Overview

• A heterogeneous chronic disease of the conducting airways.
• Characterized by intermittent and mostly reversible periods of bronchial obstruction, with bronchial hyper-reactivity, excessive mucus, and airway remodeling; in contrast, recall that COPD is characterized by constant, irreversible airway obstruction.
• Asthmatic patients experience episodes of cough, wheezing, dyspnea, and feelings of chest tightness.
• Characterized by increased total lung capacity because air is trapped in the lungs.
• The ratio of forced expiratory volume in one second to forced vital capacity is normal or low.
• The diffusing capacity of the lungs for carbon monoxide is normal or elevated.
• Ventilation to perfusion mismatches occur, which can lead to hypoxemia.
• Asthma is a heterogeneous disease with different etiologies and characteristics, and there are different ways to classify asthma types
  – Historically, asthma has been classified based on phenotypes, which are the observable characteristics – such as by the presence or absence of eosinophils.
  – Many researchers are now shifting towards classification based on endotypes, which are based on the pathophysiologic mechanisms that drive types of asthma – such as whether high levels of type 2 inflammation is involved.
• Diagnosis of asthma can include: pulmonary function tests (spirometry), methacholine bronchial challenge tests, and allergy tests.
• Treatments for asthma can be broad-based or more targeted, depending on the asthma type.

Types of Asthma

We organize these based on presence of granulocytes and the type of inflammation.

Eosinophilic asthma with high levels of type-2 inflammation

This group includes the most thoroughly studied subtypes of asthma.

• Type-2 inflammation is due to an imbalance towards T-helper 2 cells and Type-2 innate lymphoid cells and their cytokines (specifically, IL-4, IL-5, and IL-13) which promote IgE production from B cells.

• Early Onset with Allergy: because allergens are the triggers for asthma attacks, this subtype is sometimes called “Extrinsic asthma.”
  – Asthma attacks are IgE-mediated, and patients often have other allergies and history of rhinitis and atopic dermatitis. Click to review Hypersensitivity Type 1
  – Tends to be familial, is associated with early childhood respiratory viral infections (especially RSV and rhinovirus), and, is most common in boys.
  – Biomarkers include elevated eosinophils and serum IgE.
  – Common triggers include house dust mites, mold, pets, and pollen.

• Late-onset without atopy
  – Patients have fewer allergies, but often present with more severe asthma.
  – Often co-exists with chronic rhinosinusitis and nasal polyps.
  – Not familial, and tends to occur most often in adult females.
  – Biomarkers include elevated eosinophils, and, in a sub-set of patients, elevated levels of Staphylococcus aureusendotoxin-specific IgE.
  Be aware that, although most patients do not have elevated levels of IgE, it is thought that localized IgE in the airways occurs.
• Key triggers in this group include air pollution, especially diesel gas fumes and other irritants, as well as respiratory infections.

• Aspirin-exacerbated asthma (aka, aspirin-exacerbated respiratory disease – AERD)
• Form of asthma triggered by aspirin – it is often severe, and typically occurs in adults
  – Thus, some consider this to be a sub-sub-type of late-onset asthma.
  – Aspirin-exacerbated asthma is due genetic abnormalities that lead to dysregulation of arachidonic acid metabolism.

Next, let’s consider some other types of asthma.

Neutrophilic, type-2-low asthma

• Characterized by elevated levels of the cytokine IL-17 and oxidative stress.
• Neutrophilic asthma is usually adult-onset and is often severe.
  – Resistant to corticosteroids.
• Key at-risk populations include: smokers, obese people, and elderly people.

Mixed granulocytic asthma

• Characterized by elevated levels of T helper 2 and T helper 17 cytokines.

Paucigranulocytic asthma

• Characterized by non-inflammatory (or low inflammatory) changes in the bronchi: remodeling and hyper-reactivity.

Two additional asthma phenotypes that can overlap with those already listed:
Occupational, aka, work-related asthma

• Develops in response to exposure to workplace allergens or irritants (and, because it is occupation-related, tends to develop in adulthood).
  Exercise-induced/exacerbated asthma
• Triggered by exercise.
• Although the exact mechanisms are unclear, it is thought that exercise-related evaporation and water loss from the airway epithelia causes injury that leads to upregulation of pro-inflammatory mediators.

Comparison with healthy bronchi.

• Smooth muscle overgrowth, which contributes to hyper-reactivity and constriction of the airways.
• Possible inflammation and fibrosis with migration of eosinophils and/or neutrophils in the wall of the airway (depending on the type of asthma).
• The basement membrane is thickened.
• Respiratory epithelium displays goblet cell metaplasia.
• Excess mucus further narrowing the airway so that the lumen is much smaller than normal.
• Other hallmarks of asthma may be seen in the sputum:
  – Curschmann spirals are mucus plugs that comprise desquamated airway epithelial cells.
  – Charcot-Leyden Crystals are crystals formed from eosinophil proteins.

Treatments

Step-wise approach to treatment

• Short-acting beta-antagonists, such as Albuterol, are provide for quick relief during asthma attacks; they relax the smooth muscle lining the bronchi.
• Long-acting beta-antagonists, such as Salmeterol, may be used longer-term in conjunction with other drugs.
• Inhaled corticosteroids, such as beclomethasone, suppress airway inflammation and are first-line therapy for long-term asthma management.
• Leukotriene antagonists, such as montelukast, also reduce bronchoconstriction and inflammation, and are especially useful in exercise- and aspirin-exacerbated asthma.
• Anticholinergics, such as Ipratropium and Tiotropium, produce smooth muscle relaxation in the bronchi.
• Anti-IgE antibodies, such as Omalizumab, are effective in allergic asthma.
• Anti-IL-5 antibodies, such as Mepolizumab, are useful in severe eosinophilic asthma.
• Mast cell inhibitors, such as Cromolyn, prevent mast cells from releasing inflammatory mediators that lead to bronchospasm.
• Oral corticosteroids, such as prednisone, are used in severe asthma to reduce inflammation; because oral corticosteroids can have serious side effects, they are typically used for acute attacks.