Severe Asthma ToolkitSevere Asthma Toolkit
HomeAboutSpecific PopulationsRegistriesContributorsContact
Twitter
  • What is Severe Asthma?
    • Overview
    • Definition
    • Prevalence & Burden
    • Pathophysiology
    • Symptoms
    • Severe Asthma Attacks / Exacerbations / Flare-ups
    • Asthma Phenotypes
  • Diagnosis & Assessment
    • Overview
    • Diagnosis Overview
    • Assessment Overview
    • Lung Function Assessments
    • Questionnaires
    • Allergy Assessments
    • Phenotyping
    • Bronchoscopy
    • Imaging
    • Occupational Asthma
  • Management
    • Overview
    • Asthma Education
      • About Severe Asthma
      • Asthma Pathophysiology
      • Medications Education
      • Self-Monitoring
      • Triggers
      • Review
    • Written Action Plans
    • Adherence
    • Inhaler Technique
    • Physical Activity & Exercise
    • Interdisciplinary Approach & Multidimensional Assessment
    • Referral
  • Medications
    • Overview
    • Relievers
    • Preventers / Controllers
    • Add-on Therapies
    • Monoclonal Antibodies
    • Bronchial Thermoplasty
  • Co-Morbidities
    • Overview
    • Pulmonary & Upper Airways
      • Allergic & Non-Allergic Rhinitis
      • Chronic Rhinosinusitis
      • Dysfunctional Breathing
      • Vocal Cord Dysfunction
      • Chronic Obstructive Pulmonary Disease
      • Bronchiectasis
      • Obstructive Sleep Apnoea
    • Extra-Pulmonary
      • Obesity
      • Anxiety & Depression
      • Gastro-oesophageal Reflux Disease (GORD)
      • Osteoporosis
      • Cardiovascular Disease & Metabolic Disease
  • Living with Severe Asthma
    • Overview
    • Daily Symptom Burden
    • Mental & Emotional Health
    • Intimacy & Relationships
    • Self-Management Support
    • Medication Use & Costs
    • Experience of Care
    • Experience of Asthma Attacks
    • Prognosis
  • Establishing a Clinic
    • Overview
    • Set-up
    • Staffing & Multidisciplinary Team Approach
    • Facilities
    • Delivery Approach
    • Tailored Referrals
    • Evaluation
    • Opportunities for Training & Research
    • Barriers & Hurdles
  • Paediatrics
    • Overview
    • Management in Paediatrics
    • Assessment in Paediatrics
    • Alternative Diagnosis & Co-Morbidities in Paediatrics
    • Psychosocial Issues in Paediatrics
    • Medications in Paediatrics
    • Asthma in the Adolescent Population
  • Resources
    • Overview
    • Clinic Recommendations
    • Infographics
    • Asthma Assessment Resources
    • Systematic & Multidimensional Assessment Resources
      • Airway Components
      • Comorbidity Components
      • Risk Factor Components
    • Translation & Implementation
    • Case Studies
    • Presentations
    • Videos
    • Relevant Links
    • Key References

Pathophysiology

Home Severe Asthma Pathophysiology

The development of asthma and resulting asthma severity are governed by complex interactions between genetic and environmental factors. The key pathophysiological features of asthma pathology are lung inflammation, airway hyper-responsiveness, airway remodelling and mucous hypersecretion, all of which contribute to variable airflow limitation. Importantly, it is increasingly recognised that asthma is not a single or homogenous disease, but is better thought of as a condition that may arise as a combination of variations of the key pathophysiological features described above (Trejo Bittar et al. 2015, Israel et al. 2017).

Severe asthma is certainly no different in this respect; indeed, the recognition and measurement of this pathophysiological heterogeneity is increasingly important in terms of determining effective personalized treatment.

info-graphic about Severe Asthma Pathophysiology, Healthy airway and what is severe asthma

Etiology

Increased risk of developing asthma has been associated with respiratory virus infection in childhood, allergic sensitisation, reduced lung function, smoke exposure and a family history of asthma. However, what effect these factors have on the development of severe asthma remains unclear.

Airway / Lung Inflammation
Airway Hyper-Responsiveness
Mucus Hypersecretion & Airway Remodelling
Airway / Lung Inflammation

By definition, inflammation of the airway tissue and lumen in severe asthma is resistant to treatment with traditional inhaled corticosteroid medication, and in some instances, oral corticosteroids. Inflammation of the airway tissue and lumen in severe asthma is heterogeneous.

