Exacerbation and Risk Factors in Severe Asthma

Asthma is a chronic inflammatory disorder of the airways, characterised by reversible expiratory flow limitation and bronchial hyperresponsiveness (an increased sensitivity of the airways resulting in bronchoconstriction) to a variety of triggers and presents with symptoms such as wheezing, shortness of breath [1]. 

Asthma is not a homogenous disease in terms of its course, severity or response to treatment. It has variable clinical presentations (phenotypes) and distinct underlying pathophysiological pathways (endotypes) [2]. Two major asthma endotypes, Th2 and non-Th2, have been described based on the presence of T-helper cell type 2 (Th2)-driven inflammatory responses (interleukin (IL)-4-, IL-5- and IL-13-mediated). Discovery of type-2 innate lymphoid cells and their release Th-2 cytokines, contributing to the type 2 (T2)-high signature, has resulted in clearer categorisation of asthma (T2-high or T2-low). T2-high asthma is the best-defined endotype [3]. T2-low asthma presents with either neutrophilic or paucigranulocytic inflammation, tends to be more resistant to inhaled corticosteroids, and it involves various asthma phenotypes, related to obesity, smoking, late onset (usually after the age of 40 years) or occupational exposures [2 RASP]. Thus, there is an unmet need for the identification of biomarkers that can help the diagnosis and the endotyping of T2-low asthma. 

Therapeutically addressing of T2-low asthma is a problem in urgent need of resolution: 

  • Patients have poor response to steroids (the cornerstone of asthma treatment [4 RASP].
  • T2-low asthma is not a target for newer biologic agents such as anti-IgE or anti-IL-5 [5].


What is T2-low asthma?

At present, a solid definition of T2-low asthma has not been established – though one aim of the UK MRC-funded Refractory Asthma Stratification Project (RASP-UK) [RASP]. Some emphasis has been placed on noninvasive biomarkers for the detection of T2-high asthma (i.e., T2 cytokines such as IL-4, IL-5 and IL-13, exhaled nitric oxide fraction (FeNO), serum periostin, total IgE, blood and sputum eosinophils), the exact contribution of such markers is controversial [6 RASP]. T2 markers:

  • May have low concordance when measured in the same patient [7, 8] 
  • May be subject to variability over time and in response to asthma treatments [9].


Importantly, these biomarkers can be characterised by high specificity, but low sensitivity, rendering them more useful in the identification of T2-high patients. In clinical practice, the most useful tool to identify T2-low asthma phenotype is the absence of any evidence of increased values in biomarkers of T2-high asthma. In addition, it seems that there is an association of T2-low asthma with obesity, smoking, pollutants, viral or bacterial infections and advanced age. 

Pathophysiologically, T2-low asthma may be characterised by neutrophilic (NA) or the paucigranulocytic (PGA; absent sputum eosinophilia/neutrophilia) phenotype of inflammation [10]. Th1 and/or Th17 cells seem to be the key effector cells in this setting.

Several studies have related asthma severity to airway inflammation and eosinophilic inflammation to asthma management, asthma control and to predicting response to inhaled corticosteroids (ICS) [11]. Type 2 inflammation appears to be related to the fractional exhaled nitric oxide (FeNO) production, as reflected by FeNO, serum immunoglobulin (Ig)E and blood eosinophils, plays a central role in small airways dysfunction in adults with moderate to severe persistent asthma [12]. A recent study observed a correlation between 17β-oestradiol and sputum neutrophils in females with severe, postmenopausal asthma – implying a central role of neutrophils [14]. It is hoped that data from RASP-UK will serve to confirm these findings. 

Exacerbation assessment was a pre-specified secondary analysis of data from a 48-week, multicentre, randomised controlled clinical study comparing the use of biomarkers and symptoms to adjust steroid treatment in a T2-low severe asthma-enriched cohort [RASP].

Participants were phenotyped as T2-low (FeNO ≤20 ppb and blood eosinophil count [PBE] ≤150 cells/μL) or T2-high (FeNO>20 or PBE>150) at study enrolment and at each exacerbation. We have recently reported the findings of the exacerbation analyses, including comparison of exacerbators and non-exacerbators, the physiological changes at exacerbation in those who had evidence of T2 biology at exacerbation versus those that did not, and the stability of inflammatory phenotypes when stable and at exacerbation.

Involving 301 participants, the RASP-UK population is one of the most comprehensive studies of the severe asthma phenotype. In the present study, 60.8% (183/301) had one or more self-reported exacerbations. Exacerbators were more likely to be female, have a higher BMI and more exacerbations requiring oral corticosteroid and unscheduled primary care attendances for exacerbations.

At enrolment, 23.6% (71/301) were identified as being T2-low, and 76.4% (230/301) T2-high. The T2-low group had more asthma primary care attendances, were more likely to have a previous admission to HDU/ICU and to be receiving maintenance OCS. At exacerbation the T2-low events were indistinguishable from T2-high exacerbations in terms of lung function or symptom increase. We found that the inflammatory phenotype within individual patients was dynamic; inflammatory phenotype at study entry did not have a significant association with exacerbation phenotype.

In summary, asthma exacerbations demonstrating a T2-low phenotype were physiologically and symptomatically similar to T2-high exacerbations. T2-low asthma was an unstable phenotype, suggesting that exacerbation phenotyping should occur at the time of exacerbation. The clinically significant exacerbations in participants without evidence of T2 biology at the time of exacerbation highlights the unmet and pressing need to further understand the mechanisms at play in non-T2 asthma.



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  17. McDowell PJ, Busby J, Hanratty CE, et al.. Exacerbation Profile and Risk Factors in a T2-Low Severe Asthma Population. Am J Respir Crit Care Med. 2022 May 12. doi: 10.1164/rccm.202201-0129OC. Epub ahead of print. PMID: 35549845.