Asthma

Reasons to Study Asthma: 14-15 million asthmatics in the US, 100 million days of restricted activity, 470,000 hospitilizations, over 5000 asthma deaths, cost over $6,000,000,000, greatest morbidity and mortality in African Americans, Hispanic Puerto Ricans, and children.

Etiology of Inner-city asthma: socioeconomic, educational, urbanization, perceptual, airway remodeling, genetic

Inflammation in Asthma

Definition – Asthma is a chronic inflammatory disorder with mast cells, eosinophils, T lymphocytes, neutrophils, and epithelial cells playing a role. Atopy is the strongest predisposing factor to developing asthma.

Precipitating factors – viral respiratory infections, exercise, endocrine factors, drugs (aspirin, b blockers), exposure to irritants and occupational chemicals, weather changes (cold air), allergens, environmental changes, food additives (sulfites), emotional expression (anger, laughing)

Inflammation can result in:

Dyspnea, wheezing, breathlessness, chest tightness, and cough
Variable reversible airflow obstruction
Increased bronchial hyper-responsiveness

Sequence of infiltration of inflammatory cells: macrophages, mast cells, platelets (minutes)Þ eosinophils, neutrophils (hours) Þ monocytes, lymphocytes (TH₂), and eosinophils (days)

Early Phase (direct hyper-responsiveness)

Activated Mast cell Þ degranulation Þ releases histamine, tryptase Þ Immediate airway narrowing (bronchoconstriction) via direct smooth muscle stimulation. (Minutes)

Activated Mast Cells can also contribute to the late phase reaction (weeks) by causing chemotaxis and infiltration of inflammatory cells which secretes cytokines (PGD₂, TX, LTC4, PAF, IL-3, TNF alpha, GM-CSF).

Mast cell Þ Ý IgE Þ Ý cAMP Þ stimulates arachidonic acid derivative formation Þ Ý leukotriene pathway (LTC₄) and prostaglandin pathway Þ smooth muscle constriction and bronchiectasis. Aspirin can exacerbate asthma attacks due to shunting from prostaglandin pathway to the leukotriene pathway.

Late Phase (Indirect hyper-responsiveness): requires intermediary cells, includes bronchoconstriction, mucosal edema, and Ý mucus production.

Late phase Þ Epithelial cell activation. Neutrophil, eosinophil, and TH₂ cell infiltration.

Eosinophils Þ releases leukotrienes (contributes to vasoconstriction), cationic protein, major basic protein, lipid mediators, oxygen radicals Þ direct damage to epithelium.

Activated Epithelial Cells Þ Ý eosinophils, Ý TH₂ (most important), smooth muscle hyperplasia, fibroblast activation.

TH₂ cells Þ secretion of IL-4 (Ý IgE), IL-5 (activates eosinophils), and IL-1 (activates macrophages).

Epithelial damage Þ Ý smooth muscle constriction, leaky epithelium, mucus hypersecretion.

Extravasated macromolecules due to leaky epithelium Þ activation of adhesion molecules on epithelium Þ chemotaxis of more inflammatory cells Þ sloughing of epithelium

Histological changes: Bronchial epithelial damage, goblet cell hyperplasia, collagenous thickening and fibrosis of sub-basement membrane region, hyalinization and edema of lamina propria, smooth muscle hypertrophy and hyperplasia, and enhaced post-capillary venule endothelial gaps Þ buckling of alveoli.

Pharmacotherapy : stepwise approach dictated by asthma severity.

NIH Guidelines for the diagnosis and management of asthma

Asthma, whatever the severity, is always classified as a chronic inflammatory disease.

Airway inflammation is associated with airway hyper-responsiveness, airflow limitation, and respiratory symptoms of SOB, chest tightness, cough and wheeze.

Airway inflammation produces four forms of airflow limitation:

(1) Acute bronchoconstriction
(2) Swelling of airway wall
(3) Chronic mucus plug formation
(4) Airway remodeling - scarring

Classifications of Asthma Severity

Mild-intermittent: symptoms £ 2 times/ week; nocturnal symptoms £ 2 times/month; brief exacerbations – few hours to few days; FEV1 or PEF > 80% predicted; <20% variability Þ can increase the # of nocturnal symptoms; asymptomatic and normal PEF between exacerbations

Mild-persistent: symptoms > 2 times/week but < 1/day; nocturnal symptoms > 2X/month, but £ 1X/wk; exacerbations may affect activity.

Moderate-persistent: daily symptoms; nocturnal symptoms > 1time /week; exacerbations ³ 2 times/wk. May last for a while.

Severe-persistent: continual symptoms, frequent nocturnal symptoms, exacerbations frequent, physical activity limited; FEV1 or PEF £ 60%.