The best understood type of airway inflammation in asthma is referred to as ‘Type 2’ inflammation, which is estimated to occur in up to 50% of people with severe asthma. The term ‘Type 2’ stems from early studies that demonstrated that asthma inflammation was associated with increased type-2 helper CD4+ T lymphocytes (TH2), which generate the cytokines interleukin (IL)-4, -5 and -13. IL-4, -5 and -13 that drive the lung tissue and airway eosinophilia which characterises Type 2 asthma. The importance of Type 2 inflammation as a causal factor in the clinical manifestations of severe asthma (particularly the occurrence of frequent severe exacerbations or flare-ups) has been demonstrated in recent clinical trials of targeted biological therapies designed to inhibit IL-5-, IL-13- or both IL-4- and IL-13-mediated inflammation (Fricker et al. 2017). Type-2 inflammation is often associated with increased eosinophil numbers. For more information see Monoclonal Antibodies.

Although Type 2 inflammation and TH2 lymphocyte activation in asthma can be driven by atopy and allergic responses, Type 2 inflammation also frequently occurs independently of atopy. The mechanisms that govern non-atopic Type 2 inflammation in asthma are less well understood, however it is thought that both atopic and non-atopic Type 2 asthma respond to new targeted therapies against IL-5 or IL-4/-13.

Alternatively, asthma can be associated with increased numbers of neutrophils. The mechanisms that govern neutrophilic inflammation in severe asthma, and the potential contribution of elevated neutrophils to clinical outcomes in severe asthma are less well understood. However, there is growing recognition that neutrophilic inflammation in asthma can be driven by activation of Type-1 TH1 cells, which produce IFNγ, or IL-17-producing TH17 cells.

Finally, around 30-40% of severe asthma patients do not have overt Type 2 or neutrophilic inflammation, and the potential role that altered inflammatory pathways play in this severe asthma subpopulation remains poorly understood.

Key cell types and molecules involved in Type-2 vs. non-Type-2 asthma:

Type-2 Non-Type-2
Cell Types TH2 CD4+ T lymphocytes
Eosinophils
TH1 CD4+ T lymphocytes
TH17 CD4+ T lymphocytes
Neutrophils
Molecules Interleukin (IL)-4
IL-5
IL-13
IgE (in atopic asthma)
Interferon (IFN)ɣ
IL-17

Airway Hyper-Responsiveness

In individuals with asthma, the airways have an abnormal and exaggerated response to a trigger. The trigger may be an allergen, irritant or other triggers such as pollution, exercise and/or infection. Upon exposure to a trigger, a complex cascade of events results in localised release of inflammatory mediators (e.g. histamine, interleukins, prostaglandins, leukotrienes and nitric oxide). In addition to promoting tissue inflammation, these mediators act on local nerves and smooth muscle cells to initiate muscle contractions and airway narrowing.

Mucus Hypersecretion & Airway Remodelling

Chronic inflammation associated with asthma also results in long-term and ongoing structural changes within the lung. Increased numbers of mucus-secreting goblet cells in the bronchial epithelial layer secrete mucus, which along with impaired mucociliary clearance mechanisms cause a build-up of mucus in the airway lumen that can restrict airflow and increase susceptibility of patients to airway infections. Further, airway wall remodelling is observed, which include increased subepithelial fibrosis (particularly in those patients with high eosinophilic airway inflammation) and increased smooth muscle mass. In addition airway smooth muscle may become hyperresponsive, and the extent of airway smooth muscle build up has been proposed to correlate with asthma severity. Of note, airway remodelling, like inflammation, is not uniform in severe asthma.

Previous
Next

Last Updated on October 3, 2022

Generic selectors
Exact matches only
Search in title
Search in content
Search in posts
Search in pages
Filter by Categories

More results...

  • Overview
  • Definition
  • Prevalence & Burden
  • Pathophysiology
  • Symptoms
  • Severe Asthma Attacks / Exacerbations / Flare-ups
  • Asthma Phenotypes

What is Severe Asthma?

It is asthma that remains uncontrolled despite treatable factors having been addressed and maximal inhaled therapy being taken regularly.

We want to know who accesses the Severe Asthma Toolkit and how it is used. Please complete our survey.

Responses will inform the continued development of the Severe Asthma Toolkit and future translation and implementation activities. Any feedback you provide will be greatly appreciated.

Complete Survey

  • Website Terms of Use
  • Website Survey
© Copyright 2018    CRICOS Provider Number 00109J    The University of Newcastle, Australia