What is the etiology of reactive airway disease?

Etiology of Reactive Airway Disease

Reactive airway disease is fundamentally a chronic inflammatory disorder caused by the complex interplay between genetic susceptibility and environmental exposures, particularly allergen sensitization, respiratory infections, occupational exposures, and irritants. 1

Genetic and Host Factors

The development of reactive airway disease involves strong genetic predisposition:

• Parental history is the strongest predictor: 80% of children with two asthmatic parents develop the disease compared with 40% with one asthmatic parent and only 10% with no asthmatic parents 1
• Atopy (genetic susceptibility to produce IgE to environmental allergens) is one of the strongest predisposing factors, found in 30-50% of the general population but much more commonly associated with asthma development 1, 2
• Sex influences disease development: males develop disease 2-4 times more frequently than females in the first 3 years of life, though females are more likely to have persistent disease after puberty 1

Environmental Triggers and Causes

Allergen Exposures (Most Common Cause)

IgE-mediated inhalant allergen exposures are the most common cause of asthma, inducing both airway inflammation with eosinophils and airway hyperresponsiveness 3:

• Indoor allergens: house-dust mites, animal proteins (cat dander), cockroaches, and fungi 1
• Outdoor allergens: pollen and outdoor molds 1
• Mold exposure in damp buildings is an important risk factor, with approximately 30 investigations worldwide demonstrating close relationships between living in damp homes with mold growth and adverse respiratory symptoms in children 4

Respiratory Infections

• Viral respiratory infections are the most common cause of asthma symptoms in children 5 years and younger 1
• Respiratory syncytial virus (RSV) causes wheezing through bronchiolitis or acute asthma exacerbations, though recent evidence suggests severe RSV infection may be a marker rather than a cause of underlying airway hyperresponsiveness 5
• The hygiene hypothesis postulates that certain infections early in life may affect the balance between TH1 and TH2 cytokine responses, with reduced TH1 responses leading to TH2 cell dominance and allergic disease expression 1

Occupational and Environmental Exposures

Workplace exposures are responsible for 15-25% of asthma in adults 1:

• High-molecular-weight agents (≥5 kDa): proteins causing asthma via IgE sensitization 1
• Low-molecular-weight agents (<5 kDa): chemicals acting as haptens, binding to carrier proteins to form complete antigens 1
• Acute irritant-induced asthma (reactive airways dysfunction syndrome/RADS) follows very heavy irritant exposure from gas, vapors, or fumes 1, 6
• Chronic irritant-induced asthma develops after repeated high-level exposures 3

Tobacco Smoke and Air Pollution

• Environmental tobacco smoke exposure facilitates asthma development in children, with increased risk and severity in children of parents who smoke 1, 3
• Personal smoking interacts with airway responsiveness and is associated with higher likelihood of new-onset or recrudescent asthma in adulthood 1
• Indoor irritants: cooking fumes, cigarette smoke 1
• Outdoor pollutants contribute to upper and lower airway causes of cough and asthma 1

Exercise and Environmental Conditions

Exercise-induced bronchoconstriction occurs through specific environmental mechanisms 1:

• Cold, dry air inhalation combined with high ventilation (Nordic skiers, ice rink athletes) 1
• Trichloramines in indoor pool air (competitive swimmers) 1
• High allergen and ozone environments (distance runners) 1

Pathophysiologic Mechanisms

The underlying inflammation involves multiple cell types 1, 7:

• Mast cells, eosinophils, neutrophils (especially in sudden onset, fatal exacerbations, occupational asthma, and smokers) 1
• T lymphocytes, macrophages, and epithelial cells 1
• Inflammatory mediators including histamine, tryptase, and leukotrienes are released during exercise or exposure challenges 1

Psychological Factors

Psychological stress can amplify airway inflammatory responses to irritants, allergens, and infections in susceptible individuals, serving as both a trigger and consequence of difficult-to-control asthma 8

Critical Timing Factors

Environmental exposures occurring at crucial times in immune system development are particularly important, as a child's immune system develops from birth to adolescence and requires normal physiologic stimulation 4. Disturbances of this maturation process increase risk for abnormal reactions to inhaled antigens and inflammatory agents 4.