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How is severe asthma different from milder forms of asthma?

Many mild or moderate asthmatic events are amplified in severe asthma, 1and many patients with severe asthma remain symptomatic despite high-dose asthma therapies. 23

What is severe asthma? 

Severe asthma is defined as the need for high-intensity treatment. 13This definition includes patients who require high-intensity controller therapy to maintain good control, as well as patients with poor asthma control despite high-intensity treatment. 13Patients with severe asthma are frequently symptomatic, and often have serious exacerbations. 4

Characteristics of severe versus difficult-to-treat asthmaGo To Close Top

MOD4_Fig18_CS4

Adapted from Keller MD and Kamp D, 2014. 4

Learn how the latest guidelines define severe asthma here

Inflammation and remodelling processes become increasingly involved as asthma becomes more severe and chronic. 56Asthma is now recognised as a heterogeneous respiratory syndrome with different phenotypes, 378and the inflammatory profiles reflect this fact. The inflammatory profile can also indicate disease severity; for example, asthma severity is associated with the simultaneous presence of eosinophils and neutrophils. Some studies suggest that combined eosinophilic and neutrophilic inflammation may contribute to greater airflow limitation. 3

Distinguishing asthma by phenotyping is of increasing interest in severe asthma, because the distinct phenotypes may provide better options for treatment. 3

What is an asthma phenotype?

It is increasingly evident that severe asthma is not a single disease, as evidenced by the variety of clinical presentations, physiological characteristics and outcomes. To better understand this heterogeneity the concept of asthma phenotyping has emerged. 3

A phenotype is defined as the composite, observable characteristics of an organism, resulting from interaction between its genetic make-up and environmental influences, which are relatively stable, but not invariable, with time. 3

Ultimately, these phenotypes should evolve into asthma endotypes, which combine clinical characteristics with identifiable mechanistic pathways. 3

Risk factors for severe asthma

Many asthma risk factors are also the same for severe asthma. The table below shows risk factors for all severities of asthma, and those that only apply to severe asthma.

Risk factors for all asthma severities
Atopy4,8
Airway hyperresponsiveness4,8
Gender (female sex in adult-onset asthma and male sex in childhood asthma)3,8,9
Ethnicity (susceptibility linked to ethnic-specific genetic variations)4
Lower socioeconomic position10
Obesity3,4,8,9
Indoor/outdoor allergens4
Occupational exposure3,4
Tobacco smoking3,4,8
Respiratory infections3,4
Additional associations for severe asthma
Genetic factors (e.g. genetic variation in IL-4 and IL-6 receptor)3,9
Older age at onset of asthma3
Disease duration3
Exacerbations3
Inflammatory characteristics (eosinophilic and neutrophilic)3
Reduced responsiveness to therapy for asthma3

Exacerbations in severe asthma

Asthma patients can experience periodic disease flare-ups known as exacerbations. 2Asthma exacerbations consist of acute or subacute episodes of progressively worsening shortness of breath, coughing, wheezing and chest tightness. 2They are more common in patients with severe asthma, 12and in severe cases can cause cyanosis and respiratory failure. 5Asthma exacerbations are of sufficient importance that they are used as a measure of disease severity. 3Learn how the latest guidelines define severe asthma here.

One study showed that the rate of exacerbations was five times higher in severe asthma patients (1.2 exacerbations per patient per year) compared with mild/moderate asthma patients (0.24 exacerbations per patient per year).

Kupczyk et al. 2014 12

Previous asthma exacerbations are a strong predictor of future exacerbation risk. For example, a prospective analysis was conducted on data from 2780 patients in the TENOR study. 13Two severities of exacerbation were prespecified:

  1. Severe exacerbations, which were those resulting in emergency department visit, hospitalisation or death
  2. Exacerbations managed by steroid bursts

 

 

Patients with a recent severe exacerbation were six times more likely to experience a future severe exacerbation than those that had not (OR=6.33; 95% CI: 4.57–8.76). 13Patients with a recent exacerbation requiring a steroid burst were also significantly more likely to experience a future exacerbation requiring a steroid burst (OR=3.91; 95% CI: 3.28–4.67). 13

Remodelling and airflow obstruction

The airway epithelium in patients with severe asthma is thicker than that of patients with mild to moderate asthma. 3In lung function studies, correlation of airway wall thickness and FEV1 suggest that airway remodelling contributes to airway obstruction in severe asthma. 9

Chronic airway obstruction may also lead to airway closure or uneven ventilation of the small airways, which is associated with exacerbations. 3

Altogether, airway obstruction may result from a combination of: 6

  • Bronchoconstriction as a consequence of active airway smooth muscle constriction
  • Airway wall thickening associated with inflammation and remodelling
  • Luminal obstruction caused by mucous hypersecretion, which may also be thickened due to dehydration

 

 

References

  1. Kumar RK, Jeffery PK. Pathology of Asthma. Middleton's Allergy: Principles and Practice. Saunders Elsevier, Philadelphia, PA, USA: 2014.
  2. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention, 2016. Available at: http://ginasthma.org/2016-gina-report-global-strategy-for-asthma-management-and-prevention/. Last accessed May 2016.
  3. Chung KF, et al. Eur Respir J 2014;43:343–73.
  4. Barnes PJ. Chapter 254: Asthma in Harrison’s Principles of Internal Medicine. Available at: http://accessmedicine.mhmedical.com/. Last accessed August 2015.
  5. Keller MD, Kamp D. Clin Pulm Med 2014;21:1–8.
  6. Holgate ST, Sly PD. Asthma Pathogenesis. Middleton's Allergy: Principles and Practice. Saunders Elsevier, Philadelphia, PA, USA: 2014.
  7. Wenzel SE. Nat Med 2012;18:716–25.
  8. Walford HH, Doherty TA. J Asthma Allergy 2014;7:53–65.
  9. Jarjour NN, et al. Am J Respir Crit Care Med 2012;185;356–62.
  10. Chanez P, et al. J Allergy Clin Immunol 2007;119:1337–48.
  11. Kozyrskyj AL, et al. Am Jour Pub Health 2010;100:540–6.
  12. Kupczyk M, et al. Clin Exp Allergy 2014;44:212–21.
  13. Miller MK, et al. Respir Med 2007;101:481–89.