Classification and Etiology
Bronchial asthma is divided into two primary groups, along with several specific variants:
- Exogenous (Atopic). The most common type, typically presenting in childhood. It is rooted in a genetic predisposition to atopy. Environmental allergens (pollen, house dust mites, foods) act as triggers. A positive family history is often present, and attacks are frequently accompanied by allergic rhinitis, eczema, or urticaria.
- Endogenous (Non-atopic). An idiopathic variant triggered by viral respiratory infections or pollutants (ozone, nitrogen dioxide, sulfur dioxide). Blood IgE levels remain normal, and there is no family history. Viruses are thought to damage the mucosal epithelium and lower the activation threshold of vagal nerve receptors.
- Iatrogenic (Aspirin-induced). Develops in susceptible individuals following the ingestion of aspirin or other NSAIDs. These drugs block the cyclooxygenase (COX) pathway of arachidonic acid metabolism. Consequently, the pathway shifts toward the lipoxygenase cascade, leading to massive leukotriene release and profound bronchospasm.
- Occupational. Arises from regular exposure to occupational hazards such as vapors (epoxy resins), gases (toluene), or dusts (cotton, wood, platinum salts). It requires a prior sensitization period.
Pathogenesis and Cellular Mechanisms
Classic atopic asthma is driven by a type I hypersensitivity reaction mediated by IgE. T-helper 2 (Th2) lymphocytes serve as the primary regulators of this process. They produce key cytokines:
- IL-4 — stimulates B-cell class switching and IgE production.
- IL-5 — recruits and activates eosinophils.
- IL-13 — stimulates excessive mucus production.
Synthesized IgE antibodies bind to high-affinity Fc receptors on the surface of mast cells. Upon inhalation of an allergen, cross-linking of these antibodies occurs. Mast cells rapidly degranulate, releasing preformed mediators. This opens mucosal intercellular tight junctions, allowing the antigen to penetrate deeper into tissues and contact additional mast cells. The epithelium begins to secrete chemokines, amplifying leukocyte influx.
Eosinophils play a critical role. They release major basic protein and eosinophil cationic protein, which are directly toxic to the respiratory epithelium. Eosinophil peroxidase induces oxidative stress, and these cells synthesize ongoing supplies of leukotrienes, sustaining inflammation even without re-exposure to the allergen.
Clinical Presentation and Inflammatory Mediators
A typical acute attack lasts from one to several hours. The patient experiences severe expiratory dyspnea (difficulty exhaling) and wheezing. Air enters the lungs freely, but due to bronchospasm and thick mucus plugging, it cannot escape efficiently, leading to progressive hyperinflation of the distal airways. Between attacks, breathing is generally normal, though spirometry may reveal mild underlying abnormalities.
Symptoms are driven by specific mediators:
- Leukotrienes ($C_4, D_4, E_4$) cause sustained bronchoconstriction, edema, and mucus hypersecretion.
- Acetylcholine (via the vagus nerve) directly contracts airway smooth muscle.
- Histamine and prostaglandin $D_2$ enhance bronchospasm and vasodilation.
The response occurs in two phases: the acute phase (developing within minutes) and the late phase (starting 4–8 hours later and lasting up to 24 hours).
If an acute attack fails to respond to standard medications (bronchodilators, corticosteroids) and persists for days or weeks, it progresses to status asthmaticus. This is a life-threatening emergency characterized by severe hypoxia, hypercapnia, and acidosis, which can be fatal. However, in most cases, chronic disease progression leads to long-term morbidity rather than sudden death.
Pathology and Airway Remodeling
Morphological changes are best studied in patients who have succumbed to status asthmaticus. Grossly, the lungs are markedly hyperinflated due to air trapping, areas of focal atelectasis are visible, and the bronchi are occluded by viscous mucus plugs.
Microscopically, mucus secretions contain Curschmann spirals (whorled casts of sloughed epithelial cells) and Charcot-Leyden crystals (crystallized aggregates of eosinophil proteins). The bronchial walls are densely infiltrated by eosinophils.
Chronic Th2-mediated inflammation inevitably leads to airway remodeling. This process may begin years before the first clinical symptoms appear and is driven by genetic susceptibility (e.g., ADAM33 gene expression by fibroblasts and smooth muscle cells).
Key components of remodeling:
- Thickening of the bronchial epithelial basement membrane.
- Chronic edema and mucosal infiltration by mast cells and eosinophils.
- Hypertrophy of submucosal mucus glands.
- Hypertrophy of airway smooth muscle and subepithelial collagen deposition.