypes in a global real-life severe asthma cohort. Chest. 2021;160(3):814-830.
6. Menzies-Gow A et al. Clinical utility of fractional exhaled nitric oxide in severe asthma management. Eur Respir J. 2020;55(3):1901633.